Gerardo Chowell, Lone Simonsen, Cécile Viboud. Natural History. Volume 125, Issue 8, September 2017.
A century ago the human race was devastated by the global influenza pandemic of 1918-1920, which generated the highest death toll of epidemic events in recent history. Global mortality estimates range from at least 20 million to as many as 100 million deaths, 1.2 to 5.7 percent or more of the global population at the time. The most severely affected patients were often young adults, who presented with heliotrope cyanosis (a bluish coloration of the skin) and acute respiratory distress, followed by sudden death. Today the pandemic of the so-called Spanish flu remains a vivid worst-case scenario for those contemplating pandemic influenza preparedness.
The recent Ebola outbreaks were frightening in their own right, and the HIV/AIDS pandemic remains relentlessly tragic, but neither are airborne diseases with extremely short intervals between two successive cases, in the order of two to three days. Once pandemic flu has taken a foothold in a population, containment at the source is unrealistic, although medical countermeasures can help mitigate the disease burden. Isolated populations can buy a few weeks or months before the main onslaught of a pandemic, but in our globally connected world, they remain vulnerable to its subsequent attacks
The pandemic was dubbed the “Spanish flu” in part because the uncensored Spanish press widely publicized the respiratory deaths in Madrid and a few other parts of Spain in May and June 1918. The first publication to mention the outbreak was Madrid’s El Sol of May 22, 1918. In contrast, the rest of Europe censored news relating to the pandemic for fear of a decline in troop morale during World War I. But historic mortality statistics indicate that widespread respiratory disease outbreaks occurred in France as early as April 1918. Hence, it is plausible that the virus was introduced into Spain by Spanish workers traveling to and from neighboring France in search of temporary employment, given the shortage of young French workers during wartime. The term “influenza pandemic” first appeared in print on July 13, 1918, in the British Medical Journal.
What would later be viewed as the first wave of the novel influenza spread remarkably rapidly around the world, considering the limited connectivity at the time. In civilian populations, the earliest evidence of respiratory outbreaks associated with unusually high mortality among young adults came from New York City in February and March of 1918. In the United States military, the first reports came in early March in Camp Funston, Kansas, and the disease spread to other training camps during the following months. Other states such as Missouri, Illinois, Ohio, and Michigan reported increased influenza transmission in early March, followed by Georgia and South Carolina in mid- and late March, with a peak in thirty of the largest U.S. cities in April.
By May, the first wave had reached Central Mexico to the south and, to the north, Newfoundland, off the eastern coast of mainland Canada. Influenza incidence rose in France, probably associated with troop arrivals from the U.S., with a peak in hospitalizations and deaths during May through July of 1918. By early summer, influenza was widespread in Great Britain, Switzerland, Norway, Denmark, Sweden, Germany, Austria, Poland, and Greece.
Detailed morbidity and mortality data from Europe and North America indicate that the first pandemic wave caused considerable morbidity but relatively few deaths. As a rule, however, these deaths were concentrated among young adults twenty to forty years of age, in stark contrast to seasonal influenza outbreaks, which primarily kill the youngest and the oldest. This was the tell-tale sign that a most unusual outbreak was underway.
Our understanding of historical influenza pandemics, including the Spanish flu, has been mounting over the last decade as a result of collaborative efforts involving epidemiologists, demographers, medical historians, and virologists. In particular, archaeo-epidemiology studies, relying on intense efforts to locate, digitize, and analyze century-old archival disease records (church records and city- or state-level mortality statistics) have illuminated mortality age profiles, timing, and transmission patterns of the 1918 influenza pandemic in several areas of the world. Apart from the anomalous age pattern in the victims, one of the most noticeable characteristics of the Spanish flu pandemic was the occurrence of closely spaced recrudescent, or re-arising, pandemic waves over a few years. A particular lesson learned is that a relatively mild “herald” wave may occur outside of the typical winter season.
Several mechanisms have been proposed to explain the multi-wave pattern of pandemic influenza, including school schedules, weather patterns, incomplete acquired immunity, and details of the social network structure. Variation and change in the virus itself could also be a key. Unfortunately, virus genetic material from this period is not typically available for study, apart from a few precious specimens of the 1918 virus recovered from archival lung autopsies and exhumation in recent years. The first isolation of any influenza virus dates back to 1933, so there is an important gap in the first decade of adaptation of the 1918 pandemic virus. Guided by detailed historical data, epidemiological modeling studies can help in reconstructing the impact of influenza wave patterns before 1930, and hence speak to the presumed genetic changes that may have occurred during this period in the influenza virus.
Currently, identification of herald waves is complicated by the fact that most of the datasets available for the period are mortality statistics, rather than morbidity records, and the herald wave of the 1918 pandemic was generally mild. The strongest evidence of herald waves comes from settings where morbidity data were available, such as Scandinavia, where transmissibility estimates could be obtained and deemed consistent with pandemic influenza. Oslo was unique in reporting a higher influenza attack rate in summer than autumn 1918. Significantly, this epidemiological evidence of a herald 1918 pandemic wave, with tell-tale lethality among young adults, indicates the presence of a 1918-like virus in late winter and spring 1918. These observations are in line with virologic confirmation of pandemic H1N1 influenza infection among U.S. soldiers who died in May 1918.
In the U.S. and many other parts of the world, the second wave came in the fall of 1918 and proved the deadliest. After that, additional recrudescent waves occurred, primarily in the winters of 1919 and 1920. By the end of 1920, the pandemic was essentially spent, and mortality was much attenuated in young adults and more prominent among seniors. Detailed studies in Copenhagen point to a return of a typical age pattern of influenza deaths within seven to ten years of the pandemic’s emergence, indicating a return to seasonal influenza dynamics.
Mortality studies have underscored significant sparing of people over fifty years of age during the main fall 1918 pandemic wave in the U.S. and Europe, but this was not the case for populations living in Mexico, Colombia, and Newfoundland. One simple explanation is that older people in the relatively well-connected areas of the U.S. and Europe were exposed to closely related influenza viruses in their childhood, before 1870, and had developed similar immune responses to the antigens produced by them. Their existing immunity then helped protect them from the Spanish flu virus. Older people in Mexico, Colombia, and Newfoundland, instead, had a different-and as it turned out, less beneficial-exposure to antigens in their childhood.
This “antigen recycling” hypothesis gained more traction during the recent 2009 pandemic, when the sparing of older people was associated with high levels of prior antibodies, as evidenced by serological testing and direct comparison with viruses circulating in the 1950s. The story is murkier for the Spanish flu, as we do not know what circulated in the nineteenth century. The recycling hypothesis presupposes that prior to the Spanish flu, a virus antigenically similar to the 1918 pandemic strain had circulated half a century earlier. However, this is difficult to reconcile with archaeo-virology studies of parts of the virus that concluded that the 1918 pandemic virus stemmed directly from an avian reservoir. Only the recovery of influenza specimens from before the Spanish flu era may resolve this question.
The association between socioeconomic conditions, baseline health, and influenza-related mortality remains a longstanding debate among epidemiologists. Some countries had forty times as much excess mortality attributable to the 1918 pandemic compared to others, with lower-income nations generally faring the worst. The disparities can be examined and debated at the subnational level as well. Based on census tracts in Chicago, mortality rates across neighborhoods were found to increase by 32 percent on average for every 10 percent increase in the illiteracy rate.
Important gaps remain in our understanding of the 1918 pandemic, particularly owing to lack of data from low-income countries in Asia and Africa, where most pandemic-related deaths are thought to have occurred. In addition, further studies are needed to identify subpopulations at elevated risk of influenza infection and death. Research could concentrate on regions where, in addition to detailed mortality data, other types of information are available, including the prevalence of underlying risk factors or individual patient data.
A century later, the influenza research community is still struggling to fully grasp the origins and mortality impact of the most devastating influenza pandemic in recorded history. The nagging question is whether an outbreak as serious as the 1918 influenza pandemic could happen again. Could it be even worse, considering increased global population density, mobility, and urbanization? Or would those factors be balanced out by increased hygiene, availability of antibiotics, targeted vaccines (within months of the emergence of a new virus), or broadly protective vaccines that may become available in the next decade?
The question is not whether an influenza pandemic will occur in the future. It will. But where it will come from, and whether it will be devastating, remain impossibly difficult questions to tackle, despite modern scientific tools and medical advances.