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T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 372;9 nejm.org february 26, 2015 835

original article

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

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*

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. Childrens Hospital at Vander-bilt (D.J.W., K.M.E.), and Vanderbilt Vac-cine Research Program (D.J.W., K.M.E.), Nashville, and Le Bonheur Childrens Hos-pital (S.R.A., A.P., N.L., J.A.M.), Univer-sity of Tennessee Health Science Center (S.R.A., A.P., R.A.K., N.L., J.A.M.), and St. Jude Childrens Research Hospital (R.A.K., J.A.M.), Memphis all in Tennessee; University of Utah Health Sciences Cen-ter, Salt Lake City (K.A., C.S., W.H., D.D., D.R.H., A.T.P.); and Northwestern Univer-sity Feinberg School of Medicine, Chicago (E.J.A., R.G.W.). Address reprint requests to Dr. Jain at the Centers for Disease Con-trol and Prevention, 1600 Clifton Rd. NE, MS A-32, Atlanta, GA 30333, or at [email protected].

Drs. Williams, Arnold, and Ampofo con-tributed equally to this article.

* A complete list of members of the Cen-ters for Disease Control and Prevention (CDC) Etiology of Pneumonia in the Community (EPIC) Study Team is pro-vided in the Supplementary Appendix, available at NEJM.org.

N Engl J Med 2015;372:835-45.DOI: 10.1056/NEJMoa1405870Copyright 2015 Massachusetts Medical Society.

A BS TR AC T

BACKGROUNDIncidence estimates of hospitalizations for community-acquired pneumonia among children in the United States that are based on prospective data collection are lim-ited. Updated estimates of pneumonia that has been confirmed radiographically and with the use of current laboratory diagnostic tests are needed.METHODSWe conducted active population-based surveillance for community-acquired pneu-monia 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 mul-tiple methods. Chest radiographs were reviewed independently by study radiologists. RESULTSFrom 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 (


n engl j med 372;9 nejm.org february 26, 2015836

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

Contemporary estimates of the incidence and microbiologic causes of hospitalization for com-munity-acquired pneumonia among children in the United States would be of value.5 Most recent published estimates of the incidence of pneumo-nia 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 diag-nostic 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 be-cause over the past three decades, pneumococcal and Haemophilus inf luenzae 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 Preven-tion (CDC) Etiology of Pneumonia in the Com-munity (EPIC) study was a prospective, multi-center, population-based, active-surveillance study. Systematic enrollment and comprehensive diag-nostic methods were used to determine the inci-dence and microbiologic causes of community-acquired pneumonia requiring hospitalization among U.S. children.

ME THODS

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 Childrens Hospital in Memphis, the Monroe Carell Jr. Childrens Hos-pital at Vanderbilt in Nashville, and the Primary Childrens 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 as-sent 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 re-ports, 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 fi-delity of the study to the protocol.

Children were included in the study if they were admitted to one of the three study hospi-tals; resided in 1 of the 22 counties in the study catchment areas; had evidence of acute infec-tion, defined as reported fever or chills, docu-mented fever or hypothermia, or leukocytosis or leukopenia; had evidence of an acute respiratory illness, defined as new cough or sputum produc-tion, 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 hospi-talized recently (

Pneumonia Requiring Hospitalization among U.S. Children


were interviewed with the use of a standardized questionnaire, and medical charts were abstract-ed 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 in-terview and convalescent-phase serum collection.

RADIOGRAPHIC CONFIRMATION

Enrollment was based on clinicians initial inter-pretation 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 inter-stitial densities), or pleural effusion.14 Enrolled children who did not meet these criteria were ex-cluded from the final analyses.

CONTROLS

From February 1, 2011, to June 30, 2012, a con-venience sample of asymptomatic children young-er than 18 years of age without pneumonia was enrolled weekly. Nasopharyngeal and oropharyn-geal swabs were obtained to evaluate the preva-lence of respiratory pathogens among asymptom-atic 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 ob-tained 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 infor-mation obtained during a telephone interview), had received live attenuated influenza vaccine within 7 days before enrollment, or were under-going otolaryngologic surgery.

LABORATORY TESTING

Grams staining and bacterial culture were per-formed 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 endo-tracheal aspirates and quantified bronchoalveolar-lavage specimens were included (see the Supple-mentary Appendix, available with the full text of this article at NEJM.org).15,16 Real-time poly-merase-chain-reaction (PCR) assays targeting the genes for Streptococcus pneumoniae (lytA) and S. pyo-genes (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. inf luenzae and other gram-negative bacteria, Staphylococcus au-reus, S. anginosus, S. mitis, S. pneumoniae, and S. pyo-genes with the use of PCR assays (see the Supple-mentary Appendix).18,19

PCR was performed at the study sites on naso-pharyngeal and oropharyngeal swabs obtained from children with pneumonia and from con-trols with the use of CDC-developed methods for the detection of adenovirus; Chlamydophila pneu-moniae; 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 virus-es, and RSV was performed at the CDC on avail-able paired acute-phase and convalescent-phase serum specimens (see the Supplementary Ap-pendix).27-32

PATHOGEN DETECTION

A bacterial pathogen was determined to be pres-ent if H. inf luenzae or other gram-negative bacte-ria, 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 pres-ent if adenovirus, coronavirus, HMPV, human rhinovirus, influenza, parainfluenza virus, or RSV was detected in a nasopharyngeal or oro-pharyngeal swab by means of PCR assay or if an agent-specific antibody titer was increased by a

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factor of 4 or more between the acute-phase se-rum specimen and the convalescent-phase serum specimen for all viruses except human rhinovi-rus and coronaviruses. The determination of serologic findings for influenza accounted for influenza-vaccination status and timing (see the Supplementary Appendix).32 Co-detection was de-fined 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 ra-diographic evidence of pneumonia was adjusted, according to age group, for the proportion of eli-gible children enrolled at each study site and the proportion of admissions of children for pneu-monia to study hospitals in the catchment area (market share), and the adjusted number was then divided by the U.S. Census population esti-mates in the catchment area for the correspond-ing 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 chil-dren by multiplying the total incidence of pneu-monia by the proportion of each pathogen de-tected among children with radiographic evidence of pneumonia who had specimens available for the detection of both bacterial and viral patho-gens. To calculate 95% confidence intervals, boot-strap methods with 10,000 samples were used.

R ESULT S

STUDY POPULATION

Of 3803 eligible children, 2638 (69%) were en-rolled. 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 Supplemen-tary Appendix).

Of the 2638 enrolled children, 2358 (89%) had radiographic evidence of pneumonia (Fig. 1). In a review of a 10% random sample of radio-graphs, interrater agreement among the three study radiologists was 84% (95% confidence in-terval [CI], 81 to 87). The median age of the children with radiographic evidence of pneu-monia 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 chil-dren (21%) required intensive care, and 3 (



tion 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 concur-rent 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). Anti-biotic 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 tim-ing of antibiotic dosing and specimen collection, 82% of 2107 blood cultures and 47% of 2022 whole-blood samples for PCR assay were collect-ed before the inpatient administration of anti-biotics.

For the calculation of the proportions of spe-cific pathogens, data were included from only the 2222 children (94%) with radiographic evi-dence of pneumonia who had blood, pleural fluid, endotracheal aspirate, or a bronchoalveo-lar-lavage specimen available and who also had a nasopharyngeal or oropharyngeal swab or paired serum specimens available. A pathogen was de-tected 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 patho-gens 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%), para-influenza virus (in 7%), influenza virus (in 7%), coronavirus (in 5%), S. pneumoniae (in 4%), S. au-reus (in 1%), and S. pyogenes (in 1%) (Fig. 2, and Tables S2 and S3 in the Supplementary Appen-dix). RSV was detected more commonly in chil-dren 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

Pneumonia peaked in the fall and winter. The detection of RSV, influenza, HMPV, and S. pneu-

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

Characteristic

Children with Radiographic Evidence of Pneumonia

(N = 2358)

Age group no. (%)



moniae increased during the winter, whereas hu-man rhinovirus was detected year-round (Fig. 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 respira-tory symptoms after surgery; these children were excluded from the analyses. Among 521 remain-ing 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

606

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RSV

Human rhinovirus

HMPV

Adenovirus

Influenza A or B virus

Pathog

ens Detected (no.)

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Parainfluenza virusCoronavirusS. pneumoniae

M. pneumoniae

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.





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 ra-diographic evidence of pneumonia who were en-rolled 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

Among 2358 children with radiographic evidence of pneumonia, 2012 (85%) were enrolled between July 1, 2010, and June 30, 2012. The annual inci-dence 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 chil-dren 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 de-creased further with increasing age. The inci-dences of RSV, human rhinovirus, HMPV, adeno-virus, 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 young-er than 2 years of age (Table S6 in the Supple-mentary Appendix). The incidence of M. pneu-moniae 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 esti-mated from the combined data from our three study hospitals was 15.7 cases per 10,000 chil-dren 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, dif-ferences 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

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

VariableIncidence of Pneumonia-Related

Hospitalization (95% CI)

no. of cases per 10,000 children per year

Year of study

Yr 1 and 2 15.7 (14.916.5)

Yr 1 16.8 (15.618.0)

Yr 2 14.6 (13.515.7)

Study site

Memphis 19.6 (18.021.3)

Nashville 12.3 (11.213.4)

Salt Lake City 15.2 (13.816.5)

Age group



conducted with the use of hospital-discharge databases have shown decreasing rates of pneu-monia 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 pneu-monia, either as a sole pathogen or in synergy with other pathogens.35-37 However, human rhino-virus was detected in 17% of controls, as com-pared with 22% of the children with pneumonia enrolled at the same study sites during the same period. Shedding of human rhinovirus can ex-tend more than 2 weeks after infection,38 mak-ing 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 patho-gens detected, with the highest rates among children younger than 5 years of age. In similar studies of pneumonia in children, these patho-gens 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 inci-dence of M. pneumoniae was fairly similar across age groups, M. pneumoniae accounted for a stead-ily 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 detec-tion than we found.7 Although our data reflect, in part, the substantial reduction of pneumococ-

cal and Hib disease owing to conjugate vaccines, bacterial culturebased 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 de-tected 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 nonenroll-ment. Second, among enrolled children, not all the specimen types were available, potentially leading to underestimation or overestimation of pathogen-specific rates. However, 94% of chil-dren 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 character-istics 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 oropharyn-geal swabs with the use of a PCR assay could represent infection limited to the upper respira-tory 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 dura-tion 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 causal-ity. 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 clini-cal and radiologic features of bronchiolitis, reac-tive airway disease, and pneumonia, particularly in young children. Even strict radiographic defi-nitions may not distinguish among these enti-ties accurately, resulting in potential misclassifi-cation.45 Finally, although our multicenter study allowed for the investigation of diverse popula-tions with standardized procedures, our find-ings 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 de-tected. 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 patho-gens probably reflects both the effectiveness of bacterial conjugate vaccines and relatively insen-sitive diagnostic tests. The burden of commu-nity-acquired pneumonia in children was asso-

ciated with multiple different and co-detected pathogens, underscoring a need for the enhance-ment of sensitive, inexpensive, and rapid diag-nostic tests to accurately identify pneumonia pathogens.

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.

We thank the patients who participated in this study; Heather London and Torrance Meyer of Associated Regional and Univer-sity Pathologists Laboratories; Mark A. Poritz of BioFire Diag-nostics; Suzette Bartley, Bernie Beall, Nicole Burcher, Robert Davidson, Michael Dillon, Barry Fields, Phalasy Juieng, and Shel-ley 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 Bon-heur Childrens Hospital; Thomas Abramo, Gretchen Edwards, Regina Ellis, Angela Harbeson, Deborah Hunter, Romina Lib-ster, Angela Mendoza, Renee Miller, Deborah Myers, Natalee Rathert, Becca Smith, Bob Sparks, Kristy Spilman, Tanya Stein-back, Scott Taylor, and Sandy Yoder of Monroe Carell Jr. Chil-drens Hospital; Trenda Barney and Patrick Morris of Primary Childrens 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 Childrens Research Hospital; and Fumiko Alger, Alex-andra Burringo, Christopher Carlson, Lacey Collom, Gabriel Cor-tez, 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.

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