Airway smooth muscle hypertrophy/hyperplasia has been considered a hallmark of severe asthma. Thus, a thermal approach to potentially decrease smooth muscle mass through applying excess heat in the airways was developed. During a series of 3 bronchsoscopies, thermal energy is delivered to the airway wall to reduce airway smooth muscle in a procedure known as BT. A single multi-center RDB sham-controlled trial (Asthma Intervention Research2 [AIR2] Trial) of 288 adult severe asthmatic subjects, symptomatic despite high-dose ICS/LABA, found that BT had a modest effect to improve asthma quality of life and reduced health care utilization and severe exacerbations over a 12-month follow-up period.22 However, there were also significant increases in asthma exacerbations during the BT treatment phase in the BT group.22 Other measures, such as lung function, symptom scores and rescue medication use, were not significantly different between groups.22 Importantly, subjects excluded from the AIR2 trial included those with pre-bronchodilator FEV1 <60%, life-threatening asthma, chronic sinus disease, use of immunosuppressants, and history of 3 or more hospitalizations or 4 or more bursts of OCS for asthma, or 3 or more lower respiratory tract infections in the previous year, suggesting efficacy of the procedure in some of the most severe asthmatics is unknown.22 Long-term safety and efficacy are not yet clear as no placebo group has been included in the follow-ups. However, the proportion of subjects experiencing an exacerbation remained significantly decreased in the BT group at years 2 and 5 compared to the 1st year post thermoplasty.2324 These studies suggest that thermoplasty may provide long-lasting benefit in some severe asthmatics. In a small observational study of bronchial biopsies from 10 severe, uncontrolled asthmatics (all on ICS/LABA and 7 on oral CS) who underwent BT and had a baseline airway smooth muscle (ASM) area of ≥15%, ASM mass was reduced at 3 months post-BT compared to baseline biopsies (absolute decrease in ASM area=12.9%) but was not different between lung areas nor comparing the right vs left sides of the lung, or even when comparing airways that had been treated vs those that had not.25 Due to abnormalities seen on CXR following the third BT procedure in 1 patient, CT scans were performed the day after each procedure in the next 7 patients and showed alveolar and ground glass opacities in all patients in the treated lobe and in the middle (untreated) lobe in 5 of 7 patients, suggesting possible pathologic changes extending beyond the smooth muscle.25 In another small prospective study of 17 severe asthmatics who completed BT, collagen deposition and ASM mass decreased in the treated airway segments (absolute decrease of 8.3%).26 Sub-analysis of 5 subjects with a baseline ASM area of ≥15% showed a mean absolute ASM reduction of 16.2%, suggesting that those with more baseline ASM may be more responsive to BT, although the post-bronchodilator FEV1 values did not change at 1-year follow-up, suggesting that the mechanisms are not completely understood.26 In another recent prospective biopsy study of 11 severe asthmatics (8 with a baseline FEV1 <60% predicted and on chronic OCS), endobronchial biopsy post-BT showed decreased α-smooth muscle actin expression in 7 of 11 subjects and several inflammatory mediators (including transforming growth factor-β and CCL5) were decreased in all subjects in the bronchoalveolar lavage 6 weeks post-BT.27 Despite these findings, FEV1 at 3 and 6 weeks post-BT did not improve in 6 of these patients (3 with an initial FEV1 >60% and 3 with FEV1 <60% predicted), again suggesting that it may be challenging to identify those who will benefit from BT.27 A Cochrane review of 3 randomized controlled trials (totaling 429 patients) that compared BT vs any active control in adults with moderate or severe persistent asthma concluded that there were lower rates of asthma exacerbations, but no difference in asthma control scores and an increased risk of adverse event during treatment.28 While there was a modest clinical benefit in quality of life, 2 of the studies did not include a sham arm.28 Therefore, although the ERS/ATS guidelines on severe asthma do not advise against this FDA-approved procedure, they cite very low confidence in the current data on this procedure, as the potential benefits and harms may be large, the long-term consequences of this invasive approach are unknown, and there is currently a lack of understanding which patients may benefit.2 They strongly recommended that any patient undergoing this procedure be entered into an IRB-approved registry or clinical trial. Additional studies are needed to determine if patients with systemic CS-dependent, type 2 inflammation and severe obstruction would benefit from BT.

While no longer a new therapy for severe asthma, omalizumab was the first monoclonal antibody used in asthma treatment. Omalizumab binds to free IgE and prevents IgE from binding to its high-affinity receptors (FcεRI). It was initially approved for treatment of moderate to severe allergic asthma, defined by atopy (presence of perennial specific IgE on skin or serum testing) and a total serum IgE level between 30 and 700 IU/mL. In an early phase III RDBPC study of 525 allergic persistent asthmatics on ICS defined by earlier NHLBI EPR-2 criteria, subcutaneous omalizumab every 2 or 4 weeks reduced asthma exacerbations and rescue medication use.29 In another large RDBPC trial of 546 adult persistent allergic asthmatics, symptomatic despite ICS, subcutaneous omalizumab every 2 or 4 weeks also reduced asthma exacerbations during a 16-week stable steroid phase and a 12-week subsequent steroid dose-reduction phase.30 In a RDBPC study of 246 patients with more severe allergic asthma on high dose ICS, subcutaneous omalizumab every 4 weeks for 32 weeks allowed reduction in ICS dose without worsening of asthma control.31 However, these patients were not on any additional controllers. These attempts to "phenotype" asthma based on the presence of atopy and IgE level, were not very predictive of omalizumab response.

A more recent RDBPC study of 850 severe asthmatics, defined as inadequately controlled despite treatment with high-dose ICS plus LABA with 17% on systemic CS, showed that omalizumab therapy for 48 weeks decreased exacerbations by 25% and improved asthma quality of life scores, but without effect on symptoms or lung function.32 Given the modest observed efficacy and evolving biomarker development beyond IgE and atopy, a post hoc analysis of this study was performed, dividing patients by their baseline levels of Type 2 inflammatory biomarkers, particularly blood eosinophils, FeNO, and serum periostin. Those patients with levels higher than the median values for these biomarkers had greater reduction in exacerbations than those severe asthmatics without elevations in these biomarkers.33 However, differences in other outcomes (symptoms or lung function) were not affected by this approach.

While these studies suggest that omalizumab is effective in a subset of severe, allergic asthma, perhaps particularly in those with ongoing Type 2 inflammation, concerns about anaphylaxis and cardiovascular risk, cost and lack of efficacy in some patients suggest that other treatments are needed. The ERS/ATS guidelines on severe asthma suggest that anti-IgE could be considered in patients with severe allergic asthma, although the degree of improvement and the evidence to support it in guidelines-defined severe asthma was modest.2 A Cochrane review analyzed the subset of patients receiving OCS in 25 omalizumab asthma trials. Although the asthmatics receiving OCS may have had better asthma control while receiving omalizumab, the maintenance OCS dose is not significantly impacted. Thus, its utility in systemic CS-dependent patients is not clear.3435

Studies suggest that eosinophilia is present in approximately 50% of asthma cases, across the spectrum of severity. However, it is most strongly associated with a severe, generally adult-onset asthma phenotype with persistence of eosinophils despite high doses of CS and less evidence for traditional allergic markers.36373839 As a potent pro-eosinophilic cytokine, IL-5, and its receptor, IL-5R, have been targeted in severe asthma. Although earlier studies of monoclonal antibodies against IL-5 in non-phenotyped, mild-moderate asthma failed to show efficacy, subsequent studies targeting an eosinophilic phenotype of severe asthma (sputum eosinophilia of >3% in the past year), were successful.67 A RDBPC trial of 61 moderate-severe asthmatics showed that monthly intravenous (IV) mepolizumab, a monoclonal antibody against IL-5, reduced asthma exacerbations, improved asthma quality of life questionnaire (AQLQ), and decreased airway wall thickening on computed tomography of the chest.6 In 22 systemic CS-dependent asthmatics, monthly IV administration of mepolizumab decreased steroid requirements and led to some symptom improvement.7 These small studies were followed by a large multicenter RDBPC trial of anti-IL5 in 621 severe asthmatics who met the ATS criteria for refractory asthma,40 requiring at least 880 ug of fluticasone equivalent per day with or without maintenance oral CS, additional controller drugs and a history of at least 2 exacerbations requiring systemic CS in the prior year. The patients were defined as having Type 2/eosinophilic inflammation on the basis of sputum eosinophils ≥3%, blood eosinophil counts ≥300/µL, or FeNO ≥50 ppb) in the Dose Ranging Efficacy And safety with Mepolizumab (DREAM) study.41 Despite continued use of high dose ICS/LABA, IV mepolizumab decreased asthma exacerbations by 52%.41 While the earlier studies used sputum eosinophils to define a population of severe asthmatics responsive to anti-IL5, this and subsequent studies showed that blood eosinophils could be successfully used to define a responsive severe asthma phenotype. In a subsequent study of 576 severe, eosinophilic asthmatics, with a history of 2 more exacerbations in the previous year, despite high-dose ICS, subcutaneous (SQ) or IV mepolizumab, decreased exacerbations by 53% (SQ) or 47%, (IV) respectively.42 Compared to placebo, mepolizumab also had a small effect to improve lung function (FEV1% predicted) and symptom scores.42 Mepolizumab has also been studied for its systemic CS-sparing effects. In a sub-analysis of the 188 severe asthmatics in the DREAM study on high-dose ICS/LABA and additionally on daily oral CS, mepolizumab was equally effective in reducing exacerbation risk and peripheral eosinophils compared to the group not on OCS.43 This led to a prospective OCS-sparing study in 135 severe, systemic-CS-dependent patients (5-35 mg of prednisone per day). Monthly SQ mepolizumab for 20 weeks increased the likelihood of a 75% or greater reduction in CS dose by 2.39 times vs placebo and reduced the daily CS dose by a median of 50%.44 Despite a baseline FEV1% predicted <60% and a mean of 3 severe exacerbations in the prior year, SQ mepolizumab significantly improved quality of life and asthma control, and reduced exacerbations with a safety profile similar to placebo in this population of severe asthmatics.44

Similar to mepolizumab, the humanized anti-IL-5 antibody reslizumab has also been studied in a severe asthma population as defined by high-dose ICS use with at least 1 other controller medication and poor control with an asthma control questionnaire (ACQ) score ≥1.5, but with blood eosinophils >400/µL. In an earlier study of eosinophilic asthmatics (sputum eosinophils ≥3%) inadequately controlled despite high-dose ICS and additional controller medications, monthly IV reslizumab modestly improved ACQ scores and FEV1, while decreasing eosinophil counts in the sputum and blood.45 In 2 recent duplicate multicenter RDBPC phase 3 trials, 953 inadequately controlled asthmatics on medium-high doses of ICS (with 15% using daily OCS) with blood eosinophils ≥400 cells/µL and ≥1 exacerbation in the prior year, were given IV reslizumab or placebo every 4 weeks for 1 year.46 Quite similar to mepolizumab, reslizumab significantly reduced the asthma exacerbation frequency (rate ratio of 0.5 and 0.41 for Studies 1 and 2, respectively) compared to placebo.46 Finally, in addition to IL-5, the receptor for IL-5 (IL-5Rα) has been targeted using the humanized monoclonal antibody benralizumab. Unlike mepolizumab or reslizumab, benralizumab binds to the IL-5Rα and then destroys eosinophils and basophils, expressing this receptor through an opsonization process.47 In a recent trial in uncontrolled eosinophilic asthma despite ICS/LABA, SQ benralizumab (100 mg dose) for 1 year reduced exacerbations by 41% compared to placebo.48 However, there were differences in efficacy when evaluating response in patients defined as eosinophilic by the formulaic "eosinophilic index" (primary endpoint) or simple blood eosinophil counts. Interestingly, simple blood eosinophil counts were more predictive of response to treatment than the more complex eosinophil index. Of note, most of the outcomes in this trial achieved a pre-specified significance level of P=0.20 rather than the traditional P<0.05.48 In a RDBPC trial of 110 asthmatics who presented to the ED with an acute asthma exacerbation, a single dose of IV benralizumab did not achieve the primary outcome (proportion of subjects with ≥1 exacerbation at 12 weeks), but did reduce asthma exacerbation rates and exacerbations resulting in hospitalization compared to placebo when added to the usual standard of care.49 While these drugs all target the IL-5 pathway, additional studies will be needed to determine if these 3 drugs all have the same efficacy. Furthermore, the definition of eosinophilia (source and absolute numbers) will be important in moving forward as these studies used slightly different thresholds. The DREAM study showed that blood eosinophils, but not sputum eosinophils, were correlated with response to mepolizumab and post hoc analysis of this data showed that a single screening peripheral blood eosinophil count ≥150 cells predicted response to mepolizumab.41 Asthmatics with screening eosinophil count <150 cells had less reduction in asthma exacerbation rates.41 In a post hoc analysis of placebo subjects enrolled in the DREAM trial, a single measurement of blood eosinophils ≥150 cells at screening predicted the average of subsequent measurements being ≥150 in 85% of this population treated with placebo.50 Interestingly, baseline sputum eosinophils (≥3%) did not predict treatment response with mepolizumab (asthma exacerbation reduction of 69% vs 66%, respectively).50 In the benralizumab study, subgroup analysis by a baseline blood eosinophil count ≥300 cells showed reduced exacerbations vs placebo, but this effect was not seen in the subgroup with blood eosinophils <300 cells.48 Importantly, all of these targeted approaches to IL-5 or its receptor, reduced blood eosinophil counts to nearly undetectable. These studies suggest that blood eosinophil counts may be a good predictive biomarker for responses to anti-IL5 and IL-5Rα and are easily obtainable in the clinic.

The US FDA recently approved mepolizumab as an add-on maintenance treatment of patients with severe asthma aged 12 years and older with an eosinophilic phenotype given as a 100 mg SQ dose every 4 weeks.51 In severe, uncontrolled asthma with evidence for persistent eosinophilia (likely blood eosinophils of 150/µL or more) despite inhaled and systemic CSs, targeting IL-5 or its receptor appears to decrease asthma exacerbations by ~50%, considerably greater than any other currently marketed drug or device for severe asthma.

As canonical Type 2 cytokines, IL-4 and IL-13 are important drivers of Th2 and Type 2 inflammation. In a RDBPC study of a humanized monoclonal antibody to IL-4 receptor α (AMG 317), weekly SQ injections in moderate-to-severe otherwise non-Type 2 phenotyped asthmatics failed to show clinical efficacy (in terms of ACQ scores) but did reduce IgE levels in the serum, suggesting some evidence for biologic efficacy.52 A significant advance was made in this area when a monoclonal antibody against IL-13 (lebrikizumab) in 219 moderate-severe uncontrolled asthmatics, despite medium-high dose of ICS/LABA, showed a small improvement in FEV1.11 Importantly, a pre-specified sub-analysis showed that asthmatics with elevations in Type 2 biomarkers (serum periostin and FeNO) had greater increases in FEV1 with blockade of IL-13 than those without.11 However, no other outcomes beyond FEV1 were improved. Similarly, another monoclonal antibody against IL-13, tralokinumab given SQ every 2 weeks in 194 moderate-severe asthmatics, modestly decreased rescue β-agonist use and improved FEV1.53 Like the lebrikizumab study, those with measurable IL-13 (as a Type 2 biomarker) in sputum, had larger improvement in ACQ scores and FEV1 on tralokinumab than those without.53 A Phase 2b RDBPC trial of tralokinumab in 452 severe asthmatics on high-dose ICS/LABA with a history of 2-6 exacerbations in the previous year failed to reduce asthma exacerbation rates vs placebo.54 In a post hoc subanalysis of patients with elevated serum periostin, tralokinumab therapy modestly improved asthma exacerbation rates and prebronchodilator FEV1.54 Interestingly, a shortened study of lebrikizumab in a Phase 2b study of moderate-severe uncontrolled asthma patients with elevated periostin showed more modest efficacy without consistent dose-dependent effects on lung function, symptoms or exacerbations. However, this study was shortened due to discovery of guinea pig IgG peptide contamination in the monoclonal.55

While most studies have shown favorable therapeutic outcomes with blockade of IL-13 in severe asthma, use of the monoclonal antibody to IL-13 (GSK679586) in severe asthmatics on high-dose ICS and 16% on OCS failed to show clinical efficacy (exacerbation rates or symptom scores) compared to placebo even when subgrouped by those with elevated serum IgE and/or blood eosinophils.56 The reasons for these differences are not known.

The first study to prospectively target severe asthmatics with elevations in a Type 2 biomarker (blood or sputum eosinophils) with an IL-4/13 approach was performed with dupilumab, a monoclonal antibody to IL-4Rα. In a Phase 2a proof of concept study of moderate-to-severe asthmatics uncontrolled despite moderate-to-high dose of ICS/LABA and eosinophilia in the blood (≥300 cells/µL) or sputum (≥3%), weekly SQ dupilumab treatment resulted in 87% fewer patients losing control of their asthma upon withdrawal of LABA and then ICS compared to placebo.15 In contrast to studies with antibodies to IL-13, there were improvements in lung function and symptom scores both on top of background ICS/LABA therapy and when background therapy was withdrawn.15 Decreases in type 2 biomarkers, including FeNO, IgE, and eotaxin-3, were also observed with dupilumab treatment. The improvement in FEV1 inversely correlated with the change in FeNO, emphasizing the biologic mechanism for the clinical impact of this strategy.15 A phase 2b study of dupilumab has been completed with similar results, but suggesting that patients with lower levels of blood eosinophils may also respond.57

These studies confirm that IL-13 (and perhaps IL-4 as well) is a central cytokine in airway inflammation and hyperresponsiveness in asthma and in moderate-to-severe asthmatics with evidence for Type 2 inflammation, perhaps even at a lower level that initially expected. It is anticipated that further studies using IL-13 and IL-4Rα approaches will need to be performed to determine whether one approach is superior to the other and whether different patients will respond to treatment with these drugs as compared to IL-5-directed approaches.

Prostaglandin D2 (PGD2) can be generated by activated mast cells during allergic reactions and has been shown to be increased in the bronchoalveolar lavage fluid of severe asthmatics, particularly in association with recent asthma exacerbations and Type 2 biomarkers (FeNO and blood eosinophils).5859 PGD2 acts through its G-protein coupled receptor, chemoattractant receptor–homologous molecule expressed on TH2 lymphocytes (CRTH2/DP2), which is present on Th2 lymphocytes, eosinophils, and group 2 innate lymphoid cells (ILC2).60 CRTH2 activation by PGD2 can also stimulate Type 2 cytokine production by ILC2s.61 In a RDBPC trial of the CRTH2 antagonist (OC000459) in moderate persistent asthma (not on ICS), this drug was associated with improvement in asthma quality of life, night-time awakenings and FEV1 compared to placebo.62 In a RDBPC trial of 519 mild-moderate asthmatics not on ICS, oral OC000459 for 12 weeks increased FEV1 vs placebo in those with blood eosinophil counts ≥250/µL while no improvements were seen in those with blood eosinophil counts <250/µL.63 In 2 trials of poorly controlled asthmatics, the CRTH2 antagonist (BI671800) was also associated with small improvements in FEV1 in symptomatic patients not on controller medications (Trial 1) and those on ICS (Trial 2).64 Importantly, in a recent 12-week Phase 2a RDBPC trial of the oral CRTH2 antagonist (Qaw039) in 61 severe, uncontrolled asthmatics, CRTH2 blockade reduced eosinophils in the sputum and bronchial submucosa, and improved asthma quality of life and FEV1 vs placebo.65 While additional studies are needed, CRTH2 antagonism could be a useful adjunctive approach in severe poorly controlled asthma with evidence for eosinophilia, perhaps prior to addition of more expensive biologic approaches.

While previous studies suggest that monoclonal antibodies targeting IgE, IL-5, IL-4, and IL-13 may be effective for some severe asthmatic patients with evidence for Type 2 inflammation, approximately half of asthma patients do not have Type 2 inflammation.913 Thus, other pathways have been targets for therapy, particularly in a severe, uncontrolled population without evidence for Type 2 inflammation ("Type 2, low asthma"). However, very few targets have been identified. Although anti-TNF is highly effective in rheumatoid arthritis, studies in asthma have not consistently shown efficacy, and the efficacy to safety ratio is unacceptable, which has limited further development of drugs targeting TNF-α in severe asthma.666768

T helper 17 (Th17) cells produce 2 cytokines (IL-17A and IL-17F) which indirectly recruit neutrophils.69 One study has targeted the IL-17 receptor in severe asthma. Treatment with brodalumab, an anti-IL-17 receptor antibody (blocking receptor binding to IL-17A and IL-17 F and also IL-17E/IL-25) in 322 severe asthmatics in a RDBPC trial did not show any treatment differences compared to placebo.70 Minimal improvements in ACQ responses were seen only in a high-reversibility subgroup (post-bronchodilator FEV1 improvement >20%), but subgrouping by blood neutrophils or eosinophils did not affect outcomes.69 A follow-up Phase 2b study targeting the high-reversibility subgroup failed to show any efficacy, and the study was stopped.71

The presence of neutrophils in the airway may be important in the pathogenesis of severe asthma.72737475 CXCR2, a receptor for IL-8, a potent chemoattractant for neutrophils, has been a therapeutic target in severe asthma. In a RDBPC study, 34 severe asthmatics with sputum neutrophils >40% received SCH527123, a selective CXCR2 receptor antagonist, or placebo daily for 4 weeks.76 Despite decreases in blood and sputum neutrophils and fewer mild exacerbations, no other clinical benefits were observed.76

While macrolide antibiotics are FDA-approved for treating bacterial infections, use in treatment for asthma/severe asthma is investigational. In several chronic neutrophilic airway diseases, such as exacerbation-prone COPD, non-cystic fibrosis bronchiectasis, and bronchiolitis, treatment with low-dose macrolides, such as azithromycin and erythromycin, decreases exacerbations.777879 Macrolide treatment has also been studied in severe asthmatics with frequent exacerbations. In a RDBPC trial of 109 exacerbation-prone severe asthmatics but with low evidence for Type 2 inflammation on the basis of low FeNO, daily azithromycin was added to combination ICS/LABA for 6 months.80 The rate of severe exacerbations and lower respiratory tract infections requiring antibiotic treatment was not different between the azithromycin and placebo groups. However, when subanalyzed in a post hoc analysis, the severe asthma subgroup with the least evidence for any Type 2 inflammation (no/low eosinophils and low FeNO) had a lower rate of exacerbations and infections compared to placebo.80 However, the small numbers and post hoc analysis make these results less robust. Until more data are available, the ERS/ATS guidelines suggest that clinicians do not use macrolide antibiotics for the treatment of severe asthma due to concerns about the development of macrolide antibiotic resistance and uncertain clinical benefits.2

Immunosuppressive agents, such as methotrexate, have been studied for their steroid-sparing ability in systemic CS-dependent asthma for many years. However, all the studies of these agents were performed before ICSs (and LABAs) became a mainstream treatment for asthma, and before any concept of phenotyping. Therefore, their applicability today remains unclear. In 31 asthmatics who required daily prednisone (mean dose=26.8 mg/day, for 4.7 years), long-term methotrexate therapy for 18-28 months enabled a prednisone dose reduction to 6.3 mg/day, and improved FEV1 and asthma symptom scores.81 In contrast, in a RDBPC 13 weeks trial of methotrexate intramuscularly weekly in 19 patients with severe CS-dependent asthma, no differences between methotrexate and placebo were observed.82 In a Cochrane Database review of 10 randomized trials of 185 adult CS-dependent asthmatics where methotrexate was added to usual therapy for at least 12 weeks there was a small reduction in oral CS dose favoring methotrexate but no difference in FEV1 and hepatotoxicity was seen more frequently with methotrexate.83 Based on these minimal data, the lack of more recent data in patients treated with ICS/LABA and lack of any phenotyped studies, the ERS/ATS guidelines on severe asthma do not recommend the use of methotrexate in adults with severe asthma.2 If methotrexate is used, the guidelines recommend use in specialized centers in patients who require daily OCS and that labs (including CBC with differential), liver function, creatinine), chest X-ray, and DLCO are obtained before starting therapy and upon completion.2

In an observational study of 19 patients referred for evaluation of severe CS-refractory asthma, 10 patients had inconsistent abnormalities on chest CT scan and underwent video-assisted thoracoscopic biopsies.84 Pathology of these 10 cases showed findings consistent with asthma (eosinophilia, goblet cell hyperplasia), but also showed interstitial nonnecrotizing granulomas with a high frequency (70%) of personal or family history of autoimmune-like disease, termed "asthmatic granulomatosis." Of these asthmatic granulomatosis patients treated with alternative agents, such as azathioprine, mycophenolic acid, methotrexate, or infliximab, 90% showed decreased CS requirements and improved or maintained FEV1 despite lower CS doses.84 While there are no RDBPC trials in asthmatic granulomatosis, this study was the first to suggest that some severe asthmatics may have an autoimmune form of asthma and benefit from immunosuppressive therapies not previously used in asthma treatment. Further studies are clearly needed.