American Journal of Respiratory and Critical Care Medicine

The inflammatory basis of chronic cough has been slow to gain acceptance, particularly when the most common diagnostic and therapeutic approach emphasizes a search for the extrapulmonary diseases associated with chronic cough (1). The article by Birring and coworkers (2) brings us back to the airway, focusing on inflammation, and raises the possibility that neurogenic inflammation may be important in chronic cough. An early clue to the role of inflammation in chronic cough came from the recognition of eosinophilic bronchitis as a cause of chronic cough (3). While eosinophilic bronchitis is a common cause of cough in some populations (where gastroesophageal reflux is rare) (4, 5), it explains only a minority of cases of chronic cough in white patients (6, 7).

Cough, after all, is a reflex, and activation of the sensory arm of the cough reflex is crucial to our understanding of chronic cough (1). Consistent with this, Birring and coworkers (2) show that in chronic cough there are increased levels of mediators with protussive effects. What is important, however, about these observations are the following: one, the marked elevation of the mast cell–derived mediators histamine and prostaglandin D2, suggesting a role for mast cell activation in chronic cough; two, the mediator levels were elevated in the airways, indicating that the airway is an important site for cough reflex activation; three, the protussive mediators were elevated in all types of chronic cough, suggesting that activation of airway mast cells may be a common pathway leading to cough reflex activation in chronic cough, whatever the associated disease.

Mast cell numbers are elevated in idiopathic chronic cough (8) and in cough with eosinophilic bronchitis (3, 9). In addition, mast cells in bronchoalveolar lavage of patients with chronic cough are hyperresponsive to the neuropeptides neurokinin A and calcitonin gene–related peptide (10). These neuropeptides induced significantly more histamine release from mast cells in chronic cough, and like the results of Birring and coworkers (2), this effect was seen in chronic cough associated with asthma as well as cough associated with postnasal drip syndrome, gastroesophageal reflux, and idiopathic chronic cough. This again demonstrates that activation of airway mast cells is a feature of all types of chronic cough, even those associated with extrapulmonary diseases.

What is the link between sensory nerves and mast cells? The neuropeptides neurokinin A and calcitonin gene–related peptide are colocalized in unmyelinated C fibers of airway sensory nerves. In the airway epithelium, these nerves participate in the afferent limb of the cough reflex and are believed fundamental to the sensory hyperresponsiveness that characterizes chronic cough. In chronic cough with eosinophilic bronchitis, mast cells also accumulate in the airway epithelium (9), where C fibers are also located. This raises the possibility of a link between mast cells and sensory nerves in the airway epithelium in chronic cough. Studies of itchy skin show that the mast cell is closely linked to neural activation with the potential for bidirectional communication to occur. Mast cells are structurally associated with C fibers of sensory nerves in the skin (11). Sensory neuropeptides induce mast cell activation, and mast cells release cytokines that promote nerve growth, such as nerve growth factor (12). This could explain the increased density of substance P and calcitonin gene–related peptide–containing nerves in chronic cough (13). If cough represents an itch in the airways, then the recent observation that epithelial proteinase-activated receptor-2 can be activated by mast cell tryptase (14) raises intriguing possibilities for both mechanisms and treatment.

The highest levels of prostaglandin D2 and histamine occurred when chronic cough was associated with eosinophilic airway inflammation (2). This is consistent with emerging concepts of a role for eosinophils in mast cell activation (15). Basic proteins, such as eosinophil major basic protein, released from eosinophils activate mast cells via G (i3α), leading to mast cell degranulation.

Is there neurogenic airway inflammation in chronic cough? The activation of peripheral sensory neurons to release neuropeptides, which then act on mast cells, other inflammatory cells, and blood vessels to produce vasodilation, plasma extravasation, and sensory hyperreactivity, represents neurogenic inflammation (16). The neuronal activation can occur locally, via an axonal reflex, or via a dorsal root reflex. This reflex activation would plausibly link the extrapulmonary causes of cough with the current observations of airway mast cell activation in chronic cough. Some, but not all, of the features of neurogenic inflammation are known to occur in chronic cough. Thus, airway mast cell activation may be a manifestation of neurogenic inflammation in chronic cough, but confirmatory studies are needed.

The observations of elevated histamine and mast cell mediators in the airways of patients with chronic cough (2) should prompt a re-evaluation of treatment approaches in cough. Is the efficacy of antihistamines in chronic cough due to a direct effect in the airway? Could these agents be useful in cough beyond the recommended indication of postnasal drip syndrome? (5). Is the limited success of acid suppression in cough with gastroesophageal reflux due to failure to treat the associated airway sensory hyperreactivity? These questions are best addressed by carefully conducted, randomized, controlled trials, which should be performed to test the hypothesis that airway mast cell activation is an important mechanism in chronic cough.

The results of Birring and coworkers (2) stretch our notions of airway disease. Wheeze in asthma can usefully be thought of as an airway twitch, and with cough, it's an airway itch.

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