Psychological Stress, Lung Function and Exacerbation Risk in COPD: Is an Increase of Cholinergic Tone a Possible Link?

ABSTRACT

Summary at a glance: On the hypothesis that psychological distress might interfere with airway reactivity in patients suffering of mild to moderate COPD through a cholinergic-mediated-bronchial reflex.

KEYWORDS:

• Airway hyperreactivity
• anticholinergics
• COPD
• increased cholinergic tone
• stress

To the editor

We read with interest the article of Maters et al. (1) showing the high frequency of psychological distress (anxiety and/or depression) in patients suffering from chronic obstructive pulmonary disease (COPD). Although they did not find any difference in COPD severity between patients with or without a need of psychological care, identifying this subgroup may be clinically relevant as negative consequences were reported on respiratory function, symptoms, exacerbation risk, quality of life, treatment adherence and even survival (2). The results of this study are well described and discussed by a psychological point of view. However, we wish to suggest some possible mechanisms to explain how anxiety/depression could interfere with bronchial homeostasis in patients suffering from mild to moderate COPD, starting from results in asthma.

Possible relationship between psychological distress and asthma through an increased parasympathetic tone

We have previously shown that about 63% of asthmatic subjects reported the usual appearance of at least one non-respiratory symptom (n-RS) before an asthma attack (3) and these were significantly more frequent in moderate to severe asthma than in intermittent to persistent mild asthma. Near half of the patients reported less than 3 hours between the appearance of n-RSs and the onset of an asthma attack. Newton et al. (4) showed that some n-RS (e.g. irritability, anxiety, tension and sleep impairment) are associated with the loss of asthma control also in children. Behavioural symptoms such as anxiety and, to a lesser extent, depression, represented the most common n-RSs in our study (3). This finding confirms the possible role of anxiety disorders in the development and triggering of an asthma attack. Studies have shown that psychological stress may enhance bronchial hyperreactivity through several mechanisms, such as mast cell activation and mediator release, inflammation and imbalance of the autonomic system (5,6). Both in vitro and clinical studies established a significant relationship between psycho-social stress and stimulation of the cholinergic system (7,8) and even unpleasant images (e.g. bloody films) or other visual stimulations are able to increase airway resistance in asthmatic subjects (9) via a faster vagal-mediated onset response (after 1–2 minutes following the stimulus).

It is likely that some symptoms induced by cholinergic hyperactivity/hyperactivation, such as those determined by psychological stress, could be presented together with parasympathetic-associated RSs, as those elicited by airway narrowing themselves. Indirectly, the results of our previous studies confirmed the assumption that cholinergic pathway is a determinant broncho-constrictor, at least in a group of asthmatic patients. We have hypothesized that, in some individuals, this condition might play a predominant role in determining airway obstruction, compared with other well-known factors such as allergens/air pollutants, infections, exercise etc. (a definite “asthma phenotype”?) (10). The anxiety/stress-induced vagal hyperactivity in asthmatics constitutes the basis of important considerations from a therapeutic point of view such as the use of anti-cholinergic drugs (11).

The role of parasympathetic nervous system in patients suffering from COPD

Parasympathetic activity appears to be the major reversible component of airway obstruction in COPD (12–14). In the lungs, acetylcholine released from parasympathetic nerves provides the dominant control over airway smooth muscle tone. Muscarinic receptors found on glands, airway smooth muscle, and nerves control airway tone and mucus secretion. Parasympathetic nerves act as the efferent arm in vagal reflexes to various chemical and physical stimuli. Acetylcholine may also contribute to airway remodelling by acting at muscarinic receptors to increase proliferation of both fibroblasts and smooth muscle cell (15,16) and recent data suggest that muscarinic receptor antagonists have anti remodelling effect (17).

Possible relationship between psychological distress and COPD through an increased degree of parasympathetic tone

Identifying COPD subjects with an increased basal cholinergic tone and/or with vagal fluctuations induced by anxiety and stress could be of interest as it may be the rationale for a targeted therapeutic approach (i.e. the anticholinergic agents as first option). Some authors suggest the use of resting heart rate and pupillometry (18,19) for this purpose. Recently, Zannin et al. (20) compared the effect of oxygen and methacholine inhalation, neck suction, slow deep breathing, on airway tone assessed by multiple frequency forced oscillation technique (FOT). This multiple approach by using the FOT, very sensitive to changes in airway caliber and not altering respiratory pattern, represents an intriguing tool for further studies exploring the relationships between psychological distress and cholinergic tone in mild to moderate COPD. As in the case of increased cholinergic tone (i.e COPD with psychological needs) this approach can lead to a more phenotypic-oriented use of inhaled muscarinic receptor antagonists to be explored in clinical trials.

Financial disclosure / conflict of interest

All authors declare that they have no conflict of interest and that the study has been carried out without any financial support.

Authorship

All authors contributed equally in the writing and revision of the manuscript.