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Corticosteroids for first-time young wheezers: current status of the controversy

2003; Elsevier BV; Volume: 143; Issue: 6 Linguagem: Inglês

10.1016/j.jpeds.2003.10.001

1097-6833

Miles Weinberger,

Respiratory Support and Mechanisms

Bronchiolitis, the diagnostic term generally used for first-time wheezing with a viral respiratory infection, is the leading cause of hospitalization in infants. The reported annual hospitalization rate for this disorder has been ∼3 per 100 infants in the United States,1.Shay D.K. Holman R.C. Newman R.D. Liu L.L. Stout J.W. Anderson L.J. Bronchiolitis-associated hospitalizations among US children, 1980-1996.JAMA. 1999; 282: 1440-1446Crossref PubMed Scopus (1173) Google Scholar and the latest available data show no sign that these hospitalizations are decreasing.2.Centers for Disease Control Prevention Bronchiolitis-associated outpatient visits and hospitalizations among American Indian and Alaska native children—United States, 1990-2000.MMWR. 2003; 52: 707-710PubMed Google Scholar Treatment that has the potential to favorably alter the clinical course of bronchiolitis is of considerable clinical interest. Both corticosteroids and bronchodilators have commonly been used for bronchiolitis, but conflicting data among the many published trials of therapy has resulted in skepticism regarding their clinical usefulness.3.Van Woensel J.B. van Aalderen W.M. Treatment for bronchiolitis: the story continues.Lancet. 2002; 360: 101-102Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 4.Nelson R. Bronchiolitis drugs lack convincing evidence of efficacy.Lancet. 2003; 361: 939Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Contrary to previous studies showing no benefit from corticosteroids for bronchiolitis,5.Dabbous I.A. Tkachyk J.S. Stamm S.J. A double-blind study on the effects of corticosteroid in the treatment of bronchiolitis.Pediatrics. 1966; 37: 477-484PubMed Google Scholar, 6.Springer C. Bar-Yishay E. Uwayyed K. Avital A. Vilozni D. Godfrey S. Corticosteroids do not affect the clinical or physiological status of infants with bronchiolitis.Pediatr Pulmonol. 1990; 9: 181-185Crossref PubMed Scopus (104) Google Scholar, 7.Roosevelt G. Sheehan K. Frupp-Phelan J. Tanz R.R. Listernick R. Dexamethasone in bronchiolitis: a randomized controlled trial.Lancet. 1996; 348: 292-295Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 8.Klassen T.P. Sutcliffe T. Watters L.K. Wells G.A. Allen U.D. Li M.M. Dexamethasone in salbutamol-treated inpatients with acute bronchiolitis: a randomized, controlled trial.J Pediatr. 1997; 130: 191-196Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, 9.De Boeck K. Van der Aa N. Van Lierde S. Corbeel L. Eeckesl R. Respiratory syncytial virus bronchiolitis: a double-blind dexamethasone efficacy study.J Pediatr. 1997; 131: 919-921Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar the study by Csonka et al in this issue of The Journal10.Csonka P. Kaila M. Laippala P. Iso-Justajärvi M. Veskikari T. Ashorn P. Oral prednisolone in the acute management of children age 6-35 months with viral respiratory infection-induced lower airway disease: a randomized, placebo-controlled trial.J Pediatr. 2003; 143: 725-730Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar adds to other evidence that corticosteroids are, in fact, beneficial for these patients. By treating patients with 2 mg/kg of prednisolone in the emergency room and 1 mg/kg twice daily for 3 more days, these authors demonstrated significantly shorter hospital stays among patients who subsequently required hospitalization and a shorter duration of symptoms, averaging about a day less among the steroid-treated group compared with randomized control subjects who received placebo. This study demonstrated no decrease in decisions to hospitalize after 4 hours of observation in the emergency department after the initial dose of prednisolone; admissions occurred in just more than half of both prednisolone- and placebo-treated patients. In contrast, Schuh et al demonstrated that a similar percentage of patients (44%) seen in the emergency department required admission after 4 hours when given placebo, whereas fewer than half as many (17%) required admission among those given 1 mg/kg of dexamethasone.11.Schuh S. Coates A.L. Binnie R. Allin T. Goia C. Corey M. et al.Efficacy of oral dexamethasone in outpatients with acute bronchiolitis.J Pediatr. 2002; 140: 27-32Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar That dose of dexamethasone is equivalent to ∼5 mg/kg of prednisolone, 2.5 times the dose given by Csonka et al. While a meta-analysis that included 6 controlled clinical trials judged to have relevant data related to length of stay and duration of symptoms concluded there was benefit from prednisolone for bronchiolitis,12.Garrison M.M. Christakis D.A. Harvey E. Cummings P. Davis R.L. Systemic corticosteroids in infant bronchiolitis: a meta-analysis.Pediatrics. 2000; 105 (Available at:): e44http://www.pediatrics.org/cgi/content/full/105/4/e44Crossref PubMed Scopus (166) Google Scholar five of the individual trials included in that analysis showed little or no benefit.5.Dabbous I.A. Tkachyk J.S. Stamm S.J. A double-blind study on the effects of corticosteroid in the treatment of bronchiolitis.Pediatrics. 1966; 37: 477-484PubMed Google Scholar, 6.Springer C. Bar-Yishay E. Uwayyed K. Avital A. Vilozni D. Godfrey S. Corticosteroids do not affect the clinical or physiological status of infants with bronchiolitis.Pediatr Pulmonol. 1990; 9: 181-185Crossref PubMed Scopus (104) Google Scholar, 7.Roosevelt G. Sheehan K. Frupp-Phelan J. Tanz R.R. Listernick R. Dexamethasone in bronchiolitis: a randomized controlled trial.Lancet. 1996; 348: 292-295Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 8.Klassen T.P. Sutcliffe T. Watters L.K. Wells G.A. Allen U.D. Li M.M. Dexamethasone in salbutamol-treated inpatients with acute bronchiolitis: a randomized, controlled trial.J Pediatr. 1997; 130: 191-196Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, 9.De Boeck K. Van der Aa N. Van Lierde S. Corbeel L. Eeckesl R. Respiratory syncytial virus bronchiolitis: a double-blind dexamethasone efficacy study.J Pediatr. 1997; 131: 919-921Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar Only one concluded that prednisolone accelerated improvement compared with placebo.13.Van Woensel J.B.M. Wolfs T.F.W. van Aalderen W.M.C. Brand P.L.P. Kimpen J.L.L. Randomized double-blind placebo-controlled trial of prednisolone in children admitted to hospital with respiratory syncytial virus bronchiolitis.Thorax. 1997; 52: 634-637Crossref PubMed Scopus (102) Google Scholar Even accepting the validity of the meta-analysis of these 6 studies, the statistically significant benefit demonstrated was, on average, qualitatively small, less than a half day difference in hospitalization. Given the differences in outcome from various studies of the effect of corticosteroids on bronchiolitis, it is useful to examine differences in methodology among the various clinical trials. One variable of potential relevance is timing of treatment. The magnitude of benefit described was larger in the current report of patients treated in the emergency department10.Csonka P. Kaila M. Laippala P. Iso-Justajärvi M. Veskikari T. Ashorn P. Oral prednisolone in the acute management of children age 6-35 months with viral respiratory infection-induced lower airway disease: a randomized, placebo-controlled trial.J Pediatr. 2003; 143: 725-730Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar than in those included in the meta-analysis, which was limited to patients treated subsequent to hospitalization.12.Garrison M.M. Christakis D.A. Harvey E. Cummings P. Davis R.L. Systemic corticosteroids in infant bronchiolitis: a meta-analysis.Pediatrics. 2000; 105 (Available at:): e44http://www.pediatrics.org/cgi/content/full/105/4/e44Crossref PubMed Scopus (166) Google Scholar The study by Schuh et al11.Schuh S. Coates A.L. Binnie R. Allin T. Goia C. Corey M. et al.Efficacy of oral dexamethasone in outpatients with acute bronchiolitis.J Pediatr. 2002; 140: 27-32Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar found that using a considerably higher dose of corticosteroid in the emergency department substantially prevented hospitalizations; this was not seen from the lower dose of corticosteroid used in the report by Csonka et al.10.Csonka P. Kaila M. Laippala P. Iso-Justajärvi M. Veskikari T. Ashorn P. Oral prednisolone in the acute management of children age 6-35 months with viral respiratory infection-induced lower airway disease: a randomized, placebo-controlled trial.J Pediatr. 2003; 143: 725-730Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar In another emergency department study of bronchiolitis in which patients were sufficiently mild that few required hospitalization, prednisolone in a dose of 1 mg/kg twice daily for 5 days was associated with significantly more rapid improvement than those who received placebo.14.Goebel J. Estrada B. Quinonez J. Nagji N. Sanford D. Boerth R.C. Prednisolone plus albuterol versus albuterol alone in mild to moderate bronchiolitis.Clin Pediatr. 2000; 39: 213-220Crossref PubMed Scopus (50) Google Scholar What are other alternatives for treating bronchiolitis? Bronchodilators are frequently prescribed for bronchiolitis. These have included aerosols of albuterol (salbutamol), ipratropium, and epinephrine. Although associated with controversy regarding benefit, albuterol has been shown to provide physiologic improvement.15.Schuh S. Canny G. Reisman J.J. Kerem E. Bentur L. Petric M. et al.Nebulized albuterol in acute bronchiolitis.J Pediatr. 1990; 117: 633-637Abstract Full Text PDF PubMed Scopus (148) Google Scholar Ipratropium was shown to have no additive effect to albuterol.16.Schuh S. Johnson D. Canny G. Reisman J. Shields M. Kovesi T. et al.Efficacy of adding nebulized ipratropium bromide to nebulized albuterol therapy in acute bronchiolitis.Pediatrics. 1992; 90: 920-923PubMed Google Scholar In 1996, a meta-analysis concluded that modest short-term improvement in some clinical features could be demonstrated for bronchodilators.17.Kellner J.D. Ohlsson A. Gadomski A.M. Wang E.E.L. Efficacy of bronchodilator therapy in bronchiolitis: a meta-analysis.Arch Pediatr Adolesc Med. 1996; 150: 1166-1172Crossref PubMed Scopus (140) Google Scholar A subsequent report suggested that epinephrine aerosol was more effective that albuterol (salbutamol) in hospitalized infants with bronchiolitis.18.Bertrand P. Aranibar H. Castro E. Sanchez I. Efficacy of nebulized epinephrine versus salbutamol in hospitalized infants with bronchiolitis.Pediatr Pulmonol. 2001; 31: 284-288Crossref PubMed Scopus (93) Google Scholar However, more recent studies have failed to demonstrate improved outcome from use of either albuterol or epinephrine by aerosol in hospitalized infants with bronchiolitis.19.Patel H. Platt R.W. Pekeles G.S. Ducharme F.M. A randomized controlled trial of the effectiveness of nebulized therapy with epinephrine compared with albuterol and saline in infants hospitalized for acute viral bronchiolitis.J Pediatr. 2002; 141: 818-824Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 20.Wainwright C. Altamirano L. Cheny M. Cheney J. Barber S. Price D. et al.A multicenter, randomized, double-blind, controlled trial of nebulized epinephrine in infants with acute bronchiolitis.N Engl J Med. 2003; 349: 27-35Crossref PubMed Scopus (213) Google Scholar The attempts to treat bronchiolitis with corticosteroids and bronchodilators have been justified by the similar clinical presentation of bronchiolitis and acute exacerbations of asthma, a disease process that is accepted to respond to those treatments. Symptoms of both include respiratory distress and wheezing. Infants with bronchiolitis are at substantial risk for recurrences of viral respiratory infection-induced lower airway disease that result in repeated episodes of respiratory distress and wheezing consistent with a diagnosis of asthma.21.Weinberger M. Clinical patterns and natural history of asthma.J Pediatr. 2003; 142: S15-S20Abstract Full Text PDF PubMed Scopus (16) Google Scholar The infections that most commonly cause bronchiolitis, respiratory syncytial virus and the parainfluenzas, are also the same viruses that cause repeated episodes in young children.22.Lemanske R.F. Viruses and asthma: inception, exacerbation, and possible prevention.J Pediatr. 2003; 142: S3-S8Abstract Full Text PDF PubMed Scopus (56) Google Scholar The available data indicate that bronchodilators have some effect on improving airflow for both bronchiolitis and severe acute asthma. However, that physiologic effect is transient and does not alter the inflammation that is present in both of these diagnoses. Corticosteroids are unequivocally effective for acute asthma requiring emergency treatment and hospitalizations, most of which are associated with viral respiratory infections.23.Weinberger M. Treatment strategies for viral respiratory infection-induced asthma.J Pediatr. 2003; 142: S34-S39Abstract Full Text PDF PubMed Scopus (19) Google Scholar The studies of Schuh et al11.Schuh S. Coates A.L. Binnie R. Allin T. Goia C. Corey M. et al.Efficacy of oral dexamethasone in outpatients with acute bronchiolitis.J Pediatr. 2002; 140: 27-32Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar and the current report by Csonka et al10.Csonka P. Kaila M. Laippala P. Iso-Justajärvi M. Veskikari T. Ashorn P. Oral prednisolone in the acute management of children age 6-35 months with viral respiratory infection-induced lower airway disease: a randomized, placebo-controlled trial.J Pediatr. 2003; 143: 725-730Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar indicating benefit from corticosteroid treatment of bronchiolitis are consistent with the observations of corticosteroids' effectiveness for severe acute asthma. This leaves the question: Why have the studies treating bronchiolitis with corticosteroids in the hospital not shown the clinical response of the studies performed in patients seen in an emergency treatment center? Perhaps the differences in outcome relate to the earlier treatment provided in the emergency treatment center when there is substantial reversible inflammation, whereas treatment that occurs only after hospitalization encounters the characteristic dense plugs composed of alveolar debris and strands of fibrin within the bronchioles as a consequence of continued inflammation.24.Wohl M.E.B. Chernick V. State of the art: bronchiolitis.Am Rev Respir Dis. 1978; 118: 759-781Crossref PubMed Scopus (249) Google Scholar Vigorous treatment early in the course of bronchiolitis may therefore be effective in preventing the progression of airway damage from the inflammatory process, thereby preventing hospitalization as demonstrated by Schuh et al11.Schuh S. Coates A.L. Binnie R. Allin T. Goia C. Corey M. et al.Efficacy of oral dexamethasone in outpatients with acute bronchiolitis.J Pediatr. 2002; 140: 27-32Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar with a high dose of corticosteroid or at least modifying the course of the pathology as demonstrated to a more modest degree with the lower doses of corticosteroids in the current report by Csonka et al10.Csonka P. Kaila M. Laippala P. Iso-Justajärvi M. Veskikari T. Ashorn P. Oral prednisolone in the acute management of children age 6-35 months with viral respiratory infection-induced lower airway disease: a randomized, placebo-controlled trial.J Pediatr. 2003; 143: 725-730Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar and the previous report by Goebel et al.14.Goebel J. Estrada B. Quinonez J. Nagji N. Sanford D. Boerth R.C. Prednisolone plus albuterol versus albuterol alone in mild to moderate bronchiolitis.Clin Pediatr. 2000; 39: 213-220Crossref PubMed Scopus (50) Google Scholar What is the appropriate response for the clinician encountering acute bronchiolitis based on the current state of the evidence? Early treatment with a high dose of corticosteroid appears to have the potential to substantially decrease the risk of hospitalization. Bronchodilators may provide some transient clinical benefit but do not appear to alter the course of the disease. Once the disease progresses sufficiently so that hospitalization is essential, it is less clear if any pharmacotherapy alters the course of the disease. Nonetheless, the response to a trial of bronchodilator can be readily assessed clinically to determine if repeated use is warranted, and there is little risk to the use of short courses of corticosteroids. But supportive measures with adequate oxygenation and hydration are probably the least controversial treatment measures at that stage of the illness while awaiting the bronchiolitis to run its course.