Travel Medicine [4th Edition] 9780323547727

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Travel Medicine [4th Edition]

Table of contents :
Cover......Page 1
Dedication......Page 2
Travel Medicine......Page 3
Copyright Page......Page 4
Preface......Page 5
List of Contributors......Page 6
Acknowledgments......Page 11
1 Introduction to Travel Medicine......Page 12
Reference......Page 13
Cornerstones of Travel Health Epidemiology......Page 14
Keywords......Page 15
Accidents......Page 18
Travelers’ Diarrhea......Page 20
Vaccine-Preventable Infections......Page 21
Routine Immunizations.......Page 22
Other Arboviral Infections: Dengue, Chikungunya, Zika.......Page 23
References......Page 24
The Practice of Travel Medicine......Page 27
Keywords......Page 28
Are There Different Models of Care Delivery?......Page 29
What Vaccines Should Be Provided? Should the Clinic Offer Yellow Fever Vaccine?......Page 30
Documentation......Page 31
Legal Issues......Page 32
Offsite Services......Page 33
Direct Marketing Methods: Internet, Print, and Media......Page 34
Professional Development......Page 35
References......Page 36
Logistics and Mechanics of the Pretravel Consultation......Page 38
Keywords......Page 39
General Considerations......Page 40
General Topics to Be Covered......Page 41
Challenges Regarding Travel Advice......Page 42
Acknowledgments......Page 43
References......Page 44
Etiology and Risk of Waterborne Infection......Page 45
Keywords......Page 46
Clarification......Page 47
Coagulation–Flocculation.......Page 48
Filtration......Page 49
Improving Halogen Taste.......Page 50
Preferred Technique......Page 51
References......Page 54
Habitat Avoidance......Page 57
Keywords......Page 58
Physical Protection......Page 60
DEET Safety and Toxicity.......Page 61
Citronella.......Page 62
BiteBlocker.......Page 63
Alternative Repellents.......Page 64
Reducing Local Mosquito Populations......Page 65
References......Page 66
Dengue......Page 68
Keywords......Page 69
Zika......Page 71
Severe Respiratory Infections With Regional Endemicity......Page 72
Other Regionally Important Infections in Travelers......Page 73
References......Page 75
Summary of Factors Determining Medical and First-Aid Kit Construction......Page 77
Keywords......Page 78
Contents of Medical and First-Aid Kits......Page 79
More Comprehensive Kits......Page 80
References......Page 81
Active Immunization......Page 82
Keywords......Page 83
Immune Memory and Booster Doses.......Page 84
Route of Immunization.......Page 86
Intramuscular route.......Page 87
Serologic Testing Before and After Immunizations.......Page 88
Special Conditions/Contraindications......Page 89
References......Page 90
Contraindications......Page 92
Keywords......Page 93
Dosing Schedules......Page 96
Measles, Mumps, and Rubella Vaccine......Page 97
Precautions......Page 98
Dosing Schedule......Page 99
Varicella and Herpes Zoster Vaccines......Page 100
Pneumococcal Vaccine......Page 101
Human PapillomaVirus Vaccine......Page 102
Indications......Page 103
References......Page 104
Precautions......Page 106
Keywords......Page 107
Dosing Schedules......Page 108
Indications......Page 109
Dosing Schedules......Page 110
Measures of Immune Response and Duration of Immunity/Protection......Page 111
Measures of Immune Response and Duration of Immunity/Protection......Page 114
Indications......Page 115
Drug and Vaccine Interactions......Page 116
References......Page 117
Adverse Events......Page 119
Keywords......Page 120
Recommendations.......Page 121
Indications.......Page 127
Adverse Events.......Page 128
Dosing Schedules.......Page 129
Japanese Encephalitis Vaccine......Page 130
Chimeric JE Vaccine (JE-CV)......Page 131
Drug and Vaccine Interactions.......Page 132
Indications.......Page 133
Polio Vaccine......Page 134
Accelerated Schedules for Primary IPV Immunization.......Page 135
Rabies Vaccine......Page 136
Postexposure Vaccination.......Page 137
Tickborne Encephalitis Vaccine......Page 138
Measures of Immune Response and Duration of Immunity/Protection.......Page 139
References......Page 140
Intercurrent Illness and Vaccination......Page 144
Keywords......Page 145
Routine Pediatric Vaccines......Page 146
Measles–Mumps–Rubella Vaccine......Page 150
Varicella Vaccine......Page 151
Yellow Fever Vaccine.......Page 152
Typhoid Vaccine......Page 153
Rabies Vaccine......Page 154
References......Page 155
Who Is at Risk?......Page 157
Keywords......Page 158
Where Are Travelers at Risk of Acquiring Malaria?......Page 161
Primaquine......Page 163
References......Page 164
Assessing Individual Risk—Parasite, Place, and Person......Page 166
Keywords......Page 167
Description, Pharmacology, and Mode of Action.......Page 168
Efficacy and Drug Resistance.......Page 169
Contraindications, Precautions, and Drug Interactions.......Page 171
Efficacy and Drug Resistance.......Page 172
Tolerability.......Page 173
Contraindications, Precautions, and Drug Interactions.......Page 174
Efficacy and Drug Resistance.......Page 175
Contraindications, Precautions, and Drug Interactions.......Page 176
Efficacy and Drug Resistance.......Page 177
Indications and Administration.......Page 178
Indications and Administration.......Page 179
New Pipeline Drugs for Malaria Chemoprophylaxis......Page 180
Business Travelers......Page 181
Migrant and VFR Travelers......Page 182
Differences in Guidelines and Recommendations on Malaria Chemoprophylaxis......Page 183
References......Page 184
Introduction......Page 190
Keywords......Page 191
Performance of RDTs for Laboratory Diagnosis of Malaria......Page 192
Performance of RDTs for Self-Use by Travelers......Page 193
Principle and Rationale for Use.......Page 194
SBET Recommendations for Pregnant Women, Children, and Chronically Ill Patients......Page 196
Balancing of Recommendations......Page 197
References......Page 198
The Malarias......Page 201
Keywords......Page 202
Clinical Presentation of Uncomplicated Malaria......Page 203
Clinical Diagnosis......Page 204
Treatment of Uncomplicated Malaria......Page 205
Treatment of Severe Malaria......Page 206
Antirelapse Therapy With Primaquine......Page 207
References......Page 208
Clinical Characteristics......Page 210
Keywords......Page 211
Diarrhea Producing E. coli......Page 212
Giardia......Page 213
Travelers’ Diarrhea in Children......Page 214
Specific Host Factors......Page 215
Travel Packages and Meals......Page 216
Risk by Geographic Region......Page 217
Conclusion......Page 218
References......Page 219
The Impact of Prevention......Page 223
Keywords......Page 224
Education and Behavior Modification......Page 225
Probiotics and Other Nonantibiotic Forms of Prophylaxis......Page 226
Antimicrobial Agents......Page 227
References......Page 228
Syndromic Presentations and Etiology......Page 230
Keywords......Page 231
Management of Travelers’ Diarrhea......Page 232
Fluids......Page 233
Other Nonantibiotic Alternatives......Page 234
Antibiotic Resistance as Both Cause and Consequence of Travelers’ Diarrhea......Page 235
References......Page 236
Persistent Gastrointestinal Symptoms Incidence......Page 238
Keywords......Page 239
Entamoeba histolytica.......Page 240
Enterobacteriaceae.......Page 241
Postinfectious Functional Gastrointestinal Disorders Epidemiology and Pathogenesis.......Page 242
Colorectal Cancer.......Page 244
Blood Testing.......Page 245
Therapy......Page 246
References......Page 248
Access to Medical Care Abroad......Page 251
Keywords......Page 252
Water Sports and Travel by Boat.......Page 253
Travel by Automobile.......Page 255
Zika Virus and Pregnancy......Page 256
Treatment.......Page 258
Travelers’ Diarrhea......Page 259
Altitude and Pregnancy......Page 260
Medical Kit......Page 261
References......Page 262
Should Children Be Subjected to the Discomforts of International Travel? Is It Safe for Children to Travel Internationally?......Page 264
Keywords......Page 265
Does Jet Lag Occur in Children?......Page 266
Altitude.......Page 267
Immunization......Page 268
Insect-Borne Diseases......Page 269
Tickborne Diseases.......Page 270
Treatment......Page 271
Conclusion......Page 272
References......Page 273
Fitness to Travel......Page 275
Keywords......Page 276
Medications and Medical Supplies......Page 277
Jet Lag......Page 278
Travelers’ Diarrhea......Page 279
Typhoid Fever.......Page 280
References......Page 281
Choosing a Trip and Making Travel Arrangements......Page 283
Keywords......Page 284
Traveling With an Attendant......Page 286
Air Travel With a Wheelchair or Scooter......Page 287
Service Animals......Page 288
References......Page 289
Before You Go......Page 290
Keywords......Page 291
The Voyage......Page 292
Cardiac Disease......Page 293
Diabetes Mellitus......Page 294
Gastrointestinal Disease......Page 295
References......Page 296
Corticosteroids, Disease-Modifying Antirheumatic Drugs, and Biologic Therapies......Page 298
Keywords......Page 299
Asplenic Travelers......Page 301
Transplant Recipients......Page 302
Yellow Fever......Page 303
Vaccination of Family Members and Household Contacts......Page 304
Strongyloides......Page 305
References......Page 306
Introduction......Page 308
Keywords......Page 309
Pretravel Advice......Page 310
Inactivated vaccines.......Page 311
Risk and Severity of Vaccine Preventable Disease in the HIV-Infected Traveler.......Page 312
Conclusion......Page 314
References......Page 315
Health Risks of International Business Travelers......Page 317
Keywords......Page 318
Air Pollution......Page 319
Pretravel Considerations for Health Risks Before International Travel......Page 320
Travel Kits......Page 322
Conclusion......Page 323
References......Page 324
Mission-oriented Medicine and VIP Travel Medicine......Page 325
Keywords......Page 326
Operationalizing VIP Travel Support......Page 327
Medical Threat Assessment and Countermeasures......Page 328
Nothing More, Nothing Less......Page 329
Right Equipment.......Page 330
Common pitfalls.......Page 331
Knowing Where to Get Help: Host Country Solutions......Page 332
References......Page 333
The Children......Page 334
Keywords......Page 335
Skin and Intestinal Infections.......Page 336
Tuberculosis (TB).......Page 338
References......Page 339
Epidemiology of Travel by Visiting Friends and Relatives......Page 342
Keywords......Page 343
Enteric Fever......Page 344
Malaria......Page 345
Sexually Transmitted Infections and Bloodborne Viruses......Page 346
Improving Access to Pretravel Services......Page 347
Travel-Specific Immunizations......Page 348
Conclusion......Page 349
References......Page 350
Hidden Costs of Expatriation......Page 352
Keywords......Page 353
Predeparture Psychologic Assessment......Page 354
Rabies.......Page 355
Culture Shock and the U-Curve Hypothesis......Page 356
“Normal” Adjustment Difficulties......Page 357
Returning Home......Page 358
Easing Return......Page 359
References......Page 360
Tuberculosis.......Page 362
Keywords......Page 363
Chronic Viral Hepatitis.......Page 364
Noncommunicable Diseases.......Page 365
References......Page 366
Mortality in Humanitarian Workers......Page 367
Keywords......Page 368
Malaria......Page 369
Dental Care......Page 370
Health Recommendations for the Relief Worker Traveling to Challenging Work Zones......Page 371
References......Page 372
Introduction......Page 374
Keywords......Page 375
Malaria and Other Vectorborne Diseases......Page 377
Dermatologic Diseases......Page 378
References......Page 379
Questions to Ask......Page 381
Keywords......Page 382
Risk Assessment and Preparation......Page 383
Personal Preparation......Page 384
Supplies......Page 386
Field Data......Page 388
Psychiatric Problems......Page 389
Mountaineering......Page 390
Jungle/Tropical Environments......Page 391
Scuba Diving Expeditions......Page 392
Medical Care of Others......Page 393
Death Overseas......Page 394
References......Page 395
Ecotourists......Page 397
Keywords......Page 398
Infectious Disease Risks......Page 399
Risks to Other Species.......Page 400
References......Page 401
Medical Tourism Defined......Page 405
Keywords......Page 406
Cosmetic Surgery Tourism Recommendations......Page 407
Adverse Effects and Complications......Page 408
References......Page 409
International Regulations......Page 411
Keywords......Page 412
Influenza.......Page 413
Seasickness......Page 414
During Travel......Page 415
References......Page 416
Noncommunicable Diseases and Trauma......Page 418
Keywords......Page 419
Planning for Mass Gatherings......Page 420
References......Page 421
Section 8: Environmental Aspects of Travel Medicine
......Page 423
Keywords......Page 424
Epidemiology......Page 426
Clinical Presentation and Diagnosis......Page 427
Preacclimatization......Page 428
Prevention......Page 431
Travel Advice for Parents......Page 432
Pulmonary and Cardiac Problems......Page 433
Hematologic Disorders......Page 434
References......Page 435
The Ears, Nose, and Throat System and Diving......Page 438
Keywords......Page 439
Diabetes and Diving......Page 440
Medication and Diving......Page 441
Further Information and Advice......Page 442
References......Page 443
Heat Balance......Page 445
Keywords......Page 446
Heat Adaptation......Page 447
Diagnosis.......Page 448
Heat Exhaustion.......Page 449
Cold Injuries......Page 450
Treatment.......Page 451
Preventing Cold Injuries......Page 452
Rehydration......Page 453
References......Page 454
Treatments......Page 455
Keywords......Page 456
Light Therapy.......Page 457
MMAs.......Page 458
Conclusion......Page 459
References......Page 460
Triggers of Motion Sickness......Page 462
Keywords......Page 463
Nonmedicinal Prevention and Treatment Options......Page 464
Medications for Prevention and Treatment of Motion Sickness......Page 465
Treatment of Established Motion Sickness......Page 466
References......Page 467
The Pressurized Cabin......Page 469
Keywords......Page 470
Cosmic Radiation......Page 472
Measles......Page 473
Assessment Criteria......Page 474
In-Flight Medical Emergencies......Page 475
Conclusions......Page 476
References......Page 477
Treatment of Arthropod Bites.......Page 478
Keywords......Page 479
Prevention of Animal Attack.......Page 481
Venomous Bites and Stings......Page 482
Venomous Arthropods......Page 483
Hymenoptera.......Page 484
Venomous Reptiles......Page 485
Prevention of Marine Animal Stings and Attacks......Page 487
Marine Infections......Page 488
References......Page 489
Ciguatera......Page 490
Keywords......Page 491
Scombroid (Histamine Fish Poisoning)......Page 494
Pufferfish (Fugu) Poisoning......Page 495
Neurotoxic Shellfish Poisoning......Page 496
References......Page 497
Fatal Injury......Page 499
Keywords......Page 500
A Global Public Health Approach for Travel Medicine......Page 501
Water-Related Injuries......Page 502
Alcohol as a Risk Factor......Page 503
References......Page 504
Sources of Stress in International Travel......Page 505
Keywords......Page 506
Clinical Operating Environments Overseas and Their Vicissitudes......Page 507
Psychosis: Some Specifics and Relation to International Travel......Page 508
Posttravel Consultations......Page 509
References......Page 510
Size of the Risk After Travel......Page 511
Keywords......Page 512
Passenger-Related Risk Factors......Page 513
Mechanism......Page 514
Conclusions and Recommendations......Page 515
References......Page 516
Continued Globalism of Quality......Page 517
Keywords......Page 518
Health Care Resources.......Page 519
Medical assistance plans.......Page 520
Other resources for locating care.......Page 521
Paying for Care......Page 522
Pharmacy and Medication Issues......Page 523
References......Page 524
Before Departure......Page 525
Keywords......Page 526
Out and About......Page 527
Getting Sick......Page 528
References......Page 529
Who and When to Screen?......Page 530
Keywords......Page 531
Physical Examination......Page 532
Sexually Transmitted Infections......Page 533
Introduction.......Page 535
Invasive Amebiasis.......Page 536
References......Page 537
Causes of Fever in Travelers......Page 539
Keywords......Page 540
Incubation Period......Page 542
Clinical Presentations......Page 543
Rickettsial Infections.......Page 544
Acute Schistosomiasis.......Page 545
Elevated Liver Enzymes......Page 546
Conclusion......Page 547
References......Page 548
Hookworm-Related Cutaneous Larva Migrans......Page 550
Keywords......Page 551
Localized Cutaneous Leishmaniasis......Page 553
Myiasis......Page 554
Tungiasis......Page 555
Pyodermas......Page 556
Scabies......Page 557
Photosensitivity and Photo-Induced Disorders......Page 558
Urticaria......Page 559
Febrile Rash......Page 560
Sexually Transmitted Infections......Page 561
References......Page 562
Drug Hypersensitivity......Page 564
Keywords......Page 565
Helminths.......Page 566
Skin/Soft Tissue Involvement......Page 567
Gastrointestinal Symptoms......Page 568
Schistosomiasis.......Page 569
Evaluation of Patients With Eosinophilia......Page 570
References......Page 571
Epidemiology......Page 573
Keywords......Page 574
Management of Respiratory Tract Infections......Page 576
Prevention in Travelers......Page 578
Influenza......Page 579
Melioidosis......Page 580
Paragonimiasis......Page 581
Conclusion......Page 582
References......Page 583
Point-of-Care Travel Clinic Destination Resources......Page 585
Keywords......Page 586
Electronic Notifications and Feeds......Page 591
A......Page 592
B......Page 593
C......Page 594
D......Page 595
E......Page 596
G......Page 597
H......Page 598
I......Page 599
L......Page 600
M......Page 601
N......Page 602
P......Page 603
R......Page 605
S......Page 606
T......Page 607
V......Page 608
Z......Page 609

Citation preview


This edition of Travel Medicine is lovingly dedicated to our colleague, our mentor, our friend, Dr. Jay Keystone. One could easily enumerate a list of superlatives for Jay by just reeling off items from his lengthy curriculum vitae – his manuscripts, academic appointments, the many awards he has received, and the immense contributions he has made to travel and tropical medicine in his decades of service. Perhaps the most distinguished of his honors was his induction into the Order of Canada in May, 2016. The Order recognizes individuals who have exhibited lifelong exemplary achievement, service, and have made major contributions to Canada; Queen Elizabeth II is the Sovereign of the Order. This was truly well deserved. So, if it were the editors’ decision to dedicate this text to Jay just on the basis of his awards and honors, it would be enough. But many of us who use this text know Jay as a one of the fathers of the practice of clinical tropical medicine and travelers’ health. Jay received his MSc from the London School of Tropical Medicine in 1974 and since then he has cared for countless patients around the world and excelled in judgment and clinical management.


Many of us are students of Jay. Jay received the Ben Kean Medal from the American Society of Tropical Medicine and Hygiene (ASTMH) recognizing his teaching skills. His teaching style connects with students at all levels. Over the decades, he has been on the roster of invited speakers for countless educational conferences that we attend and we are always delighted to see Jay at the podium. His lectures are informative, up to date, and enormously entertaining. In fact, he is one of few who make us all laugh – at ourselves and at the human condition – no matter our background or beliefs. Some of us know Jay as an early pioneer in travel medicine. He was chosen to speak about malaria at the 1988 travel medicine conference in Zurich, and was one of the founding members of the International Society of Travel Medicine (ISTM). A former president of the Society, Jay sought greater membership from underrepresented countries, and participated in the development of the Certificate in Travel Health examination. During his tenure as ISTM President he created a “Coalition for Healthy Travel” encouraging pharmaceutical industry partners to forgo their own corporate interests and contribute to general education in travel medicine and travelers’ heath. He was the GeoSentinel site director for the Toronto clinic, which was the first GeoSentinel site recruited outside the United States. And finally, some of us are fortunate enough to know Jay as one of the most caring persons we have ever known. Jay is one of those rare individuals who is always his authentic self. He is equally willing to give his time to advise junior students as senior colleagues. For some of us, his support helped us forge our own careers in travel medicine. As a physician, he is compassionate, understanding the importance of holding the hand of a frightened patient or family member. He will stop at nothing to help his patients, and is incredibly generous with his time in consultations. As a friend, he is always available to lend an ear. He is quick to offer his opinion when asked (and sometimes even when not!). Bright, energetic, fun-loving, realistic, and kindhearted, he embodies those qualities we admire. A loving father of five and grandfather of five, he has found his soulmate, Margaret Mascarenhas, and they cherish the moments they spend together. However, Jay still manages to take time for his patients and for all of us who seek his counsel and rely on his wisdom. We thank you, Jay, with all our hearts. Your Editorial Team – Phyllis Kozarsky, Bradley Connor, Hans Nothdurft, Karin Leder, and Marc Mendelson

Travel Medicine Fourth Edition

Jay S. Keystone CM MD MSc(CTM) FRCPC Professor of Medicine, University of Toronto Tropical Disease Unit Toronto General Hospital Toronto, ON, Canada Phyllis E. Kozarsky MD Professor Emerita Department of Medicine Division of Infectious Diseases Emory University Bradley A. Connor MD Clinical Professor of Medicine Weill Cornell Medical College The New York Center for Travel and Tropical Medicine New York, NY, USA

Hans D. Nothdurft MD Professor Department of Infectious Diseases and Tropical Medicine Head, University Travel Clinic University of Munich Munich, Germany Marc Mendelson MD PhD Division of Infectious Diseases and HIV Medicine University of Cape Town Groote Schuur Hospital Observatory Cape Town, South Africa Karin Leder MD MPH PhD Head, Infectious Disease Epidemiology Unit School of Epidemiology and Preventive Medicine Monash University Melbourne, VIC, Australia

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Edinburgh London New York Oxford Philadelphia St Louis Sydney 2019

© 2019, Elsevier Inc. All rights reserved. First edition 2004 Second edition 2008 Third edition 2013 Fourth edition 2019 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Chapter 14: “Malaria: Epidemiology and Risk to the Traveler” by David Lalloo and Alan J. Magill (†) is in Public Domain. Chapter 20: “Clinical Presentation and Management of Travelers’ Diarrhea” by Mark S. Riddle is in Public Domain. Chapter 21: “Persistent Gastrointestinal Symptoms in the Ill-Returning Traveler” by Mark S. Riddle is in Public Domain. Chapter 58: “Eosinophilia” by Amy D. Klion is in Public Domain.

Notices Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-323-54696-6 e-ISBN: 978-0-323-54771-0

Content Strategist: Charlotta Kryhl Content Development Specialist: Nani Clansey Project Manager: Nayagi Athmanathan Illustration Manager: Karen Giacomucci Designer: Amy Buxton Marketing Manager: Michele Milano

Printed in the US Last digit is the print number: 9 8 7 6 5 4 3 2 1

P R E FA C E “When you travel, remember that a foreign country is not designed to make you comfortable. It is designed to make its own people comfortable.” Clifton Fadiman Clifton Fadiman pointed out correctly that travel is not without its challenges. Whether one travels first class or in no class at all, there remain a variety of health issues that may be beyond our control. For example, when it comes to adhering to food and beverage precautions, one can do everything right and become ill, or everything wrong and remain well. Sometimes luck and our body’s immune system are what keep us healthy. As the scientific base of travel medicine continues to grow, so does the need for synthesizing this material into a formal text. Yes, readers may go online now and research every travel health topic separately to find the most recently published articles, but these may not give the reader sufficient history, perspective, or the various opinions that make up all the features of the topic or this text. Our aim then has not only been to provide a review of important areas, but to update the previous edition and to include new items that comprise travel health. New information covering immunizations, prophylactic medications, and guidance are all included. As well, this fourth edition has an expanded editorial team, including representation from other parts of the world: Dr. Marc Mendelson from South Africa and Dr. Karin Leder from Australia. The importance of having a truly global team looking at the text cannot be overstated. We realize that to cover worldwide health issues, we needed to think more globally about inclusion. On the other hand, there are some things that a text cannot do. We urge all those who need information on a current or new health problem

in a particular country to investigate more widely using WHO or national websites. Certainly, one of the many things we have learned about medicine, and travel medicine in particular, is that health recommendations can change overnight with the emergence or reemergence of disease. The field’s mandate continues to be the maintenance of health of international travelers. In 1988, the first international meeting of travel medicine experts took place in Switzerland and from that initiative came the International Society of Travel Medicine, now with 3500 members from 94 countries. Since then the world of travel medicine has changed significantly, as is highlighted by changes in our text with each edition. Now the fourth edition includes chapters covering ecotourism, VIP travel, and pretravel considerations in the prevention of non-vaccine preventable infections such as Zika, chikungunya, and MERS viruses. Also, we have provided travel medicine consultants with an approach to the illnesses they might encounter in ill-returned travelers, both the investigations and the management issues. Our outstanding authors are subject matter experts who have comprehensive and authoritative knowledge in their respective fields, individuals who have been selected from a number of countries. We believe that by incorporating both a practical and evidence-based approach, our authors and editors have made this book an essential resource for all travel medicine practitioners. We hope you enjoy this edition. We believe that all of our authors and editors love to travel, knowing it enhances their careers and lives. Despite travel’s many challenges, one must also consider the alternative and why it is so important to travel, stated so succinctly here: “If you think adventure is dangerous, try routine, it’s lethal.” Anonymous


LIST OF CONTRIBUTORS Vernon Ansdell MD FRCP DTM&H Associate Clinical Professor University of Hawaii Department of Tropical Medicine Medical Microbiology and Pharmacology Honolulu, HI, USA

Trish Batchelor MD FRACGP MPH DipCH PG Dip Occ Env Med Principal Medical Adviser Australian Department of Foreign Affairs and Trade Canberra, ACT, Australia

Suzanne C. Cannegieter MD PhD Professor in Clinical Epidemiology Department of Clinical Epidemiology and Department of Internal Medicine, Thrombosis and Haemostasis Leiden University Medical Center Leiden, the Netherlands

Olivier Aoun MD MSc

Ronald H. Behrens MD FRCP

Lieutenant Colonel, French Military Health Service Chief physician of the 46th Medical Unit 5th Armed Forces Medical Center Strasbourg, Alsace, France

Director of Department of Travel Medicine, Hospital for Tropical Diseases Research Degree Director, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine London, UK

Eric Caumes MD

Jiří Beran MD


Professor of Medicine Department for Tropical, Travel Medicine and Immunization, Institute for Postgraduate Medical Education Prague, Czech Republic Vaccination and Travel Medicine Centre Hradec Králové, Czech Republic

Director, Travel Medicine Center, Mount Auburn Hospital Associate Professor, Harvard Medical School Division of Infectious Diseases and Travel Medicine Mount Auburn Hospital Cambridge, MA, USA

Howard Backer MD MPH FACEP FAWM Director California Emergency Medical Services Authority California State Government Sacramento, CA, USA

Michael Bagshaw MB MRCS FFOM DAvMed Professor of Aviation Medicine; Army Civilian Consultant Adviser in Aviation Medicine Centre of Human & Aerospace Physiological Sciences King’s College London London, UK

Joannes Clerinx MD Sarah Borwein MD Managing Partner and Physician Central Health Medical Practice and TravelSafe Hongkong, SAR China

J. Kevin Baird PhD FASTMH Eijkman-Oxford Clinical Research Unit Eijkman Institute of Molecular Biology Jakarta, Indonesia Centre for Tropical Medicine & Global Health Nuffield Department of Medicine University of Oxford Oxford, UK

Elizabeth D. Barnett MD Professor of Pediatrics Section of Pediatric Infectious Diseases Boston Medical Center Boston, MA, USA


Senior Consultant, Department of Clinical Sciences Institute of Tropical Medicine Antwerp, Belgium

Bradley A. Connor MD William B. Bunn MD JD MPH Advisor / Consultant Former VP of Health, Safety, Security & Productivity Navistar International Corporation Lisle, IL, USA Professor Medical University of South Carolina Charleston, SC, USA

Roger A. Band MD FACEP Senior Advisor, Medical, Shoreland-Travax Vice Chair, Strategic Out of Hospital Initiatives Director Quality Assurance, Peer Review and Process Improvement Medical Director Jefferson Enterprise Urgent Care Department of Emergency Medicine Thomas Jefferson University Philadelphia, PA, USA

Professor Head of Department Service des Maladies Infectieuses et Tropicales Groupe Hospitalier Pitié-Salpêtrière Paris, France

Gerd D. Burchard MD PhD Professor Department Tropical Medicine / Infectious Diseases University Medical Center Hamburg Hamburg, Germany

Clinical Professor of Medicine Weill Cornell Medical College The New York Center for Travel and Tropical Medicine New York, NY, USA

Jakob P. Cramer MD PhD Infectious Diseases Travel Medicine Tropical Medicine Specialist Hamburg, Germany

Thomas E. Dietz MD Providence Hood River Memorial Hospital, Emergency Department Portland, OR, USA

Michael V. Callahan MD DTM&H MSPH

Herbert L. DuPont MD

Director, Clinical Translation Vaccine and Immunotherapy Center Division of Infectious Diseases Massachusetts General Hospital Harvard Medical School Boston, MA, USA

Mary W. Kelsey Chair in Medical Sciences, University of Texas McGovern Medical School, Professor of Infectious Diseases, University of Texas School of Public Health, Clinical Professor, Baylor College of Medicine, President and CEO, Kelsey Research Foundation Houston, TX, USA



Yoram Epstein PhD

Philippe Gautret MD PhD DTM&H

Stephen W. Hargarten MD MPH

Head, Environmental Physiology Branch Heller Institute of Medical Research Sheba Medical Center Tel Hashomer, Israel

Senior Clinician, Travel and Tropical Medicine Head of Out-Patients Department, Infectious Diseases and Travel Clinic Aix Marseille Univ, IRD, AP-HM, SSA, VITROME, IHU-Méditerranée Infection, Marseille, France Principal Investigator, EuroTravNet

Professor and Chair of Emergency Medicine Associate Dean for Global Health Comprehensive Injury Center Director Medical College of Wisconsin Milwaukee, WI, USA

Charles D. Ericsson MD Dr. and Mrs. Carl V. Vartian Professor of Infectious Diseases McGovern Medical School Houston, TX, USA

Philip R. Fischer MD Professor of Pediatrics Mayo Clinic Rochester, MN, USA

Gerard T. Flaherty MB BSc MSc MD FRCPI FFTM RCPS (Glasg) FISTM Professor of Medical Education; Adjunct Professor of Travel Medicine and International Health School of Medicine, National University of Ireland Galway Galway, Ireland

Mark S. Fradin MD Adjunct Clinical Associate Professor of Dermatology Department of Dermatology University of North Carolina at Chapel Hill Chapel Hill, NC, USA

Tifany Frazer MPH Office of Global Health Manager Medical College of Wisconsin Milwaukee, WI, USA

David O. Freedman MD Professor Emeritus of Infectious Diseases University of Alabama at Birmingham Medical Director, Shoreland Travex Birmingham, AL, USA

Jason Gibbs Pharmacist Nomad Travel Clinics UK

Jeff Goad PharmD MPH FISTM Professor and Chair Department of Pharmacy Practice Chapman University School of Pharmacy Irvine, CA, USA

Larry Goodyer MPharm MRPharmS Phd FFTMRCPS(Glasg) FRGS FISTM Professor of Pharmacy Practice Leicester School of Pharmacy De Montfort University, Leicester, UK Consultant Travel Health Specialist Nomad Stores and Clinics, UK

Christina Greenaway MD FRCPC MSc Associate Professor Division of Infectious Diseases Jewish General Hospital Centre for Clinical Epidemiology of the Lady Davis Institute for Medical Research McGill University Montreal, QC, Canada

Kenneth Gamble MD FFTM RCPS (Glasg) President Missionary Health Institute and International Medical Services Toronto, ON, Canada

Emeritus Professor of Tropical and Travel Medicine Swiss Tropical and Public Health Institute, Basel, Switzerland Emeritus Professor of Epidemiology and Prevention of Communicable Diseases Epidemiology, Biostatistics and Prevention Institute, University of Zürich, Switzerland

Deborah M. Hawker PhD DClinPsy CPsychol AFBPsS Clinical Psychologist Nottingham, UK

Patrick Hickey MD FAAP FIDSA Lieutenant Colonel, Medical Corps, US Army Deputy Principal, PEPFAR-DOD Military HIV Research Program Walter Reed Army Institute of Research Silver Spring, MD, USA Associate Professor Division of Tropical Public Health Department of Preventive Medicine and Biostatistics Uniformed Services University Bethesda, MD, USA

Carter D. Hill MD FACEP

Sandra Grieve RGN

Evergreen Emergency Services, Inc. Evergreen Healthcare Kirkland, WA, USA

Independent Travel Health Specialist Nurse Independent Practitioner Warwickshire, UK


Joanna Gaines PhD MPH CHES Senior Epidemiologist Travelers’ Health Branch, Division of Global Migration and Quarantine Centers for Disease Control and Prevention Atlanta, GA, USA

Christoph Hatz MD DTM&H

Martin P. Grobusch Center of Tropical Medicine and Travel Medicine Department of Infectious Diseases, Division of Internal Medicine Academic Medical Center, University of Amsterdam Amsterdam, the Netherlands

Professor of Medical Sciences Director of Global Public Health Frank H. Netter MD School of Medicine Quinnipiac University Hamden, CT, USA

Euna Hwang MD FRCSC

Director, Institute for Altitude Medicine Ridgway, CO, USA

Clinical Lecturer Section of Otolaryngology-Head and Neck Surgery Department of Surgery, University of Calgary Calgary, AB, Canada

Davidson Hamer MD

Petra A. Illig MD

Professor of Global Health and Medicine Boston University Schools of Public Health and Medicine Boston, MA, USA

Senior Medical Examiner Aviation Medical Services of Alaska Anchorage, AK, USA

Peter H. Hackett MD



Clarion E. Johnson MD

David G. Lalloo MB BS MD FRCP

Alberto Matteelli MD

Advisor / Consultant Former Global Medical Director ExxonMobil Corporation Houston, TX, USA

Dean of Clinical Sciences and International Public Health Liverpool School of Tropical Medicine Liverpool, UK

Jay S. Keystone CM MD MSc(CTM) FRCPC

William L. Lang MD MHA

Associate Professor Clinic of Infectious and Tropical Diseases University of Brescia and Brescia Spedali Civili General Hospital WHO Collaborating Centre for TB/HIV and TB Elimination Brescia, Italy

Professor of Medicine, University of Toronto Tropical Disease Unit Toronto General Hospital Toronto, ON, Canada

Amy D. Klion MD Senior Clinical Investigator Head, Human Eosinophil Section Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, MD, USA

Vice President, International Medicine Inova Health System Fairfax, VA, USA

Beth Lange MB ChB Otolaryngologist Alberta Health Care Services Calgary, AB, Canada

Karin Leder MD MPH PhD Head, Infectious Disease Epidemiology Unit School of Epidemiology and Preventive Medicine Monash University Melbourne, VIC, Australia

Herwig Kollaritsch MD DTM

C. Virginia Lee MD MPH MA

Institute of Specific Prophylaxis and Tropical Medicine Center for Pathophysiology, Infectiology and Immunology Medical University of Vienna Vienna, Austria

Senior Medical Officer Travelers’ Health Branch, Division of Global Migration and Quarantine Centers for Disease Control and Prevention Atlanta, GA, USA

Michael Libman MD Camille Nelson Kotton MD FIDSA FAST Clinical Director, Transplant and Immunocompromised Host Infectious Diseases Infectious Diseases Division, Massachusetts General Hospital Associate Professor, Harvard Medical School Boston, MA, USA

Phyllis E. Kozarsky MD Professor Emerita Department of Medicine Division of Infectious Diseases Emory University

Susan M. Kuhn MD MSc DTM&H FRCPC Associate Professor Departments of Pediatrics and Medicine University of Calgary Alberta Children’s Hospital Calgary, AB, Canada

Professor of Medicine Director, J. D. MacLean Centre for Tropical Diseases McGill University Montreal, QC, Canada

Sheila M. Mackell MD Pediatrics and Travel Medicine Mountain View Pediatrics Flagstaff, AZ, USA

Alan J. Magill† Colonel US Army Emeritus, Walter Reed Army Institute of Research Associate Professor of Preventive Medicine and Biometrics Associate Professor of Medicine Uniformed Services University of the Health Sciences Bethesda, MD, USA

Poppy Markwell MD MPH MSPH Tamar Lachish MD Infectious Diseases Unit Shaare-Zedek Medical Center Jerusalem, Israel

Senior Infectious Disease Fellow Tulane University School of Medicine New Orleans, LA, USA


Anne McCarthy MD BMedSc MSc FRCPC DTM&H Director, Tropical Medicine & International Health Clinic, Division of Infectious Diseases Professor of Medicine, University of Ottawa, Faculty of Medicine UGME Lead for Global Health, Faculty of Medicine University of Ottawa Department of Infectious Disease, The Ottawa Hospital Ottawa, ON, Canada

Sarah L. McGuinness MBBS FRACP MPH DTM&H BMedSc Infectious Diseases Physician Department of Infectious Diseases, The Alfred Hospital School of Public Health and Preventive Medicine, Monash University Melbourne, VIC, Australia

D. Bruce McIndoe MS President and Founder WorldAware, Inc. Annapolis, MD, USA

Susan L F McLellan MD MPH FIDSA FASTMH Professor, Infectious Diseases Division Medical Director, Biocontainment Treatment Unit Director of Biosafety for Research-related Infectious Pathogens University of Texas Medical Branch 301 University Blvd. Galveston, TX, USA

W.A.J. (Jack) Meintjes MBChB DOM FCPHM(SA) Occ Med MMed (Occ Med) Occupational Medicine Specialist and Senior Lecturer Division of Health Systems and Public Health, Department of Global Health Faculty of Medicine and Health Sciences, Stellenbosch University Cape Town, South Africa

LIST OF CONTRIBUTORS Marc Mendelson MD PhD Division of Infectious Diseases and HIV Medicine University of Cape Town Groote Schuur Hospital Observatory Cape Town, South Africa


Patricia Schlagenhauf PhD FFTM RCPS (Glasgow) FISTM

Professor, Senior Consultant Department of Infectious Diseases The Royal Hospital Muscat Sultanate of Oman

Professor and Senior Scientist University of Zürich Centre for Travel Medicine WHO Collaborating Centre for Travellers’ Health Epidemiology, Biostatistics and Prevention Institute Zürich, Switzerland

Maria Denise Mileno MD Associate Professor of Medicine Division of Infectious Diseases Alpert Medical School of Brown University Consultant and former Director, Brown Medicine Travel Clinic, East Providence RI The Miriam Hospital Providence, RI, USA

Mark S. Riddle MD MPH&TM DrPH Chair and Professor Department of Preventive Medicine and Biostatistics F. Edward Hebert School of Medicine— “America’s Medical School” Uniformed Services University Bethesda, MD, USA

Frits R. Rosendaal MD PhD Laurie C. Miller MD Professor of Pediatrics, Tufts University School of Medicine Adjunct Professor, Friedman School of Nutrition Science & Policy Adjunct Professor, Eliot-Pearson Department of Child Study & Human Development Tufts University Boston, MA, USA

Daniel S. Moran PhD Head, Health Promotion Department School of Public Health Ariel University Ariel, Israel


Professor in Clinical Epidemiology Department of Clinical Epidemiology Leiden University Medical Center Leiden, the Netherlands

Gail Rosselot NP MS MPH COHN-S/R FRCPS (Glas) FAANP FISTM Certificate in Travel Health® President, Travel Well of Westchester, Inc. Director, The Westchester Courses President, American Travel Health Nurses Briarcliff Manor New York, NY, USA

Edward T. Ryan MD

Eli Schwartz MD DTM&H Professor of Medicine Center for Geographic Medicine and Tropical Diseases Chaim Sheba Medical Center, Tel Hashomer Sackler School of Medicine Tel Aviv University Tel Aviv, Israel

David R. Shlim MD Medical Director Jackson Hole Travel and Tropical Medicine Jackson Hole, Wyoming The New York Center for Travel and Tropical Medicine New York, NY, USA

Frédéric Sorge MD Consultation Adoption, Enfant Migrant Département de Pédiatrie Hôpital Necker Enfants Malades Paris, France

Professor and Chair Department of Anthropology Baylor University Waco, TX, USA

Director, Global Infectious Diseases, Massachusetts General Hospital Professor of Medicine, Harvard Medical School Professor of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health Boston, MA, USA

Erni J. Nelwan MD PhD

Nuccia Saleri MD PhD

Robert Steffen MD

Division of Tropical Infectious Diseases Faculty of Medicine Universitas Indonesia Jakarta, Indonesia

Tropical Medicine Specialist TB and TB/HIV Technical Advisor Independent Consultant Pondicherry, India

Emeritus Professor University of Zurich Epidemiology, Biostatistics and Prevention Institute WHO Collaborating Centre for Travellers’ Health Zurich, Switzerland Adjunct Professor Division of Epidemiology, Human Genetics & Environmental Sciences University of Texas School of Public Health Houston, TX, USA

Michael P. Muehlenbein PhD MsPH MPhil

Silvia Odolini MD Clinic of Infectious and Tropical Diseases University of Brescia and Brescia Spedali Civili General Hospital WHO Collaborating Centre for TB/HIV and TB Elimination Brescia, Italy

John W. Sanders MD Professor of Medicine Chief, Section on Infectious Diseases Wake Forest School of Medicine Winston-Salem, NC, USA

Mike Starr MBBS FRACP Pediatrician, Infectious Diseases Physician, Consultant in Emergency Medicine Honorary Clinical Associate Professor, University of Melbourne The Royal Children’s Hospital Melbourne, VIC, Australia

Philippe Parola MD PhD Professor, Infectious Diseases Head of Department, Acute Infectious Diseases Aix Marseille Univ, IRD, AP-HM, SSA, VITROME, IHU-Méditerranée Infection, Marseille, France

Kathryn N. Suh MD FRCPC MSc Division of Infectious Diseases The Ottawa Hospital Associate Professor of Medicine University of Ottawa Ottawa, ON, Canada



Andrea Summer MD

Thomas H. Valk MD MPH

Professor of Pediatrics Medical University of South Carolina Charleston, SC, USA

President VEI, Incorporated Marshall, VA, USA

David N. Taylor MD

Jenny Visser MbChB MTravMed

Chief Medical Officer Vaxart, Inc. South San Francisco, CA, USA

Senior Lecturer Department of Primary Health Care and General Practice University of Otago Wellington, New Zealand

W. Robert Taylor Mahidol Oxford Tropical Medicine Research Unit Bangkok 10400, Thailand Division of Tropical and Humanitarian Medicine University Hospitals of Geneva Geneva, Switzerland

Leo G. Visser MD PhD Professor of Infectious Disease Head of Department of Infectious Diseases Leiden University Medical Center Leiden, the Netherlands

Edward Wasser MD Shiri Tenenboim MD MSc(MIH) DTM&H Medical Doctor Chaim Sheba Medical Center, Tel Hashomer Sackler School of Medicine Tel Aviv University Tel Aviv, Israel

The Toronto East General Hospital, Sunnybrook Health Sciences Centre, Examiner, Medical Council of Canada Peer Assessor and Investigator, College of Physicians and Surgeons of Ontario Toronto, ON, Canada

Eric L. Weiss MD DTM&H Joseph Torresi MBBS BMedSci FRACP PhD Department of Microbiology and Immunology The Peter Doherty Institute for Infection and Immunity The University of Melbourne Melbourne, VIC, Australia

Richard J. Tubb MD Senior Advisor, Medical, Shoreland-Travax Brigadier General, USAF (ret) White House Physician Emeritus Washington, DC, USA

Associate Clinical Professor Department of Emergency Medicine Stanford University School of Medicine Stanford, CA, USA

Ursula Wiedermann MD PhD Professor of Vaccinology Head of Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna Vienna, Austria

Annelies Wilder-Smith MD PhD MIH FAMS FACTM Professor of Infectious Diseases Director, Global Health and Vaccinology Programme Lee Kong Chian School of Medicine Novena Campus Singapore

Mary Elizabeth Wilson MD FACP FIDSA FASTMH FISTM Clinical Professor of Epidemiology and Biostatistics School of Medicine University of California San Francisco San Francisco, CA, USA and Adjunct Professor Department of Global Health and Population Harvard T.H. Chan School of Public Health Boston, MA, USA

Henry M. Wu MD DTM&H Assistant Professor of Medicine Division of Infectious Diseases Emory University School of Medicine Atlanta, GA, USA

AC K N OW L E D G M E N T S The editors of Travel Medicine would like to thank our Elsevier publishing staff for encouraging us to embark on a 4th edition of the Textbook, and for being enthusiastic about moving forward with the addition of our new editors.

We would also like to thank our families, and particularly our partners, for their patience and understanding during the long process of writing and editing.


1  Introduction to Travel Medicine Phyllis E. Kozarsky and Jay S. Keystone

Each year the World Tourism Organization (WTO) publishes its statistics revealing staggering numbers of people crisscrossing the globe; indeed, over the last decade there have been double-digit increases in travel. International tourist arrivals reported by the WTO in 2016 grew to 1235 million, 46 million greater than in 2015. Preliminary data show the Asia-Pacific region leading the way with 8% growth, the Americas (primarily South and Central America) with 4% growth, and Europe with 2% growth, primarily in the north. Existing data from Africa show a healthy increase in travel to the sub-Saharan region—8% as well. The Middle East has seen a decrease in about 4%. Despite this continued growth and despite 2017 having been designated by the United Nations as the “International Year of Sustainable Tourism for Development,” challenges continue. Not only were there protests at a recent meeting of the WTO regarding the problem of overtourism and the need for more responsible travel (, but also the challenges of safety and security have been reawakened recently with episodes of terror and violence. Although considerations about health maintenance during travel have probably always been present, as explorers founded new regions, armies overtook others, and nomads wandered with their flocks, travel medicine’s scientific birth can probably be measured in just decades since the first international conference on travel medicine in Zurich in 1988, and the beginning of the International Society of Travel Medicine (ISTM) in 1991. Much has changed in the last several decades. Conferences and literature still feature the forever lasting topic of malaria chemoprophylaxis punctuated by debates about self-treatment. However, if we quickly scan the most recent news that encompasses our field and engages our constituency, articles in the last several months have included those highlighting tuberculosis in asylum seekers, ceftriaxone-resistant gonorrhea imported into Canada, Zika once again in Miami, and details about the use of CRISPR (gene editing tool) as a diagnostic tool for infectious diseases and the potential use of such new genomics for point-of-care-diagnosis. As well, Brazil is now facing a serious yellow fever outbreak that is challenging public health in that country as well as elsewhere as importations into other countries has occurred. At the same time, the UK Daily Mail featured interactive maps from International SOS highlighting the world’s most dangerous and safest countries by type of risk, labeling Finland, Norway, and Iceland as safest. Global mobility is now taken for granted, not something unique to any one group, any one company, or any one humanitarian effort, conflict, or migration pattern. Travel health has become the sum of all health maintenance considerations, both physical and emotional, as travelers embark on journeys from days to years for every different reason. In addition, we are now beginning to better understand the concept of One Health, that is, the importance of the interaction and intersection between human and animal health, and how this impacts the spread of emerging and reemerging diseases.

With the fourth edition of the textbook Travel Medicine, the editors needed to be cognizant of the growth of the body of knowledge ( in the field, while respecting the need to focus content on what is most important for the provider to understand practicing pretravel health. In addition, we have tried to include information concerning the more common issues facing travelers at their destinations as well as on return, being sure to capture the most recent developments. Because travel is no longer just associated with tourism, but often incorporates work, volunteerism, medical care, migration, etc., new content has also been added to assist the provider in caring for specific populations engaging in different types of travel. For example, chapters have been added on ecotourism, military travel, and the VIP traveler. In addition, we have added a section on the pretravel consultation to assist practitioners advising their clients on the prevention of vectorborne diseases such as chikungunya, dengue, and Zika viruses. Keeping up to date in the field of travel medicine is not easy. It requires a review of travel medicine, infectious disease, tropical medicine, and general medical journals as well as national government and international recommendations. Annual updates and international conferences in these fields may help. This textbook has been designed to bring it all to you, the most recent advances in the field as well as practical information on the management of pretravel and posttravelrelated issues. For example, since the third edition, new vaccines and regimens have been developed to prevent both routine and travel-related infections such as the high dose and adjuvated influenza and herpes zoster vaccines as well as a new oral vaccine from bovine colostrum for the prevention of Enterotoxigenic Escherichia coli, the most frequent cause of travelers’ diarrhea. For the last-minute traveler, both rabies and Japanese encephalitis vaccines now include 1-week accelerated regimens. Newly proposed single-dose antibiotic regimens for selftreatment of travelers’ diarrhea may help to reduce the development of drug-resistant enteric flora that make up our microbiome. In fact, the challenge of increasing antimicrobial resistance has crept into the field, impacting not only the provider but potentially the traveler, and perhaps even the traveler’s contacts on return. This important issue must be addressed not only within the context of travelers’ diarrhea, where new guidelines have been published by the ISTM,1 but also with the use of any antimicrobial agent. The World Health Organization ( and the ISTM ( remain major resources for the provider, as well as various country-specific guidelines for healthy travel. As well, there are many groups and agencies that provide national recommendations and guidance. A goal for those who choose to practice travel medicine should be to join the ISTM and to sit for the ISTM examination that awards the Certificate in Travel Health (CTH), an international standard of care for the practice of travel medicine. As guidance for healthy travel changes, disease outbreaks occur, and science advances, remaining up



SECTION 1  Practice of Travel Medicine

to date is critical as it is for any specialty. Although awareness of travel health and the possibility of the global spread of infectious diseases appeared to peak with the Ebola outbreak in West Africa from 2013 to 2016, we are aware of no recent data to support an increasing use of travel health clinics or providers; and with concerns such as vaccine shortages (e.g., yellow fever, hepatitis A), the incidence of even preventable travel-related illnesses will likely not decrease. Primary providers remain the best to ask the questions whether a person plans travel or has returned from travel. After “thinking travel,” the provider must then determine whether he or she is capable of caring

for the person or whether it is best to refer to someone with more expertise. We hope the material in this text will provide basic information for those who are new to the field, and updates for the veterans. We trust that those providers who choose to care for travelers can count this newest edition as a reliable and “go-to” reference.

REFERENCE 1. Riddle M, et al. Guidelines for the prevention and treatment of travelers’ diarrhea: a graded expert panel report. J Travel Med 2017;24(1):S63–80.

2  Epidemiology: Morbidity and Mortality in Travelers Sandra Grieve and Robert Steffen

KEY POINTS • Travel health risks are dependent on the itinerary, duration and season of travel, purpose of travel, lifestyle, and host characteristics. • Motor vehicle injuries and drownings are the major causes of preventable deaths in travelers, while malaria remains the most frequent cause of infectious disease deaths. • Complications of cardiovascular conditions are a major cause of death in travelers, particularly when senior citizens spend the winter in southern destinations.

• Travelers’ diarrhea (TD) remains the most frequent illness among travelers; the risk of TD can be divided into three risk categories based on destination. • Casual sex without the regular use of condom protection continues to be common practice by travelers.


typhoid). Thus, seroepidemiologic data from destination countries are usually of little relevance when assessing the risk in travelers. Among the infectious health risks, only those about which travel-related data have been published will be mentioned. The reader should consult current websites and tropical medicine textbooks for information about less common travel-related infections, such as trypanosomiasis.

Compared to staying at home, mortality and morbidity are increased in those who travel, especially when their destination is a developing country. Travel health risks vary greatly according to: Where • industrialized versus destination in a lower income country • city or highly developed resort versus off-the-tourist-trail locale When • season of travel (e.g., rainy versus dry, extremes of temperature) How long • duration of stay abroad For what purpose • tourism versus business versus rural work versus visiting friends or relatives (VFR) • other (military, airline crew layover, adoption, medical procedures abroad, etc.) Style • hygiene standard expected: high (e.g., multistar hotels) versus low (e.g., low-budget backpackers) • special activities (high-altitude trekking, diving, hunting, camping, etc.) Host characteristics • healthy versus preexisting condition, nonimmune versus semiimmune • age (e.g., infants, senior travelers) This chapter will concentrate on the available epidemiologic data associated with travel health risks in general (Tables 2.1 and 2.2); it will only to a limited extent describe the epidemiology of individual diseases at the destinations (Table 2.3). Such data are often unsatisfactory because they are incomplete, old, or were generated in studies that may have been biased.1 Lastly, visitors often experience far less exposure to pathogens than the native population (e.g., with respect to hepatitis B,

CORNERSTONES OF TRAVEL HEALTH EPIDEMIOLOGY Health problems in travelers are frequent. Three of four Swiss or Finnish travelers to developing countries had some health impairment, defined as having taken any therapeutic medication, or having reported being ill.2,3 At first glance, this proportion is alarming, but 50% of short-term travelers who crossed the North Atlantic had health impairments, often constipation.2,3 Acute gastroenteritis, respiratory tract infections, and ear infections were the most frequent.4 A larger follow-up study showed that only a few of these self-reported health problems were severe. Less than 10% of travelers to developing countries consulted a doctor either abroad or after returning home, or were confined to bed due to travel-related illness or an accident; 14% of such travelers are incapacitated. The most tragic consequence of travel is death abroad, which occurs in approximately 1/100,000. Sudden cardiac death, defined as an “unexpected, nontraumatic death that occurs within 24h of the onset of symptoms,” has been shown to account for up to 52% of deaths during downhill skiing and 30% of mountain hiking fatalities5 (Fig. 2.1). A study based on medical insurance claims among World Bank staff and consultants demonstrated that business travel may also pose health risks beyond exposure to infectious diseases, and that medical claims are increasing with the increasing frequency of travel.6 Such data illustrate how noninfectious problems also play a significant role.


CHAPTER 2  Epidemiology: Morbidity and Mortality in Travelers Abstract


In spite of natural disasters and turmoil in many countries, the number of people travelling abroad continues to increase. Reasons for travel vary with no barrier to age, health status, and proposed activities. Compared to staying at home, the potential for morbidity and mortality increases with travel, especially when people visit exotic or remote destinations in lower income countries. Because disease surveillance may be inadequate at some destinations, predicting the level of individual risk can be difficult and those offering travel health advice will remain uncertain about the risk behaviors of their clients. There are also limited data on people hospitalized abroad with most cases identified by anecdotal reporting on return home.

Epidemiology Morbidity Mortality Prevention Risk Travel Travelers’ health


September United States 2009– September 2010

January– December 2003

July 2003– June 2004

Balaban et al. (2014)

Dia et al. (2010)

Rack et al. (2006)





40.3 ± 13.5




43.3 (19–79)

41 (25–63)

52 (18–88)

United Statesb


Stoney et al. (2016)

35 (27–54)


December 2008– February 2010

Vilkman et al. (2016)

Epidemiology/technical assistance (66) Teaching/trainings (42) Attending professional meetings (37) Working in a laboratory (12) Working in a health care facility (12) Tourism (77) Visiting friends and relatives(12) Business (7) Missionary (3) Study (1) Tourism (100)

Tourism (71) Visiting friends and relatives (18) Business (8) Otherd (3)

Tourism/vacation (67) Business (18) Volunteer/missionary/aid (15) Visiting friends and relatives (14) Educational/research (4) Medical/dental care ( Viruses Simple to operate Mechanical filters require no holding time for treatment (water is treated as it passes through the filter) Large choice of commercial products Adds no unpleasant taste and often improves taste and appearance of water Rationally combined with halogens for removal or destruction of all microorganisms

Adds bulk and weight to baggage Most filters not reliable for high level of removal of viruses Expensive relative to chemical methods Channeling of water or high pressure can force microorganisms through the filter Filters eventually clog from suspended particulate matter; may require some maintenance or repair in field

Halogens Relative susceptibility of microorganisms to halogens: Bacteria > Viruses > Protozoa Iodine and chlorine are widely available Corrosive, stains clothing Very effective for bacteria, viruses, and Giardia Not effective for Cryptosporidia Taste can be removed Imparts taste and odor Chlorine Dioxide Relative susceptibility of microorganisms to chlorine dioxide: Bacteria > Viruses > Protozoa Volatile, so do not expose tablets to air and use generated solutions rapidly Effective against all microorganisms, including Cryptosporidia No persistent residual, so does not prevent recontamination during storage Low doses have no taste or color Sensitive to sunlight, so keep bottle shaded or in pack during treatment More potent than equivalent doses of chlorine Less affected by nitrogenous wastes Solar Ultraviolet Disinfection and Ultraviolet Relative susceptibility of microorganisms: Protozoa > Bacteria > Viruses Effective against all microorganisms Imparts no taste Simple to use Portable device now available for individual and small group field use Solar ultraviolet disinfection has no expense Can be used in austere environment

Requires clear water Does not improve water esthetics No residual effect—does not prevent recontamination during storage Commercial devices are expensive Requires power source (small units can be battery operated) Requires strong, direct, abundant sunlight, with prolonged exposure; dose low and uncontrolled bottle shaded or in pack during treatment

techniques can markedly improve the appearance and taste of water. They may reduce the number of microorganisms, but not enough to ensure potable water; however, clarifying the water facilitates disinfection by filtration or chemical treatment. Cloudy water can rapidly clog microfilters. Moreover, cloudy water requires increased levels of chemical treatment; the combined effects of the water contaminants plus chemical disinfectants result in an unpleasant taste.

Most microorganisms, especially protozoan cysts, also settle eventually but this takes much longer. Simply allow the water to sit undisturbed for about 1 hour or until sediment has formed on the bottom of the container, then decant or filter the clear water from the top through a coffee filter or finely woven cloth. A second method of disinfection must then be used to obtain potable water.

Sedimentation.  Sedimentation is the separation of suspended particles

nique in use since 2000 BC, can remove smaller suspended particles and chemical complexes too small to settle by gravity (colloids)26 (see

such as sand and silt that are large enough to settle rapidly by gravity.

Coagulation–Flocculation.  Coagulation–flocculation (C-F), a tech­


SECTION 2  The Pretravel Consultation

Table 5.2). Coagulation is achieved with the addition of a chemical that causes particles to stick together by electrostatic and ionic forces. Flocculation is a physical process that promotes the formation of larger particles by gentle mixing. Alum (an aluminum salt), lime (alkaline chemicals principally containing calcium or magnesium with oxygen), or iron salts are commonly used coagulants. Alum is nontoxic and used in the food industry for pickling. It is readily available in any chemical supply store. In an emergency, baking powder or even the fine white ash from a campfire can be used as a coagulant. Other natural substances are used in various parts of the world. C-F removes 60%–98% of microorganisms, heavy metals, and some chemicals and minerals (Table 5.3). The amount of alum added in the field—approximately one large pinch (one-eighth teaspoon) per gallon (approximately 4 L) of water— need not be precise. Stir or shake briskly for 1 minute to mix, and then agitate gently and frequently for at least 5 minutes to assist flocculation. If the water is still cloudy, add more flocculent and repeat mixing. After allowing at least 30 minutes for settling, pour the water through a fine-woven cloth or paper filter. Although most microorganisms are removed with the floc, a final process of filtration or halogenation

should be completed to ensure disinfection. Several products combine C-F with halogen disinfection.27

Granular Activated Carbon.  Granular activated carbon (GAC) purifies water by adsorbing organic and inorganic chemicals, thereby improving odor and taste. GAC is a common component of field filters. It may trap but does not kill organisms; in fact, nonpathogenic bacteria readily colonize GAC.28 In field water treatment, GAC is best used after chemical disinfection to make water safer and more palatable by removing disinfection by-products and pesticides, as well as many other organic chemicals and some heavy metals. It removes the taste of iodine and chlorine (see upcoming section “Halogens”).

Filtration Filtration is both a physical and a chemical process influenced by characteristics of filter media, water, and flow rate. The primary determinant of a microorganism’s susceptibility to filtration is its size (Fig. 5.1; see Table 5.3). Portable filters for water treatment can be divided into microfiltration with pores down to 0.1 µm, ultrafiltration that can remove particles as small as 0.01 µm, nanofiltration with

TABLE 5.3  Microorganism Susceptibility to Filtration Organism

Approximate Size (µm)

Recommended Filter Rating (µm)a

Viruses Escherichia coli Campylobacter Vibrio cholerae Cryptosporidium oocyst Giardia cyst Entamoeba histolytica cyst Nematode eggs Schistosome cercariae Dracunculus larvae

0.03 0.5 by 3–8 0.2–0.4 by 1.5–3.5 0.5 by 1.5–3.0 2–6 6–10 by 8–15 5–30 (average 10) 30–40 by 50–80 50 by 100 20 by 500

Ultrafilter, nanofilter, reverse osmosis 0.2–0.4 (microfilter)

1 (microfilter) 3–5 (microfilter) 20 (microfilter) Coffee filter or fine cloth, or double thickness closely woven cloth


Microfilters (includes most filters with pore size of 0.1–0.2 µm) can filter bacteria and protozoal cysts, but rely on electrostatic trapping of viruses or viral clumping with larger particles. Hollow fiber tubule filters with 0.02 µm (Sawyer) and reverse osmosis filters are capable of filtering viruses.

Reverse osmosis



Cloth and depth filters Ultrafiltration

Sand filters Microfiltration Algae Giardia Crypto Bacteria

Viruses Dissolved organics, proteins Aqueous salts Metal ions Microns

.0001 Ionic

.001 Molecular





10 Micro particle

100 Macro particle

Visible to naked eye

FIG. 5.1  Levels of filtration required relative to the size of microorganisms and other water contaminants.


CHAPTER 5  Water Disinfection for International Travelers pore size as small as 0.001 µm or less, and reverse osmosis with pore size 0.0001 µm or less.29 All filters require pressure to drive the water through the filter element. The smaller the pore size, the more pressure required. There are many filters available commercially for individuals and for small groups, and their ease of use is attractive to many travelers (see Tables 5.2 and 5.3). Most portable filters are microfilters that can readily remove protozoan cysts and bacteria, but may not remove all viruses that are much smaller than the pore size of most field filters.30 However, viruses often clump together or to other larger particles or organisms, and electrochemical attraction may cause viruses to adhere to the filter surface. Through these mechanisms, mechanical filters using ceramic elements with a pore size of 0.2 µm can reduce viral loads by 2–3 logs (99%–99.9%), but generally should not be considered adequate for complete removal of viruses. Recently, hollow-fiber technology has been adapted for field use. This technique uses bundles of tubules with a size that can be engineered to achieve ultrafiltration with viral removal. The large surface area allows these hollow-fiber tubule filters to have high flow rates at low pressure. Nanofiltration and reverse osmosis filtration use high pressure (100–800 psi) to force water through a semipermeable membrane that filters out dissolved ions, molecules, and solids. These processes can remove microbiologic contamination and produce highly purified water. Reverse osmosis can desalinate seawater. Although small hand pump reverse osmosis units have been developed, their high price and slow output currently prohibit use by land-based travelers. They are, however, important survival aids for ocean voyagers and the preferred field method for large military operations. Several factors influence the decision on which filter to buy: (1) how many persons are to use the filter; (2) what microbiologic demands will be put on the filter (claims); and (3) what is the preferred means of operation (function). Cost may also be an important consideration. Portable water treatment device claims for microbiologic reduction are based on consensus performance standards that serve as a guideline for testing and evaluation.31 The standards require a 3-log (99.9%) reduction for cysts, 4-log (99.99%) for viruses, and 5–6-log reduction (99.999%) for bacteria; testing is done or contracted out by the manufacturer.

Halogens Worldwide, chemical disinfection with halogens, chiefly chlorine, is the most commonly used method for improving and maintaining the microbiologic quality of drinking water and can be used by individuals and groups in the field (see Table 5.2). The germicidal activity of halogens results from oxidation of essential cellular structures and enzymes. A wealth of data supports their effectiveness.32–35 Disinfection effectiveness is determined by characteristics of the disinfectant, the microorganism, and environmental factors. Hypochlorite, the major chlorine disinfectant, is currently the preferred means of municipal water disinfection worldwide. Both calcium hypochlorite (Ca[OCl]2) and sodium hypochlorite (NaOCl) readily dissociate in water to form hypochlorite, the active disinfectant. Iodine is also effective in low concentrations for killing bacteria, viruses, and cysts, and in higher concentration against fungi and even bacterial spores; however, it is a poor algaecide. Elemental (diatomic) iodine (I2) and hypoiodous acid (HOI) are the major germicides in an aqueous solution. Given adequate concentrations and contact times, both iodine and chlorine are effective disinfectants with similar biocidal activity under most conditions. Taste preference is individual. Of the halogens, iodine reacts least readily with organic compounds and is less affected by pH, indicating that low iodine residuals should be more stable and persistent than corresponding concentrations of chlorine. Despite these advantages,


because of its physiologic activity (see “Halogen Toxicity” to come), WHO recommends iodine only for short-term emergency use. (Common sources and doses of iodine and chlorine are given in Table 5.5 later in the chapter.) Chlorine is still advocated by WHO and the Centers for Disease Control and Prevention (CDC) as a mainstay of large-scale community, individual household, and emergency use.6,36 There are extensive data on effectiveness of hypochlorite in remote settings.37–39 The CDC/WHO Safe Water System for household disinfection in developing countries provides a dosage of 1.875 mg/L or 3.75 mg/L of sodium hypochlorite with a contact time of 30 minutes, sufficient to inactivate most bacteria, viruses, and some protozoa that cause waterborne diseases.6,40 Another advantage of hypochlorite is the ease of adjusting the dose for large volumes of water.6,41 Vegetative bacteria (nonspore forming) are very sensitive to halogens; viruses have intermediate sensitivity, requiring higher concentrations or longer contact times. Protozoal cysts are more resistant than enteric bacteria and enteric viruses, but can be inactivated by field doses of halogens.35,42 Cryptosporidium oocysts, however, are much more resistant to halogens and inactivation is not practical with common doses of iodine and chlorine used in field water disinfection.29,43 Little is known about Cyclospora, but it is assumed to be similar to Cryptosporidium. Certain parasitic eggs, such as those of Ascaris, are also resistant; however, they are not commonly spread by water. All halogen-resistant cysts and eggs are susceptible to heat or filtration. Relative resistance between organisms is similar for iodine and chlorine.

The Disinfection Reaction.  Understanding factors that influence the disinfection reaction allows flexibility with greater reassurance. The primary factors of the first-order chemical disinfection reaction are concentration and contact time.33,34 Lower concentrations can be used with longer contact times. For clear surface water it is prudent to use 4 mg/L as a target halogen concentration. Lower concentrations (e.g., 2 mg/L) can be used for backup treatment of questionable tap water.

Iodine Resins.  Iodine molecules can be bound in a resin engineered into field products, but the effectiveness of the resin is highly dependent on the product design and function. Most incorporate a 1-µm cyst filter to remove Cryptosporidium, Giardia, and other halogen-resistant parasitic eggs or larvae, to avoid prolonged contact time. An activated carbon stage is incorporated to remove residual dissolved iodine. Dissolved iodine may be needed for cyst destruction; however, when residual iodine is not controlled, high levels of iodine have been reported in effluent water in very hot climates.44 Most companies have abandoned iodine resin–containing portable hand-pump filters due to excess iodine or viral breakthrough in the effluent. Only one drink-through bottle remains on the US market, but other products may still be available outside the United States.

Improving Halogen Taste.  Although objectionable taste and smell limit the acceptance of halogens, taste can be improved by several means. One method is to use the minimum necessary dose with a longer contact time, as in the CDC Safe Water System. Several chemical means are available to reduce free iodine to iodide, or chlorine to chloride, that have no color, smell, or taste. Since these halides have no disinfection action, they should be used only after the required contact time. The best and most readily available agent is ascorbic acid (vitamin C), available in crystalline or powder form. A common ingredient of flavored drink mixes, it accounts for their effectiveness in removing the taste of halogens. Other safe and effective means of chemical reduction are sodium thiosulfate and hydrogen peroxide. GAC will remove the taste of iodine


SECTION 2  The Pretravel Consultation

and chlorine, partially by adsorption and partially by chemical reduction.

bacterial growth in previously treated and stored water (see Table 5.5 later in the chapter).

Halogen Toxicity.  Chlorine has no known toxicity when used for

Photocatalytic Disinfection. Advanced oxidation processes use

water disinfection. Sodium hypochlorite is not carcinogenic; however, reactions of chlorine with certain organic contaminants yield chlorinated hydrocarbons, chloroform, and other trihalomethanes, which are considered to have carcinogenic potential in animal models. Nevertheless the risk of severe illness or even death from infectious diseases if disinfection is not used is far greater than any risk from by-products of chlorine disinfection. There is much more concern with iodine because of its physiologic activity, potential toxicity, and allergenicity. Data reviewed by Backer and Hollowell45 suggest the following guidelines as appropriate: • High levels of iodine (16–32 mg/day), such as those produced by recommended doses of iodine tablets, should be limited to short periods of ≤1 month. • Iodine treatments that produce a low residual ≤1–2 mg/L appear safe, even for long periods of time, in people with normal thyroid glands. • Those planning to use iodine for prolonged periods should have their thyroid examined and thyroid function tests done to ensure that they are initially euthyroid. Optimally, repeat thyroid function testing and examine for iodine goiter after 3–6 months of continuous iodine ingestion and monitor occasionally for iodine-induced goiter thereafter. If this is not feasible, ensure low-level iodine consumption or use a different technique. Certain groups should not use iodine for water treatment: • pregnant women (because of concerns of neonatal goiter) • those with known hypersensitivity to iodine • persons with a history of thyroid disease, even if controlled on medication • persons with a strong family history of thyroid disease (thyroiditis) • persons from countries with chronic iodine deficiency

ultraviolet (UV) light or natural sunlight to catalyze the production of potent oxidizers that are excellent disinfectants for microorganisms and can break down complex organic contaminants and even most heavy metals into nontoxic forms. Titanium dioxide (TiO2) is the most effective substance, but other metal oxides, chitins, and nanoparticles also have oxidative potential. Recent work demonstrated inactivation of Cryptosporidium by TiO2 (Table 5.4).49,50

Miscellaneous Disinfectants Ozone and chlorine dioxide are both effective disinfectants that are widely used in municipal water treatment plants, but until recently were not available in stable form for field use. These disinfectants have been demonstrated effective against Cryptosporidia in commonly used concentrations.46 New products enable chlorine dioxide generation for use in an array of small-scale, onsite applications, including solutions and tablets (see Table 5.2; also see Table 5.5 later in the chapter). Passing a current through a simple brine salt solution generates free available chlorine, as well as other “mixed species” disinfectants that have been demonstrated to be effective against bacteria, viruses, and bacterial spores.29,47 The process is well described and can be used on both large and small scales. The main effect is probably due to a combination of ClO2, ozone, superoxides, and hypochlorous acid, giving the resulting solution greater disinfectant ability than a simple solution of sodium hypochlorite.48

Silver.  Silver ion has bactericidal effects in low doses and some attractive features, including absence of color, taste, and odor. However, the concentrations are strongly affected by adsorption onto the surface of any container as well as common substances in water. Scant data for disinfection of viruses and cysts indicate limited effect, even at high doses. The use of silver as a drinking water disinfectant has been much more popular in Europe, where silver tablets are sold widely for field water disinfection. The EPA has not approved them for this purpose in the United States, but they approved as a water preservative to prevent

Ultraviolet.  UV radiation is widely used to sterilize water used in beverages and food products, for secondary treatment of wastewater, and to disinfect drinking water at the community and household level (see Table 5.3). In sufficient doses of energy, all waterborne enteric pathogens are inactivated by UV radiation.29 The ultraviolet waves must strike the organism, so the water must be free of particles that could act as a shield.51 UV rays do not alter the water, but they also do not provide any residual disinfecting power. The requirement for power has limited its adaptation for field use; however, portable, battery-operated units are available for disinfection of small quantities of water. Also larger units are available where power is accessible (see Table 5.4).

Solar UV Disinfection (SODIS).  UV irradiation by sunlight can substantially improve the microbiologic quality of water and reduce diarrheal illness in developing countries.52,53 The optimal procedure for the SODIS technique is to use transparent bottles (e.g., clear plastic beverage bottles), preferably lying on a dark surface, exposed to sunlight for a minimum of 4 hours with intermittent agitation.54 UV and thermal inactivation are strongly synergistic for the solar disinfection of drinking water.

Citrus and Potassium Permanganate.  Both citrus juice and potassium permanganate have some demonstrated antibacterial effects in an aqueous solution. However, data are few and not available for effect on cysts. In municipal disinfection, potassium permanganate is used primarily for reducing contaminants to improve taste and odor.55 Either could be used in an emergency to reduce bacterial and viral contamination, but cannot be recommended as a primary means of water disinfection.

Preferred Technique The optimal water treatment technique for an individual or group will depend on the number of persons to be served, space and weight accommodations, quality of source water, personal taste preferences, and fuel availability (Tables 5.5–5.7; also see Tables 5.2 and 5.4). Since halogens do not kill Cryptosporidia and filtration misses some viruses, optimal protection for all situations may require a two-step process of (1) filtration or C-F, followed by (2) halogenation. Heat is effective as a one-step process in all situations, but will not improve the esthetics of the water. Chlorine dioxide–generating techniques can be used as single-step processes. Expatriates or persons engaged in community projects or international relief activities where sanitation and water treatment are lacking are at higher risk than the average international traveler. Sobsey reviewed data for point-of-use methods for household disinfection in developing countries.12 In disaster situations such as floods, hurricanes, and earthquakes, sanitation and water treatment facilities are frequently damaged or inundated, so household or point-of-use water disinfection is advised. As in household disinfection in areas that do not have


CHAPTER 5  Water Disinfection for International Travelers TABLE 5.4  Examples of Commercial Devices for Field Water Disinfection Product Type and Function

Examples: Manufacturer, Product



Hand pump, individual or small group, filter elements made of various materials— ceramic, fiberglass, compressed charcoal


Gravity drip with reservoir bags


Gravity drip, bucket filters with candle filter elements


Hollow-fiber, micropore filters

Ketadyn Pocket, Combi, Mini, Expedition Cascadia Designs/MSR Miniworks EX, Sweetwater, Hyperfow General Ecology First Need XLE Sawyer biologic filter (Point One) MSR Autoflow Katadyn Basecamp Ketadyn Ceradyn, Gravidyn AquaRain 200, 400 British Berkfeld Berkey filters Sawyer Bucket Filter Sawyer Purifier (Point Zero Two)

Reverse osmosis Ultraviolet

Hand pump Battery-operated wand, individual use

Katadyn Survivor 06, Survivor 35 Hydro-Photon Inc. Steri-Pen

Portable (with truck), larger-scale water treatment units

First Water Systems Responder, Outpost-4 Global Hydration Can Pure

Mixed species disinfection

For relief operations, field hospitals, power-dependent units using combination of ultraviolet, filtration, chemicals Electrochlorination, mixed species disinfection


UV-activated oxidation using TiO2

Puralytics SolarBag

Cascade Designs SE200

Microbial Claims Protozoa Bacteria (General Ecology also makes claims for virus removal) Protozoa Bacteria Protozoa Bacteria

Protozoa Bacteria Viruses All Protozoa Bacteria Viruses Protozoa Bacteria Viruses Protozoa Bacteria Viruses Protozoa Bacteria Viruses

TABLE 5.5  Chemical Products for Field Water Disinfection Product



See text for discussion of efficacy, toxicity, and improving taste. Use extended contact times in very cold water. 1 tab/L provides 4 ppm iodine; Broad-spectrum disinfection effect, ease of handling and rapid 2 1 tab yields 8 ppm. dissolution. Taste more acceptable at 4 ppm. Limited shelf life (6–12 months) after opening. World Health Organization recommends only for short-term emergency use.

Iodine tabs Tetraglycine hydroperiodide EDWGT (emergency drinking water germicidal tablet) Potable Aqua (Wisconsin Pharmacal Co, Jackson, WI) Globaline 2% iodine solution (tincture) 10% povidone-iodine solutionb

Saturated solution: iodine crystals in water Polar Pure (Polar Equipment, Inc, Saratoga, CA)



0.2 mL (5 gttsa)/L water yields 4 ppm iodine. 0.35 mL (8 gtts)/L water yields 4 ppm iodine.

Widely available as topical disinfectant, but contains iodide, which is not an active disinfectant, but biologically active. Widely available as topical disinfectant. In aqueous solution, provides a sustained-release reservoir of halogen (normally, 2–10 ppm is present in solution). 13 ml/L water yields 4 ppm (use A small amount of elemental iodine goes into solution (no capful as measure, or can use significant iodide is present); the saturated solution is used to syringe). disinfect drinking water. Water can be added to the crystals hundreds of times before they are completely dissolved. See text for discussion of efficacy and improving taste. Can easily be adapted to large or small quantities of water.e Simple field test kits or swimming pool test kits with color strips are widely available to ensure adequate residual chlorine. Continued


SECTION 2  The Pretravel Consultation

TABLE 5.5  Chemical Products for Field Water Disinfection—cont’d Product



Sodium hypochlorite Household bleach CDC-WHO Safe Water Systemc (1% hypochlorite)

(5% hypochlorite) 0.1 mL (2 gtts)/L water yields 5 ppm hypochlorite. (8.25% hypochlorite) 1 gtt/L (1% hypochlorite) 8–10 gtts/L

Inexpensive and widely available. Safe Water System dosage provides about 2–4 ppm hypochlorite/L. Generally designed to use capful as measure.

Calcium hypochlorited Redi Chlor (0.1-gm tab) (Gripo Laboratories, Delhi, India) HTH (Arch Water Products Castleford, West Yorkshire, UK) Sodium dichloroisocyanurate Aquatabs (Medentech, Wexford, Ireland) Kintabs (Bioman Products Mottram, Cheshire, UK) NaDCC (Gripo laboratories, Delhi, India) Global Hydration (Global Hydration Water Treatment Systems, Kakabeka Falls, Ontario, Canada) Halazone Aquazone (Gripo Laboratories, Delhi, India) Chlorine plus flocculating agent Chlor-floc Purifier sachets (Proctor and Gamble Corp, Cincinnati, OH) Chlorine Dioxide

Micropur MP-1 (Katadyn Corp, Wallisellen, Switzerland) AquaMira (McNett Outdoor, Bellingham, WA) Pristine (Advanced Chemicals Ltd., Vancouver, BC) Potable Aqua Aquarius Bulk Water Treatment Silver MicroPur Classic (Katadyn Corp., Wallisellen, Switzerland) MicroPur Forte (Katadyn Corp)


tab/2 quarts water yields 10 ppm hypochlorite.


1 tab (8.5 mg NaDCC)/L water yields 10 ppm active disinfectant.

Stable, concentrated (70%), dry source of hypochlorite that is commonly used for chlorination of swimming pools. Multiple products available in various size tablets or granular form.

Stable, nontoxic chlorine compound that releases free active chlorine with additional available chlorine that remains in compound.

Each tablet releases 2.3–2.5 ppm of titratable chlorine.

Tablets contain a mixture of monochloraminobenzoic and dichloraminobenzoic acids. Limited use given other available chlorine products. One 600-mg tab yields 8 mg/L of Contain 1.4% available chlorine (sodium dichloro-striazinetrione) with flocculating agents (alum or ferric sulfate). free chlorine. Flocculant clarifies cloudy water while residual chlorine Sachet is added to 10 L water. provides disinfection. Useful for humanitarian disasters where available surface water is often highly turbid. Several new chemical methods for generating chlorine dioxide onsite can now be applied in the field for water treatment. Advantages of chlorine dioxide are greater effectiveness than chlorine at equivalent doses and the ability to inactivate Cryptosporidium oocysts with reasonable doses and contact times. 1 tab/L water. Follow product Available in tablets or liquid (two solutions that are mixed to instructions. activate prior to use).

Although widely used in some countries for disinfection, silver is approved in United States only for preserving stored water. Available in tablets, liquid, or Releases silver ions. Not recommended for primary water crystals. treatment. Available in tablets, liquid, or Tablets contain silver chloride 0.1% and NaDCC 2.5%. The crystals. chlorine kills viruses, bacteria, and Giardia. The silver prevents recontamination for up to 6 months, if water is stored.

Measure with dropper (1 drop = 0.05 mL) or small syringe. Povidone-iodine solutions release free iodine in levels adequate for disinfection, but few data are available. c For long-term household use in developing areas, CDC Safe Water System establishes a maximum of 2 mg/L, which is the limit of taste tolerance for many people. d Concentrated source of hypochlorite available as granules or tablets; useful for treating larger volumes of water; often used to treat swimming pool water. e For treatment of large volumes, see Lantagne et al.56 a


CHAPTER 5  Water Disinfection for International Travelers


TABLE 5.6  Summary of Field Water Disinfection Techniques Bacteria





+ + + +

+ +/−a + +

+ + + +

+ + − +

+ + +/−b Data not availableb

Heat Filtration Halogens Chlorine dioxide and photocatalytic a

Most filters make no claims for viruses. Ultrafiltration with hollow fiber technology and reverse osmosis are effective (see Fig. 5.1). Eggs are not very susceptible to halogens but very low risk of waterborne transmission. No data available for photocatalytic.


TABLE 5.7  Choice of Method for Various Source Water

Source Water

“Pristine” Wilderness Water With Little Human or Domestic Animal Activity

Primary concern

Giardia, enteric bacteria

Effective methods

Any single-step methodb Low-risk water source; some may choose to drink untreated


Clear Surface Water Near Human and Animal Activitya

Bacteria, Giardia, small numbers of viruses Any single-step method Risk varies depending on country; judgment required for decision to treat

All enteric pathogens, including viruses and Cryptosporidium 1) Heat 2) Microfiltration plus halogen (can be done in either order); iodine resin filters 3) Ultra- or nanofiltration 4) Chlorine dioxide 5) Ultraviolet (commercial product, not sunlight)

Cloudy Water All enteric pathogens C-F followed by second step (heat, filtration, or chemical)


Includes agricultural runoff with cattle grazing, or sewage treatment effluent from upstream villages or towns. Includes heat, filtration, or chemical methods. C-F, Coagulation–flocculation. b

sanitation and improved water, chlorine is the simplest method.6,36,56 Cloudy water should first be clarified before using hypochlorite. There are quality reviews of water disinfection techniques, effectiveness, and efficacy data available.29,48,57,58 On long-distance, ocean-going boats where water must be desalinated as well as disinfected during the voyage, only reverse osmosis membrane filters are adequate. Water storage also requires consideration. Iodine will work for short periods only (i.e., weeks) because it is a poor algaecide. For prolonged storage, water should be chlorinated and kept in a tightly sealed container to reduce the risk of contamination.59 For daily use, narrow-mouthed jars or containers with water spigots prevent contamination from repeated contact with hands or utensils.60

SANITATION Sanitation and water treatment are inextricably linked. Studies in developing countries have demonstrated a clear benefit in the reduction of diarrheal illness and other infections from safe drinking water, hygiene, and adequate sanitation. The benefit is greater when all are applied together, especially with appropriate education.12,61 Personal hygiene, particularly hand-washing, prevents spread of infection from food contamination during preparation of meals. Disinfection of dishes and utensils is accomplished by rinsing in water containing enough household bleach to achieve a distinct chlorine odor. Use of halogen solutions or potassium permanganate solutions to soak vegetables and fruits can reduce microbial contamination, especially if the surface is scrubbed to remove dirt or other particulates, but neither method reaches organisms that are embedded in surface crevices or protected by other particulate matter.62 Travelers to remote villages, wilderness areas, and disaster situations should assure proper waste disposal to prevent

additional contamination of water supplies. Human waste should be buried 8–12 inches deep, at least 100 feet from any water, and at a location from which water runoff is not likely to wash organisms into nearby water sources. Groups of three persons or more should dig a common latrine to avoid numerous individual potholes and inadequate disposal.

CONCLUSION Although foodborne illnesses probably account for most enteric problems that affect travelers, nearly all causes of travelers’ diarrhea can also be waterborne. It is not possible for travelers to judge the microbiologic quality of surface water, and it is prudent to assume that even tap water is nonpotable in many locations. Many simple and effective field techniques to improve microbiologic water quality are available to travelers. It is important to learn the basic principles and limitations of heat, filtration, and chemical disinfection, and then to become familiar with at least one technique appropriate for the destination, water source, and group composition.

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4. UNICEF, World Health Organization. Progress on Sanitation and Drinking Water—2015 Update and MDG Assessment. Geneva; 2015. 5. Wright J, Gundry S, Conroy R. Household drinking water in developing countries: a systematic review of microbiological contamination between source and point-of-use. Trop Med Int Health 2004;9(1):106–17. 6. Lantagne D. Sodium hypochlorite dosage for household and emergency water treatment. J Am Water Works Assoc 2008;100(8):106–19. 7. Yoder J, Roberts V, Craun GF, et al. Surveillance for waterborne disease and outbreaks associated with drinking water and water not intended for drinking—United States, 2005–2006. MMWR Surveill Summ 2008;57(9):39–62. 8. Wang G, Doyle M. Survival of enterohemorrhagic Escherichia coli O157: H7 in water. J Food Prot 1998;61:662–7. 9. Ford TE. Microbiological safety of drinking water: United States and global perspectives. Environ Health Perspect 1999;107(1): S191–206. 10. Hurst C, Clark R, Regli S. Estimating the risk of acquiring infectious disease from ingestion of water. In: Hurst C, editor. Modeling disease transmission and its prevention by disinfection. Cambridge University Press; 1996. p. 99–139. 11. Yoder JS, Hlavsa MC, Craun GF, et al. Surveillance for waterborne disease and outbreaks associated with recreational water use and other aquatic facility-associated health events—United States, 2005–2006. MMWR Surveill Summ 2008;57(9):1–29. 12. Sobsey M, Handzel T, Venczel L. Chlorination and safe storage of household drinking water in developing countries to reduce waterborne disease. Water Sci Technol 2003;47(3):221–8. 13. Fewtrell L, Colford JM Jr. Water, sanitation and hygiene in developing countries: interventions and diarrhoea—a review. Water Sci Technol 2005;52(8):133–42. 14. Sobsey MD, Stauber CE, Casanova LM, et al. Point of use household drinking water filtration: a practical, effective solution for providing sustained access to safe drinking water in the developing world. Environ Sci Technol 2008;42(12):4261–7. 15. Clasen T, Roberts I, Rabie T, et al. Interventions to improve water quality for preventing diarrhoea. Cochrane Database Syst Rev 2006;(3): CD004794. 16. Backer H. Field Water disinfection. In: Auerbach P, editor. Wilderness medicine. 7th ed. Elsevier; 2017. 17. World Health Organization. Guidelines for Drinking Water Quality. Geneva; 2011. 18. Frazier W, Westhoff D. Preservation by use of high temperatures. McGraw-Hill; 1978. 19. Fayer R. Effect of high temperature on infectivity of Cryptosporidium parvum oocysts in water. Appl Environ Microbiol 1994;60:273–5. 20. Bandres J, Mathewson J, DuPont H. Heat susceptibility of bacterial enteropathogens. Arch Intern Med 1988;148:2261–3. 21. Shephart M. Helminthological aspects of sewage treatment. In: Feachem R, McGarry M, Mara D, editors. Water, wastes and health in hot climates. John Wiley and Sons; 1977. p. 299–310. 22. Perkins J. Thermal destruction of microorganisms: heat inactivation of viruses. In: Thomas C, editor. Principles and methods of sterilization in health sciences. Elsevier; 1969. p. 63–94. 23. Tuladhar E, Bouwknegt M, Zwietering MH, et al. Thermal stability of structurally different viruses with proven or potential relevance to food safety. J Appl Microbiol 2012;112(5):1050–7. 24. Baert L, Debevere J, Uyttendaele M. The efficacy of preservation methods to inactivate foodborne viruses. Int J Food Microbiol 2009;131(2–3): 83–94. 25. World Health Organization. Boil Water. Technical Brief 2015. 2016 Feb 15. Available at: water_01_15.pdf?ua=1. 26. Binnie C, Kimber M, Smethurst G. Basic water treatment. 3rd ed. IWA; 2002. 27. Powers E, Boutros C, Harper B. Biocidal efficacy of a flocculating emergency water purification tablet. Appl Environ Microbiol 1994;60:2316–23.

28. Le Chevallier M, McFeters G. Microbiology of activated carbon. In: McFeters G, editor. Drinking water microbiology. Springer-Verlag; 1990. p. 104–20. 29. LeChevallier M, Kwok-Keung A. Water treatment and pathogen control. IWA Publishing; 2004. 30. Environmental Health Directorate Health Protection Branch. Assessing the Effectiveness of Small Filtration Systems for Point-of-Use Disinfection of Drinking Water Supplies. Report No.: 80-EHD-54. Ottawa: Department of National Health and Welfare; 1980. 31. US Environmental Protection Agency. Report to Task Force: Guide Standard and Protocol for Testing Microbiological Water Purifiers (Revised edition). Cincinnati: USEPA; 1987. 32. National Academy of Sciences Safe Drinking Water Committee. The disinfection of drinking water. Drinking Water Health 1980;2:5–139. 33. White G. Handbook of chlorination. 3rd ed. Van Nostrand Reinhold; 1992. 34. Hoff J. Inactivation of Microbial Agents by Chemical Disinfectants. Report No.: EPA/600/2–86/067. Cincinnati: US Environmental Protection Agency; 1986 July. 35. Hibler C, Hancock C, Perger L, et al. Inactivation of Giardia Cysts with Chlorine at 0.5C to 5.0C. AWWA Research Foundation; 1987. 36. Safe Water Systems for the Developing World: A Handbook for Implementing Household-based Water Treatment and Safe Storage Projects. Centers for Disease Control and Prevention; 2001. 37. Arnold BF, Colford JM Jr. Treating water with chlorine at point-of-use to improve water quality and reduce child diarrhea in developing countries: a systematic review and meta-analysis. Am J Trop Med Hyg 2007;76(2): 354–64. 38. World Health Organization. Water Treatment and Pathogen Control: Process Efficiency in Achieving Safe Drinking Water. London, UK: World Health Organization; 2004. 39. Pickard B, Clarke S, Bettin W. Chlorine Disinfection in the Use of Individual Water Purification Devices. US Army Center for Health Promotion and Preventive Medicine (USACHPPM); 2006. 40. Kotlarz N, Lantagne D, Preston K, et al. Turbidity and chlorine demand reduction using locally available physical water clarification mechanisms before household chlorination in developing countries. J Water Health 2009;7(3):497–506. 41. US Army. Sanitary control and surveillance of field water supplies. Report No.: TB Med 577. Washington, DC: Departments of the Army, Navy, and Air Force; 2005 Dec 15. 42. Fraker L, Gentile D, Krivoy D, et al. Giardia cyst inactivation by iodine. J Wilderness Med 1992;3:351–8. 43. Carpenter C, Fayer R, Trout J, et al. Chlorine disinfection of recreational water for Cryptosporidium parvum. Emerg Infect Dis 1999;5(4): 579–84. 44. Kettel-Khan L, Li R, Gootnick D, et al. Thyroid abnormalities related to iodine excess from water purification units. Lancet 1998;352:1519. 45. Backer H, Hollowell J. Use of iodine for water disinfection: iodine toxicity and maximum recommended dose. Environ Health Perspect 2000;108(8):679–84. 46. Clark RM, Sivagnesan M, Rice EW, et al. Development of a Ct equation for the inactivation of Cryptosporidium occysts with chlorine dioxide. Water Res 2003;37:2773–83. 47. Rutala WA, Weber DJ. New disinfection and sterilization methods. Emerg Infect Dis 2001;7(2):348–53. 48. McDonnell GE. Antisepsis, disinfection, and sterilization. ASM Press; 2007. 49. Sunnotel O, Verdoold R, Dunlop PS, et al. Photocatalytic inactivation of Cryptosporidium parvum on nanostructured titanium dioxide films. J Water Health 2010;8(1):83–91. 50. Li Q, Mahendra S, Lyon DY, et al. Antimicrobial nanomaterials for water disinfection and microbial control: potential applications and implications. Water Res 2008;42(18):4591–602. 51. Abd-Elmaksoud S, Naranjo JE, Gerba CP. Assessment of a portable handheld UV light device for the disinfection of viruses and bacteria in water. Food Environ Virol 2013;5(2):87–90.

CHAPTER 5  Water Disinfection for International Travelers 52. McGuigan KG, Conroy RM, Mosler HJ, et al. Solar water disinfection (SODIS): a review from bench-top to roof-top. J Hazard Mater 2012;235-236:29–46. 53. Berney M, Weilenmann HU, Simonetti A, et al. Efficacy of solar disinfection of Escherichia coli, Shigella flexneri, Salmonella typhimurium and Vibrio cholerae. J Appl Microbiol 2006;101(4):828–36. 54. Meierhofer R, Wegelin M, SODIS Manual. Gallen: Department of Water and Sanitation in Developing Countries, Swiss Federal Institute of Environmental Science and Technology; 2002. 55. United States Environmental Protection Agency. Alternative Disinfectants and Oxidants Guidance Manual. USEPA; 1999. 56. Lantagne D, Person B, Smith N, et al. Emergency water treatment with bleach in the United States: the need to revise EPA recommendations. Environ Sci Technol 2014;48(9):5093–100. 57. Clasen T, Menon S. Microbiological performance of common water treatment devices for household use in India. Int J Environ Health Res 2007;17(2):83–93. 58. Bielefeldt AR. Appropriate and sustainable water disinfection methods for developing communities. In: Buchanan K, editor. Water disinfection. Nova Science Publishers; 2011. p. 45–75.


59. Lantagne DS. Viability of commercially available bleach for water treatment in developing countries. Am J Public Health 2009;99(11): 1975–8. 60. Sobel J, Mahon B, Mendoza C, et al. Reduction of fecal contamination of street-vended beverages in Guatemala by a simple system for water purification and storage, handwashing, and beverage storage. Am J Trop Med Hyg 1998;59:380–7. 61. Quick RE, Kimura A, Thevos A, et al. Diarrhea prevention through household-level water disinfection and safe storage in Zambia. Am J Trop Med Hyg 2002;66(5):584–9. 62. Ortega YR, Roxas CR, Gilman RH, et al. Isolation of Cryptosporidium parvum and Cyclospora cayetanensis from vegetables collected in markets of an endemic region in Peru. Am J Trop Med Hyg 1997;57(6):683–6. 63. Theron J, Cloete TE. Emerging waterborne infections: contributing factors, agents, and detection tools. Crit Rev Microbiol 2002;28(1): 1–26.

6  Insect Protection Mark S. Fradin

KEY POINTS • Personal protection against insect-borne diseases is best achieved through habitat avoidance, wearing protective clothing, applying insect repellents, and, when appropriate, sleeping under protective bednets or shelters. • N,N-Diethyl-meta-toluamide (DEET) remains the gold standard of insect repellents with the most broad-spectrum, and often longest-lasting, efficacy. • Despite common beliefs, the risk of DEET toxicity is minimal, with fewer than 50 cases of significant DEET toxicity reported in the last 50 years (and in most of those cases, the product was improperly used or applied). • Picaridin, ethyl butylacetylaminopropionate (IR3535), and oil of lemon eucalyptus (also known as p-menthane-3,8-diol [PMD])

repellents have been carefully studied and offer US Environmental Protection Agency (EPA)–approved and Centers for Disease Control and Prevention (CDC)–approved safe and effective alternatives to DEET repellents for preventing insect-borne diseases. • Permethrin-treated clothing has also been proven to help reduce mosquito and tick bites. • Alternative currently marketed botanic repellents have not been sufficiently studied or proven enough to recommend their use in environments where insect-bone diseases are a significant concern, and should not be relied upon for protection.


chemoattractants. Different species of mosquito may show strong biting preferences for different parts of the body, related to local skin temperature and sweat gland activity. Floral fragrances found in perfumes, lotions, detergents, and soaps may also lure biting arthropods. There can be significant variability in the attractiveness of different individuals to the same or different species of mosquitoes—a point that travelers should keep in mind when visiting new areas. In some studies, men have been bitten more readily than women, and adults more than children. Adults tend to be bitten less as they get older. Heavyset individuals tend to attract more mosquitoes, perhaps due to their greater relative heat or carbon dioxide output.

In preparation for travel to many tropical and subtropical locations, the well-informed traveler needs to be aware of the potential risks of arthropod-transmitted disease. Mosquitoes, flies, ticks, chiggers, and fleas are capable of transmitting multiple bacterial, viral, protozoan, parasitic, and rickettsial infections to humans (Table 6.1). This chapter will review all available techniques for preventing arthropod bites and provide practical information to the traveler that will make it possible to distinguish between effective and ineffective methods of protection. A summary of the topics covered in this chapter, and their relative efficacy, is shown in Fig. 6.1.

STIMULI THAT ATTRACT INSECTS Scientists have not yet elucidated the exact mechanism by which arthropods are attracted to their hosts. The stimuli that attract mosquitoes have been best studied. Mosquitoes use visual, thermal, and olfactory stimuli to locate a bloodmeal.1,2 For mosquitoes that feed during the daytime, host movement and the wearing of dark-colored clothing may initiate orientation toward an individual. Visual stimuli appear to be important for in-flight orientation, particularly over long ranges. As a mosquito nears its host, olfactory stimuli then help guide the mosquito to its host. Carbon dioxide, released from breath and skin, serves as a long-range airborne attractant, at distances up to 36 m. Lactic acid, skin warmth, and moisture also serve as attractants. Volatile compounds, derived from sebum, eccrine and apocrine sweat, and/or the bacterial action of cutaneous microflora on these secretions, may also act as

PERSONAL PROTECTION A multipronged approach is necessary to prevent becoming a victim of insect-borne disease. Protection from insect bites is best achieved by avoiding infested habitats, using protective clothing and shelters, and applying insect repellents.3,4

Habitat Avoidance It is obvious that avoiding arthropods’ breeding and resting places, when feasible, will reduce the risk of being bitten. Many species of mosquito and other blood-sucking arthropods are particularly active at dusk, making this a good time to remain indoors. To avoid the usual resting places of biting arthropods, campsites should ideally be situated in areas that are high, dry, open, and as free from vegetation as possible. Any area with standing or stagnant water should be avoided, as these are ideal breeding grounds for mosquitoes.


CHAPTER 6  Insect Protection Abstract


The well-informed traveler needs to be aware of the potential risks of arthropod-transmitted disease. Mosquitoes, flies, ticks, chiggers, and fleas are capable of transmitting multiple bacterial, viral, protozoan, parasitic, and rickettsial infections to humans. Protection against bites is best achieved through avoiding infected habitats, wearing protective clothing, applying insect repellents, and, when appropriate, sleeping under protective bednets or shelters. N,N-Diethyl-meta-toluamide (DEET) remains the gold standard of insect repellents, providing broad-spectrum, long-lasting efficacy against multiple arthropod species. Based on years of safety data, the US Environmental Protection Agency (EPA) has concluded that DEET is safe to use in any individual over 2 months of age, and the Centers for Disease Control and Prevention (CDC) has approved its use even on pregnant and breastfeeding women. Based on strong scientific support for their efficacy and safety, three additional insect repellents have been approved by the CDC to reduce the risk of contracting an insect-borne disease: picaridin, ethyl butylacetylaminopropionate (IR3535), and oil of lemon eucalyptus (also known as p-menthane-3,8-diol [PMD]).

Botanical repellents DEET Insect repellents IR3535 Mosquito and tickborne diseases Oil of eucalyptus (PMD) Permethrin Picaridin



SECTION 2  The Pretravel Consultation

TABLE 6.1  Diseases Transmitted to Humans by Biting Arthropods Mosquitoes Zika virus Eastern equine encephalitis Western equine encephalitis St Louis encephalitis La Crosse encephalitis West Nile virus Japanese encephalitis Venezuelan equine encephalitis Malaria Yellow fever Dengue Lymphatic filariasis Epidemic polyarthritis (Ross River virus) Chikungunya fever Rift Valley fever Pogosta disease

Taiga encephalitis Tickborne relapsing fever 364D rickettsiosis Borrelia miyamotoi infection Bourbon virus infection Heartland virus infection Kyasanur Forest disease Crimean-Congo hemorrhagic fever Powassan disease Flies Tularemia Leishmaniasis African trypanosomiasis (sleeping sickness) Onchocerciasis Bartonellosis Loiasis Chigger Mites Scrub typhus (tsutsugamushi fever) Rickettsialpox

Ticks Lyme disease Southern tick-associated rash illness (STARI) Rocky Mountain spotted fever Colorado tick fever Relapsing fever Ehrlichiosis (human monocytotropic ehrlichiosis) Anaplasmosis (human granulocytic anaplasmosis) Babesiosis Tularemia Tick paralysis Tick typhus Rickettsialpox

Fleas Plague Murine (endemic) typhus Lice Epidemic typhus Relapsing fever Kissing Bugs American trypanosomiasis (Chagas disease)

Method of personal protection

Insect repellents


Habitat avoidance

Botanical DEET

Lemon eucalyptus/PMD


Soybean oil Geranium oil


2-Undecanone (BioUD) Geraniol Citronella oil

Physical barriers

Clothing (preferably permethrin treated)

Mesh bed nets (preferably permethrin treated)

Alternative methods


Local Garlic Vitamin B1

Proven effective in multiple studies EPA and CDC approved to help prevent arthropod-vectored disease Limited studies show efficacy Not approved by CDC Proven limited effectiveness Proven ineffective

FIG. 6.1  Methods of personal protection. CDC, Centers for Disease Control and Prevention; DEET, N,Ndiethyl-meta-toluamide; EPA, Environmental Protection Agency; PMD, p-menthane-3,8-diol.

Permethrin Yard foggers Pesticide coils Citronella plants Citronella candles Repellent wristbands Electronic repellers

CHAPTER 6  Insect Protection Physical Protection By blocking arthropods’ access to the skin, physical barriers can be very effective in preventing insect bites. A long-sleeved shirt, socks, full-length pants, and a hat will readily protect most of the skin surface. Ticks and chigger mites usually gain access to the skin around the ankle area, so tucking pant legs into socks or (ideally rubber) boots will reduce the risk of being bitten. Loose-fitting shirts made of tightly woven fabric and worn over a tucked-in undershirt will effectively reduce bites to the upper body. Light-colored clothing will attract fewer mosquitoes and biting flies, and will make it easier to see any ticks that might have crawled on to the fabric. A broad-brimmed, preferably light-colored hat will also help protect the head and neck and reduce the chance of being bitten by mosquitoes, deerflies, blackflies, and midges. Mesh overgarments, or garments made of tightly woven material, can block ready access to the skin surface, thereby reducing the risks of being bitten. Hooded jackets, pants, mittens, and head nets are available from several manufacturers in a wide range of styles for both adults and children (Table 6.2). With a mesh size of 95% protection against mosquito bites.2 Sawyer Products’s controlled-release 20% DEET lotion traps the chemical in a protein particle which slowly releases it to the skin surface, providing repellency equivalent to a standard 50% DEET preparation, lasting about 5 hours. About 50% less of this encapsulated DEET is absorbed than from a 20% ethanol-based preparation of DEET. DEET Safety and Toxicity.  Given its use by millions of people worldwide for over 50 years, DEET continues to show a remarkable safety profile. In 1980, to comply with more current standards for repellent safety, the US EPA issued an updated Registration Standard for DEET.6 As a result, 30 new animal studies were conducted to assess acute, chronic, and subchronic toxicity; mutagenicity; oncogenicity; and developmental, reproductive, and neurologic toxicity.10 The results of these studies neither led to any product changes to comply with current EPA safety standards nor indicated any new toxicities under normal usage. The EPA’s 1998 Reregistration Eligibility Decision (RED), and a subsequent review released in 2014, confirmed the agency’s position that “normal use of DEET does not present a health concern to the general population, including children.”11 Case reports of potential DEET toxicity exist in the medical literature and have been summarized in several medical literature reviews.2,12 Fewer than 50 cases of significant toxicity from DEET exposure have been documented in the medical literature over the last five decades; over three-quarters of these resolved without sequelae. Many of these cases involved long-term, excessive, or inappropriate use of DEET repellents; the details of exposure were frequently poorly documented, making causal relationships difficult to establish. These cases have not shown any correlation between the risk of toxicity and the concentration of the DEET product used or the age of user. The reports of DEET toxicity that raise the greatest concern involve 16 cases of encephalopathy, 13 in children under age 8 years.2,12 Three of these children died, one of whom had ornithine carbamoyl transferase deficiency, which might have predisposed her to DEET-induced toxicity. The other children recovered without sequelae. The EPA’s analysis of these cases concluded that they “do not support a direct link between exposure to DEET and seizure incidence.”11 Animal studies in rats and mice show that DEET is not a selective neurotoxin.6 According to the EPA, even if a link between DEET use and seizures does exist, the observed risk, based on DEET usage patterns, would be 97%

CHAPTER 6  Insect Protection protection against Aedes species mosquitoes under field conditions, even after 3.5 hours of application. During the same time period, a 6.65% DEET-based spray gave 86% protection.2 A second study showed that BiteBlocker provided a mean of 200 (SD 30) minutes of complete protection from mosquito bites.2 BiteBlocker also provided about 10 hours of protection against biting black flies; in the same test, 20% DEET offered 6.5 hours of complete protection.2 BioUD (2-undecanone).  HOMS is the sole distributor in the United States of another repellent, BioUD (2-undecanone). This repellent was derived from the wild tomato plant and registered by the US EPA in 2007 as a biopesticide for use against mosquitoes and ticks. In field studies against mosquitoes, 7.75% BioUD provided comparable repellency to 25% DEET.40 BioUD repelled the American dog tick, Dermacentor variabilis, from human skin for >2.5 hours and was still effective 8 days after its application to cotton fabric.41 Laboratory testing demonstrated that BioUD was 2–4 times more effective than 98% DEET at repelling Amblyomma americanum, D. variabilis, and Ixodes scapularis.42 BioUD was significantly better than either IR3535 or PMD (see upcoming discussion) at repelling A. americanum.42 Lemon Eucalyptus.  A derivative (p-menthane-3,8-diol, or PMD) isolated from the essential oil of the lemon eucalyptus plant has shown promise as an effective “natural” repellent. This repellent with a strong woodsy/lemony scent has been very popular in China for years, and is currently available in Europe under the brand name Mosi-Guard. PMD was registered as a biopesticide by the US EPA and licensed for sale in the United States in March 2000.43 In the United States it is currently available as Repel Lemon Eucalyptus Insect Repellent and Cutter Lemon Eucalyptus Insect Repellent (see Table 6.4). In a laboratory study against Anopheles mosquitoes, 30% PMD showed efficacy comparable to 20% DEET, but required more frequent reapplication to maintain its potency.44 Field tests of this repellent have shown mean complete protection times ranging from 4 to 7.5 hours, depending on the mosquito species and the testing methodology used.45,46 PMD-based repellents can cause significant ocular irritation, so care must be taken to keep them away from the eyes and not to use them on children under 3 years of age. In 2005 the CDC added oil of eucalyptus (PMD)–based repellents to its list of approved products that can be effectively used to prevent mosquito-borne disease. It is the only botanic repellent on that list. Geraniol.  Geraniol is a plant-derived monoterpenoid alcohol that is currently widely used in cosmetics. A study of a 5% geraniol-based repellent against Aedes aegypti mosquitoes showed 95% protection against bites for 6.5 hours and was as effective as 25% DEET in repelling A. americanum ticks. This repellent is currently available as Guardian (TyraTech, Morrisville, NC).47

Efficacy of DEET Versus Botanical Repellents.  Few data are available from studies that directly compare plant-derived repellents to DEET-based products. Available data proving the efficacy of botanic-derived repellents are often sparse, and there is no uniformly accepted standard for testing these products. As a result, different studies often yield varied results, depending on how and where the tests were conducted and which arthropod is being tested. Studies comparing plant-derived repellents to low-strength DEET products, conducted under carefully controlled laboratory conditions with caged mosquitoes, typically demonstrate dramatic differences in effectiveness among currently marketed insect repellents. Citronella-based insect repellents usually provide the shortest complete protection times. Even low-concentration DEET repellents (99.9% protection (1 bite/hour) over 8 hours; unprotected subjects were bitten an average of 1188 bites/hour.52 Permethrin-sprayed clothing also proved very effective against ticks: 100% of D. occidentalis ticks (which carry Rocky Mountain spotted fever) died within 3 hours of touching permethrin-treated cloth.3 Permethrin-sprayed pants and jackets also provided 100% protection from all three life stages of ticks, one of the vectors of Lyme disease.3 Permethrin-sprayed sneakers and socks can reduce the likelihood of

being bitten more than 73-fold.53 In contrast, DEET alone (applied to the skin) provided 85% repellency at the time of application; this protection deteriorated to 55% repellency at 6 hours, when tested against the Lone Star tick A. americanum.3 I. scapularis Say ticks, which may transmit Lyme disease, also seem to be less sensitive to the repellent effect of DEET.54 Permethrin-based insecticides available in the United States are listed in Table 6.6. To apply to clothing, spray each side of the fabric (outdoors) for 30–45 seconds, just enough to moisten, then allow to dry for 2–4 hours before wearing. Permethrin concentrate is also available for soak-treating large items, such as mesh bednets, or for treating batches of clothing. The treated fabric should maintain its efficacy through six washes or 6 weeks of outdoor exposure. For those not interested in treating their own clothing, Insect Shield (Greensboro, NC) manufactures shirts and pants that have been factory-treated with a proprietary process to tightly bind permethrin into the fabric, maintaining its efficacy for 70 washes. Their clothing can be purchased from outdoor apparel retailers such as REI, L.L. Bean, and ExOfficio. Insect Shield will also treat your own clothing; you can mail items to them and they will return the treated clothing to you.

REDUCING LOCAL MOSQUITO POPULATIONS Consumers may still find advertisements for small, ultrasonic electronic devices meant to be carried on the body, which claim to repulse mosquitoes by emitting “repellent” sounds such as that of a dragonfly (claimed to be the “natural enemy” of the mosquito), male mosquito, or bat. Multiple studies, conducted both in the field and laboratory, show that these devices do not work.55 One study even showed that electronic mosquito repellents increased the biting rates of A. aegypti.56 Pyrethrin-containing “yard foggers” set off before an outdoor event can temporarily reduce the number of biting arthropods in a local environment. These products should be dispensed before any food is brought outside, and should be kept away from animals or fish ponds. Burning coils that contain natural pyrethrins or synthetic pyrethroids (such as D-allethrin or D-transallethrin) can also temporarily reduce local populations of biting insects.57 Some concerns have been raised about the long-term cumulative safety of use of these coils in an indoor environment. Wood smoke from campfires can also reduce the likelihood of being bitten by mosquitoes.

CHAPTER 6  Insect Protection

RELIEF FROM MOSQUITO BITES Cutaneous responses to mosquito bites range from the common localized wheal-and-flare reaction to delayed bite papules, “skeeter syndrome” (which mimics cellulitis), rare systemic Arthus-type reactions, and even anaphylaxis.2 Bite reactions are the result of sensitization to mosquito salivary antigens, which lead to the formation of both specific IgE and IgG antibodies. Immediate-type reactions are mediated by IgE and histamine, whereas cell-mediated immunity is responsible for the delayed reactions. Several strategies exist for relieving the itch of mosquito bites. Topical corticosteroids can reduce the associated erythema, itching, and induration; a short, rapidly tapering course of oral prednisone can also be very effective in reducing extensive bite reactions. Topical diphenhydramine and ester-type topical anesthetics should be avoided, owing to concerns about inducing allergic contact sensitivity. Oral antihistamines can be effective in reducing the symptoms of mosquito bites. In highly sensitized individuals, prophylactic treatment with nonsedating antihistamines may safely reduce the cutaneous reactions to mosquito bites.

SUMMARY—A COMPREHENSIVE APPROACH TO PERSONAL PROTECTION An integrated approach to personal protection is the most effective way to prevent arthropod bites, regardless of where one is in the world and which species of insects may be biting. Maximum protection is best achieved through avoiding infested habitats, and using protective clothing, topical insect repellents, and permethrin-treated garments.9 When appropriate, mesh bednets or tents should be used to prevent nocturnal insect bites.9 For more than 50 years, DEET-containing insect repellents have been the most effective products on the market, providing the most broad-spectrum, longest-lasting repellency against multiple arthropod species. Based on strong scientific support for their safety and efficacy, the CDC has now approved picaridin, IR3535, and oil of eucalyptus (PMD) as alternatives to DEET that may be used to reduce the likelihood of contracting a vectorborne disease. Some of the “botanic” repellents (e.g., BiteBlocker, BioUD, Guardian) show promise, yet there are currently insufficient published studies to recommend their use in environments where it is crucial to be protected against insect-borne diseases. Insect repellents alone should not be relied upon to provide complete protection, especially against malaria vectors. Mosquitoes, for example, can find and bite any untreated skin, and may even bite through thin clothing. Deerflies, biting midges, and some blackflies prefer to bite around the head, and will readily crawl into the hair to bite where there is no protection. Wearing protective clothing, including a hat, will reduce the chances of being bitten. Treating one’s clothes and hat with permethrin will maximize their effectiveness, by causing “knockdown” of any insect that crawls or lands on the treated clothing. To prevent chiggers or ticks from crawling up the legs, pants should also be tucked into the boots or stockings. Wearing smooth, closely woven fabrics, such as nylon, will make it more difficult for ticks to cling to the fabric. After returning indoors, the skin should be inspected for the presence of ticks. Any ticks found attached to the skin should be removed to reduce the potential risk of disease transmission. Although some studies have suggested that ticks require over 48 hours of attachment to transmit Lyme disease,58 other studies have contradicted these findings by implicating much shorter attachment times.59 For these reasons, ticks should be removed as soon as possible. The best method of tick removal is to simply grasp the tick with a forceps as close to the skin surface as possible and pull upwards with a steady, even force.


The US military relies on this integrated approach to protect troops deployed in areas where arthropods constitute either a significant nuisance or a medical risk. The Department of Defense’s Insect Repellent System consists of DEET applied to exposed areas of skin, and permethrin-treated uniforms worn with the pant legs tucked into boots and the undershirt tucked into the pant waistband. This system has been proven to dramatically reduce the likelihood of being bitten by arthropods. Travelers visiting parts of the world where insect-borne disease is a potential threat will be best able to protect themselves if they learn about the indigenous insects, their biting habits, and the diseases they might transmit. For example, the malaria-transmitting Anopheles mosquito tends to bite at nighttime. Hence, when traveling to an area where malaria is endemic, it is important to make sure that you have appropriate means to protect yourself from bites from dawn to dusk. Protective clothing, insect repellent, permethrin spray, and, when appropriate, treated mesh bednets should also be carried. Travelers would be wise to check the most current World Health Organization (, CDC (, or national authorities’ recommendations about traveling to countries where immunizations (e.g., against yellow fever) or chemoprophylaxis (e.g., against malaria) should be considered. An excellent summary of information on issues related to travel health can also be found at

REFERENCES 1. Bock GR, Cardew G, editors. Olfaction in mosquito-host interactions. New York: J Wiley; 1996. 2. Fradin MS. Mosquitoes and mosquito repellents: a clinician’s guide. Ann Int Med 1998;128(11):931–40. 3. Fradin MS. Protection from blood-feeding arthropods. In: Auerbach PS, editor. Wilderness medicine. 7th ed. St. Louis: Mosby Press; 2017. p. 1032–43. 4. Alpern JD, Dunlop SJ, Dolan BJ, et al. Personal protection measures against mosquitoes, ticks, and other arthropods. Med Clin N Am 2016; 100:303–16. 5. Golenda CF, Solberg VB, Burge R, et al. Gender-related efficacy difference to an extended duration formulation of topical N,N-diethyl-m-toluamide (DEET). Am J Trop Med Hyg 1999;60(4):654–7. 6. US Environmental Protection Agency. Office of pesticides and toxic substances. Special pesticide review division. N,N-diethyl-m-toluamide (DEET) pesticide registration standard (EPA 540/RS-81–004). Washington, DC: US Environmental Protection Agency; 1980. 7. King WV. Chemicals evaluated as insecticides and repellents at Orlando, Fla. USDA Agric Handb 1954;69:1–397. 8. Maia MF, Moore SJ. Plant-based insect repellents: a review of their efficacy, development and testing. Malar J 2011;10:S11. 9. Goodyer LI, Croft AM, Frances SP, et al. Expert review of the evidence base for arthropod avoidance. J Travel Med 2010;17:182–92. 10. Completed studies for the DEET Toxicology Data Development Program. Washington, DC: The DEET Joint Venture Group, Chemical Specialties Manufacturers Association; 1996. 11. US Environmental Protection Agency. Office of pesticide programs, prevention, pesticides and toxic substances division. Reregistration Eligibility Decision (RED): DEET (EPA738-F-95-010). Washington, DC: US Environmental Protection Agency; 1998. 12. Osimitz TG, Grothaus RH. The present safety assessment of DEET. J Am Mosq Control Assoc 1995;11(2):274–8. 13. Veltri JC, Osimitz TG, Bradford DC, et al. Retrospective analysis of calls to poison control centers resulting from exposure to the insect repellent N,N-diethyl-m-toluamide (DEET) from 1985–1989. J Toxicol Clin Toxicol 1994;32(1):1–16. 14. Bell JW, Veltri JC, Page BC. Human exposures to N,N-diethylm-toluamide insect repellents reported to the American Association of Poison Control Centers 1993–1997. Int J Toxicol 2002;21:341.


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15. Sudakin DL, Trevathan WR. DEET: a review and update of safety and risk in the general population. Clin Toxicol 2003;41:831. 16. Koren G, Matsui D, Bailey B. DEET-based insect repellents: safety implications for children and pregnant and lactating women. CMAJ 2003;169:209. 17. Osimitz TG, Murphy JV, Fell LA, et al. Adverse events associated with the use of insect repellents containing N,N-diethyl-m-toluamide (DEET). Regul Toxicol Pharmacol 2010;56:93–9. 18. Murphy ME, Montemarano AD, Debboun M, et al. The effect of sunscreen on the efficacy of insect repellent: a clinical trial. J Am Acad Dermatol 2000;43:219–22. 19. Kasichayanula S, House JD, Wang T, et al. Percutaneous characterization of the insect repellent DEET and sunscreen oxybenzone from topical skin application. Toxicol Appl Pharmacol 2007;223:187–94. 20. Yiin L, Tian J, Hung C. Assessment of dermal absorption of DEET-containing insect repellent and oxybenzone-containing sunscreen using human urinary metabolites. Environ Sci Pollut Res 2015;22: 7062–70. 21. McGready R, Hamilton KA, Simpson JA, et al. Safety of the insect repellent N,N-dietyyl-m-toluamide (DEET) in pregnancy. Am J Trop Med Hyg 2001;65:285–9. 22. Wylie BJ, Hauptman M, Woolf AD, et al. Insect repellents during pregnancy in the era of Zika virus. Obstet Gynecol 2016;128: 1111–15. 23. Patel RV, Shaeer KM, Patel P, et al. EPA-registered repellents for mosquitoes transmitting emerging viral disease. Pharmacotherapy 2016;36:1272–80. 24. United States Environmental Protection Agency. Using Insect Repellents Safely and Effectively. Available at: using-insect-repellents-safely-and-effectively. 25. Centers for Disease Control and Prevention. Protection Against Mosquitoes, Ticks, & Other Arthropods. Available at: https://wwwnc protection-against-mosquitoes-ticks-other-arthropods. 26. Weil WB. New information leads to changes in DEET recommendations. AAP News 2001;19:52. 27. Comparative efficacy of IR3535 and DEET as repellents against adult Aedes aegypti and Culex quinquefasciatus. J Am Mosq Control Assn 2004;20:299–304. 28. Fradin MS, Day JF. Comparative efficacy of insect repellents. N Engl J Med 2002;347:13–18. 29. Carroll SP. Prolonged efficacy of IR3535 repellents against mosquitoes and blacklegged ticks in North America. J Med Entomol 2008;45(4):706–14. 30. Badolo A, Ilboudo-Sanogo E, Ouedraogo AP, et al. Evaluation of the sensitivity of Aedes aegypti and Anopheles gambiae complex mosquitoes to two insect repellents: DEET and KBR 3023. Trop Med Int Health 2004;9:330. 31. Frances SP, Van Dung N, Beebe NW, et al. Field evaluation of repellent formulations against daytime and nighttime biting mosquitoes in a tropical rainforest in northern Australia. J Med Entomol 2002;39:541. 32. Debboun M, Strickman D, Solberg VB, et al. Field evaluation of DEET and a piperidine repellent against Aedes communis (Diptera: Culicidae) and Simulium venustum (Diptera: Simuliidae) in the Adirondack Mountains of New York. J Med Entomol 2000;37:919. 33. Frances SP, Waterson DGE, Beebe NW, et al. Field evaluation of repellent formulations containing DEET and picaridin against mosquitoes in Northern Territory, Australia. J Med Entomol 2004;41:414–17. 34. Carroll JF, Benante JP, Kramer M, et al. Formulations of DEET, picaridin, and IR3535 applied to skin repel nymphs of the lone star tick (Aari: Ixodidae) for 12 hours. J Med Entomol 2010;47:699–704. 35. Quarles W. Botanical mosquito repellents. Common Sense Pest Control 1996;12(4):12–19. 36. Duke J. USDA-Agricultural Research Service Phytochemical and Ethnobotanical Databases. Available at:

37. Sakulku U, Nuchuchua O, Uawongyart N, et al. Characterization and mosquito repellent activity of citronella oil nanoemulsion. Int J Pharm 2009;372:105–11. 38. United States Environmental Protection Agency. Office of Pesticide Programs, Prevention, Pesticides and Toxic Substances Division: Reregistration Eligibility Decision (RED) for Oil of Citronella (EPA-738-F-97-002). Washington, DC; 1997. 39. Seyoum A, Kabiru EW, Wnade WL, et al. Repellency of live potted plants against Anopheles gambiae from human baits in semi-field experimental huts. Am J Trop Med Hyg 2002;67:191–5. 40. Bissinger BW, Stumpf CF, Donohue KV, et al. Novel arthropod repellent, BioUD, is an efficacious alternative to DEET. J Med Entomol 2008; 45(5):891–8. 41. Bissinger BW, Apperson CS, Sonenshine DE, et al. Efficacy of the new repellent BioUD against three species of ixodid ticks. Exp Appl Acarol 2009;48:239–50. 42. Bissinger BW, Zhu J, Apperson CS, et al. Comparative efficacy of BioUD to other commercially available arthropod repellents against ticks Amblyomma americanum and Dermacentor variabilis on cotton cloth. Am J Trop Med Hyg 2009;81:685–90. 43. United States Environmental Protection Agency. Office of Pesticide Programs. p-Menthane-3,8-diol. Washington, DC; 2000. Available at: 44. Trigg JK, Hill N. Laboratory evaluation of a eucalyptus-based repellent against four biting arthropods. Phytother Res 1996;10:313–16. 45. Barnard DR, Xue RD. Laboratory evaluation of mosquito repellents against Aedes albopictus, Culex nigripalpus, and Ochlerotatus triseriatus (Diptera: Culicidae). J Med Entomol 2004;41:726–30. 46. Moore SJ, Lenglet A, Hill N. Field evaluation of three plant-based insect repellents against malaria vectors in Vaca Diez Province, the Bolivian Amazon. J Am Mosq Control Assoc 2002;18:107–10. 47. Bissinger BW, Kennedy MK, Carroll SP. Sustained efficacy of the novel topical repellent TT-4302 against mosquitoes and ticks. Med Vet Entomol 2016;30:107–11. 48. Ives AR, Paskewitz SM. Testing vitamin B as a home remedy against mosquitoes. J Am Mosq Control Assoc 2005;21:213–17. 49. Banks SD, Murray N, Wilder-Smith A, et al. Insecticide-treated clothes for the control of vector-borne diseases: a review on effectiveness and safety. Med Vet Entomol 2014;28:14–25. 50. Food and Drug Administration. Drug products containing active ingredients offered over-the-counter (OTC) for oral use as insect repellents. Fed Red 1983;48:26987. 51. Insect repellents. Med Lett Drugs Ther 1989;31:45–7. 52. Lillie TH, Schreck CE, Rahe AJ. Effectiveness of personal protection against mosquitoes in Alaska. J Med Entomol 1988;25(6):475–8. 53. Miller NJ, Rainone EE, Dyer MC, et al. Tick bite prevention with permethrin-treated summer-weight clothing. J Med Entomol 2011;48:327–33. 54. Schreck CE, Fish D, McGovern TP. Activity of repellents applied to skin for protection against Amblyomma americanum and Ixodes scapularis ticks (Acari: Ixodidae). J Am Mosq Control Assoc 1995;11:136–40. 55. Coro F, Suarez S. Review and history of electronic mosquito repellers. Wing Beats 2000;2000:6–32. 56. Andrade CFS, Cabrini I. Electronic mosquito repellers induce increased biting rates in Aedes aegypti mosquitoes (Diptera: Culicidae). J Vector Ecol 2010;35:75–8. 57. Yap HH, Tan HT, Yahaya AM, et al. Field efficacy of mosquito coil formulations containing d-allethrin and d-transallethrin against indoor mosquitoes especially Culex quinquefasciatus Say. Southeast Asian J Trop Med Public Health 1990;21:558. 58. Sood SK, Salzman MB, Johnson BJ, et al. Duration of tick attachment as a predictor of the risk of Lyme disease in an area in which Lyme disease is endemic. J Infect Dis 1997;175(4):996–9. 59. Cook MJ. Lyme borreliosis: a review of data on transmission time after tick attachment. Int J Gen Med 2015;8:1–8.

7  Pretravel Considerations for Non-vaccine-Preventable Travel Infections Sarah L. McGuinness and Henry M. Wu

KEY POINTS • Pretravel advice should be tailored to the individual following a thorough review of his or her itinerary, planned activities, and host characteristics. • The pretravel consultation should include preventive advice for regionally endemic non–vaccine-preventable infections that can cause severe illness or chronic morbidity. • Special consideration should be given to common or emerging arboviral infections (including dengue, chikungunya, and Zika)

and regionally endemic severe respiratory infections such as Middle East respiratory syndrome (MERS) and certain strains of avian influenza. • Preventive advice for other infections associated with specific exposures or activities should be provided where relevant. • Understanding the epidemiology and prevention of these infections is crucial to providing a comprehensive pretravel consultation.


The Mosquito Vectors: Aedes aegypti and A. albopictus

To provide optimal advice, travel health providers should be able to educate the traveler on preventive measures against key travel-related infections, including those for which no vaccine is available. Tailoring this advice for an individual requires a thorough review of the travelers’ itinerary and planned activities, consideration of the travelers’ host characteristics, and a working knowledge of the epidemiology of relevant diseases. Travelers play an important role in the global epidemiology of infectious diseases; therefore ensuring that travelers are aware of specific preventive measures not only protects the health of the individual but has the potential to protect the health of their communities. In this chapter, pretravel considerations for major non–vaccine-preventable infectious diseases are covered, including specific advice for dengue, chikungunya, Zika, Middle East respiratory syndrome coronavirus (MERS-CoV), and avian influenza.


Aedes mosquitoes are typically daytime biters and have a preference for the morning and late afternoon hours (crepuscular periods).1 A. aegypti, the primary mosquito vector for dengue, chikungunya, and Zika, is found in tropical, subtropical, and some temperate climates and has adapted to cohabit with humans in both urban and rural environments.2 A. aegypti typically lays eggs in manmade or artificial containers in or around the home and can bite indoors.2 A. albopictus (the Asian tiger mosquito) can live in a broader temperature range and at cooler temperatures than A. aegypti and thus has a wider geographic distribution, extending into temperate regions. A. albopictus feeds on animals as well as humans, prefers natural habitats, usually bites outdoors, and is generally considered a less efficient vector of human disease than A. aegypti.1 Aedes mosquitoes can be found in temperate areas, including southern Europe (A. albopictus), northern Queensland in Australia (A. aegypti), and southeastern regions of the United States (both species)2,3 (Fig. 7.1).



Dengue virus (DENV), chikungunya virus (CHIKV), and Zika virus (ZIKV) are globally important mosquito-borne viruses spread via Aedes aegypti and A. albopictus. The public health impact of these viruses has increased dramatically over the last 50 years, with epidemics of increasing size, geographic reach, and severity recorded. With factors such as population growth, urbanization, globalization, travel, and climate change facilitating increased transmission, travel medicine practitioners in temperate countries are increasingly likely to see returned travelers with these infections. Furthermore, since the ranges of Aedes vectors extend into temperate areas, infected returned travelers can precipitate outbreaks of these viruses in nonendemic regions.

DENV is a flavivirus that is the most common and arguably most important arbovirus globally. Originating in Africa, DENV is now endemic in more than 100 countries across Africa, Southeast Asia, the Americas, the western Pacific, and the eastern Mediterranean regions.4,5 Estimates suggest 390 million infections occur worldwide annually, with 70% of cases occurring in Asia.6 DENV has four distinct serotypes (DENV 1–4), with most endemic countries reporting circulation of all four serotypes.7 Primary infection provides lifelong serotype-specific protection but only short-lived cross-protection to other serotypes.4,8 Broadly neutralizing antibodies are produced following a second dengue infection, and symptomatic disease is rarely seen with subsequent infections.9


CHAPTER 7  Pretravel Considerations for Non-vaccine-Preventable Travel Infections Abstract


Pretravel advice should be tailored to the individual following a thorough review of his or her itinerary, planned activities, and host characteristics. In addition to vaccinations and malaria chemoprophylaxis, a pretravel consultation should include advice on regionally endemic or emerging non–vaccine-preventable infections that can cause severe illness or chronic morbidity. These include mosquito-borne infections such as dengue, chikungunya, and Zika, and regionally endemic severe respiratory infections such as Middle East respiratory syndrome (MERS) and some strains of avian influenza. Zika virus is notable given its capacity for sexual transmission and association with congenital birth defects. Preventive advice for other potentially relevant infections associated with specific exposures or activities (e.g., schistosomiasis and leptospirosis from freshwater exposure) should be provided where relevant. Understanding the epidemiology and prevention of these infections is crucial to providing a comprehensive pretravel consultation.

Aedes Arbovirus Avian influenza Chikungunya Congenital Zika syndrome Dengue Middle East respiratory syndrome (MERS) Pretravel Prevention Severe acute respiratory syndrome (SARS) Zika



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Predicted distribution Aedes aegypti 1 0

Predicted distribution Aedes albopictus 1 0

FIG. 7.1  Predicted global distribution of Aedes mosquitoes. (Reproduced from Kraemer MUG, Sinka ME, Duda KA, et al. The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus. eLife 2015;4:e09347. Licensed CC0 1.0

CHAPTER 7  Pretravel Considerations for Non-vaccine-Preventable Travel Infections Following a short incubation period, with symptoms typically beginning 4–7 days (range 3–14 days) after exposure, dengue can present with a wide spectrum of illnesses, from asymptomatic infection to severe and fatal disease.5 Most infections are asymptomatic or subclinical; symptomatic infections occur in approximately one-third of cases.4 Patients who recover after a self-limited febrile illness, typically characterized by fever, headache, retroorbital pain, arthralgia, and myalgia, are classified as having dengue.5 The small proportion who progress to capillary (plasma) leakage with or without bleeding, circulatory collapse, or severe end organ impairment are designated as having severe dengue.5 Epidemiologic risk factors for severe dengue include young age, secondary infection with a different serotype, and infection with a more virulent strain of virus.4,10 Severe dengue occurs in approximately 1%–3% of dengue cases, with case fatality rates ranging from 3% of presentations to GeoSentinel surveillance clinics. Most infections are acquired in Asia, followed by the Americas, with only a small proportion acquired in Africa.12 The incidence of dengue infection in travelers ranges from 10.2–30 infections per 1000 person months, and varies according to travel destination, duration, and season of travel.11 Regionspecific peaks of travel-related dengue infections have been demonstrated for Southeast Asia (June and September), South Central Asia (October), and South America (March).13 Viraemic travelers can introduce dengue into new areas, with autochthonous transmission documented in the continental United States, Europe, and Australia.11,12 Some travelers with dengue may require hospitalization or even evacuation.10 Studies of dengue in travelers have reported a dengue hemorrhagic fever prevalence of 0.9%–3%, though this is likely an overestimate as patients experiencing more severe symptoms are more likely to seek medical attention.11 Epidemiologic studies in endemic settings have shown that the risk of severe disease is significantly higher during a second DENV infection than during a primary infection.5 However, a lack of consensus exists regarding risk factors for severe disease in travelers.11 Results of one study in travelers suggest that severe dengue may occur at similar rates among cases with primary and secondary infections.9 Given that most dengue infections are asymptomatic, and that severe dengue in travelers is rare, travelers with a history of dengue infection need not avoid known dengue areas but rather should be advised to use the personal protection strategies outlined in Box 7.1 to prevent subsequent infection.

Chikungunya CHIKV is a mosquito-borne alphavirus first isolated in Tanzania in 1952.14 In Africa, CHIKV exists in an enzootic sylvatic transmission cycle

BOX 7.1  Personal Protection Strategies

Against Aedes Mosquitoes

• Wear an insect repellent containing an active ingredient such as DEET or picaridin, particularly during daylight hours when the mosquitoes are most active. • Wear long-sleeved shirts and long pants to help protect yourself from bites. Light-colored clothes are best. • Treat clothes and shoes with an insecticide such as permethrin or purchase pretreated clothing. • Use mosquito coils, plug-in mosquito repellent devices, or insecticide surface sprays inside your accommodation; or stay in screened or air-conditioned accommodation.


between nonhuman primates, small mammals, and Aedes mosquitoes.14 However, in outbreaks CHIKV can spread without the need for animal reservoirs.14 Among populations with no prior immunity, CHIKV outbreaks can be explosive, and attack rates as high as 70% have been documented.15 Introduction of CHIKV into Asia occurred during or before the 1950s and led to outbreaks in India and Southeast Asia.16 Reemergence of CHIKV from Africa in 2004 resulted in major outbreaks involving millions of people across the islands of the Indian Ocean in 2005 (including the Comoros Islands, La Reunion, and Mauritius) and India in 2005–2006.16 Furthermore, introduction of CHIKV to temperate areas in this period resulted in autochthonous transmission in Italy and France.17,18 The first report of local transmission of CHIKV in the Americas occurred in 2013 in Saint Martin, with subsequent spread to >40 countries and territories across North, Central, and South America.15 The unprecedented magnitude of CHIKV outbreaks in recent years is probably attributable to several factors including increased urbanization, global travel, and a series of adaptive mutations in the virus which have resulted in enhanced transmission by A. albopictus.16 The incubation period of chikungunya is typically 2–4 days (range 1–14 days).14 Most chikungunya infections are symptomatic, with more than 85% of people with serologic evidence of infection reporting a history of symptoms.16 Chikungunya infection is characterized by sudden onset of fever and severe, potentially disabling arthralgia. Notably, the name chikungunya is derived from a Makonde word describing the bent posture that can be seen with severe arthralgia.16 The arthralgia/ arthritis is usually symmetric and affects multiple joints, with fingers, wrists, ankles, elbows, toes, and knees the most often affected.14 Additional symptoms include headache, myalgia, conjunctivitis, and rash. The case fatality rate of chikungunya is 35–45 years) more predisposed.14,18 Unlike Dengue, in which nonsteroidal antiinflammatory drugs (NSAIDs) are contraindicated, antiinflammatory drugs are indicated for symptomatic management of chikungunya infections.

Zika ZIKV is a flavivirus that was first isolated in 1947 from a rhesus monkey in the Zika Forest of Uganda, with the first human cases detected in Uganda and Tanzania in 1952.19,19a Following its discovery, the virus remained in relative obscurity for over 50 years, with only 14 cases reported until 2007, when an explosive outbreak infected approximately three-quarters of the population of Yap, Federated States of Micronesia.20 Subsequent outbreaks occurred across the Pacific Islands from 2013 to 2016; spread of the virus to Brazil in March 2015 preceded subsequent transmission throughout Latin America, the Caribbean, Mexico, and Florida and Texas in the United States.21,22 As of February 2018, 86 countries, territories, or subnational areas have reported evidence of vectorborne ZIKV transmission.23 Unlike DENV and CHIKV, there is now substantial evidence that direct person-to-person transmission of ZIKV is possible—both horizontally through sexual transmission, and vertically from the mother to the fetus during pregnancy.22 Transmission through blood transfusion has been reported,22 as well as a single case report of transmission probably resulting from close contact with bodily fluids from an infected patient.24 The incubation period is thought to be similar to other mosquito-borne flaviviruses21 with an estimated range from 3–14 days.25 Male-to-female, male-to-male, and femaleto-male transmission to unprotected sexual contacts of returning


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travelers has been reported with the former felt to be most prominent. Sexual transmission from patients with both symptomatic and asymptomatic disease has been described.22 Currently it appears that Zika can remain in semen longer than in other body fluids (including cervical mucus, vaginal fluids, urine, and blood).26 In semen, ZIKV RNA has been detected as long as 188 days after the onset of symptoms, and infectious virus has been cultured up to 69 days after symptom onset.22 Most ZIKV infections are asymptomatic, with serosurvey studies indicating that only 19% of those infected report clinical illness.20 In symptomatic cases, illness is generally mild and self-limiting with symptoms including fever, rash, pruritus, arthralgia, myalgia, conjunctivitis, and headache.21 ZIKV has been associated with neurologic complications including Guillain-Barré syndrome (GBS) and adverse fetal outcomes including congenital microcephaly. An association with GBS was first reported in 2013–2014 during the French Polynesian outbreak. More than 20 countries have now reported an increased incidence of GBS and/or laboratory confirmation of a ZIKV infection among GBS cases.23 In February 2016, following reports from Brazil of microcephaly in babies whose mothers had been exposed to Zika during pregnancy, the World Health Organization (WHO) declared that Zika constituted a Public Health Emergency of International Concern (PHEIC).19 Microcephaly is one of several neurologic and musculoskeletal birth defects described in congenital infection; this constellation of findings is now known as congenital Zika syndrome.27

TABLE 7.1  Web Resources for Updated

Disease and Vector Information

• Aedes Vector ranges in United States: range.html • European Centre for Disease Prevention and Control mosquito maps: VBORNET_maps.aspx • Dengue health map: (recent reports of local or imported dengue cases from official, newspaper, and other media sources) • World Health Organisation International Travel and Health (ITH) interactive map: • Zika • • • Middle East respiratory syndrome coronavirus (MERS-CoV) • • • Avian influenza • •

Prevention of Dengue, Chikungunya, and Zika Although a live attenuated tetravalent dengue vaccine (CYD-TDV; Dengvaxia) has been registered in several countries, and several other dengue vaccine candidates are in clinical development,8 at this time no dengue vaccine is licensed for travelers. Likewise no vaccines are licensed for chikungunya or Zika; therefore prevention of these viruses largely relies on personal protection strategies that limit contact between humans and Aedes mosquitoes (see Box 7.1 and Chapter 6; Insect Protection) as well as avoidance of travel during peak transmission or outbreak periods. Travelers returning to nonendemic areas with Aedes mosquitos (see Fig. 7.1) should also be advised to avoid mosquito bites on their return to prevent local transmission. Symptomatic travellers should seek medical evaluation immediately. Infection with CHIKV is thought to result in lifelong protective immunity.14 Duration of ZIKV immunity following infection is currently unknown. In contrast, due to the multiple serotypes, individuals can be infected with dengue up to four times, and travelers with a history of infection should be educated about the potential risks of subsequent infections.

Additional Considerations for the Prevention of Congenital Zika Infection Due to the high prevalence of asymptomatic infections and the risk of sexual and vertical transmission, Zika-specific preventative advice is important for those traveling to Zika affected areas. Pregnant women who do not reside in Zika transmission risk areas should be advised not to travel to areas with risk; if travel cannot be avoided, advice to prevent mosquito bites and sexual transmission should be given.28 Measures to prevent sexual transmission include abstaining from sexual activity or use of condoms during sexual activity (including vaginal, anal, and oral sex, and sharing of sex toys) during the entire pregnancy.28 Pregnant women possibly exposed to ZIKV due to travel or sexual contact should discuss the potential exposure with their

health care provider. Those with symptoms of Zika infection or fetal ultrasound findings consistent with congenital Zika virus syndrome should be tested for ZIKV.29 Testing may also be considered in asymptomatic potentially exposed pregnant women after considering risk of infection, patient preferences, and clinical judgment.29 Nonpregnant individuals and couples traveling to Zika-affected areas should also be counseled on measures to prevent sexual transmission and congenital infection. Due to the risk of prolonged viral shedding in semen, public health authorities advise men with risk of Zika exposure to wait 3 months from the last possible exposure to Zika (or after onset of symptoms following symptomatic infection) before attempting procreation.22 Most authorities advise women to wait 8 weeks from the last possible exposure to Zika (or after onset of symptoms following symptomatic infection) before attempting to conceive22; one exception is the WHO, which advises women to wait 6 months before attempting conception.30 Because many pregnancies are unplanned, all sexually active travelers and female partners of travelers should also practice measures to prevent congenital Zika infection. Readers are encouraged to review the most updated recommendations for prevention of sexual transmission of ZIKV and congenital Zika infection from public health authorities including WHO and the US Centers for Disease Control and Prevention (CDC) (Table 7.1).

SEVERE RESPIRATORY INFECTIONS WITH REGIONAL ENDEMICITY The 2003 severe acute respiratory syndrome (SARS) outbreak highlighted the potential for travelers to introduce novel respiratory infections into their home countries. More recently, concern has focused most on the emergence of Middle Eastern respiratory syndrome (MERS) and certain strains of avian influenza.

CHAPTER 7  Pretravel Considerations for Non-vaccine-Preventable Travel Infections Middle Eastern Respiratory Syndrome MERS is a respiratory infection caused by MERS coronavirus (MERSCoV). First described in 2012,31 MERS is an endemic infection in the Arabian Peninsula with epidemic potential in health care and travel settings. Following an incubation period of 2–14 days, initial symptoms of MERS are similar to many common viral respiratory infections and include fever, rhinorrhea, sore throat, and muscle aches. Rapid progression to acute respiratory distress syndrome may follow, but mild and asymptomatic infections have also been described.32,33 Nausea, vomiting, or diarrhea, and acute kidney injury can also occur.32 Risk factors for severe MERS include age >50 years and comorbid conditions such as hypertension, diabetes, heart disease, end stage renal disease, chronic lung disease, cancer, or those receiving immunosuppressive therapy.32 Among confirmed cases reported to WHO up to July 2017, 35% have been fatal.33a Seroepidemiologic studies indicate that MERS-CoV circulates in dromedary camels in the Middle East and Africa, and direct contact with camels has been described in 33% of primary cases without known exposure to MERS cases or health care settings.34 The route of transmission from dromedaries to humans is unclear, but contact with infectious bodily secretions and fluids are suspect, and consumption of raw dromedary products has also raised some concern.32 Person-to-person transmission is primarily described in health care settings, although transmission among household close contacts has been described.35 All cases of MERS reported outside of the Arabian Peninsula have occurred in returned travelers, or as a result of secondary transmission from a patient with recent travel to the Arabian Peninsula, as was the case for the 2015 health care–associated outbreak in South Korea that resulted in 186 cases and 36 deaths.32,36,37 In this outbreak, delayed MERS diagnoses and inadequate infection control precautions led to multiple generations of infections affecting other patients, visitors, and health care workers.37,38 The risk of traveler-initiated health care–associated outbreaks with MERS mirrors the global experience of SARS. Like MERS, the viral agent of SARS is a coronavirus that emerged in southern China in 2002 and subsequently caused over 8000 infections and 774 deaths in more than 20 countries.38,39 The reservoir of SARS coronavirus (SARS-CoV) is unknown, but some cases appear to have resulted from contact with animals used for human consumption such as civet cats.40 Although no cases of SARS have been reported since 2004, the potential for reemergence is possible.39

Avian Influenza While seasonal influenza is a common infection among travelers, other influenza types including certain strains of avian influenza can also pose a risk to travelers. Although avian influenza typically affects birds, human cases and outbreaks occur sporadically. Avian influenza strains associated with severe respiratory infections with high mortality rates in humans include the highly pathogenic avian influenza A H5N1,41 and more recently, novel avian influenza A H7N9.42 Although the majority of human infections caused by avian influenza are linked to direct contact with infected birds (primarily poultry), unsustained person-to-person transmission has been reported for H5N1 and H7N9.41,43 Furthermore cocirculation of different influenza A viruses in humans and animals raises the concern of reassortment leading to new strains that spread more readily from person to person.42 H5N1, first described in southern China in 1996, has since been documented in over 60 countries in Asia and Africa.41 A review of human cases reported over an 18-year period found 907 cases reported from 16 countries with a case fatality rate of 53.5%.41 Countries and


BOX 7.2  Recommendations to Prevent

Severe Respiratory Infections

• General hygiene practices that may reduce respiratory infection risk: • Hand-washing • Cough etiquette • Avoiding contact with eyes, nose, and mouth • Avoiding contact with sick individuals • Avoidance of activities that increase risk of exposure to avian influenza, including contact with live or dead poultry, wild birds, or environments contaminated with bird droppings or fluids • Avoidance of markets where live poultry and animals are kept and slaughtered in close proximity • Travelers to the Arabian peninsula and other areas with evidence of MERS-CoV (Middle East and Africa): • Practice hygiene measures around camels and areas with camels • Do not consume raw camel products • Travelers with risk factors for severe MERS-CoV infection (including diabetes, renal failure, chronic lung disease, and immunosuppression) should avoid any contact with camels Adapted from CDC. Human infection with H5N1: advice for travelers, 2017; WHO (WHO, 2014) and Ma T, Heywood A, MacIntyre CR. Chinese travellers visiting friends and relatives—a review of infectious risks. Travel Med Infect Dis. 2015 Jul–Aug;13(4):285–94.

territories reporting the most cases were (in descending order): Egypt, Indonesia, Vietnam, Cambodia, China, Thailand, Hong Kong, and Turkey.41 Travel-related cases have been reported, including a case in a Canadian traveler.44 H7N9 emerged in China in 2013, and has since caused over 1200 human cases with a case fatality rate of 40% during yearly winter-spring epidemics in China.42 While 20 of 31 provinces in China have reported H7N9 cases, most cases have been reported in the Yangtze River Delta in Eastern China and Guangdong province in southern China.42 Travel-associated cases of H7N9 have been reported in Hong Kong, Macao, Taiwan, and Canada.43,45

Preventative Advice for Severe Respiratory Infections Although no vaccines are available at this time for prevention of MERS and avian influenza (H5N1 and H7N9) in travelers, providers should routinely review the most recent epidemiology of severe respiratory infections reported by authorities such as the WHO and CDC (see Table 7.1) and promote general hygiene and other preventative measures to travelers to these areas (Box 7.2). While seasonal influenza vaccination does not protect against avian influenza or MERS, vaccine-related prevention of seasonal influenza may reduce the chance of coinfections and overall risk of respiratory infections. Travelers should also be advised to inform their health care providers of their travel history whenever seeking medical care for respiratory (and other illnesses) acquired during or soon after travel (see chapter 59).

OTHER REGIONALLY IMPORTANT INFECTIONS IN TRAVELERS Travel medicine providers should also be familiar with risk areas and specific preventive advice for other non–vaccine-preventable infectious diseases with regional distributions. Some of the more important of these infections are presented in Table 7.2, along with specific preventive advice, such as insect bite avoidance (e.g., for prevention of African trypanosomiasis) or freshwater contact avoidance (e.g., for prevention of schistosomiasis or leptospirosis).


SECTION 2  The Pretravel Consultation

TABLE 7.2  Epidemiology and Preventive Strategies for Other Diseases With Regional


Mode(s) of Transmission

Geographic Distribution

Risk Activities/At-Risk Groups

African trypanosomiasis (sleeping sickness) (Trypanosoma brucei)46

Vectorborne: tsetse fly (Glossina spp.)

Focal areas of central Africa, West Africa, eastern and southeastern Africa

Rural travel with outdoor exposure

Cutaneous larva migrans (Ancylostoma spp.)

Direct contact with soil or sand contaminated with dog or cat hookworm larvae Vectorborne: Sandflies (genus Phlebotomus)

Widespread in tropical areas, especially the Caribbean

Walking barefoot

Africa, Asia, the Middle East, Mediterranean countries, Central and South America

Adventure travelers, military personnel, researchers

Inhalation of contaminated dust/soil

United States, Central and South America, Africa, Asia

Visiting bat caves, spelunking, activities that disturb soil Immunosuppressed travelers

Direct contact with infected animals Ingestion of or direct contact with water, mud, soil, or vegetation that has been contaminated with animal urine Contact with contaminated soil (direct contact or inhalation of aerosolized particles)

Worldwide, particularly in tropical or subtropical regions

Freshwater swimming, rafting, kayaking, canoeing, fishing, hunting, caving, hiking, trail biking, contact with floodwater

Southeast Asia, northern Australia

Outdoor activities during periods of wind and rain, activities involving direct contact with soil

Murine typhus51

Vectorborne: fleas (carried by rats and mice)

Outdoor activities, contact with rats or mice

Myiasis (Cochliomyia hominivorax, Dermatobia hominis, others)52

Penetration of skin by fly larvae (may be deposited on clothing or carried to humans by a biting mosquito) Contact with contaminated fresh water

Worldwide, particularly in tropical or subtropical regions Tropical areas in Africa and Latin America

Sub-Saharan Africa (majority of exposures), Southern Africa and some areas of North Africa, the Middle East, South America, the Caribbean, and Southeast Asia (Mekong River region) South and Southeast Asia and the Pacific (including northern Australia)

Swimming, bathing, or wading in rivers, lakes, ponds, or seasonally flooded areas

Disease (Pathogen)

Cutaneous (or mucocutaneous) leishmaniasis47 (Leishmania spp.) Histoplasmosis48 (Histoplasma spp.)




Scrub typhus54 (Orientia tsutsugamushi)

Vectorborne: mites (chiggers)

Outdoor activities

Campers, trekkers, visitors to rice paddies

Preventive Strategies • Wear long clothing of medium-weight material in neutral colours (tsetse flies are attracted to bright or dark colors, especially blue, and can bite through lightweight clothing) • Use insect repellent • Wear shoes when walking on sand or soil • Use barriers such as towels or mats when seated on the ground • Personal protective measures against sandfly bites (especially between dusk and dawn) • Those with risk factors (immunosuppression) should avoid contact with bird or bat droppings, avoid exploring caves, and avoid activities that generate dust • Avoid swimming or wading in water that may be contaminated • Cover all cuts or abrasions with waterproof dressings • Doxycycline chemoprophylaxis may be considered in some cases • Avoid direct contact with soil • Those with risk factors (diabetes, chronic lung disease, chronic kidney disease, chronic alcoholism) should stay indoors during periods of heavy wind and rain • Personal protective measures against fleas • Iron clothing after line drying • Cover skin with clothing and use insect repellent • Stay in screened accommodation and use mosquito nets • Avoid swimming or wading in fresh water

• Personal protective measures against mites (e.g., long pants and long sleeves, tucking pant legs into socks or boots, insect repellents)

CHAPTER 7  Pretravel Considerations for Non-vaccine-Preventable Travel Infections


TABLE 7.2  Epidemiology and Preventive Strategies for Other Diseases With Regional

Distribution—cont’d Disease (Pathogen) Spotted fever group rickettsiosis54 NB: >10 species including Rickettsia africae (African tickbite fever) and R. rickettsii (Rocky Mountain spotted fever)

Mode(s) of Transmission

Geographic Distribution

Risk Activities/At-Risk Groups

Vectorborne: Ticks

Worldwide, but with species-specific distributions Majority of exposures in sub-Saharan Africa

Travel to game parks, outdoor activities, late summer season travel

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Preventive Strategies • Personal protective measures against ticks (e.g., long pants and long sleeves, tucking pant legs into socks or boots, insect repellents) • Tick check of skin at the end of the day

18a.  van Aalst M, Nelen CM, Goorhuis A, et al. Long-term sequelae of chikungunya virus disease: a systematic review. Travel Med Infect Dis 2017;15:8–22. 19. Kindhauser MK, Allen T, Frank V, et al. Zika: the origin and spread of a mosquito-borne virus. Bull World Health Organ 2016;94(9):675–86C. 19a.  Wikan N, Smith DR. Zika virus: history of a newly emerging arbovirus. Lancet Infect Dis 2016;16(7):e119–26. 20. Duffy MR, Chen TH, Hancock WT, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med 2009;360(24):2536–43. 21. Petersen LR, Jamieson DJ, Powers AM, et al. Zika virus. N Engl J Med 2016;374(16):1552–63. 22. Hamer DH, Wilson ME, Jean J, et al. Epidemiology, prevention, and potential future treatments of sexually transmitted Zika virus infection. Curr Infect Dis Rep 2017;19(16). 23. World Health Organization (WHO). Zika virus classification tables. Available at -tables/en/. 24. Swaminathan S, Schlaberg R, Lewis J, et al. Fatal Zika virus infection with secondary nonsexual transmission. N Engl J Med 2016;375(19):1907–9. [Epub 2016 Sep 28]. 25. Krow-Lucal ER, Biggerstaff BJ, Staples J. Estimated incubation period for Zika virus disease. Emerg Infect Dis 2017;23(5):841–5. Available at 26. Paz-Bailey G, Rosenberg ES, Doyle K, et al. Persistence of Zika virus in body fluids—preliminary report. N Engl J Med 2017. 27. Melo ASDO, Aguiar RS, Amorim MMR, et al. Congenital Zika virus infection beyond neonatal microcephaly. JAMA Neurol 2016;73(12):1407–16. doi:10.1001/jamaneurol.2016.3720. 28. Centers for Disease Control and Prevention. Available at https://www.cdc .gov/zika. 29. Oduyebo T, Polen KD, Walke HT, et al. Update: interim guidance for health care providers caring for pregnant women with possible Zika virus exposure—United States (including US territories), July 2017. MMWR 2017; doi: 30. World Health Organization. Prevention of Sexual Transmission of Zika Virus—Interim Guidance Update; 2016 Sep 6. Available at http:// -prevention/en/. 31. Zaki AM, van Boheemen S, Bestebroer TM, et al. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 2012;367(19):1814–20. doi:10.1056/NEJMoa1211721. [Epub 2012 Oct 17]. 32. Arabi YM, Balkhy HH, Hayden FG, et al. Middle East respiratory syndrome. N Engl J Med 2017;376(6):584–94. 33. Al Hammadi ZM, Chu DKW, Eltahir YM, et al. Asymptomatic MERS-CoV infection in humans possibly linked to infected dromedaries


SECTION 2  The Pretravel Consultation

imported from Oman to United Arab Emirates. Emerg Infect Dis 2015;21(12):2197–200. doi:10.3201/eid2112.151132. 33a.  World Health Organization (WHO). MERS-CoV Global Summary and Assessment of Risk. Published 2017 July 21. Available at http://www.who .int/emergencies/mers-cov/risk-assessment-july-2017.pdf?ua=1. 34. Alraddadi BM, Watson JT, Almarashi A, et al. Risk factors for primary Middle East respiratory syndrome coronavirus illness in humans, Saudi Arabia, 2014. Emerg Infect Dis 2016;22(1):49–55. Available at https:// 35. Drosten C, Meyer B, Müller MA, et al. Transmission of MERS-coronavirus in household contacts. N Engl J Med 2014;371(9):828–35. doi:10.1056/NEJMoa1405858. 36. Lee JY, Kim YJ, Chung EH, et al. The clinical and virological features of the first imported case causing MERS-CoV outbreak in South Korea, 2015. BMC Infect Dis 2017;17(1):498. doi:10.1186/s12879-017-2576-5. 37. Cowling BJ, Park M, Fang VJ, et al. Preliminary epidemiological assessment of MERS-CoV outbreak in South Korea, May to June 2015. Euro Surveill 2015;20(25):ii, 21163. doi: -7917.ES2015.20.25.21163. 38. Chowell G, Abdirizak F, Lee S, et al. Transmission characteristics of MERS and SARS in the healthcare setting: a comparative study. BMC Med 2015;13:210. doi:10.1186/s12916-015-0450-0. 39. World Health Organization (WHO). WHO Guidelines for the Global Surveillance of Severe Acute Respiratory Syndrome (SARS); October 2004. Available at _CSR_ARO_2004_1.pdf?ua=1. 40. Abdullah ASM, Tomlinson B, Cockram CS, et al. Lessons from the severe acute respiratory syndrome outbreak in Hong Kong. Emerg Infect Dis 2003;9(9):1042–5. doi:10.3201/eid0909.030366. 41. Lai S, Qin Y, Cowling BJ, et al. Global epidemiology of avian influenza A H5N1 virus infection in humans, 1997-2015: a systematic review of individual case data. Lancet Infect Dis 2016;16(7):e108–18. doi:10.1016/ S1473-3099(16)00153-5. [Epub 2016 May 17]. 42. Wang X, Jiang H, Wu P, et al. Epidemiology of avian influenza A H7N9 virus in human beings across five epidemics in mainland China, 2013-17:

an epidemiological study of laboratory-confirmed case series. Lancet Infect Dis 2017;17(8):822–32. doi:10.1016/S1473-3099(17)30323-7. [Epub 2017 Jun 2]. 43. Iuliano AD, Jang Y, Jones J, et al. Increase in human infections with avian influenza A(H7N9) virus during the fifth epidemic—China, October 2016–February 2017. MMWR 2017;66:254–5. doi: .15585/mmwr.mm6609e2. 44. Rajabali N, Lim T, Sokolowski C, et al. Avian influenza A (H5N1) infection with respiratory failure and meningoencephalitis in a Canadian traveller. Can J Infect Dis Med Microbiol 2015;26(4):221–3. 45. Skowronski DM, Chambers C, Gustafson R, et al. Avian influenza A(H7N9) virus infection in 2 travelers returning from China to Canada, January 2015. Emerg Infect Dis 2016;22(1):71–4. doi:10.3201/ eid2201.151330. 46. Brun R, Blum J, Chappuis F, et al. Human African trypanosomiasis. Lancet 2010;375:148–59. 47. Mansueto P, Seidita A, Vitale G, et al. Leishmaniasis in travelers: a literature review. Travel Med Infect Dis 2014;12(6 Pt A):563–81. doi:10.1016/j.tmaid.2014.09.007. Review. 48. Bahr NC, Antinori S, Wheat LJ, et al. Histoplasmosis infections worldwide: thinking outside of the Ohio River valley. Curr Trop Med Rep 2015;2(2):70–80. 49. Lau C, Smythe L, Weinstein P. Leptospirosis: an emerging disease in travelers. Travel Med Infect Dis 2010;8(1):33–9. 50. Wiersinga WJ, Currie BJ, Peacock SJ. Melioidosis. N Engl J Med 2012;367(11):1035–44. 51. Blanton LS. Rickettsial infections in the tropics and in the traveler. Curr Opin Infect Dis 2013;26(5):435–40. 52. Lachish T, Marhoom E, Mumcuoglu KY, et al. Myiasis in Travelers. J Travel Med 2015;22(4):232–6. 53. Clerinx J, Van Gompel A. Schistosomiasis in travelers and migrants. Travel Med Infect Dis 2011;9(1):6–24. doi:10.1016/j.tmaid.2010.11.002. Review. 54. Jensenius M, Davis X, von Sonnenburg F, et al. Multicenter GeoSentinel analysis of rickettsial diseases in international travelers, 1996-2008. Emerg Infect Dis 2009;15(11):1791–8. doi:10.3201/eid1511.090677.

8  Travel Medical Kits Larry Goodyer and Jason Gibbs

KEY POINTS • Travelers should purchase medical and health-related items prior to departure. • The contents of a medical kit should be determined by a risk assessment—consider destination, type and duration of travel, and activities. • Travelers should be aware of the legal restrictions on carrying certain medicines, particularly narcotics and psychotropics, into certain countries.

• Items should be packaged appropriately for the travel environment. • A kit should be constructed in a stepwise manner, building up from the most essential items used in all travel situations to those required in specific circumstances.


• Quality. There is wide recognition that in some developing and emerging countries there may be poor drug regulatory systems, and along with that, high levels of either forged or poor-quality pharmaceuticals. In some developing countries more than 30% of all medications available for sale could be counterfeit.7

A central function of the pretravel consultation is to provide the necessary prophylaxis together with appropriate verbal and written advice. If a traveler should become ill or injured overseas there are two choices that need to be made: whether to self-treat or to seek the advice of a health care practitioner. In either case it is likely that first aid or medication will be needed to manage the condition. This chapter addresses the issue of the range of such items that could be considered for inclusion into a first-aid/medical kit for personal use as well as the potential range of items suitable for groups of travelers and expeditions. In addition, for completeness there are a range of health-related items such as sunscreens, hand-washes, and repellents that should also be carried in many travel situations. The extent to which travelers carry or use items for self-treatment has not been well investigated. One small study identified the items used by a cohort of longer-term travelers, mostly backpackers, and concluded that the range of items frequently used was relatively limited.1 Surveys of trekkers in the Khumbu region of Nepal from 1995–1997 revealed that only 18% of respondents carried a comprehensive kit.2 A few other studies have described the use of medical kits in a variety of situations.3–6 There are a number of compelling reasons why the traveler should try to purchase all medical and health-related items before departure rather than at destination, even though the latter may involve a considerable financial saving: • Availability. In many developing countries the required products may simply not be available, and this is difficult to anticipate before arrival. This may also apply to other health products, such as certain types of insect repellent. • Equivalence. If the product is available it may be difficult to explain to the health professional precisely what is required in another language. Both the names of the ingredients and the instructions may also not be in the traveler’s own language.

SUMMARY OF FACTORS DETERMINING MEDICAL AND FIRST-AID KIT CONSTRUCTION Risk assessment is at the heart of all pretravel preparation, and this should inform the contents of any medical kit that might be carried. Following are standard questions that contribute to a risk assessment, with an indication of how they influence medical kit construction: • Destination • Diseases endemic to area—Awareness of outbreaks and endemic diseases may warrant carrying specific medications (e.g., malaria emergency standby). • Quality of medical facilities—Poor facilities would imply carrying a greater range of items if these are not available locally. • Environmental extreme—Preparation for coping with the treatment of illness relating to the environment, acute mountain sickness, or heat exhaustion/stroke are prime examples. • Security—Those venturing to areas of very poor security such as war zones may need to consider more extensive emergency first-aid items. • Type of travel • Tourists on shorter-term holidays to popular destinations may only require the most basic of items, whereas backpackers who might be visiting more remote destinations should consider a broader range, but may be constrained in the amount that can be carried. • Business travelers may well need very little if staying for short periods in major urban areas, but quite extensive kits if traveling long term and with family.


CHAPTER 8  Travel Medical Kits Abstract


A medical and first-aid kit for the traveler should take into account the particular itinerary and needs of the individual. The items included will depend upon destination, types of activity, and any particular medical requirements due to chronic or likely acute conditions. The kit should be comprehensive to anticipate needs but also not contain unnecessary or bulky items that might take up valuable luggage space. Consideration should also be given to the availability and quality of items overseas and issues of carrying medicines for personal use. This chapter considers the contents of such kits for different travel situations.

Antiseptics Dressings First aid Medical kits Medicines for personal use Self-treatment Pharmaceuticals Packaging



• • • •

SECTION 2  The Pretravel Consultation

• Those visiting friends and relatives (VFRs) in their countries of birth (typically developing countries) should be aware of the importance of carrying a medical kit as described above. • Wilderness travel demands particular attention to self-sufficiency in treating any likely medical issue or emergency. Frequently this is undertaken as a group or expedition, where a very comprehensive kit is required with sufficient supply to treat a range of people. Such a kit may be difficult to transport, so is often viewed as a “base camp” unit, with a smaller individualized kit being carried when away from base. Overland groups traveling for long periods in truck transportation visiting many different regions will also carry a group medical and first-aid kit as well as individual kits. Activities will help determine the range of first-aid items required. Duration of travel and time at destination will determine the quantities of each item. Preexisting medical conditions also inform quantity and type of prescribed medication. Legal restrictions on importation. The medications that cause the most problems when carried across borders are those defined as narcotic and psychotropic. Many countries will allow travelers to carry a supply for personal use of 0.01 IU/mL. Serology indicated in the case of unclear vaccination status and lack of documentation Precise minimal protective Ab titer not known; possibly 0.15–1 µg anti-PRP Ab. Test not routinely used See comment above In nonendemic countries, prevaccination serology might be cost effective for persons with likely prior natural infection. (ELISA >10 mIU: protective titer) Postvaccination serology indicated in high-risk persons (protective ELISA titer >10 mIU/mL) Protective antihemagglutinin titer: 1/40 (probably higher in children with less previous exposure). Concomitant cytotoxic T-cell induction. Testing may be considered in immunocompromised + (CD8+)

+ (CD8+)



Pertussis (acellular) Pneumococcal disease Pneumococcal disease Poliomyelitis, oral (OPV)

PS Protein-conjugate PS Live attenuated

++ ++ ++

(+) ++ ++

Poliomyelitis, injectable

Inactivated (IPV)



Rabies Rotavirus Rubella

Inactivated Live attenuated Live attenuated


Tickborne encephalitis






Tuberculosis (BCG)

Live mycobacteria




Varicella Yellow fever

Live attenuated Live attenuated

++ ++




++ (CD4+) (+)

+ (CD4+) + (CD4+)

Vero-cell: PRNT considered good correlate for protection (no routinely used test, no international standard) Protective titer: NT >1 : 4. Induction of cellular immune response important Correlation between postvaccination ELISA titers and vaccine efficacy suggests that >2 µg of antibody is protective See previous comment Postvaccination serology (ELISA) correlates with protection. Precise minimal protective Ab titer not known

Precise minimal protective Ab titer not known. Routine tests not available. Efficacy tested in controlled field trials Precise minimal protective Ab titer not known. Routine tests not available. Efficacy tested in controlled field trials 23 subtypes, determination of Ab titer not feasible for routine use 13 subtypes, determination of Ab titer not feasible for routine use Protective Ab titer NT ≥1 : 8. Based on genetically modified Sabin strains Protective Ab titer NT ≥1 : 8. Based on wild-type Salk strains. In recent years, first IPV based on Sabin strains have been licensed (sIPV) Protective Ab titer: RFFIT: >0.5 IU/mL or NT: 1 : 25 Mucosal IgA Protective Ab titer: >1 : 32 (hemagglutination-inhibition-test) or ELISA. Tests correlate with protection. Mucosal Ab involved in protection ELISA tests give surrogate markers for immunity. Cave: cross-reactivity of antibodies (flavivirus) – NT required! Protective Ab titer: ELISA >0.01 IU/mL but usually >0.1 IU/mL (more reliable). See also diphtheria Correlate of protection not available. Cellular immune response essential Testing almost impossible. Anti Vi-capsular polysaccharide antibodies have been used to establish protective antibody titers. Strain used in oral vaccine does not contain Vi-capsular polysaccharide included in parenteral vaccine. Mucosal antibodies following live typhoid vaccine (oral) Regular antibody testing indicated for leukemia patients ELISA. Cave: cross-reactive antibodies (flavivirus). NT only available at CDC

+, low correlation; ++, high correlation. anti-PRP Ab, Antipolyribosylribitol phosphate antibodies; BCG, Bacillus Calmette-Guérin; Enzyme-linked immunosorbent assay; NT, neutralization test; PRNT, plaque reduction neutralization test; PS, polysaccharide; RFFIT, rapid fluorescent foci inhibition test. Modified from Plotkin SA. Correlates of protection induced by vaccination. Clin Vaccine Immunol 2010;17:1055–65.


SECTION 3 Immunization

Vaccines Traditionally, two types of vaccines have been used to prevent infectious diseases: inactivated and live attenuated vaccines. Both have in common that they contain preformed immunogenic antigens: inactivated vaccines consist of entire inactivated microorganisms, subunits, or specific purified antigens; attenuated vaccines are composed of entire live microorganisms. New approaches to develop vaccines have emerged in the past years. These include new vectors to deliver the antigen—for example, recombinant/ chimeric vaccines (e.g., yellow fever virus backbone expressing dengue virus antigens, or vesicular stomatitis virus [VSV] expressing Ebola glycoprotein), viruslike particles (e.g., human papilloma vaccine), or genetic vaccines (e.g., coding sequence introduced on mRNA level, the actual antigen is then assembled by the host)—and new routes of immunization (transdermal, intradermal, intranasal application, or antigens delivered by inhalation). Furthermore, the principle of active immunization is no longer restricted to prevent infectious diseases: progress has been made in the area of therapeutic vaccines that may be available to treat cancer in the future.2

Inactivated Vaccines.  The term inactivated refers to the fact that the antigen contained in the vaccine is incapable of replicating within the vaccinee. Inactivated vaccines contain isolated antigens as protein (e.g., diphtheria or tetanus toxoid vaccine), polysaccharide (e.g., early meningococcal vaccine, injectable typhoid vaccine), glycoconjugates (e.g., modern meningococcal vaccine) or are composed of subunits (e.g., most injectable influenza vaccines) or whole inactivated microorganisms (e.g., hepatitis A or rabies vaccine). Toxins or pathogens are most often formaldehyde-inactivated. Inactivated vaccines may need to be given repeatedly for primary immunization, may contain a higher antigenic content than live attenuated vaccines, and/or may include costimulating substances in addition to the pathogen-specific antigen. These substances, called adjuvants, stimulate/enhance the host’s immune system via several mechanisms including (i) improving antigen presentation, (ii) recruiting immune cells at the vaccination site by delivering “danger signs,” (iii) facilitating antigen trafficking to germinal centers (GCs) of draining lymph nodes, and (iv) prolonging stimulatory effects by formation of an antigen depot, resulting in an adequate immunologic response, usually including B-cell and CD4+ T-cell responses. A series of single adjuvants or adjuvant systems (composition of more than one adjuvant substance) have been included in existing vaccines. Aluminum hydroxide or aluminum phosphate has been widely used as an adjuvant but also as a stabilizer of the vaccine’s antigen. More recently, various other potent adjuvant systems, such as virosomes, biodegradable microspheres, or novel adjuvant substances such as MF59 or monophosphoryl lipid A (MPL), have been introduced.3,4 Generally capsular-derived polysaccharide antigens (Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae, Salmonella typhi) are incapable of activating T cells. Polysaccharide vaccines are therefore incapable of eliciting immunologic memory and are thus booster-incompetent (see upcoming discussion). Because of the yet immature immune system, capsular polysaccharides are poorly immunogenic in vaccinees under 2 years of age. However, the coupling of polysaccharide antigens with protein carriers (conjugation) renders the polysaccharides visible to T cells and overcomes these pitfalls. For this reason, polysaccharide antigens in modern pneumococcal, meningococcal, or H. influenzae type b vaccines are conjugated to protein carriers like genetically modified cross-reacting material (CRM) of diphtheria toxin or, more simply, diphtheria or tetanus toxoid. The initial vaccine-induced immune reaction occurs regionally involving the injection site as well as corresponding lymph nodes. As inactivated vaccines do not contain replicating microorganisms they

can be given to severely immunocompromised persons without safety concerns—in contrast to live attenuated vaccines.

Live Attenuated Vaccines.  These vaccines contain live attenuated microorganisms that are still capable of replicating within the vaccinee. The microorganisms are “weakened,” meaning that they have lost nearly all of their disease-causing capacity but are still in possession of their immunogenic properties. Live attenuated vaccines are still not as good as natural infection in providing lifelong sterile immunity, but they come close by inducing both systemic innate immune processes and a strong humoral (B cells) and cellular (CD4+ T cells) immune response. Postvaccination antibody titers are high but tend to decrease more rapidly compared to after natural infection. For this reason, newborn infants are better protected by maternal antibodies—for example, against measles when the mother had been naturally infected in her childhood compared to vaccination of the mother. Yet a single vaccine administration is usually sufficient to induce long-term, generally lifelong protection due to immune memory effects (see upcoming discussion). As live attenuated but replicating (until inactivation by the vaccinee’s immune response) microorganisms induce a systemic immune response, vaccination may go in line with mild, self-limiting unspecific symptoms including febrile reactions in some, particularly in children. In this context, live attenuated vaccines must not be given to severely immunocompromised persons. Replication is also linked with another aspect: the oral polio vaccine (OPV) carries the risk of introduction of genetic mutations and reversion to virulent strains causing a symptomatic affection similar to wild-virus infection in the vaccine recipient or, by fecal spread, in unvaccinated contacts (vaccine-associated paralytic poliomyelitis [VAPP]).

Vaccine Administration Anxiety about vaccinations is widespread. Some local anesthetic agents, such as 5% lidocaine-prilocaine emulsion, also available as patch, applied 30–60 minutes before injection, may relieve discomfort during vaccination without interfering with the immune response. Contraindications apply. A topical refrigerant spray may be administered shortly before vaccination to reduce injection pain. Disinfection spray cooling the skin may have a similar effect. Experienced vaccinators will know a variety of tricks to vaccinate while calming the potentially anxious vaccine recipient. For example, infants and young children may be placed on a parent’s lap (Fig. 9.1) and a sucrose placed on the tongue immediately before injection may have a calming and/or distracting effect. More painful vaccines should be administered last.

Route of Immunization.  The type of vaccine and, with inactivated vaccines, the type of antigen as well as potential adjuvants determine the route of vaccination. In contrast to live attenuated vaccines eliciting a more systemic immune reaction, immune processes triggered by inactivated vaccines are confined to the site of application as well as regional lymph nodes or the spleen. Route and site of application of inactivated vaccines is thus of greater relevance. Some general rules apply: adjuvants (e.g., aluminum) should not be administered intradermally and no vaccine should ever be administered into the bloodstream. Intramuscular (IM) vaccinations are used for adjuvant-containing, potentially irritating antigens (e.g., tetanus-diphtheria vaccine). Administration by subcutaneous (SC) injection is preferred for live attenuated viral vaccines, to lessen the discomfort due to local inflammation (e.g., yellow fever vaccine). Intradermal (ID) injection, such as for Bacillus Calmette-Guérin (BCG) vaccine, is mainly determined by the specific immunogenicity characteristic for this mycobacterial antigen and requires careful technique to avoid inadvertent SC antigen injection and

CHAPTER 9  Principles of Immunization


Acromion Deltoid muscle (shaded area) Vastus lateralis (shaded area)

i.m. injection site

i.m. injection site area


FIG. 9.1  Intramuscular injection site for infants and toddlers (birth to 24 months of age). Insert needle at a 90-degree angle into vastus lateralis muscle in anterolateral aspect of middle or upper thigh.

consequent diminished immunologic response. The oral route is used for vaccines that are intended to trigger an immune response at the site of infection by stimulating the release of mucosal IgA and other immune mechanisms in the intestinal tract (e.g., oral poliomyelitis vaccine, oral typhoid vaccine, oral cholera vaccine, rotavirus vaccine). The intranasal route has been used with live attenuated influenza vaccine (LAIV). Vaccines for transcutaneous, rectal, and vaginal administration and even inhalation are under investigation. It is advisable to use only the administration route recommended by the manufacturer. Intramuscular route.  The choice of site for IM administration (Table 9.2) is based on the age of the vaccinee and, for passive immunization with immunoglobulins, the volume of injected material. For infants and toddlers up to 24 months of age the preferred site for IM injections is the vastus lateralis muscle in the anterolateral aspect of the thigh (see Fig. 9.1). In older children and adults, the deltoid muscle provides the best site for IM injections (Fig. 9.2). The needle length used for IM injections depends on age for infants and children and weight (diameter of subcutaneous fatty tissue) in adults (see Table 9.2). In infants, the gluteal region is mainly composed of fat. As fatty tissue is less effective in triggering an immune response to inactivated vaccines and because of the possibility of damaging the nearby sciatic nerve, the gluteal region is no longer a preferred site for active IM vaccinations in infants. However, the gluteal site is often used for IM administration of large volumes of immunoglobulin preparations in all age groups. Injection should be performed in the center of a triangle bordered by the anterior superior iliac spine, the tubercle of the iliac crest, and the upper border of the greater trochanter of the femur. To reduce discomfort and because there is no data supporting a benefit, WHO no longer recommends “aspiration” by pulling back the syringe plunger before injection.5,6 If SC or IM vaccines are applied

FIG. 9.2  Intramuscular injection site for older toddlers, children, and adults. Insert needle at a 90-degree angle into the densest portion of deltoid muscle, above armpit and below acromion.

TABLE 9.2  How to Administer Vaccines

via the Intramuscular Route. Needle Length and Injection Site of Intramuscular Injections Age

Needle Length

≤17 years  Newborna 0.63 in (16 mm)b   Infant 1–12 months 1 in (25 mm)   Toddler 1–2 years 0.63b–1 in (16–25 mm) 1–1.25 in (25–32 mm)  Child/adolescent 0.63b–1 in (16–25 mm) 3–17 years ≥18 years  Sex/weight    Male and female 1 in (25 mm) 90 kg 1.5 in (38 mm) (200 lb)   Male >118 (260 lb) a

Injection Site Anterolateral thigh Anterolateral thigh Anterolateral thighc Deltoid muscle of the arm Deltoid muscle of the armc

Deltoid muscle of the arm

First 28 days of life. If skin stretched tight, subcutaneous tissues not bunched. c Preferred site. Adapted from Petousis-Harris H. Vaccine injection technique and reactogenicity–evidence for practice. Vaccine 2008;26:6299–304. b


SECTION 3 Immunization

TABLE 9.3  How to Administer Vaccines

TABLE 9.4  Recommended Temporal


Needle Size

Injection Site

Infants (≤12 months)

0.875–1 in, 23–25 gauge

Toddlers (1–3 years)

0.63–0.75 in, 23–25 gauge

Children, adolescents, and adults

0.63–0.75 in, 23–25 gauge

Vastus lateralis muscle in anterolateral thigh Fatty area of the thigh or outer aspect of upper arm Outer aspect of upper arm

Combination of Different Vaccine Antigens

via the Subcutaneous Route

Spacing of Different Vaccines

Inactivated – inactivated Live attenuated – inactivated Inactivated – live attenuated Live attenuated – live attenuated Inactivated – immunoglobulin Immunoglobulin – inactivated Live attenuated – immunoglobulin Immunoglobulin – live

Adapted from American Academy of Pediatrics, Red Book, 2006.

correctly as recommended, there is no risk of encountering large blood vessels at the injection site. In patients with bleeding disorders, the risk of bleeding after IM injection can be reduced by the application of firm and steady pressure to the site of inoculation for at least 2 minutes, vaccinating shortly after application of clotting factor replacement, limiting the movement of the extremity for some time, or using smaller needles (≤23 gauge). Moreover, some vaccines recommended for IM application may exceptionally be given SC to persons at risk for bleeding. It is advisable to observe the injection site 30 or 60 minutes later and to ask the vaccinee to continue doing so for the next few hours. In some cases, IM may be contraindicated. Subcutaneous route.  Subcutaneous injections (Table 9.3) can be administered in the anterolateral aspect of the thigh or the upper arm by inserting the needle at about 45 degrees in a pinched-up skinfold. A 0.63-in, 23–25-gauge needle is recommended. Intradermal route.  Intradermal injections are usually administered on the volar surface of the forearm or the deltoid region by inserting the needle parallel to the long axis of the arm and raising a small bleb with the injection material. A 0.38–0.75-in, 25-gauge or 27-gauge needle is optimal. Oral application.  Vaccines given orally, such as oral typhoid (Ty21a), cholera, or rotavirus vaccines, should be swallowed and retained. The dose should be repeated if the person fails to retain the vaccine longer than 10 minutes after the first application.

Simultaneous Administration/Interchangeability of Vaccines.  Often travelers need a series of travel-specific or general booster vaccinations prior to departure in addition to primary immunizations requiring more than a single dose. A higher number of doses and, in turn, clinic visits will increase time and cost and hence decrease acceptance of and/or adherence to immunizations schedules. Timeefficient administration of different vaccines is of particular importance when preparing for international travel with often limited time left until departure. Inactivated vaccines can be administered simultaneously or at any time before or after other vaccines. A few exceptions apply: for example, pneumococcal conjugate vaccine (PCV13) should not be given simultaneously with pneumococcal polysaccharide vaccine.7 Generally most live attenuated and inactivated vaccines can also be safely and effectively (in terms of immunogenicity) administered simultaneously, that is, administered on the same day but at separate anatomic sites (Table 9.4). Because of the potential immunologic interference, live attenuated vaccines for parenteral application, if not given simultaneously, should be separated by at least 4 weeks. Otherwise this may result in both inefficiency (e.g., increased interferon levels from the previous live attenuated vaccine may inactivate vaccine virus of the subsequent vaccine when given too early) and safety (e.g.,

Minimum Interval None None None ~4 weeks, if not given simultaneously (oral typhoid vaccine: no interval required) None; if simultaneously: at different sites (special indications apply) None; if simultaneously: at different sites (special indications apply) ~2–3 weeks (oral typhoid vaccine: no interval required) ~3–11a months (oral typhoid vaccine: no interval required)


Dependent on dose and type of Ig preparation. Source: Centers for Disease Control and Prevention. General Recommendations for Vaccination & Immunoprophylaxis. 2017. Available at: -immunoprophylaxis.

thrombocytopenia). There is, however, no evidence indicating that live attenuated oral vaccines (OPV and Ty21a) interfere with other parenterally administered live vaccines when administered concurrently or within 4 weeks. The administration of immunoglobulin-containing preparations shortly before or simultaneously with injectable live attenuated vaccines against yellow fever, influenza, or zoster as well as live attenuated oral vaccines like typhoid (Ty21a), OPV, and rotavirus does not seem to adversely affect the immune response of these active immunizations. Depending on the dose of the Ig product, immune response to live attenuated vaccines against measles, mumps, and rubella (MMR) can be impaired for some time. It is recommended to apply MMR vaccines at least 2 weeks prior and 3–11 months after administering Ig preparations, depending on dose and type of the Ig product.8 Coadministration of Ig preparations with inactivated vaccines is generally uncomplicated. For example, concurrent administration of HBIg, tetanus Ig, or rabies Ig and the corresponding vaccine in the course of PEP has not been demonstrated to inhibit the immune response. Vaccines against the same diseases with comparable antigens from different manufacturers are usually considered interchangeable when used according to their licensed indication—in particular when different products are used for booster vaccinations. However, comprehensive data concerning safety, immunogenicity, and efficacy related to interchangeability of vaccines will never become available given the large number of products and potential permutations. Available data indicate that all brands of diphtheria, tetanus toxoids, live and inactivated polio, hepatitis A, hepatitis B, tickborne encephalitis, conjugate meningitis, and rabies vaccines can be used interchangeably within a vaccination series. With respect to combination vaccines (in particular those containing acellular pertussis components), primary immunization series should be completed with the same product when possible. Yet vaccination series should never be interrupted if the same brand is not available.

Serologic Testing Before and After Immunizations.  Serologic testing of the individual immune status will rarely be performed before

CHAPTER 9  Principles of Immunization providing individual vaccine recommendations. Apart from BCG, vaccination may be undertaken regardless of prior knowledge of the immune status of the vaccinee. Individuals born in areas highly endemic for hepatitis A have most likely undergone infection during infancy or childhood rendering it unnecessary to test and vaccinate. It is generally not necessary to test postvaccination antibody titers in healthy vaccinees. Antibody levels may be assessed in some special cases (e.g., titer against hepatitis B in persons with occupational risk). Seroconversion rates and antibody levels may also be reduced in immunocompromised subjects, who should be considered for postvaccination serologic testing. However, when interpreting serologic results by employing specific antibody titers as surrogate markers of protection, it must be borne in mind that serum antibodies are not reliably neutralizing and therefore may not necessarily be predictive of protection (e.g., pertussis). On the other hand, low or undetectable antibody titers may not necessarily indicate lack of protection: immune memory may be sufficient to remount antibody titers in particular when incubation periods are relatively long (e.g., hepatitis A and B) and testing of antibody levels alone may be incomplete (see Table 9.1). Although specific methods to measure cellular immunity exist, they are unsuitable for routine application.

VACCINE SAFETY AND MANAGEMENT OF ADVERSE REACTIONS Local pain, swelling, redness, and induration at the injection site are the most common side effects of vaccines given by injection and define the local reactogenicity. Systemic symptoms/conditions (including fever, headache, chills, muscle pain) may also occur in timely relation to vaccination (6–48 hours). The severity of the symptoms and number of patients experiencing them may vary from vaccine to vaccine, depending on the antigen type, antigen concentration, and other components of the vaccine including type and concentration of the adjuvant(s). Vaccine-associated side effects are usually mild and harmless and commonly disappear within 1–2 days postvaccination. It is beyond doubt that currently licensed modern vaccines are generally safe and effective, having undergone extensive and strictly controlled preclinical and clinical safety testing before being licensed for routine use by public health authorities. However, sporadic cases of undesirable vaccine-associated adverse reactions cannot absolutely be excluded. Therefore, vaccine recommendations should always be made on the basis of careful evaluation of their benefits and safety weighed against the risk of vaccine-preventable disease. Vaccine-associated anaphylactic reaction resulting in cutaneous, respiratory, cardiovascular, and/or gastrointestinal signs and symptoms is an extremely rare event. Vaccine components that may cause allergic reactions include the vaccine antigen itself (e.g., tetanus toxoid), other vaccine excipients, or traces of substances used during manufacturing. In the manufacturing process of some live attenuated and inactivated vaccines, eggs or egg-derived fibroblast cells are used for virus amplification (e.g., vaccines against yellow fever, MMR, some influenza vaccines). Some vaccines containing cell culture–amplified viruses may contain traces of neomycin (e.g., live attenuated vaccines against MMR). A history of anaphylaxis to a vaccine component is a contraindication and allergies should be explored prior to vaccine administration. Latex used in vial stoppers and syringe plungers may also be a cause of vaccine-associated anaphylaxis. All in all, the frequency of anaphylaxis after vaccination is very low, with an estimated risk of less than one case per million doses.11 Nonetheless, infrastructure (emergency equipment and drugs such as epinephrine) and regularly trained personnel should always be available for management of potential emergencies.


If there is strong suspicion of a serious adverse reaction in relation to vaccination, official reporting to the national health authority as well as the manufacturer is important.

SPECIAL CONDITIONS/CONTRAINDICATIONS Special precautions apply when vaccinating pregnant women and a thoroughly risk-benefit assessment must be performed if travel cannot be postponed until after delivery.12–14 Some live attenuated vaccines (measles, rubella, and varicella vaccines) are contraindicated before (e.g., 3 months) and during pregnancy, although there is no consistent evidence for increased risks for the pregnant women or the unborn. Nonimmune pregnant or breastfeeding women traveling at high risk for yellow fever transmission should be vaccinated. Travelers with immunodeficiency (including congenital immunodeficiency, human immunodeficiency virus [HIV]–related immunodeficiency, malignant neoplasm, or recipients of immunosuppressive therapy) have an increased risk of infection and/or severe disease and will benefit from vaccinations. On the other hand, impaired immunity may limit immune response to vaccines. Therefore travelers with immunodeficiencies should receive vaccinations (even if antibody levels and/or duration of protection is anticipated to be lower/shorter) unless there is a risk of harm: in general, patients with uncertain or severely impaired immune status should not receive live attenuated vaccines. A level of 200 T cells per microliter has generally been described as threshold below which live attenuated vaccines should not be administered. Due to increasing numbers of immunosuppressive medications paralleled by an increase in indications where these medications are being used, expert advice should be obtained in individual cases.9,10 Minor illness with symptoms suggestive of a common cold including mildly elevated body temperature (≤38°C [100°F]) will not interfere with vaccine safety and efficacy. However, in case of fever (≥38°C [100°F]) or serious illness, immunizations should be delayed until after recovery. Clinical conditions and symptoms that are sometimes falsely considered as contraindications are summarized in Table 9.5. Absolute contraindications to the administration of vaccines are most uncommon. Except for severe hypersensitivity to vaccine components (see previous discussion) no further absolute contraindication exists against inactivated vaccines. Administration of live attenuated vaccines may be contraindicated in specific situations such as pregnancy and impaired immunity. Exemption certificates may be issued for those travelers with contraindications against yellow fever vaccination.

TABLE 9.5  Summary of Factors Not

Contraindicating Vaccination(s)

• Mild illness (e.g., low-grade fever 15 years >15 years + 2 months 19–12 years (+6 months) >15 + 6 months 2 months

9 years >15 – 9 years + 6 months 6 weeks

6 months 2 months 4 months –

4 weeks

2 months

4 weeks

4 months 6 months

10 weeks 14 weeks

2 months 6 months

4 weeks 8 weeks

12–15 months 10–15 months (and at any age in seronegative/ unvaccinated persons) 4–6 years (in certain European countries: year 2 of life); minimum interval to MMRI: 4 weeks 12–15 months

12 months 10 months

– 3–5 years (most European countries: minimum 4 weeks)

– 4 weeks

13 months

12 months

3–5 years

4–6 years (in certain European countries: year 2 of life); minimum interval from Var1 6 weeks 11–12 years >11 years

15 months

12 weeks (in Europe, 6 weeks) –

7 years 10 years

10 years –

5 years –

2 years

5 years

5 years

– >50 years in Europe and United States

7 years 50 years

– –

– –

>50 years (>60 years in United States) IIV: ≥6 months LAIV: 2–49 years (United States); 2–18 years (Europe) RIV: >18 years

>50 years >2 years >18 years

– Annually (except for first influenza season; between 6 months and 8 years); two doses with ≥4 weeks interval

– Annually

HPV2 HPV3 Pneumococcal conjugate vaccine (PCV)1 PCV2 PCV3 (some European countries recommend only a 2+1 schedule) PCV4 (3) Measles, mumps, and rubella (MMR)1 MMR2

Varicella1 (Var1) Var2

Tetanus-diphtheria (Td) Tetanus-diphtheria-acellular pertussis (Tdap) Pneumococcal polysaccharide vaccine (PPV)1 PPV2 PCV conjugated 13-valent for adults Zoster Influenza

– –

HPV, Human papillomavirus; IIV, inactivated influenza vaccine; LAIV, live attenuated influenza vaccine; RIV, recombinant influenza vaccine.

TABLE 10.2  Trade Names of Important Adult Travel-Related Vaccines Worldwide Diphtheria-tetanus Diphtheria-tetanus-pertussis (Tdap) Diphtheria-tetanus-pertussis-polio Human papillomavirus Influenza

Measles-mumps-rubella Pneumococcal (polysaccharide, unconjugated) Pneumococcal conjugated Varicella Zoster

Diphtheria and tetanus toxoids adsorbed, Td-pur; Td-Rix; diTeBooster, Ditanrix; Anatoxal, dt-reduct Merieux Adacel, Boostrix, Revaxis Boostrix-Polio; Repevax Gardasil (quadrivalent), Cervarix (bivalent), Gardasil9 IIV quadrivalent: Afluria Quadrivalent, Fluarix Quadrivalent/tetra, Fluval, Fluzone Quadrivalent, Vaxigrip tetra, Fluzone intradermal quadrivalent; IIV trivalent: Aflurian, Fluvarin, Fluarix, Vaxigrip, Fluad (adjuvanted) LAIV: Flumist, Fluenz tetra MMR-II, Priorix, Vaccine-Priorix, MMR-vaxPro Pneumovax, Pneumo23 Prevenar 13, Prevnar 13 Varivax III, Varilrix, Varicela Biken, Okavax Zostervax, Shingrix

Most widely distributed trade names listed first. Vaccines are parenteral unless specified. IIV, Inactivated influenza vaccine; LAIV, live attenuated influenza vaccine; MMR, measles, mumps, and rubella.

Live attenuated viral vaccine; Varivax III (Merck); Varilrix (GlaxoSmithKline)

Live attenuated viral vaccine; Zostervax (Merck, Sanofi)



51%–63% reduction of herpes zoster; 66% reduction of postherpectic neuralgia; 61%–65% reduced burden of disease

Pneumovax: 50%–70% Efficacy studies in adults with Prevenar 13: 46% VT-CAP

95% response rate per dose

Studies ongoing

Diphtheria: 87%–98%; Tetanus: 94%; Pertussis: 92%


Adults >50 years with previous episode of chickenpox infection In the United States, FDA approved for >50 years but ACIP recommended >60 years of age

1x PCV13 intramuscularly, PPV23 after 1 year in immunocompetent persons; 1x PCV13, 1x PPV23 after ≥8 weeks in immunocompromised adults For nonimmune adults: 0.5 mL at 0 and 4–8 weeks

Adults >18 years: 0.5 mL subcutaneously one or two doses at least 1 month apart to complete a documented two-dose series with attenuated live virus vaccine

Three doses in unvaccinated Booster every 10 years (at least once with pertussis component—ACIP) Females: 9–45 years Males: 9–26 years: three doses: 0, 1(2), 6 months intramuscularly >6 months for IIV; >2 years for LAIV

Primary Course— Adult

Not known

Unknown. May be as little as 10 years

Not in immunocompetent persons Booster after 5 years


Annual application

Not known yet

Every 10 years (>60 years every 5 years in some countries)








Accelerated Schedule

Category C. Not recommended during pregnancy and for 1 month prior to onset of pregnancy because of theoretical risk to the fetus. Inadvertent vaccination not an indication for pregnancy termination. Some risk of transmission via breast milk. Patient should be advised not to breastfeed for 1 month after vaccination Not applicable

Category C. Not recommended during pregnancy and for 1 month prior to onset of pregnancy because of theoretical risk to the fetus. Inadvertent vaccination not an indication for pregnancy termination. Some risk of transmission via breast milk. Patient should be advised not to breastfeed for 1 month after vaccination Pneumovax may be used in pregnancy if indicated. PCV13: no data available


Not recommended

Recommended by ACIP and other European countries

Pregnancy or Lactation

Regardless of travel plan advisable (upon vaccine availability)

Regardless of travel plans: people >60/65 years (Pneumovax); >50 years. Particularly in travelers with comorbidities and hajj pilgrims>50 years Prevenar 13 + PPV 23 Breakthrough disease increases dramatically at 6–8 years postvaccination in those receiving only a single dose

Give on same day as PPD skin test or separate by 28 days

Vaccination of both females and males to reduce virus transmission Recommended for all travelers

Irrespective of travel immunizations should be up to date for age


ACIP, Advisory Committee on Immunization Practices; IIV, inactivated influenza vaccine; LAIV, live attenuated influenza vaccine; PPD, purified protein derivative; PPV23, 23-valent pneumococcal polysaccharide vaccine.

Pneumovax (unconjugated, 23-valent); Prevnar/Prevenar 13 (conjugated)

Inactivated trivalent or quadrivalent; live attenuated MMR, live attenuated virus vaccine (many brands)

Diphtheria and tetanus toxoid adsorbed, Adacel, Boostrix, Revaxis Gardasil (quadrivalent), Cervarix (bivalent)

Pneumococcal disease

Measles, mumps, rubella


Human papillomavirus

Diphtheria, tetanus, pertussis


Vaccine Type; Commercial Name (Manufacturer)

TABLE 10.3  Summary of Routine Adult Vaccines

CHAPTER 10  Routine Adult Vaccines



SECTION 3 Immunization

TABLE 10.4  Estimated Risk From Disease and Sequelae Versus Risk From Vaccines Disease

Risk of Acquiring Disease or Complications From Disease

Risk From Vaccine

Diphtheria Tetanus

Case fatality rate: 1 in 20 Case fatality rate: 3 in 100


Pneumonia: 1 in 8 Encephalitis: 1 in 20 Case fatality rate: 1 in 200 5%–15% infections every year (i.e., 3–5 million cases of severe illness, 290,000–650,000 deaths/year); 60% of hospitalization and 90% of deaths occur in age groups 65 years

Tetanus/diphtheria/pertussis (Tdap) vaccine Local pain, swelling, and induration at the site of injection are common Local pain, swelling, induration possible



Mumps Rubella Pneumococcal diseases Varicella


Pneumonia: 1 in 20 Encephalitis: 1 in 2000 Thrombocytopenia 1/30,000–100,000 Death: 1 in 3000 Encephalitis: 1 in 300 Congenital rubella syndrome (in newborn to a woman with infection in early pregnancy): 1 in 4 Invasive disease in adults: 80% bacteremic pneumonia, meningitis, sepsis Encephalitis: 1.8 in 10,000 Death: 1 in 60,000 cases Age-related case fatality rate:   1–14 years: 1 in 100,000   15–19 years: 2.7 in 100,000   30–49 years: 25.2 in 100,000 10%–20% of persons with previous chickenpox infection develop herpes zoster (HZ): HZ in 45%–50% of >65 years; postherpetic syndrome in 25% of >50 year olds

IIV: Local side effects, mild symptoms of fever, malaise, myalgia, headache possible; LAIV mild upper respiratory symptoms; wheezing, asthma, immunosuppression (= contraindication for LAIV) MMR vaccine: Encephalitis or severe allergic reaction: 1 in 1 million In 2%–6% rash, fever, flulike symptoms possible Same as for measles vaccine Very rare risk for rubella-vaccine-associated arthritis in adult women Pain, redness, swelling at injection site, rarely fever or severe systemic effects Generalized varicella-like rash: 4%–6% of vaccine recipients

Local reactions (pain, swelling, redness), fever, very rare varicella-like rash

IIV, Inactivated influenza vaccine; LAIV, live attenuated influenza vaccine; MMR, measles, mumps, and rubella.

• Encephalopathy not attributable to another cause within 7 days of administration of a previous dose of DTP, DTaP, or Tdap (Table 10.4).

Precautions • Moderate or severe acute illness with or without fever. • Guillain-Barré syndrome (GBS) within 6 weeks after a previous dose of a tetanus toxoid-containing vaccine. • History of Arthus-type reaction following a previous dose of a tetanus toxoid-containing vaccine.

Dosing Schedules Regardless of travel plans, adults who have completed an adequate primary series of DTP as children and who have not received a previous dose of an acellular pertussis-containing vaccine at some point during their life (either as Tdap or the pediatric DTaP) should receive a dose of Tdap vaccine, in place of the next scheduled 10-year Td booster. This should be given as soon as it is feasible, regardless of interval from the last Td dose. Some countries recommend that subsequent 10-year boosters should be with Td. The Advisory Committee on Immunization Practices (ACIP) recommends immunization schedules for adults aged ≥19 years,13 but recommendations differ as to whether routine booster vaccination every 10 years is performed with Td or Tdap. After age 60 years, due to immunosenescence14 and waning pertussis immunity, booster vaccinations with a pertussis-containing vaccine are recommended every 5 years.15 Health care workers, pregnant women,

and others expected to have very close contact with local populations in developing countries are high priority and a dose of Tdap should be given regardless of the interval since the last Td booster, to afford better protection against pertussis in a high-risk situation. ACIP and the Centers for Disease Control and Prevention (CDC) recommends that pregnant women should receive one dose of Tdap during each pregnancy regardless of prior history of Tdap vaccination, preferably administered during the early gestational period (weeks 27–36). In Europe there is no consensus regarding this strategy but several countries, such as the United Kingdom, Austria, Switzerland, and The Netherlands, have implemented recommendations for maternal pertussis vaccination in their guidelines. Some clinicians offer Td or Tdap if 5 years have elapsed since the last booster to eliminate the need for a tetanus toxoid or Td booster in a developing country should the traveler sustain a dirt-contaminated wound during the trip, a situation that normally mandates a booster if >5 years have elapsed since the previous tetanus-containing vaccine. Adults without a history of an adequate primary series should begin (or complete) a three-dose primary series. The preferred schedule is a single dose of Tdap followed by a dose of Td at least 4 weeks after the Tdap dose, and a second dose of Td 6–12 months after the previous Td dose. However, Tdap may be substituted for any one of the three doses of the series. As many doses as possible should be completed prior to travel (Table 10.5; see also Table 10.1). A recent publication shows there might be immunologic interactions between tetanus/diphtheria-containing vaccines and carrier protein cross-reacting material (CRM) presented in the conjugate vaccines,

CHAPTER 10  Routine Adult Vaccines


TABLE 10.5  Routine Adult Vaccines: Sample Immunization Schedule for Adults According to

CDC Recommendations and Recommendations of National Boards of Immunization in Europe (e.g., Austria) 2011/2012 Vaccines

19–26 years

Tetanus/diphtheria (Td) Pertussis (Tdap)a Polio MMR

Substitute one-time dose of Tdap for Td booster; Td (United States)/Tdap (A) every 10 years

Pneumococcal vaccineb Zosterc HPVd Influenza

Hepatitis A (particular for travelersa) Hepatitis B Meningococcal (quadrivalent)

27–49 years

50–59 years

60–64 years

>65 years Td/Tdap booster every 5–10 years

No routine vaccination; only when traveling in endemic countries Two doses, if seronegative, one catch-up dose if only one previous dose One dose PCV13 followed by one dose of PPV23 (ACIP, some European countries) One dose United States: one dose >60 years Three doses female and male Three doses females (>15 years) One dose annually (first influenza season two doses ≥4 weeks apart) Two doses, if not previously vaccinated Three doses, if not previously vaccinated One or two doses (in adolescence; for travelers in endemic areas for A, C, Y, W135)

Pneumococcal polysaccharide vaccine (some European countries, Australia): >65 years one vaccination in immunocompetent persons; in adults with comorbidities, immunocompromised patients a single revaccination dose in a minimum interval of 5 years. The FDA now approves the quadrivalent HPV vaccine also as an anal cancer vaccine (additional to cervical cancer and condyloma). The licensure also includes vaccination of boys and young men between ages 9 and 26 years. Meanwhile Gardasil9 has been licensed with the same inductions as for the quadrivalent HPV vaccine. a Td, TdaP: A dose of Tdap should be given at least once in place of the regular 10-year Td vaccination. In some countries in Europe Tdap every 10 years until 60 years, thereafter booster every 5 years. b Pneumococcal conjugate vaccine: >50 years one vaccination according to licensure in immunocompetent persons followed after 1 year by one dose unconjugated 23-valent pneumococcal polysaccharide (United States, some European countries); previously unimmunized asplenic, HIV-infected, and immunocompromised adults aged ≥19 years should receive one dose of 13-valent pneumococcal conjugate vaccine (PCV13) followed by one dose of pneumococcal polysaccharide vaccine (PPSV23) ≥8 weeks later. People with these conditions previously immunized with PPSV23 should follow catch-up guidelines per ACIP. c Zoster: One dose with Zoster vaccine in adults >50 (according to licensure, upon availability); one dose >60 according to ACIP (United States). d HPV: Licensure for HPV vaccine now includes vaccination of females aged 9–45 years. ACIP, Advisory Committee on Immunization Practices; HPV, human papillomavirus; MMR, measles, mumps, and rubella.

such as the pneumococcal or meningococcal vaccines (PCV13, MCV4) leading to significantly reduced geometric mean titers (GMTs) to pneumococcal serotypes in adults when such vaccines are concomitantly administered 4 weeks earlier. Administering Td/Tdap 4 weeks after the conjugate vaccine should therefore be considered if time to departure allows repeated vaccination appointments.16

Measures of Immune Response and Duration of Immunity/Protection Tests to measure serum antibody levels against tetanus and diphtheria are available, but not routinely for pertussis. Data on correlates of protection and duration of protection of the pertussis component of Tdap are not available.

Adverse Effects Local adverse effects, including injection site redness, swelling, tenderness, and/or induration, are common. Painful swelling from elbow to shoulder 2–8 hours after injection has been reported with Td but not Tdap. Rarely, anaphylaxis, generalized rash/itching, fever, systemic symptoms, occurrences of brachial neuritis, and GBS have been reported with Td. Experience with Tdap is limited, but in the principal initial safety study significant adverse events occurred in 0.9% of recipients (see Table 10.4).

MEASLES, MUMPS, AND RUBELLA VACCINE Measles remains common in most developing countries in Africa, Asia, and the Pacific; and outbreaks continue to occur in some industrialized countries, particularly in Europe, with falling measles, mumps, and rubella (MMR) vaccination coverage (particularly of the second MMR dose 200/mL.

Dosing Schedules The varicella vaccine schedule for adults consists of two doses of 0.5 mL administered by subcutaneous injection in the deltoid area, given 4–8 weeks apart (if >8 weeks elapse after the first dose, the second dose can be administered without restarting the schedule) (see Tables 10.1 and 10.5).

Measures of Immune Response and Duration of Immunity/Protection A single dose of varicella vaccine has an efficacy of 80%–85% against any presentation of disease, and about 15% of children given a single dose of vaccine do not develop antibody titers consistent with protection against disease. In addition, protection after a single dose appears to wane after about 5 years, as manifest by a dramatic increase in breakthrough disease >5 years after vaccination. The duration of protection after a two-dose series is at least 10 years.25 Varicella vaccination is effective in preventing or modifying disease severity if given to a nonimmune individual within 72 hours (or even within 5 days) of exposure to someone with varicella. The vaccine should be administered on the standard schedule presented earlier in the chapter.

Drug and Vaccine Interactions Varicella vaccine should be delayed by 3 months after having received immunoglobulin for hepatitis A (both 0.02-mL/kg and 0.06-mL/kg doses) (hepatitis A hyperimmunoglobulin is currently not available in Europe or is rarely in use). Use of salicylates (such as aspirin) should be avoided for 6 weeks after varicella vaccination because of association between aspirin use and Reye syndrome after varicella (however, no adverse reactions have been reported so far after varicella vaccination and aspirin use). Intervals for live attenuated vaccines and PPD testing should be followed.

Herpes Zoster Vaccination Herpes zoster represents a reactivation of varicella virus after years of dormancy in nerve roots in those with a previous episode of chickenpox.26 Zostavax (Merck, Sanofi), a live zoster vaccine, has been available since 2006. Live zoster vaccine is a varicella virus–containing vaccine that reduces the risk of herpes zoster (“shingles”) and leads particularly to reduction of postherpetic neuralgia.27 The vaccine is licensed to be given to persons >50 years of age. It is administered as a single 0.7-mL dose subcutaneously. Protection wanes within the first 5 years after vaccination. It is not a travel vaccine and is not particularly recommended for persons with travel plans but might be considered (upon availability) in those >50 years with a history of previous chickenpox or zoster infection28 (see Tables 10.2 and 10.3). Zostavax contains 14 times more Oka strain varicella virus than Varivax III or Varilrix and should therefore not be used to prevent varicella infection in seronegative individuals. On the other hand, Varivax III and Varilrix are ineffective for shingles and not licensed for its prevention; they should only be used for prevention of a primary varicella infection. A new two-dose herpes zoster subunit (HZ/su) vaccine, Shingrix, which consists of recombinant VZV glycoprotein E and AS01B adjuvant, has recently been licensed in North America for use in healthy adults ≥50 years of age. The two doses should be separated by 2–6 months. Even in adults ≥70 years of age, vaccine efficacy against zoster was 91.3% during a mean follow-up period of 3.7 years.29,30 Herpes zoster vaccines are contraindicated in all patients with primary or secondary immunodeficiencies.

Pneumococcal Vaccine Streptococcus pneumoniae, of which more than 91 serotypes exist, is a major cause of mortality and morbidity worldwide, affecting both children (particularly those 50 years are bacteremic pneumonia (80%) and meningitis. The estimated incidence of pneumococcal infections in travelers is not clearly defined. However, after diarrheal disease, respiratory illnesses are one of the most common afflictions related to travel; pneumococcal infections are probably included in such estimates although it is probable that most are viral in nature. Particularly during mass gathering, including the hajj, disease outbreaks due to respiratory infections are of major concern and about 33% of hajj pilgrims are estimated to be at risk of pneumococcal disease due to age or comorbidities.31,32 While data on the actual acquisition of S. pneumoniae during the hajj or other mass gathering events are sparse, a recent prospective cohort study with 1175 pilgrims evaluated an increase of carriage rates of S. pneumoniae from 1.8% before to 7.1% after the hajj.33 Furthermore, the global emergence of penicillin or multidrug-resistant S. pneumoniae, coupled with potentially limited availability of antimicrobials in numerous countries, but also the general trend of international travel by elderly persons or persons with medical comorbidities,34 need to be considered when reviewing the use of pneumococcal vaccination for the traveler.

Indications Due to an increased risk for pneumococcal diseases with age, routine pneumococcal vaccination is generally recommended in elderly persons >65 years. Some countries (e.g., United States, Austria) recommend that immunocompetent individuals (United States: >65 years; Austria: ≥51 years) should be vaccinated once with the conjugated 13-valent vaccine (PCV13) followed by the 23-valent unconjugated vaccine (PPS23) at least 1 year after 13-valent pneumococcal polysaccharide vaccine (PCV13).35 Other countries (e.g., Germany, United Kingdom, Australia) recommend routine vaccination once with PPS23 only in immunocompetent persons >65 years of age.36 In immunocompromised adults ≥19 years of age with underlying diseases such severe chronic heart or lung disease and particularly patients with immunocompromising conditions including HIV, immunization with the 7-valent pneumococcal vaccine has been shown to protect against recurrent invasive pneumococcal disease.37–39 A recent study in HIV-infected adults showed that the sequential immunization with PCV13 followed by PPV23 was highly immunogenic in these patients and adds to evidence supporting the current pneumococcal vaccination recommendation in the United States and Europe for HIV-infected individuals.37 Several countries recommend administration of PPS23 alone for adults aged 19–64 years with chronic diseases such as obstructive lung diseases, asthma, or cigarette smoking followed by sequential vaccination from ≥65 years of age. Vaccination before travel or one-time revaccination 5 years after primary vaccination is recommended for persons with chronic renal failure or nephrotic syndrome, functional or anatomic asplenia (e.g., sickle cell disease or splenectomy), chronic liver disease, diabetes mellitus, and for patients with immunocompromising conditions.38,39 People with these conditions previously immunized with PPSV23 should follow the respective catch-up guidelines, whereupon at least 1 year should elapse from the last PPSV23 before PCV13 is administered (see Tables 10.2 and 10.3). Multiple revaccinations are not recommended because of uncertainty about clinical benefit and safety. The vaccine may be considered for healthy persons 2–64 years of age if they are planning to expatriate for a prolonged duration to a country with high rates of drug-resistant pneumococci.

Contraindications • Severe allergic reaction (e.g., anaphylaxis) after a previous vaccine dose or to a vaccine component.

• Pneumococcal vaccine may be used in pregnancy if clearly indicated. For PCV13 no data on use during pregnancy exist. Nevertheless, no indications for teratogenic effects have been derived from preclinical (animal) studies. No data are available on vaccination during breastfeeding or whether the pneumococcal conjugates might be delivered via breast milk (see Table 10.4).

Precautions Precautions include moderate or severe acute illness with or without fever.

Dosing Schedule PPV23: Immunization with PPV23 consists of a single dose of 0.5 mL given by either intramuscular or subcutaneous injection. Revaccination is not routinely recommended for adults, except in the following circumstances: • For persons ≥65 years, a revaccination dose of PPV23 if the patient received vaccine ≥5 years previously and was 10 years of age, give a revaccination dose ≥5 years after the previous dose. • For immunocompromised persons (e.g., HIV, chronic renal failure and nephrotic syndrome, malignancies, solid organ transplants) give a single revaccination dose if ≥5 years have elapsed since the first dose. PCV13: According to the licensure of PCV13 a single-dose administration is recommended for adults ≥50 years13,38 (SmPC Prevenar/ Prevnar). Previously unimmunized asplenic, HIV-infected, and immunocompromised adults aged ≥19 years should receive one dose of 13-valent pneumococcal conjugate vaccine (PCV13) followed by one dose of pneumococcal polysaccharide vaccine (PPSV23) ≥8 weeks later. The need for further booster vaccinations, as well as vaccination schedules in risk populations, is currently under investigation. The vaccine should be administered intramuscularly. In patients with thrombocytopenia or other blood coagulation disorders the vaccine can be given subcutaneously.

Measures of Immune Response and Duration of Immunity/Protection The 23-valent pneumococcal polysaccharide vaccine induces type-specific antibody responses to the capsular polysaccharide antigens of 23 serotypes of S. pneumoniae. The vaccine’s efficacy is estimated to be 50%–70% in case-control studies. Vaccination is associated with a decrease in hospitalization and mortality.36 A head-to-head study with PCV13 and PPV23 in adults >70 years who had received a single dose of PPV23 5 years ago revealed that the immune responses to 10 of 12 common serotypes were significantly higher in PCV13-immunized subjects13 (SmPC Prevenar 13). Studies on clinical efficacy and duration of protection are ongoing (see Tables 10.1 and 10.5).

Adverse Events Adverse events include injection site pain, redness, swelling; rarely fever, myalgias, or severe systemic effects after application of each of the vaccines PPV23 or PCV13.

HUMAN PAPILLOMAVIRUS VACCINE Human papillomaviruses (HPVs) have worldwide distribution and about 70% of the population will contract the virus at least once in life. Over 200 different HPV types are known, of which 40 preferably affect the mucosae of the genital tract and the oropharynx. Most infections, transmitted mainly by sexual contact including oral sex, resolve spontaneously but do not induce a long-lasting immunity. Persistence

CHAPTER 10  Routine Adult Vaccines of oncogenic viruses for >1 year leads to a risk of neoplasia and invasive carcinoma, mainly of the genital tract. The most common oncogenic HPVs are 16 and 18, which are responsible for the development of cervical cancer in 75% of people, but also for other carcinomas such as cancer of the vulva, vagina, anus, larynx, and tonsils. HPVs 6 and 11 are mainly (90%) responsible for the development of genital warts.40 A bivalent HPV type 16 and 18 vaccine (HPV2, Cervarix [GSK]), a quadrivalent HPV (types 6, 11, 16, and 18) vaccine (HPV4, Gardasil [Merck, Sanofi]), and a nonvalent (HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine (HPV9, Gardasil 9) have been licensed. All three vaccines contain recombinant L1 structural protein of HPV of the various types that self-assemble to viruslike particles. To be effective, vaccination should be initiated prior to natural infection with a given HPV type. Many countries have included HPV vaccination of adolescents in their national vaccination programs. Several studies showed a decrease in high-grade cervical abnormalities within 3 years after implementation of a population-wide vaccination program.41 Nevertheless, vaccination is not a substitute for routine cervical cancer screening, and vaccinated women should continue to have cervical cancer screening as recommended.


HPV is administered intramuscularly as two separate 0.5-mL doses up to the age of 13 years (HPV4) or 14 years (HPV2, HPV9). The interval between the first and second dose should be at least 4 months to allow for effective memory B-cell maturation. For individuals ≥14 years (HPV4) or ≥15 years (HPV2, HPV9) of age a three-dose schedule is required. The second dose should be administered 2 months (1 month in case of HPV2) after the first dose and the third dose 6 months after the first. Ongoing efficacy studies indicate protection to last at least 9.5 years. Booster doses are not recommended so far (see Tables 10.1 and 10.5).

which only A and B cause predominately respiratory diseases in humans. Influenza A is further classified into two subtypes according to the surface proteins hemagglutinin (HA) and neuraminidase (NA) and cocirculate in humans worldwide as H1N1 or H3N2 subtypes. Additional influenza B viruses cocirculate, which can be divided into two lineages, either B/ Yamagata or B/Victoria lineage. The distribution of these viruses varies from year to year and between geographic areas and time of the year. In temperate regions, influenza circulates at higher levels in the colder winter months, which are October–May in the northern hemisphere and April–September in the southern hemisphere. In tropical or subtropical areas influenza can occur throughout the year.44,45 Seasonal influenza affects about 5%–15% of the population. It is most common among children, especially schoolchildren who are regarded as main spreaders of the disease. Severe illness and mortality are highest among those at the extremes of age (i.e., children 65 years). More than 60% of hospitalization rates and 90% of mortality rates are within these age groups. People with underlying medical conditions, such as chronic pulmonary disease, diabetes mellitus, obesity, malignancies, immunocompromised patients, and pregnant women, display a high risk of complicated influenza cases and hospitalization.46 Influenza is mainly transmitted via respiratory droplets but can be acquired via contact with contaminated surfaces, too. After an incubation time of 1–4 days influenza infections show a sudden onset with high fever, nonproductive cough, muscle aches, and headache. Less common and more likely in children than adults are rhinitis, diarrhea, nausea, and vomiting. The disease usually resolves within 1 week in immunocompetent children and adults, but cough and malaise can persist for >2 weeks, particularly in the elderly. Infectiousness starts from the day before until 5–7 days after onset of symptoms with a peak within 3 days. There seems to be a considerably high number of subclinical cases in immunocompetent individuals who also transmit disease.47 Seasonal influenza is among the most frequent vaccine preventable diseases in travelers,48 with an increased risk of infection beginning upon start of travel with gathering for transportation (buses, trains) or during air transportation.49,50 Close human contacts may also occur at mass gatherings (e.g., hajj, sport events or contests, and concerts)51,52 or onboard of cruise ships.53 Influenza virus infections are largely acquired from Asia (47%), Africa (28%), and Latin America (25%).54 Even though influenza is regarded as a self-limiting disease it may not only have a dramatic impact on the success of a holiday or business travel, but reports are accumulating that it can develop to severe disease-causing, life-threatening complications even in people without comorbidities or immunocompromising diseases. This highlights that influenza vaccination belongs to an important preventive measure for travelers.

Contraindications and Precautions


• Severe allergic reaction (e.g., anaphylaxis) after a previous vaccine dose or to a vaccine component. • As a precautionary measure HPV vaccine is not recommended for use during pregnancy. The remaining doses should preferably be delayed until pregnancy is completed for women who become pregnant during the vaccine series. There have been no specific safety issues identified for fetal development or pregnancy outcome in a postmarketing pregnancy registry (see Table 10.4).

Influenza vaccination is annually recommended for children ≥6 months according to ACIP and European vaccination advisory boards. Apart from the very young and the elderly, particular recommendations are given to patients with underlying diseases (e.g., chronic pulmonary diseases, cardiovascular disease, kidney disease, and metabolic diseases), pregnant women, immunocompromised patients (e.g., HIV, patients with immunomodulating medications), obese individuals, health care workers, and travelers. Any traveler, including people at high risk for complications of influenza, who did not receive an influenza vaccine during the preceding fall or winter and wants to reduce the risk for infection should consider influenza vaccination at least 2 weeks before departure to the tropics or to the southern hemisphere from April–September.55

Indications ACIP and most countries in Europe recommend vaccinating girls at age 11 or 12 years (or even at 9 years) or as catch-up vaccination for women aged 13–26. In some countries vaccinations of males aged 9–21 years is also recommended to prevent transmission and, in the case of the quadrivalent or nonvalent vaccine, to prevent genital warts. The vaccine only protects against HPV types not yet acquired. Therefore, cost effectiveness of HPV vaccination declines with increasing age and number of sex partners. Vaccination of men who have sex with men (MSM) through the age of 26 years seems to be cost effective.42 HPV vaccination has no effect on persistent HPV infection, precancerous lesions, or anogenital warts already present at the time of vaccination. Travel has not been demonstrated to increase HPV risk, but there is some evidence of increased sexual activity when people travel, so the pretravel consultation is a perfect opportunity to discuss prevention and vaccination43 (see Tables 10.2 and 10.3).

Dosing Schedules

INFLUENZA Influenza is caused by influenza viruses, which belong to the Orthomyxoviridae family. The viruses are classified into three types—A, B, and C, of


SECTION 3 Immunization

Dosing Schedules Several influenza vaccines are available as inactivated (IIV), recombinant (RIV, licensed in the United States but not in Europe), or live attenuated vaccines (LAIV). In addition to the inactivated trivalent vaccine (including two influenza A and one B component), quadrivalent inactivated vaccines including both influenza B linages (Yamagata and Victoria) have more recently been licensed. The quadrivalent vaccine is also available as LAIV, which is licensed in the United States from 2–49 years and in Europe from 2–18 years of age. For the last two influenza seasons, the CDC has recommended LAIV not be used, following analysis that indicated lower effectiveness of the vaccine compared with inactivated vaccine. This recommendation was however not supported by data derived from some European countries.56,57 The respective influenza vaccine should be chosen according to the licensure as well as the individual risk situations, such as age, medical condition, and risk of exposure. During the first influenza season, children aged 6 months through 8 years require two doses of vaccine (given ≥4 weeks apart) to induce sufficient immune responses. In adults one vaccine dose per season is sufficient. In persons >60 years a preferential use of adjuvanted influenza vaccines is recommended.

Contraindications and Precautions Influenza vaccine (IIV, RIV) is contraindicated in people who have previously had severe allergic reactions to any influenza vaccine. Immediate hypersensitivity reactions such as urticaria, angioedema, allergic asthma, or systemic anaphylaxis rarely occur after influenza vaccination. Even though residual egg proteins have been discussed as possible components that may cause allergic reactions, influenza vaccines have been shown to be tolerated in patients with clinically manifest egg allergy.58 Precautions for vaccinations should be taken in case of moderate or severe acute illness with or without fever, or with a history of GBS within 6 weeks of receipt of any influenza vaccine. The estimated risk for vaccine-related GBS is however very low, with one additional case per million people vaccinated.59 LAIV should not be given to children aged 2–4 years who have a history of wheezing in the past 2 years or who have asthma, patients who are under treatment with aspirin or salicylate-containing medications, or patients who have received antiviral medication within the previous 48 hours. Immunocompromised and pregnant women should not receive LAIV, and caretakers of severely immunocompromised people should also not receive LAIV or should avoid contact with such people for 7 days after vaccination to reduce the risk of virus transmission. Precautions for LAIV other than GBS are medical conditions that might predispose for complications of influenza infection (e.g., chronic pulmonary, renal, hepatic neurologic or hematologic disease, or metabolic disorder).

CONCLUSION Prior to travel, advice should be provided on the need for boosters of routine adult vaccines. An overview of the most common vaccines and dosing is provided but country-specific standards for adult vaccination and schedules should be recommended.

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3. ECDC technical report. Communicable disease threats report: gap analysis on securing diphtheria diagnostic capacity and diphtheria antitoxin availability in EU/EEA. 2017 July. Available at: 4. May M, McDougall R, Robson J. Corynebacterium diphtheria and the returned tropical traveler. J Travel Med 2014;21:39–44. 5. Rahim A, Koehler AP, Shaw D, et al. Toxigenic cutaneous diphtheria in a returned traveler. Commun Dis Intell Q Rep 2014;38:e298–300. 6. Gautret P, Wilder-Smith A. Vaccination against tetanus, diphtheria, pertussis and poliomyelitis in adult travellers. Travel Med Infect Dis 2010;8:155–60. 7. Cherry JD. Epidemic pertussis in 2012—the resurgence of a vaccine preventable disease. N Engl J Med 2012;367(9):785–7. 8. Barbosa F, Barnett E, Gautret P, et al. Bordetella pertussis infection in travelers: data from the Geo-Sentinel global network. J Travel Med 2017;24:1–5. 9. Gomez-Junyent J. Bordetella pertussis infection among international travelers: a need for a rigorous implementation of vaccine policies. Travel Med Infect Dis 2015;13:259–60. 10. Wilder-Smith A, Ravindran E, Paton NI. High incidence of pertussis among hajj pilgrims. Clin Infect Dis 2003;37:1270–2. 11. Salmon-Rousseau A, Piednoir E, Cattoir V, et al. Hajj-associated infections. Med Mal Infect 2016;46:346–54. 12. Algathani AS, Rashid H, Heywood AE. Vaccination against respiratory tract infections at Hajj. Clin Microbiol Infect 2015; 21:115–27. 13. Recommended Immunization Schedule for Adults Aged 19 Years or Older, United States 2018. .html. 14. Chen W-H, Kozlovsky B, Effros R, et al. Vaccination in the elderly: an immunological perspective. Trends Immunol 2009;30:351–9. 15. Boraschi D, Italiani P. Immunosenescence and vaccine failure in the elderly: strategies for improving response. Immunol Lett 2014;162: 346–53. 16. Tashani M, Heron L, Wong M, et al. Tetanus-diphtheria-pertussis vaccine may suppress the immune response to subsequent immunization with pneumococcal CRM197-conjugate vaccine: a randomized controlled trial. J Travel Med 2017;24:1–7. 17. Centers for Disease Control and Prevention. Measles (Rubeola). CDC 24/7: Saving Lives, Protecting People. 2017. Available at: measles/cases-outbreaks.html. 18. Hyle E, Sowmya R, Jentes E, et al. Missed opportunities for measles, mumps, rubella vaccination among departing US adult travelers receiving pretravel health consultations. Ann Intern Med 2017;167:77–84. 19. European Centre of Disease Prevention and Control. Rapid Risk Assessment: Ongoing Outbreak of Measles in Romania, Risk of Spread and Epidemiological Situation in EU/EEA Countries. 2017 March 3. Available at: 20. European Centre of Disease Prevention and Control. Vaccine Scheduler. Available at: 21. European Centre of Disease Prevention and Control. Monthly Rubella Monitoring, Epidemiological Update. 2017 October. Available at: 22. Jost M, Luzi D, Metzler S, et al. Measles associated with international travel in the region of the Americas, Australia and Europe, 2001-2013: a systematic review. Travel Med Infect Dis 2015;13:10–18. 23. Greenaway C, Dongier P, Boivin JF, et al. Susceptibility to measles, mumps, and rubella in newly arrived adult immigrants and refugees. Ann Intern Med 2007;146:20–4. 24. Sage Working Group on Varicella and Herpes Zoster Vaccines. Background Paper on Varicella Vaccine. Available at: immunization/sage/meetings/2014/april/1_SAGE_varicella_background _paper_FINAL.pdf. 25. World Health Organization. Systematic Review of Available Evidence on Effectiveness and Duration of Protection of Varicella Vaccines. Available at: presentations_background_docs/en/.

CHAPTER 10  Routine Adult Vaccines 26. Kimberlin DW, Whitley RJ. Varicella-zoster vaccine for the prevention of herpes zoster. N Engl J Med 2007;356(13):1338–43. 27. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271–84. 28. Centers for Disease Control and Prevention. Update on recommendations for use of herpes zoster vaccine. MMWR Morb Mortal Wkly Rep 2014;63(33):729–31. mm6333a3.htm. 29. Cunningham AL, Lal H, Kovac M, et al. Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older. N Engl J Med 2016;375(11):1019–32. 30. Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 2015;372(22):2087–96. 31. Ridda I, King C, Rashid H. Pneumococcal infections at hajj. Current knowledge gaps. Infect Disord Drug Targets 2014;14:177–84. 32. Al-Tawfiq J, Memish Z. Prevention of pneumococcal infections during mass gathering. Hum Vaccin Immunother 2016;12:326–30. 33. Memish Z, Al-Tawfig J, Akkad N, et al. A cohort study on the impact and acquisition of nasalpharyngeal carriage of Streptococcus pneumoniae during the Hajj. Travel Med Infect Dis 2016;14:242–7. 34. Hochberg N, Barnett E, Chen L, et al. International travel by persons with medical comorbidities: understanding risks and providing advice. Mayo Clin Proc 2013;88:1231–40. 35. Austrian Recommendations for Vaccination 2017. Available at: https:// 36. Epidemiologisches Bulletin des Robert Koch Instituts. Pneumococcal Vaccination. 2017:34. 37. Sadlier C, O′Dea S, Bennet K, et al. Immunological efficacy of pneumococcal vaccine strategies in HIV-infected adults: a randomized clinical trial. Sci Rep 2016;32076:1–8. 38. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guidelines for vaccination of the immunocompromised host. Clin Infect Dis 2014;58:309–18. 39. Wiedermann U, Sitte H, Burgmann H, et al. Guidelines for vaccination of immunocompromised individuals. Wien Klin Wochenschr 2016;128: 337–76. 40. Anonymous. Human papillomavirus vaccines: WHO position paper, May 2017. Wkly Epidemiol Rec 2017;92:241–68. 41. Tabrizi SN, Brotherton JM, Kaldor JM, et al. Assessment of herd immunity and cross-protection after a human papillomavirus vaccination programme in Australia: a repeat cross-sectional study. Lancet Infect Dis 2014;14:958–66. 42. Swedish KA, Factor SH, Goldstone SE. Prevention of recurrent high-grade anal neoplasia with quadrivalent human papillomavirus vaccination of men who have sex with men: a nonconcurrent cohort study. Clin Infect Dis 2012;54:891–8.


43. Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015;64(RR–03):1–137. 44. World Health Organization. Influenza Transmission Zones. Available at: EN_GIP_Influenza_transmission_zones.pdf. 45. Centers for Disease Control and Prevention. Infectious Diseases Related to Travelers. 2018. Available at: infectious-diseases-related-to-travel/influenza. 46. Constantino C, et al. Influenza vaccination in high risk groups: a revision of existing guidelines and rationale for an evidence-based prevention strategy. J Prev Med Hyg 2016;57:e13–18. 47. Hayward A, et al. Comparative community burden and severity of seasonal and pandemic influenza: results of the Flu Watch cohort study. Lancet Respir Med 2014;2:445–54. 48. Goeijbier M, van Genderen P, et al. Travellers and influenza: risks and prevention. J Travel Med 2016;24:1–10. 49. Foxwell AR, Roberts L, et al. Transmission of influenza on international flights, May 2009. Emerg Infect Dis 2011;17:1188–94. 50. Leitmeyer K, et al. Influenza transmission on aircraft. A systematic literature review. Epidemiology 2016;27:743–51. 51. Gautret P, Benkoutien S, et al. Hajj-associated viral respiratory infections: a systematic review. Travel Med Infect Dis 2016;14:92–109. 52. Gautret P, Steffen R. Communicable diseases as health risk at mass gathering other than Hajj: what is the evidence? Int J Infect Dis 2016;47:46–52. 53. Millman AJ, et al. Influenza outbreaks among passengers and crew on two cruise ships: a recent account of preparedness and response to an ever-present challenge. J Travel Med 2015;22:306–11. 54. Goeijbier M, van Genderen P, et al. Travellers and influenza: risks and prevention. J Travel Med 2016;24:1–10. 55. Centers for Disease Control and Prevention. Influenza. In: Travelers’ Health. Available at: 56. Chung JR, et al. Seasonal effectiveness of live attenuated and inactivated influenza vaccine. Pediatrics 2016;137(2):e20153279. 57. Pebody R, et al. Effectiveness of seasonal influenza vaccine for adults and children in preventing laboratory confirmed influenza in primary care in the United Kingdom: 2015/16 end of season results. Euro Surveill 2016;21:38. 58. Des Roches A, et al. Egg-allergic patients can be safely vaccination against influenza. J Allergy Clin Immunol 2010;130(5):1213–16. 59. Centers for Disease Control and Prevention. Influenza (Flu). CDC 24/7: Saving Lives, Protecting People. 2017. Available at: flu/protect/vaccine/vaccines.htm.

11  Routine Travel Vaccines: Hepatitis A and B, Typhoid Jiří Beran and Jeff Goad

KEY POINTS • On the basis of a risk assessment of the itinerary, activities, and the traveler’s underlying health, routine travel vaccines (e.g., hepatitis A and B and typhoid) should be considered by health care providers in the first line of travelers’ vaccine recommendations. • Immunization against hepatitis A should be recommended for all travelers to developing countries where the disease is endemic, especially to rural areas or places with inadequate sanitary facilities. For those who complete the full series, booster doses of vaccine are not recommended. • Hepatitis B immunization is recommended for travelers who will be residing or traveling in areas with high levels of endemic

HEPATITIS A VACCINE Hepatitis A (HA) is one of most common vaccine-preventable infections in travelers1–5 and the most common form of viral hepatitis among travelers.1–3 HA virus (HAV) is a picornavirus, an icosahedral, nonenveloped virus containing positive, single-stranded RNA.6 Virus is shed in large quantities in the stool of infected persons.1,2,6 HAV is transmitted by the fecal-oral route owing to ingestion of contaminated food or water or by close contact with infected individuals,6,7 and by occasional transmission through sexual contact and blood transfusions. The incubation period is usually 15–50 days (average 28).7,8 Childhood infection is generally asymptomatic, but 70% of adults develop mostly uncomplicated icteric disease.1,7,8 Rare complications include fulminant hepatitis, which is age dependent.9 Older nonimmune travelers are at greater risk of severe disease.3 The case fatality rate is 27/1000 in those aged 50+ years or with chronic liver disease, but only 0.004/1000 in the 5–14 age group.1 Although no chronic infection occurs, approximately 10% of apparently ill individuals have prolonged or relapsing symptoms over 5–9 months.8 Cases of travel-related HA can occur in travelers to developing countries with “standard” tourist itineraries, accommodations, and eating behaviors. Risk is highest for those who live in or visit rural areas, trek in backcountry areas, or frequently eat or drink in settings of poor sanitation.8 The risk of HAV infection in nonimmune travelers during travel to developing countries has been estimated to be as high as 1–5/1000 per month.10 More recent data suggest that the overall risk for nonimmune travelers has decreased to 6–30/100,000 per month in areas of high or intermediate endemicity.11 This still represents a significant risk of illness. Children of immigrants who were born and grew up in developed countries traveling to visit friends and relatives are at increased risk of HA infection.11

hepatitis B virus or working in health care facilities with likely contact with blood or possible unprotected sexual contact with residents of such areas. Hepatitis B vaccine booster doses are not required in individuals who have completed the vaccination course or who have adequate serologic evidence. • Typhoid vaccine is recommended for travelers who will have exposure to potentially contaminated food and water, especially those traveling in rural areas off the usual tourist itineraries in countries with a high incidence of disease. Those travelers with adventurous eating habits are also at high risk.

Indications All susceptible people aged ≥1 year traveling for any purpose, frequency, or duration to countries with high or intermediate HA endemicity should be vaccinated or receive immune globulin (Ig) before departure.8 In practice, Ig is rarely used now owing to the long-term protection afforded by active vaccination. In addition, men who have sex with men, illicit drug users, those who have occupational risk, and those with chronic liver disease should be vaccinated regardless of travel. Worldwide, geographic areas are characterized by high, intermediate, low, or very low levels of endemicity (Fig. 11.1). Australia, Canada, western Europe, Japan, New Zealand, and the United States are countries in which HA endemicity is low.11,12 Sixteen countries, including Argentina, China, Israel, and the United States, have introduced the vaccine into routine childhood immunizations.6

Contraindications Absolute contraindications are hypersensitivity after a previous vaccine dose or to any vaccine component. Relative contraindications are in subjects with an acute severe illness with or without fever. For them, HA vaccination should be delayed. Seropositivity against HA is not a contraindication, but indicates preexisting immunity.

Precautions In patients with an impaired immune system (immunosuppressive drugs, especially and very often anti-TNF alpha treatment, stem cell transplants, infected with human immunodeficiency virus [HIV]), adequate anti-HAV antibody titers may not be achieved after primary immunization.


CHAPTER 11  Routine Travel Vaccines: Hepatitis A and B, Typhoid Abstract


Hepatitis A and B and typhoid fever are ubiquitous global diseases necessitating routine vaccination for patients traveling to the developing world. Hepatitis A is one of the most common forms of viral hepatitis and immunization should be recommended for all travelers to developing countries where the disease is endemic. Hepatitis B virus causes an acute or chronic infection of the liver and immunization should be recommended for most nonimmune travelers based on their travel itinerary and behavior. Hepatitis A and B vaccines in immunocompetent individuals who complete full series induce lifelong immunity. Typhoid fever is a bacterial disease prevalent in Asia and other countries associated with poor sanitation and contaminated food and water supplies. Oral or injectable typhoid vaccine is recommended for travelers to endemic countries.

Booster dose Hepatitis A Hepatitis B Immunization Immunization schedule Protection Routine travel vaccines Travel medicine Typhoid fever Vaccines



SECTION 3 Immunization

Estimated Hepatitis A Virus Prevalence High Intermediate Low Very Low

FIG. 11.1  Estimated prevalence of hepatitis A virus. The map indicates the seroprevalence of antibody to HAV (total anti-HAV) as measured in selected cross-sectional studies among each country’s residents. Vaccination is indicated for all travelers to high- or intermediate-risk areas. (From Jacobsen KH, Wiersma ST. Hepatitis A virus seroprevalence by age and world region, 1990 and 2005. Vaccine 2010;28(41):6653–7.)

TABLE 11.1  Recommended Minimum Ages and Intervals Between Vaccine Doses for

Hepatitis A and B, and Typhoid Vaccines Vaccine and Dose Number

Recommended Age for This Dose

Minimum Age for This Dose

Recommended Interval to Next Dose

Minimum Interval to Next Dose

Hepatitis B1 Hepatitis B2 Hepatitis B3 Hepatitis A1 Hepatitis A2 Typhoid Vi Typhoid Ty21a

Birth 1–2 months 6–18 months 12–23 months 18–48 months 2 months 6 years capsules; >2 years liquid

Birth 4 weeks 24 weeks 12 months 18 months 2 months 6 years; >2 years liquid

1–4 months 2–17 months – 6 months – – –

4 weeks 8 weeks – 6 months – – –

Immunocompromised patients showed moderate to good serologic responses to HA vaccination, but may need more time to develop immunity. After the complete series of two vaccinations seroprotection rates reach 95% although success depends on the immunosuppressive drug being used. Subjects under anti-TNF alpha treatment have significantly lower seroprotection rates than subjects using classical immunosuppressive drugs after the second vaccination.13 Vaccination of subjects with chronic immunodeficiency, such as HIV infection, is recommended and well tolerated, although the antibody response may be limited.13,14 There appears to be no influence of age or gender on seroprotection rates.13,14

Dosing Schedules Several HA vaccines are available internationally. All are similar in terms of protection and reactogenicity. No HA vaccine is licensed for children 40 years, immunocompromised persons, and persons with chronic liver disease or other chronic medical conditions who are traveling to an endemic area within 2 weeks.12 Ig (0.02 mL/ kg) can be simultaneously administered with HA at a separate anatomic injection site. Screening for natural immunity in those departing in 40 years of age,7,16 those who spent their childhood in endemic areas, and those with a past history of unexplained hepatitis or jaundice. If anti-HAV antibodies are present, the individual is immune and does not require vaccination.1,6 There is no risk of increased rates of adverse events in vaccinating already immune travelers. A combined HA and HB vaccine is licensed in many countries and primary immunization consists of either three doses (given on a schedule of 0 months, 1 month, and 6 months) or an accelerated schedule (see next discussion). Also, combined HA and typhoid fever vaccine is licensed in some countries.

Accepted Accelerated Schedule Since seroconversion rates and protective antibody titers (total anti-HAV ≥20 mIU/mL at 4 or 6 weeks after a single dose of HA vaccine) uniformly approach 100% for commonly used vaccines (Havrix, Vaqta, Avaxim), there is no need for an accelerated schedule. An accelerated schedule of combined hepatitis A+B vaccine (doses at days 0, 7, and 21–30) for adult travelers has been approved by many regulators; however, in this case, a booster dose should be given at 12 months to promote long-term immunity.

Measures of Immune Response and Duration of Immunity HA vaccines confer immunity against HAV by inducing antibody titers greater than those obtained after passive immunization with immunoglobulin. The lowest protective antibody level against HAV infection


has not been clearly defined. Antibody appears shortly after the first injection, and 14 days after vaccination >90% of immunocompetent subjects are seropositive (titer ≥20 mIU/mL). One month after the first injection, almost 100% of subjects aged 2–18 or adult immunocompetent individuals have antibody titers >20 mIU/mL. To ensure long-term protection, a booster dose should be given between 6 and 12/18/36 months (depending upon formulation) after the primary dose of the particular HA vaccine. However, if the booster dose has not been given between 6 and 36 months after the primary dose, the administration of this booster dose can be delayed. In some trials, a booster dose of HA vaccine given up to several years after the primary dose has been shown to induce similar antibody levels as a booster dose given between 6 and 12–18 months after the primary dose.17–20 Flexible two-dose vaccination schedules with a delayed second dose are very important, especially for travelers, who often miss the second dose of HA vaccine.21 Clinical data demonstrate that a humoral response persists for at least 20 years.22–25 Data available after 20 years allow prediction (by mathematical modeling) that at least 97% of subjects will remain seropositive (≥20 mIU/mL) 25–35 years after vaccination.23–25 The T-cell–mediated response plays an important role in long-term protection after natural infection as well as after HA vaccination.26 Based on this demonstrated persistence of protective antibodies for 20 years, HA booster vaccination is unnecessary.21,27

Adverse Events Monovalent or combined HA vaccines are very well tolerated. Adverse events (AEs) are usually mild and confined to the first 2–3 days after vaccination. The most common local reactions are injection site pain, erythema, and induration. Less common are general symptoms such as headache, fatigue, and nausea.

Drug and Vaccine Interactions When concurrent administration is considered necessary, HA vaccines must not be mixed with other vaccines in the same syringe. Other vaccines or Ig should be administered at different sites with different syringes and needles. Concurrent administration of other vaccines such as HB, tetanus toxoid, diphtheria toxoid, polio, meningococcal, typhoid vaccines, cholera, Japanese encephalitis, rabies, or yellow fever (YF) vaccines is safe and unlikely to reduce the immune response to the HA or the coadministered vaccines. Travelers receiving Ig concurrently with HA vaccine developed similar seroconversion rates at week 4, but both the seroconversion and the titers were significantly lower after 2 years than in the subjects who received the vaccine alone. Responses after second boosters were similar.

IMMUNE GLOBULIN FOR HEPATITIS A PREVENTION Ig is concentrated preparation of gamma globulins, predominantly IgG, from a large pool of human donors. It is used for passive immunization against HA (and also for other infections) and for replacement therapy in patients with immunoglobulin deficiencies. Passive immunization provides a limited duration of protection after a single dose.

Indications Ig may be used to provide preexposure, short-term prophylaxis, but its use is discouraged in favor of active immunization with HA vaccine, which provides long-term immunity. However, travelers, those >40 years of age and those with chronic liver disease or other chronic medical conditions planning to depart to an endemic area in 3 months should receive an Ig dose of 0.06 mL/kg, which must be repeated if the duration of travel is >5 months.7,8

Adverse Events Local pain and tenderness at the injection site, urticaria, and angioedema may occur. Anaphylactic reactions, although rare, have been reported following the injection of human immunoglobulin.

Drug and Vaccine Interactions Ig can interfere with the immune response to live attenuated vaccines (measles, mumps, rubella [MMR] and varicella). The administration of MMR or varicella zoster virus (VZV) vaccines should be delayed at least 3 months after administration of Ig. Pooled intravenous immunoglobulin (IVIG) requires at least 8 months before MMR or VZV can be given.7 On the other hand, Ig should not be administered within 2 weeks after administration of injectable live attenuated vaccines.

HEPATITIS B VACCINE Hepatitis B (HB) is a viral infection that attacks the liver and can cause both acute and chronic disease.28 Disease is caused by hepatitis B virus (HBV), a small, circular, partially double-stranded DNA virus in the Hepadnaviridae family.29 The virus is 50–100 times more infectious than HIV and is transmitted through contact with the blood or other body fluids of an infected person.30 The incubation period is usually 60–150 days (average 90).30,31 The overall case fatality ratio of acute HB is lower than 0.45% and depends on age. Younger age cohorts have a case fatality ratio of 0.02% up to age 35. Acute HB progresses to chronic HBV infection in 30%–90% of people infected as infants or young children and in 1 month) travelers, expatriates, and long-term workers28–30 when traveling to regions with low, high intermediate, or high endemicity for HB, such as Asia, Africa, Latin America, and the Middle East. Thus, the World Health Organization (WHO) recommends HB vaccination for all travelers to areas considered high and intermediate risks, because it is difficult to avoid involuntary unpredictable exposures such as accidents and the need for urgent health care with invasive procedures.28 Immigrants and their children from high-prevalence countries who are returning home to visit their families should be screened for HB disease by testing for HBV surface antigen before vaccination. Persons adopting children from these higher-prevalence countries should also be vaccinated. Unvaccinated individuals who have usual indications for routine HB vaccination who are traveling to any destination should be vaccinated as part of the pretravel routine.

Contraindications Hypersensitivity after a previous vaccine dose or to any vaccine component including yeast is contraindicated.

Precautions For subjects with an acute severe illness with or without fever, HB vaccination should be delayed. A number of factors reduce the immune response to HB vaccines. They include older age, male gender, obesity, smoking, route of administration, and some chronic underlying diseases.

Dosing Schedules Conventional primary immunization schedule at 0, 1, and 6 months gives optimal protection (>90% individuals) at month 7 and produces high antibody titers in healthy adults aged 10 mIU/mL after vaccination have nearly complete protection against both acute disease and chronic infection, even if anti-HBs concentrations decline subsequently to 40 years), male gender, smoking, obesity, HIV infection, or chronic disease. Persons >40 years of age have an immune response 16 years: None antigen; Havrix weeks; >95% in 1 mL (1440 ELISA (GlaxoSmithKline) 4 weeks units) IM deltoid. One each at 0 and 6–12 months

Hepatitis A

Inactivated viral antigen; VAQTA (Merck)

~70%–80% in 2 Adult ≥19 years: 1 mL weeks; ~95% in (50 units) IM deltoid. 4 weeks One each at 0 and 6–18 months



Hepatitis A

Inactivated viral antigen; Avaxim (Sanofi Pasteur)

>90% in 2 weeks; Adult: 0.5 mL (160 100% in 4 units) IM in the weeks deltoid region at 0 and 6–36 months



Hepatitis A

Inactivated virosomeformulated antigen; Epaxal (Berna)

~97% in 2 weeks; 0.5 mL IM in the deltoid None 99% in 4 weeks region at 0 and 12 months


Hepatitis A

Immune globulin for hepatitis A prophylaxis

85%–90% protection

Hepatitis Inactivated viral 100% protective A plus antigen; Twinrix Hep A Ab hepatitis Adult levels, 94% B (GlaxoSmithKline) protective Hep B Ab levels after three doses


Deep IM deltoid None Repeat doses muscle. For a stay of are required 5 mL, give in divided doses in two sites) Adult >18/16 years: None 0, 7, 21 days plus booster 1 mL IM in deltoid at 1 year (720 units for hepatitis A and 20 µg for hepatitis B). One each at 0, 1, and 6 months


Category C. Not contraindicated during lactation

Completion of the series with the same product is preferable. However, if the originally used product is not available or not known, vaccination with either product is acceptable Category C. Not Completion of the series contraindicated with the same product during lactation is preferable. However, if the originally used product is not available or not known, vaccination with either product is acceptable Category C. Not Completion of the series contraindicated with the same product during lactation is preferable. However, if the originally used product is not available or not known, vaccination with either product is acceptable Category C. Not Completion of the series contraindicated with the same product during lactation is preferable. However, if the originally used product is not available or not known, vaccination with either product is acceptable Considered safe in See text: wait the pregnancy required interval after receipt of Ig before administration of MMR or varicella vaccines

Category C. Not contraindicated during lactation

If two doses prior to departure not possible, administer monovalent hepatitis A and hepatitis B

CHAPTER 11  Routine Travel Vaccines: Hepatitis A and B, Typhoid


TABLE 11.3  Summary of Adult Routine Travel Vaccines69–71—cont’d

Disease Hepatitis B

Hepatitis B

Typhoid, oral

Typhoid, oral


Vaccine Type; Commercial Name (Manufacturer) Efficacy

Primary Course —Adult

Inactivated viral 95% protective Adult >19/15 years: antigen; Hep B Ab levels 1 mL (20 µg hepatitis Engerix-B after three B surface antigen) IM Recombinant doses deltoid at 0, 1, and 6 vaccine months. Dialysis (GlaxoSmithKline) patients: use Engerix-B 40 µg IM at 0, 1, 2, and 6 months Inactivated viral 95% protective Adult >19 years: 1 mL antigen; Hep B Ab levels (10 µg hepatitis B Recombivax after three surface antigen) IM Recombinant doses deltoid at 0, 1, and 6 vaccine (Merck) months. Dialysis patients: use Recombivax 40 µg IM at 0, 1, 2, and 6 months Live attenuated 50%–80% 3 capsules, 1 capsule bacterial vaccine, effective taken orally every capsule. Typhoid other day on days 0, Ty21a, Vivotif 2, 4. In North (Berna) America, the schedule is 4 capsules, 1 capsule taken orally every other day on days 0, 2, 4, 6 Live attenuated 50%–70% Three doses of bacterial vaccine, effective suspension taken suspension. orally every other day Typhoid Ty21a, on days 0, 2, 4 Vivotif (Berna)

Polysaccharide 50%–70% vaccine. Typhoid effective Injectable. Typhim Vi (Sanofi Pasteur) or Typherix (GlaxoSmithKline) Typhoid Vi polysaccharide See monovalent plus and inactivated vaccines hepatitis hepatitis A A vaccine. Vivaxim (Sanofi Pasteur) or Hepatyrix (GlaxoSmithKline)


Accelerated Pregnancy or Schedule Lactation Category C. Not contraindicated during lactation

Can be used interchangeably with Recombivax or HBvaxPRO

Boosters may be 0, 7, 21 days necessary in and 12 immunomonths compromised patients with anti-HBs titer of 1 year of age (≥16 or ≥19, depending on country licensing) (see Table 11.3) who are at risk of both HA and HB infections. The indications for use of a combined HA and HB vaccine are the same as for the use of the monovalent vaccines.

Contraindications Permanent contraindications are hypersensitivity after a previous vaccine dose or to any vaccine component, including yeast. No serious attributable adverse event reported in over 25 years of widespread use No serious attributable adverse event reported

persons >65 years of age develop protective anti-HBs antibody levels.29 For persons with these risk factors and who are at high risk of HB exposure, a postvaccination serology 1–6 months after the last dose should be done. Patients without detectable anti-HBs titers after primary series should begin a standard three-dose series and have serology 1 month after each dose for up to three doses until they seroconvert, or may wait until the three additional doses are administered before being tested. A similar approach can be taken for health care providers who have received a complete HB series but have undetectable antiHBsAg titers.

Adverse Events Monovalent or combined HB vaccines are very well tolerated. AEs are usually mild and confined to the first 2–3 days after vaccination. The most common local reactions are injection site pain, erythema, and induration. Less common are general symptoms, which include headache (very common in children), malaise, fatigue, and gastrointestinal symptoms (such as nausea, vomiting, diarrhea, abdominal pain). The risk of serious AEs from the vaccine against HB is very small compared to the risk of disease and chronic sequelae (Table 11.4).

Drug and Vaccine Interactions Concurrent administration of HB immunoglobulin or vaccines such as HA, tetanus toxoid, diphtheria toxoid, polio, typhoid vaccines, meningococcal vaccines, cholera, Japanese encephalitis, rabies, or YF

Precautions In subjects with an acute severe illness with or without fever HA + HB vaccination should be delayed. Obesity (defined as BMI ≥30 kg/m2) reduces the immune response to HA vaccines. Older age, male gender, obesity, smoking, route of administration, and some chronic underlying diseases reduce the immune response to HB vaccines. Consideration should be given to serologic testing of those subjects who may be at risk of not achieving seroprotection following a complete course of Twinrix vaccine, as described under the monovalent vaccine section in this chapter.

Dosing Schedules The adult combination vaccine (Twinrix Adult) contains 720 enzymelinked immunosorbent assay (ELISA) units of HA antigen and 20 µg of recombinant HBsAg in each 1-mL dose. The pediatric combination vaccine (Twinrix Paediatric) contains 360 ELISA units of HA antigen and 10 µg of HBsAg in each 0.5-mL dose. The primary conventional immunization schedule consists of three doses of vaccine given on a schedule of 0, 1, and 6 months.35 It should be noted that two doses of the combined vaccine will protect almost 100% against HA but result in protective anti-HBs antibodies level in 50%–95% of individuals. Higher rates of seroprotection may be achieved when three doses of vaccine or accelerated schedule are given to travelers before travel.46 A single dose of hepatitis A+B vaccine will not provide adequate protection against HAV or HBV.35 Because HA is a more significant risk, combined vaccine should not be used in cases where the return of the traveler for a second predeparture dose is not certain.

Accepted and Possible Accelerated Schedules For adult travelers who present 21–28 days prior to departure an accelerated schedule of Twinrix Adult of 0, 7, and 21 days plus 12 months is licensed, which has demonstrated good protective antibody levels for both HAV and HBV.46 Two doses 7 days apart should be given to those with 100 per 100 000 per year) Medium (10–100 000 per year) Low (3 weeks have elapsed before all doses have been administered.

Measures of Immune Response and Duration of Immunity/Protection

Vi Polysaccharide Typhoid Vaccine. Field trials in endemic areas with ongoing exposure to Salmonella bacteria show an efficacy of 72% at 17 months after the vaccination. Another study showed 64% efficacy at 21 months and 55% at the 36-month follow-up. A recent study in India showed an overall 61% vaccine efficacy and 80% efficacy in children 2–5 years of age.62 The repeat doses do not have a booster effect on the primary dose. Efficacy trials in travelers have not been performed. Recently, a systematic review and meta-analysis indicated there was a 2.5- to 3-year cumulative efficacy of 55% for Typhim Vi, primarily based on indigenous Indian populations.63 When US travelers from 2008–2011 were examined, the vaccine effectiveness of typhoid vaccines (including the live and inactivated vaccines) was estimated at 80%.64 Typhim Vi and Typherix show equivalent immunogenicity.

Ty21a Oral Typhoid Vaccine.  Three doses of the enteric-coated capsules provide 79% protection over a 3-year period and 62% over 7 years in individuals with ongoing exposure to environmental salmonella in endemic areas.61,63 A four-dose series provided significantly higher protection than the three-dose series.59 Protective immunity following the four-dose series lasts up to 5–7 years in some vaccinees, but may be less in travelers. Studies have shown that the liquid formulation is significantly more immunogenic than the capsular formulation (threedose series), showing 78% protection at 5 years. Adequate efficacy trials in travelers have not been performed.

Adverse Events The injectable Vi polysaccharide vaccine is very well tolerated,65 with fever or flulike symptoms reported in 72 hours before starting the oral typhoid vaccine. Proguanil may interfere with the immune response, but the data were derived from limited studies using a higher dose of proguanil alone than is contained in the current antimalarial combination drug, atovaquone plus proguanil (Malarone). A study looking at the efficacy of the oral Ty21a vaccine taken at the same time as the combination atovaquone plus proguanil showed no effect of concurrent atovaquone plus proguanil on serum IgA or IgG response to Ty21a.68

CHAPTER 11  Routine Travel Vaccines: Hepatitis A and B, Typhoid

CONCLUSION Routine travel vaccines against HA, HB, and typhoid fever are the most applied vaccines among unvaccinated travelers before their travel to any destination. HA is one of most common forms of viral hepatitis and immunization should be recommended for all travelers to developing countries where the disease is endemic. For immunocompetent persons who complete the full series, booster doses of vaccine are not recommended. HB is a viral acute or chronic infection of the liver and immunization should be recommended to travelers individually based on their travel itinerary. HB vaccine booster doses are not required in immunocompetent individuals who have responded to a completed vaccination course. Typhoid fever is prevalent worldwide, and is a disease associated with poor sanitation and contaminated food and water supplies. Typhoid vaccine is recommended for travelers to high endemic areas. Current vaccines against typhoid fever are injectable or oral and can protect travelers for at least 3 years, depending on type of vaccine and schedule.

REFERENCES 1. Wu D, Guo CY. Epidemiology and prevention of hepatitis A in travelers. J Travel Med 2013;20(6):394–9. 2. Mayer CA, Neilson AA. Hepatitis A—prevention in travelers. Aust Fam Physician 2010;39(12):924–8. 3. Steffen R, Amitirigala I, Mutsch M. Health risks among travelers—need for regular updates. J Travel Med 2008;15:145–6. 4. Liu SJ, Sharapov U, Klevens M. Patient awareness of need for hepatitis a vaccination (prophylaxis) before international travel. J Travel Med 2015;22(3):174–8. 5. Luxemburger C, Dutta AK. Overlapping epidemiologies of hepatitis A and typhoid fever: the needs of the traveler. J Travel Med 2005;12:S12–21. 6. World Health Organization. Hepatitis A. Available at: mediacentre/factsheets/fs328/en/. 7. Centers for Disease Control and Prevention. Hepatitis A. In: Hamborsky J, Kroger A, Wolfe S, editors. Epidemiology and Prevention of Vaccine-preventable Diseases. 13th ed. Washington, DC: Public Health Foundation; 2015. p. 135–48. Available at: pubs/pinkbook/hepa.html#. 8. Centers for Disease Control and Prevention. Hepatitis A. In: CDC Health Information for International Travel 2016. New York: Oxford University Press; 2016. Available at: infectious-diseases-related-to-travel/hepatitis-a. 9. National Health and Medical Research Council. The Australian immunization handbook. 10th ed. Canberra: National Health and Medical Research Council; 2017. Available at: http://www.immunise -home~handbook10-Copyright-1. 10. Steffen R. Changing travel-related global epidemiology of hepatitis A. Am J Med 2005;118:S46–9. 11. Askling Hh, Rombo L, Andersson Y, et al. Hepatitis A risk in travelers. J Travel Med 2009;16:233–8. 12. Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC). Update: Prevention of hepatitis A after exposure to hepatitis A virus and in international travelers. Updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2007;56(41):1080–4. Available at: mmwr/preview/mmwrhtml/mm5641a3.htm. 13. van den Bijllaardt W, Siers HM, Timmerman-Kok C, et al. Seroprotection after hepatitis a vaccination in patients with drug-induced immunosuppression. J Travel Med 2013;20(5):278–82. 14. Mofenson LM, Brady MT, Danner SP, et al. Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children: recommendations from CDC, The National Institutes of Health, The HIV Medicine Association of The Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and


The American Academy of Pediatrics. MMWR Recomm Rep 2009; 58(RR–11):1–166. Available at: mmwrhtml/rr5811a1.htm. 15. Van Damme P, Banatvala J, Fay O, et al. Hepatitis A booster vaccination: is there a need? Lancet 2003;362:1065–71. 16. Grabenstein JD. Hepatitis A vaccine. ImmunoFacts 2006;175–85. 17. Landry P, Tremblay S, Darioli R, et al. Inactivated hepatitis A vaccine booster given ≥24 months after the primary dose. Vaccine 2000; 19(4–5):399–402. 18. Iwarson S, Lindh M, Widerström L. Excellent booster response 4 to 8 years after a single primary dose of an inactivated hepatitis A vaccine. J Travel Med 2004;11(2):120–1. 19. Williams JL, Bruden DA, Cagle HH, et al. Hepatitis A vaccine: immunogenicity following administration of a delayed immunization schedule in infants, children and adults. Vaccine 2003;21(23):3208–11. 20. Chappuis F, Farinelli T, Deckx H, et al. Immunogenicity and estimation of antibody persistence following vaccination with an inactivated virosomal hepatitis A vaccine in adults: a 20-year follow-up study. Vaccine 2017;35(10):1448–54. 21. Van Damme P, Leroux-Roels G, Suryakiran P, et al. Persistence of antibodies 20 y after vaccination with a combined hepatitis A and B vaccine. Hum Vaccin Immunother 2017;10:1–9. 22. Van Herck K, Van Damme P, Lievens M, et al. Hepatitis A vaccine: indirect evidence of immune memory 12 years after the primary course. J Med Virol 2004;72(2):194–6. 23. Bovier PA, Bock J, Ebengo TF, et al. Predicted 30-year protection after vaccination with an aluminum-free virosomal hepatitis A vaccine. J Med Virol 2010;82(10):1629–34. 24. Vidor E, Dumas R, Porteret V, et al. Aventis Pasteur vaccines containing inactivated hepatitis A virus: a compilation of immunogenicity data. Eur J Clin Microbiol Infect Dis 2004;23(4):300–9. 25. Van Herck K, Jacquet JM, Van Damme P. Antibody persistence and immune memory in healthy adults following vaccination with a two-dose inactivated hepatitis A vaccine: long-term follow-up at 15 years. J Med Virol 2011;83:1885–91. 26. Lemon SM. Immunologic approaches to assessing the response to inactivated hepatitis A vaccine. J Hepatol 1993;18(2):S15–19. 27. Zuckerman JN, Connor BA, von Sonnenburg F. Hepatitis A and B booster recommendations: implications for travelers. Clin Infect Dis 2005;41(7):1020–6. 28. World Health Organization. Hepatitis B. Available at: mediacentre/factsheets/fs204/en/. 29. Centers for Disease Control and Prevention. Hepatitis B. In: Hamborsky J, Kroger A, Wolfe S, editors. Epidemiology and Prevention of Vaccine-preventable Diseases. 13th ed. Washington, DC: Public Health Foundation; 2015. p. 149–74. Available at: pubs/pinkbook/hepb.html#. 30. Centers for Disease Control and Prevention. Hepatitis A. In: CDC Health Information for International Travel 2016. New York: Oxford University Press; 2016. Available at: infectious-diseases-related-to-travel/hepatitis-b. 31. Spira AM. A review of combined hepatitis A and hepatitis B vaccination for travelers. Clin Ther 2003;25:2337–51. 32. Zuckerman J, Van Damme P, Van Herck K, et al. Vaccination options for last-minute travelers in need of travel-related prophylaxis against hepatitis A and B and typhoid fever: a practical guide. Travel Med Infect Dis 2003;1:219–26. 33. Keystone JS. Travel-related hepatitis B: risk factors and prevention using an accelerated vaccination schedule. Am J Med 2005;118(10A):S63–8. 34. Connor BA, Jacobs RJ, Meyerhoff AS. Hepatitis B risks and immunization coverage among American travelers. Travel Med 2006;13(5):273–80. 35. Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on hepatitis vaccines for travelers. An Advisory Committee Statement (ACS). Can Commun Dis Rep 2008;34(ACS–2):1–24. Available at: index-eng.php. 36. Andre FE. Summary of safety and efficacy data on a yeast-derived hepatitis B vaccine. Am J Med 1989;87(3A):S14–20.


SECTION 3 Immunization

37. Zajac BA, West DJ, McAleer WJ, et al. Overview of clinical studies with hepatitis B vaccine made by recombinant DNA. J Infect 1986;13(A):S39–45. 38. Lemon SM, Thomas DL. Vaccines to prevent viral hepatitis. N Engl J Med 1997;336:196–204. 39. Mast EE, Weinbaum CM, Fiore AE, et al; Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part II: immunization of adults. MMWR Recomm Rep 2006;55(RR–16):1–33. Available at: mmwrhtml/rr5516a1.htm. Erratum in: MMWR 2007;56(42):1114. 40. Keystone JS, Hershey JH. The underestimated risk of hepatitis A and hepatitis B: benefits of an accelerated vaccination schedule. Int J Infect Dis 2008;12(1):3–11. 41. Francis DP, Hadler SC, Thompson SE, et al. The prevention of hepatitis B with vaccine: report of the Centers for Disease Control multi-center efficacy trial among homosexual men. Ann Intern Med 1982;97:362–6. 42. Hadler SC, Francis DP, Maynard JE, et al. Long-term immunogenicity and efficacy of hepatitis B vaccine in homosexual men. N Engl J Med 1986;315:209–14. 43. Jack AD, Hall AJ, Maine N, et al. What level of hepatitis B antibody is protective? J Infect Dis 1999;179:489–92. 44. Szmuness W, Stevens CE, Harley EJ, et al. Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. N Engl J Med 1980;303:833–41. 45. Banatvala JE, Van Damme P. Hepatitis B vaccine-do we need boosters? J Viral Hepat 2003;10:1–6. 46. Nothdurft HD, Zuckerman J, Stoffel M, et al. Accelerated vaccination schedules provide protection against hepatitis A and B in last-minute travelers. J Travel Med 2004;11:260–2. 47. Beran J, Van Der Meeren O, Leyssen M, et al. Immunity to hepatitis A and B persists for at least 15 years after immunisation of adolescents with a combined hepatitis A and B vaccine. Vaccine 2016;34(24):2686–91. 48. Crump JA, Luby SP, Mintz ED. The global burden of typhoid fever. Bull World Health Organ 2004;82(5):346–53. 49. Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med 2006;354(2):119–30. 50. Connor BA, Schwartz E. Typhoid and paratyphoid fever in travellers. Lancet Infect Dis 2005;5(10):623–8. 51. Steinberg EB, Bishop R, Haber P, et al. Typhoid fever in travelers: who should be targeted for prevention? Clin Infect Dis 2004;39(2):186–91. 52. Mermin JH, Townes JM, Gerber M, et al. Typhoid fever in the United States, 1985-1994: changing risks of international travel and increasing antimicrobial resistance. Arch Intern Med 1998;158(6):633–8. 53. Meltzer E, Schwartz E. Enteric fever: a travel medicine oriented view. Curr Opin Infect Dis 2010;23(5):432–7. 54. Crump JA, Mintz ED. Global trends in typhoid and paratyphoid fever. Clin Infect Dis 2010;50(2):241–6. 55. Johnson KJ, Gallagher NM, Mintz ED, et al. From the CDC: new country-specific recommendations for pre-travel typhoid vaccination. J Travel Med 2011;18(6):430–3.

56. Beran J, Beutels M, Levie K, et al. A single dose, combined vaccine against typhoid fever and hepatitis A: consistency, immunogenicity and reactogenicity. J Travel Med 2000;7(5):246–52. 57. Guzman CA, Borsutzky S, Griot-Wenk M, et al. Vaccines against typhoid fever. Vaccine 2006;24(18):3804–11. 58. Loebermann M, Kollaritsch H, Ziegler T, et al. A randomized, open-label study of the immunogenicity and reactogenicity of three lots of a combined typhoid fever/hepatitis A vaccine in healthy adults. Clin Ther 2004;26(7):1084–91. 59. Typhoid vaccines: WHO position paper. Wkly Epidemiol Rec 2008;83(6): 49–59. 60. Kaplan DT, Hill DR. Compliance with live, oral Ty21a typhoid vaccine. JAMA 1992;267(8):1074. 61. Levine MM, Ferreccio C, Abrego P, et al. Duration of efficacy of Ty21a, attenuated Salmonella typhi live oral vaccine. Vaccine 1999;17(2):S22–7. 62. Sur D, Ochiai RL, Bhattacharya SK, et al. A cluster-randomized effectiveness trial of Vi typhoid vaccine in India. N Engl J Med 2009;361(4):335–44. 63. Anwar E, Goldberg E, Fraser A, et al. Vaccines for preventing typhoid fever. Cochrane Database Syst Rev 2014;1:96. 64. Mahon BE, Newton AE, Mintz ED. Effectiveness of typhoid vaccination in US travelers. Vaccine 2014;32(29):3577–9. 65. Begier EM, Burwen DR, Haber P, et al. Postmarketing safety surveillance for typhoid fever vaccines from the Vaccine Adverse Event Reporting System, July 1990 through June 2002. Clin Infect Dis 2004;38(6):771–9. 66. Jackson BR, Iqbal S, Mahon B, et al. Updated recommendations for the use of typhoid vaccine—Advisory Committee on Immunization Practices, United States, 2015. MMWR 2015;64(11):305–8. 67. Newton A, Routh J, Mahon B. Typhoid and paratyphoid fever. In: Brunette G, editor. CDC Health Information for International Travel 2016. Washington, DC: US Department of Health and Human Services; 2016. 68. Faucher JF, Binder R, Missinou MA, et al. Efficacy of atovaquone/ proguanil for malaria prophylaxis in children and its effect on the immunogenicity of live oral typhoid and cholera vaccines. Clin Infect Dis 2002;35(10):1147–54. 69. EMEA. Available at: pages/home/Home_Page.jsp. 70. EU—National competent authorities. Available at: http://www.ema _000155.jsp&murl=menus/partners_and_networks/partners_and _networks.jsp&mid=WC0b01ac0580036d63. 71. Regulators outside of EU. Available at: index.jsp?curl=pages/partners_and_networks/general/general_content _000214.jsp&murl=menus/partners_and_networks/partners_and _networks.jsp&mid=WC0b01ac058003176d&jsenabled=true. 72. CDC—Diseases related to travel. Available at: travel/page/diseases.htm. 73. ECDC—Annual epidemiological report on communicable diseases in Europe—2014 and 2015. Available at: publications/surveillance_reports/annual_epidemiological_report/Pages/ epi_index.aspx.

12  Recommended/Required Travel Vaccines Joseph Torresi and Herwig Kollaritsch

KEY POINTS • Vaccine recommendations for travelers are based on the anticipated risks of exposure to vaccine preventable diseases on a given travel itinerary, the severity of the disease if acquired, and any risks of the vaccine itself. • Risk for each vaccine preventable disease depends on prevalence of the disease at the destination(s) as well as traveler-dependent risk factors, which include recreational and occupational activities, mode of travel and accommodations, duration of travel,

degree of close contact (including sexual relations) with local residents, and time of year the travel is undertaken. • Special travel vaccines to be considered are divided into required, recommended, and special circumstance categories: required vaccines may on certain itineraries include yellow fever and meningococcal (hajj travel only); recommended vaccines may include Japanese encephalitis, tickborne encephalitis, rabies, polio, and cholera.


The World Health Organization (WHO) develops and adopts international health regulations (IHRs), which were last updated in printed form in 2005 and subsequently web based only. These guidelines regarding vaccine requirements for international travelers can be found in International Travel and Health published annually by WHO (with electronic access through its website, IHR 2005 specifies requirements for only one vaccine, YF, but contains language allowing for rapid introduction of vaccine requirements for other vaccines for international travel in cases of international public health emergencies. The Centers for Disease Control and Prevention (CDC) also develops guidelines and information for international travelers, which are contained in its publication Health Information for International Travel (published on a biannual basis, with online access through the CDC website, Similar information and guidelines are published for use in other countries such as Canada ( im/index-eng.php) and Australia ( internet/immunise/publishing.nsf/Content/Handbook10-home). Health care providers should consult national public health agencies in the country where they work for current information on the standards of care and vaccine practices appropriate for that country.

Based on regional patterns of disease transmission, a vaccine considered routine or standard in one country may represent a travel immunization for visitors originating in another country. Examples of this are Japanese encephalitis (JE) virus vaccine, rabies vaccine, and yellow fever (YF) vaccine, each of which may be administered routinely to residents of countries where there is a high risk of transmission of the given disease, but which are considered travel vaccines for visitors to those same countries. Further complicating the consideration of international immunization practices are the variations that exist in travel vaccine product formulations, when more than one vaccine against a particular disease is produced by several manufacturers. Some confusion also arises when a given vaccine produced by a single pharmaceutical manufacturer has been licensed under different brand names, dosing schedules, and booster intervals in different countries. Trade names of the commonly used travel vaccines are given in Table 12.1. While most travelers may be able to complete a recommended primary series for a given vaccine before departure from the home country, other travelers, especially long-term travelers, expatriates, and immigrants, may start an immunization series in one country and receive additional doses to complete or boost the primary series in another country. When this is necessary, the fact that vaccine products and practices vary from country to country could impact immunization planning. When available, information on accelerated immunization schedules will be provided in this chapter. Most vaccine series have defined minimum ages for the initial doses as well as defined minimum intervals between each of the subsequent doses that may be shorter than the generally used regimen. In general, if a missed or delayed dose in a vaccine series is identified, it is not necessary to restart the vaccine series from the beginning. The vaccine dose that is due or overdue should be administered and documented, and the immunization schedule should proceed according to age-appropriate minimal intervals for each subsequent dose in the series from that point in time.

Practical Vaccine Considerations One of the common practical challenges when advising travelers about pretravel immunizations is that of scheduling the recommended vaccines in the time available before trip departure. An overview of commonly administered vaccines for adult travelers, including dosing schedules, accelerated regimens, efficacy estimates, and interchangeability, is presented in Table 12.2.

Adverse Events Discussions of major vaccine-related adverse events are found in this chapter under each individual vaccine. In counseling patients and recommending vaccines, familiarity with numerical data on the risks and benefits of each vaccine is helpful for the provider. Table 12.3


CHAPTER 12  Recommended/Required Travel Vaccines Abstract


Vaccination against destination-specific diseases plays an important role in preparing a traveler, although vaccine preventable diseases (VPDs) are rare in returning persons. While mandatory vaccinations in international travel are restricted to yellow fever, meningococcal meningitis (hajj), and rarely other vaccinations in special outbreak situations, recommendation for individual precaution by vaccination is based on data from returning travelers and from the epidemiologic situation in the visiting country. Weighing risk of vaccination against the benefit for the traveler is a prerequisite for pro/con decisions and implies detailed evaluation of personal risk of contracting a VPD. However, the currently licensed vaccines indicated for an international traveler are considered safe, well tolerated, and efficacious.

Chimeric JE vaccine Japanese encephalitis (JE) Live attenuated vaccines Meningococcal vaccine Neurotropic disease Polio Rabies vaccine Tickborne encephalitis Travel vaccines Viscerotropic disease Yellow fever



SECTION 3 Immunization

TABLE 12.1  Trade Names of Important

Adult Travel-Related Vaccines Worldwide Cholera (oral) Japanese encephalitis Meningococcal (polysaccharide)

Meningococcal (conjugate)


Rabies immune globulin Yellow fever Tickborne encephalitis

Dukoral, Shanchol, mORCVax, Euvichol, Vaxchora Ixiaro, Jespect, Imojev, Japanese Encephalitis Vaccine Live (14–14–2) Menomune, Mencevax ACWY, ACWY Vax, MenceACW, Polysaccharide Meningococcal A + C Vaccine, MenAfriVac, Menomune A/C, Meningovax A + C, Vacina Antimeningococic A + C, Meninvact, Vacina Meningococica A + C, Meningokokken-Impfstoff A + C, Imovax Meningo A + C, Mencevax AC, Menpovax A + C, Mengivac A + C, Meningococcal Polysaccharide vaccine, Vaccin Meningoccique Mérieux, MeNZB Menactra (ACWY), Menveo (ACWY), Nimenrix (ACWY), Menjugate (C), Neisvac-C, Meningitec (C), Vacina meningococcica conjugada Grupo C, Bexsero (B), Trumenba (B) Imovax Rabies, Rabies Imovax, RabAvert Rabies Vaccine BP, VeroRab, Rabipur, Rabipur, Rabies Vaccine Adsorbed, Lyssavac, Lyssavac N, Rabies MIRV, Tollwut-Impfstoff (HDC), TRC VeroRab, Rabies Vero; Rabivac, Speeda, Abhayrab Imogam, Imogam Rabies HT, Bayrab, HyperRAB, HyperRAB S/D, Berirab, Imogam Rabia, Imogam Rage, Tollwutglobulin, Favirab (equine) YF-Vax, Stamaril, Arilvax, Stabilized Yellow Fever Vaccine (live), Vacina contra Febre Amarela Encepur, FSME-Immun; Russia and neighbouring countries: TBE vaccine Chumakow, Encevir; China: SenTaiBao, CIBP

Most widely distributed trade names listed first. Vaccines are parenteral unless specified.

provides a comparison of the estimated risk of acquiring a vaccine preventable disease (VPD) or being harmed by a complication of that disease with an estimate of the risk of the vaccine for that disease.

Attenuated Live Vaccines Live virus vaccines, such as YF vaccine, in general are contraindicated in pregnant patients and those with congenital, acquired, or pharmacologically induced immune deficient states because of the concern that an attenuated vaccine virus strain may exhibit increased virulence in immune deficient persons, causing severe disease. When travel to the area of risk cannot be postponed or deferred, decisions regarding vaccination against a particular disease must consider the potential risk of life-threatening illness or death from a disease weighed against the potential risks from the vaccine itself as well as the possibility of the induction of a suboptimal response to the vaccine itself.

REQUIRED VACCINES Yellow Fever Vaccine YF is a serious viral hemorrhagic fever spread by Aedes or Haemagogus spp. of mosquitoes. Although Aedes aegypti mosquitoes are found in all warm climates, YF has only occurred in Africa and South America (Fig. 12.1). The clinical illness follows a short incubation period of 2–5 days. This is followed by an influenza-like illness with fever, myalgias,

headache, prostration, nausea, and vomiting. Most patients recover; however, approximately 15% progress to severe disease with jaundice, multiorgan failure, bleeding, and shock. The case fatality rate in severe disease is 25%–50%.1 YF has three types of transmission cycles. The first is the jungle or sylvatic cycle, an enzootic viral disease transmitted among nonhuman primate hosts by a variety of mosquito vectors, which may also bite and infect humans. The second is the urban cycle, an epidemic disease of humans transmitted from infected to susceptible persons by the A. aegypti mosquito. The third is the intermediate or savannah cycle, a mode of transmission that occurs only in Africa and involves transmission of YF virus from Aedes spp. to humans living or working in jungle border areas. In this cycle, the virus may be transmitted from monkeys to humans or from human to human via these mosquitoes. Both the sylvatic and urban transmission cycles occur in Africa, while jungle transmission predominates in South America. In South America, peak transmission of YF virus occurs during January–March, while in Africa the period of peak transmission occurs in July–October. Previous WHO estimates have shown that some 200,000 cases occur each year, with almost all of these in sub-Saharan Africa1,2 and the majority of these cases occur in West Africa.3 However, a more recent study reported the burden of disease in Africa for the year 2013 as 130,000 (95% confidence interval [CI] 51,000–380,000) cases with fever and jaundice or hemorrhage and this included 78,000 (95% CI 19,000–180,000) deaths. However, the burden of disease would have been substantially higher had it not been for the success of vaccination campaigns that were estimated to have reduced the number of cases and deaths by 27%, achieving up to an 82% reduction in countries targeted by vaccination campaigns.4 The risk of YF for the traveler is difficult to determine and to date has been based on the risk to indigenous populations.5,6 For a 2-week stay, the risks for illness and death due to YF for an unvaccinated traveler to an endemic area in West Africa is 50 per 100,000 and 10 per 100,000, respectively, while for South America the risks are 5 per 100,000 and 1 per 100,000, respectively. The vaccine is a live attenuated strain of the YF virus (17D) that was originally developed in 1927.6 Substrains of the WHO-standardized 17D virus seed-lot strains in current use are designated 17DD, 17D-204, and 17D-213 and these four strains share 99.9% sequence homology. WHO currently approves only four manufacturers of YF vaccine: (1) Sanofi Pasteur produces 17D-204 vaccine in France (Stamaril); (2) Institut Pasteur de Dakar produces 17D-204 YF vaccine in Senegal; (3) Bio-Manguinhos, Brazil produces 17DD vaccine in Rio de Janeiro; and (4) Institute of Poliomyelitis and Viral Encephalitides produces 17D-204 vaccine in the Russian Federation (see Table 12.1). Updated lists of WHO prequalified vaccines are available at immunization_standards/vaccine_quality/PQ_vaccine_list_en/en/.

Recommendations.  Under IHR 2005 any country may require a YF vaccination certificate from travelers coming from areas with risk of YF transmission, even if the travelers are only in transit through that country. Only a small number of African countries (Angola, Benin, Burkina Faso, Cameroon, Central African Republic, Congo, Cote D’Ivoire, Democratic Republic of Congo, Gabon, Guinea-Bissau, Liberia, Mali, Niger, Sierra Leone, Togo) and one in South America (French Guiana) require proof of YF vaccination from all arriving travelers.7 While most countries that have YF risk will request proof of YF vaccination for at least some arriving travelers as a requirement for entry, certain countries outside of risk areas may also designate YF vaccine as a required or mandatory vaccine. Such YF-free countries have the appropriate climatic and entomologic conditions to initiate

Meningococcal disease

Japanese B encephalitis Meningococcal disease

Japanese B encephalitis

Cholera, oral


Polysaccharide vaccine. Neisseria meningitidis groups A, C, Y, W-135. Menomune (Sanofi Pasteur), ACYW Vax (Glaxo-SmithKline), and many others Menactra (Sanofi Pasteur) Quadrivalent conjugate N. meningitidis groups A, C, Y, W-135 Conjugated to D

IMOJEV (Sanofi Pasteur)


Killed whole cell (incl. O139) Shanchol (Shanta Biotechnics Ltd. India); mORC-Vax (Vabiotech, Hanoi, Vietnam) IXIARO (IC51; Valneva) JESPECT (Australia)

>97% seroconversion to all four serogroups after 28 days

Noninferior to JE-VAX (mouse brain vaccine) in seroconversion studies 99% seroconversion rate from single dose 85%–90% efficacy after 1–2 weeks



Killed whole-cell recombinant B-subunit vaccine; Dukoral (Valneva)

Vaccine Type; Commercial Name (Manufacturer)

Every 2 years

Booster after 12–24 months, further boosters not defined None

>1 year; two doses, 2 weeks apart

>18 years old; 0.5 mL at 0, 28 days

Adults >18 years: one dose Adults: 0.5 mL s.c. Single dose

One single i.m. dose for ≥2 years old; children 9–23 months: two doses, 3 months apart, starting at age 9 months

Every 2 years for persons >6 years of age

>6 years of age: two doses orally 7–42 days apart

Not known at present, likely 3 years

Same dose. Re-dose every 3–5 years for adults at continued risk of exposure


Primary Course – Adult

TABLE 12.2  Summary of Commonly Used Special Travel Vaccines



Doses spaced by 14 days results in only 40% seroconversion No accelerated schedule available None



Accelerated Schedule

Category C. No data available during lactation

Not recommended during pregnancy Category C. No data available during lactation

Category C (add reference)

No data available

Category C. Insufficient data about pregnancy or excretion in breastmilk

Pregnancy or Lactation


Travelers should only receive quadrivalent vaccine (ACYW). A C-conjugate vaccine is marketed in many countries for routine pediatric vaccination but is not appropriate for travelers

Registered by TGA in Australia 2011 Travelers should only receive quadrivalent vaccine (ACYW). A or A + C vaccine is marketed in many countries

Pediatric approval expected in 2012 or 2013

Some cross protection against heat-labile toxin of enterotoxigenic E. coli (ETEC) (see text). Licensed for travelers’ diarrhea protection in some countries; WHO prequalified Available only in India and Indonesia, contains O139 WHO prequalified (only Shanchol)


CHAPTER 12  Recommended/Required Travel Vaccines


Inactivated viral vaccine, human diploid cell vaccine (HDCV). Imovax rabies (Sanofi Pasteur)

Inactivated viral vaccine, purified chick embryo cell vaccine (PCECV). Rabavert or Rabipur (Novartis)


Menveo (Glaxo-SmithKline) Quadrivalent conjugate Neisseria meningitidis groups A, C, Y, W-135. Conjugated to CRM 197 Nimenrix (Glaxo-Smith Kline). Quadrivalent conjugate Neisseria meningitidis groups A, C, Y, W-135. Conjugated to TT Inactivated viral injectable. IPV (many brands)




Vaccine Type; Commercial Name (Manufacturer)

1 mL i.m. deltoid. Or 0.1 mL intradermal on the forearm. Preexposure schedule of 0, 7, and 21 or 28 days 1 mL i.m. deltoid. Never use gluteal muscle. Preexposure schedule of 0, 7, and 21 or 28 days


0.5 mL s.c. three doses at 0, 2, 8–14 months

One single i.m. dose for ≥2 years old; licensure for smaller children awaited 2012 One single i.m. dose for age ≥12 months

Primary Course – Adult


81%–95% (serotypedependent) Seroprotection in hSBA >97% seroconversion to all four serogroups after 28 days 82%–95% seroconversion to all four serotypes after 1 month


Primary series accelerated: three doses at 0, 1, 2 months (minimum 4 weeks apart). Give as many doses as time permits and complete remaining doses as soon as possible thereafter Days 0, 7, and 21

Same dose. If >10 years since completion of the primary vaccine series, boost once in adult life for travel to a polio-endemic area Not needed for typical travelers. Possibly 3 years if persistent high risk. Recommend checking serology before boosting See remarks above

Days 0, 7, and 21

None None

Accelerated Schedule

Not known at present Likely 3 years


TABLE 12.2  Summary of Commonly Used Special Travel Vaccines—cont’d

Category C. No data available during lactation

Category C. No data available during lactation

Category C. If protection required during pregnancy either OPV or IPV can be given. Not contraindicated during lactation

Category C. No data available during lactation Category C. No data available during lactation

Pregnancy or Lactation

Vaccine licensed in EC for adolescents and adults 70 years. Case fatality rate 65% Mild local reactions at injection site In small children occasionally mild fever predominantly after the first vaccination SAE: according to pharmacovigilance data (spontaneous reports, causality not checked) around 1.6 × 10–5 for both brands

control the number and locations of YF vaccination center sites, which may be at either public health clinics or private health centers, depending on the population of the area served, estimated at-risk population, and national vaccine program priorities. In many countries, especially in Latin America, the YF stamp is obtainable only from government clinics that provide the YF vaccine and not from private clinics even if they can purchase and administer the vaccine. The immunization must be given no less than 10 days prior to the planned date of entry to meet official requirements and is valid for life. In 2014 the World Health Assembly (of WHO) adopted the recommendation to remove the 10-year booster dose requirement from the IHR as of June 2016. This change has now been instituted and a completed International Certificate of Vaccination or Prophylaxis will be valid for

CHAPTER 12  Recommended/Required Travel Vaccines the lifetime of the vaccinee. This change was based on a systematic review of duration of immunity following vaccination.8 The findings of the review indicated >90% of vaccine recipients still have detectable levels of serum neutralizing antibodies up to 20 years post-YF vaccination. One study included in this review found >80% of US World War II veterans had neutralizing antibody levels that were detectable up to 35 years after a single dose of YF vaccine. Sustained neutralizing antibodies are also detectable in individuals ≥60 years of age.9 However, additional doses of YF vaccine are recommended for specific groups of travelers including pregnant women, children who received their first YF vaccine before the age of 2 years, hematopoietic stem cell transplant recipients, and human immunodeficiency virus (HIV)–infected persons, who might not develop a sustained immune response to YF vaccine.9,10 Vaccine administration is documented and stamped on the appropriate page of the International Certificate of Vaccination or Prophylaxis. Unlike the IHR 1969 that specifically exempted travelers making only airport transit stops in YF-risk countries, the IHR 2005 does not provide this exemption.7 Thus at the pretravel consultation, travelers need to provide a full travel itinerary including transit stops en route as individual countries may require proof of vaccination for all passengers arriving on an airplane from a risk country even if the passenger only transited that country. Under the IHR, a letter of waiver can be provided to travelers who have medical or other contraindications for receiving the YF vaccination.

Western Sahara


The waiver letter must be on official letterhead, signed by a physician authorized to provide the YF vaccination, and bear the stamp of the authorized center. Acceptance of the waiver letter is at the discretion of the receiving country. Travelers unable to receive the vaccine and using a letter of waiver to meet the YF vaccine entry requirement for a destination in a YF-endemic area need pretravel counseling about how to decrease the risks of natural disease transmission at destination, through effective use of insect precautions and avoidance of environments where the risk of transmission is likely to be higher. YF vaccination is recommended for travel to endemic areas, but it is generally not recommended for travel to areas with low potential for exposure unless a traveler’s itinerary places him or her at increased risk for exposure to YF virus. The CDC YF maps and country-specific information now designate three levels of YF vaccine recommendations: recommended, generally not recommended, and not recommended. Countries that contain areas with low potential for exposure to YF virus are not included on the official WHO list of countries with risk of YF virus transmission. Proof of YF vaccination should therefore not be required if traveling from a country with low potential for exposure to YF virus to a country with a vaccination entry requirement unless that country requires proof of YF vaccination from all arriving travelers. Travelers to coastal Brazil or Peru, Cuzco, and Machu Picchu do not need vaccination, except during outbreak situations. It is generally not





Saudi Arabia Mauritania

Mali Tidjikdja Nouakchott Arlit Sudan Kidal Aleg Timbuktu Niger Chad Cape Verde Agadez Nema Eritrea Khartoum Gao Yemen Senegal Asmara Praia Sanaa Dakar Banjul Mao Abeche El Fasher Burkina Niamey Bamako Faso Gambia Bissau Djibouti El Obeid Ndjamena Ouagadougou Djibouti Guinea-Bissau Guinea Nigeria Addis Somalia Conakry Ababa Côte Abuja Freetown d’Ivoire South Sierra Leone Cotonou Ethiopia Cen Afr Rep Sudan Yamoussoukro Monrovia Lome Cameroon Liberia Bangui Accra Juba Malabo Yaoundé Mogadishu Eq Guinea Dem Rep Uganda Rep of Congo Kampala Kenya Libreville of São Tomé Gabon Congo Kigali Nairobi São Tomé Rwanda and Bujumbura Brazzaville Burundi Principe Kinshasa Tanzania Dar es Salaam Luanda Angola

Malawi Zambia

Vaccination recommended


Vaccination not recommended A

Lilongwe Mozambique


Vaccination generally not recommended



Botswana Windhoek

Moroni Comoros

Antananarivo Madagascar


FIG. 12.1  Yellow fever (YF) maps, areas of (A) Africa.




SECTION 3 Immunization


FIG 12.1, cont’d (B) South American map with recent outbreaks in coastal areas of Brazil (https://wwwnc.; May 2018.

recommended for coastal Ecuador or Columbia and no longer required for travel to Quito or Bogota. For these destinations a waiver letter that is stamped with an official YF licence number should be provided.

Indications.  The main purpose of vaccination is prevention of disease in individuals at risk. YF vaccine is approved for use in all persons >9 months of age who have no YF vaccine contraindication.7,11 (See Chapter 13 for considerations on immunizing children 60 years of age was no higher than recipient 60 years of age.24 YF providers should be fully conversant with actual infection risk at the traveler’s destination or have resources at hand to determine relative risk. Naturally acquired YF infection in previously nonexposed individuals most often manifests as a life-threatening hemorrhagic fever.

Drug and Vaccine Interactions.  YF vaccine can be administered concurrently with measles-mumps-rubella (MMR), varicella, and smallpox. If this cannot be achieved, they should be given 4 weeks apart. However, if time is limited, the vaccines should be given within whatever time is available. Sabin (oral poliovirus vaccine [OPV]) can be given at any time. Immune globulin does not affect the immune response to YF vaccine and may be given concomitantly. The antibody response to YF vaccine is not inhibited by simultaneous immunization with bacilli Calmette-Guérin (BCG), oral cholera vaccine, measles, diphtheriapertussis-tetanus, meningococcal vaccine, poliomyelitis (OPV and inactivated polio vaccine [IPV]), hepatitis A, hepatitis B, tetanus, typhoid oral, and parenteral vaccines.15,25 There are no data on possible interference between YF and plague, rabies, or JE vaccines. Experimental data suggest that chloroquine inhibits the replication of YF virus in vitro. However, a study in humans has shown that antibody responses to the YF vaccine are not affected by routine antimalarial doses of chloroquine.

RECOMMENDED VACCINES Cholera Vaccines Cholera is a fecal-oral toxin-induced disease that is endemic in many countries with poor sanitation and inadequate food and water hygiene, and is most often transmitted in epidemic patterns. A disease distribution map is available at Global_ChoeraCases_ITHRiskMap.png?ua=1. The risk of cholera to an average traveler is extremely low (0.01%–0.001% per month of stay in a developing country), as most travelers practice proper hygiene when confronted with epidemic situations.26 Almost all cases of cholera now occur in Africa and Asia and the island of Hispaniola (Haiti and the Dominican Republic). Almost no cases occur in Latin America despite a large outbreak in the 1990s. In Bangladesh and India, a substantial number of cases are also caused by Vibrio cholerae O139, which is covered by Shanchol but not Dukoral vaccine (see upcoming discussion).27 Dukoral, which is licensed as a cholera vaccine in 60 countries, is a killed whole-cell recombinant B-subunit (WC-rBS) oral vaccine that contains formalin and heat-inactivated whole bacterial cells from the V. cholerae O1 Inaba, Ogawa, and El Tor strains and a recombinant B subunit of the toxin (see Table 12.1). WC-rBS is widely available outside but not in the United States, so may be purchased en route or on arrival by those few travelers for whom it is indicated. Other killed oral vaccines, in composition slightly different from Dukoral, are available in several other countries: Shanchol, a bivalent inactivated vaccine against O1 and O139, no recombinant B-subunit, is currently only available in India; mORC-Vax (identical to Shanchol) is in Vietnam and Indonesia; and Oravacs (only one O1 classical biotype and recombinant B subunit) is locally produced in China.28 The oral WC-rBS subunit toxin vaccine has some protective efficacy against enterotoxigenic Escherichia coli (ETEC) infection, a common cause of travelers’ diarrhea. The basis of this is immunologic cross reactivity between the B subunit of cholera toxin and the LT toxin (heat labile) of ETEC. Dukoral is registered for protection against travelers’ diarrhea in Canada, United Kingdom, New Zealand, Sweden, Norway,

and several other countries, but EMA and FDA refused licensure for prevention of travelers’ diarrhea. Results on protective efficacy against travelers’ diarrhea vary within a broad range and are not conclusive with respect to a clear recommendation.29 Shanchol (or mORC-Vax, other manufacturer and other preparation method, but identical type of vaccine) was licensed in 1997 in Vietnam and since that time >20 million doses have been used locally, mainly in children. In 2004 it was reformulated to meet good manufacturing practices (GMP) and WHO criteria, and in 2009 was licensed in India as Shanchol and mORC-Vax in Vietnam. Recently in the United States a live oral cholera vaccine, Vaxchora, was licensed for use in adults between 18 and 64 years of age. The vaccine contains a live V. cholerae O1 Inaba, ctxA gene deleted (mercury resistance gene inserted for diagnostic purposes). This vaccine (Orochol, Mutacol) was extensively tested in the 1990s and licensed in Switzerland, Australia, Argentina, Canada, and New Zealand. The vaccine was now reintroduced by PaxVax.

Indications.  Cholera vaccine is not required for entry into any country under the current IHR 2005. Cholera vaccine is not recommended for the short-term tourist traveling to an endemic country. Indications for travelers are restricted to high-risk populations at immediate risk of cholera. This primarily includes emergency relief workers and health care workers in endemic and epidemic areas in proximity to displaced populations, especially in crowded camps and urban slums.

Contraindications and Precautions (Applies for All Vaccines) • Severe allergic reaction (e.g., anaphylaxis) may occur after a previous vaccine dose or to a vaccine component. • Moderate or severe acute illness may occur with or without fever. • Do not administer any cholera vaccine in cases of acute febrile illness or acute GI illness. • Postpone administration in the event of persistent diarrhea or vomiting. • A history of severe local or systemic reactions following a previous dose is a contraindication. • Although the safety of Dukoral has not been studied in pregnant women, the risk is considered to be minimal since this is an inactivated oral vaccine. Depending on the context, administration to a pregnant woman may be considered after careful evaluation of benefits and risks. The live vaccine CVD 103HgR is contraindicated in pregnancy. • WC-rBS vaccine has been shown to be well tolerated in breastfeeding women. • Do not administer CVD 103HgR together with antibiotics.

Dosing Schedules.  For cholera prevention in adults, Dukoral is taken in two doses separated by 7–42 days. The series should be restarted if >42 days elapse. Each dose consists of 1 mg nontoxic subunit B and 1011 killed V. cholerae taken with an alkaline buffer mixed in a glass of water. The acid-labile vaccine is taken on an empty stomach (1 hour before or 1 hour after a meal). Vaccination should be completed at least 1 week prior to exposure. A booster of the same dose is recommended every 2 years for repeated exposure to cholera. In countries where WC-rBS has an indication for travelers’ diarrhea, boosters are required every 3 months for ETEC protection (see Table 12.2). Shanchol (and similar regional preparations): The basic immunization schedule consists of two vaccinations 14 days apart; a booster is recommended after 2 years. Vaxchora: Single dose, booster not determined. Buffer and vaccine have to be reconstituted in 100 mL water and consumed immediately. No eating and drinking either 1 hour before or after intake.


CHAPTER 12  Recommended/Required Travel Vaccines Measures of Immune Response and Duration of Immunity/Protection.  Dukoral: The primary immunization series provides short-term

Adverse Events.  All vaccines: Side effects have been reported as mild GI symptoms. Rarely some individuals have reported diarrhea, abdominal cramps, nausea, or fever (see Table 12.3).

protection (6 months) against cholera, with an overall protective efficacy of 85%–90% and 50%–60% for 2 years. For adults and children >6 years of age, protective efficacy averages 63% over a 3-year period without a booster dose but drops to 1 month; however, even travel duration of less than weeks was associated with JE infection, highlighting that even travel for short periods of time may pose a risk for JE. The case fatality rate was 18%, while 44% had neurologic sequelae and only 22% recovered completely. The estimate of overall risk for JE for the average tourist to endemic areas is 1 year previously, a booster dose should be given for those traveling to high-risk destinations. A recent phase II study in Indian children aged 1–3 years has shown that the vaccine was safe and immunogenic.53 A single dose of JC-VC is also effective at boosting JE neutralizing antibody levels in military personnel who had previously received three or more doses of mouse brain–derived JE vaccine (MBDV).54 Similarly, a single dose of JE-VC effectively boosted immunity in travelers primed with MBDV. In travelers primed with mouse brain–derived JE vaccine, the response rates following vaccination with JE-CV were 98% for Nakayama strain and 95% for SA14-14-2.55 In addition, in individuals primed with MBDV, a single booster dose of JE-VC resulted in cross-protective neutralizing antibody responses against JE genotypes I–IV.56 An accelerated 1-week JE-CV vaccination regimen has also been shown to produce protective neutralizing antibody responses in 99% of recipients; however, levels wane rapidly suggesting that this regimen may only provide short-term protection lasting up to 57 days after the initial vaccine dose.57 However, a subsequent study examining the 1-year immunogenicity of a 1-week accelerated JE-VC regimen showed that up to 94% of subjects still had seroprotective antibody titers 1 year after vaccination.58 A recent prospective, open-label, uncontrolled, multicenter, phase 4 study reported the safety and immunogenicity of two doses of JE-VCs 28 days apart in persons >65 years. This study demonstrated that although the vaccine was well tolerated only 65% of recipients achieved seroprotective antibody levels.59 The vaccine has also been studied in children from JE-endemic and nonendemic regions and shown to be immunogenic with up to 100% seroconversion rates and protective antibody levels.60 Long-term follow-up immunogenicity studies in children are ongoing. In the United States and Europe the vaccine (IXIARO) is approved for use in adults, adolescents, children, and infants ≥2 months. In Australia JC-VC (JESPECT) is approved for persons ≥18 years of age. The immunogenicity and safety of JE-VC has not been studied in immunocompromised individuals and pregnant women. Smaller amounts of mouse brain–derived JEV for local use are also produced in India, Japan, Korea, Thailand, and Vietnam.35,46 In Japan, a Vero cell–derived inactivated vaccine is produced using the Beijing-1 strain. It is available under the two trade names JEBIK V and ENCEVAC. Two clinical trials have shown that a three-dose regimen of JEBIK V has superior immunogenicity with a good safety profile, as compared with the mouse brain–derived Beijing-1 vaccine.61,62

Chimeric JE Vaccine (JE-CV) A chimeric JE vaccine developed by Acambis and Sanofi Pasteur (JE-CV; IMOJEV) containing recombinant JE antigen on a backbone of live attenuated YF virus has recently been registered in Australia for use from the age of 12 months46,63–65 (see Table 12.1). The vaccine results in high seroconversion rates in both adults (99%)66 and children (100% in children aged 2–5 years and 96% in infants 12–24 months).67,68 After 1 year, the seroprotection rates in the two age groups were 97% and 84%, respectively.67 The long-term immunogenicity profile of JE-CV is also promising. In adults the reported 5-year seroprotection rate after one dose of JE-CV vaccine was 93%, increasing to 97% if a booster is

CHAPTER 12  Recommended/Required Travel Vaccines given 6 months after the initial vaccination.69 A recent study modeling the persistence of neutralizing antibody responses after a single dose of JE-CV in adults predicted median antibody titers at 10 years of 38 (ranging from 10 to 174) and a corresponding seroprotection rate of 85.5%. This study estimated a median duration of seroprotection of 21.4 years. These studies would support the use of a single dose of JE-CV for primary immunization in adult travelers, which confers a high level of protection for at least 10 years.70 The reactogenicity profile of JE-CV was significantly better than JE-VAX and comparable to placebo in adults66 and to hepatitis A vaccine in children67 (see Table 12.2). The vaccine has now been shown to be safe and immunogenic in children with cross-protective71 and durable antibody responses in children >2 years of age.72 JE-CV vaccination of naïve children aged 12–18 months is well tolerated and results in seroconversion in 95% of children.73 In children aged 36–42 months and previously immunized with a single dose of JE-CV, a booster dose resulted in seroprotective antibody levels in 96.2% within 7 days of receiving the booster. Within 28 days 100% were seroprotected and 1 year after receiving the JE-CV booster dose, 99.4% of children remained seroprotected.74 In a long-term follow-up of JE-CV immune responses in children, a single dose of JE-CV as a booster following MBDV provides a seroprotection rate of 97% persisting up to at least 5 years. In toddlers not previously vaccinated against JE a single dose of JE-CV produces protective immune response persisting up to 5 years with a seroprotection rate of approximately 60%. Consequently, for children living in endemic areas, a single booster dose at 12–24 months following a single dose of primary vaccination is recommended.75

Live Attenuated SA-14-14-2 JE Vaccine A single-dose live attenuated SA-14-14-2 JE vaccine is widely used in China and has also been approved for use in Korea, Nepal, Sri Lanka, India Cambodia, Laos, Myanmar, and Thailand. The vaccine has been shown to be phenotypically and genotypically stable.76 A single dose of the vaccine results in 85%–100% seroconversion after a single dose, almost 100% seroconversion with two doses given 1–3 months apart; high seroprotection following one dose (80%–99%), almost complete seroprotection after two doses (>98%).33,77–80 The vaccine also results in a durable neutralizing antibody response that persists for up to 5 years.33,81,82 Live SA-14-14-2 vaccine accounts for the majority of the world’s production each year and has been administered to >300 million individuals to date.

Indications.  The risk of JE in persons from nonendemic countries traveling to Asia is very low with an overall estimated incidence of JE of less than one case per 1 million travelers. However, for expatriates and travelers who stay for prolonged periods in rural areas with active JEV transmission, the risk is likely to reflect that among the susceptible resident population.43,44,83 Factors for considering the JE vaccine are the duration of stay in the endemic area, extent of outdoor activities especially in rural areas, and season of travel.83 Extremes of age are associated with a higher likelihood of developing symptomatic disease. JE infection in a pregnant woman may potentially cause an intrauterine fetal infection or death. An average short-term traveler’s risk of acquiring JE during travel to endemic countries is low.5,84 Urban-only itineraries generally present no risk although there is some transmission at the suburban-rural interface in a few cities such as Beijing and Hanoi. Typical 1- to 2-week tourist itineraries that include brief trips to sites in rural areas similarly present insignificant risk. The estimate of overall risk for JE for the average tourist to endemic areas is 0.0–0.5 >0.5– 4.0 >4.0–8.5 >8.5–18.5 Data not available for the report No surveillance Not included Non-visible countries Malta Lichtenstein




1,000 Kilometers

FIG. 12.6  Tickborne encephalitis endemic areas. (Source: ECDC.)


SECTION 3 Immunization

for postencephalitic syndrome. The disease tends to be more severe with age and there is no treatment available. Currently there are two cell culture–derived formalin-inactivated TBE vaccines in use in Europe: Encepur (Novartis) and FSME-IMMUN (Baxter), manufactured in Germany and Austria, respectively117 (see Table 12.1). The K23 and Neudoerfl strains used are highly homologous and so are assumed to induce the same immune response.118 These vaccines are not available in the United States, but the FSME-IMMUN is available by special release in Canada and both vaccines are available in the United Kingdom on a named-patient basis. Two inactivated TBE vaccines are available locally in the Russian Federation (TBE vaccine Moscow and EnceVir) and some neighboring countries.117 China has also developed an inactivated TBE vaccine (SenTaiBao®, Changchun Institute of Biological Products [CIBP]) for the local market.119

Indications.  Risk to travelers is low unless extensive outdoor activities are planned in forested regions of countries where TBE is prevalent. In highly endemic regions such as rural Austria risk is calculated to be 1/10,000/month during transmission season (April–November), but retrospective data indicate only a small risk of 0.5–1.3 × 10-5 per visit to an endemic area.120 The decision to vaccinate travelers should take into account precise itinerary, duration of stay in risk areas, activities, intensity of TBE in the risk areas, and the transmission season. Travelers hiking, camping, and engaging in similar outdoor activities in rural wooded areas in risk regions are at highest risk.120 Vaccination strategy in endemic countries varies extraordinarily: only Austria has implemented a mass vaccination program of the whole population, resulting in a decrease in yearly cases by 90% in 25 years.121

Criteria • Active immunization with the TBE vaccine is recommended for persons planning to expatriate or live for an extended period of time in endemic countries with ongoing transmission. • Short-term travelers going to work (e.g., farmers, woodcutters, field work) or planning on adventure travel, extensive outdoors exposure, or camping in the forests of the endemic countries during the endemic season should be vaccinated.

Contraindications • Severe allergic reaction (e.g., anaphylaxis) may occur after a previous vaccine dose or to a vaccine component. • Moderate or severe acute illness with or without fever may occur. • TBE vaccine is formally contraindicated in persons with hypersensitivity to eggs. • Pregnant or lactating women, or persons with a history of autoimmune diseases, should undergo vaccination only if the risk of TBE disease is high and the vaccine is considered necessary.

Dosing Schedules. There are several dosing schedules licensed for the European, Russian, and Chinese vaccines.118 For details see Table 12.4. All TBE vaccines are whole virus, alum adsorbed, and inactivated vaccines. They follow a three-dose conventional schedule (0-1–3-9–12 months) with a first booster after 3 years and consecutive boosters dependent on age after 5 years (subjects 60 years of age). However, for the Western vaccines “accelerated” schedules have been licensed, allowing two (0-14 days) or three (0-7-21 days) vaccinations for a faster immunization, and consecutive boosters depending on the respective schedule of the primary immunization. Details for immunization schedules are available in the WHO position paper ( The Chinese vaccine for TBE follows a two-dose immunization schedule (14 days apart; no booster recommendation).119

Measures of Immune Response and Duration of Immunity/Protection.  Both European TBE vaccines induce seroconversion rates of nearly 100% after three doses on the conventional schedule. Seroconversion with both Encepur and FSME-IMMUN is close to 100% after two conventional-schedule doses. On the accelerated schedules Encepur gives 100% seroconversion after three doses, and FSME-IMMUN gives 95% seroconversion after two doses.117 The antibodies induced are protective toward all strains of TBE.122 In persons with history of a flavivirus disease or vaccination, antibody tests may be biased (except the neutralization test).123 The European TBE vaccines have proved very effective. Vaccination in regularly vaccinated subjects will confer 95%–100% protection.124,125 Vaccination breakthroughs do occur, but are rare.126,127

TABLE 12.4  TBE Vaccines: Dosing Schedules Immunization Schedules for TBE Vaccines According to WHO Recommendations or Manufacturer Intervals Given in Months Unless Indicated BASIC IMMUNIZATION CONVENTIONAL SCHEDULE (DOSE 1 ON DAY 0) FSME-IMMUN Encepur TBE-Moscow vaccine EnceVir CIBP


2nd Dose

3rd Dose

2nd Dose

3rd Dose

4th Dose

1–3 1–3 (14 days) 1–7 5–7 (14 days)

5–12 9–12 12 12 None

14 days 7 days

5–12 21 days


21–35 daysc

42–70 daysc


In persons ≥50 years of age interval of 3 years (Austria: persons ≥60 years of age). Considered as first booster. c Double dose of total 1 mL. d “Booster before endemic season.” a


First Booster (Years) 3 3 3 3 1d

Subsequent Boosters (Years) 5a 5a 3 3

CHAPTER 12  Recommended/Required Travel Vaccines Immunity after basic immunization will persist for at least 3 years, and after consecutive boosters for 5 years minimum.121 In older persons (>60 years of age) there is some evidence that boosters should be given at 3-year intervals.128 There is little evidence about immunogenicity and efficacy in immunocompromised subjects, although immune response may be impaired.129 No postexposure prophylaxis (immunoglobulins) is available.

Adverse Events.  The European TBE vaccines are considered to be safe.130 Local reactions can occur with both vaccines. Occasionally fatigue, nausea, lymphadenitis, or headaches occur. Fever and rash may be seen. Rarely, neurologic side effects such as neuritis have been reported, but causal relationship is not clear.

Drug and Vaccine Interactions.  The European vaccines are interchangeable after the basic immunization course.131

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19. Khromava AY, Eidex RB, Weld LH, et al. Yellow fever vaccine: an updated assessment of advanced age as a risk factor for serious adverse events. Vaccine 2005;23(25):3256–63. 20. Vellozzi C, Mitchell T, Miller E, et al. Yellow fever vaccine-associated viscerotropic disease (YEL-AVD) and corticosteroid therapy: eleven United States cases, 1996-2004. Am J Trop Med Hyg 2006;75(2): 333–6. 21. Lindsey NP, Schroeder BA, Miller ER, et al. Adverse event reports following yellow fever vaccination. Vaccine 2008;26(48):6077–82. 22. Monath TP. Suspected yellow fever vaccine-associated viscerotropic adverse events (1973 and 1978), United States. Am J Trop Med Hyg 2010;82(5):919–21. 23. Cottin P, Niedrig M, Domingo C. Safety profile of the yellow fever vaccine Stamaril(R): a 17-year review. Expert Rev Vaccines 2013;12(11):1351–68. 24. Tanizaki R, Ujiie M, Hori N, et al. Comparative study of adverse events after yellow fever vaccination between elderly and non-elderly travellers: questionnaire survey in Japan over a 1-year period. J Travel Med 2016;23(3). 25. Kollaritsch H, Que JU, Kunz C, et al. Safety and immunogenicity of live oral cholera and typhoid vaccines administered alone or in combination with antimalarial drugs, oral polio vaccine, or yellow fever vaccine. J Infect Dis 1997;175(4):871–5. 26. Zuckerman JN, Rombo L, Fisch A. The true burden and risk of cholera: implications for prevention and control. Lancet 2007;7(8):521–30. 27. WHO. Cholera, 2015. WER 2016;91(38):433–40. 28. Lopez AL, Gonzales ML, Aldaba JG, et al. Killed oral cholera vaccines: history, development and implementation challenges. Ther Adv Vaccines 2014;2(5):123–36. 29. Jelinek T, Kollaritsch H. Vaccination with Dukoral against travelers’ diarrhea (ETEC) and cholera. Expert Rev Vaccines 2008;7(5):561–7. 30. Chen WH, Cohen MB, Kirkpatrick BD, et al. Single-dose live oral cholera vaccine CVD 103-HgR protects against human experimental infection with Vibrio cholerae O1 El Tor. Clin Infect Dis 2016;62(11): 1329–35. 31. Herzog C. Successful comeback of the single-dose live oral cholera vaccine CVD 103 HgR. Travel Med Infect Dis 2016;14:373–7. 32. Tsai TF, Kollaritsch H, Que JU, et al. Compatible concurrent administration of yellow fever 17D vaccine with oral, live, attenuated p6olera CVD103-HgR and typhoid ty21a vaccines. J Infect Dis 1999;179(2):522–4. 33. Yun SI, Lee YM. Japanese encephalitis: the virus and vaccines. Hum Vaccin Immunother 2014;10(2):263–79. 34. Wang H, Liang G. Epidemiology of Japanese encephalitis: past, present, and future prospects. Ther Clin Risk Manag 2015;11:435–48. 35. Solomon T. Control of Japanese encephalitis—within our grasp? N Engl J Med 2006;355(9):869–71. 36. Solomon T, Dung NM, Kneen R, et al. Japanese encephalitis. J Neurol Neurosurg Psychiatr 2000;68(4):405–15. 37. Tiwari S, Singh RK, Tiwari R, et al. Japanese encephalitis: a review of the Indian perspective. Braz J Infect Dis 2012;16(6):564–73. 38. Kumari R, Joshi PL. A review of Japanese encephalitis in Uttar Pradesh, India. WHO South East Asia J Pub Health 2012;1(4):374–95. 39. Arai S, Matsunaga Y, Takasaki T, et al. Japanese encephalitis: surveillance and elimination effort in Japan from 1982 to 2004. Jpn J Infect Dis 2008;61(5):333–8. 40. Olsen SJ, Supawat K, Campbell AP, et al. Japanese encephalitis virus remains an important cause of encephalitis in Thailand. Int J Infect Dis 2010;14(10):e888–92. 41. Lee DW, Choe YJ, Kim JH, et al. Epidemiology of Japanese encephalitis in South Korea, 2007-2010. Int J Infect Dis 2012;16(6): e448–52. 42. Hsu LC, Chen YJ, Hsu FK, et al. The incidence of Japanese encephalitis in Taiwan—a population-based study. PLoS Negl Trop Dis 2014;8(7):e3030. 43. Hills SL, Griggs AC, Fisher M. Japanese Encephalitis in travelers from non-endemic countries, 1973–2008. Am J Trop Med Hyg 2010;82(5):930–6.


SECTION 3 Immunization

44. Lehtinen VA, Huhtamo E, Siikamaki H, et al. Japanese encephalitis in a Finnish traveler on a two-week holiday in Thailand. J Clin Virol 2008;43(1):93–5. 45. Ratnam I, Leder K, Black J, et al. Low risk of Japanese encephalitis in short-term Australian travelers to Asia. J Travel Med 2013;20(3): 206–8. 46. Halstead SB, Thomas SJ. Japanese encephalitis: new options for active immunization. Clin Infect Dis 2010;50(8):1155–64. 47. Li X, Ma SJ, Liu X, et al. Immunogenicity and safety of currently available Japanese encephalitis vaccines: a systematic review. Hum Vaccin Immunother 2014;10(12):3579–93. 48. Erra EO, Kantele A. The Vero cell-derived, inactivated, SA14-14-2 strain-based vaccine (Ixiaro) for prevention of Japanese encephalitis. Expert Rev Vaccines 2015;14(9):1167–79. 49. Dubischar-Kastner K, Kaltenboeck A, Klingler A, et al. Safety analysis of a Vero-cell culture derived Japanese encephalitis vaccine, IXIARO (IC51), in 6 months of follow-up. Vaccine 2010;28(39):6463–9. 50. Tauber E, Kollaritsch H, Korinek M, et al. Safety and immunogenicity of a Vero-cell-derived, inactivated Japanese encephalitis vaccine: a non-inferiority, phase III, randomised controlled trial. Lancet 2007;370:1847–53. 51. Schuller E, Jilma B, Voicu V, et al. Long-term immunogenicity of the new Vero cell-derived, inactivated Japanese encephalitis virus vaccine IC51. Six and 12 month results of a multicenter follow-up phase 3 study. Vaccine 2008;26:4328–86. 52. Dubischar-Kastner K, Eder S, Buerger V, et al. Long-term immunity and immune response to a booster dose following vaccination with the inactivated Japanese encephalitis vaccine IXIARO, IC51. Vaccine 2010;28(32):5197–202. 53. Kaltenbock A, Dubischar-Kastner K, Schuller E, et al. Immunogenicity and safety of IXIARO (IC51) in a Phase II study in healthy Indian children between 1 and 3 years of age. Vaccine 2010;28(3):834–9. 54. Woolpert T, Staples JE, Faix DJ, et al. Immunogenicity of one dose of Vero cell culture-derived Japanese encephalitis (JE) vaccine in adults previously vaccinated with mouse brain-derived JE vaccine. Vaccine 2012;30(20):3090–6. 55. Erra EO, Askling HH, Rombo L, et al. A single dose of vero cell-derived Japanese encephalitis (JE) vaccine (Ixiaro) effectively boosts immunity in travelers primed with mouse brain-derived JE vaccines. Clin Infect Dis 2012;55(6):825–34. 56. Erra EO, Askling HH, Yoksan S, et al. Cross-protection elicited by primary and booster vaccinations against Japanese encephalitis: a two-year follow-up study. Vaccine 2013;32(1):119–23. 57. Jelinek T, Burchard GD, Dieckmann S, et al. Short-term immunogenicity and safety of an accelerated pre-exposure prophylaxis regimen with Japanese encephalitis vaccine in combination with a rabies vaccine: a phase III, multicenter, observer-blind study. J Travel Med 2015;22(4):225–31. 58. Cramer JP, Jelinek T, Paulke-Korinek M, et al. One-year immunogenicity kinetics and safety of a purified chick embryo cell rabies vaccine and an inactivated Vero cell-derived Japanese encephalitis vaccine administered concomitantly according to a new, 1-week, accelerated primary series. J Travel Med 2016;23(3). doi:10.1093/jtm/taw011. 59. Cramer JP, Dubischar K, Eder S, et al. Immunogenicity and safety of the inactivated Japanese encephalitis vaccine IXIARO(R) in elderly subjects: open-label, uncontrolled, multi-center, phase 4 study. Vaccine 2016;34(38):4579–85. 60. Firbas C, Jilma B. Product review on the JE vaccine IXIARO. Hum Vaccin Immunother 2015;11(2):411–20. 61. Kikukawa A, Gomi Y, Akechi M, et al. Superior immunogenicity of a freeze-dried, cell culture-derived Japanese encephalitis vaccine (inactivated). Vaccine 2012;30(13):2329–35. 62. Okada K, Iwasa T, Namazue J, et al. Safety and immunogenicity of a freeze-dried, cell culture-derived Japanese encephalitis vaccine (Inactivated) (JEBIK®V) in children. Vaccine 2012;30(41):5967–72. 63. Monath TP, Guirakhoo F, Nichols R, et al. Chimeric live, attenuated vaccine against Japanese encephalitis (ChimeriVax-JE): phase 2 clinical trials for safety and immunogenicity, effect of vaccine dose and schedule,

and memory response to challenge with inactivated Japanese encephalitis antigen. J Infect Dis 2003;188(8):1213–30. 64. Guy B, Guirakhoo F, Barban V, et al. Preclinical and clinical development of YFV 17D-based chimeric vaccines against dengue, West Nile and Japanese encephalitis viruses. Vaccine 2010;28(3):632–49. 65. Morrison D, Legg TJ, Billings CW, et al. A novel tetravalent dengue vaccine is well tolerated and immunogenic against all 4 serotypes in flavivirus-naive adults. J Infect Dis 2010;201(3):370–7. 66. Torresi J, McCarthy K, Feroldi E, et al. Immunogenicity, safety and tolerability in adults of a new single-dose, live-attenuated vaccine against Japanese encephalitis: randomised controlled phase 3 trials. Vaccine 2010;28(50):7993–8000. 67. Chokephaibulkit K, Sirivichayakul C, Thisyakorn U, et al. Safety and immunogenicity of a single administration of live-attenuated Japanese encephalitis vaccine in previously primed 2- to 5-year-olds and naive 12- to 24-month-olds: multicenter randomized controlled trial. Pediatr Infect Dis J 2010;29(12):1111–17. 68. Chokephaibulkit K, Plipat N, Yoksan S, et al. A comparative study of the serological response to Japanese encephalitis vaccine in HIV-infected and uninfected Thai children. Vaccine 2010;28(20):3563–6. 69. Nasveld PE, Ebringer A, Elmes N, et al. Long term immunity to live attenuated Japanese encephalitis chimeric virus vaccine: randomized, double-blind, 5-year phase II study in healthy adults. Hum Vaccin 2010;6(12):1038–46. 70. Desai K, Coudeville L, Bailleux F. Modelling the long-term persistence of neutralizing antibody in adults after one dose of live attenuated Japanese encephalitis chimeric virus vaccine. Vaccine 2012;30(15):2510–15. 71. Bonaparte M, Dweik B, Feroldi E, et al. Immune response to liveattenuated Japanese encephalitis vaccine (JE-CV) neutralizes Japanese encephalitis virus isolates from south-east Asia and India. BMC Infect Dis 2014;14:156. 72. Chokephaibulkit K, Houillon G, Feroldi E, et al. Safety and immunogenicity of a live attenuated Japanese encephalitis chimeric virus vaccine (IMOJEV®) in children. Expert Rev Vaccines 2016;15(2):153–66. 73. Feroldi E, Pancharoen C, Kosalaraksa P, et al. Single-dose, live-attenuated Japanese encephalitis vaccine in children aged 12-18 months: randomized, controlled phase 3 immunogenicity and safety trial. Hum Vaccine Immunother 2012;8(7):929–37. 74. Feroldi E, Capeding MR, Boaz M, et al. Memory immune response and safety of a booster dose of Japanese encephalitis chimeric virus vaccine (JE-CV) in JE-CV-primed children. Hum Vaccine Immunother 2013;9(4):889–97. 75. Chokephaibulkit K, Sirivichayakul C, Thisyakorn U, et al. Long-term follow-up of Japanese encephalitis chimeric virus vaccine: immune responses in children. Vaccine 2016;34(46):5664–9. 76. Yu Y. Phenotypic and genotypic characteristics of Japanese encephalitis attenuated live vaccine virus SA14-14-2 and their stabilities. Vaccine 2010;28(21):3635–41. 77. Update: Guillain-Barre syndrome among recipients of Menactra meningococcal conjugate vaccine—United States, June 2005-September 2006. MMWR 2006;55(41):1120–4. 78. Hennessy S, Liu Z, Tsai TF, et al. Effectiveness of live-attenuated Japanese encephalitis vaccine (SA14-14-2): a case-control study. Lancet 1996;347(9015):1583–6. 79. Liu ZL, Hennessy S, Strom BL, et al. Short-term safety of live attenuated Japanese encephalitis vaccine (SA14-14-2): results of a randomized trial with 26,239 subjects. J Infect Dis 1997;176(5):1366–9. 80. Ohrr H, Tandan JB, Sohn YM, et al. Effect of single dose of SA 14-14-2 vaccine 1 year after immunisation in Nepalese children with Japanese encephalitis: a case-control study. Lancet 2005;366(9494):1375–8. 81. Tandan JB, Ohrr H, Sohn YM, et al. Single dose of SA 14-14-2 vaccine provides long-term protection against Japanese encephalitis: a casecontrol study in Nepalese children 5 years after immunization. Vaccine 2007;25(27):5041–5. 82. Sohn YM, Tandan JB, Yoksan S, et al. A 5-year follow-up of antibody response in children vaccinated with single dose of live attenuated SA14-14-2 Japanese encephalitis vaccine: immunogenicity and anamnestic responses. Vaccine 2008;26(13):1638–43.

CHAPTER 12  Recommended/Required Travel Vaccines 83. Fischer M, Lindsey N, Staples JE, et al. Japanese encephalitis vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2010;59(RR–1):1–27. 84. Shlim DR, Solomon T. Japanese encephalitis vaccine for travelers: exploring the limits of risk. Clin Infect Dis 2002;35(2):183–8. 85. Paulke-Korinek M, Kollaritsch H, Kundi M, et al. Persistence of antibodies six years after booster vaccination with inactivated vaccine against Japanese encephalitis. Vaccine 2015;33(30):3600–4. 86. Harrison LH, Trotter CL, Ramsay ME. Global epidemiology of meningococcal disease. Vaccine 2009;27(2):S51–63. 87. Bilukha OO, Rosenstein N. Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005;54(RR–7):1–21. 88. Pelton SI. The global evolution of meningococcal epidemiology following the introduction of meningococcal vaccines. J Adolesc Health 2016;59(2):S3–11. 89. Halperin SA, Bettinger JA, Greenwood B, et al. The changing and dynamic epidemiology of meningococcal disease. Vaccine 2012;30(2):S26–36. 90. Bilukha O, Messonnier N, Fischer M. Use of meningococcal vaccines in the United States. Pediatr Infect Dis J 2007;26(5):371–6. 91. Girard MP, Preziosi MP, Aguado MT, et al. A review of vaccine research and development: meningococcal disease. Vaccine 2006;24(22):4692–700. 92. Keyserling H, Papa T, Koranyi K, et al. Safety, immunogenicity, and immune memory of a novel meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine (MCV-4) in healthy adolescents. Arch Pediatr Adolesc Med 2005;159(10):907–13. 93. Pichichero M, Casey J, Blatter M, et al. Comparative trial of the safety and immunogenicity of quadrivalent (A, C, Y, W-135) meningococcal polysaccharide-diphtheria conjugate vaccine versus quadrivalent polysaccharide vaccine in two- to ten-year-old children. Pediatr Infect Dis J 2005;24(1):57–62. 94. Snape MD, Pollard AJ. Meningococcal polysaccharide-protein conjugate vaccines. Lancet 2005;5(1):21–30. 95. Dbaibo G, Macalalad N, Aplasca-De Los Reyes MR, et al. The immunogenicity and safety of an investigational meningococcal serogroups A, C, W-135, Y tetanus toxoid conjugate vaccine (ACWY-TT) compared with a licensed meningococcal tetravalent polysaccharide vaccine: a randomized, controlled non-inferiority study. Hum Vaccin Immunother 2012;8(7):873–80. 96. Vesikari T, Forsten A, Boutriau D, et al. Randomized trial to assess the immunogenicity, safety and antibody persistence up to three years after a single dose of a tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine in toddlers. Hum Vaccin Immunother 2012;8(12):1892–903. 97. Dbaibo G, El-Ayoubi N, Ghanem S, et al. Immunogenicity and safety of a quadrivalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (MenACWY-TT) administered to adults aged 56 years and older: results of an open-label, randomized, controlled trial. Drugs Aging 2013;30(5):309–19. 98. Santolaya ME, O’Ryan ML, Valenzuela MT, et al. Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study. Lancet 2012;379(9816):617–24. 99. Vesikari T, Esposito S, Prymula R, et al. Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials. Lancet 2013;381(9869):825–35. 100. Vesikari T, Wysocki J, Beeslaar J, et al. Immunogenicity, safety, and tolerability of bivalent rLP2086 meningococcal group B vaccine administered concomitantly with diphtheria, tetanus, and acellular pertussis and inactivated poliomyelitis vaccines to healthy adolescents. J Pediatric Infect Dis Soc 2016;5(2):180–7. 101. Ostergaard L, Lucksinger GH, Absalon J, et al. A phase 3, randomized, active-controlled study to assess the safety and tolerability of meningococcal serogroup B vaccine bivalent rLP2086 in healthy adolescents and young adults. Vaccine 2016;34(12):1465–71.


102. Muse D, Christensen S, Bhuyan P, et al. A phase 2, randomized, active-controlled, observer-blinded study to assess the immunogenicity, tolerability and safety of bivalent rLP2086, a meningococcal serogroup B vaccine, coadministered with tetanus, diphtheria and acellular pertussis vaccine and serogroup A, C, Y and W-135 meningococcal conjugate vaccine in healthy US adolescents. Pediatr Infect Dis J 2016;35(6): 673–82. 103. Snape MD, Perrett KP, Ford KJ, et al. Immunogenicity of a tetravalent meningococcal glycoconjugate vaccine in infants: a randomized controlled trial. JAMA 2008;299(2):173–84. 104. Perrett KP, Snape MD, Ford KJ, et al. Immunogenicity and immune memory of a nonadjuvanted quadrivalent meningococcal glycoconjugate vaccine in infants. Pediatr Infect Dis J 2009;28(3):186–93. 105. Jackson LA, Jacobson RM, Reisinger KS, et al. A randomized trial to determine the tolerability and immunogenicity of a quadrivalent meningococcal glycoconjugate vaccine in healthy adolescents. Pediatr Infect Dis J 2009;28(2):86–91. 106. Reisinger KS, Baxter R, Block SL, et al. Quadrivalent meningococcal vaccination of adults: phase III comparison of an investigational conjugate vaccine, MenACWY-CRM, with the licensed vaccine, Menactra. Clin Vaccine Immunol 2009;16(12):1810–15. 107. Stamboulian D, Lopardo G, Lopez P, et al. Safety and immunogenicity of an investigational quadrivalent meningococcal CRM(197) conjugate vaccine, MenACWY-CRM, compared with licensed vaccines in adults in Latin America. Int J Infect Dis 2010;14(10):e868–75. 108. Lagos R, Papa T, Munoz A, et al. Safety and immunogenicity of a meningococcal (Groups A, C, Y, W-135) polysaccharide diphtheria toxoid conjugate vaccine in healthy children aged 2 to 10 years in Chile. Hum Vaccin 2005;1(6):228–31. 109. Halperin SA, Diaz-Mitoma F, Dull P, et al. Safety and immunogenicity of an investigational quadrivalent meningococcal conjugate vaccine after one or two doses given to infants and toddlers. Eur J Clin Microbiol Infect Dis 2010;29(3):259–67. 110. WHO. Polio vaccines: WHO position paper—March 2016. WER 2016;91(12):145–68. 111. Bottiger M. Polio immunity to killed vaccine: an 18-year follow-up. Vaccine 1990;8(5):443–5. 112. WHO. Human rabies transmitted by dogs: current status of global data, 2016. WER 2016;91(2):13–20. 113. WHO. Rabies vaccines: WHO position paper. WER 2010;85: 309–20. 114. Mansfield KL, Andrews N, Goharriz H, et al. Rabies pre-exposure prophylaxis elicits long-lasting immunity in humans. Vaccine 2016;34:5959–67. 115. Jelinek T, Cramer JP, Dieckmann S, et al. Evaluation of rabies immunogenicity and tolerability following a purified chick embryo cell rabies vaccine administered concomitantly with a Japanese encephalitis vaccine. Travel Med Infect Dis 2015;13(3):241–50. 116. Suss J. Tick-borne encephalitis 2010: epidemiology, risk areas, and virus strains in Europe and Asia—an overview. Ticks Tick Borne Dis 2011;2(1):2–15. 117. Kollaritsch H, Paulke-Korinek M, Holzmann H, et al. Vaccines and vaccination against tick-borne encephalitis. Expert Rev Vaccines 2012;11(9):1103–19. 118. Vaccines against tick-borne encephalitis: WHO position paper. Wkly Epidemiol Rec 2011;86(24):241–56. 119. Xing Y, Schmitt HJ, Arguedas A, et al. Tick-borne encephalitis in China: a review of epidemiology and vaccines. Vaccine 2017;35(9): 1227–37. 120. Steffen R. Epidemiology of tick-borne encephalitis (TBE) in international travellers to Western/Central Europe and conclusions on vaccination recommendations. J Travel Med 2016;23(4). doi: 10.1093/ jtm/taw018. 121. Hombach JBA, Kollaritsch H. Vaccines against tick-borne encephalitis. In: Plotkin SA, Orenstein W, Offit PA, et al, eds. Plotkin’s Vaccines. 7th ed. Philadelphia: Saunders; 2016. 122. WHO. Grading crossprotection. Available at: immunization/TBE_grad_crossprotection.pdf?ua=12011.


SECTION 3 Immunization

123. Holzmann H, Kundi M, Stiasny K, et al. Correlation between ELISA, hemagglutination inhibition, and neutralization tests after vaccination against tick-borne encephalitis. J Med Virol 1996;48(1):102–7. 124. Heinz FX, Holzmann H, Essl A, et al. Field effectiveness of vaccination against tick-borne encephalitis. Vaccine 2007;25(43):7559–67. 125. Heinz FX, Stiasny K, Holzmann H, et al. Vaccination and tick-borne encephalitis, central Europe. Emerg Infect Dis 2013;19(1):69–76. 126. Andersson CR, Vene S, Insulander M, et al. Vaccine failures after active immunisation against tick-borne encephalitis. Vaccine 2010;28(16):2827–31. 127. Stiasny K, Holzmann H, Heinz FX. Characteristics of antibody responses in tick-borne encephalitis vaccination breakthroughs. Vaccine 2009;27(50):7021–6.

128. Paulke-Korinek M, Kundi M, Laaber B, et al. Factors associated with seroimmunity against tick borne encephalitis virus 10 years after booster vaccination. Vaccine 2013;31(9):1293–7. 129. Hertzell KB, Pauksens K, Rombo L, et al. Tick-borne encephalitis (TBE) vaccine to medically immunosuppressed patients with rheumatoid arthritis: a prospective, open-label, multi-centre study. Vaccine 2016;34(5):650–5. 130. WHO. Grading of safety. 2012. Available at: immunization/TBE_grad_safety.pdf?ua=1. 131. WHO. Vaccines against tick-borne encephalitis. WHO position paper. WER 2011;24(86):241–56.

13  Pediatric Travel Vaccinations Sheila M. Mackell and Mike Starr

KEY POINTS • Polysaccharide vaccines (meningococcal, pneumococcal, and typhoid) are poorly immunogenic and therefore less effective in children 3 years: 0.5 mL IM 1 month apart (2 doses) Live (imojev) 0.5 mL SC 2 doses at 0, 2 months

Optimal interval not established: Manufacturer recommends 6 months for ages 2–6 years, and 2 years for age >6 years (see footnote c) See text Also available in combination with hepatitis B vaccine

Meningococcal polysaccharide vaccine (A, C, W135, Y)

>2 years

1 dose (0.5 mL SC)


2 months –55 years

1 dose


>12 months

1 dose

Plague vaccine Rabies vaccine

>18 years Any age

Tickborne encephalitisb

1–11 years

Typhoid, oral Ty21a Typhoid, Vi, parenteral

>3 yearsa >6 years >2 years

Not for use in children 3 doses (1 mL IM, deltoid/anterolateral thigh for infants, or 0.1 mL ID) at 0, 7, 21, or 28 days Encepur Kinder (Chiron-Behring): IM at 0, 1–3 months, and 9–12 months FSME-IMMUN Junior (Baxter): 3 doses (0.25 mL IM) at 0, 1–3 months, and 9–12 months 3 doses: 1 sachet PO in 100 mL water every other day 4 doses: 1 capsule PO every other day 1 dose (0.5 mL IM)

Yellow fever

>9 months

1 dose (0.5 mL SC)

Optimum regimen not determined but current recommendations are for single booster dose 1–2 years after primary dose in children ≥9 months to 18-year-olds. ID, Intradermally; IM, intramuscularly; PO, by mouth; SC, subcutaneously. b

the capsules whole. The capsules need to be swallowed intact so that the contained liquid suspension of live bacteria passes undisturbed through the acid milieu of the stomach. In many countries, but not the United States, a lyophilized preparation that is reconstituted in water is available in a three-dose regimen for children >3 years. The Vi polysaccharide vaccine is poorly immunogenic in children 2 years of age and confers protection for 2–3 years. The four-dose series of the oral vaccine provides protection for 4–5 years. Children 38°C is reported in children between 1 and 2 years old, therefore vaccination in this age group must be considered on an individual basis.


In some countries FSME-IMMUN Junior (Baxter), formulated for children 1–12 years old, is available. The adult formulation is recommended for those >12 years. Dosages are listed in Table 13.6 along with a summary of other pediatric travel vaccines. FSME-IMMUN is available in Canada and by a special release mechanism in the United Kingdom. Tickborne encephalitis vaccine is not available in the United States or Australia. Two additional TBE vaccines are licensed in Russia and one in China.37

BCG Tuberculosis (TB) is more rapidly progressive and more severe in children than in adults. BCG vaccine protects against disseminated and severe forms of the disease in young children, but is only 50% protective against pulmonary TB in older children and adults. BCG is included in the routine immunization schedule in most developing countries. In these countries, infants are immunized at birth with a single dose. BCG is not routinely recommended or used in children in most developed countries, where management relies on screening, case identification, and treatment. The vaccine is contraindicated in immunocompromised individuals. Although there is wide disagreement across national boundaries, BCG should be considered in infants and children 65 years compared with the >18–35 age group. Mortality among infants and children was low, with no deaths in the ≤5 age group, and a case fatality of 0.33% (11/3347) in those aged 5–18 years.18 Death rates in those


SECTION 4 Malaria

>60 years were six times higher than in younger age groups in another European study.21 Although most deaths are due to falciparum, there is also clear evidence that the chance of a fatal outcome from vivax infection increases with age.22

WHERE ARE TRAVELERS AT RISK OF ACQUIRING MALARIA? There have been major advances in malaria control and elimination over the past 15 years with substantial falls in the number of cases and deaths in endemic regions. Assessing the risk for travelers is often challenging and the risk to a traveler may not be the same as someone from an endemic population, as different activities and use of preventive measures may modify the risk substantially.23 However, there is a general correlation between intensity of transmission and risk to travelers. While the risk of malaria has diminished substantially in many parts of Asia such that many authorities no longer recommend prophylaxis, the risk to travelers to sub-Saharan Africa remains substantial. Fig. 14.3 illustrates the variation in intensity of P. falciparum transmission across the world. Data from GeoSentinel, an international network of travel medicine clinics, suggest that the incidence associated with travel to Africa was 4–20 times higher than with travel to Asia or the Americas (Table 14.3).24 Similarly, African travel was associated with an odds ratio of 7.8 for malaria being the cause of fever in returning travelers, when compared with travel to other endemic regions.25 Estimating the absolute risk of acquiring malaria for travelers is difficult. Without chemoprophylaxis, the risk of symptomatic malaria was historically estimated to be 1.2% per month in East Africa.26 In Italian travelers between 1989 and 1997, the incidence of acquiring malaria was calculated as 1.5/1000 travelers in Africa, 0.11/1000 in Asia, and 0.04/1000 in Central-South America.15 More recent rates for Canadian travelers from Ontario were estimated as 2.26/1000 travelers to Africa, compared with 0.06 for Asia and 0.018 for the Americas.27 Travel medicine practitioners can access destination risk information from many sources, including national guidelines, the World Health Organization (WHO), the Internet, and numerous commercial software and hardcopy sources, although the advice is often inconsistent and contradictory and guidelines have been criticized for their lack of a clear methodologic approach.28,29 Health Information for International Travel 2018 (the CDC Yellow Book) is a common source for many

US-based practitioners. An online version and a free download in pdf format are available at There are two types of malaria risk information in the Yellow Book. Geographic risk is described at the country level, with clarification in some cases of specific risk areas based on elevation above sea level, focal areas within countries, and some popular tourist destinations. This information is limited by the infrequent consideration of seasonal variability and the inherent difficulty in quantifying actual transmission risk to an individual traveler. For example, in much of West Africa, transmission of malaria is intense and year round, whereas in the tropical Americas the transmission risk is focal, seasonal, and often very low. Necessarily, geographic risk information is listed by political boundaries within countries in the Yellow Book and other guidelines. However, for precise risk definition, it is necessary to have access to sufficiently detailed maps or data to locate the travel destinations and the listed risk areas. The Yellow Book also provides malaria-specific recommendations concerning antimalarial drugs for chemoprophylaxis licensed for use in the United States. Although there are many other sources of geographic risk information, it is challenging for the infrequent or nonexpert practitioner of travel medicine to identify and assess the credibility of these sources in a busy practice environment. Malaria destination risk information is also available from the WHO International Travel and Health home page (, the Canadian Committee to Advise on Tropical Medicine and Travel (CATMAT) Recommendations for the Prevention and Treatment of Malaria Among International Travelers 2014 (, the UK National Travel Health Network and Centre (NaTHNaC) Health Information for Overseas Travel ( disease/113/malaria), and several other national level organizations. American readers should note that some recommendations from different authorities may differ from CDC recommendations. In the last few years, the epidemiology of travelers’ malaria has been better defined owing to the formation of traveler-specific surveillance networks such as GeoSentinel ( and the European Network on Imported Infectious Disease Surveillance, also known as TropNet ( Recent malaria-specific publications from both groups have better defined the risks of malaria in travelers,13,31–33 but there remain challenges in accurately assessing the risk for any individual traveler and any individual destination.

TABLE 14.3  Relative Risk of Travel-Associated Malaria by Destination

Region Visited b

Very low-risk area Caribbean North Africa South America Southeast Asia Central America South Asia Oceania Sub-Saharan Africa a

Cases of Malaria

No. of Travelers Visiting Region (Millions)a

Risk per 10 Million Travelers of Presenting to a GeoSentinel Clinic With Malaria

83 9 10 17 64 24 45 31 514

1766.9 50.5 30.8 43.8 118.8 13.5 17.8 8.6 52.7

0.5 1.8 3.2 3.9 5.4 17.8 25.3 36 97.5

RR (95% CI) 1 (0.7–1.4) 3.8 (1.9–7.5) 6.9 (3.6–13.3) 8.3 (4.9–13.9) 11.5 (8.3–15.9) 37.8 (24.0–59.6) 53.8 (37.4–77.4) 76.7 (50.8–115.9) 207.6 (164.7–261.8)

Estimated from World Travel Organization data. Nonrisk/very low-risk areas were Europe, Northeast Asia, Australia/New Zealand, North America, and the Middle East. CI, Confidence interval; RR, relative risk. From Leder K, Black J, O’Brien D, et al. Malaria in travelers: a review of the GeoSentinel surveillance network. Clin Infect Dis 2004; 39:1104–12. Used with permission. b

CHAPTER 14  Malaria: Epidemiology and Risk to the Traveler



FIG. 14.3  Current estimates of transmission intensity of Plasmodium falciparum (top) and Plasmodium vivax (bottom). (A, Adapted with permission from Hay SI, Guerra C, Gething PW, et al. A world malaria map: Plasmodium endemicity in 2007. PLoS Medicine 2009;Mar 6[3]; and Guerra CA, Howes RE, Patil AP, et al. The international limits and population at risk of Plasmodium vivax transmission in 2009. PLoS Negl Trop Dis 2010;4[8]:e774.)



SECTION 4 Malaria

DRUG-RESISTANT MALARIA Chloroquine Chloroquine (CQ)-resistant P. falciparum (CRPf) malaria is now found throughout most malaria-endemic areas, including all of sub-Saharan Africa, South America, the Indian subcontinent, Southeast Asia, and Oceania. CRPf was first recognized in the early 1960s in Colombia,34 spreading throughout the Amazon basin within a decade. It was then identified in Cambodia,35 spreading through South Asia and into East Africa in 1978. By the late 1980s CRPf was widely distributed throughout sub-Saharan Africa.36 There remain only a few countries with CQ-sensitive P. falciparum malaria, including all countries of Central America west of the Panama Canal, the island of Hispaniola (Haiti and the Dominican Republic), and some countries in the Middle East.13 The risk in these countries is often seasonal, focal, unpredictable, and quite low. Occasionally, small epidemic outbreaks can occur. The risk of acquiring P. vivax malaria is much higher than that of P. falciparum malaria in many of these countries with CQ-sensitive malaria, especially the Americas. CQ-resistant P. vivax (CRPv) malaria was first described in an Australian soldier returning from Papua New Guinea in 1987.37 Since that initial recognized case, studies have shown that CRPv is relatively widespread in Indonesia and Papua New Guinea, with more sporadic reports from Borneo, Thailand, Myanmar (Burma), India, Turkey, Ethiopia, Colombia, Peru, Brazil, and Guyana.38,39 Since all these areas are also coendemic with CRPf, this has minimal impact on recommendations for chemoprophylaxis for the traveler, as the optimum chemoprophylaxis choice for these areas would not be CQ. Two cases of CQ-resistant P. malariae have been reported from Indonesia, but there is no other evidence that this is a significant problem.40

China India



Thailand Cambodia


Mefloquine Significant mefloquine (MQ) resistance is geographically limited to portions of Southeast Asia (Fig. 14.4). The prevalence of MQ resistance in this region in often very high, making MQ a poor choice for chemoprophylaxis for travelers to this area.41 Sporadic cases of MQ prophylaxis failures have been reported from other locations in Africa and South America, but these few cases do not indicate widespread resistance and do not alter routine travel chemoprophylaxis recommendations.42,43



Mefloquine-Resistant Malaria

FIG. 14.4  Map depicting areas of mefloquine resistance. (CDC 2012 Yellow Book. Chap 3.)

Doxycycline There are no known geographic areas or destinations where doxycycline should not be recommended because of drug resistance. However, decreased in vitro drug susceptibility for some African P. falciparum isolates is associated with increased copy numbers and amino acid sequence polymorphisms of transporter genes.44 The clinical relevance of this observation is not known.

Atovaquone/Proguanil Resistance to either atovaquone or proguanil is based on single point mutations in the cytochrome B gene or the dihydrofolate reductase (DHFR) gene, respectively. Drug-resistant parasites can emerge rather quickly during treatment when either drug is used separately. In combination, therapeutic failures caused by treatment-emergent drug resistance are much less common. Surveillance of cytochrome B mutations in returning travelers has identified only a very few such mutations, not always associated with therapeutic failure.45 In these cases, parasite recrudescence observed >3 weeks after initial clinical improvement (late treatment failure) had been reported in returning travelers treated with atovaquone/proguanil. Despite extensive use for over a decade, prophylaxis breakthroughs on atovaquone/proguanil are incredibly rare and the limited number of prophylaxis breakthroughs have been

associated with very low or nondetectable drug levels of either atovaquone or cycloguanil, the primary metabolite of proguanil, suggesting a therapeutic failure due to pharmacokinetic reasons.46–48

Primaquine Primaquine is used as an antihypnozoite agent to prevent relapse of P. vivax or P. ovale malaria. When considering drug resistance and primaquine, it is important to distinguish the different indications for which primaquine is used. When used in combination with CQ for the radical cure of P. vivax malaria in symptomatic patients, it has long been recognized that strains of P. vivax from some areas (e.g., Oceania) require higher doses and have higher rates of failure than strains from other regions (e.g., India).49 However, there is no evidence of resistance to primaquine when used as primary prophylaxis. Primaquine is not approved by the US FDA for a primary prophylaxis indication, though the CDC and other authorities recognize its potential use as an alternative agent particularly for short-duration travel to areas with high levels of P. vivax transmission.50 However, its use is limited by the need to measure glucose-6-phosphate-dehydrogenase (G6PD) status and the recent finding in a challenge study that CYP2D6 is important for the metabolism of primaquine into active metabolites. The fact that low CYPD2D6 activity

CHAPTER 14  Malaria: Epidemiology and Risk to the Traveler may be associated with therapeutic failure and that as many as 10% of European populations may be poor metabolizers means that the utility of primaquine for primary prophylaxis may be limited.51,52

REFERENCES 1. World Health Organization. World Malaria Report 2016. Geneva; 2016. 2. United Nations World Tourism Organization. UNWTO World Tourism Barometer; 2017;15(June). 3. European Centre for Disease Prevention and Control. Annual Epidemiological Report 2016—Malaria. Stockholm; 2016. 4. Mace KE, Arguin PM. Malaria surveillance—United States, 2014. MMWR Surveill Summ 2017;66(12):1–24. 5. Knope KE, Muller M, Kurucz N, et al. Arboviral diseases and malaria in Australia, 2013-14: annual report of the National Arbovirus and Malaria Advisory Committee. Comm Dis Intel Q Rep 2016;40(3):e400–36. 6. Phillips-Howard PA, Bradley DJ, Blaze M, et al. Malaria in Britain: 1977-86. Br Med J (Clin Res Ed) 1988;296:245–8. 7. Romi R, Boccolini D, D’Amato S, et al. Incidence of malaria and risk factors in Italian travelers to malaria endemic countries. Travel Med Infect Dis 2010;8(3):144–54. 8. Centre National de Réferénce du Paludisme pour la France Métropolitaine. CNR du paludisme: rapport d’activités 2016 de l’année d’exercice 2015. 2016. 9. Tatem AJ, Jia P, Ordanovich D, et al. The geography of imported malaria to non-endemic countries: a meta-analysis of nationally reported statistics. Lancet Infect Dis 2017;17(1):98–107. 10. Abanyie FA, Arguin PM, Gutman J. State of malaria diagnostic testing at clinical laboratories in the United States, 2010: a nationwide survey. Malar J 2011;10:340. 11. Public Health England. Imported malaria cases by species and reason for travel, United Kingdom: 2016. Available from government/publications/imported-malaria-in-the-uk-statistics. 12. Leder K, Tong S, Weld L, et al. Illness in travelers visiting friends and relatives: a review of the GeoSentinel Surveillance Network. Clin Infect Dis 2006;43(9):1185–93. 13. Angelo KM, Libman M, Caumes E, et al. Malaria after international travel: a GeoSentinel analysis, 2003-2016. Malar J 2017;16(1):293. 14. Neave PE, Behrens RH, Jones CO. “You’re losing your Ghanaianess”: understanding malaria decision-making among Africans visiting friends and relatives in the UK. Malar J 2014;13:287. 15. Romi R, Sabatinelli G, Majori G. Malaria epidemiological situation in Italy and evaluation of malaria incidence in Italian travelers. J Travel Med 2001;8(1):6–11. 16. Smith AD, Bradley DJ, Smith V, et al. Imported malaria and high risk groups: observational study using UK surveillance data 1987-2006. BMJ 2008;337:a120. 17. Rees E, Saavedra-Campos M, Usdin M, et al. Trend analysis of imported malaria in London; observational study 2000 to 2014. Travel Med Infect Dis 2017;17:35–42. 18. Checkley AM, Smith A, Smith V, et al. Risk factors for mortality from imported falciparum malaria in the United Kingdom over 20 years: an observational study. BMJ 2012;344:e2116. 19. Jelinek T, Loscher T, Nothdurft HD. High prevalence of antibodies against circumsporozoite antigen of Plasmodium falciparum without development of symptomatic malaria in travelers returning from sub-Saharan Africa. J Infect Dis 1996;174:1376–9. 20. Greenberg AE, Lobel HO. Mortality from Plasmodium falciparum malaria in travelers from the United States, 1959 to 1987. Ann Intern Med 1990;113:326–7. 21. Muhlberger N, Jelinek T, Behrens RH, et al. Age as a risk factor for severe manifestations and fatal outcome of falciparum malaria in European patients: observations from TropNetEurop and SIMPID Surveillance Data. Clin Infect Dis 2003;36(8):990–5. 22. Broderick C, Nadjm B, Smith V, et al. Clinical, geographical, and temporal risk factors associated with presentation and outcome of vivax malaria


imported into the United Kingdom over 27 years: observational study. BMJ 2015;350:h1703. 23. Behrens RH, Carroll B, Hellgren U, et al. The incidence of malaria in travellers to South-East Asia: is local malaria transmission a useful risk indicator? Malar J 2010;9:266. 24. Leder K, Black J, O’Brien D, et al. Malaria in travelers: a review of the GeoSentinel surveillance network. Clin Infect Dis 2004;39(8):1104–12. 25. Nic Fhogartaigh C, Hughes H, Armstrong M, et al. Falciparum malaria as a cause of fever in adult travellers returning to the United Kingdom: observational study of risk by geographical area. QJM 2008;101(8): 649–56. 26. Steffen R, Fuchs E, Schildknecht J, et al. Mefloquine compared with other malaria chemoprophylactic regimens in tourists visiting East Africa. Lancet 1993;341(8856):1299–303. 27. Nelder MP, Russell C, Williams D, et al. Spatiotemporal dynamics and demographic profiles of imported Plasmodium falciparum and Plasmodium vivax infections in Ontario, Canada (1990-2009). PLoS ONE 2013;8(9):e76208. 28. Shellvarajah M, Hatz C, Schlagenhauf P. Malaria prevention recommendations for risk groups visiting sub-Saharan Africa: a survey of European expert opinion and international recommendations. Travel Med Infect Dis 2017. 29. Kliner M, Poole K, Sinclair D, et al. Preventing malaria in international travellers: an evaluation of published English-language guidelines. BMC Public Health 2014;14:1129. 30. Ross K. Tracking the spread of infectious disease: two networks prove the power of international collaboration. EMBO Rep 2006;7(9):855–8. 31. Jelinek T, TropNetEurop. Imported falciparum malaria in Europe: 2007 data from TropNetEurop. Euro Surveill 2008;13(23). 32. Wilson ME, Weld LH, Boggild A, et al. Fever in returned travelers: results from the GeoSentinel Surveillance Network. Clin Infect Dis 2007;44(12): 1560–8. 33. Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med 2006;354(2):119–30. 34. Moore DV, Lanier JE. Observations on two Plasmodium falciparum infections with an abnormal response to chloroquine. Am J Trop Med Hyg 1961;10:5–9. 35. Eyles DE, Hoo CC, Warren M, et al. Plasmodium falciparum resistant to chloroquine in Cambodia. Am J Trop Med Hyg 1963;12:840–3. 36. Wongsrichanalai C, PicKard AL, Wernsdorfer WH, et al. Epidemiology of drug-resistant malaria. Lancet Infect Dis 2002;2(4):209–18. 37. Whitby M, Wood G, Veenendaal JR, et al. Chloroquine-resistant Plasmodium vivax. Lancet 1989;2(8676):1395. 38. Baird JK. Chloroquine resistance in Plasmodium vivax. Antimicrob Agents Chemother 2004;48(11):4075–83. 39. Price RN, von Seidlein L, Valecha N, et al. Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis. The Lancet Infect Dis 2014;14(10):982–91. 40. Maguire JD, Sumawinata IW, Masbar S, et al. Chloroquine-resistant Plasmodium malariae in south Sumatra, Indonesia. Lancet 2002; 360(9326):58–60. 41. Khim N, Bouchier C, Ekala MT, et al. Countrywide survey shows very high prevalence of Plasmodium falciparum multilocus resistance genotypes in Cambodia. Antimicrob Agents Chemother 2005;49(8): 3147–52. 42. Wichmann O, Betschart B, Loscher T, et al. Prophylaxis failure due to probable mefloquine resistant P falciparum from Tanzania. Acta Trop 2003;86(1):63–5. 43. Lobel HO, Varma JK, Miani M, et al. Monitoring for mefloquine-resistant Plasmodium falciparum in Africa: implications for travelers’ health. Am J Trop Med Hyg 1998;59(1):129–32. 44. Briolant S, Wurtz N, Zettor A, et al. Susceptibility of Plasmodium falciparum isolates to doxycycline is associated with pftetQ sequence polymorphisms and pftetQ and pfmdt copy numbers. J Infect Dis 2010;201(1):153–9. 45. Wichmann O, Muehlberger N, Jelinek T, et al. Screening for mutations related to atovaquone/proguanil resistance in treatment failures and other


SECTION 4 Malaria

imported isolates of Plasmodium falciparum in Europe. J Infect Dis 2004;190(9):1541–6. 46. Sukwa TY, Mulenga M, Chisdaka N, et al. A randomized, double-blind, placebo-controlled field trial to determine the efficacy and safety of Malarone (atovaquone/proguanil) for the prophylaxis of malaria in Zambia. Am J Trop Med Hyg 1999;60:521–5. 47. Boggild AK, Lau R, Reynaud D, et al. Failure of atovaquone-proguanil malaria chemoprophylaxis in a traveler to Ghana. Travel Med Infect Dis 2015;13(1):89–93. 48. Boggild AK, Parise ME, Lewis LS, et al. Atovaquone-proguanil: report from the CDC expert meeting on malaria chemoprophylaxis (II). Am J Trop Med Hyg 2007;76(2):208–23.

49. Goller JL, Jolley D, Ringwald P, et al. Regional differences in the response of Plasmodium vivax malaria to primaquine as anti-relapse therapy. Am J Trop Med Hyg 2007;76(2):203–7. 50. CDC. CDC Health Information for International Travel. 2017. 51. Bennett JW, Pybus BS, Yadava A, et al. Primaquine failure and cytochrome P-450 2D6 in Plasmodium vivax malaria. N Engl J Med 2013;369(14): 1381–2. 52. Deye GA, Magill AJ. Primaquine for prophylaxis of malaria: has the CYP sailed? J Travel Med 2014;21(1):67–9.

15  Malaria Chemoprophylaxis Patricia Schlagenhauf, Mary Elizabeth Wilson, Eskild Petersen, Anne McCarthy, and Lin H. Chen

KEY POINTS • All travelers to malaria-endemic areas need to: • Be aware of the risk of malaria at the destination and understand that it is a serious, potentially fatal, infection. • Know how to best prevent malaria with personal protection measures against mosquito bites and chemoprophylaxis (where appropriate). • Seek medical attention urgently should they develop fever during travel and “think malaria” after returning from endemic areas. • The use of chemoprophylaxis drug regimens should be carefully directed at high-risk travelers where their benefit outweighs the risk of severe adverse events.

• Intending users of chemoprophylaxis need to be screened for contraindications and counseled regarding possible adverse events and drug interactions. • Making recommendations about chemoprophylaxis is a complex process that requires integrating many kinds of data. The decision process must be responsive to the dynamic epidemiology of malaria, availability of new drugs, new data about existing drugs and their prices, results from new studies, and changes in resistance patterns. Access to current guidelines is essential.


This needs to be weighed against the risk of intercurrent adverse events including serious adverse events resulting from taking a chemoprophylactic drug. Thus the risk assessment is a balancing act and the clinician needs sufficient information about the potential risk of malaria to be able to balance it against the potential adverse events associated with chemoprophylaxis. Each piece of information that suggests lower or higher risk aids in developing a composite of risk—albeit a general estimate of risk. Any traveler who will visit an area with any risk of malaria should know about steps to take in the event illness, which may be malaria, develops after travel so that they can actively seek informed care. This should be part of the consultation whether or not chemoprophylaxis is prescribed. Detailed information about insect avoidance should also be included, regardless if a chemoprophylaxis is prescribed. The latter will help to protect against multiple infections, in addition to malaria. In the risk assessment consider the following key questions: 1. Is malaria present in the destination? Is falciparum malaria present? 2. What is the intensity of transmission in the areas that the traveler will visit? Destinations with high intensity of transmission of Plasmodium falciparum would generate a strong recommendation for chemoprophylaxis. 3. What are the drug susceptibility patterns of the parasites in that geographic region? Which antimalarials are effective in that region? 4. Will the traveler visit friends and relatives (VFR) in sub-Saharan Africa? Several studies have shown that African VFRs1–4 have a high risk of malaria, are unlikely to seek pretravel advice, and many are unaware that their preexisting semiimmunity to malaria wanes over time and is no longer protective. 5. What kind of accommodation will the traveler have? Will there be air conditioning? Bednets? What medical resources are available locally?

Protection against malaria can be summarized into four principles: (1) assessing individual risk, (2) preventing mosquito bites with personal protection measures (PPMs), (3) taking the “THINK MALARIA” approach if fever develops during or after travel, and (4) using malaria chemoprophylaxis.

Assessing Individual Risk—Parasite, Place, and Person Malaria remains the top specific cause of fever in returning travelers.1 Estimating a traveler’s risk in the pretravel setting is based on a detailed travel itinerary, parasite epidemiology, and specific risk behaviors of the traveler. The risk of acquiring malaria will vary according to the geographic area visited (e.g., Africa versus Southeast Asia), the travel destination within different geographic areas (urban versus rural), type of accommodation (camping versus well-screened or air-conditioned building), duration of stay (1-week business travel versus 3-month overland trek), time of travel (high or low malaria transmission season; risk usually is highest during and immediately after the rainy season), efficacy of and adherence to preventive measures used (e.g., treated bednets, chemoprophylaxis), and elevation of destination (malaria transmission is rare above 2000 m).2–9 Constantly updated information on malaria epidemiology is available online from several sources, including the Centers for Disease Control and Prevention (CDC), the World Health Organization (WHO), NaTHNac, SafeTravel, and Health Canada.10–13 The travel medicine advisor must consider several types of information in deciding whether to recommend chemoprophylaxis. The traveler’s preferences should also inform the decision. A framework should take into account the parasite, place, and person. A key focus in preparing the traveler should be on reducing the risk of acquiring malaria and preventing severe illness and death from malaria during or after travel.


CHAPTER 15  Malaria Chemoprophylaxis Abstract


Malaria chemoprophylaxis is probably the most complex area of pretravel advice. The travel medicine advisor must have in-depth knowledge of all available chemoprophylactic drugs as well as detailed knowledge of the current epidemiology of malaria at travelers’ destinations. The current priority antimalarials are atovaquone/proguanil, doxycycline, and mefloquine. Prescribing of mefloquine is constrained by new Federal Drug Administration (FDA), European Medicines Agency (EMA), and national recommendations. Chloroquine is rarely used as a priority prophylaxis due to widespread resistance. Primaquine is an alternative for some travelers and is included in US and Canadian guidelines. Tafenoquine may be an option in the near future. Due to a risk of hemolysis, glucose-6-phosphate dehydrogenase (G6PD) testing is required prior to using primaquine or tafenoquine. The choice of drug will be influenced by tolerability, efficacy, adherence, and cost considerations and must also take into account traveler comorbidities and comedications. The ideal prophylactic agent is effective, safe, cheap, and has activity against liver stage and blood stage parasites.

Atovaquone/proguanil Chemoprophylaxis Chloroquine Doxycycline Malaria Mefloquine Primaquine Tafenoquine Traveler



SECTION 4 Malaria

6. What is the duration of travel? Longer duration of travel confers higher risk.5,6 7. Are there relevant personal factors that affect likelihood of exposure and severity of infection. Will the traveler use repellents and other PPMs? Is the traveler likely to be adherent to PPMs and chemoprophylaxis? 8. Is the traveler pregnant or planning to become pregnant? This could affect the severity of infection and would influence choice of drug. Is the traveler breastfeeding? 9. Does the traveler have contraindications or preexisting conditions such as renal or hepatic disease that could affect excretion or metabolism of certain drugs? Does the traveler have allergies or medical problems that would affect drug choice? Is the traveler taking other medication with potential for drug-drug interactions?7 More difficult decisions ensue when travelers are going to areas with low levels of malaria transmission, seasonal transmission, or predominantly or all nonfalciparum malaria. Traveler preferences can play a key role in deciding whether to use chemoprophylaxis in areas where risk of malaria is low. Standby emergency self-treatment for presumptive malaria is an option in some instances. The travel medicine advisor must have in-depth knowledge of the likely profile and contraindications of all available chemoprophylactic drugs as well as an in-depth knowledge of the current epidemiology of malaria. The choice of a specific agent is often easier than the decision whether to recommend chemoprophylaxis. In the event that drug choices are constrained because of allergies, comorbidities, or neuropsychiatric history, a different threshold may be used if one is faced with using a drug with more side effects. Some travelers strongly prefer to avoid drugs and may not adhere to a drug regimen, if prescribed. Some travelers prefer drugs administered once weekly, others prefer daily doses. For travelers visiting high-risk destinations who refuse chemoprophylaxis, clinicians have an obligation to provide clear recommendations and descriptions of consequences of malaria. Economic factors play a decisive role for some travelers, and providers should be aware the travelers may be unable to afford certain drugs and should factor that into the decision-making process. In addition to being safe, effective, easy to use, and inexpensive, the ideal prophylactic agent would have activity against liver stage and blood stage parasites.8

Preventing Mosquito Bites With Personal Protection Measures All travelers to malaria-endemic areas need to be instructed how best to avoid bites from Anopheles mosquitoes, which transmit malaria. Any measure that reduces exposure to the dusk-to-dawn female Anopheles mosquito will reduce the risk of acquiring malaria. The travel health advisor should spend time explaining the use of PPMs against mosquito bites, encouraging adherence with these measures, and advising the use of a combination of several antimosquito methods such as airconditioning, bednets, impregnated clothes, and repellents. Studies have demonstrated that N,N-diethyl-3-methylbenzamide (DEET)–based repellents provide adequate protection against mosquito bites, and preparations containing approximately 20% DEET can be recommended for adults and children.9–12 A randomized placebo-controlled trial examined the use of DEET-based repellents (20% DEET) during the second and third trimesters of pregnancy. No adverse events were identified in mother or fetus, providing reassurance regarding the use of DEET-based repellents by pregnant women.13 Another widely used repellent is icaridin (KBR 3023, Bayrepel [RS]-sec-butyl2-[2-hydroxyethyl] piperidine-1-carboxylate). This repellent appears to be less irritating than DEET products and has good cosmetic properties. One controlled

field study showed that 19% icaridin was effective and offered a protection equivalent to that of a long-acting DEET formulation.14 A recent systematic review found that DEET, icaridin, ethyl-butylacetyl-aminopropionate (EBAAP), and citriodora are all effective against Anopheles spp., providing, on average, 4–10 hours of protection.15 Insecticideimpregnated bednets (permethrin or similarly treated) are safe for children and pregnant women and are an effective prevention strategy that is often underused by travelers.

Taking the “THINK MALARIA” Approach if Fever Develops During or After Travel Travelers should be informed that although PPMs and the use of chemoprophylaxis can markedly reduce the risk of contracting malaria, these interventions do not guarantee complete protection. Symptoms of malaria may occur as early as 1 week after the first exposure, and as late as several years after leaving a malaria zone whether or not chemo suppression has been used. Approximately 90% of malaria-infected travelers do not become symptomatic until they return home.16–18 Most travelers who acquire falciparum malaria will develop symptoms within 3 months of exposure.16–18 Falciparum malaria can be effectively treated early in its course, but delays in diagnosis and therapy may result in serious and even fatal outcomes.19

Using Malaria Chemoprophylaxis The rest of this chapter will focus on malaria chemoprophylaxis. For most at-risk travelers a choice between atovaquone-proguanil, mefloquine, and doxycycline will have to be made. Less often primaquine or (increasingly rarely) chloroquine (plus proguanil) may be used. Deciding which agent is best requires an individual assessment of malaria risk and the specific advantages and disadvantages of each regimen (Tables 15.1–15.5). All chemoprophylactic medications need to be started before travel—mefloquine (3–4 weeks), doxycycline (1 day), atovaquoneproguanil (1 day), and primaquine (1 day)—taken regularly during travel and continued after leaving the malaria-endemic area (a 4-week, posttravel drug intake is required for all regimens except atovaquoneproguanil and primaquine, where only 1-week posttravel intake is required) (Fig. 15.1). Agents such as atovaquone-proguanil and primaquine are called causal prophylactics because they act on malaria parasites early in the lifecycle in the liver, and therefore may be discontinued 1 week after leaving an endemic area. This advantage makes these agents attractive for high-risk but short-duration travel (Fig. 15.2). All antimalarials are potent drugs and are associated with an appreciable risk of adverse events including visual disorders,20,21 neuropsychiatric disorders,22,23 and gastrointestinal (GI) disorders.23,24 Some events are distressing enough to lead 1%–7% of travelers to discontinue their prescribed chemoprophylactic regimen.23,25 Traveler adherence with posttravel intake has traditionally been poor.

CURRENT CHEMOPROPHYLACTIC DRUG REGIMENS This section will review currently recommended chemoprophylactic drug regimens in detail, including indications, adverse events, drug resistance, precautions, and contraindications.

Chloroquine, Hydroxychloroquine, Chloroquine/Proguanil

Description, Pharmacology, and Mode of Action.  Chloroquine was developed in Germany in the 1930s and although initially considered “too toxic for human use,” it was further evaluated by the Allied powers in the 1940s and found to be an outstanding antimalarial drug that has


CHAPTER 15  Malaria Chemoprophylaxis TABLE 15.1  Malaria Chemoprophylactic

TABLE 15.3  Incidence of Severea Events

Regimens for Persons at Risk by Zone

During Malaria Chemoprophylaxis in Travelers



Drug(s) of Choiceb


No chloroquine resistance Chloroquine resistance


Mefloquine, doxycycline, or atovaquone/proguanil First choice: primaquinec; second choice: chloroquine plus proguanild

Chloroquine and mefloquine resistance Adult Doses Chloroquine phosphate Mefloquine Atovaquone/ proguanil Doxycycline Primaquine Proguanil

Mefloquine or atovaquone/proguanil or doxycycline Doxycycline or atovaquone/proguanil

IMPORTANT NOTE: Protection from mosquito bites (insecticidetreated bednets, DEET-based insect repellents, etc.) is the first line of defense against malaria for all travelers. In the Americas and Southeast Asia, chemoprophylaxis is recommended only for travelers who will be exposed outdoors during evening or nighttime in rural areas. b Chloroquine and mefloquine are to be taken once weekly, beginning 1 week before entering the malarial area, during the stay and for 4 weeks after leaving. Doxycycline and proguanil are taken daily, starting 1 day before entering malarial areas, during the stay, and for 4 weeks after departure. Atovaquone/proguanil and primaquine are taken once daily, starting 1 day before entering the malarial area, during the stay, and may be discontinued 7 days after leaving the endemic area. c Contraindicated in glucose-6-phosphate dehydrogenase (G6PD) deficiency and during pregnancy. Not presently licensed for this use. A G6PD level must be performed before prescribing. d Chloroquine plus proguanil is less efficacious than mefloquine, doxycycline, or AP in these areas. e Should only be used in combination with chloroquine.

TABLE 15.2  Incidence of Any Adverse

Event During Malaria Chemoprophylaxis in Nonimmune Travelers




Phillips 1996 Schlagenhauf 1996 Barrett 1996 Steffen 1993 Hoghb 2000 Overboschb 2001 Schlagenhauf 2003c Terrell 2015

Australian Swiss United Kingdom European International International International UK soldiers in Kenya

11.2 11.2 17 13 – 5 10.5 12.5

– – 16 16 2 – 12.4 _

6.5 – – – – – 5.9 22.2

– – – – 0.2 1 6.7 _

TABLE 15.4  Incidence of Seriousa Adverse

Events During Malaria Chemoprophylaxis


Travelers US Marines Travelers Austral. Defense Travelers Travelers Travelers


Interferes with daily activity or impacted performance. Stopped taking antimalarials. c Sought medical attention in context of the study. A+P, Atovaquone/proguanil; C+P, chloroquine/proguanil; DX, doxycycline; MQ, mefloquine.

100 mg daily 30 mg (base) dailyc 200 mg dailye




250 mg (salt in United States; base elsewhere) weekly One tablet daily (250 mg/100 mg)




300 mg (base) weekly

Steffen 19938 Boudreau 199382 Barrett 199663 Nasveld 200097 Hogh 2000a34 Overbosch 200162 Schlagenhauf 200319






24 43 41 – – 68 88

35 46 41 – 28 – 86

– – – 58 – – 84

– – – 38 22 71 82

Drug associated. A+P, Atovaquone/proguanil; C+P, chloroquine/proguanil; DX, doxycycline; MQ, mefloquine.


Population MQ 68

MacPherson 1992 Steffen 19938 Croft 199670 Barrett 199663 Roche Drug Safety 1997

Canadian European UK soldiers UK Worldwide


1/20,000 1/10,000 1/13,600 1/6000 1/600 1/1200 1/20,000

DX A+P ?



Hospitalization. A+P, Atovaquone/proguanil; C+P, chloroquine/proguanil; DX, doxycycline; MQ, mefloquine.

been in continuous use for over 50 years. Widespread resistance limits the use of chloroquine and its combinations by travelers. This 4-aminoquinoline drug is chemically a racemate, and both enantiomers have equivalent antimalarial activity. Preparations are available as phosphate, sulfate, and hydrochloride salts, under a wide variety of trade names. In the United States, hydroxychloroquine is recommended as an alternative for chemoprophylaxis in areas with chloroquine-sensitive P. falciparum. The combination of proguanil 200 mg (usually as Paludrine) daily and chloroquine base 300 mg weekly has been used extensively. Chloroquine is a potent blood schizonticide, active against the erythrocytic forms of sensitive strains of all species of malaria, and is also gametocidal against P. vivax, P. malariae, and P. ovale. The site of action of chloroquine is within the lysosome of the blood stage parasite,26 where it complexes with hemin and prevents its conversion to the nontoxic hemozoin.26 Proguanil is converted to the active cycloguanil, which is a dihydrofolate reductase inhibitor that acts by interfering with folic-folinic acid systems. Proguanil is effective against the primary exoerythrocytic hepatic forms and is therefore a causal prophylactic. It is also a slow-acting blood schizonticide and has sporonticidal effects against P. falciparum.

Efficacy and Drug Resistance.  Chloroquine-resistant malaria began to appear in Southeast Asia and South America in 1960 and reached East Africa in 1978 and West Africa in 1985. Proguanil-resistant P.


SECTION 4 Malaria

TABLE 15.5  Antimalarial Drugs, Doses, and Adverse Effects (Listed Alphabetically) (See Text

for Contraindications) Generic Name

Trade Name


Adult Dose

Pediatric Dose

Adverse Effects



250 mg atovaquone and 100 mg proguanil (adult tablet)

1 tablet daily (see text)a

Nausea, vomiting, abdominal pain, diarrhea, increased transaminases, seizures, rash

Chloroquinec phosphate or sulfate

Aralen Avochlot Nivaquine Resochia

150-mg base

300-mg base once weeklya


Vibramycin Vibra-Tabs Doryx

100 mg

100 mg once dailya


Lariam Mephaquin

250-mg base (salt in USA)

250-mg base once weeklya

15-mg base

30-mg base/day Terminal prophylaxis or radical cure: 15-mg base/day for 14 daysd 200 mg daily: Note: Not recommended as a single agent for prophylaxis

See textb 5–8 kg: 12 pediatric tablet 8–10 kg: 3 4 pediatric tablet 10–20 kg: 1 pediatric tablet 20–30 kg: 2 pediatric tablets 30–40 kg: 3 pediatric tablets >40 kg: 1 adult tablet 5-mg base once weekly 5–6 kg: 25-mg base 7–10 kg: 50-mg base 11–14 kg: 75-mg base 15–18 kg: 100-mg base 19–24 kg: 125-mg base 25–35 kg: 200-mg base 36–50 kg: 250-mg base >50 kg or if ≥14 years: 300-mg base 1.5 mg/kg once daily (max 100 mg daily) 50 kg or if ≥14 years: 200 mg (2 tablets)




100 mg

Pruritus in black-skinned individuals, nausea, headache, skin eruptions, reversible corneal opacity, nail and mucous membrane discoloration, nerve deafness, photophobia, myopathy, retinopathy with daily use, blood dyscrasias, psychosis, seizures, alopecia

Gastrointestinal upset, vaginal candidiasis, photosensitivity, allergic reactions, blood dyscrasias, azotemia in renal diseases, hepatitis

Dizziness, diarrhea, nausea, vivid dreams, nightmares, irritability, mood alterations, headache, insomnia, anxiety, seizures, psychosis GI upset, hemolysis in G6PD deficiency, methemoglobinemia

Anorexia, nausea, mouth ulcers


Dose for chemoprophylaxis. In the United States and Europe, a pediatric formulation is available (quarter strength = 62.5 mg atovaquone and 25 mg proguanil). CDC sanctions atovaquone/proguanil for infants >5 kg. WHO allows it for infants weighing >11 kg. c Chloroquine sulfate (Nivaquine) is not available in the United States and Canada, but is available in most malaria-endemic countries in both tablet and syrup form. d Doses are increased to 30 mg-base/day for primaquine-resistant P. vivax. e Doses are increased to 0.5-mg base/kg per day for primaquine-resistant or tolerant P vivax. b

falciparum is widespread, and this agent is not conventionally recommended as a monoprophylaxis. It is believed that resistance prevents access of chloroquine to the digestive process in the parasite’s lysosome, and this process is modulated primarily by mutations in the gene PfCRT, which encodes a transmembrane digestive vacuole protein. Mutations in PfCRT permit the parasite to persist in chloroquine concentrations

that kill sensitive parasites.27,28 Some investigators suggest that chloroquine-sensitive, wild-type P. falciparum is returning in parts of Africa. A recent trial in Mozambique found that chloroquine cleared 89% of P. falciparum infections, and that only 1/108 P. falciparum isolates carried the pfcrt K76E mutation,29 which could indicate that the discontinuation of chloroquine use since the early 1990s has perhaps

CHAPTER 15  Malaria Chemoprophylaxis


Anopheles Primary Liver cycle -Atovaquone -Primaquine -Tafenoquine (limited: Azithromycin, Doxycycline, Proguanil) Relapse -Primaquine, Tafenoquine primary attack Erythrocytic cycle - Atovaquone - Azithromycin - Chloroquine - Doxycycline - Mefloquine - Proguanil - Tafenoquine

Relapse -Primaquine -Tafenoquine

Anopheles relapse

Erythrocytic cycle

Gametocyte (mature P. falciparum) - Primaquine, Tafenoquine FIG. 15.1  The lifecycle of malaria parasites in the human host, showing sites of action of antimalarial drugs.

resulted in a reversal to a chloroquine-sensitive, wild-type P. falciparum. Chloroquine-resistant P. vivax was reported in 1989 in New Guinea and later elsewhere in Oceania, India, Asia, and parts of South America, and because of the widespread distribution of P. vivax (estimated exposure of 2.85 billion people) increasing chloroquine-resistant P. vivax will have far-reaching public health implications.30 A recent study from India, looking at the PvCRT-o (P. vivax chloroquine resistance transporter-o) and PvMDR-1 (P. vivax multidrug resistance-1) genes classified 23% of P. vivax as potentially resistant to chloroquine.31 A study from Myanmar found a low chloroquine clinical failure, but genes potentially coding for chloroquine-resistant phenotypes— pvcrt-O ‘AAG’ insertion and the pvmdr1 mutation (Y976F)—were common in southern and central Myanmar.32 A study from Thailand found that chloroquine cured 99% of P. vivax cases.33 A randomized, controlled trial from Brazil comparing treatment of P. vivax with artesunate-amodiaquine and chloroquine found treatment failure of chloroquine in 11.5% of cases.34 A recent review of clinical trials including chloroquine in at least one arm found chloroquine P. vivax resistance in 59 (45%) sites in 15 endemic areas.31

Tolerability.  One RCT23 showed poor tolerability of chloroquine/ proguanil compared to doxycycline, mefloquine, or atovaquone/proguanil. Serious Adverse Event (AE), such as psychotic episodes, have been reported in 28 days † pregnancy

No Mefloquine or Atovaquone + proguanil or Doxycycline

Doxycycline Rule out contraindications such as Age 35 million travelers for this indication. Mefloquine is a potent, long-acting blood schizontocide and is effective against all malarial species,38 including the fifth species39 Plasmodium knowlesi. The exact mechanism of activity is unclear, but mefloquine is thought to compete with the complexing protein for heme binding and the resulting drug-heme complex is toxic to the parasite.40

Efficacy and Drug Resistance.  Mefloquine is recognized as a highly effective malaria chemoprophylaxis for nonimmune travelers to high-risk CRPf areas. The first report of mefloquine resistance came from Thailand in 1982, and this region remains a focus of resistance, particularly on the Thai-Cambodian and Thai-Burmese borders, where prophylaxis breakdown has been observed. As reviewed by Mockenhaupt,41 reports of mefloquine treatment or prophylactic failures have been reported

CHAPTER 15  Malaria Chemoprophylaxis from distinct foci in Asia and, to a lesser extent, from Africa and the Amazon Basin in South America. Studies in 1993 showed high efficacy of mefloquine in travelers.42 Long-term prophylaxis with mefloquine proved highly effective in Peace Corps volunteers stationed in sub-Saharan Africa, with an incidence of 0.2 infections/month in 100 volunteers. Weekly mefloquine was considered 94% more effective than prophylaxis with chloroquine and 86% more effective than prophylaxis with the chloroquine/proguanil combination.42 Mefloquine was shown to be highly efficacious (100%) in the prevention of malaria in Indonesian soldiers in Papua, and Rieckmann43 found mefloquine to be 100% effective against P. falciparum in Australian soldiers deployed in Papua New Guinea (PNG). Pergallo44 reported on the effective use of mefloquine by Italian troops in Mozambique in 1992–1994. When chloroquine/proguanil was the recommended regimen, an attack rate of 17 cases/1000 soldiers per month was noted. The rate dropped significantly to 1.8 cases/1000 soldiers per month when chloroquine/proguanil was replaced by mefloquine. The effectiveness of long-term mefloquine in the United Nations peacekeeping forces in Cambodia in 1993 was 91.4%.45 Conversely, mefloquine was found to be incompletely effective in the prevention of malaria in Dutch Marines in Western Cambodia in 1992–1993. The attack rate in Marines varied significantly according to the geographic location of the battalions. Of 260 persons assigned to the Sok San area, 43 developed malaria (16%, 6.4/1000 person-weeks) compared to 21 of 2029 stationed elsewhere (1%, 0.5/1000 person-weeks). Mefloquine-resistant parasites were isolated from Dutch and Khmer patients.46 The use of antimalarials by American troops during Operation Restore Hope in Somalia in 1992–1993 showed high prophylactic efficacy in mefloquine users. Sanchez et al.47 reported the prophylactic efficacy in an uncontrolled cross-sectional survey of troops at one location (Bale Dogle). Mefloquine users had a malaria rate of 1.15 cases/10,000 person-weeks, compared to 5.49 cases/10,000 person-weeks in doxycycline users. From this and other reports,48 mefloquine was shown to be more effective than doxycycline in US troops deployed in Somalia. The lower efficacy of doxycycline was attributed to poorer compliance. Mefloquine was shown to provide a high degree of protection in Dutch servicemen (n =125) deployed as part of a disaster relief operation to Goma, Zaire (1994). Despite evidence of exposure to P. falciparum as shown by the presence of circumsporozoite antibodies in 11.2% of the group, none developed overt malaria that was attributed to their use of mefloquine prophylaxis.49 In a German population-based case control study, mefloquine was considered to be 94.5% effective in preventing malaria in tourists to Kenya.50

Prophylactic Failures and Resistance.  The molecular basis of mefloquine resistance is currently unknown but may be the result of mutation or amplification of certain gene products such as Pgh1, an energy-dependent transporter encoded by the multidrug-resistant (mdr) homolog Pfmdr1. Studies demonstrate that mutations in pfmdr1 may confer mefloquine resistance to sensitive parasites.51 Penfluridol, a psychotropic drug, has been reported to reverse mefloquine resistance in P. falciparum in vitro.52 In many geographic regions, mapping of prophylactic failures, mainly in nonimmune individuals, has been used to detect early resistance development, although it should be emphasized that prophylactic failures do not prove resistance. Mefloquine blood concentrations of 620 ng/ mL are generally considered necessary to achieve 95% prophylactic efficacy. As defined by Lobel, a prophylactic failure is a confirmed P. falciparum infection in persons with mefloquine blood levels in excess of this protective level.53 Using this definition, an analysis of 44 confirmed P. falciparum cases acquired in sub-Saharan Africa53 showed five volunteers with mefloquine-resistant P. falciparum malaria. Other confirmed cases were attributed to poor compliance, and the authors concluded


Chemoprophylaxis choices 201X Priority antimalarial for chloroquinine resistant Pf (CRPF)

Melfloquine* 250 mg weekly

Atovaquone/proguanil* 250 mg/100 mg daily

Doxycycline 100 mg daily

Alternative options for chloroquinine resistant Pf (CRPF)

Primaquine (United States, Canada) 30 mg daily

Tafenoquine (pipeline) 200 mg daily for 3 days followed by 200 mg weekly

FIG. 15.3  Priority antimalarials—the options for chemoprophylaxis.

that prevalence of mefloquine-resistant malaria in sub-Saharan Africa is still low. With regard to P. vivax, it has been hypothesized that the P. vivax Pvmdr1 gene amplification results in reduced susceptibility to mefloquine, but one study did not find that mutations in the Pvmdr1 gene decreased P. vivax sensitivity to mefloquine.54 Plasmodium ovale, P. malariae, and P. knowlesi remain fully susceptible to mefloquine while noting the need for primaquine to eliminate the hypnozoites of P. ovale. With regard to cross-resistance, there is recent evidence that exposure of parasite populations to antimalarial drug (Fig. 15.3) pressure may select for resistance not only to the drug providing the pressure, but also to other drugs. This was clearly illustrated in the northern part of Cameroon, West Africa, where the detection of a high level of resistance to mefloquine was attributed to cross-resistance with quinine,55 a drug that had been widely used for therapy in the area. Resistance to mefloquine appears to be distinct from chloroquine resistance, as shown by the activity of mefloquine against CRPf and by the inefficacy of verapamil to reverse mefloquine resistance, although it does modulate chloroquine resistance. Moreover, in vitro studies have documented an inverse relationship between chloroquine and mefloquine resistance. Mefloquine resistance is, however, associated with halofantrine resistance56 and quinine resistance.55,56 Innate resistance (i.e., the existence of small subpopulations of intrinsically resistant malarial parasites within any infecting parasite biomass) is still controversial and may to some extent be explained by cross-resistance to other drugs. Sporadic reports from tropical Africa describe single travelers with P. falciparum malaria despite apparent compliance with mefloquine.57 This has been attributed to inadequate dosing in heavy individuals. Mefloquine remains an effective drug for chemoprophylaxis against P. falciparum malaria in tropical Africa.

Tolerability.  There is considerable controversy among international experts regarding the tolerability of mefloquine prophylaxis, and several new restrictions have been imposed.58 On July 29, 2013, the US Food and Drug Administration (FDA) issued “a boxed warning” announcement about strengthened and updated restrictions regarding mefloquine and the risk of neuropsychiatric adverse events. Following this, in Europe, in 2014, the European Medicines Agency (EMA) issued recommendations


SECTION 4 Malaria

on strengthened warnings, prescribing checklists and updates to the product information of mefloquine.58 These new restrictions mandate careful prescribing of the drug and demand that prescribers check for contraindications such as depression or other psychiatric illness and inform mefloquine users of possible AE.38,58 Some important new studies have examined specific safety aspects of mefloquine and other antimalarials. Schneider et al.21 evaluated eye disorders using the UK General Practice Research Database. Compared to nonusers of antimalarials, the adjusted odds ratio with 95% confidence interval (CI) in the nested case control analysis for users of mefloquine, chloroquine and/or proguanil, or atovaquone/proguanil were 1.33 (1.01–1.75), 1.61 (1.06–2.45), and 1.25 (1.03–1.52), respectively, indicating that ocular toxicity is an issue with many antimalarials. Regarding tolerability, an overview of the studies and databases comparing the use of malaria chemoprophylactic agents in travelers (see Tables 15.2, 15.3, and 15.4) shows largely disparate results owing to differing designs, definitions, and methodologies as well as differing study populations. Regarding the reporting of any AE, the incidence during the use of mefloquine lies in the range of 24%–88%, and when there is a comparator, is usually equivalent to the incidence reported for almost all chemoprophylactic regimens. A double-blind study comparing all regimens showed that the tolerability of atovaquone/proguanil and doxycycline is superior to that of mefloquine, and women in particular were significantly more likely to experience neuropsychiatric-type AE.23

Moderate/Severe Adverse Events.  Although often a subjective report by the traveler, when some measure of severity is applied to AE reporting it appears that 11%–17%23,59–66 of travelers using mefloquine are to some extent incapacitated by adverse events. The extent of this incapacitation is often difficult to quantify, and a good measure of the impact of adverse events is the extent of chemoprophylaxis curtailment. In a recent study67 comparing tolerability in deployed soldiers using mefloquine or doxycycline, significantly fewer mefloquine users (12.6%) reported that one or more adverse events had impacted upon their ability to do their job, compared to 22.2% of doxycycline users. In a study of 5120 Italian soldiers using either chloroquine/proguanil (C+P) or mefloquine, deployed in Somalia and Mozambique in 1992–1994, the rate of prophylaxis discontinuation in the C+P users was 1.5%, compared to a significantly lower rate of discontinuation in mefloquine users (0.9%).44 This contrasts with a study comparing mefloquine and atovaquone/proguanil (A+P), where subjects receiving the A+P combination regimen had a significantly lower rate of drugrelated AE that caused discontinuation of prophylaxis (5% versus 1%).59 A four-arm, controlled tolerability study showed intermediate withdrawal rates for mefloquine (3.9%) and doxycycline (3.9%) versus chloroquine/ proguanil (5.2%) compared with atovaquone/proguanil, which had the lowest withdrawal rate (1.8%).23

Serious Adverse Events.  These are adverse events that constitute an apparent threat to life, which require prolong hospitalization or result in severe disability.68 With mefloquine the incidence range is estimated between 1/6000 and 1/10,600,35,64,69 compared to a rate in chloroquine users of 1/13,600. In a retrospective cohort analysis, serious neuropsychiatric AE were noted for 1/607 mefloquine users versus 1/1181 chloroquine/proguanil users.60

Neuropsychiatric Adverse Events.  This is the main area of controversy with regard to the tolerability of mefloquine. Neuropsychiatric disorders include two broad categories of symptoms, namely central and peripheral nervous system disorders (including headache, dizziness, vertigo, seizures) and psychiatric disorders (including major psychiatric disorders, affective disorders, anxiety, sleep disturbances). The

neuropsychiatric profile of adverse events occurring with mefloquine has been previously shown.23,64–66 However, a large database analysis showed that the use of mefloquine or any other antimalarials is associated with neuropsychiatric events and that these cannot be specifically attributed to mefloquine.70 No large prospective controlled study has confirmed the true incidence of neuropsychiatric events during prophylaxis. The thrust of the new safety communications58 from the FDA and EMA is to reinforce communication on the potential risk of such adverse events occurring and their possible long-term duration. However even in the literature, except for occasional case reports, data on the duration and persistence of mefloquine-related AE are lacking. One Danish study examined long-term outcomes of neuropsychiatric events.71 A recent study from Tan et al. on illness in Peace Corps volunteers who used malaria prophylaxis found that the prevalence of most diseases at longterm follow-up was similar in those exposed to malaria prophylaxis compared to those not exposed to prophylaxis. This also held true for psychiatric-type diagnoses in users of all antimalarials including prescreened mefloquine users.72 Two controlled studies have shown a significant excess of neuropsychiatric events in mefloquine users versus comparators.23,59 The precise role of antimalarial drugs in neuropsychiatric adverse events is difficult to define. In terms of all AE, studies have shown that women are significantly more likely to experience them.23,59,73,74 The AE bias to women might be due to reporting bias, greater compliance with prescription,74 or to gender-related differences in drug absorption, metabolism, or CNS distribution. With respect to dose-related toxicity, there appears to be an association between low body weight and a relatively high risk of developing AE during malaria prophylaxis. Some experts recommend using a split dose (a half tablet twice weekly) for women with low body weight. Anecdotal reports suggest positive experience with this approach, but no published pharmacokinetic data are available. Computer simulations suggest that reduced dosage in women would be effective and might result in improved tolerability. An earlier tolerability study aimed to correlate nonserious AE occurring during routine chemoprophylaxis with concentrations of racemic mefloquine, its enantiomers, or the carboxylic acid metabolite.63 The disposition of mefloquine was found to be highly selective, but neither the concentrations of enantiomers, nor total mefloquine, nor metabolite were found to be significantly related to the occurrence of nonserious AE. A role has been suggested for the concomitant use of mefloquine and recreational drugs66 or an interaction between mefloquine and large quantities of alcohol,75 although concomitant use of small quantities of alcohol does not appear to adversely affect tolerability.76 Children tolerate mefloquine well,77 as do elderly travelers who report significantly fewer AE than younger counterparts.78 One report suggests that subjects with AE have slower elimination of mefloquine than the population in general. Some researchers have used animal models to propose mechanisms that may explain the neuropsychiatric profile of adverse events associated with mefloquine. The phenomenon of “connexin blockade” by mefloquine has been proposed as a possible explanation for some mefloquineassociated adverse events.79 Careful screening of travelers, with particular attention to contraindications such as personal or family history of epilepsy/seizures or psychiatric disorders, should minimize the occurrence of serious AE. Travel health advisors now recommend starting mefloquine 3 weeks before travel to allow for adverse event screening. The positive outcome of the new safety recommendations58 is that screening prior to mefloquine prescription will be mandatory and follow a checklist format. This should ensure that contraindications are observed, which in the past has not always been the case.

Contraindications, Precautions, and Drug Interactions.  Following strengthened restrictions by the FDA and the EMA,58 the package insert

CHAPTER 15  Malaria Chemoprophylaxis for mefloquine has been updated. Mefloquine is contraindicated in persons • known to be hypersensitive to mefloquine or related compounds (e.g., quinine, quinidine) • who currently suffer or who have suffered at any time from depression, generalized anxiety disorder, psychosis, schizophrenia, suicide attempts, suicidal thoughts, self-endangering tendencies, or any other psychiatric disorder or convulsions of any origin • with severe impairment of liver function New contraindications • A history of blackwater fever is now a contraindication. • Concomitant use of halofantrine is a contraindication and in some countries, including Germany, concomitant use of ketoconazole has been added as a contraindication. New precautions.  Prescribers need to highlight the risk of neuropsychiatric adverse events that can occur during the use of mefloquine, provide a detailed description of possible adverse events and their duration, and instruct the user to read the package information leaflet and provide the user an alert card. Pregnancy.  Most authorities now allow the use of mefloquine in all trimesters if travel cannot be deferred and if the expected benefit outweighs the risk. A drug safety database analysis of mefloquine exposure in the prenatal period and during pregnancy showed that the birth defect prevalence and fetal loss in maternal, prospectively monitored cases were comparable to background rates.80 Inadvertent pregnancy while using mefloquine is not considered grounds for pregnancy termination. Mefloquine is secreted into breast milk in small quantities. The effect, if any, on breastfed infants is unknown, but the amount of drug secreted in the breast milk is inadequate to protect an infant from malaria so breastfed babies require their own chemoprophylaxis. A retrospective analysis of a database of antimalarial tolerability data showed that comedications commonly used by travelers have had no significant clinical impact on the safety of prophylaxis with mefloquine.81 The coadministration of mefloquine with cardioactive drugs might contribute to the prolongation of QTc intervals, although in the light of the information currently available coadministration of mefloquine with such drugs is not contraindicated but should be monitored. Vaccination with oral live typhoid or cholera vaccines should be completed at least 3 days before the first dose of mefloquine. Caution is indicated in persons performing tasks requiring fine coordination, but a review of performance impact of mefloquine82,83 suggests that if mefloquine is tolerated by an individual then his or her performance is not undermined by use of the drug.

Indications and Administration. Mefloquine is effective in the prevention of CRPf malaria, except in clearly defined Thai border regions of multidrug resistance. It is a priority antimalarial for screened travelers, with no contraindications, to high-risk malaria-endemic areas. The recommended adult dose for chemoprophylaxis is 250 mg base weekly as a single dose (US 228 mg base). Adults weighing 5 kg require a weekly dose of 5 mg base/kg (see Table 15.5). Loading doses of mefloquine for last-minute travelers are no longer recommended due to an increased risk of AE. Mefloquine and its metabolite are not appreciably removed by hemodialysis.84 No special dosage adjustments are indicated for dialysis patients to achieve concentrations in plasma similar to those in healthy volunteers.


Description.  The tetracyclines form a class of broad-spectrum antimicrobial agents. Doxycycline and minocycline were derived semisynthetically in 1967 and 1972, respectively. In many countries


doxycycline is used “off-label” for malaria chemoprophylaxis. The only FDA-approved indication for this class of agents is the use of doxycycline for the prophylaxis of P. falciparum in short-term travelers (90% oral absorption), and in contrast to other tetracyclines its uptake does not change significantly with food intake. Doxycycline may be taken with food but should not be taken with milk. Doxycycline is highly protein bound (93%), has a small volume of distribution (0.7 L/kg), and is lipid soluble. These features may explain its high blood levels and prolonged half-life, permitting a once-daily dosing regimen. Doxycycline has a half-life of approximately 15–22 hours that is unaffected by renal impairment. Doxycycline is eliminated in the urine unchanged by glomerular filtration, and largely unchanged in the feces by biliary and GI secretion. About 40% of the dose is eliminated in the urine in individuals with normal kidney function, whereas those with renal dysfunction are able to eliminate it via the liver-biliary-GI route.

Efficacy and Drug Resistance.  A number of randomized trials have examined the efficacy of doxycycline as a chemoprophylactic against Plasmodium spp.88–92 Four of these studies were randomized, double blind, and placebo controlled. Two of these trials evaluated semiimmune children or adults in Kenya, and three trials examined nonimmune populations in Oceania. The reported protective efficacy in these trials was excellent, ranging from 92% to 99% against P. falciparum and 98% for primary P. vivax malaria. Doxycycline does not kill P. vivax hypnozoites and does not prevent relapses of P. vivax and P. ovale malaria. In comparative trials in areas with CRPf malaria, doxycycline has been shown to be equivalent to mefloquine and atovaquone-proguanil and superior to azithromycin and chloroquine/proguanil.93–95 Parasite resistance to doxycycline has not been reported to be an operational problem in any malaria-endemic areas thus far, but prophylactic failures are reported in association with poor adherence, missed doses, and inadequate doses.96,97 No systematic studies of the efficacy of doxycycline for malaria chemoprophylaxis has been performed. A study of 90 P. falciparum isolates from 14 countries found that increases in copy numbers of P. falciparum metabolite drug transporter gene (Pfmdt, PFE0825w) and P. falciparum GTPase TetQ gene (PfTetQ, PFL1710c) are associated with reduced susceptibility to doxycycline.98 The PftetQ KYNNNN motif repeats have been associated with in vitro reduced susceptibility to doxycycline.99


SECTION 4 Malaria

P. vivax.  A study from Ethiopia of Israeli travelers found that of 19 using doxycycline for prophylaxis, 10 developed malaria: 9 P. vivax and 1 a mixed-infection P. vivax and P. falciparum.100 Another study comparing mefloquine and doxycycline in Indonesian solders found no difference in the protection against P. falciparum and P. vivax,101 and the difference between the two studies could be compliance. P. ovale, P. malariae, and P. knowlesi.  A study of 328 incident P. ovale infections in French servicemen stationed in tropical Africa found that 295 (92%) had taken doxycycline as prophylaxis, 15 (5%) chloroquine-proguanil, and 10 (3%) mefloquine. The self-declared compliance overall was 53%.102 No data exist regarding the efficacy of doxycycline for the prevention of P. malariae and P. knowlesi.

Tolerability.  The most commonly reported adverse events related to doxycycline use are GI effects (4%–33%), including nausea, vomiting, abdominal pain, and diarrhea. These adverse effects are less frequent with doxycycline than with other tetracyclines. Esophageal ulceration is a rare but well-described AE associated with doxycycline use that generally presents with retrosternal burning and odynophagia 1–7 days after therapy is initiated.52,100 Limited data suggest that doxycycline monohydrate and enteric-coated hyclate formulations may have fewer GI adverse events than regular hyclate formulations.97,98 Dermatologic reactions are also a frequent adverse event associated with doxycycline use. These reactions range from mild paresthesias or exaggerated sunburn in exposed skin to photo-onycholysis (sun-induced separation of nails), severe erythema, bulla formation, and (rarely) Stevens-Johnson syndrome.97 The reported rate of photosensitivity varies from 15 and protective against both ultraviolet A [UVA] and ultraviolet B [UVB] radiation).97 Although doxycycline has a lesser effect on normal bacterial flora than other tetracyclines, it still increases the risk of oral and vaginal candidiasis in predisposed individuals. Travelers with a history of these problems who are prescribed doxycycline should be advised to carry an appropriate treatment course of antifungal therapy. Other uncommon adverse events occasionally attributed to doxycycline include dizziness, lightheadedness, darkening or discoloration of the tongue, and (rarely) hepatotoxicity, pancreatitis, or benign intracranial hypertension.97 Overall, a number of comparative studies have shown that doxycycline used as a chemoprophylactic agent is generally well tolerated and has relatively few reported side effects. In clinical trials, doxycycline was tolerated as well as or better than placebo or the comparator drug,23,97 with few serious AE reported. Randomized control trials comparing the tolerability of mefloquine and doxycycline in soldiers deployed in Thailand, and primaquine, doxycycline, proguanil/chloroquine, and mefloquine compared with placebo in semiimmune children in Kenya, found no significant differences in tolerability between these agents.94 Ohrt and colleagues compared mefloquine and doxycycline in a randomized placebo-controlled field trial in nonimmune soldiers in Papua (Irian Jaya). In this trial both drugs were well tolerated, but doxycycline was better tolerated than mefloquine or placebo with respect to the frequency of reported symptoms.101 The authors attributed this to the potential of doxycycline to prevent other infectious processes. Anderson and colleagues compared doxycycline and azithromycin in a field trial in semiimmune adults in western Kenya.93 Both drugs were well tolerated compared with placebo, but there was one case of doxycycline withdrawal due to recurrent vaginitis. There were no significant differences observed in adverse event profiles between the treatment arms, except that azithromycin was protective against dysentery. A randomized comparative trial of antimalarial tolerability reported that doxycycline monohydrate

was the best tolerated of the four regimens (compared to mefloquine, atovaquone/proguanil, and chloroquine/proguanil).23 Adherence with doxycycline, despite its daily dosing schedule, has been reported to be relatively good in studies examining short-term use. Estimating adherence rates in travelers is difficult because such studies require close daily monitoring. Ohrt and colleagues extended their initial comparative study of doxycycline and mefloquine but did not enforce adherence as they did in the first phase of the study.101 This resulted in a drop in the protective efficacy of doxycycline from 99% (95% CI 94%–100%) to 89% (95% CI 78%–96%) against all malaria, suggesting a decrease in drug adherence if close monitoring is not done. Similar experience of declining effectiveness over time due to adherence issues has been reported by the US military deployed in Somalia and in Dutch troops deployed in Cambodia. US troops in Somalia using doxycycline had fivefold higher attack rates by P. falciparum than did mefloquine users. These differences were attributed to poor adherence with daily use rather than to doxycycline resistance. Collectively these studies suggest that adherence with daily doxycycline may be challenging, especially for long-term travelers.

Contraindications, Precautions, and Drug Interactions.  Doxycycline administration is not recommended in the following situations: • Allergy or hypersensitivity to doxycycline or any member of the tetracycline class. • Infants and children 3 months) has not been adequately studied.103,104 Because lower doses of doxycycline and minocycline (a related tetracycline) are frequently used for extended periods to treat acne, it has been presumed that long-term use of doxycycline at an adult dose of 100 mg/day is safe. However, serious adverse events, including autoimmune hepatitis, fulminant hepatic failure, a serum sickness–like illness, and drug-induced lupus erythematosus, have been reported with the use of minocycline for acne.105 It is not known whether doxycycline causes similar adverse events, but doxycycline was not associated with an increased risk of hepatotoxicity in a single reported case-control study.106 A number of potentially important drug interactions have been associated with doxycycline use,97 including those involving the following drugs and substances:

CHAPTER 15  Malaria Chemoprophylaxis • Antacids containing divalent or trivalent cations (calcium, aluminum, and magnesium). Doxycycline binds cations, and concomitant administration of antacids will reduce serum levels of doxycycline. • Doxycycline should not be administered with milk and it is recommended to separate doxycycline and ingestion of dairy products by 2–3 hours. This recommendation is based on the fact that milk decreases the absorption of doxycycline and other tetracyclines because of chelation between the calcium (Ca++) in the milk and doxycycline. One early study administered doxycycline with either water or milk. Simultaneous ingestion of milk diminished the doxycycline peak plasma concentration by 24%.107 • Oral iron, bismuth salts, calcium, cholestyramine or colestipol, and laxatives that contain magnesium. Concomitant ingestion of these compounds may reduce doxycycline absorption. These agents should not be taken within 1–3 hours of doxycycline ingestion. • Barbiturates, phenytoin, and carbamazepine. These drugs induce hepatic microsomal enzyme activity and, if used concurrently with doxycycline, may reduce doxycycline serum levels and half-life and may necessitate a dosage adjustment. • Oral contraceptives. Older literature reported that concurrent use of doxycycline with estrogen-containing birth control pills might result in decreased contraceptive efficacy and recommended an additional method of birth control. However, there are few examples of oral contraceptive failure attributable to doxycycline use, and serum hormone levels in patients taking oral contraceptives have been reported to be unaffected by coadministration of doxycycline. Current evidence97 suggests that doxycycline can be used concurrently with oral contraceptives without leading to a higher rate of contraceptive failure.97,108 • Anticoagulants. The anticoagulant activity of oral anticoagulants may be enhanced with concurrent use of doxycycline. Close monitoring of prothrombin time is advised if these drugs are used together. • Vitamin A. The use of tetracyclines with vitamin A has been reported to be associated with benign intracranial hypertension.

Indications and Administration.  Doxycycline is a priority first line antimalarial for prevention of mefloquine-resistant P. falciparum malaria (evening or overnight exposure in rural border areas of Thailand with Myanmar [Burma] or Cambodia), or as an alternative to mefloquine or atovaquone/proguanil for the prevention of CRPf malaria. Doxycycline has a half-life that permits once-daily dosing. The dosage of doxycycline recommended for chemoprophylaxis against drug-sensitive and drugresistant malaria is 2 mg base/kg of body weight, up to 100 mg base daily (see Table 15.5). Studies have examined lower-dose regimens, but such regimens have provided inadequate protection.90,91 Doxycycline should be taken once daily, beginning 1–2 days before entering a malarial area, and should be continued daily while there. Because of its poor causal effect, it must be continued for 4 weeks after leaving the risk area. To reduce the occurrence of GI adverse events, it should be taken in an upright position with food and at least 100 mL of fluid or use the monohydrate form of the drug.

Atovaquone/Proguanil AP, a fixed drug combination, is a priority antimalarial for the prophylaxis of P. falciparum malaria.109 AP was first approved in Switzerland in August 1997 (as Malarone). Generic preparations are now also available.

Description.  AP is effective for both the prevention and treatment of malaria. Atovaquone is a hydroxynaphthoquinone compound and, combined with proguanil, an antifolate drug, works synergistically against the erythrocytic stages of all the Plasmodia parasites and the


liver stage (causal prophylaxis) of P. falciparum.109–111 AP is not active against hypnozoites in P. vivax and P. ovale and does not prevent relapse infections.

Pharmacology and Mode of Action.  Atovaquone acts by inhibiting parasite mitochondrial electron transport at the level of the cytochrome bc1 complex, and collapses mitochondrial membrane potential.112 The plasmodial electron transport system is 1000 times more sensitive to atovaquone than the mammalian electron transport system, which likely explains the selective action and limited side effects of this drug. Proguanil, as described, is metabolized to cycloguanil, which acts by inhibiting dihydrofolate reductase (DHFR). The inhibition of DHFR impedes the synthesis of folate cofactors required for parasite DNA synthesis. However, it appears that the mechanism of synergy of proguanil with atovaquone is not mediated through its cycloguanil metabolite. In studies, proguanil alone had no effect on mitochondrial membrane potential or electron transport, but significantly enhanced the ability of atovaquone to collapse mitochondrial membrane potential when used in combination. This might explain why proguanil displays synergistic activity with atovaquone even in the presence of documented proguanil resistance, or in patient populations who are deficient in cytochrome P450 enzymes required for the conversion of proguanil to cycloguanil.113 Atovaquone is a highly lipophilic compound with poor bioavailability. Taking atovaquone with dietary fat increases its absorption, and therefore tablets should be taken with a meal or a milky beverage. Atovaquone is >99% protein bound and is eliminated almost exclusively by biliary excretion. More than 94% can be recovered unchanged in the feces over 21 days and 37%–99%) for P. vivax.151 In placebo-controlled field studies in Colombian soldiers, primaquine was 94% efficacious (95% CI 78%–99%) against P. falciparum and 85% (95% CI 57%–95%) against P. vivax.152 In an attempt to improve the efficacy rate against P. vivax malaria, weekly chloroquine was added to the daily primaquine in a subsequent field trial; however, the results were similar to those of primaquine alone.153 Relapses of P. vivax malaria following standard courses of primaquine (15-mg base/day for 14 days) are commonly reported from Papua New Guinea, Papua, Thailand, and other parts of Southeast Asia and Oceania (failure rates 30 minutes outdoors after sundown and did not use repellents, only 4% of the flight attendants and 40% of the pilots adhered completely.179 Most recently, an analysis of GeoSentinel data on >12,000 ill business travelers seen after travel in 1997–2014 found that 9% of the diagnoses were malaria, one of the most frequent specific diagnoses overall.180 The vast majority of the >1000 patients with malaria took no chemoprophylaxis or did not adhere to their chemoprophylaxis; nearly all of

the patients with severe malaria were due to P. falciparum and nearly all had exposure in sub-Saharan Africa. Finally, over half of the 13 deaths recorded were due to malaria.180 Clearly, malaria prevention in business travelers needs improvement. Countries and companies vary in their current requirements and needs for business travelers. The degree of malaria exposure for business travelers ranges widely depending on destination, type of work, activity, and accommodations and are influenced by individual risk perception and practices.

Migrant and VFR Travelers The displacement of populations due to natural disasters or political/ economic instability in recent decades has led to migration from malaria-endemic countries to nonendemic countries. In time, the migrants return to their countries of origin to VFR, with associated risk of malaria.1,181–183 An analysis of imported malaria in Barcelona, for example, found that 41% were VFR and 14% were recently arrived immigrants.184 Among 7629 migrants from 153 countries seen in GeoSentinel clinics in 19 countries from 1997 to 2009, malaria was one of the most common diagnoses, along with latent tuberculosis, viral hepatitis, active tuberculosis, HIV/AIDS, schistosomiasis, and strongyloidiasis.181 Malaria was especially common with febrile patients and hospitalized patients. Among the patients who were hospitalized, 21% had febrile illness and 83% were attributed to malaria.181 It has been repeatedly illustrated that malaria affects VFR travelers disproportionately.1 In 2013, 1727 cases of malaria were reported to the US CDC, among which 70% with known purpose of travel was

CHAPTER 15  Malaria Chemoprophylaxis visiting friends and relatives.183 Of nine reported fatalities that described a purpose for travel, six were VFR, illustrating the high malaria risk and severe disease associated with this group of travelers.183 The disproportionate impact of malaria on VFR travelers is further evident from cases of malaria in pregnant women.171 Collaborators from Europe, the United States, and Japan pooled data and described 631 cases of pregnant women with malaria, where they found VFR was the main reason for travel (58%), and most cases were P. falciparum acquired in West Africa.171 Nevertheless, malaria species distribution may be influenced by the origin countries of migrants. Because migration patterns shift over time, there may be an accompanied shift in species identified. During the ongoing waves of migration from Africa to Europe since 2013, the Netherlands has seen a sharp increase in imported malaria in asylum seekers as well as VFR travelers.182 In 2014–2015, most malaria cases in VFR travelers in the Netherlands were due to P. falciparum that were exposed in Central and West Africa, while most asylum seekers with malaria were infected with P. vivax in the Horn of Africa.182 In the future, these asylum seekers may return to the Horn of Africa as VFR travelers and may lead to an increased proportion of vivax malaria diagnosed in the Netherlands. Additionally, a gradient of risk has been proposed within the VFR traveler population, including that for malaria.2 This may have resulted from the familiarity of a migrant with certain disease risks in the country of origin and the assumption that he or she has partial immunity from having lived in the endemic country. Therefore a “migrant VFR” may behave differently and experience divergent levels of risk compared to a “traveler VFR.” More specifically, malaria was more commonly diagnosed among “immigrant VFRs” than “traveler VFRs.” Given their increased risk for malaria, VFR travelers should ideally receive pretravel health advice, but multiple studies have found VFR travelers to be underserved by pretravel consultations.1 Earlier studies have shown that it is cost effective to subsidize chemoprophylaxis for VFRs to West Africa and thus avoid the costs of the treatment of imported malaria.185,186 When VFR travelers do receive pretravel advice, the bias toward increased imported malaria is eliminated.1 A potentially fruitful approach is to query patients during their routine primary care appointments regarding their future travel plans. Such active screening for intended travel activities can identify future VFR travelers, determine high-risk itineraries, and lead to education regarding the importance of seeking appropriate pretravel health preparation.4 Even if VFR travelers recognize their increased risk and seek pretravel health advice, malaria chemoprophylaxis still faces other challenges: cost of medication, adherence to chemoprophylaxis, and misdirection to discontinue medication from family or friends residing in endemic countries. Detailed discussions with VFR travelers regarding the many facets of malaria prevention and chemoprophylaxis will require spending extra time. But a clear understanding regarding malaria and the preventive strategies will be well worth the effort to achieve reduction of malaria in VFR travelers.

Infants/Children Because of their less mature immune system and inexperience in responding to symptoms of illness, young children are especially vulnerable to malarial infection and can develop high parasitemia rapidly. In pediatric travelers from the Boston area (≤18 years), VFR children were much more likely to travel to malaria-endemic countries, and 35% reported VFR as the purpose of travel.187 Nearly half of VFR children were 2 months (unless the product information states otherwise), except for oil of lemon eucalyptus, which should only be used in children ≥3 years. Specific tips for families include: • Adults should apply repellents on children rather than letting young children apply. • Avoid children’s hands in case they lick, and avoid eyes, mouth, and around the ears. • Upon returning indoors, cleanse off skin or bathe to remove repellent to reduce accumulation.

DIFFERENCES IN GUIDELINES AND RECOMMENDATIONS ON MALARIA CHEMOPROPHYLAXIS Many countries publish and regularly update recommendations for malaria chemoprophylaxis (e.g., Canada, United Kingdom, Scotland, France, Switzerland, Netherlands, United States, Australia) (see Table 15.5). Other organizations and groups share guidelines for the prevention of malaria (e.g., WHO, International Association for Medical Assistance to Travellers [IAMAT]). Most of these are freely available to health care providers; some are also intended for travelers. Some are official guidelines for a country; others aim for an international audience. They are updated with variable frequency, and there is notable variation in the recommendations. The recommendations may have financial implications if they determine which drugs will be covered or legal ramifications based on recommendations for specific patients or destinations. It should be noted that in general, the greatest agreement in recommendations exists for geographic areas with highest malaria risk (i.e., sub-Saharan Africa). It is worth observing that as malaria transmission decreases and is close to elimination in many countries, the number of countries or geographic regions with divergent recommendations is likely to increase. Greatest divergence exists for countries with low or moderate risk where chemoprophylaxis or standby emergency treatment may be recommended. Guidelines generally agree that all travelers to areas with malaria should use mosquito avoidance measures though they may vary in the detail provided. Three questions are relevant: How do guidelines differ? Why do they differ? What are the consequences? The drugs that are recommended differ. In most recommendations chloroquine, atovaquone-proguanil, mefloquine, and doxycycline are among the options for chemoprophylaxis. Some also list hydroxychloroquine as an alternative to chloroquine for areas with chloroquine-sensitive malaria. Several country guidelines (e.g., United Kingdom, France, Hong Kong) continue to list proguanil as a single agent or combined with chloroquine. In the United Kingdom, chloroquine and/or proguanil and atovaquone/proguanil can be


SECTION 4 Malaria

purchased from local pharmacies without a prescription (in contrast to other antimalarials available in the United Kingdom). Primaquine.  Clear differences exist for primaquine, which is not recommended for primary prophylaxis for any situation in most guidelines. UK guidelines note that primaquine is not licensed in that country; both the United States and Canada list primaquine as an option for primary prophylaxis (as well as for presumptive antirelapse therapy or terminal prophylaxis) for travelers to areas with only or primarily P. vivax malaria. Its use for primary prophylaxis is considered off-label in the United States, though it is listed as one of the recommended options in the country. The CDC’s Health Information for International Travel supports US providers who decide to recommend it. Those guidelines specifically note that it is a good choice for travel to places with >90% vivax malaria, shorter trips, and for last-minute travelers. Canadian guidelines say that primaquine is not a first line chemoprophylactic agent but may be considered as an alternative when other agents are contraindicated. All guidelines that mention primaquine highlight the need to test for G6PD deficiency before considering its use. Point-of-care G6PD testing will have increasing importance for future primaquine and tafenoquine recommendations.190 Country recommendations may reflect local availability of drugs or licensing. Ease of off-label use may vary; restrictions about use (e.g., mefloquine) may also differ. Recommendations about maximum duration that a drug can be used may vary. Some countries are mandated to use a specific checklist before prescribing mefloquine.58 Minor differences exist about dosing, duration, age cutoffs, and specific risk groups (infancy, pregnancy, breastfeeding, renal failure, hepatic dysfunction, etc.) for several of the drugs and a recent study shows wide variation in expert recommendations on malaria prophylaxis for the forementioned niche groups.191 Moderate-to-low malaria risk is defined as one infection per 10,000 travelers192 but most guidelines do not define risk quantitatively. The US guidelines specify “estimated relative risk for US traveler” and use terms very low, low, moderate, and high. The UK guidelines use descriptors that range from no risk, low to no, very low, low, moderate, to high. Some recommendations use duration of travel as a threshold for recommending prophylaxis. For example, for certain locations prophylaxis is not recommended for travel 90%.55–57 The ICT Malaria P.f./P.v. test (or RIDA MalaQuick Kombi) yields a similarly high specificity of >90% with P. vivax infections, but the overall sensitivity lies between 72% and 75% in most studies,37 with some studies yielding detection rates even lower than 50%.58 At low parasitemias (10 kg) and artemether/lumefantrine are suitable for SBET. For newborns 100,000/µL dangerous

Almost never high

Almost never high

>50,000/µL dangerous

RBC infected Organs infected

Any Vascular sinuses • Seizuresa • Coma • AKIb • Jaundice/hepatic dysfunctionb • ARDSb • Anemiaa • Shock • Metabolic acidosis

Older erythrocytes Vascular sinuses and unknown • Rare case reports of AKI and ARDS

Reticulocytes Vascular sinuses and unknown • ARDS • Anemia

Any Vascular sinuses

Salient syndromes in severe disease

Drug resistance problems

• Chloroquine (universal) • Artemisinin (Southeast Asia) Rare

Yes Temperate, subtropical, and tropical Americas, Africa, Asia Does not correlate with clinical threat Youngest reticulocytes Vascular sinuses, spleen, and marrow • Platelets 50,000 parasites/µL blood, respectively, each associated with an increased risk of severe disease. However, this is much less clear in patients with P. vivax malaria, where biomass may sequester in the spleen and marrow.9,10 Any level of parasitemia in vivax malaria should be considered potentially threatening.

Rapid Diagnostic Tests A wide variety of commercially available immunochromatographic cassettes for the diagnosis of malaria may be applied where competent microscopic diagnosis is not available. Though simple and often effective in endemic settings, the diagnosis is less sensitive than expert

microscopy—few of the many available kits detect parasitemia 2%.

Cautions: AL levels affected by CYP3A4 inducers and antiretroviral drugs. Patients with/on QTc prolongation drugs. PP dose dependent prolongation of the QTc interval. Contraindications: known congenital QTc prolongation in patient or family, on drugs or have a disease with long QTc Rarely causes transient neutropenia and transaminitis

Total dose 25 mg/kg: 15 then 10 mg/kg over 2 days. Give both for 7 days. Quinine may be given for 5 days.

Total dose 25 mg/kg in 48 hours: 10-10-5 or 10-5-5-5. Follow local recommendations. CQR common in Indonesia, Papua New Guinea, SE Asia. Foci elsewhere.

Plasmodium ovale; Plasmodium malariae First line treatment Chloroquine Alternative treatment ACTs above or ATV-PG Plasmodium knowlesi First line treatment ACTs as above Alternative treatment CQ, ATV-PG, MQ

Contraindicated in significant psychiatric disease (depression, anxiety neurosis), epilepsy. No repeat dose ≤2 months. Contraindicated acute liver disease (jaundice and symptoms), severe liver disease (i.e., decompensated cirrhosis, Child-Pugh stage B or C). Severe renal impairment. Creatinine clearance 9 million Americans would travel abroad for medical care.9 In 2016, the Centers for Disease Control and Prevention conducted novel, population-based surveillance of medical tourism behaviors, although findings are not yet available. This surveillance data will provide estimates of common destinations, procedures, and adverse outcomes. The most common categories of procedures that medical tourists pursue include cosmetic surgery, dentistry, cardiac surgery, and orthopedic surgery.4,10 Other treatments include bariatric and reproductive procedures. Common destinations include Argentina, Brazil, Costa Rica, Cuba, Dominican Republic, India, Malaysia, Mexico, Pakistan, Philippines, Singapore, and Thailand.4,6,11 The type of procedure and the destination need to be considered when evaluating the risk of medical tourism. Some insurers and large employers have developed alliances with overseas hospitals, and several major medical schools in the United

Since antiquity, people have traveled in search of healing. There are places throughout the world that are thought of as healing places, with aspects in the natural, built, symbolic, and social environments that people associate with healing.1 Many historical sites, such as Lourdes in France, continue to attract pilgrims. In more modern times, there has been a great deal of interest in creating therapeutic spaces. Florence Nightingale introduced early concepts such as facilitating healing through the provision of fresh air, adequate lighting, and good accommodations for staff.2 In 1984 Science magazine published a study by Roger Ulrich showing that patients in hospital rooms that looked out on the natural world healed faster. Architects have worked with medical researchers to design buildings such as hospitals and wellness spas to facilitate healing.3 Travelers to places in search of health care are described as medical tourists. Medical tourists include those traveling to: • Hospitals or clinics for conventional medicine, invasive treatments, state-of-the-art technology, experimental procedures, or medical treatments unobtainable in their country of residence • Wellness centers and spas that offer complementary medicine and traditional natural preventive medicine • Destination spas offering body and mind treatment backed with medical knowledge and treatments such as hydrotherapy tubs, steam baths, and therapeutic massage This chapter will focus on the first group: those individuals traveling internationally for medical treatment in hospitals or clinics.

MEDICAL TOURISM DEFINED Medical tourism is the term to describe the phenomenon of people traveling outside their home country primarily for the purpose of seeking medical treatment.4,5 Multiple factors, such as cost or interest in combining vacation activities with medical care, may influence the decision to


CHAPTER 39  Medical Tourism Abstract


Medical tourism is defined as travel primarily for the purpose of receiving health care. Medical tourists may travel for a variety of procedures, including novel or experimental treatments. Medical tourists may also travel to developing or developed countries. Medical tourism represents a growing health care market, and this group of travelers presents unique challenges for public health and clinical medicine. In addition to traditional travel health recommendations, medical tourists have unique health needs and should be advised accordingly. Some of these needs include ensuring current medical conditions are stable enough for travel and the need for appropriate follow-up care after procedures.

Cross-border health care Health care globalization Infectious disease International travel Medical tourism Transplant tourism



SECTION 7  Travelers With Special Itineraries

TABLE 39.1  Potential Advantages and

Disadvantages of Medical Tourism

Potential Advantages • Lower health care costs • Often lower total overall cost for those paying out of pocket • Co-pays and deductibles may be covered by some insurance companies • More luxurious accommodations than local hospitals, including “recovery resorts” • Ability to access novel treatments or procedures unavailable in country of residence • Possibility of combining leisure activities with medical care • Faster access to medical provider Potential Disadvantages • Accreditation standards and regulations may not provide sufficient patient protection • Experimental treatments or procedures may not be effective • Possible variations in laws regulating insurance coverage • Limited tort options in event of a bad outcome • Potential language or cultural barriers • Risks of long-distance travel, including risks of traveling postsurgery • Risks of adverse outcomes, especially infection, possibly with drugresistant organisms • Use of resources and health care personnel that might otherwise be available for local population of low-income countries

States have developed joint initiatives with overseas providers, such as the Harvard Medical School Center for Global Health Delivery in Dubai, The Johns Hopkins Singapore International Medical Center, and the Duke-National University of Singapore.11,12 At present it is not known how such joint ventures affect the number of people traveling for health care. Beyond specific institutional collaborations, the Association of American Medical Colleges has established Global Health Learning Opportunities (GHLO). The mission of the GHLO is “[t]o provide a global network that facilitates educational mobility for health professionals.” This is a network of collaborating institutions in countries throughout the world that facilitates medical and public health students interested in pursuing electives outside their home country. Students from 87 different institutions in 34 countries undertake training electives at 57 institutions in 30 countries.13 They also train in over 30 programs in 10 countries that are a part of the Child Family Health International (CFHI) global health education programs.14

GENERAL CONSIDERATIONS RELATED TO MEDICAL TREATMENT ABROAD Prospective medical tourists should consult a travel medicine provider for advice tailored to their individual health needs and destination, preferably at least 4–6 weeks before travel.15 In addition to the considerations for healthy travelers, medical tourists should be advised on the risks associated with surgery and travel—either while ill or while recovering from treatment. Travelers should also ensure that any current medical conditions are stable enough to withstand travel and any planned medical procedures. The Aerospace Medical Association has published medical guidelines for airline travel that provide useful information on the risks of travel with certain medical conditions.16 (See Chapter 4 for more information about fitness to fly.) Unfortunately it is suspected

that many individuals traveling for medical tourism would not seek the assistance of a travel health advisor prior to travel. These individuals may be at greater risk for problems on return. When advising travelers considering a trip overseas for medical care, clinicians should consider the guiding principles developed by the American Medical Association for employers, insurance companies, and other entities that facilitate or offer incentives for care outside the United States.17 These guidelines discuss ensuring the voluntary nature of the care, the need to use an accredited facility, legal recourse, and transfer of data between facilities.17 In addition, patients should be advised that they should arrange for follow-up care in their home country before they travel.17 Health care providers should advise prospective medical tourists to determine whether providers and health care facilities where they are considering receiving care are accredited. Local accreditation standards may differ from those of the United States. Some health care providers and facilities may carry additional accreditations beyond local requirements, such as being board certified in the United States. Health care facilities may be accredited by international entities such as Joint Commission International or Accreditation Canada International. Many concerns have been raised in relation to medical tourism. Medical tourists may lack access to data on quality of care; they also face challenges regarding continuity of care.18,19 It is often not possible to obtain information regarding sterility of equipment or safety procedures in other countries. Thus there are concerns regarding transmission of bloodborne infections with any procedure. In addition there may be public health implications. For example, in countries with publicly funded health care systems, the public in the patient’s home country may shoulder costs for follow-up care and ongoing treatment after patients return home, potentially creating an excessive financial burden that might not otherwise exist.20 Implications for the health care system of the country providing care for medical tourists are unknown. Proponents of medical tourism believe it will improve health for local populations by encouraging technologic advancements in the medical field and providing a source of economic growth. Others are concerned that physicians and health care resources will be diverted from local populations to provide for international patients.21 Finally, numerous concerns have been raised about exploitation of individuals who provide surrogacy services, or those who sell their organs for transplant or eggs for fertility treatments.22,23

COSMETIC SURGERY TOURISM RECOMMENDATIONS The American Society of Plastic Surgeons (ASPS) advises patients who have had cosmetic procedures of the face, eyelids, and/or nose, or who have had laser treatments, to wait 7–10 days before flying.19 Patients who have had body procedures (such as liposuction) should wait 5–7 days before flying.22 Patients also are advised to avoid “vacation” activities such as sunbathing, drinking alcohol, swimming, taking long tours, and engaging in strenuous activities or exercise after surgery.19,25 The International Society of Aesthetic Plastic Surgery (ISAPS) was organized by the United Nations and represents over 3200 boardcertified aesthetic plastic surgeons in 103 countries. ISAPS developed guidelines for plastic surgery travelers covering areas such as surgeon training and certification and facility certification.26 The guidelines also caution travelers to ensure that key personnel speak the traveler’s language fluently as a way to prevent complications. Travelers should be clear on how aftercare and complications will be handled, and whether additional payment will be required for any additional treatment.

CHAPTER 39  Medical Tourism

DENTAL WORK ABROAD The Global Dental Safety Organization for Safety and Asepsis Procedures developed the Traveler’s Guide to Safe Dental Care.27 Although these guidelines were not developed for medical tourists, they may be useful for travelers to consider when selecting a facility or planning a trip for medical or dental care. A major concern for dental procedures is infectious complications, so travelers planning dental care abroad should inquire about the sterilization and disinfection procedures in the office. Particular caution is required if the traveler is going to an area that has problems with drinking water contamination. In those areas, sterile or boiled water is required for all surgical procedures. The patient should be sure that new needles and gloves are used, and that hands are washed before and after each procedure.

TRANSPLANT TOURISM One controversial form of medical tourism is sometimes called “transplant tourism”: travel for the purpose of getting a transplant of an organ purchased from an unrelated donor.30 A 2007 report, still the most recent, on the international organ trade found that China, the Philippines, and Pakistan were the largest organ-exporting countries.28 In 2004 World Health Assembly Resolution 57.18 encouraged member states of the World Health Organization to “take measures to protect the poorest and vulnerable groups from ‘transplant tourism’ and the sale of tissues and organs.”29 In 2008 the Transplantation Society and the International Society of Nephrology convened an international summit in Istanbul, Turkey, to address the issue of transplant tourism and organ trafficking.30 That meeting resulted in the Declaration of Istanbul on Organ Trafficking and Transplant Tourism. From that declaration: “Organ trafficking and transplant tourism violate the principles of equity, justice and respect for human dignity and should be prohibited. Because transplant commercialism targets impoverished and otherwise vulnerable donors, it leads inexorably to inequity and injustice and should also be prohibited.” In response to these events, the World Health Organization revised the Guiding Principles on Human Cell, Tissue and Organ Transplantation in May 2010.31 Several studies have identified potential problems that travelers and health care providers should be aware of when considering transplantation overseas: lack of documentation related to the donor and the procedures, patients receiving less immunosuppressive medication than in current practice in the United States, and the majority of patients not receiving antibiotic prophylaxis.24,32,33 However, it is not clear whether these issues represent issues faced by all patients who travel for transplants. Data comparing complication rates between transplants performed in a patient’s home country with those in lower-income countries are limited. In 2015 the Pontifical Academy of Sciences Summit on Organ Trafficking and Transplant Tourism stated that organ trafficking and human trafficking for the purpose of organ removal are “true crimes against humanity [that] need to be recognized as such by all religious, political and social leaders, and by national and international legislation.”36

BARIATRIC TOURISM In addition to the previously described recommendations, individuals seeking bariatric surgery abroad should be reminded that obesity is considered a chronic disease, even after bariatric surgery.37 Some bariatric surgeons have suggested that a multidisciplinary care team skilled in the ongoing management of patients after bariatric surgery should be involved in the follow-up plan.37 In addition to monitoring for surgical complications, the team can assist with complications that arise due to rapid weight loss or from ongoing obesity or nutritional


or emotional problems. Patients should be encouraged to liaise with an appropriate center in their home country before undergoing surgery abroad.

REPRODUCTIVE TOURISM Increasingly patients are traveling to other countries or different regions within their own country to access fertility treatments, perhaps because of lack of local expertise, cost, long waiting times, or illegality of the procedures in their home country.21 Patients may travel to access donor eggs or surrogates, or have more embryos implanted than are allowed in their home country. In some areas reproductive care may exclude certain patient groups, such as single women or those in same-sex relationships. Finally, some may travel for added privacy. Although there are limited data on outcomes, the majority of studies have shown high patient satisfaction. Language and communication problems were the most common problems reported by patients.21

MEDICATIONS All travelers need to be aware of the global problem of counterfeit medications. The content of these medications varies widely, from insufficient active ingredients to toxic levels of active ingredients, or the presence of toxic additives. Substandard, spurious, falsely labeled, falsified, and counterfeit (SSFFC) medical products affect every region. The most commonly reported SSFFC medical products include antibiotics, a fact that has important implications for medical tourists.34 Herbal medicines may lack standardization and may not be regulated by local authorities and may carry risks similar to counterfeit medications. The Centers for Disease Control and Prevention (CDC) recommends that travelers carry a sufficient amount of their routine medications and drugs needed for the trip, considering there may be delays. Travelers should also be advised to carry copies of their prescriptions and a list of all medications they take, including the brand name, generic name, dosage, and manufacturer.13

ADVERSE EFFECTS AND COMPLICATIONS Although many medical tourists hope to achieve a quality of care similar to that in their home country at a reduced cost, there are few or no outcome data from international centers.19 Infection control practices may not be as rigorous as those in the patient’s home country, and rates of various bloodborne infections in the local population may be higher. For example, contaminated instruments or blood products could therefore lead to acquisition of HIV, or hepatitis B or C. One study comparing patients who had transplants performed abroad to those who had transplants performed in their home country of Saudi Arabia revealed that those traveling abroad were more likely to have hepatitis C seroconversion.35 Postoperative wound infections due to nontuberculous mycobacteria have also been associated with medical tourism. In 1998 nine patients who underwent liposuction or liposculpture procedures in Venezuela were found to have confirmed or probable infection due to rapidly growing mycobacteria.38 Two outbreaks of Mycobacterium abscessus, an organism ubiquitous in the environment, also were identified among US residents who had received cosmetic surgery in the Dominican Republic. The first outbreak was identified in 2003–2004, the second in 2013–2014. Both investigations found patients required extended courses of antimicrobial therapy as part of their treatment, and in some cases, debridement and reversal of the original surgical procedures.39,40 These reports highlight the difficulty of identifying outbreaks related to surgical procedures when follow-up care is not confined to the treating


SECTION 7  Travelers With Special Itineraries

institution. Many of these infections developed after patients had returned home, making it more difficult to identify that an outbreak had occurred. Foreign travel also has been identified as a risk factor for colonization with resistant organisms. A prospective study from Sweden in 2010 demonstrated that international travel is a major risk factor for colonization with extended-spectrum beta-lactamases producing Enterobacteriaceae.41 Another concerning organism is the New Delhi metallo-β-lactamase-1 (NDM-1), first described in 2009 in a Swedish man who had been hospitalized in India.42 In 2016 a Nevada resident was diagnosed with pan-resistant NDM-1 Klebsiella pneumoniae most likely acquired during hospitalization in India.43 Organisms that express NDM-1 have now been reported in Canada, the United States, Turkey, Japan, China, Singapore, Australia, and many European countries, including the United Kingdom.42 Another organism, Candida auris, has been identified as a very serious pathogen causing invasive infections transmitted in health care settings. Patients infected with multidrug-resistant strains of C. auris have been identified in many countries and also in the United States, with the origin of many of the US isolates having been traced through genome sequencing to acquisition in other countries. C. auris transmission has been reported in India, Pakistan, South Africa, and Venezuela. The organism has been isolated from urine or wound cultures and bloodstream infections; patients may remain colonized for prolonged periods. Unfortunately this organism is not easily identified in the laboratory. The US CDC has sent an alert notice to clinicians, laboratorians, and public health regarding the emergence of this new pathogen ( -alert.html). Patients may also have difficulty obtaining follow-up care upon their return home. Some providers may not wish to see patients after having procedures abroad if they disapprove of medical tourism, or worry about the potential for litigation if the patient has a complicated course following treatment.6 Therefore patients should arrange for appropriate follow-up care before traveling. Furthermore, clinicians seeing patients returning from an international trip for medical procedures face many challenges. Documentation on the procedures and treatments performed may be incomplete or unavailable. Aftercare for a patient who received a transplant or developed a wound infection, in the absence of adequate information on the immunosuppressive medications given or the antibiotics provided, can lead to the development of further complications.44 Finally, options for legal recourse may be limited by local laws and difficulty navigating a foreign legal system. Even when successful, the amount of compensation may be considerably less than that in the patient’s home country.19

CONCLUSIONS The international medical tourism market is rapidly expanding with patients traveling around the world for many different kinds of procedures. All medical procedures carry some risk and medical tourism is no exception. Healthcare providers should counsel prospective medical tourists on the risks associated with their destination and any planned procedures, as well as ensure that any current medical conditions are controlled for travel and medical care. Medical tourists should obtain copies of their medical records for any care received abroad, and seek appropriate follow-up care upon return to their country of residence.

REFERENCES 1. Gesler WM. Healing places. Lanham, MD: Rowman & Littlefield; 2003. 2. Nightingale F. Notes on hospitals: 2 papers; with evidence given to the royal commissioners on the state of the army in 1857. 1863;3rd enlarg ed.

3. Sternberg EM. Healing spaces: the science of place and well-being. Cambridge, MA: Belknap Press; 2009. 4. Reed CM. Medical tourism. Med Clin North Am 2008;92(6):1433–46. 5. Ehrbeck T, Guevara C, Mango PD. Mapping the market for medical travel. McKinsey Q 2008;11. 6. Chen LH, Wilson ME. The globalization of healthcare: implications of medical tourism for the infectious disease clinician. Clin Infect Dis 2013;57(12):1752–9. 7. Cohen IG. Medical tourism: the view from ten thousand feet. Hastings Cent Rep 2010;40(2):11–12. 8. Sameer K, Breuing R, Chahal R. Globalization of health care delivery in the United States through medical tourism. J Health Commun 2012;17(2):177–98. 9. Deloitte Center for Health Solutions. Medical tourism: customers in search of value. 2008. 10. Horowitz MD, Rosensweigh JA, Jones CA. Medical tourism: globalization of the healthcare marketplace. Med Gen Med 2007;9(4):33. 11. Bookman MZ, Bookman KR. Medical tourism in developing countries. New York: Palgrave Macmillan; 2007. 12. Galland Z. Medical tourism: the insurance debate: most insurers balk at covering medical procedures performed overseas, but some are exploring the option. Businessweek News 2008. 13. Global Health Learning Opportunities. 2017. Available at https:// 14. Child Family Health International. 2017. Available at https://www.cfhi .org/. 15. Centers for Disease Control and Prevention (CDC). CDC health information for international travel 2016. New York: Oxford University Press; 2016. 16. Aerospace Medical Association Medical Guidelines Task Force. Medical guidelines for airline travel. Aviat Space Env Med 2003;74:A1–19. 17. American Medical Association. Guidelines on Medical Tourism. 2008. Available at Whitepapers/AMAGuidelines.pdf. 18. Snyder J, Crooks VA. Medical tourism and bariatric surgery: more moral challenges. Am J Bioeth 2010;10(12):28–30. 19. American Society of Plastic Surgeons. Briefing Paper: Cosmetic Surgery Tourism. 2010. Available at briefing-papers/briefing-paper-cosmetic-surgery-tourism. 20. Johnston R, Crooks VA, Adams K, et al. An industry perspective on Canadian patients’ involvement in medical tourism: implications for public health. BMC Public Health 2011;11:416. 21. Weiss EM, Spataro PF, Kodner IJ, et al. Banding in Bangkok, CABG in Calcutta: the United States physician and the growing field of medical tourism. Surgery 2010;148(3):597–601. 22. Martin D. Professional and public ethics united in condemnation of transplant tourism. Am J Bioeth 2010;10(2):18–20. 23. Hudson N, Culley L, Blyth E, et al. Cross-border reproductive care: a review of the literature. Reprod Biomed Online 2011;22(7):673–85. 24. Gill J, Madhira BR, Gjertson D, et al. Transplant tourism in the United States: a single-center experience. Clin J Am Soc Nephrol 2008;3(6): 1820–8. 25. Doheny K. Sick? Don’t fly. But if you must, get prepped before takeoff. Los Angeles Times 2004. 26. International Society of Aesthetic Plastic Surgery. Guidelines for plastic surgery tourists. 2017 March. Available at medical-travel-guide/plastic-surgery-tourists. 27. Organization for Safety, Asepsis and Prevention. Traveler’s Guide to Safe Dental Care. Available at 28. Shimazono Y. The state of the international organ trade: a provisional picture based on integration of available information. Bull World Health Organ 2007;85(12):901–80. 29. World Health Organization (WHO). Draft Guiding Principles on Human Organ Transplantation. Available at transplantation_guiding_principles/en/index1.html. 30. Steering Committee of the Istanbul Summit. Organ trafficking and transplant tourism and commercialism: the Declaration of Istanbul. Lancet 2008;372(9632):5–6.

CHAPTER 39  Medical Tourism 31. WHO. WHO guiding principles on human cell, tissue and organ transplantation. Contract No.: WHA63.22 2010. 32. Merion RM, Barnes AD, Lin M, et al. Transplants in foreign countries among patients removed from the US transplant waiting list. Am J Transplant 2008;8(4 Pt 2):988–96. 33. Sajjad I, Baines LS, Patel P, et al. Commercialization of kidney transplants: a systematic review of outcomes in recipients and donors. Am J Nephrol 2008;28(5):744–54. 34. WHO. Substandard, Spurious, Falsely Labelled, Falsified and Counterfeit (SSFFC) Medical Products. 2016. Available at medicines/regulation/ssffc/en/. 35. Alghamdi SA, Nabi ZG, Alkhafaji DM, et al. Transplant tourism outcome: a single center experience. Transplantation 2010;90(2):184–8. 36. Statement of the Pontifical Academy of Sciences Summit on Organ Trafficking and Transplant Tourism. 2017 Aug 30. Available at http:// statement.html. 37. Birch DW, Vu L, Karmali S, et al. Medical tourism in bariatric surgery. Am J Surg 2010;199(5):604–8. 38. CDC. Rapidly growing mycobacterial infection following liposuction and liposculpture-Caracas, Venezuela, 1996–1998. Morb Mortal Wkly Rep 1998;47(49):1065–7.


39. Furuya EY, Paez A, Srinivasan A, et al. Outbreak of mycobacterium abscess wound infections among ‘lipotourists’ from the United States who underwent abdominoplasty in the Dominican Republic. Clin Infect Dis 2008;46(8):1181–8. 40. Schnabel D, Esposito DH, Gaines J, et al. Multistate US outbreak of rapidly growing mycobacterial infections associated with medical tourism to the Dominican Republic, 2013–2014. Emerg Infect Dis 2016;22(8): 1340–7. 41. Tangden T, Cars O, Melhus A, et al. Foreign travel is a major risk factor for colonization with Escherichia coli producing CTX-M-type extendedspectrum Β−lactamases: a prospective study with Swedish volunteers. Antimicrob Agents Chemother 2010;54(9):3465–568. 42. Yong D, Toleman MA, Giske CG, et al. Characterization of a metallo-betalactamase gene, bla(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother 2009;53(12):5046–54. 43. CDC. Notes from the field: pan-resistant New Delhi metallo-betalactamase-producing Klebsiella pneumoniae—Washoe County, Nevada, 2016. Morb Mortal Wkly Rep 2017;66(1):33. 44. Jones JW, McCullough LB. What to do when a patient’s international medical care goes south. J Vasc Surg 2007;46(5):1077–9.

40  Cruise Ship Travel Carter D. Hill

KEY POINTS • Cruise ships can be amplifiers of infectious diseases because of the close human proximity of semiclosed ship environments. • The most common diagnoses of cruise passengers evaluated in cruise ship infirmaries include upper respiratory infections, injury, seasickness, and gastrointestinal illness. • Cruise ship passengers may experience clusters of brief self-limited diarrheal disease, although this rate is much lower risk than on land.

• Certain groups, such as the elderly, pregnant women, and immunocompromised, might be more seriously affected by infectious diseases and stress of travel. • Ensure the traveler has medical insurance (health and repatriation) that covers conditions in international waters.


Nile and the Amazon. Ocean cruises make up the greatest portion of ship-based leisure travel, with the North American cruise industry accounting for the major part of the global ocean cruise market. The North American cruise industry consists of cruise lines that market cruises primarily to North Americans but have embarkation ports worldwide. The Caribbean remains the top cruise destination, followed by Alaska, the Mediterranean, and other parts of Europe. Depending on the type of cruise, the duration can range from hours (e.g., gambling cruises) to several months (e.g., round-the-world cruises). The average duration of a cruise is 9 days, and approximately 58% of cruising passengers choose 6–8-day cruises. The typical 7-day cruise allows passengers ample time to visit three to five ports and explore different locales and cultures.1

Cruise ship travel has gained tremendous popularity over the last four decades. In 2016, 24 million passengers on 448 ships sailed on worldwide cruises. Cruise destinations such as the Caribbean and Mediterranean have gained popularity due to climate as well as accessibility to many ports. The ever-expanding cruise itineraries (including 184 river cruise ships), which include diverse ports of call, along with a growth in the number of embarkation ports and onboard amenities, provide travelers with convenient and comfortable means to sample different parts of the world in a short amount of time.2 With the growing popularity of recreational cruises, gastrointestinal (GI) and respiratory disease outbreaks may be amplified by the densely populated, semiclosed cruise environment, which compels international passengers and crew to share many activities and resources. Moreover, passengers can acquire a new infectious disease while in port through contaminated food, water, or infected people.3 Environmental contamination of cruise ships may result in protracted outbreaks due to infected crew and passengers who remain onboard during successive voyages. Sanitation and disease surveillance programs developed through the cooperation of the cruise industry and public health agencies have led to improved detection and control of communicable diseases.4 Understanding the most frequently reported diseases on cruise ships, their source and mode of transmission, prevention measures, and available ship medical care facilities can lead to better preparedness for a healthy cruise vacation.5

THE CRUISE INDUSTRY The North American Cruise Industry Ships carrying 13 or more passengers are considered under international law to be passenger ships. They include sailboats, yachts, river cruise ships, and ocean cruise ships. Sailboats and yachts are best known for niche travel, such as “eco-touring.” River cruises are popular for providing an informal, intimate atmosphere while traveling to places such as the

The Passengers and Crew Compared to US residents on noncruise vacations (defined by those spending ≥3 nights away from home for leisure trips), cruisers tend to be older (49% are >50 years of age), have higher income levels, and are likely to plan a vacation 4–6 months in advance,1 allowing time for pretravel health preparation. A typical cruise ship will have a passengerto-crew ratio of around 3 to 1. Cruise ships employ crew from around the world: on average, 50 nationalities will be represented in a crew of 1200.6 The origin of crew will depend on the cruise line and their designated occupation on the ship. Crew members may stay aboard a cruise ship for months on successive voyages, carrying out specialized tasks with the aim of achieving higher quality service.

CRUISE HEALTH, SANITATION, AND SAFETY REGULATIONS International Regulations In 2005 the World Health Organization (WHO) revised the International Health Regulations (IHR) (in force in 2007) for international regulations and standards binding 194 countries. The overall goal of the revised ISR is to support ship and port sanitation, disease surveillance, and


CHAPTER 40  Cruise Ship Travel Abstract


Cruise ships can be amplifiers of infectious diseases because of the close human proximity of semiclosed ship environments. The most common diagnoses of cruise passengers evaluated in cruise ship infirmaries include upper respiratory infections, injury, seasickness, and gastrointestinal illness. Cruise ship passengers may experience clusters of brief self-limited diarrheal disease, although this rate is much lower risk than on land. Certain groups, such as the elderly, pregnant women, and immunocompromised, might be more seriously affected by infectious diseases and stress of travel. Ensure the traveler has medical insurance (health and repatriation) that covers conditions in international waters.

Cruise ship health care guidelines Cruise ship travel Influenza Legionella Norovirus



SECTION 7  Travelers With Special Itineraries

response to infectious diseases ( Safety regulations for international shipping, including cruise ships, are promulgated by the International Maritime Organization (IMO) in its International Convention for Safety of Life at Sea (SOLAS).7 SOLAS addresses a variety of issues pertaining to passenger and crew safety, including fire protection, lifesaving equipment and procedures, and radio communications.

US Regulations The Centers for Disease Control and Prevention (CDC) Vessel Sanitation Program (VSP) ( has the responsibility for ensuring appropriate levels of sanitation and health aboard cruise ships arriving at US ports, including facilities that could affect public health, such as food storage, ventilation systems, and pools or spas ( VSP conducts unannounced, biannual sanitation inspections of US-bound cruise ships that have international itineraries. A score of at least 86 (out of 100) is considered a pass and is published monthly in the “Summary of Inspections of International Cruise Ships” ( InspectionGreenSheetRpt.aspx). Other than acute gastroenteritis (AGE) requirements, all international passenger conveyances bound for the United States are legally required to report to US Quarantine at least 24 hours before arrival any ship cases with certain febrile syndromes suggestive of a communicable disease and any deaths. Diseases on the list are primarily those with pandemic potential such as influenza, severe acute respiratory syndrome (SARS), or plague ( ncezid/dgmq/quarantine-fact-sheet.html).

MEDICAL CARE ABOARD CRUISE SHIPS Cruise Lines International Association (CLIA) member cruise lines follow the “Health Care Guidelines for Cruise Ship Medical Facilities”8 developed by the American College of Emergency Physicians (ACEP) Cruise Ship and Maritime Medicine Section. This ACEP section is composed primarily of physicians actively involved in cruise ship medicine. Their objective is to advance the capabilities of cruise ship medical facilities and the quality of medical care provided aboard cruise ships. The guidelines address standards for medical facility design, medical staff qualifications, diagnostic equipment, and formulary selection, with a goal of providing general and emergency medical services to passengers and crew.8 Medical care aboard cruise ships is designed to provide cruise line passengers and crew members with timely access to comprehensive services for minor to severe illness and injury (Fig. 40.1) as they would be at an urgent care clinic during daytime emergencies or a free-standing emergency department (ED). More serious problems (such as myocardial infarction, respiratory distress, or cerebrovascular accidents) may require emergency evacuation to an appropriate shore-side facility after stabilization on board.9 Most modern cruise ships are equipped to perform a variety of laboratory tests (which may include complete blood count, blood sugar, electrolytes, chemistries, cardiac enzymes, pregnancy testing, and urinalysis), radiography, cardiac monitoring, and advanced life support procedures.8 The ship’s formulary includes medications for treating common medical problems and a variety of more serious conditions, including infections, injuries, respiratory distress, and cardiac disorders.

ILLNESS ON CRUISE SHIPS The spectrum of illnesses occurring aboard cruise ships generally follows land-based incidences. It can vary depending on the demographics of passengers and crew on board. Two studies involving retrospective reviews of cruise ship medical logs showed that about half of all

FIG. 40.1  Cruise ship medical examination room. (Courtesy Dr. R. Wheeler.)

passengers seeking care aboard cruise ships were older than 64 years. Respiratory tract infection was the most common diagnosis, followed by injuries, nervous system problems (e.g., seasickness), and GI illness. About 90% of illnesses on cruise ships were not considered serious or life threatening, but of those that were, asthma, arrhythmia, angina, and congestive heart failure were among the most common. In other studies, cardiac death rates ranged from 0.6 to 9.8 per million passengernights.22 More than 95% of ill persons seen by the medical clinic were treated definitively on board and 5% required consultation or disembarkation for shore-side medical care.10,11 Documented outbreaks of infectious diseases aboard cruise ships have most commonly been related to GI (norovirus) and respiratory infections (influenza, Legionella). Clusters of illnesses related to vaccinepreventable diseases (other than influenza) such as rubella and varicella have also been reported.

Respiratory Infections Upper respiratory tract infections are the most frequent diagnosis in cruise ship medical facilities, accounting for approximately 20%–30% of passenger visits.10 The semiclosed and crowded environment of cruise ships may allow for increased person-to-person transmission of respiratory viruses. In addition, ship resources such as contaminated whirlpools or water supply, and even infected crew or passengers remaining on board for multiple voyages, may serve as reservoirs for respiratory pathogens, causing continuous transmission of illness on consecutive cruises. The two most frequently documented etiologic agents of cruise ship–related pneumonia outbreaks are Legionella and influenza viruses (see Chapter 59).12

Influenza.  Influenza A and B outbreaks among the cruise ship crew and passengers can occur throughout the year, even when seasonal influenza activity is absent in the region of the cruise. The convergence and intermingling of international crew and passengers from parts of the world where influenza is in circulation can lead to the introduction and rapid amplification and spread of influenza aboard ships. Vaccination of most crew members annually helps with secondary infections. Substantial morbidity may result from cruise influenza outbreaks owing to the presence of a large percentage of elderly and chronically ill passengers, both of whom are at higher risk for complications and death due to influenza infection.

CHAPTER 40  Cruise Ship Travel Also, health care providers can play an important role in preventing influenza and other respiratory disease outbreaks aboard ships by: • Asking travelers to refrain from traveling while ill, and if illness develops during the trip to practice respiratory hygiene measures and minimize contact with other people, including the cruise staff. • Providing vaccination or, if necessary, prophylactic antiviral medication, especially to high-risk populations as well as their close contacts, and those traveling in large tour groups, even if travel occurs during summer.

Legionnaires Disease.  The most commonly established causes of outbreaks include contamination of ships’ water supply, air conditioning systems, or spa pools.13 The largest documented culture-confirmed cruise ship outbreak of legionnaires disease occurred in 1994. It involved 50 passengers during nine separate sailings of the same ship.4 Illness due to infection through bacteria-laden aerosols generated by the spas was associated with immersion in, and spending time around, the whirlpool. This outbreak was detected 3 months after it began, when a New Jersey physician notified the state health department that three hospitalized patients with atypical pneumonia had been on the same cruise ship; this outbreak highlighted the delay in detection of cruise-associated legionnaires disease. Symptom onset is typically 2–10 days postexposure without person-to-person spread. Most cruise ships have urinary antigen testing capability.

Gastrointestinal Illness The estimated likelihood of contracting gastroenteritis aboard a 7-day cruise is $100K), Europe ($100K min), Asia/Africa/Antarctica ($200K min). Many travel insurance policies (such as most cruise line plans) have limited medical coverage ($10K–$20K). Travelers should carefully assess their potential risks and needs when choosing a travel insurance plan for a cruise itinerary. For a few dollars more, they can obtain $50K+ medical coverage and $500K+ evacuation coverage. and are two travel insurance sites that offer a variety of plans from several insurance companies. Prepare first-aid kit (see Chapter 8) Infants 2500 m, especially after rapid ascent (≤1 day). Symptoms usually begin a few hours after arrival at the new altitude, but may arise a day later (often after the first night’s sleep). The cardinal symptom is headache, typically bifrontal and throbbing. Gastrointestinal symptoms (anorexia, nausea, vomiting) and constitutional symptoms (weakness, lightheadedness, lassitude) are common. AMS is thus similar to an alcohol hangover or a nonspecific viral infection,

but without fever and myalgia. Diagnosis of AMS requires a recent gain in altitude, at least several hours at the new altitude, and the presence of at least two of the typical symptoms: headache, gastrointestinal upset (anorexia, nausea, vomiting), fatigue or weakness, dizziness or lightheadedness, and difficulty sleeping.16 An additional part of the Lake Louise criteria is the clinical function score (CFS). This is based on the patient’s response to a single question, “Overall, if you had any symptoms, how did they affect your activity?” Scoring is from 0–3 for no reduction in activity to mild, moderate, or severe reduction (e.g., bedrest). A CFS score ≥2 (moderate to severe reduction in activity) indicates AMS. A recent meta-analysis comparing a variety of diagnostic questionnaires used to assess for AMS found that they all performed comparably in identifying AMS, but the CFS is the simplest to use in clinical and travel environments.17 Fluid retention is characteristic of AMS and victims often report reduced urination, in contrast to the spontaneous diuresis observed with successful acclimatization. As AMS progresses, the headache worsens, then vomiting, oliguria, and increased lassitude develop. Ataxia and altered level of consciousness herald the onset of clinical HACE (Fig. 42.2). Patients with AMS appear ill but lack characteristic physical findings, as with hangover. Heart rate and blood pressure are variable and nondiagnostic. Unless HACE is present, neurologic examination is normal. Fundoscopy may reveal retinal hemorrhages, but these are not specific to AMS. Pulmonary crackles may be present, but oxygen saturation will be normal or at most slightly lower than acclimatized persons at the same elevation. Peripheral and facial edema may be present, particularly in women. Most conditions similar to AMS can be excluded by history and physical examination. Onset of symptoms >3 days after ascent, lack of

FIG. 42.2  Magnetic resonance image (MRI) demonstrating reversible vasogenic edema in the splenium of the corpus callosum (arrow) in a climber with high-altitude cerebral edema. (Courtesy P. Hackett.)

CHAPTER 42  High-Altitude Medicine headache, or failure to improve with descent, oxygen, or dexamethasone suggests another diagnosis. Dehydration is commonly confused with AMS, as it can cause headache, weakness, nausea, and decreased urine output. The natural history of AMS varies with altitude, ascent rate, and other factors. In general, symptoms improve slowly, with complete resolution in 1–2 days. AMS symptom duration ranged from 6 to 94 hours with a mean of 15 hours in one study at 3000 m.18 A small percentage (2500 m) Moderate Acute Mountain Sickness Moderate to severe headache with marked nausea or vomiting, weakness, dizziness, lassitude, and peripheral edema 12–24 h after rapid ascent to high altitude

High-Altitude Cerebral Edema Confusion, lassitude, and ataxia 48 h after ascent to high altitude High-Altitude Pulmonary Edema Cough, weakness, dyspnea, chest congestion 60 h after arrival at a ski resort at 2750 m

Stop ascent, rest, and acclimatize Descend 500 m or more Speed acclimatization with acetazolamide (125–250 mg orally twice daily) Treat symptoms with mild analgesics and antiemetics or use a combination of these approaches Stop ascent, rest, treat medically Descend 500 m or more Give acetazolamide (250 mg orally twice daily), or dexamethasone (4 mg orally or intramuscularly every 6 h), or both Administer low-flow oxygen (1–2 L/min) or use a portable hyperbaric chamber (see Table 42.4) Treat symptoms or use a combination of these approaches Start immediate descent or evacuation If descent is delayed or not possible, use a portable hyperbaric chamber and/or administer oxygen (2–4 L/min) Administer dexamethasone 8 mg intramuscularly, intravenously, or orally initially, then 4 mg every 6 h Administer oxygen (2–4 L/min, to keep SaO2 >90%) If oxygen is not available, use a portable hyperbaric chamber (see Table 42.4) If oxygen and hyperbaric chamber unavailable, start immediate descent, minimizing exertion and cold stress If descent/oxygen unavailable, administer nifedipine (10 mg orally initially, then 30 mg extended-release formulation every 12 h), or sildenafil or tadalafil

TABLE 42.4  Portable Hyperbaric Bags More Information and Purchasing



104 mmHg


135 mmHg Trekking model 135 mmHg Mam’out expedition model



PAC (Portable Altitude Chamber) 104 mmHg

Approximate Cost, 2017



hypoxic devices that are not hypobaric, degree of acclimatization is proportional to the time at a given partial pressure of oxygen (Pio2), or simulated altitude. These exposures are by nature intermittent. Exposures of 1.5–4 hours per day at the equivalent of 2500 m or higher can boost ventilatory responses to high altitude on ascent, but protection from AMS requires a minimum of 7 hours a day, which usually means during sleep, for a minimum of 1 week prior to ascent.30 Dehnert et al., in the only randomized trial, found that 14 nights of hypoxic exposure was effective in preventing AMS on subsequent ascent.31 The duration of a protective acclimatization effect is in general proportional to its magnitude (i.e., duration and severity of hypoxia). Research on this issue, however, is minimal. Improved ventilation, arterial oxygenation, AMS protection, and exercise ability upon reascent will last for 2–3

TABLE 42.5  Practical Advice for Travelers

to Altitude

Go slowly Avoid overexertion Avoid abrupt ascent to sleeping elevations >3000 m Spend one to two nights at an intermediate elevation (2500–3000 m) before further ascent Above 3000 m, sleeping elevations should not increase by >500 m per night When topography or village locations dictate more rapid ascent, or after every 1000 m gained, spend a second night at the same elevation Day hikes to higher elevations, with return to lower sleeping elevations, help to improve acclimatization Avoid alcohol consumption in the first 2 days at a new, higher elevation Memorize the Golden Rules of Altitude: If you feel unwell at altitude, it is altitude illness until proven otherwise If you have symptoms of AMS, go no higher If your symptoms are worsening (or with HACE or HAPE), you must go down immediately Note: Thanks to Dr. David Shlim who originally popularized The Golden Rules of Altitude AMS, Acute mountain sickness; HACE, high-altitude cerebral edema; HAPE, high-altitude pulmonary edema.

weeks after 3–4 weeks acclimatization to 4000 m or higher.32,33 The Schneider study found that even a few nights above 3000 m was somewhat protective as long as it was 4–6 weeks after exposure. Until more data are available, it seems best to advise sojourners to altitude to minimize the time between hypoxic exposure and targeted ascent, and to advise that the greater the acclimatization before subsequent ascent, the more


SECTION 8  Environmental Aspects of Travel Medicine

likely AMS will be prevented, and the longer it will persist during descent to a lower altitude.

HIGH-ALTITUDE PULMONARY EDEMA Epidemiology The reported incidence of HAPE varies from 0.01% to 15%, depending on the altitude, ascent rate, and population at risk.1 Individual susceptibility based on genetic factors is perhaps the greatest risk factor, with male gender also being suggested as a risk factor. There is no clear association with age. Preexisting medical conditions associated with pulmonary hypertension or a restricted pulmonary vascular bed will greatly increase susceptibility to HAPE. Exercise increases risk of HAPE since it increases cardiac output and PA pressure at altitude.

Pathophysiology HAPE is a noncardiogenic, hydrostatic pulmonary edema characterized by pulmonary hypertension and increased capillary pressure. Left ventricular function in HAPE is normal. Although increased PA pressure due to hypoxic pulmonary vasoconstriction occurs in all who ascend to high altitude, it is exaggerated and uneven in those susceptible to HAPE, again primarily a genetically determined susceptibility.34–38

Clinical Presentation and Diagnosis HAPE occurs 2–4 days after ascent to high altitude, often worsening at night. Decreased exercise performance is the earliest symptom, usually associated with a dry cough. The early course is subtle; as the illness progresses, the cough worsens and becomes productive. Dyspnea can be severe, tachycardia and tachypnea develop, and drowsiness or other central nervous system (CNS) symptoms may develop. Patchy unilateral or bilateral fluffy infiltrates and a normal cardiac silhouette on chest x-ray are characteristics of HAPE (Fig. 42.4). The presence of a fever has led to misdiagnosis (as pneumonia) and to subsequent death. HAPE varies in severity from mild to immediately life threatening. It can be fatal within a few hours, and is the most common cause of death related to high altitude. Differential diagnosis is sometimes problematic; HAPE improves dramatically with descent or oxygen, whereas other diagnoses do not and should be pursued in patients who do not fit this pattern.

Treatment The treatment of HAPE depends on the severity of illness and logistics (see Tables 42.2 and 42.3). In remote locations, where oxygen and medical care may be unavailable, persons with HAPE need to be urgently evacuated to lower altitude. However, exertion must be minimized as it augments pulmonary hypertension and worsens hypoxemia. Mild HAPE responds rapidly to a descent of 500–1000 m. If oxygen is available, bed rest with supplemental oxygen may be adequate, but in severe HAPE high-flow oxygen (4 L/min or more) may be required for >24 hours. Hyperbaric therapy with a fabric pressure bag (104–135 mmHg) is equivalent to low-flow oxygen (2 L/min); treatments can be given in 1-hour increments. If oxygen is not available, immediate descent is lifesaving; waiting for a helicopter evacuation has resulted in needless death. If oxygen and descent are not available, drugs that reduce pulmonary artery (PA) pressure are rational to use, but are not nearly as effective. Nifedipine reduces pulmonary vascular resistance and PAP during HAPE, and slightly improves arterial oxygenation, but clinical improvement is not dramatic. Nifedipine is well tolerated, and is unlikely to cause significant hypotension in healthy persons. Sildenafil and tadalafil effectively decrease PA pressure at altitude, and have shown value for

FIG. 42.4  Chest radiograph of a patient with high-altitude pulmonary edema. Note the normal heart size and extensive bilateral infiltrates, consistent with high-altitude pulmonary edema. (Courtesy P. Hackett.)

prevention of HAPE, but have not yet been studied for treatment. No drugs are as effective as oxygen and descent. As with HACE, prognosis is excellent for survivors, with rapid clearing of the edema fluid and no long-term sequelae. Patients may need from 2 days to 2 weeks to recover completely; after all symptoms have resolved, cautious reascent is acceptable. Patients with mild to moderate HAPE at ski resorts will typically resume skiing after 3 days of oxygen therapy. See also Luks et al.20

Prevention See AMS prevention; the same staged ascent recommendations are useful for HAPE prevention. The indication for chemoprophylaxis of HAPE is repeated episodes. Whether one previous episode should encourage prophylaxis is arguable, but demonstrated susceptibility certainly requires caution. Often a slower ascent is the only preventive method required. Effective agents for prevention of HAPE (see Table 42.2) include nifedipine, salmeterol, the PDE-5 inhibitors sildenafil and tadalafil, and dexamethasone.20,39–42 Those with a history of HAPE should carry nifedipine to use either prophylactically or with the first signs of HAPE. Salmeterol reduced HAPE by 50% in susceptible persons, appears safe, and should be considered an adjunct for treatment as well, though it has not yet been studied for this indication. Both dexamethasone and PDE-5 inhibitors have been shown to decrease PA pressure at altitude, and also effectively prevent HAPE, although the optimal dose has not been established for these medications.

CHAPTER 42  High-Altitude Medicine

OTHER ALTITUDE-RELATED CONDITIONS Syncope within the first 24 hours at high altitude is a well-recognized entity, and termed “high-altitude syncope.” This form of neurocardiogenic syncope43 does not imply an underlying condition; a complete evaluation is generally unnecessary unless a second episode occurs. The occurrence of focal neurologic deficits, such as transient ischemic attacks in otherwise healthy individuals, has been noted at high altitude.1 They are not part of the altitude illness spectrum, and require further evaluation. Patients with previously undiagnosed arteriovenous malformation (AVM), cerebral aneurysm, and brain tumors have all become symptomatic on ascent to high altitude,19 and both ischemic and hemorrhagic stroke have been reported. High-altitude retinal hemorrhage (HARH) is common and usually asymptomatic. The incidence of HARH varies from 4% at 4243 m to >50% in one study at 5360 m.44 For those who develop visual changes, evacuation to a lower altitude is recommended.44 No reports claim that such visual changes are progressive in persons who remain at altitude. HARH resolves completely within a few weeks after descent. Peripheral edema is common at high altitude, especially in women.1 It is not necessarily associated with altitude illness, but anyone with edema must be evaluated for AMS. Edema will resolve with decent. Diuretics work well; however, one must be cautious to avoid dehydration. High-altitude cough increases with elevation, and is a significant cause of morbidity among extreme-altitude climbers. The cough is paroxysmal, and sometimes sufficiently forceful to fracture ribs. Sputum is frequently purulent but fever is absent. Normal exercise performance, lack of dyspnea at rest, and absence of rales or cyanosis help distinguish high-altitude cough from HAPE. A concurrent sore throat is common, without any abnormal findings on examination. The cause of high-altitude cough is unknown, but probably multifactorial, including mucosal injury from hyperventilation of cold, dry air; airway inflammation; hypoxic bronchoconstriction; and alteration in the cough threshold. Treatment is symptomatic. The intense UV light at high altitude when reflected off snow can easily cause damage to the unprotected eye, resulting in UV keratitis, also known as “snow blindness.” Although it can be intensely painful and debilitating, it is self-limited and without sequelae, resolving in 24–48 hours. Treatment consists of antibiotic ointment, analgesics, and perhaps eye patching. This injury is entirely preventable by proper use of sunglasses with good UV absorbing characteristics. If sunglasses are not available, any material can be placed across the orbits, such as tape or cloth, with horizontal slits to provide essential vision.

CHILDREN AT ALTITUDE Certain risk factors for high-altitude illness are shared with adults venturing into high altitude: rapid rate of ascent, the absolute altitude achieved, the degree of physical exertion, and cold weather. Risk factors potentially more common to children can also be identified, and are discussed in this section. Children with well-controlled asthma do not appear to have increased risk of altitude illness.


and changes in playfulness, appetite and sleep after recent ascent, and when used by parents is helpful in identifying AMS in young children. Parents should consider increased unexplained fussiness and increased intensity of fussiness, combined with decreased eating, playfulness, and sleep, as worrisome for AMS.

Treatment Treatment follows the same principles as with adults; see Table 42.2 for pediatric medication dosages: Mild: symptomatic care Moderate: oxygen or descent, acetazolamide HACE: descent, oxygen, dexamethasone. Hyperbaric treatment if oxygen unavailable

Prevention In adults a prior history of AMS is highly predictive of the disease on subsequent altitude exposure; however, this is not true in children, and a history of AMS in children should not prompt advice against going to altitude in the future, nor prescription of prophylactic medications.48 Infants and children may have a greater frequency of high-altitude illness at very high altitudes (>3500 m) when compared to adults. However, most healthy children can travel safely to moderate altitudes (2% of body weight). In addition, when water is not readily available, or if the water is unpalatable, salty, or warm, drinking is also reduced.2 The slowdown in voluntary fluid intake is termed “voluntary dehydration.” That is, individuals will drink to temporary satiety, but a water deficit remains. Voluntary dehydration is considered the main cause for dehydration during exercise.2 A water deficit accumulated between meals is usually restored during meals. Awareness of the need for fluid replenishment increases voluntary fluid intake and reduces voluntary dehydration.

Overhydration and Hyponatremia Hyponatremia is defined as sodium blood concentrations 8 L of sweat; (2) skip meals; (3) experience a caloric deficit of 8 hours) with caloric restriction or in people who suffer a gastrointestinal illness.

Rehydration At rest and thermal comfort, urination is the major cause for loss of body water (around 1.5 L/day). During physical activity or in hot environments, a considerable amount of body water is lost through sweat secretion. Sweat secretion can vary considerably, depending on environmental conditions, work intensity, clothing, gender, age, state of acclimatization, and fitness. The general concept that prevails is that during prolonged intermittent exercise, the optimal rate of fluid replacement appears to be the rate which most closely matches the rate of sweating (see Fig. 44.3). On average, sweat rates of 1–1.5 L/h during exercise in the heat are common.2,26 To reduce the rate of voluntary dehydration without exposing the individual to the dangers involved in dehydration or overhydration, the following should be remembered: • One should not assume that unlimited quantities of water can be consumed (1–1.5 L/h is the maximal volume that can be absorbed). • Fluids should be palatable and consumed at regular intervals at a rate sufficient to replace water loss through sweating. Water should be consumed in quantities that will be ingested with ease: 200–250 mL each time. • Hyponatremia is a potential risk only for activities lasting longer than 6 hours. There is little physiologic basis for adding salt to fluid if it is sufficiently available in the diet.

CHAPTER 44  Extremes of Temperature and Hydration

CONCLUSION Environmental conditions may restrict travelers. Lack of behavior modification during adverse climatic conditions and improper preparedness may result in heat-related or cold-related injuries. Preventing these potentially life-threatening problems is possible by adherence to some simple guidelines: • Only fit, healthy, acclimatized individuals should conduct physical exercise in adverse climatic conditions. • Physical exertion should be performed within the individual’s capacity. Work-rest cycles should be planned and adhered to. • Fluid intake should compensate fluid loss. Euhydration should be maintained. • Clothing should be suitable to the climatic conditions and work intensity. • Casualties of heat or cold weather should be treated promptly. The sooner body temperature returns to its normal range, the better the prognosis.

REFERENCES 1. Gagge AP, Gonzalez RR. Mechanisms of heat exchange: biophysics and physiology. In: Fregly MJ, Blatteis CM, editors. Handbook of Physiology. Section 4: Environmental Physiology, vol. 1. Oxford: Oxford University Press; 1996. p. 45–84. 2. Epstein Y, Armstrong LE. Fluid-electrolyte balance during labor and exercise: concepts and misconceptions. Int J Sport Nutr 1999;9:1–12. 3. Cheuvrout SN, Haynes EM. Thermoregulation and marathon running: biological and environmental influences. Sports Med 2001;31:743–62. 4. Young AJ. Human adaptation to cold. In: Pandolf KB, Sawka MN, Gonzalez RR, editors. Human Performance Physiology and Environmental Medicine at Terrestrial Extremes. Cooper Pub Group; 1988. p. 401–34. 5. Moran DS, Mendel L. Core temperature measurements—methods and current insights. Sports Med 2002;32:879–85. 6. Stitt JT. Fever versus hyperthermia. Fed Proc 1979;38:39–43. 7. Epstein Y, Moran DS. Thermal comfort and the heat stress indices. Indust Health 2006;44:388–98. 8. Armstrong LE, Epstein Y, Greenleaf JE, et al. ACSM position stand: heat and cold illnesses during distance running. Med Sci Sports Exerc 1987;19:529–33.


9. Shapiro Y, Seidman DS. Field and clinical observations of exertional heat-stroke patients. Med Sci Sports Exerc 1990;22:6–14. 10. Hamlet MP. Prevention and treatment of cold injury. Int J Circumpolar Health 2000;59:108–13. 11. Mills WJ. Cold injury [a collection of papers]. Alaska Med 1993;35:6–140. 12. Burr RE. Medical aspects of cold weather operations: a handbook for medical officers. USARIEM Report TN3–4, 1993. 13. Hannuksela ML, Ellahham S. Benefits and risks of sauna bathing. Am J Med 2001;110:118–26. 14. Shibolet S, Lancaster MC, Danon Y. Heat stroke: a review. Aviat Space Environ Med 1976;47:280–301. 15. Bouchama A. Knochell JP. Heat stroke. NEJM 2002;346:1978–88. 16. Epstein Y, Roberts WO, Golan R, et al. Sepsis, septic shock, and fatal exertional heat stroke. Curr Sports Med Rep 2015;14:64–9. 17. Epstein Y, Moran DS, Shapiro Y, et al. Exertional heat stroke: a case series. Med Sci Sports Exerc 1999;31:224–8. 18. Bouchama A, Debbi M, Mohamed G, et al. Prognostic factors in heat wave-related deaths: a meta-analysis. Arch Intern Med 2007;167: 2170–6. 19. Epstein Y, Roberts WO. The pathophysiology of heat stroke: an integrative view of the final common pathway. Scand J Med Sci Sports 2011;21:742–8. 20. Ariel’s checklist. 2017. Available at: uploads/sites/1222/2015/06/Ariels-Checklist.pdf. 21. Armstrong LE. Exertional heat illnesses. Human Kinetics; 2003. 22. Kempainen RR, Brunette DD. The evaluation and management of accidental hypothermia. Resp Care 2004;49:192–205. 23. Reamy BV. Frostbite: a review and current concepts. J Am Board Fam Pract 1998;11:34–40. 24. McIntosh SE, Opacic M, Freer L, et al. Wilderness Medical Society. Wilderness Medical Society practice guidelines for the prevention and treatment of frostbite: 2014 update. Wilderness Environ Med 2014;25:S43–54. 25. Murphy JV, Banwell PE, Roberts HN, et al. Frostbite: pathogenesis and treatment. J Trauma 2000;48:171–8. 26. Convertino VA, Armstrong LE, Coyle EF, et al. ACSM position stand: exercise and fluid replacement. Med Sci Sports Exerc 1996;28:1–5. 27. Montain SJ, Sawka MN, Wenger LB. Hyponatremia associated with exercise: risk factors and pathogenesis. Exerc Sports Sci Rev 2001;29:113–17.

45  Jet Lag Poppy Markwell and Susan L.F. McLellan

DEFINITION Jet lag is an informal term for the symptoms that occur when travelers rapidly cross several time zones and attempt to follow the time schedule of the new destination. Simply defined, it is a combination of malaise, fatigue, derangement of sleep-wake cycles, and poor performance, which occurs during the first days in a new time zone as the traveler adjusts to a change in the schedule of circadian signals.

PHYSIOLOGY Jet lag is due primarily to the forced recalibration of the body’s natural clock, or circadian rhythms. “Circadian rhythms” synchronize innate physiologic processes to natural time cycles. These rhythms are present at the cellular level; the periodicity of neuron firing can be observed in dissected suprachiasmatic nuclei of neonatal animals.1 In most mammalian species, circadian rhythms are synchronized with the 24-hour duration of the Earth’s rotation and the associated pattern of day and night. The suprachiasmatic nucleus (SCN) of the hypothalamus acts as the primary internal timekeeper and cycles on an approximate 24-hour schedule. Any dyssynchrony of the schedule of the SCN with the 24-hour environmental cycle is corrected on a daily basis by signals from the environment including light, food availability, activity, temperature, and social cues, a process termed “entrainment.” “Clock genes” in other parts of the brain and peripheral organs also create cycles, which are coordinated with each other and the environment by the SCN.2 Light, specifically natural daylight, is the major cue for the adjustment of the SCN’s “internal clock,” which regulates melatonin release, inducing sleepiness. Darkness is also required for the secretion of melatonin; daylight levels of light suppress release. Melatonin also provides feedback to the SCN, controlling its own production and contributing to the modulation of other circadian variables.3 Diurnal variations in body temperature and the release of cortisol and growth hormone also appear to be controlled by the SCN.4 When a traveler quickly crosses several time zones, these circadian rhythms continue to operate on the “home” schedule. Reentrainment takes a certain amount of time, approximately 1 day per time zone crossed. During this period the traveler experiences jet lag, or “circadian dyssynchronization.” Typically after eastward travel it is difficult to fall asleep at the new bedtime, and consequently difficult to arise in the

morning. After westward travel the main complaint is awakening in the early hours of the morning, causing lost and irregular sleep time. Westward travel is generally associated with less dyssynchrony than eastward because the SCN cycle of most persons, without entrainment from environmental signals, is slightly longer than 24 hours.5 In addition, mild hypoxia resulting from the incomplete pressurization of transoceanic aircraft (typically equivalent to an altitude change of 8000–12,000 ft) results in reduced nocturnal melatonin secretion, and may therefore contribute to the fatigue and other symptoms of jet lag.6 Relative dehydration and reduced mobility during long flights, stress, lack of sleep, culture shock, and the interruption of regular mealtimes and exercise routines may increase the traveler’s sense of discomfort and disorientation and contribute to “jet lag syndrome.” In addition, travelers frequently indulge in excessive alcohol and/or caffeine ingestion, both of which may compound the effects of jet lag.

CLINICAL FEATURES Most travelers experience inability to sleep during destination night and to remain alert during the day. Additional symptoms include headache, gastrointestinal complaints, clumsiness, irritability, difficulty concentrating, and reduction in cognitive and athletic functioning. Individuals vary considerably in their susceptibility to these symptoms. Studies in shift workers who suffer repeated episodes of dyssynchrony suggest more severe consequences, including increased rates of cancer, cardiovascular disease, and female reproductive problems.7 Jet lag tends to be worse for older travelers while infants appear to be less affected. Symptoms increase with the number of time zones crossed. The consequences of the jet lag syndrome extend beyond the loss of vacation time for pleasure-seeking travelers. The decline in cognitive and athletic function has obvious consequences for politicians, diplomats, soldiers, businesspeople, and professional athletes.

TREATMENTS A multitude of therapeutic interventions to reduce or eliminate jet lag have been promoted, with varying degrees of scientific evidence in support. The best studies use clearly defined measures of cognitive performance and functioning, but the protocols vary among investigators. The 2007 American Academy of Sleep Medicine (AASM) guidelines on management and treatment of circadian rhythm disorders8 and


CHAPTER 45  Jet Lag Abstract


Jet lag is a condition well known to travelers since the introduction of passenger jet aircraft. It is an informal term for the symptoms that occur when travelers rapidly cross several time zones and attempt to follow the time schedule of the new destination. The condition manifests itself differently among individuals, and the symptoms increase with age and number of time zones crossed. Eastward travel is generally more difficult than westward travel. The adjustment to a new time zone is mediated by the suprachiasmatic nucleus, which acts as our primary internal timekeeper and regulates diurnal variations in body temperature and the release of melatonin, cortisol, and growth hormone. These hormones are important in maintaining circadian rhythm. The time required to resynchronize the release of these hormones and thus reset the internal clock is generally agreed to be about 1 day per time zone crossed. A number of therapies and behaviors have been recommended to reduce jet lag, but the American Academy of Sleep Medicine guidelines give the strongest recommendation to the use of melatonin as a standard therapy based on high levels of evidence. Light therapy with sleep time adjustment can also help speed the resolution of circadian dyssynchrony.

Circadian dyssynchrony Circadian rhythm disorders Hypnotics Jet lag Light therapy Melatonin Sleep cycle Suprachiasmatic nucleus Travel fatigue Travel medicine



SECTION 8  Environmental Aspects of Travel Medicine

TABLE 45.1  Behavioral Methods of Adjusting Circadian Rhythm Method




Sleep schedule

Inexpensive, easily available

Sunlight exposure Phototherapy Diet Exercise

Inexpensive, easily available Convenient Inexpensive, easily available Inexpensive, easily available Other health benefits

Inconvenient, especially for longer time changes Requires scheduling Some devices are bulky, expensive Inconvenient, requires careful planning Requires scheduling, effort

Good, if able to achieve adjustment Good Good Inconclusive data Recent studies suggest little benefit

Recommendation by AASM Recommended Recommended Not mentioned Not mentioned Not mentioned

AASM, American Academy of Sleep Medicine.

TABLE 45.2  Pharmacologic Options for Jet Lag Therapy Product


Recommendation by AASM

Side Effects


Melatonin (and Induce sleep, reset circadian agonists) clock

Inappropriate drowsiness may occur


Induce sleep


Promotes alertness

Inappropriate drowsiness, “hangover,” addictive potential Jitteriness, hypertension, tachycardia, dependence, may prevent normal sleep Slow onset of action, many drug interactions May reduce decision-making capability; hypertension, tachycardia, addictive potential, may prevent normal sleep Few reported

Over the counter in United States, Recommended Hong Kong, and perhaps elsewhere; by prescription only in Europe and Canada; further restrictions may exist in some countries By prescription Optional. Use with caution

Armodafinil, Promotes alertness without modafinil interfering with sleep Amphetamines Promote alertness

Nicotinamide (NADH)

Promotes alertness, mental clarity, though very limited data

Easily available in various over-thecounter forms

Optional. Use with caution

By prescription

Not mentioned

By prescription

Not mentioned

Available over the counter as a nutritional supplement

Not mentioned

AASM, American Academy of Sleep Medicine.

updated sleep guidelines in 20159 provide guidance. Strategies to reduce the effects of jet lag can be classified according to their ability to achieve one or more of three goals: resetting the internal “clock,” promoting sleep at destination bedtime, and promoting alertness during destination day. Methods of adjusting circadian rhythm and associated recommendations of the AASM are summarized in Tables 45.1 and 45.2.

Resetting the Clock

Pretravel Sleep Schedule Adjustment.  Many travelers find it useful to attempt adjusting their sleep and awakening times by an hour per day for several days before travel to coincide with destination time, an option recommended for travelers by the AASM. This carries little risk but requires considerable diligence. Sleep Schedule on Arrival.  Planning sleep times on arrival is also important. Short daytime naps of 45 minutes or less may help in maintaining alertness,10 and may be most beneficial at the time of the body’s temperature nadir, which typically occurs at about 4–5 a.m. home time. Longer naps can be beneficial, but should be scheduled so as not to delay the adjustment of the internal clock. If traveling westward, it is preferable to delay sleeping until bedtime at the destination. It is more difficult to advance sleeping time when traveling eastward. In fact, for eastward travel of more than nine time zones, the body response

is often to delay the internal clock rather than advance it, as if a longer westward shift had occurred. Travelers may find themselves more easily able to adjust to a new time zone after traveling eastward, for example, 10 time zones, if they plan their sleep recalibration to delay the body clock by 14 hours rather than try to advance it by 10 hours.

Light Therapy.  Light exposure is the strongest stimulus to circadian reentrainment in mammals.4 Deliberate exposure to bright light at the appropriate time can help resolve circadian dyssynchrony. Efficacy depends on timing the light exposure around the nadir of the body temperature. Hence bright light in the internal clock’s morning will cause a phase advance, while in the evening, phase delay. An eastward traveler should seek light in the morning (05:00–11:00 hours), and a westward traveler in the evening (22:00–04:00 hours), based on home time. Exposure to bright light should be avoided at times that will produce a phase shift opposite in direction to what is desired, and judicious use of sunglasses may be helpful. However, for travelers passing more than eight or so time zones, the above recommendations for light exposure might result in morning light causing a phase delay if the light exposure occurs prior to the home time nadir of the body temperature. Light avoidance may be necessary for the first few days to prevent reentrainment in the wrong direction.11 Some studies have found that prior to travel, circadian rhythms can be successfully advanced

CHAPTER 45  Jet Lag with a combination of advancing sleep schedules by 1 hour per day in conjunction with exposure to early morning bright light. Attempting to advance by 2 hours per day was less successful.12 For most travelers, sunlight will provide an adequate light source. Even on a cloudy day, daylight is much brighter than most inside lighting. However, there is now evidence to suggest that lower levels of light, such as those in offices, homes, and electronic books, may also play a role in resynchronization.13 One study comparing light-emitting electronic books with printed books found that e-book readers experienced increased sleep latency, had reduced endogenous melatonin production (measured on day 5), and decreased REM sleep.14 Another study at Cornell showed that the application of a 3-hour pulse of light behind the knee to subjects otherwise kept in low ambient light succeeded in generating a phase response of up to 3 hours over a 4-day period compared to controls, suggesting a response to extrapineal and extraocular light sensors.15 However, this study has not been replicated. Several commercial products are also available to help travelers use light exposure to adjust to a new time zone, such as computer programs to create the appropriate exposure schedule and caps that shine light on the eyes. An Internet search for “light therapy” or “phototherapy” reveals multiple sources of devices. The benefit over natural light sources is unclear. One study found that although a head-mounted light visor resulted in a circadian shift as measured by salivary dim light melatonin onset, no improvement in jet lag symptoms, sleep, or performance occured.16

Diet.  Adjusting diet prior to travel has been suggested to ameliorate jet lag symptoms. A “feast then fast” strategy alternates days of high caloric intake and fasting over 4 days prior to departure, the hypothesis being that high-protein meals increase levels of norepinephrine and dopamine, therefore increasing alertness. High-carbohydrate meals elevate tryptophan concentrations, resulting in higher serotonin levels, thought to have a role in sleep regulation and acting as a precursor to melatonin. High-protein breakfasts and high-carbohydrate dinners are recommended, but clinical evidence is lacking. A study in military reservists suggested good efficacy, but lack of blinding and self-selection of participants may have resulted in significant placebo effect.17 Eating regular meals that correlate with the light-day cycle may help with circadian resynchronization in periods of jet lag. A randomized controlled trial evaluated whether eating three scheduled meals on the day after going through a 4-hour time change would alleviate jet lag symptoms in airline crew. The control group did not receive instructions on eating scheduled meals. The intervention group had less subjective jet lag, and, based on a psychomotor vigilance test administered by an electronic device application, were objectively more alert than the control group.18


Blind persons have “free-running” circadian rhythms and often have sleep disorders. Melatonin can help “reset” these rhythms and improve sleep.20 The drug has been evaluated for the alleviation of symptoms of jet lag and appears to show some benefit.12,21 A Cochrane review concluded that melatonin helps 50% of adults reduce symptoms of jet lag. Doses between 2 and 5 mg of melatonin are typically recommended, but 0.5–10 mg appears to be equally effective in reducing fatigue and daytime sleepiness. The hypnotic effect may be stronger with the higher doses. A 2-mg controlled-release formulation was shown to be less effective than a lower dose immediate-release formulation.23 Exogenous tryptophan administration, the precursor to melatonin production, did not show an increase in nocturnal melatonin secretion.24 As with light exposure, when using melatonin to induce a phase shift, the timing of ingestion must be scheduled to advance or delay the internal clock appropriately.15 Most studies have focused on eastward travel with a dose given at bedtime for several days after arrival to cause a phase advance. Taking the drug before the travel date did not seem to confer any benefit.22 The timing of melatonin ingestion for a situation where phase advance is desired would be 1 hour earlier each day until 15:00 home time is reached, by which time no further adjustment should be necessary. For a phase delay, melatonin would be taken 1 hour later each day until the dose falls at 06:00 home time. However for westward travelers, melatonin at bedtime may not confer much benefit, because the effect of melatonin administration after endogenous release has already occurred.12 Ramelteon, tasimelteon, and agomelatine are melatonin receptor agonists with a longer half-life and stronger affinity for the melatonin receptors than melatonin. A placebo-controlled trial comparing 1, 4, and 8 mg of ramelteon in healthy adults traveling eastward across five time zones found that even a 1-mg dose reduced sleep latency if taken in dim light. No sleep differences were noted if ramelteon was taken while in natural light.25 Agomelatine has been shown to induce a phase shift in older adults, who are more susceptible to jet lag.26 Since it is also a serotonin (5-hydroxytryptamine) receptor antagonist, it can be beneficial in treating the depressive symptoms of jet lag. To increase endogenous melatonin production at night without medication, one should increase his or her exposure to light during the day. Combining melatonin with phototherapy may potentiate the phase shifting effects. A combination of afternoon melatonin with early morning light exposure was shown to be effective in advancing circadian rhythm by 1 hour per day over a 3-day treatment period.27 Some authors propose carefully calculated adjustment of both light exposure and melatonin administration based on the direction and extent of time zones crossed.12,28

GETTING TO SLEEP (see Table 45.2)

Exercise.  For some individuals, vigorous exercise after arrival is helpful in alleviating jet lag, possibly by forcing a state of alertness, promoting more restful sleep, or inducing arousal in the central nervous system and affecting the SCN. Experiments in hamsters have suggested that exercise can help adjust the internal clock, but its effect on humans is less clear.19


Melatonin and Melatonin Agonists (MMAs) for Resetting the Clock.  Endogenous melatonin is secreted normally from approximately

on cognitive and psychomotor skills than midazolam or zolpidem.29,30 However, at least one study has shown adverse effects on vigilance and mental performance after doses of melatonin if subjects were not allowed to sleep.31 As melatonin is sold as an unregulated herbal supplement in the United States and Hong Kong, few safety studies have been performed, and the standards and quality of available preparations are uncontrolled. A review by the Agency for Healthcare Research and Quality found

21:00 to 08:00 hours. The hormone appears to directly affect the internal clock, hence altering other circadian rhythms, including temperature, resulting in temperature decrease. The ingestion of exogenous melatonin appears to help induce sleep and to induce a phase shift. There is also an apparent hypnotic effect of melatonin, which may relate to reduction in temperature, resetting the internal clock, and/or other mechanisms.

Hypnotics are a sleep-inducing class of drugs used to treat insomnia and are the primary means used to induce sleep. The choice of hypnotic must be individualized, based on the patient’s age, medical comorbidities including liver and kidney function, and desired duration of effect.

MMAs.  Melatonin has a direct hypnotic effect with relatively less effect


SECTION 8  Environmental Aspects of Travel Medicine

that melatonin is safe for short-term use; long-term safety studies are needed.32 Drug-drug interactions, especially with amiodarone, fluoroquinolones, azoles, ticlopidine, and fluvoxamine, should be highlighted to the traveler. Melatonin should be avoided in epilepsy, pregnancy, or while operating heavy machinery. Based on its apparent safety and the relatively large amount of supportive efficacy data, the use of melatonin receives the strongest recommendation of any intervention for jet lag by the AASM guidelines.8 Ramelteon is sold as a regulated pharmaceutical and the US Food and Drug Administration (FDA) has approved its use for the treatment of insomnia. A systematic review is underway on safety and efficacy of melatonin and melatonin agonists in critical illness.33 In many European countries and Canada the use of melatonin is strictly regulated or entirely prohibited. In some cases, the importation of even small amounts for personal use may be illegal. Health care providers and travelers should check local regulations before recommending or transporting melatonin.

Sedatives.  Benzodiazepines and nonbenzodiazepine receptor agonists can be used to help induce sleep at the appropriate hour in the new time zone, but may cause residual drowsiness on awakening and can be dangerous in the elderly leading to falls and withdrawal symptoms. The shorter-acting sedatives, such as zolpidem or temazepam, are less likely to produce residual symptoms but also require caution.25 Whether sedatives have any specific effect on the internal clock remains unclear. GABA type A receptors exist in the SCN, but animal studies are inconclusive regarding a direct effect, and there are no data in humans. The AASM guidelines recommend the short-term use of sedatives as optional, with cautions that side effects are a concern and that although sleep onset is improved, there is no evidence to support improvement of daytime symptoms of jet lag.8 Concern has been raised over the use of any sedative while still on a plane, as a sedated sleeper may be less mobile and more prone to deep venous thrombosis (the same, of course, applies to alcohol). It may be reasonable to restrict the use of sedatives to promoting sleep once the traveler has arrived at destination rather than during a long flight.

Dual Orexin Receptor Antagonists (DORAs).  Orexin-A and orexin-B are neuropeptides produced by the hypothalamus that stimulate wakefulness. They are deficient in narcolepsy. The FDA approved the first dual orexin receptor antagonist, Suvorexant, in 2014 as a schedule IV drug. It suppresses the wake-drive, induces and maintains REM and non-REM sleep, and improves arousal and cognitive performance. Suvorexant has a 12-hour half-life, but a double blind, randomized, placebo-controlled trial in 24 healthy 65–80-year-olds found no impairment in next-morning driving abilities at doses up to 30 mg.34 Dual orexin receptor antagonists (DORAs) have only been studied in comparison to placebo.35 Future studies are needed to evaluate effectiveness in treating jet lag. Antihistamines.  H1-receptor antagonist antihistamines, such as diphenhydramine, are sedating, and are included in many over-thecounter sleep aids. Residual drowsiness is a risk, especially in the elderly. Other drugs that promote sleep via H1-receptor antagonism include hydroxyzine, which is used for itching and may also be helpful for treating anxiety, and doxepin, a tricyclic antidepressant approved for the treatment of insomnia.

Antidepressants and Anxiolytics. Except for doxepin, few antidepressants/anxiolytics are indicated for the treatment of insomnia and most are not indicated to treat jet lag disorder. Trazodone is a serotonin antagonist and reuptake inhibitor antidepressant, commonly prescribed for insomnia, but there are few studies available to support this off-label use. There is no evidence to support the use of atypical

antipsychotics, such as quetiapine, for the treatment of insomnia.36 It is not advised to prescribe antidepressants and anxiolytics primarily for the hypnotic effect. If prescribed, each drug’s unique side effect profile should be taken into careful consideration.

STAYING AWAKE Stimulants Caffeine.  Caffeine can promote alertness and delay sleep, but has clearly recognized side effects that can include tachycardia, dependence, and “withdrawal headache” upon discontinuation. As a diuretic, overconsumption may promote dehydration. Heart arrhythmias have been reported in some cases. Caffeine is the only stimulant that is discussed as an option for the treatment of daytime jet lag symptoms in AASM guidelines, with the caution that it may disrupt sleep and that its use should be monitored.10 Long-acting pharmaceutical preparations of caffeine are available for those who do not enjoy the beverages. The long-acting preparation has been shown to be effective but may affect sleep quality.37 Amphetamines.  Amphetamines are effective in promoting alertness but have addictive potential and capacity for abuse. Additionally, they may reduce decision-making ability and psychomotor performance, rather than enhance it.13 Amphetamines are not currently recommended. Modafinil and Armodafinil.  Modafinil, and its longer-acting isomer, armodafinil, are nonamphetamine stimulants approved for the treatment of narcolepsy and sleepiness due to shift work disorder and sleep apnea. They are presynaptic activators of dopamine transmission, and promote wakefulness and the amplification of cortical serotonin release38,39 with minimal side effects, low abuse potential, and no interference with normal sleep. Modafinil has been used for narcolepsy for several years without the development of tolerance,40 and has memory-enhancing effects.41 The drugs have a slow onset of action and a long half-life; they also have significant interactions with other medications, including antiseizure medications, some cardiac medications, and oral contraceptives. However, the safety profile appears to be good. Armodafinil has been studied specifically for jet lag with evidence of efficacy,42 but has not been FDA approved for that indication. The elderly develop higher plasma drug concentrations, and although the rate of side effects is not increased, caution may be warranted.43 Nicotinamide Adenine Dinucleotide (NADH).  NADH is a coenzyme required to produce energy in cells. Its effects include the stimulation of dopamine, noradrenaline, and serotonin receptors, by which mechanism it is felt to increase mental alertness and clarity and improve concentration. In small preliminary studies, it has been investigated for jet lag as well as Alzheimer disease, Parkinson disease, and chronic fatigue syndrome. In the jet lag study, subjects who received NADH had significantly better cognitive performance and a trend toward reduced sleepiness on the first postflight day compared with controls. A smaller pilot study showed a similar trend lasting through the second day.44 A stabilized form for oral consumption is marketed as a nutritional supplement, and therefore, like melatonin, is not under FDA regulation.

CONCLUSION Jet lag is an essentially unavoidable consequence of rapid travel, and there are no highly effective therapies, although several strategies of management appear to confer some benefit. The prepared traveler will plan the journey with the expectation of having to make some accommodations for this condition. Most experts recommend ensuring adequate

CHAPTER 45  Jet Lag sleep for the several nights prior to travel, given that some sleep deficit is almost sure to occur after arrival. Immediately resetting one’s watch to destination time upon boarding the plane for a flight across several time zones may provide the traveler with an additional mental cue to adjust sleep and eating times. During the flight, moderation is recommended with regard to food, alcohol, and caffeine. For many, arriving at bedtime of the destination may be helpful. Schedules for work or play for the first few days after arrival should take into account the internal clock’s home “night” and “day”; important meetings or performances should if possible be scheduled at the time of maximal alertness or delayed until the traveler has adjusted. For very short trips it may be easier to remain on home time rather than attempt to adjust. Whether to use more specific therapeutic interventions such as those outlined in the chapter will depend on the traveler’s needs and itinerary. Of note, of the abovementioned therapies, the AASM guidelines give the strongest recommendation to the use of melatonin as a standard therapy based on high levels of evidence. Adjustment of sleep schedules, light therapy, the use of caffeine, and the short-term use of hypnotics are considered “options” based on inconclusive or conflicting evidence or expert opinion.10 Other stimulants, homeopathic remedies, and diet therapy are not addressed. The use of interventions, especially pharmacologic compounds, which have not been rigorously studied, should be considered only with careful attention to the safety of the product and potential side effects. Most travelers will find it useful to consider the possible approaches and select or modify those therapies that will fit their personal requirements.

REFERENCES 1. Hastings M. The brain, circadian rhythms, and clock genes. BMJ 1998;317(7174):1704–7. 2. Kyriacoul CP, Hastings M. Circadian clocks: genes, sleep, and cognition. Trends Cogn Sci 2010;14(6). 3. Arendt J. Melatonin and the mammalian pineal gland. London: Chapman & Hall; 1995. 4. Sack RL. The pathophysiology of jet lag. Travel Med Infect Dis 2009;7:102–10. 5. Wever RA. Light effects on human circadian rhythms: a review of recent Andechs experiments. J Biol Rhythms 1989;4(2):161–85. 6. Coste O, Beaumont M, Batejat D, et al. Hypoxic depression of melatonin secretion after simulated long duration flights in man. J Pineal Res 2004;37(1):1–10. 7. Mahoney MM. Shift work, jet lag, and female reproduction. Int J Endocrinol 2010;2010:Article ID 813764. http:// 8. Morgenthaler TI, et al. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. Sleep 2007;30(11): 1445–59. 9. Auger RR, Burgess HJ, Emens JS, et al. Clinical practice guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: advanced sleep-wake phase disorder (ASWPD), delayed sleep–wake phase disorder (DSWPD), non-24-hour sleep-wake rhythm disorder (N24SWD), and irregular sleep-wake rhythm disorder (ISWRD). An update for 2015: an American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med 2015;11(10):1199–236. 10. Naitoh P, Kelly TL, Babkoff H. Napping, stimulant, and four-choice performance. In: Broughton RJ, Ogilvie RD, editors. Sleep, arousal, and performance: problems and promises. Cambridge, MA: Birk Hauser Boston; 1992. p. 198–219. 11. Sack RL. Jet lag. N Engl J Med 2010;362:440–7. 12. Eastman CI, Gazda CJ, Burgess HJ, et al. Advancing circadian rhythms before eastward flight: a strategy to prevent or reduce jet lag. Sleep 2005;28(1):33–44. 13. Waterhouse J, Reilly T, Atkinson G. Jet lag. Lancet 1997;350(9091): 1611–17.


14. Chang A-M, Aeschbach D, Duffy JF, et al. Evening use of light-emitting ereaders negatively affects sleep, circadian timing, and next-morning alertness. Proc Natl Acad Sci U S A 2014;112(4):1232–7. 15. Campbell SS, Murphy PJ. Extraocular circadian phototransduction in humans. Science 1998;279(5349):396–9. 16. Boulos Z, Macchi MM, Sturchler MP, et al. Light visor treatment for jet lag after westward travel across six time zones. Aviat Space Environ Med 2002;73(10):953–63. 17. Reynolds NC, Montgomery R. Using the Argonne diet in jet lag prevention: deployment of troops across nine time zones. Mil Med 2002;167(6):451–3. 18. Ruscitto C, Ogden J. The impact of an implementation intention to improve mealtimes and reduce jet lag in long-haul cabin crew. Psychol Health 2017;32(1):61–77. 19. Reebs S, Mrosovsky N. Effects of induced wheel-running on the circadian activity rhythm of Syrian hamsters: entrainment and phase-response curve. J Biol Rhythms 1994;4:39–48. 20. Sack RL, Brandes RW, Kendall AR, et al. Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med 2000;343(15):1070–7. 21. Brzezinski A. Mechanisms of disease: melatonin in humans. N Engl J Med 1997;336(3):186–95. 22. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. The Cochrane Library, Copyright 2005, The Cochrane Collaboration 2005;4. 23. Suhner A, Schlagenhauf P, Johnson R, et al. Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag. Chronobiol Int 1998;15:655–66. 24. Nagashima S, Yamashita M, Toio C, et al. Can tryptophan supplement intake at breakfast enhance melatonin secretion at night? J Physiol Anthropol 2017;36(1):20. 25. Zee PC, Wang-Weigand S, Wright KP, et al. Effects of ramelteon on insomnia symptoms induced by rapid, eastward travel. Sleep Med 2010;11(6):525–33. 26. Leproult R, Van Onderbergen A, L’hermite-Baleriaux M, et al. Phase-shifts of 24-h rhythms of hormonal release and body temperature following early evening administration of the melatonin agonist agomelatine in healthy older men. Clin Endocrinol (Oxf) 2005;63(3):298–304. 27. Revell VL, Burgess HJ, Gazda CJ, et al. Advancing human circadian rhythms with afternoon melatonin and morning intermittent bright light. J Clin Endocrinol Metab 2006;91(1):54–9. 28. Kolla BO, Augur RR. Jet lag and shift work sleep disorders: how to help reset the internal clock. Cleve Clin J Med 2011;78(10):675–84. 29. Naguib M, Samarkandi AH. The comparative dose-response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study. Anesth Analg 2000;91(2):473–9. 30. Suhner A, Schlagenhauf P, Hofer I, et al. Effectiveness and tolerability of melatonin and zolpidem for the alleviation of jet lag. Aviat Space Environ Med 2001;72:638–46. 31. Zhdanova I, Wurtman R, Lynch H, et al. Sleep inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Ther 1995;57:552–8. 32. Buscemi N, Vandermeer B, Pandya R, et al. Melatonin for Treatment of Sleep Disorders. Evidence Report/Technology Assessment: 108. Available at: 33. Foster J, Burry LD, Thabane L, et al. Melatonin and melatonin agonists to prevent and treat delirium in critical illness: a systematic review protocol. Syst Rev 2016;5(1):199. 34. Vermeeren A, Vets E, Vuurmann EF, et al. On-the-road driving performance the morning after bedtime use of suvorexant 15 and 30 mg in healthy elderly. Psychopharmacology (Berl) 2016;233(18): 3341–51. 35. Tanaka Y, Aoki I, Ishine T, et al. Preclinical and clinical results of dual orexin receptor antagonist, suvorexant (Belsomra), a novel therapeutic agent for insomnia. J Pharmacol Japonica 2016;148(1):46–56. 36. Thompson TAW, Quay C, Rojas-Fernandez B, et al. Atypical antipsychotics for insomnia: a systematic review. Sleep Med 2016;22:13–17.


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37. Beaumont M, Batejat D, Pierard C, et al. Caffeine or melatonin effects on sleep and sleepiness after rapid eastward transmeridian travel. J App Physiol 2004;96(1):50–8. 38. Nishino S, Mao J, Sampathkumaran R, et al. Increased dopaminergic transmission mediates the wake-promoting effects of CNS stimulants. Sleep Res Online 1998;1(1):49–61. 39. Ferraro L, Fuxe K, Tnaganelli S, et al. Amplification of cortical serotonin release: a further neurochemical action of the vigilance-promoting drug modafinil. Neuropharmacology 2000;39(11):1974–83. 40. Lyons TJ, French J. Modafinil: the unique properties of a new stimulant. Aviat Space Environ Med 1991;62(5):432–5.

41. Turner DC, Robbins TW, Clark L, et al. Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacol (Berl) 2003;165(3):260–9. 42. Rosenberg RP, et al. A phase 3, double-blind, randomized, placebo-controlled study of armodafinil for excessive sleepiness associated with jet lag disorder. Mayo Clin Proc 2010;85(7):630–8. 43. Darwish M, Kirby M, Hellriegel ET, et al. Systemic exposure to armodafinil and its tolerability in healthy elderly versus young men. Drugs Aging 2011;28(2):140–50. 44. Birkmayer GD, Kay GG, Vurre E. [Stabilized NADH (ENADA) improves jet lag-induced cognitive performance deficit]. Wien Med Wochenschr 2002;152(17–18):450–4 [German].

46  Motion Sickness Euna Hwang, Susan M. Kuhn, and Beth Lange

KEY POINTS • In most people, if there is sustained motion (as on a cruise ship), habituation will occur in 3–4 days. • Motion sickness is thought to be caused by a “sensory conflict” of information to the central nervous system (CNS), from the visual, vestibular, and/or proprioceptive systems. • Certain physical (pregnancy, migraines, vestibular dysfunction) and environmental (heat, noxious fumes) stimuli may influence the development of motion sickness in a person.

• In general, antimotion sickness medications are more effective if taken prior to exposure; a major adverse effect is drowsiness. • Several “vestibular rehabilitation” programs are available for prevention of motion sickness (Puma method) and for treatment of mal de débarquement syndrome (MdDS), but lack validation from multicenter trials.


during spaceflight or floating in water, may also be a trigger. Scuba diving or snorkeling in rough water, for example, results in turbulent movement in the absence of both the orienting influence of gravity and a visual frame of reference. Luckily, sustained exposure to constant motion over 3–4 days results in habituation in most individuals.3 Adaptation to motion sickness occurs in two parts. The initial malaise with nausea protects by causing immobility, while the second component, an individual adaptation, takes a day or so to “reprogram” the components of the neurovestibular system. The precise mechanism of central nervous system (CNS) habituation remains uncertain. Unfortunately, this tolerance is lost within a similar time frame if the motion stops or changes. Similar symptoms can also result when the movement to which the person has adapted suddenly stops—a kind of “antimotion” sickness. The most common example is the transient “landsickness” sometimes experienced after disembarking from a ship, which usually resolves within 24 hours. Some individuals do not recover, and symptoms can persist for months or years, an unusual and persistent condition known as mal de débarquement syndrome (MdDS). MdDS sufferers are usually asymptomatic during the journey, which may include travel by ship, train, or even in space. The prolonged symptoms of this form of posttravel sensation of movement often include a sense of disorientation, impaired cognition, fatigue, ataxia, insomnia, headache, anxiety, and depression. The constant sensations of swaying or rocking may be temporarily alleviated when riding in a car or during travel on water, but the symptoms return after the ride.4 There are no predictive features of who might develop MdDS. It may respond to medication, whether first line motion sickness medications, benzodiazepines, or selective serotonin reuptake inhibitors (SSRIs).5,6 Visual suggestion of movement when the individual is stationary is an equally strong trigger for motion sickness. “Vection,” or illusory self-motion, is created with rotating drums around a stationary patient for laboratory studies.6 It is also encountered in many real-life

To travel is to move—so what condition is potentially more relevant to the traveler than motion sickness? In fact, virtually anyone can suffer from this malady, given the right—or more accurately the wrong— circumstances. Frequency and severity vary, yet impact may be significant and can ruin a long-awaited and expensive holiday. The secret is to “be prepared.” The travel health professional must gather sufficient information about an individual’s general health, motion susceptibility, and trip itinerary to identify situations in which motion sickness will be a potential risk. For some travelers, counseling on the topic may consist of suggesting the inclusion of an antimotion sickness medication in a medical kit. For others who will be sailing to the Antarctic, crossing the Sahara on camelback, or for the scuba diver with severe motion sensitivity, discussing preventive and treatment strategies may be an important component of the pretravel consultation. Therefore it is essential that the travel health professional has a clear understanding of motion sickness and how it can be prevented or treated.

TRIGGERS OF MOTION SICKNESS Motion sickness is usually produced by vestibular stimulation but can also occur with visual stimulation. Movement combining linear and angular acceleration rapidly produces motion sickness in nearly everybody (Coriolis effect).1 Traveling through water, land, air, and space may all be triggers, although seasickness is the most common type. Provocative environments include a variety of mechanical vehicles, such as ships, planes, cars, buses, trains, carnival rides, and spinning chairs. Tilting trains in Europe are a recent addition to this list of problematic transportation.2 Riding on the back of an animal can also be a powerful stimulus, particularly those that cause a lot of swaying or rocking (e.g., camels). Self-propelled motion such as gymnastics or downhill skiing during white-out conditions, or even motion in a state of weightlessness


CHAPTER 46  Motion Sickness Abstract


Motion sickness, in susceptible individuals, may ruin an expensive and much anticipated holiday, and in rare cases affect activities of daily living or employment requiring travel. Motion sickness is caused by unaccustomed repetitive movement in the visual, vestibular, and/or proprioceptive systems, particularly if there is a perceived “conflict” between the sensory information being presented to the central nervous system. The travel health professional is in a unique position to offer advice to prevent or treat motion sickness with conservative or pharmacologic advice. All medications may have associated side effects. There are some “desensitization” programs, which, although not validated by multicenter trials, may be helpful for some individuals (Puma method) or for those who develop mal de débarquement syndrome (MdDS).

Cruise ship Habituation Mal de débarquement Maladaptation Motion sickness Sensory conflict



SECTION 8  Environmental Aspects of Travel Medicine

situations such as flight simulators, computer games, and movies (e.g., often prompted by sitting close to the screen or three-dimensional films).

What Is Motion Sickness? Motion sickness refers to the syndrome of dizziness, nausea, vomiting, increased salivation, yawning, and generalized malaise induced by motion.1 The individual initially feels a vague abdominal discomfort sometimes referred to as “stomach awareness,” followed by malaise and nausea which may culminate in vomiting. These gastrointestinal symptoms are associated with measurable changes in gastric muscle activity. Electrogastrography in laboratory settings reveals increased and/ or uncoordinated muscle activity known as gastric tachyarrhythmia.7 A constellation of lethargy, fatigue, and mental slowness that persists after resolution of the gastrointestinal symptoms in some patients has been labeled the “sopite syndrome.” Electroencephalography (EEG) monitoring reveals slowing of α waves over the frontal areas for about 2 hours after severe motion sickness, which correlates with this drowsiness and loss of performance.8

WHO IS LIKELY TO GET MOTION SICKNESS? Although motion sickness can occur in virtually anyone given sufficient provocative conditions, a small proportion of the population is highly resistant while a similar number are very susceptible. In the latter group this tendency does not seem to decrease with exposure.9 The condition is also related to gender and age, and may be influenced by other personal and environmental factors. Women are more likely than men to suffer,10 particularly near menses and during pregnancy, suggesting a hormonal influence. Symptoms such as nausea and vomiting are uncommon in children 12 years: 4–6 Oral, intramuscular, Not 99% of particles, including bacteria and viruses. • There is an extremely low probability of airline passengers or crew suffering any abnormality or disease because of exposure to cosmic radiation. • Air travel continues to be a potential contributor to the spread of communicable diseases between and within countries, but the risk of transmission of serious infectious diseases during flight is low. Proper immunizations and routine hand hygiene practices are important preventive measures for air travelers. The passenger cabin of a commercial airliner is designed to carry the maximum number of passengers in safety and comfort, within the constraints of cost effectiveness. It is incompatible with providing the facilities of an ambulance, an emergency room, an intensive care unit, a delivery suite, or a mortuary. The ease and accessibility of air travel to a population of changing demographics inevitably means that there are those who wish to fly who may not cope with the hostile physical environment of the airport, or the hostile physiologic environment of the pressurized passenger cabin. It is important for medical professionals to be aware of the relevant factors, and for unrealistic public expectations to be avoided. Most airlines have a medical adviser who may be consulted prior to flight to discuss the implications for an individual passenger. Such preflight notification can prevent the development of an in-flight medical emergency that is hazardous to the passenger concerned, inconvenient to fellow passengers, and expensive for the airline. For those with disability, but not a medical problem, preflight notification of special needs and assistance will reduce the stress of the journey and enhance the standard of service delivered by the airline. Finally, the importance of adequate medical insurance coverage for all travelers cannot be overemphasized.


SECTION 8  Environmental Aspects of Travel Medicine

REFERENCES 1. Gradwell DP, Rainford DJ. Ernsting’s aviation medicine. 5th ed. CRC Press; 2016. 2. 3. Lorengo D, Porter A. Aircraft ventilation systems study. Final report. DTFA-03–84-C-0084. DOT/FAA/CT-TN86/41-I. Federal Aviation Administration, US Department of Transportation. September 1986. 4. 5. Pp. 180–1. 6. de Ree H, Bagshaw M, Simons R, et al. Ozone and relative humidity in airliner cabins on polar routes: measurements and physical symptoms. In: Nagda NL, editor. Air quality and comfort in airliner cabins, ASTM STP 1393. West Conshocken, PA: American Society for Testing and Materials; 2000. p. 243–58. 7. Nicholson AN. Dehydration and long haul flights. Travel Med Int 1998;16:177–81. 8. Campbell RD, Bagshaw M. Human performance and limitations in aviation. 3rd ed. Blackwell Science; 1999. 9. Bagshaw M, Lower MC. Hearing loss on the flight deck – origin and remedy. Aeronaut J 2002;106(1059):277–89. 10. FAA Federal Aviation Regulations (FARS, 14CFR); section 25.832. 11. Bagshaw M. Cosmic radiation measurements in airline service. Radiat Prot Dosim 1999;86:333–4. 12. Valentin J, editor. The 2007 Recommendations of the International Commission on Radiological Protection, Publication 103, Ann. ICRP, Elsevier. 13. Gratz NG, Steffen R, Cocksedge W. Why aircraft disinfection? Bull World Health Organ 2000;78:995–1004. 14. Report on the Informal Consultation on Aircraft Disinfection. Geneva: World Health Organization; November 6-10, 1995 (WHO/PCS/ 95.51). Available at _Rev.pdf. 15. The Airliner Cabin Environment and the Health of Passengers and Crew. Report of the National Research Council. Washington DC: National Academy Press; December 2001. 16. US Department of Health and Human Services. Guidelines for environmental infection control in health-care facilities. 2003. Available at 17. Abubakar I. Tuberculosis and air travel: a systematic review and analysis of policy. Lancet Infect Dis 2010;10:176–83. 18. Kornylo-Duong K, Kim C, et al. Three air travel-related contact investigations associated with infectious tuberculosis. Travel Med Infect Dis 2010;8:e120–8. 19. Marienau KJ, Burgess GW, et al. Tuberculosis investigations associated with air travel: U.S. Centers for Disease Control and Prevention. Travel Med Infect Dis 2010;8:e104–12. 20. Martinez L, Thomas K, Figueroa J. Guidance from WHO on the prevention and control of TB during air travel. Travel Med Infect Dis 2010;8:84–9. 21. Mangili A, Gendreau MA. Transmission of infectious diseases during commercial air travel. Lancet 2005;365:989–96.

22. Dawood FS. Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: a modelling study. Lancet 2012;12(9):687–95. 23. WHO. Global Alert and Response. Confirmed Human Cases of Avian Influenza A(H5N1). June 22, 2011. Available at influenza/human_animal_interface/en/. 24. Khan K, Arino J, Hu W, et al. Spread of a novel influenza A (H1N1) virus via global airline transportation. NEJM 2009;361:212–14. 25. Baker MG, Thornley CN, Mills C, et al. Transmission of pandemic A/ H1N1 2009 influenza on passenger aircraft: retrospective cohort study. BMJ 2010;340:c2424. doi:10.1136/bmj.c2424. 26. Huizer YL, Swaan CM, et al. Usefulness and applicability of infectious disease control measures in air travel: A review. Travel Med Infect Dis 2015;13:19. 27. Communicable disease X (Ebola, MERS, TB, measles) coming soon to a neighborhood near you? Lessons learned about communicable disease and air travel. Editorial. Travel Med Infect Dis 2015;13:3. 28. Mukherjee P, Lim PL, Chow A, et al. Epidemiology of travel-associated pandemic (H1N1) 2009 infection in 116 patients, Singapore. Emerg Infect Dis 2010;16:22–6. 29. Amornkul PN, Takahashi H, Bogard AK, et al. Low risk of measles transmission after exposure on an international airline flight. J Infect Dis 2004;189:S81–5. 30. CDC. Notes from the field: multiple cases of measles after exposure during air travel – Australia and New Zealand, January 2011. MMWR Morb Mortal Wkly Rep 2011;60(25):851. 31. Nelson K, Marienau K, Schembri C, et al. Measles transmission during air travel, United States. Travel Med Infect Dis 2013;11:81. 32. Widdowson MA, Glass R, Monroe S, et al. Probable transmission of norovirus on an airplane. JAMA 2005;293(15):1859–60. 33. Thornley CN, Emslie NA, Sprott TW, et al. Recurring norovirus transmission on an airplane. Clin Infect Dis 2011;53(6):515–20. 34. Public health response to commercial airline travel of a person with Ebola virus infection—United States, 2014. MMWR Morb Mortal Wkly Rep 2015;64(3):63–6. 35. -airline-travel. 36. 37. 38. 39. Bagshaw M, Byrne NJ. La sante des passagers. Urgence Pratique 1999;36:37–43. 40. Donner HJ. Is there a doctor on board? Medical emergencies at 40K feet. Emerg Med Clin North Am 2017;35(2):443–63. 41. Nable JV, et al. In-flight medical emergencies during commercial travel. N Engl J Med 2015;373(10):939–45. 42. Peterson DC, et al. Outcomes of medical emergencies on commercial flights. N Engl J Med 2013;368:2075–83. 43. Bagshaw M. Telemedicine in British Airways. J Telemed Telecare 1996;2(1):36–8. 44.

48  Bites, Stings, and Envenoming Injuries Michael V. Callahan

KEY POINTS • Pretravel counseling should include itinerary-specific advice on avoiding hazardous arthropods and animals for at-risk travelers. • At-risk travelers should be familiar with basic first aid and steps to prevent wound infection during prehospital transport. • Animal attack injuries can be prevented by avoiding behaviors that increase encounters with dangerous species. • Travelers with allergies to bee, wasp, and ant stings (Hymenoptera) should be trained and equipped for self-treatment with epinephrine autoinjection devices (e.g., Impax, EpiPen). • Treatment of jellyfish stings requires the removal of nematocysts from skin with seawater or acetic acid. Fresh water, hot water, and alcoholic beverages may increase the severity of jellyfish sting injuries.

• Venom-laden spine injuries from marine animals such as sea urchins and stingrays should be treated with warm (120°F [50°C]) water immersion, prompt removal of retained spine fragments, and irrigation to remove venomous mucus. • Care of venomous injuries should prioritize rapid transport to the nearest qualified medical facility; transport should not be delayed by any field treatment (exception: compression wrap bandages for krait, mamba, coral snake, and all Australian land snakes). • Severe venomous injuries require antivenin immunotherapy; challenges to therapy include matching antivenins to offending species and avoiding antivenin preparations that are expired, improperly stored, or counterfeit.



In recent years travel demand for more remote, extreme, and wilderness adventures has increased encounters between travelers and dangerous land and marine animals. Competition among tour operators has driven development of trips designed to maximize encounters between paying clients and dangerous species (Fig. 48.1). This chapter is divided into three sections: nonvenomous injuries resulting from blood-feeding arthropods and animal attacks; venomous injuries from arthropods and reptiles; and traumatic or traumatic envenoming injuries from dangerous marine fauna. Each section includes methods for avoiding encounters, principles of first aid and hospital-based care, and the prevention and management of primary or secondary wound infection. The most effective strategy for injury prevention is pretravel education. Pretravel education should focus on itineraries and activities that increase the risk of animal encounters, and to provide destination-specific advice. For example, travelers to Cambodia should be counseled against feeding long-tail monkeys, a human-adapted species commonly implicated in bites to travelers. Divers visiting Cape Town should be discouraged from paying to dive “cage free” with the region’s great white sharks. Travelers to remote destinations should be familiar with principles of first aid for animal bite and puncture wounds and sting injuries. Travelers with high-risk itineraries should be provisioned with basic wound care supplies and standby antibiotics for treating high-risk wounds. Clinicians requiring additional information should consult more detailed references.1

Arthropod Bites Bites from hematophagous arthropods, including insects, ticks, and mites, can cause sequelae ranging from minor pruritic bites to devastating vectorborne illness.

Prevention of Arthropod Bites.  Strategies for avoiding blood-feeding species include chemical repellents and pesticides, forgoing brightly colored clothing (or in the case of black flies and mosquitoes, dark colors), and locating camps on windy, high, dry, cool, and sparsely vegetated terrain far from insect havens (Table 48.1). A layered deterrent strategy using N,N-diethyl-m-toluamide (DEET) or picaridin (icaridin) repellents, proper clothing, and insecticide-treated ground barriers and bednets dramatically reduces the likelihood of phlebotamine bites. For example, the probability of being bitten by many species of Anopheline mosquito, which transmit malaria, is greatest at night, whereas Aedes mosquitoes, which transmit dengue, chikungunya, Zika, and yellow fever, are most active during daylight. One strategy to protect travelers while sleeping makes use of 4-mm polypropylene cord impregnated with 3%–5% permethrin, which is used to encircle the sleeping area. These “bug cords” are effective deterrents for ground-crawling arthropods.

Treatment of Arthropod Bites. Local reactions to the bite of hematophagous insects vary with species and the sensitivity of the individual. Local reactions include persistent bleeding at the bite site


CHAPTER 48  Bites, Stings, and Envenoming Injuries Abstract


Growing interest in backcountry adventure and ecotourism has increased contact between travelers and dangerous wild fauna and arthropods. Injures from local hazardous species can occur when safety education or common sense fail, or when wildlife behaves unpredictably. Strategies to prevent bites and stings require a basic familiarity with local dangerous species and a willingness to avoid risky behaviors that increase the chance of injury. Successful treatment of animal attack injuries requires both an understanding of basic principles for wound management in delayed-care settings and specialized expertise for more unfamiliar injuries. In recent years, improved medical outcomes for life-threatening injuries, including venomous injuries, are increasingly achieved by reliance on local medical and surgical expertise and access to life-saving therapeutics such as antivenins, which may not be available on medical evacuation aircraft or in the traveler’s home country.

Anaphylaxis Animal bite Arachnid Arthropod Marine Snake bite Sting Venom Wound infection



SECTION 9  Health Problems While Traveling

FIG. 48.1  Travelers should avoid high-risk wildlife encounters, such as “workshops” that teach tourists how to handle cobras.

TABLE 48.1  Important Hematophagous Insects, Recommended Deterrents and Treatments Insect




Mosquitoes fly up CO2 gradients until they are close enough to rely on thermal and visual senses.

True flies

Horseflies and tsetse flies rely on vision, whereas sand flies and black flies use CO2 and thermal detection to locate warm-blooded prey. Flea bites occur when the preferred host animal is unavailable. Eggs lie in ground cover and may last for weeks so pesticides need to be repeated at 4–6-week intervals. Lice are highly specific for certain animal species. Anthrophilic species spend their entire life in human hair. Egg cases (“nits”) are resistant to many insecticides; repeated applications are often required. Trombiculid mites are small arachnid larva that feed on epithelial cells and secrete digestive enzymes, which cause hypersensitivity reactions. Soft tissue edema and severe pruritus are typical and unremitting. Sarcoptes scabiei are transmitted under crowded pestilent conditions. Patients become sensitized to digested secretions leading to characteristic itching. Infections are identified by distinctive linear tracks, which may be highlighted with dilute povidone-iodine or gentian violet.

Minimize CO2 and heat-emitting sources such as generators. Maintain air movement to disrupt CO2 and heat gradients. Wear light-colored clothing. Use repellents containing extended-release preparations of DEET (30%–45%) or picardin (>20%), or wear permethrinimpregnated clothing. Light blue clothing attracts tsetse flies in sub-Saharan Africa. Many biting flies preferentially land on dark-colored clothing.



Chiggers (mite larvae)


due to salivary anticoagulant (e.g., black flies), inflammatory pruritic lesions (e.g., chiggers), and granulomas (e.g., hard ticks). Slapping a feeding insect may cause immunogenic mouthparts to be retained in the bite wound. Improper removal of attached ticks, tumba fly larvae, and chigger fleas may also result in retained insect parts. Close inspection of all bite sites using an illuminated magnifying glass and removal of any foreign body both reduce inflammation and secondary infection.

Long-lasting pesticides help with infestations. Diethyltoluamide (DEET) and permethrin are effective for all but the most voracious species. Mild infestations in adults may be treated with benzene hydrochloride. Heavy infestations will need topical 1% permethrin or 0.5% malathion. Children should be treated with care. DEET and permethrins are both effective for prevention. Pruritic papules are treated with antihistamines or topical corticosteroids.

Infested areas should be monitored for infection. Scabicidal agents include topical 5% permethrin or ivermectin. Treatment of close contacts is recommended.

Chronic inflammatory reactions to arthropod bites may persist for months after exposure. Antihistamines and topical steroids are helpful; systemic steroids should be avoided. A list of important hematophagous insects and recommended deterrents is provided in Table 48.1. Several large insects defend themselves with spines, powerful claws, or chelicerae. Species that can cause painful injuries include African driver or siafu ants (Dorylus), American leaf-cutter ants, and staghorn

CHAPTER 48  Bites, Stings, and Envenoming Injuries


TABLE 48.2  Annual Human Deaths From Animal Attack (1978–2007) Species



Venomous snakes


Tiger and lion Crocodile

750 600–800



Hippopotamus Cape buffalo

130 85

Hyena Feral and wild pig Bear

40 20 11



Alligator/caiman Python/anaconda Rhinoceros

4 6 hours after attack and those with evidence of infection should be cultured. The laboratory should be instructed to culture for aerobic, anaerobic, atypical, and fastidious microorganisms. Many laboratories require special notification regarding nontuberculous mycobacteria and marine species. X-rays should be obtained for all suspicious wounds and bites to joints. Devitalized tissue should be debrided until a clear base and margins are observed. The minority of bite wounds, all low risk and seen early, may be closed. Select wounds may have edges loosely approximated with sterile closure strips. Skin glue should not be used. Treatment should cover anaerobes such as Prevotella and Pasteurella, and routine species such as S. aureus. Oral antibiotics such as amoxicillin-clavulanic acid 875/125 g bid (Augmentin) may be used for mild infections. Penicillin-allergic patients will require mixed antibiotic regimens.5,6 Travelers bitten by Old World monkeys should be treated with valacyclovir to prevent transmission of herpes B virus.7 All patients with severely contaminated wounds should receive a tetanus booster. Nonimmunized patients should undergo the primary series and be treated with antitetanus immunoglobulin. The risk of rabies should be considered using revised risk criteria for animal bites and bat contact (see Chapter 12).

Clinicians providing remote support will need to sort through the patient’s description of the offending animal, the circumstances of the event, and the progression of early symptoms. This information will need to be cross-referenced with a clinician experienced with treatment of envenomation injures from species native to that region. Preloading images of medically significant species for a given destination will help guide critical decisions on compression bandages, the need for whole blood clotting assays (discussion to come), improved selection of antivenin, and use of adjunct anticholinesterase therapy. If envenoming is likely, the patient must first be directed to appropriate in-country medical services even when international medical evacuation services are immediately available. For many snake, spider, and scorpion envenomings prompt access to experienced clinicians and access to

appropriate antivenins are more important to patient outcome than hasty medical evacuation to homeland hospitals, as these facilities lack both the bedside expertise and the access to foreign antivenins that improve patient outcomes.

Prevention of Venomous Bites and Stings Methods for preventing encounters with venomous arthropods, reptiles, and marine animals are listed in Table 48.6.

Venomous Arthropods Venom may be introduced by specialized fangs, caudal stingers, or dorsal spines and seta. Envenoming often results from the defensive actions— usually the final actions—of a spider, wasp, or scorpion that has been swatted or stepped on.


SECTION 9  Health Problems While Traveling Hymenoptera.  The most medically significant venomous arthropods

FIG. 48.4  Monkey bite to wrist. Monkey bites have a high incidence of bacterial infection; bites from Old World species also risk transmission of herpes B virus, a zoonotic virus associated with fatal cases of encephalitis.

TABLE 48.5  Animal Wounds at High Risk

of Infection

• Wounds to joints, hands, feet, tendons, and ligaments • Deep puncture injuries • Older, diabetic, or immune suppressed victim • Marine and estuarine injuries • Contaminated wounds, including those treated with traditional remedies • Retained teeth, spines, mouthparts • Carnivores, particularly feline, monkey, and mongoose • Delay in wound treatment • Inappropriate (e.g., early) wound closure

belong to the order Hymenoptera, which include bees, wasps, and stinging ants. Together the Hymenoptera account for the greatest number of sting injuries, considerable morbidity and death from venom effects, or more commonly, anaphylactic reactions.16 The most dangerous Hymenoptera is the Central American bullet ant (Paraponera clavata), named after a sting so painful that it has been compared with a gunshot wound by victims unlucky enough to make the comparison.17 Most Hymenoptera venom contains serotonin, histamine, and in some hornets, acetylcholine. Africanized honeybees, also known as “killer bees,” have venom comparable to that of domesticated honeybees but are easily provoked in defense of the hive. Hymenoptera stings are identified by a raised papule, often with the stinger-wound in the center, erythema, and edema at the bite site. Honeybees have a barbed stinger. When the bee attempts to fly away, it is eviscerated, leaving the stinger and the contracting venom gland behind. In contrast to earlier precautions, grasping the gland during removal has not been shown to force more venom into the wound.18 Additional care of bee stings includes wound cleansing, verifying tetanus immunization, and monitoring for infection. Oral nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen are effective in reducing pain and swelling. Oral antihistamines are effective at reducing post-sting pruritus; and cold packs help relieve pain but should not be used on stings from unknown species. Treatment of anaphylactic reactions should be initiated as soon as systemic symptoms appear. The most effective therapy is prompt treatment with 1 : 1000 epinephrine hydrochloride (0.25–0.5 mL subcutaneous). The injection site should be massaged to speed drug absorption. Patients with severe reactions are likely to need a second injection. In recent years, handheld preloaded epinephrine autoinjectors have simplified self-treatment; however, travelers should practice with the sham device under health care supervision before attempting to use the device in an emergency. Sting injuries on the lower extremities have an increased likelihood of becoming infected. Sting injuries that develop pain, erythema, and lymphadenopathy should be treated with antibiotics active against gram-positive skin flora.

TABLE 48.6  Prevention of Venomous Injuries Venomous arthropods

Bees, wasps (Hymenoptera)

Centipedes (Scolopendra)

Venomous arachnids

Spiders: widow spiders (Latrodectus), banana leaf spiders (Phoneutria), violin spiders (Loxosceles), funnel web Scorpions: Tityus, Buthus, Centruroides

Venomous reptiles

Snakes: cobras (Naja), mambas, Australian elapids, vipers


Do not wear bright-colored clothing, perfumes, and aromatic sprays. Avoid trashcans, flowers, and rotting fruit. Keep wasps away from opened soft drinks. Ensure permethrin-treated bednets touch the floor but that bed sheets do not. Encircle sleeping pads with permethrin-impregnated ground cord. Avoid sandals; shake out shoes before wearing. Do not wear open footwear (sandals) when off pavement. Use permethrin cord and bednets. Keep bedsheets from touching floor. Use insecticide to reduce prey species. Inspect privies before sitting (widow [Atrax] spiders). Hang clothing; shake out shoes before use; check tub before entering. Use ultraviolet (UV) light wands at night (scorpions). Avoid—rather than attempt to kill or relocate—venomous snakes. Do not attract rodents (which attract snakes that feed on them). Do not handle unknown snake species, even if “dead.” Use a flashlight and walking stick after dark. Avoid sandals; wear sturdy footwear in snake country. Avoid sleeping on the ground. Do not handle Gila monsters or beaded lizards even if they are “tame.”

CHAPTER 48  Bites, Stings, and Envenoming Injuries


TABLE 48.7  Representative Venomous

Arachnids Spiders


FIG. 48.5  Necrotic loxoscelism from the bite of Loxosceles reclusa, or violin spider, in an 8-year-old boy. The child developed acute renal failure, hepatic insufficiency, and hemolysis requiring transfusion and prolonged support.



Widow spiders (Latrodectus) Violin spiders (Loxosceles) Banana spiders (Phoneutria) Sac spiders (Cheiracanthium) Funnel web spiders (Atrax) Hobo spiders (Tegenaria) Amazon yellow (Tityus) African scorpions (Leiurus; Buthus) Indian scorpions (Buthotus) American bark scorpions (Centruroides)

Worldwide Western hemisphere Tropical Americas Worldwide Australia Europe, Asia, US Northwest South America North Africa North Africa, Spain India, Sri Lanka, Bangladesh US Southwest to Colombia

into the shower or after seeking shelter in footwear. Antivenin is produced against many toxic species, notably the Middle Eastern “death stalker” (Leiurus) and American bark scorpion (Centruroides). In addition to antivenin, neurotoxic bites and stings may be treated with a compression bandage as with neurotoxic snake envenoming (see the section Venomous Reptiles). Medically important spiders and scorpions are listed in Table 48.7.

Venomous Reptiles Spiders and Scorpions.  Some spider species, such as the hobo spider (Tegenaria), the violin spider group (violin or recluse spiders; Loxosceles), and sac spiders (Cheiracanthium), possess venom capable of causing necrotic skin lesions. In the case of Loxosceles spiders, tissue necrosis may be severe. Systemic effects of Loxosceles spiders include renal failure, hepatic insufficiency, and hemolysis. No FDA-approved polyvalent antivenin is available for Loxosceles envenoming, and treatment remains supportive (Fig. 48.5). A promising new Loxosceles antivenin has been under development for a decade; however, clinical studies demonstrating efficacy have not been completed.19 Widow spiders (Latrodectus) have a worldwide distribution and are responsible for a considerable number of neurotoxic bites. All widow spiders are web-dwelling species and only female spiders bite, usually when webs are disturbed. Widow spiders prefer to build webs where insects congregate, such as near windows, trashcans, refuse piles, and latrines. Bites by widow spiders cause instant pain which escalates with onset of cramping and muscular spasms, particularly in large muscle groups. Small children are at increased risk of both envenoming and death. Highly effective antivenins against widow spider bites are produced in Australia, South Africa, and the United States. The unrelated South American banana spiders (Phoneutria), in particular one Brazilian spider (Phoneutria nigriventer), are a common neurotoxic species capable of fatal envenoming. Unlike widow spiders, the foraging behaviors of the Phoneutria spiders bring them into contact with humans. An antivenin with activity against Phoneutria sp. is produced in Brazil. The most dangerous neurotoxic spiders worldwide belong to the genus Atrax, typified by the Sydney funnel web spider (Atrax robustus), found on the East coast of Australia. These spiders are significantly venomous and possess large fangs capable of penetrating thick clothing and footwear. An antivenin is made in Australia. Scorpions are responsible for a sizable number of fatalities in Central America, India, and North Africa, particularly among small children. Travelers are frequently stung when they step on scorpions that have fallen

Snake bite accounts for the majority of severe envenomings worldwide. Snake bite experts generally agree that although elapids (cobras and kraits) account for the greatest number of deaths, vipers account for the greatest number of bites and long-lasting disability. Viper venom is rich in enzymes, which cause local pain, swelling, tissue damage, coagulopathy, and for several species damage to the kidneys, adrenals, and pituitary gland.20 Contrary to classic teaching, the venom of many cobras is in fact profoundly tissue destructive, whereas other species possess venom that is purely neurotoxic (e.g., Cape cobra, Philippine cobra). The venom of most species possesses different mixtures of neurotoxic and complex dermatomyonecrotic enzymes. Early death from cobra and krait bite is usually the result of respiratory failure; early death from viper bite usually reflects an intravenous envenoming or cardiac or cerebral catastrophe. Table 48.8 lists representative species of venomous snakes and their geographic distribution. Human anatomy plays a role in the severity of snake bite. When bites are delivered to the back of the hand, the malleolus, or other sites where superficial veins make intravenous injection likely, death may occur quickly. It is important to note that between 25% and 40% of defensive snake bites result in negligible or trivial envenoming and may be treated conservatively; the clinician is warned, however, that neurotoxic findings may be delayed for many hours after the bite. The majority of viper and cobra venoms cause local pain, swelling, and erythema. Bites from kraits, mambas, coral snakes, the Cape (Africa) Philippine (Mindanao Island) and king cobras (rural Southeast Asia), and several Australian species cause few local symptoms yet are profoundly neurotoxic. Bites from these species may initially appear to be “dry,” but if not treated promptly death from respiratory paralysis can occur quickly (Fig. 48.6). Indeed, cryptic envenoming by kraits may go unrecognized until neurotoxic symptoms such as ptosis or bulbar paralysis appear. In the case of vipers, coagulopathy is common and is usually first noted at the bite site, where unclotted blood drains from fang marks. Local necrosis may be significant following bites by most vipers and many


SECTION 9  Health Problems While Traveling

TABLE 48.8  Representative Venomous

Snakes by Region Range


Europe Africa

Vipers Elapids

Vipers Ground vipers



Rear-fanged colubrids Pit vipers

Elapids Elapids


Pit vipers

European asp (Vipera berus) Cobra (Naja, Walterinnesia) Mamba (Dendroaspis) African coral snake (Aspidelaps) Gaboon viper/puff adder (Bitis) Forest viper (Aetheris) Stiletto snake/burrowing asp (Atractaspis) Boomslang (Dispholidus) Rattlesnake (Crotalus) Cottonmouth/copperhead (Agkistrodon) Central/Southern pit viper (Bothrops) Coral snake (Micrurus) Asian coral snake (Maticora/ Caliophus) Krait (Bungarus) Cobra (Naja) Australian elapid (Notechis, Oxyuranus, Pseudechis) Sea snake (Enhydrina) Daboia (Daboia russelli) Saw-scale viper (Echis) Sand viper (Cerastes) Green tree viper group (Trimeresurus) Malayan pit viper (Calloselasma)

FIG. 48.6  Bites by vipers and many cobras cause local pain, swelling, and ecchymosis, as in the case of this Thai woman bitten on the foot by a 1-m-long Daboia (Daboia russelli) viper. The patient infarcted her pituitary gland, resulting in endocrine abnormalities.

species of cobra (Fig. 48.7). Death >12 hours after viper bite usually is related to defibrination-related coagulopathy and shock. In developing regions, patients may succumb days to weeks after the bite, owing to complications such as renal failure, secondary wound infection, or failure of manual or mechanical ventilation.

FIG. 48.7  Patients with neurotoxic symptoms and those confirmed to be bitten by neurotoxic species should be treated with compression dressings and monitored closely. This 8-year-old boy presented 9 hours after being bitten by a krait (Bungarus) with diplopia, bulbar palsy, and respiratory difficulty. The patient was intubated and treated with compression dressings while waiting for antivenin. Note the boy’s disconjugate gaze.

Snake envenoming is a medical emergency until proven otherwise. No other treatment priority, including air evacuation, is more important than immediate access to effective antivenin and clinicians with experience in treating bites from local species. Most snake bites cause local pain, swelling, and erythema, making the decision to treat obvious; however, the near absence of local findings following bites by mambas, coral snakes, and kraits requires these patients to be observed until they are symptom free for at least 18 hours. First aid for snake bite is supportive, not therapeutic, and is no substitute for antivenin therapy. Prehospital care includes removal of rings, watches, and other potentially constrictive items, splinting the bitten limb at or below heart level, and the judicious use of compression dressings (pressure bandages) for neurotoxic species.21,22 There is growing evidence that compression bandages are contraindicated for virtually all viper bites.23 In the author’s experience, compression bandages exacerbate local tissue damage when applied to bites from certain species of cobra with highly myonecrotic venoms (e.g., Naja kaouthia). Compression wraps are applied by wrapping an elasticized bandage or gauze bandage around the bitten extremity, moving centripetally from the fang marks. Patients treated with compression wraps require close supervision as increasing pain forces our patients to unwrap the dressing, releasing sequestered venom and the products of tissue destruction into the systemic circulation. Venom extraction devices, curettage, cruciate incisions, cauterization, stun guns, and native remedies (hot rocks, liniments, raw meat poultices) are certain to increase misery and very likely to increase local tissue damage. Venom coagulopathy may be assessed in austere clinics by placing 5–6 mL of the patient’s whole blood in a nonsilicate glass tube and leaving it undisturbed; after 20–30 minutes the tube should be decanted and the presence of unclotted blood noted. Unclotted blood indicates consumptive coagulopathy, which is typical of viper venoms, or defibrination from the venom of Asian rear-fanged arboreal snakes such as Rhabdophis. The author has had success adapting this technique to the field by placing three to four drops (100 µL) of blood on a clean glass microscope slide and monitoring for clot formation by tipping the slide after 15 minutes. The point is reiterated that patients bitten by a neurotoxic species require close monitoring for the development of paralysis. Early symptoms include agitation followed by diplopia, ptosis, and bulbar palsy (Fig. 48.8). Evidence of neurologic abnormalities that

CHAPTER 48  Bites, Stings, and Envenoming Injuries


TABLE 48.9  Clinical Pearls for Snake


FIG. 48.8  Patients envenomed by members of the stonefish group experience intense pain, such as this 19-year-old man who received a single spine injury to the hand.

cannot be attributed to other causes (anxiety, hyperventilation, narcotic analgesia, etc.) is an indication for immediate treatment with antivenin effective against local neurotoxic species. In Asia, a nonbreathing patient with fixed, dilated pupils should not be declared “brain dead” until krait bite is definitively ruled out. In recently initiated studies, recovery of pupillary light reflect is the earliest sign of recovery from krait-venom paralysis. Many snakes of the same species have venom that may vary in potency and clinical effects across that species’ range. For this reason, antivenin produced against local snake venom tends to be more effective than international manufactured venoms. Polyvalent antivenins, developed to protect against the venom of several species, are commonly used in sub-Saharan Africa, Asia, and the tropical Americas. The common experience is that polyvalent antivenins are less effective than are monovalent antivenins. Regardless, the majority of foreign manufactured antivenins will be unfamiliar to Western medical consultants and none are FDA or EMA approved. Antivenin supplies in rural hospitals are often stored without reliable refrigeration, are out of date, or are in limited supply. If the patient is critically envenomed and no alternatives exist, unrefrigerated and expired antivenin should be used. In recent years, counterfeit antivenins have appeared in Africa and Asia, possibly explaining recent increases in snake bite case fatality rates at several experienced African medical centers. Antivenin is stored as either hyperimmune serum or lyophilized powder, which must be reconstituted prior to intravenous (IV) infusion. Attempts to give antivenin by arterial infusion may prove catastrophic in the patient with coagulopathy. Intramuscular and local injection of antivenin is not recommended. The first vial of antivenin should be given slowly and at dilute concentrations if possible. Although potency varies between manufacturers, antivenin is generally administered in 1–2 vial aliquots over 10–20 minutes. Pain, paresthesia, anxiety, and blood clotting abnormalities often improve temporarily after antivenin, but retreatment is usually necessary. Antivenin therapy may be stopped when no further progression of pain, swelling, or erythema is noted, or when coagulation begins to improve. If neurotoxicity of bulbar or respiratory muscles is noted, anticholinesterases such as edrophonium may be administered to delay the onset of respiratory failure and allow time for antivenin to work. Multiple studies have failed to demonstrate benefit from premedicating patients for hypersensitivity reactions prior to antivenin therapy.24 Following successful resuscitation and antivenin treatment, patients should be monitored for sequelae of envenoming such as tissue necrosis,

• Local pain, swelling, and erythema are the hallmarks of viper and most cobra envenomations. • Venoms frequently possess both hemotoxic and neurotoxic activity. • The venom of most cobras causes significant tissue injury as well as neurotoxicity. • The venom of most vipers causes significant tissue injury and, often, systemic coagulopathy. • The venom of several colubrids causes minimal local reaction but may cause severe coagulopathy (e.g., Rhabdophis, Asian keel back). • Persistent bleeding from the fang marks (>15 min) suggests coagulopathy. • Bites from kraits, mambas, the Philippines cobra, and all coral snakes can cause life-threatening neuroparalysis with minimal local symptoms. • Cryptic envenomation by vipers and the majority of cobras is rare in the absence of local symptoms. • Neurotoxic effects of mambas and many cobras can be reversed with antivenin; in contrast, krait bites cannot be reversed by antivenin once symptoms are present. Krait-paralyzed patients may need to be ventilated for weeks. • In certain elapid bites anticholinesterases may delay the onset of respiratory paralysis and buy time for antivenin to work.

renal failure, endocrinopathies, and serum sickness reactions from antivenin. Wound care includes debridement of necrotic tissues until clean margins are observed, and daily wound care as for burn injuries. Travelers envenomed by dangerous species should be transported (when stable) to an appropriate medical center for wound evaluation and initiation of physical therapy. Important points regarding snake envenoming are highlighted in Table 48.9. Two New World lizards, the Gila monster and the Mexican beaded lizard (Heloderma), are venomous. These species possess mandibular venom glands which secrete venom into the wounds made by grooved teeth. Deaths from lizard envenoming are rare but have occurred with captive lizards. No antivenin is available for bites by Heloderma lizards.

MARINE ANIMAL BITES AND STINGS Sea urchins, spiny starfish, and fire corals cause many more injuries than marine predators. Sharks are frequently associated with marine attack injuries on humans, but 70 years of age.37,38 Treatment for ASP is symptomatic and supportive.39 Potentially contaminated shellfish, particularly those associated with red tides, should never be eaten.

CONCLUSION Toxin contaminated fish and shellfish are an important but generally avoidable form of poisoning in travelers. Illness may be severe and potentially life threatening. Seafood toxins are not usually detected by taste, smell, or appearance of contaminated food and cannot be destroyed by cooking, smoking, freezing, marinating, or brining. With the exception of scombroid (histamine fish poisoning) there is no effective antidote and treatment is symptomatic and supportive. Many factors are responsible for the increase in cases of seafood poisoning in travelers and effective pretravel counseling is essential. Sensible precautions will prevent most cases. Seafood poisoning is an


important consideration in symptomatic returned travelers and a high index of suspicion is necessary to avoid misdiagnosis. A careful food history is always important. Specific diagnostic tests are not readily available.

REFERENCES 1. Doherty M. Captain Cook on poison fish. Neurology 2005;65:1788–91. 2. Friedman MA, Fernandez M, Backer LC, et al. An updated review of ciguatera fish poisoning: clinical, epidemiological, environmental, and public health management. Mar Drugs 2017;15:72. 3. Lehane L, Lewis RJ. Ciguatera: recent advances but the risk remains. Int J Food Microbiol 2000;61:91–125. 4. Stewart I, Lewis RJ, Eaglesham GK, et al. Emerging tropical diseases in Australia. Part 2. Ciguatera fish poisoning. Ann Trop Med Parasitol 2010;104(7):557–71. 5. Chan TYK. Ciguatera fish poisoning in East Asia and Southeast Asia. Mar Drugs 2015;13:3466–78. 6. Skinner MP, Brewer TD, Johnstone R, et al. Ciguatera fish poisoning in the Pacific Islands (1998 to 2008). PLoS Negl Trop Dis 2011;5:e1416. 7. Lewis RJ. The changing face of ciguatera. Toxicon 2001;39:97–106. 8. Glaziou P, Legrand AM. The epidemiology of ciguatera fish poisoning. Toxicon 1994;32:863–73. 9. Hamilton B, Hurbungs M, Vernoux JP, et al. Isolation and characterisation of Indian Ocean ciguatoxin. Toxicon 2002;40:685–93. 10. Bagnis R, Kuberski T, Langier S. Clinical observations on 3009 cases of ciguatera fish poisoning in the South Pacific. Am J Trop Med Hyg 1979;28:1067. 11. Calvert GM, Hryhorczuk DO, Leikin JB. Treatment of ciguatera fish poisoning with amitriptyline and nifedipine. J Toxicol Clin Toxicol 1987;25:423–8. 12. Davis RT, Villar LA. Symptomatic improvement with amitriptyline in ciguatera fish poisoning. N Engl J Med 1986;315:65. 13. Berlin RM, King SL, Blythe DG. Symptomatic improvement of chronic fatigue with fluoxetine in ciguatera fish poisoning. Med J Aust 1992;157:567. 14. Brett J, Murnion B. Pregabalin to treat ciguatera fish poisoning. Clin Toxicol (Phila) 2015;53:568. 15. Palafox NA, Buenconsejo-Lum LE. Ciguatera fish poisoning: review of clinical manifestations. J Toxicol–Toxin Reviews 2001;20(2):141–60. 16. Palafox NA, Buenconsejo-Lum L, Riklon S, et al. Successful treatment of ciguatera fish poisoning with intravenous mannitol. JAMA 1988;259:2740. 17. Schnorf H, Taurarii M, Cundy T. Ciguatera fish poisoning: a double-blind randomized trial of mannitol therapy. Neurol 2002;58:873–80. 18. Isbister GK, Kiernan MC. Neurotoxic marine poisoning. Lancet Neurol 2005;4:219–28. 19. Perez CM, Vasquez PA, Perret CF. Treatment of ciguatera poisoning with gabapentin. N Engl J Med 2001;344:692–3. 20. Develoux M. A case of ciguatera fish poisoning in a French traveler. Eurosurveillance 2008;6:1–2. 21. Arnett MV, Lim JT. Ciguatera fish poisoning: impact for military health care provider. Mili Med 2007;172(9):1012–15. 22. Hungerford JM. Scombroid poisoning: a review. Toxicon 2010;56: 231–43. 23. Feng C, Teuber S, Gershwin ME. Histamine (scombroid) fish poisoning. Clin Rev Allergy Immunol 2016;50(10):64–9. 24. Lavon O, Lurie Y, Bentur Y. Scombroid fish poisoning in Israel, 2005–2007. IMAJ 2008;789–92. 25. Waldo OA, Snipelisky DF, Dawson LD. 46-year-old man with abdominal pain and hypotension. Mayo Clin Proc 2015;90(1):135–8. 26. Anastasius M, Yiannikas J. Scombroid fish poisoning illness and coronary artery vasospasm. Australas Med J 2015;8(3):96–9. 27. Blakesley ML. Scombroid poisoning; prompt resolution of symptoms with cimetidine. Ann Emerg Med 1983;12:104. 28. Lago J, Rodriguez LP, Blanco L, et al. Tetrodotoxin, an extremely potent marine neurotoxin: distribution, toxicity, origin and therapeutic uses. Mar Drugs 2015;13:6384–406.


SECTION 9  Health Problems While Traveling

29. Kaku N, Meier J. Clinical toxicology of fugu poisoning. In: Meier J, White J, editors. Handbook of Clinical Toxicology of Animal Venoms and Poisons. 1st ed. Boca Raton: CRC Press; 1995. p. 75–83. 30. Centers for Disease Control. Tetrodotoxin poisoning associated with eating pufferfish transported from Japan-California 1996. MMWR 1996;45:389–91. 31. Sobel J, Painter J. Illness caused by marine toxins. Clin Infect Dis 2005;41:1290–6. 32. Gessner BD, Middaugh JP. Paralytic shellfish poisoning in Alaska: a 20-year retrospective analysis. Am J Epidemiol 1995;141:766. 33. Hurley W, Wolterstorff C, MacDonald R, et al. Paralytic shellfish poisoning: a case series. West J Emerg Med 2014;15(4):378–81. 34. Morris PD, Campbell DS, Taylor TJ, et al. Clinical and epidemiological features of neurotoxic shellfish poisoning in North Carolina. Am J Public Health 1991;81:471–4.

35. Milian A, Nierenberg K, Fleming LE. Reported respiratory symptom intensity in asthmatics during exposure to aerosolized red tide toxins. J Asthma 2007;44:583. 36. Fleming LE, Kirkpatrick B, Backer LC. Aerosolized red-tide toxins (bevetoxins) and asthma. Chest 2007;131:187. 37. Peri TM, Bedard L, Kosatsky T, et al. An outbreak of toxic encephalopathy caused by eating mussels contaminated with domoic acid. N Engl J Med 1990;322:1775–80. 38. Teitelbaum JS, Zatorre RJ, Carpenter S, et al. Neurologic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels. N Engl J Med 1990;322:1781–7. 39. Schroeder G, Bates SS, Spallino J. Amnesic shellfish poisoning: emergency medical management. J Marine Sci Res Dev 2015;6:179–82.

50  Injuries and Injury Prevention Stephen W. Hargarten and Tifany Frazer

KEY POINTS • Injuries are a more significant cause of travel-related mortality and morbidity than infectious diseases. • Road traffic crashes are the leading causes of injury mortality and can be prevented by traveling in safe vehicles with seat belts, driven by a qualified driver. Motorcycles and bicycles should be avoided as well as rural travel by road in any vehicle after dark in low-resource countries. Pedestrians are highly vulnerable in unfamiliar environments. • Death by drowning can be avoided by use of personal flotation devices, abstention from alcohol during water-related activities,

and close supervision of children. Fences and safety barriers are often absent overseas. • Data deficiencies and discrepancies in the manner of reporting cause of death have made it challenging to create a profile of injury risk based upon type of tourist, nationality, destination, and travel activity. Better data on injury mortality of travelers (and all causes of mortality) should be maintained, and reviewed by respective embassies and governmental organizations.


tsunamis and earthquakes, airplane crashes, extreme environmental exposures, and animal or marine life bites and stings.2–4 Road traffic crashes have plateaued since 2007 suggesting that recent interventions to improve road safety are effective in addressing mortality.9 Since 2014 five countries have achieved fatality rates of three or less deaths per 100,000 inhabitants: Iceland, Norway, Sweden, Switzerland, and the United Kingdom.2 Conversely, low-income countries have double the fatality rates compared to those in high-income countries.9 Specifically, 90% of road traffic deaths occur in low-income and middle-income countries, yet these countries have just 54% of the globe’s vehicles.9 Nearly half of those dying on the world’s roads are vulnerable road users: pedestrians, cyclists, and motorcyclists.9 In addition to the grief and physical suffering they cause, road traffic crashes result in considerable economic losses to victims, their families, and nations as a whole, costing most countries 1%–3% of their gross national product.9 The Decade of Action for Road Safety (2011–2020) calls on countries to implement the measures identified internationally to make their roads safer. The new target of the United Nations Sustainable Development Goals is to reduce the global number of deaths and injuries from road traffic crashes by 50% by the year 2020.9 The precise number of deaths and proportion of injury deaths of travelers worldwide is not known. Injuries to US citizens traveling internationally occur at a higher proportion than to citizens residing in the United States.4 Injury is also reported to be the cause of deaths among visitors to the United States.10 Figs. 50.1 and 50.2 illustrate mortality data captured by the United States, showing types of injuries and top causes of death for their traveling citizens.11 A review of deaths of Scottish travelers showed trauma and other noninfectious causes being the two most common.12 A study of Finnish travelers identified cardiovascular diseases as the top cause of death.13 Injury deaths occur most commonly in low-income to middle-income America followed by Europe and Eastern Mediterranean countries.3,14

Injuries are one of the leading causes of travel-related mortality worldwide, accounting for up to 25 times more deaths than infectious disease.1 Annually, over 1 million people are killed in car crashes worldwide and several million more are injured during these events.2 Researchers worldwide have reported that noninfectious causes of travel-related deaths, especially injury, pose a serious health risk to travelers.2–6 Injuries to tourists are also a significant burden to hospitals and health care systems—at the tourist destination, during transport, and in terms of continuing care when the patient returns home.7 Tourists tend to be more at risk for an injury because they frequently find themselves in unfamiliar environments and participating in unfamiliar activities.1 Travel to low-resource countries can pose different hazards and outcomes after road traffic crashes or other unintentional injuries and are sometimes more severe with worse outcomes due to limitations in emergency medical systems and health facility resources.3 Injuries are predictable and preventable.3,4,8 It is important for health care providers, travel medicine specialists, tourism professionals, and government agencies issuing travel health advisories to create and communicate evidence-based injury prevention messages tailored for all categories of travelers, travel activities, and travel destinations. This chapter reviews the types of fatal and nonfatal injuries most frequently experienced by travelers, and provides evidence-based prevention and control recommendations.

FATAL INJURY Injury is a leading cause of travel-related mortality worldwide. Most mortality studies report that travelers most frequently die in road traffic crashes and drownings.2 Other causes of travel-related injury death, though less common, include violent events, natural disasters such as


CHAPTER 50  Injuries and Injury Prevention Abstract


Road traffic crashes are the leading causes of injury mortality for travelers. Injuries are a more significant cause of travel-related mortality and morbidity than infectious diseases. Injuries are predictable and preventable. This chapter outlines the injuries that travelers experience and provides injury prevention recommendations for safe travel. This chapter also reviews the types of fatal and nonfatal injuries most frequently experienced by travelers, and provides evidence-based prevention and control recommendations. Specifically, recommendations for road traffic and water safety are outlined. Better data on injury mortality of travelers and all causes of mortality would further strengthen injury prevention recommendations.

Alcohol risk Injury Injury prevention Nonfatal injuries Prevention recommendations Road traffic safety Safety Travel Water-related injuries



SECTION 9  Health Problems While Traveling

3500 Number of deaths

3000 2500 2000 1500 1000 500

th e




cl e

ac ci d r a en cc t id H ent om ic id D Te ro e rro wn ris ing ta Ve ct Ai i hi r ac on cl e c id ac Dr e u ci de g-r nt el nt a -p ed ted es tri M an ar D i iti m sas e t ac er Tr ai cide n ac nt N at ur cid e al di nt sa Ex ste ec r ut U ion n Ar k m no w n H ed co os nf ta li ge -re ct la te d


Cause of Death

FIG. 50.1  Specific injury-related deaths of US citizens traveling internationally, October 2002–December 2016. (US Department of State. Non-natural Deaths of US Citizens Abroad. 2017 Feb 15. Available at https://

traveler’s embassy or consulate in-country is the first action item. Travelers should review their country’s guidance in preparation for travel.

3% 13% 27%

Vehicle accident Other accident Homicide


Drowning Terrorist action 27%

FIG. 50.2  The top five causes of death for US citizens traveling internationally, October 2002–December 2016. (US Department of State. Non-natural Deaths of US Citizens Abroad. 2017 Feb 15. Available at

In each of these regions, US citizens have a greater proportion of injury mortality compared to host county nationals.21 Deaths of European travelers to areas of Thailand have shown natural causes were highest.13,15 Overwhelmingly, young males tend to be at greater risk for an injury leading to death during travel.16 The difficulty in counting and categorizing the causes of death among international travelers has been highlighted by the 2004 tsunami disaster in the Indian Ocean, 2010 Haitian earthquake, 2011 Japanese earthquake and tsunami, the 2015 Nepal earthquakes, and the 2015 and 2016 terrorist attacks in France. The precise mortality count for both locals and travelers from these events may never be known. Each government had a different way to count their citizens’ deaths. Apart from obtaining a visa, travelers tend not to register their trip itinerary with their appropriate home government agency. To be accounted for in the event of disaster, travelers may register their travel dates and locations with their own governmental agencies like the Smart Traveler Enrollment Program provided by the US Department of State.17 In the event of a fatality, contacting the

NONFATAL INJURIES Studies focusing on nonfatal health incidents are also important to gain a more complete understanding of the larger travel injury problem. Morbidity studies often rely on data captured by hospital inpatient admissions or emergency department data in a specific geographic locale. These types of studies can reveal injury patterns for a given location, depending upon type of tourist and popular tourist activities at the destination. A review of hospital records in Jamaica showed that injury was the main cause of hospitalization for international tourists, especially among tourists 4-hour duration following which 53 confirmed venous thromboses occurred. This led to a risk estimate of 1 per 4656 travelers (95% CI 1/7526–1/3163). For long-haul travel compared to not flying, the risk of thrombosis remained 3.2 times increased over an 8-week time window, after which time the risk returned to normal levels. The risk of thrombosis increased sharply with the duration of the flight, up to 1 per 1200 travelers for flights >16 hours. Those who made several flights within the 8-week time window also had increased risks.

FACTORS INFLUENCING THE RISK Passenger-Related Risk Factors As VT is a multicausal disease, it occurs due to a specific set of risk factors that are present simultaneously in an individual, with each of these factors affecting the probability of disease. Hence the term “travelers’ thrombosis” is not really appropriate, as an event occurring after air travel will have been caused in part by the flight, but other risk factors must also have been present, otherwise air travel would lead to thrombosis in every passenger. Therefore it can be useful to study additional risk factors in passengers with the aim of identifying high-risk groups. The first to describe two of these high-risk groups were Martinelli et al. in 2003, who found a 16-fold increased risk in subjects with factor V Leiden (FVL; a common genetic risk factor for VT), and a 14-fold increased risk for women using oral contraceptives, all compared to nonflying subjects without these risk factors.17 To study the effect of surgery on risk of travel-related thrombosis, 220 patients who flew shortly after total joint replacement were compared with 1245 such patients who did not fly. No differences in rate of VT were found, but this study may have been underpowered.18 In the WRIGHT project a large case-control study was carried out in which high-risk groups could be identified. Among 1906 patients with a first DVT or PE and 1906 controls, an additional increased risk was again found in subjects with FVL and in contraceptive pill users.19 Furthermore it was found that in tall individuals (>1.90 m) the risk of thrombosis after air travel was increased ninefold compared to individuals of average height who did not travel. This finding can be explained by the fact that tall people are subjected to even more cramped seating. Interestingly, short people also had a fivefold increased risk compared to people of average height. This finding is also biologically plausible because these people’s feet generally cannot touch the floor of the cabin when seated, leading to extra compression of the popliteal veins (Table 52.1). In the same study it was described that certain combinations of risk factors strongly increased the risk of VT; overweight women using oral contraceptives, for example, had a 60-fold increased risk after a long-haul flight, compared to nonflying women without these risk factors (Table 52.2). Please note that the odds ratios (OR) in this table are calculated from flying subjects. To determine the risk compared to nonflying individuals, the results should be multiplied by the relative risk of air travel (i.e., 2–3).20 In a case-control study based on records of general practices in the United Kingdom, most of the findings described above were confirmed. The risk increased with longer duration of the flight, and was particularly high when the patient had had surgery shortly before air travel, had a history of VTE, or was obese, with the highest risk when a combination of these factors was present (estimated risk of 1 in 60 following a flight >4 hours in obese patients with recent surgery).21


CHAPTER 52  Travelers’ Thrombosis TABLE 52.1  The Combined Effect of Other Risk Factors and Travel on the Risk of Venous

Thrombosis (DVT, PE, and Both; 1906 Pairs) Risk Factor


Factor V Leiden

− − + + − − + + 30 Height (m)

1.60–1.90 1.90

95% CI 1.3–3.7 2.3–4.1 2.7–24.7 1.3–3.7 1.6–4.1 0.3–36.6 0.8–2.6 1.2–1.7 2.1–6.3 1.4–2.1 3.6–27.6 1.5–3.7 0.5–0.9 0.3–2.8 0.7–1.1 1.4–15.4

Air Travel


− + − + − + − + − + − + − + − + − + − +

1 2.0 3.0 13.6 1 2.2 2.7 7.9 1 2.0 1.4 2.1 1.7 2.6 1 1.5 0.7 4.9 0.9 6.8

95% CI 1.0–3.9 2.3–4.0 2.9–64.2 1.3–3.6 1.7–4.4 0.9–67.2 1.0–4.1 1.2–1.7 1.0–4.4 1.3–2.1 1.0–6.4 0.9–2.8 0.5–0.9 0.9–25.6 0.7–1.2 0.8–60.6

Travel indicates journey by train, car, bus, or airplane lasting >4 h within the 8 wk before venous thrombosis, or corresponding index for control individuals. BMI, Body mass index; CI, confidence interval; DVT, deep vein thrombosis; OR, odds ratio; PE, pulmonary embolism. From Cannegieter SC, Doggen CJ, Houwelingen HC, et al. Travel-related venous thrombosis: results from a large population-based case control study (MEGA Study). PLoS Med 2006;3:e307. doi:1.0.1371/journal.pmed.0030307.t003.

TABLE 52.2  Odds Ratios for Venous Thrombosis for Combinations of Risk Factors FII FVIII FVL OC BMI Fam†





2.2 (1.3–3.7) 7.9 (3.4–18.3) 17.5 (2.3–135) 4.6 (1.1–19.8) 9.5 (3.6–25.1) 2.4 (0.9–6.1)

6.2 (3.6–10.5) 24.7 (4.4–139) 51.7 (5.4–198) 18.6 (7.0–49.9) 8.7 (3.5–21.7)

4.5 (1.9–10.4) 18.3 (2.0–171) 20.5 (2.5–170) 4.7 (1.7–16.5)

5.0 (2.1–12.1) 31.4 (3.0–334) 10.7 (1.5–75.6)


1.9 (1.4–2.7) 2.4 (1.0–5.8)


1.7 (1.0–2.9)

FVL indicates factor V Leiden mutation; OC, oral contraceptive use; BMI, body mass index >26.9 kg/m2 compared to a BMI of 30 kg/m2), the risk was sixfold increased. Anxiety or sleeping during flying slightly increased the risk, but drinking alcohol did not. Traveling business class appeared

to be associated with a slightly reduced risk that obviously can be attributed to the less cramped conditions.

MECHANISM Immobilization and venous stasis lead to thrombosis owing to impairment of the function of the calf musculature in pumping the blood upstream. Circumstances related to immobilization, such as bed rest and plaster casts, are well-known risk factors for thrombosis, but the contribution of general disease or damage to veins after a fracture will also have an effect. Immobilization as a risk factor per se has been described in the Second World War, when an increased


SECTION 9  Health Problems While Traveling

incidence of PE was observed during the bombardment of London, when people sought shelter in the underground railway system where they sat in chairs for long periods.24 A more recent case of thrombosis related to immobilization was described as “e-thrombosis” in a young man with a serious PE without any known risk factor for VT, who appeared to spend more than 12 hours per day sitting at his computer.25 That immobilization is an important explanation for travel-related thrombosis can be inferred from the finding that traveling by other modes (car, bus, train) also increases the risk, although to a lesser extent. Furthermore, the additional increased risk observed in tall, short, and obese people is also most likely due to impaired flow in cramped conditions. Nevertheless it has been suggested that other factors may attribute to the increased risk, such as dehydration or the hypobaric circumstances in the cabin. In a Norwegian study at high altitude (similar to levels in an aircraft) an effect of hypobaric hypoxia on the coagulation system was described for the first time,26 although later studies disputed these results.27,28 In the WRIGHT project the effect of an actual flight on the coagulation system was studied. Seventy-one young volunteers were exposed to an 8-hour flight with two control exposure situations: 8 hours of immobilization in a cinema and 8 hours in a daily life situation, separated by 2 weeks or more.29 The volunteers had been selected in such a way that a substantial proportion had FVL, half of whom also took oral contraceptives. Thrombin formation (the end product of the coagulation system) could be demonstrated in 17% of the participants after the flight, whereas this was the case in only 3% and 1% in the cinema and the daily life situation, respectively. Of the persons in whom such coagulation activation could be demonstrated, the largest part had the FVL mutation and used oral contraceptive pills. The results of this experiment suggest that circumstances in the airplane contribute to thrombus formation. Although other studies found opposing results, one of these circumstances could be hypobaric hypoxia, as it is possible that hypobaric hypoxia only has an effect in subjects in whom a slight procoagulant tendency is already present, such as people with FVL and oral contraceptive pill users. The other studies were all performed in subjects without risk factors. The effect of other cabin-related factors, such as stress, dehydration, virus infection, or air pollution, was also studied in the WRIGHT project. With respect to dehydration, no association was found between the amount of nonalcoholic beverages that the volunteers had drunk and hematocrit, or with osmolality.30 Furthermore, changes in parameters of fluid loss during the flight were not different in volunteers with an activated clotting system from those without. Overall, the results of several laboratory markers suggested that hypoxia was a more likely explanation than any of the others.31 Interestingly, a recent study in mice suggests that augmented calpain activity is associated with a prothrombotic tendency and increased risk of thrombosis under hypoxic environments.32

PREVENTION Although the absolute risk of a symptomatic thrombotic event is only moderately increased (1 in 4500 passengers), many travelers will still develop thrombosis; considering the large yearly number of air travelers (over 2 billion per year), this leads to a total of 150,000 extra cases per year. Since each case of thrombosis is associated with considerable morbidity and a risk of death of several percent, attempts to prevent this complication should be worthwhile. However, preventive measures will be effective in only a very small proportion of travelers; based on a risk of 1 in 4500, 4500 people need to be treated to prevent one event, using a treatment that is 100% efficacious (number needed to treat). For this reason preventive measures with side effects should not be

considered for indiscriminate use. This means that prevention by pharmacologic means (such as by LMWH or aspirin) that carry a bleeding risk is not advisable as a general preventive strategy. An alternative is mechanical prevention by the use of elastic stockings or calf compression devices. Elastic stockings prevent edema and have been shown in other risk situations to reduce thrombotic risk. From a biological viewpoint however, it is unlikely that stockings have much effect in the absence of leg muscle movement. In a recently updated Cochrane review that focused on asymptomatic clots detected by ultrasound, a decrease in such clots was observed in those wearing graduated compression stockings.33 The combined results of 11 randomized trials showed a strong reduction of asymptomatic DVT (OR 0.10; 95% CI 0.04–0.25). No data on the effect of stockings on symptomatic events are available. Elastic stockings should exert a pressure that is graded from distal to proximal, and therefore should be fitted individually. It is highly implausible that the one-size-fits-all “traveler socks” that are sold over the counter at airports have any effect in preventing thrombosis. An alternative to offering preventive measures to all passengers is to focus only on high-risk groups. This would lead to smaller numbers to treat and a better risk-benefit ratio. Some high-risk groups have already been identified, but no intervention studies have been performed to determine whether prevention of a thrombotic event outweighs the bleeding risk. In the absence of such evidence, caution should be used in prescribing any prophylaxis beyond exercise. However, although this has not been studied, patients who have a history of VT are at the highest risk of thrombosis during air travel considering their risk of recurrence of 3% per year.3 In these patients, prophylaxis with LMWH may be justified on theoretical grounds. There are guidelines, such as those that have been published by the British Thoracic Society, that include so-called commonsense advice (i.e., avoidance of alcohol, liberal intake of nonalcoholic beverages, and regular exercise of the legs).34 As it is not very likely that dehydration plays a role in the development of thrombosis, the liberal intake of beverages probably has no major effect on prevention. However, it is plausible that regular movement of the legs will be beneficial. Obviously exercise is also without a risk of side effects. Guidelines published by the American College of Chest Physicians35 additionally advise properly fitted compression stockings (providing 15–30 mmHg of pressure at the ankle) and aisle seating for flights >8 hours in the presence of a moderately strong risk factor for VT. For high-risk patients (those with a history of VT, major surgery within 6 weeks, and known malignancy) both guidelines recommend or provide consideration for LMWH injection before departure. LMWH is not necessary in those already on oral anticoagulants. Aspirin alone is never recommended as prophylaxis, as there is no evidence showing substantial benefit, while it does increase the risk of major hemorrhage.

CONCLUSIONS AND RECOMMENDATIONS A long-haul flight increases the risk of VT about threefold. In absolute terms the risk is about 1 in 4500 long-haul passengers over a period of 8 weeks. The risk becomes higher with increasing duration of the flight and with making several flights in a short time frame. Several high-risk groups are known (i.e., tall, short, and obese people, as well as people with a genetic predisposition [e.g., FVL], oral contraceptive users, and patients with cancer or who underwent recent surgery). People with a history of VT are considered to be a particularly high-risk group on theoretical grounds. In most passengers, prevention can be limited to encouraging exercise and discouraging behavior that will restrict movement, such as excessive alcohol intake and any use of sleeping medication, which tends to keep

CHAPTER 52  Travelers’ Thrombosis passengers immobile for 5 hours or more. There is a need for studies into the efficacy and safety of preventative measures in high-risk individuals. Until such data are available, patients perceived to be at high risk (subjects with a history of VT, known malignancy, or recent surgery) may benefit from a short period (1–3 days) of LMWH therapy starting 6–12 hours before the flight.

REFERENCES 1. Kuipers S, Schreijer AJM, Cannegieter SC, et al. Travel and venous thrombosis: a systematic review. J Intern Med 2007;262:615–34. 2. Chandra D, Parisini E, Mozaffarian D. Meta-analysis: travel and risk for venous thromboembolism. Ann Intern Med 2009;151:180–90. 3. Naess IA, Christiansen SC, Romundstad P, et al. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007;5:692–9. 4. Wendelboe AM, McCumber M, Hylek EM, et al. ISTH Steering Committee for World Thrombosis Day. Global public awareness of venous thromboembolism. J Thromb Haemost 2015;13:1365–71. 5. ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to the global disease burden. J Thromb Haemost 2014;12:1580–90. 6. Christiansen SC, Cannegieter SC, Koster T, et al. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA 2005;293:2352–61. 7. Ashrani AA, Heit JA. Incidence and cost burden of post-thrombotic syndrome. J Thromb Thrombolysis 2009;28:465–76. 8. Ende-Verhaar YM, Cannegieter SC, Vonk Noordegraaf A, et al. Incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: a contemporary view of the published literature. Eur Respir J 2017;49:1601792. 9. Becattini C, Agnelli G, Pesavento R, et al. Incidence of chronic thromboembolic pulmonary hypertension after a first episode of pulmonary embolism. Chest 2006;130:172–5. 10. Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257–64. 11. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999;353(9159):1167–73. 12. Sarvesvaran R. Sudden natural deaths associated with commercial air travel. Med Sci Law 1986;26:35–8. 13. Lapostolle F, Surget V, Borron SW, et al. Severe pulmonary embolism associated with air travel. N Engl J Med 2001;345:779–83. 14. Perez-Rodriguez E, Jimenez D, Diaz G, et al. Incidence of air travel-related pulmonary embolism at the Madrid-Barajas airport. Arch Intern Med 2003;163:2766–70. 15. Schwarz T, Siegert G, Oettler W, et al. Venous thrombosis after long-haul flights. Arch Intern Med 2003;163:2759–64. 16. Kuipers S, Cannegieter SC, Middeldorp S, et al. The absolute risk of venous thrombosis after air travel: a cohort study of 8,755 employees of international organisations. PLoS Med 2007;4:e290. 17. Martinelli I, Taioli E, Battaglioli T, et al. Risk of venous thromboembolism after air travel: interaction with thrombophilia and oral contraceptives. Arch Intern Med 2003;163:2771–4.


18. Cooper HJ, Sanders SA, Berger RA. Risk of symptomatic venous thromboembolism associated with flying in the early postoperative period following elective total hip and knee arthroplasty. J Arthroplasty 2014;29:1119–22. 19. Cannegieter SC, Doggen CJ, van Houwelingen HC, et al. Travel-related venous thrombosis: results from a large population-based case control study (MEGA Study). PLoS Med 2006;3:e307. 20. Kuipers S, Cannegieter SC, Doggen CJ, et al. Effect of elevated levels of coagulation factors on the risk of venous thrombosis in long-distance travelers. Blood 2009;113:2064–9. 21. MacCallum PK1, Ashby D, Hennessy EM, et al. Cumulative flying time and risk of venous thromboembolism. Br J Haematol 2011;155:613–19. 22. Kuipers S, Venemans A, Middeldorp S, et al. The risk of venous thrombosis after air travel: contribution of clinical risk factors. Br J Haematol 2014;165:412–13. 23. Schreijer AJ, Cannegieter SC, Doggen CJ, et al. The effect of flight-related behaviour on the risk of venous thrombosis after air travel. Br J Haematol 2009;144:425–9. 24. Simpson K. Shelter deaths from pulmonary embolism. Lancet 1940;2:744. 25. Beasley R, Raymond N, Hill S, et al. eThrombosis: the 21st century variant of venous thromboembolism associated with immobility. Eur Respir J 2003;21:374–6. 26. Bendz B, Rostrup M, Sevre K, et al. Association between acute hypobaric hypoxia and activation of coagulation in human beings. Lancet 2000;356:1657–8. 27. Toff WD, Jones CI, Ford I, et al. Effect of hypobaric hypoxia, simulating conditions during long-haul air travel, on coagulation, fibrinolysis, platelet function, and endothelial activation. JAMA 2006;295:2251–61. 28. Crosby A, Talbot NP, Harrison P, et al. Relation between acute hypoxia and activation of coagulation in human beings. Lancet 2003;61:2207–8. 29. Schreijer AJ, Cannegieter SC, Meijers JC, et al. Activation of coagulation system during air travel: a crossover study. Lancet 2006;367:832–8. 30. Schreijer AJ, Cannegieter SC, Caramella M, et al. Fluid loss does not explain coagulation activation during air travel. Thromb Haemost 2008;99:1053–9. 31. Schreijer AJ, Hoylaerts MF, Meijers JC, et al. Explanations for coagulation activation after air travel. J Thromb Haemost 2010;8:971–8. 32. Tyagi T, Ahmad S, Gupta N, et al. Altered expression of platelet proteins and calpain activity mediate hypoxia-induced prothrombotic phenotype. Blood 2014;123:1250–60. 33. Clarke M, Broderick C, Hopewell S, et al. Compression stockings for preventing deep vein thrombosis in airline passengers. Cochrane Database Syst Rev 2016;(9):CD004002. 34. Ahmedzai S, Balfour-Lynn IM, Bewick T, et al. British Thoracic Society Standards of Care Committee. Managing passengers with stable respiratory disease planning air travel: British Thoracic Society recommendations. Thorax 2011;66(1):S1–30. 35. Kahn SR, Lim W, Dunn AS, et al. American College of Chest Physicians. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2):e195S– e226S.

53  Health Care Abroad William L. Lang

KEY POINTS • The prepared traveler will depart home with a plan on how to access medical care at the destination, should the need arise. • Telemedicine, both for medical advice and for medical translation, is an increasingly important tool for travelers seeking medical support abroad. • The Joint Commission International is certified as a World Health Organization Collaborating Center and accredits hundreds of medical facilities in approximately 70 countries around the world, providing travelers with a reliable indication of reasonable quality. • Emergency evacuation or repatriation to the home country is often not the best course of action as competent stabilization is increasingly available locally, at least in major cities. • For those with complex medical problems or allergies, Internet-accessible medical records or records carried on a portable USB thumb drive may prove life saving.

INTRODUCTION* International travelers place themselves at greater risk for illness or injury than those remaining at home living their normal lives.4 Whether destination related, due to inadequate preparation, connected to risky behavior, or all these, the traveler usually views travel-related illness as surprising, uninvited, and intrusive. The frightening qualities of any medical event can be greatly amplified in an unfamiliar country, particularly if the traveler does not speak the local language and is not conversant with local health beliefs, customs, or expectations. Consequently, the first reaction to anything other than minor illness is often to try to “get home.” When problems do occur during international travel, however, even in less-developed countries, travelers (or long-term expatriates) need not assume they must return home to receive adequate medical care. As our world is changing, even in poor countries, wellequipped private medical facilities with well-trained staff often exist to serve the more affluent segment of the society. Overlooking or prejudging such readily available options may be dangerous and costly. Still, assessing these possibilities can prove a daunting task. In developed nations, the familiar mechanisms in place to access care have caused many to neglect to consider the entire spectrum of care available to them. In international locations, the availability of parts of this spectrum can be vastly different, so it is important to keep in mind the entire range of sources of care, from self-care to medical evacuation, in determining where to seek care when care is needed (Box 53.1). *This chapter is adapted from the similar chapter in the second edition by Dr. Nicholas Riesland.

• A list of physicians at many destinations is available from nonprofit entities, such as embassies or the International Society of Travel Medicine (, and an increasing number of membership sites, such as International Association for Medical Assistance to Travelers (IAMAT; • Many hospitals do not accept insurance from other countries and require sizable upfront cash payment prior to admission or treatment. • Medical insurance for long-stay travelers should be renewable from abroad, include hospitalization coverage with direct payments to the facility, cover preexisting conditions, include repatriation of mortal remains, and include evacuation. • Counterfeit medications are common abroad.

Risks of Needing Care Abroad The epidemiology of travel-related illness is covered in Chapter 2 and in multiple careful studies over the past several decades.1–3 Travel destination and duration are important determinants of risk. The developing world, especially, is associated with travel-related illness and risk of injury compared with travel elsewhere. Unfortunately, often the locations with higher risk are also those with less capable medical services.

FACTORS INFLUENCING DEVELOPMENT OF HEALTH CARE ABROAD Continued Globalism of Quality The most recognizable international quality certification group is The Joint Commission International (JCI). As of late 2017, JCI (founded in 1999 and certified as a World Health Organization [WHO] Collaborating Center) accredits over 1000 programs worldwide, not including major international health destinations such as the United States and Canada.5 Not only does JCI accredit specific programs but it also works with health care organizations, ministries of health, and global organizations in over 80 countries to push for greater acceptance of and adherence to common quality measures worldwide.6 In the last several years, other major regional accrediting organizations have initiated international accrediting and quality assistance programs, many under the auspices of the International Society for Quality in Health Care (ISQua), an accreditor of accreditors, which provides international frameworks for quality assistance and assessment worldwide.7 Since 2012, a number


CHAPTER 53  Health Care Abroad Abstract


International travelers should ensure they plan for the possibility of requiring health care while traveling. A risk and resources assessment prior to travel will help travelers ensure they have the key knowledge and can obtain the right risk management resources, such as travel and/or evacuation insurance before departure. Additionally, travelers from developed nations should be aware of the differences in medical services, culture, and limitations in destination countries so they are better prepared as consumers of services and better able to participate in the health services decision process up to and including the need to be medically evacuated.

Emergency care abroad Evacuation insurance Medical intelligence Medical tourism International health services Travel insurance



SECTION 9  Health Problems While Traveling

BOX 53.1  Spectrum of Acute Care

Available Overseas

• Self-care First aid to oneself administered using supplies and medications that are either brought with the traveler or available over the counter • Buddy care Similar to self-care, but involving a traveling companion to obtain and administer first aid or comfort care • Remote medical advice/teleconsultation Still using self-transported or locally available over-the-counter supplies and equipment to deliver care based on the assessment and recommendation of a health care professional remote from the traveler • Telehealth Itself a spectrum of services, but generally involving some degree of telepresence (video teleconferencing, remote diagnostic equipment, telemetry) enhancing the ability of the remote health care provider to diagnose health issues and direct treatment often done in conjunction with a local provider as a provider-to-provider consultation • Primary care provider Office (or mobile)-based care with ability to provide physical exam and, usually, basic laboratory services, but with limited treatment ability beyond prescribing medications and simple treatment modalities; can be enhanced by combination with telemedicine consultation • Rural “hospital” Typically staffed by primary care physicians but with the addition of (often limited) nursing services. Diagnostic and treatment capabilities are extremely variable, but typically very limited in developing nations • Multispecialty clinic or polyclinic Typically, a fee-for-service private clinic with multiple specialties and diagnostic (laboratory/imaging) capabilities located either onsite or close by; usually do not have inpatient capabilities but often have treatment areas for managing minor injuries or stabilizing acute medical conditions • Community hospital “Generalist”-based hospital focused on general internal medicine and general surgery for syndromes requiring surgical or inpatient care; typically with a primary care–based emergency room or urgent care facility • General hospital Greater availability of specialists but limited, if any, subspecialty services; specialized emergency department typically available; capable of stabilizing most illness or injury not requiring immediate subspecialty intervention (e.g., invasive cardiology, neurosurgery) • Medical center Highest level of care; greatest degree of subspecialist availability, including definitive management or, at least, intermediate stabilization of all medical, surgical, or traumatic emergencies; note the term “medical center” can refer simply to a cluster of medical practices or services rather that a referral inpatient institution

of hospitals and systems, especially in the Middle East and Asia, have chosen accreditation by the Australian Council on Healthcare Quality, a member of ISQua and another reliable indicator of care quality for facilities.8 This does not mean that high-quality care is available everywhere, but it does mean that there is an effective global effort to promote high-quality care, so travelers should not assume that they must travel to the more traditionally recognized locations to obtain good care especially in urgent situations.

Growth of Medical Tourism The last two decades have seen significant shifts in health care services available internationally. With the continued improvement in international

health care quality, the movement toward bidirectional medical tourism has increased. It is still very common for patients from medically less experienced locations to seek care at recognized centers of excellence in the United States, Europe, and selected locations in Asia, but increasing numbers of travelers from developed nations are traveling abroad for services.9 While there are always disputes in the absolute numbers of “medical tourists” internationally, recent estimates put the international market for medical tourism at US $45.5–72 billion.10 While cost is clearly a driver for those seeking care outside of what are typically thought of as medically advanced locations, quality of care is also a determinant when a patient chooses to seek care abroad.10–13 The importance of medical tourism in consideration of care abroad more generally is that the demand generated by medical tourism is a major driver for increased quality of care measured against common health-quality metrics worldwide (e.g., access, infection rates). See Chapter 39 for an expanded discussion on medical tourism.

OBTAINING CARE WHILE ABROAD Critical Incident Management Principles The basic principles of handling any critical incident, including health issues, are preparation, protection, response, mitigation, and recovery. For consideration of obtaining care abroad, the two key components of this paradigm are preparation and response. This chapter addresses a key component of preparation in that adequate preparation and understanding of resources available will allow for the optimal response should an event occur. The other portions of the spectrum are covered throughout this book.

Preparation.  Preparation is the base on which eventual successful outcomes are built. This requires the traveler to perform a risk-based analysis of what situations may reasonably require care, and then to ensure a plan is in place for such care that considers resources available. Risk considerations.  A basic concept about the need for care while traveling is that “common things happen commonly.” Analysis of medical claims data for international travelers indicates that three of the four most common issues are back pain, gastroenteritis, and upper respiratory disease.11 They all lend themselves well to care at the lower end of the care spectrum (self-care, remote consultation/telemedicine), at least initially. The use of these care modalities is predicated on pretravel planning to have an appropriate medical kit at hand and, possibly, access to an appropriate source of remote care. The fourth major syndrome or issue is systemic febrile illness, which in some areas of the world, including sub-Saharan Africa and Southeast Asia, is the most common syndrome group.12 These febrile syndromes can often but not always require more complex diagnostic or therapeutic activities than can be easily accomplished by self-care or remote care, although remote diagnostics combined with telemedicine are changing this for initial management. The two most important categories of deaths abroad, which are a proxy for serious conditions requiring advanced care, are consistently shown to be cardiovascular events and trauma.13,14 While initial care for these critical situations is limited to what is available in the vicinity of the event, given that time is of the essence in both situations, it is important to know the best local source of care for each reasonably possible injury or condition.

Health Care Resources.  As noted, the systems available for health care support of travelers have changed greatly in this century. At the same time, the available systems are extremely variable around the world, although there are some general categories of sources of care travelers should understand.

CHAPTER 53  Health Care Abroad Self-care or buddy-care.  Self-care or buddy care is an important source of care when abroad. In many places in the world, entering the formal care system can be difficult and time consuming and can be fraught with dangers such as infectious disease or over-exposure to radiation. Where it is appropriate to care for oneself, either directly or with the assistance of remote medical advice, this important option should not be overlooked. Often international medical/evacuation insurance (see insurance discussion, later) comes with access to nurse or physician advice services, but these interventions will be much more effective if the traveler has access to basic diagnostic and treatment items from a standard travel medical kit. Telemedicine services.  The past decade has seen immense changes in international communications which has prompted an explosion in telemedicine services. Today in urban areas worldwide, Internet service is ubiquitous, meaning that with minimal prior planning, international travelers can easily and with little cost reach back to the usual source of care in their home country. The specific mechanisms for delivery of telemedicine services are changing rapidly. Today most primary care providers have some type of online health record access, which is a first step. Some include access to tele-urgent care. Additionally, many insurers, especially those providing some aspect of travel health insurance, are providing access to urgent care or care coordination services, either online or through an international call center. Local physician offices/clinics.  In many parts of the world the best place to obtain other-than-emergency care is a local physician’s office, as long as you have a way of knowing which of the available physicians is reliable. In many cases, local physicians group themselves into polyclinics, which can function almost as small hospitals. Catering to paying patients, these multispecialty polyclinics are frequently equipped to manage or stabilize minor trauma and medical urgencies. These clinics can often be identified through local residents or hotels. In many cases embassies can provide listings of providers with whom they have had acceptable interactions in the past, although for obvious political and diplomatic reasons, the embassies are usually very careful not to recommend one source of care over another.15 Instead, they will quietly omit from their list sources of care that have had reported problems in the past. Providers of travel health insurance are also increasingly tracking networks of providers and may be able to arrange an in-person visit in combination with tele-consultation to a physician in their network.16 For-profit international health care organizations.  As the international travel market has grown, so too has the demand for health care in a manner similar to what travelers would find at home. Responding to this market, for-profit international medical assistance organizations, including both insurance-based providers and companies typically thought of as evacuation providers, have established clinics focusing on care for travelers from developed nations. Although these services are designed for patients who have presubscribed to their traveler programs, they are typically willing to take any patient willing to pay cash. These clinics provide an atmosphere akin to a developed nation health clinic, have providers who are either expatriates or trained in a developed nation environment, and who have specialized local knowledge of local health systems and key people so that higher levels of care can be facilitated. In some cases, agreements with local health authorities require that the actual hands-on care be delivered by local staff, but even in these situations the close involvement of international staff, both at the clinic level and in helping to monitor and coordinate more advanced care, can help provide an effective outcome.16,17 Foreigners’ clinics.  Many hospitals abroad, especially in major cities, have emergency departments that are overwhelmed by the volume of local patients seeking care, many of whom do not have resources to pay for care. Recognizing the importance of international business travel and tourism, as well as the need for paying patients, in many developing


nations major hospitals have clinical areas dedicated to caring for international (paying) patients. In most cases, these clinics will provide more attentive care than is provided to the general population. Additionally, providers in these clinics are usually local and focus on managing any problems locally, without early consideration of evacuation as possibly the best option. It is very difficult to make general statements about the use of these clinics, as some can be very good whereas others are simply whitewash on a very underresourced capability. Pretravel research addressing which facilities are more acceptable, or pretravel establishment of access to just-in-time medical facility/provider information, is critical to making the right decision should care be needed. Hospital care.  The developed world has seen a consolidation of hospitals in the past 20 years, with a significant reduction in “boutique” facilities and smaller hospitals.17 This has meant that many travelers from developed nations are accustomed to going to any hospital and expecting to receive urgent or emergency care. In the developing world, however, there is still a significant presence of specialty hospitals. Often these specialty hospitals cannot provide urgent or emergency care services. Additionally, the presence of the specialty hospital system can result in a “balkanization” of care such that the specialists see problems only through their own lens. One illustration from the experience of a previous author of this section comes from a large city in the former Soviet Union involving a 58-year-old man with chest pain. He was taken by ambulance to a large cardiology hospital, diagnosed as having an acute coronary syndrome, and started on thrombolytic therapy (streptokinase). During treatment he developed gastrointestinal hemorrhage, severe enough to require transfer to a gastrointestinal hospital. The bleeding was adequately treated, but he developed a fever and was sent to an infectious disease hospital. Owing to blood loss, however, renal failure ensued and he was then taken to a nephrology center on the other side of town. After several days, he became progressively dyspneic and was diagnosed with heart failure, prompting transfer back to the cardiology hospital where care had been initiated. The important message here is that patients should attempt to ensure they have someone overseeing their care with the “50,000-foot” view of the clinical progress, all of the resources available locally, and the options for evacuation to more comprehensive sources of care.

Planning for and Accessing Care.  With a basic familiarity of the risks of requiring health care abroad and the types of care that may be available in any given location, the importance of advance planning for the specific travel destination becomes evident. Box 53.2 outlines key issues every traveler should address to be medically prepared for travel. Foremost among these are consideration of purchasing an evacuation insurance plan and having the ability to provide some self-care. Self-care.  At the most basic level, travelers to medically underserved areas should prepare for as much self-care as is reasonable, given their risk tolerance, experience, and the availability of communications to reliable medical consultation. While international communications have become reliable and relatively low cost over the past decade, communications are only effective if the source of care is available around the clock. For this reason, many travelers choose to subscribe to medical assistance plans that combine 24-hour care call-in lines with aid in managing more complex care, including access to care and evacuation assistance. Medical assistance plans.  Typically known as evacuation insurance plans, medical assistance plans are offered by multiple international providers at competitive prices. The US State Department maintains a list of both US- and foreign-based travel, medical, and evacuation insurance providers at health/insurance-providers.html.18 These plans can typically be purchased


SECTION 9  Health Problems While Traveling

at reasonable expense covering a specific trip or extended expatriate assignment. Business travelers should consult with their organization, as these plans are often provided by organizations. Importantly, travelers should consider the specific offerings following the suggested questions in Box 53.3, and keep in mind that these policies are often very different than typical health insurance programs in countries of residence. In recent years, some major standard medical insurance companies have developed programs for travel insurance/assistance to their policy holders, so travelers with standard health insurance should

BOX 53.2  Key Points Every Traveler

Should Consider

• Understand differences in insurance between: Standard health insurance Travel health insurance Evacuation insurance Medical evacuation Security evacuation • Know types of places to seek care abroad: “Accident and emergency” (A&E) wards of hospitals Foreigners’ wards of hospitals Stand-alone “foreigners’ clinics” Doctors’ offices • Know how to find reliable sources of care and limitation of each method: Referrals from insurance companies Embassy physician lists Commercial subscription services (e.g., Travax) Hotel referrals Travel review sites (e.g., Lonely Planet, Trip Advisor) with caveats • Medication issues: Have copy of prescription Carry medicines in original pharmacy containers Be aware of any importation restrictions (e.g., narcotics, decongestants) Be wary of counterfeit medications

talk to their provider as part of their travel preparation information gathering. Other resources for locating care.  If travelers elect not to use a medical assistance organization or plan to use their home-based care organization for assistance, they still need to have a mechanism for identifying higher level sources of care should self-care or assisted self-care be inadequate. Although embassy clinics are usually not accessible to nongovernment travelers, embassies can still provide valuable information about local health risks and available health care resources for foreigners. For example, the American Citizen Services branch of the US Embassy keeps and makes available upon request updated lists of local medical facilities and clinics deemed reliable. Usually these lists do not indicate which facilities or consultants are preferred, however. Lists of potential sources of care are often available via Internet searches. Travelers and providers must be careful about relying too heavily on the recommendations found on the Internet, as it is very easy to “plant” favorable or unfavorable comments about certain facilities or providers. A number of global organizations maintain medical capability databases, drawing from their collective assessments of and experiences with local medical facilities and providers throughout the world. Proprietary publishing companies such as Shoreland, Inc. market products (e.g., Travax) that facilitate such information exchange among selected subscribers. The travel insurance companies listed on the US State Department website previously referenced may be able to provide assistance in locating local care through their networks of providers. In any event, these tools help determine whether an inpatient or ambulatory medical care provider in a particular overseas city is “adequate” or “preferred” for a specific diagnosis. Such data can assist in deciding where to go for initial care, when local resources are likely to be exceeded, whether resources should be committed to medical evacuation and, if so, help determine the closest suitable destination. Hotel doctors, whose main qualifications may be political or via family connections, often have tenuous reputations among peers in the local health care system. Still, in serious medical situations they may be able to move things in the proper direction. Note, however, that hotel doctors often receive some type of “referral fee” when they send

BOX 53.3  Assessing Travel Insurance Policies When assessing a travel health insurance plan, ask if it: • provides continuous coverage before departure and after return • offers coverage renewable from abroad and for the maximum period of stay • has an in-house, worldwide, 24-hour/7-day emergency contact number in your native language and/or translation services for health care providers in your destination country • includes access to medical advisory services while traveling (i.e., some form of telehealth) • pays for foreign hospitalization for illness or injury and related medical costs (treatment for some injuries may exceed $250,000) and, if so, whether it has provision to pay up front (or guarantee payment) or expects you to pay and be reimbursed later • provides coverage for doctors’ visits and prescription medicines • provides direct payment of bills and cash advances abroad so you don’t have to pay out of your own pocket • covers preexisting medical conditions (when in doubt, get an agreement in writing that you’re covered); otherwise, you could find your claim “null and void” under a preexisting condition clause

• provides for medical evacuation to your home country or the nearest location with appropriate medical care and if the latter, will it pay for follow-on transport home following stabilization • pays for a medical escort (health care provider) to accompany you during evacuation; this service can cost as much as $100,000 if it is not included • covers premature births and related neonatal care, as needed • clearly explains deductible costs (plans with 100% coverage are more expensive but may save money in the long run) • covers preparation and return of your remains to your home country if you die abroad (in most cases, costs will exceed plan coverage) • covers emergency dental care • covers emergency transportation, such as ambulance services • does not exclude or significantly limit coverage for certain regions or countries you may visit.

CHAPTER 53  Health Care Abroad a well-insured traveler to an underfunded clinic or hospital, so there is often a risk of inappropriate hospitalization or use of a less-thanoptimal facility when using the hotel physician. Finding oneself in a local hospital at the hands of a young or inexperienced doctor, it is often worth asking for an “international representative” who can assist with translation and coordination. Asking for the chief of the service or “professor” is also a useful strategy. Senior physicians often speak better English and may have more experience and training in Westernstyle medicine. A final note on potential sources of care addresses missionary clinics frequently found in the developing world. These are not generally intended for affluent travelers and so do not usually operate on a feefor-service basis, though increasingly some do in major tourist areas. Nonetheless, medical providers in these facilities often go to great lengths to assist travelers with severe problems.

EVACUATION ISSUES Local Evacuation Issues The past two decades have seen a great increase in the availability of emergency assistance phone systems in major international cities, including much of the developing world. Dialing the local emergency number however, which varies throughout the world, does not reliably call a well-trained emergency medical technician or paramedic. In much of the developing world, ambulances are strictly transport vehicles with minimal stabilization or resuscitation equipment/capability. The main advantage of an ambulance may simply be that the drivers know the best way to get to a hospital and may have better luck in negotiating traffic. Advance awareness of the ambulance capabilities of a destination city and how to call for emergency assistance, including the phone number to dial (using pretravel research tools such as Travax), will help a traveler to know whether to call and wait for an ambulance or to use a transport of convenience such as a private auto or taxi. Note that in many areas it is better to call the foreigner’s section of the selected hospital directly and have them arrange transport.

Long-Distance Evacuation With the diversity of quality and quantity of care available around the world, in the case of a significant injury or illness many travelers from developed nations desire to get to the highest possible level of care as rapidly as possible. Consequently, air evacuations from developing nations to developed home countries fall into two primary categories: first, urgent evacuation required because local care is unable to fully stabilize a patient, or the risk of local procedures is perceived to be higher than the risk of moving the patient; second, elective evacuation after the patient is stabilized, but recovery and longer-term management are more desirable at or near home. In either case, close involvement of physicians with extensive experience in the management of evacuation decisions that balance risk/benefit/cost are critical to the decision process. Providers with patients considering evacuation should be familiar with these issues and be careful not to let the emotions of the situation dictate over the careful consideration of the options.19–22 Commercial airlines meet the vast share of overseas medical evacuation needs. Air ambulances are used much less frequently. Airlines may accept seriously ill patients as stretcher cases, although procedures and policies among carriers differ widely and some airlines now provide access to specialized medical modules that can be placed in an otherwise normal flight. Each airline determines whom they will transport and under what conditions. Commercial carriers will uniformly not transport someone who is not medically stable, or who may present a risk to other passengers or crew members. While the increasing use of commercial airlines is not without controversy, the combination of longer flight segments available


commercially, higher speeds, availability of amenities for both crew and patients (including lavatories and hot meals), greater revenue for airlines, and decreased insurance losses for evacuation providers means that this trend will continue.23

PAYING FOR CARE A final consideration surrounding international health care is how to pay for care obtained abroad. For residents of the European Economic Area (EEA; i.e., European Union plus Iceland, Liechtenstein, Norway, and Switzerland) traveling within the EEA, a European Health Insurance Card entitles the traveler to the same level of public-access care as a national of that country, not including preexisting conditions.24 Outside of that, however, travelers should assume in most cases that cash—or in some cases a credit card guarantee—will be required before care is rendered. Before traveling, travelers should ask their insurance carrier three questions: (1) Does my policy apply when I am outside my home country? (2) Will it cover emergencies such as a trip to a foreign hospital? (3) Does my policy provide for medical evacuation if needed? In most cases the answer to the first two questions is yes (with limitations, especially for health maintenance organization (HMO)–based policies) but the answer is no to the evacuation question. Even when home-based health insurance will cover the cost of care, it is often only retrospectively after the submission of detailed bills (translated, at patient expense, where needed).25 Because of this, many travelers obtain supplemental travel health insurance that has mechanisms in place to guarantee payment to foreign providers. Travelers must remember however that guarantees only work if the provider accepts the guarantee and cash/credit may be required anyway. A good checklist addressing travel health insurance is provided by the Canadian government agency Foreign Affairs and International Trade Canada (see Box 53.3).25 Importantly, neither home-based health insurance nor standard travel health insurance typically covers evacuation. Because medical evacuation can cost tens of thousands of (US) dollars, many travelers choose to obtain evacuation insurance. Almost as important as paying for evacuation, purchase of this insurance carries with it access to physicians experienced in determining the method and provider of evacuation, given the specific situation and in working with local facilities to ensure stability for travel. In most cases, evacuation insurance can be obtained in two levels. The first level covers only medical situations; a higher level (typically double the cost) will also provide for evacuation in the case of an urgent security situation, such as political unrest or terrorist activity that places the insured traveler at risk. A routinely updated list of evacuation and evacuation insurance providers can be found at the US Department of State’s International Travel advisory website.26 Insurance policies require that ill travelers be inpatients for evacuation to be covered. Travelers must be aware that evacuation insurance will provide medical evacuation in situations where the insurer determines that is the only option for obtaining required inpatient care at a level comparable to what would be available in the traveler’s home country. Specific policies can vary greatly, but issues that can be adequately managed with a short stay at a local facility that has limited but adequate capability will not result in a paid evacuation. An example might be an acute appendicitis, when a local facility has a competent surgeon and good record of outcomes. In this case, the insurer may determine that the best medical outcome would result from local care and return home by standard commercial flight following an adequate recovery period. Many variables go into this decision process, which is why travelers must understand the specifics of their policy, including who has the final say on when and what type of evacuation is appropriate.


SECTION 9  Health Problems While Traveling

CRITICAL DIFFERENCES IN APPROACHES TO HEALTH CARE ABROAD The need for urgent health care is stressful, and this is compounded by having to interact with systems that are unfamiliar. While globalization is slowly bringing greater commonalities to health care systems worldwide, there are still significant differences, especially in the developing world. Travelers who understand some of these differences will be less stressed should they need to seek care.

Cultural Differences An important consideration in obtaining care abroad is the importance of language and culture. A large body of research has demonstrated the importance of effective communication to effective care.27–30 In the United States, when English-speaking providers care for “low English proficiency” patients, care is demonstrably inferior.28 Internationally, however, English has increasingly become the lingua franca of medicine, so the language effects are somewhat mitigated for English speakers traveling throughout the world. It is important to recognize however that this typically only applies to the physician staff delivering care, as nursing and ancillary support staff—that is, critical members of the care team—do not as commonly speak English in non-English-speaking countries. Additionally, even when the language barrier is successfully addressed, there are still cultural issues that can affect the quality of the medical communication. For all but the most straightforward medical situations, travelers are best served by a medically bilingual translator, followed closely by a general bilingual translator, and only as a last resort by a translator of convenience.30

Nursing Care In developed nations there is a ratio of approximately 1000 nurses to 100,000 population. This ratio drops to only 20 per 100,000 in developing nations of Africa.31 Even discounting the educational differences in nursing training in developed versus developing nations, patients should not expect to receive similar access to nursing care in developing nations. In many of these countries the nursing profession is plagued by lack of prestige, support, education, and resources, resulting in inability to attract smart, motivated students. Nurses are often actively discouraged or even prohibited from challenging physicians’ orders, even if known to be inappropriate. Sometimes cultural views on confrontation and “face” may contribute to this behavior. A similar dynamic may also exist among younger, less experienced physicians, wherein it is simply not acceptable to question a professor even though the professor may be in error or teaching obsolete medical doctrine. This means that patients and family members have to pay closer attention to the directions of the physician staff and be prepared to deliver more self-care and self-monitoring. Even where nurses are available, “universal precautions” for the prevention of infectious disease are not necessarily universal, as running water, gloves, and sterile supplies may not be as routinely available. In fact, not uncommonly, the availability of quality nursing care is an important determinant in making medical evacuation decisions.32

No “Right to Care” Outside the developed world there is typically no perceived “right” to urgent health care. In overtaxed and resource-limited communities, patients, including travelers, will often be turned away at the door to the emergency department if they cannot provide upfront payment or proof of ability to pay. Conversely, foreigners who are able to pay in hard currency or the equivalent are often shuttled to a specialized “foreigners’ clinic,” where the ambience is often much more relaxed than the busy general receiving ward. While many travelers express an

ethical discomfort with receiving “special treatment” that locals do not receive, they should understand that the additional funding they provide by paying for care keeps the medical staffs paid and enables better care in the general areas.

PHARMACY AND MEDICATION ISSUES The combination of the international “war on drugs” and the recognition of problems caused by overuse of antibiotics has resulted in a general tightening of restrictions internationally on pharmaceuticals. Japan, for example, prohibits the importation of some over-the-counter medicines commonly used in most countries, including inhalers and some allergy/ sinus medications. Specifically, products that contain stimulants (e.g., pseudoephedrine, contained in medications such as Actifed, Sudafed, and Vicks inhalers) or codeine (contained in medications such as Tylenol 3) are prohibited.33 Additionally, common medications such as insulin cannot be imported into many countries, Japan included, without lengthy procedures to obtain a specialized importation permit, even for personal use. While travelers who are on medications will generally have no issues with bringing personal use quantities of medications with them on international travel, travelers should ensure that the medications are packed in their original prescription bottles and that they carry a copy of the prescription with them. Although generally prescriptions from foreign providers are invalid in most countries, having a valid prescription lessens the risk of confiscation at border crossings and will facilitate obtaining a prescription from a local provider should it become necessary to obtain resupply of an important medication. At the other end of the spectrum, in many countries no prescription is required for medications other than narcotics. In this case, possession of a prescription from home will still assist the pharmacist in determining the closest locally available match to the required medication (Box 53.4). Travelers should also be aware of the prevalence of counterfeit medications and poor quality control of medications in many countries around the world. A first consideration is using, when possible, trusted pharmacies identified by sources such as an international clinic or an international medical assistance provider. Second, attempt to ensure

BOX 53.4  Traveling With Medications and


Medications/vitamins/supplements/etc. should be carried in their original commercial packaging when possible. For prescription medication in a typical pharmacy container, ensure you keep the medication in the pharmacy-labeled container with traveler’s name and prescribing information clearly visible. Ideally, carry a copy of the original prescription. With electronic prescribing, this is not always possible, but if you must travel with any narcotic or other psychoactive or addictive medication, work with your pharmacist to obtain a paper copy of the prescription. Be aware that some countries officially prohibit importation of even personal use quantities of certain medications with high misuse potential, such as Japan prohibiting all medications with pseudoephedrine. Carry only enough medication for your trip (with a reasonable margin to account for travel delays). Some travelers find it useful to ask their pharmacist for a copy of all required medications with international brand equivalents although with Internet access in most locations where pharmacies are available, this is no longer as critical. Long-term travelers should plan ahead with their pharmacist and physician to identify the equivalent or acceptable substitute medication at their destination, including potential sources. While many long-term travelers routinely have medications shipped to them from home, always have a contingency plan in case of customs delay or seizure of shipment.

CHAPTER 53  Health Care Abroad that medications are from international providers rather than local manufacturers, although in many areas this is not possible. Third, examine packaging carefully for signs of tampering or poorly executed “safety seals” designed to approximate the real product. (Manufacturers’ websites often have detailed descriptions and pictures of their packaging, and tamper-control seals to aid users in confirming that the medication is not counterfeit.) Finally, as with any product, if the price appears to be too good to be true, it is a red flag, although developing world prices for legitimate medications are often lower than in developed nations.

CONCLUSION In the short span of time since the first edition of this text, the availability of competent care abroad has steadily, if not dramatically, increased. There are fewer and fewer major cities that do not have access to a reasonable level of adequately trained physicians who can provide at least urgent or stabilization care. To be sure, unfortunately, there are still issues with nursing and ancillary support, but even these areas continue to improve. Additionally, the growth of telemedicine and the growing reach of the internet and other telecommunications tools mean that knowledgeable medical support can be as close as a phone or computer. Still, travelers must make advanced preparations if they are to be ready to respond to illness or injury while away from home. The degree of preparation often corresponds to the traveler’s own risk factors and the development status of the nation to which they are traveling, but even a healthy person traveling to a developed nation should take some time to understand what getting care while abroad would entail.

REFERENCES 1. Ashcroft B Most Common Claims Made on International Health Insurance. Expat Health. August 3, 2012. Available at https:// -international-health-insurance/. 2. Harvey K, Esposito DH, Han P, et al. Surveillance for travel-related disease—GeoSentinel Surveillance System, United States, 1997–2011. MMWR Surveill Summ 2013;62:1–23. 3. Redman CA, MacLennan A, Walker E. Causes of death abroad: analysis of data on bodies returned for cremation to Scotland. J Travel Med 2011;18:96–101. 4. Liese B, Mundt KA, Dell LD, et al. Medical insurance claims associated with international business travel. Occup Environ Med 1997;54: 499–503. 5. Joint Commission International. Available at https://www -organizations/. 6. Joint Commission International. About the Joint Commission. Available at 7. International Society for Quality in Health Care. Who We Are. Available at 8. Australian Council on Healthcare Standards. About Us. Available at 9. Cross M Travel abroad for low cost care. Kiplinger’s Personal Finance 2017 Jan.


10. Woodman J, editor. Patients Beyond Borders. Medical Tourism Statistics and Facts. Available at -tourism-statistics-facts. 11. Nguyen B, Gaines J. Medical tourism. The Yellow Book 2018. Centers for Disease Control and Prevention; 2017. [chap 2]. 12. Rack J, Wichmann O, Kamara B, et al. Risk and spectrum of diseases in travelers to popular tourist destinations. J Travel Med 2005;12:248–53. 13. Hanefield J, et al Medical Tourism: A Cost or Benefit to the NHS? POLS One (Public Library of Science). October 24, 2013. Available at http:// 14. Groenheide AC, van Genderen PJ, Overbosch D. East and west, home is best? A questionnaire-based survey on mortality of Dutch travelers Abroad. J Travel Med 2011;18:141–4. 15. For example, see the US State Department’s traveler assistance pages at 16. Marshall S, et al. Improving healthcare in remote environments via a new integrated online communication platform. Int Soc Telemed eHealth 2017;5(GKR):e33. 17. Wilde H, Roselieb M, Hanvesakul R, et al. Expatriate clinics and medical evacuation companies are a growth industry worldwide. J Travel Med 2003;10:315–17. 18. The Insurance listing website from the US State Department was verified October 29, 2017. 19. Teichman PG, Dnochin Y, Kot RJ. International aeromedical evacuation. N Engl J Med 2007;356:262–70. 20. Greuters S, Christiaans HMT, Veenings B, et al. Evaluation of repatriation parameters: does medical history matter? J Travel Med 2009;16:1–6. 21. Duchateau F-X, Verner L, Cha O, et al. Decision criteria of immediate aeromedical evacuation. J Travel Med 2009;16:391–4. 22. Jorge A, Pombal R, Peixoto H, et al. Preflight medical clearance of ill and incapacitated passengers: 3-year retrospective study of experience with a European airline. J Travel Med 2005;12:306–11. 23. Critical repatriations on commercial flights. AirMed Rescue Mag 2016 Sept 27. -commercial-flights. 24. European Commission, Employment, Social Affairs, and Inclusion. The European Health Insurance Card. Available at main.jsp?catId=559. 25. Foreign Affairs and International Trade Canada. Travel Insurance FAQ. Available at 26. Your Health Abroad. US State Department Travel Assistance. Available at 27. Lee S. A Review of Language and Other Communication Barriers in Healthcare. US Department of Health and Human Services; 2003. 28. Flores G. The impact of medical interpreter services on the quality of healthcare: a systematic review. Med Care Res Rev 2005;62(3): 255–99. 29. Baker DW, Hayes R, Fortier JP. Interpreter use and satisfaction with interpersonal aspects of care for Spanish-speaking patients. Med Care 1998;36:1461–70. 30. Juckett G, Unger K. West Virginia University School of Medicine. Appropriate use of medical interpreters. Am Fam Physician 2014;90(7): 476–80. 31. Nursing shortage knows no boundaries. Editorial. The Baltimore Sun 2010 Sept 13. 32. Teichman PG, op cit. 33. Customs Guidance. Consulate-General of Japan in Seattle. Available at

54  Personal Security and Crime Avoidance D. Bruce McIndoe

KEY POINTS • The cornerstone of personal security is constant situational awareness. If directly confronted, give up your valuables, not your life. • Have a detailed plan for the initial arrival in country. Do not drive or travel at night, especially outside urban areas.

• Blend in. Do not dress like a tourist or a wealthy person. Leave expensive jewelry and belongings at home. • Carry a mobile phone with local emergency and insurance assistance numbers programmed. • Know the fire escape routes from the hotel room.


more. Any traveler contemplating travel to a high-risk location should seek professional advice. There are several companies that provide country and city threat assessments, safety and security consultation, and continuous travel tracking support (Table 54.2). The basics of many of these issues are covered elsewhere.1–3 Larger organizations and corporations that may contract out their travel medicine needs to outside clinics often have corporate security departments, which may have already provided destination-specific risk ratings and written security reports to employees and expatriates on an ongoing basis. This will include very specific information on safe and unsafe districts within a destination city, and lists of hotels and residential areas considered to be the most desirable and safe. Countryand city-specific security reports are available from most of the risk consultancies (see Table 54.2).

The world has changed significantly since the last edition of this book resulting in more opportunity but also more risk while traveling. Travelers need to be more aware of the current situation in the countries being visited and properly prepare for and mitigate the hazards or threats that are present. There is a vast amount of information available on the Internet to support country or city research, hotel selection, local transportation options, and even travel safety training videos. The biggest challenge can be sorting out the clutter and resolving conflicting information. Prior to departure, a good starting point is to review the major governmental travel advice and advisory websites (Table 54.1). If there are concerns raised, then broaden your search and learn more. You can print out relevant information and take it with you for reference in the event you do not have Internet access. Most travelers perceive risk much differently than the actual risk that is present. We tend to overreact to intentional actions such as terrorism or kidnaps and underreact to accidents, slowly changing conditions such as climate change, and natural phenomena such as influenza. Since 9/11 terrorism has caused the death of about ten US persons per year outside the US. Whereas in 2015 over 35,000 people died on US roads and over 1.2 million people died on roads around the world. In fact, you are much more likely to be struck by lightning (~50 deaths per year in the United States) than die as a result of terrorism. When preparing for a trip, focus first on those safety and security issues with a higher likelihood (shown in lifetime odds) of happening and causing harm such as theft (1 in 800), accidents (1 in 2400), getting sick (1 in 5400), car accidents (1 in 37,000), fire/smoke (1 in 112,000), and assault (1 in 188,500). By properly preparing for and mitigating these potential hazards you can significantly reduce the likelihood of occurrence and if something does occur, reduce the likelihood of harm. This chapter will provide the basic strategies for personal security and safety for low-risk and medium-risk locations along with references to more in-depth information if you are venturing into a high-risk location. Travel to any high-risk destination requires careful planning, investment in mitigation approaches such as secure transportation, enhanced communications equipment, field first-aid training, and much

BEFORE DEPARTURE In addition to reviewing various consular websites shown in Table 54.2, travelers should study the basics such as making phone calls both in and out of the country, what electrical adaptors will be needed, local transportation system usage, weather, visa requirements, and access to medical care. If you do not have international health insurance, you should seriously consider getting coverage for the duration of your trip. Make copies or photos of your passport (and any required visas), credit cards (front for the number and back for the emergency phone number), and any other important information in your wallet in the event it is lost or stolen. You can scan or email these copies to yourself for quick access. Leave a copy of your detailed itinerary with a family member or other trusted person. This person should be used as your emergency contact. If staying for any length of time, travelers should register with their country’s embassy, something that is now done only via the Internet. Obtaining some local currency before departure is helpful to ensure that you have money for transportation or other needs when you arrive. Most airports have automated teller machines (ATMs) that can be used upon arrival for local currency. Just make sure that the ATM is in a protected area of the terminal.


CHAPTER 54  Personal Security and Crime Avoidance Abstract


Traveling requires advanced planning and proper preparation to ensure your and any traveling companions’ personal security and safety. People perceive risk differently and often inaccurately. Practical information is provided for each phase of a trip, when the traveler is out and about, and for other topics such as ground transportation and the need for personal communications. Strategies for dealing with an active shooter and surviving a hostage situation are provided.

Active shooter Avoiding crime Crime avoidance Hostage survival Hotel safety Personal safety Personal security Travel preparation Travel risk management Travel safety tips



SECTION 9  Health Problems While Traveling

TABLE 54.1  Consular Websites With

Comprehensive Security and Risk Information

US Department of State Travel Warnings and Consular Information Citizens register at: UK Foreign and Commonwealth Office Country Advice Canada Department of Foreign Affairs & International Trade Travel Reports Australia Department of Foreign Affairs and Trade Travel Advice by Country US Department of State Overseas Security Advisory Council (OSAC), Daily Global News Bulletins

TABLE 54.2  Major Consultancies

Specializing in Risk Management and Security Control Risks Group, iJET International, International SOS, Kroll Inc. Risk Consulting,

You should have some type of mobile communication device when traveling for emergency calls. You can talk to your mobile phone provider to see if your phone will work in the countries that you are visiting and the costs for international voice and data usage. Many providers have special programs for international travel. Alternatively, you can rent a mobile device (phone or hotspot) or purchase a local SIM card when you arrive at most international airports. Once you obtain the phone, the traveler should ideally program local emergency numbers, consulate numbers, and any other important contacts into the device. Mobile phones, laptop computers, tablet computers, mobile readers, and other personal electronic devices frequently contain sensitive financial or personal data and are easily lost or stolen. All devices should be secured with locking password access software and encrypted if possible.

PRIORITIES UPON ARRIVAL Unfortunately, the initial airport, train, or ship arrival location constitutes one of the highest threat situations of the entire trip for the typical leisure traveler. Travelers are tired from the journey, unfamiliar with the surroundings, the arrival lobby is usually crowded and noisy, and directions and signs may be in a foreign language. This is a natural magnet for criminals in any country. An advance plan needs to be in place. Travelers who are to be met at the airport in a medium-risk to high-risk destination by an individual, tour company representative, or driver not personally known to them should be instructed not to leave the arrival lobby with anyone who does not know a prearranged verbal recognition code. Company signboards as well as a traveler’s name are easily copied by anyone in the arrival area. Missed pickups often occur, no matter how meticulous the arrangements. Travelers should always know the address of exactly where they are supposed to get to on arrival, and have phone numbers for appropriate local contact people.

Major transportation hubs such as airports will have reputable taxi kiosks or stands where prepaid taxi rides can be purchased. The next best approach is to look for an organized taxi rank with cars lined up, accepting passengers in sequence, and located within the airport perimeter. At all costs avoid individuals on foot soliciting for passengers in the arrivals area. In any country, many criminals purport to be taxi drivers or taxi operators. Once you are in their vehicle, they can easily extort cash or belongings from you.

IN THE HOTEL In high-threat countries, hotel locations should be carefully selected using advance knowledge and ideally located in proximity to planned activities. Rooms on floors 3–6 are generally regarded as optimal for safety and security. They are harder to break into from the outside of the hotel, but are accessible to firefighting equipment. Travelers should look for fire safety instructions in the room upon arrival and familiarize themselves with escape routes. Travelers may consider counting doors in the corridor to find exits in case of poor visibility due to darkness or smoke. The hotel room door should be locked at all times. For those anticipating stays in budget accommodations, compact locking and door blocking devices are inexpensive and readily available. Doors should not be opened to strangers, and a call to the front desk can be made to confirm the identity of someone knocking at the door. Leave shower curtains open upon leaving the room to discourage intruders from hiding there. Room safes are less secure than individual safe deposit boxes at the front desk but may be preferable, depending on model type, to a large hotel safe readily accessible to many hotel employees. Room numbers should not be disclosed to any but the closest personal friends and colleagues. Meet visitors in the lobby. Room keys that identify the room number together with the hotel should be left with the concierge upon leaving the building. Hotel business cards with address and phone number in the local language should be carried on the person at all times.

OUT AND ABOUT Travelers should radiate confidence and know exactly where they are going. Situational awareness requires planning ahead before venturing out. If the terrain and routes are already familiar, little planning time will be required. It is important to remember that threats can change with time, so even frequent travelers need to do an assessment on each visit. Consult local media regularly to keep up with current events and potentially volatile situations. Routes should be decided either mentally or using a map before setting out. Maps or mobile devices should not be studied in the street as this broadcasts vulnerability. Travelers should not wear expensive clothing or jewelry or carry expensive cameras or electronics. They should dress to blend in as much as possible, and definitely avoid clothing that declares their nationality or any indication of local or global political beliefs. Travelers should always carry a mobile phone. Carry only the cash required for the outing. Anything more than a small amount should always be in a secure money belt or inside zippered pocket. Take only one credit or debit card at a time. Familiarize yourself quickly with the local currency and the appearance of the banknotes or coins: substitution using worthless notes or coins is always a risk. Travelers should be constantly attentive to surroundings and be wary of any stranger who engages them in any form of conversation or touches their person in any way, no matter how accidental the contact may appear to be. Travelers should never accept any sort of food or

CHAPTER 54  Personal Security and Crime Avoidance drink from strangers on the street, in bars, or from taxi drivers: drugging is common in many places. Drinks should never be left unattended at the bar. While out on foot, travelers should always have one hand free to protect themselves and their valuables. Specific targets for thieves are shoulder bags, outside pouches of backpacks, and cameras that hang from straps. Valuables should be slung across the chest and preferably under a jacket or shirt, so that they are less accessible to thieves. Pants and jackets with zippered compartments inside major pockets can provide an extra level of protection against pickpockets. Valuables are best split into more than one location, especially if a passport or relatively large amounts of currency must be carried. Luggage or personal belongings should never be given to anyone who cannot be directly supervised or observed. Even if the area is familiar, travelers need always use extra caution in tourist sites, marketplaces, elevators, crowded subways, train stations, and at festivals. Isolated beaches should always be avoided, and even popular and safe beaches should be avoided after dark and in the early morning. Joggers are at risk of losing even shoes and clothing whose brand names may have high value in many countries. Curiosity is dangerous, and political gatherings and any sort of crowd should always be avoided, particularly in potentially unstable civil environments. Travelers should be aware of special dates and anniversaries on which any public place is best avoided. Travelers should never withdraw money from ATMs or change money at a money-changing establishment after dark. Darkness makes it simple for potential assailants to observe discreetly from a relatively short distance. After obtaining cash, travelers should verify carefully that they are not being followed. In any country, many criminals pose as willing sex partners. The setup may entail a sex-for-hire scenario or may appear as a casual or accidental meeting in a hotel, bar, restaurant, or even on the street. Whether the liaison moves on to the traveler’s hotel/apartment or a location of the criminal’s choice carries an equal risk of a poor outcome. Potentially intimate encounters with host-country nationals should be avoided at all times. Travelers should avoid being intoxicated at night on the street, and taxis should be used even for short distances in this situation. Long-stay travelers should be constantly alert to their immediate environment and make mental notes of the usual neighborhood and work environments. This makes anomalies, out-of-place persons, and suspicious situations more instantly obvious.

TAXIS AND PUBLIC TRANSPORT The taxi situation varies greatly by country and the guidelines here will often need to be adapted to local conditions. In general, travelers should use only “registered” taxis, but the guidelines for identifying these require local knowledge that must be ascertained upon arrival. Many cities authorize ridesharing services such as Uber, Lyft, and Didi Chuxing. Before using one of these services, the traveler will need to have the mobile technology, appropriate mobile app, a mobile data subscription, and familiarity with the service in each specific destination. For day-to-day use, radio taxis are always the safest, although in many countries with a well-enforced system of registration, taxis found in marked ranks may be equally safe. Local colleagues can usually inform as to the phone numbers of reputable radio taxi operators. If it is possible to adequately communicate with the radio dispatcher when ordering the taxi, travelers should obtain the car number or license plate number of the taxi that has been dispatched. If the situation requires the taxi driver to ring up over an apartment block intercom, a prearranged recognition signal should be requested from the telephone dispatcher.


The fare should always be fixed before entering any taxi, even if sign language must be used. Travelers anticipating taxi travel should always have local money in small denominations, as change for large bills is never available even if it is onboard. Taxis should never be shared with unknown passengers. Hotels often have their own vehicles and drivers for hire. These are usually very overpriced but generally safe and reliable. However, travelers need to beware of hotel bellhops who, when asked for a taxi, will put the traveler into a taxi operated by an accomplice who will at best just overcharge and at worst rob the traveler. Warning signs would include a taxi parked to a side away from a marked taxi line or rank, or a taxi apparently taken out of turn. Public transportation, particularly if overcrowded, presents many safety risks that are detailed in Chapter 50. In addition, public vehicles present a situation where foreigners will both stand out and be stationary targets for a fixed period of time. Travelers should ride public transportation in pairs if possible. Thieves often work in pairs or groups, so travelers should avoid continuing to move in the direction of anyone who suddenly appears and is positioned in a way to be blocking the path forward. Gangs in crowded vehicles or trains may work to restrain arms while others search for valuables; wallets and belts under the clothes are most effective in these situations. Public transportation should be avoided late at night at all costs. Travelers should never sit in a train car that is otherwise empty of other passengers.

THEFT The best way to reduce the likelihood of theft is to not travel with the item at all. Leave expensive jewelry, electronics, and other expensive or cherished items safely at home. For those items that you do travel with, keep them on your person or hand luggage when traveling and in a hotel safe when visiting a location. If you must take money and other valuables when you are out and about, carry only the essentials. Keep a credit card and some cash in a different location from your wallet or purse in case you are pickpocketed or robbed. In most locations, carry a photocopy of your passport and leave the real one in the safe. Always carry a printed copy of any emergency numbers on your person. Do not rely on your phone address book. It could be lost, stolen, or not work.

ACCIDENTS Slips, falls, and being struck as a pedestrian are very common and can quickly ruin a trip. Slow down and pay attention to your surroundings. Always think twice or even three times before crossing a road, especially if cars are driven on a different side of the road than in your home country. Pay attention when getting in/out of a bath or shower, around pools and hot tubs, or any time there is water or ice on your walking surface.

GETTING SICK Food poisoning and foodborne illness is very common among travelers. Wash your hands frequently or use sanitizer. Eat foods that are cooked or that you must peel or skin to eat. Try only to drink bottled water or other beverages and be sure that you are the one to break the safety seal to ensure the bottle was not filled from the tap. Do not use ice cubes. They melt and can contaminate your beverage. Also, use bottled water to brush your teeth and take pills. Ensure you have proper vaccinations and antimalarials prior to departure, use sunblock to avoid sunburn, protect yourself from mosquito bites, and stay hydrated.


SECTION 9  Health Problems While Traveling

LEARN LOCAL REGULATIONS EARLY Travelers should make efforts to learn, in advance, the rules and regulations of the destination country. Procedures to follow when involved in a motor vehicle incident need to be known. Penalties for breaking the law can be surprisingly severe. An embassy or consulate can help ensure legal representation but cannot overrule local laws. Some countries have a zero-tolerance policy with severe penalties for those driving under the influence of alcohol or other drugs. Drug violations, firearms possession, photography of government or military installations, and antiques purchases are frequent causes of detention by local authorities.

MOBILE PHONES AND ELECTRONIC DEVICES Even the poorest of countries generally have a high-quality mobile phone service. Efficient and rapid communication with sources of potential help when travelers find themselves in a high-risk situation can provide solutions to that situation or can help to minimize the amount of time travelers are exposed to that threat. A locally purchased or leased mobile phone is best, because of ease of dialing local numbers and the ease with which local people can dial the traveler. A mobile phone should ideally have local emergency, consulate, and emergency assistance numbers programmed at the earliest chance. In most countries, cheap handsets with a local number can be purchased on arrival and charged from prepaid cards. Organizations or companies that have short-term visitors or staff coming in from other countries can consider providing a local mobile phone upon arrival. Alternatively, frequent travelers may carry their own mobile device if the device and carrier are supported in the various destinations to be visited. The carrier website or support line should be used to verify availability and rates. Mobile phones, laptop computers, tablet computers, mobile readers, and other personal electronic devices frequently contain sensitive financial or personal data and are easily lost or stolen. If you must travel with personal electronic devices, these should be secured with locking password access software and encrypted if possible.

ACTIVE SHOOTER The best option in an active shooter situation is to flee the area and get out of the shooter’s path. The next best option is to hide. Get out of a hallway or common area. Try to get behind a barrier. Lock the door if possible and do not open it for anyone. Law enforcement will secure keys to the facility. Silence your cell phone. Stay low to the ground. Remain quiet and still. As a final and extreme option, if you are confronted by the shooter, fight back. Act quickly and decisively by throwing

things or using an improvised weapon. Be aware of any opportunity to flee.

BEING A HOSTAGE A traveler’s chances of being taken hostage are remote. Still, the risk exists, and these tips are intended to help travelers survive a hostage situation. At the outset, kidnappers are typically tense and more likely to behave irrationally. Remain calm and alert. Breathe deeply, and prepare yourself mentally, physically, and emotionally for the possibility of a long ordeal. Remember that you are much more valuable to your captors alive and uninjured. Do not try to escape unless you are certain of being successful. Do not try to be a hero, thereby endangering yourself and others. Consciously put yourself in a mode of passive cooperation. Comply with all orders and instructions. Establish a daily program of mental and physical activity. If you are involved in a lengthy, drawn-out situation, try to establish a rapport with your captors. Avoid discussions on politics or other confrontational subjects. Family is a universal subject. You may discuss family matters with a fair degree of personal safety and success. If a rescue is attempted and shooting occurs, do exactly as the rescue force directs. Seek cover or lie flat on the floor. Do not pick up a weapon, because you may be mistaken for a kidnapper. Do not despair if you are held for a long time. Lengthy hostage situations usually result in the release of live captives.

CONCLUSION With proper preparation, common sense, maintaining situational awareness, and maintaining a low profile, a traveler can avoid becoming a victim of crime or worse. If confronted, a traveler should give up valuables without a struggle or verbal confrontation. Money, jewelry, and passports can be replaced; human lives cannot.

REFERENCES 1. Various authors. Operational Security Management in Violent Environments, rev ed. Good Practice Review 8. London: Overseas Development Institute; December 2010. Available at: http:// 2. Generic Security Guide for Humanitarian Organizations. European Commission; 2004. Available at: files-en/pdf-en/guide-en.pdf. 3. Roberts DL. Staying Alive: Safety and Security Guidelines for Humanitarian Volunteers in Conflict Areas. Geneva: ICRC; 2006. Available at:

55  Posttravel Screening Joannes Clerinx, Davidson Hamer, and Michael Libman

KEY POINTS • A detailed medical history is the cornerstone of posttravel screening. • Asymptomatic short-term travelers rarely need a posttravel medical examination unless they had a significant risk exposure. • Long-term travelers, expatriates, and highly adventurous travelers need a thorough medical interview to assess potential infectious exposures.

• When screening is indicated, minimal laboratory tests include a total blood count, white blood cell (WBC) differential count, liver transaminases, renal function tests, and serologic markers reflecting the types of exposure.


specifically addressed in this chapter. However, these migrants may later return to visit friends and relatives in their country of origin (so-called VFRs), often incurring health risks, but only rarely consult for posttravel screening if asymptomatic. Travelers should be advised to have a medical examination on their return if they: • Suffer from a chronic illness, which may increase their risk of complications of infection • Are immunocompromised, either from human immunodeficiency virus (HIV) infection, other immunologic disorders, or medically induced immunosuppression • Experience illness within 3 months after returning, particularly if fever, persistent diarrhea, nausea, vomiting, weight loss, jaundice, urinary disorders, skin disease, or genital infection has occurred • Consider that they have been exposed to a potentially severe infectious disease while traveling • Have spent >3 months in a developing country A medical examination is not necessary for asymptomatic short-term travelers who had only minor health problems such as travelers’ diarrhea or transient fever. A posttravel examination generally aims to rule out, rather than confirm, a latent (subclinical) disease. This requires knowledge of the incubation period of suspected infectious diseases and awareness of the limitations of the relevant laboratory procedures. Probing for exposures to infection may be focused and limited to contaminated food and water, arthropod exposure, freshwater contact, and sexual contacts. Screening for sexually transmitted infections (STIs) deserves special consideration. Rapid diagnosis may prevent further spread, especially in cases of importation of significant pathogens, such as emerging multidrug-resistant gonococcal strains.6 The optimal timing of a posttravel medical examination may be uncertain. Infections with a long incubation period may be overlooked if the screening process is carried out soon after exposure. Assessment up to 3 months later may be required to avoid missing infections with a potential community health impact, such as tuberculosis (TB) or HIV, as well as some parasitic infections. The traveler must be informed

Many travel clinics provide pretravel counseling as well as posttravel screening and care. During posttravel screening of asymptomatic travelers, the physician estimates their risk of having acquired occult travel-related infections, both tropical and cosmopolitan, and the potential impact on the traveler’s health.1 For long-term travelers and expatriates this may be the opportunity to review common noninfectious conditions such as cardiovascular disease, neoplasia, and trauma complications. For those intending to travel again in the future, the posttravel consultation offers an ideal opportunity to provide advice on personal precautions and to review immunization status and chemoprophylaxis. The medical history—the cornerstone of the posttravel screening process—focuses on infectious diseases transmitted by various routes.2,3 Laboratory tests, although indispensable, are often insensitive and nonspecific, and may not be available for diagnosis of latent conditions in their preclinical stage (e.g., malaria). Qualitative diagnostic tests are useful to detect infection, but quantitative or semiquantitative tests are essential to determine “parasite load.” This is important for schistosomiasis and some filarial infections, among others. The cost-benefit utility of posttravel screening activities in asymptomatic travelers is questionable. Its effect on health status is probably comparable with health checkups for cardiovascular and neoplastic diseases, and with the periodic medical examinations in occupational medicine.1,4 Relying too heavily on laboratory results alone frequently leads to repeated visits to assess the validity of the results, with dubious benefits in cases of infections with minimal morbidity.5

WHO AND WHEN TO SCREEN? A posttravel medical examination is not required for all travelers. Potential benefits can be assessed based on demographic factors (age, gender, socioeconomic status), travel characteristics (duration, destination), and specific disease exposure. Immigrants, refugees, and adopted children from tropical countries constitute a particular subgroup that is not


CHAPTER 55  Posttravel Screening Abstract


Posttravel screening is an important process for diagnosing latent infection of tropical or cosmopolitan origin in travelers returning from a region where these diseases are prevalent. Special attention needs to be paid to long-term residents and migrants, whose health concerns are different from those of short-time travelers, and involve noninfectious chronic ailments as well. Screening requires a thorough knowledge of prevailing infectious diseases and risk of exposure for each region visited. Assessing the risk of exposure to potentially latent infectious diseases, which may need treatment or precautions, is the cornerstone of posttravel screening. In frequent travelers this process is linked to an update of pretravel advice and vaccinations as well. Options for basic clinical screening and a set of relevant laboratory tests, targeting the major (infectious) diseases to which travelers are likely to have been exposed, are described in this chapter.

Infectious diseases Medical screening Periodic travel Tropical diseases



SECTION 10 Posttravel

about important febrile diseases that may occur weeks or months after return (e.g., benign tertian malaria, amebic liver abscess, acute schistosomiasis, acute HIV seroconversion).

Targeted Populations

Asymptomatic Short-Term Traveler.  Routine posttravel screening is probably redundant in most short-term travelers who had a self-limited illness, or do not report a particularly hazardous exposure. It can be restricted to individuals with chronic underlying medical conditions. For some professional corporate travelers, a posttravel screening procedure constitutes an integral part of the (often compulsory) periodic medical evaluation in occupational medicine.

Asymptomatic Long-Term Traveler or Expatriate.  This group may benefit from a thorough medical interview to assess exposure to an array of prepatent or subclinical infections: airborne diseases (TB), arthropod-borne diseases (e.g., malaria, filariasis, and trypanosomiasis), waterborne infections (schistosomiasis), soil-transmitted helminths (strongyloidiasis, hookworm, and other intestinal helminths), foodborne parasites (amebiasis, giardiasis, and intestinal helminths), and some STIs. If a specific exposure is identified, with a significant risk of infection, screening tests may be indicated. For some expatriates and long-term travelers, the screening visit is the only opportunity for a general health assessment, as these services are often lacking in the country of residence. This includes cardiovascular disorders, hypertension, and diabetes mellitus, and preventive screening for malignancies including prostate, breast, cervical, and colon cancer, according to national guidelines or practices.

physician can provide information on important late disease manifestations associated with a particular exposure (e.g., malaria, leishmaniasis). Fear of contaminating others is another incentive to consult. This is important for occupations where airborne contamination (TB), fecal-oral transmission (salmonellosis), or direct skin contact (scabies) with vulnerable groups of people may occur (health care workers [HCWs], food handlers, etc.), and for STIs.

GENERAL SCREENING Medical Interview A medical interview by an experienced physician, the foundation of the posttravel screening process, identifies exposure to specific infections and estimates the magnitude of risk. Risk perception in travelers is often unrealistically high or low. Risk assessment in asymptomatic travelers should include a basic questionnaire (Tables 55.1 and 55.2). Using a printed form or electronic template can speed the assessment and allow for a consistent approach. The responses will guide clinical and paraclinical investigations and counseling.

Physical Examination In asymptomatic travelers, a physical examination is usually of limited value. However, unsuspecting individuals may manifest lymphadenopathy, splenomegaly, skin lesions, or signs of chronic disease unrelated to travel. The extent of examination should be guided by the medical interview.

Asymptomatic Adventurous Traveler.  Adventurous travelers frequently adopt lifestyles similar to those of indigenous peoples in the countries visited, and hence present an increased risk for unusual infections, most of which have a short incubation time prior to becoming symptomatic. These are dealt with in other chapters. When asymptomatic, only a few environmental exposures matter for screening purposes, such as bathing or swimming in freshwater lakes, ponds, or rivers (schistosomiasis), bat-infested caves (histoplasmosis: rare, but specific high-risk environment), walking barefoot in feces-contaminated soil (strongyloidiasis), or certain arthropod exposures in tropical forested regions (filariasis, trypanosomiasis). STI screening is often neglected.

TABLE 55.1 Self-Administered

Questionnaire in Posttravel Screening Demographic Factors Travel characteristics Vaccinations

Travelers With Self-Identified Risk Factors and/or Disease Symptoms During Travel.  This group of travelers frequently consults because of concern about the outcome of a potentially risky exposure, or seek to confirm a diagnosis established elsewhere or proof of a complete cure. Travelers may also be alerted to specific infections in their travel companions, such as schistosomiasis (“cluster cases”). The

Malaria chemoprophylaxis

Age, Gender Destination, duration of stay, and date of return (Document year of last dose) Polio, diphtheria, tetanus Hepatitis A and B Yellow fever Typhoid fever Meningococcal meningitis type A, C, W, and Y Japanese encephalitis Other (rabies, tickborne encephalitis) Drug used and duration of intake

TABLE 55.2  Interactive Posttravel Screening Questionnaire Basic medical information Travel intentions Physical environment Specific environment Food intake habits Previous disease history Malaria protection Sexually transmitted infection (STI risk) Bloodborne risks Diseases during travel

Weight change, tobacco, alcohol and psychotropic drug use, concomitant medication Holiday, professional travel, visiting friends and relatives (VFRs), adventure sports, ecotourism, etc. Destination, duration, transport means, travel route, type of accommodation, altitude Freshwater contact (rivers, lakes, flooded areas), caves, marine environment, forests, game parks, etc. Exposure to raw meat and fish, undercooked food, unusual ingredients, unpurified water, unpasteurized dairy products Chronic diseases and allergic conditions (asthma, eczema, urticaria), potentially interfering with screening procedures Physical protection, type of antimalaria drugs, dosage, and duration of intake Protective measures, contact with risk groups Injection drug use, needle-prick accidents, trauma, blood transfusion Febrile, intestinal and skin diseases, STIs

CHAPTER 55  Posttravel Screening


count with white blood cell (WBC) differential, liver transaminases, creatinine, and C-reactive protein (CRP). These tests provide baseline information on potential infections and systemic inflammation. Urinalysis, including urine microscopy and testing for proteinuria, is essential when urinary schistosomiasis is suspected, but will usually fail to detect light infections, as is often the case in travelers. It does not often yield useful information on other disease in asymptomatic persons. Determining fasting blood glucose levels and blood lipids as a marker for diabetes and cardiovascular disease risk form part of a general health screening in long-term expatriates, if indicated.

case with active pulmonary TB. In contrast, the risk of infection outdoors is comparatively negligible. Risk will thus be minimal in short-term travelers, but increases substantially in long-term travelers, expatriates, and specifically in HCWs, in whom a >100-fold increase of the baseline risk (0.6 per 1000 person-months) has been found.11 For HCWs, followup with tuberculin testing before and after exposure remains a recommended practice. Whether screening for latent TB should be performed in all long-term travelers and residents in the tropics is debatable. The American Thoracic Society advocates tuberculin testing only for persons likely to have been recently infected, particularly those who have been in close contact with a known infectious case. Although postexposure prophylaxis averts progression to active disease in most cases, detection and treatment of clinically apparent TB is currently the most cost-effective strategy.12

Blood Eosinophil Count.  This cheap and simple screening test is

Chest X-ray

frequently used to detect active parasitic infections, especially with nematodes or trematodes, but generally not with cestodes or protozoa. Eosinophilia is more marked when blood or tissue migration occurs, as in strongyloidiasis, schistosomiasis, filariasis, and the migratory intestinal helminths (Ascaris, hookworm). The etiology of eosinophilia in travelers has been extensively reviewed.7 Unfortunately, the test is neither sensitive nor very specific. In most individuals harboring subclinical helminth infections, the eosinophil count is normal.8 A high cutoff level (>800 eosinophils/mm3) considerably increases its specificity as a screening marker for helminth infection.9 Often simple observation leads to normalization of the eosinophil counts over time.

Routine chest x-ray is both nonspecific and insensitive in detecting latent TB. In industrialized countries with low levels of TB endemicity, mass chest x-ray as a means of controlling TB has long been abandoned. Consequently, a chest x-ray cannot be recommended as a routine screening procedure for TB in asymptomatic travelers and expatriates. It should be restricted to HCWs and migrants with a positive tuberculin reaction, especially if there has been exposure to a known or strongly suspected pulmonary TB index case in the household or at the workplace.

General Paraclinical Tests General Laboratory Tests.  A basic set of tests includes a total blood

Abdominal Ultrasound.  At present ultrasound may only be considered as a secondary diagnostic procedure in asymptomatic travelers presenting with abnormal liver and/or renal function tests and/or abnormal urinalysis, or as part of a screening strategy for prostate disorders in the elderly.

Resting Electrocardiogram.  A resting electrocardiogram (ECG) can help identify individuals with the “long QT” syndrome, who are at risk for a specific malignant ventricular tachycardia (“torsade de pointes”) when treated with antimalarial drugs that enhance QT prolongation, such as quinine, quinidine, and halofantrine. Lumefantrine, part of the fixed antimalarial combination artemether-lumefantrine (AL), is structurally related to halofantrine, but it has not been associated with measurable QT prolongation in currently recommended dosages. This is also a concern with piperaquine, a component of the newer antimalarial combination, dihydroartemisinin-piperaquine, frequently used in Southeast Asia and increasingly in sub-Saharan Africa.10 Caution is warranted when these antimalarials are used in persons with long QT syndrome, or in association with other drugs causing QT prolongation. Atrioventricular (AV) conduction problems may also be detected, and are a contraindication to the use of mefloquine.

SPECIFIC SCREENING TESTS IN A POSTTRAVEL EVALUATION The main objective of these tests is to provide information on occult infection with TB, STIs, hepatitis, arboviruses, foodborne infections, and both intestinal and extraintestinal parasitic diseases (Table 55.3).

Screening for Latent Tuberculosis Infection with TB usually happens in a confined space protected from sunlight and air flow, when one inhales infected droplets from an index

Tuberculin Skin Testing and Interferon-γ Release Assay Tuberculin skin testing (TST, skin reaction after intradermal injection of 1–5 IU PPD) is the classic option to detect latent TB infection. A conversion from a negative skin reaction before travel to positive at least 6 weeks after return is suggestive of recent infection. As a diagnostic test, the TST requires reading and interpretation within a 48–72-hour interval, necessitating two visits. Indeterminate reactions frequently occur. Proper intradermal injection and reaction measurement must be performed by trained personnel to avoid incorrect results. TST is less sensitive in pregnancy, old age, diabetes, and corticosteroid treatment, and is unreliable in immunodeficient individuals. Bacillus Calmette–Guérin (BCG) vaccination during childhood may result in a positive skin test for years afterward, although vaccination in infancy, as done in much of the world, rarely has this effect. The interferon-γ release assays (IGRAs) specifically detect exposure to Mycobacterium tuberculosis using a blood sample. These are nonreactive in persons vaccinated with BCG or exposed to most nontuberculous mycobacteria. Although promising as an alternative to TST, IGRAs share similar limitations: they do not discriminate between latent and active TB, nor between recent, past, or treated TB, and sensitivity is impaired in immunodeficient persons. They also suffer from high test-retest variability, and as such are not recommended for longitudinal screening of HCWs. As with the TST, performance is best in targeted populations with a relatively high risk of TB exposure.13

Sexually Transmitted Infections Travelers have a surprisingly high rate (5%–50%) of unprotected sexual contacts with new partners, primarily with persons from the countries visited.14 STIs have become an essential part of posttravel screening, largely as a consequence of the HIV pandemic. Counseling on STI risk is integral to posttravel screening. Screening for STIs serves a dual purpose: limiting secondary transmission through prevention and treatment, and reassuring the asymptomatic traveler. It should involve detection of HIV, syphilis, hepatitis B, gonorrhea, chlamydia, genital herpes, and condylomata. HIV, hepatitis B, and syphilis are conveniently detected using serum samples. Screening for


SECTION 10 Posttravel

TABLE 55.3  Diagnosis of Exposure to Common Travel-Related Infections in Asymptomatic Travelers


Incubation or Prepatent Period


1 day–>6 months

Malaria (P. falciparum)

9–35 days

Diagnostic Procedure

Use of Test

Stool microscopy and stool antigen test Stool PCR for Entamoeba histolytica Serum antibody test Thick film, malaria antigen tests HRP-2 antigen test

Infection with E. histolytica/E. dispar Infection (E. histolytica) Tissue invasion E. histolytica

6 months, but may be longer, even years

Parasitemia in semiimmune Confirmation of recent infection/ disease Postinfection confirmation and chronic suppressed infection Active infection/disease Postinfection confirmation

Nonimmunes: 3 months Semiimmunes: 4 years

Serum antibody test Malaria (benign tertian-quartan)

10 days–>1 year


7–45 daysa


>30 days

Tuberculin test (TST) IGRA

Schistosomiasis Intestinal helminths Filariasis

21–>60 days 3–>60 days ?–>1 year

Serum antibody tests Stool microscopy Serum antibody tests Serum antigen test (Wuchereria bancrofti) Nocturnal microfilaremia (W. bancrofti) Serum antibody tests Ocular microfilaria

Filariasis (onchocercosis)

3–>15 months

Filariasis (loiasis)

?–>12 months


7–>21 days


14–>90 days


9–>90 days

Hepatitis B

1–6 months

Hepatitis C

2 weeks–6 months 5–14 days

Trypanosoma cruzi (Chagas disease) a

Time Lapse After Which Asymptomatic Infection Becomes Very Unlikely Given Negative Screen

Thick film, (antigen test) Serum antibody testa (Plasmodium ovale, P. vivax) Stool culture Serum antibody test (Widal)

Serum antibody tests Daytime microfilaremia Serum antibody tests Stool microscopy (concentration) or stool PCR or antigen test Serum antigen/antibody test (HIV-ELISA/p24) HIV-viral load RPR and VDRL TPHA, FTA Serum antigen test (HBsAg) Serum antibody tests (HBsAb, HBcAb) HBV DNA Serum antibody tests HCV-RNA Serum antibody test PCRa

Convalescent carrier state Negative test excludes recent infection, poor specificity Asymptomatic infection Asymptomatic infection in BCG vaccinees Asymptomatic infection Active infection Exposure or active infection Active infection

Benign tertian: 2–4 years Quartan: >10 years 2 months

2–4 months (asymptomatic infection—risk lifelong) 3–6 months, exceptionally longer 2 months Up to 2 years

Active infection Exposure (low sensitivity) Active infection, requires ophthalmologic examination Exposure or active infection Active infection Exposure, active infection (sensitive, nonspecific) Active infection

Up to 2 years

Active infection: screening

6 weeks–6 months

Active infection, confirmation Active infection Confirmation Postexposure, posttreatment Active or latent infection/disease Immunity, classification of infection activity Active or latent infection/disease Confirmation active infection Latent or active infection Active infection

Up to 2 years 1 month

3 months

6 months

6 months To be followed up serologically until 6 months after possible exposure

These tests are not universally available and not validated, with interspecies cross reactions occurring. BCG, Bacillus Calmette–Guérin; ELISA, enzyme-linked immunosorbent assay; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HRP-2, histidine-rich protein-2; IGRA, interferon-γ release assay; PCR, polymerase chain reaction; RPR, rapid plasma regain; VDRL, Venereal Disease Research Laboratories.

CHAPTER 55  Posttravel Screening gonorrhea and chlamydia usually involves urine sampling for nucleic acid amplification testing (NAAT), and often direct pharyngeal and/or rectal sampling for NAAT or culture.15 Direct sampling may be unacceptable to asymptomatic patients, particularly women, and may be reserved for travelers engaging in high-risk sexual behavior (i.e., frequent unprotected sex with multiple partners).16 Screening for HIV may prevent further transmission and may improve infection management, through the early initiation of antiretroviral treatment. The current combined HIV antigen (p24 or nucleic acid detection) and antibody assays are highly specific and sensitive, even in recent infection. It allows reliable screening of any traveler with a history of sexual contact with a new partner within a time period of 3 weeks to 3 months after exposure.16 In syphilis, seroconversion (Venereal Disease Research Laboratories [VDRL] or rapid plasma regain [RPR]) may happen only after disappearance of the primary chancre, which may go totally unnoticed, and testing may need to be repeated. Screening for HIV and syphilis, but also for hepatitis B and C, and for American trypanosomiasis (Chagas disease) may be indicated for recipients of blood transfusions in developing countries where blood screening procedures are often less complete and reliable.

Viral Hepatitis Hepatitis B, which may be considered an STI and/or a tropical infection, shou1ld be considered in posttravel screening. The prevalence of chronic active hepatitis B in many populations from developing countries is high even though infection is often asymptomatic. Vaccination offers satisfactory protection in 95% of people. In unvaccinated travelers with unprotected sexual contacts or exposure to blood or body fluids, including injections or tattoos using potentially contaminated equipment, testing for hepatitis B surface antigen will detect recent infection or carrier state. Testing for both hepatitis B surface and core antibodies provides information on past exposure and seroconversion, or on previous vaccination. Screening for hepatitis A virus (HAV) may be indicated for the nonvaccinated to investigate a compatible resolved illness and to assess the need for vaccination in view of future travel. Although hepatitis C virus (HCV) prevalence is relatively high in some developing country populations, heterosexual practices do not play an important role in its transmission. Systematic screening of asymptomatic low-risk travelers is probably not cost effective, unless their HCV status has not been previously tested during a general health assessment. The availability of direct-acting anti-HCV antivirals makes systematic screening of the general population for HCV an attractive option, and makes restriction to specific travel-related exposure redundant.17 HCV antibody assays are increasingly reliable, but a serum HCV-RNA test is required to demonstrate active infection. Repeated HCV screening can be restricted to men who have sex with men and those who report high-risk behaviors.

Dengue It is tempting to seek confirmation of past dengue infection in asymptomatic travelers returning to an endemic area, and to ascertain whether there is increased risk for hemorrhage and/or vascular collapse if reinfected. However, routine serology is not the best tool to achieve that goal. Interference with other (flavi)virus vaccinations (yellow fever, Japanese encephalitis, tickborne encephalitis) or infections (West Nile virus, Zika virus) frequently produces false-positive test results. Dengue serologic response wanes over time. The absolute risk of serious complications from dengue, whether primary or secondary, remains very low in travelers.

Zika.  Given the potential for devastating complications of the congenital Zika syndrome, screening pregnant women who have returned from


areas with Zika transmission is recommended, even if they are asymptomatic. Pregnant women who have had unprotected sexual contact during gestation with partners who may be infectious following travel to these areas should also be screened. Posttravel screening of male partners of women planning to conceive may also be considered even if they are asymptomatic because sexual transmission of Zika virus is possible in this context for months after exposure.18 A negative Zika IgM and IgG antibody test performed in travelers at least 3 weeks after last exposure greatly reduces the likelihood of infectiousness. However, practitioners need to be familiar with the sensitivity and specificity of the specific assays available to them to accurately counsel partners attempting conception without waiting for the contagious risk period to elapse.

Foodborne Infections Travelers’ diarrhea is a very frequent phenomenon, affecting up to 30% of short-term travelers. Most bacterial infections are self-limiting and do not require a posttravel follow-up. When traveling to countries with a high prevalence of extended spectrum beta-lactamase (ESBL) strains among the gut flora, antibiotic treatment substantially increases the likelihood of past travel carriage of these multidrug-resistant Enterobacteriaceae. These strains take many months to clear, and should be considered in case of a subsequent infection (e.g., of the urinary tract).19 Screening for carriage of enteropathogenic agents is not required unless there is a public health concern for transmission, such as salmonellosis in asymptomatic food handlers.20 There is a growing consensus that antibiotic treatment of mild to moderate travelers’ diarrhea should be discouraged, and that symptomatic treatment with loperamide may suffice. Combining loperamide with antibiotic treatment may improve diarrheal illness, but increases the ESBL carrier rate more than antibiotics alone.

Screening for Parasitic Diseases

Introduction.  Although parasitic infections other than malaria in travelers are not rare, only a handful are relatively common and may cause serious morbidity: strongyloidiasis, schistosomiasis, invasive amebiasis, and filariasis, particularly the lymphatic form.21 Some intestinal protozoa can be carried for prolonged periods with few or no symptoms, but may pose a risk of transmission to others, such as amebiasis and giardiasis. Travelers rarely acquire high burden infections with intestinal helminths, and low numbers of worms are only occasionally associated with symptoms or complications. In general the sensitivity of tests for helminth detection is limited, and these tests are often cumbersome or invasive. As a result, serology is commonly preferred for screening asymptomatic travelers, at least for those types of invasive infections where serologic assays are commonly available. When using these tests, it is important to be aware that serology has some unavoidable problems related to defining sensitivity and specificity. As a rule, many travelers will have antibodies detected, but the actual worms or eggs cannot be identified in clinical specimens. There is often no way to ascertain whether these are true or false positive results. Cross reactivity among various helminth infections remains a persistent problem. Declining antibody titers after empiric treatment provides indirect evidence of infection, but may be an effect of time alone. Sensitivity can also be difficult to define, with false negatives potentially due to low burden infection, antigenic variation among parasite strains, and individual variations in antibody production in response to these antigenically highly complex organisms. Traditional microscopic tests have been the gold standard for parasitic diagnostics for many decades. In the past few years, molecular techniques have been developed and marketed, and show great promise, at least in terms of improving turnaround time and variations in testing quality


SECTION 10 Posttravel

related to the skill of the microscopist. Some evaluations of these tests in the returning traveler have been published, and are discussed in the subsections below.22

Strongyloidiasis.  Strongyloidiasis may persist lifelong through its endogenous reinfection cycle and may produce a potentially lethal disseminated hyperinfection in patients on high-dose steroids or other immunosuppressants, or in immunocompromised persons. As such, this is one of the few travel-associated infections that may be completely asymptomatic and still pose a risk for severe morbidity. Screening is clearly warranted in potentially exposed travelers who have an immunosuppressive illness or are planning immunosuppressive treatment, no matter how remote their travel may be. Skin exposure to soil contaminated with human feces is the usual route of infection, and the use of footwear outdoors makes exposure unlikely. Symptoms may be vague or absent, and may need to be elicited by specific questioning. Common symptoms include dyspepsia unrelieved by acid reduction medication, the appearance of hives posttravel, or the intermittent appearance of rapidly migrating serpiginous skin lesion, known as larva currens, typical somewhere between the nipples and the knees. Eosinophilia is often absent or only mildly elevated.8 Sensitivity of single stool microscopy using routine concentration methods for the detection of larvae is low. Specific concentration methods such as the Strongyloides stercoralis agar plate “culture” test can increase sensitivity.23 Assays using stool antigen, or nucleic acid detection (polymerase chain reaction [PCR]) may be faster and less labor intensive, but not more sensitive than conventional examination.24 Serologic assays vary tremendously in sensitivity and specificity, and cross reactions with other helminth species frequently occur. There is no gold standard for resolving cases that are seropositive, but stool examination negative. As a result, it is prudent to consider all untreated seropositive individuals as infected.

Schistosomiasis.  Infection with human schistosomes has to be suspected in any traveler who has been in contact with potentially infected fresh water in endemic regions, primarily in sub-Saharan Africa. This includes swimming, bathing, or wading in rivers, lakes, ponds, or irrigated wet rice fields, but also wading through seasonally flooded areas with runoffs from contaminated freshwater sources. Rarely, a low burden infection may cause severe neurologic impairment, most notably transverse myelitis following embolization of schistosomal eggs or adult worms to the spinal cord and occasionally to the brain.25 The first stage of infection usually passes unnoticed, though a pruriginous papular rash (“swimmer’s itch”) can sometimes appear soon after infection. Primary infection with all human schistosome species may cause a febrile hypersensitivity reaction with fever, cough, and/or abdominal pain when schistosomules mature to adults and start producing eggs—the so-called Katayama syndrome. There is marked hypereosinophilia which typically occurs from 3 weeks to more than 3 months after infection even in asymptomatic persons. Late-stage disease manifestations such as periportal liver fibrosis, extensive colitis (Schistosoma mansoni) or irreversible urinary tract lesions (S. haematobium) are almost exclusively seen in migrants from endemic areas. In travelers, infection with S. haematobium frequently causes microscopic or gross hematuria, or hematospermia, as a result of urinary tract inflammation commonly involving the bladder wall. Urinary schistosomiasis can be a surprise diagnosis when patients undergo cystoscopy or endometrial biopsies. Screening asymptomatic travelers for latent schistosomiasis may be reasonable when there has been known exposure. Antibody detection is both sensitive and specific, and is the preferred screening test, although

it does not provide information about worm load. Serology may be less sensitive for some less common species. Seroconversion usually occurs within 3 months of exposure, but given the wide variation among assays may take up to 1 year. Antibody titers may remain detectable many years after successful eradication. To determine the worm load and the infective species, a fecal and urine sample is examined by microscopy to detect schistosome ova, after applying a concentration method to improve sensitivity (e.g., the FLOTAC test). Soluble antigen tests (e.g., CAA in urine) and molecular tests amplifying schistosome DNA by PCR are still being evaluated as diagnostic tools, and there is increasing evidence that these assays may be more sensitive than stool and urine microscopy, even in early infection, compared with antibody assays.24

(Neuro)cysticercosis.  In asymptomatic travelers, serologic testing (usually with an enzyme-linked immunoelectrotransfer blot assay with purified glycoprotein antigens) for cysticercosis reveals the problems with screening for this disease. A positive serologic test does not necessarily indicate the presence of neurologic disease that may one day become symptomatic. Although a seroprevalence of 8.2% has been reported in Peace Corps volunteers in Madagascar, exploring seropositive asymptomatic travelers thoroughly may be an expensive exercise that risks creating more anxiety than tangible benefits.26

Other Intestinal Helminths.  Other intestinal nematode infections (Ascaris lumbricoides, Trichuris trichiura, hookworm) rarely achieve parasite burdens that lead to significant symptoms in infected adult travelers and expatriates. Exceptionally, Ascaris can present with aberrant migration of adult worms into the biliary or pancreactic ducts. The lifespan of these helminths is about 1 year, and possibly sometimes as long as a few years, and they are not capable of replication within the human host.27 Therefore, even without treatment, these infections will normally resolve over this period of time. In asymptomatic travelers, it is believed that microscopy of a single stool sample subjected to a concentration method for ova and cysts is sufficiently sensitive to detect the majority of clinically significant nematode infections (A. lumbricoides, T. trichiura, A. duodenale, Necator americanus) but is insufficient for S. stercoralis (see previous discussion).

Invasive Amebiasis.  Detection of amebic infection remains problematic. Amebic colitis and liver abscess are by far the most important clinical manifestations of invasive amebiasis, but infection may remain asymptomatic for many months. Stool microscopy for Entamoeba histolytica infection is highly nonspecific in travelers, and consequently useless. The vast majority of asymptomatic amebic cyst passers in fact harbor nonpathogenic E. dispar or related species (>90%). DNA amplification tests have been developed to differentiate both species in stool samples; this is currently the preferred diagnostic tool where available.28 Serum antibody tests for E. histolytica have proven value in amebic liver abscess, and are more sensitive than serum amebic lectin antigen tests.29 Serology is unreliable for amebic colitis, or for microinvasive infection in asymptomatic cyst carriers, both because of low sensitivity and because antibodies persist for many months and even years after eradication. The benefit of treating asymptomatic cyst passers is unclear, nor has optimal treatment been defined. These individuals may be contagious, and thus could be treated as a matter of public health. Traditionally asymptomatic E. histolytica carriers have been treated with “luminal” agents alone. A positive serum antibody test in an asymptomatic traveler could indicate subclinical invasion and might warrant combination treatment with “tissue” amebicides.

CHAPTER 55  Posttravel Screening


Other Intestinal Protozoa.  In asymptomatic travelers Giardia lamblia

Leishmaniasis.  There are no tests to detect the incubation stages of

is the most commonly found intestinal protozoan. Unfortunately it cannot be reliably detected by means of microscopy. Analysis of single stool specimens may have a sensitivity of only 70%.30 Occasionally Isospora belli, Cyclospora cayetanensis, and rarely Cryptosporidium spp. are found in stools of asymptomatic travelers, but require specific staining methods for detection. The treatment of intestinal protozoa found in asymptomatic travelers has no defined benefits other than perhaps reducing the possibility of ongoing transmission in those with suboptimal fecal-oral hygiene. Currently available copro-antigen tests for G. lamblia and Cryptosporidium spp. perform similarly to microscopy in some assessments, and are less time consuming. Likewise, multiplex nucleic acid amplification tests that amplify the DNA of several intestinal nematodes and protozoa in fecal samples perform well.24,31 These platforms may be preferentially used in labs where the high level of skills needed for good microscopy is increasingly difficult to maintain. Microscopy has the advantage that stool parasites of all types can be found, while molecular tests can only identify pathogens from their predefined panels, and unexpected or other rare parasites may be missed.

cutaneous or visceral leishmaniasis. Some sensitive tests, especially molecular tests, can remain positive even after clinically successful treatment.34

Infections With Blood-Dwelling or Tissue-Dwelling Parasites.  There are no data to suggest that the infected returning traveler is likely to develop significant or irreversible pathology in the absence of symptoms. The risk of acquiring a filarial infection is very low in shortterm travelers.8,32 Thus there is little reason to screen asymptomatic travelers for other blood or tissue parasites. Onchocerciasis, lymphatic filariasis, and loiasis are nearly exclusively seen in immigrants and long-term expatriates. Occasionally, relatively mild symptoms may occur periodically in loiasis (Calabar swellings, superficial ocular migration) and in onchocercosis (itching) a long time after exposure. Blood microfilaria may sometimes be found in a “thick film” from unsuspecting travelers infected with Mansonella perstans, and occasionally in those with Loa loa. Serology for filarial disease is often based on a crude antigen which cross reacts with all species of filaria, and often with other parasites as well. However, some reference labs have developed highly species-specific serology and molecular tests which may be useful in individual cases.

Malaria.  In general, there is no reason to perform malaria testing in the asymptomatic traveler. The one exception would be the periodic “tertian” or “quartan” fevers seen in nonfalciparum malaria, and sometimes in falciparum infection as well, when “screening” during the asymptomatic days will reveal the diagnosis. There are no tests currently available to detect the latent hepatic phase of Plasmodium vivax or P. ovale, and thus identify candidates for preventive therapy with primaquine. There may be benefit to screening “semiimmune” individuals (usually immigrants) who may have low-level infection with minimal or no symptoms. Many travelers who have been treated for malaria during travel are anxious to have the diagnosis confirmed. Malaria antibody detection is sensitive but cross reactions between species occur. Antibodies against the blood-stage parasites persist for at least 2 months after treatment. It may be of use in the retrospective diagnosis of malaria in nonimmune travelers.33 The main practical benefit is in “proving” to seronegative individuals who took prophylaxis that the malaria diagnosis was in error. The antigen test targeting histidine-rich protein-2, which is specific for P. falciparum, can be used to confirm a recent infection (2 weeks after return from Thailand is not likely to be related to dengue fever. Remote travel is sometimes relevant, but most severe, acute life-threatening infections result from exposures that have occurred within the past 3 months. Important treatable infections that may occur >3 months after return include malaria, amebic liver abscess, and visceral leishmaniasis. In the study by O’Brien et al.11 analyzing patients hospitalized with fever after travel, 96% were seen within 6 months of return from travel; in the study by Bottieau et al.9 of patients referred for fever after tropical travel, fever occurred during travel or within 1 month of return home in 78%. Although the initial focus should be on travel within the past 3–6 months, the history should extend to include exposures a year or more earlier, if the initial investigation is unrevealing. More than a third of malaria-infected travelers in a study from Israel and the United States had illness that developed >2 months after return from endemic areas.19 Onset of illness >6 months after return occurred in 2.3% of malaria patients reported to the CDC in 2009.20 Table 56.2 lists many of the infections seen in travelers by time of onset of symptoms relative to the exposure and the initial clinical presentation. In assessing potential incubation period one must take into account the duration of the trip (and points of potential exposure during travel) and time since return.


SECTION 10 Posttravel

TABLE 56.2  Common Infections, by Incubation Periods Usual Incubation Period (Range)


6–30 days 4–8 days (3–14 days) 2–4 days (1–14 days) 3–14 days Few days to 2–3 weeks 7–12 days (2–26 days) 7–18 days (3–60 days) 8–30 days (often >1 month to 1 year) 1–3 days 5 days (2–14 days) 10–28 days (10 days to 6 weeks) 5–6 days (2–10 days) 3–14 days (1–20 days)

Tropics, subtropics, highest risk in sub-Saharan Africa Tropics, subtropics Tropics, subtropics (eastern hemisphere) Tropics, subtropics Widespread, causative species vary by region Widespread; most common in tropical areas Especially in Indian subcontinent and Southeast Asia Widespread in tropics/subtropics Worldwide; can also be acquired en route Middle East Worldwide Widespread Specific agents vary by region

See above distribution for relevant diseases

Hepatitis A Hepatitis E Acute schistosomiasis (Katayama syndrome) Amebic liver abscess

See above incubation periods for relevant diseases 28–30 days (15–50 days) 26–42 days (2–9 weeks) 4–8 weeks Weeks to months

Incubation >6 Weeks Malaria, amebic liver abscess, hepatitis E, hepatitis B Tuberculosis Leishmaniasis, visceral

See above incubation periods for relevant diseases Primary, weeks; reactivation, years 2–10 months (10 days to years)

Disease Incubation 15 days. The cutaneous


SECTION 10 Posttravel

FIG. 57.12  Tungiasis of the toe (Ivory Coast).

lesion is a black papule (at the site of penetration) that develops into a nodule through which the eggs of the flea are expelled (Fig. 57.12). There is a limited number of nodules (most commonly one), which are usually located on the feet (subungual, sole, toe) and lower extremities.6,26,27 The diagnosis relies on clinical findings and is confirmed by the morphology of the flea. The differential diagnosis includes myiasis, pyoderma, and foreign body reaction. The treatment is removal of the flea by curettage.1

Cutaneous Gnathostomiasis Cutaneous gnathostomiasis is increasingly reported in travelers returning from endemic countries.1 The largest series of imported cutaneous gnathostomiasis include five patients returning from Southeast Asia.28 The cutaneous lesions appeared within a mean period of 62 days (range 10–150 days) after return. They consisted of creeping eruptions in three patients, migratory swellings in two, papules and nodules in one. The mean eosinophilic count was 1556/mm3 (range 398–3245/mm3). The diagnosis relied on positive serologic tests in two patients and seroconversion in two, and was confirmed by identification of Gnathostoma hispidum in one biopsy specimen. The treatment of cutaneous gnathostomiasis consisted of repeated courses of albendazole or two courses of ivermectin.

Other Tropical Dermatoses of Interest for Travelers Many other tropical dermatoses (e.g., acute filariasis, loiasis, onchocerciasis, West and East African trypanosomiasis, mucosal leishmaniasis, genital amebiasis, Buruli ulcer, cutaneous anthrax) have been observed in travelers.1 African trypanosomiasis as well as schistosomiasis may often be revealed by dermatologic manifestations. Cutaneous signs are possible at all the phases of these two diseases. In both instances recognition of the early cutaneous sign may allow a rapid diagnosis.1 African trypanosomiasis may be revealed by trypanosomal chancre (Fig. 57.13). Cases of acute onchocerciasis acquired in West or Central Africa and responsible for limb lymphedema (Fig. 57.14) have been reported.29 Numerous cases (including clusters) of tropical diseases which cause febrile rash (e.g., rickettsial diseases, dengue fever, acute schistosomiasis) have been reported in travelers (see Febrile Rash later in the chapter 56).1

COSMOPOLITAN DERMATOSES Pyodermas Skin and soft tissue infections (SSTIs) are the first cause of skin consultations in returning travelers.6–8 The lesions usually appear while the

FIG. 57.13  Trypanosomal chancre (Congo).

patient is still abroad. The clinical spectrum is broad ranging, from impetigo (Fig. 57.15) and ecthyma to erysipelas and necrotizing cellulitis.6,30 The most common bacterial species involved are Staphylococcus aureus and Streptococcus pyogenes. Whereas ecthyma, erysipelas, and cellulitis are more likely to be due to Streptococcus spp., others such as folliculitis, carbuncles, and abscesses are more related to S. aureus while impetigo may be due to both.30 There are three causes of concern with S. aureus–related SSTI. First, S. aureus methicillin-resistant (MRSA) or methicillin-sensitive S. aureus (MSSA) can carry the Panton-Valentine leukocidin (PVL), a cytotoxin that confers higher morbidity by causing leukocyte destruction and tissue necrosis. Second, S. aureus strains acquired abroad may be subsequently transmitted after returning home in the family and then in the community.31 Long-term travelers could also present more often with posttravel recurrent S. aureus furuncles that only subside after returning home.32 Third, travelers to foreign countries are at risk of acquiring staphylococcal strains with unusual profiles of antibiotic resistance.33 Therefore culture and drug susceptibility tests should always be performed in returning travelers to assess a possible infection with multidrug-resistant strains of S. aureus.33 In addition when an empiric treatment is chosen against a presumed staphylococcus-related infection, it should be chosen according to the profile of antibiotic susceptibility at the travel destination as it has been shown that choosing antibiotics

CHAPTER 57  Skin Diseases


Most of the cases of SSTI are secondary to an insect bite.6,30 This points toward the importance of insect protection in the prevention of pyodermas. In addition, travel first-aid kits should include antibiotics effective against bacterial infections, at least in susceptible persons (history of erysipelas or infectious cellulitis, presence of venous or lymphatic insufficiency).

Dermatophytosis Dermatophytosis, or tinea, is a worldwide cutaneous fungal infection but its incidence is higher in the tropics and subtropics. Tinea infections rank among the most common skin diseases observed during travel abroad.1 According to the at-risk exposure during travel, all the forms of tinea may be described: tinea corporis, tinea barbae, tinea cruris, tinea axillaris, and tinea unguium. Tinea of the feet is probably the most common dermatophytic infection to be encountered in travelers who are not going barefoot or wearing sandals. The predominant agent of tinea pedis is Trichophyton rubrum. Three clinical varieties may be described: the intertriginous type; the vesicular, bullous, or vesiculobullous type; and the squamous or hyperkeratotic type. Scalp ringworm is a common variety of dermatophytosis in children coming back from visiting friends and relatives in Africa. Tinea versicolor is a chronic, superficial yeast infection of the epidermal stratum corneum.1 It is worldwide, but extremely common in the tropics and subtropics. Tinea versicolor is caused by the hyphal form of Malassezia furfur. The characteristic clinical lesion is a welldefined round or oval macule covered with adherent fine scales. The macules may remain isolated, but have a tendency to coalesce, and cover large areas of the body on the chest, shoulders, back, and neck. Usually asymptomatic, the eruption may become pruritic in hot climates. The diagnosis is evoked on the distribution, shape, and appearance of the patches and the fingernail test, which demonstrates the fine scales, limited to affected spots. The final diagnosis relies on the microscopic examination of a scotch tape. FIG. 57.14  Limb lymphedema related to onchocerciasis (Cameroon).

FIG. 57.15  Impetigo complicating arthropod bites (French West Indies).

among empiric recommended treatment would have led to 15% failure.34 A selective and targeted screening of travelers with risk factors for MRSA colonization should be discussed more particularly in health care professionals (to reduce the transmission of MRSA to vulnerable patient populations) and patients (to avoid nosocomial infection with such a strain).33

Arthropod-Related Dermatoses Exposure to an arthropod (Chapter 48) is a common cause of skin lesions in travelers.6–8 Attempts to identify the implicated arthropod are often difficult in that arthropods of different species may give rise to similar dermatologic manifestations.1 Nevertheless epidemiologic exposures suggested by history are useful. The clinical picture varies according to the nature of the skin injury (e.g., traumatic injury, local envenomation, hypersensitivity reaction). The predominant feature of the arthropod reaction is prurigo, an eruption of intensely pruritic erythematous and excoriated papules (Fig. 57.16). This reaction is considered to be an evolutive stage of papular urticaria related to a hypersensitivity reaction to the bites of insects such as fleas, bedbugs, and less commonly mosquitoes, chiggers, and mites. Arthropod bites may also result in vesiculobullous lesions and papular urticaria. Cutaneous lesions are self-limited. Oral antihistamines and topical corticosteroids may improve the symptoms.

Scabies Scabies is the most common cause of generalized pruritus in travelers.6,7 Scabies is acquired by skin-to-skin contact. Clinically the patient complains of pruritus within 4 weeks of contact in cases of primary exposure.1 In patients with a history of previous scabies exposure, pruritus may occur within a few days. The more specific skin findings include burrows, papulonodular genital lesions, and pustules on the hands. Other skin changes are secondary to pruritus and include excoriation, lichenification, and impetiginization.


SECTION 10 Posttravel

FIG. 57.16  Prurigo after exposure to trombiculidae (Brazil).

FIG. 57.17  Erythematous flagellations after contact with jellyfish (Thailand).

The diagnosis is made by the microscopic identification of the S. scabiei var. hominis mite, eggs, or feces on skin scrapings of a cutaneous lesion. Treatment includes permethrin cream 5%, lindane 1% (γ-benzene hexachloride), benzyl benzoate (in Europe), and ivermectin. Bedding and clothing must be laundered or removed from contact for at least 3 days. Personal and household contacts must also be treated.

Cercarial Dermatitis Cercarial dermatitis (also called clam-digger’s dermatitis, schistosome dermatitis, sedge pool itch, swimmer’s itch) is caused by the infestation of the skin by cercariae (larvae) of nonhuman schistosomes whose usual hosts are birds and small mammals.35 Cercarial dermatitis is acquired by skin exposure to fresh and, to a lesser extent, salt water. The cercariae penetrate intact human skin within a few minutes. Cercarial dermatitis occurs in swimmers and those with occupations that include water exposure. There are sporadic reports and few outbreaks reported from all continents. The time from exposure to onset of symptoms varies from a few minutes to a maximum of 24 hours after exposure.35 A prickling sensation during or shortly after exposure to infested water may be reported. Typically, and approximately 1 hour later, the cutaneous lesions begin as a pruritic macular erythematous eruption that progresses to a papular, papulovesicular, and urticarial eruption. The eruption typically covers skin surfaces that are exposed to water, but the skin surfaces that are covered by swimwear are not spared. The eruption peaks in 1–3 days and lasts 1–3 weeks. In cases of previous contact, the clinical findings may begin sooner with increased severity and a prolonged course.35 The diagnosis is made by history of exposure and the characteristic clinical findings. The differential diagnosis includes sea-bather’s eruption, contact dermatitis (secondary to marine plants, hydroids, and corals), and insect bites. Cercarial dermatitis is self-limited. Oral antihistamines and topical steroids reduce the symptoms.

Sea-Bather’s Eruption Sea-bather’s eruption (also called sea lice) is acquired by skin exposure to salt water inhabited by larvae of sea anemone and jellyfish.36 Seabather’s eruption is caused by the larvae discharging toxin from nematocysts into human skin. Sea-bather’s eruption has been reported on the Atlantic coast of the United States, the Caribbean, Central and South America, and in Southeast Asia. It probably exists worldwide in tropical and subtropical marine environments. The time from exposure to onset of symptoms is usually a few minutes to 24 hours. Individuals with a history of previous exposures

may develop a prickling or stinging sensation or urticarial lesions while in the water. The clinical features include pruritic, erythematous macules that progress to papules, vesicles, and urticarial lesions. The anatomic distribution typically includes skin surfaces covered by swimwear and uncovered skin surfaces where there is friction (e.g., axillae, medial thighs, surfer’s chest). The eruption is more pronounced in areas that are more confined (e.g., waistband). The eruption can last from 3 days to 3 weeks. The diagnosis is made by the characteristic clinical findings and history of exposure. The differential diagnoses include cercarial dermatitis, contact dermatitis (secondary to marine life inhabitants), and insect bites. Sea-bather’s eruption is self-limited. Oral antihistamines and topical steroids may reduce the symptoms.

Marine Life Dermatitis Dermatoses associated with contact with a marine creature (Chapter 48) are one of the most frequent causes of disease in travelers to tropical islands, causing about 1% of the consultations in returning travelers, the most common resulting from contact with jellyfish, corals, and stonefish.37 The most dangerous creatures are the coelenterates, which are found worldwide in tropical and subtropical waters.37 Contact with Portuguese man-of-war, fire coral, jellyfish, and sea anemone immediately produces a stinging sensation that varies from a slight burning sensation to excruciating pain. The cutaneous lesions appear at the site of exposition within a few minutes, begin as macules and papules, and may progress to vesicles, bullae, and ulceration (Fig. 57.17). Contact with a jellyfish may result in systemic symptoms such as hypotension, muscle spasm, and respiratory paralysis, and may be fatal. Sea urchins and other echinoderms may produce similar cutaneous and systemic symptoms as observed with coelenterates. Other dangers of the marine environment include shark and Moray eel bites, cones stonefish and firefish stings, sea leech burns, and coral cuts and scratches. Marine envenomations may be complicated by severe infectious complications with marine bacteria, especially Aeromonas hydrophila, Vibrio vulnificus, Chromobacterium violaceum, and Shewanella infections.38

Photosensitivity and Photo-Induced Disorders Ultraviolet (UV) irradiation has both acute and chronic effects on the skin. In the traveler, skin changes due to acute sun exposure are common,

CHAPTER 57  Skin Diseases including sunburn, phototoxic reactions, both drug induced and plant induced (phytophotodermatitis), photoallergic reactions, solar urticaria, polymorphic light eruption, actinic prurigo, and hydroa vacciniforme. Chronic sun exposure over the years results in dermatoheliosis, including chronic actinic dermatitis, lentigines, actinic keratoses, and skin cancer. Sun exposure is indeed associated with the development of squamous cell carcinomas, malignant melanomas, and basal cell carcinomas.39 Populations at increased risks of UV-associated skin cancers include children, fair-skinned persons, patients taking photosensitizing drugs, and organ transplant recipients. The public knows little about proper sunscreen protection, selection, and use. Moreover travelers often abuse sunscreens for intentional UV overexposures. Therefore the regular use of broad-spectrum sunscreens and sun protection is recommended in all sun-exposed subjects, especially children and the immunosuppressed.40

Other Cosmopolitan Dermatoses of Interest to Travelers Hypersensitivity reaction to drugs, not only daily medications but also prophylaxis, must always be considered in the differential diagnosis of urticaria and exanthema in travelers.1 Mycobacterial cutaneous infections are a possible complication of medical tourism as a growing number of westerners undergo plastic surgery in developing countries. Exacerbation of chronic diseases such as acne, atopic dermatitis, lupus erythematosus, dermatomyositis, pemphigus foliaceus, and several of the porphyries may occur, and some of them result from sun exposure. Other dermatoses of interest include miliaria rubra, frostbite, plant-related dermatoses, and contact dermatitis.


TABLE 57.3  Relevant Historical Data in

the Evaluation of Skin Lesions in the Traveler

Travel History Duration of travel Duration of time since return Geographic locations visited Recent outbreaks of disease in locations visited Fellow travelers with similar signs and symptoms Means of transportation Housing and lifestyle, dietary habits Clothing and shoes worn Exposures: beach, fresh or salt water, rural, plants, insects, animals, sexual contacts Medications: therapeutic and prophylactic Use of personal preventive measures: insect repellent, mosquito net Previous medical care Immunization against tetanus Dermatologic History Underlying skin diseases Alteration of skin integrity during travel Time of onset relative to potential exposures Time of onset relative to return Description of initial presentation and anatomic distribution of lesion(s) Description of progression of lesion(s)

DIAGNOSIS OF A SKIN LESION IN THE TRAVELER The evaluation of a traveler with skin lesions first includes an extensive history with a focus on possible epidemiologic exposures.1 The differential diagnosis is broadened. It depends on factors such as geographic location visited, length of stay, among other entities (Table 57.3). Complete physical examination will focus on the appearance of cutaneous lesions because dermatologic diseases are classified according to their morphologic characteristics—for example, type (e.g., macule, papule, nodule, vesicle, ulcer), color (e.g., skin colored, red, brown, blue, black, hyperpigmented, hypopigmented, depigmented), shape or configuration (e.g., round, oval, annular, serpiginous, linear, zosteriform, reticulated), and distribution (e.g., localized, generalized, limited to a specific anatomic location). Further diagnostic studies such as blood tests and serologies, skin biopsy and cultures, and imaging techniques may be warranted according to the results of clinical examination. Diseases with dermatologic manifestations that are encountered by travelers are listed according to the type of cutaneous lesion and history in Table 57.4. In addition some symptoms, signs, or syndromes warrant further consideration given their frequency in travelers.1

Pruritus The diagnosis of a pruritic dermatosis relies mainly on the location of the symptoms and the presence of more specific cutaneous signs (Table 57.5).1 Generalized pruritus usually orients toward scabies, one of the most common causes of skin disease in travelers. Another significant cause of pruritus is ciguatera fish poisoning. Pruritus of unknown origin (PUO) is more frequently seen in immigrants and elderly patients from Africa. PUO in this setting could be due to acclimatization. Self-limited and localized pruritus orients toward an allergic reaction to insect bites or stings.

Creeping Eruption, Cutaneous Larva Migrans Creeping eruption is a clinical sign defined by a linear or serpiginous cutaneous track, slightly elevated, erythematous, and mobile. This eruption must be distinguished from other noncreeping dermatoses that give rise to serpiginous or linear cutaneous lesions.41 More than 90% of the causes of creeping dermatitis are of parasitic origin (Table 57.6).13 Cutaneous larva migrans is a syndrome defined clinically (and parasitologically) by subcutaneous migration of a nonhuman nematode’s larva making the infected human a dead-end host.41 The hallmark is a creeping eruption. This syndrome is due to subcutaneous larval migration of various animal nematodes such as hookworms (hookworm-related cutaneous larva migrans), Gnathostoma spp. (gnathostomiasis), Pelodera strongyloides (and various zoonotic species of Strongyloides), Dirofilaria sp., and Spirurina sp.1 By definition this syndrome does not include diseases in which creeping eruption is due to the subcutaneous migration of a human nematode’s larva (Strongyloides stercoralis, i.e., larva currens), a trematode larvae (Fasciola gigantica), fly’s maggot (migratory myiasis), adult nematode (Loa loa, Dracunculus medinensis), or mites (human scabies due to Sarcoptes scabiei, Pyemotes dermatitis due to Pyemotes ventricosus). The same applies to parasites whose larvae do not give rise to migratory signs when they travel through the skin (onchocerciasis, human hookworms whose larva are just in transit through the skin, i.e., ground itch).41

Urticaria Acute urticaria is a common reason for consultation.1 The causes of urticaria are numerous (Table 57.7). The travel history may provide epidemiologic clues, such as exposure to fresh water (acute schistosomiasis), ingestion of fish (anisakiasis), undercooked meats (trichinosis) and raw vegetables (ascariasis), or walking barefoot


SECTION 10 Posttravel

TABLE 57.4  Dermatoses Encountered by Travelers According to the Type of Cutaneous

Lesion and Nature of Exposure Clinical Presentation

Short-Term Traveler

Long-Term Traveler and Immigrant

Papules and nodules

Adverse drug reaction, acne exacerbation, miliaria rubra, sea urchin granuloma Arthropod bites, tungiasis, myiasis, tick granuloma, lice Pyodermas, mycobacterial infection Leishmaniasis, scabies, cercarial dermatitis, gnathostomiasis, sea-bather’s eruption Sporotrichosis Bacterial cellulitis, pyoderma, Lyme disease Leishmaniasis Dermatophytosis (tinea) Sunburn, blister beetle dermatitis, contact dermatitis, irritant dermatitis, phytophotodermatitis, miliaria rubra, fixed drug eruption Arthropod bites Bullous impetigo Herpes simplex infection Cutaneous larva migrans, cercarial dermatitis, sea-bather’s eruption Spider bite Ecthyma, pyodermas, tache noire (tick eschar) Herpes simplex infection Leishmaniasis Sporotrichosis

Leprosy, tuberculosis, mycetoma, pinta, bartonellosis, glanders, yaws Orf, milker’s nodules Onchocerciasis, cysticercosis, schistosomiasis, dirofilariasis, sparganosis, trypanosomiasis Paracoccidioidomycosis, paragonimiasis, chromomycosis, West African histoplasmosis, lobomycosis African trypanosomiasis

Erythematous plaque

Vesicles and bullae


Varicella infection Dracunculiasis

Cupping Mycetomas, anthrax, tuberculosis, mycobacterial infection, cutaneous diphtheria, glanders, melioidosis, plaguea, yawsa, tularemiaa Cutaneous amebiasis, dracunculiasis West African histoplasmosis, North American blastomycosis, paracoccidioidomycosis, chromomycosis

Any of the diseases listed above that may affect the short-term traveler may also affect the long-term traveler and immigrant and vice versa. a Primary inoculation site.

TABLE 57.5  Causes of Pruritus in


Localized pruritus

Generalized pruritus

TABLE 57.6  Causes of Creeping Eruption Nematode: larva

Contact dermatitis, irritant dermatitis, phytophotodermatitis, arthropod bite, lice, sea-bather’s eruption Cercarial dermatitis, cutaneous larva migrans, enterobiasis (perianal), gnathostomiasis, loiasis, strongyloidiasis (larva currens) Adverse drug reactions, ciguatera fish poisoning, atopic dermatitis exacerbation Varicella (in adult) Scabies Loiasis, onchocerciasis, African trypanosomiasis Schistosomiasis, ascariasis, hookworm, trichinellosis and strongyloidiasis (in association with urticarial rash during invasive phase)

(hookworm, strongyloidiasis). Adverse drug reactions must also be considered in the differential diagnosis of urticaria.1

Febrile Rash The occurrence of febrile maculopapular rash warrants immediate attention. Indeed the association of rash and fever may herald a lifethreatening infectious disease such as hemorrhagic viral fever, meningococcemia, rickettsial infections (Fig. 57.18), or typhoid fever.1 Otherwise it points to adverse drug reaction or viral infection (Table 57.8). The most frequent cause of febrile rash in travelers is probably

Trematode larva Nematode: adult Maggot Mites

Strongyloidiasis (larva currens) Hookworm-related cutaneous larva migrans Gnathostomiasis Dirofiariasis Spirurina Fasciola gigantica Loiasis Dracunculiasis Myiasis (due to Gasterophilus spp.) Human scabies Pyemotes ventricosus

TABLE 57.7  Causes of Urticaria in

Travelers or Expatriates

Adverse drug reaction Hepatitis A infection Invasive phase of helminthic diseases: schistosomiasis, ascariasis, hookworm, strongyloidiasis, and fascioliasis Chronic phase of helminthic disease where man is a dead-end host: trichinellosis, toxocariasis Rupture of cyst during hydatidosis

CHAPTER 57  Skin Diseases


FIG. 57.19  Febrile rash in dengue fever (Thailand).

Edema Localized edematous plaque anywhere on the body surface is always suggestive of infectious cellulitis when inflammatory, and of a reaction to arthropod (cellulitis-like reaction) when pruritic. When localized to a limb, it points to acute lymphatic filariasis, lymphedema of onchocerciasis, or Calabar swelling of loiasis. It may also suggest gnathostomiasis when located elsewhere, and American trypanosomiasis or trichinosis when located on the face.1

Nodular Lymphangitis

FIG. 57.18  Febrile rash in African tick bite fever (South Africa).

Nodular lymphangitis is defined by an eruption of nodules along the lymphatic vessels of a limb, usually the arm or forearm, thus conferring the so-called sporotrichoid pattern.43 This condition primarily suggests cutaneous leishmaniasis and sporotrichosis. However, this sign has been linked to many other causes, such as tularemia, cat-scratch disease, pyogenic infection, or mycobacterial infection.



Adverse drug reaction Meningococcemia (purpura), typhoid fever, syphilis, rat-bite fever, leptospirosis, trench fever, rickettsial infections, brucellosis Measles, rubella, Epstein–Barr virus, HIV and cytomegalovirus primary infection, dengue, chikungunya, West Nile and other arboviral infections, viral hemorrhagic fever African trypanosomiasis, trichinellosis, toxoplasmosis

dengue (Fig. 57.19), with a frequency estimated at 30%.42 The development of a rash within 10 days after return is suggestive of arboviral infection. The skin manifestations of dengue fever, chikungunya fever, and Zika fever are remarkably similar, with a diffuse, sometimes pruritic, macular or maculopapular exanthema in which small islands of normal skin are spared.42 Alternatively the high prevalence of measles and the low vaccine coverage, especially (but not only) in developing countries, can be a problem for nonimmune travelers and can be responsible for measles importation into Western countries, with subsequent outbreaks.

Travel is a major factor contributing to the spread of sexually transmitted infections (STIs), as it can remove many of the social taboos that normally restrict sexual behavior. Between 5% and 51% of short-term travelers engage in casual sex while abroad. Moreover it is estimated that between 25% and 75% of travelers do not use condoms when they have casual sex abroad. Sexually transmitted diseases (STDs) are particularly frequent in travelers. STDs were the sixth cause of consultation, accounting for 3.5% of the 637 diseases diagnosed in travelers returning from the tropics to Paris.7 The spectrum of STDs acquired during travel has been found to be broad.44 The main diagnoses of STDs are gonococcal urethritis, herpes simplex virus-2 infection, and Chlamydia trachomatis infection; primary syphilis and primary human immunodeficiency infection may also be diagnosed. Gonococcal infection is the most frequent cause of STDs in travelers. STDs contracted in tropical areas may be unusual (donovanosis, lymphogranuloma venereum, chancroid) or have a different antibiotic susceptibility profile from that seen in Western countries. Genital ulceration suggests primary syphilis, herpes and chancroid, possibly donovanosis, and rarely lymphogranuloma venereum. A genital discharge points to gonococcal, C. trachomatis, or Mycoplasma genitalium infections. Inguinal suppurative bubo suggests chancroid when it is close to a genital ulcer (Fig. 57.20) and lymphogranuloma venereum when it


SECTION 10 Posttravel

FIG. 57.20  Genital ulcer associated with inguinal bubo, chancroid (Mali).

follows a self-healing genital lesion. When these pathogens are acquired abroad, it is preferable to test for antimicrobial susceptibility as some strains may be resistant to common antibiotics.

CONCLUSION Travelers abroad must be instructed to take precautions to prevent the most common skin diseases during travel. They must be appropriately vaccinated against tetanus before departure and specifically instructed to avoid arthropod bites, sun overexposure, and STIs. They should be informed of the risk of acquiring localized cutaneous leishmaniasis, hookworm-related cutaneous larva migrans, tungiasis, pyoderma, and STIs. Travel first-aid kits should include antibiotics effective against bacterial skin infection, oral antihistamines, and corticosteroid ointments.

REFERENCES 1. Hochedez P, Caumes E. Common skin infections in travelers. J Travel Med 2008;15:223–33. 2. Hochedez P, Vinsentini P, Ansart S, et al. Changes in the pattern of health disorders diagnosed among two cohorts of French travelers to Nepal, 17 years apart. J Travel Med 2004;11:341–6. 3. Raju R, Smal N, Sorokin M. Incidence of minor and major disorders among visitors to Fiji; Travel medicine 2. Proceedings of the Second Conference on International Travel Medicine. Atlanta: International Society of Travel Medicine; 1992. 4. Plentz K. Nontropical and noninfectious diseases among travelers in a tropical area during five year period (1986–1990). Travel medicine 2. Proceedings of the Second Conference on International Travel Medicine. Atlanta: International Society of Travel Medicine; 1992. 5. Caumes E, Le Bris V, Couzigou C, et al. Dermatoses associated with travel to Burkina Faso and diagnosed by means of teledermatology. Br J Dermatol 2004;150:312–16. 6. Caumes E, Carrière J, Guermonprez G, et al. Dermatoses associated with travel to tropical countries: a prospective study of the diagnosis and management of 269 patients presenting to a tropical disease unit. Clin Infect Dis 1995;20:542–8. 7. Ansart S, Perez L, Jaureguiberry S, et al. Spectrum of dermatoses in 165 travelers returning from the tropics with skin diseases. Am J Trop Med Hyg 2007;76:184–6. 8. Lederman ER, Weld LH, Elyazar IR, et al. Dermatologic conditions of the ill returned traveler: an analysis from the GeoSentinel Surveillance Network. Int J Infect Dis 2008;12:593–602. 9. Tremblay A, MacLean JD, Gyorkos T, et al. Outbreak of cutaneous larva migrans in a group of travelers. Trop Med Int Health 2000;5:330–4.

10. Green AD, Mason C, Spragg PM. Outbreak of cutaneous larva migrans among British military personnel in Belize. J Travel Med 2001;8:267–9. 11. Hochedez P, Caumes E. Hookworm-related cutaneous larva migrans. J Travel Med 2007;14:339–46. 12. Heukelbach J, Feldmeier H. Epidemiological and clinical characteristics of hookworm-related cutaneous larva migrans. Lancet Infect Dis 2008;8:302–9. 13. Vanhaecke C, Perignon A, Monsel G, et al. Aetiologies of creeping eruption: 78 cases. Br J Dermatol 2014;170:1166–9. 14. Vanhaecke C, Perignon A, Monsel G, et al. The efficacy of single dose ivermectin in the treatment of hookworm related cutaneous larva migrans varies depending on the clinical presentation. J Eur Acad Dermatol Venereol 2014;28:655–7. 15. Caumes E, Carrière J, Datry A, et al. A randomized trial of ivermectin versus albendazole for the treatment of cutaneous larva migrans. Am J Trop Med Hyg 1993;49:641–4. 16. Melby PC, Kreutzer RD, McMahon-Pratt D, et al. Cutaneous leishmaniasis: review of 59 cases seen at the National Institutes of Health. Clin Infect Dis 1992;15:924–37. 17. Weitzel T, Muhlberger N, Jelineck T, et al. Imported leishmaniasis in Germany 2001–2004: data of the SIMPID surveillance network. Eur J Clin Microbiol Infect Dis 2005;24:471–6. 18. Herwaldt BL, Stokes SL, Juranek DD. American cutaneous leishmaniasis in US travelers. Ann Intern Med 1993;118:779–84. 19. El Hajj L, Thellier M, Carriere J, et al. Localized cutaneous leishmaniasis imported into Paris: a review of 39 cases. Int J Dermatol 2004;43: 120–5. 20. Morizot G, Kendjo E, Mouri O, et al. Cutaneous Leishmaniasis French Study Group. Travelers with cutaneous leishmaniasis cured without systemic therapy. Clin Infect Dis 2013;57:370–80. 21. Blum J, Buffet P, Visser L, et al. LeishMan recommendations for treatment of cutaneous and mucosal leishmaniasis in travelers, 2014. J Travel Med 2014;2:116–29. 22. Hodiamont CJ, Kager PA, Bart AB, et al. Species-directed therapy for leishmaniasis in returning travellers: a comprehensive guide. PLoS Negl Trop Dis 2014;8:e2832. 23. McGarry JW, McCall PJ, Welby S. Arthropod dermatoses acquired in the UK and overseas. Lancet 2001;357:2105–6. 24. Jelinek T, Nothdurft HD, Rieder N, et al. Cutaneous myiasis: review of 13 cases in travelers returning from tropical countries. Int J Dermatol 1995;34:624–6. 25. Lachish T, Marhoom E, Mumcuoglu K, et al. Myiasis in travelers. J Travel Med 2015;22:232–6. 26. Belaz S, Gay E, Beaucournu JC, et al. Tungiasis outbreak in travelers from Madagascar. J Travel Med 2015;22:263–6. 27. Veraldi S, Valsecchi M. Imported tungiasis: a report of 19 cases and review of the literature. Int J Dermatol 2007;46:1061–6. 28. Menard A, Dos Santos G, Dekumyoy P, et al. Imported cutaneous gnathostomiasis: report of five cases. Trans R Soc Trop Med Hyg 2003;97:200–2. 29. Nozais JP, Caumes E, Datry A, et al. A propos de cinq nouveaux cas d’oedème onchocerquien. Bull Soc Pathol Exot 1997;90:335–8. 30. Hochedez P, Canestri A, Lecso M, et al. Skin and soft tissue infections in returning travelers. Am J Trop Med Hyg 2009;80:431–4. 31. Zanger P, Nurjadi D, Schleucher R, et al. Import and spread of Panton-Valentine leukocidin-positive Staphylococcus aureus through nasal carriage and skin infections in travelers returning from the tropics and subtropics. Clin Infect Dis 2012;54:483–92. 32. Artzi O, Sinai M, Solomon M, et al. Recurrent furunculosis in returning travelers: newly defined entity. J Travel Med 2015;22:21–5. 33. Zhou YP, Wilder-Smith A, Hsu LY. The role of international travel in the spread of methicillin-resistant Staphylococcus aureus. J Travel Med 2014;21:272–81. 34. Nurjadi D, Friedrich-Jänicke B, Schäfer J, et al. Skin and soft tissue infections in intercontinental travellers and the import of multi-resistant Staphylococcus aureus to Europe. Clin Microbiol Infect 2015;21(6): 567.e1–10.

CHAPTER 57  Skin Diseases 35. Caumes E, Felder-Moinet S, Couzigou C, et al. Failure of an ointment based on IR 3535 (ethylbutylacetylaminoproprionate) to prevent an outbreak of cercarial dermatitis during swimming races across Lake Annecy, France. Ann Trop Med Parasitol 2003;97:157–63. 36. Freudenthal AR, Joseph PR. Seabather’s eruption. N Engl J Med 1993;329:542–4. 37. Henn A, Pérignon A, Monsel G, et al. Marine envenomations in returning French travellers seen in a tropical diseases unit, 2008-13. J Travel Med 2016;23:tav022. 38. Diaz JH. Skin and soft tissue infections following marine injuries and exposures in travelers. J Travel Med 2014;21:207–13. 39. Diaz JH, Nesbitt LT Jr. Sun exposure behavior and protection: recommendations for travelers. J Travel Med 2013;20:108–18.


40. Lowe JB. Traveling sun smart starts before your patient leaves. J Travel Med 2013;20:67–8. 41. Caumes E. Creeping eruption, a sign, has to be distinguished from hookworm-related cutaneous larva migrans, a disease. Dermatology 2006;4:659–60. 42. Hochedez P, Canestri A, Guihot A, et al. Management of travelers with fever and exanthema notably dengue and chikungunya infections. Am J Trop Med Hyg 2008;78:710–13. 43. Kostman JR, DiNubile MJ. Nodular lymphangitis: a distinctive but often unrecognized syndrome. Ann Intern Med 1993;118:883–8. 44. Ansart S, Hochedez P, Perez L, et al. Sexually transmitted diseases diagnosed among travelers returning from the tropics. J Travel Med 2009;16:79–83.

58  Eosinophilia Amy D. Klion

KEY POINTS • Eosinophilia, as defined by ≥450 blood eosinophils/µL, occurs in up to 10% of travelers. • Eosinophilia may be caused by a variety of conditions, including allergies and asthma, drug hypersensitivity, infection, neoplasia, and other miscellaneous disorders. • One-third of returned travelers with eosinophilia are asymptomatic at the time of presentation, and helminth

infection, notably schistosomiasis, filariasis, strongyloidiasis, and hookworm infection, is the most common treatable cause. • An accurate exposure history is crucial to the evaluation of eosinophilia. • If no specific etiology is identified, empiric anthelmintic therapy should be considered for travelers with eosinophilia.


to helminth-endemic areas (i.e., individuals not previously exposed to helminth infections) than in residents of those areas.2

Eosinophilia, as defined by ≥450 blood eosinophils/µL in the peripheral blood, occurs in up to 10% of travelers1 and may be caused by a variety of conditions, including allergies and asthma, drug hypersensitivity, infection, neoplasm, and other miscellaneous disorders (Table 58.1). Although the utility of screening for eosinophilia in returned travelers remains controversial, eosinophilia may be the first (or only) indication of a condition associated with potentially serious sequelae, such as schistosomiasis or strongyloidiasis, and is often useful in guiding the diagnostic evaluation in symptomatic patients. In this chapter, the causes of eosinophilia in travelers will be reviewed and a systematic approach to patients with eosinophilia in the presence and absence of symptoms will be presented. Whereas blood eosinophil levels are normally ≤450/µL, they can increase dramatically in certain disease states, including acute helminth infection and hypereosinophilic syndrome, reaching levels of >20,000/µL. In these situations, blood eosinophils may undergo characteristic morphologic and functional changes associated with “cellular activation” and eosinophil-induced tissue damage, including endomyocardial fibrosis and peripheral neuropathy. Eosinophil levels may be decreased (eosinopenia) in acute bacterial and viral infections, acute malaria, pregnancy, and in response to certain medications, including corticosteroids, epinephrine, and estrogens. Conversely, the use of β-adrenergic blockers can result in a mild increase in eosinophil counts. The development of eosinophilia in response to a particular stimulus (e.g., helminth infection, allergen exposure) is dependent not only on the nature of the offending agent but also on the host immune response to that agent. In the case of helminth infection, the stage of parasite development, the location of the helminth within the host, and the parasite burden are important determinants of the host immune response, and consequently of the degree of eosinophilia. Although tissue invasion by the parasite tends to be associated with pronounced peripheral blood eosinophilia, the eosinophil response may be restricted to involved tissues. Finally eosinophilia tends to be more pronounced in travelers

CAUSES OF EOSINOPHILIA Overview The list of potential etiologies of eosinophilia is overwhelming. Although the most commonly identified cause of eosinophilia in returned travelers is unquestionably helminth infection, the absence of eosinophilia does not exclude helminth infection. Allergic diseases, including drug hypersensitivity, account for the second largest group of travelers with eosinophilia in most studies. Consequently, although the initial evaluation of travelers with eosinophilia should include screening for the most common helminth infections, noninfectious causes of eosinophilia should be considered before an extensive evaluation for unusual parasitic causes of eosinophilia is undertaken. A definitive diagnosis is found in 16%–45% of travelers with eosinophilia,1,3 and the likelihood of a definitive diagnosis increases with the duration of travel and the degree of eosinophilia (>60% in patients with ≥16% eosinophils1). Surprisingly the presence or absence of symptoms does not appear to influence diagnostic yield.3

Allergic Disorders/Asthma Allergic disorders, including allergic rhinitis, atopic disease, and asthma, are extremely common in the general population and are a common cause of mild eosinophilia. Changes in the external environment associated with travel can lead to an exacerbation (or improvement) in allergic disease; however, marked eosinophilia (≥3000 eosinophils/µL) is rare in the absence of another cause (e.g., helminth infection, drug hypersensitivity).

Drug Hypersensitivity Although drug hypersensitivity is a common cause of eosinophilia in the general population, the prevalence in travelers is unknown. Any drug has the potential to cause eosinophilia, and some are more likely to do so, including many of the agents used to prevent or treat


CHAPTER 58 Eosinophilia Abstract


Eosinophilia is a common finding in returned travelers and may be the only clue to an underlying treatable cause with potentially serious sequelae. Although helminth infection is the most common underlying cause of eosinophilia in most series, the list of potential etiologies is extensive and includes infectious and noninfectious causes. Consequently an accurate exposure history and clinical history are essential to guide the diagnostic evaluation and establish a diagnosis. Despite comprehensive evaluation, the etiology of eosinophilia cannot be identified in many returned travelers. In such cases, empiric anthelmintic therapy should be considered prior to initiating evaluation for uncommon infectious and noninfectious causes.

Allergy Drug hypersensitivity Eosinophil Helminth infection Hypereosinophilic syndrome



SECTION 10 Posttravel

TABLE 58.1  Conditions Associated With

TABLE 58.2  Common Drugs Associated

Allergic Disorders Asthma Atopic dermatitis Allergic rhinitis

Clinical Manifestation


With Eosinophilia in Travelers

Asymptomatic or skin rash

Drug Hypersensitivity (See Table 58.2) Infection Parasitic  Helminth   Ectoparasite (scabies, myiasis)   Protozoan (Cystoisospora belli, Sarcocystis) Bacterial (resolving scarlet fever, chronic tuberculosis) Fungal (e.g., coccidioidomycosis, allergic bronchopulmonary aspergillosis) Viral (human immunodeficiency virus [HIV])

Pulmonary infiltrates Hepatitis Interstitial nephritis Asthma, nasal polyps

Note: This list is limited to common drugs that may be used in the treatment and prevention of travel-related illnesses, such as malaria, travelers’ diarrhea, skin, and upper respiratory infections.

TABLE 58.3  Helminth Infections

Associated With Eosinophilia

Mild to Moderate Eosinophilia (≤3000/µL) Anisakiasisa Capillariasisa Coenurosis Cysticercosisb,c Dicrocoeliasis Dirofilariasis Dracunculiasis Echinococcosisb,c

Immunologic/Autoimmune Disorders Eosinophilic granulomatosis with polyangiitis Eosinophilic fasciitis IgG4 disease Inflammatory bowel disease Sarcoid Primary immunodeficiency (e.g., hyper-IgE syndrome) Rare Eosinophilic Disorders Idiopathic hypereosinophilic syndromes Eosinophilic gastroenteritis Familial hypereosinophilia Episodic angioedema and eosinophilia

Marked Eosinophilia (>3000/µL) Angiostrongyliasisa Ascariasisa Clonorchiasisa,b Fascioliasisa,b Fasciolopsiasis Gnathostomiasisb Hookworm infectiona,b Loiasisb Lymphatic filariasisb

Other Hypoadrenalism Radiation Cholesterol embolization Lists are not exhaustive.

Antibiotics, including penicillins, cephalosporins, quinolones, quinine and quinine derivatives, macrolides Nonsteroidal antiinflammatory agents; sulfa-containing drugs Tetracyclines; semisynthetic penicillins Cephalosporins; semisynthetic penicillins Aspirin


Neoplasm Eosinophilic leukemia (rare) Myelogenous leukemia Lymphoma, especially Hodgkin Adenocarcinoma of the bowel, lung, ovary, or other solid organs



Echinostomiasis Enterobiasis Heterophyiasis Hymenolepiasis Metagonimiasis Sparganosis Trichuriasis

Mansonellosisb Onchocerciasisb Opisthorchiasisa,b Paragonimiasisa,b Schistosomiasisa,b Strongyloidiasisa,b Trichinosisa Visceral larva migransb


Eosinophilia predominantly during acute phase of infection. Eosinophilia may persist for >2 years. c Eosinophilia is intermittent, likely due to cyst leakage. b

malaria and travelers’ diarrhea (i.e., quinine, quinolones, tetracyclines, and sulfonamides). Prescription and nonprescription drugs, as well as dietary supplements and herbal medications, have also been implicated (Table 58.2). In many instances, drug-induced eosinophilia is entirely asymptomatic. End-organ involvement, such as pulmonary infiltrates, interstitial nephritis, hepatitis, or rash, can occur however, and may be suggestive of hypersensitivity to a particular agent. In addition, some drugs are associated with specific syndromes.


Helminths.  Helminth infections are the most commonly identified cause of eosinophilia in travelers, accounting for 30%–60% of cases, depending on the study.1,4,5 Intestinal nematode infection, filariasis, strongyloidiasis, and schistosomiasis comprise the majority of cases in most studies, but the precise causes depend on the particular population studied and the location and duration of travel. Of note, although

helminth infection is a common cause of eosinophilia, not all patients with documented helminth infection have eosinophilia. In one study of 1107 travelers with schistosomiasis, only 44% had eosinophilia.6 Similar findings have been reported in other helminth infections, including strongyloidiasis and hookworm infection. In addition, helminths that do not invade tissues at all during their life cycle, such as Trichuris and Enterobius, rarely cause eosinophilia. Marked eosinophilia tends to be associated with tissue invasion and is seen in a relatively limited number of infections (Table 58.3). In some infections, including ascariasis and hookworm infection, marked eosinophilia is seen only in the early phase of infection when developing larvae migrate through the lungs or other tissues and come into contact with the cells of the host immune system. In most instances, eosinophilia gradually resolves over time with or without anthelmintic

CHAPTER 58 Eosinophilia treatment. However, chronic eosinophilia does occur in some infections (see Table 58.3).

Ectoparasites.  Scabies infestation occurs worldwide and is an unusual but treatable cause of eosinophilia in travelers.7 Sensitization to the mites and their eggs typically produces intense itching, rash, and erythema, which is accompanied by mild to moderate eosinophilia in up to 10% of cases. Although data regarding eosinophilia and other common ectoparasite infestations are lacking, hypersensitivity reactions can occur in response to flea, bedbug, and tick bites. Rare cases of hypereosinophilic syndrome secondary to myiasis (infestation by fly larvae) have been reported, with complete resolution following removal of the larvae.8

Protozoa.  Protozoan infections, including giardiasis and amebiasis, are not associated with blood eosinophilia. Consequently the identification of protozoa in the stool should prompt further search for an underlying cause. Infection with the intestinal coccidian parasite Cystoisospora belli, which causes diarrhea and malabsorption, is a rare exception to this rule and has been associated with eosinophilia in a minority of cases.9 Sarcocystis has also been associated with outbreaks of acute symptomatic eosinophilic myositis in Malaysia.10

Fungi.  Although rarely reported, peripheral eosinophilia can occur in the setting of a wide variety of fungal infections. Moreover peripheral and tissue eosinophilia are commonly seen in coccidioidomycosis11 and paracoccidioidomycosis,12 fungal infections that may be acquired during travel to endemic areas.

Other.  Bacterial and viral infections typically cause eosinopenia and may suppress eosinophilia from other causes. An important exception is human immunodeficiency virus (HIV) infection. Numerous studies have demonstrated an increased risk of sexually transmitted diseases, including HIV, in travelers. Whereas helminth infection remains the most common cause of eosinophilia in HIV-infected travelers, the differential diagnosis of eosinophilia in an HIV-infected traveler should also include immune dysregulation produced by the HIV infection itself, drug hypersensitivity (the antiretroviral agents nevirapine and raltegravir have been associated with drug reaction with eosinophilia and systemic symptoms [DRESS]), fungal infection, and eosinophilic pustular folliculitis, a chronic pruritic dermatosis seen in advanced HIV disease.13


Other Causes.  Eosinophilia can be seen in a variety of common disorders associated with dysregulation of the immune response, including neoplasms and autoimmune disorders.14 Less frequent etiologies include hypoadrenalism, irradiation, and a variety of primary eosinophilic disorders (see Table 58.1). Although these disorders are unlikely to be caused by travel, eosinophilia arising from any of these conditions may first be detected during a posttravel evaluation.

CLINICAL SYNDROMES Skin/Soft Tissue Involvement Dermatologic problems (Table 58.4) are among the most frequent complaints in returning travelers and are commonly associated with eosinophilia.7,15 In a prospective study of returning French travelers, cutaneous larva migrans, myiasis, filariasis, urticaria, and scabies, all of which can be associated with eosinophilia, were among the 10 most frequent dermatologic diagnoses.7 Exacerbations of preexisting skin conditions such as atopic dermatitis, eczema, and psoriasis can be precipitated by tropical climates and should be included in the differential diagnosis of travel-related dermatologic disorders.15 Although skin biopsy (or skin snips in suspected onchocerciasis) may be necessary in some cases, many dermatologic causes of eosinophilia can be identified by observation alone. Urticaria is a frequent symptom in the general population. In travelers with eosinophilia, urticaria may signal the presence of a drug allergy or a helminth infection. Transient pruritic skin rashes also occur in response to a variety of stimuli, including but not limited to the penetration of the skin by a variety of helminth larvae, such as hookworm species, Strongyloides, and schistosomes. The differential diagnosis of persistent or recurrent dermatitis and eosinophilia is more restrictive, with onchocerciasis, scabies, and hypersensitivity reactions among the most common causes in travelers. Subcutaneous nodules may be present in a number of infections commonly associated with eosinophilia, including onchocerciasis, dirofilariasis, paragonimiasis, fascioliasis, trichinosis, echinococcosis, cysticercosis, coenurosis, sparganosis, and myiasis. In many of these infections, including onchocerciasis and cysticercosis, subcutaneous nodules are painless and easily overlooked. Since excisional biopsy of such nodules can be diagnostic, a careful skin and soft tissue examination should be undertaken if one of these infections is suspected. Over time, with the death of the parasite, nodules may calcify and become detectable in soft tissue films.

TABLE 58.4  Evaluation of Eosinophilia With Dermatologic Manifestations Clinical Manifestation

Most Common Etiologies

Diagnostic Tests


Helminth infection Drug hypersensitivity Idiopathic Onchocerciasis Scabies Drug hypersensitivity Onchocerciasis Myiasis Loiasis Gnathostomiasis Cutaneous larva migrans Strongyloidiasis

Stool for ova and parasites, serology

Chronic pruritic dermatitis

Subcutaneous nodules Migratory angioedema Serpiginous lesions

Skin snips, serology Skin scraping Skin snips, excisional biopsy, serology Visual inspection Serology, midday blood filtration for microfilariae Serology, excision of parasite Visual inspection Serology, stool for larvae

Helminth infections that commonly cause urticaria include ascariasis, fascioliasis, gnathostomiasis, hookworm infection, filariasis, paragonimiasis, schistosomiasis, strongyloidiasis, trichinosis, and visceral larva migrans.


SECTION 10 Posttravel

Invasion of the skin by larval maggots of the Diptera species (myiasis) typically produces painful nodules that may be confused with a furuncle. Visible movement of the maggot within the characteristic central punctum is diagnostic. Painful subcutaneous nodules that migrate are the hallmark of sparganosis, a disease caused by migration of tapeworm larvae of Spirometra species through the subcutaneous tissues of humans or other paratenic hosts.16 Localized, intermittent, migratory angioedema is characteristic of loiasis, a filarial infection that is endemic in Central and West Africa. Adult worms migrating through the subcutaneous tissues are believed to provoke a hypersensitivity reaction (Calabar swelling).2 Swellings are most common on the extremities and face and typically resolve within a few days, only to recur weeks to months later. Eyeworm (migration of the adult worm across the subconjunctiva) occurs in up to 20% of infected patients and, when present, is diagnostic of loiasis. Peripheral eosinophilia is present with rare exception and is frequently marked (>3000 eosinophils/µL). Complications, including eosinophilic endomyocardial fibrosis and encephalitis, are uncommon and are thought to be due to the host immune response to the parasite. Migrating Gnathostoma larvae can cause migratory angioedema indistinguishable from that of loiasis, although localized pain, pruritus, and erythema are more frequent and the swellings tend to last longer (1–2 weeks).17 Migration of larvae to deeper tissues and organs (visceral gnathostomiasis) can occur, producing a wide variety of symptoms. Endemic in parts of Southeast Asia, Central and South America, gnathostomiasis is usually acquired by ingestion of the parasite in inadequately cooked freshwater fish or other intermediate hosts. As in loiasis, symptoms may appear months to years after infection, and eosinophilia is often striking. Whereas recovery of the parasite is necessary for a definitive diagnosis of gnathostomiasis, positive serology in a traveler with migratory subcutaneous swellings, eosinophilia, and an appropriate exposure history is highly suggestive of the diagnosis. Cutaneous larva migrans, or creeping eruption, results when the larval stages of animal hookworms inadvertently penetrate human skin. The appearance of the intensely pruritic, reddened serpiginous track, found most commonly on the feet or buttocks, is diagnostic.18 Larva currens, the serpiginous skin lesions seen in chronic strongyloidiasis, can be easily distinguished from creeping eruption by the evanescent nature of the lesions and the speed with which they migrate (5–10 cm/ hour).19 Whereas peripheral eosinophilia is present in a minority of patients with creeping eruption, it is common in patients with strongyloidiasis and may be the first clue to the diagnosis.

Pulmonary Manifestations Migration of helminth larvae through the lung can cause eosinophilia and migratory pulmonary infiltrates, or Loeffler syndrome (Table 58.5).20 The most common cause of Loeffler syndrome is infection with Ascaris lumbricoides, an intestinal nematode that is worldwide in distribution. Patients typically present with nonproductive cough and substernal burning occurring 1–2 weeks after ingestion of embryonated eggs on contaminated foodstuffs. The symptoms resolve once larval migration is complete (within 5–10 days), but chest x-ray abnormalities and eosinophilia may persist for weeks. Diagnosis is complicated by the fact that eggs may not be apparent in the stool for months, at which time the eosinophilia has generally resolved. Consequently the detection of Ascaris eggs in the stool of a traveler with marked eosinophilia should prompt a search for another cause of the eosinophilia. Although hookworm and Strongyloides larvae also pass through the lungs early in infection, this is rarely associated with pulmonary symptoms. Acute schistosomiasis may present with eosinophilia, cough, and transient pulmonary infiltrates; however, the presence of concomitant gastrointestinal and constitutional symptoms helps distinguish this from Loeffler syndrome.21

TABLE 58.5  Causes of Eosinophilia With

Pulmonary Manifestations

Transient infiltrates Ascariasis, hookworm infection, strongyloidiasis, drug hypersensitivity, acute eosinophilic pneumonia Chronic infiltrates Tropical pulmonary eosinophilia, strongyloidiasis, drug hypersensitivity reactions, hypereosinophilic syndrome, chronic eosinophilic pneumonia, Churg–Strauss vasculitis Eosinophilic pleural effusion Helminths (toxocariasis, filariasis, paragonimiasis, anisakiasis, echinococcosis, strongyloidiasis) Other infections (coccidioidomycosis, tuberculosis) Other causes (malignancy, hemothorax, drug reactions, pulmonary infarct, rheumatologic disease, pneumothorax) Parenchymal invasion with or without cavitation Paragonimiasis, tuberculosis, allergic bronchopulmonary aspergillosis, echinococcosis (rare)

Unlike the transient migratory infiltrates of Loeffler syndrome, the pulmonary infiltrates of tropical pulmonary eosinophilia, a hyperreactive form of lymphatic filariasis, persist in the absence of anthelminthic therapy.22 Nocturnal cough or wheezing is characteristic, and the eosinophilia is accompanied by extremely high levels of serum IgE and antifilarial antibodies. A similar syndrome can be seen in strongyloidiasis.23 Other causes of pulmonary infiltrates recurring over a period of weeks to months include drug reactions, eosinophilic granulomatosis with polyangiitis, chronic eosinophilic pneumonia, and other rare hypereosinophilic syndromes. Eosinophilic pleural effusions have been described in the setting of numerous helminth infections, including echinococcosis, paragonimiasis, and disseminated strongyloides infection. Fungal and mycobacterial infections, hypersensitivity reactions, malignancy, pulmonary infarct, and hemothorax have also been implicated.24 Relatively few infections give rise to eosinophilia and lesions of the pulmonary parenchyma. Although tuberculosis should be considered in any traveler with a cavitary lesion, eosinophilia in tuberculosis is exceedingly uncommon. Other infections to consider in the appropriate epidemiologic setting include paragonimiasis, which can present with cavitary infiltrates and hilar adenopathy, and pulmonary echinococcosis, which typically presents as a solitary cystic lesion.

Gastrointestinal Symptoms Gastrointestinal symptoms are the most frequent complaint in returned travelers presenting to travel clinics.25 When accompanied by peripheral blood eosinophilia, they are most often indicative of a helminth infection, although the onset of a noninfectious gastrointestinal disorder associated with eosinophilia, such as inflammatory bowel disease or eosinophilic gastroenteritis, may coincide with travel. Transient gastrointestinal symptoms, including nausea, diarrhea, vomiting, and abdominal pain, occur in the early stages of a number of helminth infections, including trichinosis, schistosomiasis, paragonimiasis, and hookworm infection. These symptoms may precede the characteristic clinical manifestations of the infection, as in trichinosis, where abdominal pain and diarrhea, if present, develop in the first week after ingestion of contaminated pork (or other meats) as the larvae migrate to the intestine. The well-recognized syndrome of eosinophilia, myalgia, fever, and periorbital edema typically does not appear until 1–2 weeks later as new larvae migrate through the tissues and encyst

CHAPTER 58 Eosinophilia in the muscle.26 Diagnosis in these early-stage infections can be difficult, as serologic tests are often negative and production of larvae and/or eggs may not have been initiated. Although liver fluke infections are uncommon in travelers, they do occur and need to be considered in the differential diagnosis of recurrent cholangitis and eosinophilia in travelers. Obstruction of the biliary system by an echinococcal cyst or aberrant migration of an adult Ascaris worm has also been reported. In Fasciola infection, migration of the fluke larvae through the liver parenchyma causes an acute syndrome of eosinophilia, abdominal pain, fever, and variable hepatomegaly that can last for up to 4 months.27 Multiple small, tunnel-like hypodense lesions can be seen in computed tomography (CT) scans of the liver, and represent microabscesses. Other helminth infections, including toxocariasis,28 can produce a similar clinical syndrome.

Neurologic Disease Neurologic syndromes (Table 58.6) associated with eosinophilia are relatively infrequent in travelers but include eosinophilic meningitis, seizures, focal neurologic deficits, peripheral neuropathy, transverse myelitis, and eosinophilic myeloencephalitis. The most common cause of eosinophilic meningitis in travelers is Angiostrongylus infection, although infection with other helminths,29 fungal infections, drug hypersensitivity, and other noninfectious causes should also be considered. Angiostrongylus infection is most prevalent in Southeast Asia and the Pacific, but occurs in other tropical areas worldwide, including the Caribbean.30 Whereas gastrointestinal symptoms may occur soon after ingestion of the larvae in an infected mollusk or uncooked food contaminated with mollusk slime, the most common presenting complaint is an intermittent excruciating headache occurring after an incubation period of 2–30 days. Lumbar puncture reveals an elevated opening pressure, pleocytosis with ≥10% eosinophils, elevated protein, and normal glucose. Peripheral eosinophilia is marked early in infection but decreases as the infection resolves. Infection is self-limited as larvae do not reach maturity in the human host, and treatment is supportive. Headache and/or seizures in a patient with eosinophilia may be the presenting symptom of a number of helminth infections that affect the central nervous system, including cysticercosis, schistosomiasis, and echinococcosis. Focal neurologic findings may also be present.


Many of these infections have a characteristic appearance on imaging studies that may facilitate diagnosis. For example, the presence of both cystic lesions with surrounding edema and calcifications in the brain parenchyma is highly suggestive of cysticercosis, whereas soap-bubble cystic lesions in a grapelike cluster with calcification are characteristic of Paragonimus infection, and septate lesions with daughter cysts are typical of echinococcal disease. In contrast, the mass lesions with surrounding edema that can occur in the brain and spinal cord in schistosomiasis are indistinguishable from the mass lesions of other causes. Other neurologic syndromes that occur in association with eosinophilia include peripheral neuropathy secondary to nerve compression by angioedema in loiasis, transverse myelitis in schistosomiasis, and potentially fatal eosinophilic myeloencephalitis due to gnathostomiasis.

Fever Because fever can suppress eosinophilia, it is not surprising that the potential etiologies of fever and eosinophilia are few. Drug hypersensitivity should be excluded in all patients. The possibility of a parasitic infection, such as acute schistosomiasis, visceral larva migrans, trichinellosis, fascioliasis, or gnathostomiasis, should also be considered, depending on the exposure history.

Other.  Life-threatening complications, including eosinophilic endo­ myocardial fibrosis, can occur in patients with marked eosinophilia of any cause, including helminth infection.31 Early treatment of the underlying cause is essential in reducing morbidity and mortality.

Asymptomatic Eosinophilia As many as one-third of returned travelers with eosinophilia are asymptomatic at the time of presentation.1 Helminth infection, notably schistosomiasis, filariasis, strongyloidiasis, and hookworm infection, is listed as the most frequently identified treatable cause in most studies.1,4,32

Schistosomiasis.  Although the acute symptoms of schistosomiasis (when present) resolve without treatment within 3–4 months after exposure, the eosinophilia may persist for many years and be the only clue to chronic infection. Central nervous system involvement is uncommon in travelers, but can lead to permanent deficits, underlining the importance of early diagnosis and treatment.

TABLE 58.6  Evaluation of Eosinophilia With Neurologic Manifestations Clinical Manifestation

Most Common Etiologies

Diagnostic Tests

Headache and meningeal signs

Angiostrongylus Gnathostomiasis Coccidioidomycosis Drug hypersensitivity Neoplasm, esp. Hodgkin lymphoma Cysticercosis Echinococcosis Schistosomiasis Paragonimiasis Fascioliasis Trichinosis Toxocariasis Sparganosis Schistosomiasis Loiasis

Lumbar puncture,a serology

Headache and/or seizures

Transverse myelitis Peripheral neuropathy a

CT, MRI, serology

Spine MRI, serology (serum and CSF), stool or urine examination for ova, rectal snip Serology, midday blood filtration for microfilariae

Larvae of Angiostrongylus may be detected in the CSF. CSF, Cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance imaging.


SECTION 10 Posttravel

Filarial Infection.  Whereas all of the filarial infections of humans can present as asymptomatic eosinophilia of many years of duration, infection rates in travelers vary dramatically depending on the location and duration of exposure. Until recently, onchocerciasis was the most common filarial infection in travelers worldwide.33 However, mass drug administration programs have markedly reduced (or eliminated) this infection in most endemic countries with a significant impact on the risk of infection in travelers. Loa loa infection is the most frequently identified filarial cause of eosinophilia in long-term travelers returning from Africa.33 Although symptoms, including urticaria, myalgias, arthralgias, migratory angioedema (Calabar swellings), and eyeworm, are common, some travelers and most residents of endemic areas remain asymptomatic despite microfilariae detectable in the peripheral blood.2

Strongyloidiasis.  In most series Strongyloides infection accounts for a high percentage (up to 38%) of unexplained eosinophilia in travelers and immigrants.5,34 Worldwide in distribution, Strongyloides infection is acquired by penetration of exposed skin by infective-stage larvae. Early in infection the developing larvae migrate through the lungs, and pulmonary symptoms may predominate. Later, infection may be associated with intermittent creeping eruption (larva currens), urticaria, or gastrointestinal symptoms, but is often asymptomatic. Because of the capacity of the third-stage larvae to reinvade the intestinal mucosa or skin of the infected host, untreated strongyloidiasis can persist for decades.35 More importantly, life-threatening dissemination may occur in the setting of immunosuppression. Eosinophilia is present in 40%–80% of immunocompetent patients with strongyloidiasis and may be the only clue to the diagnosis. However, the eosinophilia generally decreases over time and may or may not be present during hyperinfection syndromes.

Hookworm Infection.  Although some patients with chronic hookworm infection complain of vague abdominal pain or nausea, most are asymptomatic. Eosinophilia is usually mild, but may exceed 3000/µL in some cases.36 Since hookworm infection is self-limited in the absence of treatment, eosinophilia rarely persists for >3 years.

EVALUATION OF PATIENTS WITH EOSINOPHILIA Eosinophilia (Fig. 58.1) should always be confirmed with an absolute eosinophil count (eosinophils/µL blood), since an increased percentage of eosinophils may reflect a decrease in the number of noneosinophil leukocytes (e.g., neutropenia) rather than a true increase in eosinophils. Once eosinophilia has been established, the next problem is to establish the etiology. Because the potential causes of eosinophilia are many and the diagnostic tests required to distinguish between them are extensive, a careful history and physical examination are essential. Pretravel eosinophil counts, if available, are useful in determining whether the eosinophilia is related to travel or a preexistent medical problem (e.g., asthma, atopic disease). A detailed drug history, including over-thecounter medications, vitamins, and dietary supplements, should be obtained and agents associated with eosinophilia should be discontinued if possible. Since many infectious agents have restricted geographic distribution or a limited lifespan, a detailed review of recent and past travel can significantly narrow the differential diagnosis of eosinophilia.37 For example, eosinophilia and migratory angioedema in a patient who has traveled only to Southeast Asia would suggest gnathostomiasis, whereas identical symptoms in a patient from West Africa would likely be due to loiasis. Similarly, abdominal symptoms and eosinophilia occurring in a traveler whose last potential exposure was 3 years prior to evaluation is not likely due to ascariasis (lifespan 1–2 years), but could be indicative

FIG. 58.1  Peripheral blood smear from a patient with hypereosinophilia. The black arrow indicates a normal eosinophil with a bilobed nucleus and evenly distributed red-staining granules. The red arrow indicates an activated dysplastic eosinophil with a cleft nucleus and uneven granulation (cytoplasmic clearing). (Photo courtesy Dr. Irina Maric, Department of Laboratory Medicine, Clinical Center, NIH.)

of hookworm (lifespan ≤6 years) or Strongyloides infection (lifespan in decades). The duration of exposure is also helpful, as some helminth infections, such as filariasis, paragonimiasis, and cysticercosis, are uncommon in short-term travelers, whereas others, such as schistosomiasis or trichinosis, require only a single exposure. Most studies have demonstrated an increased incidence of certain infections, including schistosomiasis and HIV, in travelers who report risk-taking behavior; however, the absence of such a history does not exclude infection.3 Nevertheless significant exposures such as a history of swimming in Lake Malawi or ingestion of raw pork may prompt a more thorough search for a particular etiologic agent. Up-to-date information with respect to recent outbreaks or epidemics in the regions visited should be sought, since unusual causes of eosinophilia may be more likely in these settings (e.g., the outbreak of eosinophilic meningitis caused by Angiostrongylus in a group of students visiting the Caribbean30). A history of illness in travel companions can be extremely helpful, as some infections may occur in clusters as a result of exposure to a common contaminated source. A detailed symptom history should be elicited, including symptoms that occurred during or soon after travel but have since resolved, as they may provide important clues to the underlying diagnosis. Similarly, a careful physical examination should be performed, with particular attention to the dermatologic examination, since skin and soft tissue findings, such as larva currens (the fleeting serpiginous rash of strongyloidiasis) and the mild unilateral limb swelling due to early lymphatic filariasis, are easily missed. Although the exposure history, symptoms, and signs may narrow the possible etiologies of eosinophilia in travelers, specific features of the eosinophilia can also be useful. For example, intermittent eosinophilia is characteristic of echinococcosis and cysticercosis, and reflects the inflammatory response to leakage of cyst contents. Marked eosinophilia (≥3000/µL) is most commonly associated with tissue-invasive helminth infections and drug hypersensitivity reactions. If the history and physical examination do not point to a specific diagnosis, three stool specimens should be obtained to look for ova and parasites by direct smear and using a concentration technique. If

CHAPTER 58 Eosinophilia strongyloidiasis is suspected, sensitivity can be improved using specialized techniques such as the agar plate method or Baermann concentration. In patients with potential exposure to Schistosoma haematobium, urinalysis and examination of three midday urine specimens for ova should also be performed. Since these tests are relatively insensitive for the diagnosis of strongyloidiasis and schistosomiasis and because tissue parasites are not detectable in this manner, serologic testing for the most common helminth infections (schistosomiasis, strongyloidiasis, and filariasis) is recommended in all travelers from endemic areas. The utility of additional screening tests, including liver function tests, IgE levels, and chest radiography, remains controversial in asymptomatic returned travelers. These tests, as well as other diagnostic procedures, including biopsies, radiologic studies, and specific serologic tests, should be guided by the patient’s symptoms and exposure history. For example, the initial evaluation of a returned traveler with jaundice and eosinophilia following a trip to rural China should include stool examination for ova and parasites, liver function studies, and abdominal imaging, as well as serologies for schistosomiasis, toxocariasis, and the liver flukes. In contrast, evaluation of the same traveler complaining of dyspnea and cough should include a chest x-ray, sputum for larvae, eggs and acid-fast bacilli, and serologic studies for schistosomiasis, strongyloidiasis, and filariasis. Because of the long prepatent period characteristic of some helminth infections, eosinophilia may occur at a time when parasitologic diagnosis is not possible (e.g., prior to egg secretion or antibody positivity). The clinical manifestations of early infection may be markedly different from those occurring later, further obscuring the diagnosis (e.g., acute schistosomiasis). Repeat stool examinations and/or serology should be considered after 4–8 weeks.

APPROACH TO THE PATIENT WITH UNDIAGNOSED EOSINOPHILIA Despite extensive evaluation, up to 50% of cases of eosinophilia remain undiagnosed.4,5,38 In such cases, empiric anthelmintic therapy should be considered prior to beginning an extensive evaluation for noninfectious etiologies.4,37,38 In a recent prospective study of eosinophilia in 549 immigrants, resolution of unexplained eosinophilia after an exhaustive evaluation (including serologic testing) was observed in 31/33 patients treated with ivermectin (200 μg/kg/d for 2 days), albendazole (400 mg/d for 5 days), and praziquantel (40 mg/kg in a single dose only in patients from areas endemic for schistosomiasis).38 Eosinophilia resolved spontaneously in 20/53 patients without empiric treatment. In patients with persistently elevated eosinophil counts ≥1500/µL, evaluation for eosinophil-related end-organ damage is warranted, as well as a comprehensive evaluation for less common etiologies of eosinophilia.

CONCLUSION Although screening for eosinophilia may not be appropriate in all cases, it can be useful in the evaluation of returned travelers, particularly those with potential exposure to helminth infection. Because of the wide spectrum of causes of eosinophilia, a careful exposure and symptom history is crucial to narrow the diagnostic possibilities. The initial evaluation of all travelers with eosinophilia should include screening for the most common helminth infections to which they may have been exposed, since several of these, including strongyloidiasis, schistosomiasis, and filariasis, are associated with potentially serious long-term sequelae. Common noninfectious causes should also be considered before an extensive evaluation for unusual causes of eosinophilia is undertaken.


REFERENCES 1. Schulte C, Krebs B, Jelinek T, et al. Diagnostic significance of blood eosinophilia in returned travelers. Clin Infect Dis 2002;34:407–11. 2. Herrick JA, Metenou S, Makiya MA, et al. Eosinophil-associated processes underlie differences in clinical presentation of loiasis between temporary residents and those indigenous to Loa-endemic areas. Clin Infect Dis 2015;60:55–63. 3. Whitty CJM, Carroll B, Armstrong M, et al. Utility of history, examination and laboratory tests in screening those returning to Europe from the tropics for parasitic infection. Trop Med Int Health 2000;5:818–23. 4. Harries AD, Myers B, Bhattacharrya D. Eosinophilia in Caucasians returning from the tropics. Trans R Soc Trop Med Hyg 1986;80: 327–8. 5. Libman MD, MacLean JD, Gyorkos TW. Screening for schistosomiasis, filariasis, and strongyloidiasis among expatriates returning from the tropics. Clin Infect Dis 1993;17:353–9. 6. Whitty CJ, Mabey DC, Armstron M, et al. Presentation and outcome of 1107 cases of schistosomiasis from Africa diagnosed in a non-endemic country. Trans R Soc Trop Med Hyg 2000;94:531–4. 7. Ansart S, Perez L, Jaureguiberry S, et al. Spectrum of dermatoses in 165 travelers returning from the tropics with skin diseases. Am J Trop Med Hyg 2007;76:184–6. 8. Starr J, Pruett JH, Yunginger JW, et al. Myiasis due to Hypoderma lineatum infection mimicking the hypereosinophilic syndrome. Mayo Clin Proc 2000;75:755–9. 9. Junod C. Isospora belli coccidiosis in immunocompetent subjects (a study of 40 cases seen in Paris). Bull Soc Pathol Exot 1988;81:317–25. 10. Esposito DH, Stich A, Epelboin L, et al. Acute muscular sarcocystosis: an international investigation among ill travelers returning from Tioman Island, Malaysia, 2011-2012. Clin Infect Dis 2014;59:1401–10. 11. Harley WB, Blaser MJ. Disseminated coccidioidomycosis associated with extreme eosinophilia. Clin Infect Dis 1994;18:627–9. 12. Braga FG, Ruas LP, Pereira RM, et al. Functional and phenotypic evaluation of eosinophils from patients with the acute form of paracoccidioidomycosis. PLoS Negl Trop Dis 2017;11(5):e0005601. doi:10.1371/journal.pntd.0005601. eCollection 2017 May. 13. Chou A, Serpa JA. Eosinophilia in patients infected with human immunodeficiency virus. Curr HIV/AIDS Rep 2015;12:313–16. 14. Diny NL, Rose NR, Cihakova D. Eosinophils in autoimmune diseases. Front Immunol 2017;8:484. doi:10.3389/fimmu.2017.00484. eCollection 2017. 15. Kain K. Skin lesions in returned travelers. Med Clin North Am 1999;83:1077–102. 16. Sarma DP, Weilbaecher TG. Human sparganosis. J Am Acad Dermatol 1986;15:1145–8. 17. Rusnak JM, Lucey DR. Clinical gnathostomiasis: case report and review of the English-language literature. Clin Infect Dis 1993;16:33–50. 18. Jelinek T, Maiwald H, Nothdurft HD, et al. Cutaneous larva migrans in travelers: synopsis of histories, symptoms, and treatment of 98 patients. Clin Infect Dis 1994;19:1062–6. 19. von Kuster LC, Genta RM. Cutaneous manifestations of strongyloidiasis. Arch Dermatol 1988;124:1826–30. 20. Loeffler W. Transient lung infiltrations with blood eosinophilia. Int Arch Allergy Appl Immunol 1956;8:54. 21. Hiatt RA, Sotomayor ZR, Sanchez G, et al. Factors in the pathogenesis of acute schistosomiasis mansoni. J Infect Dis 1979;139:659–66. 22. Boggild AK, Keystone JS, Kain KC. Tropical pulmonary eosinophilia: a case series in a setting of non-endemicity. Clin Infect Dis 2004;39:1123–8. 23. Rocha A, Dreyer G, Poindexter RW, et al. Syndrome resembling tropical pulmonary eosinophilia but of non-filarial aetiology: serological findings with filarial antigens. Trans R Soc Trop Med Hyg 1995;89:573–5. 24. Krenke R, Nasilowski J, Korczynski P, et al. Incidence and aetiology of eosinophilic pleural effusion. Eur Respir J 2009;34:1111–17. 25. Ryan ET, Wilson ME, Kain KC. Illness after international travel. N Engl J Med 2002;347:505–16. 26. McAuley JB, Michelson MK, Schantz PM. Trichinella in travelers. J Infect Dis 1991;164:1013–16.


SECTION 10 Posttravel

27. Arjona R, Riancho JA, Aguado JM, et al. Fascioliasis in developed countries: a review of classic and aberrant forms of the disease. Medicine (Baltimore) 1995;74:13–23. 28. Schantz PM, Glickman LT. Toxocaral visceral larva migrans. N Engl J Med 1978;298:436–9. 29. Diaz JH. Recognizing and reducing the risks of helminthic eosinophilic meningitis in travelers: differential diagnosis, disease management, prevention and control. J Travel Med 2009;16:267–75. 30. Slom TJ, Cortese MM, Gerber SI, et al. An outbreak of eosinophilic meningitis caused by Angiostrongylus cantonensis in travelers returning from the Caribbean. N Engl J Med 2002;346:668–75. 31. Nunes MC, Guimaraes MH Jr, Diamantino AC, et al. Cardiac manifestations of parasitic diseases. Heart 2017;103:651–8. 32. Meltzer E, Percik R, Shatzkes J, et al. Eosinophilia among returning travelers: a practical approach. Am J Trop Med Hyg 2008;78:702–9. 33. Lipner EM, Law MA, Barnett E. Filariasis in travelers presenting to the GeoSentinel Surveillance Network. PLoS Negl Trop Dis 2007;1:e88.

34. Nutman TB, Ottesen EA, Ieng S, et al. Eosinophilia in Southeast Asian refugees: evaluation at a referral center. J Infect Dis 1987;155: 309–13. 35. Pelletier LL, Baker CB, Gam AA, et al. Diagnosis and evaluation of treatment of chronic strongyloidiasis in ex-prisoners of war. J Infect Dis 1988;157:573–6. 36. Maxwell C, Hussain R, Nutman TB, et al. The clinical and immunologic responses of normal volunteers to low dose hookworm (Necator americanus) infection. Am J Trop Med Hyg 1987;37:126–34. 37. Checkley AM, Chiodini PL, Dockrell DH. Eosinophilia in returning travelers and migrants from the tropics: UK recommendations for investigation and initial management. J Infect 2010;60:1–20. 38. Salas-Coronas J, Cabezas-Fernandez MT, Vazquez-Villegas J. Evaluation of eosinophilia in immigrants in Southern Spain using tailored screening and treatment protocols: a prospective study. Travel Med Infect Dis 2015;13:315–21.

59  Respiratory Infections Nuccia Saleri and Edward T. Ryan

KEY POINTS • Respiratory tract infections (RTIs) are among the most common illnesses reported by travelers. Most RTIs are viral, involve the upper respiratory tract, and do not require specific diagnosis or treatment. • Influenza is often considered the most important travel-related infection. Travelers play an integral role in the yearly and global spread of influenza. • Lower RTIs, including pneumonia, often require antimicrobial therapy. • High-risk groups such as infants, small children, the elderly, and subjects with chronic tracheobronchial or pulmonary disease are at increased risk of developing severe clinical consequences

should infection occur. All international travelers should be immunized for seasonal influenza unless otherwise contraindicated, and travelers should be instructed in hand hygiene and sneeze and cough hygiene. • All travelers should be up to date on any indicated vaccines that prevent RTIs, including measles, pneumococcal diseases, Haemophilus influenzae b (Hib), meningococcal disease, diphtheria, and pertussis. • Travelers may be at increased risk of geographically restricted RTIs, and clinicians should be familiar with the major manifestations of these illnesses.


coxsackievirus A21), coronaviruses, and metapneumonia virus. Acute laryngitis is characterized by hoarseness of voice with a deepened pitch, with possible episodes of aphonia. Often these signs are associated with those of coryza and pharyngitis. Common causes of laryngitis include parainfluenza virus, rhinovirus, influenza virus, and adenovirus. Less frequently, laryngitis can be caused by bacteria including Corynebacterium diphtheriae, Branhamella catarrhalis, and Haemophilus influenzae. Pharyngitis is also most commonly viral in origin, although streptococcal disease accounts for a significant minority. Other causes of pharyngitis include Epstein-Barr virus (EBV) and the human immunodeficiency virus (HIV). Lower respiratory tract infections (LRTIs) are characterized by bronchial and/or pulmonary parenchymal involvement. The most common etiologic agents of pneumonia are listed in Box 59.2. Viruses commonly occur, but bacteria are responsible for a significant proportion of community-acquired cases of LRTI, and include Streptococcus pneumoniae and H. influenzae, as well as Mycoplasma spp. and Chlamydia spp., Legionella spp., and mycobacteria (TB).5 Fungal and parasitic involvement of the lung is also well recognized in travelers. Young children may sometimes be affected by severe forms of tracheobronchitis and croup, characterized by the stridorous croup cough. The majority of these cases are due to viruses. Travel destination, exposure, and activities should be considered in returned travelers with an RTI, as shown in Table 59.1. A list of common manifestations and complications of RTIs is presented in Box 59.3.

Respiratory diseases are a frequent1–3 and potentially life-threatening health problem in travelers. Travelers may be at increased risk of certain respiratory tract infections (RTIs) due to travel itself (mingling and close quarters in airports, airplanes, cruise ships, and hotels; and risk of influenza, legionellosis, and tuberculosis [TB]) and due to unique exposure at travel destinations (melioidosis, plague, Q fever, coccidioidomycosis, and histoplasmosis). Travel-related respiratory infections can lead to importation and secondary transmission, as occurred during the severe acute respiratory syndrome (SARS) outbreak in 2003, and more recently with Middle East respiratory syndrome coronavirus (MERS-CoV) and H1N1 influenza.4 This chapter reviews causative agents, clinical manifestations, and management approaches for travel-related RTIs.

CAUSATIVE AGENTS AND CLINICAL PRESENTATION Respiratory infections may manifest as upper tract disease (rhinitis, sinusitis, otitis, pharyngitis, epiglottitis, tracheitis), lower tract disease (bronchitis, pneumonia), or both. Systemic manifestations may include fever, headache, and myalgia. The vast majority of RTIs are caused by agents with global distribution. The usual causative agents of acute upper RTIs are listed in Box 59.1. Most upper RTIs are caused by viruses, evolve as uncomplicated disease, and resolve without specific treatment. Acute coryzal illness, traditionally referred to as a “common cold,” manifests as nasal discharge and obstruction, sneezing, and sore throat, and is most commonly caused by viruses, including rhinovirus, parainfluenza virus, influenza virus, respiratory syncytial virus, adenovirus, enterovirus (especially

EPIDEMIOLOGY Steffen et al. estimated the monthly incidence of acute febrile RTIs to be 1261/100,000 travelers.1 In that analysis, RTI ranked third after travelers’ diarrhea and malaria among all infectious problems of travelers.


CHAPTER 59  Respiratory Infections Abstract


Respiratory tract infections (RTIs) are a common health problem of international travelers. Travelers may be at increased risk of RTIs due to travel itself (mingling and close quarters in airports, airplanes, cruise ships, and hotels), and due to unique exposure at travel destinations. The clinical spectrum of RTIs in travelers is broad and includes upper RTIs, pharyngitis, otitis, laryngitis, bronchitis, and pneumonia. Most travelers who acquire an RTI only develop mild disease, and only a minority seek medical attention. All travelers should be up to date on any indicated vaccines based on age and medical condition that prevent RTIs, including influenza, measles, pneumococcal diseases, Haemophilus influenzae b, Neisseria meningitidis, diphtheria, and pertussis.

Acute upper respiratory infection Influenza Influenza vaccine Legionellosis Lower respiratory infection Travel and exposure history Tropical and geographically restricted respiratory infections Tuberculosis



SECTION 10 Posttravel

BOX 59.1  Most Common Etiologic Agents

of Upper Respiratory Tract Infections Viral Coryzal syndrome




Rhinovirus Parainfluenza virus Influenza virus Respiratory syncytial virus Enterovirus Coronavirus Metapneumonia virus Measles Influenza virus Parainfluenza virus Rhinovirus Adenovirus Rhinovirus Adenovirus Coronavirus Enterovirus Influenza virus Parainfluenza virus Respiratory syncytial virus Epstein-Barr virus Herpes simplex virus Human immunodeficiency virus type 1

Corynebacterium diphtheriae Haemophilus influenzae Branhamella catarrhalis Streptococcus pyogenes Group C β-hemolytic streptococci Corynebacterium diphtheriae Mycoplasma pneumoniae Chlamydia pneumoniae

However, that rate, which is equivalent to 0.2 episodes/person/year, is much lower than the incidence of common respiratory diseases among adults in the United States.6 The difference is likely to be attributable to underreporting among travelers, because a large proportion of RTIs are mild, not incapacitating, and not reported. In the literature, there are large variations in the proportion of respiratory infections among all causes of illness in returning travelers. Comparison among studies, however, is difficult, and differences are likely to reflect diverse diagnostic procedures and definitions of syndromes rather than true epidemiologic differences. Still, RTIs consistently rank among the most frequently diagnosed and/or reported conditions among travelers. Attack rates in reported studies have ranged from 5% to 40%.7–13 In a large database of ill travelers from all continents within the GeoSentinel Surveillance System, Freedman described a frequency of respiratory disorders of 77 per 1000 ill returned travelers, ranging from 45/1000 in the Caribbean to 97/1000 in Southeast Asia.2 In that analysis, respiratory disorders that prompted the seeking of medical care were less commonly reported than systemic febrile illnesses, acute diarrhea, dermatologic disorders, chronic diarrhea, and nondiarrheal gastrointestinal disorders.2 Using the same database, Leder and colleagues reported that upper and lower respiratory diagnoses were found in 11% of all travelers. Most respiratory illnesses were due to infections with a worldwide distribution, including nonspecific upper respiratory infections, influenza or influenza-like illness, bronchitis, and pneumonia (lobar and atypical). Influenza A, B, or H1N1 was diagnosed in 8% of travelers with a respiratory illness. There were 35 cases of legionellosis.14

BOX 59.2  Most Common Etiologic Agents of Pneumonia and/or Pulmonary Involvement Bacterial




Streptococcus pneumoniae Staphylococcus aureus Haemophilus influenzae Mixed anaerobic bacteria Klebsiella pneumoniae Pseudomonas aeruginosa Legionella spp. Mycoplasma pneumoniae Chlamydia pneumoniae Chlamydia psittaci

Histoplasma capsulatum Coccidioides immitis Aspergillus spp. Cryptococcus neoformans Paracoccidioides brasiliensis

Influenza A Influenza B Adenovirus types 4 and 7 Hantavirus Coronavirus

Mycobacterium tuberculosis Coxiella burnetii Yersinia pestis Francisella tularensis Burkholderia pseudomallei Bacillus anthracis Leptospira spp. Schistosoma spp. (acute) Ascaris lumbricoides Strongyloides stercoralis Hookworm Paragonimus westermani Wuchereria bancrofti (tropical pulmonary eosinophilia)

TABLE 59.1  Diagnostic Possibilities Based on Region of Travel Africa Bacteria Viruses


Tuberculosis, plague Tuberculosis, melioidosis, plague Hemorrhagic fever viruses, Hemorrhagic fever viruses, influenza influenza Parasites Paragonimiasis, schistosomiasis, Paragonimiasis, schistosomiasis, strongyloidiasis, tropical strongyloidiasis, tropical eosinophilia eosinophilia Fungi Histoplasmosis

Central and South America


Tuberculosis, plague Legionellosis Hantavirus pulmonary syndrome, Influenza influenza Schistosomiasis, strongyloidiasis, tropical eosinophilia Histoplasmosis, coccidioidomycosis

North America Plague Hantavirus pulmonary syndrome, influenza

Histoplasmosis, coccidioidomycosis

Modified by Gluckman SJ. Acute respiratory infections in a recently arrived traveler to your part of the world. Chest 2008;134:163–71.

CHAPTER 59  Respiratory Infections BOX 59.3  Common Manifestations and

Complications of Respiratory Tract Infections and Common Etiologic Agents of Otitis Media Complications

Agents of Otitis Media

Otitis media Sinusitis Epiglottitis Mastoiditis Periorbital cellulitis Peritonsillar abscess Retropharyngeal abscess Adenitis

Streptococcus pneumoniae Streptococcus group A Staphylococcus aureus Haemophilus influenzae Branhamella catarrhalis

O’Brien et al. studied a group of 232 sick travelers at a tertiary hospital in Australia who had largely traveled through Asian countries: RTIs were second after malaria, accounting for 24% of cases.15 In that series, lower tract infections accounted for 50% of all RTIs, and were almost equally distributed between bacterial pneumonia and influenza.15 Bacterial pneumonia was significantly more common in patients aged >40 years, with an odds ratio (OR) of 5.5. One-quarter of upper tract infections were due to group A Streptococcus. In a multicenter hospital study in Italy, of 541 travelers with fever, 8.1% of the patients had a respiratory syndrome, one-third of whom had pneumonia. TB was responsible for 29% of pneumonia cases in this cohort. Among cases with RTI and no signs of pneumonia, malaria was the underlying disease in 11 of 27.16 In an analysis of GeoSentinel data on ill children after international travel, approximately 86% of ill children had four major syndromes: 28% had a diarrheal process; 25% had a dermatologic disorder; 23% had a systemic febrile illness; and 11% had a respiratory disorder. Upper RTI (38%), hyperactive airway disease (20%), and acute otitis media (17%) accounted for the majority of the cases of respiratory syndrome in these children.17 In a Swiss study, Hunziker et al. found that leading diagnoses in children aged up to 16 years who presented with travelassociated illness were diarrhea (39%), respiratory (29%), and febrile/ systemic illness (13%). Among travelers returning from Asia and America (South, Central, and North), respiratory illness was the most frequent diagnosis.18

RISK FACTORS In the GeoSentinel data, women were more likely than men to present with upper RTI associated with travel (OR 1.3).8 Prolonged travel, travel involving visiting friends and relatives, and travel during the Northern Hemisphere winter increased the odds of being diagnosed with influenza and lower respiratory tract infection rather than upper tract disease in this cohort, and male gender was associated with twofold increased risk odds of pneumonia compared with female gender.8 Air travel itself is not a major risk factor for transmission of RTI owing to the high cabin air exchange rate, air filtering, and relatively laminar-down pattern air flow active during flight,19 although sitting in close proximity to a person who is highly infectious can result in infection.20–22 Respiratory and intestinal infections are the most common diagnosis for passengers and crew seeking medical care on board ships.23 Reasons for increased susceptibility of cruise ship travelers to respiratory infections may include contaminated ventilator cooling systems and spas, the use of hot tubs, common points-of-fomite contact (e.g., salad bars), as well as passenger factors such as age, underlying illnesses, and physical condition.24,25


Infants, small children, the elderly, and subjects with chronic tracheobronchial or cardiopulmonary diseases are at increased risk of developing severe clinical consequences from RTIs. In a study by Gautret et al., respiratory disease ranked as the second most frequent reason for presentation to a GeoSentinel site in the older adults (age >60 years). Older travelers had a greater proportionate morbidity from lower RTI, including pneumonia and bronchitis.26

TRANSMISSION The spread of agents such as streptococci or meningococci is by direct, person-to-person contact, and via large droplets. These droplets usually fall to the ground within 1 m (3 ft) of an infectious person. Other pathogens are transmitted by tiny droplet nuclei (40 years of age, but only a fraction of cases are recognized. According to the Centers for Disease Control and Prevention (CDC), 20% of patients hospitalized with legionnaires disease in the United States acquired their infection while traveling.39 Between 2000 and 2010, 7869 hotel-associated cases (and 994 clusters) and 105 ship-associated cases of legionnaires disease (with 366 deaths) were reported by ELDSNET.40 For 2015, 1141 travelassociated legionnaires disease cases were reported through ELDSNET, 20% more than in 2014. A total of 167 new travel-associated clusters were detected in 33 countries, compared with 132 in 2014, 110 in 2013, and 99 in 2012. In 2015, 60% of the detected clusters of travel-associated legionnaires disease were characterized by initial cases from several different countries.41 The Mediterranean region in Europe has been the origin of most reported outbreaks, but no area is excluded from risk, as exemplified by the identification of a cluster of cases associated with a hotel in Bangkok.42 Transmission is airborne, but the source of infection is the environment rather than other persons. The incubation period is classically considered as 2–10 days, although 16% of 188 cases described in a large outbreak in the Netherlands reported incubation periods >10 days.43 The clinical spectrum is wide, ranging from subclinical to lethal manifestations. The overt picture of legionellosis is that of a lobar pneumonia with abrupt onset characterized by high fever, severe headache, and confusion.44 Patchy infiltrates are often present bilaterally. Mortality may be as high as 20% if diagnosis and antibiotic treatment are delayed. Diagnosis is usually based on detection of antigen in urine (for L. pneumophila type 1, with 80% sensitivity and 99% specificity). Culture can also be employed. Where available, PCR can be used to identify L. pneumophila from bronchoalveolar lavage fluid and other clinical specimens. Treatment is often empiric: macrolides are the treatment of choice. Co-trimoxazole and fluoroquinolones are also effective.

TROPICAL AND GEOGRAPHICALLY RESTRICTED RESPIRATORY INFECTIONS Travelers may be at risk of a number of geographically restricted respiratory infections, as well as those associated with travel to resourcelimited areas.

Melioidosis Melioidosis is caused by a gram-negative rod, Burkholderia pseudomallei. Cases usually occur within 20° north to 20° south of the Equator, with the vast majority of cases being reported in Southeast Asia and northern Australia. The bacterium is free-living in soil and water, and humans can become infected through inhalation or through direct contact (wounds). Melioidosis remains a risk for travelers to endemic areas, especially those with exposure to wet-season soils and surface water.45 B. pseudomallei was one of the more frequent isolates from travelers and patients affected by the 2005 Asian tsunami.46 Risk factors for clinical disease include diabetes, chronic alcoholism, chronic lung disease, and chronic renal disease. Septicemia, pneumonia, cellulitis, and abscess formation are the most frequent manifestations. Lung involvement consists of acute necrotizing pneumonia or chronic granulomatous or fibrosing lung disease mimicking TB. The diagnosis of pulmonary melioidosis is difficult. Physicians in western countries should be aware of the possibility of melioidosis not only in patients originating from endemic areas but


SECTION 10 Posttravel

also in patients returning from travel in those regions. Because it can manifest months or years after leaving the endemic area, patients may not remember the exposure event and its potential relationship to their symptoms. The diagnosis can be confirmed by Gram stain and culture of respiratory specimen and/or blood. The presumptive diagnosis of melioidosis may be based on a positive indirect hemagglutination assay (IHA) or enzyme-linked immunosorbent assay (ELISA) serology in the appropriate clinical setting.47–49 IHA titers above 1 : 80 are suggestive of active infection, but can also be seen in asymptomatic subjects in endemic regions.48 Treatment of patients with melioidosis usually involves meropenem or ceftazidime plus trimethoprim-sulfamethoxazole or doxycycline for a period of at least 2–6 weeks. Therapy should be guided by antimicrobial susceptibility tests. For severe disease, prolonged treatment for 2–6 months is recommended to prevent relapses. A vaccine against melioidosis is not commercially available; the best way to prevent infection is by avoiding contact with contaminated soil or water; travelers should be advised to always wear shoes.45

Leptospirosis Pulmonary involvement in leptospirosis is not rare, and usually manifests as a dry cough, or occasionally as a cough with blood-stained sputum. Leptospirosis is due to several serovars of a spirochetal bacterium, often Leptospira interrogans, and is a zoonosis. Transmission occurs by accidental contact with water or soil contaminated with the urine of an infected animal, often a rodent. Outbreaks have occurred among adventure travelers on group tours,50 and leptospirosis with pulmonary hemorrhage has been noted with increasing frequency.51,52 Clinical manifestation of leptospirosis may vary from asymptomatic infection to fulminant disease. Severe cases are characterized by liver and renal failure, with mortality as high as 30% in untreated cases. Pulmonary complications often contribute to the fatal outcome: They include extensive edema and alveolar hemorrhages in the context of an acute respiratory distress syndrome (ARDS) episode. The radiologic findings are those of ARDS. The diagnosis requires the isolation of the bacteria from blood or urine samples, but this is rarely performed. The diagnosis usually rests on clinical recognition and serology. Prevention of leptospirosis is difficult, especially in tropical areas where the disease is not limited to high-risk groups. Prevention of rodent-human contacts is important. A human vaccine and the use of tetracycline chemoprophylaxis (200 mg/week) are available but are rarely indicated.

Anthrax Cutaneous disease is the most commonly observed form of human anthrax. Pulmonary anthrax is less common but more deadly, and is caused by inhalation of Bacillus anthracis spores. Naturally acquired anthrax may occur in developing countries, where the risk is still significant in rural parts of Asia, Africa, Eastern Europe, South and Central America as a result of contact with contaminated soil or animal products; a few cases of anthrax have been described in travelers who import souvenirs. Inhalation anthrax is notable for its absence of pulmonary infiltrate on chest imaging, but the presence of extensive mediastinal lymphadenopathy, pleural effusions, and severe shortness of breath, toxemia, and sense of impending doom. The incubation period is 2–5 days, but spores can germinate up to 60 days after exposure. Pathogenesis is mediated by a toxin responsible for hemorrhage, edema, and necrosis. The presenting symptoms are nonspecific, with mild fever, malaise, and a nonproductive cough. After a period of a few days in which the patient’s condition apparently improves, a second phase begins with high fever, respiratory distress, cyanosis, and subcutaneous edema of the neck and

thorax. Crepitant rales are evident on auscultation. Inhalation anthrax is almost invariably fatal with a very short time between the onset of the second phase, mediastinal signs, and death. The diagnosis of inhalation anthrax is extremely difficult outside of epidemic conditions. Direct examination and Gram stain of the sputum specimen are unlikely to be positive. A serologic ELISA test is available, although a significant increase in titer is usually obtained only in convalescent subjects who survive. The most useful bacteriologic test in case of suspicion, however, is a blood culture demonstrating B. anthracis. Treatment of inhalation anthrax should be as early as possible and usually involves a carbapenem, penicillin, doxycycline, and fluoroquinolone such as ciprofloxacin. Ancillary treatment to sustain vascular volume, cardiac, pulmonary, and renal functions is essential.

Plague Plague is caused by Yersinia pestis, a gram-negative coccobacillus. It is considered a reemerging disease because of the increase in the number of reported cases worldwide, the occurrence of epidemics (such as the one in India in 1994), and the gradual expansion in areas of low endemicity (including the United States). The most heavily affected African countries are Madagascar, Democratic Republic of Congo, Uganda, the United Republic of Tanzania, and Mozambique. The Central Asian region has active plague foci in the Central Asian desert, affecting Kazakhstan, Turkmenistan, and Uzbekistan. Plague foci are distributed in 19 provinces and autonomous regions of China, and the incidence has been increasing since the 1990s. Permanent plague foci exist in the Americas among native rodent and flea populations in Bolivia, Brazil, Ecuador, Peru, and the United States.53 The 1994 Indian epidemic, where a total of 5150 suspected pneumonic or bubonic cases occurred in a 3-month period, caused travel and trade disruption and resulted in severe economic repercussions.54 Travelers are rarely affected by plague while visiting endemic areas (e.g., no visitors were affected during the 1994 epidemic in India). Campers or visitors staying in rodent-infested lodges are exposed to the highest risk of infection. In humans, pneumonia may follow septicemia or may be a primary event in the case of airborne transmission (though pneumonic plague is currently very rare). Plague should be suspected in febrile patients who have been exposed to rodents or other mammals in known endemic areas. The presence of buboes in this setting is highly suspicious. The bacterium may be isolated on standard bacteriologic media from culture samples of blood or bubo aspirates. The Gram stain may reveal gramnegative coccobacilli with polymorphonuclear leukocytes. Rapid diagnostic tests such as the direct immunofluorescence test for the presumptive identification of Y. pestis F1 antigen are of interest for the rapid management of patients with the suspicion of disease.55 Serologic tests to detect antibodies to the F1 antigen by passive HAI or ELISA method are available. A fourfold increase in titer (or a single titer of 1 : 16 or more) may provide presumptive evidence of plague in culturenegative cases. Antibiotic treatment should be started on the basis of clinical suspicion, usually involving an aminoglycoside (streptomycin, gentamicin) and/or doxycycline or chloramphenicol. Pulmonary infections present a particular risk for human epidemics owing to the contagiousness of the organism. Doxycycline (100 mg twice daily for 7 days) prophylaxis of family members of index cases is indicated within the standard 7-day maximum plague incubation period.

Paragonimiasis Paragonimiasis is caused by a lung fluke, often Paragonimus westermani. Humans become infected through the ingestion of undercooked or raw crabs, crayfish, or their juices. The infection is endemic in Southeast Asia (including Thailand, the Philippines, Vietnam, China, and Taiwan),

CHAPTER 59  Respiratory Infections South and North America,56 and Africa, with most cases being reported in Asia. The disease is well described, although rare in travelers to endemic regions.57 The incubation period may vary from one to several months after exposure. The disease presents as a chronic bronchopneumonic process with productive cough, thoracic pain, and low-grade fever. The worms produce extensive inflammation and cavity formation, and the infection should be considered in individuals with nodular cavitating lung lesions and rusty-brown bloody sputum. Acute paragonimiasis can present as pneumothorax as the worms invade the lung tissue. Diagnosis usually rests on clinical recognition and detection of the worms’ eggs in expectorated sputum. Treatment involves praziquantel. Prevention is based on avoiding eating raw crayfish and crabs.

Coccidioidomycosis and Histoplasmosis Coccidioidomycosis and histoplasmosis are two fungal infections acquired by the respiratory route and often involve the respiratory system. Coccidioidomycosis is caused by inhalation of Coccidioides immitis, a dimorphic fungus found in dust and soil. The pathogen is present only in semiarid regions of the Americas. Symptomatic disease develops in approximately 40% of individuals infected by C. immitis, presenting as a flulike syndrome. The radiologic finding is often that of hilar pneumonia with lymphadenitis and pleural involvement. In a well-described outbreak of coccidioidomycosis in a 126-member church group traveling to Mexico, the average incubation period was 12 days (range 7–20 days); chest pain was present in 76% and cough in 66% of the affected travelers.58 The diagnosis is serologic, and antibodies appear 1–3 weeks after the onset of symptoms. Histoplasmosis is caused by infection with a soil-inhabiting dimorphic fungus, Histoplasma capsulatum. The agent is ubiquitous, but diffusion is higher in the tropical belt and the United States. Outbreaks of acute histoplasmosis among travelers have been repeatedly reported.59–61 The disease may evolve as a mild, spontaneously resolving condition, but severe and systemic disease may develop in immunocompromised patients. Acute pulmonary histoplasmosis (APH) in returning travelers typically presents as a flulike illness with high-grade fever, chills, headache, nonproductive cough, pleuritic chest pain, and fatigue. Symptom onset is usually 1–3 weeks following exposure and most individuals recover spontaneously within 3 weeks. Chest x-ray may show patchy infiltrates or interstitial pneumonia. Diagnosis may be extremely difficult unless the disease is considered in the differential diagnosis, and most cases are unrecognized and considered as bacterial bronchitis or influenza. Confirmation of the disease usually involves a urine and serum antigen assay, or comparison of acute-phase and convalescent-phase serum specimens. Antifungal treatment is not usually indicated for mild to moderate APH in immunocompetent persons. For patients who continue to have symptoms for >1 month, itraconazole is recommended. Patients with moderately severe to severe APH should receive liposomal amphotericin B followed by itraconazole.

Tuberculosis TB is a widely distributed infection and a leading cause of human morbidity and mortality. Travel can increase the risk of TB, especially among individuals traveling to high burden countries, those visiting friends and relatives, those performing health care or service work overseas, and those traveling for extended periods. Most individuals who become infected with Mycobacterium tuberculosis do not develop the disease and are diagnosed as having latent TB infection (LTBI), often on the basis of a skin test or interferon-gamma-based assays. Multidrug-resistant tuberculosis (MDR TB) is now present in many regions, including a number of sites in Eastern Europe and parts of Southeast Asia popular with travelers.62


TB Among Travelers From Low-Endemic to High-Endemic Areas.  There is evidence of an association between travel and an increased risk for LTBI. Lobato first demonstrated that US children who had traveled abroad had a significantly higher probability of having a positive tuberculin skin test than children without a history of travel.62 Cobelens et al. estimated the risk of acquiring M. tuberculosis infection among long-term (≥3 months) Dutch travelers to Africa, Asia, and Latin America as 3.3% per year.63 Abubakar et al. provided the first evidence in the United Kingdom that travel to countries with high levels of TB infection may be an independent risk factor for acquiring LTBI.64 A systematic review using tuberculin skin testing (TST) conversion as a surrogate for LTBI calculated the cumulative incidence of LTBI in long-term travelers to be 2%.65 Other factors identified for increased TB risk among travelers were being a health care worker, a longer cumulative duration of travel, and a longer total time spent in TB-endemic countries.63 Air travel itself is not considered a major risk factor for transmission of TB.66 The risk of TB transmission on ships and trains has also been described but is similarly of little epidemiologic importance. Active TB (as opposed to LTBI) was 16 times more likely to be reported in individuals seeking medical care at a GeoSentinel site among those born in low-income countries and who were now living in high-income countries and traveling to their region of birth to visit friends and relatives than it was among those born and living in high-income countries and traveling to low-income countries to visit friends and relatives, and more than 60 times more common than it was among tourist travelers.66 Despite this, the evidence of association between actual travel (as opposed to demographics of travels) and active TB (as opposed to LTBI) is sparse. Where overall risk is judged to be sufficiently high, pretravel testing for LTBI (TST or interferon-gamma release assays) may be indicated. Travelers to high TB-endemic areas can employ behavioral modifications (i.e., individuals traveling to provide health care should use personal protective equipment in caring for patients with probable TB). Following travel, assessment should focus on establishing whether a significant risk of exposure to TB occurred, and on any signs or symptoms that may suggest active infection (Fig. 59.3). Asymptomatic individuals who are considered at sufficient risk of exposure (or where direct contact with TB is known to have occurred) should be tested for LTBI. Symptomatic individuals should be evaluated for active TB.62 A vaccine (Bacillus Calmette-Guérin [BCG]) is available in many countries and many national guidelines recommend vaccination for children 60 y). J Travel Med 2012;19:169–77. 27. Cooke GS, Lalvani A, Gleeson FV, et al. Acute pulmonary schistosomiasis in travelers returning from Lake Malawi, sub-Saharan Africa. Clin Infect Dis 1999;29(4):836–9. 28. Nuorti JP, Whitney CG, MD for the ACIP Pneumococcal Vaccines Working Group. Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (PPSV23). MMWR Morb Mortal Wkly Rep 2010;59(34). 29. Grohskopf L, Uyeki T, Bresee J, et al. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep 2011;60(33):1128–32. 30. Health and Safety Executive. The Control of Legionellosis Including Legionnaires’ Disease. London: Health and Safety Executive; 1991. p. 1–19. 31. Freedman DO, Kozarsky PE, Weld LH, et al. GeoSentinel: the global emerging infections sentinel network of the international society of travel medicine. J Travel Med 1999;6:94–8. 32. Jelinek T, Corachan M, Grobush M, et al. Falciparum malaria in European tourists to the Dominican Republic. Emerg Infect Dis 2000;6:537–8. 33. World Health Organization. Cumulative Number of Reported Probable Cases of Severe Acute Respiratory Syndrome. Available at: csr/sars/country/en/index.html.

CHAPTER 59  Respiratory Infections 34. World Health Organization. H5N1 Avian Influenza: Timeline of Major Events; 2011. Available at: H5N1_avian_influenza_update.pdf. 35. Li Q, Zhou L, Zhou M, et al. Epidemiology of human infections with Avian influenza A(H7N9) virus in China. N Engl J Med 2014;370: 520–32. 36. Mutsch M, Tavernini M, Marx A, et al. Influenza virus infection in travelers to tropical and subtropical countries. Clin Infect Dis 2005;40: 1282–7. 37. Jaureguiberry S, Boutolleau D, Grandsire E, et al. Clinical and microbiological evaluation of travel-associated respiratory tract infections in travelers returning from countries affected by pandemic A(H1N1) 2009 influenza. J Travel Med 2012;19:22–8. 38. Balkhy HH, Memish ZA, Bafaqeer S, et al. Influenza a common viral infection among Hajj pilgrims: time for routine surveillance and vaccination. J Travel Med 2004;11(2):82–6. 39. Surveillance for travel-associated legionnaires disease: United States, 2005–2006. MMWR Morb Mortal Wkly Rep 2007;56:1261–3. 40. Mouchtouri VA, Rudge JW. Legionnaires’ disease in hotels and passenger ships: a systematic review of evidence, sources, and contributing factors. J Travel Med 2015;22:325–37. 41. European Centre for Disease Prevention and Control. Annual epidemiological report for 2015—legionnaires’ disease. Stockholm: ECDC; 2017. Available at: Legionnaires/Pages/Annual-epidemiological-report-2017.aspx. 42. Anonymous. Cluster of cases of legionnaire’s disease associated with a Bangkok hotel. Commun Dis Rep CDR Wkly 1999;9:147. 43. Den Boer JW, Yzerman EPF, Schellekens J, et al. A large outbreak of legionnaires’ disease at a flower show, the Netherlands, 1999. Emerging Infect Dis 2002;37–43. 44. World Health Organization. Epidemiology, prevention and control of legionellosis: memorandum of a WHO meeting. Bull World Health Organ 1990;68:155–64. 45. Dan M. Melioidosis in travelers: review of the literature. J Travel Med 2015;22:410–14. 46. Allworth AM. Tsunami lung: a necrotising pneumonia in survivors of the Asian tsunami. Med J Aust 2005;182(7):364. 47. Peetermans WE, Wijngaerden EV, Eldere JV, et al. Melioidosis brain and lung abscess after travel to Sri Lanka. Clin Infect Dis 1999;28:921–2. 48. Dharakul T, Anuntagool SS, Chaowagul N, et al. Diagnostic value of an antibody enzyme-linked immunosorbent assay using affinity-purified antigen in an area endemic for melioidosis. Am J Trop Med Hyg 1997;56: 418–23. 49. Appassakij H, Silpojakul KR, Wansit R, et al. Diagnostic value of indirect hemoagglutination test for melioidosis in an endemic area. Am J Trop Med Hyg 1990;42:248–53. 50. Sejvar J, Bancroft E, Winthrop K, et al. Leptospirosis in “eco-challenge” athletes, Malaysian Borneo, 2000. Emerg Infect Dis 2003;9(6):702–7.


51. Leung V, Luong ML, Libman M. Leptospirosis: pulmonary hemorrhage in a returned traveler. CMAJ 2011;183(7):e423–7. 52. Montero-Tinnirello J, de la Fuente-Aguado J, Ochoa-Diez M, et al. Pulmonary hemorrhage due to leptospirosis. Med Intensiva 2011 May 16. 53. WHO/HSE/EPR/2008.3. Interregional meeting on prevention and control of plague. Antananarivo, Madagascar 1 –11; April 2006. Available at: _3w.pdf. 54. World Health Organization. Human plague in 1996. Wkly Epidemiol Rec 1998;47:366–9. 55. Chanteau S, Rabarijaona L, O’Brien T, et al. F1 antigenaemia in bubonic plague patients, a marker of gravity and efficacy of therapy. Trans R Soc Trop Med Hyg 1998;92:572–3. 56. Lane MA, Barsanti MC, Santos CA, et al. Human paragonimiasis in North America following ingestion of raw crayfish. Clin Infect Dis 2009;49(6): e55–61. 57. Procop GW. North American paragonimiasis (caused by Paragonimus kellicotti) in the context of global paragonimiasis. Clin Microbiol Rev 2009;22(3):415–46. 58. Cairns L, Blythe D, Kao A, et al. Outbreak of coccidioidomycosis in Washington state residents returning from Mexico. Clin Infect Dis 2000;30:61–4. 59. Morgan J, Cano MV, Feikin DR, et al. A large outbreak of histoplasmosis among American travelers associated with a hotel in Acapulco, Mexico, spring 2001. Am J Trop Med Hyg 2003;69:663–9. 60. Lyon GM, Bravo AV, Espino A, et al. Histoplasmosis associated with exploring a bat-inhabited cave in Costa Rica, 1998–1999. Am J Trop Med Hyg 2004;70:438–42. 61. Cottle LE, Gkrania-Klotsas E, Williams HJ, et al. Multinational outbreak of histoplasmosis following a biology field trip in the Ugandan rainforest. J Travel Med 2013;20:83–7. 62. Lobato MN, Hopewell PC. Mycobacterium tuberculosis infection from countries with a high prevalence of tuberculosis. Am J Respir Crit Care Med 1998;158:1871–5. 63. Cobelens FGJ, van Deutekom H, Draayer-Jansen IWE, et al. Association of tuberculin sensitivity in Dutch adults with history of travel to areas with a high incidence of tuberculosis. Clin Infect Dis 2001;33:300–4. 64. Abubakar I, Matthews T, Harmer D, et al. Assessing the effect of foreign travel and protection by BCG vaccination on the spread of tuberculosis in a low incidence country, United Kingdom, October 2008 to December 2009. Euro Surveill 2011;16(12):19826. Available at: http:// 65. Freeman RJ, Mancuso JD, Riddle MS, et al. Systematic review and meta-analysis of TST conversion risk in deployed military and long-term civilian travelers. J Travel Med 2010;17:233–42. 66. Leder K, Tong S, Weld L, et al. Illness in travelers visiting friends and relatives: a review of the Geosentinel Surveillance Network. Clin Infect Dis 2006;43:1185–93.


Sources of Travel Medicine Information David O. Freedman

KEY POINTS • Authoritative bodies such as the World Health Organization (WHO), the Centers for Disease Control and Prevention (CDC), UK National Travel Health Network and Centre (NaTHNaC), and the Public Health Agency of Canada (PHAC) host websites that contain comprehensive travel health and some outbreak information. Many national bodies as well as commercial organizations also provide excellent and often very timely travel health information on public or membership-only websites.

• Itinerary-driven databases that generate comprehensive reports for use in travel health counseling can be accessed in real time online including on mobile devices. • Broad reference texts in travel medicine can be supplemented from a list of specialized texts for uncommon patient situations. • TravelMed is an important electronic discussion forum of issues related to the practice of travel medicine (http://istmsite


these books are available and often formatted on a topical basis rather than a traditional chapter basis.

Travel medicine is concerned with keeping international travelers alive and healthy. To achieve this, travel medicine providers need to keep up to date with changing disease risk patterns in over 240 different countries. The knowledge base upon which preventative and therapeutic interventions are based continues to change rapidly. An increasingly online world allows for frequent and detailed dissemination of disease incidence patterns, information on new outbreaks, the description of new diseases affecting travelers, as well as data on new drug resistance patterns in old diseases. Travelers are going to ever more exotic and previously unvisited locales. In addition, travelers are online and are bringing ever more sophisticated and updated information with them at the time of the pretravel medical encounter. Electronic media are the major source of updated information for travel medicine providers. Many printed publications, manuals, and detailed textbooks no longer exist, or exist only in electronic format. Essentially, all the most important authoritative national and international surveillance bulletins, outbreak information, and official governmental recommendations are available online. This chapter will provide, mostly in tabular form, information on key travel medicine-oriented information resources targeted to travel medicine professionals. The electronic resources discussed in this appendix were current at the time of writing, but some information may be outdated by the time it arrives in the hands of the reader.

REFERENCE TEXTS The first section of Table A.1 lists selected core reference texts whose primary emphasis is a comprehensive approach to travel medicine and to keeping travelers alive and well. Any of these high-quality resources is certainly sufficient to cover the practical aspects of caring for those to be seen in a travel medicine practice. The next sections list, by category, large reference texts that contain detailed discussions, factual tables, and primary references that would be helpful in dealing with select or uncommon situations. Web-based, mobile, and e-reader editions of

JOURNALS Table A.2 lists selected English-language journals that consistently and frequently feature articles on travel medicine. All of these journals have their tables of contents freely accessible but the complete contents are available online restricted to their own subscribers.

TRAVEL MEDICINE WEBSITES Only selected websites that have data of generally high quality and of a broader international interest to travel medicine providers are referenced in Table A.3. Checking more than one authoritative site on a specific issue is always recommended. First, authoritative recommendations still contain some element of opinion. Thus even major sources such as the WHO, CDC, PHAC, and NaTHNaC can disagree on some issues. Second, because of changing disease patterns, what was accurate yesterday may not be accurate today, and some sites are timelier in updating than others. Commercial and nonprofit websites can often post information immediately while official websites often have delays due to internal approval processes. Fortunately, most sites put an indicator at the bottom of each page stating the date of the last update. Always be suspicious of information on a web page that carries no date.

POINT-OF-CARE TRAVEL CLINIC DESTINATION RESOURCES Electronic information systems for travel health counseling are widely used and increasingly sophisticated. These systems allow the user to query large electronic databases containing information on disease risk, epidemiology, and vaccine recommendations across more than 240 countries. These systems allow a rapid, convenient means of accessing a large body of changing information.


APPENDIX  Sources of Travel Medicine Information Abstract


Authoritative bodies such as the World Health Organization (WHO), the Centers for Disease Control and Prevention (CDC), UK National Travel Health Network and Centre (NaTHNaC), and the Public Health Agency of Canada (PHAC) host websites that contain comprehensive travel health and some outbreak information. Many national bodies as well as commercial organizations also provide excellent and often very timely travel health information on public or membership-only websites. Itinerary-driven databases that generate comprehensive reports for use in travel health counseling can be accessed in real time online including on mobile devices. Broad reference texts in travel medicine can be supplemented from a list of specialized texts for uncommon patient situations. TravelMed is an important electronic discussion forum of issues related to the practice of travel medicine. RSS and Twitter feeds are provided by many organizations and are the timeliest way to follow evolving disease outbreaks.

Internet resources Outbreak Pretravel consultation Surveillance Travel advice



APPENDIX  Sources of Travel Medicine Information

TABLE A.1 Books Comprehensive Travel Medicine Resources CDC Health Information for International Travel 2018. (The CDC Yellow Book). WHO International Travel and Health. (WHO Green Book). Walker PF, Barnett ED, editors. Immigrant Medicine. Philadelphia: Saunders; 2007. -03454-8 Jong EC, Pottinger P, editors. The Travel and Tropical Medicine Manual. 5th ed. Sanford, CA: Elsevier. Comprehensive Immunization Resources Plotkin SA, Orenstein WA, Offit PA. Vaccines. 6th ed. Philadelphia: W.B. Saunders; 2013. Epidemiology and Prevention of Vaccine Preventable Diseases (The Pink Book). 13th ed. Atlanta: CDC; 2017. html Pharmacopeias Martindale, The Complete Drug Reference. 39th ed. Brayfield A, editor. London: Pharmaceutical Press; 2017. martindale39 British National Formulary. 73th ed. Mehta DK, editor. London: Pharmaceutical Press; 2017. Specialized Resource Texts (In-depth Coverage of Important Areas) Hunter’s Tropical Medicine and Emerging Infectious Disease. 9th ed. Magill AJ, Ryan ET, Solomon T, et al., editors. London: Elsevier; 2013. Manson’s Tropical Diseases. 22nd ed. Farrar J, et al., editors. London: Elsevier; 2008. Control of Communicable Disease Manual. 20th ed. Heymann D., editor. Washington DC: American Public Health Association; 2014. Red Book. 2015 Report of the Committee on Infectious Diseases. Elk Grove, IL: American Academy of Pediatrics; 2015. aspx?bookid=1484 Wilderness Medicine. 7th ed. Auerbach PS, editor. London: Elsevier; 2016. auerbach/978-0-323-35942-9 GIDEON Guide to Outbreaks.

TABLE A.2  Journals Frequently Publishing

Papers on Travel Medicine

American Journal of Tropical Medicine and Hygiene Aviation Space and Environmental Medicine British Medical Journal Bulletin of the World Health Organization Clinical Infectious Diseases Emerging Infectious Diseases Journal Eurosurveillance International Journal of Travel Medicine and Global Health Journal of Infectious Diseases Journal of Occupational and Environmental Medicine Journal of Travel Medicine The Lancet Lancet Infectious Diseases Military Medicine Morbidity and Mortality Weekly Report Pediatric Infectious Diseases Journal PLOS Neglected Tropical Diseases Transactions of the Royal Society of Tropical Medicine and Hygiene Travel Medicine and Infectious Diseases Tropical Diseases, Travel Medicine and Vaccines Tropical Medicine and International Health Vaccine Weekly Epidemiological Record Wilderness and Environmental Medicine

With the advent of database-driven technology, these databases can be accessed online in real time. The most widely used English-language packages are listed in Table A.3 under the heading “Country-Specific Travel Medicine Database (Nongovernmental).” Most high-quality systems have at least two major components: (1) displays of information including country-by-country information on health risks and vaccine recommendations within a given country, and disease-by-disease fact sheets for major diseases; (2) an itinerary-maker feature which, after input of a complete traveler itinerary, prints out yellow-fever entry requirements and summary recommendations for the entire itinerary in the order of travel. These printouts generally include a vaccination plan, malaria recommendations, destination risks, in-country resources, and are individualized with the name of the patient and the clinic. In addition, detailed country-by-country disease maps, especially for malaria or yellow fever, are important features to consider in evaluating a system. Risk shading that overlays an interactive map with “google-like” features is important for locating a traveler’s actual destination for infrequently visited places. Printouts of these can be important in educating patients who may have indefinite or changeable itineraries. Many software packages also now include global distribution maps for a number of important tropical diseases. As described individually in Table A.3, a number of other important and useful features are included in many of the available packages. The quality and timeliness of the information contained in the vendor’s database should be the premier consideration. The listed databases all contain high-quality information and the recommendations generated consistently represent a distillation of those of authoritative


APPENDIX  Sources of Travel Medicine Information TABLE A.3  Travel Medicine Websites (Many Provide Twitter, Facebook, RSS, and

LinkedIn Feeds)

Governmental Travel Medicine Recommendations Australia Travel Guidelines CDC Travelers Health Homepage CDC Yellow Book (Health Information for International Travel) Health Protection Scotland Fit for Travel Health Protection Scotland Travaxa (“Scottish Travax”) Public Health Agency of Canada—Travel Health UK NaTHNaC US DOT Disinsection WHO Green Book (International Travel and Health)

Country-Specific Travel Medicine Databases (Nongovernmental) German Fit for Travel (English and German) GIDEONa IAMAT International SOS Assistancea MASTA SafeTravel Switzerland (French and German) Shoreland Travaxa TripPrep Tropimeda Worldwisea Travel Warnings and Consular Information Australia Consular Sheets Foreign Affairs Canada Travel Reports and Warnings France Consular Bulletins Germany Consular Sheets Swiss Consular Bulletins UK FCO Warnings US State Department Advisories

Emerging Diseases and Outbreaks Canada-ID News Brief CDC Health Alert Network European Centre for Disease Prevention & Control (ECDC) HealthMap ProMed Mail University of Minnesota CIDRAP WHO Global Response and Alert WHO Global Response and Alert Disease Links WHO Global Response and Alert Outbreak News

Surveillance and Epidemiologic Bulletins Australia Commun Dis Intellig Canada Communicable Diseases Report CDC MMWR Weekly and Summaries EpiNorth Europe EpiSouth Europe Eurosurveillance Japanese Surveillance Center PAHO Ministries of Health Links PAHO National Bulletins Links UK Health Protection Report UN ReliefWeb—Humanitarian Agencies US Military Surveillance WHO Weekly Epidemiologic Record Continued


APPENDIX  Sources of Travel Medicine Information

TABLE A.3  Travel Medicine Websites (Many Provide Twitter, Facebook, RSS, and

LinkedIn Feeds)—cont’d Vaccine Resources Australia Immunization Guide

Canadian Immunization Guide CDC Pink Book Appendices CDC Pink Book on Vaccines GSK Vaccines Merck Vaccines PaxVax Sanofi Canada Sanofi MSD Europe Sanofi US Sanofi World CorporateSite US ACIP Statements US Vaccine Information Statements US Vaccine PIs—Vaccine Safety Institute Vaccine Information from the Vaccine Action Coalition Vaccines and Biologics in United States and Other Countries Valneva WHO Prequalified Vaccines WHO Vaccine Links WHO Vaccine Schedules in All Countries WHO Vaccines

International Agencies International Air Transport Association (Airline Industry) International Civil Aviation Organization (Regulatory) WHO Africa WHO Eastern Mediterranean WHO Europe WHO Fact Sheets WHO Health Topics A–Z WHO PAHO WHO Southeast Asia WHO Western Pacific

Disability Resources American Diabetes Association Aviation Consumer Protection Home Page European Civil Aviation Mobility International Society for Accessible Travel and Hospitality

Overseas Assistance Blue Cross/Blue Shield Worldwide Providers DOS Medical Info Abroad IAMAT International SOS MedEx Insurance Trav Emerg Net (TEN)

Maps and Nonmedical Country Information CIA—The World Factbook Falling Rain Global Gazetteer and Altitude Finder Geographic Names Database Google Maps Perry Castaneda Map-Related Webstes


APPENDIX  Sources of Travel Medicine Information TABLE A.3  Travel Medicine Websites (Many Provide Twitter, Facebook, RSS, and

LinkedIn Feeds)—cont’d UN Maps US State Dept Background Notes

Security and Safety Control Risks Group EU Air Safety Portal FAA Air Safety Standards in All Countries Kroll Associates OSAC WHO Road Safety by Country

Professional Societies American Society of Tropical Medicine and Hygiene American Travel Health Nurses Association British Travel Health Association Divers Alert Network French Travel Medicine Society German Society of Tropical Medicine and International Health (DTG) Glasgow Faculty of Travel Medicine Infectious Diseases Society of America International Society of Travel Medicine Latin American Travel Medicine Society (SLAMVI) Royal Society of Tropical Medicine and Hygiene South African Society of Travel Medicine Travel Medicine Society of Ireland Undersea and Hyperbaric Medicine Society Wilderness Medical Society Disease Pages ACT Malaria—Asia CDC DPD Parasitology Diagnostic Atlas CDC TB CDC—Influenza Europe Influenza

Europe Rabies Bulletin Global Polio Eradication National Malaria Treatment Guidelines for All Countries OIE Zoonoses Reports Oxford Malaria Atlas Project PAHO Dengue PAHO Malaria Photo Thumbnails—ASTMH-Zaiman Slide Library WHO | Global Schistosomiasis Atlas WHO AFRO Malaria WHO Cholera WHO Global Malaria Program WHO Southeast Asia Malaria WHO TB WHO—Global Health Atlas Weekly_Influenza_Surveillance_Overview.aspx

Drug Resources HIV Drug Interactions Medline Drug Information for Patients Micromedex Drug Databases Sanford Guide to Antimicrobial Therapy Up to Date WHO Drug Information Continued


APPENDIX  Sources of Travel Medicine Information

TABLE A.3  Travel Medicine Websites (Many Provide Twitter, Facebook, RSS, and

LinkedIn Feeds)—cont’d

Training and Academic Institutions Bernhard Nocht Institute Global Health Education Consortium Institute Pasteur James Cook Univ Liverpool School of Tropical Medicine London School of Hygiene & Tropical Medicine Mahidol Tropical Medicine Prince Leopold Institute Swiss Tropical Institute The Gorgas Course in Clinical Tropical Medicine TropEd Europ Website Tulane Tropical Medicine University of Minnesota


Subscription fees required.

national or international bodies. In case of discrepancy between WHO, CDC, and national bodies, many of the software packages highlight these differences and allow for selection of one or the other in generating a final report.

ELECTRONIC DISCUSSION FORUMS Electronic distribution lists function using email with or without a browser-based interface. Anyone who has joined a particular group can email or post to a central server. The posting is then disseminated to all members who have subscribed to the same group. Several formats exist to join one of these forums: (1) an email message is sent to the server; (2) an online form is filled out; and (3) a menu of available groups or forums is provided by a social networking service such as LinkedIn or Facebook. Once a person is accepted as a member, the sponsor will generate, by email or onscreen, a list of instructions on how to participate in the discussion for that group. TravelMed is an unmoderated discussion of clinical issues related to the practice of travel medicine that is restricted to members of the International Society of Travel Medicine (ISTM). LinkedIn is the most professionally oriented of the social networks and all those who join (free) must post at least brief professional résumés and can then join the Travel Medicine Forum.

ELECTRONIC NOTIFICATIONS AND FEEDS Many websites, including those in Table A.3, provide short messages or “feeds” that instantly inform subscribers when updates are made; usually a direct link back to the complete text is included. One common form of electronic notification is RSS (really simple syndication). To

TABLE A.4  Twitter Feeds With Real-Time

Outbreak Information

Twitter CDC Travel (@CDCTravel) CIDRAP (@CIDRAP) PAHO-WHO (@pahowho) World Health Organization (@WHO) ECDC (@ECDC_EU) Helen Branswell (@HelenBranswell) Ian M Mackay, PhD (@MackayIM) Michael Coston (@Fla_Medic) Crawford Kilian (@crof) Laurie Garrett (@Laurie_Garrett) Martin Enserink (@martinenserink) Jon Cohen (@sciencecohen) Michael Edelstein, MbChB (@epi_michael) Jeremy Farrar MD (@JeremyFarrar) PLoS Currents (@PLOSCurrents)

receive these feeds, users must have an RSS reader, either as free-standing software or embedded in a web browser, email client, or on a mobile device. Users can customize notification settings to send multiple feeds to their different devices. Many organizations also provide feeds that can be read via Twitter ( (Table A.4), Facebook (, or LinkedIn ( for those that have accounts on these social networking services. Some websites simply provide a sign-up form to receive regular email updates or tables of contents of regular publications.

INDEX Page numbers followed by “f ” indicate figures, “t” indicate tables, and “b” indicate boxes.

A AASM. see American Academy of Sleep Medicine Abacavir (ABC), 282t Abdominal ultrasound, 489 Abroad, health care, 475–481, 476b approaches, critical differences, 480 critical incident management principles, 476–479 evacuation issues in, 479 factors influencing, 475–476 medical tourism, 476 paying for, 479 pharmacy and medication issues, 480–481, 480b planning for, 477–479, 478b resources, 476–477 risks of needing, 475 Acanthamoeba spp., 32t Accelerating routine pediatric vaccinations, 132t Accidents, 6–8, 28, 485 in expatriates, 322 in mass gatherings, 383–384 motor vehicle, 239 in older traveler, 250 pretravel advice on, 27t Acclimatization, 408–409, 409t Accreditation Canada International, 372 ACEP. see American College of Emergency Physicians Acetaminophen, for travel use, during pregnancy and lactation, 227t–228t Acetazolamide for high altitude, 239, 391, 392t for pediatric and adolescent traveler, 245t for travel use, during pregnancy and lactation, 227t–228t Aciclovir, for travel use, during pregnancy and lactation, 227t–228t Acidosis, malaria and, 182t ACIP. see Advisory Committee of Immunization Practices ACOG. see American College of Obstetrics and Gynecology Acquired immunodeficiency syndrome. see HIV/ AIDS Active shooter, personal security and crime avoidance and, 486 ACTs. see Artemisinin combination therapies Acupressure, 425 for travel use, during pregnancy and lactation, 227t–228t Acute disaster-stricken areas, morbidity among rescue teams and volunteers working in, 336 Acute injuries, from water-related activities, 364 Acute kidney injury, malaria and, 182t Acute mountain sickness (AMS) and high-altitude cerebral edema (HACE), 389–395 clinical presentation and diagnosis of, 390–391, 390f epidemiology of, 389–390 in older traveler, 250 pathophysiology of, 390 preacclimatization to, 391–394

Acute mountain sickness (AMS) and highaltitude cerebral edema (HACE) (Continued) prevention of, 391, 392t–393t, 395 treatment for, 391, 391f, 393t, 395 Acute psychosis, 355 Acute schistosomiasis (Katayama syndrome), incubation period of, 498t, 500–501 ADA. see American Diabetes Association Adenovirus, travelers’ diarrhea and, 189 Adolescents, adolescent pertussis vaccine (Tdap), 130 Adult travel-related vaccines, 101–124 adverse events of, 101–102 attenuated live, 102 practical vaccine considerations for, 101, 103t–104t recommended, 110–121 required, 102–110 trade names of, 102t Advisory Committee of Immunization Practices (ACIP), 274, 290 Aedes aegypti, 49, 53 transmission, 499 in yellow fever virus, 102 Aedes albopictus, 53, 499 Aedes spp., in yellow fever virus, 10, 102 Aedes-transmitted infections, 243 Aerobacter aerogenes, 452 Aeromedical evacuation, 8 Aeromonas spp., 32t, 215 Aerosolized red tide respiratory irritation (ARTRI), 454 Aerospace Medical Association (AsMA), 372 African tick bite fever (Rickettsia africae), 58t–59t African trypanosomiasis (sleeping sickness) (Trypanosoma brucei), 58t–59t Africanized honeybees, 442 Afterdrop, 413 AGE. see Arterial gas embolism Age diving medicine and, 404 travelers’ diarrhea and, 190, 191f yellow fever vaccine and, 109 Air Carrier Access Act, 255 Air pollution, in business travelers, 288–289 Air quality index (AQI), 288, 289t Air travel in elderly, 249 in physically challenged traveler, 258–259, 258b with preexisting disease, 262 during pregnancy, 226 Aircraft cabin environment, 429–436 cosmic radiation in, 431–432 health problems and, 28 humidity in, 431 infectious diseases and, 432–433 introduction, 429, 430f ozone and, 431 passenger health and, 433–435. see also Passenger health pesticides in, 432 pressurized cabin, 429–432, 430f

Aircraft emergency medical equipment, 435 Aircraft interior furnishings, contamination of, 433 Albendazole, 214, 215t, 507 for travel use, during pregnancy and lactation, 227t–228t Alcohol, injuries and, 460 All patient priorities, VIP traveler and, 300 Allergic disorders eosinophilia and, 519, 520t in preexisting disease, 266 during pregnancy and lactation, 227t–228t Alligator/caiman, annual human deaths from, 439t Allogeneic hematopoietic stem cell transplantation, 271 Alprazolam (Xanax), for aviophobia, 463–464 Altered immune states, yellow fever vaccine in, 109 Alternative medications, 235 Altitude exposure after diving, 404 in pediatric and adolescent traveler, 239–240 pregnancy and, 233–234 pretravel advice on, 27t Altitude sickness, in older traveler, 250 AMA. see American Medical Association Amebiasis, invasive, posttravel screening for, 490t, 492 Amebic liver abscess, 501 American Academy of Pediatrics, 241–242 American Academy of Sleep Medicine (AASM), 250 jet lag and, 417–418 American College of Emergency Physicians (ACEP), 378 American College of Obstetrics and Gynecology (ACOG), 225 American Diabetes Association (ADA), 262, 265 American Medical Association (AMA), 372 American Society of Plastic Surgeons (ASPS), 372 American Society of Tropical Medicine and Hygiene (ASTMH), 16, 19 American Travel Health Nurses Association (ATHNA), 16 Amitriptyline, for ciguatera, 451–452 Amnesic shellfish poisoning, 451t, 455 Amoxicillin, for travel use, during pregnancy and lactation, 227t–228t Amoxicillin/clavulanic acid, 272 Amphetamines, 418t, 420 Ampicillin, 500 AMS. see Acute mountain sickness Anaconda, annual human deaths from, 439t Analgesics, 402 for travel use, during pregnancy and lactation, 227t–228t Ancylostoma braziliense, 505 Ancylostoma duodenale, 32t Ancylostoma spp. see Cutaneous larva migrans Anemia, in preexisting disease, 264 Angiostrongylus cantonensis, 501




Animal attack injuries, 439–440, 439f factors influencing, 440t infection from, 440, 440f, 442f, 442t marine, 445–446 prevention of, 439–440 treatment of, 440, 441t Animal contact, in pediatric and adolescent traveler, 240 Animals, physical risks from other species, 364 Anopheles mosquitoes, 241–242 Antacids, 155 for travel use, during pregnancy and lactation, 227t–228t Anthrax, 342t, 534 Antibiotics for diarrhea, in children, 244 for travel use, during pregnancy and lactation, 227t–228t for travelers’ diarrhea, 208, 209t, 210 persistent, 221 Anticoagulants, 155 Antidepressants, 420 Antiemetics, for travel use, during pregnancy and lactation, 227t–228t Antihistamines, 242, 420 for travel use, during pregnancy and lactation, 227t–228t Antimalarials, 140 priority, 151f for travel use, during pregnancy and lactation, 227t–228t Antimicrobial agents, for travelers’ diarrhea, 200t, 202–203, 202t Antimotility agents, 251 for diarrhea, 243 Antiparasitics, for travel use, during pregnancy and lactation, 227t–228t Antipyretics, for travel use, during pregnancy and lactation, 227t–228t Antirelapse therapy, with primaquine, 184 Antiretrovirals, in HIV, 284 Antisecretory agents, for travelers’ diarrhea, 208–209 Antispasmodics, for persistent travelers’ diarrhea, 221 Antivirals, for travel use, during pregnancy and lactation, 227t–228t Anxiolytics, 420 Appointments, in travel clinics, 18 AQI. see Air quality index Arachnids, venomous, 442t–443t Armodafinil, 250, 418t Arrhythmias, 413 Artemether, 184t Artemether/Lumefantrine, 174, 174t for children, 175t Artemisinin combination therapies (ACTs), 170, 182 Arterial gas embolism (AGE), 404 Artesunate, 184t Arthropod bites, 437–439 prevention of, 437, 438t treatment of, 437–439 venomous, 441–443, 442t Arthropod-related dermatoses, 511, 512f ARTRI. see Aerosolized red tide respiratory irritation Ascaris lumbricoides, 32t Asian tiger mosquito, 499 AsMA. see Aerospace Medical Association

Aspirin, for travel use, during pregnancy and lactation, 227t–228t Asplenia, 264 Asplenic travelers, 271–272 ASPS. see American Society of Plastic Surgeons Asthma, 396–397, 402 eosinophilia and, 519, 520t during pregnancy and lactation, 227t–228t ASTMH. see American Society of Tropical Medicine and Hygiene Astrovirus, travelers’ diarrhea and, 189 Asymptomatic long-term traveler, posttravel screening and, 488 Asymptomatic short-term traveler, posttravel screening and, 488 Atazanavir (ATZ), 282t ATHNA. see American Travel Health Nurses Association Atovaquone, 282 Atovaquone/proguanil (AP), 155–157, 174, 174t, 182 administration of, 156–157 adverse effects of, 148t in children, 242 contraindications to, 156 in dialysis, 264 drug interactions of, 156 for drug-resistant malaria, 142 efficacy of, 155–156 indications for, 156–157 mode of action of, 155 in older traveler, 250 for pediatric and adolescent traveler, 245t pharmacology of, 155 precautions of, 156 in pregnancy, 227t–228t, 231, 232t resistance, 147t, 155–156 tolerability of, 156 Atropine sulfate diphenoxylate hydrochloride, for travel use, during pregnancy and lactation, 227t–228t Augmentin, for travel use, during pregnancy and lactation, 227t–228t Australian Crohn’s and Colitis Association, 265–266 Automobile, travel by, in pregnant traveler, 228–229 Avian influenza, 57, 532 Aviophobia, stress in international travel and, 463–464 Azithromycin, 251, 275 for diarrhea, in children, 244 for pediatric and adolescent traveler, 245t in pregnancy, 227t–228t, 232t for travelers’ diarrhea, 200t, 203, 208, 209t

B Bacille Calmette-Guérin (BCG) vaccine in HIV, 281, 283t pediatric, 135 Back pain, noncombat-related injuries and, 343 Backpackers, medical kit and, 61 Bacteria in persistent travelers’ diarrhea, 215–216 travelers’ diarrhea and, 188–189 Balantidium coli, 32t Barbiturates, 155 Bariatric tourism, 373 Barometric pressure, 388f

Barotrauma middle ear, 402 pulmonary, 404 Bear, annual human deaths from, 439t Bednets, 242 Behavioral methods, for circadian rhythm, 418t Behavioral precautions, in HIV, 281, 282t Benzodiazepines, 250, 420 Beverage recommendations, 201t Biologic therapies, in immunocompromised traveler, 269–271, 270t–272t Biopesticide repellents, 48t Biophilia, 365 BioUD (2-undecanone), 49 Bisacodyl, for travel use, during pregnancy and lactation, 227t–228t Bismuth subsalicylate (BSS) for travel use, during pregnancy and lactation, 227t–228t travelers’ diarrhea and, 199–200, 200t, 202, 202t BiteBlocker, 48–49 Bites, 437–447, 438f nonvenomous injuries, 437–440 animal attack injuries, 439–440 arthropod bites, 437–439 treatment of, 242 venomous, 440–445 Blastocystis hominis, 32t travelers’ diarrhea and, 190 Blisters, 357 Blood eosinophil count, 489 Blood testing, for persistent travelers’ diarrhea, 219–220 Bloodborne risk, in immunocompromised traveler, 274 Bloodborne viruses, visiting friends and relatives and, 314–315 Blood-dwelling parasite, posttravel screening for, 493 Boat, travel by, in pregnant traveler, 226 Body temperature measurement instruments for, 407 sites for, 407 monitoring, 407 normal, 407 Booster doses, 66, 91 Botanical repellents, 47–49, 48t DEET versus, 49 Boyle’s law, 401–402 Brainerd diarrhea, in persistent travelers’ diarrhea, 216 Breast milk, drugs in, 234 Breastfed infant, yellow fever vaccine for, 109 Breastfeeding, 234 doxycycline for, 154 traveler, 159 British Lung Foundation, 264 British Mt. Everest winter expedition conditions treated on, 354t Brochures, travel health program and, 22 Buclizine, 425, 426t Burkholderia pseudomallei, 501 Burns, 357 Business travelers, 287–293 environmental risks in, 288–289 fitness in, 291

INDEX Business travelers (Continued) international health risks of, 287–288 medical considerations for, 289–291 posttravel care considerations in, 291 pretravel considerations for, 289–291 travel health considerations in, 291 medical kit and, 61 special issues in, 291–292

C Cabin humidity, 226 CAD. see Coronary artery disease Caffeine, 418t, 420 Calcineurin inhibitors, 275 Calcium channel blockers, for travel use, during pregnancy and lactation, 227t–228t Campylobacter jejuni, 216 travelers’ diarrhea and, 203 Campylobacter spp., 32t, 215, 243 HIV/AIDS and, 191 incidence of, 194, 195f in postinfectious IBS, 217 in pregnancy, 233 travelers’ diarrhea and, 188–189 Canada Transportation Act, 255 Cancer chemotherapy, in immunocompromised traveler, 273 Canes, air travel with, 259 Cape buffalo, annual human deaths from, 439t Capnocytophaga canimorsus, 271 Carbamazepine, 155 in neurologic diseases, 266 Cardiac disease, in preexisting disease, 263–264 Cardiac problem, high altitude and, 396–397, 396f Cardiovascular events, 263 Cardiovascular fitness, 402 Cardiovascular problems, 27 Care delivery, models of, 16–17, 17f CATMAT. see Committee to Advise on Tropical Medicine and Travel CDC. see Centers for Disease Control and Prevention Celiac serologies, for persistent travelers’ diarrhea, 220 Celiac sprue, 218, 218f Centers for Disease Control and Prevention (CDC) atovaquone/proguanil (AP), 156 CDC/WHO Safe Water System, 35 chlorine, 35 diarrhea and, 193 guidelines, for travelers, 101 on IR3535, 47 malaria and, 137–139, 145, 169–170, 313 medications and, 373 on picaridin, 47 routine adult vaccines, 79t Vaccine Information Statements (VIS), 19 varicella, 131 Vessel Sanitation Program (VSP), 378 yellow fever, 107 Central American bullet ant (Paraponera clavata), 442 Central nervous system, fever and, 501 Cephalosporins, for travel use, during pregnancy and lactation, 227t–228t Cercarial dermatitis, 512

Certificate in Travel Health (CTH), 1–2 Cetirizine, for travel use, during pregnancy and lactation, 227t–228t Chagas disease, 280 in migrants, 333 posttravel screening, 490t Chemical repellents, 46–47 Chemokine coreceptor antagonists, 282t Chemoprophylaxis malaria, 145–167 in older traveler, 250 in special populations, 159–161 travelers’ diarrhea and, 199, 203 Chemotherapy, cancer, in immunocompromised traveler, 273 Chest X-ray, 489 Chickenpox, vaccine requirement for, 342t Chigger mites, 44t Chiggers, deterrents in, 438t Chikungunya virus, 11–12, 55, 499 in business travelers, 288 in pediatric and adolescent traveler, 243 prevention of, 56 Chilblains, 413 Children for adoption, 303–304, 304b at altitude, 395–396 expatriates and, 326 for preadoption, 303 SBET recommendations for, 174–175, 175t severe malaria in, treatment of, 184 traveler and, 161 travelers’ diarrhea in, 190–191, 191f vaccine considerations in, 125 Chimeric JE vaccine (JE-CV), 112–113 Chloramphenicol, 500 Chlorine, 37t–38t Chlorine dioxide, 33t, 37t–38t Chloroquine (CQ), 146–150, 182, 282 administration of, 150 in breastfeeding, 234 for children, 175t, 242 contraindications to, 149 drug interactions of, 149 for drug-resistant malaria, 142 efficacy of, 147–149 indications for, 150 mode of action of, 146–147 in neurologic diseases, 266 in older traveler, 250 for pediatric and adolescent traveler, 245t pharmacology of, 146–147 precautions of, 149 in pregnancy, 227t–228t, 232t in renal insufficiency, 264 resistance, 147–149 resistance of, 147t tolerability of, 149 Chloroquine phosphate adverse effects of, 148t Chloroquine/proguanil, 146–150 efficacy of, 147–149 pharmacology of, 146–147 resistance, 147–149 Chloroquine-resistant P. falciparum, 231 malaria, 142, 242 Chlorpheniramine, for travel use, during pregnancy and lactation, 227t–228t


Cholera, 11 in immunocompromised traveler, 274 Cholera vaccine, 110–111 adverse events in, 111 contraindications to, 110 dosing schedules for, 110 drug and vaccine interactions in, 111 in HIV-infected travelers, 283t immune response in, measures of, 111 immunity/protection in, duration of, 111 indications for, 110 pediatric, 127t–129t, 134t precautions for, 110 during pregnancy, 230t risks of, 106t summary of, 103t–104t trade names of, 102t for travelers’ diarrhea, 251 Chronic gastrointestinal diseases, unmasked by an enteric infection, 218 Chronic medical conditions, children with, precautions for, 240 Chronic obstructive pulmonary disease (COPD), 264, 396 Chronic travelers’ diarrhea, differential diagnosis of, 214t Chronically ill patients, SBET recommendations for, 174–175 Ciguatera, 358, 449–452, 450b, 450f, 451t Ciguatoxin (CTX), 449 Cimetidine, for travel use, during pregnancy and lactation, 227t–228t Cinnarizine, 425, 426t Ciprofloxacin, 500 for diarrhea, in children, 244 for pediatric and adolescent traveler, 245t in pregnancy, 227t–228t, 233 for travelers’ diarrhea, 202t, 209t Circadian rhythm, 418t Citronella, 47–48 Citrosa plant, 48 Citrus juice, 36 Clarification technique, 32–34 Clavulanic acid, 272 for travel use, during pregnancy and lactation, 227t–228t CLIA. see Cruise Lines International Association Clindamycin, for travel use, during pregnancy and lactation, 227t–228t Clonazepam (Klonopin), for aviophobia, 463–464 Clonorchis sinensis, 32t Clostridium difficile, in persistent travelers’ diarrhea, 216 Clothing, 413, 413t Coagulation-flocculation technique, 33–34, 33t Coca leaf tea, 391 Coccidioidomycosis, 535 Cochliomyia hominivorax, 508 Code of Practice for Access to Air Travel for Disabled People, 255 Codeine, for travel use, during pregnancy and lactation, 227t–228t Cognitively impaired traveler, 260 Coinfection, in persistent travelers’ diarrhea, 214, 214t–215t COLD acronym, 413t Cold adaptation, 409



Cold injuries, 411–414, 412f, 412t chilblains, 413 frostbite, 413 hypothermia, 412–413 preventing, 413–414, 413t trench foot (immersion foot), 413 Cold stress, 408, 409f in older traveler, 250 Colorectal cancer, 218 Colostomies, 266 Combat-related injuries, 343 Combined hepatitis A/B vaccine, 96–97 accelerated schedules of, 96 adverse events (AE) of, 97 contraindications to, 96 dosing schedules of, 96 drug and vaccine interactions of, 97 immune response of, 96–97 indication of, 96 pediatric, 133 precautions of, 96 trade names of, 91t Combined tetanus, diphtheria, and pertussis vaccine, in HIV-infected travelers, 283t Combined tetanus and diphtheria vaccine, in HIV-infected travelers, 283t Committee to Advise on Tropical Medicine and Travel (CATMAT) (Canada), 140 Communication, 348f Community events, mass gatherings in, 384 Compensation, 348 Computers, 18 Congenital rubella syndrome (CRS), 233 Congenital Zika infection, additional considerations for prevention of, 56 Conjugate vaccines, 125, 133 Consultations pretravel. see Pretravel consultation suggestions for, 29 Contaminated water, 357 Contraceptives, oral, 155 Contract services, travel clinic and, 22 Convulsive disorders, 266 COPD. see Chronic obstructive pulmonary disease Coral cuts, 358 Cordylobia anthropophaga, 508, 509f, 509t Coriolis effect, 423 Coronary artery disease (CAD), 263, 397, 402 Corticosteroids, in immunocompromised traveler, 269–271, 270t–272t Cosmetic surgery, 372 Cosmic radiation, 431–432 Cosmopolitan dermatoses, 510–513 Costs, in business travelers, 287 Counseling for expatriates, 324 for standby emergency treatment, 174, 174t in transplant recipient, 275 Country of origin, travelers’ diarrhea and, 191 CQ-resistant P. vivax (CRPv) malaria, 142 Cramps, heat, 411 Creeping eruption, 513, 514t Crocodile, annual human deaths from, 439t Crofelemer, for travelers’ diarrhea, 208–209 CRS. see Congenital rubella syndrome Cruise Lines International Association (CLIA), 378 Cruise Ship and Maritime Medicine Section, 378

Cruise ship travel, 377–382 health, sanitation, and safety, 377–378 illness on, 378–379 industry, 377 international regulations of, 377–378 medical care aboard, 378, 378f miscellaneous, 379 North America, 377 passengers and crew, 377 preparations, 380–381, 380b after travel, 381 during pretravel, 380 during travel, 380, 381b US regulations of, 378 vessel sanitation program (VSP), 378 Cruising, with wheelchair or scooter, 259 Crutches, air travel with, 259 Cryptosporidium HIV/AIDS and, 191 travelers’ diarrhea and, 190, 201 Cryptosporidium parvum, 32t, 189 in HIV, 280 in persistent travelers’ diarrhea, 215 Cryptosporidium spp., 31, 379 posttravel screening for, 493 CTH. see Certificate in Travel Health Culex spp., 111–112 Cultural differences, 480 Cultural identity, 311 Culture shock, 338 in expatriates, 324–325, 325b international travel and, 464 Cutaneous gnathostomiasis, 510 Cutaneous larva migrans (Ancylostoma spp.), 58t–59t, 513 eosinophilia and, 522 Cutaneous (or mucocutaneous) leishmaniasis, 58t–59t Cyclizine, 425, 426t Cyclospora cayetanensis, 189 in HIV, 280 in persistent travelers’ diarrhea, 215, 215f Cyclospora spp., 32t, 219 travelers’ diarrhea and, 190 Cystic fibrosis, 396 Cystoisospora belli, travelers’ diarrhea and, 190

D DAN. see Divers Alert Network Darunavir (DRV), 282t DCI. see Decompression illness Deaths in expatriates, 322 selfie-related, 366t Decompression illness (DCI), 357, 404 Decongestants, 402 Deep vein thrombosis (DVT), 249, 291, 434, 469 DEET (N,N-diethyl-m-toluamide), 46–47, 241–242, 437 BioUD versus, 49 botanical repellents versus, 49 formulation choice for, 46 mosquito bites and, 146 in older traveler, 250 permethrin, 50 picaridin versus, 47

DEET (N,N-diethyl-m-toluamide) (Continued) for pregnancy, 227t–228t, 231 safety and toxicity of, 46–47 Dehydration, 414 kayaking/rafting and, 357 pretravel advice on, 27t Deloitte Center for Health Solutions, 371 Demyelinating diseases, 266 Dengue, 53–55, 206, 207t, 499 in business travelers, 288, 290 fever, epidemiology of, 11–12 hemorrhagic fever, 499 pediatric, 127t–129t in pediatric and adolescent traveler, 243 posttravel screening for, 491 prevention of, 56 Dengue shock syndrome, 499 Dental care, HIV/AIDS and, 337–338 Dental problems, 356 Dental work abroad, 373 Department of Transportation, 226, 257 Deployed military, 341–346, 343f combat-related injuries, 343 noncombat-related injuries and back pain, 343 Deployed US personnel, vaccine requirements for, 342t Dermatitis, cercarial, 512 Dermatobia hominis, 508, 509t Dermatologic diseases, as combat-related injuries, 344–345, 345f Dermatophytosis, 511 Dermatoses arthropod-related, 511, 512f cosmopolitan, 510–513 diagnosed abroad, 505 diagnosed upon return, 505, 506t epidemiological data of, 505 tropical, 505–510 Desert environments, 356, 356f Destinations, medical kits, 61 Developmentally impaired traveler, 260 Dexamethasone for high-altitude, 239, 391, 392t for travel use, during pregnancy and lactation, 227t–228t Dextroamphetamine, 425, 426t Dextromethorphan, for travel use, during pregnancy and lactation, 227t–228t Diabetes mellitus, 398, 402–403, 403t in preexisting disease, 264–265 Dialysis, 264 Diarrhea, in pediatric and adolescent traveler, 243–244, 243t Diarrheal diseases, in expatriates, 324 Diarrheic shellfish poisoning, 451t, 455 Diazepam (Valium), for aviophobia, 463–464 Dicloxacillin, for travel use, during pregnancy and lactation, 227t–228t Didanosine (DDI), 282t Dientamoeba fragilis, in persistent travelers’ diarrhea, 215 Diet, 414, 418t, 419 Diffuse cutaneous leishmaniasis, 507 Dignitary and protective medicine (DPM), economics of, 302 Dihydroartemisinin/piperaquine, 174, 174t Dihydrofolate reductase (DHFR), 155 Diloxanide furoate, 214–215

INDEX Dimenhydrinate, 426t for pediatric and adolescent traveler, 245t for travel use, during pregnancy and lactation, 227t–228t Diphenhydramine, 242 for pediatric and adolescent traveler, 245t for travel use, during pregnancy and lactation, 227t–228t Diphenoxylate, for diarrhea, 243 Diphtheria, tetanus, acellular pertussis (DTaP) vaccine, during pregnancy, 230t Diphtheria, tetanus, pertussis (DTP) vaccine, pediatric, 126t–130t, 130 Diphtheria, vaccination for, 67t Diphyllobothrium latum, 32t Diptera, 508 Disease-modifying antirheumatic drugs (DMARDs), in immunocompromised traveler, 269–271, 270t–272t Disinfectants, 36 Disinfection, defined, 32 Divers Alert Network (DAN), 357–358 Diving, 401–406 aerobic fitness and, 404 age and, 404 altitude exposure after, 404 asthma and, 402 cardiovascular fitness, 402 diabetes and, 402–403, 403t ears, nose, and throat (ENT) system, 401–402 further information and advice for, 404–405 medication and, 403–404 -related maladies, 404 respiratory fitness, 402 unique environment and physiologic challenges of, 401 watermanship and, 404 Division of Immunization (Canada), 21 DMARDs. see Disease-modifying antirheumatic drugs Documentation, of travel health program, 17–19 Dolphinfish. see Mahi-mahi Dolutegravir (DTV), 282t DORAs. see Dual orexin receptor antagonists Doxycycline, 153–155, 282 administration of, 155 adverse effects of, 148t in children, 242 contraindications to, 154–155 in dialysis, 264 drug interactions of, 154–155 for drug-resistant malaria, 142 efficacy of, 153–154 indications for, 155 mode of action of, 153 in neurologic diseases, 266 for pediatric and adolescent traveler, 245t precautions of, 154–155 resistance, 147t, 153–154 tolerability of, 154 for travel use, during pregnancy and lactation, 227t–228t DPM. see Dignitary and protective medicine Dracunculus medinensis, 32t Dressings, wound, 63–64 Drowning, 6, 459 kayaking/rafting and, 357

Drug hypersensitivity, eosinophilia and, 519–520, 520t Drug-resistant malaria, 142–143 Dry heat exchange, 408 Dual orexin receptor antagonists (DORAs), 420 Duke-National University of Singapore, 371–372 Dukoral vaccine, 111 Dutch National Coordination Center for Traveler’s Health Advice, 16 DVT. see Deep vein thrombosis D-Xylose testing, for persistent travelers’ diarrhea, 220 Dysentery, management of, 208

E Earaches, 239 Ears, nose, and throat (ENT) system, diving and, 401–402 Ebola virus, 206, 207t in aircraft cabin, 433 Echinococcus granulosus, 32t Ecotourism, 363–369 infectious disease risks of, 364–366 to other species, 365–366 physical risks with, 364 from other species, 364 recommendations of, 366 vectorborne diseases in, 365 zoonotic disease risk of, 365 Ecotourists, 363–364 ECS. see Environmental control system Ectoparasites, 521 Edema, 515 heat, 411 Education patient, 19 for travelers’ diarrhea, 200–201, 201t Efavirenz (EFV), 282t EHS. see Exertional heatstroke EIB. see Exercise-induced bronchospasm ELDSNET. see European Legionnaires’ Disease Surveillance Network Electrocardiogram (EKG), 263 Electrolyte replacement, for travelers’ diarrhea, 207 Electronic devices email advice, travel clinic and, 22 personal security and crime avoidance and, 486 Elephant, annual human deaths from, 439t Emergencies, in-flight, in older traveler, 249 Emetics, for ciguatera, 451–452 Emetrol, for travel use, during pregnancy and lactation, 227t–228t Empiric antiinfective therapy, for persistent travelers’ diarrhea, 220–221 Emtricitabine (FTC), 282t Encephalitis, 498t Japanese, 11 tickborne, 11 Encephalitozoon intestinalis, 215 Endoscopic evaluation, for persistent travelers’ diarrhea, 220 End-stage renal disease (ESRD), 264 Enfuvirtide (T20), 282t Entamoeba dispar, 190, 214–215 posttravel screening for, 492


Entamoeba histolytica, 32, 32t, 190, 501 incidence of, 194 in persistent travelers’ diarrhea, 214–215 posttravel screening for, 492 Entamoeba spp., travelers’ diarrhea and, 190 Enteric fever, 498t, 500 visiting friends and relatives and, 312–313 Enteroadherent Escherichia coli, 32t in persistent travelers’ diarrhea, 215 Enteroaggregative Escherichia coli, 243 travelers’ diarrhea and, 189 incidence of, 195f Enterobacteriaceae, in persistent travelers’ diarrhea, 215 Enterobius, 520 Enterocytozoon bieneusi, 215 Enteroinvasive Escherichia coli, travelers’ diarrhea and, 189 Enterotoxigenic Escherichia coli, 32t, 187–189, 194, 215, 243, 379 incidence of, 195f infection, vaccine for, 110 in pregnancy, 233 vaccines and, 202 Envenoming injuries, 437–447 Environmental conditions, assessment of, 408, 408f–409f Environmental control system (ECS), 429 Environmental factors, of health problems, 12 Environmental Protection Agency (EPA), 241–242, 288 on picaridin, 47 Environmental psychology, 365–366 Enzymatic phase, of heatstroke, 410 Eosinophilia, 519–526 asymptomatic, 523–524 causes of, 519–521 clinical syndromes and, 521–524 conditions associated with, 520t evaluation of patients with, 524–525, 524f fever and, 502 EPA. see Environmental Protection Agency Ephedrine, 425, 426t Epidemiology, 3–14, 4t, 6t–7t cornerstones of, 3, 8f of malaria, 137–144 Equipments in travel clinics, 18 for VIP traveler, 299–301, 300t Erythromycin for persistent travelers’ diarrhea, 221 for travel use, during pregnancy and lactation, 227t–228t Escherichia coli, 31, 32t, 452 diarrhea producing, 188–189 enteroaggregative, 189 enteroinvasive, 189 enterotoxigenic, 188–189 in pregnancy, 233 travelers’ diarrhea and, 189–190, 199 ETEC vaccine, during pregnancy, 230t Ethnic groups, tuberculosis in, 315 Etravirine (ETV), 282t ETT. see Exercise treadmill test Eurartesim, 174t European Legionnaires’ Disease Surveillance Network (ELDSNET), 531–532 Evacuation, aeromedical, 8



Evacuation insurance plans, health care abroad, 477–478 Evacuation policies, for expatriates, 324 Evaporative heat exchange, 408 Exercise, 228, 418t, 419 high altitude on, 389 Exercise-induced bronchospasm (EIB), 396–397 Exercise treadmill test (ETT), 397 Exertional heatstroke (EHS), 409 Exhaustion, heat, 410 Expatriates, 321–329 culture shock in, 324–325, 325b deaths, accidents, and injuries in, 322 factors influencing reintegration, 327–328 factors that can facilitate cultural adaptation in, 326 illness in returning, 327 in international settings, 326 medical consultation on return home for, 327 “normal” adjustment difficulties in, 327 posttravel screening and, 488 predeparture assessment of, 322–323 psychologic, 322–323 purpose of, 322, 322b tuberculin skin test, 322 predeparture of, 323–324 diarrheal diseases, 324 health briefings, 323 immunizations, 323 infection control policies, 324 malaria, 324 psychologic training and preparation, 324, 325b risk behavior, 324 security issues and evacuation policies, 324 sexually transmitted diseases, 324 preparation and care for, 321–322 at time of repatriation, 326–327 U-curve hypothesis and, 324–325, 325b Expatriation, hidden costs of, 321–322 Expedition Advisory Center of the Royal Geographic Society, 353 Expeditions back home, 360 contents of, 351 death overseas of, 359–360 desert environments of, 356, 356f design, 351 difficult situations of, 358 field data in, 353–354 first-aid kits, 351–353 jungle/tropical environments of, 356–357 kayaking and rafting, 357 liability in, 353 local health care of, 358–359 luxury, 358 medical care, others, 358–359 medical kit for, 64, 348, 348f, 355f medicine, 347–361 mountaineering of, 355–356 personal preparation of, 349–351, 349t polar environment of, 355 preparation for, 348–351 repatriation of, 359 risk assessment of, 348–351, 350t safety and security of, 359 scuba diving, 357–358, 357f supplies for, 351–353 trip physician, 347 websites, 351t Expertise, 16

F FAA. see Federal Aviation Administration Families, of expatriates, issues for, 327 Family members, vaccination of, 274 Fasciola hepatica, 32t Fasciola infection, 523 Fatal injury, 457–458 FDA. see Food and Drug Administration Febrile rash, 514–515, 515f, 515t Federal Aviation Administration (FAA), 226, 264 Fees fee-for-service care, 20 in travel clinic, 20 Feral pig, annual human deaths from, 439t Fever, 408 in asplenic traveler, 272 eosinophilia and, 523 in returned travelers, 495–504 causes of, 495, 496t–497t clinical presentations of, 498–501, 502t CNS changes and, 501 diagnostic workup, 502 eosinophilia and, 502 epidemiology of, 495 hemorrhagic, 501 history, travel and exposure, 496t–497t incubation period, 497, 498t information and assistance for, 502 laboratory clues and, 501–502 management of, 502, 503f mode of exposure, 498 persistent and relapsing, 501 undifferentiated, 499–501 FGD. see Functional gastrointestinal disorders FHPP. see Force health protection policy Fidaxomicin, 216 Field data, in expeditions, 353–354 Field hospital, in disaster-stricken areas, 335 FIFA, mass gatherings in, 384 Filarial infection, eosinophilia and, 524 Filariasis, posttravel screening for, 490t Filtration technique, 33t–34t, 34–35, 34f Finance, in travel clinics, 20 First-aid kits, 351–353. see also Medical kits Fitness in older traveler, 247–248 to travel, 26 5HT4 agonist, for persistent travelers’ diarrhea, 221 Fleas, 44t deterrents in, 438t Flies, 44t Fludrocortisone acetate, for ciguatera, 451–452 Fluid consumption, 414 Fluid hydration, for travelers’ diarrhea, 207–208 Fluoroquinolones, 251, 275 for travelers’ diarrhea, 208 travelers’ diarrhea and, 200t, 202t, 203 Food pretravel advice on, 27t recommendations for, 201t Food and Drug Administration (FDA), 231, 234 Food and water safety issues, in gastroenteritis, 275 Food hygiene, for diarrhea, 243 Foodborne diseases, 379 Foot injury, 265 Force health protection policy (FHPP), 344 For-profit international health care organizations, 477

Fosamprenavir (FPV), 282t Freezers, for vaccines, 18 Friends and relatives, visiting, 311–319 barriers to protecting, 312b definition of, 311 general travel advice for, 317 pretravel consultation for, approaches to, 315–317 as risk group, 311 travel by, epidemiology of, 311–315 travelers, 311 Frostbite, 355, 413 Fugu poisoning, 453–454, 453b Functional gastrointestinal disorders (FGD), 216–217 Fungi, 521 Furazolidone, for travel use, during pregnancy and lactation, 227t–228t Fusion inhibitors, 282t

G Gambierdiscus toxicus, 449 Gamow Bag®, 391, 391f Gastroenteritis, in immunocompromised traveler, 275, 275b Gastrointestinal disease, in preexisting disease, 265–266 Gastrointestinal disturbances, 27 Gastrointestinal illness, on cruise ships, 379 Gastrointestinal infections, as combat-related injuries, 345 Gastrointestinal symptoms, of eosinophilia, 522–523 GBS. see Guillain-Barré syndrome Gender, travelers’ diarrhea and, 190 GeoSentinel, malaria and, 313 GeoSentinel Network (ISTM/CDC), 335 GeoSentinel Surveillance Network, on fever, 495 Geraniol, 49 German malaria prophylaxis recommendations, SBET and, 169–170 GHLO. see Global Health Learning Opportunities Giardia intestinalis, 32t, 379 international adoption and, 304 Giardia lamblia in persistent travelers’ diarrhea, 214, 214f posttravel screening for, 493 Giardia spp., 32 incidence of, 194 in persistent travelers’ diarrhea, 214 travelers’ diarrhea and, 189–190, 201 Ginger, for travel use, during pregnancy and lactation, 227t–228t Global Dental Safety Organization for Safety and Asepsis Procedures, 373 Global Health Learning Opportunities (GHLO), 372 Global Travel Clinic Directory of the International Society of Travel Medicine, 284 Gnathostoma, eosinophilia and, 522 Gnathostoma hispidum, 510 “Going on holiday with a lung condition”, 264 Group kits, medical kit and, 64 Guaifenesin, for travel use, during pregnancy and lactation, 227t–228t Guide dogs, 259 Guiding Principles on Human Cell, Tissue and Organ Transplantation (WHO), 373 Guillain-Barré syndrome (GBS), 266 Gynecology, 398


H H1 antagonists, for scombroid, 453 Habituation, 425 Haemagogus spp., 102 as yellow fever vector, 10 Haemophilus influenzae, 271 type B, 67t, 126t–129t, 272 vaccine, in HIV-infected travelers, 283t Hajj pilgrimage, 10, 384, 384f Halofantrine, 174 for travel use, during pregnancy and lactation, 227t–228t Halogens, 33t, 35–36 taste, improving, 35–36 toxicity, 36 Hand luggage, medication in, 261 HAPE. see High altitude pulmonary edema Hastings Center Report, 371 HAWs. see Humanitarian aid workers Hazardous waste supplies, 18 Headache, high altitude (HAH), 389 Health briefings, for expatriates, 323 Health Canada, 145 Health care abroad, 475–481, 476b approaches, critical differences, 480 critical incident management principles, 476–479 evacuation issues in, 479 factors influencing, 475–476 in HIV, 284 medical tourism, 476 paying for, 479 pharmacy and medication issues, 480–481, 480b planning for, 477–479, 478b resources, 476–477 risks of needing, 475 Health Care Guidelines for Cruise Ship Medical Facilities (ACEP), 378 Health care workers, in immunocompromised traveler, 274 Health evaluation, of migrant traveler, 331, 332t Health Information for International Travel 2018 (the CDC Yellow Book), 101, 140 Health insurance, 261 for older traveler, 248 Health status, of migrant traveler, 331–334 Hearing-impaired traveler, 259 Heat adaptation, 408–409 balance, 407–408 stress, 408, 408f treatment, water disinfection, 32, 33t Heat cramps, 411 Heat edema, 411 Heat exhaustion, 410 Heat-related illness, 409–411 heat cramps, 411 heat edema, 411 heat exhaustion, 410 heat syncope, 411 heatstroke, 409–410, 410t, 411f Heat stress, in older traveler, 250 Heat syncope, 411 Heatstroke, 409–410 classic, 409 clinical picture of, 410 diagnosis of, 409–410 differential diagnosis of, 410t

Heatstroke (Continued) early presentation of, 409 pathophysiology of, 409 prevention of, 410 prognosis for, 410 treatment of, 410 Helminths, 520–521, 520t Hematologic disorders, 397 Hematologic phase, of heatstroke, 410 Hematopoietic stem cell transplant (HSCT), 272t Hemodialysis (HD), 264 Hemophilus B conjugate vaccine, during pregnancy, 230t Hemorrhagic fevers, 501 Hepatic phase, of heatstroke, 410 Hepatitis A, 11, 32t expatriates and, 323 incubation period of, 498t posttravel screening for, 491 screening for, international adoption and, 306 visiting friends and relatives and, 312, 316t Hepatitis A (HA) vaccine, 67t, 89–91, 94t–95t accepted accelerated schedule of, 91 adverse events of, 91 contraindications to, 89 dosing schedules of, 79t, 90–91, 90t–91t drug and vaccine interactions of, 91 estimated risk of, 96t in HIV, 281, 283t immune response of, 91 indications for, 89 in older traveler, 251 pediatric, 126t–130t, 133, 134t precautions of, 89–90 during pregnancy, 230t prevalence of, 90f requirement for, 342t trade names of, 91t typhoid combined, 91t, 94t–95t Hepatitis B, 11 in business travelers, 288 expatriates and, 323 incubation period of, 498t posttravel screening, 490t in pregnancy, 233 screening for, international adoption and, 306 visiting friends and relatives and, 316t Hepatitis B (HB) vaccine, 67t, 92–96, 94t–95t accelerated schedules of, 93 adverse events of, 96 contraindications to, 92 dosing schedules of, 79t, 92 drug and vaccine interactions of, 96 estimated risk of, 96t in HIV, 281, 283t immune response of, 93–96 indications for, 92 in older traveler, 251 pediatric, 127t–130t, 132 precautions of, 92 during pregnancy, 230t prevalence of, 93f requirement for, 342t trade names of, 91t Hepatitis C posttravel screening, 490t screening for, international adoption and, 306 Hepatitis E, 32t, 232–233 incubation period of, 498t


Herpes simian B virus (Macacine herpesvirus 1), 365 High altitude in cardiac disease, 263 in diabetes, 265 environment, 387, 388f in infants, 238 High-altitude medicine, 387–400 acclimatization, 387–389 cough, 395 environment, 387, 388f on exercise, 389 medical conditions, effects of, 396–398, 396t online information resources on, 387, 388t parents, travel advice for, 395–396 pulmonary edema. see High-altitude pulmonary edema retinal hemorrhage (HARH), 395 syndromes, 389 High-altitude pulmonary edema (HAPE), 394–395 clinical presentation and diagnosis of, 394, 394f epidemiology of, 394 pathophysiology of, 394 prevention of, 394–395 treatment of, 392t–393t, 394–395 Hippopotamus, annual human deaths from, 439t Histamine fish poisoning, 451t, 452–453, 452b, 452f–453f. see also Scombroid Histoplasmosis (Histoplasma spp.), 58t–59t, 535 HIV/AIDS, 11, 191, 337–338 in immunocompromised traveler, 274 incubation period of, 498t in migrants, 333 mortality of, 8 posttravel screening for, 490t, 491 screening for, international adoption and, 306 traveler with, 279–286 antiretroviral prophylaxis to prevent, 284 behavioral precautions in, 281, 282t crossing international borders in, 284 drug interactions in, 284 health care abroad in, 284 health risks to, 280 neurocysticercosis, 280 pretravel advice in, 280–284 vaccination in, 281–284 vaccination for, 71 visiting friends and relatives and, 315 Hobo spider (Tegenaria), 443 Honeybees, 442 Hookworm folliculitis, 507, 507f Hookworm infection, eosinophilia and, 524 Hookworm-related cutaneous larva migrans, 505–507, 506f–507f, 506t Host, health problems and, 12 Household contacts, vaccination of, 274 HSCT. see Hematopoietic stem cell transplant Human botfly, 508 Human immunodeficiency virus. see HIV/AIDS Human papilloma virus (HPV) vaccine, 77t, 84–85 contraindications to, 85 dosing schedules for, 79t, 85 indications for, 85, 132 pediatric, 127t–130t, 132 precautions for, 85 trade names for, 76t Human populations, indigenous, 363



Humanitarian aid workers (HAWs), 335–340 health recommendations for relief worker traveling to challenging work zones, 338–339, 339t human immunodeficiency virus (HIV)/ acquired immunodeficiency syndrome (AIDS), 337–338 morbidity in, 336, 336t mortality in, 335–336 physical and laboratory screening, 338t public health aspects of, 338 specific diseases and medical conditions of, 336–337 Humidity, 431 Hydration, 414 pretravel advice on, 27t Hydrocodone, for travel use, during pregnancy and lactation, 227t–228t Hydrocortisone, for travel use, during pregnancy and lactation, 227t–228t Hydroxychloroquine, 146–150 administration of, 150 contraindications to, 149 drug interactions of, 149 efficacy of, 147–149 indications for, 150 mode of action of, 146–147 pharmacology of, 146–147 precautions of, 149 resistance, 147–149, 147t tolerability of, 149 Hyena, annual human deaths from, 439t Hymenoptera, 442 Hyperbaric chambers, 391, 391f Hyperparasitemia, malaria and, 182t Hypersensitivity, 154 to eggs, yellow fever vaccine in, 109 Hyperthermia, in older traveler, 250 Hyperthermic phase, of heatstroke, 410 Hypnotics, for jet lag, 419–420 Hypoderma lineatum, 508 Hypoglycemia, 413 malaria and, 182t Hypohydration, 414 Hyponatremia, 414 Hypothermia, 412–413 complications of, 413 diagnosis of, 412 in older traveler, 250 treatment of, 412–413 Hypoxia, 387 in air travel, 238 -inducible factor, 388

I IAMAT. see International Association for Medical Assistance to Travelers IBD. see Inflammatory bowel disease IBS. see Irritable bowel syndrome Ibuprofen, for travel use, during pregnancy and lactation, 227t–228t ICRP. see International Commission for Radiological Protection IDAN. see International Divers Alert Network Idiopathic inflammatory bowel disease, 218 IGRA. see Interferon-γ release assay IHR. see International Health Regulations Illusory self-motion, 423–424

Immigrants, core values and best practices in care of, 334 Immobility, in passenger health, 434 Immune globulin adverse events of, 92 contraindications to, 92 dosing schedules of, 92 drug and vaccine interactions of, 92 for hepatitis prevention, 91–92 indications for, 91–92 pediatric, 134t precautions of, 92 Immune memory, 66 Immune response to cholera vaccine, 111 to combined hepatitis A/B vaccine, 96–97 to hepatitis A vaccine, 91 to hepatitis B vaccine, 93–96 to measles, mumps, and rubella (MMR) vaccine, 82 to meningococcal vaccine, 115 to pneumococcal vaccine, 84 to rabies vaccine, 119 to tetanus, diphtheria, pertussis vaccine, 79 to tickborne encephalitis vaccine, 120–121 to typhoid fever vaccine, 98 to varicella and herpes zoster vaccines, 83 to yellow fever vaccine, 109 Immunity in cholera vaccine, 111 in meningococcal vaccine, 115 in rabies vaccine, 119 in tickborne encephalitis vaccine, 120–121 travelers’ diarrhea and, 191, 192f in yellow fever vaccine, 109 Immunizations active, 65–66 during breastfeeding, 234 for expatriates, 323 for migrants, 333 for older traveler, 251 passive, 66 for pediatric and adolescent traveler, 240–241 during pregnancy, 229, 230t primary, 90–91 principles of, 65–73 recommended, 11 required, 10 route of, 68–70 routine, 10–11 schedule, 92 serologic testing before and after, 70–71 for travelers, 72, 72t vaccination and, 65 visiting friends and relatives and, 316–317, 316t Immunocompromised traveler, 269–277 additional considerations for, 275–276 asplenic travelers and, 271–272 cancer chemotherapy in, 273 corticosteroids, disease-modifying antirheumatic drugs in, 269–271, 270t, 272t health care workers in, 274 immunosuppression for vaccination, suspending, 274 medical and transplant tourism in, 276 medical missions in, 274 overview of, 269, 271t rabies vaccination in, 274

Immunocompromised traveler (Continued) special vaccine-related topics in, 273–274 transplant recipients in, 272–273 Immunogenicity, 70 Immunoglobulin (Ig) administration of, 70 vaccine, during pregnancy, 230t Immunosuppression, suspending, for vaccination, 274 IMO. see International Maritime Organization Impaired consciousness, malaria and, 182t Impetiginization, 505–506, 507f Impetigo, 510, 511f Imported malaria, into United Kingdom, 138f Inactivated cell-culture vaccines, 112 Inactivated polio vaccine, in HIV-infected travelers, 283t Inactivated trivalent seasonal influenza vaccine, in HIV-infected travelers, 283t Inactivated vaccines, 68 in HIV, 281–282, 283t INCB. see International Narcotics Control Board Indigenous human populations, 363 Indinavir (IDV), 282t Infections control of, 18 policies, for expatriates, 324 eosinophilia and, 520–521, 520t in older traveler, 250–251 respiratory, 527–537 anthrax and, 534 causative agents and clinical presentation of, 527, 528b–529b, 528t coccidioidomycosis and, 535 environmental factors in, 531b epidemiology of, 527–529 influenza and, 532–533 legionellosis and, 533 leptospirosis and, 534 management of, 529–531, 530f, 531b melioidosis and, 533–534 Middle East respiratory syndrome coronavirus and, 533 paragonimiasis, 534–535 plague, 534 prevention in travelers, 531–532, 532t risk factors for, 529 severe acute respiratory syndrome and, 532 transmission of, 529 tuberculosis, 535, 536f rickettsial, 499–500 systemic, 207t Infectious diseases, 8, 341 aircraft cabin environment and, 432–433 in expatriates, 327 in pregnancy, 229–231 risk of, 364–366 screening for, international adoption and, 304–307 Inflammatory bowel disease (IBD), 265–266 idiopathic, 218 In-flight medical emergencies, 434–435 in older traveler, 249 Influenza, 532–533 in aircraft cabin, 432 in business travelers, 288 on cruise ships, 378–379 in immunocompromised traveler, 274

INDEX Influenza (Continued) incubation period of, 498t seasonal, vaccine requirement for, 342t Influenza vaccine, 67t, 77t, 85–86 contraindications to, 78t, 86 dosing schedules for, 79t, 86 in HIV, 281 indications for, 85 pediatric, 131 precautions for, 86 during pregnancy, 230t trade names for, 76t Information resources, 19 for clinician, 19 Inhaled bronchodilators, for travel use, during pregnancy and lactation, 227t–228t Inhaled steroids, for travel use, during pregnancy and lactation, 227t–228t Injuries during air travel, 238 cruise ships and, 379 in expatriates, 322 in older traveler, 250 travel-related, 457–461 alcohol and, 460 fatal, 457–458, 458f nonfatal, 458 prevention, 459t road traffic safety for, 459, 460t water-related, 459–460, 460t Insect-borne diseases, in pediatric and adolescent traveler, 241–243, 241t Insect protection, 43–52 habitat avoidance, 43 insecticides, 50 mosquitoes. see Mosquitoes personal protection, 43–50, 44f physical protection, 45, 45f, 45t repellents, 46–50, 49t stimuli, attracting, 43 Insect repellent, for travel use, during pregnancy and lactation, 227t–228t Institut Pasteur de Dakar, 102 Insulin, adjustment in, 265 Insurance, 225–226, 261 in business travelers, 292 for older traveler, 248 plans, travel and, 20 Integrase inhibitors, 282t Interferon-γ release assay (IGRA), 489 International adoption, health aspects of, 303–309 adoption, 303–307 children in, 303–304, 304b parents in, 304 postadoption visit in, 304, 305b, 305f screening for infectious diseases in, 304–307 preadoption, 303 children in, 303 parents in, 303 International Association for Medical Assistance to Travelers (IAMAT), 249, 262, 358 International borders, in HIV, 284 International business travelers health risks of, 287–288 medical considerations for, 289–291 posttravel care considerations in, 291 pretravel considerations for, 289–291 travel health considerations in, 291

International Certificate of Vaccination or Prophylaxis, 107 International Commission for Radiological Protection (ICRP), 432 International Convention for Safety of Life at Sea, 377–378 International Diabetes Federation, 265 International Diploma of Mountain Medicine, 356 International Divers Alert Network (IDAN), 404–405 International Headache Society, 389 International Health Regulations (IHR), 101, 377–378 International Maritime Organization (IMO), 377–378 International Narcotics Control Board (INCB), 62 International Porter Protection Group (IPPG), 353 International Society of Travel Medicine (ISTM), 1, 313, 358 health clinics and, 15–16, 19 travel clinics and, 380 International SOS, 249 International travel clinical operating environments overseas and, 464, 465t posttravel consultation, 466–467 pretravel risk assessment for, 465, 465t psychiatric disorders and, 464 psychosis-some specifics and, 465–466 sources of stress in, 463–464 International Travel and Health, 101, 140 Internet expatriates and, 326 travel health program and, 21–22 Intestinal helminths, posttravel screening for, 490t, 492 Intestinal infections, screening for, international adoption and, 304–306 Intestinal parasites, in migrants, 333 Into Thin Air (Krakauer), 355 Intradermal route, vaccines, 70 Intramuscular (IM) route vaccinations, 69–70, 69f, 69t Intravenous calcium gluconate, for ciguatera, 451–452 Invasive pneumococcal disease (IPD), in HIV, 283 Iodine, for travel use, during pregnancy and lactation, 227t–228t Iodine resins, 35, 37t–38t Iodoquinol, 214–215 for travel use, during pregnancy and lactation, 227t–228t IPD. see Invasive pneumococcal disease IPPG. see International Porter Protection Group IR3535 (ethyl butylacetylaminopropionate), 47 Iron supplementation, 226 Irritable bowel syndrome (IBS), 199 postinfectious, 217, 217t Isospora belli, 32t, 190, 493 HIV/AIDS and, 191, 280 in persistent travelers’ diarrhea, 215 Isotonic fluids, 414 ISTM. see International Society of Travel Medicine Ivermectin, 507 Ixodes persulcatus, 119–120 Ixodes ricinus, 119–120, 135


J Japanese encephalitis (JE), 11 in business travelers, 288 expatriates and, 323 in pediatric and adolescent traveler, 243 vaccine requirement for, 342t visiting friends and relatives and, 316t Japanese encephalitis vaccine, 67t, 111–112, 111f chimeric, 112–113 in HIV, 284 inactivated cell-culture, 112 live attenuated SA-14-14-2, 113 in older traveler, 251 pediatric, 127t–129t, 134t, 135 during pregnancy, 230t risks of, 106t summary of, 103t–104t trade names of, 102t Jaundice, malaria and, 182t JCI. see Joint Commission International Jet lag, 28, 417–422 in business travelers, 292 clinical features of, 417 definition of, 417 getting sleep, 418t, 419–420 in older traveler, 249–250 physiology of, 417 staying awake, 420 stress in international travel and, 464 treatments of, 417–419, 418t Johns Hopkins Singapore International Medical Center, 371–372 Joint Commission International (JCI), 372, 475–476 Jungle environments, 356–357

K Kaolin, 243 Karenia brevis, 454 Katayama syndrome. see also Acute schistosomiasis fever, 500–501 incubation period of, 498t posttravel screening for, 492 Kayaking and rafting, 357 Kissing bugs, 44t Klebsiella pneumoniae, 452

L La gratte, 450 Laboratory tests, 489 Lactobacillus GG, 201–202 Lamivudine (3TC), 282t Language barriers, 316 Legal issues restrictions, medical kits, 62 for travel clinic, 19–20 Legionella spp., 378 infection, epidemiology of, 12 Legionellosis. see Legionnaires disease Legionnaires disease, 533 on cruise ships, 379 epidemiology of, 12 incubation period of, 498t Leishmania braziliensis, 507 Leishmania chagasi, 280



Leishmania donovani, 280 Leishmania infantum, 280 Leishmania major, 507 Leishmania mexicana, 507 Leishmania tropica, 507 Leishmaniasis, 493 diffuse cutaneous, 507 epidemiology of, 12 in HIV, 280 incubation period of, 498t localized cutaneous, 507–508, 508f–509f mucosal, 507 recurrent cutaneous, 507 Lemon eucalyptus, 49 Leptospirosis, 58t–59t, 495, 500, 534 Levofloxacin, for travelers’ diarrhea, 202t, 208, 209t Liability, expeditions, 353 Lice, 44t deterrents in, 438t Lidocaine, for ciguatera, 451–452 Light therapy, for jet lag, 418–419 Limb lymphedema, 510, 511f Lion, annual human deaths from, 439t Listeria, 232 Listservs, 19 Live attenuated vaccines, 66 in HIV-infected travelers, 283t influenza, in HIV-infected travelers, 283t SA-14-14-2 Japanese encephalitis, 113 Live vaccines, 102 during pregnancy, 229 Liver disease, in preexisting disease, 266 Liver enzymes, elevated, 501 Loa loa, 493 Localized cutaneous leishmaniasis, 507–508, 508f–509f Lodging, travelers’ diarrhea and, 193 Loeffler syndrome, 522 Long-distance evacuation, 479 Loperamide for diarrhea, 243 for mild diarrhea, 208 for persistent travelers’ diarrhea, 221 for travel use, during pregnancy and lactation, 227t–228t Lopinavir (LPV), 282t Loratadine, for travel use, during pregnancy and lactation, 227t–228t Lorazepam, 426t Lower respiratory tract infections (LRTIs), 527 Loxosceles spiders, 443, 443f LRTIs. see Lower respiratory tract infections Lyme disease, 242 Lyssaviruses, 117

M Macacine herpesvirus 1 (herpes simian B virus), 365 Magnesium, 155 Mahi-mahi (dolphinfish), 452, 452f Mailings, travel health program and, 22 Maitotoxin, 449 Malabsorptive states, postinfectious, in persistent travelers’ diarrhea, 216 MalaQuick, 171 Malaria, 137–144, 206, 207t approach to patient with, 179–186 in business travelers, 288

Malaria (Continued) cardiac disease and, 263–264 cases in selected European countries, 138t clinical diagnosis of, 181–182 as combat-related injuries, 343–344 diagnosis of, 181–182 microscopic, 182 differential diagnosis of, 181t distribution of, 137, 139f drug-resistant, 142–143 epidemiology of, 8–9, 137–144 in expatriates, 324 lifecycle of, 149f in migrants, 333 nucleic acid diagnostic tests for, 182 in older traveler, 250 in pediatric and adolescent traveler, 242 posttravel screening for, 490t, 493 in pregnancy, treatment of, 184 pregnancy and, 231–232 prevention of, 272 in breastfeeding, 234 prophylaxis, 150f dialysis in, 264 with neurologic diseases, 266 rapid diagnostic tests for, 170–174, 170t, 171f, 182 relapse risk of, management of, 185 in returned travelers, 495, 498t, 499 risk of, 137–140, 139t risk zones, 160f screening for, international adoption and, 307 self-diagnosis and self-treatment for, 169–178 pros and cons of, 176t severe and complicated, 181, 182t, 183–184, 184t in children, treatment of, 184 as specific diseases, 336–337 threat of, 179 uncomplicated, 180–181 treatment of, 182–183, 183t visiting friends and relatives and, 313–314, 313f–314f, 317 Malaria chemoprophylaxis, 145–167 antimalarial drugs, doses, and adverse effects of, 148t approach to prevention of, 145–146 current chemoprophylactic drug regimens of, 146–157, 147t differences in guidelines and recommendations on, 161–162 future directions of, 158 incidence of serious adverse events during, 147t severe events during, 147t new pipeline drugs for, 158 personal protection measures and, 146 in pregnancy travelers, 231, 232t risk assessment of, 145–146 use of, 146 Malarone, 174t, 266 Mania, international travel and, 466 Mannitol, for ciguatera, 452 Mansonella perstans, 493 Maraviroc (MVC), 282t Marine infection, 446, 446f Marine life dermatitis, 512, 512f Marine recreation, 364 Marketing, travel health program, 21–22, 22t

Mass gatherings, 383–385 accidents, 383–384 canceling, 384 communicable disease, 383 defined, 383 individual pregathering advice, 385 management of, 383 noncommunicable diseases and trauma, 383–384 planning for, 384–385 risk of, 383 sizes of, 383 specific, 384 Measles, 10–11 in aircraft cabin, 432–433 cases of, 80f distribution of notification rate of, 81f–82f in immunocompromised traveler, 274 screening for, international adoption and, 306 vaccination, 67t Measles, mumps, and rubella (MMR) vaccine, 77t, 79–82 adverse effects of, 82 contraindications to, 78t, 80 dosing schedule for, 79t, 81 in HIV, 281, 283t indications for, 80 measures of immune response and duration of immunity/protection in, 82 pediatric, 127t–130t, 130–131 precautions for, 80–81 during pregnancy, 230t, 234 requirement for, 342t trade names for, 76t Meclizine, 425, 426t for travel use, during pregnancy and lactation, 227t–228t Media, travel health program and, 21–22 Medical assistance plans, health care abroad, 477–478, 478b Medical clearance, in passenger health, 433 Medical devices, air travel with, 259 Medical emergencies, in-flight, in older traveler, 249 Medical evacuation, for expatriates, 327 Medical insurance, in business travelers, 292 Medical interview, posttravel, 488, 488t Medical kits, 27–28 basic, 63, 63b caring for others, 63b comprehensive personal, 63b kits, 63–64 contents of, 62, 63b expeditions, 64 for expeditions, 348, 348f, 355f for families, 240, 241t group, 64 packaging of, 62f in pregnant traveler, 234–235 specialist providers of, 63t summary of factors determining, 61–62, 62b travel, 61–64 Medical legal exposure, liability, expeditions of, 353 Medical missions, in immunocompromised traveler, 274 Medical readiness, 341–346, 343f Medical threat assessment, 297–298, 297t Medical tourism, 371–375, 476 adverse effects and complications of, 373–374 bariatric tourism, 373 cosmetic surgery, 372

INDEX Medical tourism (Continued) defined, 371–372 dental work abroad, 373 general considerations related to, 372 in immunocompromised traveler, 276 medications, 373 reproductive tourism, 373 transplant tourism, 373 types of, 371, 372t Medical travel advisory, translating medical threat assessment into, 298 Medication, in hand luggage, 261 Medicines for personal use, 62 Mefloquine, 150–153, 174, 282 administration of, 153 adverse effects of, 148t, 152 in breastfeeding, 234 in children, 242 contraindications to, 152–153 in dialysis, 264 drug interactions of, 152–153 for drug-resistant malaria, 142, 142f efficacy of, 150–151 indications for, 153 mode of action of, 150 moderate/severe adverse events of, 152 in neurologic diseases, 266 for pediatric and adolescent traveler, 245t pharmacology of, 150, 153 precautions of, 152–153 in pregnancy, 227t–228t, 231, 232t prophylactic failures of, 151 resistance, 147t, 150–151 serious adverse events of, 152 tolerability of, 151–152 Melatonin, 250, 418t, 419 Melatonin and melatonin agonists (MMAs), 418t, 419–420 Melioidosis, 58t–59t Menactra vaccine, 114 pediatric, 134t MenB-4C, 114 MenB-FHbp, 114 Mencevax ACWY, 114 Meningococcal B vaccine, during pregnancy, 230t Meningococcal C conjugate vaccine, in HIV, 282 Meningococcal disease vaccine requirement for, 342t visiting friends and relatives and, 316t Meningococcal meningitis, in immunocompromised traveler, 274 Meningococcal polysaccharide vaccine, in HIV-infected travelers, 283t Meningococcal vaccine, 67t, 114–115, 114f adverse events of, 115 contraindications to, 115 dosing schedules for, 79t, 115 drug and vaccine interactions of, 115 immune response in, measures of, 115 immunity/protection in, duration of, 115 indications for, 114–115 pediatric, 126t–130t, 132–133, 134t precautions for, 115 during pregnancy, 230t risks of, 106t summary of, 103t–104t trade names of, 102t Meningoencephalitis, primary amoebic (Naegleria fowleri), 364–365

Menomune, 114 Mental health of expatriates, 327 HIV/AIDS and, 338 issues, of travelers, 463–467 epidemiology of psychiatric disorders and, 464 posttravel consultation and, 466–467 pretravel risk assessment of, 465, 465t stress in, 463–464 of migrants, 334 Menveo vaccine, 114 pediatric, 134t MERS. see Middle Eastern respiratory syndrome MERS-CoV. see Middle East respiratory syndrome coronavirus Methicillin-sensitive Staphylococcus aureus, 510–511 Metoclopramide, for travel use, during pregnancy and lactation, 227t–228t Metronidazole, 214, 215t, 216 in pregnancy, 227t–228t, 233 Mexiletine, for ciguatera, 451–452 Microsporidia, 215 Microsporidium, 191 Middle East respiratory syndrome coronavirus (MERS-CoV), 533 in aircraft cabin, 433 Middle Eastern respiratory syndrome (MERS), 57 Migrant traveler, 331–334 core values and best practices in care of immigrant patients, 334 health evaluation of, 331, 332t health status of, 331–334 Mild diarrhea, management of, 208 Military, deployed, 341–346, 343f combat-related injuries, 343 noncombat-related injuries and back pain, 343 Minnesota Immigrant Task Force, 334 Mission-oriented travel medicine, 295–302 evacuation planning in, 302 host country solutions in, 301, 301t–302t operational security in, 302 operationalizing VIP travel support in, 296–301 medical threat assessment and countermeasures, 297–298, 297t plan, 298 right equipment in, 299–301, 300t right person in, 299, 300t right place, right time in, 301 right problem in, 299 support requirements, 298, 298t translating medical threat assessment into medical travel advisory, 298 Mite larvae, deterrents in, 438t Mobile phones, personal security and crime avoidance and, 486 Mobility, health problems and, 28 Modafinil, 250, 418t, 420 Moderate diarrhea, management of, 208 Morbidity, 8–12 in humanitarian aid workers, 336, 336t Morganella morganii, 452 Mortality, 6–8 expeditions and, 356 in humanitarian aid workers, 335–336 Mosquitoes, 27t, 44t, 53, 243 bites, relief from, 51 deterrents in, 438t


Mosquitoes (Continued) global distribution of, 54f personal protection strategies against, 55b reducing population of, 50 Motion sickness, 28, 423–428 adjunctive, new, and experimental agents for, 427 candidate, 424 defined, 424 established, 426–427 mechanism of, 424 in older traveler, 249 in pediatric and adolescent traveler, 239 prevention and treatment options in individualized recommendations for, 427, 427t medications for, 425–426, 426t nonmedicinal, 424–425, 425t triggers of, 423–424 vestibular system in, 424, 424f Motor vehicles health problems and, 28 in pediatric and adolescent traveler, 239 Mountaineering, 355–356 Mucosal leishmaniasis, 507 Multiple sclerosis (MS), 266 Mumps in aircraft cabin, 433 vaccination, 67t Murine typhus, 58t–59t Myasthenia gravis, 266 Mycobacterial cutaneous infections, 513 Mycobacterium abscessus, 373–374 Mycobacterium tuberculosis, 432, 489 in HIV, 280 infection, 11 Myiasis (Cochliomyia hominivorax, Dermatobia hominis), 58t–59t, 508–509, 509f, 509t Myocardial infarction, 263

N NADH. see Nicotinamide adenine dinucleotide Naegleria fowleri. see Primary amoebic meningoencephalitis NAM. see National AIDS Manual Naproxen, for travel use, during pregnancy and lactation, 227t–228t Nasal steroids, for travel use, during pregnancy and lactation, 227t–228t