80
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Association between Respiratory Syncytial Virus Activity and Pneumococcal Disease in Infants: A Time Series Analysis of US Hospitalization Data

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Daniel Weinberger and colleagues examine a possible interaction between two serious respiratory infections in children under 2 years of age.

          Please see later in the article for the Editors' Summary

          Abstract

          Background

          The importance of bacterial infections following respiratory syncytial virus (RSV) remains unclear. We evaluated whether variations in RSV epidemic timing and magnitude are associated with variations in pneumococcal disease epidemics and whether changes in pneumococcal disease following the introduction of seven-valent pneumococcal conjugate vaccine (PCV7) were associated with changes in the rate of hospitalizations coded as RSV.

          Methods and Findings

          We used data from the State Inpatient Databases (Agency for Healthcare Research and Quality), including >700,000 RSV hospitalizations and >16,000 pneumococcal pneumonia hospitalizations in 36 states (1992/1993–2008/2009). Harmonic regression was used to estimate the timing of the average seasonal peak of RSV, pneumococcal pneumonia, and pneumococcal septicemia. We then estimated the association between the incidence of pneumococcal disease in children and the activity of RSV and influenza (where there is a well-established association) using Poisson regression models that controlled for shared seasonal variations. Finally, we estimated changes in the rate of hospitalizations coded as RSV following the introduction of PCV7. RSV and pneumococcal pneumonia shared a distinctive spatiotemporal pattern (correlation of peak timing: ρ = 0.70, 95% CI: 0.45, 0.84). RSV was associated with a significant increase in the incidence of pneumococcal pneumonia in children aged <1 y (attributable percent [AP]: 20.3%, 95% CI: 17.4%, 25.1%) and among children aged 1–2 y (AP: 10.1%, 95% CI: 7.6%, 13.9%). Influenza was also associated with an increase in pneumococcal pneumonia among children aged 1–2 y (AP: 3.2%, 95% CI: 1.7%, 4.7%). Finally, we observed a significant decline in RSV-coded hospitalizations in children aged <1 y following PCV7 introduction (−18.0%, 95% CI: −22.6%, −13.1%, for 2004/2005–2008/2009 versus 1997/1998–1999/2000). This study used aggregated hospitalization data, and studies with individual-level, laboratory-confirmed data could help to confirm these findings.

          Conclusions

          These analyses provide evidence for an interaction between RSV and pneumococcal pneumonia. Future work should evaluate whether treatment for secondary bacterial infections could be considered for pneumonia cases even if a child tests positive for RSV.

          Please see later in the article for the Editors' Summary

          Editors' Summary

          Background

          Respiratory infections—bacterial and viral infections of the lungs and the airways (the tubes that take oxygen-rich air to the lungs)—are major causes of illness and death in children worldwide. Pneumonia (infection of the lungs) alone is responsible for about 15% of all child deaths. The leading cause of bacterial pneumonia in children is Streptococcus pneumoniae, which is transmitted through contact with infected respiratory secretions. S. pneumoniae usually causes noninvasive diseases such as bronchitis, but sometimes the bacteria invade the lungs, the bloodstream, or the covering of the brain, where they cause pneumonia, septicemia, or meningitis, respectively. These potentially fatal invasive pneumococcal diseases can be treated with antibiotics but can also be prevented by vaccination with pneumococcal conjugate vaccines such as PCV7. The leading cause of viral pneumonia is respiratory syncytial virus (RSV), which is also readily transmitted through contact with infected respiratory secretions. Almost all children have an RSV infection before their second birthday—RSV usually causes a mild cold-like illness. However, some children infected with RSV develop pneumonia and have to be admitted to hospital for supportive care such as the provision of supplemental oxygen; there is no specific treatment for RSV infection.

          Why Was This Study Done?

          Co-infections with bacteria and viruses can sometimes have a synergistic effect and lead to more severe disease than an infection with either type of pathogen (disease-causing organism) alone. For example, influenza infections increase the risk of invasive pneumococcal disease. But does pneumococcal disease also interact with RSV infection? It is important to understand the interaction between pneumococcal disease and RSV to improve the treatment of respiratory infections in young children, but the importance of bacterial infections following RSV infection is currently unclear. Here, the researchers undertake a time series analysis of US hospitalization data to investigate the association between RSV activity and pneumococcal disease in infants. Time series analysis uses statistical methods to analyze data collected at successive, evenly spaced time points.

          What Did the Researchers Do and Find?

          For their analysis, the researchers used data collected between 1992/1993 and 2008/2009 by the State Inpatient Databases on more than 700,000 hospitalizations for RSV and more than 16,000 hospitalizations for pneumococcal pneumonia or septicemia among children under two years old in 36 US states. Using a statistical technique called harmonic regression to measure seasonal variations in disease incidence (the rate of occurrence of new cases of a disease), the researchers show that RSV and pneumococcal pneumonia shared a distinctive spatiotemporal pattern over the study period. Next, using Poisson regression models (another type of statistical analysis), they show that RSV was associated with significant increases (increases unlikely to have happened by chance) in the incidence of pneumococcal disease. Among children under one year old, 20.3% of pneumococcal pneumonia cases were associated with RSV activity; among children 1–2 years old, 10.1% of pneumococcal pneumonia cases were associated with RSV activity. Finally, the researchers report that following the introduction of routine vaccination in the US against S. pneumoniae with PCV7 in 2000, there was a significant decline in hospitalizations for RSV among children under one year old.

          What Do These Findings Mean?

          These findings provide evidence for an interaction between RSV and pneumococcal pneumonia and indicate that RSV is associated with increases in the incidence of pneumococcal pneumonia, particularly in young infants. Notably, the finding that RSV hospitalizations declined after the introduction of routine pneumococcal vaccination suggests that some RSV hospitalizations may have a joint viral–bacterial etiology (cause), although it is possible that PCV7 vaccination reduced the diagnosis of RSV because fewer children were hospitalized with pneumococcal disease and subsequently tested for RSV. Because this is an ecological study (an observational investigation that looks at risk factors and outcomes in temporally and geographically defined populations), these findings do not provide evidence for a causal link between hospitalizations for RSV and pneumococcal pneumonia. The similar spatiotemporal patterns for the two infections might reflect another unknown factor shared by the children who were hospitalized for RSV or pneumococcal pneumonia. Moreover, because pooled hospitalization discharge data were used in this study, these results need to be confirmed through analysis of individual-level, laboratory-confirmed data. Importantly, however, these findings support the initiation of studies to determine whether treatment for bacterial infections should be considered for children with pneumonia even if they have tested positive for RSV.

          Additional Information

          Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001776.

          Related collections

          Most cited references34

          • Record: found
          • Abstract: found
          • Article: not found

          Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993-2008.

          Age-specific comparisons of influenza and respiratory syncytial virus (RSV) hospitalization rates can inform prevention efforts, including vaccine development plans. Previous US studies have not estimated jointly the burden of these viruses using similar data sources and over many seasons. We estimated influenza and RSV hospitalizations in 5 age categories (<1, 1-4, 5-49, 50-64, and ≥65 years) with data for 13 states from 1993-1994 through 2007-2008. For each state and age group, we estimated the contribution of influenza and RSV to hospitalizations for respiratory and circulatory disease by using negative binomial regression models that incorporated weekly influenza and RSV surveillance data as covariates. Mean rates of influenza and RSV hospitalizations were 63.5 (95% confidence interval [CI], 37.5-237) and 55.3 (95% CI, 44.4-107) per 100000 person-years, respectively. The highest hospitalization rates for influenza were among persons aged ≥65 years (309/100000; 95% CI, 186-1100) and those aged <1 year (151/100000; 95% CI, 151-660). For RSV, children aged <1 year had the highest hospitalization rate (2350/100000; 95% CI, 2220-2520) followed by those aged 1-4 years (178/100000; 95% CI, 155-230). Age-standardized annual rates per 100000 person-years varied substantially for influenza (33-100) but less for RSV (42-77). Overall US hospitalization rates for influenza and RSV are similar; however, their age-specific burdens differ dramatically. Our estimates are consistent with those from previous studies focusing either on influenza or RSV. Our approach provides robust national comparisons of hospitalizations associated with these 2 viral respiratory pathogens by age group and over time.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Influenza enhances susceptibility to natural acquisition of and disease due to Streptococcus pneumoniae in ferrets.

            The role of respiratory viruses in the transmission of Streptococcus pneumoniae is poorly understood. Key questions, such as which serotypes are most fit for transmission and disease and whether influenza virus alters these parameters in a serotype-specific manner, have not been adequately studied. In a novel model of transmission in ferrets, we demonstrated that pneumococcal transmission and disease were enhanced if donors had previously been infected with influenza virus. Bacterial titers in nasal wash, the incidence of mucosal and invasive disease, and the percentage of contacts that were infected all increased. In contact ferrets, viral infection increased their susceptibility to S. pneumoniae acquisition both in terms of the percentage infected and the distance over which they could acquire infection. These influenza-mediated effects on colonization, transmission, and disease were dependent on the pneumococcal strain. Overall, these data argue that the relationship between respiratory viral infections, acquisition of pneumococci, and development of disease in humans needs further study to be better understood.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Monitoring the Impact of Influenza by Age: Emergency Department Fever and Respiratory Complaint Surveillance in New York City

              Introduction Throughout the twentieth century, epidemic and pandemic influenza was responsible for causing widespread illness, economic disruption, and considerable loss of life worldwide [1–3]. While the seasonal recurrence of influenza is anticipated each year, it remains difficult to predict the predominant seasonal strains and impossible to know when and where the next human pandemic will emerge. Timely regional monitoring of influenza-related morbidity is a priority for seasonal surveillance and pandemic preparedness [4]. Influenza surveillance currently conducted in the United States encompasses systems for monitoring influenza-related illness and death, investigating unusual respiratory disease outbreaks, and identifying and characterizing viral influenza strains [5]. The rapid epidemiological assessment of influenza-related morbidity and mortality remains a challenge for public health due to the nonspecific symptoms, rarity of laboratory confirmation, and difficulty in obtaining continuous, representative, and age-specific data [1,2]. Across the US, influenza-like illness (ILI) and pneumonia and influenza (P&I) mortality surveillance coordinated by the Centers for Disease Control and Prevention (CDC) has relied on weekly reporting of ILI visits by physicians in a voluntary sentinel network, and of P&I deaths by participating municipal vital records offices [5]. The primary shortcomings of these systems include the burden on health department and physician practices resulting in low and variable participation, with reporting delays and an absence of timely year-round data limiting their usefulness. In recent years, New York City (NYC) and other jurisdictions have tracked influenza using syndromic surveillance systems such as those based on electronically reported emergency department (ED) patient chief complaints [6]. Several studies based on these systems have reported seasonal increases in respiratory or influenza-like syndrome visits coincident with documented influenza epidemics [6–12]. Coded respiratory and influenza-like ED visits have been reported to provide a timely, sensitive, and year-round measure that enables detection of epidemic influenza 1–2 wk earlier than does P&I mortality data [7]; and age-specific respiratory visits have been reported to show that data from children aged 3–4 y provide the earliest indicator, leading P&I mortality by 7 wk [8]. The absence of viral surveillance data from these studies, however, leave important questions unanswered: To what degree do early seasonal morbidity increases correlate with actual influenza or other respiratory virus circulation? And to what degree does circulating viral type, subtype, and strain impact the timing and magnitude of age-specific morbidity and mortality? Epidemiologic community and family studies [13–18] and retrospective analyses of mortality and hospitalization data [19–27] have provided considerable insight into the age-specific patterns of seasonal and epidemic influenza. Prospective morbidity surveillance systems, however, have not taken full advantage of age-specific data. Important epidemiologic insights gained by scrutinizing how influenza impacts specific age groups include evidence that influenza often spreads earliest among school-age children [1,16–18]; that school breaks may slow or delay seasonal impact [1,16]; that age-specific impact can be related to prior antigenic exposure in the population [1–3,28]; and that each influenza pandemic last century was marked by a signature shift in relative impact from older to younger age groups [24,25]. The purpose of this study was to evaluate the use of ED visit data for monitoring the age-specific timing and impact of epidemic influenza by predominant circulating viral type, subtype, and antigenic strain. Using a broad definition of ED visits classified as fever or respiratory syndrome chief complaints, we applied a statistical method, routinely used for monitoring clinical ILI [29,30] and P&I mortality data [5,19,20], to ED surveillance data to monitor visits during periods of influenza circulation and provide a surrogate measure of incident influenza-attributable ED visits in NYC. By quantifying and visualizing the temporal and age-specific course of influenza morbidity in the context of available laboratory surveillance data, we sought to improve ongoing influenza surveillance efforts in NYC. Methods Emergency Department Surveillance Data Electronic reporting of ED chief complaint data from NYC hospitals occurred daily during the study period from mid-November 2001 through June 2006. Data received each morning were typically >90% complete for the preceding day, and data received Monday mornings >95% complete for the preceding week. During the 2001–2002 season participating hospital EDs captured an estimated 65% of all ED visits citywide. Coverage gradually increased through the study period, reaching 79% of all ED visits citywide during 2002–2003, 88% during 2003–2004 and 90% during 2004–2005 and 2005–2006. Individual ED visit data were aggregated by age group, chief complaint syndrome group, and week ending Saturday. Of the 13.3 million ED visits reported by participating NYC facilities during the study period, 2.3 million were categorized into a broad “fever and respiratory” syndrome composed of the hierarchical and mutually exclusive syndromes “respiratory,” “fever/flu,” “common cold,” and “sepsis,” as previously described [6]. These syndromes have been used as part of daily surveillance activities in NYC since 2001, and were defined as follows: The “sepsis” syndrome captured ED visits whose chief complaint contained key words representing sepsis, bacteremia, cardiac arrest, unresponsive, unconscious, or dead on arrival—the sepsis syndrome was included to capture visits with chief complaints describing potential, severe influenza outcomes that would otherwise have been missed. The “common cold” syndrome captured visits with key words representing stuffy nose or nasal or cold symptoms that were not in visits captured within sepsis. The “respiratory” syndrome captured visits with key words and International Classification of Diseases 9th edition (ICD-9) codes representing pneumonia, shortness of breath, bronchitis, upper respiratory tract infection, difficulty breathing, pleurisy, croup, cough, dyspnea, and chest cold, which were not captured within the sepsis or common cold syndromes. And the “fever/flu” syndrome captured visits with key words and ICD-9 codes representing fever, chills, malaise, body aches, viral syndrome, and influenza, which were not captured within the sepsis, common cold, or respiratory categories, and did not include key words representing acute gastroenteritis, enteritis, or diarrhea. While chief complaints of “fever with diarrhea” could potentially be due to influenza, these were excluded in our analysis to avoid confounding with coincident epidemic viral gastroenteritis. The broad “fever and respiratory” syndrome category described above was used to provide the most sensitive measure of ED visits potentially attributable to influenza. We also created a specific “ILI” syndrome following the commonly used clinical surveillance definition of fever with cough and/or sore throat: Of the 2.3 million visits categorized into the broad fever and respiratory syndrome, 260,000 visits were categorized as ILI, defined as a chief complaint composed of an influenza keyword or of a fever-related key word with a mention of “cough” and/or “sore throat.” The broad fever and respiratory and the narrow ILI syndrome data are shown in Figure 1. ED visit data aggregated by age into the groups 4 times mean noninfluenza levels during peak epidemic weeks, and 0.25 to 1.25 during nonepidemic periods. Visits were increased across all age groups during periods of influenza A/H3N2 predominance, and were most markedly increased during the 2003–2004 and 2004–2005 A/Fujian-lineage epidemics. Visit increases during periods of influenza A/H1 and B predominance impacted preschool (2–4 y) and school-aged (5–17 y) children, and were most dramatically elevated during the B/Victoria-lineage reemergence in early 2002. The autumn and early-winter predominance of RSV preceded influenza in 2001, 2002, and 2005, and coincided with increased visits in the < 2 y and 2–4 y age groups. Visits were notably increased among school-aged children and working-aged adults during the dominant tree pollen period in 2006. RSV hospitalization data were not available for 2006 (*), and viral influenza surveillance reporting was incomplete during weeks 12 to 16, 2006 (*). Results Seasonal Impact From the 2001–2002 to 2005–2006 influenza seasons in NYC, we estimate on average that 40,000 excess ED visits (5.0 visits per 1,000 population) occurred per season during the documented influenza circulation periods. We estimate that 2,800 excess P&I hospitalizations (0.35 per 1,000) on average occurred per season from 2001–2002 to 2004–2005, and 500 excess all-cause (0.065 per 1,000) and 100 excess P&I (0.012 per 1,000) deaths occurred per season from 2001–2002 to 2003–2004. The seasonal impact of excess ED visits, hospitalizations, and deaths, however, varied greatly by age group and circulating virus. We summarize our results by season and predominant viral period. 2001–2002 season: An estimated 24,000 excess fever and respiratory ED visits (3.0 visits per 1,000 population), 2,200 excess P&I hospitalizations (0.28 per 1,000), 540 excess all-cause deaths (0.067 per 1,000), and 90 excess P&I deaths (0.011 per 1,000) occurred during the influenza A/H3N2 predominant period in NYC from December 2001 to February 2002 (weeks 50–07) (Figures 1–3; Table 1). An estimated 17,000 excess ED visits (2.1 per 1,000) occurred during the influenza B/Victoria predominant period from February to April 2006 (weeks 08–13) (Figure 1; Table 1). Excess ED visits during the influenza B/Victoria-period were most notably increased among school-aged children (aged 5–12 y and 13–17 y), with no detected increase among adults (Figures 2 and 5; Table 1). There were no excess P&I hospitalizations or deaths detected during the influenza B period this season (Figure 3). 2002–2003 season: An estimated 10,000 excess ED visits (1.2 per 1,000 population) occurred during the predominant influenza A/H1 period (Figure 1; Table 1), with excess visits detected only among preschool (2–4 y) and school-aged (5–12 y and 13–17 y) children, and adults aged 18–39 y (Figure 2). Visits among children age < 2 y and 2–4 y were increased during autumn and early winter (weeks 45–01) prior to the influenza epidemic period (weeks 03–09). The autumn and early winter timing of ED visit increases among children age <2 y and 2–4 y (weeks 45–01) coincided with the retrospectively identified period of predominant RSV hospitalizations (Figures 2 and S2). An estimated 370 excess all-cause deaths (0.047 per 1,000), and few excess P&I hospitalizations or deaths, were detected during this season (Figure 3; Table 1). 2003–2004 season: An estimated 71,000 excess fever and respiratory ED visits (8.9 per 1,000 population) occurred during the influenza A/H3N2 predominant period from November 2003 to January 2004 (weeks 46–01) (Figure 1; Table 1). Excess ED visits were detected across age groups (Table 1), with the highest rates occurring among children age <2 y (Figures 2 and 5; Table 1). An estimated 4,400 excess P&I hospitalizations (0.55 per 1,000), 640 excess all-cause deaths (0.080 per 1,000), and 190 excess P&I deaths (0.023 per 1,000) occurred this season (Figure 3; Table 1). 2004–2005 season: An estimated 42,000 excess fever and respiratory ED visits (5.2 per 1,000 population) and 3,600 excess P&I hospitalizations (0.44 per 1,000) occurred during the influenza A/H3N2 predominant period from November 2004 through January 2005 (weeks 46–04) (Figures 1 and 3; Table 1). An estimated 22,000 excess ED visits (2.7 per 1,000) occurred during the period of influenza B predominance and sporadic influenza A circulation from February to April 2005 (weeks 05–14) (Table 1). Excess ED visits were increased across all age groups during the influenza A-predominant period (Figures 1 and 2). Compared to the 2003–2004 epidemic, the relative impact during the corresponding A/H3N2 epidemic weeks in 2004–2005 was shifted toward older age groups: the proportion of total excess fever and respiratory ED visits among those ≥ 65 y went from 6% in 2003–2004 to 13% in 2004–2005, and the proportion of total excess P&I hospitalizations among those ≥ 65 y went from 45% in 2003–2004 to 69% in 2004–2005 (Figure 2; Table 1). 2005–2006 season: An estimated 12,000 excess ED visits (1.5 per 1,000 population) occurred during the influenza A/H3N2 predominant period, with excess ED visits detected in the age groups 2–4 y, 5–12 y, 13–17 y, 18–39 y, and 40–64 y (Figure 2; Table 1). Fever and respiratory ED visits peaked in the < 2 y age group prior to the beginning of the identified influenza epidemic period and more than 4 wk before the peak in influenza isolate data (Figure 2). Epidemic Timing Influenza epidemic period increases were seen earlier in ED visits than in hospitalizations or deaths. During the influenza A/H3N2 epidemics in 2001–2002 and 2003–2004, excess all-ages fever and respiratory ED visits exceeded our two-standard-deviation Serfling model threshold 1 wk prior to P&I hospitalizations and, respectively, 1 and 3 wk prior to P&I deaths. During the mild influenza A/H1 epidemic in 2002–2003, all-ages fever and respiratory ED visits exceeded threshold 2 wk prior to deaths, and in the A/H3N2 epidemic in 2004–2005, all-ages ED visits exceeded threshold 3 wk prior to P&I hospitalizations (Figures 1 and 3; Table S1). Fever and respiratory ED visits among children often exceeded threshold before adults, but there were differences between seasons. During 2001–2002, ED visits exceeded model thresholds in the < 2 y and 2–4 y age groups 1 wk before the 13–17 y and 18–39 y age groups, and 2 wk before the 5–12 y and 40–64 y age groups. During the more severe 2003–2004 A/H3N2 epidemic, age-specific ED visits exceeded threshold in the 13–17 y age group 1 wk before the < 2 y, 2–4 y, 5–12 y, and 18–39 y groups, 3 wk before the 40–64 y group, and 4 wk before the ≥ 65 y group (Figure 2; Table S1). During the 2004–2005 influenza A/H3N2 epidemic, age-specific ED visits exceeded model threshold in the 2–4 y, 5–12 y, and 13–17 y age groups 1 wk prior to the < 2 y, 18–39 y, 40–64 y, and ≥ 65 y age groups (Figure 2; Table S1). The threshold level was arbitrary, with the measure of timing reflecting noninfluenza period variance and not necessarily inherent epidemic timing. In our estimation of inherent epidemic timing, we limited our analysis to the 2003–2004 season, since it was the most severe and the only one with available ED, hospitalization, and death data and significant excess estimates across age groups (Figures 1–3). Our lagged cross-correlation analysis of excess ED visits, hospitalizations, and deaths compared against viral influenza surveillance data found the greatest cross-correlation coefficients occurred when P&I deaths lagged viral data by 2 wk, and P&I hospitalizations and ED visits coincided with viral data, although the leading cross-correlation coefficients for ED visits were greater than for hospitalizations (Figure 4, top). The maximum cross-correlation coefficient for viral isolates and excess ED fever and respiratory visits by age found school-aged children (5–12 y and 13–17 y) leading viral isolates by 1 wk, preschool-aged children (2–4 y) leading viral isolates by 1 wk although lagging school-aged children slightly, younger children (<2 y) and working-aged adults (18–39 y and 40–64 y) roughly coinciding with viral isolates, and older adults (≥65 y) lagging viral isolates by 1 wk (Figure 4, middle). The maximum cross-correlation coefficient for P&I hospitalizations and deaths by age group found < 65 y hospitalizations coinciding with viral isolates, ≥ 65 y hospitalizations and < 65 y P&I deaths lagging viral isolates by 1 wk, and ≥ 65 y deaths lagging viral isolates by 3 wk (Figure 4, bottom). Visualizing Age-Specific Morbidity Patterns Observed fever and respiratory ED visits peaked annually during influenza epidemic periods as defined by laboratory evidence (Figure 1). The age pattern of observed and normalized visits varied by season and circulating virus (Figures 2 and 5). Each autumn, increased visits were seen among children aged < 2 y and 2–4 y during RSV-predominant periods, and were notably elevated between autumn and early-winter (weeks 48–01), regardless of whether influenza circulation was detected (Figure 5): for example, seasonal fever and respiratory ED visit peaks in the < 2 y age group occurred during week 52 in 2002–2003 and 2005–2006, prior to the beginning of the defined influenza epidemic period and well before viral influenza isolates and older-age group ED visits peaked (Figures 2 and 5). Otherwise, during each influenza epidemic period in our study, fever and respiratory ED visits peaked earliest in school-aged children. The ED visit peaks in the 5–12 y and 13–17 y age groups during the two most severe seasons, 2003–2004 and 2004–2005, immediately preceded the end-of-year winter holiday school breaks. The more specific subset of ILI ED visits, with mention of influenza or co-occurrence of fever with cough and/or sore throat, constituted only 11% of the broader fever and respiratory category (Figure 1), however the two trends were highly correlated (r 2 = 0.96, p < 0.001). Exceptions included tree pollen-dominant periods in spring 2005 and 2006 when the broad fever and respiratory category of ED visits saw increases among school-aged children and working-aged adults (5–12 y, 13–17 y, 18–39 y, and 40–64 y) (Figure 5), with no corresponding increase in the more specific ILI category (Figures 2 and S1). Discussion In our analysis of New York City ED data, we found that predominant increases in fever and respiratory visits corresponded in timing and magnitude with laboratory-confirmed influenza, and we suggest that our estimates of excess ED visits provide a reliable surrogate measure of the incident impact attributable to influenza. By applying standard statistical methods to electronic ED chief complaint data, and interpreting results in the context of available information about circulating viruses, we were able to evaluate and track age-specific influenza morbidity in greater detail than was previously possible in NYC. We found the burden of excess ED visits was greatest during peak influenza periods, disproportionately impacted children, often impacted children earliest, generally coincided in timing with P&I hospitalization admission data, and preceded P&I death data by roughly 1–2 wk. The age-specific pattern of excess ED visits varied depending on the predominant circulating viral type, subtype, and strain. We expand on these findings below. Reemergence of B/Victoria-Lineage Influenza, 2001–2002 Beginning the week ending February 16, 2002 (week 06–2002), a marked and sustained increase in ED fever and respiratory visits began in NYC that predominated among school-aged children (5–17 y). In the US, influenza B/Victoria-lineage viruses had last been widespread 13 y prior, during 1988–1989 in a mixed influenza B and A/H1N1 season, and had last been the predominant epidemic virus 16 y earlier, during the 1985–1986 season [23,31,32]. This pattern would suggest that in 2002, children age 13–16 y had minimal prior exposure, and children age 12 y and under had very little or no opportunity for prior exposure to this influenza B antigenic lineage, consistent with observed excess fever and respiratory (Figure 2) and ILI (Figure S1) ED visits. Local clinical and outbreak reports later noted the unusual age-specific impact of these B/Victoria viruses elsewhere in the US [33,34], and school absenteeism and ED surveillance in NYC were noted to have signaled significant increases during the epidemic [6,35]. However, ongoing morbidity surveillance at the time did not detect or characterize the impact [5,6], and no comment was made connecting previous circulation of this antigenic lineage with the age-specific groups at risk. A greater awareness of the event through routine monitoring of age-specific illness data could have informed physicians and public health officials that an influenza virus antigenically novel to children age 12 y and under was epidemic. Epidemic A/H3N2 Fujian-Lineage Influenza Antigenic variant influenza A/H3N2 Fujian-lineage viruses emerged in autumn 2003 and were widespread across the US by the beginning of winter. The 2003–2004 seasonal influenza vaccine was reported to be poorly matched with the circulating A/Fujian viruses [5]. Our analysis of fever and respiratory ED visits indicated that the epidemic impact on morbidity was significant across all age groups, though greater among children (Figure 2; Table 1) and with a distinct within-season age shift (Figure 4). Our analysis of the timing of ED visits indicates that the course of the epidemic progressed in a cascading fashion from primary school (5–17 y), to preschool (2–4 y), to younger children and working-age adults (<2 y and 18–64 y), to older adults (≥65 y) (Figure 4). Our analysis of ED visits and P&I hospitalizations and deaths indicates that the morbidity impact seen in ED visits and hospitalizations preceded the impact seen in deaths by 1–2 wk, with P&I hospitalizations and deaths following a similar age-stratified progression from younger (<65 y) to older (≥65 y) ages (Figure 4). In autumn 2004, influenza viruses reported to be antigenically A/Fujian-like [5] reemerged and were epidemic in NYC. The pattern and age distribution of morbidity in 2004–2005 presented a distinct shift in impact compared to 2003–2004, in both ED fever and respiratory and ILI visits (Figures 2 and S1) and P&I hospitalizations (Figure 3). The relative impact in children and younger adults was greater during the first reported circulation of A/Fujian-lineage viruses in NYC, while the relative impact in older adults was greater during the second (Table 1). It is not known if the age shift from 2003–2004 to 2004–2005 was due to genetic or antigenic differences in the circulating viruses, or to age-specific cohort effects in transmission and impact. It is also not known whether this interpandemic period shift was similar in character to the shift in impact to older adults seen in the successive seasons following primary pandemic waves in the last century [1,24]. Seasonal RSV While RSV surveillance data were not available during the study period, coded hospitalizations allowed us to retrospectively identify predominant RSV periods in NYC (Figure S2). The impact of RSV hospitalizations during the 2001–2002, 2002–2003, and 2005–2006 seasons occurred prior to the beginning of the influenza epidemic periods (Figure 5). During these seasons, increases in fever and respiratory ED visits occurred in the age groups < 5 y before documented influenza circulation began. Across all seasons the course of fever and respiratory ED visits in young children increased by mid-November, regardless of the timing or impact of influenza. The absence of a significant increase in ED visits among school-aged children or adults during these periods was consistent with RSV only modestly impacting older ages, and suggests that estimates of severe excess RSV-attributable mortality in older individuals [23] be reevaluated [36–38]. The age-specific impact on morbidity from RSV and other respiratory infections such as metapneumovirus [39] or novel rhinoviruses [40], should be considered when evaluating fever and respiratory morbidity surveillance and should be studied further. Spring Tree Pollenosis In NYC we have consistently observed increases in ED respiratory and asthma visits outside of influenza season during the spring and early fall. The impact seen each spring is often severe enough to affect any syndrome that includes respiratory chief complaints, but is not associated with an increase in febrile illness. Pollen data obtained for the spring of 2005 and 2006 show that increases apparent in the broad fever and respiratory syndrome group among patients aged 5–64 y were coincident with the predominant annual tree pollen release (Figures 2 and 5). A similar pattern of respiratory and asthma exacerbations associated with tree and grass pollenosis has recently been reported [41], and the age-specific pattern of morbidity due to cedar tree pollenosis has been well described in Japan [42]. Influenza Timing In our analysis, we found that increases in influenza-attributable ED visits preceded hospitalizations, which in turn preceded deaths (corresponding to the logical progression of illness). During the 2003–2004 A/Fujian epidemic season we found fever and respiratory ED visits and P&I hospitalizations and deaths strongly correlated with viral isolate data, with an optimum lag between ED visits and deaths on the order of 2–3 wk (Figure 4, top). Our age-specific analysis of this epidemic found ED visits by age strongly correlated with viral data, with the greatest lag found between the 5–17 y and ≥65 y age groups on the order of 2 wk, with younger children and working-age adults in between (Figure 4, middle). The time series of P&I hospitalizations by age group were strongly correlated with viral data, with a lag between < 65 y and ≥ 65 y hospitalizations on the order of 1 wk (Figure 4, bottom). The time series of P&I deaths by age group were most strongly correlated with a lag between < 65 y and ≥ 65 y deaths on the order of 2 wk. While we found no strict temporal age pattern across seasons, we did find late autumn increases in ED fever and respiratory visits among children age < 5 y regardless of influenza circulation (and coincident with predominant RSV), and we found that influenza epidemic period peaks occurred earliest among school-aged children each season regardless of circulating influenza viral type, subtype or strain. A study of Boston area ED surveillance data reported that ED respiratory visits increased first among preschool age children (aged 3–4 y), some 5–7 wk before ED visits among older persons [8]. This finding may have been be due to the impact of RSV, and to the use of aggregate interseasonal waves masking within-season variation by age. Analysis of the period from 2001 to 2006 using these methods on NYC ED visit data would show the age-specific impact of RSV shifting the overall timing of < 5 y ED visits earlier, while the spring influenza B/Victoria epidemic would shift 5–17 y ED visits later. Aggregate interseasonal time series analysis can be valid for seasonal influenza mortality, where a single wave of mortality predominates each season. Assessment of aggregated seasonal time series of ILI, fever, or respiratory morbidity data, where multiple etiologically distinct within-season waves are common, however, must be done with caution and at the appropriate scale [43]. Influenza Impact While the burden of influenza-attributable hospitalizations and deaths occurred predominantly among older adults, the burden of influenza-attributable excess fever and respiratory visits to NYC EDs during our study was predominantly among children (Figure 2; Table 1). Our estimated NYC-wide influenza attributable ED visit rates among young children (aged <5 y), during the 2003–2004 A/H3N2-Fujian epidemic, were greater than the ED visit rate estimates reported by Poehling and colleagues [44], and less than their outpatient clinic estimates, possibly reflecting greater utilization of EDs for pediatric primary care in NYC. While the overall impact from influenza during the study period was moderate compared to preceding A/H3N2 Sydney-lineage epidemic seasons (Figure 3), the impact seen in NYC EDs was nonetheless considerable and varied. For each estimated excess P&I death we found during the 2003–2004 A/Fujian epidemic, there were approximately 3.5 excess all-cause deaths, 24 excess P&I hospitalizations, and 390 excess fever and respiratory ED visits in NYC. Our study had several limitations. First, estimating influenza-attributable morbidity and mortality is imperfect due to the nonspecific nature of influenza symptoms and the lack of laboratory confirmation for the vast majority of influenza cases [1]. We considered excess visits as primarily attributable to influenza when they occurred during periods of virally confirmed influenza circulation, but some of the fever and respiratory syndrome visits outside of these periods were likely due to influenza infection, and to some extent excess visits during influenza periods could clearly be due to coincidentally circulating viruses. Furthermore, the free-text chief complaints used to categorize ED visits into syndrome groups are imprecise indicators of illness, and many influenza-attributable visits may have been missed. We also did not explicitly consider the influence of ED utilization on age-specific visit rates. For example, parents may be more likely to bring a young child to the ED for an evaluation of influenza-like illness than to visit the ED themselves. A greater proportion of younger patients with acute influenza infection may have had fever with respiratory symptoms and been captured in our syndrome definition, while older patients with influenza-attributable illness and complications may have presented later and with a broader range of complaints, many of which might not have been captured by our syndrome coding. Finally, we had only 5 y of data covering a unique, large, and dense urban population, and our findings may not be generalizable to other years or to other regions. Within the context of these limitations, our results highlight the fact that each influenza season and epidemic period is unique in its age-specific timing, progression, and impact. The reliance of researchers on hospitalization and death data, and the difficulty of obtaining population-based and age-detailed estimates of morbidity have contributed to the misconception that influenza affects only the very young and the very old. While the burden of severe morbidity and mortality occurs at the extremes of age, our findings support the observation that school-aged children experience early and high attack rates and exhibit significant morbidity, supporting evidence that they play an important role in communitywide transmission [16–18]. Vaccination of school-aged children has been suggested to provide both direct protection for those vaccinated and indirect protection for unvaccinated age groups within the population during interpandemic [45] as well as pandemic periods [13]. The early and specific increases in fever and respiratory ED visits that we observed among children during the first season of A/H3N2 Fujian circulation are consistent with other studies showing that epidemic influenza strains may circulate and amplify first among children before spreading to older age groups [16–18]. These findings may have implications for targeted nonpharmaceutical intervention, antiviral, and vaccination strategies, and lend support for broadening the age categories recommended for routine and pandemic vaccination. Twentieth-century influenza can inform twenty-first-century surveillance. The experience with pandemic influenza in the last century in New York City illustrates that early waves, multiple waves, and within- and between-season age shifts in morbidity and mortality can occur [46–48]. While the timing and age-specific impact in the next pandemic cannot currently be predicted, experience during the last five seasons in New York City suggests that age-stratified ED surveillance can provide a timely surrogate measure of morbidity that can be used to monitor and describe the age-specific epidemiology of influenza. Recent analyses of the 1918 pandemic in US cities have shown that even transitory and imperfect public health intervention strategies, when initiated early enough, were partially beneficial [49,50]. While our study does not identify surveillance triggers for public health intervention or address control measure efficacy, our data do show that near-time monitoring is feasible. Our results highlight the fact that influenza epidemics can differ in timing, progression, and impact by age. The integration of detailed and rapid morbidity surveillance data, such as we have presented, with viral, antigenic, and whole-genome analysis [51–54], may improve our understanding of the complex dynamics of influenza [55], and provide better opportunity for informed and successful public health responses in the future. Supporting Information Figure S1 Weekly Age-Specific ILI Visits to the ED in New York City during the 2001–2002 to 2005–2006 Seasons Observed ILI syndrome ED visits by age group are shown as black lines, and seasonally expected Serfling baseline visits as red lines. Dashed lines represent epidemic thresholds as model estimates plus two-standard deviations. Shaded areas represent estimated influenza attributable excess ED visits: blue areas correspond to periods of increasing and dominant influenza A circulation and red areas to influenza B. Vertical lines indicate the first week of continuous influenza isolate reporting each season. (249 KB PDF) Click here for additional data file. Figure S2 Weekly Influenza Viral Isolate Surveillance and RSV Hospitalizations in New York City during the 2001–2002 to 2005–2006 Seasons Vertical lines indicate the first week of continuous influenza virus isolate reporting, viral isolate surveillance is indicated as in Figure 1. The dashed horizontal lines indicate the level of influenza viral isolate and RSV hospitalization upper quartile weeks. (172 KB PDF) Click here for additional data file. Table S1 Summary of Consecutive Weeks of Influenza Circulation Reporting, Epidemic Influenza Isolate Reporting, Epidemic Fever and Respiratory ED Visits, and Epidemic P&I Hospitalizations and Deaths in New York City during the 2001–2002 to 2005–2006 Seasons Influenza isolate circulation dates are the CDC weeks from the first influenza isolate reported in continuous weeks (vertical lines in Figures 1, 2, S1, and S2), through the last week reporting an influenza isolate that season. Influenza epidemic weeks represent the upper quartile weeks of influenza isolate reporting (ie the worst 25% of weeks, shown in Figure 5). Epidemic fever and respiratory ED visits (Figures 1 and 2), and P&I hospitalizations and deaths (Figure 3) indicate the continuous weeks exceeding a two-standard-deviation threshold above each Serfling baseline during the periods of influenza circulation. Asterisks indicate continuous weeks that exceeded threshold prior to the beginning of the influenza viral isolate epidemic weeks. Dashes indicate seasons and groups where there were no continuous weeks exceeding threshold. Empty cells indicate no available data. (36 KB DOC) Click here for additional data file.
                Bookmark

                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS Med
                PLoS
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                1549-1277
                1549-1676
                January 2015
                6 January 2015
                : 12
                : 1
                : e1001776
                Affiliations
                [1 ]Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America
                [2 ]Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, Bethesda, Maryland, United States of America
                [3 ]Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America
                [4 ]Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality, Rockville, Maryland, United States of America
                [5 ]Department of Global Health, George Washington University, Washington, District of Columbia, United States of America
                University of Oxford, Thailand
                Author notes

                DMW has received research support for other projects from an investigator initiated research grant from Pfizer to Yale University. LS and KPK have previously received research support from Pfizer. DMW has received consulting fees from Merck. KPK is a member of the Editorial Board of PLOS Medicine. The other authors have declared that no competing interests exist.

                Conceived and designed the experiments: DMW CV LS KPK. Performed the experiments: DMW. Analyzed the data: DMW. Contributed reagents/materials/analysis tools: CAS. Wrote the first draft of the manuscript: DMW. Wrote the paper: DMW CAS CV KPK LS. ICMJE criteria for authorship read and met: DMW CAS CV KPK LS. Agree with manuscript results and conclusions: DMW CAS CV KPK LS.

                Article
                PMEDICINE-D-14-00010
                10.1371/journal.pmed.1001776
                4285401
                25562317
                165f5de4-cdd0-4b06-acf4-156496e89a71
                Copyright @ 2015

                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 2 January 2014
                : 21 November 2014
                Page count
                Pages: 12
                Funding
                DMW and CV were supported by the Division of International Epidemiology and Population Studies, Fogarty International Center, US National Institutes of Health. DMW is supported by the Claude D. Pepper Older Americans Independence Center at Yale University School of Medicine (#P30AG021342 NIH/NIA), the Yale Center for Clinical Investigation (UL1 TR000142), and the Bill & Melinda Gates Foundation. LS acknowledges support from the RAPIDD (Research and Policy for Infectious Disease Dynamics) program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Plant Science
                Plant Pathology
                Infectious Disease Epidemiology
                Medicine and Health Sciences
                Epidemiology

                Medicine
                Medicine

                Comments

                Comment on this article