Respiratory health of elite athletes – preventing airway injury: a critical review

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

Decreased TNF-α synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging

Immunity declines during aging, however the mechanisms involved in this decline are not known. In this study, we show that cutaneous delayed type hypersensitivity (DTH) responses to recall antigens are significantly decreased in older individuals. However, this is not related to CC chemokine receptor 4, cutaneous lymphocyte-associated antigen, or CD11a expression by CD4+ T cells or their physical capacity for migration. Instead, there is defective activation of dermal blood vessels in older subject that results from decreased TNF-α secretion by macrophages. This prevents memory T cell entry into the skin after antigen challenge. However, isolated cutaneous macrophages from these subjects can be induced to secrete TNF-α after stimulation with Toll-like receptor (TLR) 1/2 or TLR 4 ligands in vitro, indicating that the defect is reversible. The decreased conditioning of tissue microenvironments by macrophage-derived cytokines may therefore lead to defective immunosurveillance by memory T cells. This may be a predisposing factor for the development of malignancy and infection in the skin during aging

Drug Repurposing: A Systematic Approach to Evaluate Candidate Oral Neuroprotective Interventions for Secondary Progressive Multiple Sclerosis

Objective: To develop and implement an evidence based framework to select, from drugs already licenced, candidate oral neuroprotective drugs to be tested in secondary progressive multiple sclerosis. Design: Systematic review of clinical studies of oral putative neuroprotective therapies in MS and four other neurodegenerative diseases with shared pathological features, followed by systematic review and meta-analyses of the in vivo experimental data for those interventions. We presented summary data to an international multi-disciplinary committee, which assessed each drug in turn using pre-specified criteria including consideration of mechanism of action. Results: We identified a short list of fifty-two candidate interventions. After review of all clinical and pre-clinical evidence we identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil) as lead candidates for clinical evaluation. Conclusions: We demonstrate a standardised and systematic approach to candidate identification for drug rescue and repurposing trials that can be applied widely to neurodegenerative disorders

Airway hyperresponsiveness to methacholine, adenosine 5-monophosphate, mannitol, eucapnic voluntary hyperpnoea and field exercise challenge in elite cross-country skiers

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 (FENO), spirometry and bronchial challenge in random order with methacholine, AMP and mannitol were consecutively performed on three study days in the autumn. Specific 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 field 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, five and three skiers were hyperresponsive to methacholine, AMP and mannitol, respectively. Methacholine hyperresponsiveness was more prevalent in subjects without asthma-like symptoms. The FENO was not significantly 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

Bronchoalveolar Lavage Fluid IFN-γ+ Th17 Cells and Regulatory T Cells in Pulmonary Sarcoidosis

In sarcoidosis, increased Th17 cell fractions have been reported in bronchoalveolar lavage fluid, and elevated numbers of Th17 cells producing IFN-γ have 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-γ was investigated. The fractions of FoxP3+ CD4+ T cells and Th17 cells were both lower in sarcoidosis compared to controls (P=0.017 and P=0.011, resp.). The proportion of Th17 cells positive for IFN-γ was greater in sarcoidosis than controls (median 72.4% versus 31%, P=0.0005) and increased with radiologic stage (N=23, rho=0.45, and P=0.03). IFN-γ+ Th17 cells were highly correlated with Th1 cells (N=23, rho=0.64, and P=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-γ could be a consequence of a Th1-polarized cytokine milieu. Our results indicate a possible immune cell imbalance in sarcoidosis

Hyperpnea-Induced Bronchoconstriction and Urinary CC16 Levels in 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

Rhinosinusitis without nasal polyps is associated with poorer health-related quality of life in COPD

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