Influenza Seasonality: Underlying Causes and Modeling Theories

Abstract

Influenza (or “flu”) leads to the hospitalization of more than 200,000 people yearly and results in 36,000 deaths from flu or flu-related complications in the United States (15), striking both the elderly and infant populations particularly hard (24). Two members of the Orthomyxoviridae family, the influenza A and B viruses, are the primary causes of this acute viral respiratory disease. Both viruses are characterized as enveloped viruses that contain eight negative-stranded RNA segments that encode 9 structural and 2 nonstructural proteins (influenza A virus) or 10 structural and 1 nonstructural protein (influenza B virus). Because of the higher levels of morbidity and mortality associated with influenza A virus, in part due to the large reservoir of the virus in aquatic birds, we will restrict ourselves to discussions of this virus. Novel influenza virus strains can be the source of infrequent but devastating pandemics, most famously the 1918 pandemic, which killed between 20 and 40 million people (43). These pandemics are associated with major shifts in the HA and NA proteins that define viral strains. More routinely, influenza virus also generates epidemics or large outbreaks. Epidemics can be traced to a drift in the HA and NA proteins that circumvents sufficient preexisting B-cell reactivity so as to render the individual susceptible. Often the influenza virus may produce sporadic localized outbreaks. Such cases have not been the focus of research into influenza epidemiological virology, but it is likely that they are also associated with a transient viral subpopulation with immunoevasive properties, a theory which has been borne out with mathematical models (31, 68, 69). In temperate climates, flu infections at whatever level of intensity are characterized by a flu season. In these areas, the disease is thought to exist at a low level throughout the year but exhibit a marked seasonal increase, typically during the winter months. Influenza epidemics and outbreaks occur in tropical areas as well, although the timing and impact are not as well defined (16, 71, 81). Local epidemics begin suddenly, peak in 2 to 3 weeks, and last for a total of 5 to 10 weeks. It is believed that in most cases seasonal outbreaks of influenza originate in China and spread from there (19). Infectious disease dynamics offer a wide variety of intriguing and unexplained phenomena, yet none is as consistently observed while still remaining so poorly understood as the seasonality of influenza. There is a gap in how diverse studies encompassing immunology, mathematics, epidemiology, and virology combine to form a complete picture of flu seasonality. This may be due to the daunting complexity of seasonality itself, which is likely to reflect the actions of a vast multitude of variables. For whatever reason, only limited research has actually focused on supporting or rejecting each of the proposed underlying causes of the seasonality of influenza, and most of these, while thorough and well supported, are largely confined to a single discipline. This paper will provide a review of the proposed theories from the existing literature and examine possible links among them that may suggest a more-unified view of influenza seasonality, as well as call attention to gaps among the different ways of understanding seasonality. It may be that, once actually understood, the mechanisms governing the seasonal pattern in the incidence of influenza can provide greater insight into all aspects of the dynamics of transmission and maintenance of this disease (59). The authors believe that the current research has reached a stage such that advances in our understanding of influenza seasonality will emerge from an enhanced conceptual understanding of the biological dynamics of infection, not from a breakthrough in mathematical methodology. Therefore, the bulk of the review is devoted to the disease parameters being modeled rather than to modeling techniques, although these are briefly examined in their potential applications.