Exhaled nitric oxide and exhaled breath condensate pH as predictors of sputum cell counts in optimally treated asthmatic smokers

Background and objective: Smoking is thought to modify the pattern of airway inflammation. Induced sputum provides useful information on cellular phenotype in inflammatory airways disorders; however, it is time‐consuming and difficult to implement in everyday clinical practice. The aim of this study was to determine whether exhaled NO (FeNO) and exhaled breath condensate (EBC) pH differed in asthmatic smokers compared with asthmatic non‐smokers and healthy subjects, and to evaluate the performance of FeNO and EBC pH for predicting the cellular phenotype of induced sputum. Methods: Asthmatic smokers (n = 40) and non‐smoking asthmatic patients (n = 43) were recruited for the study. Healthy smoking (n = 30) or non‐smoking (n = 30) subjects served as controls. FeNO and EBC pH were measured and all subjects underwent sputum induction for assessment of cell counts. Results: EBC pH was significantly lower in asthmatic smokers compared with non‐smokers (P < 0.01). FeNO levels were also significantly lower in asthmatic smokers compared with non‐smokers (P < 0.001). EBC pH was inversely associated with sputum eosinophils in both asthmatic smokers and non‐smokers (P < 0.001), whereas it was inversely associated with sputum neutrophils only in asthmatic smokers (P < 0.001). FeNO was positively associated with sputum eosinophils both in asthmatic smokers and non‐smokers (P < 0.001) but was not associated with sputum neutrophils. In asthmatic smokers, FeNO was a better predictor of sputum eosinophilia, whereas EBC pH was a better predictor of sputum neutrophilia. A combination of FeNO ≤ 14 ppb together with EBC pH > 7.20 predicted the paucigranulocytic induced sputum phenotype. Conclusions: EBC pH and FeNO levels were significantly lower in asthmatic smokers compared with non‐smokers. Combined specific cut‐off levels for FeNO and EBC pH may predict the paucigranulocytic phenotype in asthmatic smokers.     

Smoking and airway inflammation in patients with mild asthma.

STUDY OBJECTIVES: Cigarette smoking is common in asthmatic patients, and we investigated the impact of cigarette smoking on airway inflammation in asthma. DESIGN: Single-center observational study of airway inflammation in asthmatic and healthy smokers and nonsmokers. SETTING: Asthma research unit in a university hospital. PATIENTS OR PARTICIPANTS: Sixty-seven asthmatic and 30 nonasthmatic subjects classified as smokers or nonsmokers. Asthmatics had chronic, stable asthma and were not receiving inhaled or oral steroids at the time of the study. INTERVENTIONS: We examined induced-sputum cell counts and levels of interleukin (IL)-8 and eosinophilic cationic protein (ECP). Bronchial hyperreactivity was assessed using methacholine challenge. MEASUREMENTS AND RESULTS: Asthmatic smokers had higher total sputum cell counts than nonsmoking asthmatics and both smoking and nonsmoking healthy subjects. Smoking was associated with sputum neutrophilia in both asthmatics and nonasthmatics (median, 47% and 41%, respectively) compared with nonsmokers (median, 23% and 22%, respectively), and sputum IL-8 was increased in smokers compared with nonsmokers, both in subjects with asthma (median, 945 pg/mL vs 660 pg/mL, respectively) and in healthy subjects (median, 1,310 pg/mL vs 561 pg/mL, respectively). Sputum eosinophils and ECP levels were higher in both nonsmoking and smoking asthmatics than in healthy nonsmokers. In smoking asthmatics, lung function (FEV(1) percent predicted) was negatively related to both sputum IL-8 (r = - 0.52) and sputum neutrophil proportion (r = - 0.38), and sputum IL-8 correlated positively with smoking pack-years (r = 0.57) and percent neutrophil count (r = 0.51). CONCLUSIONS: In addition to the eosinophilic airway inflammation observed in patients with asthma, smoking induces neutrophilic airway inflammation; a relationship is apparent between smoking history, airway inflammation, and lung function in smoking asthmatics.     

Airway hyperresponsiveness to mannitol and methacholine and exhaled nitric oxide in children with asthma

Objective: Asthma is characterized by airway hyperresponsiveness (AHR), inflammation, and obstruction. AHR to stimuli that indirectly cause bronchial smooth muscle (BSM) contractions via release of endogenous mediators is thought to better reflect airway inflammation than AHR to stimuli that act directly on BSM. Fractional exhaled nitric oxide (FeNO) is a useful parameter for noninvasive clinical airway inflammation assessments. Accordingly, this study aimed to examine the relationships of mannitol and methacholine challenge test outcomes with FeNO and the influence of inhaled corticosteroid treatment in children with asthma. Methods: One hundred thirty-four asthmatic children (89 males; ages: 5–17 years, median: 9 years) underwent spirometry, FeNO measurement, serum total/specific IgE testing, and blood eosinophil count. All subjects were challenged with mannitol dry powder (MDP; AridolH, Pharmaxis, Australia) and methacholine at 7-day intervals. Data of steroid-treated and steroid-naïve children were compared. Results: Positive responses to MDP and methacholine challenge tests were observed in 74.6% and 67.2% of total subject group, respectively, and 72 children had positive response to both challenge tests. The median FeNO level, response-dose ratio (RDR) of PC₂₀ methacholine, and RDR of PD₁₅ MDP were significantly higher in the steroid-treated group than in the steroid-naïve group (p < 0.001, 0.226, and 0.004, respectively). FeNO levels associated significantly with PD₁₅ MDP and RDR PD₁₅ MDP in total subject populations (p = 0.016 and 0.003, respectively); however, a significant correlation between FeNO and RDR PD₁₅ MDP was observed only in the steroid-naïve group. Conclusions: Compared with AHR to methacholine, AHR to MDP more closely reflected the level of FeNO in steroid-naïve asthmatic children.     

支气管哮喘患者呼出气一氧化氮、肺功能、ACQ7评分之间的相关性研究

目的 探讨呼出气一氧化氮(FeNO)、肺通气功能及支气管哮喘(简称哮喘)控制水平的相关关系,寻找适用于哮喘患者的气道炎症监测及管理的方法.方法 按GINA 2008标准入选我院门诊2010年3月至2011年6月就诊65例确诊为哮喘的患者 进行FeNO测定 同时测定肺功能 记录第1秒用力呼气容积(FEV1)、第1秒用力呼...     

支气管哮喘患者呼出气一氧化氮、肺功能、ACQ7评分之间的相关性研究

目的探讨呼出气一氧化氮(FeNO)、肺通气功能及支气管哮喘(简称哮喘)控制水平的相关关系,寻找适用于哮喘患者的气道炎症监测及管理的方法。方法按GINA2008标准入选我院门诊2010年3月至2011年6月就诊65例确诊为哮喘的患者,进行FeNO测定,同时测定肺功能,记录第1秒用力呼气容积(FEV1)、第1秒用力呼气容积占预计值百分比(FEV1%pred)、用力肺活量(FVC)、FEV1/FVC、呼气峰流速(PEF)、FEF25/75、FEF25/75%等指标,行诱导痰检测,记数嗜酸粒细胞的比率(EOS%)。进行哮喘控制问卷(ACQ7)及哮喘控制测试(ACT)调查表的填写。结果经多元逐步回归分析,FeNO的值主要受到年龄、FEF25/75、FEF25/75%、日间症状的影响,与体质量指数、过敏等因素无显著相关关系,与FEV1、FEV1%pred、ACQ7评分、ACT评分等亦无显著相关(P0.05),FeNO与诱导痰EOS%呈显著正相关(r=0.327,P=0.022)。ACQ7与FEV1、FEV1%pred呈显著负相关(分别是r=-0.491,P=0.000,r=-0.469,P=0.012)。结论 FeNO能够客观反映气道EOS炎症水平,年龄越小、日间症状越明显、小气道阻力越高,FeNO水平越高。结合肺功能指标和FeNO更能全面反映哮喘疾病现况及控制水平。     

Mannitol and AMP do not induce bronchoconstriction in eosinophilic bronchitis: Further evidence for dissociation between airway inflammation and bronchial hyperresponsiveness

Background and objective: Eosinophilic bronchitis (EB) shares many pathological features with asthma. However, patients with EB do not develop the characteristic physiological abnormalities of asthma: variable airflow obstruction and bronchial hyperresponsiveness (BHR) to a direct bronchial challenge with methacholine. Indirect bronchial challenges with AMP and mannitol are dependent on the presence of airway inflammation, and positive in 10% of asthmatic subjects who have a negative response to methacholine. We have therefore investigated whether subjects with EB are responsive to indirect airway challenge with AMP and mannitol. Methods: Subjects with asthma, EB and healthy controls attended on up to four occasions. After screening, subjects performed bronchial provocation tests to methacholine and then either AMP or mannitol. Each challenge was followed immediately by sputum induction for the measurement of airway inflammation and mast cell‐derived histamine. Results: No subjects with EB responded to either AMP (n = 5) or mannitol (n = 7) while 4/8 and 7/10 subjects with asthma responded to the respective challenges (P = 0.057 for AMP, P = 0.004 for mannitol). There was no difference in induced sputum concentrations of histamine or eosinophil cell counts following methacholine challenge compared with AMP or mannitol. Conclusions: The airways of patients with EB are not responsive to either direct or indirect bronchial challenge. This supports the view that it is the presence of functionally abnormal airway smooth muscle that is the key determinant of BHR in asthma, and that while this may be aggravated by the presence of mucosal airway inflammation, it is not caused by it.     

Stability of FeNO and airway hyperresponsiveness to mannitol in untreated asthmatics

Objective: Airway hyperresponsiveness and airway inflammation are important hallmarks of asthma and are useful in asthma diagnosing, monitoring and treatment. The aim of the study was to assess whether two commonly used clinical tests, the mannitol challenge and Fraction of exhaled NO (FeNO), were stable clinical indicators over time in stable untreated asthmatics. Methods: 54 non-smoking, asthma patients not treated with steroids were enrolled in the study and assessed at baseline and a median of 6 months later. At baseline and follow-up, FeNO and airway hyperesponsiveness to mannitol were measured, and asthma control was assessed with the Asthma Control Questionnaire (ACQ). Results: A total of 41 subjects completed both visits. Mean (SD) FEV1% at baseline was 94.1% (17.7) and at re-examination 94.6% (19.7) (ns). The ACQ score was unchanged from baseline (Mean (SD): 0.90 (± 0.73)) to follow-up 0.90 (± 0.74) (ns), as was the FEV₁% (94.1% (±17.1%) vs 94.6% (19.7%)(ns) indicating that patients were clinically stable during follow-up. The response to mannitol was unchanged at follow-up (Geometric mean (CI) of Response Dose Ratio (RDR) to mannitol: 0.026(0.013–0.046) vs 0.026(0.012–0.050) (ns). There was a slight decrease in FeNO at follow-up (25.5 ppb (19.7–32.9) to 21.9 ppb (17.1–28.2) (p < 0.001). Conclusions: In steroid-free non-smoking asthmatics with constant symptom scores and lung function, airway responsiveness to mannitol remained at the same level over a period of months, while a minor change in exhaled FeNO was reported. These results suggest that mannitol is a stable, reliable marker of clinical disease activity.     

Comparison of diagnostic validity of mannitol and methacholine challenges and relationship to clinical status and airway inflammation in steroid-naïve asthmatic patients

Objectives: The purpose of this study was to demonstrate and compare the diagnostic validity of two bronchial challenges and to investigate their correlation with patient clinical status, atopy and inflammation markers. Methods: Eighty-eight patients, 47 women and 41 men, mean age 38.56 ± 16.73 years who presented with asthma related symptoms and were not on any anti-asthma medication, were challenged with mannitol and methacholine on separate days. Medical history regarding asthmatic symptoms, physical examination, skin prick tests and FeNO levels were also assessed. The clinical diagnosis of asthma was based on bronchodilator reversibility test. Results: Sixty-seven patients were diagnosed with asthma and 21 without asthma. Both methacholine (P < 0.014) and mannitol (P < 0.000) challenges were significant in diagnosing asthma. The positive/negative predictive value was 93.33%/41.86% for methacholine, 97.72%/45.45% for mannitol and 97.05%/45.45%. for both methods assessed together. Worthy of note that 22% of asthmatics had both tests negative. There was a negative correlation between PC20 of methacholine and the FeNO level P < 0.001, and positive with the PD15 of mannitol P < 0.001 and the pre-test FEV₁% pred P < 0.005, whereas PD15 of mannitol was negatively correlated with the FeNO level P < 0.001. Furthermore, dyspnea was the only asthmatic symptom associated with FeNO level P < 0.035 and the positivity of mannitol P < 0.014 and methacholine P < 0.04. Conclusions: Both challenge tests were equivalent in diagnosing asthma. Nevertheless, specificity appeared to be slightly higher in mannitol challenge.     

Exhaled Nitric Oxide Decreases in Association with Attendance at an Asthma Summer Camp

Attendance at a summer asthma camp has been associated with improved outcomes in children with asthma. We hypothesized that one mechanism involved in improved asthma outcomes is reduction in airway inflammation. To investigate this, we measured the fractional concentration of exhaled nitric oxide (FeNO), lung function (forced expiratory volume in 1 sec, FEV₁) and asthma control (Juniper Asthma Control Questionnaire, ACQ) from children at the beginning and end of a 1-week asthma summer camp. We also obtained a symptoms-only ACQ at 1 and 6 months after the end of camp. We enrolled 10 girls, 17 boys, mean (± SD) age = 9.6 ± 1.3 years. At baseline, FeNO (ppb), median (25–75 IQR) = 11.4 (7.2–21.3); ACQ = 0.86 (0.43–1.21); FEV₁ (%pred, mean ± SD) = 87 ± 10. At the end of camp, FeNO = 6.2 (4.4–8.4), a change of ?45%, p < 0.0001; ACQ = 0.71 (0.43–1.14), a fall of 14%, p = 0.72; and mean FEV₁% predicted remained unchanged. There were no significant changes in the follow-up symptoms-only ACQ at 1 and 6 months. We conclude that airway inflammation, as measured by FeNO, improved during 1 week of asthma camp, but there were no significant changes in lung function or asthma control. Since no child had a change in anti-inflammatory therapy during camp, these findings suggest that airway inflammation was reduced because of improved adherence to therapy and/or reduced exposure to pro-inflammatory stimuli in the home environment. The finding of reduced inflammation following attendance at an asthma summer camp should motivate the child, the parents and the clinician to focus their efforts on improving adherence to therapy and reducing exposures at home.     

Airway hyperresponsiveness and airway inflammation in elite swimmers

Introduction: The prevalence of respiratory symptoms and airway hyperresponsiveness (AHR) is high in elite athletes; swimmers have one of the highest prevalences. No consensus exists on what airway challenge to use when identifying AHR in elite athletes. Further, knowledge is sparse about when during their active sport career AHR develops and if there is an acute effect on the airway inflammation of a swimming training session. Objectives: We aimed to (i) evaluate the airway response to a methacholine challenge, a eucapnic voluntary hyperpnoea (EVH) test, a field‐based exercise test (FBT) and a laboratory‐based exercise test (LBT) in adult elite swimmers; (ii) investigate airway responsiveness and airway inflammation in adolescent elite swimmers; and (iii) evaluate the acute effect of a training session in an indoor swimming pool on airway inflammation in adolescent elite swimmers. Materials and Methods: Two groups were studied. (i) In adult elite swimmers (n = 16), we examined airway response in four airway provocation tests: methacholine challenge, EVH test, FBT and LBT. (ii) In adolescent elite swimmers (n = 33), we examined airway responsiveness to EVH and methacholine, and airway inflammation and compared the findings with those in asthmatic adolescents (n = 32) and unselected adolescents (n = 35). Further, we examined the acute effect of swimming on airway inflammation in a subpopulation of the adolescent swimmers (n = 21). Airway inflammation was evaluated using sputum induction, measurements of exhaled nitric oxide (FeNO) and exhaled breath condensate (EBC). Results: Of 16 adult swimmers, eight (50%) had AHR; five of the eight (63%) were identified with the EVH test, four (50%) with the FBT, four (50%) with the LBT and none with the methacholine challenge [provocative dose of methacholine causing a 20% fall in FEV1 (PD₂₀) ≤ 2 µmol]. There were no differences in the prevalence of AHR to either EVH or methacholine (PD₂₀ ≤ 8 µmol) among the adolescent swimmers, the asthmatic adolescents and the unselected adolescents. When looking at airway responsiveness as a continuous variable, the swimmers were more responsive to EVH than were the unselected subjects, and less responsive to methacholine than were the asthmatic adolescents. There were no differences in FeNO, EBC pH or in the cellular composition of the sputum among the three groups. Lung function, FeNO, EBC pH, EBC lactate and differential cell counts in sputum were not acutely affected by the swimming session. Conclusion: We found that the EVH test is the most sensitive test for identifying AHR in elite athletes when using the diagnostic criteria set forward by the International Olympic Committe. Whereas a high prevalence of AHR in adult swimmers was found, the prevalence of AHR in the adolescent swimmers did not differ from that in unselected adolescents nor did the adolescent swimmers have signs of airway inflammation. There was no acute effect of a swimming training session in an indoor chlorinated pool on lung function or airway composition in adolescent swimmers. We believe that elite swimming results in airway changes with AHR and airway inflammation.     

Smoking Affects Eotaxin Levels in Asthma Patients

Background. Chronic airway inflammation is most important pathological finding in asthma. Cigarette smoking may modify type of inflammation as well as may influence disease severity and response to the treatment. Objective. Thus the aim of this study was to investigate whether cigarette smoking may have an influence on the levels of eotaxin-1, eotaxin-2, eotaxin-3 and IL-5 in patients with stable mild/moderate asthma. Methods. 45 steroid naive asthmatics (mean age: 55.2 ± 2.2 yrs) and 23 “healthy” smokers and non-smokers control subjects (mean age: 54.4 ± 9.7 yrs) were investigated. Asthmatics were divided into two subgroups according to their smoking histories: asthmatic smokers (n = 19) who currently smoke and have a history of > 10 pack-years and asthmatic never-smokers (n = 26). BAL and induced sputum were performed. Cytospins of induced sputum and BAL were stained with May-Grünwald-Giemsa for differential cell counts. Eotaxin-1, eotaxin-2, eotaxin-3 and IL-5 concentrations in serum, sputum and BAL supernatant was measured using a commercial ELISA kit. Results. In sputum supernatant from asthma smokers was significantly higher concentration of eotaxin-1 than in non-smokers asthmatics (203.4 ± 10.0 vs. 140.2 ± 9.5 respectively, p < 0.05). In non-smokers asthma patients levels of BAL eotaxin-1 strongly related to percent and absolute numbers of BAL eosinophils and neutrophils (Rs = 0.737 and Rs = 0.514 respectively, p < 0.05). The number and percent of sputum neutrophils and eosinophils, obtained from smokers asthmatics, significantly correlated with eotaxin-2 concentration in sputum supernatant (Rs = 0.58 and Rs = 0.75 respectively, p < 0.05). IL-5 levels in the serum and sputum from asthmatic never-smokers were significantly higher than they were from asthmatic smokers and “healthy” smokers. Asthmatic never-smokers showed a significantly higher amount of IL-5 in serum and sputum than the asthmatic smokers showed. Conclusions. This study showed the elevated levels of sputum eotaxin-1 as well as serum, sputum and BAL eotaxin-2 in asthmatic smokers without a significant increase of eosinophils compared to asthmatic never-smokers. The eotaxin concentrations were related not only with number of eosinophils but also with the number of neutrophils in all the studied tissue compartments. The data herein permits a suggestion that smoking may influence change in asthmatic airway inflammation by stimulating the production of eotaxins.     

Comparison of budesonide/formoterol Turbuhaler with fluticasone/salmeterol Diskus for treatment effects on small airway impairment and airway inflammation in patients with asthma

Background

A course of combination therapy with an inhaled corticosteroid (ICS) and a long-acting β₂ agonist (LABA) for asthma can improve lung function, asthma symptoms and reduce exacerbations. Because both medicinal substance and inhalation devices are associated with clinical efficacy, each ICS/LABA combination may have different features. This study aimed to compare the effects of two widely available formulations, budesonide/formoterol (BUD/FM) delivered by a Turbuhaler^®, and fluticasone/salmeterol (FP/SM) delivered by a Diskus^®, on small airway function and airway inflammation.

Methods

Asthmatic patients (n = 40) treated twice daily with FP/SM 250/50 μg with forced expiratory volume in 1 s values controlled above 80% of the predicted normal but with suspected persistent airway inflammation and small airway impairment were enrolled in the study. Patients were randomized into two groups, receiving either twice daily BUD/FM 320/9 μg or FP/SM 250/50 μg, and treatment efficacy was compared after 4 weeks. Outcomes included impulse oscillometry (IOS), fractional exhaled nitric oxide (FeNO), spirometry and Asthma Control Questionnaire (ACQ) scores.

Results

Patients in the BUD/FM group showed significant improvements in their IOS and spirometry parameters of small airway function, FeNO values and ACQ scores, compared with the FP/SM group. There were good correlations between IOS parameters, FeNO and ACQ score changes over the course of the treatment.

Conclusions

BUD/FM twice daily significantly improved small airway impairment and airway inflammation in asthmatic patients, leading to a reduction in asthma symptoms and achievement of good asthma control. In addition, improvement of small airway function may improve airway inflammation and/or lead to better controlled asthma.     

Chronic traffic pollution exposure is associated with eosinophilic,but not neutrophilic inflammation in older adult asthmatics

Abstract

Objective: Airway inflammatory patterns in older asthmatics are poorly understood despite high asthma-related morbidity and mortality. In this study, we sought to define the relationship between exposure to traffic pollutants, biomarkers in induced sputum, and asthma control in older adults. Methods: Induced sputum was collected from 35 non-smoking adults ≥65 years with a physician’s diagnosis of asthma and reversibility with a bronchodilator or a positive methacholine challenge. Patients completed the Asthma Control Questionnaire (ACQ), and Elemental Carbon Attributable to Traffic (ECAT), a surrogate for chronic diesel particulate exposure, was determined. Equal numbers of subjects with high (≥0.39?µg/m³) versus low (<0.39?µg/m³) ECAT were included. Differential cell counts were performed on induced sputum, and myeloperoxidase (MPO) and eosinophil peroxidase (EPO) were measured in supernatants. Regression analyses were used to evaluate the relationship between sputum findings, ACQ scores, and ECAT. Results: After adjustment for potential confounders, subjects with poorly controlled asthma based on ACQ?≥?1.5 (n?=?7) had significantly higher sputum eosinophils (median?=?4.4%) than those with ACQ?<?1.5 (n?=?28; eosinophils?=?2.6%; β?=?10.1 [95% CI?=?0.1–21.0]; p?=?0.05). Subjects with ACQ?≥?1.5 also had significantly higher sputum neutrophils (84.2% versus 65.2%; β?=?7.1 [0.2–14.6]; p?=?0.05). Poorly controlled asthma was associated with higher sputum EPO (β?=?2.4 [0.2–4.5], p?=?0.04), but not MPO (p?=?0.9). High ECAT was associated with higher eosinophils (β?=?10.1 [1.8–18.4], p?=?0.02) but not higher neutrophils (p?=?0.6). Conclusions: Poorly controlled asthma in older adults is associated with eosinophilic and neutrophilic inflammation. Chronic residential traffic pollution exposure may be associated with eosinophilic, but not neutrophilic inflammation in older asthmatics.     

Relationship of Mannitol Challenge to Methacholine Challenge and Inflammatory Markers in Persistent Asthmatics Receiving Inhaled Corticosteroids

Background

Mannitol is a novel osmotic indirect bronchial challenge agent used to aid asthma diagnosis and management and is thought to reflect underlying inflammatory processes in asthma. Our objective was to evaluate relationships between mannitol airway hyperresponsiveness (AHR) and other measures of airway inflammation as well as direct-acting methacholine challenge in persistent asthmatics receiving inhaled corticosteroids.

Methods

We analysed screening data of mild to moderate persistent asthmatics, all receiving inhaled corticosteroids (ICS), who had mannitol and/or methacholine challenges, fractional exhaled nitric oxide (FeNO), and salivary eosinophilic cationic protein (ECP) performed as part of the same screen. Mannitol AHR was grouped by PD₁₀ (cumulative provocative dose required to produce a 10?% fall in FEV₁): mild (315–635?mg), moderate (75–315?mg), and severe (0–75?mg). FeNO groups were low (<25?ppb), medium (25–50?ppb), and high (>?50?ppb) and methacholine PC₂₀ (provocative concentration of methacholine required to cause a 20?% fall in FEV₁) groups were mild (2–8?mg/ml), moderate (0.5–2?mg/ml), and severe (0–0.5?mg/ml).

Results

Mannitol PD₁₀ groups were significantly different overall for FeNO (p?=?0.023): 43?% higher in the severe vs. the mild group. There was a significant overall difference for methacholine PC₂₀ (p?=?0.006): a 2.1 doubling dilution difference between severe vs. mild mannitol groups. FeNO groups were significantly different overall for mannitol PD₁₀ (p?=?0.01) and methacholine PC₂₀ (p?=?0.029). Methacholine PC₂₀ groups were significantly different overall for mannitol PD₁₀ (p?p?=?0.005). No significant differences were found across any groups for salivary ECP, FEV₁ % predicted, or ICS dose. Mannitol PD₁₀, methacholine PC₂₀, and FeNO as continuous variables all correlated with each other.

Conclusions

Mannitol challenge reflects underlying inflammation using FeNO and direct AHR using methacholine. Thus, mannitol may be a useful screening tool for the assessment of asthmatic patients receiving inhaled corticosteroids.     

The Value of Sputum 8-Isoprostane in Detecting Oxidative Stress in Mild Asthma

Background. Exhaled nitric oxide and induced sputum eosinophils are well established as direct markers of inflammation/oxidative stress in asthma. Recently, it has been proposed that sputum 8-isoprostane concentrations may present a reliable index for measuring oxidative stress in asthmatic patients. We assessed the value of sputum 8-isoprostane in mild asthma in children and adolescents. Methods. Patients with newly diagnosed asthma (children, n = 23; adults, n = 14) and age-matched healthy controls (children, n = 13; adults, n = 15) were studied. Lung function was measured by spirometry, sputum was induced by hypertonic saline, and fractional exhaled nitric oxide (FeNO) was measured with standard methods. Cell differential counts were obtained from sputum slides and the concentration of 8-isoprostane was measured with an enzyme immunoassay from sputum supernatants. Results. High-quality sputum specimens could be obtained from 10 children and 10 adults, and the sputum analyses were conducted only for the representative specimens. Asthmatics had increased FeNO (children 35.5 vs. 11.9 ppb; adults 81.1 vs. 16.6 ppb; p < 0.001) and sputum eosinophils (children 2.4% vs. 1.4%; adults 10.4% vs. 0.2%; p = 0.005) compared to healthy controls. There was a significant correlation between FeNO and eosinophils (R = 0.65; p < 0.0001). Sputum 8-isoprostane was not elevated in asthmatics compared to healthy subjects (children 81.1 vs. 89.9 and adults 76.9 vs. 73.4 pg/mL) and did not correlate with lung function or other measurements of airway inflammation. However, increased 8-isoprostane levels were detected in patients with chronic obstructive pulmonary disease (n = 11, 184.7 pg/mL, used as controls for assays). Conclusions. In agreement with earlier studies, FeNo is sensitive in detecting oxidative/nitrosative stress in asthmatic airways. However, our results suggest that 8-isoprostane may not be sensitive in reflecting oxidant burden in mild asthma.     

Adiposity,Adipokines, and Exhaled Nitric Oxide in Healthy Adults Without Asthma

Background. Epidemiological studies have shown that obesity/adiposity is closely associated with asthma in terms of development, severity, and control of asthma. However, effects of obesity/adiposity on airway inflammation are not well known in subjects without asthma. We assessed whether fractional exhaled nitric oxide (FeNO), a marker of eosinophilic airway inflammation, was associated with obesity/adiposity in nonasthmatic healthy adults. Methods. We measured FeNO and serum levels of adipose-derived hormones and adipokines in 117 adult subjects without a previous diagnosis of asthma or current asthmatic symptoms. Associations between FeNO and measures of obesity/adiposity [body mass index (BMI), body fat mass, and body fat percentages] were examined by correlation analyses and uni- and multivariate linear regression analyses. Results. FeNO was not significantly associated with BMI, body fat mass, or body fat percentage by a multivariate linear regression model, adjusting for age, gender, chronic rhinitis, atopy, and lung function. No significant association of FeNO with serum levels of leptin, adiponectin, tumor necrosis factor (TNF)-α, or interleukin (IL)-6 was observed. Conclusions. These findings suggest that in healthy subjects without asthma, obesity/adiposity has no significant effect on eosinophilic airway inflammation and that hormones and systemic inflammation derived from adipose tissue do not affect eosinophilic airway inflammation.     

Asthma in elite athletes: how do we manage asthma‐like symptoms and asthma in elite athletes?

Introduction: Asthma is frequent in elite athletes and the high prevalence of asthma might be associated with specific types of sport. It has been suggested that chronic endurance training might increase the number of neutrophils in the airways, and this may reflect airway injury. The use of anti‐asthmatic medication in elite athletes is also currently under scrutiny in order to reduce the risk of under‐treatment or over treatment. Objectives: Determine the use of anti‐asthmatic medication and the prevalence of asthma‐like symptoms and asthma in Danish elite athletes. Further, to determine whether elite athletes with asthma‐like symptoms have asthma and investigate the airway inflammation and airway reactivity to mannitol. Materials and Methods: Three cross‐sectional studies: (i) Applications for Abbreviated Therapeutic Use Exemption (ATUE) certificates in 2005 were studied (N = 694); (ii) a questionnaire survey of elite athletes (N = 418); and (iii) a clinical study of elite athletes. A total of 54 elite athletes (19 with physician‐diagnosed asthma) participated together with two control groups: (i) 22 non‐athletes with physician‐diagnosed asthma (steroid naïve for 4 weeks before the examination) and (ii) 35 non‐athletes without asthma. Examinations: questionnaires, exhaled nitric oxide (eNO), spirometry, skin prick test, mannitol test and blood samples. Induced sputum was done in subjects with asthma. Results: (i) Anti‐asthmatic medication was included in 445 (64%) of all ATUE certificates. A total of 308 (69%) elite athletes applied for inhaled corticosteroids (ICS), and most ATUE certificates were handled by general practitioners (GP) (78%). (ii) A total of 329 (79%) elite athletes completed the questionnaire; 181 (55%) reported asthma‐like symptoms and 46 (14%) had asthma. Anti‐asthmatic medication was currently taken by 24 (7%) elite athletes. Elite athletes participating in endurance sports had higher prevalences of asthma‐like symptoms (74%), use of anti‐asthmatic medication (15%) and current asthma (24%) than all other athletes (P < 0.01). (iii) No difference in lung function, eNO, airway reactivity (AR) to mannitol and atopy between elite athletes with and without asthma‐like symptoms was found. Elite athletes with physician‐diagnosed asthma had less AR [Response Dose Ratio (RDR) 0.02 (0.004) vs 0.08 (0.018) P < 0.01], and fewer sputum eosinophils [0.8% (0–4.8) vs 6.0% (0–18.5), P < 0.01] than non‐athletes with physician‐diagnosed asthma. Conclusion: Most applications for ATUE certificates were handled by GPs, and the majority concerned anti‐asthmatic medication. We found signs of under‐treatment of elite athletes with asthma, and endurance athletes had the highest prevalence of asthma‐like symptoms and asthma. The prevalence of asthma‐like symptoms was higher than the prevalence of asthma, and we showed that symptoms alone should not be used to diagnose asthma. We demonstrated that asthma‐like symptoms are independent of lung function, eNO, RDR and atopy in elite athletes. Elite athletes with physician‐diagnosed asthma seem to have less airway reactivity and fewer sputum eosinophils than non‐athletes with physician‐diagnosed asthma, but more studies are needed to further investigate if and how the asthma phenotype of elite athletes differs from that of classical asthma.     

Lipopolysaccharides promote a shift from Th2-derived airway eosinophilic inflammation to Th17-derived neutrophilic inflammation in an ovalbumin-sensitized murine asthma model

Introduction: The currently available treatments for severe asthma are insufficient. Infiltration of neutrophils rather than eosinophils into the airways is an important inflammatory characteristic of severe asthma. However, the mechanism of the phenotypic change from eosinophilic to neutrophilic inflammation has not yet been fully elucidated. Methods: In the current study, we examined the effect of lipopolysaccharides (LPS) on eosinophilic asthmatic mice sensitized with ovalbumin (OVA), as well as the roles of interleukin (IL)-17A/T helper (Th) 17 cells on the change in the airway inflammatory phenotype from eosinophilic to neutrophilic inflammation in asthmatic lungs of IL-17A-deficient mice. Results: Following exposure of OVA-induced asthmatic mice to LPS, neutrophil-predominant airway inflammation rather than eosinophil-predominant inflammation was observed, with increases in airway hyperresponsiveness (AHR), the IL-17A level in bronchoalveolar lavage fluid (BALF) and Th17 cells in the spleen and in the pulmonary hilar lymph nodes. Moreover, the neutrophilic asthmatic mice showed decreased mucus production and Th2 cytokine levels (IL-4 and IL-5). In contrast, IL-17A knockout (KO) mice exhibited eosinophil-predominant lung inflammation, decreased AHR, mucus overproduction and increased Th2 cytokine levels and Th2 cells. Conclusion: These findings suggest that the eosinophilic inflammatory phenotype of asthmatic lungs switches to the neutrophilic phenotype following exposure to LPS. The change in the inflammatory phenotype is strongly correlated with the increases in IL-17A and Th17 cells.     

Relationship between Exhaled Nitric Oxide and Exposure to Low-Level Environmental Tobacco Smoke in Children with Asthma on Inhaled Corticosteroids

Objectives. The relationship between exhaled nitric oxide (FeNO) and asthma severity or control is inconsistent. Active smoking lowers FeNO, but the relationship between passive smoking and FeNO is less clear. Children may be exposed to low-level environmental tobacco smoke (ETS) or thirdhand smoke, even if parents avoid smoking in the presence of their children. Our hypothesis was that FeNO is lower in children with asthma exposed to low-level ETS when compared with those who are not exposed. Methods. Children with stable asthma, 8–18 years of age, on low- or medium-dose inhaled corticosteroids (ICS) were enrolled. Spirometry, Asthma Control Questionnaire (ACQ), FeNO, exhaled breath condensate pH (EBC pH), and EBC ammonia were compared between children with and without ETS exposure as determined by urinary cotinine. Results. Thirty-three subjects were enrolled, of which 10 (30%) had urinary cotinine levels ≥1 ng/ml. There were no significant differences between the two groups in age, sex, BMI percentile, atopy status, FEV₁, EBC pH, or EBC ammonia. Median ACQ was 0.29 (IQR: 0.22–0.57) for those with cotinine levels <1 ng/ml and 0.64 (IQR: 0.57–1.1) for those with cotinine levels of ≥1 ng/ml, p = .02. Median FeNO (ppb) was 23.9 (IQR: 15.2–34.5) for unexposed subjects and 9.6 (IQR: 5.1–15.8) for exposed subjects, p = .008. Conclusions: Children with asthma on low to medium doses of ICS and recent low-level ETS exposure have lower FeNO levels when compared with non-ETS-exposed subjects. Exposure to low-level ETS or thirdhand smoke may be an important variable to consider when interpreting FeNO as a biomarker for airway inflammation.     

The leaky lung test: a pilot study using inhaled mannitol to measure airway barrier function in asthma

Objective: Airway epithelial barrier dysfunction is emerging as an important feature of asthma pathogenesis, but this is difficult to measure in individual subjects. We aimed to develop a noninvasive way to measure airway permeability in asthma. Methods: Healthy controls and subjects with mild asthma inhaled dry powder mannitol in a dose-escalating manner on two separate occasions, stopping at 155?mg or 315?mg. Serum mannitol levels were measured at baseline and then 30, 90, and 150?min after mannitol inhalation. Mannitol absorption was compared with measurements of airflow obstruction (FEV1) and airway inflammation (FeNO). Results: Serum mannitol levels increased in a time- and dose-dependent manner in both healthy control and subjects with asthma. There were no significant differences in mannitol absorption when comparing healthy controls and subjects with asthma. Mannitol absorption did not correlate with markers of airway obstruction or inflammation. Conclusions: Measuring serum concentrations of mannitol after inhalation challenge can potentially provide insights into airway barrier function in asthma.