Respiratory syncytial virus infection: Outcome, management and ...

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R E S P I R ATO R Y T H E R A P Y

Respiratory syncytial virus infection: Outcome, management and prevention Respiratory syncytial virus (RSV) infection is very common in young children. This article describes the acute and long-term morbidity that results from RSV infection. The evidence for current therapy and the effectiveness of preventative strategies are discussed.

Anne Greenough MD, FRCP, FRCPCH, DCH, Professor of Neonatology and Clinical Respiratory Physiology, Guy’s, King’s & St Thomas’ School of Medicine, King’s College London

Simon Broughton BM, MRCP, MRCPCH Paediatric Research Fellow, Division of Asthma, Allergy and Lung Biology Guy’s, King’s & St Thomas’ School of Medicine, King’s College London

Keywords respiratory syncytial virus; asthma; prematurity; bronchiolitis; RSV pneumonia

Key points Greenough, A., Broughton, S. (2005) Respiratory syncytial virus infection: Outcome, management and prevention Infant 1(2): 50-53. 1. RSV infects almost all children by two years of age and approximately one percent of previously healthy children will require hospital admission. 2. Certain groups are at increased risk of severe RSV infection: infants less than six weeks old, those who are immunocompromised, have underlying cardiopulmonary disease or were born prematurely, particularly if they had developed bronchopulmonary dysplasia. 3. The risk of asthma at follow-up is increased following RSV infection in infancy. 4. Current therapy is supportive. 5. There is no safe, effective vaccine. 6. Immunoprophylaxis reduces hospitalisation and requirement for intensive care, its impact on long term respiratory morbidity needs assessment.

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espiratory syncytial virus (RSV) infects almost all children by two years of age and results in a spectrum of illness. The majority will have only a coryzal illness requiring no medical intervention, but others suffer respiratory compromise due to the development of bronchiolitis or RSV pneumonia, necessitating admission to hospital and even intensive care. Although, only one percent of previously healthy children who become infected will require hospitalisation, in 1996 this amounted to 411,000 inpatient days in the United States and a cost of over 300 million dollars1. Very young children are most likely to be admitted – in the United States National Hospital Discharge survey1 57% of the RSV hospitalisations were in children younger than 6 months and 81% in those younger than one year1. Approximately two per cent of infants hospitalised for RSV infection need ventilatory support. Prematurely born infants are much more likely to be infected with RSV than infants born at term, as immature infants have inadequate immunity with low passage of maternal immunoglobulin G antibodies. Prematurely born infants are also more prone to severe morbidity from RSV infection, as they have small airways, which become obstructed by oedema and necrotic debris. As a consequence they require a longer duration of paediatric intensive care stay, particularly if they had had bronchopulmonary dysplasia (BPD)2. Other groups at increased risk of severe RSV infection are infants who are less than six week old and those who are immunocompromised or have underlying cardiopulmonary disease (TABLE 1).

Long term outcome In both retrospective and prospective studies, previously healthy infants who

■ Prematurely born infants, particularly

those who have had BPD or discharged home on supplementary oxygen ■ Infants less than six weeks old ■ Immunocompromised infants ■ Infants with underlying

cardiopulmonary disease TABLE 1 Groups at increased risk of severe RSV infection.

have had an RSV infection have been reported to be at increased risk of respiratory problems at follow-up. Compared to carefully matched controls, children who had been hospitalised as infants because of bronchiolitis were three times more likely to wheeze at ten years of age and ten times more likely to use bronchodilators3. These data have been confirmed in a subsequent study in which all the index children had their infection verified by an RSV test and the antibody response to RSV was checked in the index children and the controls, who were recruited contemporaneously4, 5. In the 140 children aged 7.5 years (47 had been hospitalised for RSV infection and 93 were matched controls) seen at follow-up, the cumulative prevalence of asthma was 30% in the RSV group and 3% in the controls4. This cohort has now been re-examined at thirteen years of age5, and the occurrence of symptoms over the previous 12 months was significantly higher in the RSV group than among the controls – 43% versus 8% for asthma/recurrent wheezing. Sensitisation to common inhaled allergens was also commoner in the RSV group. In another cohort prospectively followed from birth, RSV lower respiratory tract illnesses in early childhood were found to VOLUME 1 ISSU E 2 2005

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be an independent risk factor for the development of subsequent wheezing up to age eleven years, but not at age thirteen.6 The differences in the results from the two cohorts may be explained by differences in the severity of the initial infection and it is only RSV bronchiolitis in infancy severe enough to cause hospitalisation that is a risk factor for allergic asthma in adolescence. A retrospective study has demonstrated that RSV infection also results in ongoing morbidity in prematurely born infants7, 8. In a cohort of prematurely born children who had developed BPD, those who had had at least one admission for RSV infection in the first two years after birth subsequently required more frequent and longer admissions to general paediatric wards and intensive care units, as well as more out-patient attendances and general practitioners consultations for respiratoryrelated disorders7. As a consequence, their cost of care following discharge from the neonatal intensive care unit was at least twice as great for the children who had not been hospitalised for RSV infection7. Reexamination of the cohort at five years of age, demonstrated ongoing increased morbidity in the RSV group, who between two to four years had required a greater duration of hospital stay and more outpatient appointments8. In addition, the RSV group had required more prescriptions overall and for respiratory medications and their cost of care remained higher. In a prospective study, the authors of this article have demonstrated that RSV hospitalisation in prematurely born infants, regardless of their BPD status, is associated with subsequently greater healthcare utilisation9.

Management The management of RSV is essentially supportive, involving maintenance of hydration and oxygenation status. The efficacy of bronchodilators in acute infection has been examined in at least eight randomised trials. A systematic review of the results of those trials demonstrated that a greater proportion of patients who received bronchodilator (54%) rather than a placebo (25%), had an improvement in clinical score, but there was no other positive effect, such as a reduction in the admission rate or duration of hospitalisation10. The modest short term benefit then does not justify providing bronchodilator therapy to all

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FIGURE 1 Resuscitation of an infant with bronchiolitis. Photo – Eddie Lawrence.

RSV positive infants. Nebulised adrenaline may be useful in non-ventilated infants, as it has been shown to be more effective than salbutamol in improving oxygenation, clinical severity scores, and pulmonary resistance11. Infants treated with adrenaline rather than salbutamol were also significantly less likely to require hospital admission (33% versus 88%)12. In ventilated infants, however, nebulised adrenaline should not be given routinely, as some infants may deteriorate and only modest improvements may be achieved – improvement in airway resistance, but no change in compliance, oxygenation or ventilation indices13. In early trials, use of ribavirin, a virustatic agent, was associated with positive effects, but water was used as the placebo and this has a bronchoconstricting effect. Subsequent trials, in which the placebo was saline, failed to demonstrate that ribavirin had any significant benefits14. It had been suggested that ribavirin might decrease post bronchiolitic wheezing and reactive airway disease at follow-up15; this is plausible as ribavirin augments the type 1 response and suppresses type 2 cytokine production in activated human T cells in vitro. In a randomised double-blind, placebo controlled study, however, administration of ribavirin during the acute illness did not alter the rate of clinical improvement, time to discharge, frequency of bronchial hyperresponsiveness or prescription bronchodilators or corticosteroids at follow-up16.

The majority of studies have not demonstrated that corticosteroids improve outcome in infants with RSV infection. In a large randomised trial, one milligram of nebulised budesonide twice daily from admission until two weeks after discharge did not result in a reduction in readmission rates or requirement for ‘antiasthma’ therapy17. Similarly, seven days of prednisolone did not reduce the incidence of wheezing at follow-up18. It is possible that a longer course, of at least six weeks, may be more efficacious19, 20, but in one of the trials19 comparison was made of infants treated in two successive years and in the other20 follow-up was by telephone questionnaire. The efficacy of other possible therapies has been less well tested, although there are some encouraging results. Exogenous surfactant administered to ventilated infants has been demonstrated to prevent the deterioration in lung mechanics observed in a placebo group and be associated with a more rapid improvement in oxygenation. In a small randomised study, surfactant usage was associated with a reduction in the duration of ventilatory support and PICU stay21. In bronchiolitis there are thick mucous plugs, a high concentration of DNA contributing to the increased viscosity and adhesiveness. Use of nebulised recombinant human deoxyribonuclease (rhDNase) on a once daily basis in a randomised trial22 was associated with an improvement in the chest radiograph appearance, but not 51


reduced length of stay. Both heliox and nitric oxide have been given to small numbers of patients with some positive effects. Heliox has a lower density than air and the resistance to flow in the airways is lower. In a non-blinded study, heliox inhalation was associated with a shorter duration of PICU stay23. Nitric oxide has anecdotally improved oxygenation in infants with pulmonary hypertension associated with RSV infection. These therapies need to be tested further in appropriately designed randomised trials.

RSV-IG in preventing RSV hospitalisation among infants who required respiratory support at 36 weeks of PCA or older26. There is evidence to suggest palivizumab may also be more effective. RSV upregulates substance P receptor, this makes the airways abnormally susceptible to the proinflammatory effects of substance P released from sensory nerves. In a rat model27, both RSV-IVIG and palivizumab prevented the potentiation of neurogenic inflammation in the airways, but palivizumab was twice as effective. The American Academy of Pediatrics28 has Prevention stated that palivizumab is preferred for most high-risk patients, because of its ease There is no safe and effective vaccine to of administration (intramuscular rather prevent RSV infection. A formalinthan intravenous), lack of interference with inactivated RSV vaccine was produced in measles-mumps-rubella vaccine and the 1960s, but the vaccinated infants had varicella virus and lack of the more severe pulmonary disease in the next complications associated with intravenous season. Reduction in RSV infection related administration of human immune morbidity, however, can be achieved by globulin products. The American Academy passive immunoprophylaxis. Gamma of Pediatrics has emphasised that RSVglobulin infusions were unsuccessful IVIG is contra-indicated in children with because of their low titre of neutralising cyanotic heart disease28. antibodies, but reductions in The American Academy has published hospitalisations have been achieved using recommendations regarding use of either respiratory syncytial virus immune immunoprophylaxsis for infants at risk of globulin (RSV-IGIV) or a humanised severe RSV infection. High risk infants monoclonal antibody (palivizumab). RSVrecommended for consideration for IGIV (RSV-IGIV, Respigam, Massachusetts prophylaxis included those Public Health Laboratories, born prior to 36 weeks of Boston MA) is six fold gestation and under six enriched for neutralising months of age at the start antibodies. In a multicentre of the RSV season, but randomised double blind without domicillary oxygen placebo controlled trial, the requirement and those PREVENT study, infusion born prematurely, of 750 mg of RSV-IVIG discharged home in every thirty days to supplementary oxygen and prematurely born infants under 24 months of age with or without BPD was when the RSV season associated with a 41% commences28. Subsereduction in RSV quently, many studies have hospitalisation (8.5% been undertaken and versus 13%), a 53% demonstrated, that the cost reduction in hospital days of immunoprophylaxis and a 60% reduction in would be very much higher hospital days with oxygen, than the benefits realised, but no significant impact unless prophylaxis was on intensive care unit 24 restricted to infants with admissions . RSV-IVIG BPD requiring domiciliary has, however, to be given oxygen29. If, however, intravenously and in the immunoprophylaxis PREVENT study, 1% of reduced airway hyperprematurely born infants reactivity and associated and 13% of those with problems at follow-up it BPD required diuretics at may be cost-effective for the time of treatment. In FIGURE 2 An infant with chronic lung disease managed on the neonatal other groups. addition, unanticipated intensive care unit. Photo – Eddie Lawrence. 52

cyanotic episodes and poor outcomes after surgery have been reported after use of RSV-IVIG in infants with cyanotic heart disease, possibly due to volume load or increased blood viscosity. Palivizumab (MEDI-493, Synagis, MedImmune Inc, Gaithersburg, MD) is a humanized monoclonal antibody, which is directed at an epitope on the F glycoprotein on the surface of RSV. In a multicentre, double blind randomised placebo controlled study, the Impact study25, which included 1502 infants of less than 36 weeks of gestational age, five monthly intramuscular injections of palivizumab were associated with a reduction in hospitalisation (10.6% placebo group; 4.8% palivizumab group); there was a 78% reduction in RSV hospitalisations in infants without BPD and a 39% reduction in those with BPD. The palivizumab group also required less hospital days, fewer days with oxygen therapy and less admissions to intensive care, but did not have less need for mechanical ventilation. There have been no randomised comparisons of RSV-IVIG and palivizumab, but in a historical cohort study, it was estimated that palivizumab would have been more cost effective than


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Nosocomial infection Nosocomial infection has a worse outcome than community-acquired RSV infection. Infants who acquire RSV infection nosocomially require a longer length of hospital stay and have a ten-fold increased mortality30. this reflects the fact that many affected infants will have underlying cardiorespiratory disease. RSV infection is spread by direct contact with infected secretions and contaminated objects, thus appropriate hand washing is crucial to prevent nosocomial spread. Early recognition of patients with respiratory symptoms, confirmation of RSV infection by laboratory testing, establishing cohorts of patients and nursing staff, glove and gown barrier precautions, as well as monitoring and education of staff has been shown to reduce the nosocomial RSV infection rate compared to that seen in historical controls31. Dedicated stethoscopes and pulse oximeters according to RSV status were also used. There have been anecdotal reports of RSV immunoglobulin being used to limit the nosocomial spread of infection, particularly on neonatal units. In the absence of evidence from randomised controlled trials, the American Academy of Pediatrics has recommended proper infection control practices, rather than administration of palivizumab to control nosocomial infection.

Conclusion RSV infection has a major impact on health service resource, as a consequence of the large number of admissions due to RSV infection and the resultant chronic respiratory morbidity. Further randomised trials are required to determine which management strategies improve long term outcome. Identification of infants at highest risk of adverse outcome from RSV infection is important, so that immunoprophylaxis can be used most cost-effectively.

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Arch Dis Child 1997; 76(4): 315-19. 4. Sigurs N., Bjarnason R., Sigurbergsson F., Kjellman B. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med 2000; 161(5): 150107. 5. Sigurs N., Gustafsson P.M., Bjarnason R. et al. Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13. Am J Respir Crit Care Med 2005; 171(2): 137-41. 6. Stein R.T., Sherrill D., Morgan W.J. et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 1999; 354(9178): 541-45. 7. Greenough A., Cox S., Alexander J. et al. Health care utilisation of infants with chronic lung disease, related to hospitalisation for RSV infection. Arch Dis Child 2001; 85(6): 463-68. 8. Greenough A., Alexander J., Burgess S. et al. Health care utilisation of prematurely born, preschool children related to hospitalisation for RSV infection. Arch Dis Child 2004; 89(7): 673-78. 9. Broughton S., Roberts A., Fox G., Zuckerman M., Greenough A. Prospective study of risk factors for healthcare utilisation and RSV infection in prematurely born infants. Early Human Development 2004; 80: 169-92 (abstract). 10. Kellner J.D., Ohlsson A., Gadomski A.M., Wang E.E. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev 2000(2): CD001266. 11. Sanchez I., De Koster J., Powell R.E., Wolstein R., Chernick V. Effect of racemic epinephrine and salbutamol on clinical score and pulmonary mechanics in infants with bronchiolitis. J Pediatr 1993; 122(1): 145-51. 12. Menon K., Sutcliffe T., Klassen T.P. A randomized trial comparing the efficacy of epinephrine with salbutamol in the treatment of acute bronchiolitis. J Pediatr 1995; 126(6): 1004-07. 13. Numa A.H., Williams G.D., Dakin C.J. The effect of nebulized epinephrine on respiratory mechanics and gas exchange in bronchiolitis. Am J Respir Crit Care Med 2001; 164(1): 86-91. 14. Randolph A.G., Wang E.E. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract. Cochrane Database Syst Rev 2000(2): CD000181. 15. Edell D., Khoshoo V., Ross G., Salter K. Early ribavarin treatment of bronchiolitis: Effect on long-term respiratory morbidity. Chest 2002; 122(3): 935-39. 16. Everard M.L., Swarbrick A., Rigby A.S., Milner A.D. The effect of ribavirin to treat previously healthy infants admitted with acute bronchiolitis on acute and chronic respiratory morbidity. Respir Med 2001; 95(4): 275-80. 17. Cade A., Brownlee K.G., Conway S.P., Haigh D., Short A., Brown J., et al. Randomised placebo controlled trial of nebulised corticosteroids in acute respiratory syncytial viral bronchiolitis. Arch Dis Child 2000; 82(2): 126-30. 18. van Woensel J.B., Kimpen J.L., Sprikkelman A.B., Ouwehand A., van Aalderen W.M. Long-term effects of prednisolone in the acute phase of bronchiolitis caused by respiratory syncytial virus. Pediatr Pulmonol 2000; 30(2): 92-96. 19. Kajosaari M., Syvanen P., Forars M., JuntunenBackman K. Inhaled corticosteroids during and after respiratory syncytial virus-bronchiolitis may decrease subsequent asthma. Pediatr Allergy Immunol 2000; 11(3): 198-202. 20. Hesselmar B., Adolfsson S. Inhalation of

corticosteroids after hospital care for respiratory syncytial virus infection diminishes development of asthma in infants. Acta Paediatr 2001; 90(3): 260-63. 21. Tibby S.M., Hatherill M., Wright S.M., Wilson P., Postle A.D., Murdoch I.A. Exogenous surfactant supplementation in infants with respiratory syncytial virus bronchiolitis. Am J Respir Crit Care Med 2000; 162(4 Pt 1): 1251-56. 22. Nasr S.Z., Strouse P.J., Soskolne E. et al. Efficacy of recombinant human deoxyribonuclease I in the hospital management of respiratory syncytial virus bronchiolitis. Chest 2001; 120(1): 203-08. 23. Martinon-Torres F., Rodriguez-Nunez A., MartinonSanchez J.M. Heliox therapy in infants with acute bronchiolitis. Pediatrics 2002; 109(1): 68-73. 24. The PREVENT Study Group. Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. Pediatrics 1997; 99(1): 93-99. 25. The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998; 102(3 Pt 1): 531-37. 26. Joffe S., Ray G.T., Escobar G.J., Black S.B., Lieu T.A. Cost-effectiveness of respiratory syncytial virus prophylaxis among preterm infants. Pediatrics 1999; 104(3 Pt 1): 419-27. 27. Piedimonte G., King K.A., Holmgren N.L., Bertrand P.J., Rodriguez M.M., Hirsch R.L. A humanized monoclonal antibody against respiratory syncytial virus (palivizumab) inhibits RSV-induced neurogenic-mediated inflammation in rat airways. Pediatr Res 2000; 47(3): 351-56. 28. American Academy of Pediatrics Committee on Infectious Diseases and Committee on Fetus and Newborn. Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics 2003; 112(6 Pt 1): 1442-46. 29. Thomas M., Bedford-Russell A., Sharland M. Hospitalisation for RSV infection in ex-preterm infants – implications for use of RSV immune globulin. Arch Dis Child 2000; 83(2): 122-27. 30. Langley J.M., LeBlanc J.C., Wang E.E. et al. Nosocomial respiratory syncytial virus infection in Canadian pediatric hospitals: A Pediatric Investigators Collaborative Network on Infections in Canada Study. Pediatrics 1997; 100(6): 943-46. 31. Macartney K.K., Gorelick M.H., Manning M.L., Hodinka R.L., Bell L.M. Nosocomial respiratory syncytial virus infections: The cost-effectiveness and cost-benefit of infection control. Pediatrics 2000; 106(3): 520-26.

Erratum Please note, the telephone number for contact details for the BLISS Community Health Professionals Information guide, published in the January issue of Infant, was incorrect. It should have been 0871 244 8506. 53