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Marte Rystad Øie,1,2 Anne-Sofie Helvik,1,3 Malcolm Sue-Chu,4,5 Sverre Karmhus Steinsvåg,6,7 Wenche Moe Thorstensen1,2 1Department of Otolaryngology, Head and Neck Surgery, St. Olavs hospital, 7006 Trondheim University Hospital, Trondheim, Norway; 2Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; 3Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway; 4Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; 5Department of Thoracic Medicine, St. Olavs hospital, Trondheim University Hospital, Trondheim, Norway; 6Department of Otolaryngology, Head and Neck Surgery, Sørlandet Hospital, Kristiansand, 4604, Norway; 7Haukeland University Hospital, Bergen, NorwayCorrespondence: Marte Rystad Øie, Department of Otolaryngology, Head and Neck Surgery, St. Olavs hospital, Trondheim University Hospital, 3250 Torgarden, Trondheim, NO-7006, Norway, Tel +47 926 42 329, Email marte.oie@gmail.com; marte.r.oie@ntnu.noPurpose: Sinonasal symptoms are prevalent in COPD, and knowledge of the relationship between these symptoms and clinical markers of COPD is limited. This study explores the associations between the burden of sinonasal symptoms and clinical markers and thresholds recommended for guiding treatment decisions in the GOLD guidelines.Patients and Methods: Sinonasal symptoms were quantified with the rhinological subscale of the Sino-Nasal-Outcome-Test (SNOT-22) in 93 COPD patients characterized by the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) 2012 diagnostic criteria for rhinosinusitis without nasal polyps (RSsNP). Associations between a high burden, defined as a SNOT22_rhinological score of ≥ 11, and the following markers were assessed by adjusted multivariable linear regressions; severity of dyspnea [modified Medical Research Council (mMRC)] and cough [Visual Analogue Scale (VAS)], physical activity [6-minute walking distance (6MWD)], mortality risk (BODE index), and HRQoL [disease-specific COPD Assessment Test (CAT) and St. Georges Respiratory Questionnaire (SGRQ), and physical component summary, Short Form-36 version 2.0 (PCS SF-36v2)]. Odds ratios for the association of a high burden and threshold levels for regular treatment were estimated by adjusted binomial logistic regression models.Results: A high burden was associated with greater severity of dyspnea and cough, lower 6MWD, higher BODE index and poorer HRQoL. The odds ratio of having CAT and SGRQ scores that are above the thresholds recommended for treatment was 5– 7-fold greater in the high burden group.Conclusion: A high burden of sinonasal symptoms is positively associated with the clinical markers of symptom severity and mortality risk and is inversely associated with physical activity and HRQoL in COPD. These findings add further support that the UAD concept also applies to COPD. Enquiry about sinonasal symptoms in COPD patients should be incorporated into the clinical routine.Keywords: united airways disease, chronic nasal symptoms, rhinosinusitis, HRQoL

Background: Olfaction is poorly characterized in COPD. To test the hypothesis that olfaction is reduced in COPD, we assessed olfaction with the “Sniffin’ Sticks” test and a questionnaire addressing olfaction in COPD and a corresponding control group in respect to age and sex. We also explored whether there is an association between COPD, chronic rhinosinusitis without nasal polyps (CRSsNP), and other predefined covariates with olfactory function. Methodology: Olfactory function was assessed by the score for threshold (T), discrimination (D) and identification (I), and the composite TDI score in the “Sniffin’ Sticks” test and by self-reported evaluation of impaired olfaction and of “decreased sense of smell and taste” in the 22-item Sino-Nasal Outcome Test (SNOT-22) in 90 COPD patients and 93 controls. A clinical interview and ENT-examination with nasal endoscopy, skin prick test and spirometry with reversibility were performed. Results: The TDI, D and I scores were significantly lower in the COPD group than in the control group. The T score was not significantly different between the two groups. Hyposmia and anosmia were present in up to 79% of patients with COPD. The prevalence of self-reported impaired olfactory function and for 'decreased sense of smell and taste'; - was more than two-fold greater in the COPD than in the control group. COPD, higher age, male sex and allergy were associated with a lower TDI score, while CRSsNP was not associated with the TDI score. Conclusions: COPD is associated with olfactory dysfunction and the underlying mechanisms for this dysfunction should be elucidated.

Rhinosinusitis without nasal polyps (RSsNP) is prevalent in COPD. Previous studies on its association with health-related quality of life (HRQoL) have limitations, and RSsNP is currently not recognized as a comorbidity. This study investigates HRQoL in COPD including a focus on RSsNP. Generic HRQoL was assessed with the Short Form-36 (SF-36v2) questionnaire and compared between 90 COPD and 93 control subjects and in subgroups with and without RSsNP. The association between RSsNP and COPD versus not and generic HRQoL was assessed by multivariable linear regression with adjustments for age, education, and body mass index (BMI). Disease-specific HRQoL was assessed by Sinonasal outcome test-22 (SNOT-22), St. Georges Respiratory Questionnaire (SGRQ), and COPD Assessment Test (CAT) and compared between COPD with and without RSsNP, and their association to RSsNP was assessed by multivariable linear regression with adjustments for age, BMI, and FEV1% predicted. RSsNP was associated with poorer disease-specific HRQoL, with higher SNOT-22 total score (14.67 points; 95% CI, 7.06–22.28; P < .001) and psychological subscale score (3.24 points; 95% CI, 0.37–6.11; P = .03), SGRQ symptom score (13.08 points; 95% CI, 2.73–23.4; P = .014), and CAT score (4.41 points; 95% CI, 1.15–7.66; P = .009). Generic HRQoL was poorer in COPD patients than in the control subjects. In addition to COPD, concomitant RSsNP was associated with poorer physical functioning, general health, vitality, and physical component summary. RSsNP in COPD is associated with poorer disease-specific HRQoL that is clinically relevant and, as it is amenable for treatment, should be recognized as a comorbidity of COPD.

Background: The effect of pulmonary pathology on peak nasal inspiratory flow (PNIF) remains largely unknown. We investigated an association between a diagnosis of asthma and of lung function on PNIF when adjusted for possible confounders. Further, we investigated the perception of nasal obstruction in asthmatics compared to healthy controls when adjusted for PNIF. Methodology: Eighty-seven asthmatics and 92 non-asthmatic controls underwent PNIF (categorized into groups of high, medium and low), acoustic rhinometry (AR) and spirometry, and we assessed symptoms of nasal obstruction on visual analogue scales (VAS) in three categories. Results: PNIF was significantly associated with asthma and forced expiratory volume in the first second (FEV1) (% predicted). Other factors associated with PNIF were the degree of nasal obstruction measured both subjectively on a VAS and objectively with AR, age and disease status. Asthma patients were 19 times more likely to be in a higher VAS category compared to non-asth- matic controls independent of PNIF group. Conclusion: Special care has to be taken when interpreting PNIF values in patients with asthma or reduced FEV1 (% predicted). The sensation of nasal obstruction in asthmatics is different from controls despite being in the same PNIF group.

The clinical diagnosis of pulmonary sarcoidosis is based on the presence of noncaseating granulomas in an appropriate clinical setting with either bilateral hilar adenopathy and/or parenchymal infiltrates. Lymphocytosis with an increased CD4/CD8 T cell ratio in bronchoalveolar lavage fluid is supportive. We evaluated the diagnostic accuracy of a predictive binary logistic regression model in sarcoidosis based on sex, age, and bronchoalveolar lavage fluid cell profile with and without the inclusion of HLA-DR(+) CD8(+) T cells and natural killer T-cell fractions.A retrospective analysis of differential cell counts and lymphocyte phenotypes by flow cytometry in bronchoalveolar lavage was performed in 183 patients investigated for possible diffuse parenchymal lung disease. A logistic regression model with age, sex, lymphocyte fraction, eosinophils, and CD4/CD8 ratio in bronchoalveolar lavage fluid (basic model) was compared with a final model, which also included fractions of HLA-DR(+) CD8(+) T cells and natural killer T cells. Diagnostic accuracy of the two models was assessed by receiver operating characteristic (ROC) curves.The area under the ROC curve for the basic and final model was 0.898 [95 % confidence interval (CI) 0.852-0.945] and 0.937 (95 % CI 0.902-0.972), respectively, p = 0.008.Assessment of HLA-DR(+) CD8(+) T cell and natural killer T-cell fractions may improve diagnostic accuracy and further strengthen the importance of bronchoalveolar lavage in the diagnostic workup of 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.

A higher prevalence of airway hyperresponsiveness, airway remodeling, and asthma has been identified among athletes who compete and train in environmental conditions of cold dry air and/or high air pollution. Repeated long-duration exposure to cold/dry air at high minute ventilation rates can cause airway damage. Competition or training at venues close to busy roadways, or in indoor ice arenas or chlorinated swimming pools, harbors a risk for acute and chronic airway disorders from high pollutant exposure. This article discusses the effects of these harsh environments on the airways, and summarizes potential mechanisms and prevalence of airway disorders in elite athletes.

BOLGER, C., E. TUFVESSON, M. SUE-CHU, G. DEVEREUX, J. G. AYRES, L. BJERMER, and P. KIPPELEN. Hyperpnea-Induced Bronchoconstriction and Urinary CC16 Levels in Athletes. Med. Sci. Sports Exerc., Vol. 43, No. 7, pp. 1207-1213, 2011. Purpose: Exercise-induced bronchoconstriction (EIB) is a common condition in both individuals with asthma and otherwise healthy elite athletes. Although excessive water loss by peripheral airways during hyperpnea is regarded as the initial trigger for EIB, the cascade of events that follows remains unclear. Our goal was to establish whether transient disruption of the airway epithelial barrier occurs after a short period of hyperpnea of dry air in athletes with EIB. Methods: Urinary concentration of the pneumoprotein Clara cell (CC16) was used as an assumed biomarker of lung epithelial cell damage or dysfunction. Samples were collected at baseline and for 90 min after an 8-min eucapnic voluntary hyperpnea (EVH) test in 50 female individuals (28 athletes and 22 untrained). Results: Nineteen subjects (10 athletes) demonstrated a sustained bronchoconstriction after EVH (mean +/- SE forced expiratory volume in the first second (FEV1) fall from baseline = 23.4% +/- 2.6%). The remaining subjects had a negative challenge result with an FEV1 fall of 5.9% +/- 0.6%. An increase (P 0.05). Conclusions: Urinary levels of CC16 are increased after EVH in all individuals (trained and untrained, with and without EIB) suggestive of dehydration-induced perturbation of the distal respiratory epithelium during episodes of hyperventilation. (Less)

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.

Purpose Protocadherin-15 (PCDH15) is one of the five genes currently identified as being mutated in Usher 1 syndrome and defines Usher syndrome type 1F (USH1F). When PCDH15 was systematically analyzed for mutations in a cohort of USH1 patients, a number of deletions were found. Here we characterize these deletions as to extent, position, and breakpoints. Methods Microsatellite and single nucleotide polymorphism (SNP) analyses, used in a preliminary survey of an Usher cohort of 31 patients, revealed large deletions in three patients. These deletions were further characterized by semiquantitative PCR assays to narrow down the breakpoints. Results The analysis of the three large deletions revealed that all six breakpoints are different. The breakpoint junction was identified in one patient and the four other breakpoints were mapped to 4 kb. There were no specific distinguishing features of the isolated breakpoints. Conclusions A complete screen of PCDH15 should include a search for large deletions. Failure to screen for gross genomic rearrangements is likely to significantly lower the mutation detection rate. A likely explanation for the high rate of such deletions is the unusual gene structure. PCDH15 gene spans nearly 1 Mb for a corresponding open reading frame (ORF) of 7,021 bp. The intron sizes of PCDH15 are up to 150 kb, and the first three exons of the gene cover 0.42 Mb. The genomic structure of any gene should be taken into consideration when designing a mutation screening strategy.

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.)

Guidelines on spontaneous pneumothorax are contradictory as to intervention between needle aspiration (NA) and chest tube drainage (CTD). Studies show poor adherence to guidelines.Three Norwegian hospitals included patients with primary (PSP) and secondary (SSP) spontaneous pneumothorax. Patients underwent NA or CTD as the primary intervention. The main outcome was duration of hospital stay. Secondary outcomes were immediate- and 1-week success rates and complications.127 patients were included, including 48 patients with SSP. 65 patients underwent NA, 63 patients CTD. Median (interquartile range) hospital stay was significantly shorter for NA: 2.4 days (1.2–4.7 days), compared with CTD: 4.6 days (2.3–7.8 days) (pOur study shows shorter hospital stay and higher immediate success rates for NA compared with CTD. Subgroup analyses also show clear benefits for NA for both PSP and SSP.

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.

An increased prevalence of asthma in cross-country skiers has been reported previously. This study was conducted in order to evaluate the prevalence of asthma among young, elite cross-country skiers in Trøndelag, Norway and Jämtland, Sweden. These two regions in central Scandinavia have different climates during the winter season, with a coastal type in Trøndelag while Jämtland is characterized by a colder, drier, inland type of climate. The study population consisted of 171 skiers (118 from Norway, 53 from Sweden). The investigation included an asthma questionnaire, spirometry and methacholine provocation testing. The prevalence of self-reported asthma-related symptoms was 46% in Norway and 51% in Sweden. The prevalence of bronchial hyper-responsiveness (BHR) was significantly different between the two regions. In Norway, 14% of the skiers were hyper-responsive to methacholine compared to 43% in Sweden (P < 0·001). Moreover, the estimated prevalence of clinically diagnosed asthma was 12% in Norway and 42% in Sweden (P < 0·001).The self-reported frequency of respiratory allergy was higher in Sweden (32%) than in Norway (11%). However, on an individual basis, self-reported allergy did not predict occurrence of asthma or BHR. In conclusion, there is a high prevalence of BHR and asthma among young, elite cross-country skiers in central Scandinavia, especially in Sweden. Cross-country skiing may be a risk factor for the development of asthma. Longitudinal studies of cross-country skiers, and studies to acquire further knowledge of the mechanisms involved in the development of asthma are indicated.

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.

The Unified Airways Hypothesis suggests an involvement of the upper airways in asthma. We aimed to evaluate the association between subjective sino-nasal complaints, nasal air flow, and sino-nasal quality of life (QOL) in patients with asthma compared with nonasthmatic subjects.Case-control study.A tertiary referral center.Symptoms, quality of life, and nasal airflow were assessed in 91 asthmatics and 95 nonasthmatic controls with Visual Analog Scale (VAS, 0-100), Sino-Nasal Outcome Test (SNOT-20), and Peak Nasal Inspiratory Flow (PNIF), respectively. Asthma and allergy status were assessed by Asthma Control Questionnaire (ACQ) and skin prick test or specific IgE.Asthmatic patients (men/women, 37/54; mean age, 43.7 years; range, 19-64 years) reported significantly more nasal obstruction (mean VAS, 37 mm; SD = 26, 95% CI, 32-43 vs 9 mm, SD = 11, 95% CI, 7-11, P.001) and lower sino-nasal quality of life (mean SNOT-20, 1.3; SD = 0.8, 95% CI, 1.1-1.5 vs 0.4, SD = 0.5, 95% CI, 0.3-0.5, P.001) than controls (men/women, 42/53; mean age, 43.8 years; range, 20-65 years). PNIF was significantly lower in asthmatic patients than controls (mean PNIF, 84 l/min; SD = 24, 95% CI, 79-89 vs 100 l/min SD = 24, 95% CI, 95-105, P.001).Both allergic and nonallergic asthma were associated with increased sino-nasal symptoms, reduced sino-nasal QOL, and reduced inspiratory nasal air flow compared to controls. This provides further evidence of the clinical importance of the upper airway in the diagnostic and therapeutic management of asthma patients beyond the scope of allergy.

Elite athletes, particularly those engaged in endurance sports and those exposed chronically to airborne pollutants/irritants or allergens, are at increased risk for upper and lower airway dysfunction. Airway epithelial injury may be caused by dehydration and physical stress applied to the airways during severe exercise hyperpnoea and/or by inhalation of noxious agents. This is thought to initiate an inflammatory cascade/repair process that, ultimately, could lead to airway hyperresponsiveness (AHR) and asthma in susceptible athletes. The authors review the evidence relating to prevention or reduction of the risk of AHR/asthma development. Appropriate measures should be implemented when athletes exercise strenuously in an attempt to attenuate the dehydration stress and reduce the exposure to noxious airborne agents. Environmental interventions are the most important. Non-pharmacological strategies can assist, but currently, pharmacological measures have not been demonstrated to be effective. Whether early prevention of airway injury in elite athletes can prevent or reduce progression to AHR/asthma remains to be established.

Airway symptoms and sleeplessness in patients with gastroesophageal reflux disease (GERD) may be of importance. This study validates a new questionnaire dealing with such symptoms.The Reflux, Airway and Sleep Questionnaire (RASQ) is self-administered, asks about 18 symptoms or diagnoses possibly related to GERD answered on a seven-point Likert scale and with a 1-year recall period. There are questions about heartburn/regurgitation, sleeplessness, snoring, pneumonia, and upper airway infections, as well as various bronchial and laryngeal symptoms. The study included 305 patients diagnosed with GERD (n = 65), laryngitis (n = 32), asthma (n = 30), chronic obstructive pulmonary disease (n = 45), acute bronchitis (n = 39), pneumonia (n = 42), or upper airway infection (n = 52) during the last year, and 708 matched healthy controls. Concurrent validity was based on comparisons between patients and controls. Convergent validity for sleeplessness and snoring were tested by comparing the RASQ with the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS). Test-retest reliability was examined in patients with GERD with stable symptoms (n = 29).Response rates were 64% for patients and 55% for controls. Scores for RASQ as a total and all subscales were significantly higher in patients than in controls. Sleeplessness scores correlated significantly to the global PSQI score. Snoring correlated significantly with both the ESS and relevant aspects of the PSQI. Test-retest reliability and Cronbach's alpha were satisfactory, with coefficients ranging between 0.65-0.95 and 0.88-0.92, respectively.The RASQ appears to be well suited for measuring typical reflux symptoms as well as airway symptoms and sleep disturbances.

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.

Injury to the airway epithelium has been proposed as a key susceptibility factor for exercise-induced bronchoconstriction (EIB). Our goals were to establish whether airway epithelial cell injury occurs during EIB in athletes and whether inhalation of warm humid air inhibits this injury. Twenty-one young male athletes (10 with a history of EIB) performed two 8-min exercise tests near maximal aerobic capacity in cold dry (4°C, 37% relative humidity) and warm humid (25°C, 94% relative humidity) air on separate days. Postexercise changes in urinary CC16 were used as a biomarker of airway epithelial cell perturbation and injury. Bronchoconstriction occurred in eight athletes in the cold dry environment and was completely blocked by inhalation of warm humid air [maximal fall in forced expiratory volume in 1 s = 18.1 ± 2.1% (SD) in cold dry air and 1.7 ± 0.8% in warm humid air, P < 0.01]. Exercise caused an increase in urinary excretion of CC16 in all subjects ( P < 0.001), but this rise in CC16 was blunted following inhalation of warm humid air [median CC16 increase pre- to postchallenge = 1.91 and 0.35 ng/μmol in cold dry and warm humid air, respectively, in athletes with EIB ( P = 0.017) and 1.68 and 0.48 ng/μmol in cold dry and warm humid air, respectively, in athletes without EIB ( P = 0.002)]. The results indicate that exercise hyperpnea transiently disrupts the airway epithelium of all athletes (not only in those with EIB) and that inhalation of warm moist air limits airway epithelial cell perturbation and injury.

International audience; Exercise-induced bronchoconstriction (EIB) is exaggerated constriction of the airways usually soon after cessation of exercise. This is most often a response to airway dehydration in the presence of airway inflammation in a person with a responsive bronchial smooth muscle. Severity is related to water content of inspired air and level of ventilation achieved and sustained. Repetitive hyperpnea of dry air during training is associated with airway inflammatory changes and remodeling. A response during exercise that is related to pollution or allergen is considered EIB. Ozone and particulate matter are the most widespread pollutants of concern for the exercising population; chronic exposure can lead to new-onset asthma and EIB. Freshly generated emissions particulate matter less than 100 nm is most harmful. Evidence for acute and long-term effects from exercise while inhaling high levels of ozone and/or particulate matter exists. Much evidence supports a relationship between development of airway disorders and exercise in the chlorinated pool. Swimmers typically do not respond in the pool; however, a large percentage responds to a dry air exercise challenge. Studies support oxidative stress mediated pathology for pollutants and a more severe acute response occurs in the asthmatic. Winter sport athletes and swimmers have a higher prevalence of EIB, asthma and airway remodeling than other athletes and the general population. Because of fossil fuel powered ice resurfacers in ice rinks, ice rink athletes have shown high rates of EIB and asthma. For the athlete training in the urban environment, training during low traffic hours and in low traffic areas is suggested.

Respiratory symptoms cannot be relied on to make a diagnosis of asthma and/or airways hyperresponsiveness (AHR) in elite athletes. For this reason, the diagnosis should be confirmed with bronchial provocation tests. Asthma management in elite athletes should follow established treatment guidelines (eg, Global Initiative for Asthma) and should include education, an individually tailored treatment plan, minimization of aggravating environmental factors, and appropriate drug therapy that must meet the requirements of the World Anti-Doping Agency. Asthma control can usually be achieved with inhaled corticosteroids and inhaled beta(2)-agonists to minimize exercise-induced bronchoconstriction and to treat intermittent symptoms. The rapid development of tachyphylaxis to beta(2)-agonists after regular daily use poses a dilemma for athletes. Long-term intense endurance training, particularly in unfavorable environmental conditions, appears to be associated with an increased risk of developing asthma and AHR in elite athletes. Globally, the prevalence of asthma, exercise-induced bronchoconstriction, and AHR in Olympic athletes reflects the known prevalence of asthma symptoms in each country. The policy of requiring Olympic athletes to demonstrate the presence of asthma, exercise-induced bronchoconstriction, or AHR to be approved to inhale beta(2)-agonists will continue.

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.)

Among asthmatics, exercise-induced wheeze (EIW) is a frequent symptom, and 40-77% of asthmatics demonstrate exercise-induced bronchoconstriction (EIB). In the North-Trøndelag 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 ofor= 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.

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.

Sarcoidosis and hypersensitivity pneumonitis are diffuse parenchymal lung diseases characterized by formation of non-caseating granulomas with a bronchocentric distribution. Analysis of the white blood cell differential profile in bronchoalveolar lavage fluid can be a useful supplement in the diagnostic work-up.Diagnostic markers that can improve the discrimination of sarcoidosis and hypersensitivity pneumonitis are wanted.Bronchoalveolar lavage fluid fractions of CD4+ and CD8+ T cells expressing the activation marker HLA-DR and fractions of natural killer T cells determined by flow cytometry were investigated in sarcoidosis (N=83), hypersensitivity pneumonitis (N=10) and healthy control subjects (N=15).In hypersensitivity pneumonitis, natural killer T cell fractions were over 7-fold greater [median (IQR): 5.5% (3.5-8.1) versus 0.7% (0.5-1.2), p0.0001], and HLA-DR+ fractions of CD8+ lymphocytes were almost two fold greater [median (IQR): 79% (75-82) versus 43% (34-52), p0.0001] than in sarcoidosis. In healthy control subjects, natural killer T cell fractions of leucocytes and HLA-DR+ fractions of CD8+ lymphocytes were lower [median (IQR): 0.3% (0.3-0.6) and 30% (26-34), p=0.02 and p=0.01 compared to sarcoidosis]. The combined use of these two markers seems to discriminate the diseases very well.This study suggests a role for the bronchoalveolar lavage fluid lymphocyte subsets HLA-DR+ CD8+ T cells and natural killer T cells in the diagnostic work up of sarcoidosis and hypersensitivity pneumonitis.

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.