In 2014, the first guidelines for the treatment of severe asthma in children and adults were composed by the European Respiratory Society/American Thoracic Society (ERS/ATS) . Since 2017, a multidisciplinary Task Force of asthma experts, co-chaired by Dr Fernando Holguin and Dr Andy Bush, has worked on an updated version. The Task Force made 6 recommendations that were not addressed in the previous guideline (See Table), with a particular focus on new treatment options for severe eosinophilic asthma, such as anti-IL-4Rα, anti-IL5, or IL-5Rα antibodies, biomarkers for anti-IgE therapy, and the use of long-acting muscarinic antagonists, and macrolides .
IL5 drives eosinophilic inflammation; consequently, targeting either IL5 (mepolizumab, reslizumab) or its receptor IL-5Rα (benralizumab) has demonstrated efficacy in reducing exacerbations and hospitalisation of patients with severe eosinophilic asthma in 12 randomised controlled trials [3,4,5,6,7].
IgE treatment indicators.
Based on the results from 3 randomised trials a blood eosinophil cut-off of ⩾260/µL was suggested to guide initiation of anti-IgE treatment. Additionally, a fractional exhaled nitric oxide fraction cut-off (FeNO ⩾19.5 ppb) identified adolescents or adults with the greatest likelihood of response to anti-IgE therapy [8,9,10].
In total, 5 randomised controlled trials recommended use of long-acting muscarinic antagonist (LAMA) tiotropium in children, adolescents and adults with severe asthma. Tiotropium was most effective at treating worsening asthma and in controlling symptoms and exacerbations [11,12,13]
Macrolide antibiotics were previously recommended under the condition that long-term use should be avoided. In 6 recent randomised controlled trials, chronic macrolide treatment showed overall reduction of asthma exacerbations. However, these effects are limited to participants with persistently symptomatic asthma, which may be more exacerbation-prone. Since antimicrobial resistance associated with prolonged antibiotic treatment is a pressing public health issue, this therapy did not meet the ERS/ATS criteria for recommendation for chronic use [14,15,16,17,18,19].
5 randomised controlled trials with different age groups showed that dupilumab, directed against the α subunit of IL-4 receptor, has a positive effect on exacerbations and lung function when used as an add-on therapy to medium-to-high dose inhaled corticosteroids and a long-acting β2 agonist [20,21,22].
- Chung KF, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43: 343–373.
- Holguin F, et al. Management of severe asthma : a European Respiratory Society / American Thoracic Society guideline. 2020;(April 2019).
- Bel EH, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014; 371: 1189–1197
- Ortega HG, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014; 371: 1198–1207.
- Chupp GL, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicen
- Bjermer L, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest 2016; 150: 789–798.
- Castro M, et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med 2011; 184: 1125–1132
- Ledford D, et al. A randomized multicenter study evaluating Xolair persistence of response after long-term therapy. J Allergy Clin Immunol 2017; 140: 162–169
- Hanania NA, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med 2013; 187: 804–811.
- Busse W, et al. High eosinophil count: a potential biomarker for assessing successful omalizumab treatment effects. J Allergy Clin Immunol 2013; 132: 485–486.
- Kerstjens HA, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol 2011; 128: 308–314.
- Kerstjens HA, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012; 367: 1198–1207.
- Hamelmann E, et al. A randomised controlled trial of tiotropium in adolescents with severe symptomatic asthma. Eur Respir J 2017; 49: 1601100.
- Brusselle GG, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax 2013; 68: 322–329.
- Gibson PG, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet 2017; 390: 659–668.
- Strunk RC, et al. Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate-to-severe childhood asthma study. J Allergy Clin Immunol 2008; 122: 1138–1144.
- Hahn DL, et al. Azithromycin for bronchial asthma in adults: an effectiveness trial. JAm Board Fam Med 2012; 25: 442–459.
- Sutherland ER, et al. A trial of clarithromycin for the treatment of suboptimally controlled asthma. J Allergy Clin Immunol 2010; 126: 747–753.
- Simpson JL, et al. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med 2008; 177: 148–155.
- Wenzel S, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal. The Lancet 2016; 388, P31-44.
- Castro M, C et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med 2018; 378: 2486–2496.
- Rabe KF, et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med 2018; 378: 2475–2485.