An example of ventilatory limitation during cardiopulmonary exercise testing in a patient with COPD.

A 64-year-old obese gentleman attended for further evaluation of ongoing dyspnoea in the context of a previous diagnosis of moderate COPD treated with dual long-acting bronchodilators. A cardiopulmonary exercise test (CPET) was performed, which demonstrated reduced peak work and oxygen consumption with evidence of dynamic hyperinflation, abnormal gas exchange and ventilatory limitation despite cardiac reserve. The CPET clarified the physiological process underpinning the patient's dyspnoea and limiting the patient's activities. This, in turn, helped the clinician tailor the patient's management plan.

Diagnostic Potential of Oscillometry: A Population-based Approach.

Rationale: Respiratory resistance (Rrs) and reactance (Xrs) as measured by oscillometry and their intrabreath changes have emerged as sensitive parameters for detecting early pathological impairments during tidal breathing. Objectives: This study evaluates the prevalence and association of abnormal oscillometry parameters with respiratory symptoms and respiratory diseases in a general adult population. Methods: A total of 7,560 subjects in the Austrian LEAD (Lung, hEart, sociAl, boDy) Study with oscillometry measurements (computed with the Resmon Pro FULL; Restech Srl) were included in this study. The presence of respiratory symptoms and doctor-diagnosed respiratory diseases was assessed using an interview-based questionnaire. Rrs and Xrs at 5 Hz, their inspiratory and expiratory components, the area above the Xrs curve, and the presence of tidal expiratory flow limitation were analyzed. Normality ranges for oscillometry parameters were defined. Measurements and Main Results: The overall prevalence of abnormal oscillometry parameters was 20%. The incidence of abnormal oscillometry increased in the presence of symptoms or diagnoses: 17% (16-18%) versus 27% (25-29%), P < 0.0001. All abnormal oscillometry parameters except Rrs at 5 Hz were significantly associated with respiratory symptoms/diseases. Significant associations were found, even in subjects with normal spirometry, with abnormal oscillometry incidence rates increasing by 6% (4-8%; P < 0.0001) in subjects with symptoms or diagnoses. Conclusions: Abnormal oscillometry parameters are present in one-fifth of this adult population and are significantly associated with respiratory symptoms and disease. Our findings underscore the potential of oscillometry as a tool for detecting and evaluating respiratory impairments, even in individuals with normal spirometry.

Bronchodilator response does not associate with asthma control or symptom burden among patients with poorly controlled asthma.

PURPOSE: The purpose of this study was to determine how four different definitions of bronchodilator response (BDR) relate to asthma control and asthma symptom burden in a large population of participants with poorly controlled asthma. PROCEDURES: We examined the baseline change in FEV1 and FVC in response to albuterol among 931 participants with poorly controlled asthma pooled from three clinical trials conducted by the American Lung Association - Airways Clinical Research Centers. We defined BDR based on four definitions and analyzed the association of each with asthma control as measured by the Asthma Control Test or Asthma Control Questionnaire, and asthma symptom burden as measured by the Asthma Symptom Utility Index. MAIN FINDINGS: A BDR was seen in 31-42% of all participants, depending on the definition used. There was good agreement among responses (kappa coefficient 0.73 to 0.87), but only 56% of participants met all four definitions for BDR. A BDR was more common in men than women, in Blacks compared to Whites, in non-smokers compared to smokers, and in non-obese compared to obese participants. Among those with poorly controlled asthma, 35% had a BDR compared to 25% of those with well controlled asthma, and among those with a high symptom burden, 34% had a BDR compared to 28% of those with a low symptom burden. After adjusting for age, sex, height, race, obesity and baseline lung function, none of the four definitions was associated with asthma control or symptom burden. CONCLUSION: A BDR is not associated with asthma control or symptoms in people with poorly controlled asthma, regardless of the definition of BDR used. These findings question the clinical utility of a BDR in assessing asthma control and symptoms.

European Respiratory Society/American Thoracic Society technical statement: standardisation of the measurement of lung volumes, 2023 update.

This document updates the 2005 European Respiratory Society (ERS) and American Thoracic Society (ATS) technical standard for the measurement of lung volumes. The 2005 document integrated the recommendations of an ATS/ERS task force with those from an earlier National Heart, Lung, and Blood Institute workshop that led to the publication of background papers between 1995 and 1999 and a consensus workshop report with more in-depth descriptions and discussion. Advancements in hardware and software, new research and emerging approaches have necessitated an update to the 2005 technical standard to guide laboratory directors, physiologists, operators, pulmonologists and manufacturers. Key updates include standardisation of linked spirometry, new equipment quality control and validation recommendations, generalisation of the multiple breath washout concept beyond nitrogen, a new acceptability and grading system with addition of example tracings, and a brief review of imaging and other new techniques to measure lung volumes. Future directions and key research questions are also noted.

Circulating MicroRNAs associated with Bronchodilator Response in Childhood Asthma.

Rationale: Bronchodilator response (BDR) is a measure of improvement in airway smooth muscle tone, inhibition of liquid accumulation and mucus section into the lumen in response to short-acting beta-2 agonists that varies among asthmatic patients. MicroRNAs (miRNAs) are well-known post-translational regulators. Identifying miRNAs associated with BDR could lead to a better understanding of the underlying complex pathophysiology. Objective: The purpose of this study is to identify circulating miRNAs associated with bronchodilator response in asthma and decipher possible mechanism of bronchodilator response variation. Methods: We used available small RNA sequencing on blood serum from 1,134 asthmatic children aged 6 to 14 years who participated in the Genetics of Asthma in Costa Rica Study (GACRS). We filtered the participants into high and low bronchodilator response (BDR) quartiles and used DeSeq2 to identify miRNAs with differential expression (DE) in high (N= 277) vs low (N= 278) BDR group. Replication was carried out in the Leukotriene modifier Or Corticosteroids or Corticosteroid-Salmeterol trial (LOCCS), an adult asthma cohort. The putative target genes of DE miRNAs were identified, and pathway enrichment analysis was performed. Results: We identified 10 down-regulated miRNAs having odds ratios (OR) between 0.37 and 0.76 for a doubling of miRNA counts and one up-regulated miRNA (OR=2.26) between high and low BDR group. These were assessed for replication in the LOCCS cohort, where two miRNAs (miR-200b-3p and miR-1246) were associated. Further, functional annotation of 11 DE miRNAs were performed as well as of two replicated miRs. Target genes of these miRs were enriched in regulation of cholesterol biosynthesis by SREBPs, ESR-mediated signaling, G1/S transition, RHO GTPase cycle, and signaling by TGFB family pathways. Conclusion: MiRNAs miR-1246 and miR-200b-3p are associated with both childhood and adult asthma BDR. Our findings add to the growing body of evidence that miRNAs play a significant role in the difference of asthma treatment response among patients as it points to genomic regulatory machinery underlying difference in bronchodilator response among patients. Trial registration: LOCCS cohort [ClinicalTrials.gov number: NCT00156819], GACRS cohort [ClinicalTrials.gov number: NCT00021840].

Asthma Prevalence and Phenotyping in the General Population: The LEAD (Lung, hEart, sociAl, boDy) Study.

Background: Asthma is a chronic heterogeneous respiratory disease involving differential pathophysiological pathways and consequently distinct asthma phenotypes. Objective and Methods: In the LEAD Study, a general population cohort (n=11.423) in Vienna ranging from 6-82 years of age, we addressed the prevalence of asthma and explored inflammatory asthma phenotypes that included allergic and non-allergic asthma, and within these phenotypes, an eosinophilic (eosinophils ≥300 cells/µL, or ≥150 cells/µL in the presence of ICS medication) or non-eosinophilic (eosinophils <300 cells/µL, or <150 cells/µL in the presence of ICS) phenotype. In addition, we compared various factors related to biomarkers, body composition, lung function, and symptoms in control subjects versus subjects with current asthma (current doctor's diagnosis of asthma). Results: An overall prevalence of 4.6% was observed for current asthma. Furthermore, an age-dependent shift from allergic to non-allergic asthma was found. The non-eosinophilic phenotype was more prominent. Obesity was a prevalent condition, and body composition including visceral adipose tissue (VAT), is affected in current asthma versus controls. Conclusion: This broad-aged and large general population cohort identified differential patterns of inflammatory asthma phenotypes that were age-dependent. The presence of eosinophilia was associated with worse asthma control, increased asthma medication, increased VAT, and lower lung function, the opposite was found for the presence of an allergic asthma.

Validation of the clinical utility of sGaw as a response variable in methacholine challenge testing.

BACKGROUND AND OBJECTIVE: Airway hyperresponsiveness (AHR) is commonly assessed by a methacholine challenge test (MCT), during which a provocative concentration causing a 20% reduction in forced expiratory volume in 1 second (FEV1 ) (PC20 ) < 8 mg/ml is considered a positive response. However, a fall in specific airway conductance (sGaw) may also have clinical significance. The purpose of this study was to assess whether AHR determined by a provocative concentration causing a 40% reduction in sGaw (PC40 ) < 8 mg/ml corresponds to a clinical diagnosis of asthma. METHODS: We analysed the changes in spirometry, lung volumes and sGaw during MCT in 211 randomly selected patients being evaluated for AHR to support a clinical diagnosis of asthma. RESULTS: The mean (SD) age of the group was 53 (15) years, with 141 women (67%). Overall lung function was normal, with FEV1  = 92 (15) % predicted, total lung capacity = 97 (13) % predicted and sGaw = 0.19 (0.15-0.23) L/s/cm H2 O/L, (median, 25-75 IQR). There were many more patients who responded by PC40 only (n = 120) than who responded by PC20 (n = 52). There was no significant difference in asthma diagnosis between the PC20 (98%) and PC40 (93%) groups, and we estimate 34% of patients with a diagnosis of asthma would have been classified as having no AHR if only the FEV1 criterion was used. CONCLUSION: Changes in sGaw during MCT indicate clinically significant AHR in support of a clinical diagnosis of asthma among patients being evaluated for asthma.

The Physiology of Asthma-Chronic Obstructive Pulmonary Disease Overlap.

Asthma and chronic obstructive pulmonary disease (COPD) are both characterized by airway obstruction and share similar clinical manifestations. However, they differ in many respects related to underlying cause, mechanism of airway obstruction, pattern and progression of symptoms, and response to therapy. It remains unclear whether there is a unique physiologic phenotype that characterizes asthma-COPD overlap (ACO). This review describes the common and distinct physiologic tests that help define asthma and COPD and potentially how they may contribute to understanding the underlying physiology of ACO.

Clinical significance and applications of oscillometry.

Recently, "Technical standards for respiratory oscillometry" was published, which reviewed the physiological basis of oscillometric measures and detailed the technical factors related to equipment and test performance, quality assurance and reporting of results. Here we present a review of the clinical significance and applications of oscillometry. We briefly review the physiological principles of oscillometry and the basics of oscillometry interpretation, and then describe what is currently known about oscillometry in its role as a sensitive measure of airway resistance, bronchodilator responsiveness and bronchial challenge testing, and response to medical therapy, particularly in asthma and COPD. The technique may have unique advantages in situations where spirometry and other lung function tests are not suitable, such as in infants, neuromuscular disease, sleep apnoea and critical care. Other potential applications include detection of bronchiolitis obliterans, vocal cord dysfunction and the effects of environmental exposures. However, despite great promise as a useful clinical tool, we identify a number of areas in which more evidence of clinical utility is needed before oscillometry becomes routinely used for diagnosing or monitoring respiratory disease.

Effects of Reduced Nicotine Content Cigarettes on Fractional Exhaled Nitric Oxide and Self-Reported Respiratory Health Outcomes Among Smokers With Psychiatric Conditions or Socioeconomic Disadvantage.

INTRODUCTION: This study examined whether exposure to reduced-nicotine-content cigarettes (RNCCs) for 12 weeks alters respiratory health using Fractional Exhaled Nitric Oxide (FeNO), a validated biomarker of respiratory epithelial health, and the Respiratory Health Questionnaire (RHQ), a subject-rated questionnaire on respiratory symptoms. Participants were 747 adult daily smokers enrolled in three double-blind, randomized clinical trials evaluating effects of cigarette nicotine content (0.4, 2.4, 15.8 mg nicotine/g tobacco) in people with affective disorders, opioid use disorder (OUD), or socioeconomic disadvantage. AIMS AND METHODS: FeNO levels and RHQ ratings were collected at baseline and Weeks 6 and 12 following randomization. Multiple regression was used to assess associations of FeNO and RHQ with smoking characteristics. Mixed-model repeated-measures ANOVA was used to evaluate the effects of nicotine content on FeNO and RHQ outcomes over the 12-week study period. RESULTS: FeNO levels but not RHQ ratings varied inversely with smoking characteristics at baseline (Ps < 0.0001) in smokers with affective disorders and socioeconomic disadvantage but less so in those with OUD. Participants with affective disorders and socioeconomic disadvantage, but not those with OUD, who were assigned to RNCCs had higher FeNO levels at Week 12 than those assigned to the 15.8 mg/g dose [F(2,423) = 4.51, p = .01, Cohen's d = 0.21]. No significant dose-related changes in RHQ scores were identified. CONCLUSIONS: Use of RNCCs across a 12-week period attenuates smoking-related reductions in FeNO levels in smokers with affective disorders and socioeconomic disadvantage although not those with OUD. FeNO changes were not accompanied by changes in respiratory-health ratings. TRIAL REGISTRATION: Inclusion and exclusion criteria for the sample and experimental manipulation of the nicotine content of assigned cigarettes are registered: NCT02232737, NCT02250664, NCT02250534. The FeNO measure reported in this manuscript is an exploratory outcome that was not registered. IMPLICATIONS: Should a reduced nicotine content standard be implemented; these results suggest that reduced nicotine content in cigarettes will not exacerbate and instead may attenuate smoking-related decreases in FeNO. This is significant as NO is an important component in maintaining a healthy respiratory system and necessary to defend against infection. Furthermore, the results of the current study demonstrate that the adoption of the reduced nicotine content standard may result in beneficial impacts on respiratory epithelial health among vulnerable populations that are disproportionally affected by the adverse health outcomes precipitated by combustible tobacco use.

Relationships among pulmonary function, anxiety and depression in mild asthma: An exploratory study.

In a secondary analysis of data from a prior study, we calculated the relationships among depression (PHQ-8), anxiety (GAD-7), and measures of asthma in 69 steroid-naïve patients with mild and moderate symptomatic asthma. Average levels of pulmonary function, depression and anxiety tended to be in the normal range, and asthma tended to be well controlled (Asthma Control Test). Nevertheless, PHQ-8 scores were significantly correlated with forced oscillation (FO) measures of airway reactance (AX) and resistance at a low frequency of stimulation (Rrs5 Hz). GAD-7 scores also were significantly related to Rrs5 Hz. Exploratory analyses in Supplementary data provide no evidence for vagal mediation of the association. Further research is necessary to discover mechanisms for the associations found here. Future studies might examine the utility of assessing and treating mild anxiety and depression in mild to moderate asthma.

Exercise-induced Bronchodilation Equalizes Exercise Ventilatory Mechanics despite Variable Baseline Airway Function in Asthma.

PURPOSE: We quantified the magnitude of exercise-induced bronchodilation in adult asthmatics under conditions of narrowed and dilated airways. We then assessed the effect of the bronchodilation on ventilatory capacity and the extent of ventilatory limitation during exercise. METHODS: Eleven asthmatics completed three exercise bouts on a cycle ergometer. Exercise was preceded by no treatment (trialCON), inhaled ß2 agonist (trialBD), or a eucapnic voluntary hyperpnea challenge (trialBC). Maximal expiratory flow-volume maneuvers (MEFV) were performed before and within 40 s of exercise cessation. Exercise tidal flow-volume loops were placed within the preexercise and postexercise MEFV curve and used to determine expiratory flow limitation and maximum ventilatory capacity (V˙ECap). RESULTS: Preexercise airway function was different among the trials (forced expiratory volume 1 s during trialCON, trialBD, and trialBC = 3.3 ± 0.8 L, 3.8 ± 0.8 L, and 2.9 ± 0.8 L, respectively; P < 0.05). Maximal expired airflow increased with exercise during all three trials, but the increase was greatest during trialBC (delta forced expiratory volume 1 s during trialCON, trialBD, and trialBC = +12.2% ± 13.1%, +5.2% ± 5.7%, +28.1% ± 15.7%). Thus, the extent of expiratory flow limitation decreased, and V˙ECap increased, when the postexercise MEFV curve was used. During trialCON and trialBC, actual exercise ventilation exceeded V˙ECap calculated with the preexercise MEFV curve in seven and nine subjects, respectively. CONCLUSIONS: These findings demonstrate the critical importance of exercise bronchodilation in the asthmatic with narrowed airways. Of clinical relevance, the results also highlight the importance of assessing airway function during or immediately after exercise in asthmatic persons; otherwise, mechanical limitations to exercise ventilation will be overestimated.

Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2.

BACKGROUND: Interleukin-1-dependent increases in glycolysis promote allergic airways disease in mice and disruption of pyruvate kinase M2 (PKM2) activity is critical herein. Glutathione-S-transferase P (GSTP) has been implicated in asthma pathogenesis and regulates the oxidation state of proteins via S-glutathionylation. We addressed whether GSTP-dependent S-glutathionylation promotes allergic airways disease by promoting glycolytic reprogramming and whether it involves the disruption of PKM2. METHODS: We used house dust mite (HDM) or interleukin-1ß in C57BL6/NJ WT or mice that lack GSTP. Airway basal cells were stimulated with interleukin-1ß and the selective GSTP inhibitor, TLK199. GSTP and PKM2 were evaluated in sputum samples of asthmatics and healthy controls and incorporated analysis of the U-BIOPRED severe asthma cohort database. RESULTS: Ablation of Gstp decreased total S-glutathionylation and attenuated HDM-induced allergic airways disease and interleukin-1ß-mediated inflammation. Gstp deletion or inhibition by TLK199 decreased the interleukin-1ß-stimulated secretion of pro-inflammatory mediators and lactate by epithelial cells. 13C-glucose metabolomics showed decreased glycolysis flux at the pyruvate kinase step in response to TLK199. GSTP and PKM2 levels were increased in BAL of HDM-exposed mice as well as in sputum of asthmatics compared to controls. Sputum proteomics and transcriptomics revealed strong correlations between GSTP, PKM2, and the glycolysis pathway in asthma. CONCLUSIONS: GSTP contributes to the pathogenesis of allergic airways disease in association with enhanced glycolysis and oxidative disruption of PKM2. Our findings also suggest a PKM2-GSTP-glycolysis signature in asthma that is associated with severe disease.

Spirometric Response to Bronchodilator and Eucapnic Voluntary Hyperpnea in Adults With Asthma.

BACKGROUND: The spirometric response to fast-acting bronchodilator is used clinically to diagnose asthma and in clinical research to verify its presence. However, bronchodilator responsiveness does not correlate with airway hyper-responsiveness measured with the direct-acting stimulus of methacholine, demonstrating that bronchodilator responsiveness is a problematic method for diagnosing asthma. The relationship between bronchodilator responsiveness and airway hyper-responsiveness assessed with indirect-acting stimuli is not known. METHODS: Retrospectively, the spirometric responses to inhaled bronchodilator and a eucapnic voluntary hyperpnea challenge (EVH) were compared in 39 non-smoking adult subjects with asthma (26 male, 13 female; mean ± SD age 26.9 ± 7.8 y; mean ± SD body mass index 26.3 ± 4.7 kg/m2). All subjects met one or both of 2 criteria: ≥ 12% and 200 mL increase in FEV1 after inhaled bronchodilator, and ≥ 10% decrease in FEV1 after an EVH challenge. RESULTS: Overall, FEV1 increased by 9.9 ± 7.9% after bronchodilator (3.93 ± 0.97 to 4.28 ± 0.91 L, P < .001) and decreased by 23.9 ± 15.0% after the EVH challenge (3.89 ± 0.89 to 2.96 ± 0.88 L, P < .001). However, the change in FEV1 after bronchodilator did not correlate with the change after EVH challenge (r = 0.062, P = .71). Significant bronchodilator responsiveness predicted a positive response to EVH challenge in 9 of 33 subjects (sensitivity 27%). Following EVH, the change in FEV1 strongly correlated with the change in FVC (FEV1 percent change vs FVC percent change, r = 0.831, P < .001; FEV1 ΔL vs FVC ΔL, r = 0.799, P < .001). CONCLUSIONS: These results extend previous findings that demonstrate a lack of association between bronchodilator responsiveness and methacholine responsiveness. Given the poor concordance between the spirometric response to fast-acting bronchodilator and the EVH challenge, these findings suggest that the airway response to inhaled ß2-agonist must be interpreted with caution and in the context of its determinants and limitations.

Dysregulation of Pyruvate Kinase M2 Promotes Inflammation in a Mouse Model of Obese Allergic Asthma.

Obesity is a risk factor for the development of asthma and represents a difficult-to-treat disease phenotype. Aerobic glycolysis is emerging as a key feature of asthma, and changes in glucose metabolism are linked to leukocyte activation and adaptation to oxidative stress. Dysregulation of PKM2 (pyruvate kinase M2), the enzyme that catalyzes the last step of glycolysis, contributes to house dust mite (HDM)-induced airway inflammation and remodeling in lean mice. It remains unclear whether glycolytic reprogramming and dysregulation of PKM2 also contribute to obese asthma. The goal of the present study was to elucidate the functional role of PKM2 in a murine model of obese allergic asthma. We evaluated the small molecule activator of PKM2, TEPP46, and assessed the role of PKM2 using conditional ablation of the Pkm2 allele from airway epithelial cells. In obese C57BL/6NJ mice, parameters indicative of glycolytic reprogramming remained unchanged in the absence of stimulation with HDM. Obese mice that were subjected to HDM showed evidence of glycolytic reprogramming, and treatment with TEPP46 diminished airway inflammation, whereas parameters of airway remodeling were unaffected. Epithelial ablation of Pkm2 decreased central airway resistance in both lean and obese allergic mice in addition to decreasing inflammatory cytokines in the lung tissue. Lastly, we highlight a novel role for PKM2 in the regulation of glutathione-dependent protein oxidation in the lung tissue of obese allergic mice via a putative IFN-γ-glutaredoxin1 pathway. Overall, targeting metabolism and protein oxidation may be a novel treatment strategy for obese allergic asthma.

Glutaredoxin deficiency promotes activation of the transforming growth factor beta pathway in airway epithelial cells, in association with fibrotic airway remodeling.

S-glutathionylation of reactive protein cysteines is a post-translational event that plays a critical role in transducing signals from oxidants into biological responses. S-glutathionylation can be reversed by the deglutathionylating enzyme glutaredoxin (GLRX). We have previously demonstrated that ablation of Glrx sensitizes mice to the development of parenchymal lung fibrosis(1). It remains unclear whether GLRX also controls airway fibrosis, a clinical feature relevant to asthma and chronic obstructive pulmonary disease, and whether GLRX controls the biology of airway epithelial cells, which have been implicated in the pathophysiology of these diseases. In the present study we utilized a house dust mite (HDM) model of allergic airway disease in wild type (WT) and Glrx-/- mice on a C57BL/6 background prone to develop airway fibrosis, and tracheal basal stem cells derived from WT mice, global Glrx-/- mice, or bi-transgenic mice allowing conditional ablation of the Glrx gene. Herein we show that absence of Glrx led to enhanced HDM-induced collagen deposition, elevated levels of transforming growth factor beta 1 (TGFB1) in the bronchoalveolar lavage, and resulted in increases in airway hyperresponsiveness. Airway epithelial cells isolated from Glrx-/- mice or following conditional ablation of Glrx showed spontaneous increases in secretion of TGFB1. Glrx-/- basal cells also showed spontaneous TGFB pathway activation, in association with increased expression of mesenchymal genes, including collagen 1a1 and fibronectin. Overall, these findings suggest that GLRX regulates airway fibrosis via a mechanism(s) that involve the plasticity of basal cells, the stem cells of the airways.

Biomarkers of Type 2 Airway Inflammation as Predictors of Loss of Asthma Control During Step-Down Therapy for Well-Controlled Disease: The Long-Acting Beta-Agonist Step-Down Study (LASST).

BACKGROUND: Biomarkers that can predict loss of asthma control among patients being considered for step-down therapy in well-controlled disease are lacking. OBJECTIVE: To evaluate whether baseline biomarkers of type 2 airway inflammation and/or serial measurement of fractional exhaled nitric oxide (Feno) predict loss of asthma control as therapy is stepped down. METHODS: In subanalyses of a multicenter randomized, double-blind, parallel 3-arm trial comparing strategies for step-down therapy in well-controlled asthma (Long-Acting Beta-Agonist Step-Down Study), we assessed whether baseline atopy as determined by serum aeroallergen allergy screening test (Phadiatop), baseline serum eosinophil peroxidase, or baseline or serial Feno measurements during follow-up predicted the time to loss of asthma control among participants. Loss of asthma control was defined in the study protocol. We analyzed these associations in adjusted models including all participants, after testing for interactions with assignment to each of the 3 treatment groups (continuation of stable dose of combination inhaled corticosteroid-long-acting beta-agonist, step-down of inhaled corticosteroid, or discontinuation of long-acting bronchodilator). RESULTS: Four hundred forty-seven of the 553 Long-Acting Beta-Agonist Step-Down Study participants who were randomized to 1 of 3 treatment arms and had at least 1 biomarker measurement were included in this analysis. At baseline, higher levels of Feno were significantly associated with greater levels of multiallergen IgE levels (P < .001), but not with serum eosinophil peroxidase (P = .742). Among all participants as a group, elevations in baseline biomarkers were not predictive of a higher risk of treatment failure. In addition, Feno levels measured serially at 6-week intervals demonstrated that compared with participants with low levels (<25 parts per billion), those with intermediate (25-50 parts per billion) and high (>50 parts per billion) levels did not have significantly increased likelihood of subsequent treatment failure (hazard ratios, 1.03 [95% CI, 0.59-1.78] and 1.29 [95% CI, 0.65-2.54], respectively). There were no significant interactions of treatment group and baseline biomarkers. CONCLUSIONS: In patients with well-controlled asthma, neither baseline levels of type 2 airway inflammatory biomarkers nor serial measures of Feno are strong predictors of treatment failure.