A pandemic is an outbreak of global proportions. It happens when infection due to a bacterium or virus becomes capable of spreading widely and rapidly. The disease behind a pandemic can cause severe illness and spread easily from one person to the next.

According to the WHO, a pandemic involves the worldwide spread of a new disease Trusted Source. While an epidemic remains limited to one city, region, or country, a pandemic spreads beyond national borders and possibly worldwide3. Authorities consider a disease to be an epidemic when the number of people with the infection is higher than the forecast number within a specific region. If an infection becomes widespread in several countries at the same time, it may turn into a pandemic.

The terms endemic, outbreak, epidemic and pandemic relate to the occurrence of a health condition compared to its predicted rate as well as to its spread in geographic areas4. An endemic condition occurs at a predictable rate among a population. An outbreak corresponds to an unpredicted increase in the number of people presenting a health condition or in the occurrence of cases in a new area. An epidemic is an outbreak that spreads to larger geographic areas. A pandemic is an epidemic that spreads globally.

Very few phenomena throughout human history have shaped our societies and cultures the way outbreaks of infectious diseases have; yet, remarkably little attention has been given to these phenomena.

Throughout history, pandemic outbreaks have decimated societies, determined outcomes of wars, wiped out entire populations, but also, paradoxically, cleared the way for innovations and advances in sciences, economy, and political systems. Pandemic outbreaks, or plagues, as they are often referred to, have been closely examined through the lens of humanities in the realm of history, including the history of medicine5.

An emerging infection newly appears in a population or is spread in a new geographic area. The zoonotic transmission of pathogens from animals to humans is a pivotal mechanism by which emerging infections have afflicted humans throughout history6. Climate changes also influence the transmission of pathogens (e.g., Dengue, Chikungunya, Zika, Japanese encephalitis, West Nile viruses, Borrelia burgdorferi) by expanding the habitats of various common zoonotic disease-carrying vectors (e.g., Aedes albopictus mosquitos, ticks)7. The spread of several infectious diseases (e.g., tuberculosis, malaria, cholera) to extended geographic areas are now raising health concerns for a significant proportion of the population. Furthermore, outbreaks of cholera in regions where natural disasters occurred such as earthquakes and floods were also reported7.

Infectious agents (e.g., Bacillus anthracis, Yersinia pestis, variola virus) could be used as bio weapons and could thus constitute threats for humanity. These weapons are based on natural microorganisms or microorganisms that are engineered to be more virulent, highly transmissible or resistant to therapy8. The release of these biological weapons is intended to induce diseases in humans or even death.

Let’s review major pandemics that have afflicted humankind throughout history such as plague, cholera, influenza and currently coronavirus disease. Infectious diseases still represent threats for human health as pathogens can spread rapidly through global trade and travels. Global surveillance programs are thus needed to identify pathogens spillover from animals to humans as well as to control water-borne pathogens and vector-borne diseases.

Here are some of the major pandemics that have occurred1:

The Athenian plague is a historically documented event that occurred in 430–26 B.C during the Peloponnesian War, fought between city-states of Athens and Sparta. The historic account of the Athenian plague is provided by Thucydides, who survived the plague himself and described it in his History of the Peloponnesian War. The Athenian plague originated in Ethiopia, and from there, it spread throughout Egypt and Greece. Initial symptoms of the plague included headaches, conjunctivitis, a rash covering the body, and fever1,9. The victims would then cough up blood, and suffer from extremely painful stomach cramping, followed by vomiting and attacks of “ineffectual retching”. Infected individuals would generally die by the seventh or eighth day. Those who survived this stage might suffer from partial paralysis, amnesia, or blindness for the rest of their lives. Doctors and other caregivers frequently caught the disease, and died with those whom they had been attempting to heal. The plague of Athens affected a majority of the inhabitants of the overcrowded city-state and claimed lives of more than 25% of the population.

It was another outbreak that occurred a couple of centuries later that was documented and recorded by contemporary physicians of the time. The outbreak was known as the Antonine Plague of 165–180 AD and the physician documenting it was Galen; this outbreak is also known as the Plague of Galen. The Antonine plague occurred in the Roman Empire during the reign of Marcus Aurelius (161–180 A.D.) and its cause is thought to be smallpox10. It was brought into the Empire by soldiers returning from Seleucia, and before it abated, it had affected Asia Minor, Egypt, Greece, and Italy. Unlike the plague of Athens, which affected a geographically limited region, the Antonine plague spread across the vast territory of the entire Roman Empire. The plague destroyed as much as one-third of the population in some areas, and decimated the Roman army, claiming the life of Marcus Aurelius himself10.

The Justinian plague was a “real plague” pandemic (i.e., caused by Yersinia Pestis) that originated in mid-sixth century AD either in Ethiopia, moving through Egypt, or in the Central Asian steppes, where it then traveled along the caravan trading routes11. From one of these two locations, the pestilence quickly spread throughout the Roman world and beyond. Like most pandemics, the Justinian plague generally followed trading routes. Military movement at the time also contributed to spread the disease from Asia Minor to Africa and Italy, and further to Western Europe. Described in detail by Procopius, John of Ephesus, and Evagrius, the Justinian epidemic is the earliest clearly documented example of the actual (bubonic) plague outbreak11.

The second plague pandemic, the Black Death, originated in East Asia and swept across Central Asia into Europe through the land and sea trade routes of the medieval Silk Road. The second plague pandemic lasted in Europe until the early of the 19th century and killed 200 million people12. The lineages of Y. pestis that caused the The Black Death (1347–1351) killed as many as 30% of the European population and was followed by successive waves such as the plague of Milan (1630), the great plague of London (1665–1666) and the plague of Marseille (1720–1722) plague of Justinian and the Black Death were independent emergences into human population. The plague made several encore rounds through Europe in the following centuries, occasionally decimating towns and entire societies, but never with the same intensity as the Black Death12.

Based on genomic analysis of ancient and recent genomes, it was suggested that a wave of plague may have traveled from Europe to Asia after the Black Death, eventually setting in China and giving rise to the third plague pandemic. The latter plague pandemic originated in the middle of the 19th century in the Yunnan region (China), reached Canton and spread to Hong Kong. The pandemic then reached Japan, Singapore, Taiwan and India via ships. Over the following years, plague became endemic in many countries around the world.

Since the 1990’s, plague is classified as a re-emerging infectious disease by the World Health Organization (WHO).

Spanish flu outbreak was the first true global pandemic and the first one that occurred in the setting of modern medicine, with specialties such as infectious diseases and epidemiology studying the nature of the illness and the course of the pandemic as it unfolded. It is also, as of this time, the last true global pandemic with devastating consequences for societies across the globe 13. It was caused by the H1N1 strain of the influenza virus, a strain that had an encore outbreak in the early years of the twenty-first century.

Within months, the deadly H1N1 strain of influenza virus had spread to every corner of the world. In addition to Europe, where massive military movements and overcrowding contributed to massive spread, this virus devastated the USA, Asia, Africa, and the Pacific Islands. The mortality rate of Spanish flu ranged between 10% and 20%. With over a quarter of the global population contracting that flu at some point, the death toll was immense – well over 50 million, possibly 100 million dead. It killed more individuals in a year than the Black Death had killed in a century. It affected mostly young and previously healthy individuals. This is likely due to its triggering a cytokine storm, which overwhelms and demolishes the immune system. Despite its immense effect on the global civilization, Spanish flu started to fade quickly from the public and scientific attention, establishing a precedent for the future pandemics, and leading some historians (Crosby) to call it the “forgotten pandemic”13.

Cholera is an acute often fatal disease of the gastrointestinal tract caused by Vibrio cholera. Cholera was endemic in Asia until 1817, when a first pandemic spread from India to several other regions of the world. Thereafter, five additional major pandemics of cholera that originated from India and spread to other continents occurred during the 19th and 20th centuries. At that time, health prevention strategies were essentially the same than those implemented during the Black Death14. Infected persons were isolated in lazarettos. Port entry was forbidden for ships arriving from regions where cholera was present. Travelers who had contacts with infected persons or who came from a place where cholera was circulating were quarantined.

Smallpox was a highly contagious disease for which Edward Jenner developed the world’s first vaccine in 1798. Caused by the Variola virus, it was a highly contagious disease with prominent skin eruptions (pustules) and mortality of about 30%. It may have been responsible for hundreds of millions of fatalities in the twentieth century alone. Due to the well-coordinated global effort starting in 1967 under the leadership of Donald Henderson, smallpox was eradicated within a decade of undertaking the eradication on a global scale15.

The smallpox outbreak in the former Yugoslavia in 1972 was a far cry from even an epidemic, let alone a pandemic, but it illustrated the challenges associated with a rapidly spreading, highly contagious illness in a modern world. It started with a pilgrim returning from the Middle East, who developed fever and skin eruptions. Since a case of smallpox had not been seen in the region for over 30 years, physicians failed to correctly diagnose the illness and nine healthcare providers ended among 38 cases infected by the index case and first fatality. About 10,000 individuals who may have come into contact with the infected were placed in an actual quarantine. Borders were closed, and all non-essential travel was suspended15. Within 2 weeks, the entire population of Yugoslavia was revaccinated (about 18 million people at the time). During the outbreak, 175 cases were identified, with 35 fatalities. Due to prompt and massive response, however, the disease was eradicated and the society returned to normal within 2 months.

Influenza viruses belong to the Orthomyxoviridae family. Influenza viruses are enveloped, negative-sense, single-stranded RNA viruses. In typical seasonal epidemics, influenza virus causes 3 to 5 million cases of severe illness and approximately 500,000 deaths worldwide. The Russian flu that occurred between 1889 and 1893 was the first well-described pandemic. The median clinical attack rate was 60% (interquartile range 45–70%)16. Attack rates were highest in individuals aged 1–60 years and lower in infants and seniors. Twenty five years later, the Spanish flu was caused by an A/H1N1 virus that apparently arose by genetic adaptation of an existing avian influenza virus to a new human host. The 1918–1919 pandemic spread in at least 3 distinct waves within a 9 month interval. The 1918–1919 influenza pandemic resulted in approximately 500 million infections and 50 million deaths worldwide. The 1968–1970 influenza pandemic was mild in all countries and comparable to severe seasonal epidemics16. The 2009 influenza virus emerged in Mexico and almost simultaneous outbreaks began in Mexico and in Southern United States. The virus then spread globally over the next 6 weeks. The 2009 pandemic was the first one to combine vaccines and antiviral use. Symptomatic individuals and their contacts were isolated and received antiviral treatment as prophylaxis.

HIV/AIDS is a slowly progressing global pandemic affecting different populations, bringing new challenges for treatment. It started in the early 1980s in the USA, causing significant public concern as HIV at the time inevitably progressed to AIDS and ultimately, to death. The initial expansion of HIV was marked by its spread predominantly among the gay population and by high mortality, leading to marked social isolation and stigma.

HIV affects about 40 million people globally (prevalence rate: 0.79%) and has killed almost the same number of people since 198116. It causes about one million deaths a year worldwide (down from nearly two million in 2005). While it represents a global public health phenomenon, the HIV epidemic is particularly alarming in some Sub-Saharan African countries (Botswana, Lesotho, and Swaziland), where the prevalence tops 25%1,16. In the USA, about 1.2 million people live with HIV and about 12,000 die every year (down from over 40,000 per year in the late 1990s). HIV in the USA disproportionately affects gay population, transgendered women, and African-Americans.

The 2009 H1N1 pandemic was a reprise of the “Spanish flu” pandemic from 1918, but with far less devastating consequences. Suspected as a re-assortment of bird, swine, and human flu viruses, it was colloquially known as the “swine flu” 19. It started in Mexico in April of 2009 and reached pandemic proportions within weeks 19. It began to taper off toward the end of the year and by May of 2010, it was declared over.

It infected over 10% of the global population (lower than expected), with a death toll estimated varying from 20,000 to over 500,000.

Ten years after the first emergence of SARS-CoV, MERS-CoV was reported in Jeddah in Saudi Arabia20. The potential animal reservoirs of MERS-CoV are bats and dromedary camels have been suggested as the intermediary hosts. Between 2012 and 2020, 2,519 laboratory-confirmed cases of MERS-CoV with at least 866 deaths were reported in 27 countries. All cases have been linked to persons in the Arabian Peninsula or who had returned from traveling in MERS-CoV endemic areas. Almost 50% of MERS-CoV cases were due to nosocomial transmission to inpatients, health care workers and visitors. Infection with MERS-CoV causes acute, highly lethal pneumonia and renal dysfunction with various clinical symptoms including fever, chills, rigors, headache, a non-productive cough, sore throat, arthralgia and myalgia20.

Ebola virus, endemic to Central and West Africa, with fruit bats serving as a likely reservoir, appeared in an outbreak in a remote village in Guinea in December 2013. Spreading mostly within families, it reached Sierra Leone and Liberia, where it managed to generate considerable outbreaks over the following months, with over 28,000 cases and over 11,000 fatalities21.

Zika virus was a little known, dormant virus found in rhesus monkeys in Uganda. Prior to 2014, the only known outbreak among humans was recorded in Micronesia in 2007. The virus was identified in Brazil in 2015, after an outbreak of a mild illness having a flat pinkish rash, bloodshot eyes, fever, joint pain and headaches, resembling dengue. It is a mosquito-borne disease (Aedes Aegypti), but it can be sexually transmitted. Despite its mild course, which initially made it unremarkable form the public health perspective, infection with Zika can cause Guillain-Barre syndrome in its wake in adults and, more tragically, cause severe microcephalia in unborn children of infected mothers (a risk of about 1%) 22.

In Brazil, in 2015,there were 2400 birth defects and 29 infant deaths due to suspected Zika infectio22. Since 2016, Zika has continued to spread throughout South America, Central America, the Caribbean, and several states within the USA. It remains a significant public health concern, as there is no vaccine.

In early December 2019, atypical pneumonia were reported in a cluster of patients in Wuhan (China) and were shown to be caused by a new Coronavirus, called SARS-CoV-2 23whereas the disease is referred to as COVID-19. The animal reservoirs are likely bats. SARS-CoV-2 infection may be asymptomatic (up to 40% of cases) or causes a wide spectrum of illness from mild symptoms to life-threatening disease 23. Infected individuals most commonly present with fever, dry cough, shortness of breath, fatigue, myalgia, nausea/vomiting or diarrhea, headache, weakness, rhinorrhea, anosmia and ageusia. Common complications among hospitalized patients include pneumonia, ARDS, acute liver injury, cardiac injury, prothrombotic coagulopathy, acute kidney injury and neurologic manifestations. Critically ill patients could also develop a cytokine storm and a macrophage activation syndrome.

Comorbidities such as hypertension, diabetes, cardiovascular disease, chronic pulmonary disease, chronic kidney disease, malignancy and chronic liver disease have been present in 60–90% of hospitalized patients 24. Mild symptoms occurred in 80% of laboratory-confirmed cases. Approximately 14–19% of patients are hospitalized and 3–5% of cases require transfer to ICU, most commonly due to hypoxemic respiratory failure. Among them, 29–91% necessitates invasive mechanical ventilation. Overall, mortality of hospitalized patients with COVID-19 is approximately 15–20% whereas it is as high as 40% in patients requiring ICU admission. The global estimated case fatality rate ranges between 0.25 and 3.0%.

In phase III trials, several COVID19 vaccines have demonstrated efficacy as high as 95% in preventing symptomatic COVID19 infections. As of April 2021, 16 vaccines are authorized by at least one national regulatory authority for public use: two RNA vaccines (Pfizer–BioNTech and Moderna), seven conventional inactivated vaccines (BBIBP-CorV, CoronaVac, Covaxin, WIBP-CorV, CoviVac, Minhai-Kangtai and QazVac), five viral vector vaccines (Sputnik Light, Sputnik V, Oxford–AstraZeneca, Convidecia, and Johnson & Johnson), and two protein subunit vaccines (EpiVacCorona and RBD-Dimer).

As of 18 May 2021, 1.53 billion doses of COVID19 vaccine have been administered worldwide based on official reports from national health agencies. By December 2020, more than ten billion vaccine doses had been preordered by countries, with about half of the doses purchased by high-income countries comprising 14% of the world's population.

Nowadays, the globalization of travels and trade of animals and animal-based foods pose a serious threat to the spread of infectious diseases. Land use and urbanization to accommodate agriculture and living areas modify the habitats of pathogens, hosts and disease vectors and affect the transmission dynamics of infections to humans. In order to control the transmission of water-borne pathogens such as V. cholera, the WHO has launched a water, sanitation and hygiene (WASH) 25program in developing countries. Vector control is the primary tool to control vector-borne diseases such as malaria, Dengue virus, Chikungunya virus and Zika virus.

The time of onset and the pathogen that will cause the next pandemic are unpredictable. Therefore, pandemic preparedness plans emphasize that non-pharmaceutical interventions should be implemented first to control human-to-human transmission of the pathogen at the right time. Risks of resurgence can follow once these non-pharmaceutical interventions are lifted. Pharmaceutical interventions including rapid point-of-care diagnostic tests as well as new platforms for accelerated vaccine development and production should be developed to improve the global response to the pandemic.