Exhaled nitric oxide and its relationship to airway responsiveness and atopy in asthma. BHR-Study Group.

Exhaled nitric oxide (NO) has attracted increasing interest as a non-invasive marker of airway inflammation. The purpose of this study was to determine whether exhaled nitric oxide in subjects with asthma varied according to their atopic status and to examine its correlation with airway hyperresponsiveness and lung function measurements. Forty patients with asthma and 13 controls participated in the study. Nitric oxide was measured on three occasions with intervals of at least 3 days, using a chemiluminescence method. Airway responsiveness was assessed with methacholine challenge and lung function measurements were made. All subjects recorded peak expiratory flow and kept a symptom diary during a 17-day period. There was no significant difference in lung function measurements, peak expiratory flow or symptom score between the two asthma groups. Atopic patients with asthma had a significantly higher mean amount of exhaled NO than non-atopic subjects with asthma (162 +/- 68 vs. 113 +/- 55 nl min-1; P = 0.03) and the control group (88 +/- 52 nl min-1; P = 0.004). No significant difference was found in the amount of exhaled NO between non-atopic patients with asthma and the controls. In atopic subjects with asthma the mean exhaled NO was significantly correlated to the dose-response slope for methacholine (r = -0.52; P = 0.02), while no such correlation was found in the non-atopic group. In conclusion; in this study, atopic subjects with asthma had higher levels of exhaled NO than non-atopic subjects. Atopic status should be taken into account when measuring levels of exhaled NO in subjects with asthma.     

Exhaled nitric oxide--is it really a good marker of airway inflammation in bronchial asthma?

BACKGROUND: The concentration of exhaled nitric oxide ([NO]) has been reported to reflect the inflammatory process of airways in patients with bronchial asthma, particularly when they are steroid naive. However, it is not fully understood whether it equally reflects the degree of airway inflammation in patients receiving inhaled corticosteroids, but whose symptoms are not necessarily well controlled. OBJECTIVE: To examine whether the exhaled [NO] really reflects airway inflammation in patients with bronchial asthma, regardless of treatment with inhaled steroids. METHODS: Exhaled [NO] was measured in patients with bronchial asthma (43 steroid treated and 32 steroid naive), chronic obstructive pulmonary disease (COPD) (n = 36), bronchiectasis (n = 10) and in control subjects (n = 26). We examined in each asthmatic group whether the exhaled [NO] correlated with parameters reflecting airway inflammation. RESULTS: Exhaled [NO] was significantly correlated with symptom score, clinical severity, circulating eosinophil count, and the percentage of eosinophils in induced sputum in the steroid-naive asthmatics, but not in the steroid-treated asthmatics, although airway inflammation in this group was not well controlled, as evidenced by clinical symptoms and the higher percentage of eosinophils in induced sputum. Exhaled [NO] from the patients with COPD (6.2 +/- 0. 7 ppb) or bronchiectasis (5.4 +/- 1.3 ppb) was not significantly increased compared with the controls (6.0 +/- 1.0 ppb), and was significantly lower than in the asthmatic patients as a whole (19.0 +/- 2.0 ppb). CONCLUSIONS: Although exhaled [NO] is a useful marker of airway inflammation for differential diagnosis and evaluation of severity in steroid-naive patients with bronchial asthma, it may not be as useful in steroid-treated patients.     

Bronchial hyperresponsiveness and exhaled nitric oxide in patients with cardiac disease

BACKGROUND: Increased concentrations of exhaled nitric oxide (NO) correlate with increased airway inflammation and measurement of exhaled NO is a noninvasive method for the management of bronchial asthma. In various cardiac diseases, bronchial hyperresponsiveness is observed, as is bronchial asthma. However, there have been few studies on the relationship between exhaled NO and bronchial responsiveness in cardiac diseases. OBJECTIVE: The aim of this study was to clarify the association between exhaled NO and bronchial hyperresponsiveness in patients with cardiac disease. METHODS: We measured expired NO and bronchial responsiveness to inhaled methacholine in 19 patients with cardiac diseases and 17 with bronchial asthma. We divided the cardiac disease patients into two groups according to their bronchial responsiveness to inhaled methacholine: BHR(+) group consisted of 12 patients with bronchial hyperresponsiveness and BHR(-) group consisted of 7 patients without bronchial hyperresponsiveness. RESULTS: The concentration of exhaled NO in the asthmatic patients was significantly higher than that in the BHR(+) and BHR(-) groups (142.0 +/- 17.0, 33.6 +/- 6.4 and 42.3 +/- 10.3 ppb, respectively, p < 0.01). There was no significant difference in exhaled NO between BHR(+) and BHR(-) groups. There were also no significant differences in the parameters of bronchial hyperresponsiveness between the cardiac BHR(+) and bronchial asthma groups. These results indicate that bronchial hyperresponsiveness in patients with cardiac diseases is not a consequence of eosinophilic inflammation or of exhaled NO. CONCLUSION: We conclude that bronchial hyperresponsiveness in patients with cardiac diseases can occur independently of NO production.     

Induced sputum analysis in asymptomatic young adults with bronchial hyperresponsiveness to methacholine

BACKGROUND AND OBJECTIVES: BHR is a clinical feature of asthma and factors crucial to the development of BHR remain to be elucidated. Asymptomatic BHR also occurs in the general population. This study examined the prevalence of asymptomatic BHR in a population of young Japanese atopic individuals to identify whether airway inflammation is present in asthmatic patients but not in asymptomatic subjects with BHR. METHODS: Fifty atopic volunteers (aged 18-23 years) without lower respiratory symptoms were recruited and their bronchial responsiveness to methacholine was measured in order to categorize them into two groups, those with BHR (PC(20) below 8 mg/mL) and those without BHR. We evaluated the inflammatory cell profiles and measured IL-5 and IL-13 levels in sputum from subjects of each group by ELISA. Results were compared with those for young adult asthmatic patients. RESULTS: In the young atopic group, 17 subjects (34.0%) exhibited BHR. Compared with asthmatic patients sputum from asymptomatic subjects with BHR contained significantly lower numbers of eosinophils (P < 0.001) and had significantly lower levels of IL-5 (P = 0.088) and IL-13 (P = 0.032). There were no significant differences in each inflammatory parameter between the two asymptomatic groups. CONCLUSIONS: In young adult atopic subjects with asymptomatic BHR, airway inflammation does not necessarily play a determining role in the development of BHR to methacholine itself, though it might be an important factor in the onset of asthma.     

Influence of atopy on exhaled nitric oxide in patients with stable asthma and rhinitis.

The level of exhaled NO is increased in patients with allergic asthma and seasonal rhinitis. The aim of this study was to investigate the significance of atopy on NO production in the lower airways. Measurements of exhaled NO were performed in 131 stable asthmatic patients with chronic mild asthma (95 atopics and 36 nonatopics), 72 patients with perennial rhinitis (57 atopics and 15 nonatopics) and 100 healthy controls (20 atopics and 80 non-atopics). Patients with either asthma or rhinitis had higher exhaled NO values (13.3+/-1.2 parts per billion (ppb) and 11.7+/-1.1 ppb) than control subjects (4.8+/-0.3 ppb, p<0.01). Exhaled NO levels were significantly higher in atopic asthmatics (19+/-3.6 ppb) compared with nonatopic patients (5.6+/-0.8 ppb, p<0.001). Similar findings were observed in patients with rhinitis (13.3+/-1.3 ppb in atopics and 5.8+/-1.2 ppb in nonatopics, p<0.001). No difference was found in NO levels between atopic and nonatopic control subjects (4.8+/-0.8 ppb, and 4.5+/-0.3 ppb). In summary, this study has shown that increased exhaled NO levels are detected only in atopic patients with asthma and/or rhinitis and not in nonatopic patients. These findings may suggest that it is rather the allergic nature of airways inflammation, which is mainly responsible for the higher NO production in the lower airways.     

Exhaled nitric oxide and hydrogen peroxide concentrations in asthmatic smokers

BACKGROUND: Cigarette smoking is associated with decreased nitric oxide (NO) production and increased oxidative stress in the airways. Exhaled NO levels are not higher in asthmatic smokers than in healthy non-smokers, and the value of exhaled NO for diagnosing asthma in smokers has been questioned. OBJECTIVES: To compare exhaled NO concentrations between healthy and steroid-naive and steroid-treated asthmatic smokers and non-smokers. To also assess the acute effect of cigarette smoking on exhaled NO and hydrogen peroxide (H(2)O(2)) levels in asthmatic smokers. METHODS: Exhaled NO was measured by chemiluminescence and exhaled H(2)O(2) spectrophotometrically. In 7 steroid-naive asthmatic smokers exhaled NO and H(2)O(2) was measured both before and 15 min after smoking one cigarette. Data are given as median (range). RESULTS: Exhaled NO level was significantly higher in steroid-naive asthmatic smokers than in healthy smokers [7.7 (3.4-32.5) ppb vs. 3.2 (2.0-7.2) ppb, p < 0.001]. Exhaled NO values were lower in smokers than in non-smokers both in healthy subjects and in steroid-naive asthmatic patients. Steroid-treated asthmatic smokers had a tendency for lower exhaled NO values [5.4 (1.7-12.0) ppb] compared to steroid-naive asthmatic smokers. Cigarette smoking caused an acute increase in exhaled H(2)O(2) concentrations together with a decrease in exhaled NO concentration. CONCLUSIONS: Our data suggest that an elevation in exhaled NO concentration is associated with asthma in smokers. This difference may be useful for diagnosing the disease in smokers, but its clinical value needs further evaluation. Acute increase in exhaled H(2)O(2) concentrations suggests that smoking increases the oxidative stress in the asthmatic airways.     

Exhaled nitric oxide continues to reflect airway hyperresponsiveness and disease activity in inhaled corticosteroid-treated adult asthmatic patients

OBJECTIVE: Exhaled nitric oxide (eNO) has been used as a surrogate of airway inflammation in mild asthma. However, whether eNO levels reflect disease activity in symptomatic asthmatics receiving moderate doses of inhaled corticosteroid (ICS) is more uncertain. METHODOLOGY: To examine the relationship between eNO levels, sputum and blood eosinophils (SpE and PbE), PD(20) methacholine as a marker of airway hyperresponsiveness (AHR) and clinical status in 28 ICS-treated asthmatic subjects with persistent asthma compared to that in 25 symptomatic asthmatics managed with beta2-agonists alone. RESULTS: As expected, eNO levels were normalized in ICS-treated subjects and significantly elevated in the beta2-agonist only group (P < 0.001). SpE, PbE and PD20M did not differ between asthmatic groups but FEV1 was significantly worse in ICS-treated subjects (P < 0.01). Exhaled NO levels correlated with PbE within both asthmatic groups (P < 0.005), but with SpE only in ICS-untreated subjects (r(s) = 0.6, P < 0.05). In contrast, PD20M was negatively correlated with eNO and PbE in ICS-treated subjects only (r(s) = - 0.4, r(s) = - 0.4, respectively, P < 0.05). SpE and PbE were strongly correlated in both asthmatic groups (r(s) = 0.8, r(s) = 0.7, respectively, P < 0.005). Exhaled NO levels, SpE and PbE were all positively associated with increased nocturnal awakenings ( P < 0.05) in ICS-treated subjects, but not in ICS-untreated subjects. CONCLUSIONS: In ICS-treated asthma, eNO reflects clinical activity, PbE and AHR but not eosinophilic airway inflammation. Exhaled NO levels are quantitatively and relationally different in asthmatic subjects treated with ICS and continue to have potential for use as a surrogate of asthma pathophysiology in this group.     

Combined use of exhaled nitric oxide and airway hyperresponsiveness in characterizing asthma in a large population survey.

The aim of the present study was to see whether measurements of airway hyperresponsiveness (AHR) and nitric oxide (NO) in exhaled air (ENO) either separately or in combination, could differentiate between asthmatics and healthy control subjects in a population based survey. In central Norway 8,571 adolescents participated in a large-scale epidemiological survey (Young Helseunders?kelsen i Nord-Tr?ndelag (Health Survey in North-Tr?ndelag; HUNT). Asthmatic symptoms when exposed to pollen, pets or house-dust were reported by 7.8% (suspected asthmatics), while 56% reported no asthmatic or allergic symptoms (control subjects). From these respective groups 151 and 213 adolescents were investigated with allergy screening, measurements of exhaled and nasal NO, and methacholine challenge test. AHR (provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second (PD20) <2 mg) was confirmed in 75% of the suspected asthmatics versus 25% of the control subjects, whereas 52% versus 20% had elevated levels of ENO (> or =8 parts per billion (ppb)). ENO and dose response ratio to methacholine (DRR) were positively correlated (r=0.41, p<0.001). ENO was significantly elevated in atopic versus nonatopic suspected asthmatics (11.7 ppb and 5.6 ppb respectively, p<0.001). Suspected asthmatics with both AHR and atopy had the highest levels of ENO (14.2 ppb). It is concluded that measurements of nitric oxide in exhaled air alone are not a useful tool in diagnosing asthma in population surveys, but that the combination of airway hyperresponsiveness and elevated nitric oxide in exhaled air is a very specific finding for allergic asthma. The use of dose response ratio to methacholine did not provide any additional information to the provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second in this study.     

Differences in the effect of allergen avoidance on bronchial hyperresponsiveness as measured by methacholine,adenosine 5′-monophosphate,and exercise in asthmatic children

Asthma is now considered as an inflammatory airway disease. There is evidence that allergen avoidance reduces clinical symptoms in atopic asthma. We investigated the effect of a month's stay in the hypoallergenic environment of Davos, Switzerland (1560 m) which is relatively free of house dust mite (HDM) on changes in bronchial hyperresponsiveness (BHR), using the challenge tests of adenosine 5′ monophosphate (AMP), exercise and methacholine to test for BHR. Thirteen asthmatic children with an allergy to HDM participated in the study. We measured BHR on admission to the Davos Asthma Center and after 1 month in the house dust-free environment. The medications used by the patients at the time of admission were kept unchanged during this month. No significant difference in BHR was found to methacholine challenge after a 1-month stay at high altitude (P > 0.05). By contrast, the response to AMP was significantly different as indicated by displacement of the dose-response curve to the right by 2.15 doubling concentrations (P = 0.005). We also observed a significant difference in response to exercise (P = 0.03). These results indicate that a month's stay in a hypoallergenic environment caused a reduction in BHR to AMP and exercise, but not to methacholine. In addition, the results support the concept of differences in trigger mechanisms for BHR, and that responses to a methacholine challenge are not the same as responses to an exercise challenge. The observed reduction in BHR in asthmatic children to the indirect bronchial stimuli of AMP and exercise suggest reduced airway inflammation following avoidance of house dust aeroallergens. AMP and exercise challenges may therefore be better indicators of asthmatic airway inflammation than the direct stimulus of methacholine. Pediatr Pulmonol. 1996; 22:147–153. © 1996 Wiley-Liss, Inc.     

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.     

Spontaneous changes in bronchial responsiveness in children and adolescents: an 18-month follow-up

The purpose of this study was to investigate spontaneous changes in bronchial responsiveness to inhaled histamine over a period of 18 months. The first measurements in 495 subjects, 7 to 16 years of age, were made in 1986. Bronchial hyperresponsiveness (BHR), i.e., PC-20 FEV1 less than or equal to 8.0 mg/mL, was found in 79 (16%) individuals, of whom 28 (35%) had symptoms of asthma. Twenty asthmatic and 42 non-asthmatic subjects who had BHR (78%) were re-examined 18 months later. The asthmatics had a modest change in BHR, while in the non-asthmatics bronchial response to inhaled histamine and exercise was significantly decreased. In twenty-two subjects (36%) bronchial response was within the normal range; of these 18 were non-asthmatic. Six asthmatics (30%) and two non-asthmatics (5%) had an increased BHR at follow-up. Two subjects (5%) developed symptoms of asthma by the time of follow-up, with an unchanged degree of BHR. Sex, age, atopic symptoms, and viral respiratory infections at the first examination were unrelated to changes in bronchial responsiveness. However, changes of BHR in the non-asthmatic subjects were significantly correlated to changes in bronchial response to exercise. Although spontaneous changes in bronchial responsiveness occur in asthmatic, as well as non-asthmatic subjects, asthmatics persistently have hyperresponsive airways. Development of asthma was found to occur among subjects with persistent BHR.     

Phenotypes of asthma revisited upon the presence of atopy

Immunological studies claimed that atopic and non-atopic asthma share more similarities than differences. However, these two phenotypes of asthma are considered to be distinguishable upon distinct clinical patterns, which were not systematically assessed before in a large population. We studied characteristics discriminating atopic from non-atopic asthma among 751 asthmatic patients and 80 factors were analysed in univariate and multivariate analysis. Age, age of onset of asthma, female/male ratio were higher in non-atopic (n=200) than in atopic (n=551) asthmatics. Familial asthma, seasonal symptoms, rhinitis, conjunctivitis, allergen-triggered symptoms, improvement in altitude, exercise-induced asthma were associated with atopy. Non-atopic asthmatics displayed lower FEV(1) and FVC. Smoking was more frequent and asthma was more severe in these patients. Younger age, early onset, male sex, rhinitis and smoking were independent factors discriminating atopic from non-atopic asthma. This study establishes in a large population of asthmatics that although similarities exist between atopic and non-atopic asthma, two clinical phenotypes can still distinguish both kinds of asthma.     

Determinants of airway responsiveness to adenosine 5'-monophosphate in school-age children with asthma

Airway responsiveness to adenosine 5'-monophosphate (AMP) is more specific than that to direct stimuli for asthma diagnosis and response to treatment, but is not detected in all patients with asthma. This study was planned to determine predictive factors for responsiveness to AMP in asthmatic children between 7-16 years old. We performed a retrospective analysis of data from 71 asthmatic children who were challenged by AMP in our department. All children were characterized by skin-prick and lung function tests and bronchial challenge with AMP. Data on simultaneous methacholine challenge tests were available for 46 children, 34 of whom were also challenged with a third stimulus, exercise. Potential demographic factors for responsiveness to AMP were assessed by logistic regression analysis within the study group. The proportion of school-age children with asthma responsive to AMP was 39.4%. The geometric mean provocative concentration of AMP causing a 20% decrease in forced expiratory volume in 1 sec (PC20AMP) was 20.50 mg/ml (range, 0.31-377 mg/ml). There were no significant differences either in response to methacholine below 16 mg/ml (P = 0.66) or in PC20 methacholine level (P = 0.075) when we compared AMP-responsive and -nonresponsive children. These two groups also did not differ with respect to their response to exercise challenge in subgroup analysis (P = 0.34). Among school-age children with asthma, allergic rhinitis (P = 0.004) and sensitizaton to grass mix (P = 0.001), cereal mix (P = 0.003), house dust mite (P = 0.024), and cat (P = 0.043) were found to be more frequent in AMP-responsive children than the others. There was no difference in lung function test parameters between children responsive to AMP and the others. Grass pollen sensitization was found to be the only independent predictive factor for determining AMP responsiveness in school-age children with asthma (odds ratio, 5.65; 95% confidence interval, 1.84-17.45; P = 0.003). In conclusion, atopic sensitization is the most important predictive factor for responsiveness to AMP in school-age children with asthma, as in adults.     

Exhaled nitric oxide as a diagnostic test for asthma in rhinitic patients with asthmatic symptoms

BACKGROUND: Rhinitis is a major risk factor for asthma, so that evaluation of the lower airways is recommended in patients with rhinitis. Exhaled nitric oxide (FE(NO)) is considered a marker of airway inflammation and it has been found to be useful for the screening of patients with suspected diagnosis of asthma. Our aim was to assess the validity and accuracy of FE(NO) to identify patients with asthma in 48 non-smoking patients with persistent rhinitis and asthma-like symptoms. METHODS: Asthma was diagnosed on the basis of 12% improvement in FEV1 after salbutamol or a methocholine PD(20)FEV1<800 microg. Prior to lung function FE(NO) was measured with the single exhalation method at 50 ml/s. RESULTS: The geometric mean (95% confidence interval) FE(NO) was significantly higher in the 18/48 asthmatics than in the non-asthmatic patients (60 ppb, CI 95%: 50-89, versus 30 ppb, CI 95%: 28-45, P=0.001). Receiver operating characteristic (ROC) curve for the diagnosis of asthma indicated that FE(NO) is an acceptable discriminator between patients with and without asthma (area under the ROC curve=0.78). None of the asthmatic patients had FE(NO) values<25 ppb and all the patients with FE(NO)>100 ppb (n=5) were asthmatics. The sensitivity and specificity of FE(NO) for detecting asthma, using 36 ppb as cut-off point, were 78% and 60% and the positive and negative predictive values were 54% and 82%, respectively. CONCLUSIONS: Measuring FE(NO) may be useful for the screening of rhinitic patients with asthma-like symptoms.     

Exhaled nitric oxide and bronchial responsiveness to adenosine 5'-monophosphate in subjects with allergic rhinitis

STUDY OBJECTIVES: To determine differences in exhaled nitric oxide (ENO) between subjects with allergic rhinitis with and without increased responsiveness to direct and indirect bronchoconstrictor agents. STUDY DESIGN: Cross-sectional study with the order of challenge tests randomized. SETTING: Specialist allergy unit in a university hospital. PATIENTS: Thirty-eight subjects without asthma with allergic rhinitis and 10 healthy nonatopic control subjects. MEASUREMENTS AND RESULTS: Participants were challenged with increasing concentrations of adenosine 5'monophosphate (AMP) and methacholine. ENO was measured with the single-exhalation method. A positive response to both bronchoconstrictor agents was detected in nine subjects with allergic rhinitis, whereas four subjects showed increased responsiveness to AMP but not to methacholine. The geometric mean (range) ENO values were significantly higher in subjects with allergic rhinitis with increased responsiveness to either methacholine or AMP than in subjects with normal responsiveness to both agonists: 51.3 parts per billion (ppb) [22.0 to 108.5 ppb] vs 25.1 ppb (5.7 to 102.9 ppb, respectively; p = 0.007) and healthy control subjects (11.2 ppb [5.0 to 31.9 ppb], p < 0.001). Subjects with allergic rhinitis with normal responsiveness to both agonists also had higher concentrations of ENO than healthy control subjects (p = 0.007). No correlation was found between ENO and either of the provocative concentrations of methacholine or AMP causing a 20% fall in FEV(1). CONCLUSIONS: In subjects without asthma but with allergic rhinitis, the presence of bronchoconstriction in response to methacholine or AMP is associated with increased ENO concentrations. However, elevated concentrations of ENO are detected even in subjects with allergic rhinitis without airway hyperresponsiveness. These results suggest that the presence of airway hyperresponsiveness is not the only factor that determines the increased NO levels detected in subjects with allergic rhinitis.     

Intestinal helminth infestation is associated with increased bronchial responsiveness in children

Non-atopic asthma is the predominant phenotype in non-affluent parts of Latin America. We recently reported that infestation with Ascaris lumbricoides increased the risk of non-atopic asthma in less affluent areas of Brazil but the mechanism is unclear. The present study was conducted to determine whether helminth infestation is associated with heightened bronchial responsiveness (BHR), a common finding in asthma. A random sample of 50 asthmatic and 50 non-asthmatic controls (mean age 10.1 years) were selected from a larger cohort (n = 1,011) without knowledge of their helminth infestation status. Three stool samples were collected from each child on different days and each sample was analyzed by the Kato-Katz method for quantitative determination of helminth eggs. Bronchial provocation tests were performed with inhaled 4.5% hypertonic saline using the ISAAC Phase II standardized protocol. There was no difference between the prevalence of positive BHR in the asthmatics (20.4%) compared with the controls (14.6%) (P = 1.0). Helminth infestation was detected in 24.0% of children, with A. lumbricoides being the most common. Children with high load infestation (>or=100 eggs/g) were five times more likely to have BHR than children with low load or no infestation. Despite the small sample size the results of the present study suggest that the link between high load helminth infestation and non-atopic asthma may be mediated via heightened bronchial responsiveness, possibly due to an inflammatory response to the pulmonary phase of the helminth life cycle.     

Prostaglandins mediate bradykinin-induced reduction of exhaled nitric oxide in asthma.

Bradykinin (BK) is a mediator of inflammation in asthma with potent bronchoconstrictor actions. Endogenous release of nitric oxide may inhibit BK-induced bronchoconstriction. This study investigated whether bradykinin inhalation could modulate exhaled NO levels in normal and asthmatic subjects, and whether the bradykinin-induced effects were mediated through the production of cyclo-oxygenase products in patients with asthma, by studying the effect of the cyclo-oxygenase inhibitor, L-acetylsalicylic acid (L-ASA). Exhaled NO concentration and forced expiratory volume in one second (FEV1) were measured by chemiluminescence following inhalation of increasing concentrations of BK. In asthmatics (n=11), BK induced a dose-dependent decrease in exhaled NO concentration from 21.3+/-1.6 to 6.+/-0.5 parts per billion (ppb) (p<0.01) at the highest concentration, associated with a significant fall in FEV1. In normal subjects (n=10), the exhaled NO concentration fell from 7.2+/-0.13 to 4.3+/-0.51 ppb (p<0.001) 15 min, after a single inhalation of BK, but without a significant change in FEV1. In asthmatic subjects, pretreatment with inhaled L-ASA (90 x mg x mL(-1), 4 mL) did not alter exhaled NO levels, but prevented a BK-induced fall in exhaled NO concentration, as indicated by a significant increase in exhaled NO levels at the provocative concentration of BK causing a 20% fall in FEV1, (5.7 +/- 0.94 ppb after placebo and 12.0 +/- 1.8 ppb after L-ASA; p<0.05). L-ASA significantly reduced bronchial responsiveness to BK 3.9-fold (p<0.01). Inhaled bradykinin induced bronchoconstriction and a reduction in exhaled nitric oxide levels in asthmatic subjects, an effect that is partly mediated by cyclo-oxygenase products.     

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.     

Bronchial Sensitivity to Histamine in Former Asthmatics: Redevelopment of Symptoms During a Year of Followup

The aim of this protocol was to study bronchial responsiveness in 23 former asthmatics who were free of symptoms for at least 5 years. Bronchial hyperreactivity (BHR) was evaluated with histamine challenge test and the results were compared with those of 20 normal subjects and 20 current asthmatic patients. Among the former asthmatics 65% fulfilled the criteria of BHR. During 1 year of followup, two former asthmatics redeveloped asthma symptoms. Interestingly, one patient had no BHR when initially tested. These findings suggest that the absence of BHR does not guarantee the nonrecurrence of asthma symptoms in former asthmatics.     

Bronchoscopy and bronchoalveolar lavage findings in cross-country skiers with and without "ski asthma".

Bronchial hyperresponsiveness to methacholine with asthma-like symptoms ("ski asthma") is frequent in elite cross-country skiers. To further the understanding of "ski asthma", 10 nonasthmatic, nonatopic controls and 30 adolescent elite skiers were investigated by bronchoscopy and bronchoalveolar lavage (BAL). Nine skiers were atopic without allergy symptoms. Compared with controls, the macroscopic inflammatory index in the proximal airways in skiers was three-fold greater (median (interquartile range) 3.0 (2.0-5.0) versus 1.0 (0.8-2.3), p=0.008). In the BAL fluid, skiers had significantly greater total cell (p<0.05) and percentage lymphocyte (p<0.01) and mast cell counts (p<0.05). Neutrophil and eosinophil counts were not significantly different and eosinophil cationic protein was not detected. Tumour necrosis factor-alpha and myeloperoxidase were detected in 12 (40%) and six (20%) skiers, respectively. In skiers with ski asthma, the inflammatory index was greater than in nonasthmatic skiers. Lymphocyte subtypes and activation markers, and concentration of albumin, fibronectin and hyaluronan were not different from those in controls. Cross-country skiers have a minor to moderate degree of macroscopic inflammation in the proximal airways at bronchoscopy and a bronchoalveolar lavage fluid profile which differs in several respects from healthy controls. Skiers with ski asthma tend to show even higher degrees of bronchial inflammation.