In the United States alone, seasonal (interpandemic) influenza is responsible for an average of 226 000 hospitalizations and .23 000 deaths per year [1, 2]. Although all age groups are susceptible to influenza virus infections, children experience the highest disease incidence, whereas older adults suffer the most serious diseaserelated complications and mortality. Many of these events are secondary bacterial pneumonias, most of which are thought to be caused by Streptococcus pneumoniae (the pneumococcus). Although several observations have suggested that influenza plays an important role in the pneumococcal pneumonia incidence, its contribution has been difficult to appreciate. In this issue of the Journal, Weinberger and colleagues present an elegant assessment that helps to clarify the contribution of influenza virus infections to pneumococcal pneumonia hospitalizations during the 2009 influenza pandemic [3]. Several lines of evidence indirectly support an interaction between influenza virus and the pneumococcus: First, pneumococcal nasopharyngeal acquisition patterns mirror the seasonal patterns of influenza outbreaks [4]. Second, increases in pneumococcal pneumonias during previous influenza pandemics have been documented [5, 6]. Third, concurrent influenza infections and pneumococcal pneumonias have been described [7, 8], and prevention of these pneumonias has been demonstrated in an efficacy trial of a 9-valent pneumococcal conjugate vaccine in South African children. In that randomized study, vaccination with pneumococcal conjugate vaccine reduced the incidence of influenza-associated pneumonia (ie, pneumococcal pneumonia with concurrent influenza infection) by 45% compared with controls [9]. This decline, however, was seen only in human immunodeficiency virus–infected children, and significant reductions were also observed for concurrent infections with parainfluenza viruses and human metapneumovirus [9, 10]. Last, mouse and squirrel monkey models suggest that the experimental infection with pneumococcus in animals previously infected with influenza results in severe disease and death [11–14]. Whether factors common to both pathogens (eg, neuraminidase) [12, 13, 15] or other immunological host factors (eg, interferon c) [16] mediate this interaction is unclear. More recently, studies in mouse and ferret models suggested that influenza infection also facilitates the transmission of the pneumococcus [17, 18]. Direct quantification of the burden of influenza is challenging. Influenza diagnosis requires laboratory confirmation, but testing is not routinely conducted. Furthermore, available rapid diagnostic tests have important limitations, and molecular diagnostic techniques are not widely available for routine use. Thus, the burden of influenza is usually estimated through labor-intensive active prospective surveillance or, alternatively, by using statistical modeling. Although different strategies for influenza modeling exist, the underlying principle is usually the same: During periods of influenza activity, the observed or predicted disease incidence is compared with a baseline estimated from periods when influenza was not circulating, and the difference between these values represents the excess of disease attributable to influenza. These strategies have been widely used to estimate both excess morbidity and mortality associated with influenza [1, 2]. Nevertheless, most of these comparisons have been restricted to seasonal (interpandemic) periods, where influenza circulated predominantly during winter months. An important difficulty these ecologic estimations often face is that other winter-related factors, including the concurrent activity of other noninfluenza respiratory pathogens (eg, respiratory syncytial virus or human Received and accepted 14 October 2011. Correspondence: Carlos G. Grijalva, MD, MPH, Department of Preventive Medicine, Vanderbilt University School of Medicine, 1500 21st Ave, Suite 2600, The Village at Vanderbilt, Nashville, TN 37232-2637 (carlos.grijalva@vanderbilt.edu). The Journal of Infectious Diseases The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com DOI: 10.1093/infdis/jir753
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