Baseline Fractional Exhaled Nitric Oxide Research Articles

Blood eosinophil count and FeNO to predict benralizumab effectiveness in real-life severe asthma patients

Objective Benralizumab is a promising drug for severe uncontrolled asthma. This study aimed to clarify the effectiveness of benralizumab in a real-life setting. Methods Subjects included 24 patients with severe type 2 asthma who received benralizumab between April 2018 and July 2019. Changes in parameters, exacerbation frequency, and oral corticosteroid (OCS) use after 4 and 24 weeks of administration were examined. The parameters included the Global Evaluation of Treatment Effectiveness (GETE) scale, Asthma Control Questionnaire (ACQ), Asthma Control Test (ACT), blood eosinophils, fractional exhaled nitric oxide (FeNO), and spirometry. The response to treatment was defined as follows: for patients with exacerbations or OCS use before treatment initiation, a reduction of ≥50% in exacerbation frequency or OCS use; and for patients without exacerbations or OCS use, an improvement of ≥0.5 in ACQ scores and ≥3 in ACT scores, or of ≥10.38% in FEV1. Results Twenty-one patients completed the treatment for 24 weeks. Excellent and good GETE scales and ACQ and ACT improvement were found in 67% of the patients at 4 weeks, and the effect continued until 24 weeks. The patients’ rate with exacerbations was significantly reduced compared to the previous 24 weeks before administration. In 17 patients receiving OCS, the use could be reduced or quit in 14 patients. Overall, 16 patients (76.2%) met the responder definition and could be predicted by the baseline eosinophil count and FeNO levels with the best cutoff values of 100/μL and 40 ppb, respectively. Conclusions Blood eosinophil and FeNO could predict benralizumab effectiveness.

Baseline FeNO as a prognostic biomarker for subsequent severe asthma exacerbations in patients with uncontrolled, moderate-to-severe asthma receiving placebo in the LIBERTY ASTHMA QUEST study: a post-hoc analysis

Fractional exhaled nitric oxide (FeNO) has potential as a prognostic biomarker in asthma, but its prognostic value among other recognised indicators is unclear. We assessed the added prognostic value of baseline FeNO to blood eosinophil count and prior severe asthma exacerbations for subsequent exacerbations. In this post-hoc analysis of the 52-week, double-blind, phase 3 LIBERTY ASTHMA QUEST study, we identified 620 patients with moderate-to-severe asthma who were randomly assigned to placebo; had uncontrolled asthma with inhaled glucocorticoids plus up to two controllers; one or more exacerbations in the previous year; FEV1 percent predicted 40-80%; FEV1 reversibility of 12% or higher and 200 mL; Asthma Control Questionnaire (ACQ-5) score of 1·5 or higher; and complete data on baseline type 2 biomarkers (FeNO, eosinophils, and total IgE) with no baseline minimum requirement. Annualised severe exacerbation rate was assessed by baseline FeNO (<25 ppb, ≥25 to <50 ppb, ≥50 ppb; negative binomial model) and cross-classified by baseline blood eosinophils (<150 cells per μL, ≥150 to <300 cells per μL, ≥300 cells per μL) and prior exacerbations (one, two or more), all adjusted for baseline ACQ-5, postbronchodilator FEV1, and other clinical characteristics. Post-hoc analyses were done in the intention-to-treat population. The LIBERTY ASTHMA QUEST STUDY is registered on ClinicalTrials.gov, NCT02414854, and is complete. Patients with baseline FeNO of 50 ppb or higher (n=144) had a 1·54-times higher exacerbation rate than patients with FeNO of less than 25 ppb (n=291; relative risk 1·54 [95% CI 1·11-2·14]; p=0·0097). Patients with baseline FeNO of 25 to <50 ppb (n=185) had a 1·33-times higher exacerbation rate than patients with FeNO of less than 25 ppb (1·33 [0·99-1·78]; p=0·0572). Patients with baseline FeNO of 25 ppb or higher, a blood eosinophil count of 150 cells per μL or higher, and two or more prior exacerbations (n=157) had an exacerbation rate 3·62-times higher than patients with FeNO of less than 25 ppb, a blood eosinophil count of less than 150 cells per μL, and one prior exacerbation (n=116; 3·62 [1·67-7·81]; p=0·0011). In uncontrolled, moderate-to-severe asthma, higher baseline FeNO levels were associated with greater risk of severe asthma exacerbations, particularly in combination with elevated eosinophil count and prior exacerbations, supporting the added value of FeNO as a prognostic biomarker. Further research is needed to confirm FeNO as an independent predictor for asthma exacerbations. Sanofi and Regeneron Pharmaceuticals.

Increasing utility of FeNO as a biomarker of type-2 inflammation in severe asthma

Since the discovery that nitric oxide (NO) can be measured in the exhaled breath and that the fractional exhaled NO (FeNO) is increased in asthma, FeNO has been recognised as a biomarker of type 2 inflammation in the airways, reflecting the effect of type 2-associated cytokines, interleukin (IL)-4 and IL-13, that play an important role in bronchial hyperresponsiveness, mucus secretion and goblet cell hyperplasia, and T-helper type 2 polarisation, and also in allergic and eosinophilic inflammation. Since 2011, FeNO, which remains a convenient measurement for patients as young as 5 years, has been recommended for use in the diagnosis of eosinophilic airway inflammation as a supportive adjunct towards the diagnosis of asthma and in assessing corticosteroid responsiveness. 1 Dweik RA Sorkness RL Wenzel S et al. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med. 2010; 181: 1033-1041 Crossref PubMed Scopus (220) Google Scholar Baseline FeNO as a prognostic biomarker for subsequent severe asthma exacerbations in patients with uncontrolled, moderate-to-severe asthma receiving placebo in the LIBERTY ASTHMA QUEST study: a post-hoc analysisIn uncontrolled, moderate-to-severe asthma, higher baseline FeNO levels were associated with greater risk of severe asthma exacerbations, particularly in combination with elevated eosinophil count and prior exacerbations, supporting the added value of FeNO as a prognostic biomarker. Further research is needed to confirm FeNO as an independent predictor for asthma exacerbations. Full-Text PDF The inflammatory profile of exacerbations in patients with severe refractory eosinophilic asthma receiving mepolizumab (the MEX study): a prospective observational studyExacerbations on mepolizumab are two distinct entities, which can largely be differentiated using FeNO: non-eosinophilic events are driven by infection with a low FeNO and high C-reactive protein concentration, whereas eosinophilic exacerbations are FeNO high. The results of the MEX study challenge the routine use of oral corticosteroids for the treatment of all asthma exacerbation events on mepolizumab, as well as the switching of biological therapies for treatment failure without profiling the inflammatory phenotype of ongoing asthma exacerbations. Full-Text PDF

Long-term sublingual immunotherapy provides better effects for patients with Japanese cedar pollinosis

ObjectiveJapanese cedar pollinosis is an endemic disease affecting a large proportion of Japan's population. Five seasons have passed since sublingual immunotherapy (SLIT) for Japanese cedar pollinosis was included in the public insurance coverage in Japan. In this study, we evaluated the clinical effects of long-term SLIT for Japanese cedar pollinosis on upper respiratory symptoms primarily represented by nasal symptoms and inflammation of the respiratory tract in the 2019 season, in which considerable amount of cedar pollen was dispersed. MethodsThis study involved 95 patients who were undergoing SLIT for Japanese cedar pollinosis after the initiation at some point between 2014 and 2018, and this group of patients was compared with a control group comprising 21 patients receiving preseasonal prophylactic treatment (with a second-generation antihistaminic drug). We evaluated the patients’ nasal/eye symptoms, total nasal symptom and medication score (TNSMS), and quality of life according to relevant guidelines. In addition, the levels of peripheral blood eosinophils, serum total IgE, Japanese cedar antigen-specific IgE, Cryj1-specific IgG4, and fractional exhaled nitric oxide (FENO) were measured as objective indices. ResultsFrom the fourth season (SLIT4), nasal discharge, sneezing, nasal obstruction symptoms, and TNSMS significantly decreased compared with those in the preseasonal prophylactic treatment and SLIT1 groups. In the patients suspected to have eosinophilic airway inflammation (with a baseline FENO ≥25 ppb), the interannual variability of FENO levels significantly reduced after 5 years of treatment. ConclusionThe efficacy of SLIT was noted from the first year of treatment, even in a year when pollen profusely dispersed. Thus, long-term continuous treatment with SLIT may alleviate nasal symptoms as well as eosinophilic airway inflammation.

Association Between Bedroom Particulate Matter Filtration and Changes in Airway Pathophysiology in Children With Asthma

X Cui, Z Li, Y Teng. JAMA Pediatr . 2020;174(6):533–542 To examine whether reducing fine particles of 2.5 µm or smaller in diameter (PM2.5), a risk factor for asthma exacerbation, improves small airway physiology among children with asthma. Forty-three children with mild to moderate asthma (5–13 years old) were recruited from an outpatient clinic affiliated with Shanghai General Hospital. Data were collected from a randomized, double-blind, cross-over study, and participants had 2 intervention sessions between February 14–April 24, 2017. During the true filtration session, a portable air purifier, that …

Differences in nitric oxide airway diffusion after maximum oxygen uptake test in asthmatic and nonasthmatic elite junior cross-country skiers.

Asthma is common in cross-country skiers and is often treated with β2-agonists and inhaled corticosteroids (ICS). Exhaled nitric oxide (NO) is often used to guide ICS treatment in asthma. This study investigated the change in pulmonary NO dynamics before and after a maximum oxygen uptake (V′O2max) test.An extended NO analysis was performed among Swedish elite junior cross-country skiers (n=25), with and without declared asthma, before and after a V′O2max test using roller skis. Asthma was declared by six boys and two girls among whom five occasionally used ICSs.There were no differences in baseline NO parameters between those with and without declared asthma. The median (interquartile range) diffusion capacity over airway wall (DawNO) was 21 (17–25) mL·s−1, which is much increased for this age group. After the V′O2max test, there were statistically significant differences from the baseline fraction of exhaled NO (FENO50), NO flux from airways, DawNO and alveolar NO values; but not in the NO content in airway wall (CawNO) for all subjects together as one group. However, in the asthma group, differences were only seen in FENO50 and CawNO.Interestingly, a majority of the subjects had an increase in the DawNO. An increase in DawNO has been found with allergic asthma together with elevated CawNO. The skiers did not have elevated CawNO, which indicates an absence of inflammation in the airway wall. Modelling of lung NO production clearly shows that the asthma among our skiers is distinct from the allergic asthma in nonathletes.

BLOOD EOSINOPHIL COUNT AND FRACTIONAL EXHALED NITRIC OXIDE AS A COMBINED PREDICTOR OF TREATMENT RESPONSE TO BENRALIZUMAB FOR PATIENTS WITH SEVERE, EOSINOPHILIC ASTHMA

SESSION TITLE: Allergy and Airway Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: In a Phase IIb RCT in severe, eosinophilic asthma, benralizumab (20 mg or 100 mg every 8 weeks [with the first three doses every 4 weeks] for 1 year) reduced asthma exacerbation rate (AER) for adults with blood eosinophil counts (BEC) ≥300 cells/μL (Lancet Respir Med. 2014;2:878–90). Data suggest that fractional exhaled nitric oxide (FeNO) correlates with eosinophilic inflammation. In addition, along with BEC, FeNO may provide prognostic information for a more complete assessment of treatment response to biological medication in patients with severe asthma (Am J Respir Crit Care Med. 2019;200:1308–12). To further understand the possible additive prognostic value of FeNO, we compared treatment for subgroups of severe eosinophilic asthma patients with high and low baseline FeNO measurements. METHODS: We conducted post-hoc analyses of a treatment effect for subgroups of asthma patients with BEC ≥300 cells/μL (eosinophilic patients) receiving benralizumab (combined 20 mg and 100 mg groups) or placebo with high- (≥25 ppb) or low-FeNO (<25 ppb) measurements. Treatment effects were assessed through modelled AER and change from baseline in lung function (FEV1) for the high- and low-FeNO groups. RESULTS: Eosinophilic patients with high FeNO (n=136) had a greater median baseline BEC (536 cells/μL) compared with eosinophilic patients with low FeNO (n=114 [400 cells/μL]). Benralizumab reduced AER by 58% compared with placebo (0.30 for benralizumab vs. 0.72 for placebo, nominal p<0.0424) for eosinophilic patients with high FeNO and by 41% compared with placebo (0.36 for benralizumab vs. 0.61 for placebo, nominal p=0.1074) for eosinophilic patients with low FeNO. Eosinophilic patients with either high or low FeNO treated with benralizumab improved pre-bronchodilator FEV1 at Week 52 compared with placebo (210 mL, nominal p=0.0349; 150 mL, nominal p=0.065; respectively). CONCLUSIONS: Eosinophilic patients with high-FeNO measurements had greater baseline BEC than patients with low-FeNO measurements. Although the response in AER and FEV1 was numerically greater for eosinophilic patients with high FeNO, benralizumab reduced AER and improved lung function regardless of FeNO at baseline. CLINICAL IMPLICATIONS: Benralizumab reduced AER and improved lung function in eosinophilic patients regardless of high- or low-FeNO measurement. These post-hoc analyses suggest that FeNO may provide limited additional prognostic information for patients with severe, eosinophilic asthma. DISCLOSURES: Employee relationship with AstraZeneca Please note: >$100000 Added 03/31/2020 by Esther Garcia Gil, source=Web Response, value=Salary Employee relationship with AstraZeneca Please note: >$100000 Added 04/03/2020 by Ian Hirsch, source=Web Response, value=Salary Employee relationship with AstraZeneca Please note: $20001 - $100000 Added 04/01/2020 by Rohit Katial, source=Web Response, value=Salary Removed 04/01/2020 by Rohit Katial, source=Web Response Employee relationship with AstraZeneca Please note: >$100000 Added 04/01/2020 by Rohit Katial, source=Web Response, value=Salary Employee relationship with AsraZeneca Please note: >$100000 Added 04/08/2020 by James Kreindler, source=Web Response, value=Salary Stockholder relationship with AsraZeneca Please note: >$100000 Added 04/08/2020 by James Kreindler, source=Web Response, value=Ownership interest Employee relationship with Astrazeneca Please note: >$100000 Added 04/02/2020 by Paul Newbold, source=Web Response, value=Salary

The effects of oral corticosteroids on lung function, type-2 biomarkers and patient-reported outcomes in stable asthma: A systematic review and meta-analysis

BackgroundSeveral studies have investigated the physiological effect of OCS in stable asthma, however these have included heterogeneous populations and outcomes. This paper is the first to combine their results. MethodsWe searched Medline, Embase and Web of Science databases for studies reporting the impact of OCS on FEV1, FVC, blood eosinophils, fractional exhaled nitric oxide (FeNO), Asthma Control Questionnaire (ACQ) score or Asthma Quality Of Life Questionnaire (AQLQ) score in stable asthma. We extracted data on the correlates of OCS response. Results61 studies, comprising 1608 patients, were included. FEV1 was improved by 9% (95% CI: 7, 11). There were stronger increases in FEV1 among those with a mean baseline FEV1<60% predicted (19%, 95% CI: 13, 24). Despite these improvements, substantial residual impairment remained after treatment. Blood eosinophils were reduced by 76% (95% CI: 63, 88) with larger decreases in studies of corticosteroid-naïve patients (93%, 95% CI: 73,100). Sputum eosinophils were reduced by 89% (95% CI: 79, 98) while FeNO was decreased by 35% (95% CI: 28, 41). ACQ scores were reduced by 20% (95% CI: 11, 29). Patients with higher baseline lung function impairment, sputum eosinophils, blood eosinophils and FeNO had improved OCS response. InterpretationOCS consistently improves lung function, reduces markers of type-2 inflammation, and alleviates asthma symptoms. However, substantial residual impairment remained following treatment and mean improvements were below the minimally important clinically difference. Patients with increased markers of type-2 inflammation are more responsive to treatment, suggesting these should be used to better target OCS use.

Effect of intermittent versus daily inhalation of budesonide on pulmonary function and fractional exhaled nitric oxide in children with mild persistent asthma

To study the effect of intermittent versus daily inhalation of budesonide on pulmonary function and fractional exhaled nitric oxide (FeNO) in children with mild persistent asthma. A total of 120 children, aged 6-14 years, with mild persistent asthma who attended the hospital from January 2016 to January 2018 were enrolled. The children were divided into an intermittent inhalation group with 60 children (inhalation of budesonide 200 μg/day for 6 weeks when symptoms of asthma appeared) and a daily inhalation group with 60 children (continuous inhalation of budesonide 200 μg/day) by stratified randomization. The children were followed up at months 3, 6, 9, and 12 of treatment. The two groups were compared in terms of baseline data, changes in FeNO and pulmonary function parameters, amount of glucocorticoid used, number of asthma attacks, and asthma control. At the start of treatment, there were no significant differences in baseline data, FeNO, and pulmonary function between the two groups (P>0.05). Over the time of treatment, FeNO gradually decreased and pulmonary function parameters were gradually improved in both groups (P<0.001). Compared with the intermittent inhalation group, the daily inhalation group had a better effect in reducing FeNO and increasing the predicted percentage of forced expiratory volume in 1 second (FEV1%pred) (P<0.001). The inhalation method and treatment time had an interaction effect on FeNO and pulmonary function parameters (P<0.001). In the daily inhalation group, FeNO and lung function parameters were improved rapidly and stabilized after 3 months of treatment, while those in the intermittent inhalation group stabilized after 6 months. After 12 months of treatment, there were no significant differences in the increases in body height and body weight and the degree of disease control between the two groups (P>0.05). Compared with the daily inhalation group, the intermittent inhalation group had a significantly lower amount of budesonide inhaled (P<0.05) and a significantly higher number of asthma attacks (P<0.05). Intermittent inhalation and daily inhalation of budesonide can achieve the same level of asthma control in children with mild persistent asthma and both have no influence on the increases in body height and body weight. Daily inhalation of budesonide can produce a better efficiency in reduing FeNO and increasing FEV1%pred. Although intermittent inhalation can reduce the amount of glucocorticoid used, it may lead to a higher risk of asthma attacks.

Assessing the health impact of interventions for baker’s allergy and asthma in supermarket bakeries: a group randomised trial

To assess the impact of an intervention for baker's allergy and asthma in supermarket bakeries. A group randomised trial conducted in 31 bakeries (n = 337 bakers) that were randomly assigned to one of two intervention groups (n = 244 bakers) and a control group (n = 93 bakers). Health data collected prior to and 1-year after the intervention included information obtained from an ECRHS questionnaire; tests for atopy and serum-specific IgE to cereal flours; fractional exhaled nitric oxide (FeNO). Data from the two intervention groups were combined to form one intervention group for purposes of the statistical analysis. At 1 year of follow-up, the incidence and level of decline of work-related ocular-nasal and chest symptoms, sensitisation status and elevated FeNO (FeNO > 25ppb) was similar in both intervention and control groups. The mean FeNO difference was also similar across both groups (2.2ppb vs 1.7ppb, p = 0.86). In those with FeNO > 25ppb at baseline, the decline was greater in the intervention compared to control group (16.9ppb vs 7.7ppb, p = 0.24). Multivariate logistic regression models (adjusting for smoking, baseline sensitisation to cereal flour, baseline FeNO > 25ppb) did not demonstrate an appreciable FeNO decline (≥ 10%) in the intervention compared to control group. However, stratification by the presence of work-related ocular-nasal symptoms in bakers at baseline demonstrated a significant FeNO decline (≥ 10%) in the intervention compared to the control group (OR 3.73, CI 1.22-11.42). This study demonstrates some evidence of an intervention effect on FeNO 1 year after an intervention, particularly in bakers with work-related ocular-nasal symptoms.

Dupilumab improves lung function in patients with uncontrolled, moderate-to-severe asthma.

BackgroundDupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation. In the phase 3 LIBERTY ASTHMA QUEST trial (NCT02414854) in patients with uncontrolled, moderate-to-severe asthma, add-on dupilumab 200 mg or 300 mg every 2 weeks reduced exacerbations and improved forced expiratory volume in 1 s (FEV1) and quality of life over 52 weeks. This analysis evaluates dupilimab's effect on lung function in the overall population, and subgroups with baseline elevated type 2 inflammatory biomarkers.MethodsPatients were randomised to 52 weeks of subcutaneous dupilumab 200 mg every 2 weeks, 300 mg every 2 weeks, or matched-volume placebos. Lung function outcomes were analysed in the overall population, in patients with ≥150 eosinophils·µL−1, ≥300 eosinophils·µL−1, ≥25 ppb fractional exhaled nitric oxide (FeNO), and both ≥150 eosinophils·µL−1 and ≥25 ppb FeNO, at baseline.ResultsDupilumab treatment (200 mg and 300 mg every 2 weeks) resulted in significant improvements versus placebo after 52 weeks in pre-bronchodilator FEV1 (0.20 and 0.13 L, respectively, versus placebo) and post-bronchodilator FEV1 (0.19 and 0.13 L, respectively), forced vital capacity (FVC) (0.20 and 0.14 L, respectively), forced expiratory flow (0.19 and 0.13 L·s−1, respectively) and pre-bronchodilator FEV1/FVC ratio (1.75% and 1.61%, respectively) in the overall population (p<0.001). Difference versus placebo in post-bronchodilator FEV1 slope of change (weeks 4–52) was significant (0.04 L·year−1; p<0.05). Greater improvements were achieved in patients with elevated baseline blood eosinophil and/or FeNO levels for most outcomes.ConclusionsDupilumab improves lung function outcomes, including large and small airway measurements and fixed airway obstruction, in patients with uncontrolled, moderate-to-severe asthma; particularly in patients with elevated biomarkers of type 2 inflammation.

Elevated Exhaled Nitric Oxide in Adolescents Is Associated With Incident Allergic Symptoms: A Prospective Cohort Study

Fractional exhaled nitric oxide (FeNO) is a marker of type-2 inflammation in the airways. Elevated FeNO may precede the development of allergic disease. The aim of the present study was to investigate the association between elevated FeNO and the development of allergic symptoms. A total of 959 adolescents from the general population and their parents completed a standardized questionnaire. Lung function and FeNO were assessed at baseline. Four years later, 921 of these individuals (96%) completed the same version of the baseline questionnaire. Adolescents with self-reported incident allergic symptoms to cat (n=50) or dog (n=33) had higher baseline FeNO (P<.001) than those without allergic symptoms to cat and dog at both time points (n=776 and n=838, respectively). Adolescents with incident allergic symptoms to pollen did not have elevated baseline FeNO. The adjusted odds ratio (aOR [95%CI]) for incident allergic symptoms to cat was 4.2 (2.2-8.0) times higher if FeNO was >75th percentile (vs <75th percentile) at baseline. This was consistent after exclusion of individuals with reported asthma, wheeze, or rhinitis at baseline (8.6 [3.0-24.1]). Elevated FeNO in adolescents was associated with an increased risk of developing allergic symptoms to cat and dog allergens, but not to pollen allergens, after 4 years.

Fractional exhaled nitric oxide was not associated with the future risk of exacerbations in Chinese asthmatics: a non-interventional 1-year real-world study.

Exacerbations are recognized as the most relevant predictor of future risk in asthmatics. We aimed to evaluate the association between asthma exacerbations, fractional exhaled nitric oxide (FENO), spirometry indices, and other potential risk factors in a non-interventional, real-world study performed in Guangzhou, China. We performed a prospective 12 months follow-up of Chinese asthmatics. Spirometry and FENO measurements were performed at baseline. Adherence to inhaled corticosteroids (ICS) use was divided into two categories (>80% and <80%). Patients were seen 4 times after the initial baseline visit. A total of 222 patients with asthma (49.1% males) completed the study, of which 51 (23.0%) experienced exacerbations during the study period. Of the patients, 117 (52.7%) had good compliance. We compared lung function indices between the patients with and without exacerbations. There was no difference of forced expiratory volume in 1 s (FEV1) predicted, forced vital capacity (FVC) predicted, and FEVI/FVC (all, P>0.05) between the groups. There was also no significant difference in FENO level between the two groups. Compared to those that had exacerbations, patients without exacerbations had better treatment compliance (P<0.001). Logistic regression analysis identified an association between asthma exacerbations, poor control of symptom [odds ratio (OR) =2.295; 95% confidence interval (CI): 1.130-4.663; P=0.022], and nonadherence to asthma medications (OR =4.718; 95% CI: 2.149-10.359; P<0.001). Poor adherence rather than baseline FENO and FEV1% predicted was associated with the future risk of exacerbations in Chinese asthmatics in real world.

Phenotypes favoring fractional exhaled nitric oxide discordance vs guideline-based uncontrolled asthma

BackgroundDespite potential value of identification of allergic inflammation with fractional exhaled nitric oxide (FeNO) in managing asthma, randomized clinical trials have not consistently shown better outcomes compared with guideline management alone. ObjectiveTo assess the effectiveness of FeNO vs non–FeNO-based therapeutic algorithms in managing asthma, and the phenotypic profile associated with FeNO >35 ppb yet well controlled by guidelines, as a potential model to predict better FeNO-based algorithm outcomes. MethodsThis is a randomized controlled study (RCT) in 88 high-risk children with asthma 7 to 18 years of age across 352 visits over a 1-year period. Generalized estimating equations analysis assessed algorithm group differences in outcomes and characteristics associated with higher odds uncontrolled by FeNO alone in the treatment decision algorithm. ResultsThe FeNO treatment algorithm did not show superiority in reducing exacerbations and morbidity (P > .05). Phenotypes that more than doubled the odds FeNO alone identified uncontrolled asthma included adolescence, non-adherence, high atopy (>6+), and baseline FeNO >35 ppb, whereas obesity, FEF25-75% < 65% predicted, and bronchodilator response >10% decreased the odds. Uncontrolled asthma by FeNO alone (F) vs guidelines alone (G) showed overall F/G > 1.0 in adolescents, but <1.0 in younger patients unless the FeNO threshold was reduced to >20 ppb. ConclusionOur study suggests that age and phenotypes play a key role in FeNO discordance compared with the conventional guideline-based uncontrolled asthma. The FeNO-based therapeutic algorithm, if confirmed further, could provide the clinician with an effective asthma management tool. The clinical implication could improve future FeNO-based RCTs and treatment decision algorithms in managing asthma by considering phenotypes and age-dependent FeNO thresholds.

EFFECTS OF OMALIZUMAB ON MARKERS OF TYPE 2 INFLAMMATION: RESULTS FROM THE EXTRA STUDY

Introduction Targeting type 2 (T2) inflammation in moderate-to-severe asthma with omalizumab improves asthma control and reduces exacerbations. Whether omalizumab impacts T2 inflammatory biomarkers has not been fully elucidated. We examined the impact of omalizumab on T2 inflammatory biomarkers. Methods Post-hoc analyses of moderate-to-severe, uncontrolled allergic asthmatics (12-75 years) from the prospective, randomized, placebo-controlled trial of omalizumab, EXTRA were conducted. Changes from baseline in fractional exhaled nitric oxide (FeNO), blood eosinophils (EOS) and serum interleukin-13 (IL-13) with omalizumab versus placebo were evaluated. FeNO was measured at Weeks 4, 8, 16, 32, and 48, EOS at Weeks 16, 32 and 48, and IL-13 at Week 16. FeNO was further analyzed using dichotomized baseline subgroups with cutoff points at 25ppb or 50ppb. Results Compared with placebo, omalizumab-treated patients had larger decreases in all T2 biomarkers throughout treatment. At Week 48, median [IQR]% changes of -13.1 [-43.9, 26.6]% versus 0 [-28.9, 40]% and -11.1 [-48.5, 36.2]% versus 0.0 [-36.0, 40.0]% were observed in the omalizumab and placebo-treated groups for EOS and FeNO, respectively. FeNO reductions were observed by Week 4 and were greater in omalizumab-treated patients with higher baseline FeNO (-60.2 [-71.6, -26.8]% versus -4.6 [-34.2, 42.3]% in ≥50 versus Conclusions Omalizumab treatment reduced T2 inflammatory biomarkers. Reductions were more pronounced in patients with higher baseline levels. These findings highlight the anti-inflammatory effects of omalizumab. FeNO percent change upon omalizumab treatment by baseline levels.

Anti-inflammatory duration of action of fluticasone furoate/vilanterol trifenatate in asthma: a cross-over randomised controlled trial

BackgroundFluticasone furoate/Vilanterol trifenatate (FF/VI) is an inhaled corticosteroid/long-acting beta-agonist combination with a prolonged bronchodilator duration of action. We characterised the time-course of onset and offset of airway anti-inflammatory action of FF/VI, as assessed by fraction of exhaled nitric oxide (FeNO), and compared this to the bronchodilator duration of action.MethodsA single-centre, randomised, double-blind, placebo-controlled, two-period, crossover study was undertaken in 28 steroid-naïve adults with asthma. Participants with an FEV1 ≥ 60% predicted, reversible airway disease, and FeNO > 40 ppb received FF/VI 100/25 mcg or placebo once daily for 14 days. FeNO and peak expiratory flow were measured twice-daily during treatment and during a 21-day washout period. FEV1 was measured for five days from treatment cessation. The primary outcome measure was FeNO change from baseline ratio for 21 days following treatment cessation.ResultsIn the 27 subjects who completed the study, median (range) baseline FeNO was 87 ppb (42–212). FF/VI 100/25 mcg reduced FeNO by day 3, ratio FF/VI versus placebo 0.72 (95% confidence interval 0.61–0.86) with the maximum reduction occurring at day 14, 0.32 (0.27–0.37). Following cessation of treatment FeNO remained suppressed for 18 days, ratio on day 18 0.77 (0.59–1.00), whereas improvements in FEV1 and peak flow were maintained for 3 to 4 days post-treatment.ConclusionsThe anti-inflammatory duration of action of FF/VI is consistent with the high glucocorticoid receptor affinity and long lung retention of fluticasone furoate. The anti-inflammatory effect of FF/VI was of greater duration than its bronchodilator effect in adults with mild asthma.Funding GlaxoSmithKline (201499).Trial registrationProspectively registered on ClinicalTrials.gov registry number NCT02712047.

Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials

Tralokinumab is an anti-interleukin-13 human monoclonal antibody developed for the treatment of severe, uncontrolled asthma. These clinical trials aimed to assess the efficacy and safety of tralokinumab in this population. STRATOS 1 and STRATOS 2 were randomised, double-blind, parallel-group, placebo-controlled, phase 3 clinical trials that enrolled participants aged 12-75 years with severe asthma that was inadequately controlled despite use of inhaled corticosteroids (≥500 μg per day fluticasone or equivalent) and a long-acting β2 agonist (but not oral corticosteroids). STRATOS 1 was done at 246 sites in 14 countries, and STRATOS 2 was done at 242 sites in 13 countries. In STRATOS 1, participants were randomly assigned (2:1) to receive tralokinumab 300 mg or matching placebo subcutaneously every 2 weeks or every 4 weeks for 52 weeks. In STRATOS 2, participants were randomly assigned (1:1) to receive tralokinumab 300 mg or matching placebo subcutaneously every 2 weeks for 52 weeks. STRATOS 1 attempted to identify a biomarker-positive population with enhanced tralokinumab benefit, which was then tested in STRATOS 2. The primary endpoint was the annualised asthma exacerbation rate (AAER) reduction at week 52 in the all-comers population for STRATOS 1 and in the biomarker-positive population for STRATOS 2. All efficacy analyses for both trials were done on the full analysis set by an intention-to-treat approach. The safety analysis set comprised any participant who received the investigational drug and was categorised by treatment received. These trials are registered with ClinicalTrials.gov, numbers NCT02161757 (STRATOS 1) and NCT02194699 (STRATOS 2), and with the EU Clinical Trials Register, EudraCT 2013-005614-35 (STRATOS 1) and EudraCT 2013-005615-27 (STRATOS 2). STRATOS 1 was done between June 13, 2014, and Feb 28, 2017. 1207 participants were randomly assigned and 1202 treated as follows: tralokinumab every 2 weeks (n=398), tralokinumab every 4 weeks (n=404), or placebo (n=400). STRATOS 2 was done between Oct 30, 2014, and Sept 21, 2017. 856 participants were randomly assigned and 849 treated as follows: tralokinumab every 2 weeks (n=427) and placebo every 2 weeks (n=422). In the STRATOS 1 all-comers population, tralokinumab every 2 weeks did not significantly reduce AAER compared with placebo (7·0% reduction [95% CI -20·8 to 28·4]; rate ratio 0·93 [95% CI 0·72 to 1·21]; p=0·59). Baseline fractional exhaled nitric oxide (FENO) 37 ppb or greater was identified as the preferred biomarker in STRATOS 1; in FENO-high participants, tralokinumab every 2 weeks (n=97) reduced AAER by 44·0% (95% CI 6·0 to 66·0; rate ratio 0·56 [95% CI 0·34 to 0·94]; p=0·028) compared with placebo (n=102). In the STRATOS 2 FENO-high population, tralokinumab every 2 weeks (n=108) did not significantly improve AAER (15·8% reduction [95% CI -33·7 to 47·0]; rate ratio 0·84 [95% CI 0·53 to 1·34]; p=0·47) compared with placebo (n=121). The safety profile was consistent with that of previous tralokinumab trials. Tralokinumab reduced AAER in participants with severe asthma with baseline FENO 37 ppb or higher in STRATOS 1, but not in STRATOS 2. These inconsistent effects on AAER do not support a key role for interleukin 13 in severe asthma exacerbations. AstraZeneca.

The airway hyperresponsiveness to methacholine may be predicted by impulse oscillometry and plethysmography in children with well-controlled asthma

ABSTRACTObjective: Airway hyperresponsiveness (AHR) is a hallmark of asthma. Methacholine challenge test which is mostly used to confirm AHR is not routinely available. The aim of this study was to investigate the predictive values of fractional exhaled nitric oxide (FeNO), impulse oscillometry (IOS), and plethysmography for the assessment of AHR in children with well-controlled asthma. Methods: 60 children with controlled allergic asthma aged 6–18 years participated in the study. FeNO measurement, spirometry, IOS, and plethysmography were performed. Methacholine challenge test was done to assess AHR. PC20 and dose response slope (DRS) of methacholine was calculated. Results: Mild to severe AHR with PC20 < 4 mg/ml was confirmed in 31 (51.7%) patients. Baseline FeNO and total specific airway resistance (SRtot)%pred and residual volume (RV)%pred levels in plethysmography were significantly higher and FEV1%pred, FEV1/FVC%pred, MMEF%pred values were lower in the group with PC20 < 4 mg/ml. FeNO, SRtot%pred, and RV%pred levels were found to be positively correlated with DRS methacholine. The higher baseline FeNO, frequency dependence of resistance (R5–R20) in IOS and SRtot%pred in plethysmography were found to be significantly related to DRS methacholine in linear regression analysis (β: 1.35, p = 0.046, β: 4.58, p = 0.002, and β: 0.78, p = 0.035, respectively). The cut-off points for FeNO and SRtot% for differentiating asthmatic children with PC20 < 4 mg/ml from those with PC20 ≥ 4 mg/ml were 28 ppb (sensitivity: 67.7%, specificity: 72.4%, p < 0.001) and 294.9% (sensitivity: 35.5%, specificity: 96.6%, p = 0.013), respectively. Conclusion: IOS and plethysmography may serve as reliable and practical tools for prediction of mild to severe methacholine induced AHR in otherwise “seemingly well-controlled’’ asthma.

Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility: a randomised controlled trial

Chronic non-specific respiratory symptoms are difficult to manage. This trial aimed to evaluate the association between baseline fractional exhaled nitric oxide (FeNO) and the response to inhaled corticosteroids in patients with non-specific respiratory symptoms. In this double-blind randomised placebo-controlled trial, we enrolled undiagnosed patients, aged 18-80 years, with cough, wheeze, or dyspnoea and less than 20% bronchodilator reversibility across 26 primary care centres and hospitals in the UK and Singapore. Patients were assessed for 2 weeks before being randomly assigned (1:1) to 4 weeks of treatment with extrafine inhaled corticosteroids (QVAR 80 μg, two puffs twice per day, equivalent to 800 μg per day beclomethasone dipropionate) or placebo. Randomisation was stratified by baseline FeNO measurement: normal (≤25 parts per billion [ppb]), intermediate (>25 tp <40 ppb), and high (≥40 ppb). The primary endpoint was change in Asthma Control Questionnaire (ACQ7) mean score. We used generalised linear modelling to assess FeNO as a predictor of response, estimating an interaction effect between FeNO and treatment on change in ACQ7. We did our primary and secondary analyses in the per-protocol set, which excluded patients with non-completion of the primary endpoint, non-compliance to treatment (ascertained by patient report), and study visits made outside the predefined visit windows. This study is registered on ClinicalTrials.gov, number NCT02294279. Between Feb 4, 2015, and July 12, 2016, we randomly assigned 294 patients to extrafine inhaled corticosteroid treatment (n=148) or placebo (n=146). Following exclusions due to protocol violations, we analysed 214 patients (114 extrafine inhaled corticosteroids and 100 placebo). We observed a significant interaction between baseline FeNO and treatment group for every 10 ppb increase in baseline FeNO, with the change in ACQ7 greater in the extrafine inhaled corticosteroids group than in the placebo group (difference between groups 0·071, 95% CI 0·002 to 0·139; p=0·044). The most common adverse events were nasopharyngitis (18 [12%] patients in the treatment group vs 13 [9%] in the placebo group), infections and infestations (25 [17%] vs 21 [14%]), and respiratory, thoracic, and mediastinal disorders (13 [9%] vs 17 [12%]). FeNO measurement is an easy and non-invasive tool to use in clinical practice in patients with non-specific respiratory symptoms to predict response to inhaled corticosteroids. Further research is needed to examine its role in patients with evidence of other airway diseases, such as chronic obstructive pulmonary disease. Sponsored by OPRI with partial funding by Circassia and study drugs provided by TEVA.

Utility of Fractional Exhaled Nitric Oxide in OSA

SESSION TITLE: Obstructive Sleep Apnea: Insights & Management SESSION TYPE: Original Investigation Slide PRESENTED ON: Sunday, October 29, 2017 at 01:30 PM - 03:00 PM PURPOSE: Nasal inflammation, uvula mucosal congestion and airway hyperresponsiveness is associated with Obstructive Sleep Apnea (OSA). This study evaluated exhaled nitric oxide levels in obese patients with suspected OSA and its correlation with anthropometric measures, body mass index (BMI), severity of OSA and effect of overnight CPAP. METHODS: This was a single center prospective observational study of obese patients (n=104, BMI >25 kg/m2) with suspected OSA. We excluded those with current smoking, chronic airway disease, nasal allergy, active pulmonary infections, autoimmune conditions, chronic liver disease, and current use of immunosuppression or leukotriene modifiers. All subjects underwent whole night attended polysomnography (PSG). Patients with AHI equal to or greater than 5 events/hr were included in OSA group; those with AHI <5/hr were classified as controls. All patients were subjected to detailed history, examination and anthropometry. fractional exhaled nitric oxide (FENO) was measured using hand held NIOX MINO (point of care device with electrochemical sensor based gas analyser) before and after overnight PSG. In 21 OSA patients, pre and post overnight CPAP FENO was also measured. RESULTS: Of 104 subjects, 71 were males (68.3%); 33 were females (31.7%); 53 patients (50.9%) were diagnosed as having OSA during the study, whereas 51 patients (49.1%) had an AHI < 5 events per hour, and were included in the control group. Mean age was similar, i.e., 54.1 (+13.6) years for cases as compared to 54.2 (+10.7) years for controls (p=0.95). Neck circumference & percentage predicted neck circumference were higher in cases vs controls (p=0.01). Majority had severe OSA (n=34; 64.2%); 12 (22.6%) had moderate OSA, whereas 7 (13.2%) had mild OSA. Baseline FENO was 19.6 (+2.9) ppb in cases and 19.0 (+2.2) ppb in controls (p=0.26). FENO in OSA group increased from 19.6 (+2.9) ppb at baseline to 23.7 (+4.2) ppb post PSG (p< 0.01). Post PSG FENO of 22 ppb had AUC of 0.79 (95% CI 0.70-0.88) and correctly classified 73.1% of the cases. Post PSG FENO levels were significantly high in moderate OSA (22.6 +3.1 ppb; p=0.03) and severe OSA (25.2 +3.4; p<0.001) as compared to mild OSA. Sleep duration with SpO2 < 90% was significantly correlated with post PSG FENO (r 0.68, p < 0.01). In 21 OSA cases, after overnight CPAP, post CPAP FENO levels (22.3+3.3ppb) were significantly lower as compared to baseline FENO (26.6+3.8ppb; p=0.01). Stepwise regression analysis was performed to identify independent predictors of OSA. A regression equation was derived; predicted AHI= (0.19 x PPNC) + (3.57 x Post PSG FENO) - (0.80 x Age) -37.99. This model was statistically significant (p< 0.01) and was able to explain 54.1% of the variance in AHI. CONCLUSIONS: Our study demonstrates importance of upper airway inflammation in OSA as evident by increasing FENO levels after overnight sleep and potential utility of FENO measurement in OSA. CLINICAL IMPLICATIONS: FENO should be further evaluated as a potential add on tool for diagnosis of OSA, and also to assess adequacy and compliance of CPAP therapy. DISCLOSURE: The following authors have nothing to disclose: Randeep Guleria, Pawan tiwari, Karan Madan, Anant Mohan, Vijay Hadda, Gopi Khilnani No Product/Research Disclosure Information