Defining and Treating a New Pediatric Asthma Endotype: Depression-related Asthma Mediated by the Cholinergic Pathway

It is well accepted that asthma is not a single uniform disease, but rather many different disease sub-entities with different etiologies and pathophysiologies. The term "endotype" was coined to delineate distinct subtypes of asthma; an "endotype" specifically is as "a subtype of a condition, which is defined by a distinct functional or pathophysiological mechanism". The division of asthma into endotypes is critical to the development of targeted immunomodulators and other specific treatment modalities to more effectively treat the diverse asthmatics encountered in clinical practice.

There is a clear association between depression and asthma, with evidence suggesting that depression leads to increased development of asthma rather than the reverse. If, as suggested, depression truly mediates a subset of asthma, this depression-related asthma "endotype" has not been well characterized to date. A promising theory of the pathophysiological mechanism of depression-related asthma is that of autonomic nervous system dysregulation associated with depression leading to airway compromise (Miller and Wood, 2003). Specifically, depression is associated with excess parasympathetic (cholinergic) activation, and cholinergic activation can mediate bronchoconstriction through the action of acetylcholine on the muscarinic receptors on bronchial smooth muscle. It has been demonstrated that during emotional stimuli, depressed children with asthma have increased parasympathetic activation, which associates with increased airway resistance. In contrast, when experiencing these same emotional stimuli, non-depressed children with asthma have increased sympathetic activation.

The investigators anticipate that depressed child asthmatics have cholinergically-mediated bronchoconstriction as a major mediator of their disease activity. Based upon studies of depressed asthmatic children showing increased parasympathetic/cholinergic reactivity in response to laboratory based emotional stimuli, along with a recent study showing that depressed asthmatic adults have decreased bronchodilatory response to beta-agonists, the investigators hypothesize that asthmatic children with higher depressive indices will have more bronchodilatory response on spirometry following treatment with a short-acting inhaled anticholinergic, and less additional bronchodilation with an inhaled beta-agonist, compared to children with lower depressive indices. The investigators will set out to demonstrate if during an episode of bronchoconstriction, depressed child asthmatics will achieve more bronchodilation from a short-acting inhaled anticholinergic than will non-depressed child asthmatics.

The investigators next predict that with excess cholinergic activation as a cause of bronchoconstriction in depressed pediatric asthmatics, there will be less atopic sensitization and Th2-mediated inflammation driving the airway disease in this subset of asthmatics. The investigators hypothesize that, compared to non-depressed child asthmatics, depressed pediatric asthmatics during an episode of bronchoconstriction will show less evidence of airway inflammation as measured by fractional exhaled nitric oxide (FeNO) and peripheral blood eosinophilia, and will have lower rates of atopic sensitization measured by skin prick testing to environmental allergens and/or elevated total serum immunoglobulin E (IgE). In addition, the investigators will assess patient-identified asthma triggers, which are anticipated to be different in the depressed asthmatic group, with increased identification of emotions and cold weather as triggers, and less identification of allergens as triggers.