The influenza enigma

Abstract

To disease detectives at the world's leading public health agencies, influenza is an all-too familiar foe. First isolated in 1932, the virus--a single-stranded member of the orthomyxovirus family--occurs every year in every country, seasonally and sporadically, killing between 250 000 and 500 000 people and causing severe illness in several million more, according to the World Health Organization (WHO). Over the past three centuries, there have been at least 10 global influenza pandemics and three in the last century alone, among them the so-called 'Spanish flu' of 1918-1919. The single most devastating disease outbreak in human history, that pandemic is believed to have caused between 20 million and 50 million deaths worldwide. It is the prospect of another such catastrophe, and the staggering toll of seasonal flu, that has made influenza the world's second-most studied virus, behind HIV. In recent years, those investments in influenza research have yielded important new insights about the virus's genetic makeup and capacity for mutation. Indeed, with the reconstruction of the 1918 virus at the US Centers for Disease Control and Prevention (CDC) in Atlanta in 2005, scientists were able to identify the genetic changes that allowed the virus to cross the species barrier between birds and humans, confirming fears that the avian H5N1 strain that has been circulating in Asia could one day do the same. [ILLUSTRATION OMITTED] Now, at two leading influenza laboratories at the University of Wisconsin-Madison, in the United States of America (USA) and Erasmus MC in Rotterdam, the Netherlands, researchers have broken new ground by creating mutant H5N1 strains. The controversial studies, which have been paused for a debate over the risks they may pose to public health, demonstrate that viruses equipped with a haemagglutinin protein from highly pathogenic H5N1 viruses can become transmissible in ferrets. Ferrets are believed to be the ideal small animal model for influenza because they are susceptible to human flu viruses and some of the symptoms seen in humans. It is not yet known whether this mutant H5N1 is transmissible in humans and a study to find that out would probably not be possible. But we can infer that there is a high likelihood of transmissibility based on the findings in ferrets. Yet for all of the advances afforded by new genomic technologies, our understanding of the fundamental epidemiology of influenza remains far from complete. Such broad questions as what specific forces direct the appearance and disappearance of epidemics still challenge virologists and epidemiologists, wrote the late, long-serving CDC epidemiologist Michael Gregg in 1980. This is still the case today. Take, for example, the enduring enigma of influenza seasonality. The clock-like consistency of the virus's winter incidence, which peaks in temperate zones, provides perhaps the most striking illustration of seasonality in infectious diseases. However, clouding the picture is the highly variable pattern of seasonal flu outbreaks in the tropics, says US National Institutes of Health (NIH) epidemiologist Martha Nelson. They can be associated with rainy seasons or dry seasons, and you could have one epidemic or two she says. It's really not well understood. This despite several untested and inconclusive theories being put forward as to why this is the case. Similarly puzzling is the question of where those seasonal strains come from. Although it has long been held that south-east and eastern Asia are the global source of seasonal flu epidemics, a recent study by researchers at the Duke-National University of Singapore (NUS) Graduate Medical School casts considerable doubt on that assumption. Published last November in the journal Proceedings of the National Academy of Sciences, the study compared viral migration between urban centres in seven different temperate and tropical regions between 2003 and 2006. …