Pandemic influenza: certain uncertainties

Abstract

SUMMARY For at least five centuries, major epidemics and pandemics of influenza have occurred unexpectedly and at irregular intervals. Despite the modern notion that pandemic influenza is a distinct phenomenon obeying such constant (if incompletely understood) rules such as dramatic genetic change, cyclicity, “wave” patterning, virus replacement, and predictable epidemic behavior, much evidence suggests the opposite. Although there is much that we know about pandemic influenza, there appears to be much more that we do not know. Pandemics arise as a result of various genetic mechanisms, have no predictable patterns of mortality among different age groups, and vary greatly in how and when they arise and recur. Some are followed by new pandemics, whereas others fade gradually or abruptly into long-term endemicity. Human influenza pandemics have been caused by viruses that evolved singly or in co-circulation with other pandemic virus descendants and often have involved significant transmission between, or establishment of, viral reservoirs within other animal hosts. In recent decades, pandemic influenza has continued to produce numerous unanticipated events that expose fundamental gaps in scientific knowledge. Influenza pandemics appear to be not a single phenomenon but a heterogeneous collection of viral evolutionary events whose similarities are overshadowed by important differences, the determinants of which remain poorly understood. These uncertainties make it difficult to predict influenza pandemics and, therefore, to adequately plan to prevent them.

Autopsy series of 68 cases dying before and during the 1918 influenza pandemic peak

“…With a speculative serial generation time of 4.5 d (38), basic reproductive rate of 1.8 (39), and case-fatality ratio probably no higher than 1% to 2% in the summer months, it would clearly take weeks, even under favorable circumstances, for an imported "founding virus" to produce enough cases for a small outbreak to occur or for fatalities to be detected statistically. For unknown reasons, summer (Northern Hemisphere) spread of newly introduced pandemic influenza viruses has historically (e.g., 1580, 1782) and more recently (e.g., 1957, 1968, and 2009) been indolent (40). In this respect, it is noteworthy that mortality peaks associated with respiratory disease had occurred in a few Northern European countries in July to August 1918 (37).…”

Development of a risk assessment methodological framework for potentially pandemic influenza strains (FLURISK)

“…Most reviews [7,12,36,39], including the WP1 literature review, identify similar factors that affect the capability of an influenza virus to infect humans. These include receptor binding, genetic reassortments and phylogenetic relatedness, which have been captured by the virus score model.…”

“…Zoonotic transmission of a virus to which humans are naïve has been a recurring theme in the development of past influenza pandemics, including the 1918 "Spanish flu" pandemic and the 1967 pandemic, plus intermittent outbreaks in various countries (e.g. H7N7 in the Netherlands in 2003) [7][8][9]. These pandemics focused attention on avian influenza viruses, hence the scientific community was unprepared in 2009 for the unexpected emergence and worldwide spread of the swine-origin Influenza A virus (H1N1).…”

“…Numerous reviews have been conducted to assess the driving factors behind the emergence and subsequent spread of recent (and ancient) influenza pandemics [7,[11][12], but the science is hampered by a very complex environmental and evolutionary system of interaction and feedback loops between virus(es), animal species and humans. The development of a pandemic is a chaotic and unpredictable process, where key factors will contribute varying amounts to the generation of different pandemics.…”

“…So far, no human pandemic strain of influenza has successfully been predicted, or indeed has any pandemic been attributed to any specific factor(s) such as climate, farming practices or virus genetic reassortment [7,[13][14]. The interaction between bodies identified above as author(s).…”