Fractional Exhaled Nitric Oxide Levels Research Articles

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+.

Circulating Biomarkers, Fraction of Exhaled Nitric Oxide, and Lung Function in Patients With Human Immunodeficiency Virus and Tuberculosis.

Identification of proinflammatory factors responding to Mycobacterium tuberculosis is important to reduce long-term sequelae of pulmonary tuberculosis (TB). We examined the association between plasma biomarkers, the fraction of exhaled nitric oxide (FeNO), and lung function among a prospective cohort of 105 adults newly diagnosed with TB/human immunodeficiency virus (HIV) in South Africa. Participants were followed for 48 weeks from antiretroviral therapy (ART) initiation with serial assessments of plasma biomarkers, FeNO, lung function, and respiratory symptoms. Linear regression and generalized estimating equations were used to examine the associations at baseline and over the course of TB treatment, respectively. At baseline, higher FeNO levels were associated with preserved lung function, whereas greater respiratory symptoms and higher interleukin (IL)-6 plasma levels were associated with worse lung function. After ART and TB treatment initiation, improvements in lung function were associated with increases in FeNO (rate ratio [RR] = 86 mL, 95% confidence interval [CI] = 34-139) and decreases in IL-6 (RR = -118 mL, 95% CI = -193 to -43) and vascular endothelial growth factor ([VEGF] RR = -178 mL, 95% CI = -314 to -43). Circulating IL-6, VEGF, and FeNO are associated with lung function in adults being treated for TB/HIV. These biomarkers may help identify individuals at higher risk for post-TB lung disease and elucidate targetable pathways to modify the risk of chronic lung impairment among TB survivors.

Pretreatment circulating MAIT cells, neutrophils, and periostin predicted the real-world response after 1-year mepolizumab treatment in asthmatics

BackgroundMepolizumab treatment improves symptom control and quality of life and reduces exacerbations in patients with severe eosinophilic asthma. However, biomarkers that predict therapeutic effectiveness must be determined for use in precision medicine. Herein, we elucidated the dynamics of various parameters before and after treatment as well as patient characteristics predictive of clinical responsiveness to mepolizumab after 1-year treatment. MethodsTwenty-seven patients with severe asthma were treated with mepolizumab for one year. Asthma control test scores, pulmonary function tests, fractional exhaled nitric oxide levels, and blood samples were evaluated. Additionally, we explored the role of CD69-positive mucosal-associated invariant T (MAIT) cells as a candidate biomarker for predicting treatment effectiveness by evaluating an OVA-induced asthma murine model using MR1 knockout mice, where MAIT cells were absent. ResultsThe frequencies of CD69-positive group 1 innate lymphoid cells, group 3 innate lymphoid cells, natural killer cells, and MAIT cells decreased after mepolizumab treatment. The frequency of CD69-positive MAIT cells and neutrophils was lower and serum periostin levels were higher in responders than in non-responders. In the OVA-induced asthma murine model, CD69-positive MAIT cell count in the whole mouse lung was significantly higher than that in the control mice. Moreover, OVA-induced eosinophilic airway inflammation was exacerbated in the MAIT cell-deficient MR1 knockout mice. ConclusionsThis study shows that circulating CD69-positive MAIT cells, neutrophils, and serum periostin might predict the real-world response after 1-year mepolizumab treatment. Furthermore, MAIT cells potentially have a protective role against type 2 airway inflammation.

The Potential of Fractional Exhaled Nitric Oxide as a Biomarker in Predicting and Optimizing Use of Treatment in Asthma

Asthma affects the respiratory system and causes airway inflammation. The indication of asthma includes a triad of airway inflammation, hyperresponsiveness, and obstruction. Nitric Oxide (NO) is a gas that is exhaled and is a sign of airway inflammation. NO levels in the exhaled breath of patients with type 2 asthma are elevated, and fractional exhaled nitric oxide (FeNO) is an objective biomarker of airway inflammation. Measurements of FeNO are noninvasive, require minimal patient effort, and are easy to collect in clinical settings. The current review is a systematic review performed using PubMed, Science Direct, and Google Scholar according to The Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol (PRISMA-P) guidelines. This review discusses the entanglement of understanding FeNO measurement and supplementing existing diagnostic and assessment tools for inflammatory lung diseases. Monitoring FeNO can also help identify different asthma phenotypes within the asthma syndrome and suggest the optimal administration of inhaled corticosteroids (ICS) as elevated FeNO levels indicate ICS response. Non-adherence to ICS is a significant contributor to the failure of asthma treatment. A FeNO suppression test can be done to determine non-adherence. FeNO levels should be used with a careful history, conventional spirometric testing with bronchodilator reversibility, measures of bronchial hyperreactivity using methacholine, and other measures of eosinophilic inflammation, such as a peripheral blood eosinophil cell count. FeNO is more sensitive and specific when paired with other lung function tests.

Presence and sequence of bronchiectasis onset impact on the clinical characteristics in asthmatic patients.

Asthmatic patients with comorbid bronchiectasis (ACB) show significantly severe condition with various inflammatory phenotypes; bronchiectasis is a heterogeneous disease caused by asthma and other multiple etiological factors. We aimed to investigate the inflammatory characteristics and their clinical significance in asthmatic patients according to the presence and onset time of bronchiectasis. This prospective cohort study recruited outpatients with stable asthma. All the enrolled patients were divided into the non-bronchiectasis group and the ACB group, and the ACB group was separated into the bronchiectasis-prior group and the asthma-prior group. Demographic and clinical data were collected, and peripheral blood and induced sputum eosinophil counts, sputum pathogens, the fraction of exhaled nitric oxide (FeNO), lung function, and chest high-resolution computed tomography were examined. A total of 602 patients (mean age: 55.36±14.58 years) were included, of which 255 (42.4%) were males. Bronchiectasis was present in 268 (44.5%) patients, with 171 (28.41%) in the asthma-prior group and 97 (16.11%) in the bronchiectasis-prior group. For the asthma-prior group, the presence of bronchiectasis was positively correlated with age, presence of nasal polyps, severe asthma, ≥1 pneumonia in the last 12 months, ≥1 severe exacerbation of asthma in the last 12 months (SEA), peripheral blood eosinophil counts, and sputum eosinophil ratio; the extent and severity of bronchiectasis were positively correlated with ≥1 SEA and FeNO levels; and the bronchiectasis severity index (BSI) scores were positively correlated with ≥1 SEA and immunoglobulin E levels. For the bronchiectasis-prior group, bronchiectasis was positively correlated with previous pulmonary tuberculosis or pneumonia in childhood and ≥1 pneumonia in the last 12 months and negatively correlated with forced expiratory volume in one second (FEV1) % and the FeNO level. The extent and severity of bronchiectasis were positively correlated with ≥1 pneumonia in the last 12 months and negatively correlated with FEV1%. The BSI scores were positively correlated with the duration of bronchiectasis. The sequence of bronchiectasis onset may indicate distinct inflammatory characteristics and may be helpful in targeted therapy for patients with asthma.

The association between allergic rhinitis and airway dysfunction and nasal endothelial damage and oxidative stress.

Although lower airway hyperresponsiveness is present in approximately one in three patients with allergic rhinitis (AR), the underlying mechanism remains unclear. To evaluate nasal patency and pulmonary functions in AR independently of the presence of asthma and to investigate the relationships between these and nasal oxidative stress parameters and endothelial damage. Seventy adolescents with AR (AR group - 27 with asthma and 43 without asthma) and 30 healthy controls (HC group) were included in this prospective, cross-sectional study. Endocan and oxidative biomarkers [total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI)] in nasal lavage fluid specimens; peak nasal inspiratory flow (PNIF); fractional exhaled nitric oxide (FeNO), and impulse oscillometry (zR5, zR20, and R5-20 for resistance and zX5 and zX20 for reactance) were investigated. Nasal endocan, TOS, and OSI values were higher in the AR group and TAS in the HC group. There was no difference between AR groups with and without asthma in terms of nasal endocan and oxidative biomarkers. FeNO levels and airway resistance (zR5, zR20, and R5-20) were higher in the AR group than in the HC group. However, there was no difference between the groups in PNIF. X5 was higher among the AR without asthma than in the other groups. Correlation between OSI and R5-20 was observed in the AR group. In the linear regression model, (logged) OSI was significantly predicted (logged) R5-20. The airways of adolescents with AR without asthma were as much affected as those of the AR with asthma, and this effect was associated with nasal endothelial damage and an increase in oxidative stress.

Interleukin-33 increases type 2 innate lymphoid cell count and their activation in eosinophilic asthma.

Interleukin-33 (IL-33) exacerbates asthma probably through type 2 innate lymphoid cells (ILC2s). Nevertheless, the association between eosinophilic asthma (EA) and ILC2s remains obscure, and the mechanisms by which IL-33 affects ILC2s are yet to be clarified. ILC2s were evaluated in peripheral blood mononuclear cells, induced sputum, and bronchoalveolar lavage fluid obtained from patients with EA. Confocal microscopy was performed to locate ILC2s in lung tissue and the mRNA expression of ILC2-related genes was also evaluated in the EA model. The proliferation of ILC2s isolated from humans and mice was assessed following IL-33 or anti-IL-33 stimulation. The counts, activation, and mRNA expression of relevant genes in ILC2s were higher in PBMCs and airways of patients with EA. In addition, ILC2 cell counts correlated with Asthma control test, blood eosinophil count, Fractional exhaled nitric oxide level, and predicted eosinophilic airway inflammation. IL-33 induced stronger proliferation of ILC2s and increased their density around blood vessels in the lungs of mice with EA. Moreover, IL-33 treatment increased the counts and activation of ILC2s and lung inflammatory scores, whereas anti-IL-33 antibody significantly reversed these effects in EA mice. Finally, IL-33 enhanced PI3K and AKT protein expression in ILC2s, whereas inhibition of the PI3K/AKT pathway decreased IL-5 and IL-13 production by ILC2s in EA. ILC2s, especially activated ILC2s, might be critical markers of EA. IL-33 can induce and activate ILC2s in the lungs via the PI3K/AKT pathway in EA. Thus, using anti-IL-33 antibody could be a part of an effective treatment strategy for EA.

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

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

Multiple imputation of more than one environmental exposure with nondifferential measurement error.

Measurement error is common in environmental epidemiologic studies, but methods for correcting measurement error in regression models with multiple environmental exposures as covariates have not been well investigated. We consider a multiple imputation approach, combining external or internal calibration samples that contain information on both true and error-prone exposures with the main study data of multiple exposures measured with error. We propose a constrained chained equations multiple imputation (CEMI) algorithm that places constraints on the imputation model parameters in the chained equations imputation based on the assumptions of strong nondifferential measurement error. We also extend the constrained CEMI method to accommodate nondetects in the error-prone exposures in the main study data. We estimate the variance of the regression coefficients using the bootstrap with two imputations of each bootstrapped sample. The constrained CEMI method is shown by simulations to outperform existing methods, namely the method that ignores measurement error, classical calibration, and regression prediction, yielding estimated regression coefficients with smaller bias and confidence intervals with coverage close to the nominal level. We apply the proposed method to the Neighborhood Asthma and Allergy Study to investigate the associations between the concentrations of multiple indoor allergens and the fractional exhaled nitric oxide level among asthmatic children in New York City. The constrained CEMI method can be implemented by imposing constraints on the imputation matrix using the mice and bootImpute packages in R.

Biomarkers for predicting type 2-high and uncontrolled asthma in real-world practice

BackgroundBlood eosinophil count (BEC), immunoglobulin (Ig) E, and fractional exhaled nitric oxide (FeNO) are key clinical indicators for identifying type 2 (T2) asthma. ObjectiveTo provide optimal cutoff points of T2 markers for assessing T2-high or uncontrolled asthma in real-world practice. MethodsVarious clinical and laboratory parameters were analyzed according to the result of T2 markers (BEC, serum-free IgE, and FeNO) in adults with asthma who had maintained antiasthmatic medications. The cutoff levels for representing uncontrolled asthma were determined using receiver operating characteristic analysis. Blood levels of periostin and eosinophil-derived neurotoxin were measured by enzyme-linked immunosorbent assay. Activation markers of circulating eosinophils (Siglec8+) and neutrophils (CD66+) were analyzed by flow cytometry. ResultsOf 133 patients with asthma, 23 (17.3%) had 3 T2 markers (BEC ≥ 300 cells/μL, serum-free IgE ≥ 120 ng/mL, and FeNO ≥ 25 parts per billion) and significantly higher levels of sputum eosinophils, blood eosinophil-derived neurotoxin, and Siglec8+ eosinophils but lower 1-second forced expiratory volume percentage, in addition to a higher rate of uncontrolled status (P < .05 for all). Furthermore, patients with uncontrolled asthma had significantly higher levels of FeNO and BEC with lower 1-second forced expiratory volume percentage (P < .05 for all). The optimal cutoff values for predicting uncontrolled asthma were found to be 22 parts per billion of FeNO levels, 161.4 cells/L of BECs, and 85.9 ng/mL of serum-free IgE levels. ConclusionWe suggest the optimal cutoff values of BEC, IgE, and FeNO for classifying T2-high or uncontrolled asthma, which could be applied as candidate biomarkers for targeting patients with asthma who require T2 biologics.

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.

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

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. We assessed FeNO levels in patients with CRSwNP and evaluated the diagnostic value of FeNO for screening type 2 CRSwNP (T2-CRSwNP) with asthma. 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. 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%). 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.

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.

The Use of Lactobacillus reuteri as an Adjunct in the Treatment of Children with Newly Diagnosed Asthma in a Tertiary Hospital in the Philippines

Rationale: Probiotics are live microorganisms that exert beneficial effects on the host, including a reduction of allergic disease symptoms. Lactobacillus reuteri in particular was shown to attenuate the allergic airway, and when used as an adjunct in the treatment of asthma in children, resulted in decreased fractional exhaled nitric oxide and interleukin levels when compared to placebo. However, insufficient information is available regarding the significance of L. reuteri as an adjunct in the treatment of allergic disorders, particularly in allergic airway disease. Objectives: The objective of the study was to determine the efficacy of L. reuteri as an adjunct for the control of newly diagnosed asthma in children. Methodology and Population: In this analytical, experimental, prospective, randomized controlled trial, 44 asthmatic patients aged 6–18 years were recruited from the University of Santo Tomas Hospital outpatient department, for a study period of three months. Baseline clinical assessment included skin prick test to aeroallergens, spirometry, and Childhood Asthma Control Test. Asthma severity and level of control was based on the National Asthma Education and Prevention Program’s Expert Panel 3 (EPR-3) and the Global Initiative for Asthma Guidelines 2018, respectively. Patients were randomized and half of them received L. reuteri 26.5 mg/chewable tab (at least 100 million colony forming units) once daily for 30 days, while the other half did not. Spirometry and C-ACT test were conducted at the start of intervention as baseline, after one month, two months, and three months post intervention. The results of patients from the experimental group were compared to results of patients in the control group. Results: The FEV1 of patients in the L. reuteri group was significantly higher than those in the control group (p = 0.045). The median FVC of the two groups significantly differed from each other through time (p = 0.007), with the L. reuteri group having significantly higher FVC than the control group. There were statistically significant improvements in ACT scores between patients in the L. reuteri and control groups, particularly at two months and three months of treatment. Among polysensitized patients, there were significant improvements in the FEV1, FEF25–75, and FVC between the L. reuteri and control group. Conclusion: The use of L. reuteri as an adjunct was associated with significant lung function improvement and asthma symptom control amongst newly diagnosed asthmatic children. Key Words: Lactobacillus reuteri, Probiotics, Asthma, Children

Real-life effects of dupilumab in patients with severe type 2 asthma, according to atopic trait and presence of chronic rhinosinusitis with nasal polyps.

The efficacy of dupilumab as biological treatment of severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) depends on its ability to inhibit the pathophysiologic mechanisms involved in type 2 inflammation. To assess in a large sample of subjects with severe asthma, the therapeutic impact of dupilumab in real-life, with regard to positive or negative skin prick test (SPT) and CRSwNP presence or absence. Clinical, functional, and laboratory parameters were measured at baseline and 24 weeks after the first dupilumab administration. Moreover, a comparative evaluation was carried out in relation to the presence or absence of SPT positivity and CRSwNP. Among the 127 recruited patients with severe asthma, 90 had positive SPT, while 78 reported CRSwNP. Compared with the 6 months preceding the first dupilumab injection, asthma exacerbations decreased from 4.0 (2.0-5.0) to 0.0 (0.0-0.0) (p < 0.0001), as well as the daily prednisone intake fell from 12.50 mg (0.00-25.00) to 0.00 mg (0.00-0.00) (p < 0.0001). In the same period, asthma control test (ACT) score increased from 14 (10-18) to 22 (20-24) (p < 0.0001), and sino-nasal outcome test (SNOT-22) score dropped from 55.84 ± 20.32 to 19.76 ± 12.76 (p < 0.0001). Moreover, we observed relevant increases in forced expiratory volume in one second (FEV1) from the baseline value of 2.13 L (1.62-2.81) to 2.39 L (1.89-3.06) (p < 0.0001). Fractional exhaled nitric oxide (FeNO) values decreased from 27.0 ppb (18.0-37.5) to 13.0 ppb (5.0-20.0) (p < 0.0001). These improvements were quite similar in subgroups of patients characterized by SPT negativity or positivity, and CRSwNP absence or presence. No statistically significant correlations were detected between serum IgE levels, baseline blood eosinophils or FeNO levels and dupilumab-induced changes, with the exception of FEV1 increase, which was shown to be positively correlated with FeNO values (r = 0.3147; p < 0.01). Our results consolidate the strategic position of dupilumab in its role as an excellent therapeutic option currently available within the context of modern biological treatments of severe asthma and CRSwNP, frequently driven by type 2 airway inflammation.

The association between allergic rhinitis and airway dysfunction and nasal endothelial damage and oxidative stress.

Although lower airway hyperresponsiveness is present in approximately one in three patients with allergic rhinitis (AR), the underlying mechanism remains unclear. To evaluate nasal patency and pulmonary functions in AR independently of the presence of asthma and to investigate the relationships between these and nasal oxidative stress parameters and endothelial damage. Seventy adolescents with AR (AR group - 27 with asthma and 43 without asthma) and 30 healthy controls (HC group) were included in this prospective, cross-sectional study. Endocan and oxidative biomarkers [total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI)] in nasal lavage fluid specimens; peak nasal inspiratory flow (PNIF); fractional exhaled nitric oxide (FeNO), and impulse oscillometry (zR5, zR20, and R5-20 for resistance and zX5 and zX20 for reactance) were investigated. Nasal endocan, TOS, and OSI values were higher in the AR group and TAS in the HC group. There was no difference between AR groups with and without asthma in terms of nasal endocan and oxidative biomarkers. FeNO levels and airway resistance (zR5, zR20, and R5-20) were higher in the AR group than in the HC group. However, there was no difference between the groups in PNIF. X5 was higher among the AR without asthma than in the other groups. Correlation between OSI and R5-20 was observed in the AR group. In the linear regression model, (logged) OSI was significantly predicted (logged) R5-20. The airways of adolescents with AR without asthma were as much affected as those of the AR with asthma, and this effect was associated with nasal endothelial damage and an increase in oxidative stress.

Ambient Environmental Ozone and Variation of Fractional Exhaled Nitric Oxide (FeNO) in Hairdressers and Healthcare Workers

Fractional exhaled nitric oxide (FeNO) is a breath-related biomarker of eosinophilic asthma. The aim of this study was to investigate FeNO variations due to environmental or occupational exposures in respiratory healthy subjects. Overall, 14 hairdressers and 15 healthcare workers in Oslo were followed for 5 workdays. We registered the levels of FeNO after commuting and arriving at the workspace and after ≥3 h of work, in addition to symptoms of cold, commuting method, and hair treatments that were performed. Both short- and intermediate-term effects after exposure were evaluated. Environmental assessment of daily average levels of air quality particulate matter 2.5 (PM2.5), particulate matter 10 (PM10), nitrogen dioxide (NO2), sulphur dioxide (SO2), and ozone (O3) indicated a covariation in ozone and FeNO in which a 35-50% decrease in ozone was followed by a near 20% decrease in FeNO with a 24-h latency. Pedestrians had significantly increased FeNO readings. Symptoms of cold were associated with a significant increase in FeNO readings. We did not find any FeNO increase of statistical significance after occupational chemical exposure to hair treatments. The findings may be of clinical, environmental and occupational importance.

Functional Alteration and Differential Expression of the Bitter Taste Receptor T2R38 in Human Paranasal Sinus in Patients with Chronic Rhinosinusitis.

The bitter taste receptors (T2Rs) expressed in human sinonasal mucosae are known to elicit innate immune responses involving the release of nitric oxide (NO). We investigated the expression and distribution of two T2Rs, T2R14 and T2R38, in patients with chronic rhinosinusitis (CRS) and correlated the results with fractional exhaled NO (FeNO) levels and genotype of the T2R38 gene (TAS2R38). Using the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) phenotypic criteria, we identified CRS patients as either eosinophilic (ECRS, n = 36) or non-eosinophilic (non-ECRS, n = 56) patients and compared these groups with 51 non-CRS subjects. Mucosal specimens from the ethmoid sinus, nasal polyps, and inferior turbinate were collected from all subjects, together with blood samples, for RT-PCR analysis, immunostaining, and single nucleotide polymorphism (SNP) typing. We observed significant downregulation of T2R38 mRNA levels in the ethmoid mucosa of non-ECRS patients and in the nasal polyps of ECRS patients. No significant differences in T2R14 or T2R38 mRNA levels were found among the inferior turbinate mucosae of the three groups. Positive T2R38 immunoreactivity was localized mainly in epithelial ciliated cells, whereas secretary goblet cells generally showed lack of staining. The patients in the non-ECRS group showed significantly lower oral and nasal FeNO levels compared with the control group. There was a trend towards higher CRS prevalence in the PAV/AVI and AVI/AVI genotype groups as compared to the PAV/PAV group. Our findings reveal complex but important roles of T2R38 function in ciliated cells associated with specific CRS phenotypes, suggesting the T2R38 pathway as a potential therapeutic target for promotion of endogenous defense mechanisms.

The Correlation Between Fractional Exhaled Nitric Oxide (FeNO), Blood Eosinophil Count, Immunoglobulin E Levels, and Spirometric Values in Patients With Asthma.

In patients with asthma, fractional exhaled nitric oxide (FeNO) is a biomarker for eosinophilic airway inflammation. However, the correlation with the blood eosinophil count, immunoglobulin E (IgE), and spirometric values is not well established. We aimed to investigate the correlation between FeNO, blood eosinophils, IgE, and spirometric values in asthmatic patients. Data were extracted from the electronic medical records of adult asthmatic patients, and included the FeNO, blood eosinophil count, IgE, and spirometric values. The correlation between the markers was investigated using receiver operating characteristics (ROC) and the area under the curve (AUC). A total of 135 adult patients (30% male) were analyzed. The mean FeNO was 36 ppb and almost half (48%) had a FeNO > 25 ppb. The mean blood eosinophil count was 377 cells/mm3, and 42% had a blood eosinophil count > 300 cells/mm3. There was a significant positive correlation between FeNO and the blood eosinophil count (r = 0.42, sensitivity 63%, specificity 77%, AUC 72%, p < 0.0001) as well as with the IgE (r = 0.35, sensitivity 78%, specificity 44%, AUC 68%, p < 0.0007). There was significant negative correlation between FeNO and FEV1% (r = -0.18, sensitivity 35%, specificity 85%, AUC 67%, p = 0.027). The blood eosinophil count, IgE, and spirometric values were correlated with the severity of the eosinophilic airway inflammation (high FeNO). Asthmatic patients with a higher FeNO level had a higher eosinophil count, higher IgE levels, and lower FEV1 values.

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

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