Using a combination of modeling and statistical analyses, David Fisman and colleagues show that influenza likely influences the incidence of invasive pneumococcal disease by enhancing risk of invasion in colonized individuals.
The wintertime co-occurrence of peaks in influenza and invasive pneumococcal disease (IPD) is well documented, but how and whether wintertime peaks caused by these two pathogens are causally related is still uncertain. We aimed to investigate the relationship between influenza infection and IPD in Ontario, Canada, using several complementary methodological tools.
Methods and Findings
We evaluated a total number of 38,501 positive influenza tests in Central Ontario and 6,191 episodes of IPD in the Toronto/Peel area, Ontario, Canada, between 1 January 1995 and 3 October 2009, reported through population-based surveillance. We assessed the relationship between the seasonal wave forms for influenza and IPD using fast Fourier transforms in order to examine the relationship between these two pathogens over yearly timescales. We also used three complementary statistical methods (time-series methods, negative binomial regression, and case-crossover methods) to evaluate the short-term effect of influenza dynamics on pneumococcal risk. Annual periodicity with wintertime peaks could be demonstrated for IPD, whereas periodicity for influenza was less regular. As for long-term effects, phase and amplitude terms of pneumococcal and influenza seasonal sine waves were not correlated and meta-analysis confirmed significant heterogeneity of influenza, but not pneumococcal phase terms. In contrast, influenza was shown to Granger-cause pneumococcal disease. A short-term association between IPD and influenza could be demonstrated for 1-week lags in both case-crossover (odds ratio [95% confidence interval] for one case of IPD per 100 influenza cases = 1.10 [1.02–1.18]) and negative binomial regression analysis (incidence rate ratio [95% confidence interval] for one case of IPD per 100 influenza cases = 1.09 [1.05–1.14]).
Our data support the hypothesis that influenza influences bacterial disease incidence by enhancing short-term risk of invasion in colonized individuals. The absence of correlation between seasonal waveforms, on the other hand, suggests that bacterial disease transmission is affected to a lesser extent.
Please see later in the article for the Editors' Summary
Although some pathogens (disease-causing organisms) cause illness all year round, others are responsible for seasonal peaks of illness. These peaks occur because of a complex interplay of factors such as the loss of immunity to the pathogen over time and seasonal changes in the pathogen's ability to infect new individuals. Thus, in temperate countries in the northern hemisphere, illness caused by influenza viruses (pathogens that infect the nose, throat, and airways) usually peaks between December and March, perhaps because weather conditions during these months favor the survival of influenza virus in the environment and thus increase its chances of being transferred among people. Another illness that peaks during the winter months in temperate regions is pneumonia, a severe lung infection that is often caused by Streptococcus pneumoniae. These bacteria can colonize the back of the throat without causing disease but occasionally spread into the lungs and other organs where they cause potentially fatal invasive pneumococcal disease (IPD).
Why Was This Study Done?
Although the co-occurrence of seasonal peaks of influenza and IPD is well documented, it is unclear whether (or how) these peaks are causally related. For example, do the peaks of influenza and IPD both occur in the winter because influenza enhances person-to-person transmission of S. pneumoniae (hypothesis 1)? Alternatively, do the diseases co-occur because influenza infection increases the risk of IPD in individuals who are already colonized with S. pneumoniae (hypothesis 2)? Healthcare professionals need to know whether there is a causal relationship between influenza and IPD so that they can target vaccination for both diseases to those individuals most at risk of developing the potentially serious complications of these diseases. In this study, the researchers use several mathematical and statistical methods and data on influenza and IPD collected in Ontario, Canada to investigate the relationship between these seasonal illnesses.
What Did the Researchers Do and Find?
Between January 1995 and October 2009, 38,501 positive influenza tests were recorded in Ontario by the Canadian national influenza surveillance network. Over the same time period, the Toronto Invasive Bacterial Diseases Network (a group of hospitals, laboratories, and doctors that undertakes population-based surveillance for serious bacterial infections in the Toronto and Peel Regions of Ontario) recorded 6,191 IPD episodes. The researchers used a mathematical method called fast Fourier transforms that compares the shape of wave forms to look for any relationship between infections with the two pathogens over yearly timescales (a test of hypothesis 1) and three statistical methods to evaluate the short-term effect of influenza dynamics on IPD risk (tests of hypothesis 2). Although they found wintertime peaks for infections with both pathogens, there was no correlation between the seasonal wave forms for influenza and IPD. That is, there was no relationship between the seasonal patterns of the two infections. By contrast, two of the statistical methods used to test hypothesis 2 revealed a short-term association between infections with influenza and with IPD. Moreover, the third statistical method (the Granger causality Wald test, a type of time-series analysis) provided evidence that data collected at intervals on influenza can be used to predict peaks in IPD infections.
What Do These Findings Mean?
These findings support (but do not prove) the hypothesis that influenza influences IPD incidence by enhancing the short-term risk of bacterial invasion in individuals already colonized with S. pneumoniae, possibly by increasing the permeability of the lining of the airways to bacteria. By contrast, the lack of correlation between the seasonal wave forms for the two diseases suggests that person-to-person transfer of S. pneumoniae is affected by influenza infections to a lesser extent. These findings have important implications for disease control policy. First, they suggest that the increased number of influenza infections in pandemic years may not necessarily be accompanied by a marked surge in IPD. Second, because the findings suggest that some cases of IPD may be influenza-attributable, the extension of influenza vaccination to school-age children and young adults (a group of people at particular risk of IPD who are not normally vaccinated against influenza) could reduce the incidence of IPD as well as the incidence of influenza.
Please access these Web sites via the online version of this summary at http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015493
A related research article by the same authors evaluating links between respiratory viruses and invasive meningococcal disease can be found in PLoS One (e0015493)
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of seasonal influenza and pneumococcal disease and pneumococcal vaccination
The UK National Health Service Choices website also provides information for patients about seasonal influenza and pneumococcal infection
MedlinePlus has links to further information about influenza and pneumococcal infections (in English and Spanish)
FluWatch is the Canadian national surveillance system for influenza
More information about the Toronto Invasive Bacterial Network is available
The International Association for Ecology and Health provides information on the physical environment and its influence on health