JAMA - Bronchiolitis-Associated Hospitalizations Among US Children, 1980-1996

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http://jama.ama-assn.org/issues/v282n15/full/joc81106.html

Bronchiolitis-Associated Hospitalizations Among US Children, 1980-1996

K. Shay, MD, MPH; C. Holman, MS; D. Newman, MD, MPH;

Lenna L. Liu, MD, MPH; W. Stout, MD, MPH; Larry J. , MD

Context Respiratory syncytial virus (RSV) causes more lower respiratory

tract infections, often manifested as bronchiolitis, among young children

than any other pathogen. Few national estimates exist of the

hospitalizations attributable to RSV, and recent advances in prophylaxis

warrant an update of these estimates.

Objectives To describe rates of bronchiolitis-associated hospitalizations

and to estimate current hospitalizations associated with RSV infection.

Design and Setting Descriptive analysis of US National Hospital Discharge

Survey data from 1980 through 1996.

Participants Children younger than 5 years who were hospitalized in

short-stay, nonfederal hospitals for bronchiolitis.

Main Outcome Measure Bronchiolitis-associated hospitalization rates by age

and year.

Results During the 17-year study period, an estimated 1.65 million

hospitalizations for bronchiolitis occurred among children younger than 5

years, accounting for 7.0 million inpatient days. Fifty-seven percent of

these hospitalizations occurred among children younger than 6 months and 81%

among those younger than 1 year. Among children younger than 1 year, annual

bronchiolitis hospitalization rates increased 2.4-fold, from 12.9 per 1000

in 1980 to 31.2 per 1000 in 1996. During 1988-1996, infant hospitalization

rates for bronchiolitis increased significantly (P for trend <.001), while

hospitalization rates for lower respiratory tract diseases excluding

bronchiolitis did not vary significantly (P for trend = .20). The proportion

of hospitalizations for lower respiratory tract illnesses among children

younger than 1 year associated with bronchiolitis increased from 22.2% in

1980 to 47.4% in 1996; among total hospitalizations, this proportion

increased from 5.4% to 16.4%. Averaging bronchiolitis hospitalizations

during 1994-1996 and assuming that RSV was the etiologic agent in 50% to 80%

of November through April hospitalizations, an estimated 51,240 to 81,985

annual bronchiolitis hospitalizations among children younger than 1 year

were related to RSV infection.

Conclusions During 1980-1996, rates of hospitalization of infants with

bronchiolitis increased substantially, as did the proportion of total and

lower respiratory tract hospitalizations associated with bronchiolitis.

Annual bronchiolitis hospitalizations associated with RSV infection among

infants may be greater than previous estimates for RSV bronchiolitis and

pneumonia hospitalizations combined.

JAMA. 1999;282:1440-1446

Respiratory syncytial virus (RSV) is the most important cause of lower

respiratory tract disease among infants and children worldwide.1, 2 Almost

all children have been infected with RSV by age 2 years.3 Although

reinfection throughout life is common, a child's initial RSV infection

typically is the most severe and the most likely to involve the lower

respiratory tract.3, 4 Severe RSV disease, as gauged by the requirement for

hospital admission, is most common among infants aged 1 to 3 months.3, 5

The hallmark of RSV infection is bronchiolitis, a disease of infancy

characterized by wheezing, lung hyperexpansion, and hypoxia. Other lower

respiratory tract illnesses, especially pneumonia, are also common

manifestations of RSV infection. In studies of hospitalized children in

temperate countries, RSV infection has been associated with 43% to 74% of

bronchiolitis cases6-12 and with 19% to 54% of pneumonia cases.6-10 During

the 1985-1994 winter seasons in Rochester, NY, RSV was associated with 50%

to 80% of bronchiolitis hospitalizations and with 30% to 60% of pneumonia

hospitalizations.13

The only national estimates of hospitalizations attributable to RSV

infection were made by the Institute of Medicine in 1985.14 By estimating

that 0.5% of children younger than 5 years infected with RSV would require

hospitalization, and assuming that 60% of RSV-associated hospitalizations

would occur among infants younger than 1 year, the Institute of Medicine

projected that 54,697 infants younger than 1 year and 36,465 children aged 1

through 4 years were hospitalized annually for bronchiolitis or pneumonia

associated with RSV.

Recent progress in 2 areas warrants updating national RSV-associated

hospitalization estimates. First, the Food and Drug Administration recently

licensed palivizumab, a humanized murine RSV monoclonal antibody for monthly

intramuscular administration among high-risk children during RSV seasons to

prevent lower respiratory tract disease hospitalizations.15 Palivizumab is

easier to deliver and less expensive than the previously available

prophylactic antibody preparation, RSV-enriched human immunoglobulin, which

must be intravenously administered. Recommendations from the American

Academy of Pediatrics regarding use of both products among high-risk infants

are available.16 Second, advances in the development of safe subunit and

live attenuated RSV vaccine candidates have been reported recently.17-19 To

update hospitalization estimates, we examined temporal trends in

hospitalizations among US children associated with bronchiolitis, the most

specific RSV-associated illness. We estimated recent RSV-associated

hospitalizations by using discharge data for bronchiolitis and used

bronchiolitis and pneumonia hospitalizations to estimate RSV-associated

morbidity among infants.

METHODS

Hospital discharge data from 1980 through 1996 were obtained from the

National Hospital Discharge Survey (NHDS) through the National Center for

Health Statistics (NCHS), Centers for Disease Control and Prevention

(CDC).20 The NHDS is a representative sample of patient discharge records

from short-stay, nonfederal, general and children's hospitals in the United

States.21 Hospitalizations were weighted using NCHS procedures to obtain

national estimates.22 NHDS records do not contain individual identifiers;

therefore, the unit of analysis was a hospitalization.

All discharge records from children younger than 5 years with an

International Classification of Diseases, Ninth Revision, Clinical

Modification (ICD-9-CM) code for any respiratory illness (codes 460-519)23

among the as many as 7 discharge diagnoses listed were selected for study. A

bronchiolitis-associated hospitalization was defined as a discharge with

acute bronchiolitis (code 466.1) listed anywhere on the record. Use of this

strategy detected hospitalizations for which a bronchiolitis-associated

complication (eg, respiratory failure) might be coded first and those

associated with nosocomially acquired bronchiolitis, which may represent a

substantial proportion of RSV-associated bronchiolitis among hospitalized

infants.24, 25 Severe bronchiolitis was defined as a discharge listing an

ICD-9-CM procedure code for endotracheal intubation (code 96.04) or for

receipt of continuous mechanical ventilation (codes 96.72 or 96.71

[1992-1996]; 93.92 [1988-1991]; or 93.90 [1980-1987]).23

Hospitalizations were stratified by patient age: younger than 6 months, 6

through 11 months, 12 through 23 months, or 24 through 59 months. For

approximately 1.0% of bronchiolitis hospitalizations, age data were missing;

these records were not included in analyses. Hospitalizations were also

stratified by sex, length of stay, and census geographic region (Northeast,

Midwest, South, and West).26 Because data on race/ethnicity were missing

from 23% of discharge records examined, we made no comparisons by

ethnicity.21, 27 Temporal trends in hospitalizations were examined by

discharge month and year. From 1988 through 1996, aggregate estimates of

discharges by month were made using only records sampled from hospitals

fully responding for that year (I. M. Shimizu, PhD, NCHS, written

communication, November 16, 1998).20 Bronchiolitis and pneumonia

hospitalizations attributable to RSV were estimated using winter RSV

recovery rates among children hospitalized with bronchiolitis (50% to 80%)

or pneumonia (30% to 60%).6-13 Only hospitalizations occurring from November

through April were used in estimating disease likely attributable to RSV

infection.

To determine whether changes in diagnostic coding practices during the study

period influenced the number of bronchiolitis-associated hospitalizations,

other lower respiratory tract disease hospitalizations were also examined.

Discharges associated with lower respiratory tract diseases other than

bronchiolitis were defined by the following ICD-9-CM codes: acute and

chronic/unspecified bronchitis (466.0, 490-491); pneumonia (480-486);

influenza (487); asthma (493); bronchiectasis (494); pneumonitis (507);

respiratory conditions due to unspecified external agents (508); emphysema

(492); empyema (510); pleurisy (511); and other diseases of the lower

respiratory system (512-519).23 Conditions specifically noted on discharge

records included pneumonia, organism unspecified (486), bronchopneumonia

(485), RSV pneumonia (480.1), other specified viral infection (078.9),

otitis media (382.9), congenital heart disease (745-747), chronic

respiratory distress arising in the perinatal period (770.7), and a history

of perinatal problems (V13.7).

Hospitalization rates were calculated using denominators derived from US

census data for children younger than 5 years23 or from US natality data for

children younger than 1 year.28 Population estimates of children age 1

through 4 years for each calendar year were made by subtracting natality

figures from census figures. Rates were expressed as the number of estimated

hospitalizations per 1000 children of the corresponding age group.

The NHDS was redesigned in 1988, when new methods of sampling hospitals and

collecting data were introduced; however, most estimates obtained using the

old and the new methods have not been substantially different.29 SUDAAN

software30 was used to calculate annual SEs during 1988-1996 to account for

the stratified sampling techniques used during this period.29 Overall SEs

for the entire study period were estimated using NCHS procedures.20, 28

Denominators obtained from vital records data were considered free from

sampling error.26, 28 Statistical tests for rate comparisons were performed

only with 1988-1996 hospitalization data because of the 1988 changes in

survey design. Comparisons were made by period and demographic

characteristics with 2-sided t tests incorporating weighted variance

estimates.30, 31 A weighted least squares regression method was used as a

test for trend with data obtained from 1988 through 1996.22

RESULTS

Bronchiolitis Hospitalizations

From 1980 through 1996, an estimated 1,648,281 (SE, 121,129)

hospitalizations associated with bronchiolitis occurred among US children

younger than 5 years. Eighty-one percent (1,334,566; SE, 105,396) of these

hospitalizations occurred among children younger than 1 year and 57%

(946,358; SE, 83,309) among children younger than 6 months. As expected for

an illness frequently associated with RSV infection, bronchiolitis

hospitalizations peaked annually during the winter months, usually in

January or February (Figure 1). Among children younger than 5 years, 81% of

bronchiolitis hospitalizations occurred from November through April, and

among children younger than 1 year, 83% occurred during these months.

During the study period, we estimated that bronchiolitis hospitalizations

accounted for 7.0 million inpatient days (SE, 575,554). The median length of

stay was 3 days per hospitalization (interquartile range, 2-5 days). Length

of stay did not vary substantially by age in months, by sex, or by calendar

year (data not shown).

Although the annual number of bronchiolitis hospitalizations fluctuated,

they increased among children in each age group during the study period

(Figure 2). The most dramatic rise in hospitalizations occurred among

children younger than 6 months, for whom bronchiolitis hospitalizations

increased by 239% from 1980 to 1996.

Among children aged 1 through 4 years, the bronchiolitis hospitalization

rate increased gradually, from 1.3 per 1000 in 1980 to 2.3 per 1000 in 1996

(+77%). Among children younger than 1 year, rates increased more rapidly

during this period, from 12.9 per 1000 to 31.2 per 1000 (+152%).

Bronchiolitis hospitalization rates increased proportionately among males

and females. Among infant males, the rate increased from 24.9 per 1000

during 1988-1990 to 38.4 per 1000 during 1994-1996 (+54%; P = .01); among

infant females the rate increased from 15.1 to 24.4 per 1000 (+62%; P = .02)

during these periods. Males were 1.6 times more likely to be hospitalized

with bronchiolitis than females, irrespective of age group or calendar year.

Bronchiolitis hospitalization rates among infants increased in each of the 4

regions of the United States. However, the only statistically significant

increase took place in the South, where the annual average hospitalization

rate increased from 19.0 per 1000 in 1988-1990 to 33.4 per 1000 in 1993-1995

(+75.8%; P = .03).

Hospitalization Rates for Lower Respiratory Tract Diseases

From 1980 through 1996, bronchiolitis was responsible for increasing

proportions of lower respiratory tract disease and total hospitalizations

among children younger than 1 year. The proportion of total hospitalizations

among children younger than 1 year associated with bronchiolitis increased

from 5.4% to 16.4%; for lower respiratory tract diseases, the proportion

diagnosed with bronchiolitis increased from 22.2% to 47.4% (Table 1).

To determine whether bronchiolitis hospitalization rates were influenced by

temporal trends in diagnostic coding practices, we examined hospitalization

rates for other lower respiratory tract diseases. Hospitalization rates

among children younger than 1 year for all lower respiratory diseases

increased by 13% during the study period, from 58.1 per 1000 in 1980 to 65.8

per 1000 in 1996 (Figure 3). Pneumonia hospitalization rates declined from

28.5 per 1000 in 1980 to 23.9 per 1000 in 1988, while bronchiolitis

hospitalization rates increased from 12.9 to 17.3 per 1000. The increase in

bronchiolitis rates during 1980-1988 may have resulted, in part, from a

trend to diagnose bronchiolitis instead of pneumonia among children younger

than 1 year. However, bronchiolitis hospitalization rate increases after

1989 among children younger than 1 year were not accompanied by concomitant

rate decreases for either pneumonia or asthma (Figure 3). Finally,

hospitalization rates for bronchiolitis and all lower respiratory tract

diseases increased significantly during 1988-1996 (P for trend <.001 for

each comparison), while hospitalization rates for all lower respiratory

tract diseases except for bronchiolitis did not vary significantly (P for

trend = .20).

Recent Patterns in Bronchiolitis Hospitalizations

Specific diagnoses and procedures associated with bronchiolitis discharges

were examined in detail during 1994-1996 to determine the most recent

hospitalization patterns. Bronchiolitis was the first-listed diagnosis in

83% of records. Pneumonia, organism unspecified (4.5%), RSV pneumonia

(2.9%), asthma (1.9%), and bronchopneumonia (1.1%) were other common

first-listed diagnoses. The most frequent underlying conditions recorded for

bronchiolitis-associated discharges were congenital heart disease (2.4%),

chronic respiratory distress arising in the perinatal period (2.0%), and a

history of perinatal problems (1.4%).

Severe bronchiolitis was uncommon during the entire study period, but it may

have become more prevalent in recent years. Among children younger than 1

year during the entire study, 1.0% of bronchiolitis hospitalizations were

coded for endotracheal intubation or receipt of continuous mechanical

ventilation. However, during 1994-1996, the discharges of 1.7% of children

younger than 1 year hospitalized with bronchiolitis were coded for

endotracheal intubation or for receipt of continuous mechanical ventilation.

Procedures frequently coded for the discharges of children younger than 1

year with a 1994-1996 bronchiolitis-associated hospitalization included

nebulization therapy (17.2%), receipt of supplemental oxygen (8.6%), lumbar

puncture (4.8%), and antibiotic injection (1.3%).

Estimates of RSV-Associated Hospitalizations

To provide current estimates of RSV-associated morbidity, we averaged

bronchiolitis hospitalizations among children younger than 1 year and 5

years during 1994-1996. An average of 123,471 bronchiolitis hospitalizations

occurred annually among children younger than 1 year and 154,365 among

children younger than 5 years during this 3-year period. Assuming that 50%

to 80% of bronchiolitis hospitalizations occurring during November through

April were attributable to RSV, we estimated that 51,240 to 81,985 children

younger than 1 year and 62,518 to 100,029 children younger than 5 years were

hospitalized during each of these years for RSV-associated bronchiolitis.

We also estimated the contribution of RSV to pneumonia hospitalizations

among children younger than 1 year. Assuming that 30% to 60% of November

through April pneumonia hospitalizations in 1994-1996 were RSV-related,

22,160 to 44,321 infant pneumonia hospitalizations annually were

attributable to RSV infection.

COMMENT

Our study is the first to examine temporal trends in bronchiolitis

hospitalizations and estimate RSV-associated hospitalizations by using

nationally representative data. Our finding that bronchiolitis

hospitalizations have increased substantially during the 17 years studied

was not expected. We found that infant bronchiolitis hospitalization rates

increased significantly from 1988 through 1996, while hospitalization rates

for other lower respiratory tract diseases did not vary significantly. Among

infants, bronchiolitis currently is associated with approximately 47% of

lower respiratory tract disease discharges and with 16% of total discharges.

In 1985, the Institute of Medicine estimated that 91,162 hospitalizations

for bronchiolitis and pneumonia associated with RSV occurred annually among

US children younger than 5 years.14 For bronchiolitis alone, we estimate

that 62,500 to 100,000 RSV-associated hospitalizations occur annually among

children younger than 5 years. The Institute of Medicine appeared to

underestimate the RSV-associated disease burden among infants younger than 1

year because they assumed that 60% of RSV hospitalizations among children

younger than 5 years would occur among infants. We found that 81% of

bronchiolitis hospitalizations occurred among infants. Our estimate of

51,200 to 82,000 annual infant hospitalizations for RSV-associated

bronchiolitis is similar in magnitude to the 1985 Institute of Medicine

projection of 54,700 RSV-associated infant hospitalizations for

bronchiolitis and pneumonia combined.14 Currently, we estimate that 73,400

to 126,300 annual hospitalizations among US infants for bronchiolitis or

pneumonia may be attributable to RSV infection, considerably more than the

1985 projection.

The etiology of the increase in bronchiolitis hospitalization rates is

probably multifactorial. Trends in child-care practices, changes in the

criteria for hospitalization of children with lower respiratory tract

disease, decreasing mortality among premature and medically complex infants

at high risk for RSV-associated hospitalization, changes in RSV strain

virulence, modifications in the NHDS, or alterations in diagnostic coding

practices during the study period are potential reasons for the increases.

Several of these factors are unlikely to contribute substantially to

increasing bronchiolitis hospitalization rates. Although RSV strains vary in

virulence,32-34 and strain differences may account for variation in the

severity of RSV outbreaks, documented RSV strain circulation patterns do not

suggest that increasing strain virulence is responsible for the national

temporal trends we found.35 A predominant national RSV outbreak strain or

strains have not been documented. Instead, the pattern of outbreak strains

vary by community each year.36, 37 Similarly, although modification of NHDS

procedures in 1988 could affect the comparability of discharge data

collected before and after that year, much of the increase in bronchiolitis

hospitalization rates has taken place since 1989 and cannot be explained by

design changes. Finally, if diagnostic-coding variations during the study

period substantially influenced the increase in bronchiolitis

hospitalization rates, we would expect a compensatory decrease in

hospitalization rates for other lower respiratory tract diseases with

clinical presentations similar to bronchiolitis. From 1988 through 1996,

when infant bronchiolitis hospitalization rates almost doubled,

hospitalization rates for unspecified pneumonia and asthma also increased.

Therefore, it is difficult to postulate that diagnostic substitution fully

explains the increase in bronchiolitis hospitalization rates.

Other factors may have contributed to increases in bronchiolitis

hospitalization rates. Attendance at a child-care center with 6 or more

other children is an independent risk factor for a lower respiratory tract

disease hospitalization in the first 2 years of life.38 Enrollment of

children younger than 3 years in center-based child care increased during

the study. Among children aged 1 through 2 years with employed mothers, the

proportion enrolled in child-care centers increased from 12% in 1982 to 25%

in 1993. Among children younger than 1 year, enrollment increased from 5% to

20%.39 A trend toward earlier enrollment in large child-care centers may

lead to initial RSV infection at a younger age, when hospitalization is more

likely. Specific child-care practices must be examined in relation to

bronchiolitis hospitalization trends.

Criteria for hospital admission among children with bronchiolitis may have

changed during the study period and influenced hospitalization rates.

Specifically, pulse oximetry measurements during the evaluation of wheezing

children became more common and may have led to new criteria for hospital

admission. In a prospective study of wheezing children presenting to a

pediatric emergency department, the proportion receiving pulse oximetry

increased from 87% during December 1987 through May 1988 to 96% during June

through September 1991. The corresponding hospitalization rate among

wheezing children increased from 10.4% to 15.6%.40 A study examining routine

pulse oximetry use during emergency department evaluation of children with

respiratory symptoms found that oximetry detected an oxygen saturation of

less than 92% more effectively than physical examination alone.41 If

mild-to-moderate hypoxia detected by pulse oximetry has been added to

traditional criteria for hospitalizing young children with bronchiolitis

(eg, respiratory distress or difficulty feeding), then increasing use of

pulse oximetry may explain the increase in hospitalization rates. Although

we are unaware of any data specifically examining oximetry use trends in

children with bronchiolitis, a national survey of 376 emergency departments

in 1992 found that 67% routinely used pulse oximetry in the assessment of

pediatric asthma.42

Improved survival of prematurely born infants at greater risk for serious

RSV-associated disease may have influenced bronchiolitis hospitalization

rates. Nevertheless, our data suggest that such high-risk infants represent

a small proportion of children hospitalized with bronchiolitis: only 2% of

1994-1996 bronchiolitis discharges were concurrently coded for chronic lung

disease. It is possible that underlying medical conditions were

underreported in NHDS data. Procedures were underreported in these data.

While approximately 9% of bronchiolitis discharge records during 1994-1996

were coded for receipt of supplemental oxygen, hospital-based studies have

reported that 34% to 75% of RSV-infected children received supplemental

oxygen.43-45 Underreporting of procedures may reflect a lack of

reimbursement for routine hospital care such as oxygen administration. The

possible contribution of underlying conditions, including premature birth

and congenital heart disease, to bronchiolitis hospitalization trends needs

to be more fully ascertained. However, it is unlikely the survival of more

premature infants could account for a substantial proportion of the increase

in infant bronchiolitis hospitalization rates.

This study has several limitations. First, NHDS-based hospitalization

estimates are generated by using a complex, nationally representative sample

of discharges, which in 1996 were amassed from 480 responding hospitals.21

Thus, the weighted estimates have more variability than might be expected

from the magnitude of the numbers presented. We have presented SEs where

appropriate so that this variability can be assessed. Second, the NHDS does

not include hospitalizations occurring in federal facilities providing

pediatric care, particularly Indian Health Service hospitals—and the highest

US hospitalization rate for RSV disease ever reported was among Alaska

Native infants in the southwestern part of the state (100/1000).46 Third,

data that may relate to socioeconomic status, such as race/ethnicity and

insurance coverage, are incompletely recorded in NHDS records, precluding

examination of these factors. Infants born to low-income urban families have

increased admission rates for acute lower respiratory tract disease compared

with those born to middle-income families.3, 47-51 Socioeconomic factors

need to be examined in relation to temporal trends in bronchiolitis

hospitalizations. Finally, lack of a specific ICD-9-CM code for

RSV-associated disease forced us to use a proportion of bronchiolitis

hospitalizations occurring from November through April as the primary proxy

for RSV-associated hospitalizations. We believe this approach is reasonable.

Many studies have documented that RSV is responsible for the majority of

winter bronchiolitis hospitalizations,6-13 and annual RSV detections in the

National Respiratory and Enteric Virus Surveillance System correlate closely

with annual peaks of bronchiolitis hospitalizations in NHDS data (CDC

unpublished data, 1990-1996).52, 53 In those years with a particularly

prominent mid-winter peak in bronchiolitis hospitalizations, it is likely

that a greater proportion of bronchiolitis hospitalizations are associated

with RSV infection; however, we were not able to document this possibility,

as no virologic data were abstracted for NHDS records.

In summary, nationally representative data suggest that the current number

of RSV-associated bronchiolitis and pneumonia hospitalizations among infants

is approximately 1.5 to 2 times greater than previously estimated. From 1980

through 1996, bronchiolitis hospitalization rates and the proportion of

hospitalizations associated with bronchiolitis increased substantially among

infants. Finally, despite the availability of prophylactic antibody

preparations to reduce RSV-associated hospitalizations among children with

conditions placing them at high risk for serious disease,15, 16 the majority

of US infants hospitalized with bronchiolitis are not concurrently diagnosed

with prematurity or underlying lung disease. A safe and effective RSV

vaccine is needed to reduce bronchiolitis hospitalizations.

Author/Article Information

Author Affiliations: Respiratory and Enteric Viruses Branch (Drs Shay and

) and Office of the Director (Mr Holman), Division of Viral and

Rickettsial Diseases, National Center for Infectious Diseases, Centers for

Disease Control and Prevention, Atlanta, Ga; Division of General Pediatrics,

Department of Pediatrics, University of Washington School of Medicine,

Seattle (Drs Newman, Liu, and Stout); and Department of Health Services,

University of Washington School of Public Health and Community Medicine,

Seattle (Dr Stout).

Corresponding Author and Reprints: K. Shay, MD, MPH, Centers for

Disease Control and Prevention, 1600 Clifton Rd NE, MS A-34, Atlanta, GA

30333 (e-mail: dks4@...).

Acknowledgment: We thank F. Owing, PhD, and Iris M. Shimuzu, PhD, for

technical guidance regarding NHDS data, L. , MA, and

O'Connor, MS, for editorial review, and ph S. Bresee, MD, Conrad J.

Clemens, MD, MPH, F. Dowell, MD, MPH, and Rita F. Helfand, MD, for

reading the manuscript critically.

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