Innovative Therapies for Severe Asthma
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Clinical Review Innovative Therapies for Severe Asthma Maj Anna Christensen, MD, USAF; and Michael Ott, MD Severe asthma therapies have progressed to include many options that have improved the quality of life for patients. ore than 39.5 million peo- severity and age group.3 The Inter- mation, therefore, quantifying airway ple in the U.S. have been national European Respiratory So- inflammation.6-8 diagnosed with asthma, ciety (ERS) and American Thoracic There has been some variability and about 3,400 deaths Society (ATS) task force report was in the evidence supporting the use of M 5 occur annually due to asthma com- updated in 2014. The Global Initia- fractional exhaled NO (FeNO) lev- plications.1 Although the prevalence tive for Asthma (GINA) report, up- els as a diagnostic tool. Some stud- of atopy and asthma have increased dated in 2016, now includes several ies have suggested that FeNO is also over the past few decades in west- of the advances in asthma care for elevated in other nonasthma condi- ern countries, control and outcomes those patients refractory to standard tions, such as eosinophilic bronchi- are improving.2 Use of asthma pro- treatments. tis, atopy, and allergic rhinitis. Also, tocols and early recognition by the FeNO levels have been shown to be primary care provider (PCP) are ASTHMA THERAPIES variably influenced by smoking, bron- among the main reasons for trends In this review, the authors cover choconstriction, and viral respiratory toward decreased hospitalization therapies for severe asthma that are infections.9 However, FeNO levels and fewer asthma-related deaths.3,4 becoming more important for PCPs > 50 ppb correlated most strongly In addition to the mainstay of to consider, including exhaled nitric with eosinophilic asthma and steroid treatments, including trigger avoid- oxide (NO) levels, the use of tiotro- responsiveness.9 ance, inhaled corticosteroids (ICS), pium for asthma, the applicability of Fractional exhaled NO tests now and rescue bronchodilators, new biologic agents, the use of allergen can be performed in the PCP of- therapies have been developed to immunotherapy, and the usefulness fice with NIOX VERO (Chicago, supplement the treatment of severe of roflumilast. This review also cov- IL), a small, relatively inexpensive persistent asthma, which constitutes ers antileukotriene therapy, bronchial device. Although the 2016 GINA about 5% to 10% of asthma cases. Se- thermoplasty, and a discussion of long- guidelines and the 2015 ERS/ATS vere asthma is defined as asthma that acting beta-agonist (LABA) therapy. guidelines do not offer specific rec- is unresponsive to baseline therapy.5 ommendations for use and do not Three sets of guidelines and rec- Fractional Exhaled Nitric Oxide support withholding ICS based on ommendations exist to provide Nitric oxide is present in the exhaled FeNO test results, guidelines for structure to asthma treatment deci- breath and is elevated in those with FeNO use do exist. In 2011, ATS sion making. The Expert Panel Re- eosinophilic asthma.6 The role of NO published a specific set of FeNO port-3 (EPR-3) was created by the in asthma pathology is complex, in- interpretive guidelines for office- National Education and Prevention volving proinflammatory qualities based use.9 When performed in Program (NAEPP) and was last pub- that contribute to airway hyperre- conjunction with standard testing, lished in 2007. The NAEPP favors a sponsiveness (AHR) and as a weak FeNO levels can provide valuable stepwise approach, based on asthma mediator of smooth muscle relax- clinically relevant information, such ation. In exhaled air, NO correlates as (1) detection of eosinophilic air- Maj Christensen and Dr. Ott are physicians at with up-regulation of NO synthase way inflammation; (2) determin- Eglin Air Force Hospital in Valparasio, Florida. (NOS), which occurs with inflam- ing the likelihood of corticosteroid www.fedprac.com DECEMBER 2017 • FEDERAL PRACTITIONER • 25 ASTHMA THERAPIES Table 1. FeNO Interpretation9 Diagnosis Monitoring Levels Symptoms Present Symptoms Present Symptoms Absent FeNO < 25 ppb Eosinophilic airway inflammation unlikelya Check alternative diagnoses, unlikely Adequate ICS dose (< 20 ppb for patients < 12 y) Unlikely to benefit from ICSa to benefit from increase in ICS Consider taper FeNO 25-50 ppb Be cautious, evaluate clinical symptoms Inadequate ICS dose, consider Adequate ICS dose (20-35 ppb for patients < 12 y) and FENO over timeb steroid resistance or poor adherence Persistent allergen exposure FeNO > 50 ppb Eosinophilic airway inflammation presenta Inadequate ICS dose, steroid ICS taper may result (> 35 ppb for patients < 12 y) Likely to benefit from ICSa resistance or poor adherence; in relapse increased risk for exacerbation Poor adherence or Persistent allergen response technique Abbreviations: FeNO, fraction of exhaled nitric oxide; ICS, inhaled corticosteroid; PPB, parts per billion. aStrong recommendation, moderate quality of evidence. bStrong recommendation, low quality of evidence. responsiveness; (3) monitoring of The FDA approved the addition exertional dyspnea and exercise tol- airway inflammation to determine of tiotropium for treating asthma erance. On day 42 of a randomized, the need for steroids; and (4) un- in September 2015 for patients double-blinded, placebo-controlled, masking of otherwise unsuspected aged ≥ 12 years. The use of tiotro- parallel-group study of 187 patients, nonadherence to corticosteroid pium is supported by both the ERS/ vital capacity and inspiratory capac- therapy (Table 1). ASTS and GINA 2016 guidelines. ity were noted to be increased with The recommended and approved decreases in residual volume and Tiotropium as an Adjunct Treatment dose of tiotropium for asthma is functional residual capacity. Exercise Tiotropium is a long-acting inhaled 2.5 µg daily (the recommended endurance times increased by 105 ± anticholinergic. A sentinel 1984 study dose for COPD treatment is 5 µg).12 40 sec (21%).16 This effect has not by Gross and Skorodin demonstrated A recent phase 3 study compared been studied yet in a population of that parasympathetic activity is the 2.5 µg vs 5 µg dosing with ICS but patients with asthma; however, the dominant reversible component in no LABA in adolescents, noting sig- same principles may hold true. patients with chronic obstructive pul- nificant improvement with the 2.5 µg monary disease (COPD), including dose.13 Adding tiotropium to ICS + BIOLOGIC AGENTS emphysema.10 In addition, all achiev- LABA in patients with severe symp- Recent asthma research has been fo- able bronchodilation was obtained tomatic asthma has been associated cused on disrupting the inflamma- with an inhaled anticholinergic com- with positive results in initial studies tory cascade. Both GINA and ERS/ pared with that of separate or simul- by Kersjens and colleagues.14 Even ATS divide asthma into allergic taneous administration of adrenergics. as early as 2010, the use of tiotro- vs nonallergic endotypes. Allergic Sympathetic neural pathways are pium was shown to produce statis- asthma usually is manifested by spu- sparse in human lungs and have their tically significant improvement in tum eosinophilia and high serum endings on the cells of the cholinergic morning peak expiratory flow (PEF), eosinophil counts, whereas other postganglionic fibers, because sym- with a mean difference of 25.8 L/min endotypes include aspirin-sensitive pathetic terminals on airway smooth (n = 210, P < .001).15 and exercise-induced asthmas that muscle cells are rare or nonexistent.11 Tiotropium also has been shown to present with a neutrophilic predomi- Therefore, sympathetic modulation or provide a sustained reduction in lung nance. Nonallergic asthma is more activation of beta cells could change hyperinflation for those with COPD, severe typically and has been linked the parasympathetic tone.11 thus providing an improvement in to steroid resistance.17 Many different 26 • FEDERAL PRACTITIONER • DECEMBER 2017 www.fedprac.com ASTHMA THERAPIES Table 2. Biologic Agents for the Treatment of Severe Asthma20,23,26,30,34-39 Treatment (Brand) Mechanism of Action Type of Antibody Approved for Use (y) Omalizumab (Xolair) Antibody that creates inert IgE complexes and stops Humanized MAB Yes (2003) complement activation Mepolizumab (Nucala) Binds directly to IL-5 and prevents eosinophil activation Humanized MAB Yes (2015) Reslizumab (Cinqair) Binds directly to IL-5 and prevents eosinophil activation Humanized MAB Yes (2016) Dupilumab Binds to the IL-4Rα subunit of the IL-4 receptor, blocks Human MAB No, but received FDA “break- Th2 activation through therapy” designation Fevipiprant Prostaglandin D2 receptor antagonist, blocks migration of N/A No Th2 cells, cytokines, prevents eosinophil activation Benralizumab Anti-IL-5 receptor, block eosinophil activation Humanized MAB No Abbreviations: IG, immunoglobulin; IL, interleuken; MAB, monoclonal antibody, Th2, T helper type 2. phenotypes have been identified, the newer completely human MABs. analysis of more than 10,000 patients but the main categories include eo- Omalizumab forms small, biologically did not support any relationship with sinophilic, neutrophilic, mixed, and inert IgE+ anti-IgE complexes that malignancy.27,28 A higher incidence paucigranulocytic.18 cannot activate the complement cas- of cardiovascular and cerebrovascu- Mast cells, bronchial epithelium, cade. The serum free IgE level is de- lar AEs has been observed, and the and macrophages are involved in creased.20 Approved in 2003