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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*

A BS T R AC T

BACKGROUND
Incidence estimates of hospitalizations for community-acquired pneumonia among From the Centers for Disease Control and
children in the United States that are based on prospective data collection are lim- Prevention, Atlanta (S.J., A.M.B., C.R.,
L.M.H., M.L., S.L., J.M.W., J.M.K., D.E.,
ited. Updated estimates of pneumonia that has been confirmed radiographically E.S., L.A.H., L.F.); Vanderbilt University
and with the use of current laboratory diagnostic tests are needed. School of Medicine (D.J.W., C.G.G., W.H.S.,
METHODS Y.Z., J.D.C., J.H.K., K.M.E.), Monroe
Carell Jr. Childrens Hospital at Vander-
We conducted active population-based surveillance for community-acquired pneu- bilt (D.J.W., K.M.E.), and Vanderbilt Vac-
monia requiring hospitalization among children younger than 18 years of age in cine Research Program (D.J.W., K.M.E.),
three hospitals in Memphis, Nashville, and Salt Lake City. We excluded children Nashville, and Le Bonheur Childrens Hos-
pital (S.R.A., A.P., N.L., J.A.M.), Univer-
with recent hospitalization or severe immunosuppression. Blood and respiratory sity of Tennessee Health Science Center
specimens were systematically collected for pathogen detection with the use of mul- (S.R.A., A.P., R.A.K., N.L., J.A.M.), and St.
tiple methods. Chest radiographs were reviewed independently by study radiologists. Jude Childrens Research Hospital (R.A.K.,
J.A.M.), Memphis all in Tennessee;
RESULTS University of Utah Health Sciences Cen-
From January 2010 through June 2012, we enrolled 2638 of 3803 eligible children ter, Salt Lake City (K.A., C.S., W.H., D.D.,
D.R.H., A.T.P.); and Northwestern Univer-
(69%), 2358 of whom (89%) had radiographic evidence of pneumonia. The median age
sity Feinberg School of Medicine, Chicago
of the children was 2 years (interquartile range, 1 to 6); 497 of 2358 children (21%) (E.J.A., R.G.W.). Address reprint requests
required intensive care, and 3 (<1%) died. Among 2222 children with radiographic to Dr. Jain at the Centers for Disease Con-
evidence of pneumonia and with specimens available for bacterial and viral testing, trol and Prevention, 1600 Clifton Rd. NE,
MS A-32, Atlanta, GA 30333, or at bwc8@
a viral or bacterial pathogen was detected in 1802 (81%), one or more viruses in cdc.gov.
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% confi- Drs. Williams, Arnold, and Ampofo con-
tributed equally to this article.
dence 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 * A complete list of members of the Cen-
syncytial virus was more common among children younger than 5 years of age than ters for Disease Control and Prevention
(CDC) Etiology of Pneumonia in the
among older children (37% vs. 8%), as were adenovirus (15% vs. 3%) and human Community (EPIC) Study Team is pro-
metapneumovirus (15% vs. 8%). Mycoplasma pneumoniae was more common among vided in the Supplementary Appendix,
children 5 years of age or older than among younger children (19% vs. 3%). available at NEJM.org.
CONCLUSIONS N Engl J Med 2015;372:835-45.
The burden of hospitalization for children with community-acquired pneumonia DOI: 10.1056/NEJMoa1405870
was highest among the very young, with respiratory viruses the most commonly Copyright 2015 Massachusetts Medical Society.

detected causes of pneumonia. (Funded by the Influenza Division of the National

Center for Immunization and Respiratory Diseases.)

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 The n e w e ng l a n d j o u r na l
P
neumonia 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 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 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
836 n engl j med 372;9nejm.orgfebruary 26, 2015
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of m e dic i n e
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 (<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 diagno-
sis 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 bron-
choalveolar-lavage specimens that had been ob-
tained 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
 Pneumonia Requiring Hospitalization among U.S. Children

were interviewed with the use of a standardized lavage specimens at each study site with the use
questionnaire, and medical charts were abstract- of standard techniques. Only high-quality endo-
ed after discharge; demographic, epidemiologic, tracheal aspirates and quantified bronchoalveolar-
and clinical data were collected systematically. lavage specimens were included (see the Supple-
Children and their caregivers were asked to return mentary Appendix, available with the full text of
3 to 10 weeks after enrollment for a follow-up in- this article at NEJM.org).15,16 Real-time poly-
terview and convalescent-phase serum collection. merase-chain-reaction (PCR) assays targeting the
genes for Streptococcus pneumoniae (lytA) and S. pyo-
RADIOGRAPHIC CONFIRMATION genes (spy) was performed on whole blood and
Enrollment was based on clinicians initial inter- pleural fluid at the CDC.17 Pleural fluid was also
pretation of chest radiographs obtained within tested at the University of Utah for H. influenzae
72 hours before or after admission. However, and other gram-negative bacteria, Staphylococcus au-
the final determination regarding inclusion in the reus, S. anginosus, S. mitis, S. pneumoniae, and S. pyo-
study required independent confirmation by the genes with the use of PCR assays (see the Supple-
board-certified pediatric study radiologist at each mentary Appendix).18,19
study hospital; these radiologists (all of whom PCR was performed at the study sites on naso-
are coauthors of the study) were unaware of the pharyngeal and oropharyngeal swabs obtained
patients demographic and clinical information. from children with pneumonia and from con-
Radiographic evidence of pneumonia was defined trols with the use of CDC-developed methods for
as the presence of consolidation (a dense or the detection of adenovirus; Chlamydophila pneu-
fluffy opacity with or without air bronchograms), moniae; coronaviruses 229E, HKU1, NL63, and
other infiltrate (linear and patchy alveolar or inter- OC43; human metapneumovirus (HMPV); human
stitial densities), or pleural effusion.14 Enrolled rhinovirus; influenza A and B viruses; Mycoplasma
children who did not meet these criteria were ex- pneumoniae; parainfluenza virus types 1, 2, and 3;
cluded from the final analyses. and respiratory syncytial virus (RSV).20-24 Quality-
assurance and monitoring protocols were used
CONTROLS to maintain standardization among the study
From February 1, 2011, to June 30, 2012, a con- sites.25,26 Serologic testing for adenovirus, HMPV,
venience sample of asymptomatic children young- influenza A and B viruses, parainfluenza virus-
er than 18 years of age without pneumonia was es, and RSV was performed at the CDC on avail-
enrolled weekly. Nasopharyngeal and oropharyn- able paired acute-phase and convalescent-phase
geal swabs were obtained to evaluate the preva- serum specimens (see the Supplementary Ap-
lence of respiratory pathogens among asymptom- pendix).27-32
atic children. Eligible controls were undergoing
outpatient same-day elective surgery at a study PATHOGEN DETECTION
hospital, resided in the study catchment area in A bacterial pathogen was determined to be pres-
Nashville or Salt Lake City, and were willing to be
ent if H. influenzae or other gram-negative bacte-
interviewed. Written informed consent was ob- ria, S. aureus, S. anginosus, S. mitis, S. pneumoniae, or
tained from parents or caregivers, with children S. pyogenes was detected in blood, endotracheal
providing assent when age appropriate. Exclusion aspirate, bronchoalveolar-lavage specimen, or
criteria were the same as for the children with pleural fluid by means of culture or in whole
pneumonia; controls were also excluded if they blood or pleural fluid by means of PCR assay; or
had fever or respiratory symptoms within 14 days if C. pneumoniae or M. pneumoniae was detected in
before or after enrollment (on the basis of infor-a nasopharyngeal or oropharyngeal swab by means
mation obtained during a telephone interview), of PCR assay. Other bacteria were considered to
had received live attenuated influenza vaccine be contaminants unless they met specific criteria
within 7 days before enrollment, or were under- (see the Supplementary Appendix).
going otolaryngologic surgery. A viral pathogen was determined to be pres-
ent if adenovirus, coronavirus, HMPV, human
LABORATORY TESTING rhinovirus, influenza, parainfluenza virus, or
Grams staining and bacterial culture were per- RSV was detected in a nasopharyngeal or oro-
formed on blood samples, pleural-fluid specimens, pharyngeal swab by means of PCR assay or if an
endotracheal aspirates, and bronchoalveolar- agent-specific antibody titer was increased by a

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 The n e w e ng l a n d j o u r na l of m e dic i n e

factor of 4 or more between the acute-phase se- to June 30, 2012. For the calculation of incidence
rum specimen and the convalescent-phase serum rates, the number of enrolled children with ra-
specimen for all viruses except human rhinovi- diographic evidence of pneumonia was adjusted,
rus and coronaviruses. The determination of according to age group, for the proportion of eli-
serologic findings for influenza accounted for gible children enrolled at each study site and the
influenza-vaccination status and timing (see the proportion of admissions of children for pneu-
Supplementary Appendix).32 Co-detection was de- monia to study hospitals in the catchment area
fined as the detection of two or more bacterial (market share), and the adjusted number was
or viral pathogens in any combination. then divided by the U.S. Census population esti-
mates in the catchment area for the correspond-
STATISTICAL ANALYSIS ing year.33 Market share was based on discharge-
Annual incidence rates were calculated from July diagnosis codes (see the Supplementary Appendix).
1, 2010, to June 30, 2011, and from July 1, 2011, We calculated pathogen-specific rates for
pathogens detected in more than 1% of the chil-
dren by multiplying the total incidence of pneu-
127,556 Children underwent screening 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-
3803 Were eligible
gens. To calculate 95% confidence intervals, boot-
strap methods with 10,000 samples were used.
1165 (31%) Were not enrolled
870 (75%) Had a parent or caregiver
who declined participation R E SULT S
146 (13%) Were not approached
83 (7%) Did not have a parent or STUDY POPULATION
legal guardian available
66 (6%) Did not speak English, and Of 3803 eligible children, 2638 (69%) were en-
an interpreter was not available rolled. As compared with the enrolled children,
eligible children who were not enrolled were less
2638 (69%) Were enrolled likely to be Hispanic and had a shorter length of
stay in the hospital (Table S1 in the Supplemen-
tary Appendix).
280 (11%) Were excluded from final
analysis
Of the 2638 enrolled children, 2358 (89%) had
10 (4%) Had a parent or caregiver radiographic evidence of pneumonia (Fig. 1). In
who withdrew consent
270 (96%) Did not have radiographic
a review of a 10% random sample of radio-
evidence of pneumonia graphs, interrater agreement among the three
study radiologists was 84% (95% confidence in-
2358 (89%) Had radiographic terval [CI], 81 to 87). The median age of the
evidence of pneumonia
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
2012 (85%) Had radiographic evidence of
pneumonia and were enrolled during the the children were white, 33% were black, 19%
2-yr incidence period (July 2010June 2012) were Hispanic, and 8% were of another race or
ethnic group. A total of 51% of the children had
Figure 1. Screening, Eligibility, and Enrollment of Children with Pneumonia. an underlying condition (with asthma or reactive
A total of 2354 children had chest radiographs that met the radiographic in- airway disease the most common condition). The
clusion criteria of consolidation, infiltrate, or effusion. One child had only a median length of stay in the hospital was 3 days
computed tomographic (CT) scan available that met the criteria for radio-
(interquartile range, 2 to 5). A total of 497 chil-
graphic 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 dren (21%) required intensive care, and 3 (<1%)
pneumonia on the basis of available CT scans. A total of 99% of the radio- died (Table 1, and Table S1 in the Supplementary
graphs were obtained within 48 hours before or after admission. Appendix).
Among children with information on vaccina-

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 Pneumonia Requiring Hospitalization among U.S. Children

tion status, 612 of 2053 children (30%) who were

Table 1. Characteristics of Children with Community-Acquired Pneumonia
6 months of age or older had received one or Requiring Hospitalization.
more doses of influenza vaccine for the concur-
rent season and 1101 of 1272 children (87%) 19 Children with Radiographic
Evidence of Pneumonia
months to 12 years of age had received three or Characteristic (N=2358)
more doses of pneumococcal conjugate vaccine Age group no. (%)
(Table S1 in the Supplementary Appendix). Anti-
<2 yr 1055 (45)
biotic agents had been prescribed for 18% of the
children within 5 days before hospitalization; 24 yr 595 (25)
88% of the children received antibiotics during 59 yr 422 (18)
hospitalization. 1017 yr 286 (12)
Symptom no. (%)
DETECTION OF PATHOGENS
Cough 2230 (95)
A nasopharyngeal or oropharyngeal swab was
Fever or feverish feeling 2155 (91)
obtained from 2254 of the 2358 children with
Anorexia 1766 (75)
radiographic evidence of pneumonia (96%), blood
for culture from 2143 (91%), whole blood for PCR Dyspnea 1657 (70)
assays from 2063 (87%), paired serum specimens Any underlying condition no. (%)* 1197 (51)
from 1028 (44%), pleural fluid from 86 (4%), a Asthma or reactive airway disease no. (%) 779 (33)
bronchoalveolar-lavage specimen from 23 (1%), Preterm birth among children <2 yr 218/1055 (21)
and an endotracheal aspirate from 22 (1%). no./total no. (%)
Among children for whom there was known tim- Radiographic finding no. (%)
ing of antibiotic dosing and specimen collection, Consolidation 1376 (58)
82% of 2107 blood cultures and 47% of 2022
Alveolar or interstitial infiltrate 1195 (51)
whole-blood samples for PCR assay were collect-
Pleural effusion 314 (13)
ed before the inpatient administration of anti
biotics. Hospitalization
For the calculation of the proportions of spe- Length of stay days
cific pathogens, data were included from only Median 3
the 2222 children (94%) with radiographic evi- Interquartile range 25
dence of pneumonia who had blood, pleural Intensive care unit admission no. (%) 497 (21)
fluid, endotracheal aspirate, or a bronchoalveo-
Invasive mechanical ventilation no. (%) 166 (7)
lar-lavage specimen available and who also had a
Death in the hospital no. (%) 3 (<1)
nasopharyngeal or oropharyngeal swab or paired
serum specimens available. A pathogen was de- * Any underlying medical condition included asthma or reactive airway disease,
tected in 1802 of the 2222 children (81%): one or chromosomal disorders including Downs syndrome, chronic kidney disease,
more viruses in 1472 (66%), one or more bacteria chronic liver disease, congenital heart disease, diabetes mellitus, immuno
suppression (due to chronic condition or long-term use of medication, cancer
in 175 (8%), and both bacterial and viral patho- [excluding skin cancer], or human immunodeficiency virus infection with a CD4
gens in 155 (7%). The most commonly detected cell count of >200 per cubic millimeter), neurologic disorder (including seizure
pathogens were RSV (in 28% of the children), disorder, cerebral palsy, and scoliosis), preterm birth (defined as a gestational
age of <37 weeks at birth for children <2 years of age at the time of hospital-
human rhinovirus (in 27%), HMPV (in 13%), ization), and splenectomy. Additional details regarding the prevalence of spe-
adenovirus (in 11%), M. pneumoniae (in 8%), para- cific conditions are provided in Table S1 in the Supplementary Appendix.
influenza virus (in 7%), influenza virus (in 7%), Findings were not mutually exclusive and therefore do not sum to 100%. Only
six children had pleural effusion alone.
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- of age or older than in younger children (19% vs.
dix). RSV was detected more commonly in chil- 3%) (Table S4 in the Supplementary Appendix).
dren younger than 5 years of age than in older
children (37% vs. 8%), as were adenovirus (15% SEASONALITY
vs. 3%) and HMPV (15% vs. 8%). M. pneumoniae Pneumonia peaked in the fall and winter. The
was detected more commonly in children 5 years detection of RSV, influenza, HMPV, and S. pneu-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A Detection of Bacterial and Viral Pathogens Figure 2. Pathogens Detected in U.S. Children
with Community-Acquired Pneumonia Requiring
100
Hospitalization.
90
Panel A shows the proportion of pathogen types de-
80 tected from January 1, 2010, through June 30, 2012,
70 No pathogen among 2222 hospitalized children with radiographic
evidence of pneumonia who had blood samples or
Patients (%)

60 Bacterial
pathogen pleural fluid available for bacterial culture or real-time
50 only polymerase-chain-reaction (PCR) assays or endotra-
40 Bacterialviral cheal aspirate or bronchoalveolar-lavage specimens
co-detection available for bacterial culture and who also had naso-
30
Viralviral pharyngeal or oropharyngeal swabs available for viral
20 co-detection
and atypical bacterial PCR assay or available viral sero-
10 One viral logic results. A total of 4 patients had more than one
pathogen only
0 bacterial pathogen without a virus detected. Panel B
017 <2 24 59 1017 shows the numbers (above the bars) and percentages
(N=2222) (N=980) (N=559) (N=408) (N=275)
of all children in whom a specific pathogen was detect-
Age Group (yr) ed. Among 2222 patients who had available tests for
the detection of bacterial and viral pathogens, 1802
B Specific Pathogens Detected were found to have a viral or bacterial pathogen (or both).
Because more than 1 pathogen could be detected in a
30 622 606 patient, there were a total of 2533 pathogens detected.
Patients with a Positive Result (%)

A total of 88 pathogens other than those listed here

25
were detected in 81 children, including Staphylococcus
aureus (in 22 children, of whom 17 had methicillin-re-
20
sistant S. aureus and 5 had methicillin-susceptible
S. aureus), Streptococcus pyogenes (in 16), viridans
15 streptococci (in 14), Chlamydophila pneumoniae (in 12),
285
248 Haemophilus influenzae (in 9), other gram-negative
10 bacteria (in 9), other streptococcus species (in 4), and
178
151 149 histoplasma (in 2). Darker shading in the bar graph in
110
5 79 81 Panel B indicates that only the single pathogen was de-
tected, and lighter shading indicates the pathogen was
0 detected in combination with at least one other patho-
gen. AdV denotes adenovirus, CoV coronavirus, Flu in-
e
e

er
V

RV

PV

ia
ia

Fl

th
RS

Ad

PI

Co

on
on
M
H

fluenza A or B virus, HMPV human metapneumovirus,

O
m
um
H

eu

HRV human rhinovirus, PIV parainfluenza virus, and

ne

pn
.p

S.
M

RSV respiratory syncytial virus. Panel C shows the pro-

Pathogen Detected portions of pathogens detected, according to age group.

C Detection According to Age Group

<2 Yr 24 Yr
(N=862) (N=467) moniae increased during the winter, whereas hu-
man rhinovirus was detected year-round (Fig. 3).
The detection of M. pneumoniae rose steadily from
RSV the summer through the fall of 2011 and peaked
HRV that winter.
HMPV
AdV CONTROLS
M. pneumoniae Of 726 controls, 125 (17%) could not be reached
59 Yr 1017 Yr PIV
(N=294)
for follow-up, and 80 (11%) had fever or respira-
(N=181) Flu
tory symptoms after surgery; these children were
CoV
S. pneumoniae
excluded from the analyses. Among 521 remain-
Other
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

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 B
A
Pathogens Detected (no.) Pathogens Detected (no.)
Ja Ja

0
5
10
15
20
25
30
0
10
20
30
40
50
60
70
80
90
n. n.
Fe 20 Fe 20
M b. 2 10 M b. 2 10
ar 0 ar 0
ch 10 ch 10
Ap 20 Ap 20
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ay 11 ay 11

Requiring Hospitalization, January 1, 2010, through June 30, 2012.

Ju 20 Ju 20
ne 11 ne 11
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ly 1 ly 1
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g. 11 g. 11
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pt 11 pt 11
. .
O 20 O 20

The New England Journal of Medicine

n engl j med 372;9nejm.orgfebruary 26, 2015
ct 11 ct 11
N . 20 N . 20
ov 1 ov 1
1 1
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n. 1 n. 1
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Copyright 2015 Massachusetts Medical Society. All rights reserved.

M b. 2 12 M b. 2 12
Pneumonia Requiring Hospitalization among U.S. Children

ar 0 ar 0
RSV

ch 12 ch 12
HMPV

Coronavirus

Ap 20 Ap 20
S. pneumoniae

ril 12 ril 12
M. pneumoniae
Adenovirus

M 20 M 20
ay 12 ay 12
Parainfluenza virus

Ju 20 Ju 20
ne 12 ne 12
Human rhinovirus

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20 20
Influenza A or B virus

12 12

Figure 3. Pathogens Detected, According to Month and Year, in U.S. Children with Community-Acquired Pneumonia

841
 The n e w e ng l a n d j o u r na l of m e dic i n e

period. All the other pathogens were detected in

Table 2. Estimated Annual Incidence Rates of Hospitalization for Community-
Acquired Pneumonia, According to Year of Study, Study Site, Age Group, 3% or less of controls.
and Pathogen Detected.*
OVERALL AND PATHOGEN-SPECIFIC INCIDENCE
Incidence of Pneumonia-Related
Variable Hospitalization (95% CI) Among 2358 children with radiographic evidence
of pneumonia, 2012 (85%) were enrolled between
no. of cases per 10,000 children per year
July 1, 2010, and June 30, 2012. The annual inci-
Year of study
dence of hospitalization for pneumonia was 15.7
Yr 1 and 2 15.7 (14.916.5) cases per 10,000 children (95% CI, 14.9 to 16.5)
Yr 1 16.8 (15.618.0) (Table 2). The incidence was highest among chil-
Yr 2 14.6 (13.515.7) dren younger than 2 years of age (62.2 cases per
Study site 10,000 children; 95% CI, 57.6 to 67.1), decreased
Memphis 19.6 (18.021.3)
among those 2 to 4 years of age (23.8 cases per
10,000 children; 95% CI, 21.4 to 26.3), and de-
Nashville 12.3 (11.213.4)
creased further with increasing age. The inci-
Salt Lake City 15.2 (13.816.5) dences of RSV, human rhinovirus, HMPV, adeno-
Age group virus, influenza, parainfluenza virus, coronavirus,
<2 yr 62.2 (57.667.1) and S. pneumoniae were higher among children
24 yr 23.8 (21.426.3) younger than 5 years of age than among older
59 yr 10.1 (8.911.3) children but were highest among children young-
er than 2 years of age (Table S6 in the Supple-
1017 yr 4.2 (3.64.8)
mentary Appendix). The incidence of M. pneu-
Pathogen detected
moniae was similar across age groups.
Respiratory syncytial virus 4.6 (4.35.1)
Human rhinovirus 4.1 (3.74.4) DISCUSSION
Human metapneumovirus 1.9 (1.62.1)
Adenovirus 1.6 (1.41.8) The multicenter EPIC study was a prospective,
Mycoplasma pneumoniae 1.4 (1.21.6)
population-based study of community-acquired
pneumonia among children in the United States.
Influenza A or B virus 1.1 (0.91.3)
We found that the burden of pneumonia-related
Parainfluenza virus 0.9 (0.81.1) hospitalization was highest among children
Coronavirus 0.8 (0.71.0) younger than 5 years of age. Diagnostic testing
Streptococcus pneumoniae 0.5 (0.40.6) for multiple pathogens revealed a pathogen in
81% of the children with pneumonia; a viral
* Analyses were based on 2,212,327 person-years of observation. pathogen was detected in 73% of the children,
Annual incidence rates were calculated from July 1, 2010, to June 30, 2011, for
year 1 and from July 1, 2011, to June 30, 2012, for year 2 and represent data and a bacterial pathogen in 15%.
from the 2012 children who had radiographic evidence of pneumonia and The annual incidence of hospitalization for
were enrolled during that time. community-acquired pneumonia that was esti-
Pathogen-specific incidence was calculated for the 1899 children who had ra-
diographic evidence of pneumonia during the incidence period and who had mated from the combined data from our three
at least one specimen available for both bacterial and viral testing. Pathogen- study hospitals was 15.7 cases per 10,000 chil-
specific incidence according to age is provided in Table S6 in the Supplemen dren younger than 18 years of age. The rate of
tary Appendix.
pneumonia-related hospitalization as estimated
with the use of the 2009 national Kids Inpatient
the same period at the same study sites were Database was 22.5 cases per 10,000 children
younger than the controls; 42% were younger younger than 18 years of age,3 which is similar
than 2 years of age, 25% were 2 to 4 years of age, to, but higher than, our rate. This difference
19% were 5 to 9 years of age, and 13% were 10 to might be attributed to the year of analysis, dif-
17 years of age. After adjustment for age, human ferences in the populations studied, and the
rhinovirus was detected in 17% of the controls, strict criteria of the EPIC study that included
as compared with 22% of the children with ra- standardized clinical and radiologic definitions
diographic evidence of pneumonia who were en- of pneumonia and excluded recently hospitalized
rolled at the same study sites during the same or severely immunosuppressed children. Studies

842 n engl j med 372;9nejm.orgfebruary 26, 2015

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 Pneumonia Requiring Hospitalization among U.S. Children
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-
n engl j med 372;9nejm.orgfebruary 26, 2015
The New England Journal of Medicine
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Copyright 2015 Massachusetts Medical Society. All rights reserved.
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,
843
 The n e w e ng l a n d j o u r na l of m e dic i n e

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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