Lung (1990) Supph422-429 © Spr/nger-Verlag New York Inc. 1990
Economic and Long-term Benefits of Ribavirin Therapy on Respiratory Syncytial Virus Infection N. J. C. Snell Viratek U.K and The Brompton Hospital, London, United Kingdom
Abstract. Ribavirin is a broad-spectrum antiviral agent. Administered as an aerosol, it has been shown to be clinically effective in improving the signs and symptoms of viral bronchiolitis in infancy, particularly cases due to respiratory syncytial virus (RSV). This paper reviews the evidence for economic and/or long-term clinical benefits from using ribavirin in the acute illness. There are data to suggest that use of ribavirin may lead to a reduction in therapeutic interventions and duration of hospital stay, with associated savings in hospital costs. Ribavirin reduces the production of RSV-specific IgE, and (in ~itro) inhibits the release of inflammatory mediators from mast cells, suggesting that there could be beneficial effects on the incidence of postbronchiolitis wheezing. Confirmatory studies are in progress. Key words: Ribavirin--Respiratory syncytial virus~Viral bronchiolitis. Pathophysiology of Viral Bronchiolitis Acute bronchiolitis is a common condition in infancy; in a recent large study in the United States, 17% of 1,179 newborn infants followed prospectively developed bronchiolitis during the first year of life [1]; 2% of all infants born in the previous 12 months may be ill enough to require admission to hospital [2]. Overall mortality from the disease is low, less than 1% [2, 3] but may be very much greater in specific high-risk groups, especially those with preexisting congenital heart disease, bronchopulmonary dysplasia, cystic fibrosis, or immunodeficiency states. In these groups mortality rates in excess of 30% have been reported [2]. Infants with these associated conditions, premature babies,
Offprint requests to: Dr. N. J. C. Snell, Viratek, ICN Biomedicals, Lincoln Road, High Wycombe, Cressex Estate, Bucks HP12 3XJ, UK.
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and other healthy neonates, are at risk of more prolonged and severe disease, and are most likely to require mechanical ventilation [4, 5]. The virus most commonly associated with the clinical picture of bronchiolitis is the respiratory syncytial virus (RSV), accounting for some 65% of cases; other viruses commonly isolated are the parainfluenza viruses (types 1, 2, and 3), influenza viruses (types A and B), and adenoviruses [1]. RSV shows a marked seasonality in incidence, with the great majority of cases in Europe occurring between October and April, although sporadic cases are seen throughout the year; there is a tendency for epidemics to be more severe in alternate years. Recently the existence of two subgroups o f R S V (A and B) has been established; both may cocirculate and cause identical symptoms, but the subgroup A virus appears to be associated with more severe illness [6]. The clinical picture of viral bronchiolitis is characterized by tachypnea, hyperinflation, wheezing, and fine crepitations. Apneic episodes may occur, particularly in neonates. Forced expiratory flows and lung compliance are reduced, and thoracic gas volumes and respiratory resistance increased [7]. Work of breathing may be greatly increased; this is partly due to bronchoconstriction, but may also be related to a deficiency of lung surfactant--the viruses responsible for acute bronchiolitis can all infect type II pneumonocytes (the cells that synthesize and secrete surfactant) and cause cell death [8]. Acute viral infection can also cause extensive damage to ciliated respiratory epithelium [9] with associated impairment of mucociliary clearance which may take several weeks to return to normal [I0]. Viral bronchiolitis is also associated with significant long-term morbidity; follow-up studies of infants who have recovered from acute bronchiolitis show a greatly increased incidence of recurrent wheezing episodes and lower respiratory tract infections compared with controls [11, 12], and there is increasing evidence of a link between viral respiratory infections and the onset of acute asthma [13]. This predisposition to wheeziness may be related to the marked increases that have been demonstrated in levels of leukotriene C4 [14, 15], and RSV-specific IgE [16, 17] in nasopharyngeal secretions of infants with acute viral bronchiolitis; an animal study has also shown that viral bronchiolitis early in life can induce increased numbers of bronchiolar mast cells [18]. A single small clinical study has suggested that viral bronchiolitis may lead to persistent small airway damage that might predispose to chronic bronchitis and emphysema in adult life [19]. This possibility has received support from a recent study that showed that viral bronchiolitis during early life in rats can induce abnormal alveolar development and bronchiolar hypoplasia associated with abnormalities of lung function [20]. Until recently the management of hospitalized infants with viral bronchioliris was symptomatic and supportive. Hypoxemia is common and oxygen therapy may be indicated; exhaustion, respiratory failure, or recurrent apnea may make artificial ventilatory support necessary. Treatments that have been shown to be ineffective in the acute illness include physiotherapy, mist treatment, antibiotics, and corticosteroids (although the possibility that steroid therapy during the acute illness might affect long-term morbidity has not been
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studied). Interestingly, nebulized steroids have recently been shown to be of value in the treatment of postbronchiolitis wheezing [21]. Bronchoconstriction in infants is generally resistant to B-stimulant and xanthine bronchodilators, but may respond to anticholinergic agents such as ipratropium bromide [2]. Currently the only specific antiviral therapy proven to be of benefit in this condition is the synthetic nucleoside ribavirin, although a recent study from China has purported to show benefit from the use of nebulized a-interferon [22].
Ribavirin
Background Ribavirin is a synthetic analog of guanosine, and has been shown to have a very broad spectrum of antiviral activity both in vitro and in vivo, including both RNA and DNA viruses. Activity has been demonstrated against all the pathogens commonly implicated in viral bronchiolitis, including RSV, parainfluenza types 1, 2, and 3, influenza A and B, adenoviruses, and rhinoviruses [23, 24]. Clinically ribavirin has been given orally or parenterally in a wide variety of viral infections, and efficacy has been demonstrated in acute viral hepatitis, measles, and herpes genitalis [24]; Lassa fever [25]; and the early stages of infection with the human immunodeficiency virus (HIV), the cause of AIDS [26, 27]. Administered as an aerosol via a small-particle generator, high concentrations of ribavirin can be attained within the bronchial tree, without systemic side effects; given in this way ribavirin has been shown to be efficacious in RSV infection [28] and influenza [29]. In preclinical testing ribavirin was found to be neither mutagenic nor carcinogenic. It has been shown to be teratogenic and/or embryolethal in rodent and rabbit studies, although no evidence of teratogenicity was found in a small study in primates (baboons). In Acute Viral Bronchiolitis In a series of controlled clinical trials in acute RSV bronchiolitis, aerosolized ribavirin has been shown to improve signs and symptoms [30-34], reduce the severity of illness [30, 31, 35, 36], improve oxygen saturation [30, 31, 35], hasten the resolution rate [31, 34], and reduce viral shedding [30, 35, 37]. Uncontrolled case reports have also suggested benefit in viral pneumonitis due to parainfluenza [38, 39], and adenovirus [40]. Ribavirin aerosol is clinically effective in influenza in young adults [29]; studies in infants are currently in progress. The use of ribavirin in viral bronchiolitis has been questioned, with respect to its cost benefit ratio [41]. Critics have suggested that hastening resolution of
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the acute illness is not enough to justify prescribing the drug, and that there is a need to demonstrate (1) an improvement in mortality; (2) a reduction in the duration of intensive care and hospitalization, which would save on medical costs; and (3) effects on the long-term morbidity associated with viral bronchiolitis. Is there any evidence to demonstrate benefit in these areas?
Effects on mortality. As mentioned previously, mortality from RSV infection in previously healthy infants is low, less than 1%. To demonstrate a reduction in mortality due to a therapeutic intervention an extremely large study would have to be mounted, and this has not hitherto been considered either necessary or practicable. On the other hand, mortality in infants with underlying cardiopulmonary disease has been reported to be as high as 37% [42]; an early study with ribavirin specifically enrolled such high-risk infants [35]. Those most severely ill (23 in all) were treated openly with ribavirin, and all survived. Thirteen others with congenital heart disease or bronchopulmonary dysplasia were randomly allocated to ribavirin or placebo therapy. Those on the active drug showed significantly greater improvement than those on placebo (p < 0.01); no infants died in either group. Obviously the zero mortality in the severely ill infants treated with ribavirin compares extremely favorably with the historical figure of 37% in similar infants, and strongly suggests that ribavirin therapy reduces mortality; nevertheless there are problems in making valid comparisons with historical controls, not least the fact that standards of supportive care have improved over the last few years so that mortality would probably currently be lower in the high-risk group in any case. Calls for a further placebocontroUed study of the effects of ribavirin on mortality in high-risk infants [41] have been met by counterarguments that it would be unethical to administer placebo in cases where the benefits of treatment with ribavirin have already been demonstrated, particularly since the only way in which a beneficial effect on mortality could be demonstrated would be for a number of the infants in the placebo group to die [43]. It seems improbable that parents could give genuinely informed consent for their sick child to participate in such a study, and it is unlikely now that further trials will be mounted in which effects on mortality would be the primary end-point. Effects on hospitalization. There are obvious economic and social benefits to be gained from a treatment which can reduce therapeutic interventions and shorten the duration of intensive therapy and total hospitalization time. Can ribavirin achieve these aims? The majority of controlled trials with ribavirin unfortunately did not look at duration of treatment or hospitalization as specific end-points; indeed some study protocols may have required formal follow-up of all patients for a set period of days irrespective of their fitness to be discharged. However, there are four pieces of evidence suggesting that ribavirin therapy is beneficial. Rodriguez et al. [31] conducted a controlled study in 30 infants and young children hospitalized with RSV bronchiolitis; patients were randomly assigned
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to ribavirin or placebo therapy in a ratio of 2:1 (20 active, 10 placebo). Placebo recipients required treatment for longer (mean 58.6 h) than ribavirin-treated patients (mean 55.7 h) although this difference is not statistically significant (p = 0.63). Of the ribavirin patients, only 5% required treatment for more than 4 days compared with 20% of the placebo patients. In a nonrandomized study, 33 infants who were considered to be severely ill with RSV infection, or who had coexisting disorders, were treated with ribavirin; their progress was compared with that of 97 untreated patients [34]. Despite the fact that the treated group were more seriously ill, mean duration of mechanical ventilation in those patients requiring it (13 in the treated and 8 in the control group) was significantly shorter in the patients receiving ribavirin (3.5 vs. 9.4 days, p < 0.005). Edelson et al. studied 22 infants in a double-blind placebo-controlled study. Ten cases were classified as "high-risk"; in these patients trends in favor of ribavirin were seen in all but one assessment of efficacy, and these were statistically significant in the case of the number of days requiring mechanical ventilation, and the number of days requiring supplemental oxygen (p < 0.05) [44]. Duration of hospitalization was shortened [45]. This last finding receives support from a retrospective study of length of hospital stay and associated costs of infants who either received ribavirin or were untreated, over a 2-year period in a small U.S. hospital. Ribavirin-treated patients with RSV bronchiolitis were hospitalized for an average of 3.0 days compared with 5.22 days for untreated patients; mean costs were $1096 and $1884, respectively [46]. These studies suggest that use of ribavirin may reduce the duration of treatment, need for supplemental oxygen, duration of mechanical ventilation, and overall period of hospitalization, and thereby the total costs of treatment. A number of large, prospective studies are currently in progress to attempt to confirm these findings.
Effects on long-term sequelae. The ideal agent for treating viral bronchiolitis would also reduce the long-term morbidity (wheezing and lower respiratory tract illnesses). In a controlled study of 48 patients with RSV infection, administration of ribavirin was associated with fewer subjects producing RSV-specific IgE in their nasopharyngeal secretions (p = 0.036); geometric mean titers of RSV specific IgE in convalescent-phase samples were significantly higher in placebo-treated (p < 0.025) and untreated (p < 0.05) subjects than in those receiving ribavirin [47]. Suppression of the IgE response in the acute illness might inhibit the release of inflammatory chemical mediators (histamine, leukotriene C4) that cause bronchoconstriction, modify the response to any subsequent RSV infection, and lessen the risk of precipitating asthma. Viral bronchiolitis increases the number of bronchiolar mast cells in rats [18]; in vitro, ribavirin has been shown to inhibit the release of inflammatory mediators from mast cells stimulated by both IgE- and non-IgE-related signals [48]. These findings suggest that prompt treatment of acute RSV bronchiolitis might beneficially modify the subsequent clinical course; this hypothesis is currently being tested in several long-term follow-up clinical trials.
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Conclusions What do we now know about ribavirin therapy of RSV bronchiolitis? First, treatment is safe - a recent surveillance study of an estimated 26,432 infants treated in the United States disclosed a reported adverse reaction rate of 0.07%, none of which were considered major [49]. The most common side effects were skin rash and mild bronchospasm. A single report has documented small but statistically significant increases in systemic blood pressure during aerosol administration [50]. A recent study has shown that nebulized ribavirin, even at 3 times the recommended concentration, does not adversely affect nasal mucociliary clearance, and epithelial brushings taken after exposure were normal under light microscopy and had normal ciliary beat frequency [51], an important finding in view of the deleterious effects of viral infection on ciliated epithelium [9, 10]. Second, ribavirin therapy is clearly effective in improving the signs and symptoms of RSV bronchiolitis, and in shortening the duration of the illness. These clinical benefits almost certainly translate into social and economic benefits, by reducing the utilisation of expensive therapeutic facilities and shortening the duration of hospital stay; the results of confirmatory studies are awaited. Lastly, the effects of ribavirin therapy on the release of inflammatory mediators suggest that early treatment of the acute illness might reduce the incidence of subsequent respiratory morbidity, and clinical trials to test this hypothesis are in progress.
References 1. Wright A, Taussig L, Ray C, Harrison H, Holberg C (1989) The Tucson children's respiratory study II. Lower respiratory tract illness in the first year of life. Am J Epidemiol 129:1232-1246 2. Milner A, Murray M (1989) Acute bronchiofitis in infancy: treatment and prognosis. Thorax 44:1-5 3. MacDonald N (1989) Infections with respiratory viruses and allied agents. Curr Opin Infect Dis 2:449-452 4. McMillan J, Tristram D, Weiner L, Higgins A, Sandstrom C, Brandon R (1988) Prediction of the duration of hospitalisation in patients with RSV infection: use of clihical parameters. Pediatrics 8t:22-26 5. Meert K, Heidemann S, Lieh-Lai M, Sarnaik A (1989) Does prematurity alter course of RSV infection? Am Rev Respir Dis 139 (Part 2 of 2):A317 6. Taylor C, Morrow S, Scott M, Young B, Toms G (1989) Comparative virulence of RSV subgroups A and B. Lancet i:777-778 7. Seidenberg J, Masters I, Hudson I, Olinstey A, Phelan P (1989) Disturbance in respiratory mechanics in infants with bronchiotitis. Thorax 44:660-667 8. TyrreU D (1979) Respiratory viruses: some recent advances. In: Heath R (ed) Virus diseases. Pitman, Tunbridge Wells, pp 3-7 9. Hooru B, Tyrrell D (1966) Effects of some viruses on ciliated cells. Am Rev Respir Dis 93 (3 part 2):156-161 10. Pavia D (1987) Acute respiratory infections and mucociliary clearance. Eur J Respir Dis 71:219-226
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11. Webb M, Henry R, Milner A, Stokes G, Swarbrick A (1985) Continuing respiratory problems three and a half years after acute viral bronchiolitis. Arch Dis Child 60:1064-1067 12. Sims D, Downham M, Gardner P, Webb J, Weightman D (1978) Study of 8-year old children with a history of RSV bronchiolitis in infancy. Br Med J 1:11-14 13. Busse W (1989) The relationship between viral infections and onset of allergic diseases and asthma. Clin Exp Allergy 19:1-9 14. Volovitz B, Faden H, Ogra P (1988) Release of leukotriene C4 in respiratory tract during acute viral infection. J Pediatr 112:218-222 15. Volovitz B, Welliver R, de Castro G, Krystofik D, Ogra P (1988) The release ofleukotrienes in the respiratory tract during infection with RSV: role in obstructive airway disease. Pediatr Res 24:504-507 16. Welliver R, Wong D, Sun M, Middletone E, Waughan R, Ogra P (1981) The development of RSV-specific IgE and release of histamine in nasopharyngeal secretion after infection. N Engl J Med 305:841 17. Bui R, Molinaro G, Kettering J, Heiner D, Imagawa D, St Geme J (1987) Virus-specific IgE and IgG~ antibodies in serum of children infected with RSV. J Pediatr 110:87-90 18. Castleman W (1989) Viral bronchiolitis during early life induces increased numbers of bronchiolar mast cells in rats. Am Rev Respir Dis 139 (part 2 of 2):A318 19. Kattan M, Keens T, Lapierre J-G, Levison H, Bryan C, Reilly B (1977) Pulmonary function abnormalities in symptom-free children after bronchiolitis. Pediatrics 59:683-688 20. Castleman W, Sorkness R, Lemanske R, Grasel G, Suyemoto M (1988) Neonatal viral bronchiolitis and pneumonia induces bronchiolar hypoplasia and alveolar dysplasia in rats. Lab Invest 59:387-396 21. Anonymous Editorial (1989) Inhaled steroids and recurrent wheeze after bronchiolitis. Lancet 1:999-1000 22. Dai Jia-Xiong, You Chun-hua, Qi Zhong-tian, Wang Xiong-min, Sun Pin-qing, Bi Wen-shan, Quan Yah, Ding Rong-lun, Du Ping, He Ying (1987) Children's respiratory viral diseases treated with Interferon aerosol. Chinese Med J 100:162-166 23. Gilbert B, Knight V (1986) Biochemistry and clinical applications of ribavirin. Minireview. Antimicrob Agents Chemother 30:201-205 24. Sidwell R, Revankar G, Robins R (1985) Ribavirin: review of a broad-spectrum antiviral agent. In: Shugar D (ed) International encyclopaedia of pharmacology and therapeutics, section 116 (viral chemotherapy), Vol. 2. Pergamon Press, Oxford, pp 49-108 25. McCormick J, King I, Webb P, Scribner C, Craven R, Johnson K, Elliott L, Belmont-Williams R (1986) Lassa fever: effective therapy with ribavirin. N Engl J Med 314:20-26 26. Mansell P (1988) Ribavirin therapy delays progression of the lymphadenopathy syndrome (LAS) to AIDS. In: Nicholson K (ed) HIV and other highly pathogenic viruses. Royal Society of Medicine Services International Congress and Symposium series No. 145. Royal Society of Medicine Services, London, pp 17-18 27. Crumpacker C, Heagy W, Bubley G, Monroe J, Finberge R, Hussey S, Schnipper L, Lucey D, Lee T, McLane M, Essex M, Mulder C (1987) Ribavirin treatment of AIDS and AIDS-related complex. Ann Intern Med 107:664-674 28. Rodriguez W, Parrott R (1987) Ribavirin aerosol treatment of serious RSV infection in infants. infect Dis Clin N Am 1:425-439 29. Knight V, Gilbert B (1987) Ribavirin aerosol treatment of influenza. Infect Dis Clin N Am 1:441-457 30. Hall C, McBride J, Walsh E, Bell D, Gala C, Hildreth S, Ten Eyck L, Hall W (1983) Aerosolised ribavirin treatment of infants with RSV infection. N Engl J Med 308:1443-1447 31. Rodriguez W, Kim H, Brandt C, Fink R, Getson P, Arrobio J, Murphy T, McCarthy V, Parrott R (1987) Aerosolised ribavirin in the treatment of patients with RSV disease. Pediatr Infect Dis J 6:159-163 32. Baraldi E, Zanconato S, Rebeschini G, Biban P, Donzelli F, Da Dale L (1987) Aerosolised ribavirin in the treatment of bronchiolitis due to RSV. Ital J Pediatr 13 (Suppl 1):19-20 33. Barry W, Cockburn F, Cornall R, Price J, Sutherland G, Vardag A (1986) Ribavirin aerosol for acute bronchiolitis. Arch Dis Child 61:593-597
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34. Conrad D, Christenson J, Waner J, Marks M (1987) Aerosolised ribavirin treatment of RSV infection in infants hospitalised during an epidemic. Pediatr Infect Dis J 6:152-158 35. Hall C, McBride J, Gala C, Hildreth S, Schnabel K (1985) Ribavirin treatment of RSV infection in infants with underlying cardiopulmonary disease. JAMA 254:3047-3051 36. Taber L, Knight V, Gilbert B, McClung H, Wilson S, Norton H, Thurson J, Gordon W, Atmar R, Schlaudt W (1983) Ribavirin aerosol treatment of bronchiolitis associated with RSV infection in infants. Pediatrics 72:613-618 37. Hall C, Walsh E, Hruska J, Betts R, Hall W (1983) Ribavirin treatment of experimental RSV infection. JAMA 249:2666-2670 38. Gelfand E, McCurdy D, Rao C, Middleton P (1983) Ribavirin treatment of viral pneumonitis in severe combined immunodeficiency disease. Lancet ii:732-733 39. McIntosh K, Kurachek S, Cairns L, Burns J, Goodspeed B (1984) Treatment of respiratory viral infection in an immunodeficient infant with ribavirin aerosol. Am J Dis Child 138:305-308 40. Buchdal R, Taylor P, Warner J (1985) Nebulised ribavirin for adenovirus pneumonia. Lancet ii: 1070-1071 41. Isaacs D, Moxon E, Harvey D, Kovar I, Madeley C, Richardson R, Leven M, Whitelaw A, Modi N (1988) Ribavirin in RSV infection. Arch Dis Child 63:986-987 42. McDonald N, Hall C, Suffin S (1982) RSV infection in infants with congenital heart disease. N Engt J Med 307:397-400 43. Snell N (1988) Ribavirin in RSV infection: reply. Arch Dis Child 63:987-989 44. Spinelli M, Geraci-Ciardullo K, Palumbo P, Laskin O, Edelson P (1985) Efficacy of ribavirin for treating RSV pneumonia in high-risk infants. Pediatr Res 19:304A 45. Lanfer D, Edelson P (1987) RSV infection and cardiopulmonary disease. Pediatr Ann 126:644653 46. Sullivan B (1986) RSV and ribavirin. Pediatr Infect Dis J 5:605-606 47. Rosner I, Welliver R, Edelson P, Geraci-Ciardullo K, Sun M (1987) Effect of ribavirin therapy on RSV-specific IgE and IgA responses after infection. J Infect Dis 155:1043-1047 48. Marquardt D, Gruber H, Walker L (1987) Ribavirin inhibits mast cell mediator release. J Pharrnacol Exp Ther 240:t45-149 49. Janai H, Zaleska M, Marks M, Stutman H National surveillance of ribavirin utilisation over two and a half years. In: Proceedings of 16th International Congress of Chemotherapy, Jerusalem, June 1989, p 111 50. Seaton E, Johnson G (1988) Unexpected blood pressure increase associated with aerosolised ribavirin. Pediatr Res 23(4) Part 2:381A 51. Han L-Y, Wilson R, Slater S, Rutman A, Read R, Snell N, Turner-Warwick M, Cole P (1989) Effects of ribavirin on human respiratory epithelium in vitro and nasal mucociliary clearance in vivo. Am Rev Respir Dis 139 (Part 2 of 2):A38
Economic and Long-term Benefits of Ribavirin Therapy on Respiratory Syncytial Virus Infection N. J. C. Snell Viratek U.K and The Brompton Hospital, London, United Kingdom
Abstract. Ribavirin is a broad-spectrum antiviral agent. Administered as an aerosol, it has been shown to be clinically effective in improving the signs and symptoms of viral bronchiolitis in infancy, particularly cases due to respiratory syncytial virus (RSV). This paper reviews the evidence for economic and/or long-term clinical benefits from using ribavirin in the acute illness. There are data to suggest that use of ribavirin may lead to a reduction in therapeutic interventions and duration of hospital stay, with associated savings in hospital costs. Ribavirin reduces the production of RSV-specific IgE, and (in ~itro) inhibits the release of inflammatory mediators from mast cells, suggesting that there could be beneficial effects on the incidence of postbronchiolitis wheezing. Confirmatory studies are in progress. Key words: Ribavirin--Respiratory syncytial virus~Viral bronchiolitis. Pathophysiology of Viral Bronchiolitis Acute bronchiolitis is a common condition in infancy; in a recent large study in the United States, 17% of 1,179 newborn infants followed prospectively developed bronchiolitis during the first year of life [1]; 2% of all infants born in the previous 12 months may be ill enough to require admission to hospital [2]. Overall mortality from the disease is low, less than 1% [2, 3] but may be very much greater in specific high-risk groups, especially those with preexisting congenital heart disease, bronchopulmonary dysplasia, cystic fibrosis, or immunodeficiency states. In these groups mortality rates in excess of 30% have been reported [2]. Infants with these associated conditions, premature babies,
Offprint requests to: Dr. N. J. C. Snell, Viratek, ICN Biomedicals, Lincoln Road, High Wycombe, Cressex Estate, Bucks HP12 3XJ, UK.
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and other healthy neonates, are at risk of more prolonged and severe disease, and are most likely to require mechanical ventilation [4, 5]. The virus most commonly associated with the clinical picture of bronchiolitis is the respiratory syncytial virus (RSV), accounting for some 65% of cases; other viruses commonly isolated are the parainfluenza viruses (types 1, 2, and 3), influenza viruses (types A and B), and adenoviruses [1]. RSV shows a marked seasonality in incidence, with the great majority of cases in Europe occurring between October and April, although sporadic cases are seen throughout the year; there is a tendency for epidemics to be more severe in alternate years. Recently the existence of two subgroups o f R S V (A and B) has been established; both may cocirculate and cause identical symptoms, but the subgroup A virus appears to be associated with more severe illness [6]. The clinical picture of viral bronchiolitis is characterized by tachypnea, hyperinflation, wheezing, and fine crepitations. Apneic episodes may occur, particularly in neonates. Forced expiratory flows and lung compliance are reduced, and thoracic gas volumes and respiratory resistance increased [7]. Work of breathing may be greatly increased; this is partly due to bronchoconstriction, but may also be related to a deficiency of lung surfactant--the viruses responsible for acute bronchiolitis can all infect type II pneumonocytes (the cells that synthesize and secrete surfactant) and cause cell death [8]. Acute viral infection can also cause extensive damage to ciliated respiratory epithelium [9] with associated impairment of mucociliary clearance which may take several weeks to return to normal [I0]. Viral bronchiolitis is also associated with significant long-term morbidity; follow-up studies of infants who have recovered from acute bronchiolitis show a greatly increased incidence of recurrent wheezing episodes and lower respiratory tract infections compared with controls [11, 12], and there is increasing evidence of a link between viral respiratory infections and the onset of acute asthma [13]. This predisposition to wheeziness may be related to the marked increases that have been demonstrated in levels of leukotriene C4 [14, 15], and RSV-specific IgE [16, 17] in nasopharyngeal secretions of infants with acute viral bronchiolitis; an animal study has also shown that viral bronchiolitis early in life can induce increased numbers of bronchiolar mast cells [18]. A single small clinical study has suggested that viral bronchiolitis may lead to persistent small airway damage that might predispose to chronic bronchitis and emphysema in adult life [19]. This possibility has received support from a recent study that showed that viral bronchiolitis during early life in rats can induce abnormal alveolar development and bronchiolar hypoplasia associated with abnormalities of lung function [20]. Until recently the management of hospitalized infants with viral bronchioliris was symptomatic and supportive. Hypoxemia is common and oxygen therapy may be indicated; exhaustion, respiratory failure, or recurrent apnea may make artificial ventilatory support necessary. Treatments that have been shown to be ineffective in the acute illness include physiotherapy, mist treatment, antibiotics, and corticosteroids (although the possibility that steroid therapy during the acute illness might affect long-term morbidity has not been
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studied). Interestingly, nebulized steroids have recently been shown to be of value in the treatment of postbronchiolitis wheezing [21]. Bronchoconstriction in infants is generally resistant to B-stimulant and xanthine bronchodilators, but may respond to anticholinergic agents such as ipratropium bromide [2]. Currently the only specific antiviral therapy proven to be of benefit in this condition is the synthetic nucleoside ribavirin, although a recent study from China has purported to show benefit from the use of nebulized a-interferon [22].
Ribavirin
Background Ribavirin is a synthetic analog of guanosine, and has been shown to have a very broad spectrum of antiviral activity both in vitro and in vivo, including both RNA and DNA viruses. Activity has been demonstrated against all the pathogens commonly implicated in viral bronchiolitis, including RSV, parainfluenza types 1, 2, and 3, influenza A and B, adenoviruses, and rhinoviruses [23, 24]. Clinically ribavirin has been given orally or parenterally in a wide variety of viral infections, and efficacy has been demonstrated in acute viral hepatitis, measles, and herpes genitalis [24]; Lassa fever [25]; and the early stages of infection with the human immunodeficiency virus (HIV), the cause of AIDS [26, 27]. Administered as an aerosol via a small-particle generator, high concentrations of ribavirin can be attained within the bronchial tree, without systemic side effects; given in this way ribavirin has been shown to be efficacious in RSV infection [28] and influenza [29]. In preclinical testing ribavirin was found to be neither mutagenic nor carcinogenic. It has been shown to be teratogenic and/or embryolethal in rodent and rabbit studies, although no evidence of teratogenicity was found in a small study in primates (baboons). In Acute Viral Bronchiolitis In a series of controlled clinical trials in acute RSV bronchiolitis, aerosolized ribavirin has been shown to improve signs and symptoms [30-34], reduce the severity of illness [30, 31, 35, 36], improve oxygen saturation [30, 31, 35], hasten the resolution rate [31, 34], and reduce viral shedding [30, 35, 37]. Uncontrolled case reports have also suggested benefit in viral pneumonitis due to parainfluenza [38, 39], and adenovirus [40]. Ribavirin aerosol is clinically effective in influenza in young adults [29]; studies in infants are currently in progress. The use of ribavirin in viral bronchiolitis has been questioned, with respect to its cost benefit ratio [41]. Critics have suggested that hastening resolution of
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the acute illness is not enough to justify prescribing the drug, and that there is a need to demonstrate (1) an improvement in mortality; (2) a reduction in the duration of intensive care and hospitalization, which would save on medical costs; and (3) effects on the long-term morbidity associated with viral bronchiolitis. Is there any evidence to demonstrate benefit in these areas?
Effects on mortality. As mentioned previously, mortality from RSV infection in previously healthy infants is low, less than 1%. To demonstrate a reduction in mortality due to a therapeutic intervention an extremely large study would have to be mounted, and this has not hitherto been considered either necessary or practicable. On the other hand, mortality in infants with underlying cardiopulmonary disease has been reported to be as high as 37% [42]; an early study with ribavirin specifically enrolled such high-risk infants [35]. Those most severely ill (23 in all) were treated openly with ribavirin, and all survived. Thirteen others with congenital heart disease or bronchopulmonary dysplasia were randomly allocated to ribavirin or placebo therapy. Those on the active drug showed significantly greater improvement than those on placebo (p < 0.01); no infants died in either group. Obviously the zero mortality in the severely ill infants treated with ribavirin compares extremely favorably with the historical figure of 37% in similar infants, and strongly suggests that ribavirin therapy reduces mortality; nevertheless there are problems in making valid comparisons with historical controls, not least the fact that standards of supportive care have improved over the last few years so that mortality would probably currently be lower in the high-risk group in any case. Calls for a further placebocontroUed study of the effects of ribavirin on mortality in high-risk infants [41] have been met by counterarguments that it would be unethical to administer placebo in cases where the benefits of treatment with ribavirin have already been demonstrated, particularly since the only way in which a beneficial effect on mortality could be demonstrated would be for a number of the infants in the placebo group to die [43]. It seems improbable that parents could give genuinely informed consent for their sick child to participate in such a study, and it is unlikely now that further trials will be mounted in which effects on mortality would be the primary end-point. Effects on hospitalization. There are obvious economic and social benefits to be gained from a treatment which can reduce therapeutic interventions and shorten the duration of intensive therapy and total hospitalization time. Can ribavirin achieve these aims? The majority of controlled trials with ribavirin unfortunately did not look at duration of treatment or hospitalization as specific end-points; indeed some study protocols may have required formal follow-up of all patients for a set period of days irrespective of their fitness to be discharged. However, there are four pieces of evidence suggesting that ribavirin therapy is beneficial. Rodriguez et al. [31] conducted a controlled study in 30 infants and young children hospitalized with RSV bronchiolitis; patients were randomly assigned
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to ribavirin or placebo therapy in a ratio of 2:1 (20 active, 10 placebo). Placebo recipients required treatment for longer (mean 58.6 h) than ribavirin-treated patients (mean 55.7 h) although this difference is not statistically significant (p = 0.63). Of the ribavirin patients, only 5% required treatment for more than 4 days compared with 20% of the placebo patients. In a nonrandomized study, 33 infants who were considered to be severely ill with RSV infection, or who had coexisting disorders, were treated with ribavirin; their progress was compared with that of 97 untreated patients [34]. Despite the fact that the treated group were more seriously ill, mean duration of mechanical ventilation in those patients requiring it (13 in the treated and 8 in the control group) was significantly shorter in the patients receiving ribavirin (3.5 vs. 9.4 days, p < 0.005). Edelson et al. studied 22 infants in a double-blind placebo-controlled study. Ten cases were classified as "high-risk"; in these patients trends in favor of ribavirin were seen in all but one assessment of efficacy, and these were statistically significant in the case of the number of days requiring mechanical ventilation, and the number of days requiring supplemental oxygen (p < 0.05) [44]. Duration of hospitalization was shortened [45]. This last finding receives support from a retrospective study of length of hospital stay and associated costs of infants who either received ribavirin or were untreated, over a 2-year period in a small U.S. hospital. Ribavirin-treated patients with RSV bronchiolitis were hospitalized for an average of 3.0 days compared with 5.22 days for untreated patients; mean costs were $1096 and $1884, respectively [46]. These studies suggest that use of ribavirin may reduce the duration of treatment, need for supplemental oxygen, duration of mechanical ventilation, and overall period of hospitalization, and thereby the total costs of treatment. A number of large, prospective studies are currently in progress to attempt to confirm these findings.
Effects on long-term sequelae. The ideal agent for treating viral bronchiolitis would also reduce the long-term morbidity (wheezing and lower respiratory tract illnesses). In a controlled study of 48 patients with RSV infection, administration of ribavirin was associated with fewer subjects producing RSV-specific IgE in their nasopharyngeal secretions (p = 0.036); geometric mean titers of RSV specific IgE in convalescent-phase samples were significantly higher in placebo-treated (p < 0.025) and untreated (p < 0.05) subjects than in those receiving ribavirin [47]. Suppression of the IgE response in the acute illness might inhibit the release of inflammatory chemical mediators (histamine, leukotriene C4) that cause bronchoconstriction, modify the response to any subsequent RSV infection, and lessen the risk of precipitating asthma. Viral bronchiolitis increases the number of bronchiolar mast cells in rats [18]; in vitro, ribavirin has been shown to inhibit the release of inflammatory mediators from mast cells stimulated by both IgE- and non-IgE-related signals [48]. These findings suggest that prompt treatment of acute RSV bronchiolitis might beneficially modify the subsequent clinical course; this hypothesis is currently being tested in several long-term follow-up clinical trials.
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Conclusions What do we now know about ribavirin therapy of RSV bronchiolitis? First, treatment is safe - a recent surveillance study of an estimated 26,432 infants treated in the United States disclosed a reported adverse reaction rate of 0.07%, none of which were considered major [49]. The most common side effects were skin rash and mild bronchospasm. A single report has documented small but statistically significant increases in systemic blood pressure during aerosol administration [50]. A recent study has shown that nebulized ribavirin, even at 3 times the recommended concentration, does not adversely affect nasal mucociliary clearance, and epithelial brushings taken after exposure were normal under light microscopy and had normal ciliary beat frequency [51], an important finding in view of the deleterious effects of viral infection on ciliated epithelium [9, 10]. Second, ribavirin therapy is clearly effective in improving the signs and symptoms of RSV bronchiolitis, and in shortening the duration of the illness. These clinical benefits almost certainly translate into social and economic benefits, by reducing the utilisation of expensive therapeutic facilities and shortening the duration of hospital stay; the results of confirmatory studies are awaited. Lastly, the effects of ribavirin therapy on the release of inflammatory mediators suggest that early treatment of the acute illness might reduce the incidence of subsequent respiratory morbidity, and clinical trials to test this hypothesis are in progress.
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