COLUMBA: Long-term safety and durability of mepolizumab response in patients with severe eosinophilic asthma Study design and treatment

Background: Recently, it has been shown that increasing body mass index (BMI) in asthma is associated with reduced exhaled NO. Our objective in this study was to determine if the BMIrelated changes in exhaled NO differ across asthmatics and controls, and to determine if these changes are related to increased airway oxidative stress and systemic levels of leptin and adiponectin.

Rationale: Increasing body mass index (BMI) has been associated with less fractional exhaled nitric oxide (FE NO ). This may be explained by an increase in the concentration of asymmetric dimethyl arginine (ADMA) relative to L-arginine, which can lead to greater nitric oxide synthase uncoupling. Objectives: To compare this mechanism across age of asthma onset groups and determine its association with asthma morbidity and lung function. The log of plasma L-arginine/ADMA was inversely correlated with BMI in the late-(r ¼ 20.4, P ¼ 0.0006) in contrast to the early-onset phenotype (r ¼ 20.2, P ¼ 0.07). Although FE NO was inversely associated with BMI in the late-onset phenotype (P ¼ 0.02), the relationship was lost after adjusting for L-arginine/ADMA. Also in this phenotype, a reduced L-arginine/ADMA was associated with less IgE, increased respiratory symptoms, lower lung volumes, and worse asthma quality of life. Conclusions: In late-onset asthma phenotype, plasma ratios of L-arginine to ADMA may explain the inverse relationship of BMI to FE NO . In addition, these lower L-arginine/ADMA ratios are associated with reduced lung function and increased respiratory symptom frequency, suggesting a role in the pathobiology of the late-onset phenotype.Keywords: asthma; obesity; age of asthma onset; ADMA; arginine The extent to which obesity affects the health of people with asthma, and by what mechanisms, remains largely undetermined. Although adiposity imposes an important load on the respiratory system, beyond worsening dyspnea, there is little evidence that obesity affects asthma by increasing traditional biomarkers of airway inflammation or bronchial hyperresponsiveness. In fact, increasing body mass index (BMI) has been paradoxically associated with reduced levels of fractional exhaled nitric oxide (FE NO ) and sputum eosinophils (1-4). In addition, cluster analyses identify obesity as part of a phenotype characterized by less atopy and adult-onset asthma, with additional analyses suggesting obesity may be causally related to asthma among those with adult-onset asthma with less atopy (5, 6). In contrast, in those with childhood-onset more atopic asthma, the asthma appears to be causative for the weight gain (7). This difference in relationship among early-and late-onset asthma was conditionally confirmed in a study of obese subjects with asthma undergoing bariatric surgery (8). Loss of body weight improved respiratory Author Contributions: Contributed to manuscript preparation and design: F.H., S.S.K., S.C.E., S.E.W. Analyzed samples: S.C.E., R.W.P., S.L.H., S.A.A.C. Contributed with participant recruitment/sample: S.S.K., E.R.B., W.W.B., W.J.C., M.C., A.M.F., B.G., E.I., N.N.J., W.C.M., S.P.P., W.G.T., K.F.C., S.C.E., S.E.W.Correspondence and requests for reprints should be addressed to Fernando Holguin, M.D., M.P.H., Asthma Institute, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, MUH 628, 3459 Fifth Avenue, Pittsburgh, PA 15213. E-mail: holguinf@upmc.edu This article has an on...

Rationale: As the sole nitrogen donor in nitric oxide (NO) synthesis and key intermediate in the urea cycle, arginine and its metabolic pathways are integrally linked to cellular respiration, metabolism, and inflammation. Objectives: We hypothesized that arginine (Arg) bioavailability would be associated with airflow abnormalities and inflammation in subjects with asthma, and would be informative for asthma severity. Methods: Arg bioavailability was assessed in subjects with severe and nonsevere asthma and healthy control subjects by determination of plasma Arg relative to its metabolic products, ornithine and citrulline, and relative to methylarginine inhibitors of NO synthases, and by serum arginase activity. Inflammatory parameters, including fraction of exhaled NO (FE NO ), IgE, skin test positivity to allergens, bronchoalveolar lavage, and blood eosinophils, were also evaluated. Measurements and Main Results: Subjects with asthma had greater Arg bioavailability, but also increased Arg catabolism compared with healthy control subjects, as evidenced by higher levels of FE NO and serum arginase activity. However, Arg bioavailability was positively associated with FE NO only in healthy control subjects; Arg bioavailability was unrelated to FE NO or other inflammatory parameters in severe or nonsevere asthma. Inflammatory parameters were related to airflow obstruction and reactivity in nonsevere asthma, but not in severe asthma. Conversely, Arg bioavailability was related to airflow obstruction in severe asthma, but not in nonsevere asthma. Modeling confirmed that measures of Arg bioavailabilty predict airflow obstruction only in severe asthma. Conclusions: Unlike FE NO , Arg bioavailability is not a surrogate measure of inflammation; however, Arg bioavailability is strongly associated with airflow abnormalities in severe asthma.

Bronchial thermoplasty is an endoscopic therapy for severe asthma. The previously reported, randomised sham-controlled AIR2 (Asthma Intervention Research 2) trial showed a significant reduction in severe asthma exacerbations, emergency department visits and hospitalisations after bronchial thermoplasty. More “real-world” clinical outcome data is needed.This article compares outcomes in bronchial thermoplasty subjects with 3 years of follow-up from the ongoing, post-market PAS2 (Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma) study with those from the AIR2 trial.279 subjects were treated with bronchial thermoplasty in the PAS2 study. We compared the first 190 PAS2 subjects with the 190 bronchial thermoplasty-treated subjects in the AIR2 trial at 3 years of follow-up. The PAS2 subjects were older (mean age 45.9 versus 40.7 years) and more obese (mean body mass index 32.5 versus 29.3 kg·m−2) and took higher doses of inhaled corticosteroids (mean dose 2301 versus 1961 μg·day−1). More PAS2 subjects had experienced severe exacerbations (74% versus 52%) and hospitalisations (15.3% versus 4.2%) in the 12 months prior to bronchial thermoplasty. At year 3 after bronchial thermoplasty, the percentage of PAS2 subjects with severe exacerbations, emergency department visits and hospitalisations significantly decreased by 45%, 55% and 40%, respectively, echoing the AIR2 results.The PAS2 study demonstrates similar improvements in asthma control after bronchial thermoplasty compared with the AIR2 trial despite enrolling subjects who may have had poorer asthma control.

Background: Although airway infl ammation plays a major role in the pathophysiology of asthma, quantitative markers of airway infl ammation are limited in clinical practice.Objective: To determine if the levels of noninvasive markers of eosinophil-catalyzed oxidation, lipid peroxidation, and nitric oxide (NO) production are associated with asthma.Methods: Participants were enrolled from academic medical centers participating in the Severe Asthma Research Program. Clinical characteristics, laboratory data, pulmonary function tests, and the levels of the following noninvasive markers were obtained: urinary bromotyrosine (BrTyr), a marker of eosinophil-catalyzed oxidation, urinary F 2 -isoprostanes (F 2 -IsoPs), markers of lipid peroxidation, and exhaled NO, a marker of airway infl ammation.Results: Fifty-seven asthmatic participants and 38 healthy participants were enrolled. BrTyr, F 2 -IsoPs, and exhaled NO were each signifi cantly increased in asthmatic participants versus controls ( p < 0.01). An elevated level (greater than the median) of any marker was associated with a signifi cant 3-to 6-fold greater odds of having asthma. Participants with two or more elevated marker levels showed an 18-fold greater odds of having asthma. Relationships were also noted with airfl ow obstruction and bronchodilator response. Conclusion:The fi ndings from this pilot study indicate that urinary levels of BrTyr and F 2 -IsoPs, in addition to exhaled NO levels, are associated with asthma.

Background: The fractional exhaled nitric oxide (FE NO ) test is a point-of-care test that is used in the assessment of asthma.Objective: To provide evidence-based clinical guidance on whether FE NO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered.Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FE NO . The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidencebased answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations.Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FE NO -based care. In patients with asthma in whom treatment is being considered, we suggest that FE NO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice.Conclusions: Clinicians should consider this recommendation to measure FE NO in patients with asthma in whom treatment is being considered based on current best available evidence.

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