Indirect bronchial hyper‐responsiveness: the coming of age of a specific group of bronchial challenges

Bronchial hyper-responsiveness (BHR) can be defined as an increase in the ease and the degree of airflow limitation in response to bronchoconstrictor stimuli in vivo. Although BHR is not entirely specific for asthma, it is one of its major pathophysiological features [1, 2]. Airway narrowing in asthma is the ultimate result of an interaction between multiple mechanisms, not necessarily and uniquely related to airway inflammation. BHR and noninvasive markers of airway inflammation, such as sputum eosinophilia or exhaled nitric oxide (eNO), are only loosely related to each other. This implies that no inferences about BHR can be made from measurements of airway inflammation and vice versa. It is questionable whether good correlations between the outcome of indirect challenges and markers of inflammation are important and/or desirable: bronchial challenge tests provide integrated information about multiple pathophysiological pathways within the airways, information that is not picked up by the non-invasive surrogate markers of airway inflammation, which provide rather specific information on selected inflammatory pathways [3–5]! The phenomenon of BHR is sometimes referred to as ‘nonspecific’, i.e. that most patients with active asthma will react to these stimuli. The stimuli, used to reveal it, however, act by highly specific mechanisms. As multiple pathophysiological pathways are involved, it is therefore no surprise that the results of the different challenge tests are only weakly correlated and not mutually interchangeable. Bronchoconstrictor stimuli may be classified into ‘direct’ and ‘indirect’, according to the main mechanism through which they induce airflow limitation (Table 1). Combinations of mechanisms are possible. Direct stimuli induce airflow limitation through direct action on the effector cells, involved in the airflow limitation. These comprise in the first place airway smooth muscle cells, but bronchial vascular endothelial cells and/or mucus-producing cells may also be involved. Indirect stimuli, on the other hand, act on intermediary cells such as inflammatory cells, bronchial epithelial cells and/or neuronal cells; the pro-inflammatory mediators and/or neurotransmitters, liberated by these cells will then interact with the effector cells to cause airflow limitation (Fig. 1) [6, 7]. The role of epithelial cells as active players in mediating airflow limitation following indirect stimuli is being increasingly recognized; more specifically, human bronchial epithelial cells have been shown to carry adenosine A1 [8], adenosine A2B [9], tachykinin (TK) NK1 [10], and bradykinin B2 receptors [11]. The increased clinical and research interest in indirect challenges is being reflected by the generation of a consensus document on ‘indirect airway challenges’ by an ad hoc European Respiratory Society (ERS) taskforce. This taskforce proposed the following practical working definition of an indirect challenge: ‘Indirect challenges act by causing the release of endogenous mediators that cause the airway smooth muscle to contract, with or without effect in inducing microvascular leakage. Because the responses to these challenges are modified or even completely inhibited by inhaled steroids, the airway response to these challenges may be a closer reflection of active airway inflammation’ [12]. This review will focus on the recent evolutions and the emerging new concepts concerning the clinical and research applications of indirect stimuli in asthma.