Work-related dysphonia in subjects with occupational asthma is associated with neutrophilic airway inflammation.

Vertigan et al.1 recently highlighted the comorbid association between asthma and laryngeal dysfunction, although the pathophysiological mechanisms underlying this complex association remain largely uncertain.2 It is widely acknowledged that laryngeal dysfunction, including vocal cord dysfunction, can be triggered by external stimuli, such exercise, strong odors and irritant exposures.2 In this regard, workplace exposure to respiratory irritants has been reported as an important cause of the “work-related irritable larynx syndrome”.3 We sought to assess the clinical characteristics and airway inflammatory processes associated with work-related dysphonia in a cohort of subjects with sensitizer-induced occupational asthma (OA) ascertained by a positive specific inhalation challenge (SIC). This retrospective study included 341 subjects identified among the multicenter European network for the PHenotyping of OCcupational ASthma (E-PHOCAS)4 who met the following eligibility criteria: (1) complete information on variables addressing asthma severity and control while exposed at work; (2) available information on self-reported dysphonia (i.e. hoarseness or loss of voice) at work; and (3) assessment of induced sputum cell counts at the time of the SIC procedure. Forty-nine (14.4%) subjects experienced dysphonia while exposed at their workplace. The baseline clinical features and sputum cell counts of the subjects with and without dysphonia as well as the univariate associations with dysphonia are detailed in Table 1. A multivariable logistic regression analysis was conducted in order to identify the clinical and inflammatory characteristics that were associated with work-related dysphonia. The independent variables incorporated into these regression models included gender; sinusitis; high-level treatment at work (i.e., Global Initiative for Asthma treatment step four-fifths); poor asthma control at work (i.e., need for an inhaled short-acting β2-agonist once or more a day); OA caused by a low- versus a high-molecular-weight agent; as well as eosinophil and neutrophil sputum cell counts (expressed as % of total nonsquamous cells; Table 2).The multivariate logistic regression analysis revealed that female gender (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.06–3.92; p = 0.031) and a higher sputum neutrophil count (OR for each 5%-increase in neutrophil count, 1.09; 95% CI, 1.01–1.18; p = 0.025) were significantly associated with a higher likelihood of work-related dysphonia (Table 2). There was an association of borderline significance between dysphonia and high-level treatment (OR, 1.97; 95% CI, 0.97–3.95; p = 0.057). Dysphonia showed a negative association with increased sputum eosinophil counts (OR, 0.41; 95% CI, 0.19–0.83; p = 0.017). Dysphonia is a main symptom of worked-associated irritable larynx syndrome (WILS) which has been defined as neuronal sensitization by a workplace trigger bringing about laryngeal dysfunction.3 As recently described, neutrophil inflammation can regulate sensory neuron function, especially in chronic pain.5 To our knowledge, our study is the first to describe a relationship between neutrophilic inflammation and work related dysphonia. We acknowledge the limitations inherent to the retrospective cross-sectional design of this study. The presence of dysphonia was not objectively documented through direct visualization of inappropriate laryngeal movement. In addition, dysphonia was not assessed during the SIC procedure implying that it was not possible to ascertain that the agent inducing the positive SIC response was also the cause of dysphonia at work. Despite their inherent limitations, our findings suggest that airway neutrophilic inflammation could be involved in the development of work-related laryngeal dysfunction. This study highlights the need for further prospective studies using validated questionnaires, laryngoscopy, and induced sputum analysis in order to explore the association between laryngeal dysfunction and neutrophilic airway inflammation. All E-PHOCAS investigators contributed to the conception and design of the study. All authors contributed to the acquisition, analysis and interpretation of the data. They provided input into the drafting of the manuscript, critical feedback, and final approval for submission of the manuscript for publication. NM is the guarantor of the final content of the manuscript. Olivier Vandenplas was supported in part by a grant from the Fondation Mont-Godinne. Frédéric de Blay and Nicolas Migueres were supported by a grant from the Association d'Aide aux Insuffisants Respiratoires d'Alsace (ADIRAL). The authors have no conflicts of interest to declare. Association d'Aide aux Insuffisants Respiratoires d'Alsace (ADIRAL); Fondation Mont-Godinne Research data are not shared. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.