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PEDIATRICS Vol. 108 No. 4 October 2001, pp. 1000-1003
Approximately 3% of children in the
United States will be hospitalized in the first year of life because of
a viral infection of the lower respiratory tract.1,2
Viruses that account for the vast majority of hospitalizations
resulting from pneumonia and bronchiolitis include respiratory
syncytial virus (RSV), parainfluenza viruses (particularly type 3),
influenza viruses, and adenoviruses. A recent report from the Centers
for Disease Control and Prevention provides important information on
the epidemiology of pediatric viral lower respiratory tract disease in
the United States, estimating that 123 000 hospitalizations resulting
from bronchiolitis occur each year in children in the first year of
life.1 During the 17 years covered in this report from
1980 to 1996, hospitalization rates for children <12 months with viral
infection of the lower respiratory tract increased more than twofold.
RSV alone accounts for 50% to 90% of bronchiolitis hospitalizations
and 20% to 50% of pediatric hospitalizations for pneumonia.
Approximately 500 RSV-associated deaths occur each year in the United
States.3 This mortality figure is lower than an estimate
made in 1985 by the National Institute of Medicine, at least partly
because of improvements in the management of hospitalized
infants.4 The annual cost of RSV hospitalization for
infants in the United States is estimated to be in excess of $300
million to $400 million.5
Despite the fact that about 16% of hospital admissions for children in
the first year of life are because of viral lower respiratory tract
illness, there remains a remarkable lack of consensus on the optimal
management of patients.1,6 Viral infection of the lower
airway is generally a self-limited condition. Nonetheless,
bronchiolitis is notorious for variation in disease expression based on
a number of factors, including the presence of underlying heart or lung
disease, gestational age, chronological age, and viral
strain.7 In this issue of Pediatrics, Willson
et al8 explore the intriguing issue of differences in
resource utilization for infants hospitalized with viral lower respiratory infection at 10 geographically diverse children's medical
centers and demonstrate a striking variation in practice patterns. One
of the important contributions of this paper is the use of the
Pediatric Component of the Comprehensive Severity Index to standardize
comparison of patients with similar disease acuity at different
institutions. Not surprisingly, hospital costs correlated strongly with
intensity of intervention. However, the finding of an inverse
correlation between disease severity on admission and institutional
average costs suggests an opportunity for cost savings through
reduction of inappropriate care without a compromise in quality of
care.
Standardizing clinical practice by the use of guidelines-based
education has been shown to reduce admissions, reduce resource utilization, and shorten length of stay for hospitalized infants with
bronchiolitis without increasing readmission rates or decreasing family
satisfaction.9,10 Ongoing educational efforts can sustain
changes in management over time.11 A number of issues
regarding optimal management of infants hospitalized with bronchiolitis
are yet to be resolved with appropriate placebo-controlled trials. But
the challenge raised in the report by Willson et al is to modify
practice patterns based on what is currently known and to avoid costly
interventions that do not alter the course of disease.8
What criteria form the basis for a decision to hospitalize an infant
with bronchiolitis? Certain underlying diseases place an infant at
increased risk of more severe disease. Congenital heart disease
(particularly cardiac lesions associated with increased pulmonary blood
flow or pulmonary artery hypertension), prematurity, season of birth,
and the requirement for supplemental oxygen in an infant with chronic
lung disease are well-recognized markers for more severe
disease.7 Other conditions may place a child at variable
risk of severe disease and may lower the threshold for admission:
neuromuscular disease, history of recurrent aspiration, congenital
anomaly of the airway, familial dysautonomia, myasthenia gravis, Down
syndrome, cystic fibrosis, and an immunodeficiency state. Variation in
disease presentation as a function of geographic location has been
described but is incompletely understood, perhaps reflecting
differences in altitude or differences in air quality in certain urban
cities.12 A report from New York State described a
fourfold variation in hospitalization rates for viral lower respiratory
infections with the strongest predictor of admission being low
socioeconomic status.13 Other factors influencing a
decision for admission may include reimbursement considerations, bed
availability, and referral patterns.
Once admitted, what factors contribute to the dramatic differences in
resource utilization noted in this study? Management strategies for
children with viral infections of the lower respiratory tract are
primarily supportive but the type and frequency of monitoring will add
to hospital costs.14-16 All infants hospitalized with
lower respiratory tract disease require careful clinical assessment of
respiratory status, including measurement of oxyhemoglobin saturation.
Low concentrations of supplemental oxygen are generally sufficient to
maintain adequate oxygen saturation. Monitoring of arterial carbon
dioxide tension will be needed in a small number of infants. Adequate
hydration is important and for tachypneic patients, parenteral therapy
may be necessary. Judicious use of the laboratory to confirm a viral
etiology by culture or by detection of RSV antigen in nasopharyngeal
aspirates generally is appropriate to rule out a bacterial etiology.
However, repeat testing of a patient already known to be infected or
screening of an asymptomatic contact generally is not appropriate.
Numerous studies have confirmed the importance of infection control
policies in prevention of nosocomial viral
infections.17,18 A recent report from Children's Hospital
of Philadelphia demonstrated that such policies are also
cost-effective; each dollar spent on infection control saved an
estimated $6 that would have been spent on nosocomial
disease.19 Patients who acquire nosocomial RSV disease are
more likely to have underlying cardiopulmonary abnormalities than
infants admitted with community acquired RSV disease and, therefore,
more likely to have a complicated course. Failure to initiate isolation
procedures in a timely manner may add to the cost of RSV disease.
A decision to admit to the intensive care unit (ICU) is generally based
on the possible need for intubation because of progressive hypercarbia,
increasing hypoxemia despite supplemental oxygen or apnea. Criteria for
ICU admission will vary among physicians as noted in the study by
Willson et al8, which demonstrated a range in ICU
utilization of 19% to 56%. Most infants admitted to the hospital with
bronchiolitis or pneumonia will not have underlying disease that places
them at increased risk of respiratory failure. Among otherwise healthy
infants, ICU admission because of respiratory deterioration is an
uncommon occurrence. In a study from Children's Hospital at Strong,
only 1.8% of 542 previously healthy, full-term infants required
transfer to ICU for evolving respiratory distress.20 Some
institutions lack a transitional care or step-down unit. This may add
to hospital costs when a patient spends extra time in a more expensive
ICU bed because of concern that an improving infant requires closer
observation than can be provided on the ward.
Bronchodilator therapy is commonly used in the management of
hospitalized infants with bronchiolitis although conclusive evidence of
efficacy has not been demonstrated. More than 90% of the patients in
the report by Willson et al8 received this therapy. The
results of most prospective, placebo-controlled trials with Placebo-controlled trials with corticosteroids have failed to
demonstrate a beneficial effect on the course of bronchiolitis in
hospitalized infants.25,26 Nonetheless, in the study by
Willson et al8, between 8% and 61% of patients received
corticosteroid therapy. There has been some interest in the possibility
that simultaneous administration of an antiviral agent and an
antiinflammatory agent such as a steroid might reduce the viral load
and shorten the disease process, but there is insufficient clinical
experience to support this approach at this time. There is a
theoretical concern that steroid therapy during the acute stage of
illness could result in higher viral titers and prolonged viral
shedding.27
Ribavirin, a synthetic purine nucleoside, is the only antiviral agent
which has been licensed by the Food and Drug Administration for the
management of RSV bronchiolitis/pneumonia.28,29 Early
trials documented a modest antiviral effect from ribavirin as defined
by a reduction in RSV titer in nasopharyngeal secretions relative to
controls. However, it has proven more difficult to demonstrate
clinically relevant benefit from ribavirin therapy. Well-conducted,
placebo-controlled trials with ribavirin have failed to demonstrate a
consistent difference between groups in terms of a requirement for
mechanical ventilation, duration of stay in the pediatric ICU, or
duration of hospitalization. In some placebo-controlled trials, a
modest improvement in oxygen saturation has been reported in ribavirin
recipients, but this is of uncertain clinical significance.
Furthermore, concern has been expressed regarding the choice of placebo
in these trials because both water and saline may induce bronchospasm
in control patients, introducing bias in favor of ribavirin efficacy.
It has been known for some time that infants hospitalized with severe lower respiratory tract disease resulting from RSV are at increased risk of recurrent episodes of wheezing, recurrent lower respiratory tract illness, and abnormal pulmonary function testing later in childhood.30 Long-term follow-up studies of
ribavirin-treated patients have been difficult to conduct in a rigorous
fashion but they have not provided reproducible data to suggest
ribavirin has an effect on pulmonary outcome.31-33 Use of
this antiviral agent has become difficult to justify because of the
high cost of ribavirin therapy and inconsistent reports of efficacy.
Antibiotics are unlikely to have therapeutic value in a hospitalized
patient with bronchiolitis. Nonetheless, many patients have blood
cultures obtained and receive parenteral antibiotic therapy,
particularly infants with an abnormal chest radiograph. Approximately
25% of infants will have radiographic evidence of atelectasis or
consolidation consistent with a possible bacterial infection.34 However, bacteremia or bacterial pneumonia in
hospitalized infants with bronchiolitis is unusual. Otitis media occurs
in infants with RSV bronchiolitis, but most patients can be treated
orally if antibiotic therapy is necessary.35
In view of the burden placed on patients and on the health care system
by viral infections of the lower respiratory tract, what future options
may become available for control of viral disease? Despite >35 years
of effort, it has proven difficult to develop a safe and effective RSV
vaccine for young infants that produces protective immunity but does
not enhance natural infection.36 Subunit RSV vaccines
consisting of surface glycoproteins F and G, which stimulate
neutralizing antibody, seem to be safe and immunogenic in seropositive
children as young as 12 months, although efficacy has not been
determined. A live-attenuated, temperature-sensitive RSV vaccine for
intranasal immunization that elicits both a local mucosal antibody
response and systemic immunity is under development.37
Temperature sensitive strains preferentially replicate at the lower
temperature of the nasal cavity and less efficiently at core body
temperature. Intranasal administration of the vaccine strain results in
a subclinical infection that induces immunity by simulating a natural
infection of the upper airway. To date, problems encountered with such
attenuated vaccines include lack of genetic stability (back-mutation to
virulence), overattenuation (does not induce immune response), and
underattenuation (causes symptoms in vaccinee). Currently, the only
option for prevention of RSV infection in high-risk infants is passive
immunoprophylaxis with either a polyclonal hyperimmune globulin,
Respigam, or preferentially, with a humanized murine
monoclonal anti-F glycoprotein antibody preparation,
palivizumab.38 Both preparations have been shown to be safe and efficacious in large, well-designed clinical trials.39 This intervention is restricted to a relatively select number of high-risk infants because of cost. Most infants hospitalized with RSV infection will not fall into a high-risk group
and therefore will not satisfy the recommended guidelines for passive
immunoprophylaxis. Only a relatively small number of total RSV
hospitalizations will be prevented by targeting high-risk infants,
although these infants are most likely to experience a complex hospital
course.40 To dramatically decrease the overall burden of
disease and cost associated with RSV, a vaccine will be required.
Inactivated influenza vaccines for use in infants After RSV, parainfluenza virus type 3 is the most common cause of
hospitalization attributable to bronchiolitis and pneumonia in young
children. Vaccines under consideration include subunit vaccines
containing surface glycoproteins, as well as live-attenuated vaccines.
An attenuated, intranasal parainfluenza 3 vaccine has been shown to be
safe, immunogenic, and genetically stable in seropositive as well as
seronegative infants as young as a few months of age.44 A
live, oral adenovirus vaccine consisting of serotypes 4 and 7 for use
in military recruits was available for a number of years but has not
been studied in civilians and is no longer being
produced.45
Although most infants with bronchiolitis can be safely managed as
outpatients, hospitalization rates for this illness seem to be
increasing. Because the optimal course of management of hospitalized
infants is not clear and because the course of illness is variable from
patient to patient, differences in the use of various interventions and
procedures is to be expected. Important advances in the management of
patients with bronchiolitis have dramatically reduced mortality rates
to <1% among most groups of hospitalized infants. The task now is to
carefully define those interventions that are efficacious, those
interventions that are unlikely to be effective, and those
interventions that need evaluation in controlled clinical trials.
-2-agonist inhalation fail to demonstrate a significant improvement in oxygen saturation, time to discharge, or reduction in
wheezing.21-23 Similarly, agents with 
-adrenergic or
anticholinergic activity have not conclusively shown a beneficial
effect in trials in hospitalized infants with bronchiolitis. Because of
concern that reactive airway disease may be misdiagnosed as
bronchiolitis, one approach is to assess results of bronchodilator
therapy after the initial dose. Repeat doses of an inhaled
bronchodilator are then continued only in the small number of infants
with well-documented improvement in respiratory function soon after the
first dose. Some studies report that inhalation bronchodilator therapy
can cause paradoxical bronchospasm with worsening
hypoxia.24
6 months of age are
currently recommended for high-risk infants and
children.41 A promising approach to influenza control is a
cold-adapted, live-attenuated influenza vaccine (CAIV) administered via
the intranasal route. Phase III studies suggest that CAIV containing 2 attenuated A and 1 B strains is >90% effective in children in
preventing cases of influenza resulting from strains included in the
vaccine and only slightly less effective against strains that
demonstrate antigenic drift.42,43 Hospitalization rates in
children <5 years resulting from influenza infection appear to be
equivalent to those in adults over 50 years of age for whom the
influenza vaccine is currently recommended.41 The ease
with which CAIV can be administered is likely to result in reconsideration of a recommendation for universal vaccination of
children against influenza, once the vaccine is licensed.
Floating Hospital for Children at New England Medical Center
Division of Pediatric Infectious Disease
Tufts University School of Medicine
Boston, MA 02111
FOOTNOTES
Received for publication Feb 20, 2001; accepted Feb 22, 2001.
Reprint requests to (H.C.M.) Floating Hospital for Children at New England Medical Center, Division of Pediatric Infectious Disease, Tufts University School of Medicine, 750 Washington St, Boston, MA 02111. E-mail: cmeissner{at}lifespan.org
ABBREVIATIONS
RSV, respiratory syncytial virus; ICU, intensive care unit; CAIV, cold-adapted, live-attenuated influenza vaccine.
REFERENCES
2-agonists in bronchiolitis: a
reappraisal and meta-analysis.
Pediatrics
1997;
100:233-239 This article has been cited by other articles:
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  H. C. Meissner, M. B. Rennels, S. S. Long, and L. K. Pickering Immunoprophylaxis With RespiGam Pediatrics, March 1, 2004; 113(3): 629 - 629. [Full Text] [PDF]
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 W. C. Bordley, M. Viswanathan, V. J. King, S. F. Sutton, A. M. Jackman, L. Sterling, and K. N. Lohr Diagnosis and Testing in Bronchiolitis: A Systematic Review Arch Pediatr Adolesc Med, February 1, 2004; 158(2): 119 - 126. [Abstract] [Full Text] [PDF]
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 R. G. Cox Repair of incarcerated inguinal hernia in an infant with acute viral bronchiolitis: [La reparation d'une hernie inguinale incarceree chez un enfant atteint d'une bronchiolite virale aigue] Can J Anesth, January 1, 2004; 51(1): 68 - 71. [Abstract] [Full Text] [PDF]
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 J B M van Woensel, W M C van Aalderen, and J L L Kimpen Viral lower respiratory tract infection in infants and young children BMJ, July 3, 2003; 327(7405): 36 - 40. [Full Text] [PDF]
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