Guideline sources The following summarized guidelines for the evaluation and management of severe asthma phenotypes are prepared by our editorial team based on guidelines from the National Heart, Lung, and Blood Institute (NHLBI 2020), the Canadian Thoracic Society (CTS 2017), and the European Respiratory Society (ERS/ATS 2014). 1 2 3 5 5 5 5 6 7 8 Definition Asthma is a disorder of the lower respiratory tract characterized by reversible airflow obstruction and episodic or persistent symptoms of wheezing, dyspnea, and cough. 5 Epidemiology The cause of asthma is unknown; however, a combination of genetic factors (alterations in ORMDL3, HLAG, IRAKIM, MYB, ADAM33, FLG), epigenetic changes (alterations in DNA methylation, histone modifications, mitochondrial gene silencing) and environmental factors (air pollutants, allergens, respiratory infections) have been implicated. 7 Pathophysiology The estimated prevalence of asthma in the United States is 7400 persons per 100,000 population. The incidence of adult-onset asthma is estimated at 153 cases per 100,000 person-years. 5 6 Disease course https://web.pathway.md/diseases/recXO1CHaepb58fvn 1/6 6/24/23, 3:10 PM Severe asthma phenotypes Pathway In patients with asthma, exposure to allergens causes airway inflammation, leading to airway obstruction, hyperresponsiveness, and airway remodeling. These changes are associated with the clinical manifestations of to wheezing, coughing, chest tightness, and dyspnea. 5 Prognosis and risk of recurrence Patients with asthma have excess all-cause mortality, with a standardized mortality rate estimated at 1.54 in males and 1.91 in females. Patients with frequent exacerbations have an annual loss of lung function approximately 2% greater than predicted. 5 8 Calculator Asthma Control Test ACT Guidelines 1. Screening and diagnosis Diagnosis: confirm the diagnosis of asthma based on history and objective measures of lung function in patients old enough to reliably undergo pulmonary function tests. E Show 4 more 2. Diagnostic investigations Work-up: As per CTS 2017 guidelines: Obtain total serum IgE level measurement, peripheral eosinophil count, and where available sputum eosinophils and fractional exhaled nitric oxide levels in patients with confirmed severe asthma, in order to characterize the phenotype. E Recognize that: sputum eosinophils may help in identifying responders to anti-IL-5 therapies but not in identifying responders to macrolides blood eosinophil counts may help to identify patients that will experience fewer exacerbations with anti-IL-5 therapies and omalizumab insufficient evidence for the use of fractional exhaled nitric oxide to predict response or responders to omalizumab or anti-IL-5 therapies serum IgE does not predict response to anti-IL-5 therapies or omalizumab. E https://web.pathway.md/diseases/recXO1CHaepb58fvn 2/6 6/24/23, 3:10 PM Severe asthma phenotypes Pathway As per ERS 2014 guidelines, consider obtaining HRCT in adult and pediatric patients with severe asthma only when the presentation is atypical. C 3. Medical management General principles: consider using sputum eosinophil counts, obtained in centers experienced in using this technique, in addition to clinical criteria to guide treatment in adult patients with severe asthma. C Show 2 more Inhaled corticosteroids and short-acting beta-agonists: Consider initiating either daily low-dose ICS and as-needed short-acting -agonist for quick- relief therapy or as-needed ICS and short-acting -agonist concomitantly in 12 years old patients with mild persistent asthma. C Consider avoiding the short-term increase in ICS dose for increased symptoms or decreased peak flow in 4 years old patients with mild-to-moderate persistent asthma likely to be adherent to daily ICS treatment. D Inhaled corticosteroids and long-acting beta-agonists: Offer ICS-formoterol in a single inhaler used as both daily controller and reliever therapy in 12 years old patients with moderate-to- severe persistent asthma rather than: higher-dose ICS as daily controller therapy and short-acting -agonist for quick-relief therapy same-dose ICS-long-acting -agonist as daily controller therapy and short-acting -agonist for quick-relief therapy. A Landmark trials: AUSTRI In patients with persistent asthma who had a history of a severe asthma exacerbation in the year before randomization, but not during the previous month, fluticasone-salmeterol inhaler therapy was noninferior to fluticasone-only inhaler therapy with respect to serious asthma- related events. Stempel DA et al. N Engl J Med. 2016 May 12. Long-acting muscarinic antagonists: As per NHLBI 2020 guidelines, consider avoiding adding LAMAs to ICSs rather than adding long-acting -agonist to ICSs in 12 years old patients with uncontrolled persistent asthma. D Show 2 more As per CTS 2017 guidelines, consider initiating tiotropium bromide 5 g once daily by soft mist inhaler as an add-on therapy in 12 years old patients with severe asthma, if asthma remains uncontrolled despite treatment with the combination of an ICS and long-acting -agonist. E https://web.pathway.md/diseases/recXO1CHaepb58fvn 3/6 6/24/23, 3:10 PM Severe asthma phenotypes Pathway Landmark trials: TALC In adult patients with uncontrolled asthma, the addition of tiotropium bromide to an ICS, as compared with doubling of the dose of the ICS, resulted in and improvement in morning peak expiratory flow rates (mean difference of 25.8 L/min, p < 0.001), as well as in the proportion of asthma-control days (difference 0.079, p = 0.01) and daily symptom scores (difference -0.11 points, p < 0.001). The addition of tiotropium bromide to an ICS, as compared with the addition of salmeterol to the ICS, was also noninferior for all assessed outcomes, and significantly increased the prebronchodilator FEV1 (difference 0.11 L, p = 0.003). Peters SP et al. N Engl J Med. 2010 Oct 28. Omalizumab: As per CTS 2017 guidelines, consider offering omalizumab in 6 years old patients with severe asthma meeting the following criteria: inadequate disease control despite high-dose ICSs and at least one other controller sensitization to at least one perennial allergen serum IgE levels of 30-1,300 IU/mL (for children aged 6-11 years) or 30-700 IU/mL (for adults and adolescents aged 12 years). E Show 4 more Landmark trials: EXTRA In patients with inadequately controlled severe asthma who are receiving high-dose ICS and long-acting -agonists, with or without additional controller therapy, omalizumab was superior to placebo with respect to asthma exacerbations at 48 weeks. Hanania NA et al. Ann Intern Med. 2011 May 3. As per ERS 2014 guidelines, consider offering a therapeutic trial of omalizumab in adult C and pediatric patients with severe allergic asthma. C Other biologic agents: as per CTS 2017 guidelines, consider offering anti-IL-5 therapies (mepolizumab, benralizumab, reslizumab) in 18 years old patients with severe eosinophilic asthma experiencing recurrent asthma exacerbations despite optimal asthma treatment, including a high-dose ICS and at least one other controller. E Show 3 more Allergen immunotherapy: avid using sublingual immunotherapy in patients with persistent allergic asthma. B Macrolides: As per CTS 2017 guidelines, consider offering macrolides to reduce the frequency of exacerbations in 18 years old patients with severe asthma. E Show 3 more https://web.pathway.md/diseases/recXO1CHaepb58fvn 4/6 6/24/23, 3:10 PM Severe asthma phenotypes Pathway Landmark trials: AMAZES In patients with uncontrolled persistent asthma on medium-to-high dose ICS plus a long- acting bronchodilator, oral azithromycin was superior to placebo with respect to total asthma exacerbations. Gibson PG et al. Lancet. 2017 Aug 12. As per ERS 2014 guidelines, avoid using macrolide antibiotics in adult and pediatric patients with severe asthma. D Antifungal agents: Consider initiating antifungal agents in adult patients with severe asthma and recurrent exacerbations of allergic bronchopulmonary aspergillosis. C Avoid using antifungal agents for the treatment of asthma in adult and pediatric patients with severe asthma without allergic bronchopulmonary aspergillosis, irrespective of sensitization to fungi (positive skin prick test or fungus-specific IgE in serum). D Methotrexate: avoid using methotrexate in adult and pediatric patients with severe asthma. D 4. Therapeutic procedures Bronchial thermoplasty: As per NHLBI 2020 guidelines, consider offering bronchial thermoplasty in 18 years old patients with persistent asthma placing a low value on harms (short-term worsening symptoms and unknown long-term side effects) and a high value on potential benefits (improvement in quality of life, a small reduction in exacerbations). C As per CTS 2017 guidelines: Insufficient evidence regarding the precise role of bronchial thermoplasty in 18 years old patients with severe asthma. I Perform bronchial thermoplasty in highly specialized centers because of the complexity of the procedure and the occurrence of severe events, such as hospitalizations due to asthma worsening, atelectasis, and pneumonia. E As per ERS 2014 guidelines, offer bronchial thermoplasty in adult patients with severe asthma only in the context of an IRB-approved independent systematic registry or a clinical trial. B 5. Patient education Self-management counseling: provide comprehensive self-management asthma education in patients with suspected or confirmed severe asthma, and obtain an evaluation by an asthma specialist. E https://web.pathway.md/diseases/recXO1CHaepb58fvn 5/6 6/24/23, 3:10 PM Severe asthma phenotypes Pathway References 1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute NHLBI administered and coordinated National Asthma Education and Prevention Program Coordinating Committee NAEPPCC et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146 6 1217 1270. Open 2. Kian Fan Chung, Sally E Wenzel, Jan L Brozek et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014 Feb;43 2 343 73. Open 3. FitzGerald J, Lemiere C, M. Lougheed D et al. Recognition and management of severe asthma: A Canadian Thoracic Society position statement. Can J Resp Crit Sleep Med. 2017 Oct;1 4 199 221. Open 4. Ioana Agache, Cezmi A Akdis, Mubeccel Akdis et al. EAACI Biologicals Guidelines-Recommendations for severe asthma. Allergy. 2021 Jan;76 1 14 44. Open 5. McCracken JL, Veeranki SP, Ameredes BT et al. Diagnosis and Management of Asthma in Adults: A Review. JAMA. 2017 Jul 18;318 3 279 290. Open 6. de Marco R, Locatelli F, Cazzoletti L et al. Incidence of asthma and mortality in a cohort of young adults: a 7-year prospective study. Respir Res. 2005 Aug 16;6 95. Open 7. Mims JW. Asthma: definitions and pathophysiology. Int Forum Allergy Rhinol. 2015 Sep;5 Suppl 1 S2 6. Open 8. Ringbaek T, Seersholm N, Viskum K. Standardised mortality rates in females and males with COPD and asthma. Eur Respir J. 2005 May;25 5 891 5. Open 9. Lougheed MD, Lemiere C, Ducharme FM et al. Canadian Thoracic Society 2012 guideline update: Diagnosis and management of asthma in preschoolers, children and adults: Executive summary. Can Respir J. 2012 Mar-Apr;19 2 127 64. Open 10. Larenas-Linnemann D, Luna-Pech JA, Rodriguez-Perez N et al. GUIMIT 2019, Mexican Guideline on Immunotherapy. Guideline on the diagnosis of IgE-mediated allergic disease and immunotherapy following the ADAPTE approach]. Rev Alerg Mex. 2019;66 Suppl 1 1 105. Open 11. American Academy of Allergy, Asthma & Immunology. Choosing Wisely AAAAI recommendations. Choosing Wisely. 2012. Open 12. Steve Goodacre, Judith Cohen, Mike Bradburn et al. Intravenous or nebulised magnesium sulphate versus standard therapy for severe acute asthma 3Mg trial): a double-blind, randomised controlled trial. Lancet Respir Med. 2013 Jun;1 4 293 300. Open 13. Michael Schatz, Christine A Sorkness, James T Li et al. Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists. J Allergy Clin Immunol. 2006 Mar;117 3 549 56. Open 14. Ioana Agache, Jessica Beltran, Cezmi Akdis et al. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma. Allergy. 2020 May;75 5 1023 1042. Open https://web.pathway.md/diseases/recXO1CHaepb58fvn 6/6