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In sarcoidosis, increased Th17 cell fractions have been reported in bronchoalveolar lavage fluid, and elevated numbers of Th17 cells producing IFN-γhave been observed in peripheral blood. The balance between Th1, Th17, and FoxP3+CD4+T cell subsets in sarcoidosis remains unclear. Bronchoalveolar lavage fluid cells, from 30 patients with sarcoidosis, 18 patients with other diffuse parenchymal lung diseases, and 15 healthy controls, were investigated with flow cytometry for intracellular expression of FoxP3. In a subset of the patients, expression of the cytokines IL17A and IFN-γwas investigated. The fractions of FoxP3+CD4+T cells and Th17 cells were both lower in sarcoidosis compared to controls (P=0.017andP=0.011, resp.). The proportion of Th17 cells positive for IFN-γwas greater in sarcoidosis than controls (median 72.4% versus 31%,P=0.0005) and increased with radiologic stage (N=23,rho=0.45, andP=0.03). IFN-γ+Th17 cells were highly correlated with Th1 cells (N=23,rho=0.64, andP=0.001), and the ratio of IFN-γ+Th17/FoxP3+CD4+T cells was prominently increased in sarcoidosis. IFN-γ+Th17 cells may represent a pathogenic subset of Th17 cells, yet their expression of IFN-γcould be a consequence of a Th1-polarized cytokine milieu. Our results indicate a possible immune cell imbalance in sarcoidosis.

Summary Background The Unified Airways hypothesis suggests an involvement of the upper airways in asthma. Critical parameters of the nasal airway can be quantified objectively with acoustic rhinometry (AR) and peak nasal inspiratory flow (PNIF). Objective We aimed to investigate nasal airway patency in asthmatics compared to non-asthmatic controls. Nasal volume, cross sectional area and flow were measured using acoustic rhinometry (AR) and peak nasal inspiratory flow (PNIF) in 87 asthmatics and 93 non-asthmatic controls before and after decongestion with xylometazoline. Nasal congestion index (NCI) was calculated, and allergy status was assessed by skin prick test or specific IgE. Results We found significantly smaller minimum cross sectional area and nasal cavity volume in asthmatics than controls, and the cross sectional area is at its minimum at 2–3 cm from the nasal orifice in both groups. AR and PNIF measurements are not different in allergic and non allergic subjects in either group. The effect of xylometazoline is not significantly different between the 2 groups with regard to AR, but there is a significant improvement in PNIF for the asthmatics when assessed by the NCI. Conclusion The present study demonstrates a significantly smaller nasal airway when assessed by minimum cross sectional area and nasal cavity volume in asthmatics than controls, and these findings apply to asthmatics and controls irrespective of allergy status.

Background Methacholine hyperresponsiveness is prevalent in elite athletes. Comparative studies have hitherto been limited to methacholine, eucapnic voluntary hyperpnoea and exercise. This study investigated airway responsiveness to these stimuli as well as to adenosine 5′-monophosphate (AMP) and mannitol, in 58 cross-country ski athletes. Methods Exhaled nitric oxide concentration (F E NO), spirometry and bronchial challenge in random order with methacholine, AMP and mannitol were consecutively performed on three study days in the autumn. Specifi c IgE to eight aeroallergens and a self-completed questionnaire about respiratory symptoms, allergy and asthmatic medication were also performed on day 1. Eucapnic voluntary hyperventilation (EVH) and fi eld exercise tests were randomly performed in 33 of the skiers on two study days in the following winter. Results Of 25 (43%) skiers with airway hyperresponsiveness (AHR), 23, fi ve and three skiers were hyperresponsive to methacholine, AMP and mannitol, respectively. Methacholine hyperresponsiveness was more prevalent in subjects without asthma-like symptoms. The F E NO was not signifi cantly different in skiers with and without methacholine hyperresponsiveness. Four of 14 skiers with and four of 19 skiers without methacholine hyperresponsiveness were hyperresponsive to EVH or exercise challenge. AHR to any stimulus was present in 16 asymptomatic and nine symptomatic skiers. Asthma-like symptoms were not correlated with AHR to any stimulus. Conclusions Methacholine hyperresponsiveness is more common in asymptomatic skiers and is a poor predictor of hyperresponsiveness to mannitol and hyperpnoea. The low prevalence of hyperresponsiveness to indirect stimuli may suggest differences in the pathogenesis of methacholine hyperresponsiveness in elite skiers and non-athletes.

The aim of this double-blind, placebo-controlled, cross-over study was to investigate possible improvement in physical performance at an ambient temperature of -15 degrees C by an inhaled dose of 50 micrograms salmeterol in 8 highly trained nonasthmatic cross-country skiers. FEV1 was measured before, during and after the treadmill exercise protocol, which consisted of a warm-up run, runs of 10 min at 90% and 5 min at 80% VO2max, followed by a timed run to exhaustion. Despite a significant improvement in FEV1, salmeterol did not have a beneficial effect on heart rate, blood lactate concentration, respiratory exchange ratio, oxygen uptake or minute ventilation during the exercise protocol. Running time to exhaustion was not significantly different from placebo. This lack of enhancement of exercise performance in healthy endurance athletes further supports the recent approval of salmeterol for prophylactic use by asthmatic athletes during training and competition.

Background The International Olympic Committee Medical Commission required a medical justification for athletes to inhale a β 2 -agonist before an event at the Summer Games in Athens in 2004. Objective We sought to establish the percentage of athletes applying to use an inhaled β 2 -agonist on the basis of the results of objective tests to establish a diagnosis of asthma or exercise-induced bronchoconstriction. We also sought to compare this percentage with the percentage of athletes simply notifying the intention to use a β 2 -agonist at the previous Summer Games in Sydney in 2000. Methods An analysis was made of tests that measured the change in FEV 1 in response to a bronchodilator or in response to a provoking stimulus, such as exercise, eucapnic voluntary hyperpnea, hypertonic saline, or methacholine. Results Ten thousand six hundred fifty-three athletes competed in Athens; 4.2% were approved to use a β 2 -agonist, and 0.4% were rejected. This approval rate was 26% less than the notifications in 2000 in Sydney (5.7%). Compared with Sydney 2000, there was a significant reduction of submissions and approvals for athletes from the United States, New Zealand, Australia, and Canada and in triathlon and swimming sports. Conclusion The need to provide objective testing has resulted in a reduction in the number of athletes seeking approval to use an inhaled β 2 -agonist. Objective evidence has provided information for the doctor that is likely to improve the health of the athlete because many athletes appeared to be undertreated at the time of testing. Clinical implications We show that documentation of airway narrowing in athletes, particularly in response to exercise or surrogate stimuli for exercise, aids in the diagnosis and management of asthma by providing evidence of bronchial hyperresponsiveness that will respond to treatment with inhaled corticosteroids and is usually associated with a reduction in respiratory symptoms on exercise.

Background: There has been an increase in the number and percentage of athletes competing in Olympic Games notifying use of β 2 -agonists, from 1.7% at Los Angeles (1984) to 5.5% at Sydney (2000). For Salt Lake City (2002), the International Olympic Committee requested objective evidence to use β 2 -agonists for asthma or exercise-induced asthma (EIA). Objective: The objective of this study was to evaluate the evidence submitted for approval to use a β 2 -agonist. Methods: Objective evidence for asthma or EIA included (1) an increase of 12% or more of the predicted FEV 1 in response to bronchodilator, (2) a reduction in FEV 1 of 10% or greater from baseline in response to exercise or eucapnic voluntary hyperpnea, (3) a PD 20 FEV 1 to methacholine or histamine at a dose of less than 200 μg (2 mg/mL) or less than 1320 μg (13.2 mg/mL) for those taking inhaled corticosteroids for 3 months. Results: There were 165 applications. Of these, 147 (89%) included evidence of a challenge, bronchodilator response, or both, and 163 test results were submitted. One hundred thirty (5.2%) applications were approved. For those with positive responses, the median value (1) was 16.2% of predicted FEV 1 for response to a bronchodilator (n = 13), (2) was a 15.9% decrease in FEV 1 for response to a physical challenge (n = 36), and, (3) for PD 20 FEV 1 , was 173 μg for response to a pharmacologic challenge (n = 45). Conclusion: The analysis demonstrated that it is feasible to request objective evidence to justify use of β 2 -agonists on the medical grounds of asthma or EIA. (J Allergy Clin Immunol 2003;111:45-50.)

Leukotriene antagonists are effective in the treatment of exercise-induced bronchoconstriction. Montelukast is a specific cysteinyl-leukotriene receptor1 antagonist without known effects on the pulmonary vessels, which in theory should be advantageous with respect to gas exchange. In addition to lung function, we investigated the effects of montelukast on parameters of gas exchange and physical performance in 16 asthmatics with exercise-induced bronchoconstriction in a double-blind cross-over placebo-controlled study. Subjects were tested at an ambient temperature of -15 degrees C with a tread mill exercise protocol consisting of consecutive workloads of 80% V'O(2max) (6 min), rest (4 min), 60% V'O(2max) (6 min) and step increments of exercise until exhaustion. Montelukast reduced the maximum post-exercise fall in FEV1 (P < 0.01), improved the running time to exhaustion in 11 of 16 test subjects (one unchanged) (P = 0.03), and reduced the Borg score at exhaustion (P = 0.03) and the breathing frequency after 3 min at 60% V'O(2max) (P = 0.03). V'(O2), V'CO(2), minute ventilation, ventilatory equivalents, respiratory exchange ratio, heart rate and oxygen pulse were not significantly different after montelukast and placebo. We conclude that montelukast has a beneficial effect on physical performance in most adults with exercise-induced asthma without any observed effect on gas-exchange parameters.

Among asthmatics, exercise-induced wheeze (EIW) is a frequent symptom, and 40-77% of asthmatics demonstrate exercise-induced bronchoconstriction (EIB). In the North-Trondelag population-based survey of 8,571 adolescents (YOUNG-HUNT), 26% reported wheeze during the previous 12 months (current wheeze). Of those subjects, 50% reported EIW. The aim of the present study was to investigate the association between EIW and EIB in randomly selected adolescents with EIW as the only or predominant asthma-like symptom, and to relate our findings to results from methacholine bronchoprovocation tests (MT) and measurements of exhaled nitric oxide (ENO). Sixty-three subjects with current wheeze induced by exercise, but not by allergen exposure, were investigated using a treadmill exercise test (ET) and measurements of ENO. Fifty-eight subjects completed a MT on a separate study day. EIB was defined as a fall of >or= 10% in the forced expiratory volume in 1 second (FEV1) after exercise (DeltaFEV1%ex). Twenty-one subjects (33%) had EIB and 33 (57%) had a positive MT. The degree of reported dyspnea during the ET was not correlated to the DeltaFEV1%ex. The correlation between EIB and methacholine-induced bronchoconstriction (MIB) was poor, and the DeltaFEV1%ex was more pronounced in smokers than in non-smokers. Moreover, ENO was not increased in subjects with positive vs. negative ET. Hence, EIW, when reported as the only or predominant asthma-like symptom, was linked to EIB in only one-third of the patients. We conclude that EIW is a poor predictor of EIB in epidemiological studies. The poor correlation between EIB and MIB indicates that these two tests measure different mechanisms of bronchial hyper-responsiveness.

Three studies were performed to evaluate the potential beneficial effects of inhaling the short-acting β 2 -agonist salbutamol, the long-acting β 2 -agonist salmeterol and oral administration of the leukotriene antagonist montelukast on physical performance in nonasthmatic highly trained endurance athletes at −15°C. The results show that the three asthmatic medications do not enhance physical performance during submaximal and maximal exercise in nonasthmatic highly trained athletes exposed to sub-zero conditions.

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

Observation of bronchus-associated lymphoid tissue (BALT) in whole lung specimens from healthy nonsmoking adults has questioned the hypothesis that BALT is not constitutively present in healthy adult human lungs. In our study, we investigated endobronchial biopsies of the second- and third-generation carinae from 44 cross-country ski athletes and 12 healthy control subjects, all nonsmoking young adults. The skiers had a prevalence of respiratory allergy (18%), asthma-like symptoms (59%), beta2 agonist medication (25%), and methacholine bronchial hyperresponsiveness (79%). Biopsy sections were stained by immunohistochemical and hematoxylin-eosin-saffran methods. Lymphoid aggregates of more than 50 cells were identified in 28 (64%) skiers and three (25%) control subjects (p = 0.02). They were small in comparison to those found in rabbits and rats, contained T and B lymphocytes and macrophages, and were seen more frequently in skiers using beta2 agonists (p = 0.04) and with bronchial hyperresponsiveness to methacholine (p = 0.053). The frequency of these aggregates was not significantly different at the two carinal levels (p = 0.6). The aggregates were not associated with a history of respiratory allergy or asthma-like symptoms. These aggregates share some resemblance with what is usually defined as BALT. However, their exact nature and function await further clarification.

The effects of whole-body exposure to ambient temperatures of -15 degrees C and 23 degrees C on selected performance-related physiological variables were investigated in elite nonasthmatic cross-country skiers. At an ambient temperature of -15 degrees C we also studied the effects of the selective beta2-adrenergic agonist Salbutamol (0.4 mg x 3) which was administered 10 min before the exercise test. Eight male cross-country skiers with known maximal oxygen uptakes (VO2max) of more than 70 ml x kg(-1) x min(-1) participated in the study. Oxygen uptake (VO2), heart rate (fc), blood lactate concentration ([La-]b) and time to exhaustion were measured during controlled submaximal and maximal running on a treadmill in a climatic chamber. Lung function measured as forced expiratory volume in 1 s (FEV1) was recorded immediately before the warm-up period and at the conclusion of the exercise protocol. Submaximal VO2 and [La-]b at the two highest submaximal exercise intensities were significantly higher at -15 degrees C than at 23 degrees C. Time to exhaustion was significantly shorter in the cold environment. However, no differences in VO2max or fc were observed. Our results would suggest that exercise stress is higher at submaximal exercise intensities in a cold environment and support the contention that aerobic capacity is not altered by cold exposure. Furthermore, we found that after Salbutamol inhalation FEV1 was significantly higher than after placebo administration. However, the inhaled beta2-agonist Salbutamol did not influence submaximal and maximal VO2, fc, [La-]b or time to exhaustion in the elite, nonasthmatic cross-country skiers we studied. Thus, these results did not demonstrate any ergogenic effect of the beta2-agonist used.

30 patients with malignant pleuritis were randomised to be treated, either with intrapleural instillation of mepacrine chloride or with mitoxantrone. The patients were evaluated with chest X-ray and a symptom questionnaire during a follow-up period of 12 weeks. Mitoxantrone levels in the pleural space and plasma were measured at different time points in some of the patients. High concentrations of mitoxantrone were found in the pleural fluid while the plasma concentrations were low, giving a plasma/intracavity ratio generally of less than 1:60. The chest X-rays showed excellent results for both treatment modalities. However, the patients treated with mepacrine chloride experienced greater discomfort with fever and pain, and those treated with mitoxantrone reported significantly less dyspnoea and less asthenia after 4 weeks. We conclude that both treatments are equally effective in preventing the recurrence of malignant effusion. However, mitoxantrone seems to have further advantages when it comes to improving the quality of life.

Athletes such as skaters and skiers inhale large volumes of cold air during exercise and shift from nasal to mouth breathing. Endurance athletes, like cross-country skiers, perform at 80% or more of their maximal oxygen consumption and have minute ventilations in excess of 100 l/min. Cold air is always dry, and endurance exercise results in loss of water and heat from the lower respiratory tract. In addition, athletes can be exposed to indoor and outdoor pollutants during the competitive season and during all-year training. Hyperpnoea with cold dry air represents a significant environmental stress to the airways. Winter athletes have a high prevalence of respiratory symptoms and airway hyper-responsiveness to methacholine and hyperpnoea. The acute effects of exercise in cold air are neutrophil influx as demonstrated in lavage fluid and airway epithelial damage as demonstrated by bronchoscopy. Upregulation of pro-inflammatory cytokines has been observed in horses. Chronic endurance training damages the epithelium of the small airways in mice. Airway inflammation has been observed on bronchoscopy of cross-country skiers and in dogs after a 1100-mile endurance race in Alaska. Neutrophilic and lymphocytic inflammation with remodelling is present in bronchial biopsies from skiers. Repeated peripheral airway hyperpnoea with dry air causes inflammation and remodelling in dogs. As it is currently unknown if these airway changes are reversible upon cessation of exposure, preventive measures to diminish exposure of the lower airways to cold air should be instituted by all winter sports athletes.

Study objectives: To compare the effect of montelukast and the long-acting 2-agonist salmeterol on cardiopulmonary exercise economy and physical performance in adult patients with asthma during exercise. Design and patients: Asthmatic patients (n 18), aged 18 to 35 years with exercise-induced bronchoconstriction (EIB), using a double-blind, double-dummy cross-over design. Montelukast, 10 mg/d, was compared to inhaled salmeterol, 50 g bid. The study medication was administered for at least 5 days prior to testing, with a washout period of at least 5 days. Treadmill exercise tests (5.3% inclination, 15°C ambient temperature) were performed at work loads of 80% of maximal oxygen uptake (V u O2max) [6 min], rest (4 min), 60% of V u O2max (6 min), and finally step increments until exhaustion. Measurements and results: We investigated parameters of gas exchange, physical performance, and lung function. After montelukast, the oxygen pulse was higher than after salmeterol, at 80% of V u O2max (p 0.035), and 6 min at 60% of V u O2max (p 0.011). Lung function during exercise, running time to exhaustion, Borg score, lactate levels, V u O2max, carbon dioxide elimination, minute ventilation, ventilatory equivalents, respiratory exchange ratio, and heart rate were not significantly different between the two treatments. The maximal postexercise fall in FEV1 from baseline occurred 2 min after run to exhaustion, and was greater after salmeterol than after montelukast: mean, 16.2% (SD, 11.0) vs 10.0% (SD, 12.2) [p < 0.001]. Conclusions: In adult asthmatics with EIB, montelukast may have a more favorable effect on the oxygen pulse, thus suggesting improved gas exchange during exercise. (CHEST 2004; 126:1154 –1160)

Background: The clinical benefit of combining long-acting β 2 -agonists with inhaled corticosteroids rather than doubling the dose of corticosteroid has been well-documented. However, there are concerns that this might result in a masking of underlying airway inflammation. Objective: The aim of this study was to test the hypothesis that the addition of the long-acting β 2 -agonist salmeterol (SALM) to a low dose of the inhaled corticosteroid fluticasone propionate (FP) has a steroid-sparing effect and does not result in a worsening of bronchial inflammation compared to doubling the dose of inhaled corticosteroid. Methods: Fifty-six asthmatic subjects, previously not well-controlled on inhaled corticosteroids, were randomized to receive 3 months of treatment with inhaled FP 500 μg twice a day (FP 1000) or FP 200 μg twice a day plus SALM 50 μg twice a day (FP 400 + SALM). Fluticasone propionate 200 μg twice a day served as the control (FP400). Bronchial mucosal biopsy specimens, bronchial washings (BW), and bronchoalveolar lavage were obtained before and after treatment. The primary end points for the study were submucosal mast cell and eosinophil counts. Results: There was a significant improvement in FEV 1 in the FP400 + SALM group compared to both the FP400 and FP1000 groups. This was accompanied by a significant improvement in peak expiratory flow in the FP400 + SALM group in both the morning and evening compared to the FP1000 group. There were no significant between treatment differences in the change in the number of submucosal mast cells or eosinophils. However, in the FP400 + SALM group there was a significant decrease in submucosal mast cells after 12 weeks of treatment. The addition of SALM to FP was not associated with any increases in airway inflammation in the biopsy specimens, bronchoalveolar lavage, or bronchial washings. Conclusion: These findings confirm that addition of SALM to FP has clinical benefits but does not mask or exacerbate airway inflammation and suggest that long-acting β 2 -adrenoceptor agonists might influence mast cell numbers. (J Allergy Clin Immunol 2003;112:72-8.)

Anti-leukotriene therapy represents a new principle in asthma treatment. As elite athletes can have asthma, this double-blind, placebo-controlled, randomised cross-over study investigated the effect of 10 mg oral montelukast, a specific and potent cysteinyl leukotriene receptor antagonist, on physiological responses to submaximal and maximal aerobic exercise at -15 degrees C in 14 non-asthmatic highly trained endurance male athletes (maximal oxygen uptake [VO2 max] > 70 ml x kg(-1) x min(-1)). Heart rate, capillary blood lactate, minute ventilation with tidal volume and breathing frequency, respiratory exchange ratio and oxygen uptake were measured during the warm-up run of 10 min at 50%, runs of 10 min at 90% and 5 min at 80% VO2max, and a timed run to exhaustion. Spirometry was performed at baseline, at four hours after tablet ingestion, after warm-up and exercise at 80% VO2max, and in the post exercise period. Compared to placebo, montelukast did not increase baseline FEV1, have a beneficial effect on physiological performance variables, or increase the mean (SD) running time to exhaustion (montelukast: 332.3 [45.8] s, placebo: 340.1 [53.3] s, P = 0.22). These findings do not suggest the need for disallowing the use of this drug by asthmatic athletes.

Background: Asthma-like symptoms, methacholine hyperresponsiveness, use of inhaled steroids, airway inflammation, and increased tenascin expression in the reticular basement membrane have been reported in competitive cross-country skiers. Objective: To investigate the effect of inhaled budesonide, 400 μg twice daily, on indices of airway inflammation in ‘ski asthma’, defined as asthma-like symptoms within the previous year and bronchial hyperresponsiveness to methacholine. Methods: A randomised double-blind placebo-controlled parallel-group bronchial biopsy and bronchoalveolar lavage (BAL) study of 25 (19 male) competitive cross-country skiers (mean age 18 (16–20) years for a mean (range) treatment period of 22 (10–32) weeks over the competitive season. Results: No changes were seen regarding cellular inflammation in the bronchial mucosa or tenascin expression. In the BAL fluid, both groups had a significant decrease in activated T-suppressor (CD8) lymphocytes and an increase in macrophages, with no differences across the groups. Within the budesonide group, there was a decrease in IL2 receptor-activated T-helper lymphocytes and an improvement in FEV1. Asthma-like symptoms were unchanged in 17 (68%) skiers. Methacholine provocation test was negative in 15 subjects, and remained positive in 5 subjects in each group. The improvement in bronchial responsiveness occurred in both groups and was not accompanied by a decrease in cellular inflammation. Conclusions: We were unable to show any clear beneficial effect of budesonide in ‘ski asthma’. As changes in training intensity probably accounted for the spontaneous improvement in bronchial responsiveness, more attention should be directed at reducing environmental stress to the airways than at attempting pharmacological modulation of induced inflammatory changes.

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 Helseundersøkelsen i Nord-Trøndelag (Health Survey in North-Trøndelag; 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, p0.001). ENO was significantly elevated in atopic versus nonatopic suspected asthmatics (11.7 ppb and 5.6 ppb respectively, p0.001). 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.

Asthma-like symptoms, methacholine hyperresponsiveness, and use of asthma medication are prevalent in elite cross-country skiers. We quantitated mucosal inflammatory cell infiltration and tenascin expression in the subepithelial basement membrane in endobronchial biopsy specimens of the proximal airways from 40 elite, competitive skiers (mean: 17.5; range: 16 to 20 yr) without a diagnosis of asthma, in 12 subjects with mild asthma, and in 12 healthy controls, through immunohistochemistry and indirect immunofluorescence, respectively. All of the subjects were nonsmokers. T-lymphocyte, macrophage, and eosinophil counts were, respectively, greater by 43-fold (p0.001), 26-fold (p0.001), and twofold (p0.001) in skiers, and by 70-fold (p0.001), 63-fold (p0.001), and eightfold (p0.001) in asthmatic subjects than in controls. In skiers, neutrophil counts were more than twofold greater than in asthmatic subjects, and mast cell counts were not significantly different than in controls. Tenascin expression (as measured through the thickness of the tenascin-specific immunoreactivity band in the basement membrane) was increased in skiers (median: 6.7 microm; interquartile range [IQR]: 5.3 to 8.5 microm, p0.001) and asthmatic subjects (mean: 8.8 microm; IQR: 7.2 to 10.8 microm, p0. 001) compared with controls (mean: 0.8 microm; IQR: 0 to 3.1 microm) and did not correlate with inflammatory cell counts. Inflammatory changes were present irrespective of asthmalike symptoms, hyperresponsiveness, or atopy. Prolonged repeated exposure of the airways to inadequately conditioned air may induce inflammation and remodeling in competitive skiers.

Exhaled nitric oxide is a potential marker of lower airway inflammation. Allergic rhinitis is associated with asthma and bronchial hyperresponsiveness. To determine whether or not nasal and exhaled NO concentrations are increased in allergic rhinitis and to assess the relation between hyperresponsiveness and exhaled NO, 46 rhinitic and 12 control subjects, all nonasthmatic nonsmokers without upper respiratory tract infection, were randomly selected from a large-scale epidemiological survey in Central Norway. All were investigated with flow-volume spirometry, methacholine provocation test, allergy testing and measurement of nasal and exhaled NO concentration in the nonpollen season. Eighteen rhinitic subjects completed an identical follow-up investigation during the following pollen season. Exhaled NO was significantly elevated in allergic rhinitis in the nonpollen season, especially in perennially sensitized subjects, as compared with controls (p=0.01), and increased further in the pollen season (p=0.04), mainly due to a two-fold increase in those with seasonal sensitization. Nasal NO was not significantly different from controls in the nonpollen season and did not increase significantly in the pollen season. Exhaled NO was increased in hyperresponsive subjects, and decreased significantly after methacholine-induced bronchoconstriction, suggesting that NO production occurs in the peripheral airways. In allergic rhinitis, an increase in exhaled nitric oxide on allergen exposure, particularly in hyperresponsive subjects, may be suggestive of airway inflammation and an increased risk for developing asthma.

Asthma-like symptoms and bronchial hyper-responsiveness (BHR) to methacholine are prevalent in competitive cross-country skiers. Whether these symptoms (ski asthma) in these athletes are caused by asthma remains uncertain. Bronchial responsiveness to adenosine 5'-monophosphate (AMP) and nitric oxide (NO) concentration in exhaled air, both indirect markers of asthmatic airway inflammation, were investigated in two non-smoking study populations of skiers and asthmatics. Of 18 skiers with ski asthma, 15 non-steroid and 14 steroid-treated asthmatics, BHR to AMP was present in five (28%), six (40%) and 10 (71%) subjects respectively. Although the groups were not significantly different in responsiveness to methacholine, responsiveness to AMP increased in order of magnitude from ski asthma < non-steroid-treated < steroid-treated asthma. Exhaled NO in 44 (nine with ski asthma) skiers was not significantly different from 82 healthy non-atopic controls [median [interquartile range (IQR)] 6.5 (4.1-9.9) vs. 5.2 (4.2-6.5) ppb]. Exhaled NO in 29 subjects with mild intermittent asthma was three-fold greater [median (IQR) 19.2 (5.1-25.6) ppb, P < 0.01] than in skiers. Exhaled NO was two- and four-fold greater in atopic than non-atopic subjects in the skier (P < 0.001) and asthmatic (P < 0.01) groups, respectively, and was correlated to methacholine responsiveness in atopic asthmatics (n = 22, rho = 0.55, P < 0.01). Exhaled NO was not elevated in ski asthma and may be more useful as a marker of atopic status than inflammation in the lower airway in skiers. Few skiers were hyper-responsive to AMP, indicating that pre-activated mucosal mast cells are not a predominant feature in ski asthma.