Conclusions & Biological explanations Systemic Steroids in Preschool Children with Recurrent Wheezing Exacerbations Introduction Important studies Recent meta-analysis Conclusions & Biological explanations Attilio Boner University of Verona, Italy attilio.boner@univr.it

The Dilemma of Systemic Steroids in Preschool Children with Recurrent Wheezing Exacerbations The use of systemic steroids in preschool children with recurrent wheezing asthma exacerbations has been widely debated and remains a vital question. National guidelines recommend systemic steroids to reduce inflammation during acute asthma exacerbations. National Asthma Education Prevention Program. Expert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma summary report 2007. J Allergy Clin Immunol 2007;120:S94–138. Updated international (GINA) guidelines, mention the lack of benefit of oral corticosteroids (OCS) in the outpatient setting but recommend them during hospital care for preschool children with wheezing exacerbations. Global Strategy for Asthma Management and Prevention. Available at http://ginasthma.org/: Global Initiative for Asthma (GINA); 2015. Deshpande DR, Martinez FD. Pediatr Pulmonol. 2016;51(8):775-7

The Dilemma of Systemic Steroids in Preschool Children with Recurrent Wheezing Exacerbations Systemic steroids during asthma exacerbations are efficacious in school age and older children in reducing short acting bronchodilator use, reducing relapses, and decreasing hospitalizations. Rowe BH, Corticosteroids for preventing relapse following acute exacerbations of asthma. Cochrane Database Syst Rev 2007;18:CD000195. Rowe BH, Corticosteroid therapy for acute asthma. Respir Med 2004;98:275–284. These results are often directly extrapolated to young preschool children with recurrent wheezing exacerbations, leading to frequent use of systemic steroids in this age group. Collins AD, An update on the efficacy of oral corticosteroids in the treatment of wheezing episodes in preschool children. Ther Adv Respir Dis 2014;8:182–190. Deshpande DR, Martinez FD. Pediatr Pulmonol. 2016;51(8):775-7

The Dilemma of Systemic Steroids in Preschool Children with Recurrent Wheezing Exacerbations A recent study evaluating the effect of OCS in preschool children with recurrent episodic wheezing was declared infeasible and halted prematurely due to 39% of the study children being prescribed open-label OCS, reflecting the frequent use of OCS. Bacharier LB, Guilbert TW, Mauger DT, Boehmer S, Beigelman A, Fitzpatrick AM, Jackson DJ, Baxi SN, Benson M, Burnham CA, Cabana M, Castro M, Chmiel JF, Covar R, Daines M, Gaffin JM, Gentile DA, Holguin F, Israel E, Kelly HW, Lazarus SC, Lemanske RF, Jr., Ly N, Meade K, Morgan W, Moy J, Olin T, Peters SP, Phipatanakul W, Pongracic JA, Raissy HH, Ross K, Sheehan WJ, Sorkness C, Szefler SJ, Teague WG, Thyne S, Martinez FD, National Heart L, Blood Institute’s A. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial. JAMA 2015;314: 2034–2044. Deshpande DR, Martinez FD. Pediatr Pulmonol. 2016;51(8):775-7

The Dilemma of Systemic Steroids in Preschool Children with Recurrent Wheezing Exacerbations In general, studies on the effect of OCS grouped wheezing disorders in preschool children as a single disease entity; however, there is increasing evidence of endotypes and phenotypes heterogeneity likely representing pathophysiologically distinct entities, which appear to be established in the preschool years. Preschool children with wheezing commonly have recurrent intermittent episodic wheezing typically triggered by a viral illness or may have multi-trigger wheeze with symptoms in between episodes, but these categories likely represent a disease spectrum and may not be mutually exclusive subgroups. Deshpande DR, Martinez FD. Pediatr Pulmonol. 2016;51(8):775-7

Conclusions & Biological explanations Systemic Steroids in Preschool Children with Recurrent Wheezing Exacerbations Introduction Important studies Recent meta-analysis Conclusions & Biological explanations Attilio Boner University of Verona, Italy attilio.boner@univr.it

Mean day-time symptoms score for 7 days during wheezing episodes Efficacy of a short course of parent-initiated oral prednisolone for viral wheeze in children aged 1-5 years: randomised controlled trial. Oommen A, Lancet. 2003;362:1433. Mean day-time symptoms score for 7 days during wheezing episodes Children (1-5 yrs) admitted to hospital with viral wheeze Stratified by high or low serum ECP, EPX Randomized to 5 days of prednisolone (n= 51) (20 mg OD) or placebo (n=69) for the next episode 1 0.96 0.95 ns PREDNISOLONE PLACEBO

Mean salbutamol actuation per day Efficacy of a short course of parent-initiated oral prednisolone for viral wheeze in children aged 1-5 years: randomised controlled trial. Oommen A, Lancet. 2003;362:1433. Mean salbutamol actuation per day 2.0 - 1.5 - 1.0 - Children (1-5 yrs) admitted to hospital with viral wheeze Stratified by high or low serum ECP, EPX Randomized to 5 days of prednisolone (n= 51) (20 mg OD) or placebo (n=69) for the next episode 1.66 1.59 ns Prednisolone Placebo

Efficacy of a short course of parent-initiated oral prednisolone for viral wheeze in children aged 1-5 years: randomised controlled trial. Oommen A, Lancet. 2003;362:1433. 15 – 10 – 5 – % children admitted Children (1-5 yrs) admitted to hospital with viral wheeze Stratified by high or low serum ECP, EPX Randomized to 5 days of prednisolone (n= 51) (20 mg OD) or placebo (n=69) for the next episode 12% p=0.058 3% Prednisolone Placebo

Median duration of hospitalization (hrs) Oral Prednisolone for Preschool Children with Acute Virus-Induced Wheezing Panickar J, NEJM 2009;360:329 Median duration of hospitalization (hrs) 700 children (10-60 months) with an attack of wheezing associated with a viral infection 5-day course of oral prednisolone (10 mg once a day for children 10 to 24 months of age and 20 mg once a day for older children) compared with placebo 15 – 10 – 5 – 13.9 ns 11.0 placebo prednisolone

* * * * *Placebo * Prednisolone * * Oral Prednisolone for Preschool Children with Acute Virus-Induced Wheezing Panickar J, NEJM 2009;360:329 3.0 - 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – * * * * PRAM score *Placebo * Prednisolone * * 4hr 12hr 24hr Hours post-admission

Do oral corticosteroids reduce the severity of acute lower respiratory tract illnesses in preschool children with recurrent wheezing? Beigelman A. JACI 2013;131:1518-25 Comparison of total symptom scores in the Acute Intervention Management Strategies (AIMS) cohort between episodes that were or were not treated with OCSs Bacharier LB. JACI 2008;122:1127-35

between episodes that were or were not treated with OCSs Do oral corticosteroids reduce the severity of acute lower respiratory tract illnesses in preschool children with recurrent wheezing? Beigelman A. JACI 2013;131:1518-25 Comparison of total symptom scores in the Manteinance and Intermittent Inhaled Corticosteroids in Wheezing Toddlers (MIST) cohort between episodes that were or were not treated with OCSs Zeiger RS. N Engl J Med 2011;365:1990-2001

Conclusions & Biological explanations Systemic Steroids in Preschool Children with Recurrent Wheezing Exacerbations Introduction Important studies Recent meta-analysis Conclusions & Biological explanations Attilio Boner University of Verona, Italy attilio.boner@univr.it

Systematic review with meta-analysis. Efficacy of oral corticosteroids in the treatment of acute wheezing episodes in asthmatic preschoolers: Systematic review with meta-analysis. Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76. 11 clinical trials of OCS in children <6 years of age (n = 1,733); presenting with recurrent wheezing/asthma exacerbations of any severity. hospitalizations, need of additional OCS courses unscheduled emergency department (ED) visits in following month, length of stay (ED or hospital) 4 were conducted on an outpatient basis, 5 in inpatients, and 2 in the ED

Systematic review with meta-analysis. Efficacy of oral corticosteroids in the treatment of acute wheezing episodes in asthmatic preschoolers: Systematic review with meta-analysis. Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76. outpatient ED inpatient

Systematic review with meta-analysis. Efficacy of oral corticosteroids in the treatment of acute wheezing episodes in asthmatic preschoolers: Systematic review with meta-analysis. Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76. Five studies reported hospital admission rates All studies There was no significant difference between OCS and placebo (RR: 1.00; 95%CI: 0.49–2.05),

Systematic review with meta-analysis. Efficacy of oral corticosteroids in the treatment of acute wheezing episodes in asthmatic preschoolers: Systematic review with meta-analysis. Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76. Five studies reported hospital admission rates Only outpatient studies Analyzing only outpatient studies, OCS treatment was associated with a higher hospital admission rate (RR: 2.15; 95%CI:1.08–4.29)

Systematic review with meta-analysis. Efficacy of oral corticosteroids in the treatment of acute wheezing episodes in asthmatic preschoolers: Systematic review with meta-analysis. Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76. Five studies reported hospital admission rates Only ED studies Considering only the two studies conducted in the ED, OCS treatment had a lower risk of hospital admissions (RR: 0.58; 95%CI: 0.37–0.92)

Systematic review with meta-analysis. Efficacy of oral corticosteroids in the treatment of acute wheezing episodes in asthmatic preschoolers: Systematic review with meta-analysis. Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76. Three studies reported Additional Course of Systemic Corticosteroids One outpatient study 20 and two inpatient studies 24,28 There was no significant difference between OCS and placebo (RR: 0.74; 95%CI: 0.40–1.34).

Systematic review with meta-analysis. Efficacy of oral corticosteroids in the treatment of acute wheezing episodes in asthmatic preschoolers: Systematic review with meta-analysis. Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76. Three studies reported Additional Course of Systemic Corticosteroids Only the two inpatient studies, 24,28 the difference became significant favoring the OCS group (RR: 0.57; 95%CI: 0.40–0.81;),

Systematic review with meta-analysis. Efficacy of oral corticosteroids in the treatment of acute wheezing episodes in asthmatic preschoolers: Systematic review with meta-analysis. Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76. Three inpatient studies reported unscheduled visits for asthma symptoms in the month following. There was no significant statistical difference between OCS and placebo (RR: 0.73; 95%CI: 0.35–1.52)

Systematic review with meta-analysis. Efficacy of oral corticosteroids in the treatment of acute wheezing episodes in asthmatic preschoolers: Systematic review with meta-analysis. Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76. Hospital Length of Stay Finally, four studies (25–28) reported no differences in hospital length of stay were found between OCS and placebo, while one study reported the OCS group had a shorter stay 24. However, length of stay was reported differently (means vs. medians) and thus we were not able to perform a pooled analysis. 25. Gleeson JG, Placebo controlled trial of systemic corticosteroids in acute childhood asthma. Acta Paediatr Scand 1990;79:1052–1058. 26. Fox GF, Treatment of recurrent acute wheezing episodes in infancy with oral salbutamol and prednisolone. Eur J Pediatr 1996;155:512–516. 27. Jartti T, Efficacy of prednisolone in children hospitalized for recurrent wheezing. Pediatr Allergy Immunol 2007;18:326–334. 28. Panickar J, Oral prednisolone for preschool children with acute virus-induced wheezing. N Engl J Med 2009;360:329–338.

Systematic review with meta-analysis. Efficacy of oral corticosteroids in the treatment of acute wheezing episodes in asthmatic preschoolers: Systematic review with meta-analysis. Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76. When analyzing studies performed in the ED, OCS treatment was associated with a lower hospitalization rate. Similarly, when analyzing studies performed in the inpatient setting, OCS treatment was associated with a lower need for additional courses of SCS. In the outpatient studies, on the other hand, OCS administration was associated with more hospital admissions (behavioral changes), suggesting that OCS may not be beneficial in all clinical settings for this age group.

Conclusions & Biological explanations Systemic Steroids in Preschool Children with Recurrent Wheezing Exacerbations Introduction Important studies Recent meta-analysis Conclusions & Biological explanations Attilio Boner University of Verona, Italy attilio.boner@univr.it

Systematic review with meta-analysis. Efficacy of oral corticosteroids in the treatment of acute wheezing episodes in asthmatic preschoolers: Systematic review with meta-analysis. Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76. OCS may be more effective in certain subgroups depending on exacerbation severity or timing of administration: in this age group, OCS may be more beneficial among children who present with more severe exacerbations that require urgent care or hospitalization. However, asthma in young children is a heterogeneous condition with different underlying pathophysiological pathways, which could explain why some patients may benefit from OCS prescription while others show no response.

Airway Remodeling in Preschool Children with Severe Recurrent Wheeze. Lezmi G. Am J Respir Crit Care Med. 2015;192(2):164-71. (Age months) (≤36 months) (36-59 months) preschoolers with severe recurrent wheeze, biopsies of children up to 36 months were found to contain more inflammatory cells with fewer eosinophils than those on older preschoolers.

The Dilemma of Systemic Steroids in Preschool Children with Recurrent Wheezing Exacerbations Airway pathology in preschool children with episodic wheezing due to viral illnesses resembles a neutrophil-predominant, low eosinophilic picture as compared to an eosinophilic predominance in children with classic atopic asthma making it less likely for steroids to be effective. Stevenson EC, Bronchoalveolar lavage findings suggest two different forms of childhood asthma. Clin Exp Allergy 1997;27:1027–1035. Le Bourgeois M, Bronchoalveolar cells in children <3 years old with severe recurrent wheezing. Chest 2002;122:791–797. Deshpande DR, Martinez FD. Pediatr Pulmonol. 2016;51(8):775-7

Other factors that may affect OCS response include: the timing of administration, Davis SR, Corticosteroid timing and length of stay for children with asthma in the emergency department. J Asthma 2012;49:862–867. Zemek R, Triage nurse initiation of corticosteroids in pediatric asthma is associated with improved emergency department efficiency. Pediatrics 2012;129:671–680. vitamin D deficiency, Beigelman A, The association between vitamin D status and the rate of exacerbations requiring oral corticosteroids in preschool children with recurrent wheezing. J Allergy Clin Immunol 2014;133:1489–1492. genetic predisposition. Ducharme FM, Determinants of oral corticosteroid responsiveness in wheezing asthmatic youth (DOORWAY): protocol for a prospective multicentre cohort study of children with acute moderate-to-severe asthma exacerbations. BMJ Open 2014;4:e004699. Castro-Rodriguez JA. Pediatr Pulmonol. 2016;51(8):868-76.

HOW CAN WE END THIS DEBATE? Most of the available data do not support the role of OCSs as a treatment for acute mild episodic wheeze. However, on the basis of uncertainties, we cannot recommend to completely abandon this traditional therapy. Previous editorials on this important clinical question have suggested that OCSs should be given only to a subgroup of severely ill children in the inpatient setting. National Asthma Education and Prevention Program. Expert Panel Report III: guidelines for the diagnosis and management of asthma. Bethesda, MD: US Department of Health and Human Services; 2007. Bush A. Practice imperfect-treatment for wheezing in preschoolers. N Engl J Med 2009;360:409-10. Beigelman A, J Allergy Clin Immunol Pract 2016;4:27-35

HOW CAN WE END THIS DEBATE? Moreover, because it was never shown that OCSs are not effective in preschool children hospitalized in the intensive care unit or in children who have other chronic medical conditions, these children should be treated with OCSs. Ultimately, there is a significant need to conduct efficacy trials evaluating OCS treatment in preschool-aged children with recurrent wheezing targeted at phenotypes that would be expected to respond to OCSs. Specifically, studies must examine a larger number of subjects with a positive API and/or mAPI eosinophilic airway inflammation or airway pathologic consistent with asthma as well as older preschool-aged children with more persistent asthma symptoms, and children presenting with severe exacerbations. Beigelman A, J Allergy Clin Immunol Pract 2016;4:27-35