Maj Christensen and Dr. Ott are physicians at Eglin Air Force Hospital in Valparasio, Florida.
Author disclosures The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Many biologics are being developed as medical researchers continue to understand more of the mechanisms and pathways that contribute to allergic disease (Table 2). Dupilumab is an IL-4 inhibitor designated as a “breakthrough therapy” in 2014 by the FDA. This biologic blocks the downstream signaling events induced by IL-4 and IL-13 by binding to a subunit of the IL-4 receptor in the complexes. It has been found beneficial for those with high blood eosinophil counts and moderate-to-severe asthma and decreased asthma exacerbations when LABA and ICS were withdrawn.36,37
Fevipiprant is a prostaglandin D2 inhibitor that blocks T-helper type 2 (Th2) cell migration and subsequent bronchoconstriction and cytokine effects with decreased IL-4, IL-5, and IL-13. Although sputum eosinophil percentage was noted to be decreased in a study involving 61 patients randomized to treatment for 12 weeks, asthma QOL questionnaires and prebronchodilator spirometry did not change.38,39
Benralizumab is an anti-IL-5 receptor antibody that has been more effective in reduction of airway and blood eosinophils levels compared with that of mepolizumab (undetectable vs 52% reduction), within 24 hours of IV dosing. In contrast, the anti-IL-5 antibodies take about 4 weeks to decrease eosinophil levels in blood and sputum.34 There have been no documented AEs aside from nasopharyngitis and injection site reactions and no safety concerns to date. It is currently undergoing phase 3 trials.40
Immunotherapies
Allergen immunotherapy is recommended for mild-to-moderate asthma. A 2010 Cochrane Review found that subcutaneous immunotherapy compared with placebo demonstrated improvements in bronchial hyperresponsiveness and decreased medication use.41 Expert Panel Report-3 guidelines recommend consideration of immunotherapy for mild-to-moderate asthma.5 While ERS/ATS guidelines for severe asthma do not address allergen immunotherapy, GINA guidelines incorporate it as Evidence A for treating modifiable risk factors to reduce exacerbations, although the efficacy is limited.6
Roflumilast
Roflumilast is a selective PDE4 inhibitor that has shown an anti-inflammatory effect in COPD. Studies evaluating the reversibility and prevention of airway remodeling showed good promise in mouse models.42 Data from 8 placebo-controlled, double-blind, phase 1, 2, and 3 studies conducted at 14 sites in Europe, North America, and South Africa from 1997 to 2005 showed reduced sputum eosinophil and neutrophil counts, consistent with findings during COPD treatment. However, forced expiratory volume in one second (FEV1) and PEF values were unchanged, suggesting that there was no acute bronchodilatory effect with roflumilast therapy.43 Roflumilast is not addressed in the 2016 GINA guidelines and at this time does not have a role in the treatment of severe asthma.
Antileukotrienes
After the activation of mast cells and eosinophils, leukotrienes are generated by 5-lipoxygenase from arachidonic acid and create bronchoconstriction, vasodilation, increased mucus production, increased recruitment of eosinophils, and decreased ciliary motility. Some studies have encouraged addingleukotriene receptor blockers (both montelukast and zafirlukast) to ICS therapy44,45 and to therapy for patients with aspirin-intolerant asthma or allergic asthma.46,47 However, other studies have shown them to be of limited benefit.48,49 A recent Cochrane Reviewof 18 randomized-controlled trials with 7,208 adults and children compared ICS + leukotriene receptor antagonist (LTRA) vs ICS + LABA.50 The ICS + LABA resulted in greater improvements in lung function, symptoms score, and rates of exacerbations.50
Most recommendations recognize the limitations of antileukotriene medications and agree that they are an adjunct rather than primary therapy. The GINA 2016 guidelines support the use of LTRAs in mild asthma, stating that although LTRAs are less effective than ICS (Evidence A), they may be appropriate for initial controller treatment for some patients who are unable or unwilling to use ICS or for patients with concurrent allergic rhinitis (Evidence B).51,52
Zileuton is a different type of antileukotriene. It inhibits leukotrienes B4, C4, D4, and E4 by inhibition of 5-lipoxygenase, interfering with leukotriene formation. It is approved for patients aged ≥ 12 years and is more expensive than montelukast or zafirlukast. Most studies supporting its use were conducted in patients with mild-to-moderate asthma on β-agonist therapy only. A 1988 study showed that zileuton therapy improved FEV1, reduced nasal symptoms, and decreased bronchial responsiveness to inhaled aspirin and histamine.53 All but 1 study patient were on ICS or oral corticosteroids. Zileuton was noted to be effective for patients with aspirin-intolerant asthma.
Some earlier studies reported that a small number of subjects had an increase in transaminases that resolved when they discontinued the medication. Therefore, it is recommended to check baseline laboratory results every 2 to 3 months.54,55 Neither GINA nor ERS/ATS guidelines address the use of zileuton.
Bronchial Thermoplasty
With asthma there is marked hypertrophy and hyperplasia that occurs in the airway smooth muscle. The airway of the patient with asthma also is lined with cells that promote inflammation. Thermal energy is used to perform controlled destruction of the inflammatory lining and pathologic hyperplasia. Three sequential bronchoscopies are performed 3 weeks apart to treat the right lower lobe, left lower lobe, and bilateral upper lobes. The right middle lobe is not treated due to its smaller diameter. Each bronchoscopy takes about 30 to 60 minutes. Patients are given perioperative steroids.56
