Lessons From History: What Can We Learn From 300 Years of Pandemic Flu That Could Inform the Response to COVID-19?

The unexpected temergence of the current pandemic triggered an accelerated process of research on the virus (SARS-CoV-2) and the disease (COVID-19). Since COVID-19 behaves as a typical respiratory transmitted disease, additional insights related to its epidemiology and potential containment strategies could be obtained by studying past pandemics of influenza. The history of influenza pandemics over the past 300 years has been described in much detail by K. David Patterson¹ with 10 major ones occurring at a frequency of three per century.

The first worldwide flu pandemic of the 18th century (1729–1730) had significant morbidity but relatively low mortality. The second pandemic (1732–1733), most likely caused by an antigenically different influenza virus, was also associated with high morbidity and low mortality. A more intense pandemic occurred in 1781 to 1782, infecting an estimated 70% to 80% of the population, although mortality again remained low.

The first two influenza pandemics of the 19th century occurred in 1830 to 1831 and in 1833. The first one was of moderate intensity; the second one was more lethal. The third pandemic of the century occurred in 1889 to 1890, during which the disease was rapidly disseminated around the entire world but resulted in relatively low mortality. This pandemic was the first to occur after the formulation of the germ theory of disease, when the medical community was abandoning the old ideas about miasmas, or atmospheric perturbations, as the cause of epidemics and replacing these with the modern concepts of transmissible microbial agents. The germ theory of disease provided a theoretical framework for future preventive intervention, including clean water, general hygiene, and the now popular “social-distancing” strategies.

The first pandemic of the 20th century was the infamous “Spanish flu.” It appeared in 1918 almost simultaneously in different geographically distant places, making it difficult to pinpoint its precise site of origin.² The pandemic displayed three distinct waves that occurred within a 10-month period from June 1918 to April 1919. The second wave was more intense, perhaps exacerbated by the military mobilizations during World War I.³ It is estimated that 500 million people were infected, representing 30% of the world population, and between 50 and 100 million people died. In 1957, the world experienced the second flu pandemic of the century, the “Asian flu,” which may have had comparable morbidity to the Spanish flu but had much less mortality, with a case fatality rate of 0.3% and 1 to 3 million deaths worldwide. The last pandemic of the 20th century was the so-called Hong Kong flu of 1968,⁴ which exhibited a second and more intense wave that infected most of the countries that had escaped the first one, causing an estimated 1 to 4 million deaths.

Finally, the only flu pandemic that thus far has occurred in the 21st century was the H1N1 pandemic of 2009, which started in North America in February to March 2009 and ended in August 2010, at which time virtually all countries had reported laboratory-confirmed cases. Despite the initial fears that this pandemic could exhibit the same intensity as the Spanish flu, it turned out to be relatively mild, with an estimated 125 000 to 400 000 deaths worldwide.⁵

An analysis of the characteristics of these 10 pandemics allows the identification of several common features. Most of them (but not all) initiated in Asia, probably in China, during the winter months. Most of them lasted for two to four years and exhibited several waves that traveled around the world, coming to an end, most likely, by a herd immunity mechanism, when at least 30% of the population had been infected. There is not sufficient information to conclude that the dissemination outside the northern hemisphere followed a strict seasonal pattern, especially in temperate regions. Some evidence suggests that during the summer months the virus can be preseeded in the population, waiting for the winter months to make a comeback; if the population of susceptible individuals is large, it is likely that the next wave is of increased intensity, as was the case with the Spanish flu.

However, there are several characteristics that made these pandemics different. The time between two pandemics varied from 3 to 40 years, an observation that could be explained by the evolving antigenicity of the pandemic viruses generated by the phenomenon of genetic shift. Another unpredictable feature of past flu epidemics is the transmissibility of the virus, with the estimated basic reproductive numbers (R₀) ranging from 1.2 for seasonal flu to 1.8 or more for pandemic flu. The estimated R₀ of the Spanish flu was between 3.0 and 4.0, which in part explains its severity. Likewise, the case fatality rate has been clearly different from one pandemic to another, exhibiting different morbidity and mortality levels, which taken together have been used to describe the intensity of the different pandemics.

Although the biology of the influenza virus is very different from that of SARS-CoV-2, they share the very important characteristic of respiratory transmission. In this regard, there are important potential similarities to be considered. At the global level, the seasonality of transmission of COVID-19, as has been the case of pandemic flu, is not expected to be a strict behavior especially in temperate countries. During the 2020 winter months of the northern hemisphere, SARS-CoV-2 had already spread to most countries in the world, and it is predictable that it will continue to circulate until the chain of transmission of the virus is interrupted by herd immunity, something that could take two years or more.⁶ What is not known is the seroprevalence level needed to establish herd immunity against SARS-CoV-2, which has been estimated to be between 60% and 70%. The high transmissibility of SARS-CoV-2, with an estimated R₀ of 3.0 to 6.0, may accelerate the achievement of the required level of herd immunity at the global level, but that may still require several waves of the COVID-19 pandemic. These waves may also occur at a more restricted local level if the virus is seeded in populations that have not achieved herd immunity, possibly causing more intense rebounds.

Of note, the course of the COVID-19 pandemic is not inexorable because human behavior has the power to modify it, and an eventual vaccine would contribute to the goal of controlling the COVID-19 pandemic, as is the case with influenza. With a clearer understanding of the role of microorganisms in disease causation, social-distancing (“protective sequestration”) strategies started to be implemented during the 1918 flu pandemic in the United States and elsewhere.⁷ Analysis of these strategies indicate that they were most effective if three conditions were met: early initiation, implementation at scale (including closure of schools, churches, and theaters), and prolongation. It is important to point out that when these distancing strategies were prematurely relaxed, viral spread was renewed. Interestingly, no clear historical evidence of effectiveness has been obtained for the use of facial masks.

The study of influenza pandemics is a clear example of how history can inform our response to future epidemics and pandemics, including the current one of COVID-19.