So many questions, so little time.

Fifteen years have elapsed since the first human infections with H5N1 highly pathogenic avian influenza (HPAI) virus were detected in Hong Kong SAR, China [1, 2]. Many of these human infections were fatal and represented the first documented outbreak of severe disease due to HPAI viruses. The hallmark of these H5N1 viruses is their hemagglutinin genes inherited from A/goose/Guangdong/1996, a virus first detected during an outbreak in domestic geese in China. Who could have predicted the current H5N1 situation in 1997? As of August 2012, H5N1 viruses of this lineage have caused 607 reported human cases (358 fatal), the culling of 400 million birds, and have become entrenched in poultry populations on 2 continents [3, 4]. Early expectations were that this virus would be eliminated quickly and become extinct after local bird populations were decimated by the outbreak or culled, thus recapitulating the experience with dozens of HPAI outbreaks in poultry in many countries during the past century. Rather than becoming extinct, these H5N1 viruses spread to 60 countries on 3 continents by 2006 [3]. The alarm caused by the far-ranging geographic expansion of H5N1 galvanized governments to invest resources in avian disease control. Despite many effective local and regional infection control programs in recent years, H5N1 is considered to be endemic in poultry in many countries, including Indonesia, Bangladesh, China, Vietnam, and Egypt [3]. Several of these countries also report the highest numbers of human infection. Most HPAI H5N1 human infections reported to the World Health Organization by public health authorities since 1997 were acquired by direct or indirect contact with infected birds. This spread and entrenchment of H5N1 has sparked a lively debate concerning the likelihood and severity of an H5N1 pandemic. However, recent studies conducted in the United States and The Netherlands [5, 6] demonstrated that H5N1 can gain airborne transmissibility for ferrets after acquiring a relatively small number of genetic changes (reassortment and/or mutations). Additional studies [7] indicated that the pandemic potential of H5N1 viruses currently endemic in Asia and Africa is no longer a remote theoretical risk, prompting calls for increasing the pace of research to control H5N1 infection in poultry to pre-empt a future pandemic. However, international animal health experts agree that global H5N1 eradication from poultry may take several decades [8]. Therefore, many critically important questions need to be answered in a race against the pandemic clock. Furthermore, these research questions should be translated into improved virus detection and intervention methods that can be applied globally to control influenza. The severity of a potential H5N1 pandemic is of critical importance for pandemic planning. The case-fatality rate of H5N1 infection has been difficult to establish with any certainty, mainly because current surveillance methods are likely to miss milder infections [9, 10]. Nevertheless, the potential lethality of H5N1 infections in healthy persons of all ages is undeniable, and pathogenesis observed in critically ill patients appears to be linked to the so-called “cytokine storm,” or hypercytokinemia [11–13]. The molecular basis for hypercytokinemia has puzzled scientists and clinicians for many years. An article in this issue of the Journal of Infectious Diseases (Sakabe et al, 2013; 207:262-71) and a recent article in Science [14] provide important clues. Both articles identify one of the viral polymerase complex genes as a determinant of the cytokine responses in human cell cultures and in mouse models. The research reported in this issue by Sakabe et al relied on reverse genetics to elucidate the molecular basis for striking differences between H5N1 viruses in their ability to activate macrophage cytokine secretion, which the authors observed in earlier studies [15]. A panel of reassortant viruses was created Received 13 August 2012; accepted 23 August 2012; electronically published 4 October 2012. Correspondence: Nancy J. Cox, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd, MS-A20, Atlanta, GA 30333 ([email protected]). The Journal of Infectious Diseases 2013;207:208–10 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2012. DOI: 10.1093/infdis/jis529