Sandhya Khurana, MD, on Best Practices for Managing Severe Asthma
Patients with severe asthma can be difficult to manage, especially when treatment-related comorbidities and toxicity need additional attention and care. Out of this challenging situation arose the need for evidence-based best practices for managing patients with severe asthma.
This was the topic of discussion during a session at CHEST 2019. Consultant360 caught up with speaker Sandhya Khurana, MD, after her session.
Sandhya Khurana, MD, is a Professor in the Department of Medicine, Pulmonary Diseases and Critical Care and is the Director of the Mary Parkes Center at the University of Rochester in Monroe County, New York.
C360: What are the best practices for treating and managing patients with severe asthma?
Sandhya Khurana: The last decade has seen significant advances in the field of severe asthma, and our patients now have more treatment options available than ever before. Asthma is a heterogenous disease, and identification of treatable traits can help select the best treatment strategy. Before considering advanced therapies that are effective but also expensive, it is extremely important to differentiate uncontrolled or “difficult” asthma from true severe refractory asthma. A systematic stepwise evaluation that includes confirmation of asthma diagnosis, assessment of comorbidities and medication adherence, and avoidance of triggers will result in achieving asthma control in the majority of patients. If asthma remains uncontrolled after these modifiable factors have been addressed, the patient should be considered for advanced therapies. Such patients can benefit from referral to a severe asthma clinic.
Available biomarkers that can help with patient selection include blood eosinophil count, serum immunoglobulin E (IgE), and fraction exhaled nitric oxide (FENO). Currently, 5 biologics are approved by the US Food and Drug Administration (FDA) for treatment of severe asthma. Omalizumab is an anti-IgE antibody approved for allergic asthma. Mepolizumab, benralizumab, and reslizumab are anti-IL5 therapies approved for severe eosinophilic asthma. Dupilumab is an anti-IL4R antibody that blocks signaling of IL-4/13 and is approved for severe eosinophilic asthma as well as oral corticosteroid (OCS)-dependent asthma. Mepolizumab and dupilumab can be self-administered by patients at home.
Asthma biologics appear to be well-tolerated and are effective for reducing exacerbations in patients with asthma. Mepolizumab, benralizumab, and dupilumab have been studied in patients with OCS-dependent asthma for steroid-sparing effects. No direct comparative effectiveness studies of these biologics have been performed. Therefore, selection of a therapy is based on the asthma phenotype, comorbidities, access, cost, and patient’s preference.
C360: What have clinical trials told us about tapering oral steroids in patients with severe asthma?
SK: There is no safe dose for OCS use, with a linear dose-relationship for any dose of OCS resulting in acute and chronic complications.1 Use of prednisone, more than 5 mg daily, is associated with increased hospitalizations and emergency department (ED) visits. OCS withdrawal should be considered after introduction of an alternate steroid-sparing treatment, if there is an inadequate response after adequate therapeutic trial, or if adverse effects cannot be adequately controlled with other therapy.
General principles for OCS dose management include:
- Achieving the lowest effective OCS dose even before introduction of alternate steroid-sparing treatment (optimization)
- Determining a safe tapering rate that will prevent destabilization of underlying disease and avoid hypothalamic-pituitary-adrenal (HPA) axis suppression
- Assessing risk of HPA axis suppression (>20 mg for more than 3 weeks; evening dose of >5 mg daily for more than a few weeks; anyone with Cushingoid appearance); if risk is unclear, patients should undergo additional testing
- Establish criteria for stopping OCS taper based on objective parameters
- Symptom score (Asthma Control Questionnaire or Asthma Control Test increase)
- FEV1 decline
- Level of short-acting β-agonist (SABA) use
- Increase in nocturnal symptoms
- Exacerbation requiring increase in OCS
- Symptoms of adrenal insufficiency or steroid withdrawal
Mepolizumab, benralizumab, and dupilumab have been systematically studied in randomized controlled steroid-sparing trials of asthma.2,3,4 Each trial included a steroid optimization phase before randomization, followed by a gradual steroid reduction phase and a maintenance phase. Treatment with all 3 biologics was associated with significant decrease in maintenance OCS dose as well as an increase in the proportion of patients who were able to discontinue OCS completely. Simultaneously, there was a decrease in frequency of asthma exacerbations.
C360: What other updates should pulmonologists and pediatricians know about asthma or severe asthma?
SK: There are significant changes in the 2019 update to GINA (Global Initiative for Asthma)5 recommendations. As-needed low-dose inhaled corticosteroid (ICS)/formoterol is the preferred therapy at step 1 and an alternative to low-dose maintenance ICS at step 2 of GINA for adolescents and adults. This change is based on several large clinical trials that have found as-needed low-dose ICS/formoterol strategy to be superior to as-needed SABA and as effective as maintenance ICS for preventing exacerbations.6,7,8,9 Although recommended by GINA, adopting this in the United States may be challenging, since the FDA label for ICS/formoterol is still for maintenance use. Also, it is important to note that this approach is only recommended for ICS/long-acting β-agonists (LABA)-containing formoterol due to its fast onset of action.
European Respiratory Society (ERS) and American Thoracic Society (ATS) published updated guidelines on management of severe asthma in adults and children.10 The taskforce provides recommendations on the use of biomarkers for selecting biologic therapies, as well as the role of anti-IL5 agents, anti-IL4/13 antibody, long-acting muscarinic antagonist (LAMA), and chronic macrolide therapy for severe asthma.
GINA also released a “difficult-to-treat and severe asthma” guide in 2018 and updated it in April 2019.11 This is free to access online and provides guidance for managing severe asthma in adolescents and adults.
There were many other notable publications that advanced our knowledge in the field of asthma, including:
- Long-term safety and efficacy data on biologics12,13
- Safety of omalizumab in pregnancy14
- Effects of asthma management in pregnancy on the offspring15
- Differential response to step up therapy in black children and adults16
- Role of steroids in managing mild non-eosinophilic asthma17
- Volmer T, Effenberger T, Trautner C, Buhl R. Consequences of long-term oral corticosteroid therapy and its side-effects in severe asthma in adults: a focused review of the impact data in the literature. Eur Respir J. 2018;52(4):pii: 1800703. https://doi.org/10.1183/13993003.00703-2018.
- Nair P, Wenzel S, Rabe KF, et al; ZONDA Trial Investigators. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med. 2017;376(25):2448-2458. https://doi.org/10.1056/NEJMoa1703501.
- Bel EH, Wenzel SE, Thompson PJ, et al; SIRIUS Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189-1197. https://doi.org/10.1056/NEJMoa1403291.
- Rabe KF, Nair P, Brusselle G, et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med. 2018;378(26):2475-2485. https://doi.org/10.1056/NEJMoa1804093.
- Global Strategy for Asthma Management and Prevention [published online June 2019]. Global Initiative for Asthma (GINA). https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdf.
- Beasley R, Holliday M, Reddel HK, et al; Novel START Study Team. Controlled trial of budesonide–formoterol as needed for mild asthma. N Engl J Med. 2019;380(21):2020-2030. https://doi.org/10.1056/NEJMoa1901963.
- Bateman ED, Reddel HK, O’Byrne PM, et al. As-needed budesonide–formoterol versus maintenance budesonide in mild asthma. N Engl J Med. 2018;378(20):1877-188 https://doi.org/10.1056/NEJMoa1715275.
- O’Byrne PM, FitzGerald JM, Bateman ED, et al. Inhaled combined budesonide–formoterol as needed in mild asthma. N Engl J Med. 2018;378(20):1865-1876. https://doi.org/10.1056/NEJMoa1715274.
- Hardy J, Baggott C, Fingleton J, et al; PRACTICAL Study Team. Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, superiority, randomised controlled trial. Lancet. 2019;394(10202):919-928. https://doi.org/10.1016/S0140-6736(19)31948-8.
- Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society Guideline. Eur Respir J. 2019;pii: 1900588. https://doi.org/1183/13993003.00588-2019.
- Difficult-to-Treat & Severe Asthma in Adolescent and Adult Patients: Diagnosis and Management [published online April 2019]. Global Initiative for Asthma (GINA). https://ginasthma.org/wp-content/uploads/2019/04/GINA-Severe-asthma-Pocket-Guide-v2.0-wms-1.pdf.
- Busse WW, Bleecker ER, FitzGerald JM, et al; BORA study investigators. Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial. Lancet Respir Med. 2019;7(1):46-59. https://doi.org/10.1016/S2213-2600(18)30406-5.
- Lugogo N, Domingo C, Chanez P, et al. Long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma: a multi-center, open-label, phase IIIb study. Clin Ther. 2016;38(9):2058-2070. https://doi.org/10.1016/j.clinthera.2016.07.010.
- Namazy JA, Blais L, Andrews EB, et al. The Xolair Pregnancy Registry (EXPECT): Perinatal outcomes among pregnant women with asthma treated with omalizumab (Xolair) compared against those of a cohort of pregnant women with moderate-to-severe asthma. J Allergy Clin Immunol. 2019;143(2 Suppl):AB103. https://doi.org/10.1016/j.jaci.2018.12.312.
- Morten M, Collison A, Murphy VE, et al. Managing Asthma in Pregnancy (MAP) trial: FENO levels and childhood asthma. J Allergy Clin Immunol. 2018;142(6):1765-1772. https://doi.org/10.1016/j.jaci.2018.02.039.
- Wechsler ME, Szefler SJ, Ortega VE, et al; NHLBI AsthmaNet. Step-up therapy in black children and adults with poorly controlled asthma. N Engl J Med. 2019;381(13):1227-1239. https://doi.org/10.1056/NEJMoa1905560.
- Lazarus SC, Krishnan JA, King TS, et al; National Heart, Lung, and Blood Institute AsthmaNet. Mometasone or tiotropium in mild asthma with a low sputum eosinophil level. N Engl J Med. 2019;380(21):2009-2019. https://doi.org/10.1056/NEJMoa1814917.