PEDIATRICS Vol. 99 No. 3 March 1997,
p. e7
Copyright ©1997 by the American Academy of Pediatrics
ELECTRONIC ARTICLE:
Does Ribavirin Impact on the Hospital Course of Children With
Respiratory Syncytial Virus (RSV) Infection? An Analysis Using the
Pediatric Investigators Collaborative Network on Infections in Canada
(PICNIC) RSV Database
,
,
,
From the * Winnipeg Children's Hospital and University of
Manitoba, Winnipeg, Manitoba; the
Hospital for Sick Children and
University of Toronto, Toronto, Ontario; the § Children's Hospital of
Eastern Ontario and University of Ottawa, Ottawa, Ontario; the
Montreal Children's Hospital, and McGill University, Montreal,
Quebec; ¶ British Columbia Children's Hos- pital and University of
British Columbia, Vancouver, British Columbia; # Centre Hospitalier de
l'Universite Laval, Quebec City, Quebec; ** Izaak Walton Killam
Hospital and Dalhousie University, Halifax, Nova Scotia;

Children's Health Centre and the University of Alberta,
Edmonton, Alberta; and §§ Alberta Children's Hospital, and University
of Calgary, Calgary, Alberta.
Objectives. To determine the relationship between receipt of aerosolized ribavirin and the hospital course of high-risk infants and children with respiratory syncytial virus (RSV) lower respiratory infection (LRI).
Methods. The 1993-1994 Pediatric Investigators
Collaborative Network on Infections in Canada (PICNIC) RSV database
consists of prospectively enrolled children with acute RSV LRI,
admitted to nine Canadian pediatric tertiary care centers. After
excluding cases with compromised immunity and/or nosocomial infection,
subsets with any congenital heart disease (CHD), chronic lung disease (CLD), age
6 weeks (INFANT), gestation
36 weeks (PREM), or severe disease within 48 hours of admission as shown by an oxygen saturation
90% or an FiO2 requirement of >.35 (EARLY HYPOXIA) were
studied in two ways. First, each risk group subset was analyzed
separately to assess the association between ribavirin receipt and
measures of disease severity including duration of intensive care,
mechanical ventilation, hy- poxia and RSV-attributable hospital
stay. Secondly, ribavirin was added as an independent variable to a
previously described multiple regression model for RSV-attributable
length of hospital stay and two mutually exclusive subsets were
analyzed: 1) previously healthy patients with
1 of: INFANT, PREM, or
EARLY HY- POXIA; 2) patients with CHD and/or CLD.
Results. Between January 1993 and June 1994, 1425 community-acquired hospitalized cases of RSV LRI were entered into the RSV database. Among these 750 (52.6%) fit into one or more of the defined subsets including 97 CHD, 134 CLD, 213 INFANT, 211 PREM, and 463 EARLY HYPOXIA. The proportion ventilated in each group was 20.6%, 20.9%, 15.5%, 15.2%, and 13.3%, respectively. Across the subsets ribavirin use ranged from 36% to 57% of ventilated patients and 6% to 39% of nonventilated patients. For nonventilated patients in each subset the median RSV-attributable hospital length of stay (RSV-LOS) was 2 to 3 days longer for ribavirin recipients and the duration of hypoxia was significantly increased. Duration of intensive care unit (ICU) stay was also increased for all ribavirin-treated subgroups except those with CHD. In contrast, for ventilated patients, ribavirin therapy was not significantly associated with any of the outcome measures regardless of risk group. In the multiple regression model, ribavirin was significantly associated with a prolonged RSV-LOS both for children with CHD and/or CLD as well as for those whose only risk factors included INFANT, PREM, and/or EARLY HY- POXIA.
Conclusions. These data raise further doubts about the clinical effectiveness of ribavirin in infants and children with risk factors for severe disease. Selection bias, with ribavirin used for sicker children, may have influenced outcome. Nevertheless the long durations of hospitalization, ICU, ventilation, and oxygen supplementation in nonventilated ribavirin recipients stress the need for further randomized trials to assess its efficacy. ribavirin, respiratory syncytial virus, pneumonia, bronchiolitis.
Respiratory syncytial virus (RSV) is the major cause of lower
respiratory infection (LRI) and hospitalization among infants and
toddlers in North America.1 Nearly all children are
infected by age 2 years and 1% to 2% of those infected require
hospitalization.2 Among those admitted to hospital with no
apparent risk factors for severe disease, 4% to 15% are admitted to
the intensive care unit (ICU), 1% to 5% require assisted ventilation,
and <1% die.3 In contrast, among children with
underlying heart/lung disease, prematurity (gestation
36 weeks) and
young age (
6 weeks) the corresponding figures for ICU, ventilation,
and mortality range from 10% to 40%, 8% to 27%, and up to 10%,
respectively.3
Ribavirin, first approved in the United States in 1986, is the only licensed antiviral therapy for RSV infection. In 1993 the American Academy of Pediatrics (AAP) recommended that ribavirin should be given to selected infants and children at risk for or already manifesting severe disease as well as for all ventilated patients.8 Although several randomized trials suggested that ribavirin was efficacious among nonventilated patients,9 the use of the drug remained controversial, due to the small numbers studied, and concern over the validity, generalizability, and clinical relevance of the outcome measures used. For ventilated patients, controversy existed as well, with one trial supporting a beneficial effect for ribavirin15 while another failed to show a difference.16 Large increases in the cost of ribavirin since 1993 raised further questions about its relative cost-benefit. In Canada over 90% of RSV-related hospital costs are due to daily bed charges.17 With the daily cost of ribavirin at approximately $1500 (Canadian funds), therapy would have to lead to a substantial reduction in the duration of hospital stay to justify the costs of ribavirin. Accordingly, the AAP recommendations for patients who should receive ribavirin were used to select cases enrolled in a prospective study of children hospitalized for RSV LRI and outcomes were examined to determine the relationship between ribavirin therapy and length of hospitalization.
The Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) RSV Database includes prospectively collected data on demographic factors, disease severity, and daily management in hospital of 1516 infants and children with acute RSV LRI, admitted to nine Canadian pediatric tertiary care hospitals between January 1993 and June 1994. Details of study design and methodology have been reported previously.18 After enrollment each child was followed daily by a study nurse to assess respiratory status and oxygen saturation and to record management regimens including the use of supplemental oxygen, ribavirin, bronchodilators, steroids, and antibiotics. The durations of mechanical ventilation, receipt of intensive care, and hospitalization were recorded. For all analyses, hypoxia was defined as an oxygen saturation of
90% on room air or a
fraction of inspired oxygen (FiO2) requirement of
.35.
Hypoxia occurring within 48 hours of hospital admission was used as an
indicator of moderate or severe disease.
2 or Fisher's exact tests of
proportion were used to compare distribution of demographic factors,
coexisting risk factors, and indicators of disease severity among the
ribavirin and no-ribavirin therapy groups.
Study Groups
Between January 1, 1993 and June 6 1994, 2116 children were hospitalized with acute RSV LRI at the participating PICNIC study centers. Of these 1516 (72%) were enrolled in the prospective RSV study. Excluded from this analysis were 91 cases of hospital-acquired RSV infection. Among the remaining 1425 community-acquired cases of RSV LRI, previously recognized chronic disease affected 220 (15%). From these, the 173 cases with underlying cardiopulmonary disease and no known immunodeficiency were chosen for analysis, including 97 CHD and 134 CLD. Among the CHD group, 49 (50%) had a left to right shunt and 20 (21%) had pulmonary hypertension. Among the CLD group 88 (66%) had a history of current or past home oxygen supplementation. The other 1205 patients with community-acquired RSV LRI had no known underlying disease. From this group 577 (48%) fit one or more of the recommended guidelines for use of ribavirin, including 213 INFANT, 211 PREM, and 463 with EARLY HY- POXIA. The proportion of the PREM group with a gestational age range of
28 weeks, 29 to
32 weeks, and 33 to
36
weeks was 8%, 21%, and 71%, respectively. The proportion ventilated
in each subset was CHD (20.6%), CLD (20.9%), INFANT (15.5%), PREM
(15.2%), and EARLY HYPOXIA (13.3%). Within the ventilated and
nonventilated strata of each risk group category, the respective
proportions treated with ribavirin were: CHD (45% and 39%), CLD (57%
and 32%), INFANT (36% and 12%), PREM (44% and 10%), and EARLY
HYPOXIA (39% and 6%).
Specific Risk Group Analysis for Effect of Ribavirin
The use of ribavirin was determined by the attending physician and study personnel were not involved in the decision. Consistent with previous reports, there was marked variation in the use of ribavirin among the nine participating centers.7,18 Among ventilated patients the individual centers varied in the use of ribavirin from 0% to 100% for CHD, CLD, and INFANT, and from 25% to 85% for PREM. Among nonventilated cases ribavirin use varied from 0% to 43% for CHD, 12% to 62% for CLD, 0% to 43% for INFANT, and 2% to 33% for PREM.
Table 1.
Impact of Ribavirin on Total Hospital Days Attributable to Respiratory
Syncytial Virus, as Well as Days of Hypoxia, Intensive Care Stay, and
Mechanical Ventilation, Among Children With Community-acquired Respiratory Syncytial Virus Lower Respiratory Infection
Table 2.
Distribution of Factors Associated With Duration of RSV-Attributable
Hospital Stay18 Among Specified Risk Groups According to
Whether or Not They Received Ribavirin
Effect of Ribavirin in a Multiple Regression Model for Duration of RSV-Attributable Hospitalization
After adjustment for other prognostic factors children receiving ribavirin had longer hospitalization: +1.44 days (95% CI, 1.18-1.70; P = .0001) for children with underlying cardiopulmonary disease and +1.40 days (95% CI 1.26-1.63; P < .0001) for previously healthy children.Mortality
There were a total of six deaths among the 577 cases included in the analysis. The case fatality rates for each of the subgroups are shown in Table 1. None of the rates were significantly different but the numbers were small. For the groups used in the multivariate analysis the mortality was: CHD/CLD group-3.3% (2/61) of those treated with ribavirin and 2.0% (2/99) of those not given ribavirin; previously healthy INFANT/PREM/EARLY HYPOXIA group-0% (0/61) of ribavirin treated and .4% (2/453) of those not given ribavirin. These differences were not significant.The randomized placebo-controlled trials used to support ribavirin as an efficacious therapy for RSV LRI used outcomes based on respiratory status scores, duration of viral shedding, and hypoxemia.9 The studies on healthy children differed in terms of eligibility criteria such that some included premature infants9,13 whereas others did not10,12 and none stratified by age group making it difficult to extrapolate the results to specific populations such as those mentioned in the AAP guidelines. Furthermore the clinical significance of improvement in respiratory score as well as the effect on viral shedding and hypoxemia are not clear. A high mortality rate among children with cardiopulmonary disease has been cited as a reason for ribavirin therapy,3 but ribavirin has not been shown to reduce the RSV case fatality rate. More recent series have reported mortality as much as 10-fold lower than previously reported rates.6,7,18,19 One retrospective study did not find any difference in pulmonary function tests between ribavirin recipients and nonrecipients, but the recipients appear to have been sicker.20
Received for publication Feb 23, 1996; accepted May 10, 1996.
This work was presented in part at the Annual Society for Pediatric Research Meeting, in San Diego, CA (May 1995).
Reprint requests to (B.J.L.) Department of Medical Microbiology, Room 530, 730 William Ave, Winnipeg, Manitoba, Canada, R3E 0W3.
This work was funded by a grant-in-aid of research from American Cyanamid/Lederle Praxis Biologics Inc, West Henrietta, NY.
The work was conceived and carried out solely by the authors, who gratefully acknowledge the laboratory support provided by other members of the RSV Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC). The authors also thank C. Pierce, C. Milne, and the dedicated research nurses without whom the work would not have been completed.
RSV, respiratory syncytial virus.
LRI, lower
respiratory infection.
ICU, intensive care unit.
CHD, congenital heart
disease.
CLD, chronic lung disease.
PREM, gestation
36 weeks.
INFANT, postnatal age
6 weeks.
EARLY HYPOXIA, oxygen saturation
90%.
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Pediatrics (ISSN 0031 4005). Copyright ©1997 by the American Academy of Pediatrics
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