Fractional Concentration Of Exhaled Nitric Oxide Research Articles

Identification and treatment of persistent small airway dysfunction in paediatric patients with asthma: a retrospective cohort study

BackgroundAsthma is a common respiratory disease. In asthma, the small airways have more intensive inflammation and prominent airway remodelling, compared to the central airways. We aimed to investigate the predictive value of risk factors and the fractional concentration of exhaled nitric oxide (FeNO) for persistent small airway dysfunction (p-SAD), and compare the effects of different treatment modalities.MethodsThis retrospective cohort study included 248 children with asthma (aged 4–11 years). Binary logistic regression was used to analyse the risk factors for p-SAD. Correlations among FEV1/FVC, small airway function parameters, and FeNO levels in patients with asthma were analysed using Spearman’s rank correlation. The receiver operating characteristic curve and the Delong test were used to analyse the predictive value of FeNO for p-SAD. Differences in the treatment effects of inhaled corticosteroids (ICS) and ICS with a long-acting beta-agonist (ICS/LABA) on p-SAD were analysed using Fisher’s exact test.ResultsAsthmatic children with older age of receiving the regular treatment (OR 1.782, 95% CI 1.082–2.935), with younger age at the time of onset of suspected asthma symptoms (OR 0.602, 95% CI 0.365–0.993), with longer duration of using ICS or ICS/LABA (OR 1.642, 95% CI 1.170–2.305) and with worse asthma control (OR 3.893, 95% CI 1.699–8.922) had increased risk for p-SAD. Significant negative correlations of small airway function parameters with FeNO at a 200 mL/s flow rate (FeNO200), and the concentration of nitric oxide in the alveolar or acinar region (CaNO) were observed. The areas under the curve of FeNO200 (cut-off:10.5ppb), CaNO (cut-off:5.1ppb), and FeNO200 combined with CaNO were 0.743, 0.697, and 0.750, respectively, for asthma with p-SAD. After using ICS or ICS/LABA, switching to ICS/LABA was easier than continuing with ICS to improve small airway dysfunction (SAD) in the 8th month.ConclusionsPaediatric asthma with p-SAD is associated with older age at receiving regular treatment, younger age at the time of onset of suspected asthma symptoms, longer duration of using ICS or ICS/LABA, worse asthma control, and higher FeNO200 and CaNO levels, all of which can be combined with small airway function indicators to distinguish p-SAD from asthma. ICS/LABA improves SAD better than ICS alone.

Ultrasensitive Online NO Sensor Based on a Distributed Parallel Self-Regulating Neural Network and Ultraviolet Differential Optical Absorption Spectroscopy for Exhaled Breath Diagnosis.

The concentration of fractional exhaled nitric oxide (FeNO) is closely related to human respiratory inflammation, and the detection of its concentration plays a key role in aiding diagnosing inflammatory airway diseases. In this paper, we report a gas sensor system based on a distributed parallel self-regulating neural network (DPSRNN) model combined with ultraviolet differential optical absorption spectroscopy for detecting ppb-level FeNO concentrations. The noise signals in the spectrum are eliminated by discrete wavelet transform. The DPSRNN model is then built based on the separated multipeak characteristic absorption structure of the UV absorption spectrum of NO. Furthermore, a distributed parallel network structure is built based on each absorption feature region, which is given self-regulating weights and finally trained by a unified model structure. The final self-regulating weights obtained by the model indicate that each absorption feature region contributes a different weight to the concentration prediction. Compared with the regular convolutional neural network model structure, the proposed model has better performance by considering the effect of separated characteristic absorptions in the spectrum on the concentration and breaking the habit of bringing the spectrum as a whole into the model training in previous related studies. Lab-based results show that the sensor system can stably achieve high-precision detection of NO (2.59-750.66 ppb) with a mean absolute error of 0.17 ppb and a measurement accuracy of 0.84%, which is the best result to date. More interestingly, the proposed sensor system is capable of achieving high-precision online detection of FeNO, as confirmed by the exhaled breath analysis.

Efficacy of dupilumab and risk factors for dupilumab-induced hypereosinophilia in severe asthma: a preliminary study from China

Objective Dupilumab has been approved for the treatment of severe asthma with type 2 inflammation by inhibiting interleukin (IL)-4 and IL-13 signaling. However, dupilumab-induced hypereosinophilia (HE) has been reported and should not be ignored. The aim of this study was to investigate the efficacy of dupilumab in Chinese patients with severe asthma, whether HE affects its efficacy, and the possible risk factors for HE. Methods 20 patients with severe asthma who received dupilumab treatment for at least 12 months in the First Affiliated Hospital of Guangzhou Medical University from 2019 to 2022 were included. We compared clinical data and laboratory tests results before dupilumab treatment and at 4 and 12 months after treatment. Based on whether dupilumab treatment triggers HE defined as blood eosinophil count (BEC) ≥ 1.5 × 109 cells/L, the patients were allocated into non-HE and HE groups. Results The patients showed a significant increase in asthma control test (ACT) scores, a decrease in the number of exacerbations, a decrease in the proportion of patients taking an oral corticosteroid (OCS) and in the dose, and a significant improvement in the pulmonary function parameters FEV1/FVC (%) and FEV1 (% predicted) after 4 and 12 months of treatment with dupilumab. For type 2 inflammatory biomarkers, the levels of fractional concentration of exhaled nitric oxide (FeNO), sputum eosinophil count percentage (SEC%) and total immunoglobulin E (TIgE) decreased significantly, whereas BEC were higher after 4 months of treatment, but returned to baseline levels after 12 months. 8 patients (40%) developed asymptomatic HE after dupilumab, and the efficacy was not significantly different between the HE and non-HE groups. The earliest BEC elevation appeared at 1 month after treatment, but most of them declined after 6 months, and basically returned to the baseline level around 12 months of treatment. In addition, we further found that when patients had FeNO ≥ 60 ppb, food allergens positive and combined eosinophilic otitis media (EOM), their BEC increased significantly more than that of the control group after 4 months as well as 12 months of treatment. Conclusions This study demonstrated that dupilumab was efficacious in Chinese patients with severe asthma, and some patients developed asymptomatic, self-limited HE, which did not affect its efficacy. Additionally, FeNO ≥60 ppb, food allergens positive, and co-morbidities with EOM may be the risk factors for developing HE.

Effects of training flights of combat jet pilots on parameters of airway function, diffusing capacity and systemic oxidative stress, and their association with flight parameters

BackgroundFighter aircraft pilots are regularly exposed to physiological challenges from high acceleration (Gz) forces, as well as increased breathing pressure and oxygen supply in the support systems. We studied whether effects on the lung and systemic oxidative stress were detectable after real training flights comprising of a wide variety of exposure conditions, and their combinations.MethodsThirty-five pilots of the German Air Force performed 145 flights with the Eurofighter Typhoon. Prior to and after flight lung diffusing capacity for carbon monoxide (DLCO) and nitric oxide (DLNO), alveolar volume (VA), and diffusing capacities per volume (KCO, KNO) were assessed. In addition, the fractional concentration of exhaled nitric oxide (FeNO) was determined, and urine samples for the analysis of molecular species related to 8-hydroxy-2’-deoxyguanosine (8-OHdG) were taken. For statistical analysis, mixed ANOVA models were used.ResultsDLNO, DLCO, KNO, KCO and VA were reduced (p < 0.001) after flights, mean ± SD changes being 2.9 ± 5.0, 3.2 ± 5.2, 1.5 ± 3.7, 1.9 ± 3.7 and 1.4 ± 3.1%, respectively, while FeNO decreased by 11.1% and the ratio of 8-OHdG to creatinine increased by 15.7 ± 37.8%. The reductions of DLNO (DLCO) were smaller (p < 0.001) than those of KNO (KCO). In repeated flights on different days, baseline values were restored. Amongst various flight parameters comprising Gz-forces and/or being indicative of positive pressure breathing and oxygenation support, the combination of long flight duration and high altitude appeared to be linked to greater changes in DLNO and DLCO.ConclusionsThe pattern of reductions in diffusing capacities suggests effects arising from atelectasis and increased diffusion barrier, without changes in capillary blood volume. The decrease in exhaled endogenous NO suggests bronchial mucosal irritation and/or local oxidative stress, and the increase in urinary oxidized guanosine species suggests systemic oxidative stress. Although changes were small and not clinically relevant, their presence demonstrated physiological effects of real training flights in a modern 4th generation fighter jet.

Mepolizumab in children and adolescents with severe eosinophilic asthma not eligible for omalizumab: a single Center experience

Background Mepolizumab is an anti-interleukin-5 monoclonal antibody shown to reduce asthma exacerbations in adults and adolescents with severe eosinophilic asthma. Aim To assess the impact of mepolizumab on children and adolescents over 12 months by examining steroid usage, asthma-related hospitalizations, Asthma Control Test (ACT) scores, fractional exhaled nitric oxide concentration (FeNO), forced expiratory volume in 1 s (FEV1), mid expiratory flow (FEF25–75%), and blood eosinophil count. Methods Retrospective analysis performed between October 2015 and December 2022. Data was reviewed 12 months before and after commencing mepolizumab. Mepolizumab was offered if the patient had severe eosinophilic asthma and were unresponsive to or ineligible for omalizumab. Results Sixteen participants (age 7–17, 8 males, 8 females) received subcutaneous mepolizumab monthly with no serious adverse reactions. Incidence of hospital admissions fell significantly (IRR 0.33, p = 0.007). Among the 11 patients receiving daily oral corticosteroids, 3 were weaned off daily oral steroids and 3 patients’ daily dose was significantly reduced (mean Δ-0.095 ± 0.071 mg/kg, p = 0.0012). Eosinophil count was decreased (mean Δ-0.85 x 109/L, p < 0.001). There was no significant change in mean overall steroid burden per patient (mean Δ-1445.63 ± 1603.18 mg, p = 0.10), ACT scores (mean Δ2.88 ± 6.71, p = 0.17), FEV1 z-scores (mean Δ-0.99 ± 1.88, p = 0.053), FEF25–75% z-scores (mean Δ-0.65 ± 1.61, p = 0.13), FeNO (mean Δ-20.09 ± 80.86, p = 0.34), or number of courses of oral steroids given for asthma attacks (IRR 0.71, p = 0.09). Conclusion Among children and adolescents with severe eosinophilic asthma ineligible for or not responsive to omalizumab, mepolizumab therapy exhibited significant reduction in rate of asthma-related hospitalizations and significant decrease in daily steroid dosage.

Effect of overweight/obesity on relationship between fractional exhaled nitric oxide and airway hyperresponsiveness in Chinese elderly patients with asthma.

Purpose: This retrospective study investigates the influence of overweight and obesity status on pulmonary function, airway inflammatory markers, and airway responsiveness in elderly asthma patients. Methods: Patients with asthma older than 65years old who completed a bronchial provocation test (BPT) or bronchial dilation test (BDT) and a fractional exhaled nitric oxide (FeNO) test between December 2015 and June 2020 were identified retrospectively for this study. All of the patients were categorized into overweight/obesity and non-obesity groups based on their BMI. Pulmonary function test (PFT) and FeNO measurements were accomplished according to the 2014 recommendations of the Chinese National Guidelines of Pulmonary Function Test and American Thoracic Society/European Respiratory Society recommendations, respectively. Results: A total of 136 patients with an average age of 71.2 ± 5.40years were identified. The average BMI was 23.8 ± 3.63, while the value of FeNO was 42.3 ± 38.4 parts per billion (ppb). In contrast to the non-obesity group, which had a value of 48.8 ± 43.1 ppb for FeNO, the overweight/obesity group had a significant lower value of 35.4 ± 31.4 ppb. There was no significant difference in the proportion of individuals with high airway hyperresponsiveness between the overweight/obesity and non-obesity groups (96 patients in total). Multiple linear regression analysis established an inverse correlation between FeNO and Provocation concentration causing a 20% fall in FEV1(PC20) but excluded significant relationships with age and BMI. The model's R is 0.289, and its p value is 0.045. Conclusion: The elderly Chinese Han asthmatics with overweight/obesity had lower FeNO levels than those with non-obese according to our findings. In addition, the FeNO level was inversely correlated between FeNO levels and PC20 in elderly asthmatics.

Simultaneous real-time detection of fractional exhaled nitric oxide and end-tidal carbon dioxide by quantum cascade laser absorption spectroscopy

The simultaneous detection of fractional exhaled nitric oxide (FeNO) and end-tidal carbon dioxide (ETCO2) is of great importance for the distinguishing and diagnosis of asthma and chronic obstructive pulmonary disease (COPD), providing more comprehensive information on respiratory disorders. This work demonstrates a simultaneous ETCO2 and FeNO detection system based on quantum cascade laser absorption spectroscopy (QCLAS) technology was presented. The system employs wavelength modulation spectroscopy (WMS) technology and the Herriott multi-pass cell, achieving a detection limit of 2.82 ppb for nitric oxide (NO) and 0.05 % for carbon dioxide (CO2). Real-time exhalation measurements were performed on volunteers with varying ETCO2 and FeNO levels, and the results of the test can accurately distinguish whether the corresponding volunteer was healthy, had asthma or COPD. The effect of exhalation flow rate on the concentration of the two gases was explored. A range of expiratory flow rates were tested in the flow rate interval from 1 to 4 L/min, and there was always an inverse relationship between expiratory flow rate and FeNO concentration, but flow rate changes did not affect ETCO2 concentration. The results indicate that this detection system can simultaneously and effectively measure ETCO2 and FeNO concentrations in real-time.

Use of digital measurement of medication adherence and lung function to guide the management of uncontrolled asthma (INCA Sun): a multicentre, single-blinded, randomised clinical trial

The clinical value of using digital tools to assess adherence and lung function in uncontrolled asthma is not known. We aimed to compare treatment decisions guided by digitally acquired data on adherence, inhaler technique, and peak flow with existing methods. A 32-week prospective, multicentre, single-blinded, parallel, randomly controlled trial was done in ten severe asthma clinics across Ireland, Northern Ireland, and England. Participants were 18 years or older, had uncontrolled asthma, asthma control test (ACT) score of 19 or less, despite treatment with high-dose inhaled corticosteroids, and had at least one severe exacerbation in the past year despite high-dose inhaled corticosteroids. Patients were randomly assigned in a 1:1 ratio to the active group or the control group, by means of a computer-generated randomisation sequence of permuted blocks of varying sizes (2, 4, and 6) stratified by fractional exhaled nitric oxide (FeNO) concentration and recruitment site. In the control group, participants were masked to their adherence and errors in inhaler technique data. A statistician masked to study allocation did the statistical analysis. After a 1-week run-in period, both groups attended three nurse-led education visits over 8 weeks (day 7, week 4, and week 8) and three physician-led treatment adjustment visits at weeks 8, 20, and 32. In the active group, treatment adjustments during the physician visits were informed by digital data on inhaler adherence, twice daily digital peak expiratory flow (ePEF), patient-reported asthma control, and exacerbation history. Treatment was adjusted in the control group on the basis of pharmacy refill rates (a measure of adherence), asthma control by ACT questionnaire, and history of exacerbations and visual management of inhaler technique. Both groups used a digitally enabled Inhaler Compliance Assessment (INCA) and PEF. The primary outcomes were asthma medication burden measured as proportion of patients who required a net increase in treatment at the end of 32 weeks and adherence rate measured in the last 12 weeks by area under the curve in the intention-to-treat population. The safety analyses included all patients who consented for the trial. The trial is registered with ClinicalTrials.gov, NCT02307669 and is complete. Between Oct 25, 2015, and Jan 26, 2020, of 425 patients assessed for eligibility, 220 consented to participate in the study, 213 were randomly assigned (n=108 in the active group; n=105 in the control group) and 200 completed the study (n=102 in the active group; n=98 in the control group). In the intention-to-treat analysis at week 32, 14 (14%) active and 31 (32%) control patients had a net increase in treatment compared with baseline (odds ratio [OR] 0·31 [95% CI 0·15-0·64], p=0·0015) and 11 (11%) active and 21 (21%) controls required add-on biological therapy (0·42 [0·19-0·95], p=0·038) adjusted for study site, age, sex, and baseline FeNO. Three (16%) of 19 active and 11 (44%) of 25 control patients increased their medication from fluticasone propionate 500 μg daily to 1000 μg daily (500 μg twice a day; adjusted OR 0·23 [0·06-0·87], p=0·026). 26 (31%) of 83 active and 13 (18%) of 73 controls reduced their medication from fluticasone propionate 1000 μg once daily to 500 μg once daily (adjusted OR 2·43 [1·13-5·20], p=0·022. Week 20-32 actual mean adherence was 64·9% (SD 23·5) in the active group and 55·5% (26·8) in the control group (between-group difference 11·1% [95% CI 4·4-17·9], p=0·0012). A total of 29 serious adverse events were recorded (16 [55%] in the active group, and 13 [45%] in the control group), 11 of which were confirmed as respiratory. None of the adverse events reported were causally linked to the study intervention, to the use of salmeterol-fluticasone inhalers, or the use of the digital PEF or INCA. Evidence-based care informed by digital data led to a modest improvement in medication adherence and a significantly lower treatment burden. Health Research Board of Ireland, Medical Research Council, INTEREG Europe, and an investigator-initiated project grant from GlaxoSmithKline.

Clinical efficacy of omalizumab for treatment of moderate or severe allergic asthma in children with serum immunoglobulin E levels >1 500 IU/mL: a prospective study

To evaluate the clinical efficacy of omalizumab in the treatment of moderate or severe allergic asthma in children with serum total immunoglobulin E (IgE) levels >1 500 IU/mL. A total of 95 children with moderate or severe allergic asthma, who were treated at the Department of Respiratory Medicine in Anhui Provincial Children's Hospital from December 2020 to May 2022, were enrolled. Based on their serum total IgE levels and whether they received omalizumab treatment, they were divided into a control group (IgE >1 500 IU/mL, no omalizumab treatment), a normal treatment group (IgE levels between 30 and 1 500 IU/mL, omalizumab treatment), and an ultra-high IgE treatment group (IgE >1 500 IU/mL, omalizumab treatment). The differences in clinical characteristics, Childhood Asthma Control Test (C-ACT) scores before and after treatment, the proportion of acute attacks, IgE levels, pulmonary function indicators, and fractional exhaled nitric oxide (FeNO) concentrations were analyzed among the three groups. At the 8th week of treatment, the normal treatment group and the ultra-high IgE treatment group had higher C-ACT scores, forced expiratory volume in first second (FEV1) as a percentage of predicted value (FEV1%pred), FEV1/forced vital capacity (FVC) ratio (FEV1/FVC), and peak expiratory flow (PEF) as a percentage of predicted value (PEF%pred), as well as a lower proportion of acute attacks and FeNO concentration compared to the control group (P<0.05). There were no statistically significant differences in the comparison of various indicators between the ultra-high IgE treatment group and the normal treatment group (P>0.05). At the 16th week of treatment, the normal treatment group and the ultra-high IgE treatment group had higher C-ACT scores and pulmonary function indicators including FEV1%pred, FEV1/FVC, PEF%pred, and forced expiratory flow at 25% vital capacity (FEF25) as a percentage of predicted value (FEF25%pred) compared to the control group (P<0.05). The proportion of acute attacks and FeNO concentration in the ultra-high IgE treatment group were lower than those in the control group (P<0.05). There were no statistically significant differences in the comparison of various indicators between the ultra-high IgE treatment group and the normal treatment group (P>0.05). Omalizumab therapy has a certain clinical efficacy in children with moderate or severe allergic asthma and serum total IgE levels >1 500 IU/mL, with no significant difference in efficacy compared to children with serum total IgE levels between 30 and 1 500 IU/mL.

Is tezepelumab the ubiquitous biologic for severe asthma?

Biologic therapies have transformed severe asthma management.1 The use of these treatments has been based on the identification of specific phenotypic characteristics, which predict patient response to specific monoclonal antibody therapies. Measurements of total serum immunoglobulin (Ig)-E, blood eosinophil counts, and fractional concentration of exhaled nitric oxide (FeNO), enable the identification of specific type 2-high phenotypes responsive to specific biologic therapies. However, in clinical practice the paucity of biologics effective for both type 2-high and type 2-low asthma phenotypes is an important limitation of this therapeutic approach.

Evaluation of fractional exhaled nitric oxide in school-age children with asthma and sensitization to cat allergens

bronchial asthma is a chronic condition that is considerably prevalent among children. According to scientific evidence, cat allergens are most frequently responsible for the onset of asthma manifestations in children. Children are more likely to develop atopic asthma with eosinophilic inflammation. Under these circumstances, specific biomarkers are used as indicators of this inflammation. Fractional exhaled nitric oxide has been identified as a marker of eosinophilic airway inflammation in asthma. The aim of the research was to determine the fractional exhaled nitric oxide concentrations in school-age children with bronchial asthma and sensitization to cat allergens in order to predict asthma control status and assess therapeutic response. A total of 430 children aged between 6 and 17 years with asthma and sensitization to cat allergens participated in the study. The sensitization profile was investigated using a multicomponent molecular allergy diagnostic test (ALEX², Austria). The fractional exhaled nitric oxide levels were evaluated (NIOX VERO, Sweden). A total of 302 patients were enrolled in a retrospective study to find out how likely they were to gain bronchial asthma control over the course of therapy. As a result, a one-factor logistic regression analysis was conducted. A total of 128 children were included in the 12-month prospective research. All patients had a rise in fractional exhaled nitric oxide of &gt; 20 ppb, with children with severe asthma having levels of 35 ppb or higher. The study discovered that changes in the fractional exhaled nitric oxide concentrations at the end of a three-month therapy could be linked to the maintenance of bronchial asthma control after a 12-month treatment period (r = 0.619; p &lt;0.001). After a year of therapy, increasing baseline fractional exhaled nitric oxide levels reduced the probability of establishing bronchial asthma control in children (OR &lt;1; p &lt;0.001). The dynamics of fractional exhaled nitric oxide reduction increased the probability of achieving bronchial asthma control after completion of a three-month therapy (OR&gt; 1; p &lt;0.001). The effect of allergen-specific immunotherapy on the specified indicator of eosinophilic inflammation was demonstrated by a statistically significant difference in the mean values of fractional exhaled nitric oxide after a 12-month treatment period in the group of patients who received allergen-specific immunotherapy in combination with controller therapy versus the group of patients who received only controller therapy (p = 0.012). Thus, among school-age children with asthma and sensitization to cat allergens, the levels of fractional exhaled nitric oxide increased, especially in severe asthma. Not only the baseline fractional exhaled nitric oxide levels but also their dynamics after a three-month therapy should be considered when predicting the probability of establishing asthma control in these children. The inclusion of allergen-specific immunotherapy in the complex treatment of bronchial asthma in school-age children with sensitization to cat allergens has been shown to have a favourable therapeutic effect on the fractional exhaled nitric oxide levels.

Airway inflammation in adolescents and elderly women: Chronic air pollution exposure and polygenic susceptibility

Background and aimThe fractional exhaled nitric oxide (FeNO) concentration in the exhaled breath is a biomarker for eosinophilic airway inflammation. We explored the interplay between chronic air pollution exposure and polygenic susceptibility to airway inflammation at different critical age stages. MethodsAdolescents (15 yr) enrolled in the GINIplus/LISA birth cohorts (n = 2434) and 220 elderly women (75 yr on average) enrolled in the SALIA cohort with FeNO measurements available were investigated. Environmental main effects of the mean of ESCAPE land-use regression air pollutant concentrations within a time window of 15 years and main effects of the polygenic risk scores (PRS) using internal weights from elastic net regression of genome-wide derived single nucleotide polymorphisms were investigated. Furthermore, we examined gene-environment interaction (GxE) effects on natural log-transformed FeNO levels by adjusted linear regression models. ResultsWhile we observed no significant environmental and polygenic main effects on airway inflammation in either age group, we found robust harmful effects of chronic nitrogen dioxide (NO2) exposure in the GxE models for elderly women (16.2 % increase in FeNO, p-value = 0.027). Stratified analyses found GxE effects between the PRS and chronic NO2 exposure in never-smoker elderly women and in adolescents without any inflammatory respiratory conditions. ConclusionsFeNO measurement is a useful biomarker to detect higher risk of NO2-induced eosinophilic airway inflammation in the elderly. There was limited evidence for GxE effects on airway inflammation in adolescents or the elderly. Further GxE studies in subpopulations should be conducted to investigate the assumption that susceptibility to airway inflammation differs between age stages.

Fractional exhaled nitric oxide and mortality in asthma and chronic obstructive pulmonary disease in a national cohort aged 40 years and older

BackgroundLittle is known about Fractional concentration of exhaled Nitric Oxide (FeNO) as a predictor of mortality in persons with asthma or chronic obstructive pulmonary disease (COPD). ObjectiveThis study tested the hypotheses that FeNO level ≥ 25 ppb was associated with mortality in a national cohort of persons with asthma or COPD age ≥ 40 years. MethodsIn the 2007–2012 National Health and Nutrition Examination Survey (NHANES), FeNO was measured using an electrochemical sensor. Mortality was determined through 2015 using linkage to the National Death Index. Weighted Cox proportional hazards survival analysis was performed taking the complex survey design into account using STATA V.17. ResultsAmong the 611 participants with current asthma, 5.16% died during the follow-up period. FeNO ≥ 25 ppb was associated with a hazard ratio (HR) of 0.20, (p = 0.006, 95% CI:0.068–0.618) alone or with little change after controlling for confounding variables. Due to effect modification, the analysis was repeated in persons with and without a history of emergency department (ED) visit for asthma in the previous year. In 522 persons without ED visits, FeNO ≥ 25 ppb was significantly associated with mortality HR 0.094, 95 CI 0.034–0.26, p < 0.001. In 83 persons with ED visits no significant association remained after controlling for all confounders. (Six persons were omitted from this analysis due to missing data on confounders in the extended regression model.) Among 614 with COPD, FeNO ≥ 25 ppb was not associated with mortality. ConclusionIn persons with current asthma at baseline, FeNO ≥ 25 ppb was associated with reduced hazard of mortality during follow up among those with no history of ED visits in the previous year. No significant association of FeNO with mortality was seen in persons with COPD.

Epidemic thunderstorm asthma

Epidemic thunderstorm asthma

Benralizumab Effectiveness in Severe Asthma Is Independent of Previous Biologic Use

Benralizumab is an IL-5 receptor alpha-directed cytolytic mAb that depletes eosinophils, reducing exacerbations and oral corticosteroid (OCS) use, and improves asthma control for patients with severe eosinophilic asthma (SEA). Data on response in patients previously treated with other biologic therapies are limited. To describe real-world clinical outcomes with benralizumab for patients with and without prior biologic use for uncontrolled SEA. This retrospective study compared clinical outcomes before and after benralizumab initiation in adults with uncontrolled SEA with 3 or more asthma exacerbations in the previous 12 months or on maintenance OCS treatment. Outcomes included exacerbations, OCS use, patient-reported outcomes, and health care resource utilization, including emergency department visits and hospitalizations. In all, 208 patients were enrolled, including 90 (43.3%) with previous experience with an alternate biologic for SEA. Benralizumab led to an 81% reduction in exacerbation rate, with 48% of patients with previous exacerbations experiencing none after 48 weeks. Overall, 67% of patients requiring baseline maintenance OCS achieved greater than or equal to 50% reduction in daily OCS dosage, and 53% eliminated maintenance OCS. Clinically meaningful improvements in patient-reported outcomes were seen, with response at 4 weeks predicting longer-term benefits. Health care resource utilization also decreased. Improvements were observed irrespective of previous biologic experience, fractional exhaled nitric oxide concentrations, atopic status, or other baseline characteristics. In a multicenter real-world setting, patients with uncontrolled SEA achieved substantial improvements in all clinical outcome measures with benralizumab irrespective of previous biologic use, atopic status, or baseline fractional exhaled nitric oxide concentration.

Factors Influencing the Concentration of Exhaled Nitric Oxide (FeNO) in School Children Aged 8-9-Years-Old in Krakow, with High FeNO Values ≥ 20 ppb.

Background and Objectives: Measurement of fractional exhaled nitric oxide (FeNO) concentration is currently used as a non-invasive biomarker to assess airway inflammation. Many factors can influence the FeNO level. However, there have been no reports concerning factors attributed to FeNO levels in different age groups of children, especially those with high FeNO values. Therefore, this study aimed to assess the influence of selected factors on nitric oxide concentration in exhaled air in children aged 8–9 attending class 3 of public primary schools in Krakow with high FeNO values ≥ 20 ppb. Materials and Methods: The population-based study covered all third-grade pupils attending primary schools in the city of Krakow. Five thousand, four hundred and sixty children participated in the first screening stage, conducted from October 2017 to January 2018. Then, 792 participants with an FeNO level ≥ 20 ppb were selected. Finally, those selected pupils were invited to participate in the second stage, diagnostic, in April 2018. Four hundred and fifty-four children completed the diagnostic stage of the study, and their data was included in the presented analysis. Results and Conclusions: Significantly higher FeNO levels were observed in children diagnosed with the following diseases: asthma, allergic rhinitis, atopic dermatitis, and allergy (p < 0.05). In addition, it was observed that a higher FeNO concentration characterised children taking antihistamines compared to children not taking those medications (p = 0.008). In multivariate models, we observed that regardless of sex, age, BMI value, home smoking, and whether they were taking medications, children who had allergic rhinitis, or atopic dermatitis, or allergies had significantly higher FeNO levels. The strongest relationship was noted with allergic diseases. The results of our study may be of importance to clinicians when interpreting FeNO results, for example, when making a therapeutic decision.

Hierarchical Bayesian estimation of covariate effects on airway and alveolar nitric oxide

Exhaled breath biomarkers are an important emerging field. The fractional concentration of exhaled nitric oxide (FeNO) is a marker of airway inflammation with clinical and epidemiological applications (e.g., air pollution health effects studies). Systems of differential equations describe FeNO—measured non-invasively at the mouth—as a function of exhalation flow rate and parameters representing airway and alveolar sources of NO in the airway. Traditionally, NO parameters have been estimated separately for each study participant (Stage I) and then related to covariates (Stage II). Statistical properties of these two-step approaches have not been investigated. In simulation studies, we evaluated finite sample properties of existing two-step methods as well as a novel Unified Hierarchical Bayesian (U-HB) model. The U-HB is a one-step estimation method developed with the goal of properly propagating uncertainty as well as increasing power and reducing type I error for estimating associations of covariates with NO parameters. We demonstrated the U-HB method in an analysis of data from the southern California Children’s Health Study relating traffic-related air pollution exposure to airway and alveolar airway inflammation.

ACUTE DIETARY NITRATE MAY IMPAIR CUTANEOUS VASCULAR CONDUCTANCE DURING LOCAL SKIN HEATING IN POSTMENOPAUSAL WOMEN

Declining estradiol production during menopause is linked to increased oxidative stress and reduced endothelial-dependent vasodilation. It is unknown whether supplementation with dietary nitrate may improve nitric oxide (NO) bioactivity and microvascular function in postmenopausal women. PURPOSE: To determine the effects of acute dietary nitrate ingestion on NO-mediated cutaneous vascular conductance (CVC) in a cohort of postmenopausal women. METHODS: In eight women (mean ± SD: age = 62 ± 4 y, BMI = 31 ± 2 kg/m2), two laser-Doppler flowmetry probes were affixed to the dorsal aspect of the forearm for measurement of red blood cell (RBC) flux during local skin heating to 39 °C and 44 °C. Assessments were made before and 3 h after ingesting 140 mL of beetroot juice containing 12.9 mmoL of inorganic nitrate. Fractional exhaled nitric oxide (FeNO) concentrations were measured at the same time points. Cutaneous vascular conductance (CVC) at 39 °C was calculated as RBC flux/ mean arterial pressure then normalized as a proportion of maximal CVC at 44°C. During the plateau phase at 39 °C, median spectral power of the endothelial NO-dependent frequency interval was analyzed using a Morlet wavelet transform. Pre-post comparisons were performed using within-sample t-tests. RESULTS: Following beetroot juice ingestion, FeNO concentrations (mean ± SD: 18 ± 8 ppb vs. 35 ± 16 ppb; p = 0.006, dz = 1.4) and spectral power of the NO-dependent frequency interval (0.01 - 0.02 Hz; p = 0.018, dz = 1.1) increased. Despite evidence for greater NO bioavailability, CVC at 39 °C was reduced (76 ± 12% vs. 50 ± 18%; p < 0.001, dz = 2.3). There was no change in maximal CVC at 44 °C (p = 0.287). CONCLUSION: A functional consequence of increased NO-bioavailability with acute dietary nitrate ingestion appears to be a diminished NO-mediated CVC response to local skin heating in our cohort of postmenopausal women with overweight and obesity. Future research should consider the effects of dietary nitrate coupled with an antioxidant supplement as means to further support NO-mediated endothelial function in such populations.

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

Measurement of Nitrogen Oxide in Expired Breath Using Porous Glass Analytical Chips

Introduction Fractional exhaled nitric oxide (FeNO) is present in high concentrations in the breath of asthma patients with type 2 airway inflammation. In addition, FeNO concentration varies with asthma symptoms and treatments. The cutoff point for FeNO in adults with asthma is 20 - 25 ppb, and > 50 ppb is considered severe inflammation [1]. FeNO measurement is used worldwide for clinical examination of asthma [1-2]. However, FeNO measurement is limited to specific medical institutions. Therefore, patients need to return to the institution for exhaled breath analysis of FeNO concentration.We have developed an analytical chip—based on porous glass—for a simplified NO analysis [3-4]. This chip can detect ~ 19 ppb of FeNO in adults; ppb-level sensitivity is achieved by collecting exhaled breath in a sampling bag. However, the detection took several hours. In this study, low NO concentration was detected in tens of minutes by combining a porous glass analytical chip with a small sampling pump. We believe this method will enable at-home FeNO measurement. Method Preparation of porous glass analytical chip All chemical reagents were purchased from Tokyo-Kasei Co. (Japan) and FUJIFILM Wako Pure Chemical Corporation (Japan). The substrate of the analytical chip was a porous glass (Vycor #7930, Corning Co.) with a size of 8 mm × 8 mm × 1 mm, a specific surface area of 200 m2g-1, and an average pore size of 4 nm. The NO/NO2 conversion and NO2 analytical chips were prepared using our previously reported method [4]. Three different NO/NO2 conversion chips were prepared by immersing the porous glass in a 2-phenyl-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl (PTIO) ethanol solution (3.3 × 10–3, 33 × 10–3, and 160 × 10–3 mol L- 1), followed by drying. The NO2 analytical chip was prepared by immersing the porous glass in an alcohol solution of 2.5 × 10–3 mol L- 1 N, N-dimethyl-1-naphthyl-amine, and 2.0 × 10–2 mol L- 1 sulfanilamide and then drying it. Exposure to the NO atmosphere The exposure experiment was carried out by placing a NO/NO2 conversion chip and a NO2 analytical chip adjacent to each other in the chip holder. Using a small sampling pump (MP-∑30NII, SIBATA SCIENTIFIC TECHNOLOGY LTD., Japan), the NO atmosphere flowed through the two chips for 20 min at 0.05 L min- 1 (Fig. 1). The NO atmosphere (30, 75, 145, and 200 ppb) was prepared by mixing 100 ppm NO/NO2 gas with nitrogen gas in a Tedlar® bag. The relative humidity of the NO atmosphere was adjusted to 40% by vaporizing deionized water (235 - 280 mL) injected into the Tedlar® bag. The absorbance of the chips was measured using an ultraviolet-visible spectrophotometer (U-4100, HITACHI, Japan). The NO and NO2 concentrations in the NO atmosphere before and after passing through the chips were measured via a NO-NO2-NOx analyzer (42C, Nippon Thermo Co. Ltd., Japan). Results and Conclusions The NO/NO2 conversion efficiencies of the three prepared conversion chips (3.3 × 10–3, 33 × 10–3, and 160 × 10–3 mol L- 1) were 11%, 31%, and 61%, respectively. Increasing the PTIO content in the conversion chip improved the NO/NO2 conversion efficiency. Therefore, a low NO concentration measurement in an active system was evaluated using a conversion chip with an efficiency of 61%. Fig. 2 shows the relationship between the change in absorbance at 525 nm of the NO2 analytical chip and the initial NO concentration. The absorbance of the NO2 analytical chip at 525 nm increased due to the azo dye produced by the chemical reaction between NO2 and the detection reagents [4], and there was a positive linear relationship between the change in absorbance of the NO2 chip and NO concentration at 525 nm. Therefore, the formula for NO concentration measured at a flow rate of 0.05 L min- 1 for 20 min is as follows:[NO]0 = 4760 × ΔAbs525 where is the NO concentration (ppb) in the atmosphere, and is the change in absorbance at 525 nm of the NO2 analytical chip before and after exposure. This result suggests that FeNO can be measured in 20 min by using the analytical chip with an active method. References A. Hanania, M. Massanari, N. Jain, Measurement of fractional exhaled nitric oxide in real-word clinical practice alters asthma treatment decisions, Ann. Allergy Asthma Immunol.120 (2018) 414-418. doi: 10.1016/j.anai.2018.01.031.W. Pijnenburg, The Role of FeNO in Predicting Asthma, Front. Pediatr. 7 (2019) 1-5. doi: 10.3389/fped.2019.00041.Asanuma, S. Hino, Y. Y. Maruo, Development of an analytical chip for nitrogen monoxide detection using porous glass impregnated with 2-phenyl-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl, Microchem. J. 151 (2019) 104251. doi: 10.1016/j.microc.2019.104251.Asanuma, K. Numata, Y. Y. Maruo, A colorimetric method for the measurement of ppb-level NO in exhaled air using porous glass analytical chip, Sensors and Actuators Reports 2 (2020) 100019. doi: 10.1016/j.snr.2020.100019. Figure 1