What Is New In Small Airways Research
Ves Dimov, MD
Allergist/Immunologist at Cleveland Clinic
Clinical Associate Professor
FAU Charles E. Schmidt College of Medicine
Asthma endotypes: does it matter when considering which treatment to recommend?
Two major endotypes for asthma have been described:
- TH2-high, manifested by increased eosinophils in the sputum and airways of patients
- TH2-low, with increased neutrophils or a pauci-granulocytic profile
This review article evaluated human clinical trials using biologics for T-helper type 2 cell (TH2)-low and TH2-high asthma.
Multiple immune response modifiers have been evaluated in TH2-high asthma geared at blocking interleukin (IL)-5, IL-13, immunoglobulin E, prostaglandin D2, and other pathways. As of year 2016, 3 immune response modifiers approved by the Food and Drug Administration are available for treating severe TH2-high asthma:
- anti-immunoglobulin E, omalizumab, available for more than 10 years
- anti–IL-5 monoclonal antibodies, mepolizumab (SC) and reslizumab (IV)
Many of the TH2-high therapies have shown better efficacy when certain biomarkers are elevated, especially blood eosinophils. The TH2-low endotype does not have any readily available point-of-care biomarkers, and development of therapies has lagged behind that for TH2-high asthma.
Source: Stokes JR and Casale TB. Characterization of asthma endotypes: implications for therapy. Annals of Allergy, Asthma and Immunology 2016; 117(2): 121–125. (doi:10.1016/j.anai.2016.05.016)
Image source: Wikipedia, Asthma, public domain.
The immunology of asthma: phenotypes and personalized treatment
Inhaled corticosteroids are likely to be only effective in asthma patient with eosinophilic inflammation. Similarly, biotherapeutic agents currently available have been efficacious only in relevant phenotypes.
Future therapeutic targets for type 2 cytokine–driven asthma are airway-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), epigenetically programmed to remain constitutively expressed.
Targeting these epigenetically programmed epithelial-derived mediators may be more likely to improve day-to-day asthma symptoms, in contrast to targeting mediators of the adaptive immune system, which primarily ameliorates asthma exacerbations.
Source: Borish L. The immunology of asthma. Annals of Allergy, Asthma and Immunology 2016; 117(2): 108-114. (doi:10.1016/j.anai.2016.04.022)
Once-daily tiotropium improved lung function when added to ICS maintenance therapy in adolescents with moderate symptomatic asthma
This 48-week study was conducted at 65 sites in 12 countries and included 398 patients aged 12 to 17 years. They were randomized to receive 5 μg (2 puffs of 2.5 μg) or 2.5 μg (2 puffs of 1.25 μg) of once-daily tiotropium or placebo (2 puffs) administered through the Respimat device every evening, each as add-on treatment to inhaled corticosteroid (ICS) background therapy, with or without a leukotriene receptor antagonist. Of note, long-acting beta-2-agonists were not permitted during the study.
The primary end point was improvement in peak FEV1 within 3 hours after tiotropium dosing at 24 weeks, and it was achieved during the study. Trends for improvement in asthma control and health-related quality of life over the 48-week treatment period were observed.
Once-daily tiotropium improved lung function and was well tolerated when added to ICS maintenance therapy in adolescents with moderate symptomatic asthma. The effect was larger with the higher tiotropium dose (5 μg).
Source: Hamelmann E, Bateman ED, Vogelberg C, Szefler SJ, Vandewalker M et al. Tiotropium add-on therapy in adolescents with moderate asthma: A 1-year randomized controlled trial. Journal of Allergy and Clinical Immunology 2016; 138(2): 441–450. (doi:10.1016/j.jaci.2016.01.011)