Conventional wisdom of influenza A; a historical perspective
Many years ago, one of the authors, Donald Kaye, MD, had the good fortune to work with Edwin D. Kilbourne, MD, who was one of the leading researchers in the area of influenza. It was several years after the influenza A(H2N2) pandemic of 1957 and the A(H2N2) virus was circulating yearly causing interpandemic epidemics. At that time, there were a number of dogmas of conventional wisdom about influenza A.
A leading dogma was that pandemics of influenza A occurred only when there was a total switch of hemagglutinin from the existing circulating H1, H2 or H3 to an entirely different numerical hemagglutinin, ie, H2 to H3 or to H1. Another dogma was that only H1, H2, or H3 hemagglutinins were capable of causing influenza A in humans. A third dogma was that only one A hemagglutinin, H1, H2, or H3 could circulate at a time so that A(H2N2) would circulate until the next pandemic, and then the only influenza A virus to circulate after that would be the next pandemic strain.
Patterns of influenza
In fact, as far as we know, events from 1889 up until 1977 followed this simple pattern. From serological data, there was an A(H2N2) pandemic in 1889, presumably followed by yearly A(H2N2) circulation; then an A(H3N8) pandemic in 1901, presumably followed by yearly A(H3N8) circulation until the A(H1N1) pandemic of 1918; followed by yearly A(H1N1) circulation until the A(H2N2) pandemic of 1957; followed by yearly A(H2N2) circulation until the A(H3N2) pandemic of 1968; followed by yearly A(H3N2) circulation until 1977.
One of the first to articulate the periodicity of influenza was Alexander D. Langmuir, MD, MPH, with whom the other author, Theodore C. Eickhoff, MD, had the privilege of working. During and after WWII, Langmuir was the resident epidemiologist with the Commission on Acute Respiratory Diseases stationed at Fort Bragg, N.C. After the war, he published a paper, titled “The Periodicity of Influenza.” This was based on excess mortality data recorded in public health data dating from 1918 to 1946, the date of publication, during which time A(H1N1) viruses were circulating yearly.
Allowing for a bit of biological variation, the data clearly indicated that excess mortality from the type A(H1N1) influenza viruses recurred every 2 to 3 years, and influenza B viruses every 4 to 6 years. No other types of influenza viruses needed to be postulated to explain the excess mortality.
Theodore C. Eickhoff
This led to forecasting influenza epidemics. According to Langmuir, the A epidemic of 1943-44 came just as they were formulating their ideas. The B epidemic of 1945-46 was right on schedule, as was the A epidemic of 1946-47. But in the early 1950s, things began to fall apart, and there was very little influenza A activity in the world for about 5 years. Langmuir’s pet theory to explain the cyclical nature of influenza epidemics — exhaustion of susceptibles, and the changing balance of immunes and susceptibles — could simply not be sustained. Some other phenomena must clearly be at work.
Conventional wisdom gone awry
In early 1957, the “Asian” H2N2 influenza virus was first identified and hand-carried by Thomas Francis Jr., MD, of the Commission on Influenza, Armed Forces Epidemiologic Board to the United States. Langmuir and others confidently predicted that the virus would “seed” throughout the United States during the late spring and summer, and would be followed by a major pandemic that fall and winter; that is exactly what happened. Following prevailing dogma, the previously circulating H1N1 virus simply disappeared.
In 1977, the conventional wisdom went completely to pot. An outbreak of A(H1N1) influenza virus occurred (some have labeled this a pandemic and others have not), and thereafter A(H1N1) started to co-circulate yearly, along with the persistent A(H3N2).
So now, there were two influenza A viruses circulating simultaneously — so much for only one hemagglutinin at a time. This continued until 2009 when more conventional wisdom was proved wrong as a new A(H1N1) caused a pandemic, despite the previously circulating A(H1N1), which it replaced, ie, no change in hemagglutinin number. Furthermore, the A(H3N2) continued to circulate, leaving us where we are today with A(H3N2) and A(H1N1) co-circulating as the major or essentially only strains of influenza A in humans in the United States and most of the world.
The rest of the conventional wisdom about only H1, 2 or 3 causing significant influenza A infections in humans disappeared with the outbreak of A(H5N1) in 1997 and A(H7N9) in 2013. Although not A(H1, 2, or 3), these viruses certainly caused major outbreaks of influenza A in humans. Hopefully neither will ever result in a pandemic.
One of Langmuir’s great strengths was his capacity to look back at his own career and critique some of his earlier thinking. In his 1986 Maxwell Finland lecture to the Infectious Diseases Society of America, he reflected on the influenza periodicity paper and remarked: “I now read this with unmitigated horror — such pious, pompous poppycock!”
What controls the periodicity of influenza? We still don’t really know.
Fortunately, we are in a different and better prepared world today with much better methods to rapidly diagnose influenza outbreaks and the ability to promptly sequence influenza viruses and hopefully rapidly manufacture vaccines. We also have active chemotherapeutic agents in the neuraminidase inhibitors that can prevent and treat influenza.
However, when all is said and done, the final realization must be that if there is anything absolutely predictable about influenza and how it will evolve is that it remains totally unpredictable.
Commission on Acute Respiratory Diseases. Am J Hyg. 1946;43:29-37.
Kilbourne ED. Emerg Infect Dis. 2006;12:9-14.
Langmuir AD. J Infect Dis.1987;155:349-358.
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Theodore C. Eickhoff, MD, is Editor Emeritus of Infectious Disease News and professor emeritus in the division of infectious diseases at the University of Colorado School of Medicine, Denver. He can be reached at Theodore.Eickhoff@ucdenver.edu.
Donald Kaye, MD, is a professor of medicine at Drexel University College of Medicine, associate editor of ProMED-mail, section editor of news for Clinical Infectious Diseases and is an Infectious Disease News Editorial Board member.
Disclosure: Eickhoff and Kaye report no relevant financial disclosures.