Cough and Airway Responses to Direct and Indirect Challenges: An Integrative Review

Individuals with classic asthma can present with wheezing, dyspnea, chest tightness, and/or cough. Notably, cough can be the main or only symptom of asthma, termed cough variant asthma. Although there are numerous guidelines for asthma, the diagnosis and management of cough in asthma remain challenging because of its complex physiology. By definition, cough variant asthma excludes individuals with normal airway sensitivity to methacholine (MCh). However, many individuals with chronic cough who are being evaluated for possible cough variant asthma have normal airway sensitivity, yet cough during MCh challenge test (termed COUGH). Despite normal airway sensitivity, individuals with COUGH develop small airway obstruction, dynamic hyperinflation, and gas trapping. The clinical importance of COUGH remains to be determined, but it may be a distinct airway disease phenotype. Previous studies examining pathophysiological differences between classic asthma, cough variant asthma, and COUGH have concluded that differences may lie in individuals’ sensitivity to MCh and the degree of bronchodilation and bronchoprotection obtained from deep inspirations. These observations were made exclusively using MCh challenges; however, indirect inhalation challenges (eg, mannitol, hypertonic saline, and eucapneic voluntary hyperventilation) have greater specificity for asthma and may reveal additional pathophysiological distinctions between classic asthma, cough variant asthma, and COUGH. This review highlights opportunities to gain insight into the related airway phenotypes of classic asthma, cough variant asthma, and COUGH by examining impulse oscillometry measurements and the degree of bronchodilation and bronchoprotection from deep inspirations using indirect inhalation challenges, including eucapneic voluntary hyperventilation, hypertonic saline, and mannitol.