PEDIATRICS Vol. 99 No. 2 February 1997,
p. e7
Copyright ©1997 by the American Academy of Pediatrics
ELECTRONIC ARTICLE:
Twenty Years of Outpatient Respiratory Syncytial Virus
Infection: A Framework for Vaccine Efficacy Trials
Randall G. Fisher*,
William C. Gruber*,
Kathryn M. Edwards*,
George W. Reed
,
Sharon J. Tollefson*,
Juliette M. Thompson*, and
Peter F. Wright*
From the Departments of * Pediatric Infectious Diseases and
Preventive Medicine, Vanderbilt University Medical Center,
Nashville, Tennessee.
ABSTRACT
- INTRODUCTION
- METHODS
- RESULTS
- DISCUSSION
- ACKNOWLEDGMENTS
- ABBREVIATIONS
- REFERENCES
ABSTRACT 
Background. Respiratory syncytial
virus (RSV) is the most important viral respiratory pathogen of infancy
and childhood. Much has been written about inpatients with severe
disease. Inpatients, however, represent only a minority of RSV-infected
children. We studied the characteristics of symptomatic outpatient RSV
infection in healthy children to gain a better understanding of RSV
disease and to provide a background for the testing of intervention
strategies in children without high-risk conditions.
Methods. A total of 1113 children were followed during 20 consecutive RSV seasons. Signs and symptoms of respiratory infection were monitored. Cultures were obtained for febrile upper respiratory infection, acute otitis media, and lower respiratory infection (LRI).
Rates of febrile upper respiratory infection, acute otitis media, LRI,
and hospitalization were calculated. Given those rates, numbers of
children needed to demonstrate efficacy of a vaccine product were
calculated.
Results. Mild disease from RSV infection lacked some of
the classic features of RSV infection seen in hospitalized children. Involvement of the lower respiratory tract was, however, noted to be
much higher in RSV infection than it was in infection with other viral
respiratory pathogens. LRI was, therefore, considered the best
candidate endpoint for vaccine trials. A product with 60% efficacy
could be proven, with a power of 0.8, to be efficacious with as few as
1500 infants.
Conclusions. RSV infection is common and often involves
the lower respiratory tract, even in outpatients. Our 20-year study of
RSV infection provides a basis for calculation of sample sizes to be
used in trials of vaccine candidates. respiratory syncytial virus, outpatient, epidemiology, vaccine, bronchiolitis.
INTRODUCTION
Respiratory syncytial virus (RSV) is widely recognized as the most
important viral respiratory pathogen of infancy and
childhood.1 It causes distinct winter epidemics in a
predictable fashion each year2 and leads to frequent
hospitalizations for bronchiolitis and pneumonia. Newborns and young
infants are particularly prone to developing more severe lower
respiratory tract disease.3
More than 50% of infants acquire the infection during their first RSV
season,4 and it is thought that most primary RSV infections
are symptomatic.4 By the time they have lived through two
RSV seasons, more than 90% of children demonstrate serologic evidence
of infection.4
Accordingly, the development of a vaccine for RSV has received a high
priority.5 Many vaccine products are currently undergoing animal studies and early clinical trials. A thorough understanding of
the clinical syndrome of RSV infection, including attack rates and
symptom frequency in an otherwise healthy outpatient population, will
be critical to the design of such trials.
Although many studies of RSV infection in hospitalized patients have
been reported,6 surprisingly little is written about outpatient RSV infection.13,14 We report a longitudinal
study of RSV infection that spans 20 years and project, using
symptomatic illness endpoints, population requirements for trials of
RSV vaccine candidates.
METHODS
Data detailing RSV infection in the outpatient population were
obtained from the Vanderbilt Vaccine Clinic of a National Institutes of
Health-supported vaccine treatment and evaluation unit for a 20-year
period from 1973 to 1993. Healthy full-term infants were enrolled into
the clinic population at birth. Children in whom chronic diseases
developed were excluded from the study. Children had all of their well
and sick care provided by members of the pediatric infectious diseases
faculty and staff. Well child care followed American Academy of
Pediatrics guidelines as to timing of well infant examinations and
routine vaccine administration. At enrollment in the clinic, they were
encouraged to participate in vaccine trials as suitable candidates
became available and agreed to surveillance for respiratory and enteric
pathogens. Parents were instructed to bring their children to the
clinic if runny nose, cough, fever, or symptoms suggesting ear
infection developed. Members of the faculty and staff were available by telephone 24 hours a day, and patients were seen preferentially by our
clinic rather than through emergency departments. During the study
period, two trials of vaccine products to RSV were performed. Children
who participated in either of these trials were excluded from this
study. Enrolled infants represented a cross-section of the Nashville
community. Fifty-one percent were male, 53.5% were white, 43.8% were
African-American, and 2.8% were of other races. Just more than half
had no siblings. Ninety percent were from urban sites, and 10% lived
in rural areas. Children were followed for an average of 3.5 years,
after which their care was transferred to other sources in the
community. Children leaving the clinic were replaced by newborns, to
maintain a population of approximately 200 children. An approximation
of the age distribution of children in the clinic follows. During the
20-year period, of 3615 child-years followed in the clinic, 17% were
of children younger than 6 months, 15% were of children from 6 to 12 months of age, 25% were of children 1 to 2 years of age, 19% were of children between the ages of 2 and 3 years, and 24% were of children 3 years or older. All symptoms and signs of respiratory illness were
recorded on a standardized clinical form; one upper respiratory tract
infection (URI) diagnosis and/or one lower respiratory infection (LRI)
diagnosis was made at each respiratory illness visit. Informed consent
for participation in surveillance for respiratory and enteric pathogens
was obtained with the approval of the Vanderbilt Institutional Review
Board.
Nasal wash cultures for virus isolation were obtained for any of the
following indications: URI accompanied by fever of 38.4°C or greater,
signs or symptoms suggesting LRI, and acute otitis media (AOM). Because
this study was begun before the availability of rapid antigen detection
tests, these were not performed. Wheezing, rales, rhonchi, respiratory
distress, and retractions were considered signs of LRI. AOM was defined
as redness and bulging of the tympanic membrane, with loss of normal
light reflex and decreased mobility on pneumatic otoscopy.
Bronchiolitis was defined as a wheezing illness without evidence of
focal infiltrate on a chest roentgenogram. Pneumonia was defined as
presence of infiltrate or consolidation on a chest roentgenogram in a
patient with rales or decreased breath sounds at physical examination.
Nasal washes were performed by instilling 15 mL of sterile saline into
one nostril and collecting the wash in a medicine cup. Contents of the
cup were immediately transferred to a vial containing 0.5 mL of
Pen-Genta-Gel (200 000 units of penicillin and 50 mg of gentamicin in
100 mL of sterile water and 10% gelatin) and placed on ice. Specimens
were taken to the laboratory within 3 hours, where they were cultured
on human neonatal kidney, human embryonic lung, HEp 2, rhesus monkey kidney, Maden-Darby canine kidney, and Vero cells.
The RSV season was defined as the time between the first RSV isolate
after November 1 and the last isolate before April 30 obtained from the
clinic population.
Statistical Methods
Relative risks and corresponding confidence intervals are
Mantel-Haenszel estimates computed using SAS PROC FREQ (version 6.10; SAS Institute, Cary, NC). Comparison of rates of hospitalization and LRI in RSV-positive children by age group were made using Fisher's
exact test computed with StatXact version 2 (CYTEL Software Corp,
Cambridge, MA). Power calculations were done using a public domain
program by Dupont and Plummer15 as well as Monte Carlo simulations to confirm the sample sizes for Table 5. A significance level of P = .05 was assumed in all calculations.
|
Table 5.
Sample Sizes Needed for Vaccine Trials Using Respiratory Syncytial
Virus Lower Respiratory Infection as the Endpoint
[View Table]
|
RESULTS
Demographics
A total of 1427 children were followed over 20 years in the
Vanderbilt Vaccine Evaluation Unit. Of these, 1113 were followed during
one or more yearly RSV epidemics.
The mean age of patients with positive RSV cultures was 15.7 months.
The median age was 13.4 months, with a range of from 2 weeks to 5 years. There was a total of 241 positive cultures. Fourteen cultures
were positive in months outside of seasonal outbreaks. Seventeen of the
cultures were second isolates.
Presenting Signs and Symptoms
The presenting signs and symptoms of children whose cultures were
positive for RSV are summarized in Table 1. Coryza and cough were the most common respiratory symptoms. About half of the
patients were irritable and had decreased appetite. Vomiting was
reported in about one third of patients. Pharyngitis was found by
physical examination in more than half of the patients; it was much
more common in older children and was not seen in infants.
|
Table 1.
Presenting Signs and Symptoms in 241 Outpatients With Respiratory
Syncytial Virus Infection
[View Table]
|
Comparison With Other Respiratory Viruses
Ninety-two percent of RSV-positive patients were given a diagnosis
of URI. This figure did not differ from that associated with other
respiratory viruses isolated, ie, influenza A and parainfluenza types 1 through 3. Not surprisingly, because AOM was a criterion for obtaining
viral cultures, AOM was the most common upper respiratory diagnosis, at
51.5%. However, the frequency of associated AOM was relatively even
spaced among the common respiratory viruses (Table 2).
|
Table 2.
Incidence and Relative Risk of Acute Otitis Media (AOM) and Lower
Respiratory Infection (LRI) in Respiratory Syncytial Virus (RSV) Versus
Other Respiratory Viral Infections
[View Table]
|
In contrast, RSV was found to be much more likely than other
respiratory viruses to involve the lower respiratory tract. Table 2
shows the percentage of RSV-infected patients who had LRI and the
relative risk compared with that of other respiratory viruses. Of
children who presented with wheezing during an RSV season and had a
culture positive for any respiratory virus; 70% grew RSV. Physical
examination signs of LRI, ie, wheezing, rhonchi, and rales, were seen
in 34%, 18%, and 17% of RSV-infected children, respectively.
Involvement of the lower respiratory tract in RSV infection was age
related and exceeded 50% in early infancy, as data on the very young
age of hospitalization would suggest. After a steep decline, the
incidence of LRI in RSV culture-positive children did not change
significantly from 18 months to 4 years of age (Figure;
P = .78). Of RSV-positive patients who had an LRI
diagnosis, 67% had bronchiolitis, and 23% had pneumonia. Young infants were more likely to be given a diagnosis of bronchiolitis. The
median age of patients with a diagnosis of bronchiolitis was 7.9 months; for pneumonia, it was 14.2 months.
Fig. 1.
Graph showing the proportion of lower respiratory
tract infection in subjects with cultures positive for respiratory
syncytial virus, by age. Please note that children are grouped by
3-month intervals to 12 months of age, then by 6-month intervals to 24 months of age, and finally all children 24 months or older are grouped
together. The fractions above each bar indicate the number of children
who had lower respiratory infection, over the total number of
respiratory syncytial virus isolates. Nonseasonal isolates were
excluded. The difference in proportion with lower respiratory infection
between those younger than 12 months and those older than 12 months is
significant (P = .0007).
[View Larger Version of this Image (27K GIF file)]
Primary Versus Secondary Infection
Of the 241 positive cultures, all but 17 were primary isolates.
Nine of the 17 had LRI at the time of their first RSV isolation. Of
those nine, 7 had a URI diagnosis on second infection. Of the 8 patients whose primary infection caused a URI, only 1 had a LRI
diagnosis on second infection.
Hospitalization
Almost 5% of all RSV culture-positive patients (n = 227)
required hospitalization for their disease. Forty-two percent of the
hospitalized patients were younger than 3 months, although they made up
only 9% of the clinic population with positive cultures. Table
3 compares hospitalization rates of RSV-positive
children by age.
|
Table 3.
Hospitalization Rate of Respiratory Syncytial Virusinfected
Patients by Age Groups*
[View Table]
|
Table 4 shows AOM, URI, LRI, and hospitalization rates
by age in patients with positive RSV cultures. Of those four possible endpoints, LRI and hospitalization are the most practical. Using the
rate of LRI with RSV infection for the 20-year period as an endpoint,
it becomes possible to calculate sample sizes of healthy children
needed to show efficacy of an investigational vaccine product or
immunoprophylaxis in a randomized, placebo-controlled, prospective
clinical trial. Table 5 depicts sample sizes needed to
show vaccine efficacy rates of 40% to 80% against RSV LRI with a
power of 0.8 or 0.9.
|
Table 4.
Seasonal Illness and Hospitalization Rates Attributable to Respiratory
Syncytial Virus
[View Table]
|
DISCUSSION
The characteristics of symptomatic RSV infection in outpatient
populations have not been well described. Our outpatient evaluation in
the Vanderbilt Vaccine Clinic for 20 years defines the spectrum of RSV
disease and provides help in designing clinical trials in healthy
infants.
Isolation of RSV from a nasal wash was associated with upper
respiratory tract disease in virtually all children. Afebrile children
with mild cold symptoms and asymptomatic children were not cultured.
Prior studies have shown that recovery of RSV from well children is
rare.4 RSV was largely an afebrile illness, with only 33%
of patients having fever at the time of their clinic visits. Physical
examination revealed coryza in most. The tympanic membrane was seen to
be abnormal in 71%, although only 50% met the diagnostic criteria of
AOM. The incidence of AOM was highest in late infancy and the early
toddler months (9 to 15 months), a time that parallels the increased
incidence of AOM seen in conjunction with a variety of viral agents.
Because we did not routinely perform tympanocentesis, we cannot define
the microbiologic causes of these infections. The bacteriology of AOM
is well known; the possible role of RSV in the middle ear is not
clearly understood. In one study, RSV antigens were found in the middle
ear fluid of 15% of children with AOM, and in 7% RSV was the sole
pathogen found.16 Studies in both hospitalized
patients17 and in a day-care setting18 have
suggested that the incidence of AOM is higher in RSV infection than it
is in infection with other respiratory viruses (especially parainfluenza 1 through 3 and rhinovirus). Our outpatient data do not
reveal striking relative differences among viruses in viral-associated AOM. In the present study, cultures were obtained during acute illness
rather than as surveillance. This difference in study design may
explain the disparate results.
One third of outpatients with culture-proven RSV disease had wheezing
either by history or by physical examination. Our culture criteria,
which emphasize obtaining cultures in children with signs of LRI, may
tend to bias the data toward an overestimation of RSV-associated
wheezing. However, the propensity of RSV to involve the lower
respiratory tract is unique among the common respiratory viruses and
lends support to the idea that when young children, especially infants,
present during RSV season with signs and symptoms suggesting LRI, RSV
is by far the most likely pathogen. In fact, the incidence of influenza
A and parainfluenza types 1 and 2 often drop precipitously when RSV is
circulating.1 The incidence of LRI is highest in early
infancy. After an initial drop, however, it remains steady through at
least 4 years of age (Figure1).
Although our number of second infections was too small to establish
statistical significance, the trend toward less severe disease with
subsequent reinfection was clear and parallels data from experimental
infection in adult volunteers.19 This is also consistent
with the observation that most hospitalization occurs after primary
exposure to RSV during the first year of life.20
Using our data to establish endpoints of RSV-associated disease in
a group of unimmunized healthy controls allows the determination of
power calculations for clinical trials of investigational vaccines. URI
is unlikely to be a satisfactory endpoint because of its frequency and
the variety of causative agents. Culturing all patients with URI would
be burdensome; our experience shows a yield of only 13.4% in culturing
those with febrile URI. URI without fever would likely be even less
efficient. AOM would be a poor choice for an endpoint measure as well,
owing to the fact that even during RSV season patients with AOM are not
more likely to have RSV than they are to have other respiratory
pathogens. Because previously published4,10 and our
hospitalization rates attributable to RSV infection are low (only 0.9%
in patients from birth to age 12 months and 0.58% in patients from
birth to 24 months in our study), we view hospitalization as an
impractical endpoint; very large numbers of children would need to be
enrolled to prove efficacy. Effectiveness of intervention strategies
against hospitalization for RSV infection could be more easily
evaluated in cardiac and pulmonary patients because of their higher
risk of severe disease.21 LRI, on the other hand, is a
common enough occurrence in RSV infection to be a useful clinical
endpoint, especially in children younger than 1 year. Fewer than 1500 infants would need to be enrolled in a trial to demonstrate 60% or
greater efficacy of an investigational vaccine product against
culture-proven LRI.
In summary, our data underscore the enormity of the public health
problem created by RSV. We more fully describe the characteristics of
RSV infection in nonhospitalized infants and young children and provide
a numerical framework for vaccine trials. It is this group of young
children, at highest risk for severe RSV disease, that will need to be
targeted for intervention, both prophylactic and therapeutic. It is a
complex problem; immunization will have to be completed in the first
few months of life. It may prove more difficult to stimulate immunity
in very young infants. Additionally, the exact immune correlates of
protection and the degree of protection afforded by a single exposure
are not clearly elucidated. Our experience with prior RSV vaccine
preparations, as well as with influenza vaccines,22
suggests that two doses may be required to stimulate protective
immunity. Ongoing studies of novel treatment strategies such as passive
immunization offer possible alternatives, especially for those in the
highest risk group for universal vaccination.
FOOTNOTES
Received for publication Feb 2, 1996; accepted Sep 10, 1996.
Reprint requests to (R.G.F.) D-7235 Medical Center North,
Vanderbilt University Medical Center, Nashville, TN 37232-2581.
ACKNOWLEDGMENTS
This work was funded in part by National Institutes of Health
grants N01-AI-05050 and 5 MO1-RR-00095.
ABBREVIATIONS
RSV, respiratory syncytial virus.
URI, upper
respiratory infection.
LRI, lower respiratory infection.
AOM, acute
otitis media.
REFERENCES
-
Glezen WP,
Denny FW
Epidemiology of acute lower respiratory
diseases in children.
N Engl J Med.
1973;
288:498-505
-
Brandt CD,
Kim HW,
Arrobio JO,
Epidemiology of respiratory
syncytial virus infection in Washington, DC. III. Compositive analysis
of eleven consecutive yearly epidemics.
Am J Epidemiol.
1973;
98:355-364 [Medline][Abstract/Free Full Text]
-
Belshe RB,
VanVoris LP,
Mufson MA,
Hyler L
Epidemiology of severe
respiratory syncytial virus infections in Huntington, West Virginia.
W V Med J.
1981;
77:49-52 [Medline][Medline]
-
Kim HW,
Arrobio JD,
Brandt CD,
Epidemiology of respiratory
syncytial virus in Washington, DC. I. Importance of the virus in
different respiratory tract disease syndromes and temporal distribution
of infection.
Am J Epidemiol.
1973;
98:216-225 [Medline][Abstract/Free Full Text]
-
Cohen J
Bumps on the vaccine road.
Science.
1994;
265:1371-1373 [Medline][Free Full Text]
-
Parrott RH,
Kim HW,
Brandt CD,
Chanock RM
Respiratory syncytial virus
in infants and children.
Prev Med.
1974;
3:473-480 [Medline][CrossRef][Medline]
-
Green M,
Brayer AF,
Schenkman KA,
Wald ER
Duration of hospitalization
in previously well infants with respiratory syncytial virus infection.
Pediatr Infect Dis J.
1989;
8:601-605 [Medline][Medline]
-
LaVia WV, Grant SW, Stutman HR, Marks MI. Clinical profile of pediatric
patients hospitalized with respiratory syncytial virus infection.
Clin Pediatr. 1993;450-455
-
Hall CB,
Powell KR,
MacDonald NE,
Respiratory syncytial viral
infection in children with compromised immune function.
N
Engl J Med.
1986;
315:77-81 [Medline][Abstract]
-
Clarke SKR,
Corner BD,
Haines C,
Respiratory syncytial virus
infection: admissions to hospital in industrial, urban, and rural
areas.
Br Med J.
1978;
2:796-798
-
MacDonald NE,
Hall CB,
Suffin SC,
Alexson C,
Harris PJ,
Manning JA
Respiratory syncytial viral infection in infants with congenital heart
disease.
N Engl J Med.
1982;
307:397-400 [Medline][Abstract]
-
Meert K,
Heidemann S,
Abella B,
Sarnaik A
Does prematurity alter the
course of respiratory syncytial virus infection?
Crit Care
Med.
1990;
18:1357-1359 [Medline][Medline]
-
Monto AS,
Lim SK
The Tecumseh study of respiratory illness, 3.
Am J Epidemiol.
1971;
94:290-301 [Medline][Abstract/Free Full Text]
-
Henderson FW,
Clyde WA Jr,
Collier AM,
Denny FW
The etiologic and
epidemiologic spectrum of bronchiolitis in pediatric practice.
J Pediatr.
1979;
95:183-190 [Medline][CrossRef][Medline]
-
Dupont WD,
Plummer WD Jr
Power and sample size calculations
a review
and computer program.
Controlled Clin Trials.
1990;
11:116-128 [Medline][CrossRef][Medline] -
Sarkinen H,
Ruuskanen O,
Meurman O,
Puhakka H,
Virolainen E,
Eskola J
Identification of respiratory syncytial virus antigens in middle ear
fluids of children with acute otitis media.
J Infect
Dis.
1985;
151:444-448[Medline]
-
Uhari M,
Hietala J,
Tuokko H
Risk of acute otitis media in relation to
the viral etiology of infections in children.
Clin Infect
Dis.
1995;
20:521-524 [Medline][Medline]
-
Henderson FW,
Collier AM,
Sanyal MA,
A longitudinal study of
respiratory viruses and bacteria in the etiology of acute otitis media
with effusion.
N Engl J Med.
1982;
306:1377-1383 [Medline][Abstract]
-
Hall CB,
Walsh EE,
Long CE,
Schnabel KC
Immunity to and frequency of
re-infection with respiratory syncytial virus.
J Infect
Dis.
1991;
163:693-698 [Medline][Medline]
-
Glezen WP,
Taber LH,
Frank AL,
Kasel JA
Risk of primary infection and
reinfection with respiratory syncytial virus.
Am J Dis
Child.
1986;
140:543-546 [Medline][Abstract]
-
Groothius JR,
Simoes EAF,
Levin MJ,
Prophylactic administration
of respiratory syncytial virus immune globulin to high-risk infants and
young children.
N Engl J Med.
1993;
329:1524-1529[Abstract/Free Full Text]
-
Clements ML,
Makhene M,
Karron RA,
Effective immunization with
live attenuated influenza A virus can be achieved in early infancy.
J Infect Dis.
1996;
173:44-51 [Medline]
[Medline]
