Median Fractional Exhaled Nitric Oxide Research Articles

Lack of association between Inhaled Corticosteroid use based on the Exhaled Nitric Oxide and Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Fractional exhaled nitric oxide (FeNO) is known to useful biomarker for detecting eosinophilic airway inflammation. However, there is a lack of evidence regarding the role of FeNO in chronic obstructive pulmonary disease (COPD). We aimed to assess whether elevated FeNO and its impact on treatment change into an inhaled corticosteroid (ICS)-containing regimen and association with acute exacerbation (AE) in patients with COPD. We retrospectively analyzed 107 COPD patients without history of asthma from March 2016 to December 2019. The patients whose FeNO value was more than 50 parts per billion [ppb] were defined into the high FeNO group. Multivariable analysis with logistic regression was used to identify factors associated with AE in COPD. The median FeNO value was 32 (Interquartile range [IQR], 19-45) ppb, and 34 (20.0%) patients were classified as high FeNO group (median 74ppb). In the high FeNO group, changes in inhaler treatment into an ICS-containing regimen occurred in 23 of 34 patients after the measurement of FeNO. In multivariate analysis, high FeNO was not a contributing factor for AE, but only the high blood eosinophil count (≥ 300 cells/µL) was associated with AE (adjusted odds ratio, 2.63; 95% confidence interval, 1.01-6.91; p = 0.049). High FeNO value had a significant impact on the prescription of ICSs in COPD patients, but it did not show a significant association with AE either on its own or with changes in treatment.

Analysis of the correlation between serum Klotho and FeNO: a cross-sectional study from NHANES (2007–2012)

BackgroundKlotho is an anti-aging protein that has multiple functions and may play a key role in the pathogenesis and progression of chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD). Fractional Exhaled Nitric Oxide (FeNO) is a non-invasive and novel biomarker that has the advantages of being simple, fast and reproducible. It can effectively assess the degree of airway inflammation in diseases such as asthma and COPD. Despite these insights, the relationship between serum Klotho levels and FeNO has not been explored yet.MethodsLeveraging data from the National Health and Nutrition Examination Survey (NHANES) spanning 2007 to 2012, we investigated the correlation between FeNO and serum Klotho levels. This association was scrutinized both as continuous variables and within quartile distributions, utilizing the Kruskal-Wallis H test. The correlation between the two variables was assessed through Spearman rank analysis. Employing survey weight-adjusted linear regression models, we gauged the strength of these associations.ResultsThis study included 6,527 participants with a median FeNO level of 14.5 parts per billion (ppb). We found that FeNO levels varied significantly across different quartiles of Klotho protein (H = 7.985, P = 0.046). We also found a significant positive correlation between serum Klotho levels and FeNO levels in the whole population (Spearman’s rho = 0.029, P = 0.019). This correlation remained significant after adjusting for covariates such as age, gender, lung function, smoking status, alcohol use, BMI, cardiovascular disease (including hypertension, heart failure, coronary heart disease, and myocardial infarction), diabetes, inflammatory markers, serum vitamin D level and BUN (P < 0.05 for all). Furthermore, this correlation was stronger at the high (K3) and super high (K4) levels of Klotho than at the low (K1) and medium (K2) levels (β = 1.979 ppb and β = 1.993 ppb for K3 and K4 vs. K1, respectively; 95% CI: 0.497 ~ 2.953 and 95% CI: 0.129 ~ 2.827, respectively; P = 0.007 and P = 0.032, respectively). The β coefficient for serum Klotho was 0.002 ppb/pg/ml.ConclusionsOur study illuminates a positive correlation between serum Klotho levels and FeNO. Further study is needed to verify the causality of this association and elucidate the underlying mechanisms.

Real-World Characteristics of Patients with Severe Asthma prior to Starting Dupilumab: The ProVENT Study

Introduction: Dupilumab is approved for the treatment of severe type 2 (T2) asthma; however, the characteristics of patients receiving dupilumab in routine clinical practice are incompletely understood. This study describes the characteristics of patients with severe asthma before dupilumab treatment in a real-world setting. Methods: This interim analysis of an ongoing real-life study of dupilumab assessed baseline characteristics of the first patient cohort enrolled in the ProVENT study. Results: A total of 99 patients (59% females) were analyzed (17% received another biologic before dupilumab treatment and 15% were on maintenance oral corticosteroid treatment). Adult-onset asthma (>18 years) and an allergic phenotype were documented in 58% and 48% of patients, respectively. Median (interquartile range) age was 54 (40–61) years; the median number of exacerbations in the last 24 months was 1 (0–3); median fractional exhaled nitric oxide (FeNO) value was 38 (23–64) ppb; and median blood eosinophils (bEOS) count was 184 (8–505) cells/µL. According to the United Kingdom Severe Asthma Registry classification, 53% of patients had T2 intermediate asthma (bEOS ≥150 cells/µL or FeNO ≥25 ppb), 17% had T2 high asthma (bEOS ≥150 cells/µL and FeNO ≥25 ppb), and 4% had T2 low asthma (bEOS <150 cells/µL and FeNO <25 ppb). At least one GINA criterion for T2 airway inflammation was documented in 70% of patients. T2 comorbidities were observed in 64% of patients. Conclusions: This analysis suggests that patients eligible for dupilumab treatment display various clinical and biochemical characteristics rather than one clear-cut phenotype.

Exhaled nitric oxide in intubated ICU patients on mechanical ventilation—a feasibility study

It can be a clinical challenge to distinguish inflammation from infection in critically ill patients. Therefore, valid and conclusive surrogate markers for infections are desired. Nitric oxide (NO) might be that marker since concentrations of exhaled NO have shown to change in the presence of various diseases. This observational, prospective, single-center feasibility study aimed to investigate if fractional exhaled NO (FeNO) can be measured in intubated patients with or without infection, pneumonia and septic shock in a standardized, reliable setting. 20 intubated patients in the intensive care unit (ICU) were included for analysis. FeNO mean values were measured in the endotracheal tube via the suction channel using a chemiluminescence based analyzer. We developed a pragmatic method to measure FeNO repeatedly and reliably in intubated patients using a chemiluminescence based analyzer. We found a median of 0.98 (0.59–1.44) FeNO mean (ppb) in exhaled breath from all 20 intubated patient. Intubated patient with suspected infection had a significantly lower median FeNO mean compared with the intubated patients without suspected infection. Similarly did patients with septic shock demonstrate a significantly lower median FeNO mean than without septic shock. We found no statistical difference in median FeNO mean for intubated patients with pneumonia. It was feasible to measure FeNO in intubated patients in the ICU. Our results indicate decreased levels of FeNO in infected intubated patients in the ICU. The study was not powered to provide firm conclusions, so larger trials are needed to confirm the results and to prove FeNO as a useful biomarker for distinguishment between infection and inflammation in the ICU.

Diagnostic role of fractional exhaled nitric oxide in pediatric eosinophilic esophagitis, relationship with gastric and duodenal eosinophils

Eosinophilic esophagitis (EoE) is an eosinophilic-predominant inflammation of the esophagus diagnosed by upper endoscopy and biopsies. A non-invasive and cost-effective alternative for management of EoE is being researched. Previous studies assessing utility of fractional exhaled nitric oxide (FeNO) in EoE were low powered. None investigated the contribution of eosinophilic inflammation of the stomach and duodenum to FeNO. To assess the utility of FeNO as a non-invasive biomarker of esophageal eosinophilic inflammation for monitoring disease activity. Patients aged 6-21 years undergoing scheduled upper endoscopy with biopsy for suspected EoE were recruited in our observational study. Patients on steroids and with persistent asthma requiring daily controller medication were excluded. FeNO measurements were obtained in duplicate using a chemiluminescence nitric oxide analyzer (NIOX MINO, Aerocrine, Inc.; Stockholm, Sweden) prior to endoscopy. Based on the esophageal peak eosinophil count (PEC)/high power field on biopsy, patients were classified as EoE (PEC ≥ 15) or control (PEC ≤ 14). Mean FeNO levels were correlated with presence or absence of EoE, eosinophil counts on esophageal biopsy, and abnormal downstream eosinophilia in the stomach (PEC ≥ 10) and duodenum (PEC ≥ 20). Wilcoxon rank-sum test, Spearman correlation, and logistic regression were used for analysis. P value < 0.05 was considered significant. We recruited a total of 134 patients, of which 45 were diagnosed with EoE by histopathology. The median interquartile range FeNO level was 17 parts per billion (11-37, range: 7-81) in the EoE group and 12 parts per billion (8-19, range: 5-71) in the control group. After adjusting for atopic diseases, EoE patients had significantly higher FeNO levels as compared to patients without EoE (Z = 3.33, P < 0.001). A weak yet statistically significant positive association was found between the number of esophageal eosinophils and FeNO levels (r = 0.30, P < 0.005). On subgroup analysis within the EoE cohort, higher FeNO levels were noted in patients with abnormal gastric (n = 23, 18 vs 15) and duodenal eosinophilia (n = 28, 21 vs 14); however, the difference was not statistically significant. After ruling out atopy as possible confounder, we found significantly higher FeNO levels in the EoE cohort than in the control group.

Value of Fractional Exhaled Nitric Oxide in Diagnosing Mild Asthma Responsive to Inhaled Corticosteroids.

Mild asthma is often characterized by normal spirometric values and a negative bronchodilation test (BDT), which makes accurate diagnosis challenging. The aim of our study was to evaluate the diagnostic accuracy of fractional exhaled nitric oxide (FeNO) in mild asthma. In adults with symptoms suggestive of asthma and normal spirometry values, BDT, FeNO, BPT and skin prick testing were performed. Patients with positive BPT started inhaled corticosteroid (ICS) therapy. Those with positive response to ICS were considered asthmatics. There were 142 asthmatics and 140 non-asthmatics. No significant difference was found in BDT between the groups, p = 0.233. Median FeNO levels were significantly higher in the asthma group (49.5 ppb) than in the non-asthma group (23 ppb), p < 0.001. BPT was positive in 145 (51.42%) and negative in 137 (48.58%) patients. Positive response to ICS treatment was recorded in 142/145 (97.9%) patients. In diagnosing asthma, FeNO ≥ 25 ppb had a sensitivity of 75.4% and specificity of 47.9%. FeNO has insufficient sensitivity and specificity in mild asthma and the application of BPT is often necessary to establish an accurate diagnosis.

History of atopy reduces predictive value of fractional exhaled nitric oxide for eosinophilic airway inflammation in chronic cough

To investigate the impact of a history of atopy on the value of fractional exhaled nitric oxide (FENO) for predicting sputum eosinophils in patients with chronic cough. A total of 868 patients with persistent cough lasting more than 3 weeks without pulmonary infection were enrolled, including 119 patients with subacute cough (defined as cough lasting 3-8 weeks) and 749 with chronic cough (longer than 8 weeks). The predictive value of FENO level for sputum eosinophilia was analyzed using receiver-operating characteristic (ROC) curve analysis, and the area under the curve (AUC) was calculated. The atopy status of the patients was determined by screening for history of allergy, hay fever, or animal or food allergies. Of the 868 patients enrolled, 173 patients (19.9%) had eosinophilic airway inflammation (EAI). In the overall patients, the median (Q1, Q3) FENO level was 18 (12, 35) ppb, ranging from 5 to 300 ppb. The patients with chronic cough and a positive history of atopy had a higher median FENO level than those without atopy (24 [13, 50] vs 18 [11, 34]; Z=2.25, P= 0.029), and FENO level was significantly correlated with EAI (r=0.281, P < 0.001). The AUCs of FENO for diagnosis of airway eosinophilia in patients with atopy and those without atopy were 0.677 (95% CI: 0.548-0.806) and 0.708 (95% CI: 0.660-0.756), respectively. The optimal cut-off value of FENO for diagnosing EAI was higher in patients with atopy than in those without atopy (72 vs 28.5 ppb). A history of atopy reduces the predictive value of FENO level for EAI in patients with chronic cough, suggesting the importance of examining the atopic status when interpreting test results of FENO.

AIRWAY INFLAMMATION IS ASSOCIATED WITH PULMONARY FUNCTION IN OBESE ASTHMATIC INDIAN CHILDREN

Objective: Obesity and asthma are related conditions, however, the underlying mechanism between the two is not understood. This study aims to determine the correlations between fractional exhaled nitric oxide (FeNO) and spirometry parameters in obese asthmatic children. Design and method: In this study, 47 overweight/ obese asthmatic children (physician-diagnosed children with partly/ uncontrolled asthma as per Global Initiative forAsthma guidelines) were recruited from Pediatrics Chest Clinic, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), New Delhi, India. The measured height and weight were used to calculate BMI. BMI derived was categorized by using Z score tables of WHO-BMI for age standards for boys and girls between 5 and 19 years. Children were assessed using measurement of FeNO(NIOX1; Aerocrine, Solna, Sweden), and spirometry parameters were assessed using Superspiro MK2 Micro Medical Ltd, UK. Correlation between FeNO levels and spirometry parameters were investigated using Spearman’s correlation coefficients. Results: The mean ± SDage was 11.3 ± 2.5 years (males, n = 37), BMI = 24.91 ± 7.05 Kg/m2 and median (interquartile range) FeNO levels were 22.0 (17.0, 65.0) ppb. The mean ± SD predicted forced expiratory flow (FEF25–75) predicted was 83.5 ± 16.3%. The mean age of onset of asthma was 6.3 years. Twenty-four children had partly controlled asthma and 23 children had uncontrolled asthma. FeNO was significantly and inversely correlated with predicted FEF25-75 (r = -0.378, p &lt; 0.001). Conclusions: FeNO an easily measurable indicator of airway inflammation in combination with lung function may prove a useful tool in the asthma assessment and management in obese Indian asthmatic children.

Effects of inhaled JAK inhibitor GDC-4379 on exhaled nitric oxide and peripheral biomarkers of inflammation

BackgroundJanus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations. AimTo assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation. MethodsThis study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18–65y) with a diagnosis of asthma for ≥6 months, forced expiratory volume in 1 s (FEV1)> 70% predicted, FeNO >40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers, including blood eosinophils, serum CCL17, and serum CCL18, were also assessed. ResultsOf 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41–222) ppb. GDC-4379 treatment led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was: −6 (−43, 32) at 10 mg QD, −26 (−53, 2) at 30 mg QD, −55 (−78, −32) at 40 mg BID and −52 (−72, −32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma drug concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful. ConclusionsIn patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns.Australian New Zealand Clinical Trials Registry: ACTRN12619000227190.

Reducing asthma attacks in children using exhaled nitric oxide (RAACENO) as a biomarker to inform treatment strategy: a multicentre, parallel, randomised, controlled, phase 3 trial

The benefit of fractional exhaled nitric oxide (FeNO) in guiding asthma treatment is uncertain. We evaluated the efficacy of adding FeNO to symptom-guided treatment in children with asthma versus only symptom-guided treatment. RAACENO was a multicentre, parallel, randomised, controlled, phase 3 trial done in 35 secondary care centres and 17 primary care recruitment sites (only seven primary care sites managed to recruit patients) in the UK. Patients with a confirmed asthma diagnosis, aged 6-15 years, prescribed inhaled corticosteroids, and who received a course of oral corticosteroids for at least one asthma exacerbation during the 12 months before recruitment were included. Participants were randomly assigned to either FeNO plus symptom-guided treatment (intervention) or symptom-guided treatment alone (standard care) using a 24 h in-house, web-based randomisation system. Participants and the clinical and research teams were not masked to the group allocation. A web-based algorithm gave treatment recommendations based on the Asthma Control Test (ACT) or Childhood ACT (CACT) score; current asthma treatment; adherence to study treatment in the past 3 months; and use of FeNO (in the intervention group). Follow-up occurred at 3-month intervals for 12 months. The primary outcome was any asthma exacerbation treated with oral corticosteroids in the 12 months after randomisation, assessed in the intention-to-treat population. This study is registered with the International Standard Randomised Controlled Trial Registry, ISRCTN67875351. Between June 22, 2017, and Aug 8, 2019, 535 children were assessed for eligibility, 20 were ineligible and six were excluded post-randomisation. 509 children were recruited and at baseline, the mean age of participants was 10·1 years (SD 2·6), and 308 (60·5%) were male. The median FeNO was 21 ppb (IQR 10-48), mean predicted FEV1 was 89·6% (SD 18·0), and median daily dose of inhaled corticosteroids was 400 μg budesonide equivalent (IQR 400-1000). Asthma was partly or fully controlled in 256 (50·3%) of 509 participants. The primary outcome, which was available for 506 (99%) of 509 participants, occurred in 123 (48·2%) of 255 participants in the intervention group and 129 (51·4%) of 251 in the standard care group, the intention-to-treat adjusted odds ratio (OR) was 0·88 (95% CI 0·61 to 1·27; p=0·49). The adjusted difference in the percentage of participants who received the intervention in whom the primary outcome occurred compared with those who received standard care was -3·1% (-11·9% to 5·6%). In 377 (21·3%) of 1771 assessments, the algorithm recommendation was not followed. Adverse events were reported by 27 (5·3%) of 509 participants (15 in the standard care group and 12 in the intervention group). The most common adverse event was itch after skin prick testing (reported by eight participants in each group). We found that the addition of FeNO to symptom-guided asthma treatment did not lead to reduced exacerbations among children prone to asthma exacerbation. Asthma symptoms remain the only tool for guiding treatment decisions. National Institute for Health Research.

A PROSPECTIVE COHORT RESEARCH COMPARED FRACTIONAL EXHALED NITRIC OXIDE, SPIROMETRY, AND THE ASTHMA CONTROL TEST IN PREDICTING ASTHMA EXACERBATIONS

Background’: Fractional exhaled nitric oxide (FeNO) is a quick, accurate, noninvasive tool to detect the measurement of airway inflammation. FeNO is therefore vastly used in the diagnosis and treatment of asthma. Aim: The purpose of the study is to evaluate and compare the accuracy of spirometry, the asthma control test (ACT), and fractional exhaled nitric oxide in predicting future asthma attacks, as well as their association with each other. Materials and Methods: Patients with asthma between the ages of 21 to 60 were included. Patients with a smoking history of more than 8 packs per year, as well as, patients in whom spirometry was not recommended were excluded. Fractional exhaled nitric oxide (FeNO) and spirometry were performed on patients who gave their consent to conduct the study. The Asthma Control Test (ACT) questionnaire was used to analyze asthma control. Over the course of the three-month follow-up, several exacerbations were recorded. The effectiveness of FeNO, spirometry, and ACT in predicting exacerbations was compared using the Mann-Whitney test, and the correlation between them was determined using Spearman's correlation coefficient. Results: Exacerbations occurred in 27% of the 100 trial participants. Patients with and without exacerbations had similar levels of FeNO, according to our research. The median (interquartile range [IQR]) FEV1% in patients with and without exacerbations was 67 (54-78) and 74 (64-87), respectively (P = 0.012). In contrast to those without exacerbations, whose median (IQR) ACT scores were 14 (13-17), patients with exacerbations had a median (IQR) ACT score of 11 (9–15), which was considerably lower (P = 0.002). ACT and FeNO had a poor connection (correlation coefficient: -0.166, P = 0.037). The median (IQR) FeNO level (ppb) was lower in patients taking inhaled corticosteroids (ICS) than in the other group, with values of 21 (13-37) and 29 (16-57), respectively (P = 0.04). Conclusion: FeNO level and ACT score had an inverse relation. FEV1% and ACT scores were better than FeNO at predicting asthma attacks, as per the research conducted in the present study. The utilization of inhaled corticosteroids caused a drop in FeNO levels.

Agreement of parent‐ and child‐reported wheeze and its association with measurable asthma traits

ObjectivesIn epidemiological studies, childhood asthma is usually assessed with questionnaires directed at parents or children, and these may give different answers. We studied how well parents and children agreed when asked to report symptoms of wheeze and investigated whose answers were closer to measurable traits of asthma.MethodsLuftiBus in the school is a cross‐sectional survey of respiratory health among Swiss schoolchildren aged 6–17 years. We applied questionnaires to parents and children asking about wheeze and exertional wheeze in the past year. We assessed agreement between parent–child answers with Cohen's kappa (k), and associations of answers from children and parents with fractional exhaled nitric oxide (FeNO) and forced expiratory volume in 1 s over forced vital capacity (FEV1/FVC), using quantile regression.ResultsWe received questionnaires from 3079 children and their parents. Agreement was poor for reported wheeze (k = 0.37) and exertional wheeze (k = 0.36). Median FeNO varied when wheeze was reported by children (19 ppb, interquartile range [IQR]: 9–44), parents (22 ppb, IQR: 12–46), both (31 ppb, IQR: 16–55), or neither (11 ppb, IQR: 7–19). Median absolute FEV1/FVC was the same when wheeze was reported by children (84%, IQR: 78–89) and by parents (84%, IQR: 78–89), lower when reported by both (82%, IQR: 78–87), and higher when reported by neither (87%, IQR: 82–91). For exertional wheeze findings were similar. Results did not differ by age or sex.ConclusionOur findings suggest that surveying both parents and children and combining their responses can help us to better identify children with measurable asthma traits.

Reducing Asthma Attacks in Children Using Exhaled Nitric Oxide as a Biomarker to Inform Treatment Strategy – A Randomised Trial

Background: The benefit of Fractional Exhaled Nitric Oxide (FeNO) in guiding asthma treatment is uncertain. Our hypothesis was that FeNO plus symptom-guided treatment reduces exacerbations in children with asthma compared to symptom-guided treatment alone. Methods: A multicentre randomised controlled trial recruited 6-15 year olds with asthma treated with inhaled corticosteroids (ICS) with an exacerbation in the previous year. Randomisation was to asthma treatment guided by FeNO plus symptoms (intervention) or by symptoms only (standard care). A web-based algorithm using symptom control, ICS adherence, current treatment and (within the intervention group) FeNO gave treatment recommendations. Participants attended assessments 3, 6, 9 and 12-months post-randomisation. The primary outcome was exacerbation requiring oral corticosteroid over the 12 months post-randomisation. Findings: There were 509 children recruited. At randomisation, the mean (SD) age was 10∙1y (2.6), median (IQR) FeNO 21 ppb (10, 48), mean (SD) %FEV 1 90% (18), 56% received ≤400 microg budesonide equivalent ICS and 50% had controlled symptoms. The primary outcome occurred in 123/255 (48%) of the intervention group and 129/251 (51%) of the standard care group. The adjusted difference in percentage of participants who received the intervention where the primary outcome occurred exacerbation compared to those receiving standard care was -3∙13% (95% CI: -11∙9% to 5∙6%). In adjusted intention-to-treat analysis, the odds ratio (OR) for primary outcome was 0 ∙88 [95%CI 0∙61 to 1∙27]. In 377 of 1771 assessments, the algorithm recommendation was not followed. In complier average causal effect analysis, adjusting for algorithm adherence, the OR for those fully adherent was 0∙82 [95% CI 0∙48 to 1∙41]. There were no differences in secondary outcomes between groups. Interpretation: In this exacerbation-prone population, adding FeNO to symptom-guided treatment did not reduce exacerbations. Trial Registration: ISRCTN number #67875351. Funding: This study was funded by the Efficacy and Mechanisms Evaluation programme of the National Institute for Health Research (reference 15-18-14). Declaration of Interest: David Price has board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Thermofisher; consultancy agreements with Airway Vista Secretariat, AstraZeneca, Boehringer Ingelheim, Chiesi, EPG Communication Holdings Ltd, FIECON Ltd, Fieldwork International, GlaxoSmithKline, Mylan, Mundipharma, Novartis, OM Pharma SA, PeerVoice, Phadia AB, Spirosure Inc, Strategic North Limited, Synapse Research Management Partners S.L., Talos Health Solutions, Theravance and WebMD Global LLC; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Theravance and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. Ethical Approval: The study was approved by the North of Scotland Research Ethics Committee (16/NS/0106).

Combination of Fractional Exhaled Nitric Oxide (FeNO) Level and Asthma Control Test (ATC) in Detecting GINA-Defined Asthma Control in Treated Asthmatic Patients in Vietnam.

Background FeNO has been used as a marker for Th2-mediated airway inflammation in asthma. There is evidence which recommends the use of this biomarker in asthma management. Little is known about whether the FeNO test alone or in combination with the ACT score can reflect asthma control in Vietnamese patients. Materials and Methods A cross-sectional study was conducted in asthmatic patients (≥18 years old) recruited at the University Medical Center, Ho Chi Minh City, Vietnam from March 2016 to March 2017. Asthma control levels were assessed following the GINA 2017 guidelines, and FeNO was measured by a Niox Mino device. FeNO cut-offs predicting asthma control status were determined using the ROC curve analysis. The combination of FeNO and ACT was investigated in detecting well-controlled and uncontrolled asthma. The results of the study are as follows: 278 patients with 68% females, mean age of 44 years, and mean asthma duration of 10 years were analyzed. All patients were treated following step 2 to 4 of GINA guidelines. Mean (SD) FeNO was 30.6 (24) ppb. Patients with uncontrolled (16%), partly controlled (29%), and well-controlled asthma (55%) had a median (IQR) FeNO of 50.0 (74), 25.0 (23), and 21.0 (22.3) ppb, respectively, and the mean of FeNO in the uncontrolled group was significantly higher than that in other groups (p < 0.001). The area under the ROC curve (AUC) for FeNO detecting uncontrolled asthma was 0.730 with an optimal cut-off point of FeNO > 50 ppb, and this AUC increased to 0.89 when combining FeNO and ACT. The AUC for FeNO detecting well-controlled asthma was 0.601 with an optimal cut-off point of FeNO <25 ppb and this AUC increased to 0.78 if combining FeNO and ACT. Conclusions FeNO can predict asthma control status with an estimated cut-off point of <25 ppb for well-controlled and >50 ppb for uncontrolled asthma. The combination of FeNO and ACT provides better information regarding asthma control than FeNO alone, and this combination is useful to predict asthma control statuses in asthmatic patients in Viet Nam.

Comparison of fractional exhaled nitric oxide, spirometry, and Asthma Control Test, in predicting asthma exacerbations: A prospective cohort study.

Context:Fractional exhaled nitric oxide (FeNO) is a noninvasive test for airway inflammation in asthma. The usefulness of FeNO in predicting exacerbations is uncertain.Aims:The study aims to assess and compare the ability of FeNO, spirometry, and asthma control test (ACT) in predicting future exacerbations of asthma and their correlation with each other.Settings and Design:This prospective, cohort study was conducted at the Department of Respiratory Medicine, Kasturba Medical College, Manipal.Materials and Methods:Adult asthma patients of age 18–65 years were included. Patients with a smoking history of >10 pack-years and those in whom spirometry was contraindicated were excluded. Patients who consented underwent FeNO and spirometry. The control of asthma was assessed using the ACT questionnaire. We captured the number of exacerbations in the follow-up period of 4 months.Statistical Analysis Used:Mann–Whitney test was used to compare the utility of FeNO, spirometry, ACT in predicting exacerbations and Spearman's correlation coefficient was used to ascertain the correlation among them.Results:Of 154 study patients, 28% had exacerbations. We found that there was no significant difference in FeNO in patients with and without exacerbations. The median (interquartile range [IQR]) FEV1% in the patients with and without exacerbations were 68 (55–79) and 75 (65–88), respectively (P = 0.013). The median (IQR) ACT score in patients with exacerbations was 12 (10–16) which was significantly lower than in those without exacerbation in whom it was 16 (14–18) (P = 0.003). There was a negative correlation of ACT with FeNO (Correlation coefficient: −0.167, P = 0.038). The median (IQR) FeNO level (ppb) was lower in patients who were on inhaled corticosteroid (ICS) than in the other group values being 22 (14–38) and 30 (17–58), respectively (P = 0.05).Conclusions:In our study, FEV1% and ACT score could predict exacerbations of asthma whereas FeNO could not. FeNO level correlated inversely with ACT score. FeNO level decreased with inhaled corticosteroid usage.

Agreement between self-reported asthma symptoms and exhaled nitric oxide levels: impact on inhaled corticosteroid prescribing in general practice. An observational study

BackgroundThe National Review of Asthma Deaths UK highlighted that 46% of deaths could be avoided and recommended that all sufferers receive a structured asthma annual review which assess asthma control. In primary care this is commonly achieved using symptom-based questionnaires such as the Asthma Control Test (ACT). A newer method of assessing asthma control is Fractional Exhaled Nitric Oxide (FeNO) testing, which is currently recommended for the diagnosis of asthma, but not for monitoring of asthma control. The study aim was to assess the correlation between self-reported symptoms as measured by the ACT and FeNO testing and the subsequent impact of FeNO testing on prescribing of asthma medication.MethodsA retrospective review of 65 patients who had received both ACT and FeNO testing as part of their asthma annual review. A spearman correlation was used to estimate the correlation between ACT scores and FENO levels. A χ2 test was used to compare prompting frequency of the measures and Kendalls τ statistic was made to estimate their concordance and influence on subsequent ICS medication prescription.ResultsThe mean age of the participants was 41 years (4–93 years). There was no statistically significant correlation between ACT and FeNO (ρ = 0.195, p = 0.120). The median FeNO was 26 ppb (range 8–279 ppb), and the ACT score 20 (range 5 to 25 points). Furthermore, FeNO more frequently prompts a change in medication than ACT, 66% versus 42% (p = 0.005). A low concordance between the measures was found (Kendall’s τ statistic − 0.321).ConclusionFeNO should be considered for monitoring of control in asthma. To balance the cost of implementing this technology into primary care a risk stratified approach could be applied to testing.

Weight Status and Respiratory Health in Asthmatic Children.

In this study,we explored the effect of adiposity as measured by BMI on lung function in 72 asthmatic school children (5-12years) using baseline data from the Mediterranean diet enriched with fatty fish intervention study. Bronchial function was assessed using spirometry and fractional exhaled nitric oxide (FeNO). BMI categories were classified as normal and overweight/obese based on International Obesity Task Force cut-offs. Weak correlations were observed between BMI and FVC (p = 0.013) and FEV1 (p = 0.026). Median FeNO was lower in the overweight/obese as compared to normal weight group (p = 0.027). Linear regression showed an increment in FEF25-75% in the overweight/obese group as compared to normal weight after controlling for confounders namely age, height, sex, regular physical activity, medication and KIDMED score (p = 0.043; β = 11.65 units, 95% CI 0.36-22.94), although with no effect on FeNO. In conclusion, the findings of this study suggest that excess body weight could impact pulmonary dynamics in childhood asthma.

Difference between two exhaled nitric oxide analyzers, NIOX VERO® electrochemical hand-held analyzer and NOA280i® chemiluminescence stationary analyzer

Background: Fractional exhaled nitric oxide (FENO) is useful for the evaluation of eosinophilic airway inflammation, including that seen in asthma. Although a new electrochemical hand-held FENO analyzer, the NIOX VERO® (Aerocrine AB, Solna, Sweden), is clinically convenient to use, it has not been fully compared with the chemiluminescence stationary electrochemical analyzer NOA280i® (Sievers Instruments, Boulder, CO, USA) in terms of the level of measured FENO. The aim of this study was to determine whether there is a difference between the two analyzers. Methods: The FENO levels measured with both NIOX VERO® and NOA280i® were evaluated in 1,369 adults at Juntendo University Hospital from May 2016 to October 2016. Results: The median FENO level measured with the NIOX VERO® was significantly lower than that measured with the NOA280i® (41 ppb, range 5–368 ppb vs. 29 ppb, range 5–251 ppb; p < 0.001). There was a strong positive correlation in the measurement of FENO level between the NOA280i® and the NIOX VERO® (r = 0.942, p < 0.001). The following conversion equation was calculated: FENO (NOA280i®) = 1.362 (SE, 0.661) + 1.384 (SE, 0.021) × FENO (NIOX VERO®). Conclusions: To our best knowledge, we have provided the first report showing that the measured FENO level with the NIOX VERO® was approximately 30% lower than that with the NOA280i® and that there was a significant correlation between the measurements of these two devices. The correction equation that we provided may help assess the data obtained by these two analyzers.AbbreviationsATSAmerican Thoracic SocietyBMIBody mass indexERSEuropean Respiratory SocietyFENOFractional exhaled nitric oxideGINAGlobal Initiative for AsthmaNONitric oxideppbParts per billionROCReceiver operating characteristicSDStandard deviation

The influence of dilution on the offline measurement of exhaled nitric oxide

Objective: Measurement of fractional exhaled nitric oxide (FeNO) is used to determine the presence and severity of eosinophilic airway inflammation in asthma and other wheezing illnesses. The gold standard of online measurement during a single prolonged exhalation is not suitable for use in young children. The international guidelines for offline measurements recommend collection of exhaled gas in an appropriate reservoir for later analysis in young children. The apparatus required for gas collection, however, creates dead space within the system, which may result in sample dilution and hence inaccuracy. Our objective was to investigate the effect such dilution might have on the accuracy of offline FeNO by comparing the results to online results. Approach: Thirty-five adult subjects without respiratory disease underwent online measurement of FeNO and, thereafter, undertook offline FeNO measurements via exhalation into a collection reservoir using one, five or ten inhalation–exhalation cycles. Fifteen of the subjects also exhaled using the five-breath technique via apparatus with additional dead space. An equation incorporating dead space volume and the number of breaths was used to predict the degree of dilution; the predicted results were compared to the measured results. Main results: The median (IQR) FeNO from a one-breath technique (22 (15–28) ppb was not significantly different to online values (19 (12–27) ppb, p = 1.00), but the results from the five-breath technique (11 (4–19) ppb, p < 0.0001), the ten-breath technique (6 (4–15) ppb, p < 0.0001) and the additional dead space experiment (6 (3–8) ppb, p = 0.0006) were significantly lower than online FeNO. Measured values were consistently significantly different to those predicted by the dilution equation, even when incorporating the exact exhaled volume of gas. Significance: Offline FeNO results may be inaccurate when subjects are unable to fill the collection reservoir with a single exhalation, thus the technique may not be suitable for preschool children.

Feasibility of high-intensity training in asthma

ABSTRACTBackground: High-intensity interval training is an effective and popular training regime but its feasibility in untrained adults with asthma is insufficiently described.Objective: The randomized controlled trial ‘EFFORT Asthma’ explored the effects of behavioural interventions including high-intensity interval training on clinical outcomes in nonobese sedentary adults with asthma. In this article we present a sub analysis of data aiming to evaluate if patients’ pre-intervention levels of asthma control, FEV1, airway inflammation and airway hyperresponsiveness (AHR) predicted their training response to the high-intensity interval training program, measured as increase in maximal oxygen consumption (VO2max).Design: We used data from the EFFORT Asthma Study. Of the 36 patients randomized to the 8-week exercise intervention consisting of high-intensity training three times per week, 29 patients (45% females) completed the study and were included in this data analysis. Pre-intervention assessment included the asthma control questionnaire (ACQ), spirometry, fractional exhaled nitric oxide (FeNO) and AHR to mannitol. VO2 max was measured during an incremental cycle test.Results: The majority of included patients had partly or uncontrolled asthma reflected by a mean (SD) ACQ at 1.7 (0.6). Median (IQR) FeNO was 28.5 (23.8) ppb and 75% had a positive mannitol test indicating AHR.The association between patients’ training response measured as increase in VO2max and pre-intervention ACQ scores was not statistically significant (p = 0.49). Likewise, the association between patients’ increase in VO2max and FeNO as well as AHR was not statistically significant (p = 0.80 and p = 0.58).Conclusions: Included asthma patients could adhere to the high-intensity interval protocol and improve their VO2max regardless of pre-intervention levels of asthma control, airway inflammation and AHR.