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

edi t or i a l s

Therapy for Bronchiolitis: When Some Become None

Caroline Breese Hall, M.D.

In past centuries, infant mortality in the first year
of life was described as the greatest plague.1 In­
fants in the 21st century continue to be plagued
by high rates of hospitalization, and bronchiolitis
is the number one cause.2,3 Despite therapeutic
advancements, hospitalizations for bronchiolitis
have continued to increase. The annual rate of
emergency department visits for bronchiolitis dur­
ing the season of respiratory syncytial virus, the
major cause of this condition, has been estimated
as 22.8 per 1000 for children 12 months of age or
younger.2 Yearly costs for bronchiolitis hospitali­
zations exceed $700 million. Yet even these strik­
ing figures underestimate the health care burden
imposed by bronchiolitis. They do not reflect the
costs associated with the many more frequent of­
fice visits of less ill children or with the second­
ary infections among high-risk family contacts.4
A better indicator of the need for control of
bronchiolitis is the increasing accumulation of
therapeutic studies and the continued conun­
drums and controversies they engender.5,6 The
clinical manifestations, course, and pathology of
bronchiolitis have been well described, but the
pathogenesis has not. Whether the pulmonary
disease results from the acute lytic effects of the
virus, the infant’s immune response, or both re­
mains unclear.7,8 This may partially explain why
effective interventions remain elusive.
Current therapeutic options for bronchiolitis
are few — primarily antiviral drugs, bronchodila­
tors, and corticosteroids — and all are controver­
sial. Not one is routinely recommended.5,6 Yet
one or more of these agents, as well as antibi­
otics, are administered to as many as 50 to 80%
of infants with bronchiolitis admitted to hospi­
tals in the United States and other countries.9,10
Part of the rationale for their use is their ac­
knowledged benefit of diminishing the respiratory
distress from other obstructive airway illnesses,
such as asthma.11 Furthermore, corticosteroids
may affect the pathogenesis of bronchiolitis at­
tributed to respiratory syncytial virus. Both clin­
ical and experimental studies indicate that an
altered and augmented immune response of the
young infant contributes to the phenotypic ex­
pression and severity of respiratory syncytial vi­
rus disease and may predispose the infant to
pulmonary sequelae.7,8 The variable compliance
with the recommen­dations against the routine
use of corticosteroids may also relate to the
conflicting results of the studies.5,6 They have
been heterogeneous in design and generally in­
volved small numbers of patients, thus reducing
the strength of their evidence-based recommen­
dations.
In this issue of the Journal, Corneli and col­
leagues12 report on a randomized trial examining
whether dexamethasone administered to previous­
ly healthy infants presenting with a first episode
of wheezing diagnosed as moderate-to-severe
bronchiolitis reduces the need for hospitalization.
The results, although negative, are important and
will probably be accompanied by close scrutiny
of the study’s design and the extent of its clini­
cal relevance.
The study, which involved 20 emergency de­
partments, was designed to avoid many of the
deficits of previous corticosteroid trials. It was
conducted over three respiratory seasons, and
personnel at each site received yearly training in
study procedures. The infants in the trial received
a single oral dose of dexamethasone (1 mg per
kilogram of body weight) or placebo, and during
the next 4 hours their respiratory status was as­
sessed with use of a standardized scoring instru­

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 editorials
ment. The study is singular in the number of in­
fants enrolled (600) and in the broad spectrum of
contributing emergency departments.
Nonetheless, variations in practice among the
sites probably existed. The primary outcome —
the decision to hospitalize or discharge the infant
— was determined by individual physicians, but
it was corroborated as a valid measure of the
effect of dexamethasone by the secondary out­
come — the change in the respiratory status
after 4 hours as measured by the Respiratory As­
sessment Change Score. No significant difference
was found between the infants treated with the
corticosteroid and those receiving placebo. The
trial was designed to closely duplicate the meth­
ods of a previous controlled study of 70 infants
that demonstrated, in contrast with this trial, sig­
nificant benefit from the oral administration of
dexamethasone as compared with placebo.13 How­
ever, the degree of change in score that is pre­
dictive of a relevant change in clinical status has
not been determined. The short period of obser­
vation also potentially limits the study’s value for
predicting the subsequent prognosis.
The strict criteria for inclusion in the study
by Corneli et al. enhanced the uniformity of
the enrolled population, but these criteria also
limited the study’s representation of the overall
population of infants presenting with bronchi­
olitis. What should be considered, therefore, is
whether the results of this carefully defined seg­
ment of bronchiolitis cases can and should be
applied to the treatment of other infants with a
first episode of bronchiolitis. If not, will the con­
clusions be clinically and economically relevant?
Of 8686 patients initially assessed, 93% were
considered ineligible, 91% of whom did not meet
the inclusion criteria. A notably large proportion,
41%, was excluded because the infants had had
a previous episode of wheezing; one fourth were
not considered ill enough to meet the criteria for
moderate-to-severe bronchiolitis. Still, these in­
fants were judged by their parents or primary
physician to be ill enough to require evaluation
in an emergency department, and they would
make up an even larger proportion of the bron­
chiolitis cases seen in office practices than the
infants who were enrolled in the study.
Infants younger than 2 months and children
older than 12 months were also excluded from
the study. Knowing the proportion of children
with bronchiolitis presenting to the participating
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emergency departments within these age groups
would be of interest. The majority of infants hos­
pitalized with bronchiolitis are less than 6 months
of age, and most are 2 to 3 months old.3,14 These
youngest infants are the most likely to have acute
complications, such as apnea, and altered respons­
es to corticosteroid therapy. Children older than
1 year of age, although less likely to be hospital­
ized because of their larger airways and more
competent immune systems, continue to have
considerable rates of hospitalization.3,15 The char­
acteristics of bronchiolitis among these younger
and older children may differ from those of the
illness as it occurs in children between 2 and 12
months of age. For this very reason, their exclu­
sion from the study is warranted, but applying
the findings of the study to these children is
not justified.
An important question is whether corticoste­
roid administration diminishes the risk of the re­
current wheezing that develops in 20 to 50% of
infants diagnosed with bronchiolitis.7,8 Although
these episodes of recurrent wheezing are most
frequent in the first several years after an infant
contracts bronchiolitis, they have been linked to
the later occurrence of asthma and chronic lung
abnormalities.7,8 The effect of corticosteroid
therapy on the development of later pulmonary
dysfunction is unresolved. Among the limited
number of studies examining this issue, a few
have suggested benefit, but more have not.16
Follow-up of the children enrolled in the Cor­
neli study could extend its value and answer a
major clinical question.
These questions and the potential limitations
of the study should not diminish recognition of
the soundness of the study’s results and their
clinical pertinence. The findings are bolstered by
the study’s size and the controlled, randomized
design. The conclusions are corroborated by
the additional demonstration that the findings
were independent of site and extended beyond
the 4 hours of initial observation, according to
an interview with the parent or guardian and
chart review. Corticosteroid therapy did not sig­
nificantly affect the duration of hospitalization
or the need for subsequent medical visits or re­
admission.
Despite the value of this study, the long his­
tory of therapies and recommendations attending
bronchiolitis suggest that the study’s results will
not appreciably change the nature of the care pro­
403
 The n e w e ng l a n d j o u r na l
vided by the primary physician faced with a young,
distressed infant and anxious parents. Withhold­
ing therapy is much more difficult than giving it.
No potential conflict of interest relevant to this article was re­
ported.
From the Department of Infectious Diseases, University of Roch-
ester School of Medicine and Dentistry, Rochester, NY.
1. Knapp VJ. Major medical explanations for high infant mor­
tality in nineteenth-century Europe. Can Bull Med Hist 1998;15:
317-36.
2. Leader S, Kohlhase K. Recent trends in severe respiratory
syncytial virus (RSV) among US infants, 1997-2000. J Pediatr
2003;143:Suppl:S127-S132.
3. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Ander­
son LJ. Bronchiolitis-associated hospitalizations among US chil­
dren, 1980-1996. JAMA 1999;282:1440-6.
4. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE.
Respiratory syncytial virus infection in elderly and high-risk
adults. N Engl J Med 2005;352:1749-59.
5. American Academy of Pediatrics Subcommittee on Diagno­
sis and Management of Bronchiolitis. Diagnosis and management
of bronchiolitis. Pediatrics 2006;118:1774-93.
6. Management of bronchiolitis in infants and children. Evi­
dence report/technology assessment. No. 69. Rockville, MD:
Agency for Healthcare Research and Quality, January 2003:1-5.
(AHRQ publication no. 03-E009.)
7. Openshaw PJ, Dean GS, Culley FJ. Links between respira­
tory syncytial virus bronchiolitis and childhood asthma: clini­
Network Medicine — From Obesity to the “Diseasome”
Albert-László Barabási, Ph.D.
A recent study reported that among people who
carried a single copy of the high-risk allele for
the FTO gene, which is associated with fat mass
and obesity, the risk of obesity increased by 30%.
The risk of obesity increased by 67% among peo­
ple who carried two alleles, and on average they
gained 3.0 kg (6.6 lb) or more.1 Given that ap­
proximately one sixth of the population of Euro­
pean descent is homozygous for this allele, this
link between the FTO gene and obesity appears
to be one of the strongest genotype–phenotype
associations detect­ed by modern genome-screen­
ing techniques.
That obesity has a genetic component is not
surprising: researchers have long known that it
often runs in families. In this issue of the Journal,
Christakis and Fowler suggest that friends have
an even more important effect on a person’s risk
of obesity than genes do.2 The authors recon­
structed a social network showing the ties between
friends, neighbors, spouses, and family members
among participants of the Framingham Heart
404 n engl j med 357;4  www.nejm.org  july 26, 2007
The New England Journal of Medicine
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Copyright © 2007 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
cal and research approaches. Pediatr Infect Dis J 2003;22:Suppl:
S58-S65.
8. Martinez FD. Respiratory syncytial virus bronchiolitis and
the pathogenesis of childhood asthma. Pediatr Infect Dis J 2003;
22:Suppl:S76-S82.
9. Behrendt CE, Decker MD, Burch DJ, Watson PH. Interna­
tional variation in the management of infants hospitalized with
respiratory syncytial virus. Eur J Pediatr 1998;157:215-20.
10. Christakis DA, Cowan CA, Garrison MM, Molteni R, Mar­
cuse E, Zerr DM. Variation in inpatient diagnostic testing and
management of bronchiolitis. Pediatrics 2005;115:878-84.
11. Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA, Bota GW.
Early emergency department treatment of acute asthma with
systemic corticosteroids. Cochrane Database Syst Rev 2001;1:
CD002178.
12. Corneli HM, Zorc JJ, Mahajan P, et al. A multicenter, random­
ized, controlled trial of dexamethasone for bronchiolitis. N Engl
J Med 2007;357:331-9.
13. Schuh S, Coates AL, Binnie R, et al. Efficacy of oral dexa­
methasone in outpatients with acute bronchiolitis. J Pediatr
2002;140:27-32.
14. Parrott RH, Kim HW, Arrobio JO, et al. Epidemiology of
respiratory syncytial virus infection in Washington, D.C. II. Infec­
tion and disease with respect to age, immunologic status, race
and sex. Am J Epidemiol 1973;98:289-300.
15. Nicholson KG, McNally T, Silverman M, Simons P, Stockton
JD, Zambon MC. Rates of hospitalisation for influenza, respira­
tory syncytial virus and human metapneumovirus among infants
and young children. Vaccine 2006;24:102-8.
16. Gern JE. Mechanisms of virus-induced asthma. J Pediatr 2003;
142:Suppl:S9-S14.
Copyright © 2007 Massachusetts Medical Society.
Study, making use of the fact that the participants
had been asked to name their friends to facilitate
follow-up in the study. The authors observed that
when two persons perceived each other as friends,
if one friend became obese during a given time
interval, the other friend’s chances of following
suit increased by 171%. Among pairs of adult sib­
lings, if one sibling became obese, the chance
that the other would become obese increased by
40%. The results of this study also indicate that
obesity is clustered in communities. For example,
the risk that the friend of a friend of an obese
person would be obese was about 20% higher in
the observed network than in a random network;
this effect vanished only by the fourth degree of
separation.
In the past 7 years, our understanding of net­
works has undergone a revolution because of the
emergence of a new array of theoretical tools
and techniques for mapping out real networks.
These advances have included some surprises in­
dicating that most real networks in technologi­