Chronic cough is a burdensome health problem for patients and diagnostic and treatment challenge for the managing physicians. While cough in asthma is usually brought under control by treatment as outlined in the GINA guidelines, the treatment of UACS and GER as triggers of cough, occurring separately or concomitantly, has not been well standardized. Moreover, in both of these conditions cough can be the sole presenting symptom [26, 27]. CysLTRAs have been approved for additional treatment of asthma and their effect of cough variant asthma has also been explored [16, 18, 19, 28]. Nevertheless, the effectiveness of montelukast and other CysLTRAs has not been investigated in patients with other most frequent CC triggers. Cysteinyl-leukotrienes are pivotal inflammatory mediators which exert their biological effects through interaction with their receptors and are known to mediate plenty of pathological processes including submucosal edema, airway smooth muscle cell proliferation and contraction, mucus production, recruitment and activation of inflammatory cells, mainly eosinophils . Several studies indicate elevated levels of Cys-LTs in induced sputum in different conditions causing chronic cough [30, 31]. Our results indicate an effect of the CysLTRA montelukast on different markers of inflammation in the heterogeneous group of 14 consecutive patients with CC referred to our tertiary clinic.
ECP as a marker of eosinophil activation showed a decrease resulting from the treatment, which can possibly indicate that although the absolute eosinophil count is not out of the limits, eosinophil priming is still present in patients with UACS, some of them with underlying allergic rhinitis and atopy.
Lactoferrin is a multifunctional protein that among other things is present in the secondary granules of neutrophil granulocytes. Our results showed significant reduction of the lactoferrin levels which might be interpreted to be due to the ability of leukotrienes to stimulate lactoferrin release from neutrophils . Hence, their blockage will prevent them from exerting this effect.
Myeloperoxidase is most abundantly expressed in neutrophils and its major role is to aid in microbial killing and facilitate neutrophilic inflammation. We observed that MPO values rose after treatment contrary to common sense expectations. Several studies have attempted to elucidate the interplay between MPO and leukotrienes [33, 34]. In the light of these the increase in MPO can be explained with the role of MPO in inactivation of leukotrienes. Montelukast as a Cys-LT1R blocker only affects the mechanism of their action not the amounts of CysLTs. As a consequence of the receptor blockage unutilized leukotrienes could pile up and a feedback increase of MPO would be needed to inactivate them. This is an interesting interrelation that to our knowledge has not been described so far.
As opposed to the systemic biomarkers of inflammation, montelukast did not affect the outcomes of the study related to the lower airways, EBT and lung function tests. EBT is an airway inflammatory marker which reflects the thermal rise due to inflammation mainly in the intrathoracic airways. The initial values of EBT and the lung function tests were fairly uniform and did not change significantly after treatment, suggesting that our patient population was rather homogeneous and free from lower airway involvement. Indeed, only one patient had a positive methacholine test in the moderate range. Additionally, he did not present with any other symptoms characteristic for asthmatic state.
Two week therapy with montelukast selectively decreased the cough reflex sensitivity to capsaicin with high statistical significance, and while a decrease was outlined also for citric acid, it was not significant. Allegedly, montelukast lowers the inflammatory load making the cough receptors less prone to activation. The significant decrease of the cough threshold sensitivity to capsaicin could be interpreted as a much more specific effect of montelukast on the inflammatory substances implicated in CC such as histamine, bradykinin, prostaglandins and substance P than the non-specific mechanical and acidic irritants [28, 35].
None of our patients had typical GER symptoms alone. It may be speculated that altered state of the tissues of laryngeal and pharyngeal region in UACS may enhance the tussigenic effects of GER supporting the notion of pathological cough reflex hypersensitivity .
In our study we made use of a real-life design to test the potential of a well-known therapeutic agent with good safety profile to help patients with CC. It can only be viewed as preliminary proof-of-concept to be further elaborated by blinded controlled trials. We realize that our pilot study has limitations, mostly related to its sample size and lack of “gold standard” procedures for diagnostic confirmation. The starting point of the approach we assumed was that in real life physicians rarely have the time and resources to carry out all investigations to confirm or to rule out the separate options. We thought of montelukast as a safe means to try out in CC patients without firm signs of undisputed pathology like asthma, UACS, GERD or other organic causes. If negative within the time span used in this study, this strategy should have been substituted by further diagnostic/therapeutic attempts. It was an attempt to confirm an initial hypothesis for local and systemic involvement of cysteinyl- leukotrienes in different configurations of CC. As montelukast is applied through the oral route and has systemic anti-inflammatory effects, it may have advantages over routinely prescribed antitussive drugs without such activity. If the leading bothersome symptom of cough is suppressed in the treated patients, the further elucidation and management of the condition should continue along the same line basically pointing to UACS alone or with superimposed features of GER. Thus montelukast could be a valuable therapeutic alternative with proven safety profile and overall cost-effectiveness. A different study design is needed to assess the optimal duration of montelukast treatment and the sustainability of its therapeutic effect.