Changes In Fractional Exhaled Nitric Oxide Research Articles

Evaluation of multiple-flows exhaled nitric oxide and its clinical significance in severe asthmatic patients treated with biologics: a prospective real-life study

Background Specific biomarkers, such as eosinophilia in peripheral blood or fractional exhaled nitric oxide (FeNO), can guide us in the choice of biologic therapy, allowing a more personalized approach. Although there are multiple evidences in the literature about the role of FeNO as a predictor of response to different biologic treatments, there are no data on the relationship between FeNO changes and clinical response to the four biologic drugs currently in use. Objective To evaluate and to compare the expression of multiple-flows FeNO parameters in a cohort of patients with severe asthma (SA) before and during the treatment with biologics to evaluate the performance of these biomarkers in predicting the achievement of clinical remission. Methods We prospectively enrolled 50 patients with severe asthma eligible for biologic therapy. Patients underwent clinical and functional monitoring at baseline (T0) and after 1, 6, and 12 months of treatment (T1, T6, T12), including multiple flows FeNO assessment. Results A statistically significant reduction of FeNO50 values and J’awNO was observed only in benralizumab and dupilumab subgroups. Among biomarkers, the reduction of FeNO 50 values at T1 was associated with a higher probability of achieving clinical remission at T12 (p = 0.003), which was also confirmed by ROC curve analysis (AUC 0.758, p = 0.002; sensitivity 60% and specificity 74% for a reduction of 16 ppb). Conclusion These data confirm the potential of this biomarker in predicting clinical response to biologic treatment in patients with severe asthma in order to guide clinical decisions and evaluate a shift to other biologic therapy.

Dupilumab Reduces Exacerbations Independent of Changes in Biomarkers in Moderate-to-Severe Asthma

Changes from baseline in fractional exhaled nitric oxide (FeNO) and blood eosinophil count (Eos) may be related to efficacy outcomes in dupilumab-treated patients with moderate-to-severe asthma. This post-hoc analysis investigated biomarker changes in placebo- and dupilumab-treated patients with uncontrolled moderate-to-severe asthma enrolled in QUEST (NCT02414854). Spline analyses of annualized severe exacerbation rate (AER) and change from baseline in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) at Week 52 were performed as a function of fold-change in FeNO at Week 52, and maximum fold-change in Eos over Week 0-12 (also change from baseline in pre-bronchodilator FEV1 at Week 12). The combined placebo and dupilumab groups comprised 638 and 1264 patients, respectively. FeNO levels declined rapidly by Week 2 then gradually to Week 52 in patients treated with dupilumab vs placebo; Eos counts, after initially increasing with dupilumab, declined slightly from baseline in both treatment groups. AER during QUEST showed no significant association with change in biomarkers in either treatment group. Change from baseline in pre-bronchodilator FEV1 at Week 52 was inversely associated with fold-change in FeNO in both groups, with significant difference between the dupilumab and placebo curves (P = .014) and was positively associated with fold-change in Eos in both groups (P = .022). Relative changes in FeNO and Eos were not associated with AER, regardless of treatment arm. However, changes in both biomarkers showed predictive value for lung function improvement; for FeNO this was specific to the dupilumab treatment arm.

Changes in FeNO, d-ROMs, and BH4 by Intravenous L-Arginine in Children and Its Putative Role in Asthma Treatment.

Pteridines are metabolites of tetrahydrobiopterin (BH4), being coenzymes for nitric oxide synthase (NOS). No study has clarified the relationship among pteridines and NOS, fractional exhaled nitric oxide (FeNO) generated by pteridines, and reactive oxygen species. In this study, we administered arginine, a precursor of NO, and confirmed changes in the levels of pteridines, FeNO, and reactive oxygen species and their relationship to clarify the pathogenesis of airway inflammation in which oxidative stress is involved, such as bronchial asthma. This is a prospective, randomized open-label study. Children, aged 2 to 15 years, who were scheduled for growth hormone stimulation tests and were able to undergo a respiratory function test were recruited. They were randomly divided into two groups: arginine-administered and control groups. In the former, L-arginine hydrochloride was intravenously administered. After administration, the levels of diacron-reactive oxygen metabolites (d-ROMs), serum pteridines, serum amino acids, and fractional exhaled NO (FeNO) were measured. We analyzed 15 children aged 4 to 14 years. In the arginine-administered group, there was an increase in the FeNO level and a decrease in the d-ROMs level, reaching a peak 30 min after administration, compared with the control group. In addition, there was a decrease in the serum biopterin level and an increase in the d-ROMs level, reaching peak 60 min after administration. The administration of L-arginine increased the NO level and decreased the d-ROMs level. Due to this, biopterin may be consumed and decreased, leading to an increase in the d-ROMs level. As a reduction in reactive oxygen species leads to the relief of inflammation, arginine and biopterin may be useful for inhibiting inflammation.

Interval change in fractional exhaled nitric oxide (FENO) reflects short-term change in adherence following electronic inhaler reminders

Background In asthma, suppression of fractional exhaled nitric oxide (FENO) is a marker of adherence in the short-term. The usefulness of FENO to indicate change in adherence in the longer term is unknown. The aims of this study were to determine the relationship between changes in adherence and corresponding changes in FENO over short (1 week) and long-term (3 month) periods. Methods After establishing initial ICS adherence using electronic inhaler monitor (EIM) devices, reminders were switched on for 1 week (‘short-term’) to optimize adherence. Reminders were then switched off and patients followed up after 3 months (‘long-term’). FENO was measured at the start and end of each period. Using linear regression, we analyzed change in FENO in relation to change in adherence. Results Forty-two patients contributed complete data for analysis. In the short-term, change in adherence was independently associated with change in FENO (β = -0.36, p = 0.036) even after adjusting for initial adherence and ICS dose. The higher the initial FENO, the greater the decline in FENO with improved adherence. This relationship between change in adherence and change in FENO was not observed in the long-term. Conclusion Change in adherence over 1 week following the use of EIM reminders independently predicted change in FENO. This relationship was not maintained at 3 months.

Variability of fractional exhaled nitric oxide is associated with the risk and aetiology of COPD exacerbations.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are heterogeneous in aetiology and accelerate disease progression. Here, we aimed to investigate the association of fractional exhaled nitric oxide (FeNO) and its variability with AECOPD of different aetiology. FeNO was determined in 2157 visits (1697 stable, 133 AECOPD and 327 follow-up) of 421 COPD patients from the PREVENT study, an investigator-initiated, longitudinal and interventional study, who were on daily treatment with inhaled corticosteroids/long-acting β2-agonists. Longitudinal measurements of FeNO revealed an intra-subject variability of FeNO that was significantly higher in exacerbators compared to non-exacerbators (p< 0.001) and positively associated with the number of AECOPD. As FeNO variability increased, the probability of patients to remain AECOPD-free decreased. In patients included in the highest FeNO variability quartile (≥15.0ppb) the probability to remain free of AECOPD was only 35% as compared to 80% for patients included in the lowest FeNO variability quartile (0.50-4.39 ppb). The change of FeNO from the last stable visit to AECOPD was positively associated with the probability of viral infections and this association was stronger in current smokers than ex-smokers. In contrast, the change in FeNO from the last stable visit to an AECOPD visit was inversely associated with the probability of bacterial infections in ex-smokers but not in current smokers. FeNO variability was associated with the risk and aetiology of AECOPD differentially in current and ex-smokers.

Use of FeNO to predict anti-IL-5 and IL-5R biologics efficacy in a real-world cohort of adults with severe eosinophilic asthma

Introduction Severe eosinophilic asthma (SEA) is associated with multiple exacerbations. Fractional exhaled nitric oxide (FeNO), a biomarker of airway T2 inflammation, is known to be correlated with the risk of exacerbations. While the use of FeNO is well established to predict the therapeutic response to dupilumab (anti-IL-4/IL-13), it remains uncertain for biologics targeting the IL-5 pathway. Methods We conducted an observational, retrospective, monocentric analysis of adults with SEA who started mepolizumab (anti-IL-5) or benralizumab (anti-IL-5R) between January 1, 2016 and December 31, 2020. Results Data were collected for 109 patients. All participants reported uncontrolled asthma with a median of 3 annual exacerbations and a median Asthma Control Test score of 12. They all had an initial blood eosinophilia >300/mm3, with a median at 610/mm3 (IQR 420-856). Patients with a baseline FeNO ≥50 ppb reported more exacerbations in the previous year than those with a FeNO <50 ppb (p = 0.02). After initiation of treatment, change in FeNO was not associated with therapeutic response. However, decrease in the annual number of exacerbations was significantly greater in patients with a baseline FeNO ≥50 ppb than in those with a baseline FeNO <50 ppb (-3.3 ± 2.7 vs −0.9 ± 2.4, respectively; p = 0.01). There was no association between baseline FeNO values and subsequent lung function, asthma control or reduction of oral corticosteroids use. Conclusion In this real-world cohort, adults with SEA who had a baseline FeNO ≥50 ppb experienced a greater decrease in exacerbations after 12 months of anti-IL-5 or IL-5R biologics than those with a FeNO <50 ppb.

Short- and medium-term effect of inhaled corticosteroids on exhaled breath biomarkers in severe asthma

Inhaled corticosteroids (ICS) are the mainstay of therapy in asthma, but benefits vary due to disease heterogeneity. Steroid insensitivity is a particular problem in severe asthma, where patients may require systemic corticosteroids and/or biologics. Biomarkers sensitive to ICS over a short period of time could inform earlier and more personalised treatment choices. To investigate how exhaled breath biomarkers change over two-hours and one-week following monitored ICS dosing in severe asthma patients with evidence of uncontrolled airway inflammation. Patients with severe asthma and elevated fractional exhaled nitric oxide (FeNO) (⩾45 ppb, indicative of active airway inflammation) were recruited. Exhaled breath biomarkers were evaluated using (FeNO), exhaled breath temperature (EBT), particles in exhaled air (PExA) and volatile organic compounds (VOCs). Samples were collected over 2 h following observed inhalation of 1000 mcg fluticasone propionate, and at a second visit 1 week after taking the same dose daily via an inhaler monitoring device that recorded correct actuation and inhalation. Changes in parameters over 2 h were analysed by the Friedman test and 1 week by Wilcoxon’s test (p-value for significance set at 0.05; for VOCs false discovery rate q of 0.1 by Benjamini–Hochberg method applied). 17 participants (9 male) were recruited, but three could not complete PExA and two FeNO testing, as they were unable to comply with the necessary technique; complete datasets were available from 12 (9 male) with median (interquartile range) age 45 (36–59) yrs. EBT (p < 0.05) and levels of six VOCs (q < 0.1) fell over the 2 h after high dose ICS; there were no changes in FeNO or PExA. After one week of using high dose ICS, there were falls in FeNO, EBT and two VOCs (p < 0.05), but no changes in PExA. Reduction in EBT over the short and medium term after high dose ICS may reflect airway vascular changes, and this, together with the observed changes in exhaled VOCs, merits further investigation as potential markers of ICS use and effectiveness.

Association of fractional exhaled nitric oxide with asthma morbidity in urban minority children

Objective Fractional exhaled nitric oxide (FeNO) is a well-established measure of allergic airway inflammation and possible useful adjunct disease management tool. We investigated the association of baseline and follow-up FeNO measurements with disease burden in minority children with persistent asthma. Methods A retrospective chart review was conducted on 352 African American and Hispanic children seen at an urban Asthma Center in Bronx, NY. Demographic, clinical characteristics, and pulmonary function tests (PFTs) were compared between children with low, intermediate, and high baseline FeNO levels. Among 95 children with subsequent follow up visits, associations of change in FeNO with demographics, clinical characteristics, and PFTs were examined using mixed effects linear regression models. Results A higher proportion of children with intermediate (54%) and high FeNO (58%) levels had lower airways obstruction compared to those with low FeNO levels (33%). Children with intermediate FeNO levels had more annual hospitalizations (2.8 ± 6.2) compared to those with low and high FeNO levels (1.3 ± 2.8 and 1.3 ± 2.5). These associations did not differ between ethnicities. An increase in FeNO over time was associated with higher BMI z-scores (β = 6.2, 95% CI: 1.0 to 11.4) and two or more hospitalizations in the past year (β = 16.1, 95% CI: 1.5 to 30.8). Conclusions Intermediate and high FeNO levels are associated with lower airways obstruction and hospitalizations. Initial and serial FeNO measurements can be a useful adjunctive tool in identifying asthma-related morbidity in urban African American and Hispanic children.

Fractional Exhaled Nitric Oxide Guided-Therapy in Chronic Obstructive Pulmonary Disease: A Stratified, Randomized, Controlled Trial

IntroductionChronic obstructive pulmonary disease (COPD) with eosinophilic airway inflammation represents a distinct phenotype that might respond to treatment with inhaled corticosteroids. Fractional exhaled nitric oxide (FENO) might predict eosinophilic inflammation and guide treatment option. We hypothesized that COPD patients with different baseline levels of FENO might have differentiated response to treatment with salmeterol/fluticasone (SFC) or tiotropium (TIO). MethodsThis open-label, randomized-controlled trial enrolled treatment-naïve COPD patients who were stratified into high- (≥23.5ppb) and low-FENO group, followed by 12-week treatment with SFC or TIO. A linear mixed model with repeated measures was applied to analyze the changes in FENO (primary outcome), COPD assessment test (CAT) score, FEV1, and parameters in induced sputum and blood after treatment. Results134 patients were divided into 4 subgroups: low-FENO/SFC (n=30), low-FENO/TIO (n=29), high-FENO/SFC (n=37), and high-FENO/TIO (n=38). At baseline, FENO 23.5ppb clearly differentiated between eosinophilic and non-eosinophilic inflammation groups based on the eosinophils in induced sputum and blood. FENO significantly correlated with sputum and blood eosinophils at baseline. High-FENO/SFC (vs. high-FENO/TIO) subgroup had significant reduction in FENO and sputum inflammation profiles (including eosinophils, macrophages, matrix metalloproteinase-9, and interlukin-8) after treatment. These differences were not replicated between low-FENO/SFC and low-FENO/TIO subgroups. The improvement in CAT and FEV1 after treatment was indiscriminate between SFC and TIO in the low- and high-FENO groups. ConclusionHigh baseline FENO can serve as an indicator of eosinophilic airway inflammation in COPD patients who may respond favorably to treatment with inhaled corticosteroids/long-acting β2-agonists. Trial registration numberClinicalTrials.gov Identifier: NCT02546349.

Measurement of Diacetyl and Related Compounds in Coffee Roasteries and Breweries.

α-Diketones such as diacetyl (2,3-butanedione) and 2,3-pentanedione are generated during the roasting and fermentation of foods and are also used as flavoring compounds. Exposure to these compounds has been associated with obliterative bronchiolitis in workers. We report indoor air concentrations of diacetyl and 2,3-pentanedione, as well as acetoin (3-hydroxy-2-butanone), in several small coffee roasteries and breweries using standard integrated air sampling sorbent tubes followed by gas chromatography tandem mass spectrometry as well as the first use of on-site continuous real-time proton-transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS). Diacetyl and 2,3-pentanedione were detected in most of the sorbent samples at concentrations between 0.02 and 8 ppbv, and in general were higher in coffee roasteries compared with breweries. Three integrated air samples, all from the barista area at one facility, exceeded the NIOSH recommended exposure limit (REL) of 5 ppbv for diacetyl. 2,3-Pentanedione concentrations in these three samples were greater than 50% of its REL, but did not exceed it. Acetoin, a precursor to diacetyl, was also detected at concentrations between 0.03 and 5 ppbv in most sorbent tube samples, with concentrations generally higher in breweries. PTR-ToF-MS measurements exhibited similar trends and provided continuous real-time volatile organic compound data that showed episodic excursions with peak concentrations of diacetyl and 2,3-pentanedione between 15 and 20 ppbv. Examination of the time series data identified specific activities associated with peak diketone emissions, including transfer of freshly roasted coffee beans to the cooling tray, or the opening of a brew kettle. Additional indoor air quality parameters including CO2, NO2, and PM2.5 were also assessed on-site. Airway inflammation was assessed in 19 workers before and after each work shift using online measurements of fractional exhaled nitric oxide (FENO). The pre-shift mean FENO was 3.7 (95% confidence interval: -3.6, 11.0) ppbv higher and the post-shift FENO was 7.1 (-1.9, 16.1) ppbv higher for workers at coffee roasteries compared with breweries. The cross-shift change in FENO was 3.4 (-2.8, 9.6) ppbv higher for workers at coffee roasteries compared with breweries. However, none of these differences were statistically significant, and the cross-shift change in FENO was not statistically different from zero for either group of workers. The findings from this pilot study demonstrate that α-diketones and related compounds are present in the indoor air of both breweries and coffee roasteries and may exceed health protective guidelines in coffee roasteries. Additional studies are required to fully characterize worker exposures in these settings and to identify specific work activities and processes associated with high exposures. Engineering controls, including targeted exhaust ventilation and the use of low-cost sensors, are recommended as an approach to protect workers from exposure to hazardous levels of α-diketones.

Influence of Dose Metrics on Associations between Exposure to Black Carbon and Exhaled Nitric Oxide in Children with Asthma

BACKGROUND AND AIM: Few studies examined the associations between fractional exhaled nitric oxide (FeNO) and traffic-related air pollution (TRAP) from individual dosimetry models. Our study aimed to assess the associations between FeNO and black carbon (BC, as a surrogate of TRAP) from four dose metrics. Besides, we aimed to examine if more refined dose metrics would impact the health risk estimates. METHODS: We recruited 35 children with asthma living in environmental justice communities. Daily FeNO measurements were followed for up to 30 days for each child. Four dose metrics were calculated based on measurements from a central-site and personal monitors, with and without estimates of inhalation rates based on a self-reported time-activity questionnaire. Linear mixed effect models were used to test the associations of BC at different lag periods and FeNO. RESULTS:Exposure to BC was positively associated with FeNO within the first 24 hours of exposure. A log-transformed interquartile range increase in inhaled dose from metrics that used central-site estimates (Model A, C) increased 7% (95% CI: 1% - 14%) and 6% (95% CI: 0% - 13%) in FeNO at lag 0-6 hours in the adjusted model 4. The strength of association persisted at lag 7-12 hours and then decreased and became insignificant at longer lag periods. Similarly, the inhaled dose from personal monitored estimates (Model B, D) was positively associated with FeNO within the first 24 hours. Using personal BC measurements or dynamic inhalation rate did not improve prediction of changes in FeNO. CONCLUSIONS:Our findings revealed that inhaled BC dose significantly increases FeNO level within the first 24 hours of exposure. Our results provide evidence that personal exposure to BC was associated with airway inflammation among children with asthma. Our results also add to the limited number of studies that compared the effect estimates among alternative dose metrics within a single study. KEYWORDS: traffic-related, air pollution, Short-term exposure, asthma, Children's environmental health

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.

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. 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. 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. 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. 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. 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.

Variability Of&nbsp;Fractional Exhaled Nitric Oxide is Associated with the Risk and Etiology of Acute Exacerbations in COPD

Background: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are heterogeneous in etiology and accelerate disease progression. This study aimed to evaluate if variability of fractional exhaled nitric oxide (FeNO) can predict the risk and etiology of AECOPD. Methods: FeNO was determined in 2157 visits (1697 stable, 133 AECOPD and 327 follow-up) of 421 COPD patients from the PREVENT study, an investigator-initiated, longitudinal, interventional study, who were on daily controlled treatment with inhaled corticosteroids/long-acting β2-agonists. Findings: Longitudinal measurements of FeNO revealed an intra-subject variability of FeNO that was significantly higher in exacerbators compared to non-exacerbators (p<0.001) and positively associated with the number of AECOPD. As FeNO variability increased, the probability of patients to remain free of AECOPD decreased. In patients included in the highest FeNO variability quartile (≥15.0 ppb) the probability to remain free of AECOPD was only 35% as compared to 80% for patients included in the lowest FeNO variability quartile (0.50-4.39 ppb). The change in FeNO from the last stable visit to AECOPD was positively associated with the probability of viral infections and this association was strongerin current smokers than ex-smokers. In contrast, the change in FeNO from the last stable visit to an AECOPD visit wasinversely associated with the probability of bacterial infections in ex-smokers but not in current smokers. Interpretation: FeNO variability was associated with the risk of AECOPD and was predictive of the etiology of AECOPD differentially in current and ex-smokers. Funding: SNF (PP00-P3_128412/1), Pneumology, University Hospital Basel, Switzerland, Astra AG, unrestricted grant. Declaration of Interest: None to declare. Ethical Approval: The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the guidelines on good clinical practice (GCP) and was approved by the institutional review board (EKNZ 306/10). The study was registered at www.controlled-trials.com (identifier ISRCTN 45572998).

Annual Fractional Exhaled Nitric Oxide Measurements and Exacerbations in Severe Asthma

PurposeFractional exhaled nitric oxide (FENO) reflects eosinophilic inflammation of the airways. However, the significance of longitudinal assessment of FENO, including its variability, in the clinical course of severe asthma remains unclear. The aim of this study is to examine the association between long-term changes in FENO and the development of exacerbations in severe asthma.Patients and MethodsAmong the severe asthma patients enrolled in the Hokkaido Severe Asthma Cohort Study, 100 patients with severe asthma who completed a 3-year follow-up in which FENO was measured annually were included. According to the FENO level at baseline, 1 year, and 2 years, the patients were classified into three groups: the sustained high group (≥50 ppb at all three visits), the sustained low group (<25 ppb at all three visits), and the intermediate group (other). Subjects in the intermediate group were further classified into two groups based on the median value of the coefficient of variation (CV) of FENO during the 3 years (high CV and low CV intermediate groups).ResultsThe sustained high group experienced shorter exacerbation-free survival and more frequent exacerbations than the sustained low group (median number of exacerbation events, 3 vs 0, p = 0.01). In the intermediate group, the high CV group experienced shorter exacerbation-free survival than the low CV group, and the CV of FENO was an independent contributing factor to the development of exacerbations.ConclusionPersistence of FENO above 50 ppb over the years as well as the presence of large variations in FENO levels was associated with the development of exacerbations in patients with severe asthma.

Airway mechanics after withdrawal of a leukotriene receptor antagonist in children with mild persistent asthma: Double-blind, randomized, cross-over study.

To determine the response of airway mechanics and the changes in asthma symptoms to stepping down of leukotriene receptor antagonist (LTRA) therapy. Thirty children (mean age: 7.1 years) with mild, well-controlled, and persistent asthma who took LTRA as maintenance treatment were randomized into a double-blind, placebo-controlled, cross-over study. Each group received an LTRA (montelukast) or placebo daily for 2 weeks, followed by a 1-week washout period, and then the alternate treatment for 2 weeks. Spirometry and impulse oscillation system (IOS) measurements before and after four puffs of salbutamol inhalation, fractional exhaled nitric oxide (FeNO), and the childhood asthma control test (C-ACT) were evaluated at baseline, the end of placebo treatment, and the end of LTRA treatment. Changes of FEV1 /FVC (p = .113) and FEV1 (p = .109) from baseline to posttreatment did not differ significantly between the placebo and montelukast groups. In the placebo group, prebronchodilator (pre-) FEV1 /FVC was decreased (83% vs. 86%) and bronchodilator response (BDR) in FEV1 was diminished (10.7% vs. 6.4%) at posttreatment compared with baseline. However, the montelukast group had no significant changes in pre-FEV1 /FVC (p = .865) and BDR in FEV1 (p = .461). In addition, compared with the montelukast group, the placebo group showed no significant changes in Rrs5 (total airway resistance), Rrs5-20 (peripheral airway resistance), FeNO, and symptoms by the C-ACT. In children with well-controlled mild persistent asthma, changes in spirometry, IOS, FeNO, and C-ACT results did not differ between the placebo and montelukast groups within 2 weeks.

Respiratory effects of acute milk consumption among asthmatic and non-asthmatic children: a randomized controlled study

BackgroundA commonly held public belief is that cow’s milk products increase mucus production and respiratory symptoms. Dietary milk elimination is often attempted despite lack of evidence. Our objective was to investigate whether a single exposure to cow’s milk is associated with respiratory symptoms and changes in pulmonary functions in asthmatic and non-asthmatic children.MethodsWe conducted a prospective double blind, placebo-controlled trial on non-asthmatic and asthmatic children aged 6–18 years evaluated at a pediatric pulmonology unit.The children were randomly challenged with cow’s milk or soy milk substitute. Symptoms, spirometry, fractional-exhaled nitric-oxide (FeNO), and pulse oximetry findings were obtained at baseline and at 30, 60, 90, and 120 min following challenge.A two-way ANCOVA (with repeated measures when required) was used to compare the performances of all groups and subgroups over time. The outcome measures of each participant were compared to his/her own variables over time and in relation to his/her baseline values. In case of missing data points, missingness analysis was performed using Little’s missing completely at random (MCAR) test.ResultsFifty non-asthmatic children (26 assigned to the cow’s milk group and 24 to the soy substitute group), and 46 asthmatic children (22 in the cow’s milk group and 24 in the soy substitute group) were enrolled. Age, gender, and body mass index Z-score were comparable between the two groups. No changes in symptoms, spirometry, FeNO, or oxygen saturation measurements were observed following challenge in any of the participants in both groups, at any time point compared to baseline.ConclusionsA single exposure to cow’s milk is not associated with symptoms, bronchial inflammation, or bronchial constriction in both non-asthmatic and asthmatic children. Our findings do not support the strict elimination of dairy products from a child’s diet for the prevention of respiratory symptoms.Trial registrationThis study was approved by the Tel Aviv Sourasky Medical Center Institutional Review Board and the Israeli Ministry of Health review board (Helsinki Committee, NIH #NCT02745899). Registered April 2016 https://clinicaltrials.gov/ct2/show/NCT02745899?cond=milk+asthma&rank=1.

Association between biomarkers and house dust mite sublingual immunotherapy in allergic asthma.

House dust mite (HDM) sublingual immunotherapy (SLIT) has demonstrated efficacy in clinical trials of patients with asthma. Airway inflammation is a characteristic of respiratory allergy, but its relationship to SLIT remains unclear. We evaluate the association between clinical outcomes with pulmonary function and biomarkers in before and after HDM SLIT (UMIN Number 000022390). One hundred twelve patients with asthma sensitized to HDM were randomized to add-on 6 standardized quality (SQ)-HDM SLIT to pharmacotherapy or pharmacotherapy alone for 48weeks. At baseline and end of study, biomarkers, blood eosinophils, serum IgE, serum periostin, fractional exhaled nitric oxide (FeNO), and spirometry and clinical symptoms were measured. Association between biomarkers and an increase in FEV1 of 120mL or greater were analysed. Sublingual immunotherapy (SLIT) demonstrated a significant reduction of serum periostin (P<.001), FeNO (P<.01), and increase in HDM-specific IgE (P<.05), FEV1 (P<.001) and improvement of clinical symptom scores, when compared to pharmacotherapy. The change in FEV1 correlated with the changes in serum periostin (r=.696, P<.001) and the changes in FeNO (r=.682, P<.001). The independent predictor of improvement in airflow limitation was changed in serum periostin (r2 =.753, P=.013) and FeNO (P=.038). Based on cut-off values derived by receiver operating characteristic analysis (periostin 30.9ng/mL, FeNO 28.0ppb), patients were distinguished responders from non-responders, but with no predictive value for blood eosinophils or total IgE. The proportion of patients with both high periostin and FeNO levels was significantly higher in responder than in non-responder (P=.026). Adding HDM SLIT to pharmacotherapy resulted in reduced serum periostin and FeNO, and improved pulmonary function. Serum periostin and FeNO may be useful biomarkers for prediction of SLIT.

Reducing Asthma Attacks in Children using Exhaled Nitric Oxide as a biomarker to inform treatment strategy: a randomised trial (RAACENO)

BackgroundChildhood asthma is a common condition. Currently there is no validated objective test which can be used to guide asthma treatment in children. This study tests the hypothesis that the addition of fractional exhaled nitric oxide (FENO) monitoring in addition to standard care reduces the number of exacerbations (or attacks) in children with asthma.MethodsThis is a multi-centre, randomised controlled study. Children will be included of age 6–16 years who have a diagnosis of asthma, currently use inhaled corticosteroids (ICSs) and have had an exacerbation in the previous 12 months. Exclusion criteria include being unable to provide FENO measurement at baseline assessment, having another chronic respiratory condition and being currently treated with maintenance oral steroids. Participants will be recruited in both primary and secondary care settings and will be randomised to either receive asthma treatment guided by FENO plus symptoms (FENO group) or asthma treatment guided by symptoms only (standard care group). Within the FENO group, different treatment decisions will be made dependent on changes in FENO. Participants will attend assessments 3, 6, 9 and 12 months post randomisation. The primary outcome is asthma exacerbation requiring prescription and/or use of an oral corticosteroid over 12 months as recorded by the participant/parent or in general practitioner records. Secondary outcomes include time to first attack, number of attacks, asthma control score and quality of life. Adherence to ICS treatment is objectively measured by an electronic logging device. Participants are invited to participate in a “phenotyping” assessment where skin prick reactivity and bronchodilator response are determined and a saliva sample is collected for DNA extraction. Qualitative interviews will be held with participants and research nurses. A health economic evaluation will take place.DiscussionThis study will evaluate whether FENO can provide an objective index to guide and stratify asthma treatment in children.Trial registrationISRCTN, ISRCTN67875351. Registered on 12 April 2017. Prospectively registered.

Effect of Sublingual Immunotherapy on Airway Inflammation and Airway Wall Thickness in Allergic Asthma

The efficacy of the standardized quality (SQ) house dust mite (HDM) sublingual immunotherapy (SLIT) has been demonstrated for respiratory allergic disease. However, the effects of SLIT on inflammation and structural changes of the airways are still unknown. The aim of this study was to assess the effects of the 6 SQ-HDM SLIT on airway inflammation and airway geometry in allergic asthma and rhinitis. One hundred two asthmatic patients with rhinitis sensitized to HDM were randomized to receive either SLIT plus pharmacotherapy or standard pharmacotherapy alone, for 48 weeks. Fractional exhaled nitric oxide (FeNO), pulmonary function, quantitative computed tomography, and clinical symptoms were performed at baseline and end of the study. Compared with pharmacotherapy, SLIT demonstrated a significant reduction of FeNO (P < .01), airway wall area/body surface area (WA/BSA, P < .001), wall thickness (T/√BSA, P < .001), percentage wall area (WA/Ao, P < .01), increase in luminal area (Ai/BSA, P < .05), improvement of airflow limitation (P < .001), and clinical symptom scores (P<.05). The change in forced expiratory volume in 1 second (FEV1) was correlated with both changes in FeNO and airway dimensions. Multiple regression analysis showed that the change in FeNO was independently associated with an increase in FEV1 in the SLIT group (r2= 0.623, P= .037). Adding 6 SQ-HDM SLIT to standard asthma therapy provides a significant improvement in symptoms and pulmonary function compared with pharmacotherapy. Improvement of airflow limitation with SLIT was associated with the decrease in eosinophilic airway inflammation.

Validation of ATS clinical practice guideline cut-points for FeNO in asthma.

The American Thoracic society (ATS) has suggested using fractional exhaled nitric oxide (FeNO) to monitor the level of eosinophilic (EOS) airway inflammation in asthma, but validation of the proposed cut-points is required in real-life populations. To validate FeNO cut-points suggested by ATS in relation to sputum EOS count in a real life population of asthma patients. All patients referred consecutively over a 12-months period for specialist assessment of asthma, were examined with FeNO and induced sputum, and re-examined 12 months later. The predicted values of a positive and a negative test (PPV and NPV) for a cut off ≥3% EOS in sputum were calculated. Change in FeNO was defined in accordance with ATS (>20% or 10 ppb if FeNO was <50 ppb). 144 adult asthma patients were examined (59% female). Low FeNO (<25 ppb) at baseline was found in 94 (65%), FeNO between 25 and 50 ppb in 34 (24%) subjects and high FeNO >50 ppb in 16 (11%) subjects. The PPV for FeNO >25 ppb and >50 ppb to predict EOS ≥3% was 45% and 77%, NPV was 88% and 83%. The sensitivity decreased from 70% to 37% at the >50 ppb cut-off. A significant reduction in FeNO was associated with a reduction in sputum EOS (p = 0.01). The findings support the validity of the FeNO cut-points suggested by ATS to monitor eosinophilic airway inflammation in asthma. However, in this real-life population, a large proportion of patients had intermediate FeNO values, which may limit the clinical usefulness of the ATS FeNO cut-points.