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Epidemiology of Infectious Diseases: Pandemics Throughout History


Pandemics have plagued humankind since before the dawn of civilization. In fact, they were an unforeseen result of civilization. There is no question that our prehistoric ancestors struggled with infectious diseases, i.e., diseases caused by the transmission of pathogenic microorganisms (bacteria, viruses, fungi, or parasites) to humans from other humans, animals, or the environment. However, because our ancestors were confined to small, remote communities, there was little opportunity for disease to spread elsewhere. This situation changed drastically 10,000 years ago when the Agricultural Revolution replaced a nomadic existence with a sedentary one, marking the transition from hunter-gatherer societies to farming communities (Dobson & Carper, 1996). When humanity began to live in villages, towns, and especially cities, communicable, that is, transmissible diseases became more common. Humanity has been living this way ever since. Increased trade between civilizations has facilitated human-animal interactions and prompted the spread of zoonotic infections, whereby pathogens are transmitted between different species, namely from animals to humans. Subsequently, greater urbanization, expansion of industrial areas and the adverse effects of climatic change have led to the emergence and spread of infectious diseases, raising the likelihood of outbreaks, epidemics, and even pandemics (Lindahl & Grace, 2015).


Before delving into the history and intricacies of the most notable pandemics that have afflicted humankind, one should first understand the subtle but important differences between endemic, outbreak, epidemic, and pandemic in an epidemiological context. Although they are often incorrectly used interchangeably, these epidemiological terms do not signify the same. From an epidemiological perspective, these terms are defined based on the occurrence of a health condition versus its predicted frequency, as well as its geographic spread (Grennan, 2019). In this context, an endemic disease refers to any disease that persists in a specific location or population affecting it with a high, yet constant and predictable frequency; while an outbreak is defined as an unexpected increase in the number of people with a specific disease or the emergence of cases in a new location. An epidemic is an outbreak of disease that spreads over a larger geographic region. Finally, a pandemic is an epidemic that has spread globally, often at great speed, with new cases emerging every day, such as the infamous COVID-19 pandemic (Piret & Boivin, 2021; Public Health 101, 2022). It is important to note that the definitions above do not refer to the severity of a disease but rather to its prevalence, and can be used for infectious and non-infectious diseases such as cancer and diabetes.

Figure 1: For millennia, humankind has been at odds with infectious diseases (Emejulu, 2022).
Plague: The Oldest and Deadliest Foe

For most of history, city dwellers have endured the need to live in crowded, unsanitary environments. The rise of zoonoses has been favored by this lifestyle (Bengis et al., 2004). The plague is a prime example of how zoonotic disease transmission underlies the emergence of several pandemics that have devastated entire civilizations throughout history (Wolfe et al., 2007). Plague is caused by the bacterium Yersinia pestis, which was spread from infected rats to humans via flea bites, with human-human transmission also contributing to the disease's spread. Yersinia pestis has been linked to at least three human plague pandemicsthe Justinian Plague, the Black Death, and the Third Plague (Zietz & Dunkelberg, 2004). Plague manifests in three clinical forms according to the route of infection: bubonic, septicemic, and pneumonic. Bubonic plague is the most frequent and mildest form of the disease, with flu-like symptoms followed by painful, swollen lymph nodes (known as buboes) and death rates ranging from 40-70% (Yang, 2018). Septicemic plague occurs when bacteria grow in the blood, resulting in gangrene of the extremities, whereas pneumonic plague occurs when bacteria infect the lungs by aerosol transmission, resulting in hemoptysis, or blood expectoration. Without appropriate antibiotic treatment, pneumonic and septicemic plague are almost invariably lethal (Tognotti, 2013).


The Justinian plague, named after the Byzantine emperor at the time, struck Egypt in AD 541 and spread across the Mediterranean, killing an estimated 60% of people in Mediterranean countries (Mordechai et al., 2019). This was the Old World's first major plague pandemic which had disastrous consequences, profoundly altering Western culture and severely impacting food supply, resulting in an eight-year famine (Plague Manual-Epidemiology, Distribution, Surveillance and Control, 1999). The Black Death was a bubonic plague that spread from Asia to Europe and Africa between 1347 and 1353. With an estimated 200 million deaths, it is considered the deadliest pandemic in human history. It is estimated that up to 60% of the European population fell victim to the Black Death. Other waves followed, including the plague of Milan (1630) and the great plague of London (1665–1666) (Piret & Boivin, 2021). Since there were no treatment options for the plague at the time, avoiding contact with sick people and infected animals was the only way to prevent infection. In 1377, the city of Dubrovnik introduced a quarantine and in 1423 the Republic of Venice established the first plague hospital (lazaretto). The third Plague pandemic began in the Chinese region of Yunnan in 1894, with ships eventually disseminating it to Japan, Singapore, Taiwan and India. In the years that followed, the disease spread to every inhabited continent, killing more than 12 million people in India and China (Bramanti et al., 2019). Alexandre Yersin solved the plague riddle in 1894 when he identified the bacteria responsible for the disease, now known as Yersinia pestis (previously Pasteurella pestis), in samples from plague victims and dead rats in Hong Kong (Butler, 2014). Improvements in sanitation, personal hygiene, and medical treatment, as well as the practice of isolating sick individuals (quarantine), eventually halted the plague terror's march. Nonetheless, plague remains an ongoing concern in many parts of the world, particularly in Africa, where the number of cases and nations reporting plague has increased in recent decades (Schrag & Wiener, 1995). Despite being one of the deadliest diseases documented in human history, the plague is nowadays simple to cure with appropriate antibiotics yet, virtually impossible to eradicate.

Figure 2: In the early 16th century, these plague doctor suits were the earliest form of personal protective clothing (Traynor, 2021).

Cholera: The Strange Case of the Broad Street Pump

Cholera is an acute intestinal infection caused by the ingestion of food or water contaminated with the bacteria Vibrio cholerae (Faruque et al., 1998). Upon ingestion, the bacteria colonize the small intestine and produce a toxin that causes extremely watery diarrhea and massive loss of body fluids, which can lead to dehydration and even death (Jensen et al., 2021). Although cholera is easily treated with a rehydration solution, it remains a global health problem due to high morbidity and death among vulnerable populations who do not have access to a qualified health care system or sanitation. The first cholera pandemic, commonly referred to as Asiatic cholera, began in Calcutta in 1817 and spread across an unprecedented area, stretching as far as China and the Mediterranean Sea (Hays, 2005). This was prompted by the arrival of steamships and railways allowing for considerable reductions in travel time and increased trade. Millions of people perished as a result of this pandemic, including many British soldiers, which caught Europe’s attention (Dutta, 2021). This was the first cholera pandemic that ravaged Asia and Europe, yet the 19th and 20th centuries had witnessed the arrival of six other cholera pandemics. As during the Black Death, strategies to limit cholera's spread included isolating affected people in military hospitals while retaining ships carrying cholera-infected crew members and passengers outside ports (Tognotti, 2013). Although quarantine was effective in containing plague, it proved virtually ineffective in preventing cholera, suggesting another route of transmission. To keep urban areas clean and reduce disease transmission, quarantine was superseded by sanitation in the 1840s (Tognotti, 2000).


A turning point in the history of cholera transmission and control came with the revelation that cholera was a waterborne disease. The 1854 Broad Street cholera outbreak reached Soho, in London, claiming the lives of 616 people in just a month. Importantly, the outbreak pattern was documented on a map that forever changed the world. How can a map change the course of history? This leads back to John Snow, a doctor who first used epidemiological methods to trace the source of the outbreak. In the 1850s, it was assumed that cholera was spread by miasma, i.e., bad air. Snow, on the other hand, suspected that cholera transmission could be linked to polluted water. To prove this, Snow interviewed residents of Golden Square to gather information about where cholera sufferers got their water and thus determine the origin of the outbreak (Begum, 2016). Snow was able to map the geographic distribution of cholera cases and mortality and found that the majority of those infected lived nearby and used water from the Broad Street water pump. After Snow presented his findings to municipal officials, the pump handle was removed on September 8, 1854. Removing the handle prevented further cholera deaths and hastened the end of the Broad Street London epidemic, supporting Snow's theory that cholera was in fact a waterborne disease (Ramsay, 2006). Despite the success of this study, the causative agent of cholera remained a matter of debate. Later, Robert Koch identified and isolated the cholera bacteria and emphasized the need for clean water to stem the spread of disease. The seventh cholera pandemic began in Indonesia in 1961 and is the largest in terms of geographic spread and duration, spanning into modern times (Hu et al., 2016; Mutreja et al., 2011). In fact, cholera cannot be eradicated since it is a naturally occurring resident of aquatic environments. While the disease is no longer a concern in nations with sanitation facilities, it remains a serious problem in countries that lack access to safe drinking water and adequate sanitation (Talavera & Perez, 2009). The global cholera burden is virtually unknown, with most cases going unreported, but it is estimated that the first six cholera pandemics claimed about 1 million lives and the seventh 2.9 million cases and 95,000 deaths per year. However, the introduction of oral rehydration therapy, antibiotic treatment, and novel oral vaccinations have resulted in a higher survival rate and better prognosis (World Health Organization, 2022).

Figure 3: Illustration depicting John Snow with the Broad Street pump during London's cholera outbreak in 1866 (Bertram-Powell, n.d.).

Influenza: The Mother of all Pandemics

Humans have been plagued by the flu for generations. Influenza, often known as flu, is an infectious disease caused by an RNA virus from the Orthomyxoviridae family. It is exclusively airborne to humans and symptoms include fever, sore throat, muscular aches, severe headache, coughing, and fatigue. More severe episodes of influenza result in pneumonia, which can be fatal, particularly in young children, the elderly, and those with chronic diseases ("Influenza [Avian and Other Zoonotic]", 2016). Seasonal influenza epidemics are caused by types A and B viruses, with influenza A virus being the catalyst for the devastating pandemics occurring between 1918 and 2009 (Uyeki et al., 2022). Reassortment, or the exchange of RNA segments between two different influenza viruses simultaneously infecting the same cell, is an important evolutionary process of such viruses. As a result, in extremely rare situations, non-human influenza viruses, such as avian or swine flu viruses, can evolve to easily infect humans and spread efficiently from person to person (Trifkovic et al., 2021).


Influenza A viruses come in different subtypes based on the external spikes that each virus uses to either attach itself to cells (proteins called H for hemagglutinin) or exit cells into which it has invaded (proteins called N for neuraminidase). The existing 18 H and 11 N subtypes offer outstanding potential for 198 different influenza virus subtypes (Pineo, 2021). The Spanish flu pandemic of 1918 was one of the deadliest events in human history, with 50 million people dying - more than double the number recorded during World War I (Johnson & Mueller, 2002). It is interesting to note that geographically speaking, the Spanish flu did not originate in Spain. However, the Spanish government was one of the first to acknowledge that a novel and unusual disease had emerged in their country, hence the disease's current name. Spanish's flu patient zero (the first person to be infected) might have been a World War I soldier who quickly disseminated infection to the overcrowded military base at Fort Riley, Kansas. The disease was then carried by the sick soldiers as they marched over the European battlefields and beyond (Rizzo, 2017). The virus was then carried by the sick as they marched over the European battlefields and beyond (Rizzo, 2017). Within the first year, the Spanish flu arrived in three waves and presented an unexpected W-shaped age-specific mortality curve, i.e., an inexplicable peak of deaths among healthy young adults. To prevent the spread of the disease, several theaters, churches and other closed public venues have been shuttered for a year. With no vaccine discovered yet, quarantine and personal hygiene have been the main pillars of prevention. Face masks, mostly made of cloth, served as the first line of defense in the fight against the virus. Without a mask, access to trams, workplaces and other public areas was denied (Hauser, 2020).

Figure 4: A group of citizens in California wearing masks during the 1918 flu pandemic, the primary method for preventing the spread of the disease (Greenwood, 2020).

The causative agent of the Spanish flu was an avian H1N1 virus, which is the direct ancestor of all influenza A viruses currently circulating in humans (Taubenberger et al., 2007). Remarkably, the pandemic decimated sufficient young individuals to reduce average life expectancy in the US by 12 years (Sampath et al., 2021).The ensuing Asian (1957) and Hong Kong (1968) flues followed the same pattern of surfacing first in east Asia and then spreading globally, yet their expansion and mortality rates were not as stunning as the preceding pandemic. Furthermore, while the death toll from bird flu (1977) was not as high, it was the first time an influenza virus was proven to be transferred directly from birds to humans, with infections connected to Hong Kong's chicken markets (Taubenberger & Morens, 2006). Attempts to prevent and control an influenza pandemic are currently hampered by the constant adaptability and gene exchange between influenza viruses from different species, which is also the main reason for the lack of a universally effective anti-influenza vaccine (Yewdell, 2013).


HIV/AIDS: From Pandemics to Epidemics

Fear, stigma, and disinformation characterized the human immunodeficiency virus (HIV) pandemic that ravaged the world in the 1980s. Among the earliest incidents were young homosexual men succumbing to unusual opportunistic infections and rare malignancies due to compromised immune systems (CDC, 1981; Greene, 2007). This condition was eventually termed Acquired Immune Deficiency Syndrome (AIDS), the latest stage of HIV (Greene, 2007). Since its discovery nearly three decades ago, the pandemic form of human HIV (HIV-1), which originated from a species of chimpanzee in central Africa, has infected at least 60 million people and killed more than 25 million (Barré-Sinoussi et al., 1983; Merson et al., 2008) With the advent of antiretroviral therapy (ART), which prevents disease progression, opportunistic infections, and HIV transmission, the number of new HIV infections and AIDS-related deaths has decreased significantly. ART avoided an estimated 7.6 million AIDS-related deaths globally between 1995 and 2013, including 4.8 million fatalities in Sub-Saharan Africa, the region with the highest rates of HIV/AIDS morbidity, mortality, and prevalence (UNAIDS, 2014). However, HIV remains a major global public health problem (UNAIDS, 2013).

Figure 5: Gay Pride marchers hoist a banner that reads: "A.I.D.S.: We need research, not hysteria!" as they march through Manhattan in June of 1983 (Dawnson, 2022).

Although ongoing ART therapy allows for HIV management, a comprehensive HIV cure, as observed in the “Berlin patient”, poses an extraordinary challenge at a therapeutic level since it requires extensive chemotherapy to destroy the patient's bone marrow, whole-body radiation and a subsequent bone marrow transplant. The “Berlin patient” received bone marrow from a donor who had a rare mutation in a specific part of his DNA, the CCR5 gene, conferring him natural resistance to HIV (Brown, 2015). Thus, the chances of finding a cure and an effective vaccine for HIV are seriously doubtful, and AIDS will remain a public health threat for decades to come, underscoring the need for epidemiological and global public health responses to halt the HIV endemic.


Conclusions

Communicable diseases have affected mankind since the dawn of civilization. However, with the shift to an agricultural lifestyle, there was a chance for infectious diseases to spread and turn epidemics. Diseases such as influenza, smallpox, leprosy, malaria, and tuberculosis have taken hold since that shift. The risk of disease spreading across borders has risen dramatically as societies have become more connected, paving the way for some of history's most devastating pandemics: plague, cholera, Russian and Spanish flu, and COVID-19. In the realm of current pandemics, few topics have garnered as much intrigue and interest as the COVID-19 pandemic yet, this modern age pandemics will be extensively discussed later throughout this series. As we move forward from the recent COVID-19 pandemic, we have observed the great hardship, death, and everyday uncertainty that a pandemic brings. However, throughout human history, catastrophic pandemics have erupted, killing people, toppling political regimes, and inflicting financial and psychological burden on people. They did, however, occasionally lead to scientific breakthroughs. Understanding the variables that cause pandemics is vital for controlling current pandemics and preventing future ones. It is therefore critical that governments, public health organizations, and healthcare specialists collaborate to strengthen the country's emergency preparedness in order to prevent and better manage future pandemics.

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