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Pediatric Infectious Disease Journal:
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Chronic Manifestations of Respiratory Syncytial Virus Infection in Premature Infants

Greenough, Anne MD; Broughton, Simon BM

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From the Division of Asthma, Allergy and Lung Biology, Guy's, King's and St. Thomas’ School of Medicine, King's College, London, United Kingdom.

Address for reprints: Professor Anne Greenough, Neonatal Intensive Care Centre, 4th floor Golden Jubilee Wing, King's College Hospital, London SE5 9RS United Kingdom. Fax 44 20 7346 8284; E-mail anne.greenough@kcl.ac.uk.

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Background: Respiratory syncytial virus (RSV) infection in healthy infants born at term results in long term sequelae. Infants born prematurely are at increased risk of severe acute RSV infection; thus it would seem likely that such infants would be at increased risk of long term respiratory sequelae.

Methods: Methods of assessing the long term outcome of RSV infection are discussed and the results of retrospective and prospective studies investigating chronic respiratory morbidity after RSV infection in premature infants are reviewed.

Results: Documentation of all health care utilization, parental documentation of symptom status and lung function measurement provide a comprehensive and quantitative assessment of respiratory outcome. Studies that have included such outcome measures have demonstrated that RSV hospitalization in infants born between 32 and 35 weeks of gestational age and in those born more prematurely who developed chronic lung disease was associated with more hospital admissions, inpatient days, physician contacts and outpatient visits in the first 2 years after birth. Children born before 32 weeks of gestation who developed chronic lung disease also required more outpatient attendances and prescriptions and respiratory medications in years 2 through 4. Prospective data collection has demonstrated that chronic respiratory morbidity occurs in very premature infants, regardless of whether their RSV infection required hospitalization.

Conclusion: Chronic respiratory morbidity is increased in premature infants after RSV infection. The duration of this increased morbidity and the impact of other viral infections, particularly dual infection with RSV, on long term sequelae merit investigation.

Respiratory syncytial virus (RSV) is a common respiratory pathogen in childhood; most children will have suffered an RSV infection by the age of 2 years. It causes a spectrum of illnesses; many children have a coryzal illness requiring no medical intervention, but others develop bronchiolitis or RSV pneumonia requiring hospital admission and even intensive care. RSV infection in otherwise healthy infants born at term can result in long term sequelae; this has been documented in numerous retrospective and prospective studies. For example, in comparison to carefully matched controls, children who had been hospitalized as infants because of bronchiolitis were 3 times more likely to wheeze and 10 times more likely to use bronchodilators at 9–10 years of age.1 In addition, among 140 children examined at a mean age of 7.5 years (47 of whom had been hospitalized for RSV infection in infancy, and 93 of whom were contemporaneously recruited matched controls), the cumulative prevalence of asthma was 30% in the RSV group and 3% in the controls.2 Multivariate evaluation of the possible risk factors for asthma and allergic sensitization in all 140 children demonstrated that RSV infection had the highest independent risk ratio for asthma (odds ratio,12.7; 95% confidence limits, 3.4–47.1).2

Premature infants are much more likely to be infected with RSV than infants born at term because premature infants have inadequate immunity with low passage of maternal antibodies. Infants born prematurely, particularly if they have developed chronic lung disease (CLD), are also at increased risk of severe acute RSV infection because they have smaller airways that can become obstructed by edema and necrotic debris. Such infants have a much higher admission rate with RSV infection.3 Although only 7% of infants are born prematurely, 25 to 50% of those admitted to intensive care with bronchiolitis have been born prematurely. In addition, analysis of retrospective data from 304 infants, including 89 born before 37 weeks of gestation, demonstrated that the premature infants were significantly more likely to require intubation and have longer hospital and intensive care stays.4 The mortality due to bronchiolitis is also increased in low birth weight (<2500 g) and particularly very low birth weight (<1500 g) infants compared with infants of normal birth weight.5

It would seem likely that premature infants would be at particular risk of long term respiratory sequelae following RSV infection. The aims of this review are to discuss methods used to assess long term outcomes and further our knowledge of the chronic effects of RSV infection, describe data demonstrating that chronic respiratory morbidity does follow RSV infection in prematurely born infants and highlight questions currently being addressed in clinical studies with regard to the sequelae of severe RSV infection in prematurely born infants.

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Comparison of the subsequent hospitalization rate of infants who have had an RSV infection to that of a control group is an attractive method of assessing if outcome is affected by RSV infection because the data are readily available from the hospital records. Such data, however, will only capture whether the relatively short term outcome is affected by RSV infection because hospitalizations in premature children are uncommon after the first 2 years.6 Yet, many children who have had RSV infection have ongoing respiratory morbidity, as evidenced by troublesome respiratory symptoms and a requirement for treatment.6

Thus, relying on hospitalization rates will underestimate the magnitude and chronicity of the adverse effect of RSV infection in premature infants. It is also important to remember that many factors influence whether a child is admitted to a hospital, for example whether a bed is available or the mother is able to cope with the child's illness at home; thus hospitalization may not reflect severity of illness.

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Health Care Utilization.

Assessment of all healthcare utilization, ie, not only hospitalization but also outpatient attendance and care required in the community, gives a comprehensive assessment of the long term outcome and can be used to determine the cost of care. Obtaining such data, however, is arduous because it requires obtaining information from all practitioners involved in the child's care. Dedicated research nurses are essential to such an approach.6

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Assessment of Symptom Status.

It cannot be assumed that all parents will contact or inform practitioners if their child is symptomatic. Therefore, if the true extent of the child's morbidity is to be determined it is essential that information be collected directly from the parents. Fortunately, questionnaires completed by a pediatrician with the parents in an outpatient setting7 or by the parents at home8 can be successfully used to document respiratory symptom status and hence identify risk factors for chronic morbidity7 or assess the impact of perinatal interventions.8 An alternative or additional strategy is to ask the parents to complete symptom diary cards.9 On a daily basis, parents are asked to record whether their child has a cough or wheeze and/or requires treatment. From such data, a score can be generated that facilitates comparison of interventions9 or can be used to assess the impact of a potentially adverse event such as a symptomatic RSV infection on long term outcome.10

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Lung Function.

Measurement of lung function at follow-up gives a quantitative assessment of the child's respiratory status and, if reproducible techniques are used, can detect a relatively small but potentially important difference in outcome. At 1 year of age, lung function test results can predict those infants at high risk of chronic respiratory morbidity,11 but to obtain a comprehensive assessment of lung function, sedation is required. Lung function at follow-up is assessed by plethysmographic and helium gas dilution methods or, more recently, by the rapid thoracoabdominal compression technique.12 Preterm infants have been shown to have a high airways resistance measured by plethysmography and a low functional residual capacity (FRC) measured by helium gas dilution to FRC measured by plethysmography ratio, indicating gas trapping; such abnormalities are greater in infants who are symptomatic at follow-up.13 These assessments have been used to demonstrate treatment effects, for example bronchodilator therapy can reduce airway resistance and gas trapping13 and facilitate determination of the longer term efficacy of neonatal strategies.14

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Infants Born Between 32 and 35 Weeks of Gestation.

RSV hospitalization in healthy premature infants is associated with increased subsequent health care utilization and mortality.15 Comparison of the outcome of 2415 infants born between 32 to 35 weeks of gestational age and hospitalized for proven or probable RSV infection with that of 20,254 control infants revealed that the RSV group had significantly more hospitalizations, inpatient days, physician contacts, outpatient visits and mortality. The overall deaths were 8.1% in the RSV group and 1.6% in the controls; the sudden death rate was 6.1% in the RSV group and 0.3% in the controls (P < 0.001).15 A weakness of the study, however, was that infants were classified on the basis of the International Classification of Disease, and not all infants included in the RSV group had proven RSV infection.

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Outcome of Infants Born Very Prematurely.

Our retrospective data3,6 have demonstrated that RSV hospitalization in very premature infants (ie, born at less than 32 weeks of gestational age) who developed CLD also results in chronic respiratory morbidity. The outcome of a cohort of infants admitted to 4 regional neonatal intensive care units who developed CLD (defined as an oxygen dependency beyond 28 days) was assessed at 23 and then at 56 years of age. A retrospective review was made of their medical records. Data were collected on all their care in the community and during any readmission until the children were 2 years of age. From the general practitioner (GP) records for each child the following data were retrieved: venue of all hospital readmissions; number of GP consultations; all medication prescribed; use and duration of home oxygen; number of referrals to a health visitor or community pediatric nurse; and use of community support services. For each hospital admission the following information was recorded: diagnosis or symptoms leading to the admission; duration of stay; whether the child was admitted to a pediatric ward or high dependency or intensive care unit (ICU); days of supplementary oxygen and intravenous fluids; surgical or therapeutic procedures; and duration and frequency of all medications. Each infant's hospital records were also examined to ascertain the number of outpatient attendances. Costs for all aspects of care were summarized under 6 headings (primary care total, primary care respiratory-related, primary care drugs, hospital drugs, hospital stay and outpatient attendance) and calculated for the 2-year period.

After discharge from their neonatal unit, 45 of the children had at least one hospital admission for proven RSV infection in the first 2 years after birth; ie, the RSV antigen had been identified from a nasopharyngeal aspirate. Compared with the rest of the cohort, the RSV group required more frequent and longer admissions to general pediatric wards and ICUs and more outpatient attendances and GP consultations for respiratory-related disorders in the first 2 years. Sixty of the infants were admitted to the hospital for respiratory diagnoses other than RSV infection or probable bronchiolitis, and 106 had admissions for nonrespiratory causes or no admission. The hospital admission rate and the duration of hospital and ICU stay of the proven RSV group were significantly longer than those of the other respiratory and the nonrespiratory groups (Table 1). The total cost of care after discharge from the neonatal unit in the RSV group was twice that of the respiratory group and more than 4 times that of the nonrespiratory group (Table 1).

Table 1
Table 1
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Of the original cohort, 199 children, including 33 who had been hospitalized in the first 2 years for a proven RSV infection, were reassessed when they were 5 years old.6 Their hospital admissions and the community care they had required when aged 2 through 4 years were reviewed, and the cost of care over the 3-year period was calculated. The mean cost of each admission was calculated using data from the National Scheme of Reference Costs (2002). Drug costs, including all domestic oxygen therapy costs, were calculated from the British National Formulary prices. Costs were also calculated for attendances as an outpatient, care by a GP and domiciliary visits by community staff. Routine visits to practice nurses or health visitors, for example for immunizations, were not recorded because they were considered the usual costs for children.

Data were also collected from their neonatal admissions, which demonstrated that, compared with the rest of the cohort, the RSV group was similar with respect to their gestational age and birth weight. The RSV group compared with the rest of the cohort had required a significantly longer neonatal admission (median, 91 versus 76 days), but the proportions of the 2 groups that had required postnatal treatment with dexamethasone (40% versus 38%) and were discharged home on supplementary oxygen (39% versus 35%) were similar, suggesting that they did not differ with regard to their severity of chronic neonatal respiratory illness. Hospital admissions were much less common in the cohort in years 2 through 4 than in the first 2 years, but the RSV group still required significantly more days in the hospital and twice the number of outpatient attendances than the rest of the cohort during years 2 through 4 (Table 2). In addition, the RSV group required significantly more prescriptions overall and more prescriptions for respiratory medications. The cost of care of the RSV group was double that of the rest of the cohort (Table 2).

Table 2
Table 2
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When the children were 5 years of age, their parents completed a respiratory questionnaire. This demonstrated that the RSV group had no excess of risk factors for chronic respiratory morbidity, such as antenatal or current parental smoking, day care attendance, a family history of atopy or siblings younger than 5 years of age in the house. Yet, 82% of the RSV group had used an inhaler compared with 63% of the rest of the cohort (P = 0.038). At 5 years of age, the children's health-related quality of life was also assessed using the Health Utilities Index.16 The Health Utilities Index describes a family of generic health status and health-related quality-of-life measures. The parents were asked to respond to 15 questions about their child's health over the previous 4 weeks. Health status was determined according to the following attributes: sensation, mobility, emotion, cognition, self-care, pain, vision, hearing, speech, ambulation and dexterity. The RSV group results demonstrated a lower multiattribute score than the rest of the cohort, suggesting a lower health-related quality of life at 5 years of age. These data highlight that hospitalization due to RSV infection in the first 2 years is associated with increased morbidity at least until 5 years of age in very premature children. Therefore, it is important to determine how long the morbidity of the affected children is increased. Consequently we will reevaluate the cohort when they are 8 years of age.

Data from infants born at term have demonstrated that infants who develop symptomatic RSV infection but do not need hospitalization are still at risk for chronic respiratory morbidity.17 As a consequence, in our ongoing, prospective follow-up study, we are investigating whether very premature infants who suffer a symptomatic RSV infection, regardless of whether they need hospitalization, have an adverse outcome. In a hospital- and community-based study, very premature infants are being followed until they are 2 years old. The parents are asked to telephone a member of the research team whenever their infant has symptoms compatible with a lower respiratory tract infection (LRTI). In addition, the parents are contacted every 2 weeks to determine whether their infant is or had been symptomatic. If the infants have a LRTI, they are visited and a nasopharyngeal aspirate collected for immunofluorescence and culture for RSV and identification of other viral infections. Nasopharyngeal aspirates are also collected if the infant is admitted to a hospital with a LRTI. Data are collected on all hospital admissions and GP visits for respiratory problems. When the infants are 11 months old (corrected for prematurity), the parents are asked to complete a daily diary card over the subsequent month recording whether their infant coughs or wheezes. Preliminary analysis10 has demonstrated that infants who had a proven RSV LRTI subsequently required significantly more admissions and days in the hospital. The RSV group was also more likely to cough and wheeze at follow-up, regardless of whether the infants had required hospitalization for their RSV infection. Whether RSV infections in the community or requiring hospitalization have similar adverse longer-term outcomes requires investigation.

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Is Premorbid Abnormal Lung Function a Risk for Symptomatic RSV Infection in Premature Infants? It has been suggested that premorbid abnormal lung function is a risk factor for severe RSV infection and, therefore, hospital admission in infants born at term. In a prospective study of 253 infants born at term and recruited at birth, 17 infants subsequently developed bronchiolitis (2 required hospitalization).18 The bronchiolitic group had significantly worse lung function, that is, lower maximum flows at FRC (Vmax FRC) measured by the “squeeze” technique, at 5 weeks of age (ie, before the RSV infection) than those infants who did not suffer a symptomatic RSV infection.18 In addition, in the Tucson Children's Respiratory Study, infants who had at least 1 wheezing LRTI (44% of which were due to RSV infection) in the first 3 years after birth had a lower Vmax FRC prior to the LRTI.19 Premature infants are at high risk of lung function abnormalities as a result of perinatal insults. It is, therefore, important to determine if premorbid lung function abnormalities also predispose premature infants to symptomatic RSV infection, because this could inform targeting of prophylactic interventions to high-risk infants. Our preliminary evidence suggests that a high respiratory resistance at 36 weeks postmenstrual age prior to discharge from the neonatal unit may identify very premature infants at the highest risk of developing a symptomatic RSV infection.20

What is the Long Term Impact of Other Viral Infections, Particularly in Relationship to RSV Infection? A number of viruses, other than RSV, can cause bronchiolitis. Approximately 10 to 20% of cases of bronchiolitis are due to rhinovirus, parainfluenza, influenza, adenovirus or human metapneumovirus. Epidemiological data suggest that human metapneumovirus infection may occur in between 1.5 to 8% of children with respiratory tract infections admitted to a hospital.21,22 In some children, there is evidence of dual infection. In 1 study, 70% of infants with bronchiolitis admitted to pediatric intensive care for mechanical ventilation had both RSV and metapneumovirus infection.23 It has been suggested that such dual infection may confer a 10-fold increase in the relative risk of admission to a pediatric ICU for mechanical ventilation.24 Whether affected infants have a more adverse long term outcome merits investigation. Viral infections other than RSV may increase chronic respiratory morbidity in premature infants. In a small study,25 infants with bronchopulmonary dysplasia (BDP) who had suffered a nosocomial viral infection were more likely to be symptomatic at follow-up and have worse lung function than BDP infants who had not suffered a viral infection. It is, therefore, important to further investigate the role of other viral infections with regard to chronic respiratory morbidity in premature children and whether dual infection may be particularly disadvantageous regarding their long term respiratory outcome.

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Question: Was palivizumab used in the study population you referenced in your article?

Anne Greenough, MD: Palivizumab isn't nearly as widely used in the United Kingdom as it is in the United States. We used palivizumab only for babies who were going home on oxygen immediately before the RSV season. Thus, 6 of 98 babies had palivizumab, which is extremely different from what happens in the United States. I'm pleased to say that the U.K. Department of Health recommendations regarding use of palivizumab are currently being reconsidered.

Question: How do you view the effect of antioxidants on the need for bronchodilators? While conducting a study on superoxide dismutase, for conventional BPD, a surprising finding was that the need for respiratory admissions and need for bronchodilators in the first 2 years of life was significantly reduced, even though the incidence of BPD was not different than seen with placebo. What are your thoughts on the role of antioxidants in persistent lung abnormalities?

Anne Greenough, MD: The problem with all of the follow-up studies with premature babies is that BPD—just the length of oxygen dependency—is a very poor outcome measure. It can be influenced by so many things, for example, most importantly by the level of oxygen saturation. It's much more important to assess lung function. Look at wheeze and cough and actually measure lung function. I think antioxidants, including superoxide dismutase, have a lot of potential in improving the outcome of these premature babies, and I believe a study is about to begin in the United States soon to look at that.

Question: Can lung function measurement lead to quality improvement in the prevention of RSV?

Anne Greenough, MD: Lung function measurement can detect potentially important differences in outcome. At 1 year of age, lung function test results can predict those infants at high risk of chronic respiratory morbidity. Plethysmographic assessment measures the total lung volume of the infant. Functional lung volume is measured by helium gas dilution. A comparison of the ratio of the 2 reveals gas trapping. There is no significant difference between these 2 groups, yet when we look at a plethysmographic assessment of airway resistance, difficulty with breathing out is significantly higher in infants with a history of RSV infection.

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We are grateful to the other members of the bronchopulmonary dysplasia study group, J. Alexander, W. Lenney, P. A. J. Chetcuti, N. J. Shaw, S. Coles, J. Boorman and J. Turner, and the research nurses, S. Cox, F. Turnball, S. Burgess, A. Woods, J. Bytham, J. Hagan, S. Melville and A. Roberts, who were funded by Abbott Laboratories. We thank Mrs. Deirdre Gibbons for her secretarial assistance.

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respiratory syncytial virus; prematurity; lung function testing; asthma

© 2005 Lippincott Williams & Wilkins, Inc.


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