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Original Article

Community-Acquired Pneumonia Requiring Hospitalization among U.S. Children

List of authors.
  • Seema Jain, M.D.,
  • Derek J. Williams, M.D., M.P.H.,
  • Sandra R. Arnold, M.D.,
  • Krow Ampofo, M.D.,
  • Anna M. Bramley, M.P.H.,
  • Carrie Reed, Ph.D.,
  • Chris Stockmann, M.Sc.,
  • Evan J. Anderson, M.D.,
  • Carlos G. Grijalva, M.D., M.P.H.,
  • Wesley H. Self, M.D., M.P.H.,
  • Yuwei Zhu, M.D.,
  • Anami Patel, Ph.D.,
  • Weston Hymas, M.S.,
  • James D. Chappell, M.D., Ph.D.,
  • Robert A. Kaufman, M.D.,
  • J. Herman Kan, M.D.,
  • David Dansie, M.D.,
  • Noel Lenny, Ph.D.,
  • David R. Hillyard, M.D.,
  • Lia M. Haynes, Ph.D.,
  • Min Levine, Ph.D.,
  • Stephen Lindstrom, Ph.D.,
  • Jonas M. Winchell, Ph.D.,
  • Jacqueline M. Katz, Ph.D.,
  • Dean Erdman, Dr.P.H.,
  • Eileen Schneider, M.D., M.P.H.,
  • Lauri A. Hicks, D.O.,
  • Richard G. Wunderink, M.D.,
  • Kathryn M. Edwards, M.D.,
  • Andrew T. Pavia, M.D.,
  • Jonathan A. McCullers, M.D.,
  • and Lyn Finelli, Dr.P.H.
  • for the CDC EPIC Study Team*

Abstract

Background

Incidence estimates of hospitalizations for community-acquired pneumonia among children in the United States that are based on prospective data collection are limited. Updated estimates of pneumonia that has been confirmed radiographically and with the use of current laboratory diagnostic tests are needed.

Methods

We conducted active population-based surveillance for community-acquired pneumonia requiring hospitalization among children younger than 18 years of age in three hospitals in Memphis, Nashville, and Salt Lake City. We excluded children with recent hospitalization or severe immunosuppression. Blood and respiratory specimens were systematically collected for pathogen detection with the use of multiple methods. Chest radiographs were reviewed independently by study radiologists.

Results

From January 2010 through June 2012, we enrolled 2638 of 3803 eligible children (69%), 2358 of whom (89%) had radiographic evidence of pneumonia. The median age of the children was 2 years (interquartile range, 1 to 6); 497 of 2358 children (21%) required intensive care, and 3 (<1%) died. Among 2222 children with radiographic evidence of pneumonia and with specimens available for bacterial and viral testing, a viral or bacterial pathogen was detected in 1802 (81%), one or more viruses in 1472 (66%), bacteria in 175 (8%), and both bacterial and viral pathogens in 155 (7%). The annual incidence of pneumonia was 15.7 cases per 10,000 children (95% confidence interval [CI], 14.9 to 16.5), with the highest rate among children younger than 2 years of age (62.2 cases per 10,000 children; 95% CI, 57.6 to 67.1). Respiratory syncytial virus was more common among children younger than 5 years of age than among older children (37% vs. 8%), as were adenovirus (15% vs. 3%) and human metapneumovirus (15% vs. 8%). Mycoplasma pneumoniae was more common among children 5 years of age or older than among younger children (19% vs. 3%).

Conclusions

The burden of hospitalization for children with community-acquired pneumonia was highest among the very young, with respiratory viruses the most commonly detected causes of pneumonia. (Funded by the Influenza Division of the National Center for Immunization and Respiratory Diseases.)

Introduction

Pneumonia is a leading cause of hospitalization among children in the United States,1-3 with medical costs estimated at almost $1 billion in 2009.4 Despite this large burden of disease, critical gaps remain in our knowledge about pneumonia in children.5

Contemporary estimates of the incidence and microbiologic causes of hospitalization for community-acquired pneumonia among children in the United States would be of value.5 Most recent published estimates of the incidence of pneumonia have used administrative data, which are limited because a strict clinical and radiographic definition of community-acquired pneumonia is difficult to apply to such data and because diagnostic testing is not performed systematically and thus detailed etiologic data are lacking.6 Other etiologic studies of pneumonia among children in the United States have been limited to single sites and have been of short duration.5,7 This is a critical time for an etiologic study because over the past three decades, pneumococcal and Haemophilus influenzae type b (Hib) conjugate vaccines have markedly reduced the incidence of diseases associated with these pathogens.8-11 Improvements in molecular diagnostic testing also provide new opportunities to advance our knowledge.12,13

The Centers for Disease Control and Prevention (CDC) Etiology of Pneumonia in the Community (EPIC) study was a prospective, multicenter, population-based, active-surveillance study. Systematic enrollment and comprehensive diagnostic methods were used to determine the incidence and microbiologic causes of community-acquired pneumonia requiring hospitalization among U.S. children.

Methods

Active Population-Based Surveillance

From January 1, 2010, to June 30, 2012, children younger than 18 years of age were enrolled in the EPIC study at Le Bonheur Children's Hospital in Memphis, the Monroe Carell Jr. Children's Hospital at Vanderbilt in Nashville, and the Primary Children's Hospital in Salt Lake City. We sought to enroll all eligible children; therefore, trained staff screened children for enrollment at least 18 hours per day, 7 days per week. Written informed consent was obtained from parents or caregivers before enrollment, with children providing assent when age appropriate. The study protocol was approved by the institutional review board at each institution and at the CDC. Weekly study teleconferences, required weekly enrollment reports, data audits, and annual study-site visits were conducted to ensure uniform procedures among the study sites. All the authors vouch for the accuracy and completeness of the data and analyses presented in this article and for the fidelity of the study to the protocol.

Children were included in the study if they were admitted to one of the three study hospitals; resided in 1 of the 22 counties in the study catchment areas; had evidence of acute infection, defined as reported fever or chills, documented fever or hypothermia, or leukocytosis or leukopenia; had evidence of an acute respiratory illness, defined as new cough or sputum production, chest pain, dyspnea, tachypnea, abnormal lung examination, or respiratory failure; and had evidence consistent with pneumonia as assessed by means of chest radiography within 72 hours before or after admission.

Children were excluded if they had been hospitalized recently (<7 days for immunocompetent children and <90 days for immunosuppressed children), had already been enrolled in the EPIC study within the previous 28 days, resided in an extended-care facility, had an alternative diagnosis of a respiratory disorder, or were newborns who never left the hospital. We also excluded children if they had a tracheostomy tube, if they had cystic fibrosis or cancer with neutropenia, if they had received a solid-organ or hematopoietic stem-cell transplant within the previous 90 days, if they had active graft-versus-host disease or bronchiolitis obliterans, or if they had human immunodeficiency virus infection with a CD4 cell count of less than 200 per cubic millimeter (or a percentage of CD4 cells <14%).

Data and Specimen Collection

Trained staff obtained blood samples, acute-phase serum specimens, and nasopharyngeal and oropharyngeal swabs from all the enrolled children as soon as possible after presentation. Pleural fluid, endotracheal aspirates, and bronchoalveolar-lavage specimens that had been obtained for clinical care were also analyzed for the study. Only specimens obtained within 72 hours before or after admission were included, except for pleural fluid, which was included if it was collected within 7 days after admission.

Enrolled children, their caregivers, or both were interviewed with the use of a standardized questionnaire, and medical charts were abstracted after discharge; demographic, epidemiologic, and clinical data were collected systematically. Children and their caregivers were asked to return 3 to 10 weeks after enrollment for a follow-up interview and convalescent-phase serum collection.

Radiographic Confirmation

Enrollment was based on clinicians' initial interpretation of chest radiographs obtained within 72 hours before or after admission. However, the final determination regarding inclusion in the study required independent confirmation by the board-certified pediatric study radiologist at each study hospital; these radiologists (all of whom are coauthors of the study) were unaware of the patients' demographic and clinical information. Radiographic evidence of pneumonia was defined as the presence of consolidation (a dense or fluffy opacity with or without air bronchograms), other infiltrate (linear and patchy alveolar or interstitial densities), or pleural effusion.14 Enrolled children who did not meet these criteria were excluded from the final analyses.

Controls

From February 1, 2011, to June 30, 2012, a convenience sample of asymptomatic children younger than 18 years of age without pneumonia was enrolled weekly. Nasopharyngeal and oropharyngeal swabs were obtained to evaluate the prevalence of respiratory pathogens among asymptomatic children. Eligible controls were undergoing outpatient same-day elective surgery at a study hospital, resided in the study catchment area in Nashville or Salt Lake City, and were willing to be interviewed. Written informed consent was obtained from parents or caregivers, with children providing assent when age appropriate. Exclusion criteria were the same as for the children with pneumonia; controls were also excluded if they had fever or respiratory symptoms within 14 days before or after enrollment (on the basis of information obtained during a telephone interview), had received live attenuated influenza vaccine within 7 days before enrollment, or were undergoing otolaryngologic surgery.

Laboratory Testing

Gram's staining and bacterial culture were performed on blood samples, pleural-fluid specimens, endotracheal aspirates, and bronchoalveolar-lavage specimens at each study site with the use of standard techniques. Only high-quality endotracheal aspirates and quantified bronchoalveolar-lavage specimens were included (see the Supplementary Appendix, available with the full text of this article at NEJM.org).15,16 Real-time polymerase-chain-reaction (PCR) assays targeting the genes for Streptococcus pneumoniae (lytA) and S. pyogenes (spy) was performed on whole blood and pleural fluid at the CDC.17 Pleural fluid was also tested at the University of Utah for H. influenzae and other gram-negative bacteria, Staphylococcus aureus, S. anginosus, S. mitis, S. pneumoniae, and S. pyogenes with the use of PCR assays (see the Supplementary Appendix).18,19

PCR was performed at the study sites on nasopharyngeal and oropharyngeal swabs obtained from children with pneumonia and from controls with the use of CDC-developed methods for the detection of adenovirus; Chlamydophila pneumoniae; coronaviruses 229E, HKU1, NL63, and OC43; human metapneumovirus (HMPV); human rhinovirus; influenza A and B viruses; Mycoplasma pneumoniae; parainfluenza virus types 1, 2, and 3; and respiratory syncytial virus (RSV).20-24 Quality-assurance and monitoring protocols were used to maintain standardization among the study sites.25,26 Serologic testing for adenovirus, HMPV, influenza A and B viruses, parainfluenza viruses, and RSV was performed at the CDC on available paired acute-phase and convalescent-phase serum specimens (see the Supplementary Appendix).27-32

Pathogen Detection

A bacterial pathogen was determined to be present if H. influenzae or other gram-negative bacteria, S. aureus, S. anginosus, S. mitis, S. pneumoniae, or S. pyogenes was detected in blood, endotracheal aspirate, bronchoalveolar-lavage specimen, or pleural fluid by means of culture or in whole blood or pleural fluid by means of PCR assay; or if C. pneumoniae or M. pneumoniae was detected in a nasopharyngeal or oropharyngeal swab by means of PCR assay. Other bacteria were considered to be contaminants unless they met specific criteria (see the Supplementary Appendix).

A viral pathogen was determined to be present if adenovirus, coronavirus, HMPV, human rhinovirus, influenza, parainfluenza virus, or RSV was detected in a nasopharyngeal or oropharyngeal swab by means of PCR assay or if an agent-specific antibody titer was increased by a factor of 4 or more between the acute-phase serum specimen and the convalescent-phase serum specimen for all viruses except human rhinovirus and coronaviruses. The determination of serologic findings for influenza accounted for influenza-vaccination status and timing (see the Supplementary Appendix).32 Co-detection was defined as the detection of two or more bacterial or viral pathogens in any combination.

Statistical Analysis

Annual incidence rates were calculated from July 1, 2010, to June 30, 2011, and from July 1, 2011, to June 30, 2012. For the calculation of incidence rates, the number of enrolled children with radiographic evidence of pneumonia was adjusted, according to age group, for the proportion of eligible children enrolled at each study site and the proportion of admissions of children for pneumonia to study hospitals in the catchment area (market share), and the adjusted number was then divided by the U.S. Census population estimates in the catchment area for the corresponding year.33 Market share was based on discharge-diagnosis codes (see the Supplementary Appendix).

We calculated pathogen-specific rates for pathogens detected in more than 1% of the children by multiplying the total incidence of pneumonia by the proportion of each pathogen detected among children with radiographic evidence of pneumonia who had specimens available for the detection of both bacterial and viral pathogens. To calculate 95% confidence intervals, bootstrap methods with 10,000 samples were used.

Results

Study Population

Of 3803 eligible children, 2638 (69%) were enrolled. As compared with the enrolled children, eligible children who were not enrolled were less likely to be Hispanic and had a shorter length of stay in the hospital (Table S1 in the Supplementary Appendix).

Figure 1. Figure 1. Screening, Eligibility, and Enrollment of Children with Pneumonia.

A total of 2354 children had chest radiographs that met the radiographic inclusion criteria of consolidation, infiltrate, or effusion. One child had only a computed tomographic (CT) scan available that met the criteria for radiographic evidence of pneumonia. A total of 3 children did not have evidence of pneumonia on the basis of chest radiography but did have evidence of pneumonia on the basis of available CT scans. A total of 99% of the radiographs were obtained within 48 hours before or after admission.

Table 1. Table 1. Characteristics of Children with Community-Acquired Pneumonia Requiring Hospitalization.

Of the 2638 enrolled children, 2358 (89%) had radiographic evidence of pneumonia (Figure 1). In a review of a 10% random sample of radiographs, interrater agreement among the three study radiologists was 84% (95% confidence interval [CI], 81 to 87). The median age of the children with radiographic evidence of pneumonia was 2 years (interquartile range, 1 to 6). A total of 45% of the children were girls; 40% of the children were white, 33% were black, 19% were Hispanic, and 8% were of another race or ethnic group. A total of 51% of the children had an underlying condition (with asthma or reactive airway disease the most common condition). The median length of stay in the hospital was 3 days (interquartile range, 2 to 5). A total of 497 children (21%) required intensive care, and 3 (<1%) died (Table 1, and Table S1 in the Supplementary Appendix).

Among children with information on vaccination status, 612 of 2053 children (30%) who were 6 months of age or older had received one or more doses of influenza vaccine for the concurrent season and 1101 of 1272 children (87%) 19 months to 12 years of age had received three or more doses of pneumococcal conjugate vaccine (Table S1 in the Supplementary Appendix). Antibiotic agents had been prescribed for 18% of the children within 5 days before hospitalization; 88% of the children received antibiotics during hospitalization.

Detection of Pathogens

A nasopharyngeal or oropharyngeal swab was obtained from 2254 of the 2358 children with radiographic evidence of pneumonia (96%), blood for culture from 2143 (91%), whole blood for PCR assays from 2063 (87%), paired serum specimens from 1028 (44%), pleural fluid from 86 (4%), a bronchoalveolar-lavage specimen from 23 (1%), and an endotracheal aspirate from 22 (1%). Among children for whom there was known timing of antibiotic dosing and specimen collection, 82% of 2107 blood cultures and 47% of 2022 whole-blood samples for PCR assay were collected before the inpatient administration of antibiotics.

Figure 2. Figure 2. Pathogens Detected in U.S. Children with Community-Acquired Pneumonia Requiring Hospitalization.

Panel A shows the proportion of pathogen types detected from January 1, 2010, through June 30, 2012, among 2222 hospitalized children with radiographic evidence of pneumonia who had blood samples or pleural fluid available for bacterial culture or real-time polymerase-chain-reaction (PCR) assays or endotracheal aspirate or bronchoalveolar-lavage specimens available for bacterial culture and who also had nasopharyngeal or oropharyngeal swabs available for viral and atypical bacterial PCR assay or available viral serologic results. A total of 4 patients had more than one bacterial pathogen without a virus detected. Panel B shows the numbers (above the bars) and percentages of all children in whom a specific pathogen was detected. Among 2222 patients who had available tests for the detection of bacterial and viral pathogens, 1802 were found to have a viral or bacterial pathogen (or both). Because more than 1 pathogen could be detected in a patient, there were a total of 2533 pathogens detected. A total of 88 pathogens other than those listed here were detected in 81 children, including Staphylococcus aureus (in 22 children, of whom 17 had methicillin-resistant S. aureus and 5 had methicillin-susceptible S. aureus), Streptococcus pyogenes (in 16), viridans streptococci (in 14), Chlamydophila pneumoniae (in 12), Haemophilus influenzae (in 9), other gram-negative bacteria (in 9), other streptococcus species (in 4), and histoplasma (in 2). Darker shading in the bar graph in Panel B indicates that only the single pathogen was detected, and lighter shading indicates the pathogen was detected in combination with at least one other pathogen. AdV denotes adenovirus, CoV coronavirus, Flu influenza A or B virus, HMPV human metapneumovirus, HRV human rhinovirus, PIV parainfluenza virus, and RSV respiratory syncytial virus. Panel C shows the proportions of pathogens detected, according to age group.

For the calculation of the proportions of specific pathogens, data were included from only the 2222 children (94%) with radiographic evidence of pneumonia who had blood, pleural fluid, endotracheal aspirate, or a bronchoalveolar-lavage specimen available and who also had a nasopharyngeal or oropharyngeal swab or paired serum specimens available. A pathogen was detected in 1802 of the 2222 children (81%): one or more viruses in 1472 (66%), one or more bacteria in 175 (8%), and both bacterial and viral pathogens in 155 (7%). The most commonly detected pathogens were RSV (in 28% of the children), human rhinovirus (in 27%), HMPV (in 13%), adenovirus (in 11%), M. pneumoniae (in 8%), parainfluenza virus (in 7%), influenza virus (in 7%), coronavirus (in 5%), S. pneumoniae (in 4%), S. aureus (in 1%), and S. pyogenes (in 1%) (Figure 2, and Tables S2 and S3 in the Supplementary Appendix). RSV was detected more commonly in children younger than 5 years of age than in older children (37% vs. 8%), as were adenovirus (15% vs. 3%) and HMPV (15% vs. 8%). M. pneumoniae was detected more commonly in children 5 years of age or older than in younger children (19% vs. 3%) (Table S4 in the Supplementary Appendix).

Seasonality

Figure 3. Figure 3. Pathogens Detected, According to Month and Year, in U.S. Children with Community-Acquired Pneumonia Requiring Hospitalization, January 1, 2010, through June 30, 2012.

Pneumonia peaked in the fall and winter. The detection of RSV, influenza, HMPV, and S. pneumoniae increased during the winter, whereas human rhinovirus was detected year-round (Figure 3). The detection of M. pneumoniae rose steadily from the summer through the fall of 2011 and peaked that winter.

Controls

Of 726 controls, 125 (17%) could not be reached for follow-up, and 80 (11%) had fever or respiratory symptoms after surgery; these children were excluded from the analyses. Among 521 remaining asymptomatic controls, 28% were younger than 2 years of age, 24% were 2 to 4 years of age, 24% were 5 to 9 years of age, and 25% were 10 to 17 years of age (Table S5 in the Supplementary Appendix). The 832 children with radiographic evidence of pneumonia who were enrolled during the same period at the same study sites were younger than the controls; 42% were younger than 2 years of age, 25% were 2 to 4 years of age, 19% were 5 to 9 years of age, and 13% were 10 to 17 years of age. After adjustment for age, human rhinovirus was detected in 17% of the controls, as compared with 22% of the children with radiographic evidence of pneumonia who were enrolled at the same study sites during the same period. All the other pathogens were detected in 3% or less of controls.

Overall and Pathogen-Specific Incidence

Table 2. Table 2. Estimated Annual Incidence Rates of Hospitalization for Community-Acquired Pneumonia, According to Year of Study, Study Site, Age Group, and Pathogen Detected.

Among 2358 children with radiographic evidence of pneumonia, 2012 (85%) were enrolled between July 1, 2010, and June 30, 2012. The annual incidence of hospitalization for pneumonia was 15.7 cases per 10,000 children (95% CI, 14.9 to 16.5) (Table 2). The incidence was highest among children younger than 2 years of age (62.2 cases per 10,000 children; 95% CI, 57.6 to 67.1), decreased among those 2 to 4 years of age (23.8 cases per 10,000 children; 95% CI, 21.4 to 26.3), and decreased further with increasing age. The incidences of RSV, human rhinovirus, HMPV, adenovirus, influenza, parainfluenza virus, coronavirus, and S. pneumoniae were higher among children younger than 5 years of age than among older children but were highest among children younger than 2 years of age (Table S6 in the Supplementary Appendix). The incidence of M. pneumoniae was similar across age groups.

Discussion

The multicenter EPIC study was a prospective, population-based study of community-acquired pneumonia among children in the United States. We found that the burden of pneumonia-related hospitalization was highest among children younger than 5 years of age. Diagnostic testing for multiple pathogens revealed a pathogen in 81% of the children with pneumonia; a viral pathogen was detected in 73% of the children, and a bacterial pathogen in 15%.

The annual incidence of hospitalization for community-acquired pneumonia that was estimated from the combined data from our three study hospitals was 15.7 cases per 10,000 children younger than 18 years of age. The rate of pneumonia-related hospitalization as estimated with the use of the 2009 national Kids' Inpatient Database was 22.5 cases per 10,000 children younger than 18 years of age,3 which is similar to, but higher than, our rate. This difference might be attributed to the year of analysis, differences in the populations studied, and the strict criteria of the EPIC study that included standardized clinical and radiologic definitions of pneumonia and excluded recently hospitalized or severely immunosuppressed children. Studies conducted with the use of hospital-discharge databases have shown decreasing rates of pneumonia with increasing age of children, a finding that is consistent with our results.1,3,10

RSV was the most common pathogen detected (in 28% of the children), with the greatest burden observed among children younger than 2 years of age. In another study that used PCR assays, RSV was detected in 31% of children younger than 14 years of age who had been hospitalized with radiographic evidence of pneumonia34 — a finding that is similar to our results.

Human rhinovirus was detected in 27% of the children with pneumonia. The literature supports the association of human rhinovirus with pneumonia, either as a sole pathogen or in synergy with other pathogens.35-37 However, human rhinovirus was detected in 17% of controls, as compared with 22% of the children with pneumonia enrolled at the same study sites during the same period. Shedding of human rhinovirus can extend more than 2 weeks after infection,38 making it challenging to interpret the detection of human rhinovirus in children with pneumonia.

HMPV, adenovirus, parainfluenza virus, and coronavirus accounted for one third of the pathogens detected, with the highest rates among children younger than 5 years of age. In similar studies of pneumonia in children, these pathogens accounted for 25 to 40% of the pathogens detected.12,34 In our study, although PCR assays were used to detect the viral pathogens in the majority of cases, serologic testing was a useful adjunct.27,28 Our study was conducted after the 2009 H1N1 influenza pandemic, during a period when the influenza seasons were mild,39 which made the burden of influenza less than it was during seasons with more widespread circulation.

Bacterial pathogens were detected in 15% of the children with pneumonia. Although the incidence of M. pneumoniae was fairly similar across age groups, M. pneumoniae accounted for a steadily increasing proportion of cases of pneumonia with increasing age of the children.40 An earlier etiologic study of pneumonia in U.S. children, in which a PCR assay targeting pneumolysin, a test with limited specificity, was used7,41 and which was conducted before the universal use of the Hib and pneumococcal conjugate vaccines, showed a higher proportion of bacterial detection than we found.7 Although our data reflect, in part, the substantial reduction of pneumococcal and Hib disease owing to conjugate vaccines, bacterial culture–based diagnostic tests have limited sensitivity, and bacteremia is detected in a minority of pneumococcal pneumonias.8-11,41,42 In the absence of a reference standard for the detection of bacterial pathogens in pneumonia, our findings, which are based on current state-of-the-art diagnostic testing, suggest that the incidence of bacterial pneumonia is lower than previously reported.

In our study, multiple pathogens were detected in 26% of the children. Another etiologic study that included 154 children hospitalized with community-acquired pneumonia in the United States showed a similar prevalence.7 Given the large proportion and diversity of co-detected pathogens, further study is needed.

This study has some limitations. First, not every eligible child was enrolled, although the incidence calculations accounted for nonenrollment. Second, among enrolled children, not all the specimen types were available, potentially leading to underestimation or overestimation of pathogen-specific rates. However, 94% of children with radiographic evidence of pneumonia had specimens available for the detection of both bacterial and viral pathogens, and no significant differences in demographic or clinical characteristics were noted between the group of children with specimens available and the group of those without specimens available.

Third, despite a comprehensive diagnostic approach, the sensitivity of current tests for bacterial pneumonia (particularly in the context of antibiotic use) is not optimal.43,44 Owing to ethical and feasibility considerations, invasive procedures to obtain direct samples from the lung were usually not performed. The detection of pathogens in nasopharyngeal or oropharyngeal swabs with the use of a PCR assay could represent infection limited to the upper respiratory tract or convalescent-phase shedding, and thus detection may not denote causation. Fourth, our controls were a convenience sample and may not have represented the underlying population. Controls were not enrolled for the entire duration of the study; in addition, enrollment was restricted to two study sites and was focused on the prevalence of pathogens in asymptomatic children, thus limiting extrapolations of causality. However, except for human rhinovirus, pathogens were not detected often in controls, suggesting that the other viruses and atypical bacteria contribute to pneumonia. We believe that the control data helped in the interpretation of the detection of pathogens in the children with pneumonia and are an important strength of the study.

Fifth, there is substantial overlap in the clinical and radiologic features of bronchiolitis, reactive airway disease, and pneumonia, particularly in young children. Even strict radiographic definitions may not distinguish among these entities accurately, resulting in potential misclassification.45 Finally, although our multicenter study allowed for the investigation of diverse populations with standardized procedures, our findings may not be representative of the entire U.S. pediatric population or may not be generalizable to other settings.

In conclusion, the burden of community-acquired pneumonia requiring hospitalization was highest among children younger than 5 years of age, with respiratory viruses frequently detected. Effective antiviral vaccines or treatments, particularly for RSV infection, could have a mitigating effect on pneumonia in children. The low prevalence of detection of bacterial pathogens probably reflects both the effectiveness of bacterial conjugate vaccines and relatively insensitive diagnostic tests. The burden of community-acquired pneumonia in children was associated with multiple different and co-detected pathogens, underscoring a need for the enhancement of sensitive, inexpensive, and rapid diagnostic tests to accurately identify pneumonia pathogens.

Funding and Disclosures

The views expressed in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention (CDC).

Supported by the Influenza Division of the National Center for Immunization and Respiratory Diseases at the CDC through cooperative agreements with each study site.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Williams, Arnold, and Ampofo contributed equally to this article.

We thank the patients who participated in this study; Heather London and Torrance Meyer of Associated Regional and University Pathologists Laboratories; Mark A. Poritz of BioFire Diagnostics; Suzette Bartley, Bernie Beall, Nicole Burcher, Robert Davidson, Michael Dillon, Barry Fields, Phalasy Juieng, and Shelley Magill of the CDC; John Devincenzo, Tonya Galloway, Vivian Lebaroff, Moses Lockhart, Lakesha London, Tekita McKinney, Amanda Nesbit, Chirag Patel, Tina Pitt, Shante Richardson, Naeem Shaikh, Davida Singleton, and Mildred Willis of Le Bonheur Children's Hospital; Thomas Abramo, Gretchen Edwards, Regina Ellis, Angela Harbeson, Deborah Hunter, Romina Libster, Angela Mendoza, Renee Miller, Deborah Myers, Natalee Rathert, Becca Smith, Bob Sparks, Kristy Spilman, Tanya Steinback, Scott Taylor, and Sandy Yoder of Monroe Carell Jr. Children's Hospital; Trenda Barney and Patrick Morris of Primary Children's Hospital; Edwina Anderson, Nancy Foster, Donna Nance, Ryan Heine, Amanda Anderson-Green, Amy Iverson, Shane Gansebom, Pat Flynn, Randall Hayden, and Kim Allison of St. Jude Children's Research Hospital; and Fumiko Alger, Alexandra Burringo, Christopher Carlson, Lacey Collom, Gabriel Cortez, Kristina Grim, Keith Gunnerson, David Halladay, Caroline Heyrend, Jarrett Killpack, Kevin Martin, Brittany McDowell, Francesca Nichols, Parker Plant, Margaret Reid, Joshua Shimizu, Luke Schunk, Melanie Sperry, John Sweeley, and Lucy Williams of the University of Utah.

Author Affiliations

From the Centers for Disease Control and Prevention, Atlanta (S.J., A.M.B., C.R., L.M.H., M.L., S.L., J.M.W., J.M.K., D.E., E.S., L.A.H., L.F.); Vanderbilt University School of Medicine (D.J.W., C.G.G., W.H.S., Y.Z., J.D.C., J.H.K., K.M.E.), Monroe Carell Jr. Children's Hospital at Vanderbilt (D.J.W., K.M.E.), and Vanderbilt Vaccine Research Program (D.J.W., K.M.E.), Nashville, and Le Bonheur Children's Hospital (S.R.A., A.P., N.L., J.A.M.), University of Tennessee Health Science Center (S.R.A., A.P., R.A.K., N.L., J.A.M.), and St. Jude Children's Research Hospital (R.A.K., J.A.M.), Memphis — all in Tennessee; University of Utah Health Sciences Center, Salt Lake City (K.A., C.S., W.H., D.D., D.R.H., A.T.P.); and Northwestern University Feinberg School of Medicine, Chicago (E.J.A., R.G.W.).

Address reprint requests to Dr. Jain at the Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, MS A-32, Atlanta, GA 30333, or at .

A complete list of members of the Centers for Disease Control and Prevention (CDC) Etiology of Pneumonia in the Community (EPIC) Study Team is provided in the Supplementary Appendix, available at NEJM.org.

Supplementary Material

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    Figures/Media

    1. Figure 1. Screening, Eligibility, and Enrollment of Children with Pneumonia.
      Figure 1. Screening, Eligibility, and Enrollment of Children with Pneumonia.

      A total of 2354 children had chest radiographs that met the radiographic inclusion criteria of consolidation, infiltrate, or effusion. One child had only a computed tomographic (CT) scan available that met the criteria for radiographic evidence of pneumonia. A total of 3 children did not have evidence of pneumonia on the basis of chest radiography but did have evidence of pneumonia on the basis of available CT scans. A total of 99% of the radiographs were obtained within 48 hours before or after admission.

    2. Table 1. Characteristics of Children with Community-Acquired Pneumonia Requiring Hospitalization.
      Table 1. Characteristics of Children with Community-Acquired Pneumonia Requiring Hospitalization.
    3. Figure 2. Pathogens Detected in U.S. Children with Community-Acquired Pneumonia Requiring Hospitalization.
      Figure 2. Pathogens Detected in U.S. Children with Community-Acquired Pneumonia Requiring Hospitalization.

      Panel A shows the proportion of pathogen types detected from January 1, 2010, through June 30, 2012, among 2222 hospitalized children with radiographic evidence of pneumonia who had blood samples or pleural fluid available for bacterial culture or real-time polymerase-chain-reaction (PCR) assays or endotracheal aspirate or bronchoalveolar-lavage specimens available for bacterial culture and who also had nasopharyngeal or oropharyngeal swabs available for viral and atypical bacterial PCR assay or available viral serologic results. A total of 4 patients had more than one bacterial pathogen without a virus detected. Panel B shows the numbers (above the bars) and percentages of all children in whom a specific pathogen was detected. Among 2222 patients who had available tests for the detection of bacterial and viral pathogens, 1802 were found to have a viral or bacterial pathogen (or both). Because more than 1 pathogen could be detected in a patient, there were a total of 2533 pathogens detected. A total of 88 pathogens other than those listed here were detected in 81 children, including Staphylococcus aureus (in 22 children, of whom 17 had methicillin-resistant S. aureus and 5 had methicillin-susceptible S. aureus), Streptococcus pyogenes (in 16), viridans streptococci (in 14), Chlamydophila pneumoniae (in 12), Haemophilus influenzae (in 9), other gram-negative bacteria (in 9), other streptococcus species (in 4), and histoplasma (in 2). Darker shading in the bar graph in Panel B indicates that only the single pathogen was detected, and lighter shading indicates the pathogen was detected in combination with at least one other pathogen. AdV denotes adenovirus, CoV coronavirus, Flu influenza A or B virus, HMPV human metapneumovirus, HRV human rhinovirus, PIV parainfluenza virus, and RSV respiratory syncytial virus. Panel C shows the proportions of pathogens detected, according to age group.

    4. Figure 3. Pathogens Detected, According to Month and Year, in U.S. Children with Community-Acquired Pneumonia Requiring Hospitalization, January 1, 2010, through June 30, 2012.
      Figure 3. Pathogens Detected, According to Month and Year, in U.S. Children with Community-Acquired Pneumonia Requiring Hospitalization, January 1, 2010, through June 30, 2012.
    5. Table 2. Estimated Annual Incidence Rates of Hospitalization for Community-Acquired Pneumonia, According to Year of Study, Study Site, Age Group, and Pathogen Detected.
      Table 2. Estimated Annual Incidence Rates of Hospitalization for Community-Acquired Pneumonia, According to Year of Study, Study Site, Age Group, and Pathogen Detected.

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