Respiratory
Syncytial
Virus
Infection
in
Children
With Bronchopulmonary
Dysplasia
Jessie
R. Groothuis,
MD,
Kathleen
M. Gutierrez,
MD, and
Brian A.
Lauer,
MD
From the Department of Pediatrics, UnWersity of Colorado School of Medicine, Denver
ABSTRACT. Little is known about the risk of severe
illness from respiratory syncytial virus infection in
chil-dren with bronchopulmonary dysplasia. A prospective study was done of the natural history of respiratory
syncytial virus infection in 30 children <2 years of age with bronchopulmonary dysplasia who were in a home oxygen program. Surveillance to identify children with
acute respiratory symptoms was done by weekly tele-phone interview. Symptomatic children were examined,
oxygen saturation was determined by oximetry, and na-sopharyngeal lavage fluid was collected for virus cultures and rapid respiratory syncytial virus antigen tests. Dur-ing the 4-month study period (December to April), 27 children had one or more acute respiratory illnesses, and
respiratory syncytial virus developed in 16/27 (59%).
Passive smoking and four members in the home in-creased the risk of symptomatic respiratory syncytial
virus (P < .01 and P < .03, respectively). Of 16 children, 11 (69%) required hospitalization. Of the 11 hospitalized children with respiratory syncytial virus, nine were either still receiving oxygen at home or required oxygen therapy within the previous 3 months u none of five nonhospital-ized children (P < .005). Five of the hospitalized children
were >12 months ofage and five had respiratory syncytial virus infection previously that had been confirmed by
culture results. Hospitalizations were prolonged and
coin-plicated. Seven of 11 children were hospitalized for >1
week; four were admitted to the intensive care unit; four were treated with ribavirin aerosol, and two needed
me-chanical ventilation. There were no deaths. We conclude
that respiratory syncytial virus infection is a major cause
of acute respiratory deterioration and rehospitalization
in young children with bronchopulmonary dysplasia, par-ticularly those with current or recent supplemental oxy-gen requirements. Pediatrics 1988;82:199-203; respiratory syncytial virus, brorwhopulmonwy dysplasia
Received for publication July 16, 1987; accepted Nov 6, 1987. Presented at the Society for Pediatric Research, Anaheim, CA,
May 1987.
Reprint requests to (J.R.G.) Department of Pediatrics,
Univer-sity of Colorado School of Medicine, 4200 E Ninth Aye, Box C-230, Denver, CO 80262.
PEDIATRICS (ISSN 0031 4005). Copyright © 1988 by the
American Academy of Pediatrics.
Bronchopulmonary dysplasia is a chronic lung
disease of preterm mechanically ventilated infants.
Morbidity from this disease is great even after
discharge from the intensive care nursery. Fifty
percent of children with bronchopulmonary dyspla-sia will be rehospitalized within the first 2 years after nursery discharge, primarily because of acute viral respiratory infection.’’
Respiratory syncytial virus is the most important
cause of respiratory infection in young children.5’6 Clinical experience suggests that children with bronchopulmonary dysplasia, like children with
congenital heart disease and immunodeficiency
dis-ease, are at special risk for serious respiratory syn-cytial virus infection,79 but prospective studies of the impact ofrespiratory syncytial virus on children with bronchopulmonary dysplasia have not been done. Therefore, we prospectively studied respira-tory syncytial virus infection in young children with bronchopulmonary dysplasia during the winter-spring of 1986, the season of highest risk of respi-ratory infection. The purpose was to determine the
incidence of symptomatic respiratory syncytial
vi-rus infection, the course ofthe illness, the frequency of complications, and the factors that predispose children with bronchopulmonary dysplasia to se-vere respiratory syncytial virus disease.
METHODS
The study population consisted of 30 children
with bronchopulmonary dysplasia who were <2 years old at the beginning of the study period. All
pat-ent ductus anteriosus) or immunodeficiency dis-ease. The study was approved by the Human Sub-jects Committee at our institution.
Bronchopulmonary dysplasia was defmed as: (1) severe lung disease necessitating positive pressure ventilation and oxygen within the first week of life; (2) respiratory insufficiency necessitating oxygen supplementation and/or mechanical ventilation to maintain a
Pao2
>55 mm Hg beyond 30 days of life; (3) clinical evidence of respiratory distress (retractions, tachypnea, or rales); and (4) a radio-graphic pattern of emphysema and ate1ectasis.”Perinatal
data
included gestational age, birth weight, number of days ventilated, and duration of hospitalization in the neonatal intensive care unit.Epidemiologic data included the number of individ-uals living in the home, past or present need for home oxygen, previously documented respiratory syncytial virus infection, presence of smokers in the home, and a history of asthma in parents or siblings.
The study period extended from Dec 1, 1985, through April 30, 1986, and all 30 children were followed-up for the entire period. Active surveil-lance for respiratory infection in the home was performed by a research nurse who telephoned fam-ilies weekly. Families were asked whether the study infants had rhinitis, cough, wheezing, retractions, cyanosis, or fever, and, if so, the time of onset and duration of symptoms were recorded. If a child had acute respiratory symptoms, the family was in-structed to come to the clinic.
In the clinic, the severity of illness was assessed by one of the investigators using a standardized respiratory scoring system.’#{176} Pulse oximetry was performed (model 100, Nelcor Laboratories), and oxygen flow was adjusted if necessary to maintain an oxygen saturation 91%. Nasopharyngeal la-vage specimens were obtained for rapid respiratory syncytial virus antigen tests (fluorescent antibody test and enzyme immunoassay) and for virus cul-tore using multiple cell lines, including HE,-2 cells, human embryonic fibroblasts, and rhesus monkey kidney cells. Sampling of asymptomatic children was not done. The methods of specimen collection and respiratory syncytial virus testing have been described previously.1’ Sera for respiratory syncy-tial virus antibodies were not obtained.
The decision to hospitalize a child or resume
administering oxygen at home was made by the
pediatric staff. Usual indications for hospitalization were severe respiratory distress requiring >1 L/min of oxygen to maintain an oxygen saturation of 91%, inadequate fluid intake, need for aggressive treatment of reactive airway symptoms, apnea, or systemic toxicity. Children who did not require
hospitalization were monitored by telephone and were seen when indicated for repeat examination and pulse oximetry.
For statistical analysis, x2 and Fisher exact
prob-ability tests were used.
RESULTS
Of 30 children, 27 had one or more acute respi-ratory illnesses during the study period (range zero to eight). Respiratory syncytiab virus infection de-veboped in 59% (16/27) of the children and adeno-virus infection in two; in nine children, no viruses were isolated.
In Table 1, the perinatal and epidemiologic char-acteristics of the 16 children with respiratory syn-cytial virus infection are compared with those of the 14 children without respiratory syncytial virus. The perinatal histories of the two groups were similar. Children living in households with four or more individuals were significantly more likely to acquire symptomatic respiratory syncytial virus in-fection than were children in smaller households
(P < .03). The number of siblings, however, was not a significant risk factor. Adults smoking in the home was also a risk factor. Fifteen of the children with symptomatic respiratory syncytial virus infec-tion lived in households with smokers compared with seven of 14 children without respiratory syn-cytial virus infection (P < .01). The proportion of mothers who smoked was similar in the two groups.
During the study period, 11 of 15 hospitalizations were due to respiratory syncytial virus infection. The clinical features of the children hospitalized with respiratory syncytial virus infection are shown in Table 2. Five children were >1 year of age, and four had culture-proven respiratory syncytial virus infection in the previous year. One child was hos-pitalized twice within 6 weeks for separate episodes of respiratory syncytial virus infection confirmed by culture results. The course of the disease in most hospitalized children was prolonged and compli-cated, but there were no deaths. Two children were hospitalized with acute lower respiratory tract
dis-ease, but no respiratory pathogen was identified.
Two other children were admitted for poor weight gain.
Five children who had mild respiratory syncytial virus infection did not require hospitalization. Two ofthese children, however, required reinstitution of home oxygen therapy for 2 to 3 weeks.
TABLE 1. Perinatal and Epidemiologic Characteristics of Children With
Bronchopul-monary Dysplasia With and Without Respiratory Syncytial Virus Infection Without Respiratory
Syncytial Virus
(n= 14)
Gestational age (mean wk ± SD) 28 ± 2.9 29 ± 2.8 NS
Birth wt (mean g ± SD) 1,101 ± 366 1,116 ± 367 NS
Mechanical ventilation (mean d 21 ± 20 28 ± 30 NS
± SD)
Neonatal intensive care (mean d 40 ± 21 42 ± 28 NS
± SD)
Family history of asthma (%) 5 (31) 5 (36) NS Smokers in household (%) 15 (94) 7 (44) <.01 4 individuals in household (%) 14 (88) 7 (50) <.03 * Fisher exact probability test.
TABLE 2. Features of 11 Children With
Bronchopul-monary Dysplasia Hospitalized With Respiratory Syn-cytial Virus Infection
Variables With Respiratory Syncytial Virus
(n= 16)
Clinical Features No. (%) of Children
Age >12 mo 5 (46)
Previous respiratory syncytial vi- 5 (44)
rus infection
Nosocomically acquired 1 (9)
Hospitalized >7 d 7 (63)
Intensive care 4 (36)
Ribavirin treatment 4 (37)
Mechanical ventilation 2 (18)
Deaths 0
home oxygen therapy was associated with severe respiratory syncytial virus infection requiring
hos-pitalization. Of the 11 hospitalized children, nine were still receiving home oxygen or required oxygen therapy within the previous 3 months v none of five nonhospitalized children (P < .005). Factors found not be be significantly different between the two groups included gestational age, birth weight, pen-natal course, admission age, on known previous respiratory syncytial virus infection.
DISCUSSION
As neonatal intensive care units have
prolifen-ated, the survival of mechanically ventilated
pre-mature infants has improved. Unfortunately, bron-chopulmonary dysplasia develops in many of the survivors. Bronchopulmonary dysplasia has
emerged as a leading cause of chronic lung disease
in early childhood. At least half of all children with
bronchopulmonary dysplasia will require nehospi-talization within the first 2 years of life, primarily for lower respiratory tract viral infection.2’3 This
prospective study was designed to examine the
im-pact of respiratory syncytial virus infection on a cohort of young children with bronchopulmonany dysplasia. We found that respiratory syncytial virus
infection was the major cause of rehospitalization
P Value*
of infants with bronchopulmonary dysplasia during
the winter. Children currently or recently receiving home oxygen therapy were at greatest risk for se-vene respiratory syncytial virus disease.
We anticipated that the incidence of respiratory syncytial virus infection in children with broncho-pulmonary dysplasia would be similar to that seen in children without bronchopulmonary disorders. Symptomatic respiratory syncytial virus infection developed in 59% of the children during the study period. This rate is consistent with those observed by others of 25% to 70% in the first year of life, with 100% of “normal” children acquiring the virus by 2 years of age.5”2”3 During this winter, a large respiratory syncytial virus epidemic occurred in Colorado, but there was little other respiratory vi-rus activity. We therefore could not assess the morbidity from other viruses such as influenza or parainfluenza on this high-risk population. The relative absence of other respiratory viruses may reflect interference by respiratory syncytial virus.5 Two children who acquired adenovirus infection were only mildly ill and did not require
hospitali-zation.
The risk of acquisition of respiratory syncytial virus by children without bronchopulmonary
dis-ease has been correlated with crowding, smoking,
the presence of other children in the household, and young age.5”’6 In this study, large family size and passive smoking in the home emerged as sig-nificant risk factors. Children living in households with four or more individuals were significantly
more likely to acquire respiratory syncytial virus
than were children from smaller families (P < .03). Monto and Lim’4 observed that both the incidence
of infections within a household and the number of recurrent respiratory syncytial virus infections in a
single season increased with family size. In families with three or fewer members, only 5% of persons
were infected, compared with an incidence of 16%
in families of six members or more.14 Large family
* Fisher exact probability test.
TABLE 3. Risk Factors for Hospitalization With Respiratory Syncytial Virus Infection
Variables Hospitalized Not Hospitalized P Value*
(n=11) (n=5)
28±2.5 28±2.8 NS
Gestational age (mean wk ±
SD) wk
Birth wt (mean g ± SD) 1,115 ± 324 1,103 ± 367 NS
Previous respiratory syncy- 5 1 NS
tial virus infection
Age<l2mo 6 4 NS
Smokers in home 11 4 NS
Home supplemental oxygen 9 1 <.005
currently or within
pre-vious 3 mo
to infected individuals and may also increase the inoculum size of an exposure.15
Passive smoking increased the risk of sympto-matic respiratory syncytial virus disease in this
study. Of the children with symptomatic respira-tory syncytial virus infection, 94% were from homes with smokers compared with 50% of children in whom respiratory syncytial virus did not develop
(P < .01). Others have found that infants without bronchopulmonary dysplasia also are at increased
risk for serious respiratory syncytial virus disease
when there is a history of parental smoking.’5”6 The morbidity due to respiratory syncytial virus infection in children with bronchopulmonary dys-plasia was great. More than two thirds of infected children required hospitalization, four in an inten-sive care unit. Hospitalizations generally were pro-longed, seven of 11 children were hospitalized for more than seven days. In contrast, hospitalization rates for children with respiratory syncytial virus infection in the general population range from 1 in 50 to 1 in 500.’”” The usual duration of hospital-ization ofotherwise normal infants with respiratory syncytial virus bronchiolitis or pneumonia is four to seven days. The morbidity due to respiratory syncytial virus disease in children with broncho-pulmonary dysplasia is comparable to that de-scribed in children with severe congenital heart disease or immunodeficiency disease.8’9
There were no deaths in our study population. Children with congenital heart disease in whom respiratory syncytial virus develop have been re-ported to have a high case fatality rate. The higher mortality rate among children with cardiac disease
is probably due to pulmonary hypertension, as noted by MacDonald et al.5
Children >1 year of age with bronchopulmonary dysplasia were as likely to have severe illness and to be hospitalized as were younger children. Chil-dren <6 months of age tend to have more severe respiratory syncytial virus disease than do older children.’9’#{176} Previous known respiratory syncytial
virus infection also afforded no protection against severe disease in this population. In most studies, respiratory syncytial virus reinfection has been as-sociated with milder disease, but some investigators have found that the first reinfection may be as severe as the primary infection.’2’21’22 One child in our study was hospitalized with severe respiratory syncytial virus pneumonia three times in three consecutive respiratory seasons. The severity of
illness with reinfection is probably a consequence
of the underlying lung disease.
We found that the major risk factor for severe
respiratory syncytial virus disease in children with bronchopulmonary dysplasia was a current or re-cent need for home oxygen therapy. Children with recent supplemental oxygen requirements have re-sidual pulmonary abnormalities and may be only marginally compensated. Nine of 11 children requiring hospitalization were having oxygen ad-ministered at home at the time or had received oxygen therapy at home within the peceding 3 months. In contrast, the five children with mild respiratory syncytial virus had not had oxygen ad-ministered for >3 months prior to infection.
We conclude that respiratory syncytial virus in-fection is a major cause of acute respiratory dete-rioration and rehospitalization of children with bronchopulmonary dysplasia. Children who are from large families and who live with smokers are
at increased risk of acquiring respiratory syncytial
bronchopulmonary dysplasia prior to the develop-ment of severe disease. Finally, parents should be educated about the special hazards ofpassive smok-ing for this group of high-risk children.
ACKNOWLEDGMENTS
This work was supported, in part, by BRSG-05357
awarded by the Biomedical Research Grant Program, Division of Research Resources, National Institutes of
Health.
The authors thank Glenda Lauch, Mary House, Sally Onyan, Kim Weber, and Helen Masters for technical
assistance, and Dr Myron Levin for critical review. Sher-ne Moore and Caroline Adams typed the manuscript.
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