Exhaled nitric oxide and asthma in young children

Exhaled nitric oxide (eNO) has been used to diagnose asthma in adults and children using either the slow vital capacity method (SVCm) or, in younger children, the tidal breathing method (TBm). Adenosine 5'-monophosphate (AMP) challenge also has been found to be a sensitive and specific test for the diagnosis of asthma. In the present study, we used the AMP provocation concentration that caused wheezing (PCW) to confirm the diagnosis of asthma (PCW < or = 200 mg/mL). We studied 36 children (2-7 years) with mild intermittent asthma, 13 children (3-7 years) with moderate persistent asthma treated with inhaled steroids, 20 nonasthmatic children (2-7 years) with chronic cough and recurrent pneumonia, and 15 healthy children (4-6 years). Expired gas was collected in collection bags by the TBm, and eNO was measured. We evaluated the efficacy of eNO values in diagnosing asthma. The mean eNO level of the mild intermittent asthmatic children (5.6 +/- 0.4 ppb) not receiving inhaled corticosteroids was significantly higher (ANOVA P < 0.0001) than that of the moderate persistent asthmatics who were treated with inhaled steroids, the nonasthmatic children with chronic cough, and the group of healthy children (3.7 +/- 0.6 ppb, P < 0.05; 3.2 +/- 0.3 ppb, P < 0.001; 2.2 +/- 0.2 ppb, P < 0.001, respectively). The points of intersection for sensitivity and specificity curves of eNO to differentiate mild intermittent asthmatics from nonasthmatic children with chronic cough and from healthy children were 77% and 88% for eNO values of 3.8 ppb and 2.9 ppb, respectively. We conclude that eNO collected by the TBm can differentiate steroid-naive young children with intermittent asthma from healthy children, from nonasthmatic children with chronic cough, and from asthmatic children treated with inhaled steroids.     

Inhaled ultrasonically nebulized distilled water decreases exhaled nitric oxide in asthma

Abstract Exhaled nitric oxide (eNO) is increasingly used as a marker of disease activity in asthma. Inhaled hypertonic saline has been shown to induce bronchoconstriction and to decrease eNO in asthmatic subjects, whereas the effects of hypotonic solutions on eNO in these patients have not been studied. To evaluate the effect of ultrasonically nebulized distilled water (UNDW), an indirect hypotonic stimulus, on eNO, 17 asthmatic patients were enrolled and eNO from lower airways was measured by chemiluminescence. UNDW significantly reduced FEV₁ ≥ 20% in 9 subjects (UNDW+), but had no effect in eight patients (UNDW−). Baseline eNO concentration were found to be 51.3 ± 11.1 ppb in UNDW+ and 32.9 ± 7.5 ppb in UNDW− patients, respectively (p = 0.199, NS). UNDW inhalation significantly decreased eNO (from 51.3 ± 11.1 ppb to 31.0 ± 7.1 ppb in UNDW+ (p < 0.020, n = 9) and from 32.9 ± 7.5 ppb to 26.2 ± 7.3 ppb in UNDW− subjects (p < 0.024, n = 8), respectively). eNO percentage reduction in UNDW+ patients was significantly higher compared with UNDW− subjects (−37 ± 4% vs −23 ± 3%, p = 0.021). There was no correlation between FEV₁ changes and eNO percentage decreases in both UNDW+ and UNDW− subjects. In UNDW+ patients, acute bronchodilation induced by salbutamol caused a recovery in both FEV₁ and eNO, though eNO levels remained lower than baseline values. We concluded that UNDW inhalation can significantly decrease eNO in asthmatic patients, either responders or nonresponders to this indirect osmotic challenge; the reduction in eNO levels was only partly dependent on acute changes in airway caliber.     

Exhaled breath condensate nitrite/nitrate and pH in relation to pediatric asthma control and exhaled nitric oxide

BACKGROUND: Combining exhaled breath condensate (EBC) and exhaled nitric oxide (eNO) may be a useful, non-invasive method to assess airway inflammation in pediatric asthma. This cross-sectional study evaluated the relationship of both EBC nitrite/nitrate (NOx) and EBC pH with asthma control and eNO in asthmatic, normal, and atopic children. METHODS: A total of 92 children were recruited, comprising 62 with asthma, 14 with atopy only, and 16 who were normal and non-atopic. All completed a questionnaire for asthma symptoms and control. Variables measured were spirometry, EBC NOx, pH, and eNO. RESULTS: EBC NOx in those with asthma (mean 8.4 microM, CI 7.5-9.4) was significantly elevated when compared with normal (4.8 microM, CI 3.4-6.2, P = 0.0007) and atopic children (6.5 microM, CI 4.0-9.1, P = 0.02). The mean level of eNO was significantly higher in those with asthma (43.7 ppb, CI 34.7-51.1, P < 0.001) and atopy (24 ppb, CI 16.7-31.2, P < 0.05) when compared with normal children (11.5 ppb, CI 6.7-16.2). There was a significantly lower pH in those with asthma and a FEV(1) < 80% predicted (P = 0.03), but no significant overall differences in EBC pH between the three groups of children. There was a significant correlation between eNO and EBC NOx in the group as a whole, but not between eNO and EBC pH. CONCLUSIONS: Mean EBC NOx levels differ between children with asthma, atopy, and those who are normal, but it is not interchangeable with eNO. EBC pH may be an additional marker of asthma control.     

血清嗜酸性细胞阳离子蛋白与可溶性白细胞介素Ⅱ受体在支气管哮喘中的应用

目的 研究ＥＣＰ与ｓＩＬ－２Ｒ在哮喘病中的致病机制和关系。方法 采用酶免疫荧光法和ＢＡ－ＥＬＩＳＡ法分别测定３０例健康者,６１例重症支气管哮喘患者的血清ＥＣＰ和ｓＩＬ－２Ｒ值,并追踪测试３７例患者治疗后血清ＥＣＰ和ｓＩＬ－２Ｒ水平。结果 急性期患者血清ＥＣＰ,ｓＩＬ－２Ｒ含量均明显高于对照组（Ｐ〈０．０１）,治疗后二者水平明显下降,较治疗前非常显著性差异（Ｐ〈０．０１）。结论 ＥＣＰ是促进气道炎症     

粒细胞活化、组蛋白去乙酰化酶2与重症哮喘关系的临床研究

目的 了解粒细胞活化和组蛋白去乙酰化酶2 (histone deacetylase 2,HDAC2)表达与重症哮喘的关系,以探索早期预测和辨别重症哮喘的生物标志物.方法 采用ELISA法测定受试者血清粒细胞活化标志物髓过氧化物酶(myeloperoxidase,MPO)、基质金属蛋白酶9(matrix metalloproteinase 9,MMP-9)、中性粒细胞弹性蛋白酶(neutrophil elastase,NE)及嗜酸粒细胞阳离子蛋白(eosinophil cationicprotein,ECP)水平,Western-blot测定外周血单个核细胞(peripheral blood mononuclear cells,PBMCs) HDAC2活性,分别比较重症哮喘组、轻中度哮喘组及健康对照组各指标并进行统计学分析.结果 ①重症哮喘组受试者粒细胞活化指标MPO[(102.43±28.19)μg/L]、MMP-9[(992.97±176.44) ng/L]、NE[(9.40±0.99)μg/L]及ECP[(232.85±48.37) μg/L]浓度值均显著高于轻中度哮喘组[MPO、MMP-9、NE及ECP分别为:(48.56±8.78) μg/L、(554.35±99.03) ng/L、(8.01±1.27) μg/L、(105.30±26.93) μg/L,P值均＜0.05]和正常对照组[MPO、MMP-9、NE及ECP分别为:(37.46±9.93) μg/L、(374.00±79.08) ng/L、(4.66±0.64) μg/L、(40.87±15.35) μg/L,P＜0.05];轻中度哮喘组受试者外周血MMP-9、NE及ECP浓度值显著高于正常对照组(P＜0.05);轻中度哮喘组与正常对照组比较MPO浓度值差异无统计学意义(P＞0.05);②重症哮喘组PBMCs HDAC2活性(HDAC2/GAPDH:0.19±0.09)较轻中度哮喘组(0.60±0.08)及正常对照组(1.09±0.26)均显著降低,差异有统计学意义(P＜0.05);轻中度哮喘组PBMCs HDAC2活性较正常对照组低,差异有统计学意义(P＜0.05);③MPO、MMP-9、NE及ECP与FEV1％ pred之间呈负相关,双侧Pearson检验差异有统计学意义(r值分别为:-0.60、-0.75、-0.43和-0.67,P＜0.01);与FEV1/FVC之间呈负相关,双侧Pearson检验差异有统计学意义(r值分别为:-0.52、-0.60、-0.42和-0.50,P＜0.05);与ACT之间呈负相关,双侧Pearson检验差异有统计学意义(r值分别为:-0.69、-0.67、-0.50和-0.70,P＜0.01);④HDAC2与FEV1％pred及FEV1/FVC之间呈正相关,双侧Pearson检验差异有统计学意义(r值分别为0.68和0.61,P＜0.01);与ACT之间呈正相关,双侧Pearson检验差异有统计学意义(r=0.68,P＜0.01).结论 粒细胞活化指标MPO、MMP-9、NE和ECP升高提示重症哮喘患者存在中性粒细胞和嗜酸粒细胞活化,其程度显著高于轻中度哮喘患者;PBMCs HDAC2在重症哮喘组明显降低提示该类患者的皮质激素敏感性降低,激素治疗的效果可能不佳.     

Airway hyperresponsiveness,peak flow variability and inflammatory markers in non‐asthmatic subjects with respiratory infections

Objective: The aim of this study was to characterise non‐asthmatic subjects with asthma‐like symptoms during a common cold, particularly in relation to airway hyperresponsiveness (AHR). Materials and Methods: Subjects with acute respiratory infections and a group of controls (n = 20 + 20), age 20–65 years, underwent bronchial provocations with methacholine, adenosine and cold air. All were non‐smokers and had no history of asthma or heart disease. Those with infection had asthma‐like symptoms (>2). Measurements of exhaled nitric oxide (eNO), serum levels of eosinophil cationic protein (ECP), eosinophil peroxidase, myeloperoxidase and human neutrophil lipocalin were made at each provocation. A 17‐day symptom and peak flow diary was calculated. Results: No differences between the two groups were found, regarding responsiveness to methacholine, adenosine or cold air challenge, as well as the inflammatory markers measured. In the infected group, the mean (standard deviation) ECP was higher in those with AHR to methacholine or cold air [15.7 (6.5) and 11.4 (4.2) µg/L, respectively; P < 0.05]; furthermore, eNO was higher in the infected group [116 (54) and 88 (52) nL/min, respectively; P = 0.055]. The infected group had, at all times, more symptoms and higher peak flow, with a decrease in the symptoms (P = 0.02) and a tendency to change in peak flow variation (P = 0.06). Conclusion: AHR does not seem to be the main cause of asthma‐like symptoms in adults with infectious wheezing. Peak flow variation and symptom prevalence during the post‐infection period may imply airway pathology different from AHR. Please cite this paper as: Björnsson E, Lúdvíksdóttir D, Hedenström H, Eriksson B‐M, Högman M, Venge P and Janson C. Airway hyperresponsiveness, peak flow variability and inflammatory markers in non‐asthmatic subjects with respiratory infections. The Clinical Respiratory Journal 2007;1:42–50.     

Once-Daily Fluticasone Propionate in Stable Asthma: Study on Airway Inflammation

Children with stable asthma receiving twice-daily fluticasone propionate (FP) were studied. Spirometry, exhaled nitric oxide (eNO) and sputum eosinophils were measured at baseline and 8 weeks after FP was changed to once-daily use while keeping the same total dosage. Visual analogue scores on asthma severity, symptoms, and dosing regimen preference were obtained. Twenty-nine children of mean age 10.6 years (SD 2.5) were recruited. There was significant improvement in eNO (47.1 ppb [30.3] vs. 39.9 ppb [27.1], p = 0.037), and sputum eosinophils (5.7% [6.5] vs. 2.5% [3.9], p = 0.024] after 8 weeks. All subjects preferred the once-daily dosing regimen. Once-daily FP is effective in controlling airway inflammation. This frequency of medication use is also the preferred regimen.     

Lower airway inflammation before and after house dust mite nasal challenge: an age and allergen exposure-related phenomenon

BACKGROUND: Upper and lower airways allergic disease is currently considered unitarily. Allergic inflammation in one site can extend to other sites of the respiratory tract. OBJECTIVE: To evaluate bronchial inflammation before and after allergen-specific nasal challenge (ASNC) in rhinitic and asthmatic children, considering the different levels of allergen exposure, i.e. summer (low) and winter (high). METHODS: Fourteen children with rhinitis and 15 with rhinitis and asthma, all monosensitized to mites and 10 healthy controls were studied. Nasal IgE were measured before ASNC in summer and in winter season. Nasal clinical score, eosinophil cationic protein (ECP), nasal tryptase, bronchial clinical score, FEV(1), PEF, sputum ECP, sputum tryptase and exhaled nitric oxide (eNO) were evaluated before and after ASNC in summer and winter season. RESULTS: Nasal scores significantly increased after ASNC in rhinitic and asthmatic children in both seasons. Nasal IgE were significantly higher in summer compared to winter. Bronchial symptoms, FEV(1) and PEF showed no mean differences in rhinitic and asthmatic children after ASNC, with an increase of bronchial symptoms and a decrease of FEV(1) and PEF occurring in 3/15 asthmatic children. In both groups nasal tryptase and ECP after ASNC significantly increased in summer and winter, while sputum tryptase was undetectable before or after ASNC in both groups. Sputum ECP and eNO at baseline were significantly higher in patients than in controls (summer P=0.002, winter P=0.001). Sputum ECP significantly increased after ASNC in 3/15 asthmatics in summer and in 11/15 in winter, as well as in 3/14 rhinitics in summer and in 4/14 in winter. eNO significantly increased after ASNC in 3/15 asthmatics in summer and in 10/15 in winter, and in 1/14 rhinitics in summer and in 4/14 in winter. A significant median increase of sputum ECP (P=0.0007) and eNO (P=0.0012) after ASNC in asthmatic and of eNO (P=0.013) in rhinitic children was also found in winter. CONCLUSIONS: Basal sputum ECP and eNO values, significantly higher before ASNC in rhinitic patients compared to control subjects, confirm the inflammatory link of upper and lower airways. The more frequent detection of inflammatory changes induced by ASNC in winter suggests that allergen exposure favours the transfer of nasal inflammation to lower airways.     

Effect of inhaled preservatives on asthmatic subjects. I. Sodium metabisulfite

Sodium metabisulfite (MBS) is used as a preservative in food and wine and frequently triggers attacks of asthma. To determine the characteristics of responses to inhaled MBS, 30 asthmatic subjects and 16 nonasthmatic subjects inhaled MBS, in concentrations of 6.2, 12.5, 50, and 100 mg/ml, from a DeVilbiss No. 40 nebulizer (DeVilbiss Co., Somerset, PA) in doses ranging from 0.1 to 12.8 mumol. Response was measured as the dose that caused a 20% fall in FEV1 (PD20FEV1). All the asthmatic subjects responded; one of the atopic, nonasthmatic subjects responded and none of the nonatopic, nonasthmatic subjects responded. The response occurred within 1 min, and most subjects recovered to within 10% of baseline after 30 to 40 min. Dose-response curves to MBS were steep and were reproducible, within a 7-day period, to within one doubling dose, with mean PD20FEV1 values of 2.17 and 2.11 mumol in 11 subjects. There was no correlation between PD20FEV1 values to MBS and histamine, and inhalation of MBS did not enhance responses to subsequent challenge with histamine (mean PD20FEV1 to histamine was 0.65 mumol and to histamine 1 h after MBS was 0.74 mumol). Challenge with MBS (mean PD20FEV1 4.07 mumol) did not cause refractoriness to a second challenge 1 h later (mean PD20FEV1 5.39 mumol). Of 20 subjects tested, prior inhalation of 8 mg nedocromil sodium blocked the response to MBS in 15 subjects and reduced it in two others. Cromolyn sodium (4 mg) blocked the response to MBS in three subjects but did not alter the mean PD20FEV1 in the remaining 17 subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Value of surrogate tests to predict exercise-induced bronchoconstriction in atopic childhood asthma

Exercise challenge tests are helpful in the diagnosis and management of childhood asthma, but methodology is complex and time-consuming. The aim of this study was to investigate whether exercise-induced bronchoconstriction (EIB) can be predicted by the results of different surrogate tests in a pediatric population. Eighty-five children (mean age: 11 years, range: 5-16 years) with atopic asthma were studied. Measurements of exhaled nitric oxide (eNO), spirometry and whole body plethysmography were performed followed by a standardized exercise testing. Questionnaires were completed asking for respiratory symptoms within 2 weeks preceding the study protocol. In 12/85 children (14%), forced expiratory volume in 1 sec (FEV1) was significantly reduced by > or = 15% after exercise testing. eNO was significantly elevated in this group of 12 patients as compared to patients without EIB (51.3 (31.1-67.3) parts per billion (ppb) versus 20.2 (10.9-42.3) ppb; P = 0.003). All children with normal eNO levels (< or = 25 ppb) had normal lung function results after exercise; hence the negative predictive value (NPV) of elevated eNO levels for prediction of EIB was 100%. However, the positive predictive value (PPV) was only 28%. The NPV and PPV for reported asthma symptoms within 2 weeks preceding the study were 96% and 26%, respectively. Considering recent symptom history in addition to elevated eNO improved the PPV to 40%, and resulted in the best combination of sensitivity and specificity. No baseline lung function parameter predicted whether a patient would develop EIB or not. In conclusion, eNO measurements, symptom questionnaires and most efficiently a combination of both surrogate tests can be used as time-saving methods to exclude EIB in atopic childhood asthma.     

Effect of atmospheric nitric oxide (NO) on measurements of exhaled NO in asthmatic children

The measurement of exhaled nitric oxide concentrations [NO] may provide a simple, noninvasive means for measuring airway inflammation. However, several measurement conditions may influence exhaled NO levels, and ambient NO may be one of these. We measured exhaled NO levels in 47 stable asthmatic children age 5 to 17 years and in 47 healthy children, gender and age matched. Exhaled [NO] in expired air was measured by a tidal breathing method with a chemiluminescence analyzer, sampling at the expiratory side of the mouthpiece. NO steady-state levels were recorded. In order to keep the soft palate closed and avoid nasal contamination, the breathing circuit had a restrictor providing an expiratory pressure of 3–4 cm H₂O at the mouthpiece. To evaluate the effect of [NO] in ambient air, measurements were randomly performed by breathing ambient air or NO-free air from a closed circuit. Breathing NO-free air, exhaled [NO] in asthmatics (mean ± SEM) was 23.7 ± 1.4 ppb, significantly higher (P < 0.001) than in healthy controls (8.7 ± 0.4 ppb). Exhaled NO concentrations measured during ambient air breathing were higher (49 ± 4.6 ppb, P < 0.001) than when breathing NO-free air (23.7 ± 1.4 ppb) and were significantly correlated (r = 0.89, P < 0.001) with atmospheric concentrations of NO (range 3–430 ppb). These findings show that (1) exhaled [NO] values of asthmatic children are significantly higher than in healthy controls, and (2) atmospheric NO levels critically influence the measurement of exhaled [NO]. Therefore, using a tidal breathing method the inhalation of NO-free air during the test is recommended. Pediatr Pulmonol. 1998; 26:30–34. © 1998 Wiley-Liss, Inc.     

Increased Exhaled Nitric Oxide Levels After Exercise in Patients With Chronic Systolic Heart Failure With Pulmonary Venous Hypertension

BackgroundFractional exhaled nitric oxide (eNO) is recognized as a marker of pulmonary endothelial function. Oxidative stress is associated with systemic endothelial nitric oxide production, but its correlation with eNO in heart failure (HF) patients has not been described. Previous studies have reported increased eNO levels after exercise in symptomatic HF patients but decreased levels with pulmonary arterial hypertension. Our objective was to prospectively examine the potential myocardial and functional determinants of exercise-induced rise of eNO in HF.Methods and ResultsThirty-four consecutive ambulatory patients with chronic systolic HF (left ventricular ejection fraction [LVEF] ≤45%) underwent symptom-limited cardiopulmonary stress testing and echocardiography. eNO was determined immediately after exercise. Systemic endothelial dysfunction was assessed by asymmetric dimethylarginine (ADMA) and the L-arginine/ADMA ratio. In our study cohort (mean age 53 ± 13 years, 76% male, median LVEF 31%, interquartile range [IQR] 25%–40%), the mean eNO was 23 ± 9 ppb. eNO levels were higher in patients with diastolic dysfunction stages 2 or 3 than stage 1 or normal diastology (26.1 ± 9 vs 19.5 ± 7 ppb; P = .013). eNO had a positive correlation with estimated systolic pulmonary artery pressure (r = 0.57; P = .0009) and indexed left atrium volume (r = 0.43; P = .014), but it did not correlate with cardiopulmonary exercise test parameters, ADMA, or symptom score.ConclusionsIn contrast to earlier reports, the increase in postexercise eNO observed in stable chronic systolic HF patients may be attributed to the presence of underlying pulmonary venous hypertension probably secondary to advanced diastolic dysfunction.     

Correlation between reversibility of airway obstruction and exhaled nitric oxide levels in children with stable bronchial asthma

Recent trials measuring exhaled nitric oxide (eNO) concentrations have suggested that it may be a useful measure of ongoing airway inflammation in patients with asthma. The purpose of this study was to examine the relationship between eNO levels and baseline as well as postbronchodilator spirometry, a measurement commonly used in the clinical setting to determine the severity of asthma and as a guide to therapeutic decisions. Forty-nine patients between the ages of 5-16 years with physician-diagnosed asthma who attended the pediatric pulmonary clinic for a routine asthma visit with spirometric evaluation were recruited for the study. eNO levels prior to spirometry were obtained before and after receiving inhaled beta(2) agonist. eNO samples were collected in impermeable bags (Tedlar) and assayed within 24 hr by chemiluminescence. Regression analysis was used to assess the relationships between pre- and postbronchodilator eNO and spirometric variables. eNO was also compared in patients receiving and not receiving inhaled corticosteroids (ICS), as well as those whose therapy had been increased after evaluation by a pediatric pulmonologist or allergist. We found no significant difference between the levels of eNO before and after inhalation of beta(2) agonist (P = 0.60 paired t-test). Positive correlation was found between eNO vs. percentage change in FEV(1) (r = 0.35, P = 0.01) and percentage change in FEF(25-75% )(r = 0.29, P = 0.04). A negative correlation was found between prebronchodilator FEV(1) and eNO (r = -0.29, P = 0.03). Patients on ICS had lower mean eNO levels (29.9 vs. 47.6 parts per billion (ppb), P = 0.053) than those not receiving ICS. Patients whose ICS therapy was increased had higher mean eNO levels (47.2 vs. 26.9 ppb, P = 0.018) than those not having ICS therapy increased. We suggest that eNO levels could be a clinically useful measurement of asthma severity and could be used as an adjunct to spirometry to determine appropriate treatment plans. Longitudinal clinical trials are needed to determine if eNO can enhance therapeutic decisions for asthmatic children.     

呼出气一氧化氮在儿童支气管哮喘诊疗中的应用进展

目的检测典型支气管哮喘（简称哮喘）以及咳嗽变异性哮喘（cVA）患儿中呼出气一氧化氮（eNO）的水平以及和肺功能（PEF）两者的相关性,并探讨eNO检测在儿童哮喘以及CVA中的诊疗价值。方法采用电化学法对6～16岁患有典型哮喘（n=23）、CVA（n=29）的患者进行eNO测定,同时测定呼气峰流速（PEF）。37例无特异性疾病史和家族过敏史,且近两周内无急性呼吸道感染史的儿童作为对照组。结果典型哮喘组,CVA组的eNO水平均明显高于对照组（P〈0．01）,典型哮喘组和CVA的PEF水平均明显低于对照组（P〈0．05）;CVA组的eNO水平高于典型哮喘组（P〈0．05）,PEF水平高于典型哮喘组（P〈0．05）;但是eNO水平与PEF水平无相关性（r=0．061,P〉0．05）;29例CVA患者中,有21例eNO水平〉30ppb（正常水平为5～25ppb）。给予上述29例患者舒利迭或是都保治疗1个月,发现21例eNO水平偏高的患者中,有19例反复咳嗽症状明显减轻,2例症状改善。其余8例,有3例症状减轻,其余5例未见明显疗效。结论典型哮喘患者以及CVA患者的eNO水平均较高,eNO水平和PEF水平无相关性;CVA患者若eNO增高,对激素治疗有效。     

The ECP/Eo Count Ratio in Children with Asthma

We hypothesized that the serum eosinophil eationic protein (ECP) concentration to peripheral blood eosinophil count ratio (ECP/Eo ratio), reflecting active eosinophils, could better correlate with asthma severity in asthmatic patients, than each of these parameters alone. One hundred twenty children with mild to moderate persistent stable asthma were included into the study. At the first visit, previous asthma medications were withheld and patients were administered β‐2 agonists “as needed.” At the second visit peripheral blood eosinophil count, serum ECP, sIL‐2R, and sICAM‐1 were measured, and spirometry and histamine challenge tests were performed. During the study, patients filled daily diary cards to assess symptoms score. One hundred seventeen patients completed the study. The univariate logistic regression analysis showed that asthma severity is related to PC20H, ECP, ECP/Eo ratio, sIL‐2R, and sICAM‐1. In general, patients with higher level of ECP, ECP/Eo ratio, sIL‐2R, sICAM‐1 and with lower PC20H exhibited the higher risk of moderate asthma. Multivariate regression analysis showed that only PC20H and ECP/Eo ratio were the best predictors of asthma severity; higher PC20H (1 mg/mL change) slightly decrease (OR = 0.656; 95% CI: 0.44–0.99) and higher ECP/Eo ratio (0.1 pg/cell change) increase (OR = 1.84; 95% CI: 1.02–3.34) a risk of moderate asthma. These data show that the ECP/Eo ratio is a better and more useful marker than ECP or peripheral blood eosinophil count separately in assessing asthma in children.     

Peripheral Inflammation in Patients with Asthmatic Symptoms but Normal Lung Function

Some patients with asthmatic symptoms and eosinophilic airway inflammation have normal lung function and thus do not meet the current diagnostic criteria of asthma. Exhaled nitric oxide (NO) measurement at multiple exhalation flow rates can be used to assess alveolar and bronchial NO output and inflammation. We tested whether alveolar or bronchial NO output is increased in subjects having asthmatic symptoms but normal lung function. Exhaled NO concentration was measured at three exhalation flow rates (100, 175, and 370 mL/s) to assess alveolar NO concentration and bronchial NO flux in 23 patients with asthmatic symptoms but normal lung function (“asthmatic symptoms group”), 40 patients with asthma, and 40 healthy control subjects. The asthmatic symptoms group had increased bronchial NO flux (1.7 ± 0.3 nL/s, p = 0.016) and alveolar NO concentration (1.8 ± 0.2 parts per billiant (ppb), p = 0.010) compared with healthy controls (0.7 ± 0.1 nL/s and 1.0 ± 0.1 ppb, respectively). Patients with asthma had even higher bronchial NO flux (2.5 ± 0.3 nL/s, p = 0.024) but normal alveolar NO concentration (1.1 ± 0.2 ppb, p = 0.664). In asthmatic symptoms group, alveolar NO concentration correlated positively with blood eosinophil count and negatively with small airway function (FEF_50% and FEF_75%). In conclusion, patients with asthmatic symptoms but normal lung function have increased alveolar NO concentration and mildly elevated bronchial NO flux suggesting a more peripheral inflammation than in patients with asthma.     

Leukotriene E(4) in urine in patients with asthma and COPD--the effect of smoking habit

Leukotriene E(4) (LTE(4)) is implicated in asthma pathophysiology and possibly in chronic obstructive pulmonary disease (COPD) as one of the causes of persistent bronchoconstriction and mucus hypersecretion. Cigarette smoking stimulates cysteinyl leukotrienes (CysLTs) production. We investigated whether LTE(4) is equally increased in asthma and COPD and whether smoking significantly affects LTE(4) levels. Secondary outcomes involved correlations with inflammatory and functional parameters. We studied 40 patients with COPD [20 smokers], 40 asthmatics [20 smokers] and 30 healthy subjects [15 smokers]. Spirometry (FEV(1)% pred., FEV(1)/FVC) was performed, urine was collected for measurement of LTE(4) and creatinine, induced sputum was collected for differential cell counts and serum for ECP. LTE(4)/creatinine levels (pg/mg) [mean (sd)] were increased in asthmatic patients compared to COPD and controls, [125.6(54.5) vs. 54.5(19) vs. 55.9(18.9)pg/mg, respectively, P<0.0001 for asthma]. Smoking significantly affects LTE(4) levels only in asthmatic patients [164 (48) vs. 87 (26.3), P<0.0001 for smokers]. The only significant correlation was between eosinophils in induced sputum and LTE(4)/creatinine levels in asthmatics. In conclusion, patients with asthma presented higher LTE(4) values compared to normals and patients with COPD. Smoking significantly affects LTE(4) values only in asthmatics indicating a different underlying CysLTs inflammatory process in this condition.     

Fractional Exhaled Nitric Oxide (FENO), Lung Function and Airway Hyperresponsiveness in Naïve Atopic Asthmatic Children

Background. Measurement of fractional exhaled nitric oxide (FENO) is a noninvasive, simple, well‐tolerated, and reproducible marker of airway inflammation. Asthmatic children with normal respiratory function could be affected by airway inflammation. The aim of this study was to assess the correlation between FENO and bronchial hyperesponsiveness (BHR) to methacholine, and between FENO and lung function in atopic children with intermittent asthma. Methods. Thirty‐seven children (21 male), aged 7.2–14.4 years (median: 10.9 years), suffering from mild intermittent atopic asthma with a physician‐diagnosed history of wheezing and/or chest tightness were studied. None had taken anti‐asthmatic therapy for at least three months before the study. No child had symptoms of respiratory tract infection in the month before the study. All subjects underwent FENO measurement, pulmonary function testing and the methacholine provocation tests. Results. The mean percentages of FEV₁ and FEF_25–27 were 91.9 ± 10.5 and 88.3 ± 11.8, respectively. The mean FENO was 62.2 ± 39.2 ppb and PC20 methacholine was 0.93 mg/ml ± 0.54. Significant correlations were identified between FENO and FEV1 (p < 0.0059, r = 0.468) and between FENO and FEF25–75 (p < 0.0098, r = 0.439). There was no correlation between FENO and logPC20 (p = 0.14). Conclusions. A single FENO measurement is probably of scarce prognostic and predictive value and it is not surprising to find discordance with BHR. We suggest that FENO measurement could represent a good marker of airway inflammation also in naïve atopic children with intermittent asthma. Repeated measurements over time are probably necessary to understand better the clinical implications of the data obtained in this study.     

Increased perception of airway narrowing in patients with mild asthma

To compare the perception of airway narrowing of nonasthmatic subjects with those having wheeze or mild asthma (doctor-diagnosed), the relationship between FEV1 and breathlessness was examined in 123 subjects from a general population sample. Scores for breathlessness, using the Borg scale, were recorded before and after inhaling incremental doses of methacholine to a maximal dose of 196 mcmol or a maximum change in FEV1 of 50%. A history of asthma symptoms, including wheeze in the previous 12 months, and doctor-diagnosed asthma was obtained by questionnaire. At any given level of FEV1 there was wide variation in Borg scores between subjects, however median Borg scores and the mean slope of Borg score on FEVI was greater in the asthmatic subjects or those with wheeze compared with nonasthmatic subjects or those without wheeze. In both nonasthmatic and asthmatic subjects, those with airway hyperresponsiveness had increased maximum symptom scores and maximum changes in FEVI, but similar Borg scores relative to change in FEVI, compared with those without hyperresponsiveness. We conclude that the perception of mild and moderate degrees of airway narrowing varies widely between individuals but is increased in subjects with a history of mild asthma or wheeze in the last 12 months, independently of airway responsiveness.     

The effect of cigarette smoking on exhaled nitric oxide in mild steroid-naive asthmatics.

STUDY OBJECTIVES: It has been demonstrated previously that exhaled nitric oxide (eNO) is increased in steroid-naive asthmatics and that inhaled steroids reduce eNO in these patients. Cigarette smoking has also been reported to reduce the eNO in healthy volunteers. Recently a correlation has been demonstrated between eNO and airway hyperresponsiveness in steroid-naive, mild asthmatics. We hypothesized that cigarette smoking would reduce the eNO level in steroid-naive asthmatics and might, therefore, affect the correlation between eNO and airway hyperresponsiveness. DESIGN: Comparison of eNO in healthy smoking and nonsmoking volunteers with the level of eNO in steroid-naive and steroid-treated asthmatics. Correlate the eNO level with the provocative concentration of histamine causing a 20% fall in FEV1 (PC20hist) in the asthmatic smoking and nonsmoking patients. SETTING: University outpatient asthma clinic. PATIENTS AND METHODS: eNO levels and PC20hist were measured in three different asthmatic patient groups (group A = 29 steroid-naive, nonsmoking asthmatics; group B = 19 steroid-treated, nonsmoking asthmatics; and group C = 13 smoking, steroid-naive asthmatics) and in two healthy volunteer groups (group D = 18 nonsmoking; and group E = 16 smoking). RESULTS: eNO in group A was significantly increased compared with the values in groups B and D (21.8+/-12.7, 12.8+/-4.9, and 10.6+/-2.2 parts per billion [ppb], respectively). Cigarette smoking decreased eNO in healthy volunteers (7.4+/-1.8 ppb, group E) as well as in steroid-naive asthmatics (12.7+/-5.1 ppb, group C). There was a significant correlation between eNO and PC20hist in group A (r = -0.45, p < 0.05); this correlation was, however, lost in both groups B and C. CONCLUSION: Cigarette smoking and inhaled steroids reduce the eNO in patients with mild asthma to a comparable extent. Because the correlation between eNO and airway hyperresponsiveness was lost in steroid-treated and smoking, steroid-naive asthmatics, we question the value of eNO as a marker of airway inflammation, at least in mild asthmatics who are already being treated with inhaled steroids or who are currently smoking.