The Fractional exhaled Nitric Oxide (FeNO)- test as add-on test in the diagnostic work-up of asthma: a study protocol.

BACKGROUND: Asthma is a common disease characterized by chronic inflammation of the lower airways, bronchial hyperactivity, and (reversible) airway obstruction. The Global Initiative of Asthma Guideline recommends a flowchart to diagnose asthma with first-step spirometry with reversibility and a bronchial challenge test (BPT) with histamine or methacholine as a second step [1]. The BPT is considered burdensome, time-consuming for patients and staff, can cause side effects, and is expensive. In addition, this test strongly encumbers lung function capacity. Elevated Nitric Oxide (NO) is associated with airway eosinophilic inflammation in asthma patients and can be measured in exhaled air with the Fractional exhaled (Fe) NO-test. This low-burden FeNO-test could be used as an 'add-on' test in asthma diagnostics [2, 3]. METHODS AND ANALYSIS: This multi-center prospective study (Trial number: NCT06230458) compares the 'standard asthma diagnostic work-up' (spirometry with reversibility and BPT) to the 'new asthma diagnostics work-up' (FeNO-test as an intermediate step between the spirometry with reversibility and the BPT), intending to determine the impact of the FeNO-based strategy, in terms of the number of avoided BPTs, cost-effectiveness and reduced burden to the patient and health care. The cost reduction of incorporating the FeNO-test in the new diagnostic algorithm will be established by the number of theoretically avoided BPT. The decrease in burden will be studied by calculating differences in the Visual Analogue Scale (VAS) -score and Asthma Quality of Life Questionnaire (AQLQ) -score after the BPT and FeNO-test with an independent T-test. The accuracy of the FeNO-test will be calculated by comparing the FeNO-test outcomes to the (gold standard) BPTs outcomes in terms of sensitivity and specificity. The intention is to include 171 patients. ETHICS AND DISSEMINATION: The local medical ethics committee approved the proposed study and is considered a low-burden and risk-low study. The local medical ethics committee registration number: R23.005. STRENGTHS AND LIMITATIONS OF THIS STUDY: Strengths: This is the first study that investigates the value of the FeNO-test (cut off ≥ 50 ppb) as an add-on test, to determine the impact of the FeNO-based strategy, in terms of the number of avoided BPTs, cost-effectiveness, and reduced burden on the patient and health care. LIMITATIONS: High FeNO levels may also be observed in other diseases such as eosinophilic chronic bronchitis and allergic rhinitis. The FeNO-test can be used to rule in a diagnosis of asthma with confidence, however, due to the poor sensitivity it is not suitable to rule out asthma.

Fractional exhaled nitric oxide in idiopathic pulmonary arterial hypertension and mixed connective tissue disease complicating pulmonary hypertension.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) has been extensively studied in various causes of pulmonary hypertension (PH), but its utility as a noninvasive marker remains highly debated. The objective of our study was to assess FeNO levels in patients with idiopathic pulmonary arterial hypertension (IPAH) and mixed connective tissue disease complicating pulmonary hypertension (MCTD-PH), and to correlate them with respiratory functional data, disease severity, and cardiopulmonary function. METHODS: We collected data from 54 patients diagnosed with IPAH and 78 patients diagnosed with MCTD-PH at the Shanghai Pulmonary Hospital Affiliated to Tongji University. Our data collection included measurements of brain natriuretic peptide (pro-BNP), cardiopulmonary exercise test (CPET), pulmonary function test (PFT), impulse oscillometry (IOS), and FeNO levels. Additionally, we assessed World Health Organization functional class (WHO-FC) of each patient. RESULTS: (1) The fractional exhaled concentration of nitric oxide was notably higher in patients with IPAH compared to those with MCTD-PH. Furthermore, within the IPAH group, FeNO levels were found to be lower in cases of severe IPAH compared to mild IPAH (P = 0.024); (2) In severe pulmonary hypertension as per the WHO-FC classification, FeNO levels in IPAH exhibited negative correlations with FEV1/FVC (Forced Expiratory Velocity at one second /Forced Vital Capacity), MEF50% (Maximum Expiratory Flow at 50%), MEF25%, and MMEF75/25% (Maximum Mid-expiratory Flow between 75% and 25%), while in severe MCTD-PH, FeNO levels were negatively correlated with R20% (Resistance at 20 Hz); (3) ROC (Receiving operator characteristic curve) analysis indicated that the optimal cutoff value of FeNO for diagnosing severe IPAH was 23ppb; (4) While FeNO levels tend to be negatively correlated with peakPETO2(peak end-tidal partial pressure for oxygen) in severe IPAH, in mild IPAH they had a positive correlation to peakO2/Heart rate (HR). An interesting find was observed in cases of severe MCTD-PH, where FeNO levels were negatively correlated with HR and respiratory exchange ratio (RER), while positively correlated with O2/HR throughout the cardiopulmonary exercise test. CONCLUSION: FeNO levels serve as a non-invasive measure of IPAH severity. Although FeNO levels may not assess the severity of MCTD-PH, their significant makes them a valuable tool when assessing severe MCTD-PH.

Lower Arginine Bioavailability, Increased FeNO Levels, and Airway Resistance on Impulse Oscillometry Are Characteristics of Asthma in Children and Young Adults with Sickle Cell Disease.

Background and Objectives: Data on characteristics of asthma in children with sickle cell disease (SCD) is conflicting. Recently, the L-arginine pathway has gained attention in the pathogenesis of asthma and SCD. This study aimed to determine the distinctive clinical and laboratory features and the role of arginine metabolism in asthmatic children with SCD. Materials and Methods: A total of 52 children and adolescents with SCD, including 24 with asthma (SCD-A) and 28 without asthma (SCD-NA), and 40 healthy controls were included. A questionnaire, atopy tests, fractional exhaled nitric oxide (FeNO), and lung function tests were employed. Serum metabolites of the arginine pathway were measured. The results of the three groups were compared. Results: The demographic characteristics and atopy markers of the three groups were similar. FEV1%, FEV1/FVC, MMEF%, and total lung capacity (TLC%) values of SCD-A patients were not significantly different from the SCD-NA group, but they were significantly lower than the values measured in the controls. FeNO values greater than 35 ppb were present only in the SCD-A group. In impulse oscillometry, median resistance values at 5 Hz (R5)% were higher in both SCD subgroups than in healthy controls (p = 0.001). The (R5-20/R5)% values were higher in the SCD-A group (p = 0.028). Serum arginine levels and arginine bioavailability indices were significantly lower in the SCD-A group than in the SCD-NA group and healthy controls (p = 0.003 and p < 0.001). Conclusions: Asthma in children with SCD was not associated with atopy or low FEV1/FVC levels. However, lower arginine bioavailability and higher FeNO levels differentiated asthma in patients with SCD. High R5% and (R5-20/R5)% values indicated increased airway resistance in SCD, with a predominance of small airway disease in asthmatics.

The value of bronchodilator response in FEV1 and FeNO for differentiating between chronic respiratory diseases: an observational study.

BACKGROUND: There is no uniform standard for a strongly positive bronchodilation test (BDT) result. In addition, the role of bronchodilator response in differentiating between asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap (ACO) in patients with a positive BDT result is unclear. We explored a simplified standard of a strongly positive BDT result and whether bronchodilator response combined with fractional exhaled nitric oxide (FeNO) can differentiate between asthma, COPD, and ACO in patients with a positive BDT result. METHODS: Three standards of a strongly positive BDT result, which were, respectively, defined as post-bronchodilator forced expiratory volume in 1-s responses (ΔFEV1) increasing by at least 400 mL + 15% (standard I), 400 mL (standard II), or 15% (standard III), were analyzed in asthma, COPD, and ACO patients with a positive BDT result. Receiver operating characteristic curves were used to determine the optimal values of ΔFEV1 and FeNO. Finally, the accuracy of prediction was verified by a validation study. RESULTS: The rates of a strongly positive BDT result and the characteristics between standards I and II were consistent; however, those for standard III was different. ΔFEV1 ≥ 345 mL could predict ACO diagnosis in COPD patients with a positive BDT result (area under the curve [AUC]: 0.881; 95% confidence interval [CI] 0.83-0.94), with a sensitivity and specificity of 90.0% and 91.2%, respectively, in the validation study. When ΔFEV1 was < 315 mL combined with FeNO < 28.5 parts per billion, patients with a positive BDT result were more likely to have pure COPD (AUC: 0.774; 95% CI 0.72-0.83). CONCLUSION: The simplified standard II can replace standard I. ΔFEV1 and FeNO are helpful in differentiating between asthma, COPD, and ACO in patients with a positive BDT result.

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

BACKGROUND: Klotho 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. METHODS: Leveraging 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. RESULTS: This 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 (ß = 1.979 ppb and ß = 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 ß coefficient for serum Klotho was 0.002 ppb/pg/ml. CONCLUSIONS: Our 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.

Predictive Value of Fractional Exhaled Nitric Oxide (FeNO) in the Diagnosis of Asthma for Epidemiological Purposes-An 8-Year Follow-Up Study.

At the population level, respiratory symptoms in children can be estimated cross-sectionally. However, such methods require additional objective support parameters, such as the measurement of fractional exhaled nitric oxide (FeNO). The aim of the present study was to analyze if the FeNO value measured at baseline can have a predictive value for asthma-like symptoms after 8 years of measurement. METHODS: The follow-up included 128 (out of 447) children, 70 girls and 58 boys. The FeNO was measured at baseline only. The prevalence of asthma-like symptoms was measured with the adopted version of the ISAAC questionnaire. RESULTS: After 8 years of FeNO measurement, 5 new cases of asthma, 2 cases of attacks of dyspnoea, 1 case of wheezy in the chest, and 18 cases of allergic rhinitis occurred. The FeNO values, measured at the baseline of the study, for new cases of the above diseases were 53.4 ± 75.9 ppb, 11 ± 1.5 ppb, 12.0 ppb, and 16.3 ± 12.4 ppb, respectively. The best diagnostic accuracy parameters were found in the new cases of asthma, where the sensitivity was 40.0%, the specificity was 98.6%, and the AUC was 66.6%. The diagnostic odds ratio was 46.9 when considering the FeNO cut-off >35 ppb. CONCLUSIONS: The FeNO measurement is a fair method for asthma prognosis in early school-aged children with asthma-like symptoms measured on the population level but requires further confirmation at the clinical level with more accurate diagnostic tools.

The diagnostic value of bronchial provocation testing combined with fractional exhaled nitric oxide (FeNO) in children with chest tightness-variant asthma (CTVA).

BACKGROUND: Chest tightness-variant asthma (CTVA) is a novel atypical asthma characterized by chest tightness as the sole or primary symptom. OBJECTIVES: To investigate the value of bronchial provocation testing combined with fractional exhaled nitric oxide (FeNO) in the diagnosis of CTVA in children. METHODS: This study included 95 children aged 6-14 years with chest tightness as the sole symptom, with a duration of symptoms exceeding 4 weeks. All subjects underwent FeNO measurement, pulmonary function testing, and bronchial provocation testing using the Astograph method. Subjects with positive bronchial provocation testing were classified as the CTVA group, while those with negative results served as the non-CTVA control group. RESULTS: The lung function of children in both groups was normal. The FeNO level in the CTVA group was (22.35 ± 9.91) ppb, significantly higher than the control group (14.85 ± 5.63) ppb, with a statistically significant difference (P < 0.05). The value of FeNO in diagnosing CTVA was analyzed using an ROC curve, with an area under the curve of 0.073 (P < 0.05). The optimal cutoff point for diagnosing CTVA using FeNO was determined to be 18.5 ppb, with a sensitivity of 60.3 % and specificity of 77.8 %. There was a negative correlation between FeNO and Dmin as well as PD15 (P = 0.006). CONCLUSION: FeNO can serve as an adjunctive diagnostic tool for CTVA, with the optimal cutoff point for diagnosing CTVA being 18.5 ppb. However, FeNO is not a specific diagnostic marker for CTVA and should be used in conjunction with bronchial provocation testing to enhance its diagnostic value.

Fractional exhaled nitric oxide-a possible biomarker for risk of obstructive sleep apnea in snorers.

STUDY OBJECTIVES: Airway inflammation in patients with obstructive sleep apnea (OSA) has been described and can be assessed by measuring the biomarker fractional exhaled nitric oxide (FeNO). In this pilot study, we investigated FeNO measurements in identification of OSA among persons with snoring. METHODS: In this study we aimed to investigate (1) if FeNO could be used in screening for OSA, (2) if daytime sleepiness correlated to FeNO levels, and (3) whether asthma affected FeNO levels. Persons with snoring were prospectively included in three primary care ear, nose, and throat clinics. Patients underwent spirometry, FeNO tests, and partial polygraphy. They filled out questionnaires on sinonasal and asthma symptoms, daytime sleepiness, and quality of life. Current smokers, patients with upper airway inflammatory conditions, and patients treated with steroids were excluded. RESULTS: Forty-nine individuals were included. Median apnea-hypopnea index was 11.4, mean age was 50.9 years, and 29% were females. OSA was diagnosed in 73% of the patients of whom 53% had moderate-severe disease. Patients with moderate-severe OSA had significantly higher FeNO counts than patients with no or mild OSA (P = .024). Patients younger than 50 years with a FeNO below 15 had the lowest prevalence of moderate-severe OSA. No correlation was found between FeNO measurements and daytime sleepiness, and asthma did not affect FeNO levels. CONCLUSIONS: We found a low prevalence of moderate-severe OSA in persons with snoring when FeNO and age were low. This might be considered in a future screening model, though further studies testing the FeNO cutoff level and the diagnostic accuracy are warranted. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: NO Measurements in Screening for Asthma and OSA, in Patients With Severe Snoring; URL: https://clinicaltrials.gov/study/NCT03964324; Identifier: NCT03964324. CITATION: Kiaer E, Ravn A, Jennum P, et al. Fractional exhaled nitric oxide-a possible biomarker for risk of obstructive sleep apnea in snorers. J Clin Sleep Med. 2024;20(1):85-92.

Association between fractional exhaled nitric oxide and therapeutic adherence to controller management in pediatric asthma patients.

OBJECTIVES: Guidelines for asthma management recommend, before establishing additional therapeutic behaviors, to confirm correct use and adequate therapeutic adherence to treatment. Evidence exists on the use of fractional exhaled nitric oxide (FeNO) values for monitoring therapeutic adherence in adults. It is important to establish whether there is a correlation between FeNO and therapeutic adherence in children. This study aims to provide new knowledge about the relationship between FeNO and therapeutic adherence in asthmatic children. MATERIALS AND METHODS: Analytical cross-sectional study including asthma patients 5-18 years of age, attending follow-up at Hospital Militar Central (HMC) between May and November 2022 in Colombia. A sociodemographic survey was carried out, followed by the Pediatric Inhaler Adherence Questionnaire (PIAQ), and asthma control test (ACT) or childhood asthma control test (cACT). We defined adequate therapeutic adherence as not missing a single application of inhaled steroids in the last 15 days according to PIAQ. A poisson regression model was carried out including relevant predictors for therapeutic adherence such as FeNO values, age, tobacco exposure at home, atopy, and time since initiation of use of inhaled controller. RESULTS: Eighty-two children with a median age of 10 years (interquartile range: 7-12 years) were included. Adequate therapeutic adherence was reported by 68.3%. After adjusting for age, sex, exposure to cigarette smoke, duration of controller therapy, and atopy, FeNO < 20 ppb was independently associated with adequate therapeutic adherence (RR = 1.5, p = .04, 95% confidence interval: 1.03-2.19). CONCLUSIONS: FeNO values seem to be useful to identify pediatric patients with asthma who have adequate adherence to inhaled steroids in a MIC.

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.

Association of alpha globin gene copy number with exhaled nitric oxide in a cross-sectional study of healthy Black adults.

INTRODUCTION: The genetic determinants of fractional exhalation of nitric oxide (FeNO), a marker of lung inflammation, are understudied in Black individuals. Alpha globin (HBA) restricts nitric oxide signalling in arterial endothelial cells via interactions with nitric oxide synthase; however, its role in regulating the release of NO from respiratory epithelium is less well understood. We hypothesised that an HBA gene deletion, common among Black individuals, would be associated with higher FeNO. METHODS: Healthy Black adults were enrolled at four study sites in North Carolina from 2005 to 2008. FeNO was measured in triplicate using a nitric oxide analyzer. The -3.7 kb HBA gene deletion was genotyped using droplet digital PCR on genomic DNA. The association of FeNO with HBA copy number was evaluated using multivariable linear regression employing a linear effect of HBA copy number and adjusting for age, sex and serum immunoglobulin-E levels. Post-hoc analysis employing a recessive mode of inheritance was performed. RESULTS: 895 individuals were in enrolled in the study and 720 consented for future genetic research; 643 had complete data and were included in this analysis. Median (25th, 75th) FeNO was 20 (13, 31) ppb. HBA genotypes were: 30 (4.7%) -a/-a, 197 (30.6%) -a/aa, 405 (63%) aa/aa and 8 (1.2%) aa/aaa. Subjects were 35% male with median age 20 (19, 22) years. Multivariable linear regression analysis revealed no association between FeNO and HBA copy number (ß=-0.005 (95% CI -0.042 to 0.033), p=0.81). In the post-hoc sensitivity analysis, homozygosity for the HBA gene deletion was associated with higher FeNO (ß=0.107 (95% CI 0.003 to 0.212); p=0.045). CONCLUSION: We found no association between HBA copy number and FeNO using a prespecified additive genetic model. However, a post hoc recessive genetic model found FeNO to be higher among subjects homozygous for the HBA deletion.

The Relationship of Fractional Exhaled Nitric Oxide in Patients with AECOPD.

Objective: To identify the relationship between patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and their fractional-exhaled nitric oxide (FeNO) levels. Methods: Patients diagnosed with AECOPD in the respiratory department of Beijing Chaoyang Hospital from June 2017 to August 2019 were recorded. The demographic data, FeNO value, peripheral blood eosinophil count, number of acute exacerbations in the past year, pulmonary function test, use of inhaled glucocorticoids (ICS) and other data were collected and analyzed. FeNO was measured again three months after discharge, the participants were assessed to determine if the stable period criteria were met. Results: A total of 214 patients met the requirements of this study. 25ppb for FeNO was used as the cutoff for further analysis. The proportion of males, number of acute exacerbations in the past year, number of ICS users, leukocyte count and eosinophil count in the high FeNO-level group was significantly higher than that in the low-level group (P < 0.05). The results showed that the number of acute exacerbations in the past year, number of ICS users, and eosinophil count were statistically significant in the model (P < 0.05). The study also showed that the level of FeNO in the acute exacerbation phase was significantly higher than that in the stable phase. The ROC curve that the area under the curve used by FeNO to predict ICS used is 0.631 (95% CI: 0.526-0.736), and the corresponding P value is 0.022. Conclusion: FeNO is closely related to activated T2 inflammation and eosinophil count in COPD patients. The FeNO levels can be used as an index to evaluate the severity of COPD and predict the recovery of activity after ICS treatment. FeNO can predict the use of ICS and is a beneficial supplement to eosinophils.

Evaluation of the Relationship between FeNO and Clinical Risk Stratification for Early Mortality in Pulmonary Embolism.

BACKGROUND: Pulmonary embolism (PE) is a common complication of deep vein thrombosis that causes high mortality and morbidity. This study aimed to determine the relationship between clinical risk scoring for early mortality and fractional exhaled nitric oxide (FeNO) in PE patients. METHODS: The study included a total of 98 subjects, 68 patients diagnosed with PE in the emergency department, and 30 healthy controls. Patients with PE were grouped according to clinical scoring of early mortality risk as low (n = 20), moderate-low (n = 24), and moderate-high (n = 24) risk. FeNO levels were measured after diagnosis. RESULTS: FeNO levels were significantly higher in patients with moderate-high risk PE compared to the other three groups and in those with moderate-low risk PE compared to the control group (p < 0.001 for all). Moderate to strong positive correlations were observed between FeNO level and mean pulmonary artery pressure (r = 0.818, p = 0.01), troponin-I (r = 0.67, p = 0.01), pro-BNP (r = 0.762, p = 0.01), and D-dimer levels (r = 0.652, p = 0.01). A FeNO cutoff value of 7.5 ppb had 84% sensitivity and 78% specificity in differentiating moderate-high risk PE from moderate-low risk PE. CONCLUSIONS: FeNO may be as reliable, noninvasive, and easily accessible as cardiac biomarkers in clinical risk scoring for early mortality in PE patients.

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

OBJECTIVE: 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. METHODS: 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 ≥25 ppb; BEC ≥200/µL). RESULTS: 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. CONCLUSIONS: 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.

Use of fractional exhaled nitric oxide as a potential predictor of bronchodilator response.

Nitric oxide (NO) is an important product of eosinophilic metabolism, and its increase is associated with bronchial remodeling and airway hyperresponsiveness. Fractional exhaled NO (FENO) in the expired air of patients with suspected or diagnosed asthma has been used as a marker for eosinophilic inflammation. This cohort study included asthmatic patients classified under steps 3, 4, or 5 of the global strategy for asthma management and prevention. In the morning of the same day, all patients underwent blood collection for eosinophil counts, followed by FENO measurement and spirometry. We considered 2 groups based on the bronchodilation (BD) response on spirometry (>10% of FVC or FEV1): positive (BD+) and negative (BD-). Differences between the 2 groups were analyzed for demographic features, FENO values, and predictive correlations between FENO and BD. Both groups of patients showed an increase in the eosinophil count (BD+, P = .03; BD-, P = .04) and FENO values (P = .015 for both) with an increase in the asthma severity from step 3 to step 5 of the global strategy for asthma management and prevention. The correlations of FENO and eosinophils as well as FENO values and BD + were 0.127 (95% confidence interval,-0.269 to -0.486) and 0.696 (95% confidence interval, 0.246-0.899; P = .007), respectively. Measuring FENO levels may be useful for identifying patients with BD+.

A cross-sectional analysis of medical conditions and environmental factors associated with fractional exhaled nitric oxide (FeNO) in women and children from the ISA birth cohort, Costa Rica.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is a marker of airway inflammation. Elevated FeNO has been associated with environmental exposures, however, studies from tropical countries are limited. Using data from the Infants' Environmental Health Study (ISA) birth cohort, we evaluated medical conditions and environmental exposures' association with elevated FeNO. METHODS: We performed a cross-sectional analysis of 277 women and 293 8-year old children who participated in the 8-year post-partum visit in 2019. We measured FeNO and collected information on medical conditions and environmental exposures including smoke from waste burning, work in banana plantations, and home pesticide use. We defined elevated FeNO as >25 ppb for women and >20 ppb for children. To evaluate factors associated with elevated FeNO, we used logistic regression models adjusted for obesity in women and unadjusted in children. RESULTS: Overall elevated FeNO was common (20% of women, 13% of children). Rhinitis diagnosis was significantly associated with elevated FeNO in both women (odds ratio (OR): 3.67 95% Confidence Interval (CI): 1.81,7.35) and children (OR: 8.18 95%CI: 3.15, 21.22); wheeze was associated with elevated FeNO in women (OR: 4.50 95% CI: 2.25, 8.99). Environmental exposures were associated with elevated FeNO, but not significantly. Waste burning was associated with elevated FeNO in both women (OR: 1.58 95%CI 0.68, 4.15) and children (OR: 2.49 95%CI:0.82, 10.79). Para-occupational pesticide exposures were associated with elevated FeNO in women and children. For women, having a partner working in agriculture was associated with elevated FeNO (OR: 1.61 95%CI:0.77, 3.58) and for children, maternal work in agriculture was associated with elevated FeNO. (OR 2.08 95%CI 0.86, 4.67) CONCLUSION: Rhinitis and wheeze were associated with elevated FeNO in this rural, agricultural population. Smoke from waste burning as well as para-occupational pesticide exposure may contribute to elevated FeNO in rural communities.

Frequency of exacerbation and degree of required asthma medication can characterize childhood longitudinal asthma trajectories.

BACKGROUND: To the best of our knowledge, there have been no investigations of longitudinal asthma trajectories based on asthma exacerbation frequency and medications required for asthma control in children. OBJECTIVE: To investigate longitudinal asthma trajectories based on the exacerbation frequency throughout childhood and asthma medication ranks. METHODS: A total of 531 children aged 7 to 10 years were enrolled from the Korean childhood Asthma Study. Required asthma medications for control of asthma from 6 to 12 years of age and asthma exacerbation frequency from birth to 12 years of age were obtained from the Korean National Health Insurance System database. Longitudinal asthma trajectories were identified on the basis of asthma exacerbation frequency and asthma medication ranks. RESULTS: Four asthma clusters were identified: lesser exacerbation with low-step treatment (8.1%), lesser exacerbations with middle-step treatment (30.7%), highly frequent exacerbations in early childhood with small-airway dysfunction (5.7%), and frequent exacerbations with high-step treatment (55.6%). The frequent exacerbations with high-step treatment cluster were characterized by a high prevalence of male sex, increased blood eosinophil (counts) with fractional exhaled nitric oxide, and high prevalence of comorbidities. The highly frequent exacerbation in early childhood with small-airway dysfunction cluster was characterized by recurrent wheeze in preschool age, with high prevalence of acute bronchiolitis in infancy and a greater number of family members with small-airway dysfunction at school age. CONCLUSION: The present study identified 4 longitudinal asthma trajectories on the basis of the frequency of asthma exacerbation and asthma medication ranks. These results would help clarify the heterogeneities and pathophysiologies of childhood asthma.

The Role of Fractional Exhaled Nitric Oxide in Diagnosing Asthmatic Type 2 Chronic Rhinosinusitis With Nasal Polyps.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is useful in the management of asthma and predicting the efficacy of standard corticosteroids and biologics. However, the diagnostic value of FeNO in asthmatic chronic rhinosinusitis with nasal polyps (CRSwNP) remains unclear. OBJECTIVE: We assessed FeNO levels in patients with CRSwNP and evaluated the diagnostic value of FeNO for screening type 2 CRSwNP (T2-CRSwNP) with asthma. METHODS: We enrolled 94 patients who were diagnosed with CRSwNP and underwent functional endoscopic sinus surgery. FeNO levels, the blood eosinophil percentage, total IgE, spirometry tests (FEV1/FVC), Lund-Mackay CT score, and percentage of patients with comorbid asthma were compared among CRSwNP subgroups. Spearman rank correlation test was used to assess the degree of association between variables. ROC curve analysis was conducted to evaluate the diagnostic capability to differentiate T2-CRSwNP based on clinical and histological classifications. RESULTS: FeNO levels and the blood eosinophil percentage were significantly higher in patients with T2-CRSwNP(h) based on histological data (P < .05). FeNO was correlated with the blood eosinophil percentage (r = 0.420, P < .001) and FEV1/FVC (r = -0.324, P = .001). A FeNO level of 27 ppb had a good ability to discriminate patients with asthmatic T2-CRSwNP(h) (AUC = 0.848; 95% CI = 0.7602-0.9361; sensitivity = 90.9%; specificity = 63.9%). The optimal cutoff values for FeNO and the blood eosinophil percentage for diagnosing asthmatic T2-CRSwNP(h) were 68 ppb and 5.6% (sensitivity = 95.5%; specificity = 86.1%; AUC = 0.931; 95% CI = 0.8832-0.9791). In the diagnosis of severe T2-CRSwNP(c) based on clinical data, a FeNO level of 36 ppb showed the highest AUC (0.816; 95% CI = 0.7173-0.914; sensitivity = 72.7%; specificity = 79.2%). CONCLUSION: FeNO is a useful marker for screening asthmatic T2-CRSwNP even prior to biopsy or asthma evaluation and may assist in selecting a proper treatment.

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

BACKGROUND: Lipid 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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: In 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.