PEDIATRICS Vol. 99 No. 3 March 1997,
p. e9
Copyright ©1997 by the American Academy of Pediatrics
ELECTRONIC ARTICLE:
PICNIC (Pediatric Investigators Collaborative Network on
Infections in Canada) Study of the Role of Age and Respiratory
Syncytial Virus Neutralizing Antibody on Respiratory Syncytial Virus
Illness in Patients With Underlying Heart or Lung Disease
Elaine E. L. Wang*,
Barbara J. Law
,
Joan L. Robinson§,
Simon Dobson
,
Suliman al Jumaah*,
Derek Stephens*,
François D. Boucher¶,
Jane McDonald#,
Ian Mitchell**, and
Noni E. MacDonald
From the * Hospital for Sick Children and University of Toronto,
Toronto, Ontario; the
Winnipeg Children's Hospital and University
of Manitoba, Winnipeg; the § University of Alberta Hospital and
University of Alberta, Edmonton;
British Columbia's Children's
Hospital and University of British Columbia, Vancouver; ¶ Centre
Hospitalier de l'Université de Laval and L'Université de
Laval, Québec City; # Montreal Children's Hospital and McGill
University, Montreal; ** Alberta Children's Hospital and University of
Calgary, Calgary; and 
Children's Hospital of Eastern Ontario and
University of Ottawa, Ottawa.
ABSTRACT
INTRODUCTION
PATIENTS AND METHODS
RESULTS
DISCUSSION
FOOTNOTES
ACKNOWLEDGMENTS
ABBREVIATIONS
REFERENCES
ABSTRACT
Objective. To determine the effects
of age and respiratory syncytial virus (RSV) antibody status on
frequency and severity of RSV infections in children with underlying
heart or lung disease.
Design. Cohort study conducted during two consecutive RSV
seasons.
Setting. Ambulatory patients at eight Canadian pediatric
tertiary care centers.
Methods. Subjects under 3 years old with underlying heart
disease who were digoxin-dependent or had not received corrective cardiac surgery or with underlying lung disease were enrolled. Demographic information and an acute sera for RSV neutralizing antibody
was obtained on enrollment. Weekly telephone follow-up consisting of a
respiratory illness questionnaire was followed with a home visit to
obtain a nasopharyngeal aspirate when there was new onset of
respiratory symptoms. The specimen was used to detect RSV antigen. RSV
illnesses were grouped as upper or lower respiratory tract infection
(LRI) based on clinical and radiographic findings. RSV hospitalizations
were considered to be those RSV infections that resulted in
hospitalization.
Results. Of 427 enrolled subjects, 160 had underlying lung
disease only, 253 had underlying heart disease only, and 14 had both.
Eleven percent and 12% of lung and heart disease groups, respectively,
had an RSV LRI. Three percent and 6% of lung and heart disease groups,
respectively, were hospitalized with RSV infection. A significant
decrease in frequency of RSV LRI and RSV hospitalization occurred with
increasing age, with a major drop in those older than 1 year vs those
younger than 1 year. Acute sera were available from 422 subjects.
Geometric mean RSV antibody titers demonstrated a U-shaped distribution
with increasing age. The trend to lower antibody concentrations in
premature infants did not reach statistical significance. The frequency
of RSV infection and RSV LRI was lower in patients with antibody at a
titer more than 100, although the difference for RSV hospitalization
was not statistically significant. These differences remained
significant after age adjustment.
Conclusion. Both age and RSV antibody status impact on RSV
illness and LRI. Reduction in illness frequency with increasing age may
lead to more informed targeting of those children most likely to
benefit from RSV immune globulin prophylaxis. respiratory syncytial virus, cohort study, passive prophylaxis, neutralizing antibody.
INTRODUCTION
Compared with its course in otherwise healthy children,
respiratory syncytial virus (RSV) infections lead to higher mortality and morbidity measured by hospital duration, transfer to intensive care, and ventilation in children with underlying heart or lung disease.1,2 Recently, a polyclonal RSV immune globulin
preparation, containing high titers of RSV neutralizing antibodies, was
approved in the United States for use as a prophylactic agent against
severe RSV infections. Licensure followed the demonstration of efficacy in terms of reduced frequency and duration of hospitalizations for RSV
lower respiratory tract infection (LRI) among children with underlying
lung disease and premature infants.3 Such prophylaxis, however, is expensive and requires monthly intravenous infusions during
the RSV season. Given the expense, time commitment, and difficulty
gaining intravenous access in premature infants, RSV immune globulin
may be more appropriately reserved for those children with the highest
risk for complicated disease.
Studies in otherwise healthy children have shown that the frequency of
primary and recurrent RSV infection is inversely correlated with the
titer of RSV neutralizing antibodies measured before the onset of the
RSV season.6 Information on illness or hospitalization frequency obtained in this population, however, is likely to
underestimate disease in patients with underlying cardiac or pulmonary
conditions.
This study was conducted to determine whether preseason RSV
neutralizing antibody titers reduced the frequency of RSV infection in
children with underlying heart or lung disease. In addition, current
information was obtained regarding hospitalization risk in this
population. Such data may be helpful in determining the population who
would be most likely to benefit from receipt of prophylactic RSV immune
globulin.
PATIENTS AND METHODS
Children followed at eight pediatric hospitals were eligible for
enrollment if they had underlying complex congenital heart disease or
chronic lung disease diagnosed before the 1993 to 1994 or 1994 to 1995 RSV season. They also had to be 3 years old or younger on September 1 before RSV season. Complex congenital heart disease was defined as a
congenital heart abnormality with the need for cardiac surgery or
dependence on cardiac medications. Chronic lung disease included
bronchopulmonary dysplasia, cystic fibrosis, pulmonary malformation,
and recurrent gastroesophageal reflux. Bronchopulmonary dysplasia is
defined as beginning with acute lung injury and diagnosed at 28 days of
age or later with clinical symptoms of tachypnea and retractions,
radiologic findings of hyperinflation or obvious cystic areas with
fibrotic strands, and blood gas abnormalities if in ambient
air.9 Outpatients were enrolled from September 1 until the
beginning of the RSV season, defined at each center as the first week
in which three or more children were hospitalized with proven RSV
infection. The only exceptions to this were hospitalized premature
infants who could be enrolled up to December 1 provided they had been discharged home. Prior RSV infection was not a cause for exclusion unless it occurred during a given center's defined enrollment period.
The protocol was accepted by the Research Ethics Boards of all
participating hospitals and patients were enrolled only after informed
consent was obtained. Consent was sought by the study nurse at each
center, who also was responsible for follow-up.
After enrollment, demographic data including details about the
underlying illness and gestational age, and a serum sample were
obtained. Weekly telephone follow-up inquired about respiratory illnesses using a previously described questionnaire.10
Subjects with a new respiratory illness identified by new respiratory
symptoms on the questionnaire were seen by the study nurse to collect
nasopharyngeal secretions by aspiration with a syringe and infant
feeding catheter. Because of financial constraints, such home visits to
collect nasopharyngeal aspirates were made only after the onset of RSV season at each center. Each new illness was classified as an upper or
lower respiratory infection with the latter distinguished by radiographic evidence of pneumonia or the new onset of wheezing or
exacerbation of preexisting wheezing. Any hospitalizations were noted.
Patients continued to have weekly follow-up until an RSV infection was
identified or the RSV season ended, defined as the month of May at all
sites. Once a nasopharyngeal aspirate had been positive for RSV for a
particular patient, no further specimens were obtained in that season.
Nasopharyngeal aspirates were processed in the virology laboratory at
each site using immunofluorescence microscopy or enzyme immunoassay as
previously described.2 Sera were stored at
70°C until
sent on dry ice to the study central laboratory in Winnipeg, Manitoba.
RSV neutralizing antibody was performed using previously described
methods.11 Briefly, sera were heat-inactivated and tested
in duplicate without exogenous complement. A 60% plaque reduction
assay was performed on microtiter plates lined with HEP2 cells. The RSV
test strains A2 (RSV subgroup A) and 18537 (RSV subgroup B),
immunoreagents and control sera were provided by Lederle Praxis
Biologicals Inc (Rochester, NY). A RSV neutralizing antibody was
considered high if the assay was positive at a dilution of 1:100. This
approximated the titer of 128 used as a cut-off for high antibody in a
study of RSV antibody in healthy children.6
A Fisher's exact test was used to compare the proportion of patients
with RSV LRI or RSV-associated hospitalization in different age groups.
Analysis of covariance was used to determine the effect of age and
prematurity on antibody concentrations. Prematurity was defined as a
gestational age of less than 33 weeks in this analysis, because one
would predict less maternal transfer of RSV antibody in more premature
neonates.
2 analyses were used to compare RSV
neutralizing antibody concentrations with frequency of RSV infection,
RSV LRI, RSV hospitalization, and all hospitalizations. A stratified
analysis was used to assess the effect of antibody after controlling
for the effect due to age.
RESULTS
Four hundred twenty-seven patients were enrolled. Their
demographic characteristics are summarized in Table 1.
Fourteen patients had both underlying heart and lung disease.
Eighty-four patients were followed in both RSV seasons. The most common
cardiac lesions included ventriculoseptal defect (59), pulmonary
stenosis (39), patent ductus arteriosus (29), atrial septal defect
(37), aortic coarctation (27), tetralogy of Fallot (20), atrial
ventricular canal defect (17), aortic stenosis (16), and transposition
of great vessels (11). Patients with patent ductus arteriosus or atrial
septal defect had these anomalies in conjunction with other cardiac
defects. Of patients with underlying lung disease, 72 never received
home oxygen supplementation, 85 had received it in the past, and 17 were receiving it at the time of study enrollment. Patients were
followed for an average of 23.6 weeks. A total of 558 nasopharyngeal
aspirates were obtained over the two seasons for an average of 1.3 specimens/patient.
|
Table 1.
Demographic Characteristics of Enrolled Patients
[View Table]
|
Eleven percent and 12% of lung and heart disease groups, respectively,
experienced an RSV LRI. Six percent and 3% of lung and heart groups
were hospitalized with RSV infection. There was a reduction in
frequency of RSV LRI and RSV hospitalization with increasing age in
both heart and lung disease subgroups (Table 2). The
subgroup of 114 patients with bronchopulmonary dysplasia was examined
separately because their premature birth may lead to their having
narrower airways and lower RSV neutralizing antibodies predisposing
them to more severe disease. Their RSV LRI and RSV-associated hospitalization rates were 11% and 6%, respectively, with similar age
specific rates to those observed in the overall group of children with
chronic lung disease of any kind. In the entire group, RSV LRI rates
were approximately threefold higher and RSV-associated hospitalizations
were over fivefold higher in those in the first year of life compared
with those rates in older children.
|
Table 2.
Frequency of Respiratory Syncytial Virus (RSV) Lower Respiratory
Infection and RSV Hospitalization by Age
[View Table]
|
Preseason sera was obtained from 422 patients. Antibody titers
varied by age (P = .0001) with trends to lower
titers in premature versus term infants that did not reach statistical
significance (Figure). There was a U-shaped distribution
with an initial fall to a nadir at 6 to 9 months followed by a rise in
antibody titers. The trends to lower antibody titers in subgroup B
patients in the younger age group as compared with subgroup A did not
reach statistical significance. In this analysis, prematurity was
defined as gestational age less than 33 weeks. When this analysis was performed again using gestational age less than 37 weeks as the definition of prematurity, the above observations remained the same.
Fig. 1.
Geometric mean respiratory syncytial virus antibody
by age and gestation.
[View Larger Version of this Image (26K GIF file)]
When baseline antibody concentrations were at least 100, a
significant reduction was observed in the frequency of RSV infections and LRIs. The reduction in frequency of RSV hospitalizations did not
reach statistical significance (Table 3). The
significant differences were maintained after age stratification.
That the effect was specific for RSV infection was confirmed
by the lack of difference in overall LRIs and hospitalizations when
children with high and low antibody titers were compared.
|
Table 3.
Antibody Status and Frequency of Respiratory Syncytial Virus (RSV)
Infection and Hospitalization
[View Table]
|
DISCUSSION
The reduction in incidence of RSV LRI and hospitalization with
increasing age observed in this patient population is similar to that
previously reported in healthy children.6,12,13 Because of
their compromised cardiopulmonary status, these subjects have a higher
RSV- associated hospitalization rate than that observed in otherwise
healthy children.6 The high rates of LRI and
hospitalization in young infants underscore the limited effectiveness
of active immunization against RSV if a series of three doses is
required. Thus, passive prophylaxis with RSV antibody-enriched
immunoglobulin has emerged as an option for prevention of RSV. The
overall hospitalization rates of 3% to 6% observed in this study were
much lower than the 20% found in controls participating in a
randomized controlled trial of RSV hyper immune
globulin.3,4 This difference may be attributable to at
least four reasons. First, there was a conscious effort to enroll more
infants, who are likelier to be hospitalized, into the randomized
trial.3 The mean age of children enrolled in the trial
approximated 8 months, whereas it was 18 months in our cohort study.
Second, given the complexity of the intervention, it is likely that
sicker children were enrolled in that trial. Third, the trial only
enrolled patients with bronchopulmonary dysplasia, whereas this cohort
included term infants with other pulmonary diseases as well. However,
the hospitalization rate in our patients with bronchopulmonary
dysplasia was the same as the rate for the group with underlying lung
disease. Finally, it is possible that there was less complete follow-up
in this cohort study compared with that in the trial. This would be
supported by the relatively low frequency of procurement of
nasopharyngeal aspirates. The limited funds for the study prevented
more exhaustive specimen collection: specimens for RSV diagnosis were
obtained when patients had respiratory symptoms only after the season
had started and further specimens were not obtained in children after their first RSV infection of the season. Such a bias toward
underdiagnosis may lead to less detection of LRIs than RSV-associated
hospitalizations, because RSV diagnostic testing is routinely performed
on all patients admitted to the study hospitals with respiratory
illness. In fact, the age-specific LRI rates observed in this study are
comparable to those reported in otherwise healthy children6
and in the randomized trial of prophylaxis with RSV hyperimmune
globulin.3,4 Thus, the lower hospitalization rates observed
in this cohort are probably related to the first two factors. The
hospitalization rate of 13.4% in the control group in another
randomized trial of RSV immune globulin5 falling in-between
that observed in this cohort study and that of the initial
trial3 further supports the variability in this outcome
measure even between those participating in randomized trials.
The rates of RSV LRI rates were 18.2% and 20.4% in infants with
underlying lung or heart disease. Corresponding hospitalization rates
in these groups were 14.5% and 6.9%, respectively. One can use the
`number needed to treat' to help in making a decision on the children
who should receive prophylaxis. The number needed to treat to prevent
one hospitalization can be calculated using the risk reduction of 67%
observed with RSV immune globulin in the randomized
trial3,4 and an estimate of baseline event rate.14 Using a baseline event rate of 20% observed in the
trial, approximately eight subjects would need to receive prophylaxis to prevent one hospitalization. Using a baseline event rate of 15% as
observed in infants with lung disease in this study, 10% in all
infants in this study, or 1.4% in 1- to 3-year-old children in this
study, then 10, 15, or 100 subjects, respectively, would require
prophylaxis to achieve the same benefit. From these calculations, children older than 12 months are less likely to benefit from RSV
immune globulin and a cost-benefit analysis may not support its use in
this population. Other factors such as prematurity in addition to
cardiac or pulmonary compromise should be considered in selecting
infants who could most benefit from prophylaxis if the main purpose is
the avoidance of hospitalization. Other important benefits of this
product are avoidance of the need for intensive care or ventilation.
However, these are much rarer events.
Why was there a higher hospitalization rate in patients with underlying
pulmonary vs cardiac disease? The bulk of the former group are made up
of premature infants. The nadir of endogenous, presumably maternally
derived, antibody occurred in both preterm and term infants at about 6 to 9 months. Although the difference did not reach statistical
significance, the antibody concentrations in preterm infants are lower
throughout the first year of life in the preterm infants. Premature
infants have two features contributing to more severe illness: the
abnormal lung structure with reduced surface area for gas exchange and
the relative lack of maternally derived RSV antibody. As their lung
function normalizes, their antibody levels decline during their first
year. One would, therefore, predict that the maximum benefit from
exogenous immune globulin in preventing RSV infection would occur early
in the first year of life in this group when the airways have not had a
chance to grow and there is little RSV neutralizing antibody.
Randomized trials provide the highest quality of evidence about the
efficacy of interventions.15 However, the generalizability of findings from such trials may be limited by differences in trial
participants and compliance with the regimen compared with that in the
usual clinical setting. This observational study provides additional
data to estimate the effectiveness of interventions in the usual
setting. The expected reductions in effects compared with those
observed in a trial are particularly relevant to decisions regarding
implementation of costly interventions.
FOOTNOTES
Dr al Jumaah is presently at King Faisal Specialist Hospital,
Riyadh, Saudi Arabia.
Received for publication Jul 1, 1996; accepted Sep 24, 1996.
Presented in part at the Annual Meeting of the Pediatric
Academic Societies, Washington, DC, May 10, 1996.
Reprint requests to (E.E.L.W.) Clinical Epidemiology Unit,
Hospital for Sick Children, 555 University Avenue, Toronto, Ontario,
Canada M5G 1X8.
ACKNOWLEDGMENTS
This study was funded by a grant from Lederle Praxis Biologicals
Inc, Rochester, NY.
We wish to thank the dedicated study nurses, the patients and their
parents.
ABBREVIATIONS
RSV, respiratory syncytial virus.
LRI, lower
respiratory tract infection.
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