Towards a Comprehensive Definition of Pandemics and Strategies for Prevention: A Historical Review and Future Perspectives

PMCID: PMC11433773

PMID:

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Abstract

The lack of a universally accepted definition of a pandemic hinders a comprehensive understanding of and effective response to these global health crises. Current definitions often lack quantitative criteria, rendering them vague and limiting their utility. Here, we propose a refined definition that considers the likelihood of susceptible individuals contracting an infectious disease that culminates in widespread global transmission, increased morbidity and mortality, and profound societal, economic, and political consequences. Applying this definition retrospectively, we identify 22 pandemics that occurred between 165 and 2024 AD and were caused by a variety of diseases, including smallpox (Antonine and American), plague (Justinian, Black Death, and Third Plague), cholera (seven pandemics), influenza (two Russian, Spanish, Asian, Hong Kong, and swine), AIDS, and coronaviruses (SARS, MERS, and COVID-19). This work presents a comprehensive analysis of past pandemics caused by both emerging and re-emerging pathogens, along with their epidemiological characteristics, societal impact, and evolution of public health responses. We also highlight the need for proactive measures to reduce the risk of future pandemics. These strategies include prioritizing surveillance of emerging zoonotic pathogens, conserving biodiversity to counter wildlife trafficking, and minimizing the potential for zoonotic spillover events. In addition, interventions such as promoting alternative protein sources, enforcing the closure of live animal markets in biodiversity-rich regions, and fostering global collaboration among diverse stakeholders are critical to preventing future pandemics. Crucially, improving wildlife surveillance systems will require the concerted efforts of local, national and international entities, including laboratories, field researchers, wildlife conservationists, government agencies and other stakeholders. By fostering collaborative networks and establishing robust biorepositories, we can strengthen our collective capacity to detect, monitor, and mitigate the emergence and transmission of zoonotic pathogens.

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Full Text

There is no agreed definition of a pandemic in the scientific literature [1]. Classically, a pandemic is defined as “an epidemic that occurs worldwide, or over a very large area, crosses international borders, and usually affects a large number of people” [2,3]. However, this definition ignores population immunity, pathogen virulence, the severity of symptoms [4], and even the metapopulation structure [5]. Until the COVID-19 pandemic, the World Health Organization (WHO) defined a pandemic simply as a “new disease with worldwide spread” [6]. This term has not been updated by the WHO since. On the other hand, Madhav et al. [7] define a pandemic as “large-scale outbreak of infectious disease that greatly increases morbidity and mortality over a large geographic area and causes significant economic, social, and political disruption”. The latter definition adds to the classical definition the need to prioritize the consequences of pandemics, be they economic, social, or political.
These definitions are at best qualitative and vague, using terms such as “very large area”, “a large number of people”, “large-scale” or “greatly increase”. Some available definitions of a pandemic at best approach the quantitative aspect by using terms such as “sustained transmission” or “emergence of new pathogens” [1]. In any case, the likelihood of pandemics has increased in recent centuries due to global transportation and integration, urbanization, changes in land use, exploitation of the natural environment, and climate change. These trends have simultaneously increased the need for international preparedness for new pandemics and the capacity of health systems [7]. For this reason, in the event of an outbreak, it would be important to estimate the likelihood of it becoming a pandemic, in order to predict its impact on health services and the global economy.
In addition to the speed of spread, a pandemic concept should take into account the likelihood that susceptible individuals will become infected. In this sense, some vector-borne or seasonal diseases cannot be transmitted to all susceptible individuals in a given period of time because not all regions of the world would be under the same risk of transmission, either because of the absence of vectors or because of favorable climatic conditions. Therefore, if the vectors are not cosmopolitan, i.e., regionally specific, or if the disease requires a specific climatic condition as a determining factor, the disease in question should not be considered a pandemic. For example, the vectors of dengue fever, chikungunya and zika, the mosquitoes of the Aedes genus, mainly Aedes aegypti and A. albopictus, are currently distributed in tropical and subtropical areas. Although they have a tendency to expand their range in the Northern Hemisphere in the coming years due to environmental changes, they do not occur in temperate and cold climates [8] and therefore could not transmit these diseases in these regions. Plague, on the other hand, can be considered a pandemic because both the vector (the flea Xenopsylla cheopis) [9] and its reservoirs (commensal rats) [10] are cosmopolitan.
Lack of information in the literature can make it difficult to classify even a significant health event as a pandemic, for example, because it is difficult to define the pathogen involved. An example is the Athenian Plague, described by Thucydides, which broke out in Ethiopia between 430 and 26 BC. The pathogen has not been identified, nor has the death toll [11], but it is thought to have been caused by the influenza virus [12]. Another example is a global flu spread that originated in Asia and traveled from southeast to northwest to Europe between 1557 and 1558, presumably caused by the influenza virus. Recurrence with peak mortality between 1558 and 1561, occurred first in large urban centers, then in smaller and smaller cities, and finally in the interior. By 1580, it had reached major urban centers around the world [12].
Some scientific papers have compiled the pandemics that have occurred in history [13], without mentioning inclusion criteria, most of which were published during the COVID-19 pandemic [11,14]. This is the first work to consider inclusion criteria in a pandemic compilation and to provide insights into changes in epidemiological patterns that may be useful in preparing for new pandemics.
Smallpox has struck humanity in devastating waves for most of our modern history. It has caused more suffering and death than any other disease. The disease may have originated in East Africa between 3000 and 4000 years ago [15,16], from where it may have been introduced to India by ancient Egyptian traders [17]. The first evidence of lesions compatible with smallpox was found in Egyptian mummies from 1570 to 1085 BC, including the Pharaoh Ramses V, who died in 1156 BC [17,18]. The disease was also described in China in 1122 BC and in Sanskrit medical texts from India around 1500 BC [17,18].
Smallpox is an acute infectious disease caused by the variola virus (VARV), a DNA virus of the genus Orthopoxvirus and family Poxviridae that infects humans [15]. The genus Orthopoxvirus includes several other viruses that infect humans and animals, such as the monkeypox virus (MPXV), vaccinia virus (VACV), and the viruses most closely related to VARV, camelpox virus (CMLV) and taterapox virus (TATV) (which infects gerbils) [16]. Although the recent evolutionary history of VARV is known, its origin is still unknown [16], but it may have been zoonotic. The two lineages of VARV, P-I (“variola major”) and P-II (“variola minor”), diverged just before the end of the 17th century (when vaccination began, see below), but experienced severe bottlenecks, less severe for P-II, probably because this lineage was less virulent, maintained at endemic levels and in low transmission, and for these reasons, less recognizable and less susceptible to control measures (isolation and quarantine) [16].
The virus is airborne and can also be spread by fomites such as clothing and bedding [19]. Congenital infection also occurs in pregnant women, causing abortions or stillbirths [20]. Most smallpox outbreaks have been caused by “variola major” with a case fatality rate of up to 30% [19]. Occasionally, some outbreaks have resulted in case fatality rates as low as 1%, which were caused by “variola minor” [20]. The incubation period is between 10 and 14 days, usually 12 days. The early symptom of smallpox is fever, and if it develops, the infected person becomes contagious. Other early symptoms, in addition to fever, include headache, chills, and back pain, and less commonly, vomiting [20]. After two to four days, rashes more commonly appear on the face. After two days of rash all over the body, the macules raise to the surface of the skin due to fluid effusion and become vesicles. By day 7, the vesicles become pustules, and by week 2, the fluids are absorbed and the lesion dries, forming crusts that dry and fall off after approximately three weeks [19,20]. The fever persists until the crusts form. When the crusts fall off by the end of the 3rd week of illness, the person is no longer infectious, but may be left with blindness, sterility, and disfigurement. In fatal cases, death occurs between 10 and 16 days after the onset of the symptoms [20]. Immunity following the infection declines slowly over time and remains virtually stable for decades after recovery [21].
This was the first pandemic ever recorded, but probably not the first that humans have faced in history. The smallpox pandemic began in the city of Seleucia (Mesopotamia) in late 165 AD during a campaign by the Roman army and spread to Rome the following year [22]. It lasted until 180 AD and became a disruptive event in Roman history [23]. It is estimated that between 7 and 10 million people died during the pandemic [23], approximately 20% of the population of the Roman Empire [24], or approximately 5% of the world’s population based on the global population estimate in the first year of the pandemic [25] (Figure 1). One of the victims was the Emperor Lucio Vero himself in 166 AD [26], and the plague was named after his co-ruler, Marcus Aurelius Antoninus, because of the end of the Pax Romana era.
The impact of this pandemic was so severe that it reduced military conscription, food production and economic activity. Conversely, traditions were affected, paving the way for the spread of monotheistic religions such as Mithraism and Christianity. This crisis also allowed the barbarian invasion of the Empire. In conclusion, the Antonine Plague paved the way for the decline of the Roman Empire and ultimately the fall of the West in the 5th century AD [27].
A well-documented history of smallpox comes from Japan. The disease was introduced by Korean merchants and Buddhist missionaries in 735 AD. The first smallpox epidemic killed approximately 30% of the Japanese population. A further 27 epidemics were recorded up to 1206 AD, mainly affecting children. The long-term effects of smallpox in Japan were a shortage of labor, a decline in agricultural production, and a reduction in tax revenue for the empire [28].
As the population grew, smallpox became more prevalent in cities worldwide. The demographics of the disease were the same, affecting mostly children and killing approximately 30% of those infected. The predominance of children as mostly affected suggests an endemic behavior of the VARV [20]. By the 16th century, smallpox was already a major cause of morbidity and mortality in Europe, Southeast Asia, China, and India. Europe was particularly important in the global spread of smallpox that accompanied the successive waves of exploration and colonization [20].
Smallpox first appeared in the New World, in 1507 AD on the island of Hispaniola, introduced by the Spanish conquistadors. An epidemic ensued, wiping out tribes, but eventually exhausting itself. In 1517, an outbreak occurred among the African slaves and spread to the Amerindians, killing approximately one-third of the native population of Hispaniola. Smallpox managed to spread to Cuba in 1518 AD and to Puerto Rico in 1519 AD, killing half of the native population of those islands. In 1519 AD, Hernán Cortés sailed from Cuba on an expedition to explore and conquer what is now Mexico. In 1520 AD, the governor of Cuba sent Pánfilo de Narváez to replace Cortés, bringing with him an African slave who had contracted smallpox [20]. This was the beginning of the most devastating event for the Aztec Empire. From the coast, the disease reached the capital, Tenochtitlán, in five months. The loss of the chiefs Mexixcatl and Cuitláhuac and men, to smallpox, rather than the Spaniards (who were immune), was demoralizing and allowed for a quick Spanish conquest [20]. From Mexico, the disease spread to the Yucatan Peninsula, decimating the dense Mayan population [20]. The estimated Amerindian population before the Spanish occupation was 25 million [20], and one-fifth to one-third (5 to 8 million people) died of smallpox within 6 months [29].
The disease also spread to the Inca Empire even before the arrival of the Spanish conquistador Francisco Pizarro. Between 1524 and 1527 AD, the smallpox is believed to have killed 200,000 of the empire’s 6 million people, including the emperor Huayna Capac and his heir Ninan Cuyochi. A civil war ensued, making it easy for a small band of Spanish conquistadors to enter Cuzco, in 1533 AD. No part of South America was spared, and the disease even reached the interior of Brazil, killing more than 60,000 Indians [20].
In North America in the 17th century, the population was sparsely distributed, living much like hunter-gatherers or primitive farmers, estimated at approximately 3 million Native Americans [20]. The continent was colonized by the British, French, and Dutch. The first smallpox outbreak occurred on the Massachusetts coast between 1617 and 1619, killing most of the natives in the region and opening the way for the European settlers. The outbreaks became more frequent as the disease spread inland, affecting people of all ages, compatible with infection of a naïve population. Because the settlements were smaller than the cities of Central America, the outbreaks soon disappeared, and the reintroduction of smallpox would occur only after long intervals, with the accumulation of new susceptible individuals, and usually by ship arriving on the East coast. The distinct smallpox endemicity of the colonies and Great Britain is demonstrated by the fact that young colonists who had lived in smallpox-free areas and went to Great Britain for further study contracted the disease. The risk of infection in Britain was one of the reasons for funding colleges and universities in the colonies [20].
As military activity increased in the late 17th century, the British and French, using Indian allies, waged war in what is now Canada. Sometimes, epidemics were deliberately started. For example, in 1763, during the French and Indian War in the British colonies of North America, British soldiers distributed blankets that had been used by the sick to the native population in an act of biological warfare. Smallpox outbreaks declined until the end of the 1880s, just as railroads began to spread the disease across the continent [20].
As a result of the 360-year circulation of smallpox in the Americas, the Amerindian population of the Caribbean islands was replaced by African slaves, while the Aztec and Inca populations on the mainland survived to the present day and comprise approximately half of the current population. In contrast, in North and South America, the Native Americans make up only a small fraction of the population [20]. Several other diseases were introduced to the Americas by European conquerors. A hemorrhagic syndrome, called “cocoliztli” [30], probably caused by the bacterium Salmonella enterica paratyphi C [31], associated with typhus, measles, and/or smallpox, killed between 7 and 17 million Mesoamericans in two outbreaks, between 1545 and 1576 AD [30]. The resulting social and economic disruption is the likely cause of the abandonment of several cities and the decline of the Mesoamerican civilizations. By the end of the 19th century, smallpox and other diseases may have contributed to the decline of up to 90% of the indigenous population of the Americas [20,29,30], or 6.4% of the world’s population (using 1500 AD as reference) [25] (Figure 2).
The observation that smallpox survivors were pockmarked and never became re-infected was the starting point for the first attempts at prevention. In addition, those who were accidentally infected by scratching their skin, developed a mild form of the disease. These observations led to the administration of pustular fluid or dried scabs to people who had never had smallpox, resulting in a much milder disease. This practice, known as “variolation”, began independently in China (by blowing ground dried scabs into the nostrils) and India (by cutaneous inoculation) in the 10th century. Cutaneous variolation was introduced in Egypt in the 13th century. Variolation was widely used in China in the 17th century, but it was not until the 18th century that these ancient Chinese methods were introduced to Europe and its colonies. Variolation produced satisfactory immunity, although it caused a mortality rate of 0.5–2% [20].
In the 18th century, smallpox was endemic worldwide, except in Australia and the small islands of the Pacific. The disease was introduced into Australia in 1789 and in 1829, affecting the Aboriginal population, but eventually declined in both cases [20]. In Europe, variolation was increasingly used as a preventive measure, but probably more people died from its side effects than from natural infection [20].
In some parts of the European countryside, the observation that milkmaids were rarely pockmarked attracted the attention of a British physician. Edward Jenner demonstrated that inoculation of susceptible individuals with cowpox material would protect them from natural smallpox infection, and even challenged these individuals with the inoculation of smallpox virus. Jenner used his own child as a test subject. The results of the vaccinia inoculation were published in 1798, but it was not until 1881 that Louis Pasteur, in honor of Jenner, used the term “vaccination” as a synonym for preventive inoculation against all infectious agents [20].
Smallpox vaccine was the first vaccine ever produced and proved to be a safer method than variolation. The vaccine was introduced in Europe in the early 19th century, and as the incidence of smallpox declined, most governments made smallpox vaccination mandatory. Mass vaccination eliminated smallpox from North and Central America in 1951 and from Europe in 1953, but it remained endemic in the rest of the world [20]. In the 20th century, smallpox still killed between 300 and 500 million people [26].
In 1959, the WHO began a global program to eradicate smallpox. The last case of smallpox in the Western Hemisphere occurred in Brazil in 1971, and the last case worldwide occurred in Somalia in 1977. The WHO declared smallpox eradicated in 1980, 21 years after the start of the global eradication program [20]. Smallpox is the only human disease that has ever been eradicated. Although smallpox is officially eradicated, samples with VARV stains are stored in two laboratories: Centers for Disease Control and Prevention (CDC) in Atlanta (United States) and the Russian State Center for Research on Virology and Biotechnology in Koltsovo, Siberia (Russian Federation), raising concerns about accidents and use of the virus as a biological weapon and subsequent reintroduction of smallpox [26].
Plague has afflicted humanity for thousands of years. The disease has killed more than 200 million people [32] and produced the worst pandemic that humanity has ever experienced.
Plague is a vector-borne disease caused by the Gram-negative bacterium Yersinia pestis that is transmitted to humans primarily by the bite of the flea Xenopsylla cheopis, which infests a wide variety of wild and commensal rodent reservoirs and occasionally humans, although over 80 flea species may also be vectors [32]. Bactrian camels are also hosts for the bacterium and can be infected by flea bites while grazing and resting near rodent burrows. Bactrian camels can transmit the plague to humans if they are ridden or their meat is processed or eaten, a common practice among the Mongolians [33].
Virulence factors of the Y. pestis allow it to efficiently infect fleas and subvert the immune system of the mammalian host, leading to a rapid death in the absence of treatment [34]. Long-term antibodies against some antigens of the Y. pestis are found in recovered patients even after decades of infection, but the cellular immune response is still unknown [35].
The maintenance of Y. pestis in nature is thought to involve enzootic cycles involving rodent reservoirs and fleas that transmit the bacteria at low levels. These enzootic cycles probably pose little risk to humans, but periodic changes in climatic conditions may affect rodent population dynamics and infection may spread to more susceptible rodent species, amplifying the enzootic and causing mass rodent die-offs and immediate dispersal of the infected fleas. The risk of human infection increases when synanthropic rodents such as Rattus rattus or R. norvegicus and their fleas are involved [36].
The closest bacterium to Y. pestis is the enteric pathogen Y. pseudotuberculosis, which causes a mild disease [37]. The former diverged from the latter between 5700 and 6000 years ago, by the acquisition of virulence plasmids and inactivation of a virulence-associated gene. The contemporary bacterial lineage diverged from the basal Y. pestis lineage between 5000 and 5700 years ago. Approximately 4000 years ago, a new divergence gave rise to an extinct lineage and to lineages that persist to the present day, improving the flea-borne transmissibility and the host invasiveness. However, the geographic origin of this successful lineage has not yet been determined [34].
The most common clinical form of plague is called “bubonic”, in which the infected person suddenly develops high fever, body and abdominal pain, and headache between 3 and 7 days after infection. The bacteria multiply in the lymph nodes closest to the flea bite, causing painful swellings called “buboes”, hence the name “bubonic plague”. Approximately 60% of the untreated individuals die within a week of exposure as the pus-filled buboes suppurate [32]. Rarely, a septicemic or a pneumonic form may occur, accounting for 15% of plague cases [38].
In the septicemic form, the onset of high fever is sudden, with no “buboes” or any other obvious symptoms. The disease progresses rapidly, leading to sepsis, organ failure, and death within a few days. Sometimes patients present with nausea, vomiting, diarrhea and abdominal pain, which can be confused with several other diseases, making the mortality rate usually higher than the bubonic form [36].
Pneumonic plague is the rarest of the clinical forms of plague [32], and is due to the spread of the Y. pestis bacterium from a “bubo” to the lungs (referred to as secondary). It begins as an interstitial pulmonary process, resulting in productive cough and abundant sputum, 5–6 days after the infection. If untreated, sputum becomes copious, eventually bloody, and death may occur within 3–4 days. The pneumonic form can also occur when the Y. pestis bacterium is inhaled from another pneumonic plague patient or even from an infected animal (referred to as primary). Symptoms are fulminant, and begin within 1–4 days of infection, with sudden onset of fever, chills, headache, malaise, tachypnea, dyspnea, hypoxia, chest pain, cough, and hematoptysis. The sputum is often purulent and copious [36]. In both cases, the Y. pestis bacterium is airborne and can be transmitted from person-to-person [32].
The first plague pandemic is poorly documented, and may in fact have been a process. The first outbreak occurred between 541 and 544 AD, but at least 18 subsequent outbreaks occurred by 750 AD in the Mediterranean, Persia [32,39], and the British Isles [40].
Molecular analysis suggests that it originated in the Tien Shan and Talas Mountains of present-day Kyrgyzstan [40,41]. For this reason, the Huns are thought to have brought the plague to Europe [40]. The first plague outbreak in the Byzantine Empire was reported in Pelusium (Egypt) in 541 AD and reached Constantinople, the capital of the empire, in 542 AD [32]. The spread of the disease was made possible by the maritime trade routes that served the entire empire (Figure 3). Not only were infected rats and fleas inadvertently carried in the ship’s cargo, but so were infected crew members.
It is estimated that between 15 and 100 million people, approximately 25–60% of the population of the Byzantine Empire [39], or approximately 19% of the global population [25], died during this pandemic. The Emperor Justinian the Great, who contracted the disease and survived, was blamed for the plague, as the deaths of peasants led to a collapse of supplies [42] and subsequent famine. These facts were not necessary causes of the fall of the Byzantine Empire, but may have contributed to its vulnerability to foreign invasions.
Although the first pandemic has killed tens of millions of people, it bears little resemblance to the next [39], which could be defined as the single stochastic event that brought humanity the closest to an extinction bottleneck. This may be related to the evolution of the Y. pestis lineages. A divergence event in the Tien Shan and Talas Mountains of present-day Kyrgyzstan [40,41], just before the first pandemic gave rise to the Justinian lineage (which went extinct immediately after the pandemic) and new lineages associated with the subsequent pandemics [34].
A mortality crisis between 1338 and 1339 AD in the Chu Valley, near the Lake Issyk-Kul’ in present-day Kyrgyzstan, may be the earliest evidence for the origin of the Black Death. This evidence comes from an epigraphic corpus of gravestone inscriptions from three cemeteries in the Issyk-Kul’ region [33]. Further paleogenetic analysis of two of these cemeteries provided the definitive link between the Issyk-Kul’ mortality crisis and the Black Death [43]. Conversely, the peak mortality and the demographics of the dead were similar to the subsequent Black Death, with significantly more males affected [33].
Sporadic mass mortality events among Mongol soldiers in the early 14th century, during the incursions into China, and three outbreaks in southeastern China in 1333 AD, between 1344 AD and 1345 AD, and in northern China in 1353 AD, have been referred to since the 19th century as the “Chinese origin” thesis of the Black Death [44], but these localized outbreaks were actually unrelated to the pandemic [33].
In the early 14th century, the Central Asian landscape was largely pastoral, providing the Mongols with horses, livestock and Bactrian camels. Pastoralism was directly correlated with rainfall levels, which in turn were directly correlated with the abundance of rodents and livestock [33]. The first half of the 14th century was characterized by intermittent droughts and floods. For example, the year 1339 AD was the driest year and 1343 AD was the wettest year of the period [45]. The drought may have reduced vegetation to the point where it could barely support the rodent population, which in turn may have increased mortality and decreased both fertility and immune response, making the surviving rodents increasingly susceptible to flea infestation and Y. pestis infection. This condition may have led to spillover of the bacterium from rodents to humans, while the fleas actively sought alternative hosts for survival [33].
Issyk-Kul’ was an important hub of international trade at that time. Spices, silk, cotton, linen, and jewelry traveled westward. Silk, cotton, and linen clothing may have been used by the fleas as hiding places until they jumped onto a human host. Y. pestis can survive in clothing for long periods of time without the need for live fleas. Infected fleas could also be transported in grain or flour. Commensal rats infected with the bacterium or infested with fleas may have been transported on cargo ships that allowed the rats to disembark through the mooring ropes when docking at destination ports. Although Bactrian camels are hosts for Y. pestis, they were rare in Central Asia and may have played a minor role in the spread of the plague from Issyk-Kul’ [33].
In late 1346 AD, while the Mongol army was besieging the city of Caffa, Crimea, the soldiers began to die. Their bodies were then catapulted into the city in an attempt to create terror and also to infect the city’s population [33]. Genoese merchants, fleeing war and death, imported the plague to Constantinople in May and to Messina (Sicily, Italy) in June of 1347 AD. Wine ships from Gascony (southwestern France) brought the disease to Borset (southwestern England) in June 1348 AD. Merchant ships from England introduced the disease to Scotland, Shetland, the Faroe Island, and Bergen, Norway [33]. From the coast, the disease spread inland, terrifying citizens who saw their relatives, friends, and neighbors die within a week of contracting the disease. The plague spread rapidly to North Africa by 1349 AD, to all Europe by 1350 AD, and to the Middle East by 1351 AD [32] (Figure 4).
In 1377 AD, Ragusa (nowadays Dubrovnik, Croatia) established that suspected plague cases should spend thirty days in a landing station far from the city, a period referred to as “trentena”. In 1403 AD, the “trentena” was extended (mostly for biblical reasons) to 40 day (“quaranta giorni”) isolation, referred to as “quarantena” from which the term quarantine derived from [46].
The impact of the Black Death was enormous, changing European society and economies in many ways, including a severe labor shortage, the decline of the Italian city-states, and the Christian belief that the plague was carried by Jews, which led to persecution and massacres. In addition, the miasma theory proposed by the ancient physicians Hippocrates (460–377 BC) and Galen (129-c. 216 AD), which attributed disease to poisoned air, gained relevance [32].
This pandemic heavily massacred the European population, already devastated by famine and war, and became the deadliest pandemic in human history. The Black Death is thought to have killed between 75 and 200 million people, approximately 30–60% of the European population [47] or up to 51% of the world’s population [25]. Despite recent research suggesting that the death toll may have been lower [48], by 1430 AD, the population of Europe was lower than it had been in 1290 AD, and it was not until the 16th century that pre-Black Death numbers were recovered [46]. The Black Death was followed by successive plague outbreaks over the centuries until the next pandemic broke out [38].
The third plague pandemic began in the Chinese province of Yunnan. The region had experienced several plague outbreaks since 1772 AD [49], but this pandemic began in 1855 AD [40]. After reaching Canton and Hong Kong in 1894 AD, the disease was spread by rat-infested steamships to port cities in Japan, Singapore, Taiwan, and India. After a few years, the disease spread to several other port cities around the world (Figure 5).
The plague bacterium was identified in Hong Kong in 1894 AD, by the Swiss-French physician and bacteriologist, Alexander Yersin [49]. Later, the plague bacterium was named in his honor, Y. pestis. In addition, in 1897, the French scientist Paul-Louis Simond identified the Y. pestis bacterium in dead rats while studying the plague in Bombay, India. He proposed that the bacterium was transmitted between rats and from rats to humans [38].
Following these discoveries, international regulations for rat control in ports and inspection of ships were established in the early 20th century. However, the Y. pestis established in urban and rural rodent hosts plague-free areas in Americas, Europe, Africa and Asia, resulting in scattered outbreaks that still exist in some parts of the world [38].
Deaths were concentrated in India, where mitigation measures were instituted by the British colonial government imposed mitigation measures such as quarantines, isolation camps, traffic restrictions, and bans on traditional medical techniques, considered leonine by the local population, leading to riots [50].
The enforcement of sanitary standards and, from the mid-20th century on, and the availability of effective insecticides, rodenticides, and antibiotics for treatment, made the plague sporadic and rural. Outbreaks developed more slowly and were easier to control [38]. By 1960 AD, the plague had caused at least 15 million deaths worldwide [46], or at least 1% of the world’s population [25], with the majority occurring in India [46].
However, scattered outbreaks of plague still occurred in Vietnam, during the 1962–1975 war [38], China and Tanzania in 1983 AD, Zaire in 1992 AD, and India, Mozambique and Zimbabwe in 1994 [46].
In 1892, a vaccine against the plague was developed by a Russian scientist named Waldemar Mordecai Haffkine, while working at the Pasteur Institute in Paris. The same researcher developed the first vaccine against a bacterium, Vibrio cholera, in 1882, against cholera (see below). Clinical trials for the plague vaccine were conducted in India from 1893 to 1896 in India, using prisoners and Haffkine himself as test subjects [51]. When the plague reached Bombay, in 1896, Haffkine became a bacteriologist for the British colonial government of India, and his effective vaccine was used in a major vaccination campaign. In 1902, however, 19 people died of tetanus as a result of vaccine poisoning. Haffkine was fired, but the vaccine stigma remained in India [51].
Cholera has plagued humanity for thousands of years. Although the origin of the disease is unknown, the first records of a cholera-like disease, in the Ganges River delta, are found in Sanskrit medical texts dating from 500 to 400 BC [52]. Historically, and especially during the 19th century, the Ganges river was known for its polluted waters, where corpses were thrown. Moreover, along its course, the lack of hygienic conditions and the use of domestic water reservoirs exposed to air, excrement and urine, created the perfect conditions for a waterborne pathogen to thrive [53].
Cholera is a severe and dehydrating diarrheal disease that is considered one of the most rapidly fatal human infections if not treated promptly. It is a waterborne disease caused by the Gram-negative aquatic bacterium Vibrio cholerae. The bacterium is motile, and occurs naturally in marine environments, using the chitin of crustaceans as a source of carbon and nitrogen [52]. Over 200 serogroups of V. cholerae have been identified, based on its lipopolysaccharides. Serogroups, O1 and O139, are those associated with epidemics and are the only serogroups that secrete the cholera toxin. Serogroup O1 is subdivided into the classical biotype and the El Tor biotype. The first six cholera pandemics were caused by the classical O1 biotype, and the ongoing seventh pandemic is caused by the El Tor biotype [54].
The V. cholerae is transmitted by the fecal–oral route. A high infectious dose (108 vibrios) is required to cause disease. Human-to-human transmission is possible and well documented. V. cholerae is present in human stool both as individual vibrios and as biofilm aggregates. Cholera outbreaks are associated with water sources, natural disasters (such as floods, hurricanes and earthquakes), and host immunity. The bacterium enters the host through contaminated food or water. In the small intestine, it invades the epithelial cells, multiplies and secretes cholera toxin, resulting in an efflux of ions and water into the intestinal lumen. The resorptive capacity of the colon may be overwhelmed, resulting in profuse and severe diarrhea [52]. Taken together, these factors lead to the association of cholera with poor sanitation, poor food hygiene and poverty [55].
Clinical signs are variable, ranging from asymptomatic to mild to severe. The incubation period is between 0.5 and 5 days, after which there is a sudden onset of diarrhea and often vomiting. In severe cases, the stool output can reach 1000 mL/h in an adult patient. If untreated, the disease can lead to severe dehydration, hypovolemic shock. And death [52]. Without treatment, the case fatality rate can exceed 50% [54].
Asymptomatic patients shed the bacterium for a few days, but symptomatic patients may shed it for up to 2 weeks or even longer. Cholera infection protects against subsequent serogroup homologous infection for at least 3 years [54]. Therefore, less severe disease is observed in cholera-endemic areas [52].
It is difficult to distinguish between the first six cholera pandemics because they were separated by only a few years. Nevertheless, many authors divide them in one way or another, following the description of Pollitzer [56]. Seven cholera pandemics have occurred in history, killing up to 40 million people [11].
Cholera had long been endemic in some regions of South Asia when the first pandemic began. Some cases had been recorded in India since 1814, but in 1817, 10,000 people died in a village near Calcutta. Moreover, British soldiers stationed in Calcutta also fell ill, and the disease spread rapidly across the Indian subcontinent in the following year [53]. The disease spread to the north to China and Nepal, east to what is now Sri Lanka, Myanmar, Mauritius, Thailand, Malaysia, Singapore, the Dutch East Indies (now Indonesia), the Philippines and Japan, and west to Zanzibar (Africa), the Middle East, Russia, Georgia, Syria, Egypt, and the Mediterranean coast in 1823 [57] (Figure 6).
Colonialism, i.e., European colonial rule, and globalization, i.e., the increased speed of worldwide transportation (especially by steamship), have been cited as the causes of the spread of cholera beyond the Indian subcontinent [13]. Conversely, the reluctance of British Indians to accept that cholera was communicable led to the disease being associated with climate or miasma. Elsewhere, on the other hand, quarantines and isolation of victims were instituted. Even when traditional treatments were introduced, the course of the disease was so rapid that there was no time for them to have any effect (good or bad) [13].
The exact number of deaths from the first cholera pandemic is unknown, but estimates vary from 1 million [11] to 2 million based on local reports, although several authors have reported much higher numbers [13,53,57], accounting for up to 0.3% of the world’s population [25]. It is believed that this pandemic is poorly described because it did not reach Europe, despite the European fears of the so-called “Asian cholera” [13].
In less than two years after the remission of the first pandemic, cholera began to spread again in the Ganges River delta region between 1826 and 1827. During the same period, the disease was reintroduced into China [53,56]. Like the first pandemic, this one reached Persia and Afghanistan in 1829 [13], Japan in 1831 [56], and Java in 1834 [13]. On the other hand, it first reached the Russian Empire in 1830, Western Europe in 1831, and North America, in 1832. Muslim pilgrims brought the disease from Mecca to Palestine, Syria, and Egypt in 1831. Pilgrims carried the pandemic even further into East Africa (Sudan, Abyssinia, the Horn of Africa, and Zanzibar) [13] and Tunisia by 1835 [56,57] (Figure 7).
The impact of the pandemic was more dramatic in Europe, but in Asia, the effects of the second pandemic were less severe than the first pandemic. The significance of this pandemic has more to do with the social and political situation in Europe than with the mortality itself. This pandemic highlighted poverty and unsatisfactory sanitary conditions, leading to social tensions and to attacks on the authorities [13]. At least 1 million people died in this pandemic [53,58], or 0.2% of the world’s population [25].
The third cholera pandemic also began in the Bengal region of India, less than four years after the previous pandemic. Cholera has been endemic in India, and some authors disagree about when the second pandemic ended and the third began, but there was a pause in the number of cholera cases in India between 1836 and 1839 AD, when a new surge began [13].
This pandemic spread almost worldwide, reaching Latin America for the first time, and returning to Europe and North America. The disease spread westward, to Bombay in 1839 and from there, to Aden in 1846, and to the Red Sea region and North Africa in 1848. Again, the pilgrim traffic to and from Mecca was associated with the spread of cholera in the region. Also from Bombay, another branch of the disease spread to the Persian Gulf region in 1846, and from there, the Russian Empire via the Caspian Sea in 1847, and to Western Europe the following year [13]. The Crimean War helped spread cholera to the Mediterranean ports and the Balkans [53]. From Europe, the disease reached North and Central America in 1849 and South America for the first time in 1855. Apart from India, the highest mortality was observed in Brazil [13,57].
From the Bengal region to the east, the disease reached Malaysia, Singapore, and southeastern China in 1840, probably carried by British troops and trade during the Opium War between China and the United Kingdom. From the coast, the disease spread inland, reaching Burma, western China and from there, Central Asia in 1844 [13] (Figure 8).
The third cholera pandemic killed between 1 and 1.5 million people [13,53], or 0.08 to 0.12% of the world’s population [25]. In some places, such as Brazil, the Caribbean, parts of the United States, and Europe, the mortality rate was high, making the third cholera pandemic the worst of the 19th century. The mortality rate was associated with slavery and killed mostly men in Brazil and the Caribbean. Although the mortality rate of the third cholera pandemic was higher than that of the second, the former was not accompanied by social unrest [13].
The British physician John Snow suspected that cholera was waterborne ever since the second cholera pandemic hit London in 1834. Although cholera struck London again in 1848, it was not until 1854, when the number of deaths peaked, that Dr. Snow began to investigate the outbreak in the Soho district by plotting the deaths on a map. The deaths were clustered around a particular water pump on Broad Street (now Broadwick Street), and Dr. Snow hypothesized that the contaminated water from this pump was the source of the outbreak. Although the number of cholera cases declined, Dr. Snow convinced the local authorities to remove the handle of the pump, which further reduced the number of cases. Proving that cholera was waterborne was a major breakthrough in understanding its transmission. This work is the earliest example of epidemiological investigation, and for this reason Dr. Snow is referred to as the father of epidemiology [13,53].
The fourth cholera pandemic began in 1863, like the previous ones, in the Ganges River delta region. The following year, the disease reached Bombay, on the west coast of India, and from there spread around the world, following the path of previous cholera pandemics, but with a difference. From India, the disease reached the port of the British protectorate of Aden in 1864. From Aden, the disease spread to Somalia and Ethiopia in 1865 and, more importantly, to Jidda, the seaport of Mecca, where Muslim pilgrims from all over the world were gathered. That year, approximately 17% of the 90,000 pilgrims died of cholera. From Egypt, the disease spread across the Mediterranean Sea. In 1865, cholera reached Great Britain, the Netherlands, Prussia and Russia. From Europe, the disease was transported to the West Indies and North America, in 1866. From Aden, cholera spread not only to Egypt, but also to Algeria, Tunisia and Morocco in 1867 and to Senegal in 1868. From Ethiopia, the disease spread across the African continent to Zanzibar, Mozambique, and Madagascar in 1869 [13,57] (Figure 9).
The fourth cholera pandemic killed approximately 700,000 people worldwide [57], or 0.06% of the world’s population [25]. The pandemic was more severe in India, especially when it coincided with a year of famine, when droughts forced the people to drink from contaminated wells. Famine was associated with rural-urban migration and consequently poor water supply and sanitation [13].
This pandemic was particularly associated with religious pilgrimages by Western societies, and Western empires began to regulate these pilgrimages. It was also the first time that cholera was associated with human movement, being imported from somewhere else. The belief that cholera was associated with water pollution grew, but it was not until the next cholera pandemic that the pathogen was discovered [13].
In 1881, cholera spread around the world for the fifth time, again starting in the Ganges River delta area, again. In 1882, the pandemic spread outside India to the Dutch East Indies (now Indonesia) and the Philippines, causing high mortality in both places. The following year, the disease again reached the Muslim pilgrims in the Hijaz and Mecca regions of Arabia, and from there to Egypt. In 1884, the disease moved through the Mediterranean ports and spread to Italy, France and Spain. In 1886, the pandemic reached Argentina, and from there it spread through South America the following year. Between 1888 and 1891, the disease retreated to Asia, causing new outbreaks, but reappeared in Europe in 1892, using the same route as the second cholera pandemic, up the Volga River into the Russian Empire. From the Russian Empire, the disease spread to Germany and to Western Europe [13,57] (Figure 10).
The fifth cholera pandemic killed approximately 750,000 people worldwide [57], or 0.06% of the world’s population [25]. The pandemic hit India severely, and especially affected the Russian Empire, causing social unrest due to the high mortality rate [13].
In 1854, the Italian doctor Filippo Pacini described an active vibrio in stool samples from cholera patients in the city of Florence, Italy. The discovery of Vibrio cholerae, which called into question the theory of miasmas, was ignored by the scientific community of the time. The causative agent of cholera only came to prominence in 1883, when Robert Koch, who was already a renowned microbiologist, managed to isolate the bacterium during a visit to India during a cholera outbreak [59]. In addition, between 1889 and 1896, at the end of the pandemic, a clinical trial carried out by the Russian scientist Waldemar Haffkine with approximately 40,000 volunteers in Calcutta, India, made it possible for the first time to use an attenuated human vaccine against cholera [57]. Unfortunately, even the existence of a vaccine was not enough to prevent a new cholera pandemic.
The sixth cholera pandemic began in 1899 in the same place as the previous five: the Ganges River delta. The disease had long been endemic in India, but this would be the last time a cholera pandemic broke out in this location. As usual, the disease spread westward to Bombay, Madras, and Punjab, and from there to other countries. In 1901, the disease reached Singapore and the Dutch East Indies (now Indonesia) from Indian ports. In 1902, it reached China and the Philippines, Muslim pilgrims in the Hijaz, and eventually Egypt. The disease reached Persia in 1903 and the Russian Empire in 1904. In 1905, cholera reached the Austro-Hungarian Empire [13,57].
The disease seemed to disappear between 1905 and 1909, but reappeared in some places such as India, the Dutch East Indies, and the Russian Empire. The disease reached Western Europe in 1910, particularly Italy and the Balkans. From Italy, it reached the Ottoman colony of Tripolitania in 1911, probably brought by the Italian soldiers occupying that territory [13] (Figure 11).
The First World War and the Russian Revolution, whose ensuing civil war lasted until 1921, greatly facilitated the spread of cholera, especially in Russia and on the Eastern and Southeastern European fronts. This cholera pandemic occurred at a troubled time in history, during the World War I and the most severe influenza pandemic of 1918–1919, the Spanish flu. Even so, as in the previous cholera pandemic, the United States had cases, but they were contained by quarantines of passengers on ships coming from affected countries [13].
The sixth cholera pandemic caused a large number of deaths, particularly in India, where approximately 8 million people may have died from cholera [13]. Outside of India, cholera killed approximately 800,000 people worldwide [57]. The total death toll of the sixth cholera pandemic was approximately 8.8 million people, or 0.6% of the world’s population [25].
In the early 20th century, cholera was responsible for 10% of deaths in India. In the Philippines, cholera was responsible for nearly 1/3 of deaths. In Persia (now Iran), cholera caused social disruption due to the high mortality rate [13]. With the growing consensus on the cause of the disease, some governments began to adopt public policies to control cholera, but without success due to the difficulty of adapting scientific knowledge to the reality of societies [13].
This time, the cholera pandemic began in Southwest Asia in 1961, for the first time outside the Ganges River delta. The seventh cholera pandemic continues to this day and has so far been bimodal, i.e., with cases and deaths accumulating at two different times: from 1970 to 1980 and after 1991 [13].
The seventh cholera pandemic began on the island of Celebes, near the city of Makassar, Indonesia. From there, it spread throughout Southeast Asia, including the Philippines and Hong Kong, in 1961. The following year, it reached Borneo (and the rest of Indonesia) and Taiwan. In 1963, it reached Korea, Burma and Bangladesh. Between 1964 and 1965, the disease spread westward, reaching India, Iran, Iraq and Bahrain. After this breakthrough, the pandemic did not advance further geographically until 1970, when it expanded dramatically into Africa and Europe, using two previously used routes: (a) into the Soviet Union via the Caspian Sea to Astrakhan and Odessa on the Black Sea, (b) via the Arabian Peninsula to the Middle East and East Africa, and a new route, via air transport to West Africa, specifically Guinea. The following year, the disease spread to East and Southwest Africa. Europe was also hit that year, especially Portugal and Spain, and then the entire southern part of the continent. The main European country affected was Italy in 1973. Muslim pilgrims were affected again in 1974, hitting the countries of origin as the pilgrims returned to their countries of origin [13,57].
Cholera took on an endemic pattern from the late 1970s until 1991, when it hit Peru and, from then on, almost all of Latin America. As early as 1991 (the year the disease was introduced), cholera cases in Latin America accounted for two-thirds of the world’s cases [13] (Figure 12).
The exact number of deaths during this pandemic is controversial, mainly because the different countries did not have organized epidemiological surveillance services from the beginning of the pandemic. Nevertheless, the WHO counted approximately 235,000 deaths from cholera between 1961 and 1989 [60], and Ilic and Ilic [61] estimated the total number of deaths between 1990 and 2019 at approximately 3 million or 0.1% of the world’s population [25].
The reasons for the spatio-temporal dimension of this pandemic may be related to the appearance of a milder biotype of V. cholerae (El Tor), which allows for rapid spread and the generation of undetectable cases without causing panic in the population due to the low perception of a crisis. In addition, air travel and labor migration meant that, even for one of the diseases with the fastest known clinical course, patients could be transported from one place to another without dying and then transmitting the disease to new susceptible people. Currently, the disease has been controlled through the use of vaccines, antibiotics and fluid replacement, resulting in the lowest mortality rate of any cholera pandemic [13,57].
The first reference to influenza is found in 412 BC, in Hippocrates’ sixth book on “Epidemics” [62]. However, the term influenza was not proposed until 1357, in Florence, as “influenza di fredo”, from the Italian “influence of the cold” [12].
Influenza is a highly contagious airborne disease that commonly occurs in winter and eventually causes seasonal epidemics. Although the virus is mainly transmitted directly by aerosols it can also be transmitted by fomites [63]. The disease manifests itself as an acute fever with varying degrees of respiratory involvement. Other symptoms include, in addition to fever, chills, headache, weakness, red eyes, sore throat, dry cough and nasal discharge. The disease is caused by the influenza virus, which belongs to the Orthomyxoviridae family. The Orthomyxoviridae family consists of nine genera, four of which are involved in in vertebrate influenza [64]. Influenza viruses are enveloped with a genome consisting of segmented, negative single-stranded RNA. The four genera, or types, of vertebrate influenza are differentiated by antigenic combinations of two proteins encoded by the viral genome: hemagglutinin and neuraminidase. The antigenic combinations of these proteins (16 for hemagglutinin and 9 for neuraminidase) determine the four known types of the virus: A (IAV or α-influenzavirus), B (IBV or β-influenzavirus), C (ICV or γ-influenzavirus) and D IDV or δ-influenzavirus). Type A is the most common and causes mild to severe seasonal illness in humans and animals and is involved in the vast majority of outbreaks and pandemics. Type B is highly contagious and can cause severe disease in humans and pinnipeds. Type C primarily and sporadically infects humans, but can also infect pigs. Finally, type D primarily infects pigs and cattle and has not been detected in humans [63,65]. It is currently believed that influenza viruses originated in sturgeon fish, and that these animals were the first hosts of Orthomixoviridae [66].
The virus evolves rapidly through antigenic variation, through mutations resulting from antigenic drift and shift. These new variants show differences in the expression of hemagglutinin and neuraminidase. Antigenic shift is responsible for influenza pandemics, mainly associated with type A [65]. Anseriformes (aquatic waterfowl) can carry type A influenza viruses with all the hemagglutinin subtypes (H1-H16) and neuraminidases (N1-N9) and are therefore considered natural reservoirs of the virus [65]. As a consequence, human epidemics have been caused by avian viruses: H5, H7 and H9.
After infection, symptoms begin between 18 and 72 h and the virus begins to be transmitted 24 to 48 h after the onset of symptoms. Symptoms can last for up to seven days, but fever lasts only three days [65]. Complications of the viral infection include secondary bacterial infections, mainly in the form of pneumonia, which significantly increase mortality [63]. Mortality from influenza can be determined by the excess of deaths in non-pandemic years, which has been estimated at 9.1 per 100,000 in the United States, or approximately 0.001% of registered deaths, with high seasonal variation [67], and 0.004–0.009% worldwide [68]. In interpandemic years, approximately 90% of deaths occur in individuals over 65 years of age [68].
Seasonal influenza kills between 295,000 and 518,000 people worldwide each year [69], whereas 15–25% of the population is infected [70]. The first influenza pandemic is thought to have occurred between 1557 and 1580, affecting the entire world, persisting in the United Kingdom and Europe [71], but the involvement of the influenza virus and the number of deaths have not yet been confirmed. At least six confirmed influenza pandemics have occurred in history, killing between 25 and 113 million people [72,73,74,75,76].
The first documented influenza pandemic began in late 1889 in a city in the south of the Russian Empire, Bukhara (now Turkmenistan) [77]. Using railroads and waterways, the disease spread rapidly westward, reaching Moscow and the empire’s capital, St. Petersburg [13]. The increase in hospitalizations caused the health system to collapse, and even Tsar Alexander III was infected [77]. From the Russian Empire, the disease spread in approximately a month to the major European cities, especially Paris, Berlin and Vienna. By the end of 1889, railroad transportation was largely responsible for the spread of influenza throughout the European continent, except for a few islands (the United Kingdom and Sardinia). Maritime transportation brought the disease to the United States in December 1889, and it spread to the Midwest in January 1890 [13].
Passenger transportation, both by rail and especially by steamship, was the primary vector for the introduction of the influenza virus, and where this transportation network was less dense or absent, the rate of spread was slower. By December 1889, the disease had spread to Mediterranean ports and, by January 1890, to ports in Africa, South America, Japan and the United States. The following month, more African ports were affected, as well as Hong Kong and Singapore, and in March, Bombay, and India [13] (Figure 13).
Almost everywhere, the epidemic curve was the same: approximately 15 days after the first cases, the peak incidence was reached, which lasted for up to three weeks, and then, a month after the first cases, it suddenly declined due to the lack of susceptible individuals. The disease affected all ages, sexes, and social classes without discrimination. During the epidemic period, the morbidity rate was extremely high worldwide [13]. The number of deaths is estimated at between 3.7 and 5.1 million worldwide [76], or 0.2 to 0.3% of the world’s population [25]. It is also estimated that one-third to one-half of the world’s population may have been infected during this period. Although the usual mortality rate from influenza is very low, the large number of people infected led to a large number of deaths. Although the pandemic ended quickly in the mid-1890s, some isolated outbreaks occurred in cities until 1893, mostly affecting the elderly [13].
The influenza virus that may have been involved in this pandemic was the A-H3N8, which also causes epizootics in horses [12]. In 1889, there was an epidemic of equine influenza in the United Kingdom. The hypothesis of H3N8 as the cause of Russian flu was based on serologic studies, which provide only indirect evidence and are subject to technical artifacts and cross-reactions [77]. There is also a conflicting speculation that the pandemic was caused by the HCoV-OC43 coronavirus, which, along with other coronaviruses, is currently responsible for up to 30% of cases of the common cold. HCoV-OC43 is similar to the bovine coronavirus (BCoV), from which it was derived around 1890. Workers may have been exposed to bovine respiratory viruses during the eradication of a panzootic disease thought to be caused by Mycoplasma mycoides peripneumonia between 1870 and 1890. It was observed that in 1889, cattle showed the same signs as humans affected by Russian flu. Thus, the hypothesis that the Russian flu was caused by a coronavirus rather than influenza is based on the assumption that a mutant coronavirus emerged from a bovine coronavirus as a result of exposure of humans in direct contact with cattle [77]. However, this hypothesis remains unproven.
One of the most devastating pandemics humans have has ever faced, the Spanish flu, began in early 1918 and lasted until early 1919. The name given to the pandemic does not reflect its origin, but rather the fact that Spain, by staying out of the First World War (between 1914 and 1918), allowed the press to report on the disease, without the having to hide it from its enemies [13]. RNA was extracted for molecular characterization from formalin-fixed lung tissue samples and unfixed and frozen samples from influenza victims buried in the Alaskan permafrost in 1918 and found to be compatible with the influenza A-H1N1 virus [78].
This pandemic was characterized by three epidemic waves [13]. The first wave began in March 1918 in the hospital ward of the U.S. Army training camp called Camp Funston, in Kansas, United States [79], and spread to Western Europe in April, with the arrival of American troops entering World War I, to China and India in May, and to Northern Europe, Oceania and Southwest Asia in June. At that time, Germany planned to launch a major offensive on the Western Front, and found the timing perfect with the collapse of the Soviets on the Eastern Front and the beginning of the American offensive in the West. The Germans failed precisely because of an influenza outbreak in June that affected approximately half a million soldiers. The German offensive ended in June, just as the first wave of the pandemic ended [13].
The second wave began in France in August 1918 and spread to Boston, United States, and to the coast of West Africa. By the following month, it had already spread to the west coast of the United States, virtually all of Europe and West Africa. By October, South and Southwest Asia were affected, and by November, Siberia and the Pacific Islands. Very few places were unaffected, such as Iceland and some Pacific islands. This wave was characterized by a change in the clinical pattern of influenza: a high incidence of pulmonary complications, such as pneumonia, leading to high mortality. In the United States and Europe, the mortality rate was approximately 5 per 1000, but in some regions of the world, particularly Africa and Asia, it was much higher. Another change was the age group affected, mainly young adults, who have been the most resilient age group in other pandemics. Nevertheless, the pattern of the epidemic curve remained the same, with a rapid increase in incidence, a peak lasting up to three weeks, and a rapid decline, due to the lack of susceptible individuals. The end of the second wave coincided with the end of World War I, in November 1918 [13].
Between November and December 1918, the incidence of influenza had declined, but increased again between January and February 1919, beginning the third wave of the pandemic. However, this wave was not as severe as the previous one and quickly subsided [13] (Figure 14).
The H1N1 virus was uniquely virulent, and the number of deaths has been estimated at 17.4 to 100 million worldwide [72,73,76], or 0.95 to 5.4% of the global population [25], and approximately one-third of the world’s population was infected [80]. As in other influenza pandemics, a significant proportion of the population was infected with the influenza virus, resulting in high morbidity worldwide [13].
The severity of the pandemic led to the adoption of restrictive preventive measures, mainly in the United States and Europe, such as the prohibition of public gatherings (closing of schools, churches, theaters, etc.) and the use of masks covering the mouth in public places. Such measures were met with varying degrees of acceptance by populations and governments. Governments have also had to deal with the collapse of health services. In addition, several essential services (garbage collection, undertakers, gravediggers, etc.) were affected by the demand for military conscription. In countries under European imperial control, the same preventive measures were not taken, due to the war effort, and influenza spread more rapidly [13]. After the pandemic, the influenza virus returned to its usual pattern of virulence and endemicity, until the next pandemic [81].
Since the first isolation of a human virus occurred in 1933, this would be the first influenza pandemic to be studied in the laboratory, beginning with the characterization of a new influenza A virus, H2N2 [81]. The H2N2 virus was the result of a mixture of genetic material from different influenza viruses (human H1N1 with avian H2N2) generated in pigs. Pigs are susceptible to both human and avian influenza viruses, allowing the exchange of genetic material from these strains and the generation of new viruses that are more easily transmitted to humans [82] and between humans. A new influenza virus would once again challenge the world’s population, 38 years after the last pandemic [81].
In 1957, even with a surveillance system less prepared than today’s, researchers from Australia, the United Kingdom and the United States had already isolated the new virus shortly after recognizing a severe influenza outbreak in Hong Kong [81]. In fact, the first wave of the pandemic began in February 1957 in Guizhou Province in southwestern China and spread to Hong Kong in April. From there, it spread to Japan and Singapore in May [83]. By the end of May, the disease had already spread to Southwest Asia, Indonesia, the Philippines [84] and Taiwan [85]. In June, the disease reached India, the United Kingdom and the United States [85] (Figure 15). The second wave, which occurred between January and February 1958, primarily affected the elderly and was therefore more deadly than the first wave.
During the Spanish flu, secondary bacterial lung infections were the main cause of high mortality, but during the Asian flu, sudden death with consolidation or pulmonary edema without secondary bacterial infection was more common. Also differently, those with chronic lung or heart disease were most affected [81]. The number of deaths during the Asian flu pandemic has been estimated at 1.1 to 2.7 million worldwide [76,86], or 0.04 to 0.1% of the global population [25].
In 1942, an influenza vaccine was developed by the U.S. Armed Forces [87] and introduced to U.S. troops in 1946, with a protocol of annual revaccination beginning in 1954. This was the first time that the response to vaccination of a population exposed to a new influenza strain could be observed. An increase in population antibody levels in the population was observed in the years following the pandemic, demonstrating a good response to vaccination [81]. The post-pandemic circulation of H2N2 in the human population was short, and it was replaced by a new strain of the influenza virus in the next pandemic 11 years later.
A new influenza pandemic began in July 1968, again in Southeast Asia. Although its exact origin has not been determined, it was dubbed the Hong Kong flu because the influenza epidemic in this place had attracted attention, especially from the West [81]. This time, the influenza virus involved was A-H3N2, also the result of mixing the genetic material from different influenza viruses using pigs as an intermediate host to optimize for human transmission [82].
In August, it st

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"[{\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B1-microorganisms-12-01802\", \"B2-microorganisms-12-01802\", \"B3-microorganisms-12-01802\", \"B4-microorganisms-12-01802\", \"B5-microorganisms-12-01802\", \"B6-microorganisms-12-01802\", \"B7-microorganisms-12-01802\"], \"section\": \"1. Introduction\", \"text\": \"There is no agreed definition of a pandemic in the scientific literature [1]. Classically, a pandemic is defined as \\u201can epidemic that occurs worldwide, or over a very large area, crosses international borders, and usually affects a large number of people\\u201d [2,3]. However, this definition ignores population immunity, pathogen virulence, the severity of symptoms [4], and even the metapopulation structure [5]. Until the COVID-19 pandemic, the World Health Organization (WHO) defined a pandemic simply as a \\u201cnew disease with worldwide spread\\u201d [6]. This term has not been updated by the WHO since. On the other hand, Madhav et al. [7] define a pandemic as \\u201clarge-scale outbreak of infectious disease that greatly increases morbidity and mortality over a large geographic area and causes significant economic, social, and political disruption\\u201d. The latter definition adds to the classical definition the need to prioritize the consequences of pandemics, be they economic, social, or political.\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B1-microorganisms-12-01802\", \"B7-microorganisms-12-01802\"], \"section\": \"1. Introduction\", \"text\": \"These definitions are at best qualitative and vague, using terms such as \\u201cvery large area\\u201d, \\u201ca large number of people\\u201d, \\u201clarge-scale\\u201d or \\u201cgreatly increase\\u201d. Some available definitions of a pandemic at best approach the quantitative aspect by using terms such as \\u201csustained transmission\\u201d or \\u201cemergence of new pathogens\\u201d [1]. In any case, the likelihood of pandemics has increased in recent centuries due to global transportation and integration, urbanization, changes in land use, exploitation of the natural environment, and climate change. These trends have simultaneously increased the need for international preparedness for new pandemics and the capacity of health systems [7]. For this reason, in the event of an outbreak, it would be important to estimate the likelihood of it becoming a pandemic, in order to predict its impact on health services and the global economy.\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B8-microorganisms-12-01802\", \"B9-microorganisms-12-01802\", \"B10-microorganisms-12-01802\"], \"section\": \"1. Introduction\", \"text\": \"In addition to the speed of spread, a pandemic concept should take into account the likelihood that susceptible individuals will become infected. In this sense, some vector-borne or seasonal diseases cannot be transmitted to all susceptible individuals in a given period of time because not all regions of the world would be under the same risk of transmission, either because of the absence of vectors or because of favorable climatic conditions. Therefore, if the vectors are not cosmopolitan, i.e., regionally specific, or if the disease requires a specific climatic condition as a determining factor, the disease in question should not be considered a pandemic. For example, the vectors of dengue fever, chikungunya and zika, the mosquitoes of the Aedes genus, mainly Aedes aegypti and A. albopictus, are currently distributed in tropical and subtropical areas. Although they have a tendency to expand their range in the Northern Hemisphere in the coming years due to environmental changes, they do not occur in temperate and cold climates [8] and therefore could not transmit these diseases in these regions. Plague, on the other hand, can be considered a pandemic because both the vector (the flea Xenopsylla cheopis) [9] and its reservoirs (commensal rats) [10] are cosmopolitan.\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B11-microorganisms-12-01802\", \"B12-microorganisms-12-01802\", \"B12-microorganisms-12-01802\"], \"section\": \"1. Introduction\", \"text\": \"Lack of information in the literature can make it difficult to classify even a significant health event as a pandemic, for example, because it is difficult to define the pathogen involved. An example is the Athenian Plague, described by Thucydides, which broke out in Ethiopia between 430 and 26 BC. The pathogen has not been identified, nor has the death toll [11], but it is thought to have been caused by the influenza virus [12]. Another example is a global flu spread that originated in Asia and traveled from southeast to northwest to Europe between 1557 and 1558, presumably caused by the influenza virus. Recurrence with peak mortality between 1558 and 1561, occurred first in large urban centers, then in smaller and smaller cities, and finally in the interior. By 1580, it had reached major urban centers around the world [12].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\", \"B11-microorganisms-12-01802\", \"B14-microorganisms-12-01802\"], \"section\": \"1. Introduction\", \"text\": \"Some scientific papers have compiled the pandemics that have occurred in history [13], without mentioning inclusion criteria, most of which were published during the COVID-19 pandemic [11,14]. This is the first work to consider inclusion criteria in a pandemic compilation and to provide insights into changes in epidemiological patterns that may be useful in preparing for new pandemics.\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B15-microorganisms-12-01802\", \"B16-microorganisms-12-01802\", \"B17-microorganisms-12-01802\", \"B17-microorganisms-12-01802\", \"B18-microorganisms-12-01802\", \"B17-microorganisms-12-01802\", \"B18-microorganisms-12-01802\"], \"section\": \"2. Smallpox\", \"text\": \"Smallpox has struck humanity in devastating waves for most of our modern history. It has caused more suffering and death than any other disease. The disease may have originated in East Africa between 3000 and 4000 years ago [15,16], from where it may have been introduced to India by ancient Egyptian traders [17]. The first evidence of lesions compatible with smallpox was found in Egyptian mummies from 1570 to 1085 BC, including the Pharaoh Ramses V, who died in 1156 BC [17,18]. The disease was also described in China in 1122 BC and in Sanskrit medical texts from India around 1500 BC [17,18].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B15-microorganisms-12-01802\", \"B16-microorganisms-12-01802\", \"B16-microorganisms-12-01802\", \"B16-microorganisms-12-01802\"], \"section\": \"2. Smallpox\", \"text\": \"Smallpox is an acute infectious disease caused by the variola virus (VARV), a DNA virus of the genus Orthopoxvirus and family Poxviridae that infects humans [15]. The genus Orthopoxvirus includes several other viruses that infect humans and animals, such as the monkeypox virus (MPXV), vaccinia virus (VACV), and the viruses most closely related to VARV, camelpox virus (CMLV) and taterapox virus (TATV) (which infects gerbils) [16]. Although the recent evolutionary history of VARV is known, its origin is still unknown [16], but it may have been zoonotic. The two lineages of VARV, P-I (\\u201cvariola major\\u201d) and P-II (\\u201cvariola minor\\u201d), diverged just before the end of the 17th century (when vaccination began, see below), but experienced severe bottlenecks, less severe for P-II, probably because this lineage was less virulent, maintained at endemic levels and in low transmission, and for these reasons, less recognizable and less susceptible to control measures (isolation and quarantine) [16].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B19-microorganisms-12-01802\", \"B20-microorganisms-12-01802\", \"B19-microorganisms-12-01802\", \"B20-microorganisms-12-01802\", \"B20-microorganisms-12-01802\", \"B19-microorganisms-12-01802\", \"B20-microorganisms-12-01802\", \"B20-microorganisms-12-01802\", \"B21-microorganisms-12-01802\"], \"section\": \"2. Smallpox\", \"text\": \"The virus is airborne and can also be spread by fomites such as clothing and bedding [19]. Congenital infection also occurs in pregnant women, causing abortions or stillbirths [20]. Most smallpox outbreaks have been caused by \\u201cvariola major\\u201d with a case fatality rate of up to 30% [19]. Occasionally, some outbreaks have resulted in case fatality rates as low as 1%, which were caused by \\u201cvariola minor\\u201d [20]. The incubation period is between 10 and 14 days, usually 12 days. The early symptom of smallpox is fever, and if it develops, the infected person becomes contagious. Other early symptoms, in addition to fever, include headache, chills, and back pain, and less commonly, vomiting [20]. After two to four days, rashes more commonly appear on the face. After two days of rash all over the body, the macules raise to the surface of the skin due to fluid effusion and become vesicles. By day 7, the vesicles become pustules, and by week 2, the fluids are absorbed and the lesion dries, forming crusts that dry and fall off after approximately three weeks [19,20]. The fever persists until the crusts form. When the crusts fall off by the end of the 3rd week of illness, the person is no longer infectious, but may be left with blindness, sterility, and disfigurement. In fatal cases, death occurs between 10 and 16 days after the onset of the symptoms [20]. Immunity following the infection declines slowly over time and remains virtually stable for decades after recovery [21].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B22-microorganisms-12-01802\", \"B23-microorganisms-12-01802\", \"B23-microorganisms-12-01802\", \"B24-microorganisms-12-01802\", \"B25-microorganisms-12-01802\", \"microorganisms-12-01802-f001\", \"B26-microorganisms-12-01802\"], \"section\": \"2.1. Antonine Plague (165\\u2013180 AD)\", \"text\": \"This was the first pandemic ever recorded, but probably not the first that humans have faced in history. The smallpox pandemic began in the city of Seleucia (Mesopotamia) in late 165 AD during a campaign by the Roman army and spread to Rome the following year [22]. It lasted until 180 AD and became a disruptive event in Roman history [23]. It is estimated that between 7 and 10 million people died during the pandemic [23], approximately 20% of the population of the Roman Empire [24], or approximately 5% of the world\\u2019s population based on the global population estimate in the first year of the pandemic [25] (Figure 1). One of the victims was the Emperor Lucio Vero himself in 166 AD [26], and the plague was named after his co-ruler, Marcus Aurelius Antoninus, because of the end of the Pax Romana era.\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B27-microorganisms-12-01802\"], \"section\": \"2.1. Antonine Plague (165\\u2013180 AD)\", \"text\": \"The impact of this pandemic was so severe that it reduced military conscription, food production and economic activity. Conversely, traditions were affected, paving the way for the spread of monotheistic religions such as Mithraism and Christianity. This crisis also allowed the barbarian invasion of the Empire. In conclusion, the Antonine Plague paved the way for the decline of the Roman Empire and ultimately the fall of the West in the 5th century AD [27].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B28-microorganisms-12-01802\"], \"section\": \"2.2. Smallpox Taking over the World\", \"text\": \"A well-documented history of smallpox comes from Japan. The disease was introduced by Korean merchants and Buddhist missionaries in 735 AD. The first smallpox epidemic killed approximately 30% of the Japanese population. A further 27 epidemics were recorded up to 1206 AD, mainly affecting children. The long-term effects of smallpox in Japan were a shortage of labor, a decline in agricultural production, and a reduction in tax revenue for the empire [28].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B20-microorganisms-12-01802\", \"B20-microorganisms-12-01802\"], \"section\": \"2.2. Smallpox Taking over the World\", \"text\": \"As the population grew, smallpox became more prevalent in cities worldwide. The demographics of the disease were the same, affecting mostly children and killing approximately 30% of those infected. The predominance of children as mostly affected suggests an endemic behavior of the VARV [20]. By the 16th century, smallpox was already a major cause of morbidity and mortality in Europe, Southeast Asia, China, and India. Europe was particularly important in the global spread of smallpox that accompanied the successive waves of exploration and colonization [20].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B20-microorganisms-12-01802\", \"B20-microorganisms-12-01802\", \"B20-microorganisms-12-01802\", \"B20-microorganisms-12-01802\", \"B29-microorganisms-12-01802\"], \"section\": \"2.3. Smallpox in the Americas (1520\\u20131880 AD)\", \"text\": \"Smallpox first appeared in the New World, in 1507 AD on the island of Hispaniola, introduced by the Spanish conquistadors. An epidemic ensued, wiping out tribes, but eventually exhausting itself. In 1517, an outbreak occurred among the African slaves and spread to the Amerindians, killing approximately one-third of the native population of Hispaniola. Smallpox managed to spread to Cuba in 1518 AD and to Puerto Rico in 1519 AD, killing half of the native population of those islands. In 1519 AD, Hern\\u00e1n Cort\\u00e9s sailed from Cuba on an expedition to explore and conquer what is now Mexico. In 1520 AD, the governor of Cuba sent P\\u00e1nfilo de Narv\\u00e1ez to replace Cort\\u00e9s, bringing with him an African slave who had contracted smallpox [20]. This was the beginning of the most devastating event for the Aztec Empire. From the coast, the disease reached the capital, Tenochtitl\\u00e1n, in five months. The loss of the chiefs Mexixcatl and Cuitl\\u00e1huac and men, to smallpox, rather than the Spaniards (who were immune), was demoralizing and allowed for a quick Spanish conquest [20]. From Mexico, the disease spread to the Yucatan Peninsula, decimating the dense Mayan population [20]. The estimated Amerindian population before the Spanish occupation was 25 million [20], and one-fifth to one-third (5 to 8 million people) died of smallpox within 6 months [29].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B20-microorganisms-12-01802\"], \"section\": \"2.3. Smallpox in the Americas (1520\\u20131880 AD)\", \"text\": \"The disease also spread to the Inca Empire even before the arrival of the Spanish conquistador Francisco Pizarro. Between 1524 and 1527 AD, the smallpox is believed to have killed 200,000 of the empire\\u2019s 6 million people, including the emperor Huayna Capac and his heir Ninan Cuyochi. A civil war ensued, making it easy for a small band of Spanish conquistadors to enter Cuzco, in 1533 AD. No part of South America was spared, and the disease even reached the interior of Brazil, killing more than 60,000 Indians [20].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B20-microorganisms-12-01802\", \"B20-microorganisms-12-01802\"], \"section\": \"2.3. Smallpox in the Americas (1520\\u20131880 AD)\", \"text\": \"In North America in the 17th century, the population was sparsely distributed, living much like hunter-gatherers or primitive farmers, estimated at approximately 3 million Native Americans [20]. The continent was colonized by the British, French, and Dutch. The first smallpox outbreak occurred on the Massachusetts coast between 1617 and 1619, killing most of the natives in the region and opening the way for the European settlers. The outbreaks became more frequent as the disease spread inland, affecting people of all ages, compatible with infection of a na\\u00efve population. Because the settlements were smaller than the cities of Central America, the outbreaks soon disappeared, and the reintroduction of smallpox would occur only after long intervals, with the accumulation of new susceptible individuals, and usually by ship arriving on the East coast. The distinct smallpox endemicity of the colonies and Great Britain is demonstrated by the fact that young colonists who had lived in smallpox-free areas and went to Great Britain for further study contracted the disease. The risk of infection in Britain was one of the reasons for funding colleges and universities in the colonies [20].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B20-microorganisms-12-01802\"], \"section\": \"2.3. Smallpox in the Americas (1520\\u20131880 AD)\", \"text\": \"As military activity increased in the late 17th century, the British and French, using Indian allies, waged war in what is now Canada. Sometimes, epidemics were deliberately started. For example, in 1763, during the French and Indian War in the British colonies of North America, British soldiers distributed blankets that had been used by the sick to the native population in an act of biological warfare. Smallpox outbreaks declined until the end of the 1880s, just as railroads began to spread the disease across the continent [20].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B20-microorganisms-12-01802\", \"B30-microorganisms-12-01802\", \"B31-microorganisms-12-01802\", \"B30-microorganisms-12-01802\", \"B20-microorganisms-12-01802\", \"B29-microorganisms-12-01802\", \"B30-microorganisms-12-01802\", \"B25-microorganisms-12-01802\", \"microorganisms-12-01802-f002\"], \"section\": \"2.3. Smallpox in the Americas (1520\\u20131880 AD)\", \"text\": \"As a result of the 360-year circulation of smallpox in the Americas, the Amerindian population of the Caribbean islands was replaced by African slaves, while the Aztec and Inca populations on the mainland survived to the present day and comprise approximately half of the current population. In contrast, in North and South America, the Native Americans make up only a small fraction of the population [20]. Several other diseases were introduced to the Americas by European conquerors. A hemorrhagic syndrome, called \\u201ccocoliztli\\u201d [30], probably caused by the bacterium Salmonella enterica paratyphi C [31], associated with typhus, measles, and/or smallpox, killed between 7 and 17 million Mesoamericans in two outbreaks, between 1545 and 1576 AD [30]. The resulting social and economic disruption is the likely cause of the abandonment of several cities and the decline of the Mesoamerican civilizations. By the end of the 19th century, smallpox and other diseases may have contributed to the decline of up to 90% of the indigenous population of the Americas [20,29,30], or 6.4% of the world\\u2019s population (using 1500 AD as reference) [25] (Figure 2).\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B20-microorganisms-12-01802\"], \"section\": \"2.4. Steps to the Smallpox Eradication\", \"text\": \"The observation that smallpox survivors were pockmarked and never became re-infected was the starting point for the first attempts at prevention. In addition, those who were accidentally infected by scratching their skin, developed a mild form of the disease. These observations led to the administration of pustular fluid or dried scabs to people who had never had smallpox, resulting in a much milder disease. This practice, known as \\u201cvariolation\\u201d, began independently in China (by blowing ground dried scabs into the nostrils) and India (by cutaneous inoculation) in the 10th century. Cutaneous variolation was introduced in Egypt in the 13th century. Variolation was widely used in China in the 17th century, but it was not until the 18th century that these ancient Chinese methods were introduced to Europe and its colonies. Variolation produced satisfactory immunity, although it caused a mortality rate of 0.5\\u20132% [20].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B20-microorganisms-12-01802\", \"B20-microorganisms-12-01802\"], \"section\": \"2.4. Steps to the Smallpox Eradication\", \"text\": \"In the 18th century, smallpox was endemic worldwide, except in Australia and the small islands of the Pacific. The disease was introduced into Australia in 1789 and in 1829, affecting the Aboriginal population, but eventually declined in both cases [20]. In Europe, variolation was increasingly used as a preventive measure, but probably more people died from its side effects than from natural infection [20].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B20-microorganisms-12-01802\"], \"section\": \"2.4. Steps to the Smallpox Eradication\", \"text\": \"In some parts of the European countryside, the observation that milkmaids were rarely pockmarked attracted the attention of a British physician. Edward Jenner demonstrated that inoculation of susceptible individuals with cowpox material would protect them from natural smallpox infection, and even challenged these individuals with the inoculation of smallpox virus. Jenner used his own child as a test subject. The results of the vaccinia inoculation were published in 1798, but it was not until 1881 that Louis Pasteur, in honor of Jenner, used the term \\u201cvaccination\\u201d as a synonym for preventive inoculation against all infectious agents [20].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B20-microorganisms-12-01802\", \"B26-microorganisms-12-01802\"], \"section\": \"2.4. Steps to the Smallpox Eradication\", \"text\": \"Smallpox vaccine was the first vaccine ever produced and proved to be a safer method than variolation. The vaccine was introduced in Europe in the early 19th century, and as the incidence of smallpox declined, most governments made smallpox vaccination mandatory. Mass vaccination eliminated smallpox from North and Central America in 1951 and from Europe in 1953, but it remained endemic in the rest of the world [20]. In the 20th century, smallpox still killed between 300 and 500 million people [26].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B20-microorganisms-12-01802\", \"B26-microorganisms-12-01802\"], \"section\": \"2.4. Steps to the Smallpox Eradication\", \"text\": \"In 1959, the WHO began a global program to eradicate smallpox. The last case of smallpox in the Western Hemisphere occurred in Brazil in 1971, and the last case worldwide occurred in Somalia in 1977. The WHO declared smallpox eradicated in 1980, 21 years after the start of the global eradication program [20]. Smallpox is the only human disease that has ever been eradicated. Although smallpox is officially eradicated, samples with VARV stains are stored in two laboratories: Centers for Disease Control and Prevention (CDC) in Atlanta (United States) and the Russian State Center for Research on Virology and Biotechnology in Koltsovo, Siberia (Russian Federation), raising concerns about accidents and use of the virus as a biological weapon and subsequent reintroduction of smallpox [26].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B32-microorganisms-12-01802\"], \"section\": \"3. Plague\", \"text\": \"Plague has afflicted humanity for thousands of years. The disease has killed more than 200 million people [32] and produced the worst pandemic that humanity has ever experienced.\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B32-microorganisms-12-01802\", \"B33-microorganisms-12-01802\"], \"section\": \"3. Plague\", \"text\": \"Plague is a vector-borne disease caused by the Gram-negative bacterium Yersinia pestis that is transmitted to humans primarily by the bite of the flea Xenopsylla cheopis, which infests a wide variety of wild and commensal rodent reservoirs and occasionally humans, although over 80 flea species may also be vectors [32]. Bactrian camels are also hosts for the bacterium and can be infected by flea bites while grazing and resting near rodent burrows. Bactrian camels can transmit the plague to humans if they are ridden or their meat is processed or eaten, a common practice among the Mongolians [33].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B34-microorganisms-12-01802\", \"B35-microorganisms-12-01802\"], \"section\": \"3. Plague\", \"text\": \"Virulence factors of the Y. pestis allow it to efficiently infect fleas and subvert the immune system of the mammalian host, leading to a rapid death in the absence of treatment [34]. Long-term antibodies against some antigens of the Y. pestis are found in recovered patients even after decades of infection, but the cellular immune response is still unknown [35].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B36-microorganisms-12-01802\"], \"section\": \"3. Plague\", \"text\": \"The maintenance of Y. pestis in nature is thought to involve enzootic cycles involving rodent reservoirs and fleas that transmit the bacteria at low levels. These enzootic cycles probably pose little risk to humans, but periodic changes in climatic conditions may affect rodent population dynamics and infection may spread to more susceptible rodent species, amplifying the enzootic and causing mass rodent die-offs and immediate dispersal of the infected fleas. The risk of human infection increases when synanthropic rodents such as Rattus rattus or R. norvegicus and their fleas are involved [36].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B37-microorganisms-12-01802\", \"B34-microorganisms-12-01802\"], \"section\": \"3. Plague\", \"text\": \"The closest bacterium to Y. pestis is the enteric pathogen Y. pseudotuberculosis, which causes a mild disease [37]. The former diverged from the latter between 5700 and 6000 years ago, by the acquisition of virulence plasmids and inactivation of a virulence-associated gene. The contemporary bacterial lineage diverged from the basal Y. pestis lineage between 5000 and 5700 years ago. Approximately 4000 years ago, a new divergence gave rise to an extinct lineage and to lineages that persist to the present day, improving the flea-borne transmissibility and the host invasiveness. However, the geographic origin of this successful lineage has not yet been determined [34].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B32-microorganisms-12-01802\", \"B38-microorganisms-12-01802\"], \"section\": \"3. Plague\", \"text\": \"The most common clinical form of plague is called \\u201cbubonic\\u201d, in which the infected person suddenly develops high fever, body and abdominal pain, and headache between 3 and 7 days after infection. The bacteria multiply in the lymph nodes closest to the flea bite, causing painful swellings called \\u201cbuboes\\u201d, hence the name \\u201cbubonic plague\\u201d. Approximately 60% of the untreated individuals die within a week of exposure as the pus-filled buboes suppurate [32]. Rarely, a septicemic or a pneumonic form may occur, accounting for 15% of plague cases [38].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B36-microorganisms-12-01802\"], \"section\": \"3. Plague\", \"text\": \"In the septicemic form, the onset of high fever is sudden, with no \\u201cbuboes\\u201d or any other obvious symptoms. The disease progresses rapidly, leading to sepsis, organ failure, and death within a few days. Sometimes patients present with nausea, vomiting, diarrhea and abdominal pain, which can be confused with several other diseases, making the mortality rate usually higher than the bubonic form [36].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B32-microorganisms-12-01802\", \"B36-microorganisms-12-01802\", \"B32-microorganisms-12-01802\"], \"section\": \"3. Plague\", \"text\": \"Pneumonic plague is the rarest of the clinical forms of plague [32], and is due to the spread of the Y. pestis bacterium from a \\u201cbubo\\u201d to the lungs (referred to as secondary). It begins as an interstitial pulmonary process, resulting in productive cough and abundant sputum, 5\\u20136 days after the infection. If untreated, sputum becomes copious, eventually bloody, and death may occur within 3\\u20134 days. The pneumonic form can also occur when the Y. pestis bacterium is inhaled from another pneumonic plague patient or even from an infected animal (referred to as primary). Symptoms are fulminant, and begin within 1\\u20134 days of infection, with sudden onset of fever, chills, headache, malaise, tachypnea, dyspnea, hypoxia, chest pain, cough, and hematoptysis. The sputum is often purulent and copious [36]. In both cases, the Y. pestis bacterium is airborne and can be transmitted from person-to-person [32].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B32-microorganisms-12-01802\", \"B39-microorganisms-12-01802\", \"B40-microorganisms-12-01802\"], \"section\": \"3.1. Justinian Plague (541\\u2013750 AD)\", \"text\": \"The first plague pandemic is poorly documented, and may in fact have been a process. The first outbreak occurred between 541 and 544 AD, but at least 18 subsequent outbreaks occurred by 750 AD in the Mediterranean, Persia [32,39], and the British Isles [40].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B40-microorganisms-12-01802\", \"B41-microorganisms-12-01802\", \"B40-microorganisms-12-01802\", \"B32-microorganisms-12-01802\", \"microorganisms-12-01802-f003\"], \"section\": \"3.1. Justinian Plague (541\\u2013750 AD)\", \"text\": \"Molecular analysis suggests that it originated in the Tien Shan and Talas Mountains of present-day Kyrgyzstan [40,41]. For this reason, the Huns are thought to have brought the plague to Europe [40]. The first plague outbreak in the Byzantine Empire was reported in Pelusium (Egypt) in 541 AD and reached Constantinople, the capital of the empire, in 542 AD [32]. The spread of the disease was made possible by the maritime trade routes that served the entire empire (Figure 3). Not only were infected rats and fleas inadvertently carried in the ship\\u2019s cargo, but so were infected crew members.\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B39-microorganisms-12-01802\", \"B25-microorganisms-12-01802\", \"B42-microorganisms-12-01802\"], \"section\": \"3.1. Justinian Plague (541\\u2013750 AD)\", \"text\": \"It is estimated that between 15 and 100 million people, approximately 25\\u201360% of the population of the Byzantine Empire [39], or approximately 19% of the global population [25], died during this pandemic. The Emperor Justinian the Great, who contracted the disease and survived, was blamed for the plague, as the deaths of peasants led to a collapse of supplies [42] and subsequent famine. These facts were not necessary causes of the fall of the Byzantine Empire, but may have contributed to its vulnerability to foreign invasions.\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B39-microorganisms-12-01802\", \"B40-microorganisms-12-01802\", \"B41-microorganisms-12-01802\", \"B34-microorganisms-12-01802\"], \"section\": \"3.1. Justinian Plague (541\\u2013750 AD)\", \"text\": \"Although the first pandemic has killed tens of millions of people, it bears little resemblance to the next [39], which could be defined as the single stochastic event that brought humanity the closest to an extinction bottleneck. This may be related to the evolution of the Y. pestis lineages. A divergence event in the Tien Shan and Talas Mountains of present-day Kyrgyzstan [40,41], just before the first pandemic gave rise to the Justinian lineage (which went extinct immediately after the pandemic) and new lineages associated with the subsequent pandemics [34].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B33-microorganisms-12-01802\", \"B43-microorganisms-12-01802\", \"B33-microorganisms-12-01802\"], \"section\": \"3.2. Black Death (1338\\u20131353 AD)\", \"text\": \"A mortality crisis between 1338 and 1339 AD in the Chu Valley, near the Lake Issyk-Kul\\u2019 in present-day Kyrgyzstan, may be the earliest evidence for the origin of the Black Death. This evidence comes from an epigraphic corpus of gravestone inscriptions from three cemeteries in the Issyk-Kul\\u2019 region [33]. Further paleogenetic analysis of two of these cemeteries provided the definitive link between the Issyk-Kul\\u2019 mortality crisis and the Black Death [43]. Conversely, the peak mortality and the demographics of the dead were similar to the subsequent Black Death, with significantly more males affected [33].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B44-microorganisms-12-01802\", \"B33-microorganisms-12-01802\"], \"section\": \"3.2. Black Death (1338\\u20131353 AD)\", \"text\": \"Sporadic mass mortality events among Mongol soldiers in the early 14th century, during the incursions into China, and three outbreaks in southeastern China in 1333 AD, between 1344 AD and 1345 AD, and in northern China in 1353 AD, have been referred to since the 19th century as the \\u201cChinese origin\\u201d thesis of the Black Death [44], but these localized outbreaks were actually unrelated to the pandemic [33].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B33-microorganisms-12-01802\", \"B45-microorganisms-12-01802\", \"B33-microorganisms-12-01802\"], \"section\": \"3.2. Black Death (1338\\u20131353 AD)\", \"text\": \"In the early 14th century, the Central Asian landscape was largely pastoral, providing the Mongols with horses, livestock and Bactrian camels. Pastoralism was directly correlated with rainfall levels, which in turn were directly correlated with the abundance of rodents and livestock [33]. The first half of the 14th century was characterized by intermittent droughts and floods. For example, the year 1339 AD was the driest year and 1343 AD was the wettest year of the period [45]. The drought may have reduced vegetation to the point where it could barely support the rodent population, which in turn may have increased mortality and decreased both fertility and immune response, making the surviving rodents increasingly susceptible to flea infestation and Y. pestis infection. This condition may have led to spillover of the bacterium from rodents to humans, while the fleas actively sought alternative hosts for survival [33].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B33-microorganisms-12-01802\"], \"section\": \"3.2. Black Death (1338\\u20131353 AD)\", \"text\": \"Issyk-Kul\\u2019 was an important hub of international trade at that time. Spices, silk, cotton, linen, and jewelry traveled westward. Silk, cotton, and linen clothing may have been used by the fleas as hiding places until they jumped onto a human host. Y. pestis can survive in clothing for long periods of time without the need for live fleas. Infected fleas could also be transported in grain or flour. Commensal rats infected with the bacterium or infested with fleas may have been transported on cargo ships that allowed the rats to disembark through the mooring ropes when docking at destination ports. Although Bactrian camels are hosts for Y. pestis, they were rare in Central Asia and may have played a minor role in the spread of the plague from Issyk-Kul\\u2019 [33].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B33-microorganisms-12-01802\", \"B33-microorganisms-12-01802\", \"B32-microorganisms-12-01802\", \"microorganisms-12-01802-f004\"], \"section\": \"3.2. Black Death (1338\\u20131353 AD)\", \"text\": \"In late 1346 AD, while the Mongol army was besieging the city of Caffa, Crimea, the soldiers began to die. Their bodies were then catapulted into the city in an attempt to create terror and also to infect the city\\u2019s population [33]. Genoese merchants, fleeing war and death, imported the plague to Constantinople in May and to Messina (Sicily, Italy) in June of 1347 AD. Wine ships from Gascony (southwestern France) brought the disease to Borset (southwestern England) in June 1348 AD. Merchant ships from England introduced the disease to Scotland, Shetland, the Faroe Island, and Bergen, Norway [33]. From the coast, the disease spread inland, terrifying citizens who saw their relatives, friends, and neighbors die within a week of contracting the disease. The plague spread rapidly to North Africa by 1349 AD, to all Europe by 1350 AD, and to the Middle East by 1351 AD [32] (Figure 4).\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B46-microorganisms-12-01802\"], \"section\": \"3.2. Black Death (1338\\u20131353 AD)\", \"text\": \"In 1377 AD, Ragusa (nowadays Dubrovnik, Croatia) established that suspected plague cases should spend thirty days in a landing station far from the city, a period referred to as \\u201ctrentena\\u201d. In 1403 AD, the \\u201ctrentena\\u201d was extended (mostly for biblical reasons) to 40 day (\\u201cquaranta giorni\\u201d) isolation, referred to as \\u201cquarantena\\u201d from which the term quarantine derived from [46].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B32-microorganisms-12-01802\"], \"section\": \"3.2. Black Death (1338\\u20131353 AD)\", \"text\": \"The impact of the Black Death was enormous, changing European society and economies in many ways, including a severe labor shortage, the decline of the Italian city-states, and the Christian belief that the plague was carried by Jews, which led to persecution and massacres. In addition, the miasma theory proposed by the ancient physicians Hippocrates (460\\u2013377 BC) and Galen (129-c. 216 AD), which attributed disease to poisoned air, gained relevance [32].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B47-microorganisms-12-01802\", \"B25-microorganisms-12-01802\", \"B48-microorganisms-12-01802\", \"B46-microorganisms-12-01802\", \"B38-microorganisms-12-01802\"], \"section\": \"3.2. Black Death (1338\\u20131353 AD)\", \"text\": \"This pandemic heavily massacred the European population, already devastated by famine and war, and became the deadliest pandemic in human history. The Black Death is thought to have killed between 75 and 200 million people, approximately 30\\u201360% of the European population [47] or up to 51% of the world\\u2019s population [25]. Despite recent research suggesting that the death toll may have been lower [48], by 1430 AD, the population of Europe was lower than it had been in 1290 AD, and it was not until the 16th century that pre-Black Death numbers were recovered [46]. The Black Death was followed by successive plague outbreaks over the centuries until the next pandemic broke out [38].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B49-microorganisms-12-01802\", \"B40-microorganisms-12-01802\", \"microorganisms-12-01802-f005\"], \"section\": \"3.3. Third Plague (1855\\u20131960 AD)\", \"text\": \"The third plague pandemic began in the Chinese province of Yunnan. The region had experienced several plague outbreaks since 1772 AD [49], but this pandemic began in 1855 AD [40]. After reaching Canton and Hong Kong in 1894 AD, the disease was spread by rat-infested steamships to port cities in Japan, Singapore, Taiwan, and India. After a few years, the disease spread to several other port cities around the world (Figure 5).\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B49-microorganisms-12-01802\", \"B38-microorganisms-12-01802\"], \"section\": \"3.3. Third Plague (1855\\u20131960 AD)\", \"text\": \"The plague bacterium was identified in Hong Kong in 1894 AD, by the Swiss-French physician and bacteriologist, Alexander Yersin [49]. Later, the plague bacterium was named in his honor, Y. pestis. In addition, in 1897, the French scientist Paul-Louis Simond identified the Y. pestis bacterium in dead rats while studying the plague in Bombay, India. He proposed that the bacterium was transmitted between rats and from rats to humans [38].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B38-microorganisms-12-01802\"], \"section\": \"3.3. Third Plague (1855\\u20131960 AD)\", \"text\": \"Following these discoveries, international regulations for rat control in ports and inspection of ships were established in the early 20th century. However, the Y. pestis established in urban and rural rodent hosts plague-free areas in Americas, Europe, Africa and Asia, resulting in scattered outbreaks that still exist in some parts of the world [38].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B50-microorganisms-12-01802\"], \"section\": \"3.3. Third Plague (1855\\u20131960 AD)\", \"text\": \"Deaths were concentrated in India, where mitigation measures were instituted by the British colonial government imposed mitigation measures such as quarantines, isolation camps, traffic restrictions, and bans on traditional medical techniques, considered leonine by the local population, leading to riots [50].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B38-microorganisms-12-01802\", \"B46-microorganisms-12-01802\", \"B25-microorganisms-12-01802\", \"B46-microorganisms-12-01802\"], \"section\": \"3.3. Third Plague (1855\\u20131960 AD)\", \"text\": \"The enforcement of sanitary standards and, from the mid-20th century on, and the availability of effective insecticides, rodenticides, and antibiotics for treatment, made the plague sporadic and rural. Outbreaks developed more slowly and were easier to control [38]. By 1960 AD, the plague had caused at least 15 million deaths worldwide [46], or at least 1% of the world\\u2019s population [25], with the majority occurring in India [46]. \"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B38-microorganisms-12-01802\", \"B46-microorganisms-12-01802\"], \"section\": \"3.3. Third Plague (1855\\u20131960 AD)\", \"text\": \"However, scattered outbreaks of plague still occurred in Vietnam, during the 1962\\u20131975 war [38], China and Tanzania in 1983 AD, Zaire in 1992 AD, and India, Mozambique and Zimbabwe in 1994 [46].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B51-microorganisms-12-01802\", \"B51-microorganisms-12-01802\"], \"section\": \"3.3. Third Plague (1855\\u20131960 AD)\", \"text\": \"In 1892, a vaccine against the plague was developed by a Russian scientist named Waldemar Mordecai Haffkine, while working at the Pasteur Institute in Paris. The same researcher developed the first vaccine against a bacterium, Vibrio cholera, in 1882, against cholera (see below). Clinical trials for the plague vaccine were conducted in India from 1893 to 1896 in India, using prisoners and Haffkine himself as test subjects [51]. When the plague reached Bombay, in 1896, Haffkine became a bacteriologist for the British colonial government of India, and his effective vaccine was used in a major vaccination campaign. In 1902, however, 19 people died of tetanus as a result of vaccine poisoning. Haffkine was fired, but the vaccine stigma remained in India [51].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B52-microorganisms-12-01802\", \"B53-microorganisms-12-01802\"], \"section\": \"4. Cholera\", \"text\": \"Cholera has plagued humanity for thousands of years. Although the origin of the disease is unknown, the first records of a cholera-like disease, in the Ganges River delta, are found in Sanskrit medical texts dating from 500 to 400 BC [52]. Historically, and especially during the 19th century, the Ganges river was known for its polluted waters, where corpses were thrown. Moreover, along its course, the lack of hygienic conditions and the use of domestic water reservoirs exposed to air, excrement and urine, created the perfect conditions for a waterborne pathogen to thrive [53].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B52-microorganisms-12-01802\", \"B54-microorganisms-12-01802\"], \"section\": \"4. Cholera\", \"text\": \"Cholera is a severe and dehydrating diarrheal disease that is considered one of the most rapidly fatal human infections if not treated promptly. It is a waterborne disease caused by the Gram-negative aquatic bacterium Vibrio cholerae. The bacterium is motile, and occurs naturally in marine environments, using the chitin of crustaceans as a source of carbon and nitrogen [52]. Over 200 serogroups of V. cholerae have been identified, based on its lipopolysaccharides. Serogroups, O1 and O139, are those associated with epidemics and are the only serogroups that secrete the cholera toxin. Serogroup O1 is subdivided into the classical biotype and the El Tor biotype. The first six cholera pandemics were caused by the classical O1 biotype, and the ongoing seventh pandemic is caused by the El Tor biotype [54].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B52-microorganisms-12-01802\", \"B55-microorganisms-12-01802\"], \"section\": \"4. Cholera\", \"text\": \"The V. cholerae is transmitted by the fecal\\u2013oral route. A high infectious dose (108 vibrios) is required to cause disease. Human-to-human transmission is possible and well documented. V. cholerae is present in human stool both as individual vibrios and as biofilm aggregates. Cholera outbreaks are associated with water sources, natural disasters (such as floods, hurricanes and earthquakes), and host immunity. The bacterium enters the host through contaminated food or water. In the small intestine, it invades the epithelial cells, multiplies and secretes cholera toxin, resulting in an efflux of ions and water into the intestinal lumen. The resorptive capacity of the colon may be overwhelmed, resulting in profuse and severe diarrhea [52]. Taken together, these factors lead to the association of cholera with poor sanitation, poor food hygiene and poverty [55].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B52-microorganisms-12-01802\", \"B54-microorganisms-12-01802\"], \"section\": \"4. Cholera\", \"text\": \"Clinical signs are variable, ranging from asymptomatic to mild to severe. The incubation period is between 0.5 and 5 days, after which there is a sudden onset of diarrhea and often vomiting. In severe cases, the stool output can reach 1000 mL/h in an adult patient. If untreated, the disease can lead to severe dehydration, hypovolemic shock. And death [52]. Without treatment, the case fatality rate can exceed 50% [54].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B54-microorganisms-12-01802\", \"B52-microorganisms-12-01802\"], \"section\": \"4. Cholera\", \"text\": \"Asymptomatic patients shed the bacterium for a few days, but symptomatic patients may shed it for up to 2 weeks or even longer. Cholera infection protects against subsequent serogroup homologous infection for at least 3 years [54]. Therefore, less severe disease is observed in cholera-endemic areas [52].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B56-microorganisms-12-01802\", \"B11-microorganisms-12-01802\"], \"section\": \"4. Cholera\", \"text\": \"It is difficult to distinguish between the first six cholera pandemics because they were separated by only a few years. Nevertheless, many authors divide them in one way or another, following the description of Pollitzer [56]. Seven cholera pandemics have occurred in history, killing up to 40 million people [11].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B53-microorganisms-12-01802\", \"B57-microorganisms-12-01802\", \"microorganisms-12-01802-f006\"], \"section\": \"4.1. First Cholera Pandemic (1817\\u20131824 AD)\", \"text\": \"Cholera had long been endemic in some regions of South Asia when the first pandemic began. Some cases had been recorded in India since 1814, but in 1817, 10,000 people died in a village near Calcutta. Moreover, British soldiers stationed in Calcutta also fell ill, and the disease spread rapidly across the Indian subcontinent in the following year [53]. The disease spread to the north to China and Nepal, east to what is now Sri Lanka, Myanmar, Mauritius, Thailand, Malaysia, Singapore, the Dutch East Indies (now Indonesia), the Philippines and Japan, and west to Zanzibar (Africa), the Middle East, Russia, Georgia, Syria, Egypt, and the Mediterranean coast in 1823 [57] (Figure 6).\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\", \"B13-microorganisms-12-01802\"], \"section\": \"4.1. First Cholera Pandemic (1817\\u20131824 AD)\", \"text\": \"Colonialism, i.e., European colonial rule, and globalization, i.e., the increased speed of worldwide transportation (especially by steamship), have been cited as the causes of the spread of cholera beyond the Indian subcontinent [13]. Conversely, the reluctance of British Indians to accept that cholera was communicable led to the disease being associated with climate or miasma. Elsewhere, on the other hand, quarantines and isolation of victims were instituted. Even when traditional treatments were introduced, the course of the disease was so rapid that there was no time for them to have any effect (good or bad) [13].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B11-microorganisms-12-01802\", \"B13-microorganisms-12-01802\", \"B53-microorganisms-12-01802\", \"B57-microorganisms-12-01802\", \"B25-microorganisms-12-01802\", \"B13-microorganisms-12-01802\"], \"section\": \"4.1. First Cholera Pandemic (1817\\u20131824 AD)\", \"text\": \"The exact number of deaths from the first cholera pandemic is unknown, but estimates vary from 1 million [11] to 2 million based on local reports, although several authors have reported much higher numbers [13,53,57], accounting for up to 0.3% of the world\\u2019s population [25]. It is believed that this pandemic is poorly described because it did not reach Europe, despite the European fears of the so-called \\u201cAsian cholera\\u201d [13].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B53-microorganisms-12-01802\", \"B56-microorganisms-12-01802\", \"B13-microorganisms-12-01802\", \"B56-microorganisms-12-01802\", \"B13-microorganisms-12-01802\", \"B13-microorganisms-12-01802\", \"B56-microorganisms-12-01802\", \"B57-microorganisms-12-01802\", \"microorganisms-12-01802-f007\"], \"section\": \"4.2. Second Cholera Pandemic (1826\\u20131835 AD)\", \"text\": \"In less than two years after the remission of the first pandemic, cholera began to spread again in the Ganges River delta region between 1826 and 1827. During the same period, the disease was reintroduced into China [53,56]. Like the first pandemic, this one reached Persia and Afghanistan in 1829 [13], Japan in 1831 [56], and Java in 1834 [13]. On the other hand, it first reached the Russian Empire in 1830, Western Europe in 1831, and North America, in 1832. Muslim pilgrims brought the disease from Mecca to Palestine, Syria, and Egypt in 1831. Pilgrims carried the pandemic even further into East Africa (Sudan, Abyssinia, the Horn of Africa, and Zanzibar) [13] and Tunisia by 1835 [56,57] (Figure 7).\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\", \"B53-microorganisms-12-01802\", \"B58-microorganisms-12-01802\", \"B25-microorganisms-12-01802\"], \"section\": \"4.2. Second Cholera Pandemic (1826\\u20131835 AD)\", \"text\": \"The impact of the pandemic was more dramatic in Europe, but in Asia, the effects of the second pandemic were less severe than the first pandemic. The significance of this pandemic has more to do with the social and political situation in Europe than with the mortality itself. This pandemic highlighted poverty and unsatisfactory sanitary conditions, leading to social tensions and to attacks on the authorities [13]. At least 1 million people died in this pandemic [53,58], or 0.2% of the world\\u2019s population [25].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\"], \"section\": \"4.3. Third Cholera Pandemic (1839\\u20131860 AD)\", \"text\": \"The third cholera pandemic also began in the Bengal region of India, less than four years after the previous pandemic. Cholera has been endemic in India, and some authors disagree about when the second pandemic ended and the third began, but there was a pause in the number of cholera cases in India between 1836 and 1839 AD, when a new surge began [13].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\", \"B53-microorganisms-12-01802\", \"B13-microorganisms-12-01802\", \"B57-microorganisms-12-01802\"], \"section\": \"4.3. Third Cholera Pandemic (1839\\u20131860 AD)\", \"text\": \"This pandemic spread almost worldwide, reaching Latin America for the first time, and returning to Europe and North America. The disease spread westward, to Bombay in 1839 and from there, to Aden in 1846, and to the Red Sea region and North Africa in 1848. Again, the pilgrim traffic to and from Mecca was associated with the spread of cholera in the region. Also from Bombay, another branch of the disease spread to the Persian Gulf region in 1846, and from there, the Russian Empire via the Caspian Sea in 1847, and to Western Europe the following year [13]. The Crimean War helped spread cholera to the Mediterranean ports and the Balkans [53]. From Europe, the disease reached North and Central America in 1849 and South America for the first time in 1855. Apart from India, the highest mortality was observed in Brazil [13,57].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\", \"microorganisms-12-01802-f008\"], \"section\": \"4.3. Third Cholera Pandemic (1839\\u20131860 AD)\", \"text\": \"From the Bengal region to the east, the disease reached Malaysia, Singapore, and southeastern China in 1840, probably carried by British troops and trade during the Opium War between China and the United Kingdom. From the coast, the disease spread inland, reaching Burma, western China and from there, Central Asia in 1844 [13] (Figure 8).\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\", \"B53-microorganisms-12-01802\", \"B25-microorganisms-12-01802\", \"B13-microorganisms-12-01802\"], \"section\": \"4.3. Third Cholera Pandemic (1839\\u20131860 AD)\", \"text\": \"The third cholera pandemic killed between 1 and 1.5 million people [13,53], or 0.08 to 0.12% of the world\\u2019s population [25]. In some places, such as Brazil, the Caribbean, parts of the United States, and Europe, the mortality rate was high, making the third cholera pandemic the worst of the 19th century. The mortality rate was associated with slavery and killed mostly men in Brazil and the Caribbean. Although the mortality rate of the third cholera pandemic was higher than that of the second, the former was not accompanied by social unrest [13].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\", \"B53-microorganisms-12-01802\"], \"section\": \"4.3. Third Cholera Pandemic (1839\\u20131860 AD)\", \"text\": \"The British physician John Snow suspected that cholera was waterborne ever since the second cholera pandemic hit London in 1834. Although cholera struck London again in 1848, it was not until 1854, when the number of deaths peaked, that Dr. Snow began to investigate the outbreak in the Soho district by plotting the deaths on a map. The deaths were clustered around a particular water pump on Broad Street (now Broadwick Street), and Dr. Snow hypothesized that the contaminated water from this pump was the source of the outbreak. Although the number of cholera cases declined, Dr. Snow convinced the local authorities to remove the handle of the pump, which further reduced the number of cases. Proving that cholera was waterborne was a major breakthrough in understanding its transmission. This work is the earliest example of epidemiological investigation, and for this reason Dr. Snow is referred to as the father of epidemiology [13,53].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\", \"B57-microorganisms-12-01802\", \"microorganisms-12-01802-f009\"], \"section\": \"4.4. Forth Cholera Pandemic (1863\\u20131875 AD)\", \"text\": \"The fourth cholera pandemic began in 1863, like the previous ones, in the Ganges River delta region. The following year, the disease reached Bombay, on the west coast of India, and from there spread around the world, following the path of previous cholera pandemics, but with a difference. From India, the disease reached the port of the British protectorate of Aden in 1864. From Aden, the disease spread to Somalia and Ethiopia in 1865 and, more importantly, to Jidda, the seaport of Mecca, where Muslim pilgrims from all over the world were gathered. That year, approximately 17% of the 90,000 pilgrims died of cholera. From Egypt, the disease spread across the Mediterranean Sea. In 1865, cholera reached Great Britain, the Netherlands, Prussia and Russia. From Europe, the disease was transported to the West Indies and North America, in 1866. From Aden, cholera spread not only to Egypt, but also to Algeria, Tunisia and Morocco in 1867 and to Senegal in 1868. From Ethiopia, the disease spread across the African continent to Zanzibar, Mozambique, and Madagascar in 1869 [13,57] (Figure 9).\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B57-microorganisms-12-01802\", \"B25-microorganisms-12-01802\", \"B13-microorganisms-12-01802\"], \"section\": \"4.4. Forth Cholera Pandemic (1863\\u20131875 AD)\", \"text\": \"The fourth cholera pandemic killed approximately 700,000 people worldwide [57], or 0.06% of the world\\u2019s population [25]. The pandemic was more severe in India, especially when it coincided with a year of famine, when droughts forced the people to drink from contaminated wells. Famine was associated with rural-urban migration and consequently poor water supply and sanitation [13].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\"], \"section\": \"4.4. Forth Cholera Pandemic (1863\\u20131875 AD)\", \"text\": \"This pandemic was particularly associated with religious pilgrimages by Western societies, and Western empires began to regulate these pilgrimages. It was also the first time that cholera was associated with human movement, being imported from somewhere else. The belief that cholera was associated with water pollution grew, but it was not until the next cholera pandemic that the pathogen was discovered [13].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\", \"B57-microorganisms-12-01802\", \"microorganisms-12-01802-f010\"], \"section\": \"4.5. Fifth Cholera Pandemic (1881\\u20131896 AD)\", \"text\": \"In 1881, cholera spread around the world for the fifth time, again starting in the Ganges River delta area, again. In 1882, the pandemic spread outside India to the Dutch East Indies (now Indonesia) and the Philippines, causing high mortality in both places. The following year, the disease again reached the Muslim pilgrims in the Hijaz and Mecca regions of Arabia, and from there to Egypt. In 1884, the disease moved through the Mediterranean ports and spread to Italy, France and Spain. In 1886, the pandemic reached Argentina, and from there it spread through South America the following year. Between 1888 and 1891, the disease retreated to Asia, causing new outbreaks, but reappeared in Europe in 1892, using the same route as the second cholera pandemic, up the Volga River into the Russian Empire. From the Russian Empire, the disease spread to Germany and to Western Europe [13,57] (Figure 10).\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B57-microorganisms-12-01802\", \"B25-microorganisms-12-01802\", \"B13-microorganisms-12-01802\"], \"section\": \"4.5. Fifth Cholera Pandemic (1881\\u20131896 AD)\", \"text\": \"The fifth cholera pandemic killed approximately 750,000 people worldwide [57], or 0.06% of the world\\u2019s population [25]. The pandemic hit India severely, and especially affected the Russian Empire, causing social unrest due to the high mortality rate [13].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B59-microorganisms-12-01802\", \"B57-microorganisms-12-01802\"], \"section\": \"4.5. Fifth Cholera Pandemic (1881\\u20131896 AD)\", \"text\": \"In 1854, the Italian doctor Filippo Pacini described an active vibrio in stool samples from cholera patients in the city of Florence, Italy. The discovery of Vibrio cholerae, which called into question the theory of miasmas, was ignored by the scientific community of the time. The causative agent of cholera only came to prominence in 1883, when Robert Koch, who was already a renowned microbiologist, managed to isolate the bacterium during a visit to India during a cholera outbreak [59]. In addition, between 1889 and 1896, at the end of the pandemic, a clinical trial carried out by the Russian scientist Waldemar Haffkine with approximately 40,000 volunteers in Calcutta, India, made it possible for the first time to use an attenuated human vaccine against cholera [57]. Unfortunately, even the existence of a vaccine was not enough to prevent a new cholera pandemic.\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\", \"B57-microorganisms-12-01802\"], \"section\": \"4.6. Sixth Cholera Pandemic (1899\\u20131923 AD)\", \"text\": \"The sixth cholera pandemic began in 1899 in the same place as the previous five: the Ganges River delta. The disease had long been endemic in India, but this would be the last time a cholera pandemic broke out in this location. As usual, the disease spread westward to Bombay, Madras, and Punjab, and from there to other countries. In 1901, the disease reached Singapore and the Dutch East Indies (now Indonesia) from Indian ports. In 1902, it reached China and the Philippines, Muslim pilgrims in the Hijaz, and eventually Egypt. The disease reached Persia in 1903 and the Russian Empire in 1904. In 1905, cholera reached the Austro-Hungarian Empire [13,57].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\", \"microorganisms-12-01802-f011\"], \"section\": \"4.6. Sixth Cholera Pandemic (1899\\u20131923 AD)\", \"text\": \"The disease seemed to disappear between 1905 and 1909, but reappeared in some places such as India, the Dutch East Indies, and the Russian Empire. The disease reached Western Europe in 1910, particularly Italy and the Balkans. From Italy, it reached the Ottoman colony of Tripolitania in 1911, probably brought by the Italian soldiers occupying that territory [13] (Figure 11).\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\"], \"section\": \"4.6. Sixth Cholera Pandemic (1899\\u20131923 AD)\", \"text\": \"The First World War and the Russian Revolution, whose ensuing civil war lasted until 1921, greatly facilitated the spread of cholera, especially in Russia and on the Eastern and Southeastern European fronts. This cholera pandemic occurred at a troubled time in history, during the World War I and the most severe influenza pandemic of 1918\\u20131919, the Spanish flu. Even so, as in the previous cholera pandemic, the United States had cases, but they were contained by quarantines of passengers on ships coming from affected countries [13]. \"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\", \"B57-microorganisms-12-01802\", \"B25-microorganisms-12-01802\"], \"section\": \"4.6. Sixth Cholera Pandemic (1899\\u20131923 AD)\", \"text\": \"The sixth cholera pandemic caused a large number of deaths, particularly in India, where approximately 8 million people may have died from cholera [13]. Outside of India, cholera killed approximately 800,000 people worldwide [57]. The total death toll of the sixth cholera pandemic was approximately 8.8 million people, or 0.6% of the world\\u2019s population [25].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\", \"B13-microorganisms-12-01802\"], \"section\": \"4.6. Sixth Cholera Pandemic (1899\\u20131923 AD)\", \"text\": \"In the early 20th century, cholera was responsible for 10% of deaths in India. In the Philippines, cholera was responsible for nearly 1/3 of deaths. In Persia (now Iran), cholera caused social disruption due to the high mortality rate [13]. With the growing consensus on the cause of the disease, some governments began to adopt public policies to control cholera, but without success due to the difficulty of adapting scientific knowledge to the reality of societies [13].\"}, {\"pmc\": \"PMC11433773\", \"pmid\": \"\", \"reference_ids\": [\"B13-microorganisms-12-01802\"], \"section\": \"4.7. Seventh Cholera Pandemic (1961 AD\\u2013Today)\", \"t

Metadata

"{}"