2000 Years of Pandemics: Past, Present, and Future [1 ed.] 3031100344, 9783031100345, 9783031100352, 9783031100376

This book analyzes the factors that have sparked pandemics over the past 2000 years, from the Antonine Plague to COVID-1

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2000 Years of Pandemics: Past, Present, and Future [1 ed.]
 3031100344, 9783031100345, 9783031100352, 9783031100376

Table of contents :
Preface
Introduction
Zoonosis and Pandemics
Pandemics: The Price of Progress
Acknowledgments
Contents
Abbreviations
1: The First 1000 Years CE of Pandemics: Smallpox and Plague
Introduction
The Antonine Plague: Smallpox (165–190 CE)
Description of the Disease
Propagation of the Disease
Perception of the Disease in the Roman Empire
Fatality Rates
Attempts for Treatments
Justinian Plague (541–749 CE)
The Origin and Propagation of the Pandemic
The Pandemic and the Yersinia pestis Bacteria
The High Fatality Rate of the Justinian Plague
Justinian Plague and Climate Change
The Social and Cultural Impact of the Justinian Pest
Justinian Plague and the Divine Punishment
Japanese Smallpox Epidemic (733–737 CE)
The Disease Outbreak and Propagation
The Impact of the Japanese Smallpox on Society
References
2: The Plagues Pandemics: 2000 Years of Recurrent Devastations: The Black Death
Introduction
The Disease and Bacteria Yersinia pestis
The Plague Zoonosis
The Clinical Characteristics of the Plague
The Black Death (1346–1353)
The Initial Conditions: When Asia Meets Europe in Caffa
The Tartar Horsemen and the Black Death
The Biological Warfare Attack and the Consequences
Escaping Hell: The Propagation Towards Europe Through the Mediterranean
The Black Death Arrives in Italy: The Implementation of Quarantine
The Black Death Strikes Stronger in the United Kingdom
The Search for Cause and Remedies During the Black Death
The Miasma Theory
The Plague Doctors
The Search for Redemption
The Black Death and the Blame on Others
The Aftermath of the Black Death
The Third Plague Pandemic
The Plague in the Twentieth and Twenty-First Centuries: The Endemic Situation
Global Distribution of Natural Plague Foci
Treatment
The Plague and the Antibiotic Resistance Problem
References
3: Outbreaks in the New World: 1492–Mid-Nineteenth Century
Introduction
Features of Infectious Disease Outbreaks in the New World
The Indigenous Populations of the New World Experienced Disease Outbreaks Before the Europeans Arrived
There Was a Large Scale of Deaths Which Affected the Indigenous Populations of the New World
There Were Many Diseases Introduced into the New World
There Were Multiple Sources of Disease Outbreaks
There Were Multiple Outbreaks of the Same Disease
The Native Populations Were Not Passive Victims of Disease
There Was Transmission of Disease from the New World to Europe
Disease Was Used as a Weapon in Conflicts in the New World
The Colonial Administrations Used Variolation and Vaccination to Fight Smallpox
Conclusion
References
4: Syphilis, Cholera, and Yellow Fever
Syphilis: The Great Pretender
General Considerations
The Zoonotic Theory of Syphilis and the Climate
Syphilis: The Great Pretender
Syphilis Transmission and Symptomatology
Syphilis in the Post-antibiotic Era
Syphilis: Maternofetal Mode of Transmission and Clinical Manifestations
Syphilis Diagnosis Testing Recommendations
Treatment
Classic Regimen
Considerations
Cholera Pandemics
Incubation and Clinical Manifestations
Cholera Treatment
Sanitary Interventions to Prevent the Development of Cholera Pandemics
Yellow Fever
Introduction
Transmission and Symptoms
Virus Isolation and Vaccine
Current Outbreaks
Conclusion
References
Syphilis
Cholera
Yellow Fever
5: The World Since 1900: Background to Pandemics in the Present
Introduction
Population
Urbanization
Food Production and Deforestation
Climate Change
Travel
Medical Science
Conclusion
References
6: Influenza Pandemics
The Spanish Flu
Introduction
Deadly Virus Struck in Three Waves
The Virus
Aspirin Poisoning and the Flu
Spanish Flu Pandemic Ends
Virus Mutates into Seasonal Flu
The Flu Takes Heavy Toll on Society
The 1957 Influenza Pandemic
Introduction
Origins
Spread
How Many Were Affected?
Symptoms, Course, and Treatment
The 1957 Pandemic Pathogen: A/H2N2
Pathophysiology
Protective Measures
Vaccine
Mortality
Impact
The 1968 Influenza Pandemic
Introduction
Origins
Spread
How Many Were Affected?
Symptoms and Course
Pathogen: H3N2
Protective Measures
Vaccine
Mortality
Economic Impact and Aftermath
Comparing the 1957 and 1968–1969 Pandemics
Swine Flu Pandemic 2009–2010
Introduction
Viral Pathogen Associated with the Swine Flu Pandemic
Incubation Time and Symptoms
Treatments for Swine Flu
Conclusion
References
Spanish Flu
The 1957 Influenza Pandemic
The 1968 Influenza Pandemic
The Swine Flu Pandemic 2009–2010
7: Coronavirus Pandemics
Severe Acute Respiratory Syndrome (SARS): 2002–2003
Origins
Hong Kong Index Case
The WHO Reacts
Pathogen
Symptoms and Course of the Disease
Diagnosis
SARS-CoV Treatment
Epidemiology
How Did SARS End?
SARS-CoV Vaccine
Impact
Significance of SARS Pandemic
Middle East Respiratory Syndrome (MERS): 2012–Present
Origins
Pathogen
Pathogenesis
Spread
MERS Outside of the Middle East
Symptoms: Course
Diagnosis
Treatment
MERS and Travel
Mortality
Vaccine
Impact
Conclusion
SARS-CoV-2/COVID-19
Introduction
COVID-19 as a Pandemic
Transmission
Symptoms
COVID-19-Associated Acute Respiratory Distress Syndrome (ARDS)
Viral Dose
Early Prediction of Disease Progression in COVID-19 Pneumonia Patients
Indicators of COVID-19 Spread in the Population
Therapeutic Interventions: Potential Treatments
Hypoxia-Inducible Factor (HIF) Activators
HIF-PHD Inhibitors
Vadadustat
Roxadustat
Daprodustat
Treatment Options During Lung Disease (Predominantly for ARDS)
Conclusions and Challenges to the Field
SARS-CoV-2 Variants
Variant Epsilon
Lambda, the “Peruvian” Variant
Omicron
Incubation
Symptoms
Treatments
BA.2 Subvariant
Emerging Variants in Africa
Risk of Recombination Between SARS-CoV-2 Variants
Social Impact of COVID-19
Introduction
COVID-19 and Restriction of Mass Gatherings
COVID-19 and Fear, Anxiety
COVID-19 and Mental Health
COVID-19 and Economy
COVID-19 and Global Ban on Wildlife Trade
COVID-19, a Moment to Step Up for the Vulnerable
The Pandemic and Quarantines Have Accentuated Violence Towards Women
What Is the Doctor’s Role?
Conclusion: How Can Humanity Pull Together in These Times? By the Dalai Lama
COVID-19: Artwork from a Modern Artist
References
Severe Acute Respiratory Syndrome
Middle East Respiratory Syndrome
SARS-CoV-2-COVID-19
SARS-CoV-2 Variants
Social Impact of COVID-19
8: HIV/AIDS, the Pandemic that Went from Initial Despair to a Contained Threat
Introduction
The Consequences of the Presence of HIV in the Human Body
HIV: A Zoonotic Illness
The Primate SIV
Conspiracy Theories About the Initial HIV Transmission to Humans
The Oral Vaccine Theory
The Bush Meat Trade
The Zaire 59 and DRC 60 Strains: Evidence for an Earlier Crossover?
HIV Dissemination
Early HIV Contamination History in the Twentieth Century
Redeeming Patient Zero
How did the Current HIV Pandemic Start?
The Initial Powerless Search for the Cause of Immunodeficiency
The Breakthrough: HIV Identification
Human-to-Human Transmission
Discrimination and Stigmatization
The Treatment of HIV-Infected Individuals
Mother-to-Child Transmission: In Collaboration with Prof. Stephane Blanche
HIV: A Chronic Disease
The Role of Activism in HIV Drug Development and Cure
The HIV Prevention Efforts
HIV Prevention Efforts
The Unfinished Quest for Vaccines
Conclusion
References
9: Vaccines
Introduction
1798: Variola (Edward Jenner)
1885: Rabies (Louis Pasteur)
1921: Tuberculosis (Albert Calmette and Camille Guérin)
1955: Polio (Jonas Salk)
1938: Yellow Fever (Max Theiler)
1963–1969: Measles (John F. Enders); Mumps (Michiaki Takahashi); Meningococcal Infections (Emil C. Gotschlich); Rubella (Stanley A. Plotkin)
1976–Present: Hepatitis B (Philippe Maupas/Maurice R. Hilleman)
2007: Human Papillomaviruses
2019–Present: COVID-19
China
European Union (EU)
United States
Herd Immunity
Why Is Herd Immunity Important?
How Is Herd Immunity Achieved?
Let Us Take COVID-19 as an Example
How Have We Achieved Herd Immunity for Other Infectious Diseases?
What Is the Outlook for Achieving Herd Immunity in the United States?
How Can We Slow the Transmission of COVID-19
References
Vaccines
Herd Immunity
10: Zoonosis
Introduction
The Landscape Anthropization
Travel
Intense Agriculture and Farming
Transmission Chains from Animals to Humans: Hosts and Vectors
Zoonotic Transmission Illustrations
The Impact of Human Activity on the Zoonotic Transmission Chain
The Threat Caused by Tropical Rainforest Exploitation and Destruction
SARS-CoV-2: The Origins of Evil
Is a New Pandemic Inevitable?
Have Humans Given Nature the Tools that Will Ultimately Defeat Mankind?
Should We Fear the Appearance of an Ever-Increasing Number of Zoonosis?
References
11: Hemorrhagic Fevers: Candidates for Pandemics
Chikungunya Fever
The Epidemics and the Virus
The Zoonotic Origin
Chikungunya and Ecological Imbalances
Symptoms
Treatments
Dengue Hemorrhagic Fever
The Epidemics and the Virus
The Zoonotic Origin
Dengue Hemorrhagic Fever and Ecological Imbalance
Symptoms and Cure
Dengue Vaccine
Rift Valley Fever
The Epidemics and the Virus
Animal Transmission
The Rift Valley Hemorrhagic Fever Human Transmission
Symptoms and Incubation
Risk Factors for the Dissemination of the Rift Valley Hemorrhagic Fever
The Crimean-Congo Hemorrhagic Fever
The Epidemics and the Virus
The Zoonotic Origin
Transmission
Symptoms and Incubation
Crimean-Congo Hemorrhagic Fever Treatment
Argentine Hemorrhagic Fever or O’Higgins Disease
The Epidemics and the Virus
The Zoonotic Origin
Symptoms
Vaccine Treatment
Bolivian Hemorrhagic Fever
Epidemics and the Virus
The Zoonotic Origin
Symptoms
Treatment
Prevention
Lassa Hemorrhagic Fever
The Epidemics and the Virus
Lassa Fever History
Ecological Imbalance
Transmission
Treatment
Marburg Hemorrhagic Fever
The Epidemics and the Virus
The Zoonotic Origin
Marburg in History
Transmission of Marburg Hemorrhagic Fever
Pathogenesis of Marburg Hemorrhagic Fever
Symptomatology
Virology
Marburg Hemorrhagic Fever: Lack of Treatment
Ebola Virus Disease
The Epidemics
The Ebola Virus
Ebola Virus in Animals
Ebola Virus Transmission
Ebola Virus History
Ebola-Zaire Outbreaks
Ebola Variants
Ebola-Sudan Variant
Ebola Variant in the Developed World
Ebola Variant Thai Forest
Ebola Bundibugyo
Ebola Virus Symptoms and Incubation Period
Ebola Virus: Consequences and Risks of Complications
Treatment
Ebola from an Epidemic as a Potential Pandemic Threat
Conclusions
References
Chikungunya
Dengue Hemorrhagic Fever
The Rift Valley Hemorrhagic Fever
Crimean-Congo Hemorrhagic Fever
Argentine Hemorrhagic Fever
Bolivian Hemorrhagic Fever
Lassa Hemorrhagic Fever
Ebola
12: Bioterrorism
Definition
Background
What Is a Bioagent?
The Threat of Bioterrorism
Bioterrorism in History
Emerging Diseases and Bioterrorism: A New Concern?
The Definition of Creutzfeldt-Jakob Disease
General Public Awareness About Bioterrorism
The Role of the Health Professionals in Bioterrorism
Biological Warfare: What to Look For?
Symptoms Potentially Associated with Bioterrorism Agents
Hospital Preparedness for Bioterrorism
The Defense of Houston Program
Risk of Outbreaks from Unintended Consequences of Research and Laboratory Accidents
References
13: Climate Change and the Risk of Future Pandemics
Introduction
How Does Climate Change Affect Human Health?
How Does Climate Change Influence the Risks of Infectious Disease Outbreaks?
Examples from History
Vector-Borne Diseases
Mosquitoes
Dengue
Malaria
Zika Virus
Yellow Fever
Ticks
Lyme Disease
Waterborne Diseases
Drinking Water
Vibriosis and Cholera
Coastal Flooding/Heavy Rainfall
Vibriosis from Oysters
Arctic Region
Influenza
What Can Be Done?
References
14: Antibiotic Resistance, a Different Pandemic
Introduction
A Brief History of Antibiotics Discovery
Antibiotic Resistance
Antibiotic Resistance: State of the Emergency
References
15: The Next Pandemic: Challenges and Hopes
Are We Ready for the Next Pandemic?
Challenges
Challenge #1: The Risk for Emergence of New Pandemic Pathogens Is Poorly Controlled
Challenge #2: The Current Global Health Security Infrastructure Needs to Be Improved
Challenge #3: Gain-of-Function Experiments
Challenge #4: Shortage of Healthcare Workers
Challenge #5: Misinformation
Reasons for Being Hopeful
Reason for Being Hopeful #1: COVID-19 Is Still Fresh in Our Minds
Reason for Being Hopeful #2: Advances in Vaccine Development
Reason for Being Hopeful #3: The Pandemic Spurred Innovation
Reason for Being Hopeful #4: The Spirit of Collaboration
Reason for Being Hopeful #5: More Venues for Dissemination of Information About the Pandemic
References
Glossary

Citation preview

2000 Years of Pandemics Past, Present, and Future Claudia Ferreira Marie-Françoise J. Doursout Joselito S. Balingit

123

2000 Years of Pandemics

Claudia Ferreira  •  Marie-­Françoise J. Doursout Joselito S. Balingit

2000 Years of Pandemics Past, Present, and Future

Claudia Ferreira Private Practice Marnes la Coquette, France Joselito S. Balingit Paris, France

Marie-Françoise J. Doursout Department of Anaesthesiology The University of Texas Health Science C Houston, TX, USA

ISBN 978-3-031-10034-5    ISBN 978-3-031-10035-2 (eBook) https://doi.org/10.1007/978-3-031-10035-2 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

In loving memory of Prof. Hans Hoekstra, Prof. Don Cameron, Prof. Ward Casscells and Prof. Thomas F. Burks II

Preface

Never has our modern civilization experienced such an impactful event as the SARS-CoV-2/COVID-19 pandemic. At least half of the Earth’s inhabitants have been directly affected by SARS-CoV-2/COVID-19 in their daily life, requiring major adjustments caused by confinements, travel restrictions, and trade route reorganizations and necessitating new forms of communication and education. These profound changes in our lives have been driven by the threat of sickness and death caused by this pandemic. Had we done nothing, it is likely that 70–100 million people could have died, and health systems could have collapsed under the pressure of hundreds of thousands of very sick people brought to the hospitals. Since January 2020, the COVID-19 pandemic has made worldwide headlines. Through a combination of healthcare management and vaccines, the pandemic is considered to be controlled in most countries at the present time (mid-2022). The lifting of mask mandates and the easing of travel restrictions herald a possible return to normalcy for a majority of the world’s countries. However, the pandemic is still far from over. This situation, however, is not new to humanity. Pandemics have always been present, as long as contagious diseases could propagate through travel, trade, and wars. They have brought more casualties than all wars combined and have impacted the course of history. In most cases, the causes of these pandemics remain unknown, previously considered as acts of God against sinners or more frequently as a result of the other culture’s weakness. For over 2000 years, pandemics have been documented by historians, described as rare but dramatic events, such as the various plagues that have virtually destroyed cities and seriously jeopardized an empire’s or kingdom’s stability. Beginning with the European colonization of North America 500 years ago, and to a greater extent with the start of globalization 200 years ago, epidemics spread farther and faster, with some propagating over continents and some spreading globally. Since then, pandemics have occurred with increasing frequency: a few prior to 1000 CE and then increasing every century until the 1800s and almost every decade since then. At the same time, advances in medical science led to treatments which partially controlled the adverse consequences of the population growth. This was sufficient to ensure the survival of our civilization but fell short in preventing contagious disease outbreaks or effectively curing such diseases.

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Preface

The etiologies of infectious diseases have been discovered over the last 150 years: bacteria, viruses, and other microorganisms taking advantage of the human biology to reproduce and attack the different bodily systems. In the vast majority of cases, humans have been minimally affected by viruses and bacteria. But ultimately, along comes a microorganism that is capable of causing suffering and death and is easily transmitted among humans. Where do they come from? What enabled these microorganisms to reach humans, infect them, and lead to severe illness and even death? There is strong evidence that human behaviors are often responsible for the emergence of these microorganisms that cause pandemic viruses and bacteria to flourish. This history and the questions raised here lead us to view the pandemics of the last 2000  years through a wider lens—not only as diseases with microbiological origins, but also as consequences of humans’ impact on the environment, such as eating habits, travel, and trade. In this book, we illustrate the paths of disease propagation and some of their dire consequences, through individual pandemic histories. We have developed numerous ways to deal with these diseases, from simple but effective isolation measures to complex endeavors, such as global vaccination programs. Ultimately, our objective is to bring awareness of the consequences of human activity on global health and to contribute to informed decisions when choices need to be made for the health of our children and the future of the human race. Marnes la Coquette, France Houston, TX, USA  Paris, France 

Claudia Ferreira Marie-Françoise J. Doursout Joselito S. Balingit

Introduction

Keywords Pandemics; Human development; Changes in natural ecosystems; Migration; Travel; Zoonoses A pandemic is considered as an outbreak of a disease occurring over a wide geographic area, crossing national borders, and affecting a high proportion of the world’s population. Throughout human history, pandemics have caused more deaths than even the most powerful army combat. Through the past 2000 years, pandemics have led to discrimination, confrontations, demographic pressure, starvation, and forced massive immigration. Pandemics occur because of human development, changes in natural ecosystems, migrations, and travels. These factors enable viruses from wildlife to infect humans and facilitate their spread to the general population. Consequently, we must address these harsh conditions by mitigating the effects of zoonoses, preventing future pandemics. In this book, we have analyzed the factors that initiated pandemics over the past 2000  years. During the 1st millennium AD, three main pandemics emerged. The Antonine plague (165–190 ad) [1], caused by the hemorrhagic smallpox, killed 5 million people and contributed to the downfall of the Roman Empire [2]. Four hundred years later, the Justinian plague [3] caused by Yersinia pestis decimated the Byzantine Empire [4], killing 50 million people [5, 6]. Between 1346 and 1353, the Black Death, also caused by the Yersinia pestis bacteria, took 200 million lives [7–9]. With the American colonization, Europeans brought several infectious diseases to the New World including Yersinia pestis, smallpox, influenza, and enteric salmonella, among others [10], subsequently devastating 90% of the local Native American population and bringing down the Mayan and Aztec civilizations [11]. Since 1497, several outbreaks of cholera have been reported worldwide with a mortality of 54–68% in the absence of treatment [12]. From 1629 to 1667, outbreaks of Yersinia pestis were reported mostly in Europe, killing about 1/3 of the population [13]. During the late nineteenth century and through the mid-twentieth century, several influenza outbreaks emerged. Combined, the Russian flu (H2N2), Spanish flu (H1N1), Asian flu (H2N2), and Hong Kong flu (H3N2) killed around two billion people worldwide [14]. Previously unknown viruses, such as Marburg, Ebola, and HIV, came into public awareness in the mid-1970 [15]. From 2002 to present, influenza virus and several coronavirus pandemics have emerged worldwide. Influenza

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(H1N1), swine flu, SARS, MERS, and SARS-CoV-2/COVID-19 have killed and infected several million people [16]. What is noteworthy is that in the last 100 years, intervals between pandemics have become shorter. In this book, we have identified three main causes for the development of pandemics: 1. Human development, including trade, commerce, intensive agricultural methods, animal domestication, farming, and crowded cities 2. Changes in natural ecosystems, including climate change, natural disasters, human interface with wild ecosystems, and deforestation 3. Migration and transportation, which we have defined as human movement caused by wars, political and economic displacement, natural disasters, business travel, and vacation travel It is important to note that with the advent of the industrial era, pandemics’ timeline has shortened. For instance, SARS-CoV-2/COVID-19 is certainly not the last pandemic we will face, which is why it is of paramount importance to learn from the various missteps made over the past 2000 years. Therefore, it is urgent to educate the population and bring a heightened awareness to the scientific community, public health officials, as well as governments to plan for the next pandemic. Never has been so striking to our modern civilization the negative impact of the SARS-CoV-2 pandemic in society. Over half of the Earth’s inhabitants have seen the direct impact of a communicable disease in their daily life, through travel restrictions, trade route reorganizations, new forms of communication, new ways to reorganize societies, and even facing mandatory confinements [17]. These profound changes have been driven by the sickness and death threat caused by the SARS-CoV-2 pandemic. The pandemic has made major headlines in January 2020, and as of January 2023 with the Omicron variant which, as of now, is far from being controlled. Could we have done better? It is thinkable that 70–100 million people could have died from the disease, and the health systems of various nations could have collapsed under the pressure of hundreds of thousands of sick people brought to the hospitals [18]. This situation is, however, not new to humanity. Pandemics have always happened, as long as communicable diseases could propagate through travel, natural disasters, trade, and war. They have brought more casualties than all wars cumulated and have impacted the course of history’s civilizations dealing with imported epidemics. In most cases, the causes remained unknown, considered as acts of God to punish sinners or most frequently as the other’s fault [19]. In the last 2000 years, pandemics have been mainly documented by physicians and historians, although described as rare but dramatic events, such as the various plagues destroying cities and seriously endangering empires’ or kingdoms’ stability. Five hundred years ago, we developed the ability to sail around the globe, enabling the epidemics to spread over continents, in some cases becoming global. Interestingly, the frequency of pandemics slowly increased until 1000 ad; then the pace accelerated, occurring every century until 1800 and almost every decade in the last 70 years. At the same time, advances in medical sciences led to cures, partially managing adverse consequences of population growth. This health management

Introduction

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was indeed efficient enough to ensure steady development of the civilizations, but far from avoiding contagious disease outbreaks, nor curing such diseases efficiently [20]. The causes of the diseases have been found during the past 100–150 years: bacteria and viruses taking advantage of the human biology to reproduce and attack the immune system. However, these biological organisms have to first reach humans before wreaking havoc. In the vast majority, humans are affected by viruses and bacteria by acute self-limited infections. Where do they come from? What are the factors that enhance their capability to reach and then transmit between humans? There is strong evidence that human activities and behaviors are one of the main causes that contribute to the development of pandemics. This vision and the questions raised led us to review through a broader angle the past pandemics over 2000 years, not only as diseases and their microbiological origins, but also as consequences of our impact on the environment, such as eating habits, travel, and trade. In this book, we have illustrated the path of the propagation of diseases causing pandemics and its dire consequences, through individual human histories and documents from local physicians, historians, and philosophers who witnessed and described previous pandemics. Scientists have also developed tools to lessen diseases, using initially simple but efficient isolation measures such as (1) quarantines to control the spread of diseases, (2) identification of pathogens, (3) treatments, and (4) effective global vaccination programs to eradicate pandemics. Ultimately, our objective is to bring awareness for the future when choices have to be made for our children and the future of mankind. Progress in science and technology has been important to understand, improve, and mitigate healthcare and the social impact of pandemics. If we carefully look at the past, a little more than 100 years ago, the world faced the deadliest pandemic in human history that gripped the world’s attention. The culprit then was an H1N1 influenza virus that became known as the “Spanish flu.” In only 2 years, 1918–1920, the pandemic claimed at least 50 million lives, after having infected around half billion people, one-third of the world’s population at the time. Approximately 675,000 people died in the United States alone. The Spanish flu’s first cluster, identified in the United States, was detected in soldiers stationed at an army base in Kansas during the spring of 1918 [21]. The mortality patterns of the 1918–1920 Spanish flu differed from SARS-CoV-2/COVID-19. In both pandemics, individuals over age 65 were at particular risks, but children younger than 5 years old and adults between 20 and 40 years old also faced a high rate of death from the Spanish flu. Spanish flu was particularly virulent among young adults and women with childbearing potential or who were pregnant, while SARS-CoV-2/COVID-19 was particularly deadly for older adults and patients with previous comorbidities. However, the shape of the pandemic was altered when younger people got admitted into intensive care units, who later died. Moreover, the ability of SARS-CoV-2/COVID-19 to quickly mutate led us to apply more extensive epidemiological methods to identify clusters of new viral variants. Beyond the high death toll, the full impact of the 1918–1919 pandemic (also known as the Spanish flu—first wave) would not be understood until more than 60 years later. In 2009, an interesting study from Finch and Crimmins analyzed epidemiological data on individuals born in 1919,

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newborns, or second- or third-trimester fetuses during the height of the Spanish flu pandemic. Results revealed that these individuals had approximately 25% more heart disease after age 60, as well as increased diabetes risk, compared to a similar cohort of individuals not born in 1919, including those who were older infants during the pandemic [22]. A major bias on this study was the fact that researchers did not have data on individuals exposed to the flu either in utero or as offspring in 1918–1919. The results were nevertheless strikingly different between the two age cohorts. In addition to higher levels of ischemic heart disease as well as diabetes in patients who could have been exposed prenatally, the US census data indicated that the cohort of children born in early 1919 had less levels of education and lower economic productivity over their lifetime, suggesting a higher level of developmental impairment or other long-term health issues in those with prenatal flu exposure at the height of the outbreak. In addition, adult’s height (as recorded at World War II enlistment) was also slightly lower for the 1919 birth cohort than for those born in adjacent years, suggesting that overall growth was also negatively affected.

Zoonosis and Pandemics According to the Merriam Webster’s medical dictionary, zoonosis is defined as an infection or disease that is transmissible from animals to humans under natural conditions [23]. Seas and rainforests are recognized as the lungs of the Earth, standing as the main indicators of the human population’s health. For instance, in only 5 years (2010–2015), six million hectares of rainforests were destroyed by humans, not counting natural disasters as flooding and natural fires due to high recorded temperatures [24]. Since 1990, above-average temperatures in the United States due to “El Niño” have been associated with increased outbreaks of zoonotic illnesses, for example, hantaviruses, a deadly disease carried out by mice and rats causing a severe pulmonary syndrome in humans [25]. When SARS-CoV-2/COVID-19 struck, the scientific community understood that another pandemics would emerge, and hints gave a sense of “déjà vu”: primates and the origins of HIV, civets and SARS, bats and Ebola, and camels and MERS, among many others. The human consumption of exotic animals, taken from their natural habitats, for either economical or cultural demand, has brought despair and tragedy for humankind [26]. SARS-CoV-2/COVID-19 and other novel disease outbreaks have been triggered by accelerated wildlife trade and decreasing wild habitat. Wildlife is indeed the natural host to several thousands of viruses which, as a natural consequence of their replication processes, mutate. Continued contact between humans and wildlife provide an opportunity for these viruses to hurdle species, creating pandemics as previously seen in the case of HIV, hemorrhagic fevers, coronavirus, avian influenza, and most recently SARS-CoV-2/COVID-19 [27]. These trends are driven by commercial demand, weak wildlife protection protocols, and destruction of natural habitats.

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Pandemics: The Price of Progress The illegal trade of pangolins is not just an environmental problem. Pangolins are the most trafficked mammals in the world, representing a threat to international health. Pangolins carry viruses remarkably close to coronaviruses and may have acted as one of the intermediary carriers of COVID-19 [28]. Pangolins are trafficked for their meat, organs, and fetuses which are expensive exotic food. Moreover, their scales are ground into powder to be used as activating ingredients in a variety of traditional Chinese medicines. As a result, 1  kg of Pangolin is worth more than $3500  USD in the black market [29]. Pangolin powder is traditionally used in Chinese medicine to disperse blood stasis, reduce swelling, promote discharge of pus for abscesses and boils, as well as treat pain due to rheumatism/arthritis [30]. Today, the world’s population exceeds 7 billion inhabitants, about 13.7 persons/ km2 or 35 persons/miles2, most of them living in highly populated cities such as Asian cities [31]. Through the past 2000 years, humans have been forced to change agricultural methods to provide food that helped to conquer new territories for human development. For instance, food production that includes human and animal excrements, used as fertilizers, led to an easier transmission of already existing pathogens. The development of intensive agriculture allowed infectious agents to be transmitted from animals to humans [32]. As the Arctic and Antarctic glaciers melt, it is believed that new viral and bacterial pathogens will resurface. Recently, researchers from the Byrd Polar and Climate Research Center, Ohio State University (Columbus, Ohio), USA, discovered ancient bacteria in two melting plateau ice cores near Tibet [33]. Well-­known bacteria mostly present in the human microbiome such as Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes are believed to be the most important bacterial communities found in glaciers. Methylobacterium are gram-negative bacilli present in oceans [34], as well as glacier soils [35], lakes [36], and deserts [37]. This kind of pathogens are considered of great severity particularly in immunocompromised individuals. In the article “Glacier ice archives fifteen-thousand-­year-old viruses” by Zhi-Ping Zhong et  al. [33], the authors discovered over 30 viruses hidden in frozen ice, most of them never detected before. Campaigns to reduce the risks of pandemics are desperately needed to address the root of all zoonotic outbreaks, rampant wildlife trade, and the destruction of natural habitats. Unless these causes are suitably addressed in pandemic preparedness responses and strategies, none of today’s new vaccines will work against tomorrow’s new viruses. Importantly, it is predicted that by 2050, the Earth will be home of 10 billion people. This high number leads us to assume that to feed a large population, intensive animal breeding and agricultural measures will increase, leading populations to concentrate in crowded cities, producing even more aggravation to natural ecosystems. As an estimate, the United Nations quotes that two in three people will live in urban areas by 2050. The role of wildlife in emerging and reemerging zoonotic diseases has been well documented in scientific literature. Its frequency seems to have been increasing exponentially since the twentieth century AD.  For example, during the first

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1000  years of pandemics, we observed three main pandemics with a duration of about 500 years. During the Middle Ages until the twentieth century, we observed an increase in pandemics over a shorter period of time, accelerated by trade, wars, and colonization of new lands. At the beginning of the twenty-first century, the frequency of new pandemics accelerated, with a new pandemic occurring every 10 years. Since 1950, new pathogens have emerged from animals and are transmitted to humans due to globalization. Pandemics need to be seen from multiple disciplinary aspects: medicine, biology, veterinary sciences, economics, and demographics, among others. To understand how humans relate to natural habitat conditions is an important way to understand and prevent the way pandemics develop and expand. The history of previous pandemics needs to be reconsidered in order to learn from mistakes of the past, building a better future. “Two Thousand Years of Pandemics” seems like a long litany of misery inflicted on humans by countless viruses, bacteria, and protozoa. However, this is only true from a point of view centered on humans alone. We cannot act as if planet Earth exists solely for the benefit of Homo sapiens. We share the planet with a multitude of species of plants, animals, microorganisms, and other living creatures yet to be discovered. We are all bound together in one interconnected system, and it would be the height of folly to think that we can change one part of this interconnected system (for the purposes of food, progress, pleasure, or profit) without experiencing some consequences down the line. Pandemics are an example of how extreme these consequences can be. Pandemics are a sign that something has been disrupted. Pandemics are a sign that we have created an imbalance, and the microorganisms, in their own limited way, are seeking a new balance. Are pandemics inevitable? The painful answer seems to be “yes”. The advances necessary for our standard of living to progress from 2000 years ago to the present—from tropical fruits imported halfway around the world to international air travel and modern surgery—have disrupted some invisible balance and enabled the microscopic cohabitants of our planet to spread and do what their genetic instructions unfailingly tell them to do. Pandemics are the price of progress. If we are to stave off the next pandemic, we must learn more about how the systems of interconnectedness among the living organisms in our planet work and understand that we, as humans, cannot simply disrupt these systems for short-sighted, human-centric reasons without facing consequences. References 1. Littman RJ, Littman ML. Galen and the Antonine plague. American J Philol 1973;94:243–55. 2. Sabbatani S, Fiorino S.  La peste antonina e il declino dell'Impero Romano. Ruolo della guerra partica e della guerra marcomannica tra il 164 e il 182 d.c. nella diffusione del contagio [The Antonine Plague and the decline of the Roman Empire]. Infez Med. 2009;17(4):261–275. 3. Baras C. The year of darkness. New Scientist 2014 ; 221 :, pp. 34–38.

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4. Hadhazy A. Plague prequels and sequels. Nat History, Vol: 122, 2014, p. 6. 5. Harbeck M, et al. Yersinia pestis DNA from skeletal remains from the 6th century AD reveals insights into Justinianic plague. PLOS Pathogens. 9 ; 2013, : 1–8. 6. North J.  The death toll of Justinian’s plague and its effect on the byzantine empire. Armstrong Undergraduate J History 3(1) (Jan. 2013). 7. Huremović D.  Brief history of pandemics (pandemics throughout history). Psychiatry Pandem. 2019;7–35. Published 2019 May 16. doi:10.1007/978-3-030-15346-5_2 8. McNeill BP, Dunkelberg H. The history of the plague and the research on the causative agent Yersinia pestis. Int J Hyg Environ Health. 2004;207(2):165–178. 9. Duncan CJ, Scott S.  What caused the Black Death? Postgraduate Medical Journal 2005;81:315–320. 10. Bianchine PJ, Russo TA. The role of epidemic infectious diseases in the discovery of America. Allergy Proc. 1992 Sep-Oct;13(5):225–32. 11. Darling MI, Donoghue HD. Insights from paleomicrobiology into the indigenous peoples of pre-colonial America— a review. Mem Inst Oswaldo Cruz. 2014;109(2):131–139. 12. Matthew Phelps, Mads Linnet Perner, Virginia E Pitzer, Viggo Andreasen, Peter K. M. Jensen, Lone Simonsen Cholera epidemics of the past offer new insights into an old Enemy. J Infect Dis. 2018; 217(4): 641–649. Published online 2017 Nov 20. 13. Glatter KA, Finkelman P. History of the Plague: An Ancient Pandemic for the Age of COVID-19. Am J Med. 2021;134(2):176–181. doi: 10.1016/j. amjmed.2020.08.019 14. Kilbourne ED.  Influenza pandemics of the 20th century. Emerg Infect Dis. 2006;12(1):9–14. doi:10.3201/eid1201.051254. 15. Snowden FM.  Emerging and re-emerging diseases: a historical perspective. Immunol Rev. 2008;225(1):9–26. doi: 10.1111/j.1600-065X.2008.00677.x 16. Peeri, Noah C et al. “The SARS, MERS and novel coronavirus (COVID-19) epidemics, the newest and biggest global health threats: what lessons have we learned? Int J Epidemiol 2020 ; 49(3) (2020): 717–726. doi: 10.1093/ije/dyaa033 17. Ibn-Mohammed T, Mustapha KB, Godsell J, et  al. A critical analysis of the impacts of COVID-19 on the global economy and ecosystems and opportunities for circular economy strategies. Resour Conserv Recycl. 2021;164:105169. doi: 10.1016/j.resconrec.2020.105169. 18. https://www.who.int/director-­g eneral/speeches/detail/director-­g eneral-­s -­ opening-­r emarks-­a t-­t he-­w orld-­h ealth-­a ssembly%2D%2D-­2 4-­m ay-­2 021 (Accessed 30 Dec 2021). 19. https://www.newyorker.com/news/q-­and-­a/how-­pandemics-­change-­history (Accessed 18 Nov 18 2021). 20. Diamond J. Vintage; London: 1998. Guns, germs and steel: a short history of everybody for the last 13000 years. 21. Barry JM.  The site of origin of the 1918 influenza pandemic and its public health implications. J Transl Med. 2004;2(1):3. Published 2004 Jan 20. doi: https://doi.org/10.1186/1479-­5876-­2-­3.

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22. https://gero.usc.edu/2020/12/08/century-­covid-­pandemic-­risk/ Consulted November 20, 2021. 23. https://www.merriam-­webster.com/medical (Accessed 30 Dec 2021). 24. https://www.who.int/globalchange/publications/climchange.pdf (Consulted November 2, 2021). 25. Morand S, Owers KA, Waret-Szkuta A, McIntyre KM, Baylis M. Climate variability and outbreaks of infectious diseases in Europe. Sci Rep. 2013;3:1774. doi: https://doi.org/10.1038/srep01774. 26. Brennan, Andrew and Yeuk-Sze Lo, “Environmental Ethics”, The Stanford Encyclopedia of Philosophy (Winter 2021 Edition), Edward N.  Zalta (ed.), forthcoming https://plato.stanford.edu/archives/win2021/entries/ ethics-­environmental/. 27. Baker RE, Mahmud AS, Miller IF, et al. Infectious disease in an era of global change. Nat Rev Microbiol (2021). https://doi.org/10.1038/s41579-­021-­00639-­z. 28. Lam TTY, Jia N, Zhang YW, et al. Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins. Nature 583, 282–285 (2020). https://doi. org/10.1038/s41586-­020-­2169-­0. 29. Kelly G.  Pangolins: 13 facts about the world’s most hunted animal. The Telegraph [Internet]. 2016 Mar 15 [cited 2021 Dec 18]; Available from: https://www.telegraph.co.uk/science/2016/03/15/pangolins-13-­facts­about-­the-­worlds-­most-­hunted-­animal/. 30. https://wildaid.org/wp-­content/uploads/2017/09/WildAid-­Pangolins-­on-­the-­ Brink.pdf (Consulted November 21 2021). 31. Matt Rosenberg Population Density. Geography.about.com. March 2, 2011. Retrieved on December 10, 2011. 32. Jones BA, Grace D, Kock R, Alonso S, Rushton J, Said MY, McKeever D, Mutua F, Young J, McDermott J, Pfeiffer DU. (2013). Zoonosis emergence linked to agricultural intensification and environmental change. Proc Natl Acad Sci U S A 110(21), 8399–8404. https://doi.org/10.1073/pnas.1208059110. 33. Zhong ZP, Tian F, Roux S, et al. Glacier ice archives nearly 15,000-year-old microbes and phages. Microbiome 2021; 9  : 160. https://doi.org/10.1186/ s40168-­021-­01106-­w. 34. Brum JR, Ignacio-Espinoza JC, Roux S, Doulcier G, Acinas SG, Alberti A, et al. Patterns and ecological drivers of ocean viral communities. Science. 2015; 348(6237):1261498. https://doi.org/10.1126/science.1261498. 35. Zhong ZP, Rapp JZ, Wainaina JM, Solonenko NE, Maughan H, Carpenter SD, et  al. Viral ecogenomics of Arctic cryopeg brine and sea ice. mSystems. 2020;5:e00246–20. 36. Han LL, Yu DT, Zhang LM, Wang JT, He JZ. Unique community structure of viruses in a glacier soil of the Tianshan Mountains, China. J Soils Sediments. 2017;17(3):852–60. https://doi.org/10.1007/s11368-­016-­1583-­2. 37. Adriaenssens EM, Van Zyl L, De Maayer P, Rubagotti E, Rybicki E, Tuffin M, et al. Metagenomic analysis of the viral community in Namib Desert hypoliths. Environ Microbiol. 2015;17(2):480–95. https://doi.org/10.1111/1462-­2920. 12528.

Acknowledgments

Prof. Donald Cameron, Australia Prof. Stéphane Blanche Paris, France Prof. Kentaro Sugano, Tochigi, Japan Dr. Patricia Enel Marseille, France Dr. Florence Brunel Lyon, France Dr. Marilou Cardenas Turanzas, Houston, Texas, USA Journalist Agustin Barral, Paris, France Dr. Marianne Besson London, UK Dr. Pierre-Yves Chenet Paris, France Dr. Alicia Farinatti, Buenos Aires, Argentine

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1

 The First 1000 Years CE of Pandemics: Smallpox and Plague��������������   1 Introduction������������������������������������������������������������������������������������������������    1 The Antonine Plague: Smallpox (165–190 CE)����������������������������������������    1 Description of the Disease ������������������������������������������������������������������������    2 Propagation of the Disease������������������������������������������������������������������������    4 Perception of the Disease in the Roman Empire ��������������������������������������    4 Fatality Rates ��������������������������������������������������������������������������������������������    5 Attempts for Treatments����������������������������������������������������������������������������    6 Justinian Plague (541–749 CE)������������������������������������������������������������������    7 The Origin and Propagation of the Pandemic��������������������������������������������    8 The Pandemic and the Yersinia pestis Bacteria������������������������������������������    9 The High Fatality Rate of the Justinian Plague ����������������������������������������    9 Justinian Plague and Climate Change��������������������������������������������������������   10 The Social and Cultural Impact of the Justinian Pest��������������������������������   10 Justinian Plague and the Divine Punishment ��������������������������������������������   11 Japanese Smallpox Epidemic (733–737 CE)��������������������������������������������   12 The Disease Outbreak and Propagation����������������������������������������������������   13 The Impact of the Japanese Smallpox on Society ������������������������������������   13 References��������������������������������������������������������������������������������������������������   14

2

 The Plagues Pandemics: 2000 Years of Recurrent Devastations: The Black Death ����������������������������������������������������������������  17 Introduction������������������������������������������������������������������������������������������������   17 The Disease and Bacteria Yersinia pestis��������������������������������������������������   17 The Plague Zoonosis����������������������������������������������������������������������������������   18 The Clinical Characteristics of the Plague������������������������������������������������   19 The Black Death (1346–1353)������������������������������������������������������������������   20 The Initial Conditions: When Asia Meets Europe in Caffa ����������������������   20 The Tartar Horsemen and the Black Death������������������������������������������������   22 The Biological Warfare Attack and the Consequences������������������������������   23 Escaping Hell: The Propagation Towards Europe Through the Mediterranean��������������������������������������������������������������������������������������������   23 The Black Death Arrives in Italy: The Implementation of Quarantine������   25 The Black Death Strikes Stronger in the United Kingdom������������������������   29 xix

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The Search for Cause and Remedies During the Black Death������������������   31 The Miasma Theory ����������������������������������������������������������������������������������   32 The Plague Doctors������������������������������������������������������������������������������������   32 The Search for Redemption ����������������������������������������������������������������������   34 The Black Death and the Blame on Others������������������������������������������������   35 The Aftermath of the Black Death ������������������������������������������������������������   35 The Third Plague Pandemic����������������������������������������������������������������������   37 The Plague in the Twentieth and Twenty-First Centuries: The Endemic Situation ����������������������������������������������������������������������������������������������������   37 Global Distribution of Natural Plague Foci ������������������������������������������   39 Treatment ��������������������������������������������������������������������������������������������������   40 The Plague and the Antibiotic Resistance Problem ����������������������������������   54 References��������������������������������������������������������������������������������������������������   55 3

 Outbreaks in the New World: 1492–Mid-­Nineteenth Century��������������  59 Introduction������������������������������������������������������������������������������������������������   59 Features of Infectious Disease Outbreaks in the New World��������������������   59 The Indigenous Populations of the New World Experienced Disease Outbreaks Before the Europeans Arrived ��������������������������������   59 There Was a Large Scale of Deaths Which Affected the Indigenous Populations of the New World��������������������������������������������   60 There Were Many Diseases Introduced into the New World ����������������   62 There Were Multiple Sources of Disease Outbreaks ����������������������������   63 There Were Multiple Outbreaks of the Same Disease ��������������������������   64 The Native Populations Were Not Passive Victims of Disease��������������   64 There Was Transmission of Disease from the New World to Europe����������������������������������������������������������������������������   65 Disease Was Used as a Weapon in Conflicts in the New World������������   67 The Colonial Administrations Used Variolation and Vaccination to Fight Smallpox����������������������������������������������������������������������������������   70 Conclusion ������������������������������������������������������������������������������������������������   71 References��������������������������������������������������������������������������������������������������   71

4

 Syphilis, Cholera, and Yellow Fever ��������������������������������������������������������  77 Syphilis: The Great Pretender��������������������������������������������������������������������   77 General Considerations��������������������������������������������������������������������������   77 The Zoonotic Theory of Syphilis and the Climate��������������������������������   77 Syphilis: The Great Pretender����������������������������������������������������������������   78 Syphilis Transmission and Symptomatology����������������������������������������   78 Syphilis in the Post-antibiotic Era���������������������������������������������������������   80 Syphilis: Maternofetal Mode of Transmission and Clinical Manifestations����������������������������������������������������������������������������������������   81 Syphilis Diagnosis Testing Recommendations��������������������������������������   81 Treatment ����������������������������������������������������������������������������������������������   82 Classic Regimen��������������������������������������������������������������������������������   82 Considerations����������������������������������������������������������������������������������������   82

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Cholera Pandemics������������������������������������������������������������������������������������   82 Incubation and Clinical Manifestations ������������������������������������������������   86 Cholera Treatment����������������������������������������������������������������������������������   86 Sanitary Interventions to Prevent the Development of Cholera Pandemics����������������������������������������������������������������������������������������������   88 Yellow Fever����������������������������������������������������������������������������������������������   88 Introduction��������������������������������������������������������������������������������������������   88 Transmission and Symptoms ����������������������������������������������������������������   88 Virus Isolation and Vaccine��������������������������������������������������������������������   91 Current Outbreaks����������������������������������������������������������������������������������   91 Conclusion ������������������������������������������������������������������������������������������������   92 References��������������������������������������������������������������������������������������������������   92 5

 The World Since 1900: Background to Pandemics in the Present��������  97 Introduction������������������������������������������������������������������������������������������������   97 Population��������������������������������������������������������������������������������������������������   97 Urbanization����������������������������������������������������������������������������������������������   99 Food Production and Deforestation ����������������������������������������������������������  100 Climate Change������������������������������������������������������������������������������������������  100 Travel ��������������������������������������������������������������������������������������������������������  100 Medical Science ����������������������������������������������������������������������������������������  101 Conclusion ������������������������������������������������������������������������������������������������  102 References��������������������������������������������������������������������������������������������������  102

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Influenza Pandemics���������������������������������������������������������������������������������� 105 The Spanish Flu ����������������������������������������������������������������������������������������  105 Introduction��������������������������������������������������������������������������������������������  106 Deadly Virus Struck in Three Waves ����������������������������������������������������  109 The Virus������������������������������������������������������������������������������������������������  110 Aspirin Poisoning and the Flu���������������������������������������������������������������  111 Spanish Flu Pandemic Ends������������������������������������������������������������������  112 Virus Mutates into Seasonal Flu������������������������������������������������������������  112 The Flu Takes Heavy Toll on Society����������������������������������������������������  113 The 1957 Influenza Pandemic��������������������������������������������������������������������  114 Introduction��������������������������������������������������������������������������������������������  114 Origins����������������������������������������������������������������������������������������������������  114 Spread����������������������������������������������������������������������������������������������������  114 How Many Were Affected?��������������������������������������������������������������������  115 Symptoms, Course, and Treatment��������������������������������������������������������  116 The 1957 Pandemic Pathogen: A/H2N2������������������������������������������������  117 Pathophysiology������������������������������������������������������������������������������������  119 Protective Measures ������������������������������������������������������������������������������  120 Vaccine��������������������������������������������������������������������������������������������������  121 Mortality������������������������������������������������������������������������������������������������  121 Impact����������������������������������������������������������������������������������������������������  122

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The 1968 Influenza Pandemic��������������������������������������������������������������������  123 Introduction��������������������������������������������������������������������������������������������  123 Origins����������������������������������������������������������������������������������������������������  123 Spread����������������������������������������������������������������������������������������������������  123 How Many Were Affected?��������������������������������������������������������������������  124 Symptoms and Course ��������������������������������������������������������������������������  124 Pathogen: H3N2������������������������������������������������������������������������������������  125 Protective Measures ������������������������������������������������������������������������������  125 Vaccine��������������������������������������������������������������������������������������������������  127 Mortality������������������������������������������������������������������������������������������������  127 Economic Impact and Aftermath ����������������������������������������������������������  128 Comparing the 1957 and 1968–1969 Pandemics����������������������������������  128 Swine Flu Pandemic 2009–2010 ��������������������������������������������������������������  129 Introduction��������������������������������������������������������������������������������������������  129 Viral Pathogen Associated with the Swine Flu Pandemic ��������������������  129 Incubation Time and Symptoms������������������������������������������������������������  130 Treatments for Swine Flu����������������������������������������������������������������������  131 Conclusion ������������������������������������������������������������������������������������������������  132 References��������������������������������������������������������������������������������������������������  132 7

Coronavirus Pandemics���������������������������������������������������������������������������� 141 Severe Acute Respiratory Syndrome (SARS): 2002–2003������������������������  141 Origins����������������������������������������������������������������������������������������������������  141 Hong Kong Index Case��������������������������������������������������������������������������  141 The WHO Reacts ����������������������������������������������������������������������������������  144 Pathogen������������������������������������������������������������������������������������������������  144 Symptoms and Course of the Disease����������������������������������������������������  146 Diagnosis������������������������������������������������������������������������������������������������  147 SARS-CoV Treatment ��������������������������������������������������������������������������  148 Epidemiology����������������������������������������������������������������������������������������  148 How Did SARS End?����������������������������������������������������������������������������  149 SARS-CoV Vaccine ������������������������������������������������������������������������������  150 Impact����������������������������������������������������������������������������������������������������  150 Significance of SARS Pandemic������������������������������������������������������������  151 Middle East Respiratory Syndrome (MERS): 2012–Present��������������������  152 Origins����������������������������������������������������������������������������������������������������  152 Pathogen������������������������������������������������������������������������������������������������  153 Pathogenesis������������������������������������������������������������������������������������������  155 Spread����������������������������������������������������������������������������������������������������  155 MERS Outside of the Middle East��������������������������������������������������������  157 Symptoms: Course ��������������������������������������������������������������������������������  159 Diagnosis������������������������������������������������������������������������������������������������  160 Treatment ����������������������������������������������������������������������������������������������  160 MERS and Travel����������������������������������������������������������������������������������  161 Mortality������������������������������������������������������������������������������������������������  163 Vaccine��������������������������������������������������������������������������������������������������  164

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Impact����������������������������������������������������������������������������������������������������  165 Conclusion ��������������������������������������������������������������������������������������������  165 SARS-CoV-2/ COVID-19��������������������������������������������������������������������������  166 Introduction��������������������������������������������������������������������������������������������  166 COVID-19 as a Pandemic����������������������������������������������������������������������  166 Transmission������������������������������������������������������������������������������������������  169 Symptoms����������������������������������������������������������������������������������������������  171 COVID-19-Associated Acute Respiratory Distress Syndrome (ARDS)��������������������������������������������������������������������������������  173 Viral Dose����������������������������������������������������������������������������������������������  174 Early Prediction of Disease Progression in COVID-19 Pneumonia Patients��������������������������������������������������������������������������������  175 Indicators of COVID-19 Spread in the Population��������������������������������  175 Therapeutic Interventions: Potential Treatments ����������������������������������  178 Hypoxia-Inducible Factor (HIF) Activators������������������������������������������  179 HIF-PHD Inhibitors ������������������������������������������������������������������������������  180 Vadadustat ����������������������������������������������������������������������������������������  180 Roxadustat����������������������������������������������������������������������������������������  180 Daprodustat ��������������������������������������������������������������������������������������  181 Treatment Options During Lung Disease (Predominantly for ARDS)��  181 Conclusions and Challenges to the Field ����������������������������������������������  183 SARS-CoV-2 Variants��������������������������������������������������������������������������������  183 Variant Epsilon��������������������������������������������������������������������������������������  185 Lambda, the “Peruvian” Variant������������������������������������������������������������  185 Omicron ������������������������������������������������������������������������������������������������  186 Incubation����������������������������������������������������������������������������������������������  187 Symptoms����������������������������������������������������������������������������������������������  187 Treatments����������������������������������������������������������������������������������������������  187 BA.2 Subvariant ������������������������������������������������������������������������������������  188 Emerging Variants in Africa������������������������������������������������������������������  189 Risk of Recombination Between SARS-CoV-2 Variants����������������������  190 Social Impact of COVID-19����������������������������������������������������������������������  190 Introduction��������������������������������������������������������������������������������������������  190 COVID-19 and Restriction of Mass Gatherings������������������������������������  191 COVID-19 and Fear, Anxiety����������������������������������������������������������������  191 COVID-19 and Mental Health ��������������������������������������������������������������  193 COVID-19 and Economy����������������������������������������������������������������������  194 COVID-19 and Global Ban on Wildlife Trade��������������������������������������  194 COVID-19, a Moment to Step Up for the Vulnerable ��������������������������  195 The Pandemic and Quarantines Have Accentuated Violence Towards Women������������������������������������������������������������������������������������  195 What Is the Doctor’s Role?��������������������������������������������������������������������  196 Conclusion: How Can Humanity Pull Together in These Times? By the Dalai Lama ��������������������������������������������������������������������������������  196 COVID-19: Artwork from a Modern Artist ����������������������������������������������  196 References��������������������������������������������������������������������������������������������������  197

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 HIV/AIDS, the Pandemic that Went from Initial Despair to a Contained Threat����������������������������������������������������������������� 221 Introduction������������������������������������������������������������������������������������������������  221 The Consequences of the Presence of HIV in the Human Body ��������������  222 HIV: A Zoonotic Illness ����������������������������������������������������������������������������  223 The Primate SIV����������������������������������������������������������������������������������������  224 Conspiracy Theories About the Initial HIV Transmission to Humans������  224 The Oral Vaccine Theory ����������������������������������������������������������������������  224 The Bush Meat Trade��������������������������������������������������������������������������������  225 The Zaire 59 and DRC 60 Strains: Evidence for an Earlier Crossover?����  226 HIV Dissemination������������������������������������������������������������������������������������  227 Early HIV Contamination History in the Twentieth Century��������������������  227 Redeeming Patient Zero������������������������������������������������������������������������  227 How did the Current HIV Pandemic Start? ����������������������������������������������  229 The Initial Powerless Search for the Cause of Immunodeficiency������������  231 The Breakthrough: HIV Identification������������������������������������������������������  231 Human-to-Human Transmission����������������������������������������������������������������  233 Discrimination and Stigmatization������������������������������������������������������������  233 The Treatment of HIV-Infected Individuals����������������������������������������������  235 Mother-to-Child Transmission: In Collaboration with Prof. Stephane Blanche������������������������������������������������������������������������������  237 HIV: A Chronic Disease����������������������������������������������������������������������������  238 The Role of Activism in HIV Drug Development and Cure����������������������  238 The HIV Prevention Efforts ����������������������������������������������������������������������  238 HIV Prevention Efforts������������������������������������������������������������������������������  239 The Unfinished Quest for Vaccines������������������������������������������������������������  240 Conclusion ������������������������������������������������������������������������������������������������  241 References��������������������������������������������������������������������������������������������������  241

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Vaccines������������������������������������������������������������������������������������������������������ 245 Introduction������������������������������������������������������������������������������������������������  245 1798: Variola (Edward Jenner)������������������������������������������������������������������  246 1885: Rabies (Louis Pasteur) ��������������������������������������������������������������������  247 1921: Tuberculosis (Albert Calmette and Camille Guérin) ����������������������  250 1955: Polio (Jonas Salk)����������������������������������������������������������������������������  253 1938: Yellow Fever (Max Theiler) ������������������������������������������������������������  255 1963–1969: Measles (John F. Enders); Mumps (Michiaki Takahashi); Meningococcal Infections (Emil C. Gotschlich); Rubella (Stanley A. Plotkin)����������������������������������  257 1976–Present: Hepatitis B (Philippe Maupas/Maurice R. Hilleman)��������  258 2007: Human Papillomaviruses ����������������������������������������������������������������  259 2019–Present: COVID-19��������������������������������������������������������������������������  261 China������������������������������������������������������������������������������������������������������  262 European Union (EU)����������������������������������������������������������������������������  263 United States������������������������������������������������������������������������������������������  263

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Herd Immunity������������������������������������������������������������������������������������������  265 Why Is Herd Immunity Important?��������������������������������������������������������  265 How Is Herd Immunity Achieved?��������������������������������������������������������  266 Let Us Take COVID-19 as an Example ������������������������������������������������  267 How Have We Achieved Herd Immunity for Other Infectious Diseases?������������������������������������������������������������������������������������������������  268 What Is the Outlook for Achieving Herd Immunity in the United States?����������������������������������������������������������������������������������������  269 How Can We Slow the Transmission of COVID-19������������������������������  269 References��������������������������������������������������������������������������������������������������  270 10 Zoonosis������������������������������������������������������������������������������������������������������ 275 Introduction������������������������������������������������������������������������������������������������  275 The Landscape Anthropization������������������������������������������������������������������  277 Travel ��������������������������������������������������������������������������������������������������������  277 Intense Agriculture and Farming ��������������������������������������������������������������  278 Transmission Chains from Animals to Humans: Hosts and Vectors����������  279 Zoonotic Transmission Illustrations����������������������������������������������������������  279 The Impact of Human Activity on the Zoonotic Transmission Chain ������  281 The Threat Caused by Tropical Rainforest Exploitation and Destruction������������������������������������������������������������������������������������������  282 SARS-CoV-2: The Origins of Evil������������������������������������������������������������  285 Is a New Pandemic Inevitable?������������������������������������������������������������������  285 Have Humans Given Nature the Tools that Will Ultimately Defeat Mankind?����������������������������������������������������������������������������������������  286 Should We Fear the Appearance of an Ever-Increasing Number of Zoonosis?��������������������������������������������������������������������������������  286 References��������������������������������������������������������������������������������������������������  288 11 Hemorrhagic  Fevers: Candidates for Pandemics ���������������������������������� 293 Chikungunya Fever������������������������������������������������������������������������������������  293 The Epidemics and the Virus ����������������������������������������������������������������  293 The Zoonotic Origin������������������������������������������������������������������������������  293 Chikungunya and Ecological Imbalances����������������������������������������������  294 Symptoms����������������������������������������������������������������������������������������������  295 Treatments����������������������������������������������������������������������������������������������  296 Dengue Hemorrhagic Fever ����������������������������������������������������������������������  296 The Epidemics and the Virus ����������������������������������������������������������������  296 The Zoonotic Origin������������������������������������������������������������������������������  297 Dengue Hemorrhagic Fever and Ecological Imbalance������������������������  297 Symptoms and Cure������������������������������������������������������������������������������  297 Dengue Vaccine��������������������������������������������������������������������������������������  298 Rift Valley Fever����������������������������������������������������������������������������������������  298 The Epidemics and the Virus ����������������������������������������������������������������  298 Animal Transmission ����������������������������������������������������������������������������  299

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The Rift Valley Hemorrhagic Fever Human Transmission��������������������  299 Symptoms and Incubation����������������������������������������������������������������������  300 Risk Factors for the Dissemination of the Rift Valley Hemorrhagic Fever��������������������������������������������������������������������������������  300 The Crimean-Congo Hemorrhagic Fever��������������������������������������������������  301 The Epidemics and the Virus ����������������������������������������������������������������  301 The Zoonotic Origin������������������������������������������������������������������������������  301 Transmission������������������������������������������������������������������������������������������  301 Symptoms and Incubation����������������������������������������������������������������������  302 Crimean-Congo Hemorrhagic Fever Treatment������������������������������������  303 Argentine Hemorrhagic Fever or O’Higgins Disease��������������������������������  303 The Epidemics and the Virus ����������������������������������������������������������������  303 The Zoonotic Origin������������������������������������������������������������������������������  303 Symptoms����������������������������������������������������������������������������������������������  304 Vaccine Treatment����������������������������������������������������������������������������������  304 Bolivian Hemorrhagic Fever����������������������������������������������������������������������  304 Epidemics and the Virus������������������������������������������������������������������������  304 The Zoonotic Origin������������������������������������������������������������������������������  305 Symptoms����������������������������������������������������������������������������������������������  305 Treatment ����������������������������������������������������������������������������������������������  305 Prevention����������������������������������������������������������������������������������������������  305 Lassa Hemorrhagic Fever��������������������������������������������������������������������������  306 The Epidemics and the Virus ����������������������������������������������������������������  306 Lassa Fever History ������������������������������������������������������������������������������  306 Ecological Imbalance����������������������������������������������������������������������������  306 Transmission������������������������������������������������������������������������������������������  307 Treatment ����������������������������������������������������������������������������������������������  307 Marburg Hemorrhagic Fever����������������������������������������������������������������������  307 The Epidemics and the Virus ����������������������������������������������������������������  307 The Zoonotic Origin������������������������������������������������������������������������������  307 Marburg in History��������������������������������������������������������������������������������  308 Transmission of Marburg Hemorrhagic Fever��������������������������������������  308 Pathogenesis of Marburg Hemorrhagic Fever ��������������������������������������  309 Symptomatology������������������������������������������������������������������������������������  309 Virology ������������������������������������������������������������������������������������������������  310 Marburg Hemorrhagic Fever: Lack of Treatment����������������������������������  311 Ebola Virus Disease ����������������������������������������������������������������������������������  311 The Epidemics ��������������������������������������������������������������������������������������  311 The Ebola Virus��������������������������������������������������������������������������������������  311 Ebola Virus in Animals��������������������������������������������������������������������������  312 Ebola Virus Transmission����������������������������������������������������������������������  312 Ebola Virus History��������������������������������������������������������������������������������  313 Ebola-Zaire Outbreaks ��������������������������������������������������������������������������  313 Ebola Variants����������������������������������������������������������������������������������������  314 Ebola-Sudan Variant��������������������������������������������������������������������������  314

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Ebola Variant in the Developed World����������������������������������������������  314 Ebola Variant Thai Forest������������������������������������������������������������������  314 Ebola Bundibugyo���������������������������������������������������������������������������������  315 Ebola Virus Symptoms and Incubation Period��������������������������������������  315 Ebola Virus: Consequences and Risks of Complications����������������������  315 Treatment ����������������������������������������������������������������������������������������������  315 Ebola from an Epidemic as a Potential Pandemic Threat����������������������  316 Conclusions������������������������������������������������������������������������������������������������  316 References��������������������������������������������������������������������������������������������������  316 12 Bioterrorism ���������������������������������������������������������������������������������������������� 323 Definition ��������������������������������������������������������������������������������������������������  323 Background������������������������������������������������������������������������������������������������  323 What Is a Bioagent? ����������������������������������������������������������������������������������  325 The Threat of Bioterrorism������������������������������������������������������������������������  325 Bioterrorism in History������������������������������������������������������������������������������  326 Emerging Diseases and Bioterrorism: A New Concern? ��������������������������  330 The Definition of Creutzfeldt-Jakob Disease����������������������������������������  330 General Public Awareness About Bioterrorism�����������������������������������������  331 The Role of the Health Professionals in Bioterrorism ������������������������������  331 Biological Warfare: What to Look For?����������������������������������������������������  332 Symptoms Potentially Associated with Bioterrorism Agents��������������������  332 Hospital Preparedness for Bioterrorism����������������������������������������������������  332 The Defense of Houston Program��������������������������������������������������������������  334 Risk of Outbreaks from Unintended Consequences of Research and Laboratory Accidents��������������������������������������������������������������������������  334 References��������������������������������������������������������������������������������������������������  335 13 Climate  Change and the Risk of Future Pandemics������������������������������ 339 Introduction������������������������������������������������������������������������������������������������  339 How Does Climate Change Affect Human Health?����������������������������������  341 How Does Climate Change Influence the Risks of Infectious Disease Outbreaks?������������������������������������������������������������������������������������  341 Examples from History������������������������������������������������������������������������������  342 Vector-Borne Diseases ������������������������������������������������������������������������������  343 Mosquitoes��������������������������������������������������������������������������������������������  344 Dengue ��������������������������������������������������������������������������������������������������  345 Malaria ��������������������������������������������������������������������������������������������������  346 Zika Virus����������������������������������������������������������������������������������������������  346 Yellow Fever������������������������������������������������������������������������������������������  347 Ticks������������������������������������������������������������������������������������������������������  348 Lyme Disease ����������������������������������������������������������������������������������������  349 Waterborne Diseases����������������������������������������������������������������������������������  351 Drinking Water��������������������������������������������������������������������������������������  351 Vibriosis and Cholera����������������������������������������������������������������������������  351

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Coastal Flooding/Heavy Rainfall����������������������������������������������������������  352 Vibriosis from Oysters ��������������������������������������������������������������������������  353 Arctic Region������������������������������������������������������������������������������������  353 Influenza��������������������������������������������������������������������������������������������  355 What Can Be Done?����������������������������������������������������������������������������������  355 References��������������������������������������������������������������������������������������������������  357 14 Antibiotic  Resistance, a Different Pandemic ������������������������������������������ 367 Introduction������������������������������������������������������������������������������������������������  367 A Brief History of Antibiotics Discovery��������������������������������������������������  367 Antibiotic Resistance ��������������������������������������������������������������������������������  368 Antibiotic Resistance: State of the Emergency������������������������������������������  369 References��������������������������������������������������������������������������������������������������  369 15 The  Next Pandemic: Challenges and Hopes�������������������������������������������� 371 Are We Ready for the Next Pandemic? ����������������������������������������������������  371 Challenges��������������������������������������������������������������������������������������������������  372 Challenge #1: The Risk for Emergence of New Pandemic Pathogens Is Poorly Controlled ������������������������������������������������������������  372 Challenge #2: The Current Global Health Security Infrastructure Needs to Be Improved����������������������������������������������������������������������������  373 Challenge #3: Gain-of-Function Experiments ��������������������������������������  373 Challenge #4: Shortage of Healthcare Workers ������������������������������������  374 Challenge #5: Misinformation ��������������������������������������������������������������  374 Reasons for Being Hopeful������������������������������������������������������������������������  375 Reason for Being Hopeful #1: COVID-19 Is Still Fresh in Our Minds������������������������������������������������������������������������������������������  375 Reason for Being Hopeful #2: Advances in Vaccine Development������  375 Reason for Being Hopeful #3: The Pandemic Spurred Innovation��������  376 Reason for Being Hopeful #4: The Spirit of Collaboration ������������������  376 Reason for Being Hopeful #5: More Venues for Dissemination of Information About the Pandemic������������������������������������������������������  377 References��������������������������������������������������������������������������������������������������  378 Glossary �������������������������������������������������������������������������������������������������������������� 393

Abbreviations

ACE2 Angiotensin-converting enzyme 2 AI Artificial intelligence AIDS Acquired immunodeficiency syndrome ALP Alkaline phosphatase AmFAR American Foundation for AIDS Research AMR Antimicrobial resistance ARDS Acute respiratory disease syndrome ARV Antiretroviral therapy ASTHO Association of State and Territorial Health Officers AZT Azidothymidine BCG Bacillus Calmette-Guérin BD Black Death CCR5 C-C chemokine receptor type 5 CDC Centers for Disease Control and Prevention CJD Creutzfeldt-Jakob disease CKD Chronic kidney disease CMV Cytomegalovirus CNS Central nervous system CO2 Carbon dioxide COVID-19 Coronavirus disease 2019 CPR Cardiopulmonary resuscitation CRP C-reactive protein CT Computed tomography DNA Deoxyribonucleic acid DPP-4 Dipeptidyl peptidase IV DRC Democratic Republic of the Congo EBOV Ebola virus ECMO Extracorporeal membrane oxygenation ELISA Enzyme-linked immunosorbent assay EMA European Medicines Agency EPO Erythropoietin EU European Union EUA Emergency Use Authorization FDA United States Food and Drug Administration xxix

xxx

Abbreviations

FNV French neurotropic vaccine G6PD Glucose-6-phosphate dehydrogenase deficiency GALT Gut-associated lymphoid tissue GCBR Global Catastrophic Biological Risk GDP Gross domestic product GGT Gamma-glutamyl transferase GPEI Global Polio Eradication Initiative H&E Hematoxylin and eosin stain HA Hemagglutinin HAART Highly active antiretroviral therapy HBsAg Hepatitis B surface antigen HCoV Human coronavirus HCoV-EMC Human coronavirus-Erasmus Medical Center HIF Hypoxia-inducible factor HIT Herd immunity threshold HIV Human immunodeficiency virus HPV Human papillomavirus ICU Intensive care unit IES Impact of Event Scale IgM Immunoglobulin M IHR International Health Regulations IHR-EC International Health Regulations-Emergency Committee INSTI Integrase strand transfer inhibitors INTERPOL International Criminal Police Organization IPV Inactivated polio vaccine LASV Lassa hemorrhagic fever LMIC Low- and middle-income countries MERS Middle East respiratory syndrome MERS-CoV Middle East respiratory syndrome coronavirus MMR Measles, mumps, and rubella vaccine MMRV Measles, mumps, rubella, and chicken pox vaccine MMWR Morbidity and Mortality Weekly Report mRNA Messenger RNA MSM Men who have sex with men NA Neuraminidase NIP National Immunization Program NLR Neutrophil-to-lymphocyte ratio NNRTI Non-nucleoside reverse transcriptase inhibitor NRTI Nucleoside reverse transcriptase inhibitor NTD N-terminal domain OPV Oral polio vaccine PAHO Pan American Health Organization PCR Polymerase chain reaction PD Pharmacodynamic PEP Postexposure prophylaxis

Abbreviations

PHEIC Public Health Emergency of International Concern PI Protease inhibitor PK Pharmacokinetic PPE Personal protective equipment PrEP Pre-exposure prophylactic PTSD Post-traumatic stress disorder PWA People with AIDS RBD Receptor-binding domain RCT Randomized clinical trial RdRP RNA-dependent RNA polymerase RNA Ribonucleic acid RT-PCR Reverse transcription-polymerase chain reaction SADS-CoV Swine acute diarrhea syndrome coronavirus SARS Severe acute respiratory syndrome SARS-CoV Severe acute respiratory syndrome coronavirus SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 SIV Simian immunodeficiency virus STD Sexually transmitted diseases TasP Treatment as prevention TB Tuberculosis TMP-SMX Trimethoprim-sulfamethoxazole TP Treponema pallidum UI Uncertainty interval UK United Kingdom UNAIDS United Nations Programme on HIV and AIDS USA United States VOC Variant of concern VOI Variant of interest VUM Variant under monitoring WHO World Health Organization WHOQOL World Health Organization Quality of Life scale YF Yellow fever

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The First 1000 Years CE of Pandemics: Smallpox and Plague

Introduction While outbreaks of diseases have been described as early as man have been holding on history, determining which ones are pandemics is a difficult task. A pandemic contains elements of wide geographic spread, disease movement, high attack rates, minimal population immunity, novelty, infectiousness, and severity [1]. The paucity of corroborating historical records in ancient times makes it difficult to ascertain if the outbreaks they mentioned fit this criterion. The study of pandemics begins at the start of the Common Era, allowing enough written records to closely study these epidemics. During the first millennium CE, two main pandemics emerged: The Antonine plague between 165 and 190 CE, also historically referred as the “Plague of Galen” who was the first physician to describe the symptoms of the illness. The Antonine plague was believed to be caused by hemorrhagic smallpox that killed five million people. Four hundred years later, between 541 and 749 CE, the Justinian plague, caused by Yersinia pestis, decimated the Byzantine empire, killing 50 million people. Both are documented examples of pandemics development as consequences of trade, wars, and pathogens circulating through transport. The Great Japanese Smallpox Epidemic, which occurred between 735 and 737 CE, exterminated half of the Japanese population and is a representative example of smallpox transmission and societal impact of the disease.

The Antonine Plague: Smallpox (165–190 CE) Between 165 and 190  CE, a new disease spread across the Roman Empire. The Antonine plague originated in East Asia. Historians believe that the plague might have emerged in China under the Kingdom of the Old Han dynasty and Mongolia before arriving in Europe through trade. The Antonine plague was reported as the first of a long series of pandemics, mostly spreading in Asia, the Middle East, and © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 C. Ferreira et al., 2000 Years of Pandemics, https://doi.org/10.1007/978-3-031-10035-2_1

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1  The First 1000 Years CE of Pandemics: Smallpox and Plague

the European continent. The Antonine plague was described by the Greek physician and writer Galen, Aelius Aristides, and Lucian of Samosata among others and later through historiographical texts (Historia Augusta Colloquium Bonn 1963 by History Augustus; Histoires, XXIII, by Ammien Marcellin; Breviarium ab urbe condita, VIII, 12, 2, by Eutropius; Histoires, VII, 15, 4–7, by Orose) [2]. Why start this chapter with the Antonine plague in the twenty-first century? First, because the Antonine plague is felt as such as a not insignificant part of the history of pandemics by his contemporaries, and as a result it appeared in scarce sources. Second, because the Antonine plague was closely linked to soldiers invading unknown territories and introducing an illness unknown in the Roman Empire. In Greek, the term “disaster” (kata + strophein) literally means “overturn,” while in Latin, (dis-astrum) means “ominous star.” In both languages, the word disaster was used only in the literary sense because in the description of the Antonine plague, the term disaster was used to refer to the pandemic. Pestis refers to epidemics in Latin, but with a much broader connotation. Epidemics are far from exceptional in the history of Rome and its empire, but some differ from this mundane recurrence of plagues. The sources obtained by Galen individualize them by specifying the vocabulary using adjectives or periphrases indicating their peculiarity: it is “a plague like no other.” The Antonine plague was named after the family name of the Roman Emperor and conqueror, Marcus Aurelius Antoninus [3]; it is also referred to as the Galenic plague, after the Greek physician, Galen, who wrote about the epidemic [4].

Description of the Disease The Antonine plague was caused by smallpox according to the symptomatology described by the physician Galen (129–c. 200  CE), which included pustules or boils. The Antonine plague affected the densely populated Greek and Roman cities and later expanded to affect the entire Roman Empire, causing a death toll in between five and ten million (20–30%) of the population. Consequently, this plague contributed to the destabilization of the Roman Empire [5]. Researchers identified the Antonine plague as smallpox from the family of Orthopoxvirus, a member of the Poxviridae viral family. It is believed that the disease conferred some immunity to the survivors. However, its impact on naive population was catastrophic, leading to a high fatality rate as mentioned above [6]. Symptoms of smallpox resemble the flu-like symptoms. Seven to nineteen days after exposure, a patient will develop hyperthermia and red spots predominantly in the buccal cavity. These spots change into sores, spreading large amounts of the virus into the mouth, upper thorax, hands, and feet typically within 24 h [7]. According to Galen, patients presented a black exanthema (rash) that appeared on the whole body. It was ulcerated in most cases and always dry. The exanthema, also described by Galen, was characteristic of smallpox, e.g., its whole-body topography, vesiculopustular morphology, and crusty morphology and then evolution. Galen repeatedly emphasized the blackish color of the skin elements, which was, as he assumed, due to intralesional blood extravasations. Other described additional signs including fever, gastrointestinal symptoms

Description of the Disease

3

like diarrhea, stomach discomfort, vomiting, and fetidity of breath are all found in the classic description of the disease. “Everyone who had very black stools died,” Galen wrote. Although Galen’s description of the Antonine plague was fragmentary and incomplete, the particularly dire prognosis of hemorrhagic smallpox was well known, making it possible to identify the disease with smallpox, due to the excellent description of the exanthema. Other researchers were not convinced that smallpox could have been the pathogen caused by the Antonine plague. Gourevitch et  al. (2005) pointed out that Galen did not mention the scars that would be present on patients that recovered from smallpox [8]. Silver et  al. (2012) recalled Aelius Aristides, a teacher who survived the Antonine plague who suffered a “monstrous tumor” in his groin [9]. Both Silver et al. [9] and Flemming et al. [4] refer to Aelius Aristides, who in his reports about the pandemic also mentioned the death of livestock happening at the same time as the Antonine plague [4]. Since smallpox only affects humans, this raises the possibility of another pathogen that could have been the cause of the pandemic. However, it is possible that other diseases might have affected the animals. The bubonic plague is therefore mostly suspected, as for both the Justinian plague and the Black Death. Deaths of animals as well as people have been documented. At present, we know that the smallpox incubation period is from 7 to 19 days after exposure. Two days after the symptoms appear, exanthema particularly in the tongue and mouth will later disseminate to the whole body (Fig. 1.1). Once the exanthema is enlarged, the lesions break, liberating millions of novel viral particles generally projected by aerosol to infect the human host [10].

Fig. 1.1 Credit: Gloucester smallpox epidemic, 1896: George Allen, a smallpox patient. Photograph by H.C.F., 1896. Credit: Wellcome Collection. License: Public Domain Mark

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Propagation of the Disease In the middle of the second century CE, tensions have been brewing between the Roman Empire and the Parthian Empire to the East. This erupted into a full-blown conflict. In 165 CE, the Roman army laid siege to the city of Seleucia on the Tigris River (now in modern-day Iraq) [2]. The Roman armies were victorious and destroyed the city of Seleucia. Upon their return to Rome in the winter of 165–166 CE, the Roman soldiers were struck by a disease they believed emerged from Seleucia [3]. The disease was later called the Antonine plague. Our knowledge of the Antonine plague mainly comes from Galen, who had treated himself several victims of the plague, however without success. As such, the description of the disease was succinct, scattered, and incomplete [11]. As mentioned above, Aelius Aristides and Lucian, having personal knowledge about the disease, also wrote about the Antonine plague [12]. With the fall of the Roman Empire, it was assumed that the Antonine plague’s archives were lost. Other narrations which mentioned the plague were written 100 years later, and considered unreliable [13]. From Seleucia, the Antonine plague spread to Rome, and then its provinces (now France and Germany), and north beyond the Danube River. The spread may have been helped by the established trade routes within the Roman Empire. The Antonine plague hit slaves extremely hard as their living conditions were harsh, sleeping arrangements were often communal, and nutrition was inevitably inferior. Galen recorded that the Antonine plague killed almost all his slaves in Rome. The social imbalance was no longer immediate but diffuse and omnipresent: “for if the natural imbalance cannot be appeased by medicine, nor the religious imbalance by rituals, it is because the threat is constant and secret. It is a conspiracy of magicians and criminals,” as reported by Littman et  al. [11]. According to Cassius, the Antonine plague pandemic was a moment that required meaning because things and facts no longer correspond to themselves; the pandemic extended to the totality of the Roman Empire in a few months.

Perception of the Disease in the Roman Empire The Antonine plague occupied a prominent place in the historiography of the moderns: For many, it marked the end of the golden age of the Antonines and the beginning of a crisis in the Roman Empire and paganism [14]. It is true that ancient literary sources speak of its unheard-of and sudden magnitude of the Antonine plague’s catastrophic damage and of the panic it caused. Paradoxically,

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Fatality Rates

the general historiography of the Roman Empire emphasized the seriousness and consequences of the epidemic (depopulation, poverty, invasion, etc.). Beyond the magnitude and virulence of the Antonine plague, we find the ordinary characteristics of the ancient understanding of epidemics [15]. Documents evoke the religious perception of the epidemic and are fundamentally new and original. It is easy to postulate a causal link between the catastrophic epidemic and a certain climate of religious anxiety. As such, by this climate, one wants to easily explain the progression of new forms of religiosity, Christian or Eastern. The Antonine plague was even more dreadful as compared to other pandemics because its memory was perennial and not diminished by other epidemics that followed. Interestingly, the unification of the Roman Empire made it possible to observe and verify this magnitude, at least for a small number of leaders and scholars who were able to gather and cross-reference information. It also implied a high rate of spread of the epidemic and continued attention on the part of its early chroniclers. It is considered that the Antonine plague claimed the life of a Roman emperor, Lucius Verus, at the age of 38 in March 169 CE.

Fatality Rates The number of deaths caused by the Antonine plague cannot be exactly ascertained. One of the most common quotes is from Cassius Dio, who wrote the plague in 189 CE, “often, two thousand persons died in Rome in a single day” [13]. There are no surviving records of tallies of deaths nor records detailing the total population of the Roman Empire at the time. It is estimated that the Antonine plague took the life of 6 to 7 million people in the Roman Empire. There is also no reliable indicator that the mortality rates, mentioned as pertaining to cities, also apply to the countryside. Table 1.1 shows the range of estimates of the total death toll of the Antonine plague. Table 1.1  Estimated death toll of Antonine plague according to different authors Authors Gilliam [13] Harper [16] Littman [11]

Estimated total Roman population 50 million 75 million 100 million

Estimated death toll (%) 1–2 10 7–10

Estimated death toll 500,000–1 million 7–8 million 7–10 million

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Attempts for Treatments Centuries before the Antonine plague erupted, ancient medicine was centered on the patient and not on a specific pathogen as the contagion was justified by either a disturbance of the climate or the environment. For example, Hippocrates already described disorders in the air and water, explaining that simultaneous disorders of the bodies linked to illnesses are related to environmental phenomena. In the case of the Antonine plague, the epidemic indiscriminately hit all ages and constitutions [17]. Moreover, a seasonality was linked with the Antonine plague, facilitated by cold winters and low rainfall [16]. Although many different treatments were attempted, none really helped. For instance, Galen had reported the use of milk from mountain cattle, Armenian dirt, and urine of young boys. Others believed that the plague was caused by “something in the air” and used incense and herbs or filled their ears and noses with perfume. It was also believed that the plague was a form of punishment from the god Apollo (Fig.  1.2), inducing the population to make appeals and offerings to the deity [18].

Fig. 1.2  Punishment by the god Apollo. An engraving by Levasseur after Jules-Elie Delaunay depicts the angel of death at the door during the 165 A.D. Plague in Rome. Credit: Wellcome Library no. 10134i public domain

Justinian Plague (541–749 CE)

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Justinian Plague (541–749 CE) The Justinian plague, also referred to as “the Justinianic Plague,” began in 541 CE. The Justinian plague is considered the first pandemic in history as it has affected three continents. This is the first documented pandemic caused by the bacteria Yersinia pestis [19]. It started in year 541 CE, lasting until 749 CE, arising in waves at irregular intervals, 6–20 years apart [20]. It is believed that as many as 38 separate waves occurred within this period. Our knowledge of the Justinian plague mainly comes from the writings of Procopius, John of Ephesus, and Gregory of Tours, describing its effects in Constantinople, Palestine, and Gaul, respectively [21]. The plague took its name from the Byzantine emperor Justinian, who ruled from 527 to 565 CE in the Eastern Roman Empire. Just as Emperor Justinian was trying to rebuild his empire to the glory of ancient Rome, the Justinian plague struck and left him devastated as the plague destroyed the Byzantine Empire’s army and economy. Emperor Justinian was also infected with the plague and died on 14th November 14, 565 AD (Fig. 1.3). Fig. 1.3  Last of the Latins: a sixth-century fresco of Justinian, San Vitale, Ravenna. Credit: https://commons. wikimedia.org/wiki/ File:Meister_von_San_ Vitale_in_Ravenna.jpg. Public Domain

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The Origin and Propagation of the Pandemic Procopius of Caesarea, a Greek historian, mentioned Pelusium, a port city along the Nile River in Egypt, as the origin of the plague, spreading westward to Alexandria and eastward to Palestine [22]. In 1 year, it reached Jerusalem, Antioch, and Myra. The next year, it reached the capital of the empire, Constantinople (now Istanbul). The following year, the disease was reported in Rome, Arles (in Gaul), and Carthage (in North Africa) (Fig. 1.4). By 544 CE, it had reached Britain. Procopius noted that the disease would start from the coast and moved slowly inland [20]. Other affected areas included Spain and Ireland. There are suggestions that the plague may have reached as far as Finland and Yemen. It is thought that the highly developed network of transportation at the time helped spread the disease [23]. From where did the plague originate before coming to Pelusium? There are two schools of beliefs. One is that the offending pathogen originated from sub-Saharan Africa [24]. In 1974, Dols referred to writings in “Islamic areas” mentioning recurrent disease outbreaks severe enough to lessen the population in the said region but could not be certain that it was caused by Yersinia pestis [25]. Cunha (2004) also mentioned Africa as a possible source [26]. An African source was also supported by Gallagher et  al. (2018) who cited contemporary writings such as Ethiopia or Eritrea as the source of dissemination of Yersinia pestis [27]. A second school of beliefs suggested Central Asia as the source of the Justinian plague. It was believed

Fig. 1.4  Dissemination of Justinian plague [19]. Map realized by the authors. “Origins of The Justinian plague.” Sources have traced the origins of the Justinian plague in Nepal; it is believed that the pandemic originated among the troops fighting in the Parthia war against the Romans (1). Roman soldiers are believed to carry the Justinian plague on their way back to Rome, disseminating the disease through other geographic areas as the Middle East and the ports in where they make their return to Rome. Map 1.3 ©Ferreira/Doursout/Balingit 2022. All Rights Reserved

The High Fatality Rate of the Justinian Plague

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that Yersinia pestis traveled from China, then spread to India, and then to the Middle East by Indian trade ships that docked at Clysma, an Egyptian port on the Red Sea. From Clysma, the plague traveled north to Pelusium. Recent DNA research on Yersinia pestis seems to support this hypothesis [28]. The plague occurred more than ten times between 541 CE and 565 CE. This fact is corroborated by the historians Procopius of Caesarea (500–565) and Evagrius Scholasticus, a Syrian scholar who reported that the plague broke out several times during the reign of Emperor Justinian, indicating a periodic appearance from 541 CE [29].

The Pandemic and the Yersinia pestis Bacteria The Justinian plague was caused by a zoonotic gram-negative coccobacillus bacterium, Yersinia pestis, a highly pathogenic agent with broad dissemination to humans through rodents and their fleas [30]. When a flea feeds from an animal carrying the bacterium Yersinia pestis, it blocks the flea’s digestive system, causing the insect to empty its stomach. Being hungry, the flea needs to bite another host, animal, or human, therefore disseminating the bacterium. Three main forms characterize Yersinia pestis infection: bubonic, septicemic, and pneumonic plague [31]. Two to six days after the flea’s bite, individuals with bubonic plague develop hyperthermia, chills, muscle aches, headache, and extreme weakness. Within 24  hours, one or more buboes appear. Infection by Yersinia pestis is associated with hyperventilation and lymphadenopathy. Once the bacteria enter the bloodstream, the infected individual develops septicemic plague. Pneumonic infection due to Yersinia pestis is associated with major lung infection and subsequent pneumonia that can cause human-to-human contagion through bacterium-infected droplets [32].

The High Fatality Rate of the Justinian Plague Another theory suggests that Yersinia pestis came from Ethiopia. Pelusium, a city located near the Nile Delta, was believed to be the only point of arrival for the disease from Ethiopia [33]. Procopius wrote that in the city of Constantinople, more than 10,000 people died every day, while John of Ephesus reported that 16,000 died per day. Procopius described a city so full of corpses that it was difficult to bury them all. In the end, he estimated that about half the city’s population died [34]. The plague may have started in Asia or Africa and was transported to other continents by commercial vessels infested with disease-carrying rodents. When the Justinian plague reached Constantinople, it killed about 300,000 people in the first year with a total death toll of 25 million fatalities [35]. The estimates for the final death toll were as high as 50% initial mortality in the Eastern Roman Empire (estimated population of 30 million). Recently, others have argued that the evidence from the historical record does not support a claim of remarkably high estimates of mortality [36].

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Justinian Plague and Climate Change Gregory of Tours, a Gallo-Roman historian and Bishop of Tours in France, reported an increase of meteorological events in Gaul during the sixth century, including flooding and thunderstorms [37]. As an example, the bubonic plague that followed the flood in Rome in 589 CE claimed the life of Pope Pelagius II on February 7, 590 CE. Ioannis Telelis reported 95 meteorological events in the 500s, surpassing any meteorological events between 300 and 1200 CE [38]. The decade preceding the start of the pandemic was colder than average for that time, and it may have been linked to volcanic eruptions that occurred at the same time. It is believed that the change in climate led to conditions favorable for increasing the local rodent population, acting as a host population for the fleas carrying Yersinia pestis. Other authors believe that correlating the colder weather in the previous decade and the first pandemic is not a simple matter: They pointed out that the areas affected by the plague did not have a uniform climate at the time [39]. The sixth century CE was a period of major cultural religious and climate changes with empires rising or falling across the world. The Byzantines were attempting to conquer the old Roman west. The Justinian plague came at the time where the European population was recovering from years of famine but led to a colossal scale of death that would not be seen again until the “Black Death” 800 years later [40].

The Social and Cultural Impact of the Justinian Pest Several major cities of the Empire were affected such as Constantinople, Alexandria, Carthage, and Rome. Procopius reported that at the height of its first eruption, the plague killed 10,000 people a day in Constantinople, the capital of the Roman/Byzantine Empire, where it raged for 4 months. Archaeological evidence, in truth, suggests that the various waves of plague of the sixth, seventh, and eighth centuries were of similar importance to the inhabitants of the Byzantine Empire. In the various affected regions, the disease initially caused the death of a large part of the urban population, and it probably took several generations to compensate for this general decline in the population [41]. With the seeming ineffectiveness of available cures during the Justinian plague, there was an increased focus on religion. In some cities, aside from religious rites and offerings, processions were held to protect their residents from the plague. As the outbreak raged, fewer farmers were working in the fields, and food became harder to find. Except for churches, construction of new structures stopped [41] (Fig. 1.5). Therefore, the Justinian plague affected the financial situation of the Empire under Emperor Justinian, as the Empire was unable to collect enough taxes from the people. By one estimate, the population of Italy declined to one-fourth to one-half that of Roman levels before the plague struck [42]. In 2002, Peter Sarris at the

Justinian Plague and the Divine Punishment

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Fig. 1.5  Impact of the disease in a church. Credit: Wikimedia Commons/ Public Domain

Cambridge University used various clues from epigraphic, legal, numismatic, and papyrological evidence to show that the Justinian plague had a major effect on the Eastern Roman Empire [43]. The Justinian plague helped to end Antiquity and bring in the Middle Ages [44].

Justinian Plague and the Divine Punishment The Justinian plague, like any pandemic, was also a sociodemographic phenomenon. Historian Procopius told us how it spread: First, it hit the coastal regions, and then it touched the cities before visiting successively the interior of the islands and the remote mountains. While modern societies fight diseases primarily through the weapons of medicine, preindustrial societies reacted very differently. Even a highly sophisticated society such as the Byzantine society in the sixth and seventh centuries faced the deadly epidemic [45]. The citizens of the Byzantine Empire perceived the plague, like any epidemic disease, in both apocalyptic and metaphysical terms. Its seniority and wide acceptance prevailed in the theoretical approach, according to which the plague expressed a divine punishment, and it was considered the result of the human transgression of divine law. It was a central notion of both Greek and Latin thoughts of Late Antiquity [46]. Indeed, the consolidation of Christianity radically changed the worldviews that previously prevailed. One of the advantages of Christians over their pagan contemporaries was that the care of the sick, even in times of the plague, represented for them an undisputed religious duty. When all normal services collapse, the most basic care significantly reduced mortality [47]. Among the Byzantine Christian thoughts, religious teaching preached by their bishops in churches in various cities of the Empire, gave meaning to the life of the simple Christians. Escape from suffering, after all, was considered attractive, at least in principle, if not in practice. Moreover, even the survivors found warm and immediate consolation in the vision of a paradise that had welcomed their dead relatives as good Christians. The divine omnipotence thus gave meaning to life and death for the Byzantines in times of disaster and pandemic [48].

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Japanese Smallpox Epidemic (733–737 CE) Seven hundred years after the first outbreak of smallpox during the Antonine plague, a major smallpox pandemic occurred in 710 CE in Japan. At the time, Nara was the capital of the kingdom where large Buddhist monasteries were built. The monasteries quickly gained such strong political influence. Emperor Shōmu ordered the construction of the Great Buddha. One characteristic of the Nara period was the gradual decline of Chinese influence which, nevertheless, remained strong. Many of the imported ideas were gradually “Japanized.” To meet Japanese needs, several governmental offices were established in addition to the government system, which was copied after the Chinese model including the arts and ancient medicine [49] (Fig. 1.6). At the time, landowners hired samurai for the protection of their properties. That is how the military class became more and more influential [50].

Fig. 1.6  Watercolour illustration from a Japanese work on smallpox entitled Toshin seiyo [The essentials of smallpox] consisting of a manuscript in two volumes. It contains numerous coloured illustrations of different symptoms of smallpox, which were executed on separate sheets of paper: they were then cut out and pasted into place. According to the beginning of book two, the author was Kanda Gensen (c1670–1746) and the text was edited and supplemented by one Enokimoto Gensho, whose dates are unknown and about whom all that is known is that he practiced medicine. Kanda was a doctor who is known for his illustrated explanatory works on natural science and materia medica. Source: Wellcome collection https://wellcomecollection.org/works/gjay6b7j Public domain

The Impact of the Japanese Smallpox on Society

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The Disease Outbreak and Propagation During 733–737 CE, a smallpox outbreak struck the country. The “Japanese smallpox pandemic” was transmitted from person to person by air or close contact. It is believed that the Japanese pandemic was introduced to Japan by fishermen who had contracted the virus in the Korean peninsula. The pandemic was later disseminated by official dignitaries returning from the court of Korea in 736 CE [51]. Affecting much of Japan, the smallpox epidemic devastated the insular Asian nation, inflicting adult mortality at rates as high as 35% upon the Japanese population, with some regions suffering even worse casualties. Japanese smallpox, originating on the island of Kyushu, quickly spread to Nara, the capital, affecting all classes of society equally. The rigid hierarchy of Japanese culture was laid bare, with all four brothers of the powerful Fujiwara clan killed in 737 CE by the outbreak. It has been reported that in between 735 CE and 998 CE, Japan experienced 12 outbreaks with an interval of ~23 years [52].

The Impact of the Japanese Smallpox on Society The Japanese believed that the epidemic was caused by Onryō, a mythological spirit that was able to return to the physical world to seek vengeance. In response, they used certain customs to deal with the demon. It was believed that the spirit feared red color and dogs, which led to the Japanese displaying dolls colored in red or dressed in red. While traditional medicine and physicians were able to cure only a disease caused by the unbalance between the spirit and the body, esoteric rituals to Onryō were also capable to cure all kinds of diseases [50] (Fig. 1.7). The large scale of death from the epidemic created a serious shortage of labor, which greatly affected rice farming. Following the epidemic, the Japanese imperial government took the extraordinary step of offering land to the commoners to raise agricultural productivity [53]. Irwin et al. reported that several other outbreaks of smallpox were reported in centuries before until the XVII century [54].

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Fig. 1.7 Credit: Tametomo banishes the smallpox demon from the Island of Oshima. Color woodcut by Yoshikazu, 1851/1853. Credit: Wellcome Collection. Attribution 4.0 International (CC BY 4.0)

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37. Shane Bjornlie M. Gregory of tours and the Decem Libri Historiarum between religious belief and rhetorical habit. Stud Late Antiquity. 2020;4(2):153–84. 38. Margaritelli G, Cacho I, Català A, et al. Persistent warm Mediterranean surface waters during the Roman period. Sci Rep. 2020;10(1):10431. https://doi.org/10.1038/s41598-­020-­67281-­2. Published 2020 Jun 26 39. Richard Christian Bilich Climate Change and the Great Plague Pandemics of History: Causal Link between Global Climate Fluctuations and Yersinia Pestis Contagion? A Thesis Submitted to the Graduate Faculty of the University of New Orleans in partial fulfillment of the requirements for the degree of: Master of Art in History B.A. Tulane University, 2005 December 2007. 40. Bar-Oz G, Weissbrod L, Erickson-Gini T, Tepper Y, Malkinson D, Benzaquen M, Langgut D, Dunseth ZC, Butler DH, Shahack-Gross R, Roskin J, Fuks D, Weiss E, Marom N, Ktalav I, Blevis R, Zohar I, Farhi Y, Filatova A, Gorin-Rosen Y, Yan X, Boaretto E. Ancient trash mounds unravel urban collapse a century before the end of Byzantine hegemony in the southern Levant. Proc Natl Acad Sci. 2019;116(17):8239–48. https://doi.org/10.1073/pnas.1900233116. 41. https://www.thoughtco.com/the-­sixth-­century-­plague-­1789291 (Accessed 24 Nov 2021). 42. Atkinson J. The plague of 542: not the birth of the clinic. Acta Classica Vol. 2002;45:1–18. (18 pages) Published By: Classical Association of South Africa 43. Sarris P.  Bubonic plague in Byzantium: The evidence of non-literary sources. In: Little LK, editor. Plague and the End of Antiquity. Cambridge, UK: Cambridge University Press; 2007. p. 119 44. Retief F, Cilliers L. The epidemic of Justinian (AD 542): a prelude to the Middle Ages. Acta Theologica. 2010;26 https://doi.org/10.4314/actat.v26i2.52567. 45. Natasha Sophie Stange. Politics of plague: ancient epidemics and their impact on society Pomona College August 13, 2020. 46. Gage KL, Kosoy MY. Natural history of the plague: perspectives from more than a century of research. Annu Rev Entomol. 2005;50:505–28. 47. Huremović D.  Brief history of pandemics (pandemics throughout history). Psychiatry Pandemics. 2019:7–35. https://doi.org/10.1007/978-­3-­030-­15346-­5_2. 48. Humfress C. “5: Laws’ Empire: Roman Universalism and Legal Practice”. New Frontiers: Law and Society in the Roman World. Edinburgh: University Press; 2013. ISBN 978 0 7486 6817 5 49. https://droitromain.univ-­grenoble-­alpes.fr/Anglica/CJ1_Scott.htm. Consulted on November 26th 2021. 50. Suzuki A. Smallpox and the epidemiological heritage of modern Japan: towards a total history. Med Hist. 2011;55(3):313–8. https://doi.org/10.1017/s0025727300005329. 51. https://www.japan-­guide.com/e/e2132.html (Accessed 26 Nov 2021). 52. Pauli G, Blümel J, Burger R, et  al. Orthopox viruses: infections in humans. Transfus Med Hemother. 2010;37(6):351–64. https://doi.org/10.1159/000322101. 53. https://www.worldhistory.org/article/1059/ghosts-­in-­ancient-­japan/ (Accessed 26 Nov 2021). 54. Irwin F. “Smallpox in Japan.” Public Health Reports (1896–1970). 1910;25(35):1205–1208. JSTOR, www.jstor.org/stable/4565307 (Accessed 18 June 2020).

2

The Plagues Pandemics: 2000 Years of Recurrent Devastations: The Black Death

Introduction Plagues have been affecting humanity for at least 2000 years. The contagion rate and processes were such that this disease turned into pandemics until antibiotic treatments were found in the twentieth century [1]. Throughout the history, plagues have been characterized by a high mortality rate (>30%), which dramatically impacted the growth of the populations and led to profound changes in the kingdoms or empires. After a description of the plague disease and its vectors, we will evaluate the causes of propagation and the responses given by the authorities [2].

The Disease and Bacteria Yersinia pestis The plague disease is associated with pestilence and has been defined by the Cambridge dictionary as: “A very serious disease that spreads quickly and kills large numbers of people.” On June 10, 1947, French author Albert Camus published the book “The Plague.” This well-documented novel gives us a glimpse of the situation lived at the times of the various plague episodes. In his novel “The Plague,” Albert Camus wrote: “Pestilence is in fact very common, but we find it hard to believe in a pestilence when it descends upon us. There have been as many plagues in the world as there have been wards, yet plagues and wards always find people equally unprepared. Dr. Rieux, the main character of the book was unprepared, as was the rest of the townspeople, and this is how one should understand his reluctance to believe. One should also understand that he was divided between anxiety and confidence. When war breaks out people say: ‘It won’t last, it’s too stupid.’ And war is certainly too stupid, but that doesn’t prevent it from lasting. Stupidity always carries doggedly on, as people would notice if they were not always thinking about themselves. In this respect, the citizens of Oran (A port city in Algeria) were like the rest of the world, they thought about themselves; in other words, they were © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 C. Ferreira et al., 2000 Years of Pandemics, https://doi.org/10.1007/978-3-031-10035-2_2

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humanists: they did not believe in pestilence. A pestilence does not have human dimensions, so people tell themselves that it is unreal, that it is a bad dream which will end. But it does not always end and, from one bad dream to the next, it is people who end, humanists first of all because they have not prepared themselves. The people of our town were no more guilty than anyone else, they merely forgot to be modest and thought that everything was still possible for them, which implied that pestilence was impossible [3].” At least three main plague pandemic episodes have been recorded in the last 2000 years, and historic material is available for analyzing the propagation and the societal responses to the pandemics [4].

The Plague Zoonosis What made the plague particularly lethal was that it had an almost perfect vector for transmission. The fleas carried by the rats are well suited to allow the pathogen responsible Yersinia pestis, to spread the disease [5]. The black rat or Rattus rattus, thought to be one of the major species involved in transmission, the animal vector, evolved in Asia approximately 10–15,000 years ago6. While this rat is half the size of its cousin, the brown rat, it compensates with its ability to reproduce, meaning that black rats mating continuously for 3 years can lead to a population of over three million. Rattus rattus are also extremely resilient creatures. They can climb nearly vertical surfaces, enter through openings a quarter inch thick, and survive a fall of five stories, and (recalling that “rodent” comes from the Latin word “rodere” meaning “gnaw”) its powerful jaws can cut its way through lead, adobe, and unhardened concrete. Medieval city walls simply did not stand a chance. Once inside a city or on board a ship, Rattus rattus can exhibit problem-solving intelligence: after establishing a nest or a den, it purposefully creates an escape route before cautiously foraging for food [6]. Indeed, it essentially conducts reconnaissance, changing the areas that it explores and adapting quickly to its environment. However, its most unsettling aspect is that it serves as an almost perfect reservoir for fleas [7]. The Oriental flea known as Xenopsylla cheopis, another zoonotic carrier of fleas infected with Yersinia pestis, is also called for obvious reasons “the rat flea” (Fig. 2.1). It has a preference to get its blood meal from a rat or other rodents, but if that source is limited or exterminated, the flea is pleased to try something else. This flea can endure for more than a month without a host, and during this time, it can remain on clothing, baggage, fur, hair, or, for that matter, corpses that are tossed through the air. Once a target is sensed, its powerful hind legs allow it to jump over half a meter, and once it lands, its exceptional bite can penetrate directly into the bloodstream of its host where it can suck up a meal. While in a normal flea this blood would flow without interruption into the fleas’ stomach, on the other hand, in plague-infested fleas the process is different. Once infected, the plague bacterium would multiply within the flea itself, blocking its foregut and more importantly its ability to ingest a meal. This would make the flea even more voracious resulting in multiple bites and with each bite the plague bacteria Yersinia pestis would be regurgitated into the host. Now this brings us to our main culprit [8].

The Clinical Characteristics of the Plague

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The Plague Transmission Cycle • The Bacteria Yersinia Pestis is responsible for the plague

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Yersinia Pestis is found in small rodents 1

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yersinia pestis is transmitted to humans through the bite of infected fleas.

Fig. 2.1  Updated fact sheet on The Plague WHO October 2017. Permission obtained by WHO on August 6th, 2021, WHO https://twitter.com/who/status/915864775225200640

As mentioned above, the plague is caused by the bacterium Yersinia pestis, and to emphasize, this is not a virus. Once Yersinia pestis gets inside the human host, it reproduces aggressively using its own unique enzymes, invading organs and the lymphatic system. The lymphatic system, a key member of our immune defenses, is responsible for eliminating foreign contagion. The reason for this is that the plague is extremely adaptable, avoiding the human immune system. While the immune system is busy achieving very little, Yersinia pestis spreads from lymph node to lymph node and multiplies at a ferocious rate [9]. Needless to say, in 1345, for the defenders of the city of Caffa (now Ukraine) with no knowledge of germ theory or epidemiology and no insight on how the disease was spreading (not to mention that antibiotics would not come around for 600 years), this was nothing less than a glimpse into the apocalypse as well as the first documented act of bioterrorism using Yersinia pestis-catapulted bodies of Mongols deceased from the plague [10].

The Clinical Characteristics of the Plague The plague has an astounding death rate, with a short incubation period (the time of exposure to the onset of symptoms) anywhere between one or 2 days and 1 week. An infected individual who does not have any symptoms is able to pass on the disease without even knowing it [11]. According to the American Centers of Disease Control (CDC), there are three major known variants of the plague [12]. The bubonic form is the least lethal. Once a person shows flu-like symptoms, most notably hyperthermia, fatigue, and cough will be revealed, from which the latter could become very bloody. This would occur as the Yersinia pestis bacteria make its way through the body’s organs causing some of them to shut down. Reports indicated that those infected and

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in the later stages of the disease would have an odor, consistent with internal gangrene. Eventually, the contagion would make its way into the lymphatic system accumulating in the lymph nodes. These nodes would swell resulting in the characteristic plague pustules, usually in the groin, the armpit, or the neck. Some of these nodes could grow immensely and could cause major disfigurement. If the swollen lymph nodes were able to rupture through the skin, they would open, spilling the fluid contents from within, teeming with bacteria and ready to infect another human being. In infected patients, most body fluids would be carrying the bacteria, whether by coughing, bleeding, vomiting, or even worse if ingested. The mortality rate of the bubonic variant is approximately 50% [13]. The pneumonic form of the plague occurs when the Yersinia pestis bacteria get into the lungs of infected people. In this case, the patient would start vomiting and coughing up blood almost immediately. This variant is extremely infectious and could be passed through airborne transmission. As one can imagine, this is more common in the wintertime when people stay cloistered together. On average, one would have approximately 3 days to live once the onset of symptoms occurred. The mortality rate of this variant would run in the 95–100% range depending on the region [14]. If considering that less than 5% chance of survival is bad, the last variant could be even worst: the septicemic plague. If the bacterial count in the body reaches maximum density and then spills into the bloodstream, one ends up with the septicemia variant of the plague. The body simply goes into massive shock and shuts down. It has been related that the time frame between the beginning of the symptoms and the time of death is approximately 14 days [15]. Before the Black Death pandemic, one previous pandemic occurred in Europe as previously described in the chapter “1000 Years of Pandemics.” The Justinian plague of 541–549 AD devastated the Byzantine Empire.

The Black Death (1346–1353) The story of the Black Death is the story of a perfect storm. Its focal point stood by expansion of the cities and population as well as religious movements. The explosion of trade and just the right political situations met a powerfully lethal bacterium with an equally powerful vector of transmission [16]. The Black Death was named in many ways, the Plague and the Great Mortality to name a few, as we know it so well because of its infamy. It was after all estimated that 30–40% of Europe population died. But Europe was not alone: Africa, the Middle East, India, and East Asia were all in its path of destruction. In the end, it was estimated that, worldwide, 200 million people died. A number so high that every outbreak past or present has not even come close, particularly impressive given that the world population at the time was approximately 500 million [17].

The Initial Conditions: When Asia Meets Europe in Caffa Our story begins not in Europe but far to the East. No one is exactly certain where the plague originated, but many agree that it may be somewhere where the Great Eurasian steppe meets the Gobi Desert. Some historians claim that it

The Initial Conditions: When Asia Meets Europe in Caffa

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came from the Mongolian plateau from a region of the Great Desert itself (a place that Marco Polo on his journey would say that when a traveler became isolated, he would hear the voices of devils leading him lost), whereas others felt that it was on the banks of lake Issyk-Kul in Kyrgyzstan, one of the deepest lakes in the world where the contagion might lay. The plague infected small rodents, and because of its lethal nature, it would not have easily escaped its isolated territories [18]. By the mid-fourteenth century, the steppe was unified by the Pax Mongolica and trade had rebounded on a massive scale. What was once a desolated and isolated land was now crisscrossed by the Silk Road. It was traversed by hordes of merchants hoping to make their fortune along a multitude of trade stations. The plague had a mechanism to expand its domain, and it eagerly awaited its chance to do so in the Crimean Peninsula [19]. Quite a distance to the west was the city of Caffa (now known as Feodosia in modern Ukraine). At this time, the world was changing, and trade which had languished since the fall of the Roman Empire had emerged as a powerful force [20]. A good example was the Italian cities and states, which struggled fiercely with one another for monetary hegemony: nothing would stop them from expanding their bottom line. By 1340, Caffa had a population of 80,000 souls. Buildings dotted the horizon. Its market was a flurry of activity, and the docks of Caffa were renowned to house over 200 ships. The location was perfect for the savvy business [10]. The Silk Road ran just to the north and divided into several paths before going into Europe. The Volga and the Don rivers were relatively nearby adding to a commercial sphere of influence, and from its warm water port, ships would come and go from Constantinople. At the time, the city of Caffa had blossomed into a major focal point for bringing in luxury goods from both East and West [21]. As is the case so often in history, one civilization’s success usually comes at the expense of its neighbors, in this case, the Mongols. The Mongol Empire was one of the largest land empires in history by the time of Kublai Khan’s death in 1294 (Fig. 2.2).

Fig. 2.2  Image citations (Creative Commons): Mongol Empire Accessed 1st December 2021

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It had split into four separate khanates with their own agenda and modus operandi. Each khanate was still immensely powerful, of which the Golden Horde exercised authority over the Crimea. To them, it was a small portion of their vast realm. Now the armies of the Golden Horde were comprised to a certain extent with the Tartars. This was a nomadic tribe from eastern Mongolia that was conquered in the days of Genghis Khan [1, 22]. They had been integrated into the Mongolian armies and helped with the western expansion of the empire. By the mid-fourteenth century, the Golden Horde relied on the Tartars to help govern their land. To put this into context, Caffa and for that matter the Genoese presence existed only because the Golden Horde allowed it. The land on which the trading city flourished was essentially a grant for the purposes of enriching the khanates’ wealth. For two decades by early 1340s, political, economic, and religious frictions between the Mongols and the Caffas took place. By this time, tensions with the Genoese region were mounting. Thus, by the year 1343, very little was needed to ignite a precarious situation into open hostility. Not too far from Caffa was the trading city of Tana. It was nested at the south of the Don River and renowned as being the starting point to get to China from Italy. It was in this city that a small angry exchange on a market street blossomed into a full-blown riot, resulting in spilled blood: a Muslim died at the hands of Italians, or at least as a tale goes. Word of the incident spread, and the local Mongol Khan, a man by the name of Jani Beg, decided to arrive at the city gates and brought with him an impressive Tartar army under the auspices of being a defender of Islam. Jani Beg demanded that the city capitulate immediately. In those times, a besieged city had the option of either adhering to the terms of surrender completely or taking their chances fighting back, which usually resulted in the city and its people being wiped from the surface of the Earth. The Genoese opted for the latter option and responded to Jani Beg terms with a particularly insolent response in retrospect [23]. Perhaps, this was not the best idea. The attacker did not expect this kind of response laid into Tana with a revenge, and therefore, the city was quickly overrun. However, some of the defenders managed to escape and then ran for their lives back to Caffa. As mentioned before, Caffa was an impressive city and inner-city walls were equally impressive and thus the Tartar army and their Khan had to settle in for a siege. This was supposed to be a long siege; as it dragged out something else was coming in on the doorstep of the European continent.

The Tartar Horsemen and the Black Death By 1346, tales of a strange disease (the Black Death) had begun to filter their way into the West. Most of the stories were ignored. Vast tracts of China and India lay dying of a mysterious pestilence, and the disease, like the stories about, it was making its way West by early 1346 [24]. Russian chroniclers had recounted that the shores of the Caspian Sea were affected with the Black Death and in less than a year it had spread across the Volga River, descended into the Crimean Peninsula, and onto the Tartar army. It did not take long before the encampment was infected and

Escaping Hell: The Propagation Towards Europe Through the Mediterranean

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soon after the soldiers began to die massively. For the Genoese protected by their city walls, this affliction was heaven-sent. To them, it was nothing less than their God’s retribution against the heathen race, and if they had any faith in this belief, they were soon to find out just how wrong they were [25]. The situation in the Tartar camps was degrading by the day to the point where more people were dying than could be easily attended to. The scene, if one could imagine, was that of putrid swollen corpses stacked like cordwood as far as the eye could see. But perhaps what motivated the survivors was not so much the site but rather the disgusting, gut-­ wrenching stench.

The Biological Warfare Attack and the Consequences The Khan, at this point, disgusted and revolted by the smell, gave the command to load the corpses on the catapults and then had the corpses launched into the city of Caffa with the hope that the smell would accomplish what his army could not [10]. This situation drove the inhabitants to surrender. The bodies were well into different phases of decomposition by the time they were weaponized [26]. As the body rotted, gases formed within the various layers of the decomposed bodies and internal organs. Moreover, some corpses would explode into chunks and aerosolize fragments spraying the area. These events went on for weeks [27]. The city was essentially inundated with human remains. The rats that were infesting the camp would follow the scent in short order, and with them the plague entered the city [28].

 scaping Hell: The Propagation Towards Europe Through E the Mediterranean By April 1347, there was very little left of the Tartar army around the city of Caffa. By the springtime, the straggling survivors had retreated. Many who left were infected and took the plague with them to other destinations. However, by then the contagion had made its way into the city, and there the scenario had become equally appalling. John Kelly in his book “The Great Mortality” describes what the situation in the city was like before the Tartars left: “As the death toll mounted, the streets would have been filled with feral animals feeding on human remains, drunken soldiers eluding and raping old women dragging corpses through rubble and burning buildings spewing jets of flame and smoke into the Crimean sky.” There would have been swarms of rodents and piles of bodies in every public square, and in every eye, a look of wild panic or dull resignation. The same scenes are replayed in the harbor, the only means of escape by the besieged. “Caffa would have been equally horrific surging crowds and sword wielding guards, children wailing for lost or dead parents, shouting and cursing, everybody pushing towards teeming ships and beyond them lay on the departing galleys prayerful passengers hugging one another under great white sheets of unfurling sails, ignorant that below the decks in dark sultry, hundreds, if not thousands of plague-bearing rats were scratching themselves and

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sniffing at the cool sea air” [29]. As said before, Caffa was an impressive city, and equally impressive was its port, which could shelter nearly 200 ships at this point in history. Panic had engulfed the populace, and getting out was the only resort the inhabitants could think of. Thus, it was not just one Genoese galley that managed to depart but several others. Their journey would take them South through the Black Sea and then through the narrow Bosporus or the strait of Istanbul in Turkey and the Sea of Marmara. Their destinations were the great ports of the entire Mediterranean world [30]. The world in which the plague was sailing into seemed almost perfectly set up for a pandemic. From the thirteenth century onward, trade had expanded like never seen before, not just on land but also by sea. The sea lanes and the trade routes of the Mediterranean had prominently emerged not just as a simple means to expand a country’s income, but also being vital to the success of any emerging power. Thus, ports and harbors grew to facilitate this need and became strategically crucial as the world made its first steps into becoming a global community. At that time, it became a relatively common sight to see luxury goods from China being sold in Italy, France, or even England [24]. Also, the time leading up to the fourteenth century was also a period of dramatic increase in the human population. This was a phase of prolonged favorable weather leading to impressive crop harvests, as the extra food would be required to feed extra mouths. Europe’s population was estimated to be at someplace in the 75–80 million range. However, good things came to an end. By the 1330s, the weather had changed for the worse, and this was accompanied by various ecological disasters, like droughts, earthquakes, and flooding. These ecological disasters would have a dramatic effect by instigating rat migrations; this was also a time when crops began to fail, malnutrition became more rampant, and rural populations began to flock to the cities [31]. Urban planning was not able to keep up with this massive influx of rural population, and so cities became disorganized, overcrowded, and even filthier. City dwellers could not effectively keep up with all the garbage that they produced [32]. For instance, sewage was literally thrown out the window on the streets. Likewise, the early fourteenth century was also one of the most gruesome periods when it comes to military history. John Kelly in his book “The Great Mortality” brings us to life. From Caffa to Vietnam and Afghanistan, no human activity has been more strongly associated with plague than war, and few centuries have been as violent as the fourteenth century. Decades before the plague, the Scottish were killing the English, the English the French, the French the Flemish, and the Italians the Spanish. In these savage decades, the nature of the battle changed in fundamental ways. For example, armies grew larger, battles were bloodier, civilians were attacked with more frequency, and property was destroyed routinely, and each helped to make the medieval battlefield a source of the plague dissemination, as a medieval soldier was a more effective vector to transmit disease [33]. Usually, the ships that sailed from Caffa had multiple destinations. In the summer of 1347, some of these ships arrived at Constantinople where Yersinia pestis landed and killed an estimated 50–70% of the population. The court scholar Demetrios, who was an eyewitness remarked, “Every day we bring out our own friends for burial and every day the city becomes emptier, and the number of graves increases. Men inhumanely shun each other’s

The Black Death Arrives in Italy: The Implementation of Quarantine

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company for fear of contagion, fathers do not bury their own sons and sons do not perform last duties for their fathers” [34]. From the great city on the Bosporus, the Black Death began to spread in land by two directions: to the West, it disseminated through Bulgaria, Greece, and Romania; then in the North, it spread towards Poland; and to the East, it dispersed across Asia Minor before heading into Persia. Nonetheless, the Genoese plague ships of Caffa were not done yet. They continued to sail South through the Dardanelles and onwards to ports in Cyprus the Levant Egypt and then all the way across North Africa [10]. In October 1347, 12 Genoese galleys arrived in the port of Messina in Italy. It was here that the great mortality first seemed to appear in the historical narrative. The local authorities who first witnessed incoming ships observed scores of men and women encrusted with lesions, many in the various stages of the disease. Stacks of dead bodies were later discovered below deck. After a period of deliberation, the decision was made to turn these ships out, but by then it was too late [10]. The Black Death invaded the city with unbound enthusiasm and then spread through the entire island, killing on average a third of the population as before with Constantinople, and began to spread over land in a noticeably short time. At this time, Yersinia pestis had jumped the Strait of Messina and then began to make its way up the Italian inner land, arriving in Rome a few months later [33]. In retrospect, it was estimated that the plague on average moved approximately two and a half miles a day, crossing rivers, gaining over mountain passes, and entering nearly every city it came across. Then, the plague ships that were forced to depart Messina went on towards new destinations with sailors on board, managing to survive by trading their goods. Thus, these very same ships would move on to Marseille, Genoa, Malta, Tunis, and ports in Spain, Sardinia, and Corsica to name a few [35].

 he Black Death Arrives in Italy: The Implementation T of Quarantine The city of Genoa, with an estimated population of ninety thousand inhabitants, was infected in late November of the same year where 30–40% citizens died [24]. The port city of Marseille would fare no better and served as the major entry point for France. It is from here that the plague would move north towards the town of Avignon where it arrived in January of the next year. It was also in January 1348 that Venice with an estimated population of 120,000 people was also affected. The Venetian response was vigorous and highly structured [36]. The Great Council declared that all entering ships were to be seized and searched. The ships that were found to have even the slightest indication of plague were immediately set to the torch on a nearby island isolated from the rest of the population [37]. A strict quarantine was established; in fact, the very word “quarantine” comes from the Italian term “quaranta giorni,” meaning 40 days, which was the amount of time ships and their crew were held in isolation [38]. A municipal fleet of gondolas was created to pass through the canals chanting “bring out your dead.” This rather macabre taunt summoned the population to throw their dead bodies into the waiting ships below. The corpses were then systematically

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interred in specialized burial locations. Despite these measures, the death rates soared up to over 60% of the population (Fig. 2.3). It was later estimated that over 72,000 people died. This death toll was so high and so rapid that in many instances the complex network of society would either fail or vanish entirely [39]. Once again, the Venetian Government stepped up to the challenge as society began to disintegrate all around it. As such, draconian measures and martial law were invoked. Civilization would endure but it held on by a very tiny thread. However, as Venice desperately grappled to maintain order and to save the rest of the population, the Black Death had already moved on. The decade that led up to 1348 was an exceedingly difficult time for Florence, as floods, disease, drought, and famine had all visited the city. Warfare engulfed the land as Genoa was up in arms against Venice and the papacy [40]. Moreover, Edward III, King of England, who had used Florentine banks to fund his portion of the Hundred Years’ War, defaulted on his loans. The magnitude of these loans was so immense that it caused financial ruin in the Italian city. At the time, the over 100,000 citizens of the city had no idea on what was about to hit them. Arising from what seemed like thin air, the stigmata of purple-black swellings in the armpit and the groin, known as buboes, began to suddenly appear, seemingly on

Fig. 2.3  The Plague by Arnold Böcklin, 1827–1901 CE. (Kunstmuseum, Basel, Switzerland) Public domain

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everyone [39]. This was followed by bloody vomiting, hyperthermia, delirium, and, in most situations, an agonizing death as never seen before. Society began to break down as entire families and neighborhoods would be wiped out in a few days [40]. Panic mounted in cities, and riots and looting spread like wildfire. Those that could attempted to barricade themselves, while afflicted and deceased people were simply abandoned to their fate, and there were many who would desperately try just to escape the carnage altogether [41]. By most estimates, 50% of the population perished. Giovanni Boccaccio, an Italian writer, poet, and an important Renaissance humanist, who some say lived in the times of the plague in Florence gave a testament of what he saw: “A great many people died who would have perhaps survived had they received some assistance. Indeed, the number of deaths reported in the city whether by day or night was so enormous that it astonished all who heard tell of it, to say nothing of the people who actually witnessed the carnage. Thus, a great number departed this life without any one at all to witness their going. Few indeed were those to whom the lamentations and bitter tears of their relatives were accorded.” Boccaccio continues, “Such was the magnitude of corpses that huge trenches were excavated in the church yards into which new arrivals were placed in their hundreds stored tier upon tier like ships’ cargo. Each layer of corpses being covered with a thin layer of soil till the trench was filled to the top” [42] (Fig. 2.4). The term “plague pits” would later be coined but even more gruesome would follow. Under these circumstances, it is possible that the very same human remains would then serve as the food source for rats, pigs, and other animals. The death that

Fig. 2.4  The plague of Florence in 1348, as described in Boccaccio’s Decameron. Etching by L. Sabatelli. Credit: Wellcome Collection. Public Domain Mark

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surrounded the individual was near impossible to grasp for the population, since there was no scientific knowledge of what was exactly going on. The magnitude was just too much. But why was it so that the Black Death, as mentioned before, was the perfect storm? The plague caused by Yersinia pestis was nothing new on the world stage. It had affected humanity before and would do so afterwards. As we have seen before, the plague of Justinian in 540 which caused millions of deaths was also caused by Yersinia pestis, and yet, the death rate, the duration, and the extent of carnage were never as high as it was during the Black Death [43]. The Black Death in the middle of the fourteenth century also had some unusual characteristics. It appeared to advance, though a bit slower, even during the winter months. The question is: Were fleas responsible as most of the fleas would have died because of extremely low temperatures? [44]. Also unusual, this particular plague infected people at a rate that modern Yersinia pestis just does not seem to possess. Today, some forensic scientists sense that this bacterium was assisted. Aside from the warfare at the time, the sanitary conditions of cities, the extent of the trade routes, and having an ideal vector of transmission, the Black Death may not have been alone. The contagion process was indeed greatly enhanced by the civilization pattern at that time [45]. Among other continents, the plague would wash over one area only to return with vengeance from another direction. As such, some areas of Europe would be hit several times as the second wave was even more devastating than the first. The reasons for this statement are obvious. For instance, the European population at the time of the first wave or Justinian plague was lower as compared to the second wave: During the course of the Black Death, the economic growth and the settlement of different religious communities, wars, and crowded cities and ports also contributed to the high dissemination of the Black Death in the Middle Ages [46]. By mid-1348, the Black Death had been rampaging through Europe for nearly a year. Avignon and southern France had run out of space to bury their deads. A wave of plagues that originated in Constantinople had blazed the path into the Balkans and Italy, prompting the historian Giovanni Boccaccio to comment: “One citizen avoided another hardly, any neighbor troubled about others. Such terror was struck into the hearts of men and women by this calamity, that brother abandoned brother and very often the wife or own husband. What is even worse and nearly incredible is that fathers and mothers refused to see and tend their own children as if they had not been theirs” [47]. Through the remaining of 1348, at an average rate of two and a half miles a day, the Black Death made its way North. Rural communities along the way were sometimes wiped out entirely; in some places, the devastation was so complete that nature would retake the land and traces of civilization would only be rediscovered by aerial photography prior to the First World War. By October 1348, the great mortality caused by the Black Death arrived in one of its most prominent hunting grounds: the city of Paris with a population of approximately 80,000–200,000 people, one of the larger cities of Europe. Once the plague made its way in, it began to worsen. Gaining in virulence by the time it left a year later, over half the city was left silent and lifeless. But the plague was only getting started. As it continued its path North, it seemed that in the hot summer days, it acquired even more momentum. And its most destructive time was still ahead [48].

The Black Death Strikes Stronger in the United Kingdom

29

The Black Death Strikes Stronger in the United Kingdom By the late summer 1348, a fisherman in the English Channel could see the plague flag flying from nearly every French town and villages along the coast. It would not be long before the Black Death would engage in its most sinister work. A cross-­ Channel invasion was imminent as the battle for Britain would soon begin. The plague after all had killed in France, on the seas and the oceans [49]. In England, it would do its work with a brutal efficiency never seen before. There, plagues would kill on the beaches, on the landing grounds, in the fields, in the streets, and in the hills as if it would never surrender. As Avignon, Paris, Florence, and many other cities were running out of space to bury their deceased people, England was enjoying a relatively good summer in the year 1348. Popular King Edward III had replaced the rather unpopular Edward II.  Edward III had gone on to achieve glory against the French at the Battle of Crécy. In 1346, his victorious troops would steadily bring back the spoils of war to the ports of Calais in France, where they would be shipped across the English Channel to a triumphant Britain [50]. Although this train of goods increasingly made its way through the French countryside, several cities displayed the plague flag. It is important to mention that English wool at this point in history was in extremely high demand. Trade continued relatively unabated despite the looming threat of the plague. In mid-1348, the number of English sheep was estimated at approximately eight million, outnumbering the English people by a decent margin. The Black Death came with a vengeance never seen before. In retrospect, historians feel that the plague came from Calais and landed on several ports along the Channel coast. The great mortality arrived at Southampton and Portsmouth as well as in the small port of Malcomb, now part of Weymouth, where it was suspected that a ship from Gascony docked with a cargo of French wine [51]. The effect of its landing was striking and immediate. A local monk Henri Knighton described it as “a cruel death took just two days to break out all over town. For many it was nothing less than sudden death.” From these two separate beaches, one along the Channel Coast and the other from Bristol, the plague began to move inland along the roads and the river. While the average death rate in a city in continental Europe was approximately 33%, it would soar to an incredible 55% in England. Some cities would see figures as high as 80–90% of their population perish. Many towns and cities could simply not bury their deads fast enough and would then resort to incinerating the remains [52]. Under these circumstances, a traveler along an English road would see a horrendous landscape of giant black smoke plumes emanating from every direction, with the ash of the death raining down upon them. So many people died that industries were left abandoned, fields were unattended, livestock died by thousands in the pastures, and the streets of small villages and towns would be overgrown and retaken by nature (Fig. 2.5). By the late autumn of 1348, the combined two fronts wrapped the City of London which as John Kelly, the author of “The Great Mortality,” would say “sanitary conditions of the city were appalling, even by medieval standards.” London at this time was estimated to have had 80–1,000,000 people, of which over half of them would be taken by a particular sinister: first, by the pneumonic variant of Yersinia pestis as

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2  The Plagues Pandemics: 2000 Years of Recurrent Devastations: The Black Death

Fig. 2.5  Credit: Lead mortuary crosses, England, 1300s and 1600s. Science Museum, London. Attribution 4.0 International (CC BY 4.0)

the fall cooler weather would drive people indoors, and second, by the bubonic form of the plague that emerged in the spring as the warming months brought back fleas and rats. Despite the alarming death rate, features were just getting started. For the rest of 1349, the plague advanced towards the North. And just like in France, it overran one city after the next. But again, in England, it seemed to inflict death at an unusually high rate as it continued its relentless drive, and by the latter part of that year, it had arrived at the borders of Scotland. John Kelly, using primary source material, gives the Scottish an assessment of what happened next: “The Scots, who were still laboring under the impression that the plague was an English phenomenon, were enjoying themselves immensely in the summer at 1349. They were laughing at their enemies and swearing by the foul death of England. In March of 1350 the, very next year, they amassed the large army in the forest of Selkirk near the English border” [53]. They did this with the intention of invading the whole kingdom, but before the attack could be launched, the “Revengeful hand of God reached across the border and shattered the gathering Scots with sudden and savage death.” This would not be the only time an army would be defeated by the plague. Far to the South of Europe, the plague had arrived at the Iberian Peninsula in 1348. It had come to the Emirates of Granada in 1349, and by 1350 (the same year the Scots were dying at Selkirk), the warrior King Alfonso XI of Castille was on the verge of taking Gibraltar and planned to bring down the emirate. Instead, at the siege of Gibraltar, his army would be destroyed by Yersinia pestis, and Alfonso XI would be remembered in history as the only reigning European monarch to die of the Black Death [53]. Although the emirate of Granada was saved, it would take another 150  years before the “Reconquista” of Granada by the Spanish would be finally completed. By late 1349, 50–60% of the British Isles had succumbed to the plague. Traveling at a speed of two and a half miles a day, the Black Death had crossed the Rhine River, entering what would one day be Southern Germany, and then advanced to the gates of Vienna. On the North Sea, the Black Death crossed the water and invaded Scandinavia. Ships would later be found adrift with nothing on board except ravaged corpses. The city of Bergen in Norway was one of the first cities to be hit,

The Search for Cause and Remedies During the Black Death

31

but the Black Death would not stop there. It moved East, entering even into remote areas such as Tyssedal in Norway, a secluded village located high in the mountains. It was so badly devastated that nearly everyone died. When a rescue crew arrived in 1350, nearly a year later, the only survivor was a young girl. The child, due to a lack of human interaction and guidance, had returned into an animalistic existence by losing the ability to communicate with words and by hunting wild game [54]. Despite these harrowing stories, the plague would move on [55]. By 1351, the Black Death arrived in Poland but was not able to inflict as much damage, as cities were more spread out. The king Casimir III (also known as Casimir the Great) had closed the borders of his kingdom and enforced extremely strict quarantine measures [33]. As mentioned before, anybody in Poland who showed the slightest signs of plague was literally detained into their homes. As a side note, there is one theory that says that Poland had an abundance of cats which helped curb the rat population and thus saved the population in some way. By 1352, the plague had made it to the gates of Moscow and continued to move East and back into the Eurasian steppe from where it came. Meanwhile, Europe was left devastated in its wake, but by 1353, the Black Death was finally over [56], although the plague remained at endemic levels, causing further epidemics and pandemics.

The Search for Cause and Remedies During the Black Death With such massive mortality descending on seemingly everyone, a shattered and desperate Europe began to look for answers. While many felt and turned to religion, others looked to astrology: The city of Paris was considered at the time the pinnacle of medical knowledge. Forty-six masters from Paris Medical University congregated and determined that the Black Death was caused by an unusual conjunction of Saturn, Mars, and Jupiter, which they determined happened at one hour in the afternoon on March 20, 1345. Now, the erudite masters got together and assembled an essay to explain this further: “The first cause of this pestilence was and is the configuration of the heavens which occurred in 1345 at one hour after noon on the 20th of March when there was a major conjunction of the three planets in Aquarius.” What happened according to the masters was that “many of the vapors, corrupted at the time of conjunction, mixed with the air and were spread abroad by frequent gusts of wind. This corrupted air, when breathed in, corrupted this substance of spirit and thus the heat generated destroyed the life force” [57]. Keeping all this information in perspective, it is accurate to point out that the scientific method, germ theory, and even the medical need for handwashing were still way in the future, not to mention entities like IV fluids, vaccines, and antibiotics. The medicine of the time was based on ideas that ranged back to the time of Aristotle and Galen. It was based on the four humors of the body: blood, phlegm, yellow bile, and black bile which could cause illness if they were unbalanced, though the preferred treatment was usually bloodletting. However, this method would usually result in the introduction of more infections and/or hemorrhages, which would usually hasten death. But when this did not seem

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2  The Plagues Pandemics: 2000 Years of Recurrent Devastations: The Black Death

to work, new methods were developed [58]. For instance, doctors would lance the swollen boils, draining the extremely infectious contents out. In some situations, this would work, but in others more infections would simply set in through the new openings. In some cases, this would be taken a step further, the buboes were cut, and then a concoction of herbs and human excrement was rubbed into the cutaneal lesions [59].

The Miasma Theory One theory that came about was the idea that the plague was an airborne vapor, a miasma or bad air [60]. This was thought as something that could be countered by inhaling extremely pure air, the reason some people sought solace in the countryside. This led entire communities rushing to stick their heads into the local latrines. Along the same lines, drinking urine became very popular, and specifically urine from non-plague victims developed into a treatment. The procurement of this treatment became its own cottage industry. For those rich enough and who decided not to drink urine, a crushed-up sapphire was ingested as a remedy against the plague. There were those who also employed fire; initially, it was applied directly to the body. In some cases, hot pokers were even jabbed into the boils of those with the disease [61]. One way to look at it is that one person’s treatment is another person’s torture, but in other scenarios, fire was used as a means to ward off what was considered evil vapors, and of course fire was also highly effective at warding off fleas [62]. Thus, the Pope at the time, Clement VI, would sit between two log fires when he was giving mass, and for the record, he was noted to have survived the plague. Throughout Europe, quarantine would be used more effectively. The extreme examples would include the city of Milan and a good majority of Poland. In those areas, anyone who showed the first signs of the great mortality would be literally confined. In many cases, they would be confined alongside their own families within their own homes which by now became their own tombs. As vicious and brutal as this may sound, Milan’s death rate was only 15% and Poland’s rate was much lower than the rest of Europe [63].

The Plague Doctors During the years of the great mortality, there were a lot of different treatment modalities that were developed, but perhaps the greatest legacy of medical intervention was the plague doctors. To look upon a plague doctor was a foreboding experience. If you imagine being there at this time, there was a good chance that you were dying when you saw them. Their appearance alone was astonishing as they wore the equivalent of a medieval hazmat suit and donned a thick leather covering with solid boots and thick gloves. Their bodies were nearly sealed off from direct contact. The birdlike masks were designed to shield their breathing, with the beaks being full of herbs and flowers to neutralize some of the putrid odors, and the eyepieces were

The Search for Redemption

33

made of glass but would later be filled with crystal and then dyed red in color giving one an almost sinister gaze. Some of these eyes would also be offset so that the doctor could not look directly at his patient as some thought that eye contact could lead to contracting the disease. In many cases, these frightening bird-human hybrids would be the last thing a person would see, and unfortunately most plague doctors are remembered by history as being nothing more than icons of death; that said, people who took up this job placed their lives on the line and began to study what they saw. The old beliefs that treating patients and medicine in general came under increasing scrutiny, and new methods at treating wounds, pain, and fever along with investigating the disease itself were developed [64]. Even if they could not cure the Black Death in many cases, these plague doctors still managed to ease the suffering of those they treated. Now not all would put their faith in medicine or science; many also turned to religion for comfort, but some would take this to an extreme movement known as the flagellants. During the fourteenth century, plague doctors visited villages affected by the plague. As public servants, their primary duties were to treat and cure victims of the plague, perform autopsies, bury the dead, and count the number of victims affected. Plague doctors were not necessarily physicians, but also barbers, apothecaries, midwives, herbalists, and priests. They wore an outfit designed by Charles de Lorme (1584–1678), the chief physician of three French kings (Henri IV, Louis XIII, and Louis XIV) (Figs. 2.6 and 2.7). At the time, plague doctors covered themselves head to toe and wore a mask. The outfit consisted of a coat covered in scented wax, breeches connected to boots, a tucked-in shirt, and a hat and gloves made of goat leather. In addition, they wore a mask with a nose “half a foot long, shaped like a beak, filled with perfume and ointments, a compound of more than 55 herbs and Fig. 2.6  Engraving of the plague doctor, Paul Fürst, c. 1656. Public domain

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2  The Plagues Pandemics: 2000 Years of Recurrent Devastations: The Black Death

Fig. 2.7  Portrait of Charles Delorme, 1630 Jacques Callot, French, 1592–1635 Princeton University Art Museum

other components like viper flesh powder, cinnamon, myrrh, and honey with only two holes, one on each side near the nostrils, outfits were completed  with round glass goggles” [65]. 

The Search for Redemption Emerging in late 1348 or early 1349, as the Black Death ravaged Europe, men and women, as many as 500, would engage in pilgrimages across the continent as self-­ punishment for what they perceived as sins of humanity and/or an angered God [66]. As such, they would whip themselves as they went. The whips were composed of three or four ropes with a piece of metal or hooks embedded at the end. Many would march naked; others were dressed in white robes and hoods sometimes with a red cross printed on them. A contemporary witness, a Dominican friar, would comment that the movement was like a race without a head and would describe one of the members as “he stripped himself naked and beat his body and arms and legs till blood poured off of them, then in an ecstasy of pain and joy he fell to his knees and in his cold “monk’s cell” naked and covered in blood and shivering in the frosty air, he prayed to God to wipe out his sins.” Officially, from a religious perspective, this type of action was rejected by Pope Clement VI as being heretical. Furthermore, pilgrimages served as a vector for the disease spread. People along the way would know that the flagellants had come, not to mention the bodies left behind of those who had died in the attempt to find forgiveness for their sins [1].

The Aftermath of the Black Death

35

The Black Death and the Blame on Others Increasingly, as the great mortality took more lives at an unprecedented rate, various people from Europe began to look for someone to blame as it was the case with syphilis. The Jewish community of Europe would be one of the major victims. The plague was put into the light of being an elaborate scheme where a vast underground Jewish network had poisoned all the wells, causing the disease. Many Jews were thus rounded up and faced torture to extract forced confessions, after which the massacres began [67]. The first one occurred in the Mediterranean city of Toulon, France, on April 13, 1348, as many would follow almost throughout the entire scale of Europe. Heinrich Truchsess von Diessenhofen wrote the canon of Constance saying: “Within the revolution of one year that is from All Saints Day November 1st, 1348, until Michael mass September 29th, 1349, all of the Jews between Cologne and Austria were burnt and killed.” In Strasbourg, now France, it was reported that half the Jewish population was stripped naked, marched into a local cemetery, and incinerated in a stone house. In Brandenburg, they were placed on a giant grill and burnt alive. But even in these dark tumultuous times, there were those who provided sanctuary. The city of Marseille in southern France, for example, offered a great deal of protection. The king of Poland, Casimir the Great, would take in Jewish refugees and even prohibited persecution. Even the Pope Clement VI in a papal bull on July 6, 1348, would say, “It cannot be true that the Jews are the cause of the plague for it affects the Jews themselves.” Even with the Pope’s blessings, not all would listen. In some communities where the Jewish population was slightly less affected, they would be blamed for the plague and killed. In other communities where the Jews were dying from the Black Death, the locals would justify killing them as completing God’s work [68]. This situation went on for years.

The Aftermath of the Black Death There is a famous statement from Rounsevelle Wildman in his book Tales of the Malayan Coast from Penang to the Philippines: “Civilization is only skin deep, and so is barbarism. Had your country never broken its word and been as just as it is powerful, your red men would have been to-day where our brown men are—our equals” [69]. The Black Death was certainly the greatest human pandemic in humanity. After all, it is estimated that a third of Europe did not survive the pestilence, and now historians feel that that number is deplorably low. Worldwide, it is also thought that over 200 million people died. The fragile network of society in some places broke down or was destroyed entirely, and yet civilization persisted. A new equilibrium was established, and some say that Europe has intensely emerged [70]. With so many dead, the cost of labor skyrocketed, and the cost of food plummeted. Even the wealthy were forced to make an effort to pay higher wages; peasants and serfs saw their standard of living improve. Indeed, some could even build up wealth to pass on to their children. Furthermore, one who was previously indebted to the land now had a better chance of moving to a new location with the knowledge that they could be employed. With the need for labor in such high demand, even the

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position of women was elevated as some took traditionally male roles. In his book “The Decline of Serfdom in Late Medieval England: From Bondage to Freedom,” Mark Bailey even went so far to say this was “the beginning of the end of serfdom” [71]. This was going to be a time when old ideas and institutions that had previously floundered in satisfaction were now put to the test. People began to take a very insightful re-examination of their own mortality. As such, art, literature, and music were all drastically affected by the plague as can be seen with the emergence of the Danse Macabre or Dance of Death genre in the Middle Ages (Fig. 2.8). Many historians would also add that a new breed of doctors would begin to question their methods of treatment and out-of-date ideas. A now growing middle class would hunger for new concepts and books, and an ever-growing disappointment with religious institutions would hasten Europe into the Reformation. Humanity took a major hit, but it stood the test. John Kelly summarized this extremely well: “that after two and a half centuries, rapid demographic growth, the balance between people and resources had become very precarious.” Nearly everywhere, living standards were either falling or stagnating; poverty, hunger, and malnutrition were widespread; social mobility was rare; technological innovation was stifled; and new ideas and modes of thinking were denounced as dangerous heresies. The Black Death helped end this malaise and allowed the European continent to recapture its momentum. A smaller population meant a larger share of resources for the survivors and better use of resources. Human ingenuity also flowered as people sought ways to substitute machine power for manpower. As a result, Europe had a more diversified economy, a more intensive use of capital, a more powerful technology, and improved standard of living (Fig.  2.9). The plague, in some areas, broke the Malthusian catastrophe or overpopulation, which otherwise would threaten to hold Europe in its traditional ways for an indefinite future. Horrific as a century of unremitting death had been, “Europe was able to emerge from the charnel-house of pestilence, renewed, like the sun after the rain” [72]. Fig. 2.8  Illustration from Liber Chronicarum, 1. CCLXIIII; Skeletons are rising from the dead for the dance of death (Image credit: Anton Koberger, 1493/Public domain)

The Third Plague Pandemic

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Fig. 2.9  Credit: Bow, open end, spectacle case, ivory (?), with judgement of Solomon and Death of the Doctor depicted, repaired, English or Dutch, 1490–1550. Full view, back of case, matt black background. Science Museum, London. Attribution 4.0 International (CC BY 4.0)

The Third Plague Pandemic During the mid-nineteenth century, a third pandemic of the plague originated in the Yunnan peninsula, reaching Hong Kong in 1894. In the same year on June 20, a French bacteriologist named Alexandre Yersin discovered the causative organism that caused the illness: “bacillus Pasteurella pestis,” now called Yersinia pestis [73]. From there, due to increasing globalization and immigration through ships, it disseminated across much of the world. Unlike the Black Death, the third plague pandemic never attained the levels of mortality seen in previous outbreaks. Some scholars hypothesized that the rat fleas developed a sort of herd immunity to the virus, making it less virulent. From 1897 to 1908, textbooks on infectious diseases described the symptomatology of the third plague pandemic as “pyogenic, necrotic, infarctive, inflammatory, hemorrhagic, and edematous lesions.” In 1909, during the Bombay pandemic in India, from 13,600 cases, only 3.7% developed “cellulocutaneous plague” [24].

 he Plague in the Twentieth and Twenty-First Centuries: T The Endemic Situation According to the Centers for Disease Control (CDC) in the United States, the plague was first introduced into the United States in 1900 by rat-infested steamships that had sailed from affected areas, mostly from Asia [74]. The most important epidemic took place in Los Angeles from 1924 through 1925. Between 1900 and 2012, 1006 confirmed cases of plague occurred in the United States. The plague continues to affect the United States nowadays with 12 deaths recorded from 2004 to 2015 mostly in rural areas and 106 cases between 2000 and 2019 mostly in Southwest areas of the United States (Figs. 2.10 and 2.11). During 1930–1940, cases were described in South America. During the twenty-­ first century, outbreaks were reported in Madagascar and nine other countries in

2  The Plagues Pandemics: 2000 Years of Recurrent Devastations: The Black Death

38 18

Cases

Deaths

16 14

Cases

12 10 8 6 4 2 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 Year

Fig. 2.10  Documented cases of plague in the United States in the twenty-first century. Source: CDC public domain

Fig. 2.11  Plague ecology in the United States. Source: CDC public domain

The Plague in the Twentieth and Twenty-First Centuries: The Endemic Situation

39

Africa and the Indian Ocean (Ethiopia, Kenya, Tanzania, Mozambique, South Africa, Seychelles, Comoros, Reunion, and Mauritius) because of frequent trade and travel with Madagascar. This led to a warning from the World Health Organization (WHO). From 2010 to 2015, the WHO reported 3248 cases of plague worldwide, including 584 deaths. Currently, the three most endemic countries are Madagascar, Peru, and the Democratic Republic of Congo (Figs. 2.12 and 2.13).

Global Distribution of Natural Plague Foci

Areas with potential plague natural foci based on historical data and current information (based on data from WHO, March 2016)

Fig. 2.12  Global distribution of natural plague foci as of March 2016. Based on data published by the WHO in March 2016

Reported cases ** 1-10 11-100 101-1,000 >1,000

* Data reported to World Health Organization (WHO) **Squares placed in center of reporting countries

Fig. 2.13  Reported plague cases by country, 2013–2018. Adapted from data published by the CDC and WHO. https://www.cdc.gov/plague/maps/index.html

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Treatment Three main forms of plague have been reported: bubonic plague, septicemic plague (caused by the bite of an infected flea), and pneumonic plague, in which the illness can be transmitted through aerosolized infective droplets. Yersinia pestis incubation rate is short from 3 to 7 days with a mortality rate from 30% to 100% if untreated [75]. Since the advent of antibiotics, the death toll of the plague has been reduced up to 8%. Yersinia pestis is susceptible to all antimicrobial agents active against gram-negative bacteria. In early 1938, sulfonamide was used as a treatment for the plague; later in 1946, streptomycin was introduced as an antimicrobial agent for treatment. Nowadays, streptomycin, tetracycline, and chloramphenicol are the three antibiotics recommended for the treatment of Yersinia pestis infection, with streptomycin being the first choice. Sulfonamide, trimethoprim-sulfamethoxazole, or tetracycline is recommended as a prophylactic therapy to be administered to close contacts of pneumonic or bubonic plague patients (Tables 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, and 2.9). Table 2.1  Treatment of adults and children with pneumonic or septicemic plague Population Adults Aged ≥18 years

Category First-line

Alternatives

Antimicrobiala,b Class Ciprofloxacin Fluoroquinolone Levofloxacin Fluoroquinolone Moxifloxacin Fluoroquinolone Gentamicind Aminoglycoside Streptomycine Aminoglycoside Doxycycline Tetracycline Chloramphenicold,e Amphenicol Ofloxacind,h Fluoroquinolone Gemifloxacind Fluoroquinolone Amikacind Aminoglycoside Tobramycind Aminoglycoside Plazomicind,e Aminoglycoside Trimethoprim-­ sulfamethoxazoled Sulfonamide

Dosagec 400 mg every 8 h IV or 750 mg every 12 h PO 750 mg every 24 h IV or PO 400 mg every 24 h IV or PO 5 mg/kg every 24 h IV or IM 1 g every 12 h IVf or IM 200 mg loading dose, then 100 mg every 12 h IV or PO 12.5–25 mg/kg every 6 h IVg (Maximum 1 g/dose) 400 mg every 12 h POi 320 mg every 24 h PO 15–20 mg/kg every 24 h IV or IM 5–7 mg/kg every 24 h IV or IM 15 mg/kg every 24 h IV 5 mg/kg (trimethoprim component) every 8 h IV or PO

Treatment

41

Table 2.1  (continued) Population Children Aged ≥1 month to ≤17 years (unless otherwise noted)

Category First-line

Antimicrobiala,b Class Ciprofloxacin Fluoroquinolonej

Levofloxacin Fluoroquinolonej

Alternatives

Gentamicind Aminoglycoside Streptomycine Aminoglycoside Doxycycline Tetracyclinej Chloramphenicold,e Amphenicol Moxifloxacink Fluoroquinolonej

Ofloxacind,h Fluoroquinolonej Amikacind Aminoglycoside Tobramycind Aminoglycoside Trimethoprimsulfamethoxazoled Sulfonamide

Dosagec 10 mg/kg every 8 or 12 h IV or 15 mg/kg every 8 or 12 h PO

(Maximum 400 mg/dose IV, 500 mg/dose every 8 h PO, or 750 mg/dose every 12 h PO) Body weight