Community Acquired Pneumonia

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

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.)
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 Vanderbilt (D.J.W., K.M.E.), and Vanderbilt Vaccine Research Program (D.J.W., K.M.E.),
Nashville, and Le Bonheur Childrens 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 Childrens 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 bwc8@
cdc.gov.
Drs. Williams, Arnold, and Ampofo contributed equally to this article.
* 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.
N Engl J Med 2015;372:835-45.
DOI: 10.1056/NEJMoa1405870
Copyright 2015 Massachusetts Medical Society.
n engl j med 372;9nejm.orgfebruary 26, 2015
The New England Journal of Medicine

Downloaded from nejm.org on July 31, 2016. For personal use only. No other uses without permission.
Copyright 2015 Massachusetts Medical Society. All rights reserved.
835
The
neumonia 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 communityacquired pneumonia requiring hospitalization
among U.S. children.
ME THODS
836
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 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%).
ACTIVE POPULATION-BASED SURVEILLANCE
DATA AND SPECIMEN COLLECTION
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 Hospital 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 assent when age appropriate. The study protocol
Trained staff obtained blood samples, acutephase 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

Pneumonia Requiring Hospitalization among U.S. Children
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.
lavage specimens at each study site with the use

of standard techniques. Only high-quality endotracheal aspirates and quantified bronchoalveolarlavage 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 Qualityassurance 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
LABORATORY TESTING
rhinovirus, influenza, parainfluenza virus, or
Grams staining and bacterial culture were per- RSV was detected in a nasopharyngeal or oroformed 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

837
The
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m e dic i n e
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.
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 correspondSTATISTICAL ANALYSIS
ing year.33 Market share was based on dischargeAnnual 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 children by multiplying the total incidence of pneumonia by the proportion of each pathogen de127,556 Children underwent screening
tected among children with radiographic evidence
of pneumonia who had specimens available for
the detection of both bacterial and viral patho3803 Were eligible
gens. To calculate 95% confidence intervals, bootstrap methods with 10,000 samples were used.
1165 (31%) Were not enrolled
870 (75%) Had a parent or caregiver
who declined participation
146 (13%) Were not approached
83 (7%) Did not have a parent or
legal guardian available
66 (6%) Did not speak English, and
an interpreter was not available
2638 (69%) Were enrolled
280 (11%) Were excluded from final

analysis
10 (4%) Had a parent or caregiver
who withdrew consent
270 (96%) Did not have radiographic
evidence of pneumonia
2358 (89%) Had radiographic
evidence of pneumonia
2012 (85%) Had radiographic evidence of

pneumonia and were enrolled during the
2-yr incidence period (July 2010June 2012)
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.
838
R E SULT S
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).
Of the 2638 enrolled children, 2358 (89%) had
radiographic evidence of pneumonia (Fig. 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 vaccina-

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

Requiring Hospitalization.
Characteristic
Children with Radiographic

Evidence of Pneumonia
(N=2358)
Age group no. (%)

<2 yr
1055 (45)
24 yr
595 (25)
59 yr
422 (18)
1017 yr
286 (12)
Symptom no. (%)
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 anti
biotics.
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%) (Fig. 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
Cough
2230 (95)
Fever or feverish feeling
2155 (91)
Anorexia
1766 (75)
Dyspnea
1657 (70)
Any underlying condition no. (%)*
1197 (51)
Asthma or reactive airway disease no. (%)

Preterm birth among children <2 yr
no./total no. (%)
779 (33)
218/1055 (21)
Radiographic finding no. (%)

Consolidation
1376 (58)
Alveolar or interstitial infiltrate
1195 (51)
Pleural effusion
314 (13)
Hospitalization
Length of stay days
Median
Interquartile range
3
25
Intensive care unit admission no. (%)
497 (21)
Invasive mechanical ventilation no. (%)
166 (7)
Death in the hospital no. (%)
3 (<1)
* Any underlying medical condition included asthma or reactive airway disease,

chromosomal disorders including Downs syndrome, chronic kidney disease,
chronic liver disease, congenital heart disease, diabetes mellitus, immuno
suppression (due to chronic condition or long-term use of medication, cancer
[excluding skin cancer], or human immunodeficiency virus infection with a CD4
cell count of >200 per cubic millimeter), neurologic disorder (including seizure
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 hospitalization), and splenectomy. Additional details regarding the prevalence of specific conditions are provided in Table S1 in the Supplementary Appendix.
Findings were not mutually exclusive and therefore do not sum to 100%. Only
six children had pleural effusion alone.
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-

839
The
100
90
Patients (%)
80
No pathogen
60
Bacterial
pathogen
only
50
40
Bacterialviral
co-detection
30
Viralviral
co-detection
20
One viral
pathogen only
10
0
017
<2
24
59
1017
(N=2222) (N=980) (N=559) (N=408) (N=275)
Age Group (yr)
B Specific Pathogens Detected

Patients with a Positive Result (%)
30
622
606
25
20
15
285
10
248
178
151
149
110
79
81
th
er
e
on
m
S.
.p
pn
ne
eu
ia
V
Co
u
Fl
PI
on
e
ia
V
Ad
um
PV
M
H
RV
0
RS
m e dic i n e
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.
A Detection of Bacterial and Viral Pathogens
70
of
Pathogen Detected
C Detection According to Age Group

<2 Yr
(N=862)
24 Yr
moniae increased during the winter, whereas human 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.
(N=467)
RSV
HRV
HMPV
59 Yr
(N=294)
1017 Yr
(N=181)
AdV
CONTROLS
M. pneumoniae
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
PIV
Flu
CoV
S. pneumoniae
Other
840
n engl j med 372;9
nejm.org
february 26, 2015

Ja
n.
Fe 20
M b. 2 10
ar 0
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.
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.
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.
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n. 1
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20
12
Pathogens Detected (no.)

Ja
n.
Fe 20
M b. 2 10
ar 0
ch 10
Ap 20
ril 10
M 20
ay 10
Ju 20
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Ju 201
ly 0
Au 20
g. 10
Se 20
pt 10
.
O 20
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ov 1
0
D . 20
ec 10
.
Ja 201
n. 0
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ar 0
ch 11
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ril 11
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ly 1
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g. 11
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pt 11
.
O 20
ct 11
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1
D . 20
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.
Ja 201
n. 1
Fe 20
M b. 2 12
ar 0
ch 12
Ap 20
ril 12
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ay 12
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20
12
Pathogens Detected (no.)
A
90
RSV
80
Human rhinovirus
HMPV
70
Adenovirus
Influenza A or B virus
60
50
40
30
20
10
B
30
25
M. pneumoniae
Parainfluenza virus
Coronavirus
S. pneumoniae
20
15
10
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.

841
The
Table 2. Estimated Annual Incidence Rates of Hospitalization for CommunityAcquired Pneumonia, According to Year of Study, Study Site, Age Group,
and Pathogen Detected.*
Incidence of Pneumonia-Related
Hospitalization (95% CI)
Variable
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
<2 yr
62.2 (57.667.1)
24 yr
23.8 (21.426.3)
59 yr
10.1 (8.911.3)
1017 yr
4.2 (3.64.8)
Pathogen detected
Respiratory syncytial virus
4.6 (4.35.1)
Human rhinovirus
4.1 (3.74.4)
Human metapneumovirus
1.9 (1.62.1)
Adenovirus
1.6 (1.41.8)
Mycoplasma pneumoniae
1.4 (1.21.6)
Influenza A or B virus
1.1 (0.91.3)
Parainfluenza virus
0.9 (0.81.1)
Coronavirus
0.8 (0.71.0)
Streptococcus pneumoniae
0.5 (0.40.6)
* Analyses were based on 2,212,327 person-years of observation.

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
from the 2012 children who had radiographic evidence of pneumonia and
were enrolled during that time.
Pathogen-specific incidence was calculated for the 1899 children who had radiographic evidence of pneumonia during the incidence period and who had
at least one specimen available for both bacterial and viral testing. Pathogenspecific incidence according to age is provided in Table S6 in the Supplemen
tary Appendix.
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
842
of
m e dic i n e
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 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 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 detection 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 stateof-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,

843
The
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 assoREFERENCES
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Copyright 2015 Massachusetts Medical Society.
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Community Acquired Pneumonia

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Community Acquired Pneumonia

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The

Community-Acquired Pneumonia Requiring

Incidence estimates of hospitalizations for community-acquired pneumonia among

The burden of hospitalization for children with community-acquired pneumonia

From the Centers for Disease Control and

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

The New England Journal of Medicine

neumonia is a leading cause of hospitalization among children in the United

was approved by the institutional review board at

ACTIVE POPULATION-BASED SURVEILLANCE

DATA AND SPECIMEN COLLECTION

From January 1, 2010, to June 30, 2012, children

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

The New England Journal of Medicine

Pneumonia Requiring Hospitalization among U.S. Children

were interviewed with the use of a standardized

lavage specimens at each study site with the use

The New England Journal of Medicine

to June 30, 2012. For the calculation of incidence

2638 (69%) Were enrolled

280 (11%) Were excluded from final

2012 (85%) Had radiographic evidence of

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

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

The New England Journal of Medicine

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

Children with Radiographic

Age group no. (%)

Symptom no. (%)

A nasopharyngeal or oropharyngeal swab was

Fever or feverish feeling

Any underlying condition no. (%)*

Asthma or reactive airway disease no. (%)

Radiographic finding no. (%)

Alveolar or interstitial infiltrate

Intensive care unit admission no. (%)

Invasive mechanical ventilation no. (%)

Death in the hospital no. (%)

* Any underlying medical condition included asthma or reactive airway disease,

of age or older than in younger children (19% vs.

Pneumonia peaked in the fall and winter. The

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

The New England Journal of Medicine

Age Group (yr)

B Specific Pathogens Detected

Figure 2. Pathogens Detected in U.S. Children

A Detection of Bacterial and Viral Pathogens

C Detection According to Age Group

Of 726 controls, 125 (17%) could not be reached

n engl j med 372;9

february 26, 2015

The New England Journal of Medicine

Pathogens Detected (no.)

Pathogens Detected (no.)

Pneumonia Requiring Hospitalization among U.S. Children

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

The New England Journal of Medicine

no. of cases per 10,000 children per year

Salt Lake City

* Analyses were based on 2,212,327 person-years of observation.

the same period at the same study sites were