Invasive Pneumococcal Pneumonia and Respiratory Virus Co-infections

Each year, especially in the winter, many get sick and some die of invasive pneumococcal pneumonia. Does this type of pneumonia increase in the winter because people are in closer contact indoors? Or are people more susceptible to this bacterial disease after having had a seasonal respiratory virus infection? A season-by-season analysis found an association between pneumococcal pneumonia and two viruses (influenza and respiratory syncytial virus). The association varied by season and was strongest when the predominant influenza virus subtype was H3N2. Vaccination against influenza and RSV should also help protect against pneumococcal pneumonia.

To confi rm whether respiratory virus infections increase susceptibility to invasive pneumococcal pneumonia, we examined data from 11 infl uenza seasons (1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005) in the United States. Invasive pneumococcal pneumonia was signifi cantly associated with infl uenza and respiratory syncytial virus activities in 5 seasons. Association strength was higher when strain H3N2 was the predominant infl uenza A virus strain. I nvasive pneumococcal pneumonia (IPP) diseases cause high rates of illness and death every year. Existing evidence supports the biological plausibility that preceding respiratory viral infections, particularly with infl uenza virus and respiratory syncytial virus (RSV), increase susceptibility to IPP diseases (1). Although it has been generally believed that the increases in IPP diseases in winter relate to increased activity of respiratory viruses, especially infl uenza virus and RSV (2)(3)(4)(5)(6), evidence of association of IPP diseases and respiratory virus infections is not conclusive. If such an association is likely, then public health authorities should emphasize that vaccination against infl uenza, as well as other interventions against infl uenza and RSV, can reduce incidence of IPP diseases. We believe that cold temperatures, lack of sunshine, and rainy and snowy weather are the main reasons that persons increase their indoor activities during the winter and that respiratory diseases are mainly transmitted by close person-to-person contact (5,7,8). Therefore, we conducted separate analyses of the association of IPP with seasonal infl uenza virus and RSV activities, adjusted by climate variables, for each of 11 infl uenza seasons from 1994-95 through 2004-05.

The Study
All data used in this study were recorded for each infl uenza season (surveillance weeks 40-20) from 1994-95 through 2004-05. Weekly IPP cases were obtained from the Active Bacterial Core Surveillance for Georgia Health District 3. Cases of IPP were defi ned by isolation of Streptococcus pneumoniae from normally sterile sites, e.g., cerebrospinal fl uid or blood. Only IPP case-patients (defi ned as persons with S. pneumoniae isolated from pleural fl uid or persons with a clinical diagnosis of pneumonia and S. pneumoniae isolated from blood or another sterile body site) were included in this study. Infl uenza virus surveillance data were obtained from the World Health Organization. Weekly data were collected from each state from October through May of each infl uenza season. The infl uenza virus-positive isolate percent was defi ned as the percentage of infl uenza virus-positive isolates out of all infl uenza specimens. Percentages of isolates positive for infl uenza A (H1N1), A (H3N2), and B viruses were also calculated.
Weekly RSV data were obtained from the National Respiratory and Enteric Virus Surveillance System (www. cdc.gov/surveillance/nrevss/). For each season, hospitals and laboratories reported to the Centers for Disease Control and Prevention the numbers of specimens tested for RSV by antigen detection each week. The RSV detection percent was defi ned as the percentage of RSV-positive isolates out of all RSV specimens. The infl uenza virus and RSV data used in this study were from the US Census South Atlantic Region (www.census.gov/geo/www/us_regdiv.pdf). Data on daily mean temperature (in o F), total sunshine (in hours), and total precipitation (in inches) were obtained from the National Weather Service Atlanta regional weather center at Hartsfi eld-Jackson International Airport (9). The weekly mean temperature, total sunshine, and total precipitation were calculated from daily data.
For each of the 11 infl uenza seasons, we applied negative binomial regression models with multiple predictors to relate the weekly IPP rates with the indicators of infl uenza and RSV activities while adjusting for the weekly mean temperature, total sunshine, and total precipitation. The full model used to explore the association of IPP with infl uenza and RSV was as follows: where for week t, Y t is the incidence of IPP, X t is the infl uenza virus-positive isolate percent, Z t is the RSV detections percent, W t is the mean temperature, U t is the total sunshine, V t is the total precipitation, and N t is the population size. The reduced model excluded the infl uenza and RSV terms. We calculated the difference in the log-likelihood ratio statistic between the full and reduced models and used it to test the hypothesis that IPP incidence is not associated with infl uenza and RSV activities when weekly temperature, sunshine, and precipitation were adjusted for. For infl uenza seasons 1994-95 through 2004-05, the average annual incidence of IPP was 19.78 per 10 million persons (Table 1). Table 1 also shows the means of total number of IPP cases; infl uenza-positive isolates; RSV detections; and the average temperature, sunshine, and precipitation for each of these infl uenza seasons. Table 2 shows the result of the negative binomial regression analysis for each infl uenza season. Signifi cant associations between IPP and both infl uenza-positive isolate percent and RSV detection percent were found for 5 of the 11 seasons. Table 2 also shows the percentages of the infl uenza A (H1N1), A (H3N2), and B virus strains in each season. The predominant infl uenza virus strain (percentage >50%, [10]) varied across seasons. Infl uenza A (H3N2) virus was predominant in 8 seasons, and infl uenza B virus was predominant in 2 seasons. One season had no predominant infl uenza virus strain. Table 2 also shows a signifi cant association between IPP incidence and infl uenza virus and RSV activities in 5 of the 8 seasons in which A (H3N2) was the predominant infl uenza virus strain; there was no signifi cant association in any of the 3 seasons in which infl uenza A (H3N2) virus was not predominant (p = 0.12, 2-sided mid-p-value exact test).
To demonstrate the association of IPP incidence with infl uenza virus and RSV activities and the climate data, we displayed the weekly IPP, infl uenza virus, RSV, temperature, sunshine, and precipitation data for seasons 1998-99 and 2003/04 (Figure). Similar fi gures for the other 9 seasons can be found in the online Technical Appendix (wwwnc.cdc.gov/eid-static/spreadsheets/10-2025-Techapp.xls).

Conclusions
To explore the temporal variability in the association of IPP incidence with infl uenza virus and RSV activities over a long period, we conducted a season-by-season analysis over 11 infl uenza seasons. We adjusted the association of IPP with infl uenza virus and RSV by temperature, precipitation, and sunshine because these factors are  believed to be associated with pneumococcal and viral respiratory infections (5,7,8).
The results indicated substantial variability across seasons in the strength of association of IPP incidence with infl uenza virus and RSV activities. This variability explains why fi ndings from previous studies (2)(3)(4)(5)11), which were based on data from a single season or on combined data from several seasons, are inconsistent. We found signifi cant associations of IPP incidence with infl uenza virus and RSV activities for 5 of 11 infl uenza seasons from 1994-95 through 2004-05. Notably, in each of the 5 seasons for which we found a signifi cant association, infl uenza A virus strain H3N2 was predominant (this strain predominated in 8 seasons). Alternatively, we did not fi nd a signifi cant association in any of the 3 seasons in which strain A (H3N2) was not the predominant infl uenza virus strain. Although this difference was not statistically signifi cant, it suggests that the association between IPP and infl uenza virus and RSV activities might be stronger in seasons in which strain A (H3N2) is predominant. This fi nding is consistent with the idea that excess neuraminidase expression of strain H3N2 compared with strain H1N1 infl uenza viruses may lead to an excess number of pneumococcal superinfections (12).
In summary, in this season-by-season analysis, we found substantial variation in the strength of the association of IPP incidence with infl uenza virus and RSV activities across seasons. We also found that this association may be associated with the predominant infl uenza virus strain. More studies, using data from more seasons and from several geographic areas, are needed to better explain the variation in the association between invasive pneumococcal diseases and respiratory viral infections. Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 18, No. 2, February 2012