Foundations of Infectious Disease: A Public Health Perspective 1284179648, 9781284179644

Table of contents :
Cover Page
Title Page
Copyright Page
Dedication
Brief Contents
Contents
Preface
Acknowledgments
About the Author
CHAPTER 1 Historical Perspectives
Introduction
Plague
Smallpox
Syphilis
Studying Infectious Diseases: Historical Roots
Early Attempts at Cure and Prevention of Infectious Diseases
Categorizing Infectious Diseases
19th-Century Theories of Disease Transmission
Quantifying Infectious Diseases
The Germ Theory of Disease
Vector-Borne Diseases
20th-Century Infectious Disease Initiatives
20th-Century Advances In Antimicrobial Drugs
Emerging Infectious Diseases
Conclusion
Key Terms
Review Questions
Bibliography
CHAPTER 2 Basics of Infectious Disease Epidemiology
Introduction
Key Concepts
Prevalence and Incidence
Diagnostic Screening Tests
Herd Immunity
Transmission and Distribution of Infectious Diseases
The Epidemiologic Triangle
Modeling Infectious Disease Transmission
Outbreaks, Epidemics, and Pandemics: Contributing Factors
Dynamic Models of Disease Transmission
The Structure of the Host Population
Conclusion
Key Terms
Review Questions
Bibliography
CHAPTER 3 Study Designs
Introduction
Key Concepts
Target, Source, and Study Populations
Descriptive Studies
Analytical Studies
Meta-Analyses and Ecologic Studies
Randomized Controlled Trials
Measures of Association in Epidemiologic Studies
Internal and External Validity and Reliability of Study Results
Confounding and Bias
Conclusion
Key Terms
Review Questions
Bibliography
CHAPTER 4 Infectious Disease Prevention
Introduction
Key Concepts
Vaccines
Types of Vaccines
Other Vaccine Issues
The Public Health Impact of Vaccines
Vaccines and Infectious Disease Eradication
Infectious Disease Prevention at the Individual Level: The Importance of Handwashing
Prevention of Foodborne Infections
Prevention of Diarrheal Illness
Prevention of Vector-Borne Infectious Diseases
Blood Donor Screening and Infectious Disease Prevention
Quarantine and Isolation in Infectious Disease Prevention
Conclusion
Key Terms
Review Questions
Bibliography
CHAPTER 5 Investigating Infectious Disease Outbreaks
Introduction
Key Concepts
Infectious Disease Surveillance
The Starting Point
Planning an Outbreak Investigation
Choosing a Study Design
Person, Place, and Time
Types of Outbreaks
The Role of the Laboratory in Infectious Disease Investigations
Environmental Assessments
Communication of Findings
Conclusion
Key Terms
Review Questions
Bibliography
CHAPTER 6 The Immune System and Infectious Disease
Introduction
Key Concepts
Overview of Innate and Adaptive Immune Defenses
Phagocytosis
Thanks for the Complement
Complement–Phagocyte Synergism and the Acute Inflammatory Response
Interferons
Innate Lymphoid Cells
Enter the Eosinophils
Adaptive Immune Responses and the Importance of Specificity
The Structure and Function of Antibodies
T Cell Activation and Antigen- Presenting Cells
Memory, the Immunological Sort
Controlling the Immune Response
Collectins and Ficolins
You Give Me Fever
Natural Killer Cells
More on Phagocytosis: Surround, Dispatch, and Absorb
Cytokines: Their Role in Infection Control and Disease
Antibody-Mediated Immune Response
Cell-Mediated Host Immunity
The Downside of the Host Immune Response
Conclusion
Key Terms
Review Questions
Bibliography
CHAPTER 7 Prion Infections
Introduction
Key Concepts
Sheep Scrapie
Kuru
Bovine Spongiform Encephalopathy
Creutzfeldt-Jakob Disease
Variant Creutzfeldt-Jakob Disease
Conclusion
Key Terms
Review Questions
Bibliography
CHAPTER 8 Viral Infections
Introduction
Key Concepts
Influenza
Measles
Hepatitis B
Ebola
Zika Virus
Conclusion
Key Terms
Review Questions
Bibliography
CHAPTER 9 HIV/AIDS
Introduction
Key Concepts
Transmission of HIV
Clinical Aspects of HIV/AIDS
Epidemiology of HIV/AIDS
Prevention of HIV/AIDS
Conclusion
Key Terms
Review Questions
Bibliography
CHAPTER 10 Bacterial Infections
Introduction
Key Concepts
Classification of Bacteria
Antibiotic Resistance
Tuberculosis
Cholera
Conclusion
Key Terms
Review Questions
Bibliography
CHAPTER 11 Parasitic Infections
Introduction
Key Concepts
Types of Parasites
Types of Hosts
Modes of Transmission
Protozoal Infection: Malaria
Protozoal Infection: Chagas Disease (American Trypanosomiasis)
Protozoal Infection: Human African Trypanosomiasis
Protozoal Infection: Cryptosporidiosis
Helminthic Infections
Trematode Infection: Schistosomiasis
Nematode Infection: Hookworm
Nematode Infection: Lymphatic Filariasis
Nematode Infection: Onchocerciasis (Non-lymphatic Filariasis)
Conclusion
Key Terms
Review Questions
Bibliography
CHAPTER 12 Foodborne Infections
Introduction
Key Concepts
Food Safety Standards in the United States
Foodborne Salmonella spp. Infections
Foodborne Clostridium perfringens Infections
Foodborne Clostridium botulinum Infections
Foodborne Listeria monocytogenes Infections
Foodborne Trichinella spp. Infections
Foodborne Taenia Solium Infections
Foodborne Norovirus Infections
Conclusion
Key Terms
Review Questions
Bibliography
CHAPTER 13 Sexually Transmitted Infections
Introduction
Key Concepts
Chlamydia trachomatis as an STI
Neisseria gonorrhoeae Infections
Syphilis
Chancroid Ulcers
Oral and Genital Herpes Simplex Virus Infections
Human Papilloma Virus (HPV) Infections
Behavioral Models and STI Prevention
Addressing High-Risk Sexual Behaviors
Conclusion
Key Terms
Review Questions
Bibliography
CHAPTER 14 Healthcare- Acquired Infections
Introduction
Key Concepts
Historical Overview of HAIs
Why Do HAIs Occur?
Common Etiologies of HAIs
HAI Surveillance in the United States
Risk Factors for HAIs
Transmission Routes of HAIs
CDC and NHSN Categories of HAIs
Emerging HAIs
Viral HAIs
Fungal HAIs
Conclusion
Key Terms
Review Questions
Bibliography
CHAPTER 15 Neglected Tropical Diseases
Introduction
Key Concepts
Buruli Ulcer
Chikungunya Virus (CHIKV)
Chromoblastomycosis
Dengue Fever
Foodborne Trematodiases: Clonorchiasis, Opisthorchiasis, Fascioliasis, and Paragonimiasis
Dracunculiasis (Guinea-Worm Disease)
Leishmaniasis
Leprosy (Hansen’s Disease)
Mycetoma
Rabies
Ocular Trachoma
Yaws
Conclusion
Key Terms
Review Questions
Bibliography
CHAPTER 16 Future Trends
Introduction
Key Concepts
Global Preparedness for Emerging Infectious Disease Outbreaks, Epidemics, and Pandemics
Global Warming, Climate Change, and Infectious Diseases
Conclusion
Key Terms
Review Questions
Bibliography
Glossary
Index

Citation preview

DAVID P. ADAMS, PHD, MPH, MSC

FOUNDATIONS OF INFECTIOUS DISEASE A PUBLIC HEALTH PERSPECTIVE

World Headquarters Jones & Bartlett Learning 5 Wall Street Burlington MA 01803 978-443-5000 [email protected] www.jblearning.com Jones & Bartlett Learning books and products are available through most bookstores and online booksellers. To contact Jones & Bartlett Learning directly, call 800-832-0034, fax 978-443-8000, or visit our website, www.jblearning.com.. Substantial discounts on bulk quantities of Jones & Bartlett Learning publications are available to corporations, professional associations, and other qualified organizations. For details and specific discount information, contact the special sales department at Jones & Bartlett Learning via the above contact information or send an email to [email protected]. Copyright © 2021 by Jones & Bartlett Learning, LLC, an Ascend Learning Company All rights reserved. No part of the material protected by this copyright may be reproduced or utilized in any form, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without written permission from the copyright owner. The content, statements, views, and opinions herein are the sole expression of the respective authors and not that of Jones & Bartlett Learning, LLC. Reference herein to any specific commercial product, process, or service by trade name, trademark, manufacturer, or otherwise does not constitute or imply its endorsement or recommendation by Jones & Bartlett Learning,

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For Valerie.

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Brief Contents Preface Acknowledgments About the Author

CHAPTER 1 Historical Perspectives CHAPTER 2 Basics of Infectious Disease Epidemiology CHAPTER 3 Study Designs CHAPTER 4 Infectious Disease Prevention CHAPTER 5 Investigating Infectious Disease Outbreaks CHAPTER 6 The Immune System and Infectious Disease CHAPTER 7 Prion Infections CHAPTER 8 Viral Infections CHAPTER 9 HIV/AIDS CHAPTER 10 Bacterial Infections CHAPTER 11 Parasitic Infections CHAPTER 12 Foodborne Infections CHAPTER 13 Sexually Transmitted Infections CHAPTER 14 Healthcare-Acquired Infections CHAPTER 15 Neglected Tropical Diseases CHAPTER 16 Future Trends Glossary Index

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Contents Preface Acknowledgments About the Author CHAPTER 1 Historical Perspectives Introduction Plague Smallpox Syphilis Studying Infectious Diseases: Historical Roots Early Attempts at Cure and Prevention of Infectious Diseases Categorizing Infectious Diseases 19th-Century Theories of Disease Transmission Quantifying Infectious Diseases The Germ Theory of Disease Vector-Borne Diseases 20th-Century Infectious Disease Initiatives 20th-Century Advances In Antimicrobial Drugs Emerging Infectious Diseases Conclusion Key Terms Review Questions Bibliography CHAPTER 2 Basics of Infectious Disease Epidemiology Introduction

Key Concepts Prevalence and Incidence Diagnostic Screening Tests Herd Immunity Transmission and Distribution of Infectious Diseases The Epidemiologic Triangle Modeling Infectious Disease Transmission Outbreaks, Epidemics, and Pandemics: Contributing Factors Dynamic Models of Disease Transmission The Structure of the Host Population Conclusion Key Terms Review Questions Bibliography CHAPTER 3 Study Designs Introduction Key Concepts Target, Source, and Study Populations Descriptive Studies Analytical Studies Meta-Analyses and Ecologic Studies Randomized Controlled Trials Measures of Association in Epidemiologic Studies Internal and External Validity and Reliability of Study Results Confounding and Bias Conclusion Key Terms Review Questions Bibliography CHAPTER 4 Infectious Disease Prevention Introduction Key Concepts Vaccines Types of Vaccines

Other Vaccine Issues The Public Health Impact of Vaccines Vaccines and Infectious Disease Eradication Infectious Disease Prevention at the Individual Level: The Importance of Handwashing Prevention of Foodborne Infections Prevention of Diarrheal Illness Prevention of Vector-Borne Infectious Diseases Blood Donor Screening and Infectious Disease Prevention Quarantine and Isolation in Infectious Disease Prevention Conclusion Key Terms Review Questions Bibliography CHAPTER 5 Investigating Infectious Disease Outbreaks Introduction Key Concepts Infectious Disease Surveillance The Starting Point Planning an Outbreak Investigation Choosing a Study Design Person, Place, and Time Types of Outbreaks The Role of the Laboratory in Infectious Disease Investigations Environmental Assessments Communication of Findings Conclusion Key Terms Review Questions Bibliography CHAPTER 6 The Immune System and Infectious Disease Introduction Key Concepts Overview of Innate and Adaptive Immune Defenses

Phagocytosis Thanks for the Complement Complement–Phagocyte Synergism and the Acute Inflammatory Response Interferons Innate Lymphoid Cells Enter the Eosinophils Adaptive Immune Responses and the Importance of Specificity The Structure and Function of Antibodies T Cell Activation and Antigen- Presenting Cells Memory, the Immunological Sort Controlling the Immune Response Collectins and Ficolins You Give Me Fever Natural Killer Cells More on Phagocytosis: Surround, Dispatch, and Absorb Cytokines: Their Role in Infection Control and Disease Antibody-Mediated Immune Response Cell-Mediated Host Immunity The Downside of the Host Immune Response Conclusion Key Terms Review Questions Bibliography CHAPTER 7 Prion Infections Introduction Key Concepts Sheep Scrapie Kuru Bovine Spongiform Encephalopathy Creutzfeldt-Jakob Disease Variant Creutzfeldt-Jakob Disease Conclusion Key Terms

Review Questions Bibliography CHAPTER 8 Viral Infections Introduction Key Concepts Influenza Measles Hepatitis B Ebola Zika Virus Conclusion Key Terms Review Questions Bibliography CHAPTER 9 HIV/AIDS Introduction Key Concepts Transmission of HIV Clinical Aspects of HIV/AIDS Epidemiology of HIV/AIDS Prevention of HIV/AIDS Conclusion Key Terms Review Questions Bibliography CHAPTER 10 Bacterial Infections Introduction Key Concepts Classification of Bacteria Antibiotic Resistance Tuberculosis Cholera Conclusion Key Terms

Review Questions Bibliography CHAPTER 11 Parasitic Infections Introduction Key Concepts Types of Parasites Types of Hosts Modes of Transmission Protozoal Infection: Malaria Protozoal Infection: Chagas Disease (American Trypanosomiasis) Protozoal Infection: Human African Trypanosomiasis Protozoal Infection: Cryptosporidiosis Helminthic Infections Trematode Infection: Schistosomiasis Nematode Infection: Hookworm Nematode Infection: Lymphatic Filariasis Nematode Infection: Onchocerciasis (Non-lymphatic Filariasis) Conclusion Key Terms Review Questions Bibliography CHAPTER 12 Foodborne Infections Introduction Key Concepts Food Safety Standards in the United States Foodborne Salmonella spp. Infections Foodborne Clostridium perfringens Infections Foodborne Clostridium botulinum Infections Foodborne Listeria monocytogenes Infections Foodborne Trichinella spp. Infections Foodborne Taenia Solium Infections Foodborne Norovirus Infections Conclusion

Key Terms Review Questions Bibliography CHAPTER 13 Sexually Transmitted Infections Introduction Key Concepts Chlamydia trachomatis as an STI Neisseria gonorrhoeae Infections Syphilis Chancroid Ulcers Oral and Genital Herpes Simplex Virus Infections Human Papilloma Virus (HPV) Infections Behavioral Models and STI Prevention Addressing High-Risk Sexual Behaviors Conclusion Key Terms Review Questions Bibliography CHAPTER 14 Healthcare- Acquired Infections Introduction Key Concepts Historical Overview of HAIs Why Do HAIs Occur? Common Etiologies of HAIs HAI Surveillance in the United States Risk Factors for HAIs Transmission Routes of HAIs CDC and NHSN Categories of HAIs Emerging HAIs Viral HAIs Fungal HAIs Conclusion Key Terms Review Questions

Bibliography CHAPTER 15 Neglected Tropical Diseases Introduction Key Concepts Buruli Ulcer Chikungunya Virus (CHIKV) Chromoblastomycosis Dengue Fever Foodborne Trematodiases: Clonorchiasis, Opisthorchiasis, Fascioliasis, and Paragonimiasis Dracunculiasis (Guinea-Worm Disease) Leishmaniasis Leprosy (Hansen’s Disease) Mycetoma Rabies Ocular Trachoma Yaws Conclusion Key Terms Review Questions Bibliography CHAPTER 16 Future Trends Introduction Key Concepts Global Preparedness for Emerging Infectious Disease Outbreaks, Epidemics, and Pandemics Global Warming, Climate Change, and Infectious Diseases Conclusion Key Terms Review Questions Bibliography Glossary Index

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Preface I became interested in infectious diseases as a child. For better or worse, I was likely the only kid at my grammar school who knew about Lister, Köch, Pasteur, Reed, and Fleming—thanks to my dad who proudly gave me David Dietz’s All About Great Medical Discoveries as a birthday gift. I must have been in the second grade when I received the book. It was perhaps typical of many books of that time that praised seemingly invincible medical professionals as they conquered diseases and (to hear Dietz tell it) together saved humanity from gangrene, yellow fever, and staph infections. Such was my introduction to the individuals who line the hallowed annals of medicine. Several decades later, infectious diseases continue to kill millions, particularly in developing countries. Scarcely a week passes that contaminated food recalls and infectious disease outbreaks, epidemics, and pandemics do not make the headlines. Why do these things capture the attention of the person on the street? To borrow an oft-cited phrase from broadcast news networks, “if it bleeds, it leads.” Although this dictum perhaps suits murder and mayhem better than an Ebola outbreak or antibioticresistant superbugs, it is not altogether irrelevant to infectious diseases and the public’s health. Some of this fascination may reflect the ubiquitous nature of infectious agents. They live in us, on us, and among us. Moreover, their effects on people may include the unsightly (toenail fungus), the annoying (the common cold), the potentially lethal (Ebola virus disease), and the disfiguring (Hansen’s disease). Nor are infectious diseases necessarily a product of recent history. For several millennia they have afflicted human populations, sometimes with a lethality that beggars the imagination. A classic example is the sweep of the so-called Black Death across Asia and Europe in the mid-14th century. Indeed,

history students today can scarcely escape a mention of it in a high school or university Western Civilization course. For moderns who live in a world of antibiotics, however, such a cataclysmic event must seem surreal. And yet, infectious diseases continue to sicken us, linger in us, and—sometimes—kill us. The promise of the first antimicrobials such as the sulfonamides and penicillin—investigators discovered just years after their introduction—proved a chimera. Drugresistant pathogens all too often have proven themselves far better at adapting to newer antibiotics than many investigators had ever imagined. Terms such as emerging infections, reemerging infections, and superbugs have been become staples of the popular and biomedical press. No textbook—not least one on infectious diseases—can be comprehensive. As such, the conditions discussed in this work are but the proverbial tip of the iceberg. It is hoped, however, that the infectious diseases discussed in the following chapters will provide readers with a foundation for further study.

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Acknowledgments I would like to acknowledge the assistance of a number of individuals. Among them, of course, are Michael Brown, Sara Bempkins, Sophie Teague, Kelly Sylvester, and Shannon Sheehan at Jones & Bartlett Learning. They were extremely helpful with the overall guidance and preparation of the manuscript. Jennifer McCarthy, JessMarie Gonzalez, Colette Ryset, Amanda Lee Skarlupka, Luigi Mincella, Mark Calcamuggio, Gustaf Lilliehöök, Melissa Reams, and Laura Greene proved invaluable in reading and commenting on early drafts. I would also like to thank my professors from the London School of Hygiene and Tropical Medicine for further nurturing my interest in infectious diseases. Most of all though, I would like to thank my wife, Valerie, for her support and encouragement of this project.

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About the Author David P. Adams earned his doctorate from the University of Florida, his MPH from the Ohio State University, and his MSc from the London School of Hygiene and Tropical Medicine. He studied at Louisiana State University, McGill University, the University of Costa Rica, and the University of Tennessee-Knoxville. He has more than three decades of teaching and research in infectious diseases, the history and sociology of medicine, and public health. He has held faculty positions in the Ohio State University Medical School, Department of Family Medicine, the Duke University School of Medicine, Department of Community and Family Medicine, and the Mercer University School of Medicine, Department of Community Medicine.

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CHAPTER 1 Historical Perspectives LEARNING OBJECTIVES Trace the history of infectious diseases and their impact on human societies. Assess the impact of key individuals who have shaped and influenced the modern understanding of infectious disease epidemiology. Describe the impact of epidemics and pandemics on human societies from ancient times to the present. Outline the steps in the Köch-Henle postulates.

Introduction Infectious diseases have plagued humankind for centuries upon centuries. Egyptian mummies, for example, bear the scars of smallpox. In other cases, infectious disease has influenced the outcomes of military campaigns, as in the case of dysenteryridden French knights at Agincourt or Napoleon’s typhus-ridden troops retreating from Moscow. The ability to prevent or cure infectious diseases, save for the use of Jesuit’s bark for malaria and vaccination for smallpox, is largely a 20th century phenomenon. Witness, for example, the introduction of antibiotics to treat Staphylococcal and Streptococcal infections and vaccines to prevent common childhood diseases such as diphtheria.

Plague Ancient “Plagues” Infectious diseases have played an important role in the history of humankind. One of the first historical accounts of an infectious disease dates from Thucydides’s History of the Peloponnesian War (431–404 BCE; see Figure 1-1). Fleeing the approaching Spartan army, thousands of war refugees sought shelter in the city of Athens. Amidst the overcrowded living conditions, “plague” began to sweep through the city. According to Thucydides, half the population succumbed to the Plague of Athens.

Figure 1-1 Frontispiece to Thucydides’s Plague of Athens, 1709 edition. Wellcome Collection

But what exactly killed all those Athenians? From their perspective more than two millennia ago, Athenians would likely have blamed one, if not two, causes: angry deities or ill-balanced bodily humors. The bodily humors were blood, phlegm, yellow bile, and black bile. Each humor corresponded, in turn, to the four elements of ancient Greek scientific thought: air, water, fire, and earth, respectively. Although the precise nature of the Athenian plague remains shrouded in mystery, modern scholars have suggested that influenza, Ebola, smallpox, or typhoid fever, or even an act of bioterrorism may have dispatched the hapless victims.

Plagues During the Late Roman and Early Medieval Period “Plagues” continued to reemerge over the next millennia. As the Roman Empire faded in the 5th and 6th centuries CE, the Plague of Justinian (541–542 CE) killed more than a third of Constantinople’s (modern- day Istanbul, Turkey) population. Fortunately for Western Europeans, Justinian’s plague would be one of the last for nearly eight centuries. Explanations of the causes of epidemic disease had shifted significantly during the centuries since the Plague of Athens. Perhaps the most significant difference between the Greeks of the 4th century BCE and the Romans of the 6th century CE was the hegemony of Christianity in Western Europe. No longer did death and disease simply reflect the vengeance of multiple GrecoRoman deities or imbalanced humors, but rather the JudeoChristian God’s displeasure with the fundamental depravity of humanity. To attribute sickness and suffering to insects, rodents, poor living conditions, overcrowding, or microbes would have seemed preposterous at the time.

Reemergence of Plague in the Mid-14th Century By the 14th century, Western Europe had begun to emerge from the tumultuous interlude that had followed the fall of the Roman Empire in 476 CE. Noteworthy by this time was the expansion of economic markets that linked Asia and Western Europe. By the

14th century, Italian traders had established active commercial routes between the Far East and the Mediterranean. They were quick to realize the substantial profits that exotic goods such as silk, spices, and other commodities could bring them. Trade routes from the Far East, however, brought more than riches to Italian businessmen. Whether caravanned on pack animals or transported on cargo ships, something far more insidious accompanied commercial goods: fleas, rats, and the pathogen they harbored, Yersinia pestis. Ironically, the very roadways that the Romans had built more than a thousand years earlier to haul their goods and legions throughout the empire proved equally adept at providing a transmission route for bubonic and, ultimately, pneumonic plague throughout Western Europe (Figure 1-2). Y. pestis is spread via the bites of infected rat fleas (Xenopsylla cheopsis; Figure 1-3) or from inhalation of infected respiratory droplets. Between 1347 and 1351, the so-called Black Death killed more than 20 million Europeans, roughly a third of the European population at that time.

Figure 1-2 Plague in Florence, Italy, 1348. Wellcome Collection

Figure 1-3 Xenopsylla cheopsis. Courtsey of CDC/Ken Gage, 2017. https://phil.cdc.gov/Details.aspx?pid=22259. Accessed December 31, 2018.

Plague in the Modern Era: The Third Pandemic The third plague pandemic originated in the interior of China around 1860. Within three decades, it had traveled to the island of Hong Kong. From there, the plague reached global port cities by ship, killing 12 million in China and India alone. No longer, however, were diseases such as the plague attributed to divine wrath or ill-balanced humors; rather, specific microorganisms were theorized as the cause of specific infectious diseases. Moreover, fleas were determined to be intermediate hosts in transmission of bubonic plague.

Smallpox Smallpox, caused by the variola virus, has affected humankind for at least several millennia. One of the earliest records of smallpox dates from the Egyptian–Hittite War of the 1200s BCE. Mummies from this era bear facial scarification that is suggestive of the disease. Epidemic smallpox struck the Roman Empire more than a millennium later. The Antonine “plague,” also known as the Plague of Galen, swept through the empire during the 2nd century CE. Some historians believe that this so-called plague was in fact smallpox. Overall, the epidemic is thought to have killed 5 million people. Among the dead were the Roman emperors Marcus Aurelius and Lucius Vera. Smallpox continued to strike Western Europe and the Middle East throughout the medieval period. Military campaigns such as the Crusades (1190s–1290s) unknowingly spread the disease throughout Europe and into the Holy Land. European colonization of the Americas brought smallpox and other infectious diseases into the New World. One quarter of the Aztec population of Tenochtitlán (modern-day Mexico City) succumbed to these diseases in 1520 after a 3-month siege by Hernán Cortés and his small group of Spanish conquistadors. Several decades later, the Franciscan missionary Fray Motolinia described 1,000 deaths a day in his Historia de Los Indios de la Nueva España (History of the Indians of New Spain, 1541). He estimated that as many as 150,000 in all fell to smallpox in Tlaxcala, located east of modern-day Mexico City. Epidemics, it would appear, helped to accomplish what Spanish powder and steel often could not. Nor did smallpox spare colonial North America. During the Seven Years’ War (1756–1763), British General Lord Amherst, eager to bring the anti-British—and pro-French—Pontiac Indians to heel, devised a sinister solution that echoed Spanish successes 200 years earlier in Mexico: epidemic disease. Taking advantage of a smallpox outbreak among his own troops, he ordered that their contaminated blankets be offered to the Pontiacs as a gesture of peace. Smallpox soon achieved what British musketry could not achieve; it ravaged the Pontiac ranks, just as Lord

Amherst had planned. Smallpox epidemics continued throughout the globe for more than another century (see Figure 1-4).

Figure 1-4 Smallpox patient in Gloucester, Rijksmuseum England, 1896. Wellcome Collection

Syphilis Syphilis is a sexually transmitted infection caused by the bacterial spirochete Treponema pallidum. Renaissance-era observers chronicled its rapid spread throughout 15th- and 16th-century Europe (see Figure 1-5). Contemporaries such as the Italian Giorlamo Fracastoro (1478–1553) published a poem that squarely blamed syphilis on the French, Syphilis sive Morbus Gallicus (Syphilis as the French Disease). His lurid verse achieved wide circulation in the mid-1530s. It is not surprising that the French referred to syphilis as “the Italian disease”!

Figure 1-5 Fracastoro warning against yielding to temptation and contracting syphilis. Rijksmuseum

Studying Infectious Diseases: Historical Roots Scholars often attribute the early study of infectious diseases to the Greek physician Hippocrates (c. 460–377 BCE; see Figure 16). His On Air, Waters, and Places is notable for its dismissal of magical and supernatural explanations of illness. Hippocrates’s categories of disease—endemic and epidemic—have endured to this day. The former refers to conditions that linger quietly in a population but never quite disappear; the latter to ones that appear sporadically, often with great severity over a broader geographical area.

Figure 1-6 Marble bust of Hippocrates. © clu/DigitalVision Vectors/Getty Images

Fracastoro, the author of Syphilis sive Morbus Gallicus, is also known for his treatise on infectious diseases, De Contagione, Contagiosis Morbis et Eorum Curatione (On Contagion, Contagious Diseases, and Their Treatment, 1546). In De Contagione, he suggested that small, invisible particles (seminaria) caused infectious diseases. By disrupting bodily humors, he believed that they were not only disease specific but also self-replicating. Infectious disease transmission, Fracastoro continued, occurred by three routes: person to person, via the air, and through contaminated objects, such as Lord Amherst’s smallpoxladen blankets. Although his influence continued into the late 19th century, Fracastoro remained a product of his own time. He did not consider seminaria to be microbes per se, nor did he necessarily reject religious or supernatural causes of disease. He also attributed some epidemics to atmospheric and cosmological factors.

Early Attempts at Cure and Prevention of Infectious Diseases Jesuit’s Bark The therapeutic use of botanicals occupies an important place in the history of infectious diseases. Jesuit missionaries traveling through Peru in the early 17th century learned of a malarial fever treatment obtained from cinchona tree (Cinchona officinalis) bark. Brought to Europe around 1630, it soon became widely known as Jesuit’s bark. The substance was used to treat malaria, if not “fevers” in general. Not until two centuries later did chemists isolate the bark’s active alkaloids for their use as an antimalarial.

Rudimentary Immunization Smallpox, as discussed previously, has affected humankind for thousands of years. It was not until the early 18th century, however, that physicians attempted to prevent the disease. The process of variolation involved inoculating healthy persons with exudate obtained from smallpox victims. Lady Mary Wortley Montagu had observed this method in the early 18th century while residing in Constantinople with her husband, a British Ambassador. Within several years, the practice became fashionable in Europe, and soon became popular in colonial America. By 1721, the noted New England cleric Cotton Mather had introduced the practice into New England. Unfortunately, variolation is not without an inherent risk. Recipients can die from the procedure or it may inadvertently spark a smallpox outbreak.

Vaccination Vaccination, however, eclipsed variolation in less than a century. Vaccination, the name of which is derived from the Latin word for cow (vacca), was first attempted in Britain by the British physician Edward Jenner (1749–1823) in the 1790s (Figure 1-7). Jenner, a rural general practitioner, observed poxlike lesions on the hands of local milkmaids—an occupational group that somehow appeared to be protected from smallpox.

Figure 1-7 Edward Jenner. Wellcome Collection

Jenner hypothesized that this “cowpox” might somehow prevent human smallpox infections. Vaccination differed from variolation in one important aspect. Rather than inoculating the exudate from smallpox victims into healthy individuals, vaccination involved inoculation of the exudate from the cowpox sufferers into otherwise healthy people. Jenner’s first vaccination case was a local farm boy, James Phipps, who, luckily for Jenner, survived the ordeal. Phipps lived another half-century, dying in 1853.

Far less risky than variolation, vaccination soon received wide acclaim. One of Jenner’s greatest admirers was the Napoleon Bonaparte, who mandated vaccination of his Grand Armée in 1805. Despite his hatred of the British, he often acknowledged that Jenner’s methods had kept his troops relatively smallpox-free. Jenner, he admitted, had proven “a most faithful servant.” His vaccination did not, however, spare Napoleon’s troops from epidemic typhus, an infection caused by Rickettsia prowazekii and transmitted by the body louse (Pediculus humanus) during the disastrous Russian campaign several years later.

Categorizing Infectious Diseases Thomas Sydenham The English physician Thomas Sydenham (1624–1689; Figure 1-8), sometimes known as the “English Hippocrates,” is perhaps best known for his opus, Observationes Medicae (Medical Observations), published in 1676. This work presented what still remain classic descriptions of common infectious diseases. In his Observationes, Sydenham categorized diseases by type as well as their similarities and differences.

Figure 1-8 Thomas Sydenham. © duncan1890/DigitalVision Vectors/Getty Images

Giovanni Morgagni The Italian anatomist Giovanni Morgagni (1682–1771; Figure 19) expanded Sydenham’s approach to the study of all types of diseases, not just infectious ones. He outlined his approach in De Sedibus et Causis Morborum per Anatomen Indigatis (On the Seats and Causes of Diseases Investigated through Anatomy), published in 1761. Writing in the De Sedibus, Morgagni compared more than 700 patients’ clinical conditions with postmortem findings.

Figure 1-9 Giovanni Battista Morgagni.

Wellcome Collection

19th-Century Theories of Disease Transmission Peter Ludwig Panum The Danish physician Peter Ludwig Panum (1820–1885) represents another important figure in the history of the study of infectious diseases. His investigation of an 1846 measles outbreak in the Danish Faroe Islands, the first in 60 years, is considered a classic of epidemiologic investigation. Panum noted in his Observations Made during the Epidemic of Measles on the Faroe Islands in the Year 1846 that the islanders were not uniformly affected by measles. He observed that a mere 3% of those older than age 65 years contracted measles, whereas among persons younger than age 65 years it approached 100%. Panum concluded that the islanders 65 years and older who had survived the measles outbreak some six decades earlier had somehow acquired lifelong immunity to the infection. Younger inhabitants, born since the 1780s, had no acquired immunity, and thus were susceptible to measles.

John Snow and Cholera The English physician John Snow (1813–1858), often called the father of modern epidemiology, also occupies an important place in the history of infectious diseases (Figure 1-10). He is best remembered for his investigation of cholera in mid-1850s London. Snow, working several decades prior to the acceptance of the germ theory of disease, blamed municipal waterworks for the cholera cases.

Figure 1-10 John Snow, 1856. U.S.National Library of Medicine

The British epidemiologist William Farr (1807–1883) dismissed Snow’s “there’s something in the water” hypothesis. Instead, he argued that offensive miasmas that arose daily from the Thames River were to blame for the cholera outbreak. Indeed, his miasma theory was well in step with contemporary medical thought. Snow’s waterworks hypothesis seemed preposterous to miasmatheory devotees such as Farr.

Snow seized upon the waterworks hypothesis in an ingenious manner. Armed with a street map of London’s Soho District where he worked, he marked the households that did (or did not) report cholera cases (Figure 1-11). Snow then determined which of three waterworks supplied these neighborhoods. Concluding that the culprit was the Lambeth Waterworks, Snow famously disabled the Broad Street pump, supplied by none other than the Lambeth Company. Unable to gather water from the Broad Street location, locals accessed other public sources, and the number of cholera cases began to abate.

Figure 1-11 Snow’s map of cholera cases, London, 1854. Wellcome Collection

Although Snow had demonstrated an apparent association between the Lambeth-supplied water and the cholera cases, the exact nature of that association remained unclear. Was it the water

per se, or was it something in the water? Sadly, Snow did not survive to witness Köch’s identification of Vibrio cholerae in the 1880s, as he died in London in June 1858. Indeed, it was something about the water; what that “something” was remained a mystery during Snow’s lifetime.

Ignaz Semmelweis and “Childbed Fever” The importance of the Hungarian physician Ignaz Semmelweis (1818–1865; Figure 1-12) in the history of infectious disease lies in the study of puerperal fever. Working in the Vienna Lying-In Hospital in the 1840s and 1850s, he grew increasingly concerned about the number of postpartum deaths in the maternity ward. How might they be reduced, if not eliminated completely, he wondered.

Figure 1-12 Ignaz Semmelweis. © YANGCHAO/Shutterstock

Semmelweis hypothesized that physician and medical-student birth attenders might somehow convey infectious substances from patient to patient. The number of postpartum infections, he noticed, was far lower among midwife-attenders than among the

medical staff and students. He also observed that midwives— unlike their medical counterparts—typically washed their hands between births. Perhaps the handwashing had removed these mysterious particles from the hands of the midwives, Semmelweis thought. It would not be until 1938 that investigators would determine that Group B streptococci caused puerperal fever. Semmelweis devised a simple experiment: institute a handwashing protocol for all birth attenders—midwives, medical staff, and students alike. Not surprisingly, the medical staff bristled at the mere suggestion that they were somehow to blame for the deaths of their maternity patients. Semmelweis’s hunch proved correct; that is, the hand-washing intervention began to reduce inpatient maternal mortality. He published his findings in 1861 in Die Ätiologie, der Begriff und die Prophylaxis des Kindbettfiebers (The Etiology, Concept and Prophylaxis of Childbed Fevers).

The Legacy of Panum, Snow, and Semmelweis The work of Panum, Snow, and Semmelweis rests largely in their pre-germ–theory insights about infectious disease causation. Although, in the case of Snow and Semmelweis, they may well have used a microscope to observe the bacteria responsible for cholera and puerperal fever. In Panum’s case, microscopic observation of the measles virus would have been impossible. His work on the Faroe Islands’ outbreak, however, did suggest that some infections might confer lifelong immunity on survivors.

Quantifying Infectious Diseases Sir William Petty and John Graunt Fellow Britons Sir William Petty (1623–1687) and John Graunt (1620–1674) were among the first to quantify disease mortality, not least from infectious diseases. Their approach to disease epidemiology was what Petty termed “political arithmetic.” Graunt is especially important for his application of this method—the study of “vital statistics”—to assess mortality trends in Restoration-era London. Beginning in 1662, Graunt’s Natural and Political Observations —Bills of Mortality provided an annual detailed accounting of deaths in mid-17th-century London (Figure 1-13). Included in these records were deaths from diseases; accidental and nonaccidental deaths; the number of children (by gender) born, died, and christened; and a specific category for plague victims. Graunt observed trends that may seem obvious to us today: uneven ratios of male-to-female deaths (the former faring worse than the latter), uneven urban–rural mortality ratios (with citydwellers on the losing end), and seasonal mortality trends.

Figure 1-13 Bills of Mortality, London, 1664. © Universal History Archive/UIG/Shutterstock

Vital Statistics, Social Reform, and Public Health in Victorian England

The Industrial Revolution of the 19th century brought significant change to British society. Populations in search of work migrated from rural into urban areas, a shift that produced squalid workingclass districts in metropolitan areas such as Manchester and London where the working-class eked out an existence. Public health reformers such as England’s Edwin Chadwick (1800–1890; Figure 1-14) backed efforts to improve not only the lives of workers but of urban populations in general. Writing in his Report on the Sanitary Conditions of the Labouring Population of Great Britain (1842), Chadwick argued that social reform provided a means to improve public health. Personal hygiene, health, and morality, Chadwick argued, were closely associated.

Figure 1-14 Sir Edwin Chadwick. U.S.National Library of Medicine

Chadwick believed that filthy urban settings lay at the root of the problem. Slums, often lacking access to clean water and

proper sanitation, became hotbeds of infectious disease, with children being disproportionately affected. These urban ghettos, he noted, bred criminality—especially immorality and vice—and failed to provide the young with proper life-examples. Psychologically demoralized, the poor lived more like animals than human beings. Chadwick’s proposal was simple: improve sanitation and access to “clean” drinking water. Such basic interventions, he reasoned, would foster moral lives among the working poor and, in turn, benefit the entire population. His efforts culminated in the Public Health Act of 1848.

The Germ Theory of Disease Enter the Microscope Historians credit the Dutch scientist Antonie van Leeuwenhoek (1632–1723; Figure 1-15) with the invention of the microscope in the late 17th century. Commonly known as the father of microbiology, he observed with his rudimentary invention animalcules cavorting “a prettily” in a specimen of his own stool (see Figure 1-16). Van Leeuwenhoek failed, however, to associate these microscopic curiosities with human disease.

Figure 1-15 Antonie van Leeuwenhoek. U.S.National Library of Medicine

Figure 1-16 Animalcules. © NNehring/DigitalVision Vectors/Getty Images

But how could such tiny creatures cause sickness and suffering? It was not until the late 19th century that scientists began to associate microorganisms with disease. As noted earlier, neither Panum, Snow, Semmelweis, nor Farr gave the idea much consideration. Indeed, Farr remained convinced that the stinking, miasmatic vapors from the Thames River were to blame for cholera, if not infectious diseases in general.

Henle, Köch, and Pasteur The germ theory of disease provided an important paradigm shift in the explanation of the cause of infectious diseases. The French scientist Louis Pasteur (1822–1895) and the German scientists Jacob Henle (1809–1885) and Robert Köch (1843–1910; Figure 1-17) proposed that specific microorganisms caused specific infections. Indeed, Köch and Henle proposed four postulates to determine whether a specific pathogen caused a specific disease. For example, did Vibrio cholerae actually “cause” cholera, nothing at all, or (perhaps) other diseases as well?

Figure 1-17 Robert Köch. © Mario Breda/Shutterstock

The Köch-Henle postulates are fundamental to the study of infectious diseases. First, a specific pathogen must be present in all cases of a specific infectious disease. Second, isolated from these cases, the pathogen must be able to grow in pure culture. Third, when a susceptible host such as a laboratory animal is inoculated with the suspected pathogen, the microbe must be able to produce the disease in question and be present in the newly infected host. Finally, the pathogen must be recoverable from an infected host such as a laboratory animal. One of the first applications of the germ theory of disease occurred during a plague epidemic in Hong Kong during the 1890s. Examining bubo specimens, the Swiss physician Alexandre Yersin (1863–1943) and the Japanese physician Kitasato Shibasaburo (1853–1931; Figure 1-18) determined that the bacterium Yersinia pestis caused plague. It fell to the French physician Paul Louis-Simond (1858–1947) to determine that a flea

(Xenopsylla cheopsis; see Figure 1-3) provided the arthropod vector that transmitted bubonic plague. His work on the role of the flea in its transmission prompted contemporaries such as Walter Reed, Patrick Manson, and Ronald Ross to consider other insects —most notably the mosquito—in infectious disease transmission.

Figure 1-18 Kitasato Shibasaburo. Wellcome Collection

Vector-Borne Diseases Yellow Fever Outbreaks of yellow fever periodically struck the colonial and postcolonial Americas. Firsthand accounts describe its impact on populations throughout the Caribbean, South America, and North America. One of the most notable outbreaks occurred in the 1790s in Philadelphia. Likely introduced into the Americas via the African slave trade, the disease was especially feared throughout the western hemisphere. The American physician Benjamin Rush (1746–1813; Figure 1-19), prominent not only because of his reputation as a physician but also as a signatory to the American Declaration of Independence, is often associated with yellow fever epidemics of the 1790s. Rush, nearly a century before the development of the germ theory of disease, blamed the infection on two factors: foulsmelling miasmas (the same ones Farr blamed for cholera) and person-to-person contact. The true mode of transmission, the Aedes aegypti mosquito, was simply not part of his medical worldview. Given the so-called miasmas that loomed over Philadelphia, Rush advocated the firing of cannon—sans projectiles, one hopes—in the belief that the fiery smoke from the ignited gunpowder would somehow dispel them.

Figure 1-19 Benjamin Rush. Wellcome Collection

Benjamin Rush treated his patients with what medical historians call “heroic therapy.” Simply put, he viewed yellow fever, as did many physicians of his day, as an imbalance in the bodily humors—the same disease-causing humors of Greek medicine more than two millennia earlier. Regimens included bleeding and copious doses of mercury and botanical purgatives and laxatives. Rush, so certain that such measures were beneficial, bled and dosed himself when stricken with yellow fever. It is worth noting that he managed to survive the disease in spite of his therapeutics. He lived another two decades.

American doctor Stubbins Ffirth (1784–1820) remained unconvinced of Rush’s person-to-person theory of yellow fever transmission. While conducting research for his medical thesis at the University of Pennsylvania, he noticed that people who attended yellow fever patients did not seem more prone to the malady. To test his hypothesis, Ffirth decided on a plan of selfexperimentation by consuming vomitus and excreta from yellow fever victims. He failed to contract the infection, findings he presented in A Treatise on Malignant Fever; with an Attempt to Prove Its Non-Contagious Nature (1804). Although Ffirth rejected direct person-to-person transmission in the case of yellow fever, he failed to consider the role of insects such as mosquitoes. Researchers did not acknowledge the role of mosquitoes in yellow fever transmission until the turn of the 20th century. The Cuban physician Carlos Finlay (1833–1915; Figure 1-20), the Cuban delegate to the Fifth International Sanitary Conference in Washington, D.C., in 1881, proposed that mosquitoes were responsible for yellow fever transmission. He specifically fingered the Aedes aegypti mosquito. More research, he stressed, was needed to determine its precise role. For the most part, Finlay’s hunch initially fell on deaf ears.

Figure 1-20 Carlos Finlay. © BasPhoto/Shutterstock

Cuba during the Spanish-American War of 1898 provided a proving ground for Finlay’s mosquito hypothesis. American commanders quickly realized that tropical diseases such as yellow fever could produce as many casualties as the Mauser rifles that were standard issue to Spanish troops. The Cuban situation

allowed the U.S. Army Medical Corps an outstanding opportunity to test the association between mosquitoes and yellow fever transmission. The army assigned Major Walter Reed (1851–1902; Figure 121) to head the United States Army Yellow Fever Commission. Its objective was to investigate the mosquitoes’ role in deaths from yellow fever among garrisons in Cuba. Using human volunteers pulled largely from the ranks, Reed confirmed Finlay’s theory. Not only did he advocate quarantine of yellow fever cases—in wiremesh enclosures—he also recommended sanitary improvements to reduce the number of potential mosquito-breeding sites, applying a thin film of oil to them, and producing pyrethrum fogs to “stupefy” the insects. Sadly, Reed did not survive to see the full impact of his work on yellow fever eradication; he died in Washington, D.C. in 1902 from peritonitis.

Figure 1-21 Walter Reed. Wellcome Collection

Malaria Hippocrates was the first to describe malaria and its characteristic fever-cycles. According to Hippocrates, malaria—literally from the Italian “bad air” (mal + aria)—more often struck people who lived near swamps or marshes than those who lived elsewhere. Although he never entertained the mosquitoes’ role in malaria transmission, he did note that the disease appeared to occur

seasonally. The number of cases seemed to increase during warmer weather and decrease during cooler weather. Italian scientist and physician Giovanni Lancisi (1654–1720; Figure 1-22), writing more than 2,000 years later, echoed Hippocrates’s association of swamps, marshes, and fevers. In his De Noxiis Paludum Effluviis Eorumque Remediis (On the Noxious Effluvia of Swamps and Their Remedies, 1717), Lancisi hypothesized that they emanated disease-causing substances, or animalcules. Mosquitoes, in turn, were infected by them and subsequently passed them to humans. To prevent malaria, Lancisi advocated an aggressive campaign of swamp drainage.

Figure 1-22 Giovanni Lancisi. Wellcome Collection

The modern understanding of malaria dates from the late 19th century. Much of that early history is linked to European colonial aspirations in Africa, the Indian subcontinent, and Indochina. The French physician Alphonse Laveran (1845–1922; Figure 1-23), working in Algeria, is credited with the identification of Plasmodium falciparum in 1880, one of the five Plasmodium species that cause human malaria. After observing numerous specimens, he finally found the protozoa moving about in blood samples drawn from human malaria victims. His studies prompted others, most notably British and Italian investigators, to follow his example.

Figure 1-23 Alphonse Laveran. © Natata/Shutterstock

The British physician Ronald Ross (1857–1932; Figure 1-24), working in India in the 1890s, elaborated upon Laveran’s work while studying plasmodial life cycles in canaries. He wrote to Scottish physician Patrick Manson (1844–1922), known as the father of tropical medicine, to announce the central role of female mosquitoes’ bloodmeals in malaria transmission. With Manson’s help, Ross presented his findings at the annual meeting of the British Medical Association in the summer of 1898. The proverbial cat—or rather the mosquito—was now out of the bag.

Figure 1-24 Ronald Ross. © Natata/Shutterstock

Italian investigators also played an important role in the history of malariology. Building upon Ross’s work, Giovanni Battista

Grassi (1854–1925; Figure 1-25) confirmed the role of female mosquitoes (specifically Anopheles spp.) in malaria transmission. The life cycle of avian malarias, such as Ross had observed in canaries, mirrored that of human malarias. Unfortunately, a contentious dispute erupted between Ross and Grassi, each claiming precedence in the recent malaria discoveries. Both parties leveled charges of fraudulent findings and scientific misconduct at one another. In the end, the Nobel Prize in Physiology or Medicine went to Ronald Ross in 1902.

Figure 1-25 Giovanni Grassi. Wellcome Collection

Other Vector-Borne Diseases The work of Ross and Grassi on mosquitoes and Louis-Simond on fleas stirred interest in the association of other insects and infectious disease. In 1906, Australian Thomas Bancroft (1860– 1933) confirmed the role of Aedes aegypti in the transmission of dengue fever. That same year, American pathologist Howard Ricketts (1871–1910; Figure 1-26) determined that the Rocky

Mountain wood tick (Dermacentor andersoni) transmitted Rocky Mountain spotted fever (Rickettsia rickettsiae). Three years later, working at the Pasteur Institute in Tunis, French bacteriologist Charles Nicolle (1866–1936) determined that the human body louse (Pediculus humanus) was responsible for the transmission of epidemic typhus, the disease that killed thousands of Napoleon’s troops during his ill-fated Russian campaign.

Figure 1-26 Howard Ricketts. Wellcome Collection

20th-Century Infectious Disease Initiatives The Need for an Institutional and Organizational Infrastructure The institutionalization of biomedical research, a part of which focused on infectious diseases, at national and international levels dates from around the turn of the 20th century. One of the first regional (and multinational) organizations was the Pan American Health Organization (PAHO, 1902). Headquartered in Washington, D.C., the PAHO soon emerged as an important regional health organization with its focus on Central and South America and the Caribbean. Two similar organizations, focused primarily on the United States, were also established around the turn of the 20th century. The first was the National Hygienic Laboratory (1887), which became the National Institutes of Health (NIH) under the Ransdell Act of 1930. Today, the NIH is now headquartered in Bethesda, Maryland. The second, the Centers for Disease Control and Prevention (CDC), was first established as the Communicable Disease Center in Atlanta, Georgia, in 1946. Its weekly MMWR (Morbidity and Mortality Weekly Report) provides ongoing updates of infectious disease outbreaks throughout the United States. The World Health Organization (WHO), established in 1948, remains the premier global health organization. Headquartered in Geneva, Switzerland, it coordinates global public health efforts. One of its most successful achievements has been the eradication of smallpox. Following the last documented natural case in Somalia in 1977, WHO officials 3 years later declared the disease eradicated. European imperialism also contributed to the institutionalization of infectious disease research. As European powers sought more colonial outposts throughout Africa and Asia in the late 19th century, individual countries established schools designed to train medical teams to work in these regions. In the United Kingdom, the Liverpool School of Tropical Medicine (LSTM) was founded in

1898, the London School of Hygiene and Tropical Medicine (LSHTM) a year later in 1899. Similar efforts emerged in other European countries. In France, Le Institut Pasteur (the Pasteur Institute) was established in 1887. In Germany the Institut für Schiffs und Tropenkrankheiten (Institute for Maritime and Tropical Diseases, now known as the BernhardNocht-Institut für Tropenmedizin, or Bernhard-Nocht-Institute for Tropical Medicine) was founded in 1900.

Legislative Efforts to Address Infectious Disease Issues in the United States A series of public health legislation was initiated in the United States at the turn of the 20th century. Sadly, some were in response to tragic events that surrounded efforts to control or cure infectious diseases. Congress passed the Biologics Act of 1902 after the deaths of more than a dozen children who had received a Clostridium tetani–contaminated diphtheria antitoxin. Four years later, the Pure Food and Drug Act of 1906 followed, broadening the controls of the Biologics Act. Another tragedy associated with infectious disease occurred three decades later in the 1930s. Sulfonamide drugs, developed by the interwar German synthetic dye industry, had emerged as the first compound that could cure common bacterial infections, among them those caused by streptococcal organisms. It quickly became one of the first so-called wonder drugs, one penicillin would eclipse during the Second World War. The compound, difficult to dissolve into solution, was available only in tablet form. Capitalizing on demands for a liquid, more child-friendly preparation, the S.E. Massengill Company of Bristol, Tennessee, began marketing Elixir Sulfanilamide in 1937. Physicians around the country placed orders for Massengill’s child-friendly preparation. Within weeks, however, tragic reports of children who had died after taking Elixir Sulfanilamide began to fill the newspapers. The culprit? Not the drug per se, but rather the radiator fluid–based solvent it was dissolved in. The Massengill chemist who concocted the liquid preparation apparently had overlooked the toxicity of radiator fluid in humans. Legislators in Washington quickly responded with the Food, Drug, and Cosmetic Act of 1938, but not in time to save more than 100 children from the lethal Elixir.

20th-Century Advances In Antimicrobial Drugs Pathogen-Specific Drugs and the “Magic Bullet” German physician and scientist Paul Ehrlich (1854–1915; Figure 1-27) developed the first so-called magic-bullet drug in 1909. The compound, Salvarsan, targeted the causative agent of syphilis (Treponema pallidum), a discovery that earned Ehrlich the Nobel Prize in Medicine that same year. Although Salvarsan proved efficacious against T. pallidum, the drug’s organoarsenical base often proved toxic in some patients. The wide availability of penicillin four decades later, however, would eclipse Salvarsan in treating syphilis.

Figure 1-27 Paul Ehrlich. U.S. Department of Health & Human Services

Development of Other Pre–World War II Antimicrobials European researchers developed numerous synthetic drugs between the Great War and the Second World War. Among them were various antimalarial drugs. The first three were pamaquine (1924), quinacrine (1931), and chloroquine (1935). Although effective, patients sometimes complained of troubling side effects such as nausea, vomiting, skin discoloration, and mental disturbances. The first antibiotic drugs, the sulfonamides (e.g., sulfanilamide, originally named prontosil; Figure 1-28) and penicillin, also emerged during the interwar years. Sulfonamide proved effective against streptococcal infections, however, it was soon overshadowed by penicillin. Both played an important role in military medicine during World War II.

Figure 1-28 Tube of prontosil tablets, c. 1940. Science Museum, London/Wellcome Collection

The sulfonamides and penicillin followed different developmental paths. Whereas the former were synthetic compounds developed by German dye researchers, the discovery of penicillin came from a serendipitous observation by Scottish physician Alexander Fleming (1881–1955). He first documented

the in vitro antibacterial properties of the mold Penicillium notatum in 1928, but failed to pursue its clinical application at that time. The world inched once again toward global war during the 1930s. Eager to develop antimicrobial drugs to treat infections that the sulfas could not—staphylococcal infections, in particular— investigators such as the Australian pharmacologist Howard Florey (1898–1968) and the German biochemist Ernst Chain (1906–1979) turned their attention to penicillin (see Figure 1-29). By the time Britain entered the war against Germany in 1940, Florey and Chain had clinically demonstrated its broad antibacterial spectrum. Florey, Chain, and Fleming would jointly receive the Nobel Prize in Physiology or Medicine in 1945.

Figure 1-29 Group portrait of penicillin researchers (back row, left to right) S. Waksman, H. Florey, J. Trefouel, E. Chain, A. Gratia, (front row left to right) P. Fredericq and Maurice Welsch. Wellcome Collection

But there was no efficient way to mass produce penicillin. At the outset of the war, it was grown in low-yield surface cultures. Once the United States entered the war in December 1941, chemical engineers at a U.S. Department of Agriculture (USDA) research station in Peoria, Illinois, developed a method to mass produce penicillin in, rather than on, a corn-liquor culture medium. Although civilian access to the “wonder drug” remained tightly controlled throughout most of the war, production climbed sharply between 1943 and 1945 (Figure 1-30). Most penicillin went to

treating the wounded overseas; the rest went to the National Research Council’s Committee on Chemotherapeutic and Other Agents, a consortium of clinical investigators coordinated by American physician Chester Keefer (1897–1972) at Boston University School of Medicine, to study the drug’s efficacy against different pathogens. He and American physician Donald Anderson (1913–1995) coauthored The Therapeutic Value of Penicillin: A Study of 10,000 Cases (1948).

Figure 1-30 Advertisement about penicillin in Life, c. 1943. Science Museum, London/Wellcome Collection

The advent of the sulfonamides and penicillin sparked enormous optimism about the treatment of infectious diseases. For some contemporaries, penicillin seemed to herald an end to

such illnesses. Might such drugs transform common infectious diseases into a vestige of a bygone era? Such enthusiasm, however, proved premature; previously penicillin-sensitive bacteria, most notably Staphylococcus aureus, slowly began to develop resistance to it. To address this issue, researchers developed new antibiotics that, in turn, often developed their own drug-resistance problems.

Emerging Infectious Diseases Emerging infectious diseases began to attract the attention of biomedical researchers during the final decades of the 20th century. In January 1995, the CDC began monthly publication of Emerging Infectious Diseases. David Satcher, the CDC director at that time, penned its lead article, “Emerging Infections: Getting Ahead of the Curve.” The goal was to be proactive rather than reactive.

Acquired Immunodeficiency Syndrome The first case reports of what soon became known as acquired immunodeficiency syndrome, or AIDS, appeared in the Morbidity and Mortality Weekly Report (MMWR) in June 1981. Investigators presented accounts of five young adult males with mysteriously failing immune systems. Subsequent reports soon documented cases of rare cancers and uncommon infections among AIDS patients. Most of these reports involved homosexual males (i.e., MSMs, men who have sex with men) who lived in New York and California. Over the next decades, AIDS deaths continued to mount not only among MSMs but among heterosexuals as well. The emergence of AIDS struck a stunning blow to postwar optimism about the end of infectious diseases as significant causes of morbidity and mortality. Its etiology, the human immunodeficiency virus (HIV), continues to infect millions each year. By 2012, more than 25 million people had succumbed to AIDS, although the development of highly active antiretroviral therapies (HAARTs) has slowed overall mortality rates. More than 33 million people are living with HIV/AIDS at present. The condition remains neither curable nor vaccine preventable.

Severe Acute Respiratory Syndrome The first reports of severe acute respiratory syndrome, or SARS, emerged from Southeast Asia in 2003. One of its first victims was Italian doctor and microbiologist Carlo Urbani (1956–2003), a WHO infectious disease specialist, who had worked in Hanoi, Vietnam, and had helped to identify the virus. The pathogen, the SARS-associated corona virus (SARS-CoV), sickened nearly 8,100 people worldwide and killed almost 800. Eight laboratoryconfirmed cases—all of whom had traveled to countries where SARS was active—were identified in the United States.

Ebola Hemorrhagic Fever The Ebola virus, which causes Ebola hemorrhagic fever (EHF), was first discovered in 1976 in the central African country of Zaire (now the Democratic Republic of the Congo). It achieved global recognition in 2014 during outbreaks in Guinea, Liberia, and Sierra Leone, where health officials reported case-fatality rates as high as 90%. By August of that year, the WHO declared a Public Health Emergency of International Concern (PHEIC) that continued until officials announced an end to the outbreak nearly 2 years later in June 2016. Since that time sporadic outbreaks have continued to occur in Sub-Saharan Africa, the most recent in mid-2019.

Middle East Respiratory Syndrome The first reports of Middle East respiratory syndrome (MERS) came from the Arabian Peninsula in 2012. Dromedary camels appear to be reservoirs of the infection; however, the precise mode of MERS transmission remains unclear. Since 2012, more than 2,000 lab-confirmed cases of MERS caused by the MERScoronavirus (MERS-CoV) have been reported to the WHO, with nearly 800 deaths occurring in more than two dozen countries.

Conclusion Our understanding of infectious diseases has undergone considerable transformation since antiquity. The germ theory of disease, rather than divine wrath, ill-balanced humors, or human iniquity, has guided the study of these conditions for well over a century. Indeed, disease mortality has shifted significantly from infectious diseases at the turn of the 20th century to chronic, debilitating ones by the turn of the 21st century, a phenomenon called the epidemiologic transition. Average life expectancy at birth in the United States has shifted from just shy of 50 years in 1900 to nearly 80 years in 2010. Pediatric deaths under the age of 5, accounting for nearly a third of all deaths in 1900, had dropped to less than 2% a century later. The reasons for these changes are complex. Undoubtedly, drugs such as penicillin have played a significant role, however, one cannot ignore the significance of population-based interventions such as improved sanitation, vaccines (especially in the case of children), and vector control in the case of insect-borne diseases. In the industrialized world, morbidity and mortality from chronic diseases such as diabetes and cardiovascular disease have largely replaced conditions such as pneumonia, what Canadian physician Sir William Osler (1849–1919) famously called in 1901 the “captain of the men of death” in his landmark The Principles and Practice of Medicine (pneumonia, in his view, had replaced his previous choice, syphilis). It is ironic that Osler’s “captain,” pneumonia, killed him in December 1919.

Key Terms animalcules Black Death Chadwick, Edwin Ffirth, Stubbins Finlay, Carlos Fracastoro, Giorlamo Grassi, Giovanni Battista Graunt, John Hippocrates Jenner, Edward Jesuit’s bark Köch-Henle postulates Lancisi, Giovanni Manson, Patrick miasma Morgagni, Giovanni Panum, Peter Ludwig Plague of Athens Plague of Justinian Reed, Walter Ross, Ronald Rush, Benjamin Semmelweis, Ignaz Shibasaburo, Kitasato smallpox Snow, John Sydenham, Thomas syphilis third plague pandemic vaccination van Leeuwenhoek, Antonie variolation Yersin, Alexandre

Review Questions 1. In what ways has our understanding of infectious disease epidemiology changed from ancient times to the present day? Give three examples. 2. How have epidemics and pandemics affected human society? Explain. 3. Identify three advances in infectious disease research that can be attributed to agencies of the U.S. government. 4. Discuss the significance of the contributions by the following individuals in the development of our understanding of infectious diseases: a. Hippocrates b. Fracastoro c. van Leeuwenhoek d. Jenner e. Snow f. Ffirth g. Finlay h. Reed i. Rush j. Morgagni k. Panum l. Semmelweis m. Graunt n. Chadwick o. Köch p. Yersin q. Shibasaburo r. Lancisi s. Ross t. Grassi

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CHAPTER 2 Basics of Infectious Disease Epidemiology LEARNING OBJECTIVES Define key concepts in infectious disease epidemiology. Describe the relationships between pathogens and their hosts. Explain the difference between incidence and prevalence. Interpret results of sensitivity, specificity, positive predictive value, and negative predictive value tests. Characterize the different disciplinary perspectives used to study infectious diseases. Explain the significance of pre-20th-century concepts of disease transmission. Describe the dynamics and different routes of infectious disease transmission. Explain the significance of the basic reproductive number and reproductive number in infectious disease transmission. Explain the importance of the Ross and Ross–MacDonald models of malaria transmission.

Introduction Several questions are fundamental to the study of infectious diseases: (1) How do pathogens and hosts interact? (2) What circumstances make transmission of a pathogen to a susceptible host more (or less) likely to occur? (3) What factors make a suspected case a bona fide case? (4) How long does it take for an infected host to display clinical signs and symptoms? Infectious disease epidemiology is essentially an interdisciplinary enterprise. Whereas clinicians focus primarily on patients’ signs and symptoms, microbiologists focus on the suspected pathogens that produce that clinical picture. The epidemiologists’ perspective, the emphasis of this chapter, considers variables such as disease frequency, distribution, transmission, the appearance of new cases and disappearance of existing ones in a specific population at a given time and place.

Key Concepts Pathogens are microorganisms that can produce disease in a susceptible host. They seldom—if ever—immediately cause illness. Rather, an interval exists between exposure to the pathogen and the appearance of signs, symptoms, and/or positive laboratory findings. This gap is called the incubation period. But what amount of a given pathogen is required to produce an infection in a susceptible host? This is the infective dose. Pathogens such as Clostridium botulinum may require only an infinitesimal amount to produce an infection—and often a lethal one at that. The size of the infective dose also depends on the immune status of a potential host. A patient with HIV/AIDS, for example, would require a far smaller amount of an infective pathogen than someone in generally good health with a normally functioning immune system. Whereas the pathogen’s infective dose reflects the amount of a pathogen needed to produce infection, its infectivity reflects its ability, or inability, to produce an infection. Infective dose and infectivity differ from a microorganism’s pathogenicity and virulence. Pathogenicity is a qualitative assessment: Can a microorganism cause disease in a host or not? That’s pathogenicity, yes or no. Virulence, however, is a quantitative measure: What is the degree of severity of the infection? That’s virulence. Some organisms may certainly qualify as pathogenic but may produce only mild symptoms. Others, equally pathogenic, may prove fatal. Consider, for example, Tinea unguium, a common cause of toenail fungus. Unsightly? Perhaps. Annoying? Possibly. Fatal? Seldom. Alternatively, consider the Ebola virus. Often fatal? You bet. Both pathogens cause disease but to significantly different degrees. Virulence also may vary over time. The annual appearance of different influenza strains provides a good example of this phenomenon. Case fatality rates can offer a useful measure of disease virulence. Several factors can influence pathogenicity and virulence. Evolutionary forces are one. The selective pressures antibiotics exert on bacteria may cause antibiotic-resistant strains, (e.g., methicillin-resistant Staphylococcus aureus [MRSA]). Other factors

that can alter pathogenicity and virulence are antigenic drift and shift, concepts often associated with viral pathogens. The former refers to a gradual process of genomic variations that may produce new, possibly more virulent, strains. The latter refers to a sudden process where two or more viral strains combine to form a new viral subtype, such as in the case of seasonal influenza viruses. Some infections may produce no detectable symptoms at all. In the case of inapparent infections, an infected host remains asymptomatic yet continues to harbor a pathogen. These symptom-free hosts, unaware they are infected, may be able to transmit an infection to others. Such healthy carriers can be of considerable epidemiologic significance. Consider, for example, the case of Mary Mallon, the much maligned “Typhoid Mary” of early 20th-century New York City (see Box 2-1).

Box 2-1 The Case of Mary Mallon The tale of Mary Mallon, aka “Typhoid Mary,” dates from early 20th-century New York City. By all accounts, it appears that Mallon was a healthy carrier, an infected person who showed no discernible clinical disease. Nonetheless, she left a trail of typhoid victims at the homes and institutions where she worked as a cook. More than four dozen people were infected, and several died. Mary died in 1938, yet the moniker “Typhoid Mary” continues to haunt her today. Modified from Leavitt JW. Typhoid Mary: Captive to the Public’s Health. 10th ed. Boston, MA: Beacon Press; 1997.

Infections come in two basic types: acute and chronic. Acute infections are short term, although not necessarily benign or selflimiting. Consider the case of the common cold and Ebola hemorrhagic fever (EHF). Both are acute infections; however, their outcomes differ significantly. Alternatively, chronic infections may linger for the life of the host, as in the case of HIV/AIDS. The goal of treatment is to manage the disease rather than to necessarily cure it. Immunogenicity is another important concept in the study of infectious diseases. It refers to the ability of a pathogen to evoke an immune response in a susceptible host. In some infections— and measles virus is a good example—the pathogen can spark a

host immune response that typically confers lifetime immunity, a point not lost on Peter Panum over a century and a half ago.

Prevalence and Incidence Prevalence Prevalence characterizes the number of existing cases in a population at a given place and time. The prevalence rate refers to the total number of infected cases in a population divided by the population at risk (PAR), which is the total number of people who could have been infected in that same population, in the same place, and at the same period, multiplied by a constant, such as 100,000 (see Box 2-2), in which case the prevalence rate becomes the number of infected cases per 100,000 population.

Box 2-2 Calculating Prevalence Rate Prevalence rate = Number of existing cases of “Disease X” at a given place and time/PAR × 100,000

Modified from Jekel J, Katz DL, Elmore JG, et al. Epidemiology, Biostatistics, and Preventive Medicine. 3rd ed. Philadelphia, PA: Saunders; 2007.

Prevalence comes in two general varieties: point and period. Point prevalence provides a “snapshot” of disease in a population at a specific time and place. In other words, what is the disease burden right now? Period prevalence, however, provides a snapshot not necessarily of the “now,” but of a specific time and place over a defined period such as days, months, or years. Neither provides an estimation of disease risk nor addresses disease causation. Cross-sectional studies rely on measures of prevalence.

Incidence Incidence, although related to prevalence, provides a somewhat different picture of disease in a population. Rather than measuring the existing cases, as prevalence does, incidence measures new cases in a given population at a specified place and time. The incidence rate, which is calculated in a similar manner as the prevalence rate, considers the number of new cases divided by the total PAR, which is then multiplied by a constant such as 100,000 (see Box 2-3).

Box 2-3 Calculating Incidence Rate Incidence rate = Number of new cases of “Disease X” at a given place and time / PAR × 100,000

Modified from Jekel J, Katz DL, Elmore JG, et al. Epidemiology, Biostatistics, and Preventive Medicine. 3rd ed. Philadelphia, PA: Saunders; 2007.

Diagnostic Screening Tests Sensitivity and Specificity Investigators sometimes use screening tests to identify infected and uninfected cases in a group of subjects. Although they may be extremely accurate in this regard, no test is without its flaws. Invariably, cases will test “positive” for an infection yet remain infection-free, or “negative.” Alternatively, cases that test “negative” for an infection may in fact be “positive” for that infection. Sensitivity and specificity, measured as percentages, help to quantify the accuracy of screening tests (see Table 2-1 and Box 2-4). Sensitivity reflects the ability of a test to correctly identify infected or diseased cases as “positives.” Specificity reflects its ability to correctly identify uninfected cases as negatives. Table 2-1 Sensitivity and Specificity

Modified from Jekel J, Katz DL, Elmore JG, et al. Epidemiology, Biostatistics, and Preventive Medicine. 3rd ed. Philadelphia, PA: Saunders; 2007.

Box 2-4 Calculating Sensitivity and Specificity Sensitivity = (A/A + C) × 100 Specificity = (D/B + D) × 100

Modified from Jekel J, Katz DL, Elmore JG, et al. Epidemiology, Biostatistics, and Preventive Medicine. 3rd ed. Philadelphia, PA: Saunders; 2007.

Positive and Negative Predictive Values Positive and negative predictive value screening tests are related to tests of sensitivity and specificity (see Box 2-5). Positive predictive value (PPV) measures the proportion of positive cases that have the disease in question; for example, how many cases that test positive for HIV have actually been infected with the virus? Alternatively, negative predictive value (NPV) measures the proportion of cases who test negative for a disease and are in fact disease-free.

Box 2-5 Calculating PPV and NPV Positive predictive value (PPV) = A/(A + B) Negative predictive value (NPV) = D/(C + D)

Modified from Jekel J, Katz DL, Elmore JG, et al. Epidemiology, Biostatistics, and Preventive Medicine. 3rd ed. Philadelphia, PA: Saunders; 2007.

Herd Immunity British microbiologists W. W. Topley (1866–1944) and G. S. Wilson (1895–1987) coined the term herd immunity in the early 1920s. Fellow Briton and medical statistician Major Greenwood (1880– 1949) further expanded the concept throughout the 1920s and 1930s. Person-to-person transmission of infectious diseases, they determined, reflects the proportion and susceptibility of potential hosts in a population. Given a disproportionate number of “immune” individuals in a “herd”—population, that is—then susceptible individuals will have relatively few opportunities to interact with infected persons and thereby run the risk of infection.

Transmission and Distribution of Infectious Diseases The transmission and distribution of infectious diseases change over time. Disease dynamics may reflect environmental conditions, such as the presence or absence of arthropod vectors or human behavior, such as spending more time outdoors during warmer months, and so on. These factors help to drive infectious disease transmission in a population over time and space. Mathematical modeling provides a useful tool to measure the dynamics of an infectious disease. Several additional concepts apply to the transmission and distribution of infectious diseases. For example, some infectious diseases are endemic, lingering in a population over time, such as human African trypanosomiasis (HAT) in sub-Saharan Africa or plague in China. Disease outbreaks are usually defined as the local appearance of more than the expected number of disease cases or more than two linked cases of the same disease, such as foodborne illness among banquet attendees. Infectious diseases outbreaks may be epidemic or pandemic. With an epidemic, an abrupt spike occurs in the number of cases normally expected in a population. An epidemic, unlike an outbreak, which typically occurs in a relatively small area of population, encompasses a larger geographical area such as a state, province, or country. The yellow fever epidemics that struck American port cities in the 1870s are a good example. A pandemic is essentially an epidemic that spreads globally across countries and continents, such as the influenza pandemic of 1918–1919. Infectious diseases can also be characterized by the chain of infection (see Figure 2-1). Transmission occurs when a pathogen (or agent) exits its host or reservoir via a portal of exit (e.g., the respiratory tract via coughing or sneezing). Once in the environment, transmission can commence either directly or indirectly when a pathogen encounters a port of entry such as the respiratory tract of a susceptible host. Infectious diseases transmitted from animals to humans are known as zoonotic diseases.

Figure 2-1 Chain of infection. Centers for Disease Control and Prevention. Principles of Epidemiology. 2nd ed. Atlanta, GA: U.S. Department of Health and Human Services;1992. https://www.cdc.gov/csels/dsepd/ss1978/lesson1/section10.html. Accessed August 6, 2019.

The Epidemiologic Triangle The epidemiologic triangle, shown in Figure 2-2, provides a useful conceptual tool for the study of infectious disease epidemiology. It consists of three primary components: host, agent, and environment. The first component, hosts, are the susceptible, infectious, or recovered disease cases. In the case of infectious diseases, host susceptibility often reflects factors such as immune status, age, ethnicity, and gender. Agents, the second component, are the pathogens that produce disease in otherwise susceptible hosts. (In a more general sense, an agent might be a “force” such as electricity; in the case of infectious diseases, however, an agent is typically understood as a pathogen of some type.) Finally, environment refers to the physical context in which the potential hosts and agents live. Unlike hosts and agents, it may be possible to modify environmental factors, such as eradication of mosquito-breeding sites or improvements in sanitation.

Figure 2-2 Epidemiologic triangle. Courtesy of Schmidt NA. Evidence Based Practice for Nursing. 4th ed. Burlington, MA: Jones & Bartlett Learning; 2019.

Modeling Infectious Disease Transmission The Swiss mathematician and physicist Daniel Bernoulli (1700– 1782; Figure 2-3) was one of the first to apply mathematical modeling to the study of infectious diseases. In 1766 he published an assessment of how variolation might reduce smallpox-related deaths, Essai d’une nouvelle analyse de la mortalité causée par la petite vérole et des avantages de l’inoculation pour la prevenir (Essay concerning a new analysis of the mortality caused by smallpox and some advantages of inoculation to prevent it). Bernoulli assumed two things: (1) that infection risk did not fluctuate over time and (2) that crowding had no effect on smallpox transmission.

Figure 2-3 Daniel Bernoulli. Wellcome Collection

Writing a more than a century later, British epidemiologists William Farr (1807–1883) and Arthur Ransome (1834–1922) expanded upon Bernoulli’s work. Farr, however, failed to explain how epidemics waxed and waned, and Ransome lacked an explicit model of disease transmission. Nonetheless, Ransome did observe that the decline of susceptible hosts often signaled a decline in infectious disease cases and that epidemics fluctuated over time. Ransome attributed these changes to the introduction of new susceptibles into a population. Another Briton, Ronald Ross (1857–1932), is notable for the Ross model used to study malaria transmission. Reduction of mosquito populations, not necessarily their eradication, he theorized, hindered transmission of the disease, thus reducing the number of cases in a population. Four decades later, British scientist George MacDonald (1903–1967) expanded Ross’s model by adding an additional variable, tau (τ), to allow for the developmental time, the extrinsic incubation period, that the Plasmodia spent inside the female Anopheles spp. (see Box 2-6).

Box 2-6 The Ross and Ross–MacDonald Models Ross model R0 = ma2bc/rµ Ross–MacDonald model R0 = ma2bce−µτ/rµ where: N = Human population size M = Female mosquito population size M/N = m = Female mosquitoes per human host b = Probability of malaria transmission from an infected mosquito to a human host c = Probability of malaria transmission from an infected human host to a mosquito r = The proportion of individuals who recover from malaria during a given period of time

a = The number of Anopheles mosquitoes that bite individuals during a given period µ = Mosquito mortality rate Τ = Malaria latency period in a mosquito e−µΤ = Probability that a mosquito can survive the latency period Modified from Thomas JC and Weber DJ, eds. Epidemiologic Methods for Infectious Diseases. New York, NY: Oxford University Press; 2004.

Ross proposed an equation with which to evaluate the effects of interaction of mosquitoes and their human hosts on transmission. His model includes factors such as the estimated size of the human and mosquito populations; the estimated number of mosquitoes per human host; the estimated daily biting rate of a single mosquito; the probability of transmission from a human host to a mosquito, and vice versa; the infected host’s recovery rate; the daily mosquito mortality rate; the population density of Anopheles mosquitoes; the percentage that will survive long enough to transmit disease; and the percentage of humans who are gametocyte-positive.

Outbreaks, Epidemics, and Pandemics: Contributing Factors So, just how bad is an outbreak, epidemic, or pandemic? This is where the reproductive number (R) can be handy. R is defined as the likely number of infected cases that a single infective case can produce. The time interval between consecutive generations of infective cases is known as the generational time. Together, they provide an indicator of whether epidemics are growing or receding. R represents the expected number of cases that follow contact with one infected case in a population of susceptibles and immunes. In a completely susceptible population R is referred to as the basic reproductive number (R0). Interpretation of the reproductive numbers is rather straightforward. If R0 is greater than 1.0—that is, a single infected case can produce more than one infected case—then an epidemic is intensifying. If R0 is less than 1.0, then an epidemic is dying out. In other words, the infected cases are unable to infect enough susceptibles to sustain the spread of infectious disease within a given population. It is herd immunity that refers to the overall health status of a population. If the level of herd immunity is high due to high vaccination rates, then an infective will have relatively little chance of infecting susceptibles. There are simply too few of them.

Progression of Infectious Diseases in a Population The incubation period of an infectious disease is the interval between the point of infection and the onset of clinical disease. Its significance for disease transmission lies in the fact that the incubation period can provide a rough estimate of an approximate point of infection and when clinical illness is likely to appear. With an idea of the incubation period, health officials can more accurately assess the potential disease burden and implement prevention measures. An infection’s latency period is the interval between exposure and infectiousness (not necessarily clinical signs). Many infectious diseases, however, share similar incubation and latency periods; HIV/AIDS represents a notable exception; its incubation period may exceed its latency period. The significance of this is that interventions may target only symptomatic cases, although an HIV-positive individual may be able to spread the infection prior to obvious clinical onset. The infectious period of a disease is the interval during which an infected person can infect a susceptible person or an appropriate vector such as a mosquito. In the case of influenza, for example, the infectious period is rather short (days or weeks); in the case of HIV/AIDS, the infectious period is lengthy—a lifetime, perhaps. The length of the infectious and latency periods both significantly affect generation time, the period between an infection’s onset and when an individual can transmit the infection to someone else.

Dynamic Models of Disease Transmission Another aspect of disease progression and transmission is the issue of just how infections are transmitted. Infectious diseases can be spread directly from person-to-person, such as through coughing or unprotected sex, or indirectly from insects, food, water, or another environmental reservoir (see Figure 2-4).

Figure 2-4 Modes of disease transmission. Courtesy of Shors T. Understanding Viruses. 3rd ed. Burlington, MA: Jones & Bartlett Learning; 2017.

Compartmental Models Compartmental models of disease transmission separate or “compartmentalize” individuals according to their status as susceptible (S), infectious (I), or recovered (R). The last category (sometimes referred to as “removed”) includes cases that have acquired full immunity or have exited a population due to death or emigration (see Box 2-7). These three categories form the basis of the SIR model. An expanded version, the SIRS model (the final S stands for “susceptible”), assumes that recovered status is only temporary; there is no lifelong immunity. Another version, the SEIR model, takes into account “exposed” (E) persons who may not yet be infectious.

The dynamics of infectious disease transmission reflect the degree to which the S, I, E, and R compartments interact. For example, individuals who began the week as susceptibles may end the week as infectious thanks to the common cold, only to begin the following week as recovereds. The rate at which they move from category to category reflects the transmission rate of an infection (ϐ) as well as the rate of recovery among infected individuals (γ). The transmission rate (ϐ) and recover rate (γ) are conceptually related to the density of the infected population. Transmission that relies on density assumes that the contact rate—that is, the number of infectious contacts susceptibles make within a given time period—increases as population density increases. Alternatively, transmission that relies on frequency of contacts in a population assumes that the per capita contact rate between susceptibles and infectives is of greater importance than the density of the population.

The Structure of the Host Population Assumption of Homogeneous Mixing The makeup of a host population significantly affects the impact of infectious disease transmission within it. Homogenous mixing assumes that each member of a population has an equal chance of a potentially infectious contact as any other member, regardless of their infected status. The problem with this assumption, however, is that individuals might not have an equal chance of interacting with others. If an individual only speaks Spanish, for example, he or she may not normally associate with English-only speakers.

Demographic Characteristics Populations may have a cross-section of different age cohorts— young, middle-aged, and elderly. Infants, for example, may benefit from maternal antibodies yet otherwise be disadvantaged by lack of timely vaccinations. Members of age-specific cohorts may tend to interact with people who are of a similar age group. Schoolchildren, for example, may spend 6 or 7 hours a day with dozens of other children but relatively few adults. High-risk sexual behavior can also alter disease transmission rates. Individuals who engage in high-risk behaviors such as men who have sex with men (MSMs), those with multiple sexual partners, those who engaged in unprotected sex, and so on, face far greater risk of contracting a sexually transmitted infection (STI) than those who do not.

Conclusion Surveillance is critical to the study of infectious diseases. The ability to optimize surveillance efforts, however, reflects several factors. Among them are the efficacy of screening tests, the degree to which specific infections affect a given population, pathogenic virulence, and the ability to adequately measure disease within a population. The understanding of infectious disease transmission dynamics has evolved significantly since Bernoulli’s smallpox work in the mid-18th century. Some advances have been more conceptual, as in the case of Farr and Ransome, whereas others have relied heavily on mathematics, as in the case of Ross and MacDonald.

Key Terms basic reproductive number (R0) Bernoulli, Daniel chain of infection epidemiologic triangle Farr, William healthy carriers herd immunity immunogenicity inapparent infections incidence incubation period infectious (I) infectious period infective dose infectivity latency period MacDonald, George negative predictive value (NPV) pathogenicity positive predictive value (PPV) prevalence Ransome, Arthur recovered (R) reproductive number (R) Ross model SEIR model SIR model SIRS model susceptible (S) virulence

Review Questions 1. Compare and contrast incubation period, pathogenicity, virulence, and immunogenicity. 2. Explain the public health significance of a healthy carrier such as Mary Mallon (“Typhoid Mary”). 3. Compare and contrast prevalence and incidence of disease. 4. Compare and contrast sensitivity and specificity values of diagnostic tests. 5. Explain the significance of herd immunity for infectious disease transmission. 6. Compare and contrast positive and negative predictive values of diagnostic tests. 7. Briefly explain each historical figure’s contribution to infectious disease epidemiology: a. Daniel Bernoulli b. William Farr c. Arthur Ransome d. Ronald Ross 8. What is the reproductive number? What does R0 mean? What three parameters does R0 have? 9. How can knowing the incubation, latency, and infectious periods of a particular disease help to control its spread? 10. Describe the different ways in which humans can become infected with an infectious agent. 11. Explain the basic concepts of the SIR, SIRS, and SEIR models.

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CHAPTER 3 Study Designs LEARNING OBJECTIVES Describe the types of study designs commonly used to investigate infectious diseases. Explain the concepts of causality, bias, reliability, and validity. Assess the strengths and weaknesses of study designs commonly used to investigate infectious diseases. Describe the design of cohort studies. Describe the design of case-control studies. Describe the protocol for randomized controlled trials (RCTs). Distinguish between “single-blind” and “double-blind” studies. Describe the types of populations used in epidemiologic studies.

Introduction Who or what is a study population? What data are needed to conduct a study in a given population? What, if any, confounding variables exist? What types of potential bias(es) should the investigators consider? What type of study design would be best suited to investigate the outbreak at hand?

Key Concepts Three important concepts when considering a population from an epidemiologic perspective are person, place, and time. Person provides the epidemiologic “who” and “what” that characterize the proposed study population, such as age distribution, ethnicity, educational level, gender, and so on. Place defines the epidemiologic “where”; that is, the geographical location where the study population lives and interacts. Finally, time refers to the epidemiologic “when”; these are the temporal parameters related to where a given study population lives, such as how many cases were reported between two dates.

Target, Source, and Study Populations Target, source, and study populations, although similar in some respects, bear important differences. Target populations are those populations that investigators try to draw inferences from regarding disease risk. Source populations are essentially portions or subsets (e.g., the study subjects per se) of a study population. Study populations are a subset of a source population. Members of a study population are individuals who meet a study’s inclusion criteria and, perhaps of greatest importance, consent to participate to begin with. Inclusion criteria typically include variables such as medical history, age, gender, and ethnicity.

Descriptive Studies Descriptive studies do just what their name implies; they describe. Their strengths lie in their ability to provide a snapshot, as it were, of morbidity and mortality in a given population at a given time and place. Descriptive findings often can generate hypotheses about possible disease risk(s). Their greatest weakness, however, is that researchers are unable to draw inferences from exposures and disease outcomes.

Case Reports and Case Series Case reports typically provide descriptions of a single (often unusual) clinical case (see Box 3-1). Some medical journals, particularly the New England Journal of Medicine, publish interesting case reports on a weekly basis. In the case of infectious diseases, they typically discuss a case’s clinical features, possible transmission route(s) (if known), treatment method(s), and resolution (if known). Although they can be intriguingly descriptive, case reports do not permit any causal inference(s). A case series highlights not one but several related cases.

Box 3-1 Case Report Example Meningococcal Pneumonia in a Young Healthy Male A 23-year-old male arrived at the emergency department complaining of a history of pleuritic chest pain, bloody sputum, and fever of 40°C. On examination, the attending physician noted crackling sounds and right-sided infrascapular bronchial breathing. Laboratory results showed raised white blood cell counts and abnormal chest radiographs. Blood culture proved positive for Neisseria meningitidis. The patient initially received IV ceftriaxone and doxycycline. On discharge he also received oral amoxicillin for an additional 3 days. On follow-up the patient had returned to his former health. Modified from Al Alawi AM. Meningococcal pneumonia in a young healthy male. Case Rep Infect Dis. 2018: 2179097. https://doi.org/10.1155/2018/2179097. Accessed January 2, 2019.

Cross-Sectional Studies Investigators sometimes employ a cross-sectional study design to assess the health status of a population or a specific portion of it (see Box 3-2). Providing a “snapshot” of a given place and time, it can reveal important details of infectious disease prevalence, demographic characteristics, and other salient features of a selected population. It does not, however, permit causal inferences concerning the cause of any disease(s) in the population.

Box 3-2 Cross-Sectional Study Example HIV-1 Viremia and Drug Resistance Among Female Sex Workers, Soweto, South Africa Investigators enrolled 508 subjects, median age of 32 years; more than half (55%) were HIV-positive (n = 280). Among this group, about half (51.8%) met the inclusion criterion for being virologically suppressed (viral load < 400 copies/mL). Of 119 individuals with unsuppressed viral loads, nearly 40% (37.8%) had detectable antiretroviral drug resistance. Modified from Coetzee J, Hunt G, Jaffer M, et al. HIV-1 viraemia and drug resistance amongst female sex workers in Soweto, South Africa: a cross sectional study. SluisCremer N, ed. PLoS ONE. 2017;12(12):e0188606. https://doi.org/10.1371/journal.pone.0188606. Accessed January 2, 2019.

Analytical Studies Case-Control Studies A case-control study design, a type of analytical study, offers several benefits (see Boxes 3-3 and 3-4). Useful in the investigation of rare or low-prevalence diseases, they often can be carried out quickly and at relatively low cost when compared to other analytical designs. With a case-control study, investigators draw their subjects from exposed individuals who suffer from the infectious disease in question and nonexposed individuals. The “case” group includes those with the disease; individuals who are considered to be disease-free are the “control” group (Figure 3-1). When time is of the essence, such as in a multistate or national outbreak of some kind, case-control studies can be especially useful.

Box 3-3 Case-Control Study Example 1 Endemic Cryptosporidiosis, AIDS Patients, and Municipal Tap Water Investigators used a matched, case-control design to study cryptosporidiosis risk among AIDS patients who drank municipal tap water. They selected their subjects from the San Francisco AIDS Registry from May 1996 to September 1998 and matched them according to age, gender, race and ethnicity, CD4+ T lymphocyte counts, and diagnosis date. The investigators found subjects’ consumption of municipal tap water at home and away was significantly associated with cryptosporidiosis. The odds ratio for drinking tap water at home was 6.76 (95% confidence interval [CI] = 1.37–33.5), and away from home was 3.16 (95% CI = 1.23–8.13). Given these initial findings, the investigators recommended that AIDS patients should avoid drinking tap water. Modified from Aragón TJ, Novotny S, Enanoria W, et al. Endemic cryptosporidiosis and exposure to municipal tap water in persons with acquired immunodeficiency syndrome (AIDS): a case-control study. BMC Pub Health. 2003;6:2. https://dx.doi.org/10.1186%2F1471-2458-3-2. Accessed January 2, 2019.

Box 3-4 Case-Control Study Example 2 Risk Factors Associated with Hepatitis E Outbreak in Napak District, Uganda Investigators used a case-control design to study a hepatitis E (HEV) outbreak in the Napak district of Uganda during 2013 and 2014. The host, environment, and agent as well as person, place, and time factors (other than the suspected HEV) that fueled the outbreak remained unclear. Reports indicated that some 1,359 cases and 30 deaths had already occurred. Variables included average age (29 years), gender (57.9% females vs. 42.1% males), overall case fatality ratio (2.2% in the general population vs. 65.2% among pregnant women), and the reported cases’ place of residence (94.3% in the subcounties of Napak vs. 5.7% in adjacent districts). Investigators determined that HEV-associated risk factors were drinking untreated water (odds ratio [OR] = 6.69, 95% CI = 3.15–14.16), consumption of roadside food (OR = 6.11, 95% CI = 2.85–13.09), lax cleaning of cooking utensils (OR = 3.24, 95% = 1.55–1.76), and hunting (OR= 1.14, 95% = 1.03–12.66). Modified from Amanya G, Kizito S, Nabukenya I, et al. Risk factors, person, place and time characteristics associated with hepatitis E virus outbreak in Napak District, Uganda. BMC Infect Dis. 2017;17(1):451. https://doi.org/10.1186/s12879-017-2542-2. Accessed January 2, 2019.

Figure 3-1 Basic case-control design. Courtesy of Aschengrau A, Seage GR. Essentials of Epidemiology in Public Health. 4th ed. Burlington, MA: Jones & Bartlett Learning; 2020.

Case-control studies are not without their flaws, however. They can be subject to recall bias when subjects are not sure whether they have—or have not—been exposed to a particular infectious agent. Case-control studies also lack clearly defined temporality. Although they can measure whether a person has or has not been exposed, they cannot define the precise time of that exposure. Moreover, they can study only one disease outcome at a time.

Cohort Studies Cohort studies, another group of analytical designs, derive their name from the Latin cohors, a term that originally designated a unit of 300 to 600 Roman soldiers. In a modern research context, a cohort represents a group of people who share common characteristics, such as smoking, regular exercise, ethnicity, age, and exposure or nonexposure status, to name but a few. Cohort studies offer an important advantage over case-control studies. Carried out over a defined period, they can assess disease incidence and risk. Cohort studies can be time-

consuming, labor-intensive, and potentially expensive, however. Given the oftentimes extended time frame of cohort studies, investigators must enroll enough participants to allow for those subjects who elect to quit the study for some reason or are otherwise lost to follow-up. Prospective cohort studies are one type of cohort design (see Box 3-5 and Figure 3-2). They typically follow two groups— cohorts—of otherwise healthy individuals into the future for a given period. They are matched as closely as possible according to gender, age, ethnicity, and other characteristics; they are “diseasefree” at the start of the study. They differ, however, in one important respect: one group has experienced (or are experiencing) an exposure that the other appears to have not. For example, a cohort study that examines the association between oral contraceptives and risk of sexually transmitted infection (STI) among freshmen university students might include two groups similar in almost every way possible—age, ethnicity, smoking behavior, sexual behaviors, etc.—except for oral contraceptive use.

Box 3-5 Prospective Cohort Study Example Epidemiology and Transmission of Respiratory Infections Among Thai Army Recruits Investigators studied respiratory infections among recruits in a 10-week military training program at two Royal Thai Army barracks from May 2014 to July 2015. At baseline, they determined a high level of bacterial colonization by H. influenzae Type B (82.3%) and non-Type B (31.5%), Klebsiella pneumoniae (14.6%), Staph. aureus (8.5%), and Strep. pneumoniae (8.5%). At follow-up, however, the level of H. influenzae non-type B had increased to 74.1% and S. pneumoniae to 33.6%. Modified from Tam CC, Anderson KB, Offeddu V, et al. Epidemiology and transmission of respiratory infections in Thai army recruits: a prospective cohort study. Am J Trop Med Hyg. 2018;99(4):1089–1095.

Figure 3-2 A prospective cohort study design. Courtesy of Aschengrau A, Seage GR. Essentials of Epidemiology in Public Health. 4th ed. Burlington, MA: Jones & Bartlett Learning; 2020.

Retrospective cohort studies, sometimes called “historical” cohort studies, offer another option (see Box 3-6). Using existing medical records, investigators follow two groups backward rather than forward in time. When compared to prospective cohort studies, retrospective ones can generate findings relatively quickly. They rely, however, on the clinical judgments and data collection that have occurred in the past—ones that might be flawed in some respect. In the Kenyan pneumonia study, for example, might some degree of clinical subjectivity have resulted in misclassification of the degree of pallor (see Box 3-6)?

Box 3-6 Retrospective Cohort Study Example Appropriateness of New WHO Pediatric Pneumonia Guidelines Low- and middle-income countries utilize WHO criteria to determine whether pediatric pneumonia cases should receive inpatient or outpatient treatment. Investigators examined

whether some cases given outpatient treatment might, in fact, have required inpatient treatment. They used a retrospective cohort study design of pneumonia cases aged 2 months to 5 years admitted to one of Kenya’s 14 hospitals between March 2014 and March 2016. They compared outcomes of children before and after the WHO revised its pneumonia guidelines in 2013. A total of 16,031 were admitted to the hospital prior to the guideline revision and 11,788 after it. Investigators identified three characteristics associated with children categorized as having nonsevere pneumonia. These were severe pallor (adjusted risk ratio [RR] = 5.9, 95% CI = 5.1– 6.8), mild-to-moderate pallor (adjusted RR = 3.4, 95% CI = 3.0– 3.8), and weight-for-age Z-score less than three standard deviations (adjusted RR = 3.8, 95% CI = 3.4–4.3). They found other factors independently associated with death. These included age of less than a year, respiration rate above 70 breaths per minute, female gender, treatment in a hospital located in an area with endemic malaria, moderate dehydration, and an axillary temperature of 39°C or higher. The investigators concluded that the WHO guidelines should not be the only hospital-admission criteria clinicians consider. Modified from Agweyu A, Lilford RJ, English M, et al. Appropriateness of clinical severity classification of new WHO childhood pneumonia guidance: a multihospital, retrospective, cohort study. Lancet Glob Health. 2018;6:e74–e83. https://dx.doi.org/10.1016%2FS2214-109X(17)30448-5. Accessed January 2, 2019.

Meta-Analyses and Ecologic Studies Meta-analyses are essentially assessments of the pooled statistical findings of a group of published studies. They often rely on information found in summary results. Although easily conducted with databases such as PubMed and PubMed Central, they may fall prey to publication bias. Meta-analyses may also amplify the methodological flaws of the studies they are based on. Ecologic studies (see Box 3-7) examine disease occurrences at an extreme population level. Instead of examining individual subjects, they study entire populations, such as the inhabitants of an entire region or country. Ecologic studies often rely heavily on published national or regional datasets for their analyses. Nonetheless, their strength lies in the ease with which they are done and, by relying on existing published data, their low cost. Weaknesses, however, reflect their inability to demonstrate causal relationships between specific exposures and outcomes. They are especially prone to the ecologic fallacy; that is, what may be true at the extreme population level may not necessarily be true at the local or individual level.

Box 3-7 Ecologic Study Example Male Circumcision, Religious Beliefs, and Infectious Diseases in Developing Countries Investigators examined associations between prevalence of male circumcision (MC), HIV, and other STIs in 118 developing countries. Specifically, they assessed associations between MC prevalence, religious preference (Christian or Muslim), and HIV prevalence where HIV transmission occurred via sexual intercourse. Investigators found 53, 14, and 51 countries had a high (> 80%), intermediate (20–80%), and low (