Blood eosinophils and fractional exhaled nitric oxide are prognostic and predictive biomarkers in childhood asthma.

BACKGROUND: Blood eosinophils and fractional exhaled nitric oxide (Feno) are prognostic biomarkers for exacerbations and predict lung function responses to dupilumab in adolescents and adults with asthma. OBJECTIVE: We evaluated the relationship between baseline blood eosinophils and Feno and response to dupilumab in children with asthma. METHODS: Children aged 6 to 11 years with uncontrolled moderate-to-severe asthma (n = 408) were randomized to receive dupilumab 100/200 mg by body weight or volume-matched placebo every 2 weeks for 52 weeks. Annualized exacerbation rate (AER) reduction and least squares mean change in prebronchodilator percent predicted forced expiratory volume in 1 second (ppFEV1) at week 12 were assessed according to cutoff baseline levels for Feno (<20 ppb vs ≥20 ppb) and blood eosinophil count (<150, ≥150 to <300, ≥300 to <500, and ≥500 cells/µL). Quadrant analyses in populations defined by biomarker thresholds and spline models across continuous end points assessed the relationship with Feno and eosinophil count. Interaction testing evaluated the independent roles of Feno and blood eosinophils as predictive markers. RESULTS: Exacerbation risk and magnitude of AER reduction increased in subgroups with higher baseline biomarker levels. Quadrant analyses revealed that disease of patients with either elevated Feno or eosinophil counts demonstrated a clinical response to dupilumab. Interaction testing indicated blood eosinophil counts or Feno independently added value as predictive biomarkers. CONCLUSIONS: In children with uncontrolled moderate-to-severe asthma, blood eosinophil counts and Feno are clinically relevant biomarkers to identify those at risk for asthma exacerbations, as well as those with disease with clinical response to dupilumab. TRIAL REGISTRATION: Liberty Asthma VOYAGE ClinicalTrials.gov NCT02948959.

Allergy in Young Adults Associates with Elevated Fractional Exhaled Nitric Oxide Levels and IgE-Verified Parental Allergy but Is Confounded by Self-Reported Symptoms.

INTRODUCTION: Knowledge of IgE-verified allergy in young adults is limited as most studies are based on self-reported data. Allergic heredity is important in allergy development in early life, but less is known about the hereditary component later in life. The aim was to investigate IgE-verified and self-reported allergy and asthma at 20 years of age in association to parental allergy and environmental factors. METHODS: In total, 281 individuals born into the cohort of well-characterized parents regarding allergic disease were followed to 20 years of age. The participants were categorized by parental allergy and examined regarding allergic diseases (IgE sensitization and allergic symptoms) at 2, 5, 10, and 20 years of age. FeNO was measured at 10 and 20 years. RESULTS: In total, 45% of the study participants were allergic, with twice as many self-reported cases at age 20. Rhinitis was key to distinguishing confirmed allergy from self-reported. Having two allergic parents and increased FeNO were associated with an increased prevalence of allergic disease at 20 years. From a longitudinal perspective, rhinitis increased from childhood to young adulthood, in all heredity groups. CONCLUSION: In this longitudinal study, we have shown that two allergic parents as well as increased FeNO levels seem to be of importance for being allergic at 20 years old. Self-reported allergy was overreported - a result that should be considered in future survey-based reports on allergic diseases.

Prediction of Clinical Response to Dupilumab in Patients with Severe Asthma Using Fractional Exhaled Nitric Oxide Combined with Pulmonary Function Testing.

INTRODUCTION: This study aimed to assess the effectiveness of fractional exhaled nitric oxide (FeNO) combined with pulmonary function testing (PFT) for predicting the treatment outcome of patients with severe asthma receiving dupilumab. METHODS: A total of 31 patients with severe asthma visiting our hospital from January 2022 to June 2023 were included in this study, with 28 patients completing a 16-week course of dupilumab treatment. Baseline clinical data, including demographic information, blood eosinophil counts, serum IgE levels, FeNO, asthma control test (ACT), asthma control questionnaire (ACQ), and other parameters, were collected. A predictive model using a generalized linear model was established. RESULTS: Following the 16-week course of dupilumab treatment, 22 patients showed effective response based on GETE scores, while 6 patients were nonresponders. Notably, significant improvements were observed in clinical parameters such as blood eosinophil counts, serum IgE levels, FeNO, FEV1, FEV1%, ACT, and ACQ in both response groups (p < 0.05). FeNO and pulmonary function tests demonstrated AUC values of 0.530, 0.561, and 0.765, respectively, in predicting the clinical efficacy of dupilumab, which were lower than when FeNO was combined with FEV1%. The combination of FeNO and FEV1% had a sensitivity of 1.000 and specificity of 0.591 in predicting treatment response. CONCLUSION: The combined assessment of FeNO and FEV1% provides improved accuracy for predicting the clinical efficacy of dupilumab in managing severe asthma. However, further larger scale clinical studies with comprehensive follow-up data are needed to validate the therapeutic efficacy and applicability across diverse patient populations.

Asthma control associated with anxiety and depression in asthmatic children following post-acute COVID-19.

BACKGROUND: Poor asthma control may adversely affect mental health. Our study investigates the correlation between inadequate asthma control, exhaled nitric oxide (FENO) levels, and anxiety and depression among pediatric asthma patients with COVID-19. METHODS: This prospective case-control study enrolled 520 asthmatic children (8-15 years), including 336 patients diagnosed with COVID-19 after rapid antigen testing at home and 184 age-matched asthmatic patients without COVID-19 infection. FENO and spirometry were performed 1 month after COVID-19 infection. Scores for Child Anxiety-Related Disorders (SCARED) and depression screen derived from Patient Health Questionnaire-9 (PHQ-9) to assess their mental health status. Childhood asthma control test (C-ACT), FENO levels, and spirometry were correlated with the SCARED and PHQ-9 questionnaires. RESULTS: SCARED subscales, including generalized anxiety disorder, social anxiety disorder, school avoidance, and depression scores from PHQ-9, exhibited a significant increase in asthmatic patients diagnosed with COVID-19 (p < .05). Among asthmatic children with SARS-CoV-2 infection, the poor asthma control group exhibited the highest SCARED and PHQ-9 measurements (p < .01). Multiple linear regression analysis indicated that reduced C-ACT scores and elevated FENO levels in asthmatic children with COVID-19 were significant risk factors for both anxiety and depression scores (p < .05). Lower C-ACT scales were associated with high scores of SCARED (r = -0.471) and PHQ-9 (r = -0.329) in asthmatic children (p < .001). CONCLUSIONS: The current study emphasizes the need for healthcare professionals to closely monitor asthma control in asthmatic children to prevent heightened risks of depression and anxiety during the ongoing COVID-19 pandemic.

Fractional exhaled nitric oxide (FeNO) among school children in Java and Sumatra, Indonesia: associations with respiratory symptoms, house dust mite sensitization and the home environment.

OBJECTIVE: To study associations between fractional exhaled nitric oxide (FeNO) and asthma, airway symptoms, sensitization to common allergens, outdoor pollution and home environment among 380 students in eight junior high schools in two areas in Indonesia. METHODS: Data on health and home were collected by a face-to face interview before measuring FeNO and performing skin prick test against common allergens. Exploratory linear mixed and logistic regression models were employed. RESULTS: Geometric mean of FeNO was 17.8 ppb (GSD 2.09) and 139 students (36.6%) had elevated FeNO (>20 ppb). In total, 107 students (28.2%) were sensitized to house dust mite (HDM) (Der p1 or Der f1), 4 (1.1%) to cat and 3 (0.8%) to mold (Cladosporium or Alternaria). Moreover, 20 students (5.3%) had diagnosed asthma, 38 (10.0%) had current wheeze, and 107 (28.2%) had current rhinitis. HDM sensitization, diagnosed asthma, current wheeze, and current rhinitis were associated with FeNO. In total, 281 students (73.9%) had mold or dampness, 232 (61.1%) had environmental tobacco smoke (ETS) and 43 (11.3%) had other odor at home. Indoor mold or dampness and other odor at home were associated with FeNO. ETS was negatively associated with FeNO. CONCLUSION: HDM sensitization and elevated FeNO can be common among children in this part of Indonesia. The high prevalence of elevated FeNO indicate that undiagnosed childhood asthma is common. Dampness, mold and odor at home can be associated with increased FeNO while ETS can be associated with decreased FeNO.

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.

Cough Response to High-Dose Inhaled Corticosteroids in Patients with Chronic Cough and Fractional Exhaled Nitric Oxide Levels ≥ 25 ppb: A Prospective Study.

This study aimed to investigate the effects of high-dose inhaled corticosteroids (ICS) on chronic cough patients with elevated fractional exhaled nitric oxide (FeNO) levels. In a prospective study, adults with chronic cough and FeNO ≥ 25 ppb, without any other apparent etiology, received fluticasone furoate (200 mcg) for three weeks. Outcomes were evaluated using FeNO levels, cough severity, and Leicester Cough Questionnaire (LCQ) before and after treatment. Of the fifty participants (average age: 58.4 years; 58% female), the treatment responder rate (≥ 1.3-point increase in LCQ) was 68%, with a significant improvement in cough and LCQ scores and FeNO levels post-treatment. However, improvements in cough did not significantly correlate with changes in FeNO levels. These findings support the guideline recommendations for a short-term ICS trial in adults with chronic cough and elevated FeNO levels, but the lack of correlations between FeNO levels and cough raises questions about their direct mechanistic link.

Type 2 Biomarkers and Their Clinical Implications in Bronchiectasis: A Prospective Cohort Study.

PURPOSE: Bronchiectasis is predominantly marked by neutrophilic inflammation. The relevance of type 2 biomarkers in disease severity and exacerbation risk is poorly understood. This study explores the clinical significance of these biomarkers in bronchiectasis patients. METHODS: In a cross-sectional cohort study, bronchiectasis patients, excluding those with asthma or allergic bronchopulmonary aspergillosis, underwent clinical and radiological evaluations. Bronchoalveolar lavage samples were analyzed for cytokines and microbiology. Blood eosinophil count (BEC), serum total immunoglobulin E (IgE), and fractional exhaled nitric oxide (FeNO) were measured during stable disease states. Positive type 2 biomarkers were defined by established thresholds for BEC, total IgE, and FeNO. RESULTS: Among 130 patients, 15.3% demonstrated BEC ≥ 300 cells/µL, 26.1% showed elevated FeNO ≥ 25 ppb, and 36.9% had high serum total IgE ≥ 75 kU/L. Approximately 60% had at least one positive type 2 biomarker. The impact on clinical characteristics and disease severity was variable, highlighting BEC and FeNO as reflective of different facets of disease severity and exacerbation risk. The combination of low BEC with high FeNO appeared to indicate a lower risk of exacerbation. However, Pseudomonas aeruginosa colonization and a high neutrophil-to-lymphocyte ratio (NLR ≥ 3.0) were identified as more significant predictors of exacerbation frequency, independent of type 2 biomarker presence. CONCLUSIONS: Our study underscores the distinct roles of type 2 biomarkers, highlighting BEC and FeNO, in bronchiectasis for assessing disease severity and predicting exacerbation risk. It advocates for a multi-biomarker strategy, incorporating these with microbiological and clinical assessments, for comprehensive patient management.

Utility of exhaled nitric oxide to guide mild asthma treatment in atopic patients and its correlation with asthma control test score: a randomized controlled trial.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is used for the diagnosis and monitoring of asthma, although its utility to guide treatment and its correlation with other tools is still under discussion. We study the possibility to withdraw inhaled corticosteroid treatment in atopic patients with mild asthma based on the FeNO level, as well as to study its correlation with other clinical control tools. METHODS: Prospective and randomized study including atopic patients aged 18 to 65 with mild asthma, stable, on low-dose inhaled corticosteroid (ICS) treatment, who had their treatment withdrawn based on a FeNO level of 40 ppb. Patients were randomized into two groups: control group (treatment with ICS was withdrawn regardless of FeNO level) and experimental group (according to the FeNO levels, patients were assigned to one of two groups: FeNO > 40 ppb on treatment with budesonide 200 mcg every 12 h and SABA on demand; FeNO ≤ 40 ppb only with SABA on demand). Follow-up was conducted for one year, during which medical assessment was performed with FeNO measurements, asthma control test (ACT), lung function tests (FEV1, FEV1/FVC, PEF, and RV/TLC), and recording of the number of exacerbations. RESULTS: Ninety-two patients were included, with a mean age of 39.92 years (SD 13.99); 46 patients were assigned to the control group, and 46 patients to the experimental group. The number of exacerbations was similar between the groups (p = 0.301), while the time to the first exacerbation was significantly shorter in the control group (30.86 vs. 99.00 days), p < 0.001, 95% CI (43.332-92.954). Lung function tests (FEV1, FEV1/FVC, PEF, and RV/TLC) showed no differences between the groups (p > 0.05). Both FeNO and ACT showed significant changes in the groups in which ICS was withdrawn (p < 0.05 for both parameters). A significant negative correlation was observed between FeNO and ACT (r = -0.139, p = 0.008). CONCLUSIONS: In atopic patients with mild asthma, withdrawal of ICS based on an FeNO of 40 ppb led to worsened symptoms but without changes in lung function tests or an increase in exacerbations. There was a negative correlation between FeNO values and symptomatic control measured by the ACT. TRIAL REGISTRATION: Clinical Trial Number: 2012-000372-42. Start Date: 2012-07-23. Trial registered prospectively ( https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-000372-42 ). This study adheres to CONSORT guidelines of randomised control trials.

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.

Economic impact of a more extensive use of FENO testing on the Italian population with asthma.

BACKGROUND: Asthma is a common chronic inflammatory airway affecting over 260 million people worldwide, and characterized, in the large majority of cases, by the so-called "type 2 inflammation". Fractional exhaled nitric oxide (FENO) testing is noninvasive point-of-care tool to assess type 2 inflammation and therefore improve asthma management. It has been suggested to determine eligibility for a specific biologic therapy and predict likelihood to respond. The aim of this study was to estimate the overall economic impact of an extensive use of FENO testing on the Italian population with asthma, including extra costs of testing and savings generated by more appropriate prescriptions, increased adherence and lower frequency of exacerbations. METHODS: A cost of illness analysis was firstly performed to estimate the yearly economic burden from the National Healthcare Service (NHS) perspective in Italy of the management of asthmatic patients with standard of care (SOC) according to the application of GINA (Global Initiative for Asthma) guidelines; then, we evaluated the changes in the economic burden in patient management by introducing FENO testing into clinical practice. The cost items considered were: visits/exams, exacerbations, drugs, management of adverse events caused by short-term oral corticosteroids use. Efficacy of FeNO test and SOC is based on literature evidence. Costs refer to published data or Diagnosis Related Group/outpatient tariffs. RESULTS: Considering one asthma visit every 6 months, the total yearly cost for the management of patients with asthma in Italy is 1,599,217,876€ (409.07€ per patient), while for FENO testing strategy this figure is 1,395,029,747€ (356.84€ per patient). An increased utilization rate of FENO testing from 50 to 100% of patients may lead to savings for the NHS from about 102 to 204 million € compared to SOC. CONCLUSIONS: Our study showed that FeNO testing strategy may improve the management of asthmatic patients leading to significant savings for the NHS.

Oral bacterial composition associated with lung function and lung inflammation in a community-based Norwegian population.

BACKGROUND: The oral cavity is the gateway to the bacteria community in the lung. Disruption of the symbiotic balance of the oral microbiota has been associated with respiratory diseases. However, little is known about the relationship between oral bacteria and respiratory outcomes in the general population. We aimed to describe the associations between oral bacteria, lung function, and lung inflammation in a community-based population. METHODS: Oral (gingival) samples were collected concurrently with spirometry tests in 477 adults (47% males, median age 28 years) from the RHINESSA study in Bergen, Norway. Bacterial DNA from the 16S rRNA gene from gingival fluid were sequenced by Illumina®MiSeq. Lung function was measured using spirometry and measurement of fractional exhaled nitric oxide (FeNO) were performed to examine airway inflammation. Differential abundance analysis was performed using ANCOM-BC, adjusting for weight, education, and smoking. RESULTS: The abundance of the genera Clostridiales, Achromobacter, Moraxella, Flavitalea and Helicobacter were significantly different among those with low FEV1 (< lower limit of normal (LLN)) as compared to normal FEV1 i.e. ≥ LLN. Twenty-three genera differed in abundance between among those with low FVC < LLN as compared to normal FEV1 ≥ LLN. The abundance of 27 genera from phyla Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria and Sacchribacteria differed significantly between elevated FeNO levels (≥ 50 ppb) compared to FeNO ≤ 25 ppb. CONCLUSION: Oral bacterial composition was significantly different for those with low FEV or FVC as compared to those with normal lung function equal to or higher than LLN. Differential bacterial composition was also observed for elevated FeNO levels.

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

BACKGROUND AND OBJECTIVE: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are heterogeneous in aetiology and accelerate disease progression. Here, we aimed to investigate the association of fractional exhaled nitric oxide (FeNO) and its variability with AECOPD of different aetiology. METHODS: FeNO was determined in 2157 visits (1697 stable, 133 AECOPD and 327 follow-up) of 421 COPD patients from the PREVENT study, an investigator-initiated, longitudinal and interventional study, who were on daily treatment with inhaled corticosteroids/long-acting ß2-agonists. RESULTS: Longitudinal measurements of FeNO revealed an intra-subject variability of FeNO that was significantly higher in exacerbators compared to non-exacerbators (p < 0.001) and positively associated with the number of AECOPD. As FeNO variability increased, the probability of patients to remain AECOPD-free decreased. In patients included in the highest FeNO variability quartile (≥15.0 ppb) the probability to remain free of AECOPD was only 35% as compared to 80% for patients included in the lowest FeNO variability quartile (0.50-4.39 ppb). The change of FeNO from the last stable visit to AECOPD was positively associated with the probability of viral infections and this association was stronger in current smokers than ex-smokers. In contrast, the change in FeNO from the last stable visit to an AECOPD visit was inversely associated with the probability of bacterial infections in ex-smokers but not in current smokers. CONCLUSION: FeNO variability was associated with the risk and aetiology of AECOPD differentially in current and ex-smokers.

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.

[LOWER RESPIRATORY TRACT SCREENING USING FRACTIONAL EXHALED NITRIC OXIDE IN PATIENTS WITH EOSINOPHILIC CHRONIC RHINOSINUSITIS].

BACKGROUND: It is known that eosinophilic chronic rhinosinusitis is often associated with adult-onset bronchial asthma, and undiagnosed bronchial asthma is also known to be included. The purpose of this study is to screen patients with eosinophilic chronic rhinosinusitis using fractional exhaled nitric oxide, and to examine its usefulness in detecting undiagnosed bronchial asthma. METHODS: We retrospectively examined the data of patients with eosinophilic chrnoic rhinosinusitis who underwent surgical treatment at Kagawa University from April 2015 to July 2022. Patients were included if they received examinations of fractional exhaled nitric oxide and spirometry before surgical treatment. RESULTS: Of the 127 subjects, 52 had no history of treatment or diagnosis of bronchial asthma at the initial consultation. Among them, 15 patients who had high fractional exhaled nitric oxide value were diagnosed with bronchial asthma by the respiratory medicine department. Comorbid of bronchial asthma was eventually increased to 70.9% even though it was 59.1% at initial consultation. CONCLUSION: A certain number of patients with eosinophilic chronic rhinosinusitis have undiagnosed bronchial asthma, which can be difficult to detect with basic examination alone therefore fractional exhaled nitric oxide is useful as an additional screening examination.

The Use of Exercise Challenge Testing and Fractional Exhaled Nitric Oxide in Diagnosis of Chest Tightness Variant Asthma in Children.

BACKGROUND: Chest tightness variant asthma (CTVA) in children presents with chest tightness as the sole manifestation. Diagnostic tests are needed given the lack of typical asthma symptoms. The present study aimed to investigate the diagnostic value of exercise challenge testing (ECT) and fractional exhaled nitric oxide (FeNO) in pediatric CTVA. METHODS: We included 98 children aged 6-13 years with chest tightness as the sole symptom for >4 weeks. All subjects underwent FeNO measurement, spirometry and ECT, and received 4-week budesonide/formoterol treatment. According to treatment responses, children were categorized into CTVA (n = 12) and non-CTVA (n = 86) groups. Differences in clinical characteristics and FeNO, spirometry, and ECT results were compared between the two groups. The FeNO and ECT diagnostic performances were determined using receiver operating characteristic (ROC) curve analysis. RESULTS: Children with CTVA exhibited significantly higher Mycoplasma pneumoniae IgG, total IgE, and FeNO values; greater post-ECT forced expiratory volume in 1 s (FEV1) fall; and more frequent sensitization to mites and pets than those without CTVA. Further logistic regression revealed that higher FEV1 fall (OR, 1.39; 95% CI: 1.11-1.74; p = 0.004) and higher FeNO values (OR, 1.04; 95% CI: 1.01-1.08; p = 0.014) were risk factors associated with CTVA. FEV1 fall and FeNO had similar areas under the ROC curve (AUCs) (0.79 vs. 0.78; p = 0.924), and their optimal CTVA-prediction cutoff values were 9.9% and 15.0 ppb, respectively. The AUC of FEV1 fall and FeNO combination was higher at 0.86 (95% CI: 0.78-0.93); however, no difference was observed using the single test (p > 0.05). Their combination exhibited a relatively higher sensitivity than that of FEV1 fall alone (0.75 vs. 0.67) and higher positive predictive value than that of FeNO alone (0.60 vs. 0.29). CONCLUSION: CTVA is a cause of unexplained recurrent chest tightness in children. FeNO ≥15.0 ppb and post-ECT FEV1 fall ≥9.9% are diagnostically valuable for CTVA in children, with their combination potentially contributing to greater diagnostic accuracy.

Exacerbations of asthma following step-up and step-down inhaled corticosteroid and long acting beta agonist therapy in the managing asthma in pregnancy study.

OBJECTIVE: Guidelines for asthma management contain a consensus recommendation that inhaled corticosteroid (ICS) dose should not be stepped down in pregnancy. However, this is not consistent with consumer preferences and pharmacological principles to minimize medication exposure during pregnancy. We investigated exacerbations after changes to ICS and long acting beta agonist (LABA) therapy in pregnant women with asthma. METHODS: Pregnant women (n = 220) were recruited to a randomized controlled trial (RCT) where maintenance treatment was adjusted monthly based on either symptoms (control group), or fractional exhaled nitric oxide (FeNO, to alter ICS) and symptoms (to alter LABA, FeNO group). Exacerbations were monitored prospectively. RESULTS: ICS were used by 137 (62.3%) women at some time during pregnancy. ICS dose remained unchanged in 16 women (11.7%, 95% confidence interval [CI] 7-18%), increased in 37 women (27%, 95%CI 20-35%), decreased in 34 women (24.8%, 95%CI 18%-33%), or both increased and decreased in 50 women (36.5%, 95%CI 29-45%). Exacerbations occurred within 14 days of ICS step-down in 11 women (13%, 95%CI 7.5%-22%). This was not significantly different from exacerbations occurring within 14 days of step-up, in 7 women (8.1%, 95%CI 4%-16%, P = 0.294). There were no differences between management groups. Exacerbations occurred within 14 days of step-down in 14.7% (95%CI 7%-30%) of women in the control group, and in 12% (95%CI 6%-24%) of women in the FENO group. CONCLUSIONS: ICS step-down could be considered when eosinophilic inflammation or symptoms are low, and may be a useful management approach for women, doctors, and midwives wishing to minimize ICS exposure during pregnancy.

School-age obese asthmatic children have distinct lung function measures from lean asthmatics and obese children.

BACKGROUND: The lung functions of children with obese asthma seem to be distinct from those of obese children or lean asthmatics. AIM: To measure baseline lung function, exercise-induced bronchoconstriction (EIB), and bronchial hyperreactivity (BHR) in school-age obese asthmatics (OA group) and to compare the data with obese children (O group), lean asthmatics (A group), and healthy controls (H group). METHODS: One hundred seventy school-age children were enrolled in this prospective cross-sectional study. Baseline fractionated exhaled nitric oxide (FeNO), and baseline, post-exercise (post-E), and post-bronchodilation (post-BD) impulse oscillometry (IOS) and spirometry tests were performed. EIB and BHR were evaluated based on the difference (Δ) in post-E - baseline, and post-BD - baseline values. RESULTS: The mean FeNO level was higher in the OA group than in the other groups (p = 0.002). Baseline zR5 and R5-20 were higher (p = 0.013 and p = 0.044), but zFEF25-75 was lower (p < 0.01), in the OA group. ΔPost-E - baseline zFEV1 was lower in the A group (p = 0.003) but was higher in the OA group (p = 0.014) than the other groups. ΔPost-BD - baseline zFEV1 was lower in the H group compared to the other three groups (p = 0.004), but no significant difference was observed among the O, A, and OA groups (p > 0.05). CONCLUSION: Higher airway inflammation (high FeNO), peripheral airway resistance (high zR5 and zR5-20) and a lower peripheral airway flow (low FEF25-75) were observed at baseline measurement in school-age obese asthmatics compared to lean asthmatics and obese children. Obese asthmatics had no EIB but exhibited a similar BHR to that of asthmatics.

Usefulness of diurnal variation of fractional exhaled nitric oxide for predicting early therapeutic response to asthma treatment.

OBJECTIVE: Fractional exhaled nitric oxide (FeNO) is considered to be an adjunct for asthma management, although its usefulness remains controversial. Therefore, it may be necessary for new approaches to use FeNO for asthma management. We evaluated whether diurnal variations of FeNO can predict response to asthma treatment. METHODS: This pilot study consisted of 22 uncontrolled asthmatics and 16 healthy subjects. FeNO and peak expiratory flow (PEF) were measured by themselves twice daily at home for three weeks (asthmatics) or two weeks (healthy subjects), and daily mean and diurnal variations of FeNO and PEF levels were calculated. In uncontrolled asthmatics, treatment was intensified a week after study entry, and then control status was reevaluated after three to four weeks. Asthmatics were then divided into two groups; good or poor responders. RESULTS: Diurnal variations of FeNO levels, as well as daily mean FeNO and PEF levels, in uncontrolled asthmatics before intensive treatment were significantly higher than those in healthy subjects, regardless of treatment response (p < 0.01). Furthermore, in the good responders, diurnal variations of FeNO levels were significantly decreased in the 1st week (p < 0.05) of intensive treatment, whereas the daily mean FeNO levels significantly dropped in the 2nd week (p < 0.05). In the poor responders, no such changes were observed in FeNO levels. In terms of PEF, only the daily mean levels were significantly elevated after the initiation of intensive treatment, regardless of treatment response. CONCLUSIONS: Diurnal variations of FeNO may contribute to predicting early therapeutic response to asthma treatment.

Association between exposure to a mixture of metals, parabens, and phthalates and fractional exhaled nitric oxide: A population-based study in US adults.

The effects of environmental endocrine-disrupting chemicals (EDCs) (e.g., phthalates) on fractional exhaled nitric oxide (FeNO) in children have received much attention. However, few studies evaluated this relationship in adults, and the previous studies have considered only a unitary exposure or a set of similar exposures instead of mixed exposures, which contain complicated interactions. We aimed to evaluate simultaneously the relationship between three types of EDCs (six phthalate metabolites and two parabens in urine, two heavy metals in blood) and FeNO (as a continuous variable) in adults. Data of adults aged ≥20 years from the National Health and Nutrition Examination Survey (NHANES, 2007-2012) were collected and analyzed. The generalized linear (GLM) regression model was used to explore the association of chemicals with FeNO. The combined effect of 10 chemicals on the overall association with FeNO was evaluated by the weighted quantile sum regression (WQS) model. In addition, The Bayesian kernel machine regression (BKMR) model was explored to investigate the interaction and joint effects of multiple chemicals with FeNO. Of the 3296 study participants ultimately included, among the GLMs, we found that mercury (Hg) (ß = 0.84, 95%CI:0.32-1.36, FDR = 0.01) and methyl paraben (MPB) (ß = 0.47, 95%CI:0.16-0.78, FDR = 0.015) were positively correlated with FeNO. In the WQS model, the combined effect of chemicals almost had a significantly positive association with FeNO and the top three contributors to the WQS index were Hg (40.2%), MECPP (22.1%), and MPB (19.3%). BKMR analysis showed that there may be interactions between MPB and Hg, Mono (carboxyoctyl) phthalate (MCOP) and Hg and the overall effect of the mixture showed a positive correlation with FeNO. In conclusion, our study strengthens the credibility of the view that EDCs can affect respiratory health. In the future, we should be particularly careful with products containing Hg, MECPP, MPB, and MEHP for the prevention of respiratory diseases.