A parsimonious hypothesis to the cause of influenza lethality and its variations in 1918–1919 and 2009

Abstract

Current explanations to the high 1918-1919 mortality involve either a higher pathogenicity of the virus or bacterial super-infection in the absence of adequate therapeutic resources. However, neither of these hypotheses accounts for the age-distribution of severe cases and deaths, or for the geographic and other variations in rates and explosiveness of mortality during the Pandemic. It will be shown here that, alternatively, the epidemiology of the influenza lethality could be completely explained by a combination of two determinants: (1) acquired immune-differentiation of birth-cohorts, within populations, through developmental epigenetic adaptation (and selection) secondary to maternal or early-life episodes of influenza infection and (2) a triggering context - emergence of a new sub-type/strain, and its co-circulation (competition?) with seasonal viruses immunologically related to ones that had circulated in the past and primed particular population birth-cohorts. This article (1) presents age, geographic, and temporal variations in 1918-1919 and 2009 influenza severity, (2) presents and discusses ecologic evidence in favor of the hypothesis to influenza lethality advanced here, (3) suggests biologic mechanisms capable of explaining it, (4) retrospectively, proposes co-circulation between the Pandemic and a 1918 seasonal (H3?) influenza virus as the context for the increased lethality during the second wave of the 1918 Pandemic, and (5) predicts an increase in influenza severity in the northern hemisphere as the 2009-2010 season advances and H3 circulation increases.

The 1918 influenza and 20th century CHD

“…Based on my previous studies, I would not expect H1 infections, supposedly dominant in 1918–1919, to initiate CHD. But their findings would agree with the idea of co-circulation of H1 and H3 viruses in 1918 4 …”

“…But their findings would agree with the idea of co-circulation of H1 and H3 viruses in 1918. 4 Since 2000-2004, there has been a growth of investigations tackling the link between influenza and CHD. A recent paper by Warren-Gash et al does an excellent job of reviewing these studies.…”

Comparison of influenza A virus infection in high‐ and low‐birth‐weight pigs using morphometric analysis

“…A number of studies have linked influenza susceptibility to low‐ birth‐weight and epigenetic programming. Firstly, it is proposed that the explosive mortality associated with the 1918 H1N1 pandemic may be associated with acquired epigenetically mediated immunological differences among birth cohorts in combination with the emergence of a new strain/subtype . It is difficult to prove whether or not this theory is valid; however, epigenetic programming has been linked to the metabolic syndrome (hypertension, insulin resistance, dyslipidemia, obesity), and obesity indirectly increases the susceptibility to a number of community‐borne pathogens, including influenza, through number of potentially altered immunological mechanisms …”

Influenza Recycling and Secular Trends in Mortality and Natality

“…In the U.S., both events disproportionately affected cohorts born before the turn of the 20th century (Reinert- Azambuja, 1994;Azambuja & Duncan, 2002). A complex hypothesis was developed during the following years to explain this observation, involving the concepts of original antigenic sin, recycling of influenza A viruses and cross-reactive auto-immune responses to hetero-subtypic influenza re-infections (Azambuja & Levins, 2007;Azambuja, 2009b). These concepts and an updated version of the Influenza-CHD hypothesis are briefly summarized below.…”

“…The original antigenic sin is a phenomenon recognized since 1953 (Francis et al, 1953) and described by Davenport et al (1969) as follows: "the major antigens of the [influenza] strains of first infection of childhood permanently orient the antibody-forming mechanisms so that, on subsequent exposures to influenza viruses, the cohort of the population would respond with marked reinforcement of the primary antibody'' (p453). This mechanism would explain, for example, the resistance shown by very old individuals against the 1969 H3 Pandemic (Simonsen et al, 2004), and now, of individuals older than 60 years of age against severe effects of the 2009 pandemic (Azambuja, 2009b). Their antibody forming mechanisms were prepared to promptly react and produce antibodies against those viruses, because they were similar to the ones associated with their first influenza experience.…”