Clinical Review & Education
JAMA Clinical Evidence Synopsis
Glucocorticoids for Acute Viral Bronchiolitis in Infants and Young Children Ricardo M. Fernandes, MD; Lisa Hartling, PhD
CLINICAL QUESTION Are glucocorticoids, alone or combined with bronchodilators, associated with reduced admission rates, length of stay, or improvements in clinical severity scores without increased adverse effects in infants and young children with acute viral bronchiolitis? BOTTOM LINE There is no consistent clinically relevant association of single therapy with systemic or inhaled glucocorticoids and improved outcomes in either outpatient or inpatient settings. Exploratory evidence suggests that combined glucocorticoids and nebulized epinephrine may be associated with lower hospitalization rates in outpatients, but these findings must be interpreted cautiously.
Nebulized epinephrine and hypertonic saline are potential options for improving outcomes in infants with bronchiolitis.1,2 Glucocorticoids for the treatment of bronchiolitis are controversial. Glucocorticoid responsiveness varies in children with wheezing.3 Further, although the combination of glucocorticoids with bronchodilators improves outcomes in asthma more than either individual therapy, this combined therapy has been studied only recently for bronchiolitis.4 Previous glucocorticoid trial results, with or without bronchodilators, have yielded inconsistent results. This JAMA Clinical Evidence Synopsis summarizes data from a recent update of a Cochrane review5 of randomized clinical trials evaluating the use of systemic and inhaled glucocorticoids in infants and young children with acute viral bronchiolitis.
Summary of Findings
Discussion Our results do not suggest a clinically relevant association of single glucocorticoid therapy for reducing hospitalizations or length of stay in children with bronchiolitis. This finding was consistent despite substantial heterogeneity in disease severity, glucocorticoid therapy, and outcome measures across settings. One trial suggests that combined high-dose dexamethasone and epinephrine may be associated with lower rates of hospitalizations in outpatients with moderately severe bronchiolitis. Limitations
Limitations include heterogeneity in outcomes and measurement timing, potential risk of bias in the included studies, and small sample sizes Evidence Profile
Baseline severity of participants recruited in outpatient or inpatient settings was often moderate based on clinical severity scores. Considerable variability was found in hospitalization rates (0%44% at 1-day follow-up) and length of stay (mean, 0.8-6.6 days). Among outpatients, there was no difference between glucocorticoids and placebo in hospital admission rates at 1-day follow-up (relative risk [RR], 0.92 [95% CI, 0.78 to 1.08]; absolute rates, 14.9/100 for glucocorticoids and 16.2/100 for placebo) and 7-day follow-up (RR, 0.86 [95% CI, 0.70 to 1.06]; absolute rates, 21.5/100 for glucocorticoids and 25/100 for placebo) (Figure). Among inpatients, there were no differences in length of hospital stay (mean difference, −0.18 days [95% CI, −0.39 to 0.04]; 2.85 days for glucocorticoids and 3.08 days for placebo). Strength of evidence (GRADE) for these outcomes was moderate to high. Although clinical severity scores (such as the Respiratory Distress Assessment Instrument) favored glucocorticoids at 12-hour follow-up in inpatients, no consistent differences were found at later time points, in outpatients, or for any other secondary outcomes. Afactorialtrialconductedintheoutpatientsettingfoundcombined high-dosesystemicdexamethasoneandnebulizedepinephrinereduced admissions by day 7 compared with placebo (RR, 0.65 [95% CI, 0.440.95]; number needed to treat, 11 [95% CI, 7-76]; absolute rates, 16.9/ 100 for glucocorticoids and 26.4/100 for placebo; n = 399).4
No. of randomized trials: 17 Study years: 1994-2009 No. of patients: 2596 children aged < 24 months Boys: 1390 (58%) Girls: 1005 (42%)a Race/ethnicity: Unavailable Age, mean (SD): 5.6 (3.1) months Setting: 8 outpatient trials (n = 1824), 9 inpatient trials (n = 772) Countries: United States, Canada, Turkey, Israel, United Kingdom, Mexico, Brazil, Paraguay, Belgium, Thailandb Comparisons: Glucocorticoids vs placebo, glucocorticoids vs other active drug(s), glucocorticoids + salbutamol vs placebo, glucocorticoids + epinephrine vs placebo, glucocorticoids + salbutamol vs epinephrine, glucocorticoids + epinephrine vs salbutamol Primary outcomes: Hospitalization rates at 1- and 7-day follow-up for outpatient studies, length of hospital stay for inpatient studies Secondary outcomes: Clinical severity scores, oxygen saturation, respiratory rate, heart rate, hospital readmissions, return visits, lung function tests, symptoms and quality of life, adverse events (follow-up range, 30 min-6 mo) a
Data available from 14 studies.
b
Data include 5 multicentered trials.
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Clinical Review & Education JAMA Clinical Evidence Synopsis
Figure. Hospitalizations in Outpatients (Days 1 and 7) for Glucocorticoids vs Placebo Glucocorticoid Study or Subgroup Admissions day 1 Barlas, 1998 (G vs P) Barlas, 1998 (G + S vs S) Berger, 1998 Corneli, 2007 Goebel, 2000 Kuyucu, 2004 Mesquita, 2009 Plint, 2009 (G + E vs P + E) Plint, 2009 (G + P vs P + P) Schuh, 2002 Subtotal (95% CI) Admissions day 7 Corneli, 2007 Goebel, 2000 Kuyucu, 2004 Plint, 2009 (G + E vs P + E) Plint, 2009 (G + P vs P + P) Schuh, 2002 Subtotal (95% CI)
No. of Total No. of Admissions Patients
Placebo No. of Total No. of Admissions Patients
Favors Glucocorticoid
Relative Risk (95% CI)
4 2 5 121 4 0 8 23 31 7 205
30 15 20 305 24 46 33 199 199 36 907
3 2 2 121 2 0 7 29 36 15 217
15 15 18 295 24 23 32 198 201 34 855
0.67 (0.17-2.60) 1.00 (0.16-6.20) 2.25 (0.50-10.20) 0.97 (0.80-1.18) 2.00 (0.40-9.91) Not estimable 1.11 (0.45-2.70) 0.79 (0.47-1.31) 0.87 (0.56-1.35) 0.44 (0.21-0.95) 0.92 (0.78-1.08)
133 6 0 34 51 7 231
284 24 46 199 199 35 787
131 5 0 47 53 15 251
265 24 23 198 201 32 743
0.95 (0.80-1.13) 1.20 (0.42-3.41) Not estimable 0.72 (0.48-1.07) 0.97 (0.70-1.35) 0.43 (0.20-0.91) 0.86 (0.70-1.06) 0.1
Favors Placebo
1.0
10
Relative Risk (95% CI)
Source: Data have been adapted with permission from the Cochrane Collaboration.5 The relative risk was calculated using the Mantel-Haenszel random effect method. Kuyucu and Plint (both factorial trials) and Barlas (parallel multi-
group trial) contribute 2 independent comparisons, which are shown separately. The size of the data markers indicate the weight assigned to each study in the meta-analysis. G indicates glucocorticoid; S, salbutamol; E, epinephrine; P, placebo.
for many outcomes and comparisons. The definition of bronchiolitis is often controversial and distinct wheezing phenotypes cannot be reliably discriminated.6 We focused on first-time wheezing so results could be applicable to infants with “typical” viral bronchiolitis. Favorable findings for combined dexamethasone and epinephrine should be interpreted cautiously, because these data are from a single trial and the synergistic interaction was not anticipated. Finally, data are not available on long-term safety.
Pediatrics and the Scottish Intercollegiate Guidelines Network (both published in 2006).7,8 Neither specifically addresses combined use of glucocorticoids and bronchodilators. A National Institute for Health and Care Excellence guideline is currently in development.
Comparison of Findings With Current Practice Guidelines
Glucocorticoid treatment is not recommended for bronchiolitis by evidence-based guidelines from the American Academy of ARTICLE INFORMATION Author Affiliations: Department of Pediatrics, Santa Maria Hospital, Lisbon Academic Medical Centre, Portugal (Fernandes); Clinical Pharmacology Unit, Instituto de Medicina Molecular, University of Lisbon, Portugal (Fernandes); Department of Pediatrics, Alberta Research Centre for Health Evidence, University of Alberta, Edmonton, Canada (Hartling). Corresponding Author: Ricardo M. Fernandes, MD, Department of Pediatrics, Santa Maria Hospital, Lisbon Academic Medical Centre, Avenida Professor Egas Moniz, 1649-035 Lisboa, Portugal ([email protected]). Section Editor: Mary McGrae McDermott, MD, Senior Editor. Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr
88
Areas in Need of Future Study
Efficacy, harms, and applicability of combined therapy need to be clarified further. Future studies should identify the minimum efficacious glucocorticoid dose, the most beneficial bronchodilator, and long-term safety. Future bronchiolitis trials should focus on patientimportant outcome measures and use validated outcomes.
Hartling reports receiving grant funding from the Canadian Institutes of Health Research. No other disclosures were reported. Additional Contributions: We thank the authors in the Cochrane review on which this Clinical Evidence Synopsis is based. REFERENCES 1. Hartling L, Fernandes RM, Bialy L, et al. Steroids and bronchodilators for acute bronchiolitis in the first 2 years of life. BMJ. 2011;342:d1714. 2. Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP. Nebulised hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev. 2013;7:CD006458. 3. Ducharme FM, Krajinovic M. Steroid responsiveness and wheezing phenotypes. Paediatr Respir Rev. 2011;12(3):170-176.
4. Plint AC, Johnson DW, Patel H, et al; Pediatric Emergency Research Canada (PERC). Epinephrine and dexamethasone in children with bronchiolitis. N Engl J Med. 2009;360(20):2079-2089. 5. Fernandes RM, Bialy LM, Vandermeer B, et al. Glucocorticoids for acute viral bronchiolitis in infants and young children. Cochrane Database Syst Rev. 2013;6:CD004878. 6. Savenije OE, Kerkhof M, Koppelman GH, Postma DS. Predicting who will have asthma at school age among preschool children. J Allergy Clin Immunol. 2012;130(2):325-331. 7. American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics. 2006;118(4):1774-1793. 8. Scottish Intercollegiate Guidelines Network (SIGN). Bronchiolitis in children. http://www.sign.ac .uk/pdf/sign91.pdf. Accessed December 3, 2013.
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JAMA Clinical Evidence Synopsis
Glucocorticoids for Acute Viral Bronchiolitis in Infants and Young Children Ricardo M. Fernandes, MD; Lisa Hartling, PhD
CLINICAL QUESTION Are glucocorticoids, alone or combined with bronchodilators, associated with reduced admission rates, length of stay, or improvements in clinical severity scores without increased adverse effects in infants and young children with acute viral bronchiolitis? BOTTOM LINE There is no consistent clinically relevant association of single therapy with systemic or inhaled glucocorticoids and improved outcomes in either outpatient or inpatient settings. Exploratory evidence suggests that combined glucocorticoids and nebulized epinephrine may be associated with lower hospitalization rates in outpatients, but these findings must be interpreted cautiously.
Nebulized epinephrine and hypertonic saline are potential options for improving outcomes in infants with bronchiolitis.1,2 Glucocorticoids for the treatment of bronchiolitis are controversial. Glucocorticoid responsiveness varies in children with wheezing.3 Further, although the combination of glucocorticoids with bronchodilators improves outcomes in asthma more than either individual therapy, this combined therapy has been studied only recently for bronchiolitis.4 Previous glucocorticoid trial results, with or without bronchodilators, have yielded inconsistent results. This JAMA Clinical Evidence Synopsis summarizes data from a recent update of a Cochrane review5 of randomized clinical trials evaluating the use of systemic and inhaled glucocorticoids in infants and young children with acute viral bronchiolitis.
Summary of Findings
Discussion Our results do not suggest a clinically relevant association of single glucocorticoid therapy for reducing hospitalizations or length of stay in children with bronchiolitis. This finding was consistent despite substantial heterogeneity in disease severity, glucocorticoid therapy, and outcome measures across settings. One trial suggests that combined high-dose dexamethasone and epinephrine may be associated with lower rates of hospitalizations in outpatients with moderately severe bronchiolitis. Limitations
Limitations include heterogeneity in outcomes and measurement timing, potential risk of bias in the included studies, and small sample sizes Evidence Profile
Baseline severity of participants recruited in outpatient or inpatient settings was often moderate based on clinical severity scores. Considerable variability was found in hospitalization rates (0%44% at 1-day follow-up) and length of stay (mean, 0.8-6.6 days). Among outpatients, there was no difference between glucocorticoids and placebo in hospital admission rates at 1-day follow-up (relative risk [RR], 0.92 [95% CI, 0.78 to 1.08]; absolute rates, 14.9/100 for glucocorticoids and 16.2/100 for placebo) and 7-day follow-up (RR, 0.86 [95% CI, 0.70 to 1.06]; absolute rates, 21.5/100 for glucocorticoids and 25/100 for placebo) (Figure). Among inpatients, there were no differences in length of hospital stay (mean difference, −0.18 days [95% CI, −0.39 to 0.04]; 2.85 days for glucocorticoids and 3.08 days for placebo). Strength of evidence (GRADE) for these outcomes was moderate to high. Although clinical severity scores (such as the Respiratory Distress Assessment Instrument) favored glucocorticoids at 12-hour follow-up in inpatients, no consistent differences were found at later time points, in outpatients, or for any other secondary outcomes. Afactorialtrialconductedintheoutpatientsettingfoundcombined high-dosesystemicdexamethasoneandnebulizedepinephrinereduced admissions by day 7 compared with placebo (RR, 0.65 [95% CI, 0.440.95]; number needed to treat, 11 [95% CI, 7-76]; absolute rates, 16.9/ 100 for glucocorticoids and 26.4/100 for placebo; n = 399).4
No. of randomized trials: 17 Study years: 1994-2009 No. of patients: 2596 children aged < 24 months Boys: 1390 (58%) Girls: 1005 (42%)a Race/ethnicity: Unavailable Age, mean (SD): 5.6 (3.1) months Setting: 8 outpatient trials (n = 1824), 9 inpatient trials (n = 772) Countries: United States, Canada, Turkey, Israel, United Kingdom, Mexico, Brazil, Paraguay, Belgium, Thailandb Comparisons: Glucocorticoids vs placebo, glucocorticoids vs other active drug(s), glucocorticoids + salbutamol vs placebo, glucocorticoids + epinephrine vs placebo, glucocorticoids + salbutamol vs epinephrine, glucocorticoids + epinephrine vs salbutamol Primary outcomes: Hospitalization rates at 1- and 7-day follow-up for outpatient studies, length of hospital stay for inpatient studies Secondary outcomes: Clinical severity scores, oxygen saturation, respiratory rate, heart rate, hospital readmissions, return visits, lung function tests, symptoms and quality of life, adverse events (follow-up range, 30 min-6 mo) a
Data available from 14 studies.
b
Data include 5 multicentered trials.
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Copyright 2014 American Medical Association. All rights reserved.
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Clinical Review & Education JAMA Clinical Evidence Synopsis
Figure. Hospitalizations in Outpatients (Days 1 and 7) for Glucocorticoids vs Placebo Glucocorticoid Study or Subgroup Admissions day 1 Barlas, 1998 (G vs P) Barlas, 1998 (G + S vs S) Berger, 1998 Corneli, 2007 Goebel, 2000 Kuyucu, 2004 Mesquita, 2009 Plint, 2009 (G + E vs P + E) Plint, 2009 (G + P vs P + P) Schuh, 2002 Subtotal (95% CI) Admissions day 7 Corneli, 2007 Goebel, 2000 Kuyucu, 2004 Plint, 2009 (G + E vs P + E) Plint, 2009 (G + P vs P + P) Schuh, 2002 Subtotal (95% CI)
No. of Total No. of Admissions Patients
Placebo No. of Total No. of Admissions Patients
Favors Glucocorticoid
Relative Risk (95% CI)
4 2 5 121 4 0 8 23 31 7 205
30 15 20 305 24 46 33 199 199 36 907
3 2 2 121 2 0 7 29 36 15 217
15 15 18 295 24 23 32 198 201 34 855
0.67 (0.17-2.60) 1.00 (0.16-6.20) 2.25 (0.50-10.20) 0.97 (0.80-1.18) 2.00 (0.40-9.91) Not estimable 1.11 (0.45-2.70) 0.79 (0.47-1.31) 0.87 (0.56-1.35) 0.44 (0.21-0.95) 0.92 (0.78-1.08)
133 6 0 34 51 7 231
284 24 46 199 199 35 787
131 5 0 47 53 15 251
265 24 23 198 201 32 743
0.95 (0.80-1.13) 1.20 (0.42-3.41) Not estimable 0.72 (0.48-1.07) 0.97 (0.70-1.35) 0.43 (0.20-0.91) 0.86 (0.70-1.06) 0.1
Favors Placebo
1.0
10
Relative Risk (95% CI)
Source: Data have been adapted with permission from the Cochrane Collaboration.5 The relative risk was calculated using the Mantel-Haenszel random effect method. Kuyucu and Plint (both factorial trials) and Barlas (parallel multi-
group trial) contribute 2 independent comparisons, which are shown separately. The size of the data markers indicate the weight assigned to each study in the meta-analysis. G indicates glucocorticoid; S, salbutamol; E, epinephrine; P, placebo.
for many outcomes and comparisons. The definition of bronchiolitis is often controversial and distinct wheezing phenotypes cannot be reliably discriminated.6 We focused on first-time wheezing so results could be applicable to infants with “typical” viral bronchiolitis. Favorable findings for combined dexamethasone and epinephrine should be interpreted cautiously, because these data are from a single trial and the synergistic interaction was not anticipated. Finally, data are not available on long-term safety.
Pediatrics and the Scottish Intercollegiate Guidelines Network (both published in 2006).7,8 Neither specifically addresses combined use of glucocorticoids and bronchodilators. A National Institute for Health and Care Excellence guideline is currently in development.
Comparison of Findings With Current Practice Guidelines
Glucocorticoid treatment is not recommended for bronchiolitis by evidence-based guidelines from the American Academy of ARTICLE INFORMATION Author Affiliations: Department of Pediatrics, Santa Maria Hospital, Lisbon Academic Medical Centre, Portugal (Fernandes); Clinical Pharmacology Unit, Instituto de Medicina Molecular, University of Lisbon, Portugal (Fernandes); Department of Pediatrics, Alberta Research Centre for Health Evidence, University of Alberta, Edmonton, Canada (Hartling). Corresponding Author: Ricardo M. Fernandes, MD, Department of Pediatrics, Santa Maria Hospital, Lisbon Academic Medical Centre, Avenida Professor Egas Moniz, 1649-035 Lisboa, Portugal ([email protected]). Section Editor: Mary McGrae McDermott, MD, Senior Editor. Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr
88
Areas in Need of Future Study
Efficacy, harms, and applicability of combined therapy need to be clarified further. Future studies should identify the minimum efficacious glucocorticoid dose, the most beneficial bronchodilator, and long-term safety. Future bronchiolitis trials should focus on patientimportant outcome measures and use validated outcomes.
Hartling reports receiving grant funding from the Canadian Institutes of Health Research. No other disclosures were reported. Additional Contributions: We thank the authors in the Cochrane review on which this Clinical Evidence Synopsis is based. REFERENCES 1. Hartling L, Fernandes RM, Bialy L, et al. Steroids and bronchodilators for acute bronchiolitis in the first 2 years of life. BMJ. 2011;342:d1714. 2. Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP. Nebulised hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev. 2013;7:CD006458. 3. Ducharme FM, Krajinovic M. Steroid responsiveness and wheezing phenotypes. Paediatr Respir Rev. 2011;12(3):170-176.
4. Plint AC, Johnson DW, Patel H, et al; Pediatric Emergency Research Canada (PERC). Epinephrine and dexamethasone in children with bronchiolitis. N Engl J Med. 2009;360(20):2079-2089. 5. Fernandes RM, Bialy LM, Vandermeer B, et al. Glucocorticoids for acute viral bronchiolitis in infants and young children. Cochrane Database Syst Rev. 2013;6:CD004878. 6. Savenije OE, Kerkhof M, Koppelman GH, Postma DS. Predicting who will have asthma at school age among preschool children. J Allergy Clin Immunol. 2012;130(2):325-331. 7. American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics. 2006;118(4):1774-1793. 8. Scottish Intercollegiate Guidelines Network (SIGN). Bronchiolitis in children. http://www.sign.ac .uk/pdf/sign91.pdf. Accessed December 3, 2013.
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