Low Fractional Exhaled Nitric Oxide Research Articles

Correlation of fractional exhaled nitric oxide (FeNO) and clinical outcomes in patients with chronic obstructive pulmonary disease: A prospective cohort study

BackgroundFractional exhaled nitric oxide (FeNO) is an acceptable and noninvasive marker for defining eosinophilic airway inflammation. Further study is necessary to clarify the role of FeNO in patients with chronic obstructive pulmonary disease (COPD). This study aimed to determine the association between FeNO levels and clinical outcomes. MethodsA prospective observational study was conducted at Songklanagarind Hospital from October 2020 to November 2022. FeNO testing and spirometry were performed at the initial visit and 12-month follow-up. Exacerbation, hospitalization, lung function decline, and all-cause mortality were analyzed to determine the association between FeNO levels and clinical outcomes. ResultsA total of 60 patients with COPD were enrolled, 88.3% of whom were male, with a mean age of 71.3±9.5 years. There were 18 patients (30%) in the high FeNO group (≥25 ppb) and 42 patients (70%) in the low (<25 ppb) FeNO group. The mean blood eosinophil count (BEC) was significantly higher in the high FeNO group (p<0.001). After a 12-month follow-up period, high FeNO group had higher exacerbation events (HR of 1.26, 95% confidence interval (CI), 1.10–1.97, p 0.025). Hospitalization and mortality rates were significantly higher in the high FeNO group. Regardless of the inhaled corticosteroids used, patients with high BEC and FeNO levels tended to have a greater risk of exacerbation. ConclusionIn patients with COPD, FeNO levels are strongly correlated with BEC. Poor clinical outcomes were reported in patients with high FeNO levels. FeNO may be a useful biomarker for predicting clinical outcomes in patients with COPD.

Associations of fractional exhaled nitric oxide with airway dimension and mucus plugs on ultra-high-resolution computed tomography in former smokers and nonsmokers with asthma

BackgroundAssociations of fractional exhaled nitric oxide (FeNO) with airway wall remodeling and mucus plugs remain to be explored in smokers and nonsmokers with asthma. Ultra-high-resolution computed tomography (U-HRCT), which allows accurate structural quantification of airways >1 mm in diameter, was used in this study to examine whether higher FeNO was associated with thicker walls of the 3rd to 6th generation airways and mucus plugging in patients with asthma. MethodsThe retrospective analyses included consecutive former smokers and nonsmokers with asthma who underwent U-HRCT in a hospital. The ratio of wall area to summed lumen and wall area was calculated as the wall area percent (WA%). Mucus plugging was visually scored. ResultsNinety-seven patients with asthma (including 59 former smokers) were classified into low (<20 ppb), middle (20–35 ppb), and high (>35 ppb) FeNO groups (n = 24, 26, and 47). In analysis including all patients and subanalysis including nonsmokers or former smokers, WA% in the 6th generation airways was consistently higher in the high FeNO group than in the low FeNO group, whereas WA% in the 3rd to 5th generation airways was not. In multivariable models, WA% in the 6th generation airways and the rate of mucus plugging were higher in the high FeNO group than in the low FeNO group after adjusting for age, sex, body mass index, smoking status, lung volume, and allergic rhinitis presence. ConclusionsHigher FeNO may reflect the inflammation and remodeling of relatively peripheral airways in asthma in both former smokers and nonsmokers.

Exhaled Nitric Oxide and Olfactory Dysfunction in Patients with Asthma: Association with Chronic Rhinosinusitis.

Objectives: Olfactory dysfunction is a clinical sign that is important to detect with coexistent upper airway comorbidities in patients with asthma. This study aimed to investigate the etiology of olfactory dysfunction in patients with asthma and the relationship between fractional exhaled nitric oxide (FeNO) levels. Materials and Methods: This study included 47 asthma patients who were evaluated for olfactory dysfunction at Hiroshima University Hospital between 2012 and 2020. The etiologies of olfactory dysfunction were evaluated, and they were classified according to the FeNO levels of patients with asthma. Results: Olfactory dysfunction was observed in 30 patients with asthma, with chronic rhinosinusitis (77%) being the most prevalent etiology. Eosinophilic chronic rhinosinusitis (ECRS) was the most prevalent etiology of olfactory dysfunction in asthma patients with high FeNO levels (≥25 ppb), while non-eosinophilic chronic rhinosinusitis (NCRS) was the most prevalent etiology in asthma patients with low FeNO levels (<25 ppb). Additionally, the prevalence of ECRS was significantly higher in asthma patients with olfactory dysfunction and high FeNO levels (74%) than in those with either high FeNO levels or olfactory dysfunction and those with low FeNO levels and no olfactory dysfunction (12% and 9%, respectively). Conclusions: We found that ECRS was the predominant cause of olfactory dysfunction in patients with high FeNO levels, while NCRS was more common in those with low FeNO levels. The present study showed that both ECRS and NCRS are common etiologies of olfactory dysfunction in patients with asthma. Additionally, this study supports the link between upper and lower airway inflammation in patients with asthma complicated with olfactory dysfunction.

Biomarker-guided withdrawal of inhaled corticosteroids in asthma patients with a non-T2 inflammatory phenotype – a randomized controlled trial study protocol

BackgroundNon-T2 asthma is characterized by the absence of elevated type 2 inflammatory biomarkers such as blood-eosinophils, total and allergen-specific Immunoglobulin E and Fractional exhaled Nitric Oxide (FeNO). According to guidelines, inhaled corticosteroids (ICS) are the cornerstone of asthma management. However, ICS treatment is associated with a risk of local side effects, including hoarseness and thrush, and long-term high-dose therapy may cause systemic adverse effects. Furthermore, whereas treatment with ICS is highly effective in T2 asthma, studies have shown a markedly reduced ICS efficacy in patients with a lower degree of T2 inflammation, thus posing a clinical challenge in this subgroup of patients. Hence, owing to the ICS dosage step-up approach in current clinical guidelines, patients with low T2 biomarkers are at risk of being exposed to high doses of ICS, and by that at risk of side effects. Thus, an ICS-treatment regime guided by biomarkers that reflects the inflammatory phenotype is warranted in order to reduce the corticosteroid burden in patients with non-T2 asthma. This study combines a panel of non-T2 inflammatory markers (low periostin, low blood-eosinophils, and low FeNO), to determine if this group of patients can maintain asthma control during ICS withdrawal.MethodsThis is an ongoing prospective multicenter open-label randomized, controlled trial aiming to assess if ICS can be safely tapered in patients with non-T2 asthma. The patients are randomized 1:1 to either standard of care or an ICS tapering regimen (n = 55 in each group) where the initial ICS dose is reduced by 50% for 8 weeks followed by total ICS removal. The primary endpoint is change in asthma control questionnaire (ACQ) from baseline to post-tapered ICS. The secondary endpoints are time from baseline to drop-out caused by loss of asthma control, changes in serum-periostin, blood-eosinophils, FeNO, Forced Expiratory Volume in 1 s (FEV1) and in sputum-eosinophils.DiscussionThis study aims to provide data on ICS tapering in non-T2 asthma patients and to contribute to a more individualized and corticosteroid-sparing treatment regime in this group of patients.Trial registrationClinicaltrials.gov Identifier: NCT03141424. Registration date: May 5th, 2017.

Association between lipid-A-producing oral bacteria of different potency and fractional exhaled nitric oxide in a Norwegian population-based adult cohort

BackgroundLipid A is the primary immunostimulatory part of the lipopolysaccharide (LPS) molecule. The inflammatory response of LPS varies and depends upon the number of acyl chains and phosphate groups in lipid A which is specific for a bacterial species or strain. Traditional LPS quantification assays cannot distinguish between the acylation degree of lipid A molecules, and therefore little is known about how bacteria with different inflammation-inducing potencies affect fractional exhaled nitric oxide (FeNO). We aimed to explore the association between pro-inflammatory hexa- and less inflammatory penta-acylated LPS-producing oral bacteria and FeNO as a marker of airway inflammation.MethodsWe used data from a population-based adult cohort from Norway (n = 477), a study center of the RHINESSA multi-center generation study. We applied statistical methods on the bacterial community- (prediction with MiRKAT) and genus-level (differential abundance analysis with ANCOM-BC) to investigate the association between the oral microbiota composition and FeNO.ResultsWe found the overall composition to be significantly associated with increasing FeNO levels independent of covariate adjustment, and abundances of 27 bacterial genera to differ in individuals with high FeNO vs. low FeNO levels. Hexa- and penta-acylated LPS producers made up 2.4% and 40.8% of the oral bacterial genera, respectively. The Bray–Curtis dissimilarity within hexa- and penta-acylated LPS-producing oral bacteria was associated with increasing FeNO levels independent of covariate adjustment. A few single penta-acylated LPS producers were more abundant in individuals with low FeNO vs. high FeNO, while hexa-acylated LPS producers were found not to be enriched.ConclusionsIn a population-based adult cohort, FeNO was observed to be associated with the overall oral bacterial community composition. The effect of hexa- and penta-acylated LPS-producing oral bacteria was overall significant when focusing on Bray–Curtis dissimilarity within each of the two communities and FeNO levels, but only penta-acylated LPS producers appeared to be reduced or absent in individuals with high FeNO. It is likely that the pro-inflammatory effect of hexa-acylated LPS producers is counteracted by the dominance of the more abundant penta-acylated LPS producers in this population-based adult cohort involving mainly healthy individuals.

Pesticide exposure and asthma morbidity in children residing in urban, multi-family housing.

Children are potentially more susceptible to the adverse effects of pesticides due to more sensitive organ systems and lower capacity to metabolize and eliminate chemicals compared to adults. The health risks are particularly concerning children with asthma, living in low-income neighborhoods in multi-family housing because of their impaired respiratory health, and factors associated with low-income, multi-family environments. To assess the association between pesticide exposure and asthma morbidity among children 7-12 years residing in low-income, multi-family housing. The concentrations of seven urinary pesticide biomarkers: 3,5,6-trichloro-2-pyridinol (TCPy), 2-isopropyl-4-methyl-6-hydroxypyrimidine, para-nitrophenol (PNP), 3-phenoxybenzoic acid (3-PBA), 4-fluoro-3-phenoxybenzoic acid, trans-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid, and 2,4-dichlorophenoxyacetic acid (2,4-D) were measured. Children (n = 162) were followed for one year with three measures of pesticides biomarkers. Associations between individual biomarkers and asthma attack, asthma related health care utilization, and fraction of exhaled nitric oxide (FeNO), adjusting for demographic and household factors were examined with Generalized Estimating Equations (GEE). Weighted Quantile Sum (WQS) regression was used to examine the effect of pesticide mixture on asthma attacks and asthma-related health care utilization (HCU). In adjusted GEE models, positive non-significant associations were found between PNP and HCU (adjusted Odds Ratio(aOR):2.05 95% CI:0.76-5.52) and null associations for 3-PBA and HCU (aOR:1.07 95% CI: 0.88-1.29). Higher concentrations of PNP and 2,4-D were associated with significantly lower FeNO levels (PNP: -17.4%; 2,4-D:-19.74%). The mixture was positively associated with HCU in unadjusted (OR: 1.56 97.5% CI: 1.08-2.27) but not significant in adjusted models (aOR: 1.40 97.5% CI: .86-2.29). The non-specific pyrethroid biomarker 3-PBA at baseline contributed the greatest weight to the index (45%). There were non-significant associations between pesticide biomarkers and respiratory outcomes in children with asthma. There was a suggestive association between urinary pesticide biomarkers and HCU. Further studies with larger sample sizes could help to confirm these findings. Pesticide exposure among children in the urban environment is ubiquitous and there is a dearth of information on the impact of low-level chronic exposure in vulnerable populations. This study suggested that pesticide exposure at concentrations below the national average may not affect asthma morbidity in children. However, different biomarkers of pesticides showed different effects, but the mixture suggested increasing pesticide exposure results in asthma related HCU. The results may show that children with asthma may be at risk for negative health outcomes due to pesticides and the need to further examine this relationship.

Simultaneous evaluation of the fractional exhaled nitric oxide and blood eosinophil count of T2-high endotype in patients with non-cystic fibrosis bronchiectasis.

Recently, a type 2 inflammation (T2) high endotype in bronchiectasis was identified. The fraction of exhaled nitric oxide (FeNO) and blood eosinophil count (BEC) are recognized as representative biomarkers of T2 inflammation. Herein, we investigate the clinical characteristics of T2-high endotype in non-cystic fibrosis bronchiectasis patients classified by FeNO and BEC. This retrospective study included 164 bronchiectasis patients treated in the First Affiliated Hospital of Sun Yat-sen University from December 2017 to July 2022. Clinical characteristics were analyzed after classifying patients into four groups according to T2 inflammation biomarkers (FeNO ≥25ppb; BEC ≥200/µL). Among the 164 bronchiectasis patients, 35.3% (58/164) presented with high FeNO, 30.5% (50/164) presented with high BEC, and 10.4% (17/164) had high FeNO and BEC. Patients with high FeNO and low BEC presented with better lung function, fewer affected lobes, and lower dyspnea prevalence compared with the three other groups. Moreover, decreased FeNO, instead of decreased BEC, is revealed to be an independent predictor for disease severity and airflow obstruction in bronchiectasis. Simultaneous evaluation of FeNO and BEC proposed different endotypes of bronchiectasis established that patients with low BEC and high FeNO had better lung function, fewer affected lobes, lower dyspnea prevalence, and less disease severity. This result will contribute to a more comprehensive assessment of the disease severity and lead to more precise treatment of T2 inflammation in bronchiectasis patients.

Long-Term Outcome of Occupational Asthma From Irritants and Low-Molecular-Weight Sensitizers

The short-term asthma outcome of irritant-induced asthma (IIA) is poorer than that of low-molecular-weight (LMW) sensitizer-induced occupational asthma (OA). To evaluate the long-term asthma outcome of IIA and LMW-induced OA and to determine which baseline features are associated with a poor long-term outcome. This follow-up questionnaire study assessed 43 patients diagnosed with IIA and 43 patients with LMW-induced OA at the Finnish Institute of Occupational Health in 2004-2018. The baseline results were analyzed to detect features associated with uncontrolled asthma (Asthma Control Test [ACT] score of ≤19, or ≥2 exacerbations or ≥1 serious exacerbation within 1 year) at follow-up. The median interval since OA diagnosis was 6.3 years (interquartile range [IQR]: 4.4-11.3 years). Uncontrolled asthma was more frequent with IIA than with LMW-induced OA (58% vs 40%, adjusted odds ratio [OR]: 3.60, 95% confidence interval [CI]: 1.20-10.81). Poor symptom control was the main factor for this difference (median [IQR] ACT score of 18 [15-22] vs 21 [18-23], P= .036, respectively). Among all participants, older age (OR: 1.08 per year, 95% CI: 1.02-1.15), a fractional exhaled nitric oxide (FeNO) value <20 ppb (OR: 5.08, 95% CI: 1.45-17.80), and uncontrolled asthma at baseline (OR: 3.94, 95% CI: 1.31-11.88) were associated with uncontrolled asthma at follow-up. Long-term asthma control of IIA appears to be inferior to that of LMW-induced OA. Older age, a low FeNO value, and uncontrolled asthma at baseline might indicate a worse long-term outcome among those with IIA and LMW-induced OA.

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.

Treatment Resistance in Severe Asthma Patients With a Combination of High Fraction of Exhaled Nitric Oxide and Low Blood Eosinophil Counts.

Background: Combining a fraction of exhaled nitric oxide (FeNO) and blood eosinophil count (B-EOS) may be a useful strategy for administration of biologics such as anti-IgE or anti-IL-5 to patients with type 2 inflammatory-predominant severe asthma and is important to be elucidated considering the increasing use of biologics. Methods: This cross-sectional study analyzed the clinical data from 114 adult patients with severe asthma, who were treated at Saitama Medical University Hospital. The eligible patients were stratified into four subgroups defined by thresholds of FeNO and blood eosinophil (B-EOS) counts to detect sputum eosinophilia, using the receiver operating characteristic curve analysis. A total of 75 patients with optimal samples were stratified into four subtypes defined by thresholds of sputum eosinophilia and neutrophilia. Clinical characteristics, pattern of biologics, and distribution of sputum subtypes were analyzed in the stratified subclasses according to the FeNO and B-EOS thresholds. The asthma exacerbation (AE)-free time of the FeNO/B-EOS subgroups and any biologics treatment including anti-IgE or anti-IL-5 use were examined using the Kaplan–Meier method. The hazard ratios (HRs) for AE-free time were examined using the Cox proportional hazard model. Results: The optimal cutoff values for prediction of sputum eosinophilia were defined as ≥2.7% wherein for FeNO as ≥27 ppb and B-EOS as ≥265/µL were considered. The high-FeNO subgroups showed significant high total IgE, compared with the low FeNO. The high-FeNO/high-B-EOS and the high-FeNO/low-B-EOS subgroups showed the largest prevalence of mepolizumab and benralizumab use among the other FeNO/B-EOS, respectively. The high-FeNO/low-B-EOS showed the largest frequency of AEs, high HR, and the shortest AE-free time, among the other FeNO/B-EOS. The sputum eosinophil-predominant subtype was the great majority in the high FeNO/high B-EOS. A diverse distribution of sputum leukocyte-predominant subtype was observed in the other FeNO/B-EOS. The subsequent AE-free time and its HR were comparable among the biologics use groups. Conclusion: The strategy of classifying severe asthma based on the combination of FeNO and B-EOS proposes particular refractory type 2 severe asthma and underlying airway inflammation as a feasible trait for optimal biologics use.

The levels and correlations of FeNO, blood eosinophils and lung function in well-controlled asthma.

Whether biomarkers (i.e., fractional exhaled nitric oxide (FeNO) and blood eosinophils) or lung function are additional ultimate outcomes in asthma treatment among patients with clinical remission has been the subject of previous research, the study of the correlations between FeNO, blood eosinophils and lung function among well-controlled asthmatic patients is less clear. To investigate the clinical application of the correlation between FeNO, blood eosinophils and lung function parameters in well-controlled asthmatic patients. This was a prospective cross-sectional study. We measured FeNO, blood eosinophil and lung function in 84 asthmatic patients with clinical remission who were assessed by asthma control questionnaires. The correlation coefficient was used to ascertain among those parameters. The diagnostic accuracy of blood eosinophil to identify low FeNO (< 25 ppb) was calculated using the area under the receiver operating characteristics (AUROC). Of 84 patients analyzed, the median ACT was 25 and the median ACQ-7 was 0.43. The median duration of being well-controlled asthma was 14.5 months. The median FeNo was 23 ppb and the median blood eosinophils was 375 cell/mm³. A significant positive correlation was found between FeNo and blood eosinophil (r = 0.310, p = 0.004). No correlation was detected between either FeNO or blood eosinophil and all lung function parameters. The AUROC results for blood eosinophils was 64.4% (p = 0.024) to detect FeNO < 25 ppb at a cutoff point of 295 cell/mm3 (sens tivity = 83.5%, specificity = 50%). Measuring FeNO and blood eosinophils in patients with a clinical remission of asthma may determine which of those patients have achieved complete remission. As the level of blood eosinophils has a significant correlation with FeNO, it may easily be a feasible biomarker to evaluate inactive airway inflammation before stepping down asthma treatment.

Correlation study of cytokine levels in alveolar lavage fluid with exhaled nitric oxide and lung function in children with bronchial asthma.

BackgroundThe associations between cytokines in the bronchoalveolar lavage fluid (BALF), lung cytokine expression, fractional exhaled nitric oxide (FeNO) and pulmonary function test results in pediatric asthmatics have not been extensively characterized. This study sought to explore correlations between cytokines BALF, FeNO, and pulmonary function test results.MethodsFrom October 2018 to October 2020, a prospective study was conducted on 42 children with asthma and 17 children with pulmonary foreign bodies that required bronchoscopy. Pulmonary function tests and FeNO tests were performed on all patients. Patients were divided into a high FeNO group or low FeNO group based on their FeNO results. Interleukin (IL)-4, IL-5, IL-6, IL-8, IL-13, and IL-17 in the BALF were measured by enzyme-linked immunosorbent assays. Pearson correlations were used to assess the correlations between the cytokines in BALF, the pulmonary function test results, and the FeNO results. Pearson correlation was used to calculate the correlation coefficient “r” among alveolar lavage fluid cytokines, lung function, and FeNO. Receiver operating characteristic (ROC) curves were used to determine the area under the curve (AUC), sensitivity, and specificity of BALF cytokines for the high and low FeNO groups.ResultsIL-4, IL-5, IL-6, IL-8, IL-13, and IL-17 in BALF were significantly correlated with FeNO, but were not significantly correlated with the pulmonary function test results. Cytokine IL-4, IL-5, IL-6, IL-8, IL-13, and IL-17 in BALF were significantly different in the high FeNO, low FeNO, and control groups (all P<0.05). The AUCs for differentiating between low and high FeNO based on BALF cytokines ranged from 0.72 to 0.95. The sensitivity and specificity for discriminating between low and high FeNO based on IL-5 and IL-13 reached 95.7% and 100%, respectively.ConclusionsThe cytokine levels of the BALF of children with asthma were significantly elevated, correlated with FeNO, and can be used evaluate airway inflammation in children with asthma.

Neonatal FeNO, risk factors, and respiratory morbidity in infants: A cohort study.

Respiratory symptoms in infancy are more common in premature infants. Nitric oxide (NO) is involved in prenatal and neonatal lung development. Measurement of exhaled NO is easy and well-tolerated by neonates. We investigated whether neonatal exhaled NO can be used to predict subsequent respiratory symptoms. Furthermore, we sought to determine prenatal and postnatal factors associated with increased respiratory symptom risk during the first year of life in premature and mature infants. Tidal fractional exhaled NO (FeNO) was measured in a birth cohort (n = 135) of premature and mature infants, up to six times during the first month of life. Primary outcomes were troublesome respiratory symptoms (TRS) and doctor-diagnosed asthmatic bronchitis (AB) at 1 year of age. The correlation between FeNO and TRS changed significantly in an age-dependent pattern in moderately premature infants (p = .02). Moderately premature infants with a low FeNO of 2 ppb on postnatal Day 3 had a 48% (95% confidence interval [CI]: 17%-80%) probability of TRS, compared with a probability of 12% (95% CI: 1%-64%) for otherwise similar infants with a FeNO of 11 ppb. Respiratory syncytial virus infection and parental smoking significantly increased the TRS risk in premature infants. Parental asthma and maternal antibiotic use during pregnancy significantly increased the TRS risk in mature infants. An age-specific association between neonatal FeNO and respiratory symptoms was seen in moderately premature infants. TRS risk was associated with postnatal factors in premature and prenatal factors in mature infants.

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

The inflammatory profile of exacerbations in patients with severe refractory eosinophilic asthma receiving mepolizumab (the MEX study): a prospective observational study

Clinical trials with mepolizumab, a humanised monoclonal antibody against interleukin-5, show a 50% reduction in severe asthma exacerbations in people with severe eosinophilic asthma. Exacerbations in patients treated with mepolizumab seem to be different to exacerbations in those given placebo, as patients treated with mepolizumab report fewer symptoms, have a lower sputum eosinophil count, and smaller fall in peak expiratory flow. We aimed to investigate the inflammatory phenotype and physiological characteristics of exacerbation events in patients with severe eosinophilic asthma who were treated with mepolizumab. This multicentre, prospective, observational cohort study was carried out at four UK specialist severe asthma centres. Participants were aged 18-80 years, with severe eosinophilic asthma (Global Initiative for Asthma steps 4 and 5), and were eligible for mepolizumab therapy. All participants received mepolizumab 100 mg subcutaneously every 4 weeks, had a scheduled study visit when stable on mepolizumab (≥3 months on treatment), and measured daily peak flow and completed symptoms diaries throughout the course of the study. Participants attended their study centre for unscheduled exacerbation assessment when symptoms worsened outside of their normal daily variation and before commencing rescue treatment. If a participant was unable to attend their study centre for exacerbation or had initiated rescue treatment before the study visit, clinical details of the missed exacerbation were collected by clinical staff. In this exploratory study, the endpoint was 100 clinical assessments at exacerbation completed across all sites for participants on mepolizumab before initiation of rescue treatment. Characteristics of those who had exacerbations on mepolizumab were compared with those who did not, peak flow and symptoms diaries were compared for assessed versus missed exacerbations, and exacerbation phenotypes defined by sputum eosinophil cell count were compared. The utility of fractional exhaled nitric oxide (FeNO) and C-reactive protein in determining exacerbation phenotype on mepolizumab treatment were also assessed. This study is registered with ClinicalTrials.gov, NCT03324230. Between Nov 30, 2017, and May 29, 2019, 145 participants were enrolled and treated with mepolizumab, five were excluded from the analysis. 172 exacerbations occurred, with 96 (56%) assessed before commencing rescue treatment. Compared with patients who did not exacerbate, patients who exacerbated had a higher exacerbation rate and more emergency department attendances in the year before commencing mepolizumab. The change in peak expiratory flow at nadir in the assessed exacerbation group was mean -40·5 L/min (SD 76·3) versus mean -37·0 L/min (93·0; p=0·84) in the missed exacerbation group, and there was no difference in reported symptom burden. When comparing exacerbations with a high sputum eosinophil count (≥2%; SEHIGH) with exacerbations with a low sputum eosinophil count (<2%; SELOW), the SEHIGH exacerbations were FeNO high (median difference 33 parts per billion [ppb; 95% CI 8 to 87]; p=0·0004), with lower FEV1 percent predicted (mean difference -15·9% [-27·0 to -4·8]; p=0·0075), lower FEV1 to forced vital capacity ratio (mean difference -10·3 [-17·0 to -3·6]; p=0·0043), and higher blood eosinophil counts (median difference 40 cells per μL [20 to 70]; p=0·0009). By contrast, SELOW exacerbations had higher C-reactive protein concentrations (median difference 12·7 mg/L [3·5 to 18·5]; p<0·0001), higher sputum neutrophil counts (median difference 52·7% [34·5 to 59·2]; p<0·0001), and were more likely to be treated with antibiotics (p=0·031). FeNO (≤20 or ≥50 ppb) was the most useful discriminator of inflammatory phenotype at exacerbation. The most common adverse event was hospital admission due to asthma exacerbation (17 [50%] of 34 events), none of the adverse events were study procedure related. Exacerbations 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. The results highlight clinically available tools to enable profiling of these residual exacerbations in patients treated with mepolizumab. UK Medical Research council.

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

Clinical Features of Chronic Obstructive Pulmonary Disease with High Fractional Exhaled Nitric Oxide.

Background The fractional exhaled nitric oxide (FENO) test is useful in asthma patients. However, a few studies on its usefulness in chronic obstructive pulmonary disease (COPD) patients have been reported. We analyzed the FENO level distribution and clinical characteristics according to the FENO level in COPD patients.Methods From December 2014 to June 2019, COPD patients who underwent pulmonary function and FENO tests at Chonnam National University Hospital were retrospectively evaluated for FENO, comorbidities, asthma history, blood eosinophil, and pulmonary function test. The high FENO group was defined as those with FENO level>25 parts per billion (ppb).Results A total of 849 COPD patients (mean age, 70.3±9.4 years) were included. The mean forced expiratory volume at 1 second was 66.5±21.7% and the mean FENO level was 24.3±20.5 ppb. Patients with FENO ≤25 ppb were 572 (67.4%) and those with FENO >25 ppb were 277 (32.6%). Blood eosinophil percentage was significantly higher (4.2±4.8 vs. 2.7±2.5, p<0.001) in patients with the high FENO group than the low FENO group. The high FENO group revealed a significantly higher frequency of patients with blood eosinophil percentage >3% (46.9% vs. 34.8%, p=0.001) and asthma history (25.6% vs. 8.6%, p<0.001) than the lower FENO group. Asthma history, blood eosinophil percentage >3%, and positive bronchodilator response (BDR) were independent risk factors for the high FENO level (adjusted odds ratio [aOR], 3.85; p<0.001; aOR, 1.46; p=0.017; and aOR, 1.57, p=0.034, respectively) in the multivariable analysis.Conclusion The FENO level distribution varied in COPD patients and the mean FENO value was slightly elevated. Asthma history, eosinophil percent, and positive BDR were independent risk factors for the high FENO level.

Fractional exhaled nitric oxide in adult congenital heart disease

BackgroundFractional exhaled nitric oxide levels are related to various clinical diseases. This study investigated the associations between the clinical characteristics and the level of fractional exhaled nitric oxide in patients with adult congenital heart disease. Methods and resultsFractional exhaled nitric oxide values were measured in 30 adult patients with stable congenital heart disease who had undergone right heart catheterization and 17 healthy individuals (controls). There was no significant difference in fractional exhaled nitric oxide values between patients with congenital heart disease and healthy controls. Depending on whether their fractional exhaled nitric oxide values were above or below the median value, patients with congenital heart disease were divided into two groups (low vs. high fractional exhaled nitric oxide groups). The relationship between fractional exhaled nitric oxide values and clinical characteristics was investigated. There was a higher percentage of patients with cyanosis in the low fractional exhaled nitric oxide group (50%) than in the high fractional exhaled nitric oxide group (7.1%). There was no significant difference in right heart catheterization data between the low and high fractional exhaled nitric oxide groups. The fractional exhaled nitric oxide value was correlated to the number of neutrophils in patients with cyanosis (r = 0.84 (N = 8), p = 0.005). ConclusionsIn this cohort of patients with adult congenital heart disease, lower levels of fractional exhaled nitric oxide corresponded to the presence of cyanosis.

Fractional Exhaled Nitric Oxide is Associated with the Severity of Stable COPD

The value of fractional exhaled nitric oxide (FeNO) in patients with chronic obstructive pulmonary disease (COPD) remains unclear. We aimed to assess whether FeNO is a more valuable biomarker than blood eosinophil count for identifying clinical characteristics of COPD. Stable COPD patients (n = 390) were included and stratified by FeNO and blood eosinophil counts at recruitment. The demographic characteristics, lung functions, St George Respiratory Questionnaire (SGRQ), serum inhaled allergen-specific IgE and the exacerbations in the preceding 12 months were compared. Risk factors for moderate or severe exacerbation in the preceding 12 months were examined by binary regression analysis. The cross-sectional study showed that 167 patients had high level of FeNO (≥25 ppb) and 223 in low level (<25 ppb), while 138 patients had high blood eosinophil count (≥200 cells/μL) and 252 had low (<200 cells/μL). Compared with the high FeNO group, there were higher proportion of patients with GOLD III–IV, higher SGRQ scores, more exacerbations in the preceding 12 months, and with lower positive proportion of sIgE in the low FeNO group (p < 0.05 for all). However, these phenomena above were not associated with blood eosinophil count. Finally, high FeNO level was associated with a lower moderate or severe exacerbation in preceding 12 months (RR: 0.541 [95%CI 0.319–0.917], p = 0.023). In stable COPD patients, FeNO, but not blood eosinophil count was associated with the COPD severity and allergic airway inflammation. However, the role of FeNO in guiding personalized treatment of COPD patients need to be further investigated.

Concurrence of elevated FeNO and airway hyperresponsiveness in nonasthmatic adolescents

The aim of this study was to investigate airway responsiveness and eosinophil and neutrophil inflammatory markers in clinically confirmed nonasthmatic adolescents with elevated fractional exhaled nitric oxide (FeNO), a marker of type-2 inflammation in the airways. A total of 959 subjects from a general population, aged 12 to 15 years, answered a standardised questionnaire and underwent FeNO measurements at a screening visit at school. Adolescents without asthma, who had elevated FeNO (FeNO100 > 15 ppb) (n = 19), and control subjects, with low FeNO (FeNO100 < 5 ppb) and without reported symptoms of asthma or allergy (n = 28), participated in a follow-up study where FeNO50 , airway responsiveness to methacholine (PD20 ), blood eosinophil counts, and serum neutrophil lipocalin (HNL) and myeloperoxidase (MPO) levels were measured. Questionnaire follow-ups were performed 4 and 16 years later. Airway responsiveness (PD20 : 6.94 [1.87, 11.39] vs 11.42 [6.33, 59.4] µmol; P < .05) and blood eosinophil counts (0.31 [0.20, 0.44] vs 0.13 [0.1, 0.22] 109 /L; P < .001) (geometric mean [95% CI]) were higher among cases than controls. A significant correlation between blood eosinophils and FeNO was found (rho = 0.41; P = .005). In contrast, serum HNL and MPO were lower in cases than controls (P < .05 both), and there was a negative correlation between HNL and FeNO (r = -0.31; P = .04). At both follow-ups, a higher proportion of subjects reported allergic symptoms compared with baseline (P = .02, P = .01). Elevated FeNO in nonasthmatic adolescents was associated with airway hyperresponsiveness, elevated blood eosinophil counts, and lower systemic activation of neutrophils.