New Insights Into Pathogenesis of Exercise-induced Bronchoconstriction

Teal S. Hallstrand

Disclosures

Curr Opin Allergy Clin Immunol. 2012;12(1):42-48. 

In This Article

Abstract and Introduction

Abstract

Purpose of review Exercise-induced bronchoconstriction (EIB) refers to acute airflow obstruction that is triggered by a period of physical exertion. Here we review recent findings about the epidemiology of EIB, immunopathology leading to EIB, and the latest understanding of the pathogenesis of EIB.
Recent findings Longitudinal studies demonstrated that airway hyper-responsiveness to exercise or cold air at an early age are among the strongest predictors of persistent asthma. Patients that are susceptible to EIB have epithelial disruption and increased levels of inflammatory eicosanoids such as cysteinyl leukotrienes (CysLT)s. The leukocytes implicated in production of eicosanoids in the airways include both a unique mast cell population as well as eosinophils. A secreted phospholipase A2 (sPLA2) enzyme that serves as a regulator of CysLT formation is present in increased quantities in asthma. Transglutaminase 2 (TGM2) is expressed at increased levels in asthma and serves as a regulator of secreted phospholipase A2 group X (sPLA2-X). Further, sPLA2-X acts on target cells such as eosinophils to initiate cellular eicosanoid synthesis.
Summary Recent studies have advanced our understanding of EIB as a syndrome that is caused by the increased production of inflammatory eicosanoids. The airway epithelium may be an important regulator of the production of inflammatory eicosanoids by leukocytes.

Introduction

Exercise-induced bronchoconstriction (EIB) is a syndrome in which a brief period of exercise or increase in ventilation triggers airflow obstruction that lasts 30–90 min in the absence of treatment. Although EIB occurs predominantly among patients with established asthma, there is evidence from cross-sectional studies that only a portion of patients with asthma have EIB when tested with a specific challenge test. For example, in Algeria the prevalence of EIB was 47% among children with established asthma.[1] These data are consistent with the largest prior study that established a prevalence of EIB of 46% out of 164 asthmatic children.[2] Also consistent with prior studies,[3] the Algerian study also found that 13.9% of children without a history of asthma had EIB.[1] In accordance with smaller studies showing that EIB identifies children at risk for chronic asthma, two recent large cohort studies have extended these findings. Parent-reported exercise-induced wheeze and a history of atopy were the strongest predictors of asthma over at least 6 years of longitudinal follow-up among 628 children who were evaluated prior to the age of five.[4] In a longitudinal birth cohort that included follow-up data on 849 children, airway hyper-responsiveness (AHR) to cold dry air hyperpnea was associated with a increased odds ratio (OR) of 4.5 of asthma at 22 years of age.[5]

Exercise-induced bronchoconstriction is a prototypical manifestation of indirect AHR similar to the airway response to hypertonic aerosols, eucapnic voluntary hyperpnea (EVH) and adenosine, but is only weakly related to baseline lung function or direct airway responsiveness to histamine or methacholine.[6] However, several recent population-based studies in patients with symptoms of asthma have found that tests of indirect and direct AHR perform similarly to screening tests.[7,8] Among 509 adolescents and adults with signs and symptoms of asthma, the sensitivity of mannitol to identify EIB was 59% and for methacholine was 56%;[7] the prevalence of EIB in the study population was 43.5%. In a population of 99 children with suspected asthma, 21% of whom had EIB, the positive and negative predicted values of mannitol challenge for EIB were 68 and 89%.[8]

The abnormal distribution of alveolar ventilation (Va) and perfusion (Q) that occurs during EIB can lead to arterial hypoxemia during exercise. Images of the airways during EIB obtained by hyperpolarized helium demonstrate areas of closure or near closure of segmental airways of the lungs during EIB.[9] Of interest is a recent comparison of exercise and mannitol-induced bronchoconstriction demonstrating that Va/Q imbalance was more pronounced in EIB than mannitol-induced bronchoconstriction, but there was less hypoxemia because of the residual increase in ventilation after exercise.[10] The danger of bronchoconstriction triggered by exercise was highlighted several years ago by a population-based study[11] that found 61 of 263 sports-related fatalities in young adults were caused by asthma exacerbation.

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