Illuminating Airway Nerve Structure and Function in Chronic Cough.

Airway nerves regulate vital airway functions including bronchoconstriction, cough, and control of respiration. Dysregulation of airway nerves underlies the development and manifestations of airway diseases such as chronic cough, where sensitization of neural pathways leads to excessive cough triggering. Nerves are heterogeneous in both expression and function. Recent advances in confocal imaging and in targeted genetic manipulation of airway nerves have expanded our ability to visualize neural organization, study neuro-immune interactions, and selectively modulate nerve activation. As a result, we have an unprecedented ability to quantitatively assess neural remodeling and its role in the development of airway disease. This review highlights our existing understanding of neural heterogeneity and how advances in methodology have illuminated airway nerve morphology and function in health and disease.

Is there cardiac autonomic dysfunction in children and adolescents with exercise-induced bronchospasm?

BACKGROUND: The pulmonary impairment in patients with bronchoconstriction induced by eucapnic voluntary hyperpnea(EVH) goes beyond the respiratory system, also impairing autonomic nervous modulation. This study aimed to evaluate the behavior of cardiac autonomic modulation in young asthmatics with and without EIB after the EVH test. RESEARCH DESIGN AND METHODS: A cross-sectional study design using 54 asthmatics(51.9% female), aged between 10 and 19 years, investigated with the EVH test. Forced expiratory volume in one second(FEV1) was measured at 5, 10, 15, and 30 min after EVH. Heart rate variability(HRV) measures of time were assessed pre and 30 min-post EVH. The diagnosis of Exercise-Induced bronchoconstriction with underlying clinical asthma(EIBA) was confirmed by a fall in FEV1 ≥10% compared to baseline. RESULTS: Thirty(55.5%) asthmatics had EIBA. Subjects with EIBA have reduced mean of the R-R intervals in relation to baseline until 15 minutes after EVH. Individuals without EIBA had increased parasympathetic activity compared to baseline(rMSSD) from 5 min after EVH(p < 0.05). This parasympathetic activity increase in relation to baseline was seen in individuals with EIBA after 25 minutes (rMSSD = 49.9 ± 5.3 vs 63.5 ± 7.2, p < 0.05). CONCLUSION: Young asthmatics with EIBA present a delay in the increase of the parasympathetic component after EVH when compared to asthmatics without EIBA.

Activation of epithelial and inflammatory pathways in adolescent elite athletes exposed to intense exercise and air pollution.

RATIONALE: Participation in high-intensity exercise in early life might act as stressor to the airway barrier. OBJECTIVES: To investigate the effect of intense exercise and associated exposure to air pollution on the airway barrier in adolescent elite athletes compared with healthy controls and to study exercise-induced bronchoconstriction (EIB) in this population. METHODS: Early-career elite athletes attending 'Flemish-Elite-Sports-Schools' (12-18 years) of 4 different sport disciplines (n=90) and control subjects (n=25) were recruited. Presence of EIB was tested by the eucapnic voluntary hyperventilation (EVH) test. Markers at mRNA and protein level; RNA-sequencing; carbon load in airway macrophages were studied on induced sputum samples. RESULTS: 444 genes were differentially expressed in sputum from athletes compared with controls, which were related to inflammation and epithelial cell damage and sputum samples of athletes contained significantly more carbon loaded airway macrophages compared with controls (24%, 95% CI 20% to 36%, p<0.0004). Athletes had significantly higher substance P (13.3 pg/mL, 95% CI 2.0 to 19.2) and calprotectin (1237 ng/mL, 95% CI 531 to 2490) levels as well as IL-6, IL-8 and TNF-α mRNA levels compared with controls (p<0.05). The incidence of EIB in athletes was 9%. The maximal fall in forced expiratory volume in 1 s (%) after EVH test in athletes was significantly associated with prior PM10 and PM2.5 exposure. CONCLUSION: Early-career elite athletes showed increased markers of air pollution exposure, epithelial damage and airway inflammation compared with controls. Acute exposure to increased air pollution PM10 levels was linked to increased airway hyper-reactivity. TRIAL REGISTRATION NUMBER: NCT03587675.

Effect of exercise-induced bronchoconstriction on the configuration of the maximal expiratory flow-volume curve in adults with asthma.

We determined the effect of exercise-induced bronchoconstriction (EIB) on the shape of the maximal expiratory flow-volume (MEFV) curve in asthmatic adults. The slope-ratio index (SR) was used to quantitate the shape of the MEFV curve. We hypothesized that EIB would be accompanied by increases in SR and thus increased curvilinearity of the MEFV curve. Adult asthmatic ( n  = 10) and non-asthmatic control subjects ( n  = 9) cycled for 6-8 min at 85% of peak power. Following exercise, subjects remained on the ergometer and performed a maximal forced exhalation every 2 min for a total 20 min. In each MEFV curve, the slope-ratio index (SR) was calculated in 1% volume increments beginning at peak expiratory flow (PEF) and ending at 20% of forced vital capacity (FVC). Baseline spirometry was lower in asthmatics compared to control subjects (FEV1 % predicted, 89.1 ± 14.3 vs. 96.5 ± 12.2% [SD] in asthma vs. control; p  < 0.05). In asthmatic subjects, post-exercise FEV1 decreased by 29.9 ± 13.2% from baseline (3.48 ± 0.74 and 2.24 ± 0.59 [SD] L for baseline and post-exercise nadir; p  < 0.001). At baseline and at all timepoints after exercise, average SR between 80 and 20% of FVC was larger in asthmatic than control subjects (1.48 ± 0.02 vs. 1.23 ± 0.02 [SD] for asthma vs. control; p < 0.005). This averaged SR did not change after exercise in either subject group. In contrast, post-exercise SR between PEF and 75% of FVC was increased from baseline in subjects with asthma, suggesting that airway caliber heterogeneity increases with EIB. These findings suggest that the SR-index might provide useful information on the physiology of acute airway narrowing that complements traditional spirometric measures.

Insulin increases sensory nerve density and reflex bronchoconstriction in obese mice.

Obesity-induced asthma responds poorly to all current pharmacological interventions, including steroids, suggesting that classic, eosinophilic inflammation is not a mechanism. Since insulin resistance and hyperinsulinemia are common in obese individuals and associated with increased risk of asthma, we used diet-induced obese mice to study how insulin induces airway hyperreactivity. Inhaled 5-HT or methacholine induced dose-dependent bronchoconstriction that was significantly potentiated in obese mice. Cutting the vagus nerves eliminated bronchoconstriction in both obese and nonobese animals, indicating that it was mediated by a neural reflex. There was significantly greater density of airway sensory nerves in obese compared with nonobese mice. Deleting insulin receptors on sensory nerves prevented the increase in sensory nerve density and prevented airway hyperreactivity in obese mice with hyperinsulinemia. Our data demonstrate that high levels of insulin drives obesity-induced airway hyperreactivity by increasing sensory innervation of the airways. Therefore, pharmacological interventions to control metabolic syndrome and limit reflex-mediated bronchoconstriction may be a more effective approach to reduce asthma exacerbations in obese and patients with asthma.

Ventilation Rates Achieved in Eucapnic Voluntary Hyperpnea Challenge and Exercise-Induced Bronchoconstriction Diagnosis in Young Patients with Asthma.

PURPOSE: Exercise-induced bronchoconstriction (EIB) affects approximately 50% of young asthma patients, impairing their participation in sports and physical activities. Eucapnic voluntary hyperpnea (EVH) is an approved surrogate challenge to exercise for objective EIB diagnosis, but the required minimum target hyperventilation rates remain unexplored in this population. This study aimed to evaluate the association between the achieved ventilation rates (VRs) during a challenge and EIB-compatible response (EIB-cr) in young asthma patients. METHODS: This cross-sectional study included 72 asthma patients aged 10-20 years. Forced expiratory volume in the first second (FEV1) was measured before and 5, 15, and 30 min after the EVH. The target VR was set at 21 times the individual's baseline FEV1. A decrease of > 10% in FEV1 after the challenge was considered an EIB-cr. The challenge was repeated after 48-72 h in those without an EIB-cr. RESULTS: Thirty-six individuals had an EIB-cr at initial evaluation. The median VRs achieved was not different between individuals with and without an EIB-cr (19.8 versus 17.9; p = 0.619). The proportion of individuals with an EIB-cr was nor different comparing those who achieved (12/25) or not (24/47) the calculated target VRs (p = 0.804). At the repeated EVH challenge an EIB-cr was observed in 14/36 individuals with a negative response in the first evaluation, with no differences in achieved VRs between the two tests (p = 0.463). CONCLUSION: Irrespective of the achieved VR, an EIB-compatible response after an EVH challenge must be considered relevant for clinical and therapeutic judgment and negative tests should be repeated.

The interest of rehabilitation of respiratory disorders in athletes: Myth or reality?

BACKGROUND: Healthy trained athletes generally have an "overbuilt" respiratory system in order to face the huge ventilation and gas-exchange demand imposed by strenuous exercise. Athletes frequently complain of respiratory symptoms regardless of whether they have a diagnosed respiratory disease, therefore evoking a kind of respiratory limitation during exercise. Some respiratory pathologies athletes present are closely linked to exercise and include asthma, exercise-induced bronchoconstriction (EIB) or exercise-induced laryngeal obstruction. Management of asthma and EIB are mainly based on pharmacological treatments. However, many athletes still complain of respiratory symptoms despite optimal pharmacological treatments, which highlights the need for non-pharmacological approaches including breathing retraining, inspiratory muscle training and/or laryngeal exercise performed under the guidance of a physiotherapist in this specific population. OBJECTIVES: With this literature overview, we aimed to report evidence supporting the interest of rehabilitation for athletes with respiratory disorders and discuss whether inspiratory muscle training programs can improve performance in healthy athletes. METHODS: We searched MEDLINE and Cochrane databases for trials, reviews and meta-analyses assessing respiratory rehabilitation and muscle training programs in athletes by using the MesH terms "athletes", "asthma", "dyspnea", "rehabilitation" and "education" published from January 2010 to March 2020. The selection of articles was based on the author's expertise to elaborate this review of the literature. RESULTS: Major findings suggest that breathing retraining may help asthmatic athletes better control their respiratory symptoms and that inspiratory muscle training may improve respiratory symptoms of exercise-induced laryngeal obstruction in athletes. Improvement of performance by respiratory muscle training still remains controversial. CONCLUSIONS: Respiratory rehabilitation could be of interest in the specific population of athletes but should be further evaluated to improve the level of evidence of such strategies.

Impact of obesity and ovariectomy on respiratory function in female mice.

Obesity and the corresponding variations in female sex hormones are associated with severe lung disease. We determined the potential effects of obesity and sex hormones in female mice by investigating changes in lung structure and respiratory function in an obesity model induced by postnatal overnutrition. Obese female mice exhibited pronounced weight gain, abdominal fat accumulation and collagen type I deposition in the airways. However, neither elastic tissue nor estrogen receptors-α/-ß were affected in obese female mice after ovariectomy or sham-operated mice. Bronchoconstriction in response to methacholine challenge in obese sham-operated mice was higher than in the obese group after ovariectomy. Our results suggest that the coexistence of obesity and ovariectomy impacted on respiratory system and airway resistance (attenuates bronchoconstriction after methacholine), on collagen I deposition and on airway estrogen ß-receptors of mice.

Airway diameter at different transpulmonary pressures in ex vivo sheep lungs: implications for deep inspiration-induced bronchodilation and bronchoprotection.

Deep inspiration (DI)-induced bronchodilation is the first line of defense against bronchoconstriction in healthy subjects. A hallmark of asthma is the lack of this beneficial effect of DI. The mechanism underlying the bronchodilatory effect of DI is not clear. Understanding the mechanism will help us unravel the mystery of asthma pathophysiology. It has been postulated that straining airway smooth muscle (ASM) during a DI could lead to bronchodilation and bronchoprotection. The hypothesis is currently under debate, and a central question is whether ASM is sufficiently stretched during a DI for its contractility to be compromised. Besides bronchoconstriction, another contributor to lung resistance is airway heterogeneity. The present study examines changes in airway diameter and heterogeneity at different lung volumes. Freshly explanted sheep lungs were used in plethysmographic measurements of lung resistance and elastance at different lung volumes, whereas the airway dimensions were measured by computed tomography (CT). The change in airway diameter informed by CT measurements was applied to isolated airway ring preparations to determine the strain-induced loss of ASM contractility. We found that changing the transpulmonary pressure from 5 to 30 cmH2O led to a 51% increase in lung volume, accompanied by a 46% increase in the airway diameter with no change in airway heterogeneity. When comparable airway strains measured in the whole lung were applied to isolated airway rings in either relaxed or contracted state, a significant loss of ASM contractility was observed, suggesting that DI-induced bronchodilation and bronchoprotection can result from strain-induced loss of ASM contractility.

Identifying bronchoconstriction from the ratio of diaphragm EMG to tidal volume.

BACKGROUND: A fall of ≥ 20 % in forced expiratory volume in the first second (FEV1) with a cumulative dose of histamine ≤ 7.8 µmol is considered to indicate bronchial hyperactivity, but no method exists for patients who cannot perform spirometry properly. Here we hypothesized that increases in respiratory central output measured by chest wall electromyography of the diaphragm (EMGdi-c) expressed as a function of tidal volume (EMGdi-c/VT) would have discriminative power to detect a 'positive' challenge test. METHODS: In a physiological study EMGdi was recorded from esophageal electrode (EMGdi-e) in 16 asthma patients and 16 healthy subjects during a histamine challenge test. In a second study, EMGdi from chest wall surface electrodes (EMGdi-c) was measured during a histamine challenge in 44 asthma patients and 51 healthy subjects. VT was recorded from a digital flowmeter during both studies. RESULTS: With histamine challenge test the change in EMGdi-e/VT in patients with asthma was significantly higher than that in healthy subjects (104.2 % ± 48.6 % vs 0.03 % ± 17.1 %, p < 0.001). Similarly there was a significant difference in the change of EMGdi-c/VT between patients with asthma and healthy subjects (90.5 % ± 75.5 % vs 2.4 % ± 21.7 %, p < 0.001). At the optimal cut-off point (29 % increase in EMGdi-c/VT), the area under the ROC curve (AUC) for detection of a positive test was 0.91 (p < 0.001) with sensitivity 86 % and specificity 92 %. CONCLUSIONS: We conclude that EMGdi-c/VT may be used as an alternative for the assessment of bronchial hypersensitivity and airway reversibility to differentiate patients with asthma from healthy subjects.

Asthma, atopy, and exercise: Sex differences in exercise-induced bronchoconstriction.

Asthma is a chronic inflammatory lung disease affecting approximately 7.7% of the US population. Sex differences in the prevalence, incidence, and severity of asthma have been widely described throughout the lifespan, showing higher rates in boys than girls before puberty, but a reversed pattern in adults. Asthma is often associated with atopy, i.e. the tendency to develop allergic diseases, and can be worsened by environmental stimuli and/or exercise. While not exclusive to patients with asthma, exercise-induced bronchoconstriction (EIB) is a common complication of athletes and individuals who exercise regularly. Currently, there is limited research on sex differences in EIB and its relationship with atopy and asthma in men and women. In this minireview, we summarize the available literature on this topic. Overall, the collective knowledge supports the notion that physiological changes triggered during exercise affect males and females differently, suggesting an interaction among sex, exercise, sex hormones, and atopic status in the course of EIB pathophysiology. Understanding these differences is important to provide personalized management plans to men and women who exercise regularly and suffer from underlying asthma and/or atopy.

RSV infection potentiates TRPV1-mediated calcium transport in bronchial epithelium of asthmatic children.

The transient receptor potential vanilloid 1 (TRPV1) channel is expressed in human bronchial epithelium (HBE), where it transduces Ca2+ in response to airborne irritants. TRPV1 activation results in bronchoconstriction, cough, and mucus production, and may therefore contribute to the pathophysiology of obstructive airway disease. Since children with asthma face the greatest risk of developing virus-induced airway obstruction, we hypothesized that changes in TRPV1 expression, localization, and function in the airway epithelium may play a role in bronchiolitis and asthma in childhood. We sought to measure TRPV1 protein expression, localization, and function in HBE cells from children with versus without asthma, both at baseline and after RSV infection. We determined changes in TRPV1 protein expression, subcellular localization, and function both at baseline and after RSV infection in primary HBE cells from normal children and children with asthma. Basal TRPV1 protein expression was higher in HBE from children with versus without asthma and primarily localized to plasma membranes (PMs). During RSV infection, TRPV1 protein increased more in the PM of asthmatic HBE as compared with nonasthmatic cells. TRPV1-mediated increase in intracellular Ca2+ was greater in RSV-infected asthmatic cells, but this increase was attenuated when extracellular Ca2+ was removed. Nerve growth factor (NGF) recapitulated the effect of RSV on TRPV1 activation in HBE cells. Our data suggest that children with asthma have intrinsically hyperreactive airways due in part to higher TRPV1-mediated Ca2+ influx across epithelial membranes, and this abnormality is further exacerbated by NGF overexpression during RSV infection driving additional Ca2+ from intracellular stores.

The novel TRPA1 antagonist BI01305834 inhibits ovalbumin-induced bronchoconstriction in guinea pigs.

BACKGROUND: Asthma is a chronic respiratory disease in which the nervous system plays a central role. Sensory nerve activation, amongst others via Transient Receptor Potential Ankyrin 1 (TRPA1) channels, contributes to asthma characteristics including cough, bronchoconstriction, mucus secretion, airway hyperresponsiveness (AHR) and inflammation. In the current study, we evaluated the efficacy of the novel TRPA1 antagonist BI01305834 against AHR and inflammation in guinea-pig models of asthma. METHODS: First, a pilot study was performed in a guinea-pig model of allergic asthma to find the optimal dose of BI01305834. Next, the effect of BI01305834 on (1) AHR to inhaled histamine after the early and late asthmatic reaction (EAR and LAR), (2) magnitude of EAR and LAR and (3) airway inflammation was assessed. Precision-cut lung slices and trachea strips were used to investigate the bronchoprotective and bronchodilating-effect of BI01305834. Statistical evaluation of differences of in vivo data was performed using a Mann-Whitney U test or One-way nonparametric Kruskal-Wallis ANOVA, for ex vivo data One- or Two-way ANOVA was used, all with Dunnett's post-hoc test where appropriate. RESULTS: A dose of 1 mg/kg BI01305834 was selected based on AHR and exposure data in blood samples from the pilot study. In the subsequent study, 1 mg/kg BI01305834 inhibited AHR after the EAR, and the development of EAR and LAR elicited by ovalbumin in ovalbumin-sensitized guinea pigs. BI01305834 did not inhibit allergen-induced total and differential cells in the lavage fluid and interleukin-13 gene expression in lung homogenates. Furthermore, BI01305834 was able to inhibit allergen and histamine-induced airway narrowing in guinea-pig lung slices, without affecting histamine release, and reverse allergen-induced bronchoconstriction in guinea-pig trachea strips. CONCLUSIONS: TRPA1 inhibition protects against AHR and the EAR and LAR in vivo and allergen and histamine-induced airway narrowing ex vivo, and reverses allergen-induced bronchoconstriction independently of inflammation. This effect was partially dependent upon histamine, suggesting a neuronal and possible non-neuronal role for TRPA1 in allergen-induced bronchoconstriction.

The sensitivity and specificity of the forced oscillation technique in the diagnosis of bronchoconstriction in children.

OBJECTIVE: The forced oscillation technique (FOT) is a useful diagnostic respiratory system for children. However, the final value of the FOT in the diagnosis of bronchoconstriction is still open. The aim of the study was to evaluate the sensitivity and specificity of the FOT vs. body plethysmography tests in the measure of bronchoconstriction in asthmatic children. MATERIALS AND METHODS: A total of 102 children aged 2 to 6 years diagnosed with early-onset asthma and 52 healthy controls were included in this prospective, randomized study. All asthmatic patients and healthy controls underwent a basic FOT as one measurement, according to the recommendation of the Resmon Pro FOT. Then, the reversibility test was performed 20 min after the administration of 200 mg salbutamol using the FOT and body plethysmography in all patients. RESULTS: The mean basic Rrs, Xrs and sRaw in asthmatic patients were, respectively, 11.13 ± 1.28 kPa sL-1, -4.6 ± 1.18 kPa sL-1 and 1.72 ± 0.58 kPa s. Similar parameters were significantly better in the control group (p < 0.05). A total of 73 (71.6%) asthmatic patients had a positive test using the FOT according to Calogero. In 4 (7.7%) patients in the control group, a positive test was obtained. In body plethysmography, similar results were reached, with a positive test in 76 (74.5%) study patients and 5 (9.6%) control patients. CONCLUSIONS: A bronchial reversibility test with the use of the FOT is useful for the diagnosis of bronchial asthma, especially with the use of an Rrs parameter, such as the body plethysmography test.

Extracellular adenosine 5'-triphosphate in pulmonary disorders.

Adenosine 5'-triphosphate (ATP) is found in every cell of the human body where it plays a critical role in cellular energetics and metabolism. ATP is released from cells under physiologic and pathophysiologic condition; extracellular ATP is rapidly degraded to adenosine 5'-diphosphate (ADP) and adenosine by ecto-enzymes (mainly, CD39 and CD73). Before its degradation, ATP acts as an autocrine and paracrine agent exerting its effects on targeted cells by activating cell surface receptors named P2 Purinergic receptors. The latter are expressed by different cell types in the lungs, the activation of which is involved in multiple pulmonary disorders. This succinct review summarizes the role of ATP in inflammation processes associated with these disorders including bronchoconstriction, cough, mechanical ventilation-induced lung injury and idiopathic pulmonary fibrosis. All of these disorders still constitute unmet clinical needs. Therefore, the various ATP-signaling pathways in pulmonary inflammation constitute attractive targets for novel drug-candidates that would improve the management of patients with multiple pulmonary diseases.

Prevalence of exercise-induced bronchoconstriction and laryngeal obstruction in adolescent athletes.

OBJECTIVES: To study the prevalence of exercise-induced bronchoconstriction (EIB) and exercise-induced laryngeal obstruction (EILO) in adolescent athletes. METHODS: All adolescents (n = 549) attending first year at a sports high school in 2016 and 2017, were invited to answer a questionnaire on respiratory symptoms. The 367 responding participants were divided into two groups based on whether they reported exercise-induced dyspnea (dyspnea group) or not (nondyspnea group). Randomly selected participants in each group were invited to undergo two standardized exercise tests, an EIB test and a continuous laryngoscopy exercise (CLE) test, to investigate EILO. RESULTS: In total, 98 participants completed an EIB test, 75 of whom also completed a CLE test. Positive EIB tests: eight of 41 in the dyspnea group and 16 of 57 in the nondyspnea group. Positive CLE tests: 5 of 34 in the dyspnea group and three of 41 in the nondyspnea group. The estimated prevalence of EIB was 23.1% (95% confidence interval [CI]: 14.5-33.8) and of EILO 8.1% (95% CI: 2.5-18.5) in the whole study population. No differences in prevalence of EIB or EILO were found between the dyspnea and the nondyspnea groups. CONCLUSION: EIB was highly prevalent in this cohort of adolescent athletes. EILO was less prevalent, but represents an important differential diagnosis to EIB. Self-reported exercise-induced dyspnea is a weak indicator for both EIB and EILO and standardized testing should be provided.

[Extracellular molecules controlling the contraction of airway smooth muscle and their potential contribution to bronchial hyperresponsiveness]. / La contractilité du muscle lisse des voies respiratoires est régulée par de nombreuses molécules extracellulaires qui pourraient contribuer à l'hyperréactivité bronchique.

INTRODUCTION: A significant portion of symptoms in some lung diseases results from an excessive constriction of airways due to the contraction of smooth muscle and bronchial hyperresponsiveness. A better understanding of the extracellular molecules that control smooth muscle contractility is necessary to identify the underlying causes of the problem. STATE OF KNOWLEDGE: Almost a hundred molecules, some of which newly identified, influence the contractility of airway smooth muscle. While some molecules activate the contraction, others activate the relaxation, thus acting directly as bronchoconstrictors and bronchodilators, respectively. Other molecules do not affect contraction directly but rather influence it indirectly by modifying the effect of bronchoconstrictors and bronchodilators. These are called bronchomodulators. Some of these bronchomodulators increase the contractile effect of bronchoconstrictors and could thus contribute to bronchial hyperresponsiveness. PROSPECTS: Considering the high number of molecules potentially involved, as well as the level of functional overlap between some of them, identifying the extracellular molecules responsible for excessive airway constriction in a patient is a major contemporary challenge.

Prevalence and risk factors for wheeze, decreased forced expiratory volume in 1 s and bronchoconstriction in young children living in Havana, Cuba: a population-based cohort study.

OBJECTIVES: Asthma has not been extensively studied in low-income and middle-income countries, where risk factors and access to treatment may differ from more affluent countries. We aimed to identify the prevalence of asthma and local risk factors in Havana, Cuba. SETTING: Four municipalities in Havana, Cuba. PARTICIPANTS: A population-based cohort study design of young children living in Havana, Cuba. Children were recruited from primary care centres at age 12-15 months. PRIMARY AND SECONDARY OUTCOME MEASURES: Data on wheeze in the past 12 months, asthma treatment and environmental exposures collected regularly until the age of 6 years, when forced expiratory volume in 1 s (FEV1) and reversibility to aerosolised salbutamol were also measured. RESULTS: 1106 children provided data at the age of 6 years old. The prevalence of wheeze in the previous 12 months was 422 (38%), and 294 (33%) of the study population had bronchodilatation of 12% or more in FEV1 after administration of inhaled salbutamol. In the previous 12 months, 182 (16%) of the children had received inhaled corticosteroids, 416 (38%) salbutamol inhalers and 283 (26%) a course of systemic steroids.Wheeze in the first year and a family history of asthma were both positively associated with bronchodilatation to inhaled salbutamol (1.94%; 95% CI 0.81 to 3.08 and 1.85%; CI 0.14 to 3.57, respectively), while paracetamol use in the first year was associated with wheeze at 6 years (OR 1.64, 95% CI 1.14 to 2.35). There were large differences in FEV1, bronchodilatation and risk of wheeze across different geographical areas. CONCLUSIONS: Asthma is common in young children living in Havana, and the high prevalence of systemic steroids administrated is likely to reflect the underuse of regular inhaled corticosteroids. If replicated in other comparable low-income and middle-income countries, this represents an important global public health issue.

Exploring the role of nerves in asthma; insights from the study of cough.

Cough in asthma predicts disease severity, prognosis, and is a common and troublesome symptom. Cough is the archetypal airway neuronal reflex, yet little is understood about the underlying neuronal mechanisms. It is generally assumed that symptoms arise because of airway hyper-responsiveness and/or airway inflammation, but despite using inhaled corticosteroids and bronchodilators targeting these pathologies, a large proportion of patients have persistent coughing. This review focuses on the prevalence and impact of cough in asthma and explores data from pre-clinical and clinical studies which have explored neuronal mechanisms of cough and asthma. We present evidence to suggest patients with asthma have evidence of neuronal dysfunction, which is further heightened and exaggerated by both bronchoconstriction and airway eosinophilia. Identifying patients with excessive coughing with asthma may represent a neuro-phenotype and hence developing treatment for this symptom is important for reducing the burden of disease on patients' lives and currently represents a major unmet clinical need.

Cysteinyl Leukotriene Synthesis via Phospholipase A2 Group IV Mediates Exercise-induced Bronchoconstriction and Airway Remodeling.

It is well known that the prevalence of asthma is higher in athletes, including Olympic athletes, than in the general population. In this study, we analyzed the mechanism of exercise-induced bronchoconstriction by using animal models of athlete asthma. Mice were made to exercise on a treadmill for a total duration of 1 week, 3 weeks, or 5 weeks. We analyzed airway responsiveness, BAL fluid, lung homogenates, and tissue histology for each period. In mice that were treated (i.e., the treatment model), treatments were administered from the fourth to the fifth week. We also collected induced sputum from human athletes with asthma and analyzed the supernatants. Airway responsiveness to methacholine was enhanced with repeated exercise stimulation, although the cell composition in BAL fluid did not change. Exercise induced hypertrophy of airway smooth muscle and subepithelial collagen deposition. Cysteinyl-leukotriene (Cys-LT) levels were significantly increased with exercise duration. Montelukast treatment significantly reduced airway hyperresponsiveness (AHR) and airway remodeling. Expression of PLA2G4 (phospholipase A2 group IV) and leukotriene C4 synthase in the airway epithelium was upregulated in the exercise model, and inhibition of PLA2 ameliorated AHR and airway remodeling, with associated lower levels of Cys-LTs. The levels of Cys-LTs in sputum from athletes did not differ between those with and without sputum eosinophilia. These data suggest that AHR and airway remodeling were caused by repeated and strenuous exercise. Cys-LTs from the airway epithelium, but not inflammatory cells, may play an important role in this mouse model.