Community-Acquired Pneumonia Requiring Hospitalization Among U.S. Adults

8/18/2019 Community-Acquired Pneumonia Requiring Hospitalization Among U.S. Adults

1/13


2/13

n engl j med 373;5 nejm.org July 30, 2015416

T h e n e w e n g l a n d j o u r n a l o f medicine

Pneumonia is a leading infectious

cause of hospitalization and death amongadults in the United States,1,2 with medical

costs exceeding $10 billion in 2011.3 Routine ad-ministration of the pneumococcal conjugate vac-cine in children has resulted in an overall reductionin the rate of invasive disease and pneumonia

among adults, owing to herd immunity.4-8 The lastU.S. population–based incidence estimates ofhospitalization due to community-acquired pneu-monia were made in the 1990s,9 before the avail-ability of the pneumococcal conjugate vaccine andmore sensitive molecular and antigen-based labo-ratory diagnostic tests. Thus, contemporary pop-ulation-based etiologic studies involving U.S. adults with pneumonia are needed.10-13

The Centers for Disease Control and Prevention(CDC) Etiology of Pneumonia in the Community(EPIC) study was a prospective, multicenter, pop-ulation-based, active surveillance study. Radio-graphic confirmation and extensive diagnosticmethods were used to determine the incidence andmicrobiologic causes of community-acquiredpneumonia requiring hospitalization among U.S.adults.

Methods

Active Population-Based Surveillance

From January 1, 2010, to June 30, 2012, adults 18

years of age or older were enrolled at three hos-pitals in Chicago (John H. Stroger, Jr., Hospitalof Cook County, Northwestern Memorial Hospi-tal, and Rush University Medical Center) and attwo in Nashville (University of Tennessee HealthScience Center–Saint Thomas Health and Vander-bilt University Medical Center). We sought toenroll all eligible adults; therefore, trained staffscreened adults for enrollment at least 18 hoursper day, 7 days per week. Written informed con-sent was obtained from all the patients or theircaregivers before enrollment. The study protocol

was approved by the institutional review boardat each participating institution and at the CDC.Weekly teleconferences, enrollment reports, dataaudits, and annual study-site visits were con-ducted to ensure uniform procedures among thestudy sites. Patients or their caregivers provideddemographic and epidemiologic data, and medi-cal charts were abstracted for clinical data. All theauthors vouch for the accuracy and completenessof the data and analyses reported and for the

fidelity of the study to the protocol. All the au-thors made the decision to submit the manuscriptfor publication.

Adults were eligible for enrollment if they were admitted to a study hospital on the basis ofa clinical assessment by the treating clinician;resided in the study catchment area (see the Sup-

plementary Appendix, available with the full textof this article at NEJM.org); had evidence ofacute infection, defined as reported fever orchills, documented fever or hypothermia, leuko-cytosis or leukopenia, or new altered mental sta-tus; had evidence of an acute respiratory illness,defined as new cough or sputum production,chest pain, dyspnea, tachypnea, abnormal lungexamination, or respiratory failure; and had evi-dence consistent with pneumonia as assessed bymeans of chest radiography by the clinical team within 48 hours before or after admission.

Patients were excluded if they had been hos-pitalized recently (


3/13

n engl j med 373;5 nejm.org July 30, 2015 417

Pneumonia Requir ing Hospitalization among U.S. Adults

asked to return 3 to 10 weeks after enrollment forconvalescent-phase serum collection.

Radiographic Confirmation

Initial enrollment was based on the clinical inter-pretation of chest radiographs that were ob-tained at admission. Inclusion in the final study

analyses required independent confirmation bya board-certified chest radiologist who reviewedall the chest radiographs and computed tomo-graphic scans obtained within 48 hours beforeor after admission; these radiologists, who arecoauthors of the study, were unaware of the clini-cal data. Radiographic evidence of pneumonia wasdefined as the presence of consolidation (a denseor fluffy opacity with or without air broncho-grams), other infiltrate (linear and patchy alveolaror interstitial densities), or pleural effusion.5,15,16

Controls

From November 1, 2011, to June 30, 2012, a con- venience sample of asymptomatic adults from theNashville study catchment area who presentedfor nonacute care to a general medicine clinic atVanderbilt University Medical Center was enrolled weekly. Nasopharyngeal and oropharyngeal swabs were obtained to assess the prevalence of respi-ratory pathogens among asymptomatic adults.Exclusion criteria were the same as those for theadults with pneumonia, except that controls were

also excluded if they had fever or respiratorysymptoms within 14 days before or after enroll-ment (on the basis of information obtained dur-ing a telephone interview) or had received liveattenuated influenza vaccination within 7 daysbefore enrollment.

Laboratory Testing

Bacterial culture was performed, with the use ofstandard techniques, on blood samples, pleuralfluid, high-quality sputum samples and endotra-cheal aspirates, and quantified bronchoalveolar-

lavage specimens.17,18

A real-time polymerase-chain-reaction (PCR) assay for legionella wasperformed on sputum regardless of the qualityof the sample.19,20 PCR assays targeting Entero-bacteriaceae, Haemophilus influenzae , pseudomonas,Staphylococcus aureus , Streptococcus anginosus , S. mitis ,S. pneumoniae , and S. pyogenes were also performedon pleural fluid.21-23 Urinary antigen testing wasperformed for the detection of Legionella pneumophi-la and S. pneumoniae (BinaxNOW, Alere).20,24

A PCR assay was performed on nasopharyn-geal and oropharyngeal swabs with the use ofCDC-developed methods for the detection of ad-enovirus; Chlamydophila pneumoniae ; coronaviruses229E, HKU1, NL63, and OC43; human metapneu-movirus (HMPV); human rhinovirus; influenzaA and B viruses; Mycoplasma pneumoniae ; parain-

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

CT denotes computed tomography.

2488 (68%) Were enrolled

3634 Were eligible

1146 (32%) Were not enrolled795 (69%) Declined to participate152 (13%) Were not approached108 (9%) Were not able to provide

informed consent, and asurrogate was not available

91 (8%) Did not speak English, andan interpreter was not available

168 (7%) Were excluded from finalanalysis

161 (96%) Did not have radiographicevidence of pneumonia7 (4%) Withdrew consent

100,050 Adults underwent screening

2320 (93%) Had radiographic evidenceof pneumonia

2241 (97%) Had chest radiographs thatmet final radiographic inclusioncriteria of consolidation, infiltrate,or effusion

71 (3%) Had a chest radiograph com-pleted that did not meet the criteriafor radiographic evidence of pneumonia, but had CT scans thatmet the criteria

8 (


4/13


5/13



was detected in a nasopharyngeal or oropharyn-geal swab by means of PCR assay or if a patho-gen-specific antibody titer was increased by afactor 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. Fungal or mycobacterialdetections were determined according to clinicalguidelines (see the Supplementary Appendix).

Statistical Analysis

Annual incidence rates were calculated from July1, 2010, to June 30, 2011, and from July 1, 2011,to June 30, 2012. The number of enrolled adults with radiographic evidence of pneumonia was

adjusted, according to age group, for the propor-tion of eligible adults enrolled at each study siteand for the estimated proportion of admissionsof adults for pneumonia to study hospitals in thecatchment area (i.e., the market share, which was

based on discharge-diagnosis codes). The adjustednumber was then divided by the U.S. Census popu-lation estimates in the catchment area for thecorresponding year (see the Supplementary Ap-pendix).33

We calculated pathogen-specific incidencerates by multiplying the total incidence of pneu-monia by the proportion of each pathogen de-tected among adults with radiographic evidenceof pneumonia who had samples available for the

Characteristic

Adults with Radiographic Evidence of Pneumonia

(N = 2320)

Pneumonia severity index∥

Median 76

Interquartile range 52–103

Risk class — no. (%)

1–3 1510 (65)

4 606 (26)

5 204 (9)

* Race and ethnic group were self-reported.† Data were missing for three patients.‡ Any underlying medical condition included chronic lung disease (asthma, chronic obstructive pulmonary disease, or

obstructive sleep apnea), chronic heart disease (i.e., coronary artery disease or congestive heart failure, but not hyper-tension), immunosuppression (either due to chronic condition or medication, cancer [but not skin cancer], or humanimmunodeficiency virus [HIV] infection with a CD4 cell count of >200 per cubic millimeter), diabetes mellitus, chronickidney disease (with or without dialysis), neurologic disorders (epilepsy, cerebral palsy, dementia, or history of stroke),

chronic liver disease (hepatitis, cirrhosis, or hepatic failure), and splenectomy. The specific conditions that affected atleast 25% of patients are l isted here. Among the 685 patients with immunosuppression, 416 had nondermatologic can-cer (but did not have neutropenia), 381 had immunosuppression due to a chronic condition or a medication, and 68had HIV infection with a CD4 cell count of more than 200 per cubic millimeter. The groups were not mutually exclusive.

§ Data were based on verified vaccine information and not self-report. For influenza vaccine, the season was defined asSeptember 1 through August 31 of the following year, and the percentage of patients vaccinated was based on the 1898of 2320 adults (82%) for whom information was available. For pneumococcal polysaccharide vaccine, the percentage ofpatients vaccinated was based on 704 of 832 adults (85%) who were 65 years of age or older and had available infor-mation. For both vaccines, patients were considered to be vaccinated if they had received the vaccine at least 2 weeksbefore admission. Outpatient antibiotics were defined as those received within 5 days before admission. Inpatient anti-biotics were defined as those received at any point during the hospitalization.

¶ The categories were not mutually exclusive and therefore do not sum to 100%. Only 23 adults (1%) had pleural effu-sion alone. Among all the patients with pleural effusion, 481 had unilateral pleural effusion, 232 had bilateral pleural ef-fusion, and 1 had unknown status. Among the 853 patients in whom a pathogen was detected, 65% had consolidation,38% had infiltrate, and 26% had pleural effusion. There were radiographic differences between the 530 patients whohad only viruses detected and the 247 who had only bacteria detected with respect to consolidation (59% vs. 73%), in-

filtrate (42% vs. 31%), and pleural effusion (23% vs. 33%).∥ The pneumonia severity index is a clinical prediction rule for mortality related to community-acquired pneumonia that

is based on sex, age, nursing home status, mental status, heart rate, respiratory rate, blood pressure, temperature, se-lected underlying medical conditions, selected laboratory values, and the presence or absence of pleural effusion.34 Theindex is divided into five classes, with higher class indicating greater risk. Class 1 to 3 indicates a low risk of death,class 4 moderate risk, and class 5 high risk.

Table 1. (Continued.)

The New England Journal of Medicine

Downloaded from nejm.org by carlos gonzalez on January 9, 2016. For personal use only. No other uses without permission.

Copyright © 2015 Massachusetts Medical Society. All rights reserved.


6/13



P a t i e n t s w i t h a P o s i t i v e R e s u l t ( % )

9

8

7

6

4

3

1

5

2

0

P a t i e n t s ( n o . )

160

140

120

100

60

40

80

20

0

30

25

20

15

5

0

10

15

10

5

0

H u m a

n r h i n

o v i r u

s

J a n. F e

b.

M a r c

h A p

r i l M a y

J u n e

J u l y

A u g .

S e p t. O c

t. N o

v. D e

c.

I n f l u e

n z a A

o r B

S . p n

e u m o

n i a e

H u m a n

m e t a

p n e u

m o v i r

u s

R e s p i r a t o

r y s y n

c y t i a l

v i r u

s

P a r a i

n f l u e

n z a v

i r u s

C o r o

n a v i r

u s

M y c o p l a

s m a p

n e u m

o n i a e

S . a u

r e u s

A d e n

o v i r u

s

L e g i o n

e l l a p

n e u m

o p h i l

a

E n t e r

o b a c

t e r i a c

e a e

O t h e

r

B

A Specific Pathogens Detected

Pathogens Detected, According to Month and Year

Copathogen

Single pathogen

Pathogen

Detected

2010 2011 2012

J a n. F e

b.

M a r c

h A p

r i l M a y

J u n e

J u l y

A u g .

S e p t. O c

t. N o

v. D e

c. J a n. F e

b.

M a r c

h A p

r i l M a y

J u n e

194

132

115

88

68 67

53

3732 32 31

74

43

Viral pathogen only (22%)

Viral–viral co-detection (2%)

Bacterial–viral co-detection (3%)

Bacterial pathogen only (11%)

Fungal or mycobacterial detection (1%)

No pathogendetected(62%)

Influenza A or B

Human rhinovirus

Respiratory syncytial virus

S. pneumoniae

S. aureus

Human metapneumovirus

All causes of pneumonia





7/13



detection of both bacterial and viral pathogens.

Bootstrap methods with 10,000 samples wereused to calculate 95% confidence intervals.

Results

Study Population

Of 3634 eligible adults, 2488 (68%) were enrolled(Fig. 1). As compared with persons who wereeligible but not enrolled, the enrolled patients were significantly less likely to be 65 years of ageor older and less likely to require invasive me-chanical ventilation; in addition, a smaller propor-

tion of the enrolled patients subsequently died(Table S1 in the Supplementary Appendix).

Of 2488 enrolled patients, 2320 (93%) hadradiographic evidence of pneumonia (Fig. 1).The median age of the patients with radiographicevidence of pneumonia was 57 years (interquar-tile range, 46 to 71) (Table 1), and the medianlength of hospital stay was 3 days (interquartile

range, 2 to 6). A total of 498 patients (21%) re-quired admission to the intensive care unit (ICU),131 (6%) required invasive mechanical ventilation,and 52 (2%) died during hospitalization.

Detection of Pathogens

Nasopharyngeal and oropharyngeal swabs were

obtained from 2272 of the 2320 adults (98%) with radiographic evidence of pneumonia, bloodfor culturing from 2103 (91%), a specimen for uri-nary antigen detection from 1973 (85%), a sputumspecimen from 960 (41%) (of whom 272 had ahigh-quality specimen), paired serum specimensfrom 859 (37%), a bronchoalveolar-lavage speci-men from 84 (4%), a pleural-fluid specimenfrom 78 (3%), and an endotracheal aspirate from4 (


8/13



tary Appendix). A pathogen was detected less fre-quently in nasopharyngeal and oropharyngealswabs obtained from 238 asymptomatic controlsthan in swabs obtained from 192 patients withpneumonia who were enrolled during the sameperiod in the same catchment area (2% vs. 27%,P


9/13



the increased specificity of radiographic confir-mation in our case definition.1,2,6

Despite our efforts to use more sensitive andspecific diagnostic methods than had beenavailable previously,11-13,19-29 pathogens were de-tected in only 38% of adults. Possible reasons forsuch few detections include an inability to ob-tain lower respiratory tract specimens, antibioticuse before specimen collection, insensitive diag-

nostic tests for known pathogens, a lack of test-ing for other recognized pathogens (e.g., coxi-ella), unidentified pathogens, and possiblenoninfectious causes (e.g., aspiration pneumoni-tis).10,13,35,36 We may also have missed precedingmicrobiologic insults that triggered a subse-quent hospitalization for pneumonia. Neverthe-less, our pathogen-detection yield is within therange (20 to 76%) of the yield in other etiologic

Figure 3. Estimated Annual Pathogen-Specific Incidence Rates of Community-Acquired Pneumonia Requiring Hospitalization,

According to Age Group.

Circles indicate the annual number of hospitalizations for pneumonia per 10,000 adults, and the horizontal lines 95% confidence inter-

vals. Rates are based on 10,511,911 person-years of observation. Note the differences in the scale of the x axis for the groups of pa-tients 65 to 79 years of age and 80 years of age or older, as compared with the groups of patients 18 to 49 years of age and 50 to 64

years of age.

Adenovirus

M. pneumoniae

Coronavirus

Respiratory

syncytial virusParainfluenza

virus

Human meta-pneumovirus

Influenza A or B

L. pneumophila

S. aureus

S. pneumoniae

Humanrhinovirus

0.0 0.5 1.0 1.5 2.0 2.5

Incidence per 10,000 Persons

C Persons 65–79 Yr of Age D Persons ≥80 Yr of Age

A Persons 18–49 Yr of AgeAdenovirus

M. pneumoniae

Coronavirus

Respiratorysyncytial virus

Parainfluenzavirus


Influenza A or B

L. pneumophila

S. aureus

S. pneumoniae

Humanrhinovirus

0.0 0.5 1.0 1.5 2.0 2.5


B Persons 50–64 Yr of Age

Adenovirus

M. pneumoniae

Coronavirus


Parainfluenzavirus


Influenza A or B

L. pneumophila

S. aureus

S. pneumoniae

Humanrhinovirus

0 5 10 15 20


Adenovirus

M. pneumoniae

Coronavirus


Parainfluenzavirus


Influenza A or B

L. pneumophila

S. aureus

S. pneumoniae

Humanrhinovirus

0 5 10 15 20






10/13



studies of pneumonia in adults, although it iscloser to the lower end of the range9,37-43 andcontrasts with the detection yield in the pediat-ric EPIC study, in which pathogens were detectedin 81% of children who had been hospitalized with community-acquired pneumonia.44 The lowpathogen-detection yield among adults who were

hospitalized for pneumonia highlights the needfor more sensitive diagnostic methods and in-novative discovery of pathogens.45

Viruses were detected in 27% of the patients.Human rhinovirus was the most commonly de-tected virus in patients with pneumonia but wasrarely detected in asymptomatic controls, a f ind-ing similar to that in other studies.37,46 Althoughour understanding of human rhinovirus remainsincomplete, these data suggest a role for humanrhinovirus in adult pneumonia.35,47 Influenza vi-rus was the second most common pathogendetected, despite mild influenza seasons duringthe study.48 The incidence of influenza virus wasalmost twice that of any other pathogen (exceptfor human rhinovirus) among adults 80 years ofage or older, which underscores the need forimprovements in influenza-vaccine uptake andeffectiveness.49

Together, HMPV, RSV, parainfluenza viruses,coronaviruses, and adenovirus were detected in13% of the patients, a proportion similar to thosefound in other PCR-based etiologic studies of

pneumonia in adults (11 to 28%).

11,37-41

Amongadults 80 years of age or older, the incidence ofRSV, parainfluenza virus, and coronavirus each was similar to that of S. pneumoniae . Our studyadds to the growing evidence of the contributionof viruses to hospitalizations of adults, high-lighting the usefulness of molecular methodsfor the detection of respiratory pathogens.35,47,50,51 The lower circulation of respiratory viruses in the2011–2012 season (Fig. 2B), as compared with theprevious year, probably contributed to the lowerincidence of pneumonia in that year and is sup-

ported by national surveillance data.48

Bacterial pathogens were detected in 14% ofthe patients. S. pneumoniae was the most commonlydetected bacterium, with an incidence that wasalmost 5 times as high among adults 65 years ofage or older as among younger adults. Theprevalence of pneumococcal disease of 5% that was observed in our study was lower than the 13%found by Marston et al.9 Although both studiesused sputum culture, our study included only

high-quality sputum specimens for the detectionof non-legionella bacteria, which probably im-proved specificity but decreased sensitivity.17 Bac-terial cultures, especially in the context of antimi-crobial use, are insensitive.13,52 Urinary antigentests for pneumococcus, which were not availablefor the study by Marston et al., were responsible

for the majority (67%) of pneumococcal detec-tions in our study. These tests are more sensitivethan blood culture and improve the detection ofnonbacteremic pneumococcal pathogens with areported sensitivity of 70 to 80% and a specific-ity of more than 90%.9,13,24,52 Moreover, the indi-rect protection of adults as a result of pediatricpneumococcal vaccination in the United Statesprobably contributed to the lower observed inci-dence of pneumococcal infection in our studythan in the study by Marston et al.4-9 Our esti-mates provide an important benchmark to mon-itor the effect of the 2014 vaccination recommen-dations for the 13-valent pneumococcal conjugate vaccine in persons 65 years of age or older.53

M. pneumoniae , L. pneumophila, and C. pneumoniae combined were detected in 4% of the adults. Mar-ston et al. found that these pathogens wereidentified in 10% of patients with definitecases of pneumonia and in 44% of those withpossible cases.9 Although both our study andthat of Marston et al. used urinary antigen testsfor L. pneumophila, the detections of M. pneumoniae

and C. pneumoniae in the study by Marston et al.relied exclusively on serologic testing, whichhas less specificity than the PCR assay used inour study.9,19,20,54-56

Overall S. aureus was detected in 2% of adults— a lower rate than that of S. pneumoniae or vi-ruses. The low prevalences of Enterobacteriaceae(1%) and other gram-negative bacteria were prob-ably due to the exclusion of patients with knownrisk factors for these bacteria (e.g., patients withrecent hospitalization, patients with severe immu-nosuppression, and functionally dependent nurs-

ing home residents), which is consistent with thecontemporary concept of community-acquiredpneumonia.10 S. pneumoniae , S. aureus , and Entero-bacteriaceae were significantly more commonamong severely ill patients, accounting for 16%of the detected pathogens among patients in theICU, as compared with 6% among patients notin the ICU.

This study has limitations. First, we were notable to enroll every eligible patient; patients who





11/13



were 65 years of age or older and those who wereundergoing invasive mechanical ventilation wereless likely to be enrolled; a greater proportion ofnonenrolled patients than of enrolled patientsdied during hospitalization. Although the inci-dence calculations were adjusted for the enroll-ment differences according to age, market share

data on severity were not available and preventedthe calculations of severity-related incidence.

Second, specimens were not obtained frompatients who were not enrolled, and amongthose who were enrolled, not all specimen types were available, which could have led to underes-timation or overestimation of the pathogen-spe-cific rates, including the rates associated withsevere disease and older age. Owing to ethicaland feasibility considerations, invasive proceduresto obtain specimens directly from the lung werenot usually performed, which may have reducedthe microbiologic yield.35 However, 97% of theadults had at least one specimen type availablefor bacterial and viral detection.

Third, the sensitivities and specificities of theavailable diagnostic tests were imperfect. Al-though the majority of blood-culture samples were collected before the administration of anti-biotics, the yield was lower in the samples col-lected after the administration of antibiotics.Thus, despite extensive testing, pathogens mayhave been missed. Moreover, molecular detec-

tion of viruses and atypical bacteria in the naso-pharynx and oropharynx does not necessarilyindicate causation and could represent infectionthat is limited to the upper respiratory tract orconvalescent-phase shedding. Similarly, urinarypneumococcal antigen can be present for weeksafter the onset of pneumococcal pneumonia,and recent pneumococcal vaccination can leadto false positive results.52

Fourth, we were not able to enroll asymptom-atic controls for the entire study period or inboth Chicago and Nashville, so it is possible that

we missed detecting pathogens that were morecommonly circulating at other times or in otherplaces. However, as in other studies,37,40,46 patho-gens were rarely detected among adult asymp-tomatic controls, which suggests that the respi-ratory viruses and atypical bacteria that wereidentified in patients with pneumonia may havecontributed to disease.

Fifth, the clinical and radiographic featuresof pneumonia overlap with those of other syn-

dromes, including chronic lung disease and con-gestive heart failure, such that even strict defini-tions may not accurately distinguish amongthese entities, resulting in potential misclassifi-cation. However, this situation is consistent withthe real-world challenges of diagnosing pneu-monia and of its subsequent management. Fi-

nally, data from our five urban hospitals (threeacademic, one public, and one community), al-though inclusive of diverse communities, may notbe representative of the entire U.S. adult popula-tion or generalizable to other settings, since thecirculation of respiratory pathogens varies ac-cording to geographic region, timing, and otherfactors.

In conclusion, the burden of community-acquired pneumonia requiring hospitalizationamong adults is substantial and is markedlyhigher among the oldest adults. Although patho-gens were not detected in the majority of pa-tients, respiratory viruses were more frequentlydetected than bacteria, which probably reflectsthe direct and indirect benefit of bacterial vac-cines and relatively insensitive diagnostic tests.These data suggest that improving the coverageand effectiveness of recommended influenzaand pneumococcal vaccines and developing ef-fective vaccines and treatments for HMPV, RSV,and parainfluenza virus infection could reducethe burden of pneumonia among adults. Further

development of new rapid diagnostic tests thatcan accurately identify and distinguish amongpotential pneumonia pathogens is needed.45

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

Supported by the Influenza Division of the National Centerfor Immunizations and Respiratory Diseases at the CDCthrough cooperative agreements with each study site. The study was based on a competitive research funding opportunity.

Dr. Self reports receiving fees for serving on an advisory boardfrom BioFire Diagnostics, research supplies from CareFusion,grant support through his institution from bioMérieux, AffiniumPharmaceuticals, Astute Medical, Crucell Holland, Thermo FisherScientific, Pfizer, Rapid Pathogen Screening, Venaxis, and Cem-

pra, and holding a pending patent (13/632,874) related to a sterileblood-culture collection system; Dr. Wunderink, receiving con-sulting fees from Roche, the Medicines Company, Vical, CubistPharmaceuticals, Bayer, Cerexa, and Visterra; Dr. Grijalva, receiv-ing consulting fees from Pfizer; Dr. Anderson, receiving grantsupport through his institution from MedImmune, editorial sup-port for an unrelated study from Roche, and consulting fees fromAbbVie; Dr. Courtney, receiving fees through his institution fromThermo Fisher Scientific; Dr. Chappell, holding a patent (U.S.8,293,498 B2) related to a system for generation of viable reovirusfrom cloned complementary DNA and a pending patent(13/639,564) related to reovirus vaccines and methods of usetherefor; Dr. Arnold, receiving grant support from GlaxoSmith-





12/13



Kline; Dr. Ampofo, receiving fees through his institution fromGlaxoSmithKline and Cubist Pharmaceuticals for the enrollmentof patients in other studies, and collaborating with BioFire Diag-nostics on grants funded by the National Institutes of Health; Dr.Katz, receiving grant support through her institution f rom JuvarisBioTherapeutics and GlaxoSmithKline; Dr. Pavia, receiving feesfor serving on an advisory board from BioFire Diagnostics, feesfor the preparation of educational material from Medscape, androyalties from Antimicrobial Therapy; and Dr. Edwards, serving

on a data and safety monitoring board for Novartis for which herinstitution receives fees. No other potential conflict of interestrelevant to this article was reported.

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

We thank the patients who consented to participate in thisstudy; Suzette Bartley, Bernie Beall, Nicole Burcher, Robert Da- vidson, Michael Dillon, Barry Fields, Phalasy Juieng, and ShelleyMagill of the CDC; Bharat Reddy Dhanireddy and Pinal Modi of John H. Stroger, Jr., Hospital of Cook County; Alison Chevrier,Ashraf Luqman, Cecilia Scholcoff, and Jill Sears of Northwest-ern Memorial Hospital; Alexander Baldridge, Kelly Harris, RajivMidha, and Denetra Smith of University of Tennessee HealthScience Center–Saint Thomas Health; and Heather Diggs, Regi-

na Ellis, Timothy Girard, Charity Graves, Angela Harbeson,Deborah Hunter, Donna Jones, Romina Libster, Karen Miller,Kelly Moser, Deborah Myers, Rabon Lee Smalling, Tanya Stein-back, Scott Taylor, and Sandy Yoder of the Vanderbilt UniversityMedical Center.

Appendix

The authors’ full names and academic degrees are as follows: Seema Jain, M.D., Wesley H. Self, M.D., M.P.H., Richard G. Wunderink,M.D., Sherene Fakhran, M.D., M.P.H., Robert Balk, M.D., Anna M. Bramley, M.P.H., Carrie Reed, Ph.D., Carlos G. Grijalva, M.D.,M.P.H., Evan J. Anderson, M.D., D. Mark Courtney, M.D., James D. Chappell, M.D., Ph.D., Chao Qi, Ph.D., Eric M. Hart, M.D., FrankCarroll, M.D., Christopher Trabue, M.D., Helen K. Donnelly, R.N., B.S.N., Derek J. Williams, M.D., M.P.H., Yuwei Zhu, M.D., San-dra R. Arnold, M.D., Krow Ampofo, M.D., Grant W. Waterer, M.B., B.S., 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., Jonathan A.McCullers, M.D., Andrew T. Pavia, M.D., Kathryn M. Edwards, M.D., and Lyn Finelli, Dr.P.H., for the CDC EPIC Study Team

The authors’ affiliations are as follows: the Centers for Disease Control and Prevention, Atlanta (S.J., A.M.B., C.R., M.L., S.L., J.M.W., J.M.K., D.E., E.S., L.A.H., L.F.); Vanderbilt University School of Medicine (W.H.S., C.G.G., J.D.C., F.C., D.J.W., Y.Z., K.M.E.) andUniversity of Tennessee Health Science Center–Saint Thomas Health (C.T.), Nashville, and Le Bonheur Children’s Hospital (S.R.A., J.A.M.), University of Tennessee Health Science Center (S.R.A., J.A.M.), and St. Jude Children’s Research Hospital (J.A.M.), Memphis— all in Tennessee; Northwestern University Feinberg School of Medicine (R.G.W., E.J.A., D.M.C., C.Q., E.M.H., H.K.D., G.W.W.), John H. Stroger, Jr., Hospital of Cook County (S.F.), and Rush University Medical Center (R.B.) — all in Chicago; University of UtahHealth Sciences Center, Salt Lake City (K.A., A.T.P.); and University of Western Australia, Perth (G.W.W.).

References

1. Pfuntner A, Wier LM, Stocks C. Mostfrequent conditions in U.S. hospitals,2011. HCUP statistical brief #162. Rock- ville, MD: Agency for Healthcare Re-search and Quality, 2013 (http://www.hcup-us.ahrq.gov/reports/statbriefs/

sb162.pdf).2. Health, United States, 2012: with spe-cial features on emergency care. Hyatts- ville, MD: National Center for Health Sta-tistics, 2013:297-9.3. Pfuntner A, Wier LM, Steiner C. Costsfor hospital stays in the United States,2011. HCUP statistical brief #168. Rock- ville, MD: Agency for Healthcare Re-search and Quality, 2013 (http://www.hcup-us.ahrq.gov/reports/statbriefs/sb168-Hospital-Costs-United-States-2011.pdf).4. Grijalva CG, Nuorti JP, Arbogast PG,Martin SW, Edwards KM, Griff in MR. De-cline in pneumonia admissions after rou-tine childhood immunisation with pneu-mococcal conjugate vaccine in the USA: atime-series analysis. Lancet 2007;369:1179-86.5. Nelson JC, Jackson M, Yu O, et al. Im-pact of the introduction of pneumococcalconjugate vaccine on rates of communityacquired pneumonia in children andadults. Vaccine 2008;26:4947-54.6. Griff in MR, Zhu Y, Moore MR, Whit-ney CG, Grijalva CGUS. U.S. hospitaliza-tions for pneumonia after a decade of

pneumococcal vaccination. N Engl J Med2013;369:155-63.7. Lexau CA, Lynfield R, Danila R, et al.Changing epidemiology of invasive pneu-mococcal disease among older adults inthe era of pediatric pneumococcal conju-

gate vaccine. JAMA 2005;294:2043-51.8. Pilishvil i T, Lexau C, Farley MM, et al.Sustained reductions in invasive pneumo-coccal disease in the era of conjugate vac-cine. J Infect Dis 2010;201:32-41.9. Marston BJ, Plouffe JF, File TM Jr, etal. Incidence of community-acquiredpneumonia requiring hospitalization: re-sults of a population-based active surveil-lance study in Ohio. Arch Intern Med1997;157:1709-18.10. Mandell LA, Wunderink RG, AnzuetoA, et al. Infectious Diseases Society ofAmerica/American Thoracic Society con-sensus guidelines on the management ofcommunity-acquired pneumonia inadults. Clin Infect Dis 2007;44:Suppl 2:S27-S72.11. Pavia AT. Viral infect ions of the lowerrespiratory tract: old viruses, new viruses,and the role of diagnosis. Clin Infect Dis2011;52:Suppl 4:S284-S289.12. Caliendo AM. Multiplex PCR andemerging technologies for the detectionof respiratory pathogens. Clin Infect Dis2011;52:Suppl 4:S326-S330.13. Bartlet t JG. Diagnostic tests foragents of community-acquired pneumo-

nia. Clin Infect Dis 2011;52:Suppl 4:S296-S304.14. Katz S, Ford AB, Moskowitz RW, Jack-son BA, Jaffe MW. Studies in the aged: theindex of ADL: a standardized measure ofbiological and psychological function.

JAMA 1963;185:914-9.15. Cherian T, Mulholland EK, Carlin JB,et al. Standardized interpretation of pae-diatric chest radiographs for the diagno-sis of pneumonia in epidemiologicalstudies. Bull World Health Organ 2005;83:353-9.16. Watt JP, Moïsi JC, Donaldson RLA, etal. Measuring the incidence of adult com-munity-acquired pneumonia in a NativeAmerican community. Epidemiol Infect2010;138:1146-54.17. Bartlett RC. Medical microbiology:quality, cost and clinical relevance. NewYork: John Wiley, 1974:24-31.18. Pollock HM, Hawkins EL, Bonner JR,Sparkman T, Bass JB Jr. Diagnosis of bac-terial pulmonary infections with quanti-tative protected catheter cultures ob-tained during bronchoscopy. J ClinMicrobiol 1983;17:255-9.19. Thurman KA, Warner AK, Cowart KC,Benitez AJ, Winchell JM. Detect ion of My-coplasma pneumoniae, Chlamydia pneu-moniae, and Legionella spp. in clinicalspecimens using a single-tube multiplexreal-time PCR assay. Diagn Microbiol In-fect Dis 2011;70:1-9.





13/13



20. Murdoch DR. Diagnosis of Legionella infection. Clin Infect Dis 2003;36:64-9.21. Carvalho MGS, Tondella ML, Mc-Caustland K, et al. Evaluation and im-provement of real-time PCR assays target-ing lytA, ply, and psaA genes for detectionof pneumococcal DNA. J Clin Microbiol2007;45:2460-6.22. Blaschke AJ, Heyrend C, Byington CL,

et al. Molecular analysis improves patho-gen identification and epidemiologicstudy of pediatric parapneumonic empy-ema. Pediatr Infect Dis J 2011;30:289-94.23. Blaschke AJ, Heyrend C, Byington CL,et al. Rapid identification of pathogensfrom positive blood cultures by multiplexpolymerase chain reaction using the Fil-mArray system. Diagn Microbiol InfectDis 2012;74:349-55.24. Murdoch DR, Laing RTR, Mills GD, etal. Evaluation of a rapid immunochro-matographic test for detection of Strepto-coccus pneumoniae antigen in urine samplesfrom adults with community-acquiredpneumonia. J Clin Microbiol 2001;39:

3495-8.25. Weinberg GA, Schnabel KC, ErdmanDD, et al. Field evaluation of TaqMan Ar-ray Card (TAC) for the simultaneous de-tection of multiple respiratory viruses inchildren with acute respiratory infection. J Clin Virol 2013;57:254-60.26. Dare RK, Fry AM, Chittaganpitch M,Sawanpanyalert P, Olsen SJ, Erdman DD.Human coronavirus infections in ruralThailand: a comprehensive study usingreal-time reverse-transcription poly-merase chain reaction assays. J Infect Dis2007;196:1321-8.27. Sawatwong P, Chittaganpitch M, HallH, et al. Serology as an adjunct to poly-merase chain reaction assays for surveil-lance of acute respiratory virus infect ions.Clin Infect Dis 2012;54:445-6.28. Feikin DR, Njenga MK, Bigogo G, etal. Additional diagnostic yield of addingserology to PCR in diagnosing viral acuterespiratory infections in Kenyan patients5 years of age and older. Clin Vaccine Im-munol 2013;20:113-4.29. Manual for the laboratory diagnosisand virological surveillance of influenza.Geneva: World Health Organization,2011:43-77 (http://www.who.int/influenza/gisrs_laboratory/manual_diagnosis_surveillance_influenza/en).

30. Monto AS, Maassab HF. Ether treat-ment of type B influenza virus antigen forthe hemagglutination inhibition test. J Clin Microbiol 1981;13:54-7.31. Kendal AP, Cate TR. Increased sensi-tivity and reduced specificity of hemag-glutination inhibition tests with ether-treated influenza B/Singapore/222/79. J Clin Microbiol 1983;18:930-4.

32. Fiore AE, Bridges CB, Katz JM, CoxNJ. Inactivate inf luenza vaccines. In: Plot-kin SA, Orenstein WA, Off it PA, eds. Vac-cines. 6th ed. Philadelphia: Elsevier, 2012:257-93.33. Vintage 2012 postcensal estimates ofthe resident population of the UnitedStates by year, county, single-year of age,bridged race, Hispanic origin, and sex.

Atlanta: National Center for Health Sta-tistics, 2012 (http://www.cdc.gov/nchs/nvss/bridged_race.htm).34. Fine MJ, Auble TE, Yealy DM, et al. Aprediction rule to identify low-risk pa-tients with community-acquired pneumo-nia. N Engl J Med 1997;336:243-50.35. Karhu J, Ala-Kokko TI, Vuorinen T,Ohtonen P, Syrjälä H. Lower respiratorytract virus findings in mechanical ly venti-lated patients with severe community-acquired pneumonia. Clin Infect Dis2014;59:62-70.36. Lanspa MJ, Peyrani P, Wiemken T,Wilson EL, Ramirez JA, Dean NC. Charac-teristics associated with clinician diagno-

sis of aspiration pneumonia: a descriptivestudy of afflicted patients and their out-comes. J Hosp Med 2015;10:90-6.37. Jennings LC, Anderson TP, BeynonKA, et al. Incidence and characteristics of viral community-acquired pneumonia inadults. Thorax 2008;63:42-8.38. Johansson N, Kalin M, Tiveljung-Lin-dell A, Giske CG, Hedlund J. Etiology ofcommunity-acquired pneumonia: in-creased microbiological yield with newdiagnostic methods. Clin Infect Dis 2010;50:202-9.39. Johnstone J, Majumdar SR, Fox JD,Marrie TJ. Viral infection in adults hospi-talized with community-acquired pneu-monia: prevalence, pathogens, and pre-sentation. Chest 2008;134:1141-8.40. Lieberman D, Shimoni A, Shemer-Avni Y, Keren-Naos A, Shtainberg R, Li-eberman D. Respiratory viruses in adults with community-acquired pneumonia.Chest 2010;138:811-6.41. Templeton KE, Scheltinga SA, van denEeden WC, Graffelman AW, van denBroek PJ, Claas EC. Improved diagnosis ofthe etiology of community-acquiredpneumonia with real-time polymerasechain reaction. Clin Infect Dis 2005;41:345-51.42. Charles PGP, Whitby M, Fuller AJ, et

al. The etiology of community-acquiredpneumonia in Australia: why penicillinplus doxycycline or a macrolide is themost appropriate therapy. Clin Infect Dis2008;46:1513-21.43. Musher DM, Thorner AR. Communi-ty-acquired pneumonia. N Engl J Med2014;371:1619-28.44. Jain S, Williams DJ, Arnold SR, et al.

Community-acquired pneumonia requir-ing hospitalization among U.S. children.N Engl J Med 2015;372:835-45.45. Caliendo AM, Gilbert DN, GinocchioCC, et al. Better tests, better care: im-proved diagnostics for infectious diseas-es. Clin Infect Dis 2013;57:Suppl 3:S139-S170.46. Fry AM, Lu X, Olsen SJ, et al. Human

rhinovirus infections in rural Thailand:epidemiological evidence for rhinovirusas both pathogen and bystander. PLoSOne 2011;6(3):e17780.47. Ruuskanen O, Järvinen A. What is thereal role of respiratory viruses in severecommunity-acquired pneumonia? ClinInfect Dis 2014;59:71-3.48. FluView: a weekly influenza surveil-lance report prepared by the InfluenzaDivision. Atlanta: Centers for DiseaseControl and Prevention (http://www.cdc.gov/flu/ weekly).49. Prevention and control of seasonalinfluenza with vaccines: recommenda-tions of the Advisory Committee on Im-

munization Practices (ACIP) — UnitedStates, 2014–2015. MMWR Morb MortalWkly Rep 2014;63:691-7.50. Falsey AR, Hennessey PA, FormicaMA, Cox C, Walsh EE. Respiratory syncy-tial virus infection in elderly and high-risk adults. N Engl J Med 2005;352:1749-59.51. Walsh EE, Peterson DR, Falsey AR.Human metapneumovirus infections inadults: another piece of the puzzle. ArchIntern Med 2008;168:2489-96.52. Werno AM, Murdoch DR. Medical mi-crobiology: laboratory diagnosis of inva-sive pneumococcal disease. Clin InfectDis 2008;46:926-32.53. Use of 13-valent pneumococcal conju-gate vaccine and 23-valent pneumococcalpolysaccharide vaccine among adultsaged ≥65 years: recommendations of theAdvisory Committee on ImmunizationPractices (ACIP). MMWR Morb MortalWkly Rep 2014;63:822-5.54. Kumar S, Hammerschlag MR. Acuterespiratory infection due to Chlamydia

pneum oniae : current status of diagnosticmethods. Clin Infect Dis 2007;44:568-76.55. Nilsson AC, Björkman P, Persson K.Polymerase chain reaction is superior toserology for the diagnosis of acute Myco-

plasma pneumoniae infection and reveals ahigh rate of persistent infect ion. BMC Mi-crobiol 2008;8:93.56. Nir-Paz R, Michael-Gayego A, Ron M,Block C. Evaluation of eight commercialtests for Mycoplasma pneumoniae antibod-ies in the absence of acute infection. ClinMicrobiol Infect 2006;12:685-8.

Copyright © 2015 Massachusetts Medical Society.


Documents

Community-Acquired Pneumonia Requiring Hospitalization Among U.S. Adults