Reduction In Fractional Exhaled Nitric Oxide Research Articles

Evaluation of multiple-flows exhaled nitric oxide and its clinical significance in severe asthmatic patients treated with biologics: a prospective real-life study

Background Specific biomarkers, such as eosinophilia in peripheral blood or fractional exhaled nitric oxide (FeNO), can guide us in the choice of biologic therapy, allowing a more personalized approach. Although there are multiple evidences in the literature about the role of FeNO as a predictor of response to different biologic treatments, there are no data on the relationship between FeNO changes and clinical response to the four biologic drugs currently in use. Objective To evaluate and to compare the expression of multiple-flows FeNO parameters in a cohort of patients with severe asthma (SA) before and during the treatment with biologics to evaluate the performance of these biomarkers in predicting the achievement of clinical remission. Methods We prospectively enrolled 50 patients with severe asthma eligible for biologic therapy. Patients underwent clinical and functional monitoring at baseline (T0) and after 1, 6, and 12 months of treatment (T1, T6, T12), including multiple flows FeNO assessment. Results A statistically significant reduction of FeNO50 values and J’awNO was observed only in benralizumab and dupilumab subgroups. Among biomarkers, the reduction of FeNO 50 values at T1 was associated with a higher probability of achieving clinical remission at T12 (p = 0.003), which was also confirmed by ROC curve analysis (AUC 0.758, p = 0.002; sensitivity 60% and specificity 74% for a reduction of 16 ppb). Conclusion These data confirm the potential of this biomarker in predicting clinical response to biologic treatment in patients with severe asthma in order to guide clinical decisions and evaluate a shift to other biologic therapy.

Tezepelumab for Patients with Severe Uncontrolled Asthma: A Systematic Review and Meta-Analysis.

Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial-cell-derived cytokine implicated in the pathogenesis of asthma. It was approved by the United States Federal Drug Administration (US FDA) as an add-on maintenance treatment for patients with severe uncontrolled asthma in December 2021. We conducted a systematic review and meta-analysis to investigate the safety and efficacy of tezepelumab on forced expiratory volume (FEV1) (L), the rate of asthma exacerbations, health-related quality of life, fractional exhaled nitric oxide (FeNO) (ppb), and blood eosinophil count (cells/mL) in patients with severe, uncontrolled asthma. Mean changes for efficacy and proportions (safety) with their corresponding 95% confidence intervals (CIs) were used to provide pooled estimates. A total of six randomized controlled trials comprising 2667 patients were included, of whom 1610 were treated with tezepelumab and 1057 received placebo. The pooled analysis showed that tezepelumab treatment resulted in an improvement in FEV1 of 0.15 L (95% CI: 0.12 to 0.17), a reduction in the asthma exacerbation rate per year of 0.60 (95% CI: 0.51 to 0.70), and a reduction in FeNO of -12.41 ppb (95% CI: -14.28 to -10.53) when compared to placebo. Improvements in FEV1 and FeNO levels were maintained at 24 and 52 weeks. As for safety, patients did not experience a higher incidence of adverse drug reactions with tezepelumab (0.79 (95% CI: 0.55 to 1.12)) as compared to placebo. As for quality of life, different doses of the tezepelumab intervention group depicted non-significant improvement in the QoL, from 0.15 (95% CI: -0.09 to 0.38) for 70 mg, 0.18 (95% CI: -0.10 to 0.46) for 210 mg, 0.08 (95% CI: -0.16 to 0.32) for 280 mg as compared to the placebo. Tezepelumab significantly reduced exacerbation rates and improved FEV1 with an acceptable safety profile.

Obesity affects type 2 biomarker levels in asthma

Objective Type 2 (T2) inflammation offers a therapeutic target for biologics. Previous trials suggest obesity influences T2-biomarker levels in asthma, though have not accounted for key variables, e.g. inhaled (ICS)/oral corticosteroid (OCS) use. We hypothesized that body mass index (BMI) would affect T2-biomarker levels, after adjusting for covariates. Methods A retrospective analysis of data from two recent local trials of 153 participants with asthma (102 difficult-to-treat, 51 mild). Measurements included BMI, fractional exhaled nitric oxide (FeNO) and eosinophils. Correlation and regression analysis were performed for each biomarker to describe their relationship with BMI. Data was analyzed overall, and by asthma severity, T2-status and BMI tertile. Results Increasing BMI was associated with reduction in FeNO when stratified by BMI tertile (25 ppb lowest tertile, 18 ppb highest tertile; p = 0.014). Spearmans rank showed a negative correlation between BMI and FeNO in difficult-to-treat asthma (ρ= −0.309, p = 0.002). Linear regression adjusting for sex, age, smoking, atopy, allergic/perennial rhinitis, ICS and OCS confirmed BMI as a predictor of FeNO overall (β= −2.848, p = 0.019). Eosinophils were reduced in the highest BMI tertile versus lowest in difficult-to-treat asthma (0.2x109/L, 0.3x109/L respectively; p = 0.02). Conclusions Increasing BMI is associated with lower FeNO in asthma when adjusted for relevant covariates, including steroid use. There also appears to be an effect on eosinophil levels. Obesity, therefore, affects T2 biomarker levels with implications for disease endotyping and determination of eligibility for biologic therapy. Whether this is due to masking of underlying T2-high status or development of a truly T2-low endotype requires further research.

Fractional Exhaled Nitric Oxide Guided-Therapy in Chronic Obstructive Pulmonary Disease: A Stratified, Randomized, Controlled Trial

IntroductionChronic obstructive pulmonary disease (COPD) with eosinophilic airway inflammation represents a distinct phenotype that might respond to treatment with inhaled corticosteroids. Fractional exhaled nitric oxide (FENO) might predict eosinophilic inflammation and guide treatment option. We hypothesized that COPD patients with different baseline levels of FENO might have differentiated response to treatment with salmeterol/fluticasone (SFC) or tiotropium (TIO). MethodsThis open-label, randomized-controlled trial enrolled treatment-naïve COPD patients who were stratified into high- (≥23.5ppb) and low-FENO group, followed by 12-week treatment with SFC or TIO. A linear mixed model with repeated measures was applied to analyze the changes in FENO (primary outcome), COPD assessment test (CAT) score, FEV1, and parameters in induced sputum and blood after treatment. Results134 patients were divided into 4 subgroups: low-FENO/SFC (n=30), low-FENO/TIO (n=29), high-FENO/SFC (n=37), and high-FENO/TIO (n=38). At baseline, FENO 23.5ppb clearly differentiated between eosinophilic and non-eosinophilic inflammation groups based on the eosinophils in induced sputum and blood. FENO significantly correlated with sputum and blood eosinophils at baseline. High-FENO/SFC (vs. high-FENO/TIO) subgroup had significant reduction in FENO and sputum inflammation profiles (including eosinophils, macrophages, matrix metalloproteinase-9, and interlukin-8) after treatment. These differences were not replicated between low-FENO/SFC and low-FENO/TIO subgroups. The improvement in CAT and FEV1 after treatment was indiscriminate between SFC and TIO in the low- and high-FENO groups. ConclusionHigh baseline FENO can serve as an indicator of eosinophilic airway inflammation in COPD patients who may respond favorably to treatment with inhaled corticosteroids/long-acting β2-agonists. Trial registration numberClinicalTrials.gov Identifier: NCT02546349.

Fractional Exhaled Nitric Oxide Response to Oral Corticosteroids in Children With Mild-to-Moderate Asthma: Influence of Race

To evaluate the magnitude of reduction in fractional exhaled nitric oxide (FeNO) after an oral corticosteroid (OCS) course in children with mild-to-moderate asthma and assess for any differential response from such treatment on the basis of race.In the study, the researchers included 92 children (aged 11 ± 3.3 years; White: n = 46 [50%]; Hispanic: n = 30 [33%]; African American [AA]: n = 16 [7%]) who presented to 1 urgent care in Denver, Colorado, for an acute asthma exacerbation from June 2010 to May 2011.In this prospective cross-sectional cohort study, children aged 7 to 18 years with a physician diagnosis of mild-to-moderate persistent asthma and FeNO measurements within the past 6 months who received a short course of prednisone for acute exacerbation were enrolled. FeNO measurements were obtained at the time of exacerbation and at a 1 week follow-up.At baseline, AA children had significantly higher mean FeNO values, compared with that of both White (48.9 vs 25.6 parts per billion; P < .5) and Hispanic children (22.5 parts per billion; P < .5), despite similar inhaled corticosteroid doses. During exacerbation, AAs had the highest FeNO values, without a difference in lung function compared with that of non-AAs. After OCSs, there was a 56.6% reduction in FeNO among all children, whereas the relative reduction was similar between that in AAs and non-AAs (53.9% vs 57.8%).FeNO values were reduced by >50% after a short course of OCSs among all children. AA children showed higher levels of FeNO at baseline and after treatment of exacerbation, although the relative reduction in FeNO was similar among groups.FeNO is a noninvasive tool for evaluating type 2 airway inflammation and predicting responses to inhaled corticosteroids, but less is known about how FeNO levels change in acute exacerbation or from OCSs. This study reveals clearly that such inflammation is likely alleviated by OCSs across racial and ethnic groups. Given the significantly higher FeNO levels in AA children, however, this also suggests that further research into racial differences in FeNO and how they are clinically correlated is warranted. It may help to explain disparities in health outcomes seen among AA children with asthma or guide therapies. Knowledge of participant environmental factors would be helpful in assessing the significance of the baseline results.

Association Between Bedroom Particulate Matter Filtration and Changes in Airway Pathophysiology in Children With Asthma

X Cui, Z Li, Y Teng. JAMA Pediatr . 2020;174(6):533–542 To examine whether reducing fine particles of 2.5 µm or smaller in diameter (PM2.5), a risk factor for asthma exacerbation, improves small airway physiology among children with asthma. Forty-three children with mild to moderate asthma (5–13 years old) were recruited from an outpatient clinic affiliated with Shanghai General Hospital. Data were collected from a randomized, double-blind, cross-over study, and participants had 2 intervention sessions between February 14–April 24, 2017. During the true filtration session, a portable air purifier, that …

Anti-alarmins in asthma: targeting the airway epithelium with next-generation biologics.

Monoclonal antibody therapies have significantly improved treatment outcomes for patients with severe asthma; however, a significant disease burden remains. Available biologic treatments, including anti-immunoglobulin (Ig)E, anti-interleukin (IL)-5, anti-IL-5Rα and anti-IL-4Rα, reduce exacerbation rates in study populations by approximately 50% only. Furthermore, there are currently no effective treatments for patients with severe, type 2-low asthma. Existing biologics target immunological pathways that are downstream in the type 2 inflammatory cascade, which may explain why exacerbations are only partly abrogated. For example, type 2 airway inflammation results from several inflammatory signals in addition to IL-5. Clinically, this can be observed in how fractional exhaled nitric oxide (FeNO), which is driven by IL-13, may remain unchanged during anti-IL-5 treatment despite reduction in eosinophils, and how eosinophils may remain unchanged during anti-IL-4Rα treatment despite reduction in FeNO. The broad inflammatory response involving cytokines including IL-4, IL-5 and IL-13 that ultimately results in the classic features of exacerbations (eosinophilic inflammation, mucus production and bronchospasm) is initiated by release of “alarmins” thymic stromal lymphopoietin (TSLP), IL-33 and IL-25 from the airway epithelium in response to triggers. The central, upstream role of these epithelial cytokines has identified them as strong potential therapeutic targets to prevent exacerbations and improve lung function in patients with type 2-high and type 2-low asthma. This article describes the effects of alarmins and discusses the potential role of anti-alarmins in the context of existing biologics. Clinical phenotypes of patients who may benefit from these treatments are also discussed, including how biomarkers may help identify potential responders.

Mepolizumab for severe eosinophilic asthma: a real-world snapshot on clinical markers and timing of response

ABSTRACTBackground: Few studies have provided real-world evidence of mepolizumab efficacy and safety. We aimed to evaluate mepolizumab for severe eosinophilic asthma in daily clinical practice.Research design and methods: Patients included in the RINOVA (Interdisciplinary Network for the management of severe asthma in Veneto region, Italy) database were investigated. Blood eosinophil count, forced expiratory volume in 1 second, % of predicted (FEV1%), fractional exhaled nitric oxide (FeNO), asthma control test (ACT), oral steroid (OCS) intake, and exacerbation rate were evaluated during mepolizumab treatment.Results: 69 patients were enrolled (mean age: 55.1 years; 60.9% females). A significant improvement was detected at one month with respect to blood eosinophils (median level at baseline: 710/μl; −620/μl, p < 0,001), FEV1% (median value at baseline 87; range: 79–101; +4, p = 0.001) and ACT (median value at baseline 18; range: 14–20.5;+4, <0.001). A significant reduction of FeNO was observed six months after the treatment start, when the exacerbation rate and the mean OCS dose significantly decreased (respectively: Δ reduction −3; p < 0.001 and −5 mg; p < 0.001).Conclusions: Our study provides real-world evidence of mepolizumab safety and confirms its dramatic steroid sparing effect. The greatest clinical change (ACT and FEV1) was observed within the first month.

Effect of Sublingual Immunotherapy on Airway Inflammation and Airway Wall Thickness in Allergic Asthma

The efficacy of the standardized quality (SQ) house dust mite (HDM) sublingual immunotherapy (SLIT) has been demonstrated for respiratory allergic disease. However, the effects of SLIT on inflammation and structural changes of the airways are still unknown. The aim of this study was to assess the effects of the 6 SQ-HDM SLIT on airway inflammation and airway geometry in allergic asthma and rhinitis. One hundred two asthmatic patients with rhinitis sensitized to HDM were randomized to receive either SLIT plus pharmacotherapy or standard pharmacotherapy alone, for 48 weeks. Fractional exhaled nitric oxide (FeNO), pulmonary function, quantitative computed tomography, and clinical symptoms were performed at baseline and end of the study. Compared with pharmacotherapy, SLIT demonstrated a significant reduction of FeNO (P < .01), airway wall area/body surface area (WA/BSA, P < .001), wall thickness (T/√BSA, P < .001), percentage wall area (WA/Ao, P < .01), increase in luminal area (Ai/BSA, P < .05), improvement of airflow limitation (P < .001), and clinical symptom scores (P<.05). The change in forced expiratory volume in 1 second (FEV1) was correlated with both changes in FeNO and airway dimensions. Multiple regression analysis showed that the change in FeNO was independently associated with an increase in FEV1 in the SLIT group (r2= 0.623, P= .037). Adding 6 SQ-HDM SLIT to standard asthma therapy provides a significant improvement in symptoms and pulmonary function compared with pharmacotherapy. Improvement of airflow limitation with SLIT was associated with the decrease in eosinophilic airway inflammation.

Efficacy and safety of AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator, in patients with asthma: a phase 2a randomized, double blind, placebo-controlled crossover trial

BackgroundInhaled corticosteroids reduce inflammation in asthma but chronic use may cause adverse effects. AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator, has the potential of an improved risk-benefit profile. We investigated the safety and efficacy of AZD7594 in asthma.MethodsThis phase 2a multi-center, randomized, double-blind, placebo-controlled crossover study enrolled adults with asthma aged 18 to 75 years. Patients were treated with budesonide 200 μg twice daily for 2–3 3 weeks (run in part one). If controlled, as demonstrated by an asthma control questionnaire-5 score of < 1.5, patients entered a three-week run-in (part two) where they received a short acting bronchodilator alone. Thereafter, patients with a fractional exhaled nitric oxide (FENO) ≥25 ppb and pre-dose FEV1 40 to 90% predicted were randomized to one of nine treatment sequences. Each patient received placebo and two of three dose levels of AZD7594 (58, 250, 800 μg) once daily via inhalation, in 14-day treatment periods, separated by three-week washout periods. The primary endpoint was the change from baseline in morning trough FEV1 versus placebo on day 15. Secondary endpoints included measures of airway inflammation and asthma control.ResultsFifty-four patients were randomized and received at least 1 dose of treatment, 48 patients completed the study. Overall 52 patients received placebo, 34 received AZD7594 58 μg, 34 received AZD7594 250 μg, and 34 received AZD7594 800 μg. AZD7594 800 μg demonstrated a significant improvement in Day 15 morning trough FEV1versus placebo (LS means difference 0.148 L 95% CI 0.035–0.261, p = 0.011), with a dose-dependent response seen in the 250 μg (0.076 L -0·036–0·188, p = 0.183) and 58 μg (0·027 L -0·086–0·140, p = 0.683). All secondary endpoints showed statistically significant improvement at the 800 μg dose. All doses demonstrated a significant reduction in FENO at day 15 p < 0.01. No statistically significant difference in plasma cortisol level was observed between AZD7594 and placebo at any dose. AZD7594 was considered safe and well tolerated.ConclusionsTwo-week treatment with AZD7594 demonstrated a favorable risk-benefit profile in patients with mild to moderate asthma. Further clinical studies are needed to fully characterize AZD7594.Trial registrationClinicalTrials.gov number NCT02479412.

Validation of ATS clinical practice guideline cut-points for FeNO in asthma.

The American Thoracic society (ATS) has suggested using fractional exhaled nitric oxide (FeNO) to monitor the level of eosinophilic (EOS) airway inflammation in asthma, but validation of the proposed cut-points is required in real-life populations. To validate FeNO cut-points suggested by ATS in relation to sputum EOS count in a real life population of asthma patients. All patients referred consecutively over a 12-months period for specialist assessment of asthma, were examined with FeNO and induced sputum, and re-examined 12 months later. The predicted values of a positive and a negative test (PPV and NPV) for a cut off ≥3% EOS in sputum were calculated. Change in FeNO was defined in accordance with ATS (>20% or 10 ppb if FeNO was <50 ppb). 144 adult asthma patients were examined (59% female). Low FeNO (<25 ppb) at baseline was found in 94 (65%), FeNO between 25 and 50 ppb in 34 (24%) subjects and high FeNO >50 ppb in 16 (11%) subjects. The PPV for FeNO >25 ppb and >50 ppb to predict EOS ≥3% was 45% and 77%, NPV was 88% and 83%. The sensitivity decreased from 70% to 37% at the >50 ppb cut-off. A significant reduction in FeNO was associated with a reduction in sputum EOS (p = 0.01). The findings support the validity of the FeNO cut-points suggested by ATS to monitor eosinophilic airway inflammation in asthma. However, in this real-life population, a large proportion of patients had intermediate FeNO values, which may limit the clinical usefulness of the ATS FeNO cut-points.

Reduction of FENO by tap water and carbonated water mouthwashes: magnitude and time course

Fractional exhaled nitric oxide (FENO) assesses eosinophilic inflammation of the airways, but FENO values are also influenced by oral nitric oxide (NO). The aim of this pilot study was to measure FENO and compare the effect of two different mouthwashes on FENO and analyse the duration of the effect. FENO was measured in 12 randomized volunteers (healthy or asthmatic subjects) with a NIOX VERO® analyser at an expiratory flow rate of 50 mL/s. After a baseline measurement, a mouthwash was performed either with tap water or carbonated water and was measured during 20 min in 2 min intervals. The procedure was repeated with the other mouthwash. We found that both mouthwashes reduced FENO immediately at the beginning compared to the baseline (p < .001). The carbonated water mouthwash effect lasted 12 min (p ranging from <0.001 to <0.05). The tap water mouthwash reduced FENO statistically significantly only for 2 min compared with the baseline. We conclude that a single carbonated water mouthwash can significantly reduce the oropharyngeal NO contribution during a 12 min time interval.

The effect of omalizumab treatment on severe allergic asthma and allergic comorbidities: real-life experience from the Czech Anti-IgE Registry

IntroductionOmalizumab is indicated for the treatment of severe allergic asthma (SAA) and chronic spontaneous urticaria, although a number of studies have confirmed the effectiveness of this therapy also for other IgE-mediated diseases.AimTo assess the impact of anti-IgE therapy on SAA and comorbid IgE-mediated allergic diseases in patients treated with omalizumab for SAA enrolled in the CAR (Czech Anti-IgE Registry).Material and methodsThree hundred and ten patients with SAA treated with omalizumab were enrolled in the CAR. Two hundred and twenty-nine individuals were evaluated after 12 months of omalizumab treatment for asthma control test (ACT), examination of fractional exhaled nitric oxide (FENO), forced expiratory volume in 1 s (FEV1), the use of systemic corticosteroids, side effects of treatment and clinical effect of omalizumab on allergic comorbidities (allergic rhinitis, chronic urticaria, atopic dermatitis and food allergy).ResultsAfter 12 months of treatment with omalizumab, patients experienced a significant improvement of ACT and FEV1, reduction of FENO, use of systemic corticosteroids for asthma exacerbations and dose of maintenance oral corticosteroid therapy. The positive effect of treatment with omalizumab was observed in 82.2% of patients with allergic rhinitis, in 85.7% of patients with chronic urticaria, in 82.1% of patients with atopic dermatitis, and in 67.3% of patients with food allergy.ConclusionsIn the CAR registry, patients with SAA treated with omalizumab showed a significant positive effect of anti-IgE therapy not only on the asthma control, but also on allergic comorbidities.

Cross-shift Reduction in Fractional Exhaled Nitric Oxide among Cement Workers

Objective: Assessment of changes in fractional exhaled nitric oxide (FENO) across the shift was performed among cement production workers and controls. FENO was used as a possible marker of eosinophilic inflammation in the airways. In addition, the relations between personal total dust exposure and FENO changes across the work shift were examined. Methods: Pre-and post-shift FENO levels were determined among 55 non-smoking dust exposed cement production workers and among 31 non-smoking mineral water factory workers as controls. The FENO levels were examined for three consecutive days among the exposed and two consecutive days among controls. Personal total dust levels were collected in the breathing zone of each participant using cellulose acetate filters on the first day of FENO examination. A three-piece Millipore cassette was used to place the filters and the cassette was connected to a Side Kick Cassela pump at a flow rate of 2 l/minute. Results: There was a statistically significant reduction in FENO levels among exposed workers, but not among controls. The reduction in FENO levels among the exposed was observed on each day of FENO examination. The cross-shift reduction in FENO levels among the exposed did not show possible associations with personal total dust exposure levels (r=-0.175, 95% CI: -0.36, 0.04). The geometrical mean for total dust exposure were 8.3 mg/m3 and 0.28 mg/m3, among exposed workers and controls, respectively. Conclusion: The results show a cross-shift reduction of FENO among cement workers and indicate that dust exposure is not associated with this finding. The reason for the reduction in FENO across the shift is unknown. Researchers in this field should be aware of potential unknown confounders when performing future studies.

The Utility of Fractional Exhaled Nitric Oxide Suppression in the Identification of Nonadherence in Difficult Asthma

Nonadherence to inhaled corticosteroid therapy (ICS) is a major contributor to poor control in difficult asthma, yet it is challenging to ascertain. Identify a test for nonadherence using fractional exhaled nitric oxide (Fe(NO)) suppression after directly observed inhaled corticosteroid (DOICS) treatment. Difficult asthma patients with an elevated Fe(NO) (>45 ppb) were recruited as adherent (ICS prescription filling >80%) or nonadherent (filling <50%). They received 7 days of DOICS (budesonide 1,600 μg) and a test for nonadherence based on changes in Fe(NO) was developed. Using this test, clinic patients were prospectively classified as adherent or nonadherent and this was then validated against prescription filling records, prednisolone assay, and concordance interview. After 7 days of DOICS nonadherent (n = 9) compared with adherent subjects (n = 13) had a greater reduction in Fe(NO) to 47 ± 21% versus 79 ± 26% of baseline measurement (P = 0.003), which was also evident after 5 days (P = 0.02) and a Fe(NO) test for nonadherence (area under the curve = 0.86; 95% confidence interval, 0.68-1.00) was defined. Prospective validation in 40 subjects found the test identified 13 as nonadherent; eight confirmed nonadherence during interview (three of whom had excellent prescription filling but did not take medication), five denied nonadherence, two had poor inhaler technique (unintentional nonadherence), and one also denied nonadherence to prednisolone despite nonadherent blood level. Twenty-seven participants were adherent on testing, which was confirmed in 21. Five admitted poor ICS adherence but of these, four were adherent with oral steroids and one with omalizumab. Fe(NO) suppression after DOICS provides an objective test to distinguish adherent from nonadherent patients with difficult asthma. Clinical trial registered with www.clinicaltrials.gov (NCT 01219036).

A cross-shift study of lung function, exhaled nitric oxide and inflammatory markers in blood in Norwegian cement production workers

ObjectivesTo study possible effects of aerosol exposure on lung function, fractional exhaled nitric oxide (FeNO) and inflammatory markers in blood from Norwegian cement production workers across one work shift (0...

Sputum induction with hypertonic saline reduces fractional exhaled nitric oxide in chronic smokers and non-smokers

Nitric oxide (NO) measurements in exhaled air and hypertonic saline-induced sputum are commonly used biomarker sampling methods of the lower airways. Both sampling methods have been validated in asthmatic patients and healthy controls, however, data from chronic smokers are scarce. To evaluate the reproducibility and differences in fractional exhaled NO (FeNO) values in asymptomatic chronic smokers and healthy, non-smoking controls. Furthermore, to test the effect of hypertonic saline sputum induction (SI) on FeNO levels in both study groups. 16 asymptomatic chronic smokers and 16 non-smokers participated in this study. Baseline FeNO and forced expiratory volume in 1 s (FEV(1)) were recorded pre- and 30 min post NaCl 4.5% SI (3 x 5 min) on 2 study days (+/-2 h; 4-10 days apart). Mixed ANOVA was used to estimate the intra-subject Coefficient of Variation (CV) % over days; changes in FeNO and FEV(1) values before and after SI, were analyzed by a Student's paired t-test.The difference between smokers and non-smokers was estimated by a Student's t-test. On day 1, FeNO values in smokers were significantly lower than in non-smokers, 10.6 ppb, and 18.4 ppb, respectively, (42% difference, p = 0.0028, 95% CI: -59%, -19%). In both study groups, FeNO measurements were reproducible, with an intra-subject CV of 27.2% and 19.2%, for smokers and non-smokers, respectively. SI significantly decreased FeNO levels in both study groups on day 1. In smokers, there was a mean reduction in FeNO of almost 37% (p = 0.0045, 95% CI: -53%, -14%), and in non-smokers a mean decrease of almost 37% (95% CI : -53%, -14%; p = 0.0045). In both study groups SI did not affect FEV(1) (p > 0.94). Our data extend previous findings in asthmatics and healthy controls to asymptomatic chronic smokers: 1. FeNO measurements are reproducible in both smokers and non-smokers; 2. baseline FeNO levels in chronic smokers are lower than in non-smokers and 3. sputum induction by hypertonic saline reduces FeNO levels in both study groups, without affecting lung function.