DOI: 10.1002/clt2.12218 LETTER Work‐related dysphonia in subjects with occupational asthma is associated with neutrophilic airway inflammation To the editor, well as eosinophil and neutrophil sputum cell counts (expressed as 1 Vertigan et al. recently highlighted the comorbid association be- % of total nonsquamous cells; Table 2).The multivariate logistic tween asthma and laryngeal dysfunction, although the pathophysio- regression analysis revealed that female gender (odds ratio [OR], logical mechanisms underlying this complex association remain 2.04; 95% confidence interval [CI], 1.06–3.92; p = 0.031) and a largely uncertain.2 It is widely acknowledged that laryngeal higher sputum neutrophil count (OR for each 5%‐increase in dysfunction, including vocal cord dysfunction, can be triggered by neutrophil count, 1.09; 95% CI, 1.01–1.18; p = 0.025) were signif- external stimuli, such exercise, strong odors and irritant exposures.2 icantly associated with a higher likelihood of work‐related In this regard, workplace exposure to respiratory irritants has been dysphonia (Table 2). There was an association of borderline signif- reported as an important cause of the “work‐related irritable larynx icance between dysphonia and high‐level treatment (OR, 1.97; 95% 3 syndrome”. CI, 0.97–3.95; p = 0.057). Dysphonia showed a negative association We sought to assess the clinical characteristics and airway in- with increased sputum eosinophil counts (OR, 0.41; 95% CI, 0.19– flammatory processes associated with work‐related dysphonia in a 0.83; p = 0.017). cohort of subjects with sensitizer‐induced occupational asthma (OA) Dysphonia is a main symptom of worked‐associated irritable ascertained by a positive specific inhalation challenge (SIC). This larynx syndrome (WILS) which has been defined as neuronal sensi- retrospective study included 341 subjects identified among the tization by a workplace trigger bringing about laryngeal dysfunction.3 multicenter European network for the PHenotyping of OCcupational As recently described, neutrophil inflammation can regulate sensory ASthma (E‐PHOCAS)4 who met the following eligibility criteria: (1) neuron function, especially in chronic pain.5 complete information on variables addressing asthma severity and To our knowledge, our study is the first to describe a rela- control while exposed at work; (2) available information on self‐ tionship between neutrophilic inflammation and work related reported dysphonia (i.e. hoarseness or loss of voice) at work; and dysphonia. (3) assessment of induced sputum cell counts at the time of the SIC We acknowledge the limitations inherent to the retrospective procedure. cross‐sectional design of this study. The presence of dysphonia was Forty‐nine (14.4%) subjects experienced dysphonia while not objectively documented through direct visualization of inappro- exposed at their workplace. The baseline clinical features and priate laryngeal movement. In addition, dysphonia was not assessed sputum cell counts of the subjects with and without dysphonia as during the SIC procedure implying that it was not possible to well as the univariate associations with dysphonia are detailed in ascertain that the agent inducing the positive SIC response was also Table 1. A multivariable logistic regression analysis was conducted the cause of dysphonia at work. in order to identify the clinical and inflammatory characteristics Despite their inherent limitations, our findings suggest that that were associated with work‐related dysphonia. The independent airway neutrophilic inflammation could be involved in the develop- variables incorporated into these regression models included ment of work‐related laryngeal dysfunction. This study highlights the gender; sinusitis; high‐level treatment at work (i.e., Global Initiative need for further prospective studies using validated questionnaires, for Asthma treatment step four‐fifths); poor asthma control at work laryngoscopy, and induced sputum analysis in order to explore the (i.e., need for an inhaled short‐acting β2‐agonist once or more a association between laryngeal dysfunction and neutrophilic airway day); OA caused by a low‐ versus a high‐molecular‐weight agent; as inflammation. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, pro- vided the original work is properly cited. © 2023 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology. Clin Transl Allergy. 2023;e12218. wileyonlinelibrary.com/journal/clt2 1 of 4 https://doi.org/10.1002/clt2.12218 2 of 4 - LETTER TABLE 1 Univariate associations with self‐reported dysphonia at work Subjects without dysphonia Subjects with dysphonia Characteristics Missing values at work (n = 292) at work (n = 49) OR (95% CI) p value a Age, year 0 43 (34–51) 42 (38–52) 1.02 (0.99–1.05) 0.279 Sex, female 0 97 (33.2) 23 (46.9) 1.78 (0.96–3.28) 0.065 Body mass index ≥30 kg/m2a 0 82 (28.1) 15 (30.6) 1.13 (0.57–2.15) 0.717 Ex‐smokers 0 83 (28.4) 10 (20.4) 0.66 (0.29–1.38) 0.286 Current smokers 0 62 (21.2) 12 (24.5) 1.05 (0.49–2.17) 0.890 Atopyb 4/0 146 (50.7) 28 (57.1) 1.30 (0.71–2.41) 0.405 Chronic rhinosinusitis 2/0 21 (7.2) 8 (16.3) 2.50 (0.99–5.83) 0.041 Exposure before symptom onset, monthsa 2/0 108 (48–204) 150 (21–230) 1.00 (1.00–1.00) 0.218 Duration of asthma symptoms at work, monthsa 3/0 36 (16–84) 33 (21–68) 1.00 (0.99–1.00) 0.522 Type of causal agent, LMW 0 191 (65.4) 25 (51.0) 1.81 (0.98–3.33) 0.057 Asthma treatment at work Daily dose of ICS, μga,c 0 500 (0–1000) 500 (0–1000) 1.00 (1.00–1.00) 0.827 High level treatmentd 0 19 (6.5) 6 (12.2) 2.12 (1.14–3.94) 0.017 e Poor asthma control while at work 0 74 (25.3) 21 (42.9) 2.21 (1.17–4.11) 0.013 ≥2 exacerbations last 12 months at work 0 26 (8.9) 1 (2.0) 0.21 (0.01–1.04) 0.134 Baseline spirometry FVC, % preda 0 101 (90–110) 103 (94–110) 1.01 (0.99–1.03) 0.610 a FEV1, % pred 0 90 (79–98) 91 (78–98) 1.01 (0.98–1.03) 0.602 a FEV1/FVC, % 0 74 (67–80) 75 (67–78) 1.00 (0.97–1.03) 0.981 f Airflow obstruction 0 56 (19.2) 13 (26.5) 1.52 (0.73–3.00) 0.238 Baseline NSBH 22/0 Absent 56 (20.7) 11 (22.4) 1.11 (0.51–2.24) 0.787 Mild 139 (51.5) 27 (55.1) 1.16 (0.63–2.15) 0.641 Moderate/severe 75 (27.8) 11 (22.4) 0.75 (0.35–1.50) 0.440 a Blood eosinophils, cells/μl 58/10 280 (199–400) 249 (140–390) 1.00 (1.00–1.00) 0.335 a Baseline FeNO, ppb 184/10 22 (12–41) 22 (10–28) 0.98 (0.96–1.00) 0.049 Baseline sputum eosinophils %a 0 2.0 (1.0–6.0) 1.2 (0.2–2.5) 0.87 (0.77–0.95) 0.011 ≥3% 125 (42.8) 12 (24.5) 0.43 (0.21–0.84) 0.018 Baseline sputum neutrophils %a 0 51.0 (36.0–70.0) 60.0 (48.2–78.5) 1.02 (1.00–1.03) 0.017 ≥76% 57 (19.5) 15 (30.6) 1.82 (0.91–3.52) 0.081 Note: Data are presented as n (% of available data) unless otherwise specified. Bold indicates variable with univariate association demonstrating a p value under 0.1. Abbreviations: FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in one‐second; FVC, forced vital capacity; ICS, inhaled corticosteroid; LMW, low‐molecular‐weight; NSBH, nonspecific bronchial hyperresponsiveness; SIC, specific inhalation challenge. a Median value with interquartile range (IQR) within parentheses. b Atopy defined by the presence of at least one positive skin prick test result to common allergens. c Daily dose of inhaled corticosteroid expressed as beclomethasone dipropionate equivalent. d High‐level treatment defined as treatment step 4 or 5 of the Global Initiative for Asthma (http://www.ginasthma.org). e Poor asthma control at work is defined as the use of SABA more than once a day. f Airflow obstruction defined by an FEV1 <80% predicted and an FEV1/FVC ratio <70%. LETTER - 3 of 4 TABLE 2 Logistic multivariate model for dysphonia at work Dysphonia at work (n = 49/341) Independent variables OR (95% CI) p value Sex, female 2.04 (1.06–3.92) 0.031 Chronic rhinosinusitis Poor asthma control while at worka 1.84 (0.91–3.71) 0.087 Type of causal agent, LMW High level treatmentb 1.97 (0.97–3.95) 0.057 Eosinophil sputum cell counts ≥3% 0.41 (0.19–0.83) 0.017 Neutrophil sputum cell counts, 5% increase 1.05 (1.03–1.07) <0.001 Note: The model included 338 patients, selection of variables was realized by a stepwise procedure based on Akaike information criterion. Bold indicates variable associated with a statistical significance, demonstrating a p value under 0.05. Abbreviation: LMW, low‐molecular‐weight. a Poor asthma control at work is defined as the use of SABA more than once a day. b High‐level treatment defined according to GINA as treatment step 4 or 5. 1 A U TH O R C O N TR IB UT I O N S Department of Chest Diseases, Division of Pulmonology, All E‐PHOCAS investigators contributed to the conception and University Hospital of Strasbourg and Fédération de Médecine design of the study. All authors contributed to the acquisition, anal- translationnelle, Strasbourg University, Strasbourg, France 2 ysis and interpretation of the data. They provided input into the UMR 7357 Laboratoire des sciences de l'ingénieur, de drafting of the manuscript, critical feedback, and final approval for l'informatique et de l'imagerie ICUBE, Strasbourg, France 3 submission of the manuscript for publication. NM is the guarantor of Service de Pneumologie, Centre Hospitalier Universitaire UCL the final content of the manuscript. Namur, Université Catholique de Louvain, Yvoir, Belgium 4 Department of Occupational Diseases and Environmental Health, K E YW O R DS Nofer Institute of Occupational Medicine, Lodz, Poland dysphonia, neutrophilic inflammation, occupational asthma 5 Servei Pneumologia, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona and CIBER de Enfermedades Respiratorias A C K N O WL ED GM E N T S (CIBERES), Barcelona, Spain Olivier Vandenplas was supported in part by a grant from the Fon- 6 Occcupational Health, Finnish Institute of Occupational Health, dation Mont‐Godinne. Frédéric de Blay and Nicolas Migueres were Helsinki, Finland supported by a grant from the Association d'Aide aux Insuffisants 7 Institute for Prevention and Occupational Medicine of the Respiratoires d'Alsace (ADIRAL). German Social Accident Insurance (IPA), Ruhr University, Bochum, Germany C O N F LI C T O F IN T ER E S T 8 Department of Cardiac‐Thoracic‐Vascular Sciences and Public The authors have no conflicts of interest to declare. Health, University of Padova, Padova, Italy 9 Department of Allergy, La Paz University Hospital, IdiPAZ and F U N D IN G I N FO R M A T I O N CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain Association d'Aide aux Insuffisants Respiratoires d'Alsace (ADIRAL); Fondation Mont‐Godinne Correspondence Nicolas Migueres, Department of Chest Diseases, Division of Nicolas Migueres1,2 Pulmonology, University Hospital of Strasbourg and Fédération de Olivier Vandenplas3 Médecine translationnelle, Strasbourg University, Strasbourg, Jolanta Walusiak‐Skorupa4 France. 5 Xavier Munoz Email: nicolas.migueres@chru-strasbourg.fr Hille Suojalehto6 Vera van Kampen7 D A T A A V A I L A B I L I T Y S T A TE M E N T Paola Mason8 Research data are not shared. 9 Santiago Quirce Frédéric de Blay1 ORCID on behalf of the European network for the PHenotyping Nicolas Migueres https://orcid.org/0000-0002-3923-8505 of OCcupational ASthma (E‐PHOCAS) Vera van Kampen https://orcid.org/0000-0002-5694-4663 4 of 4 - LETTER REFERENCES Immunol Pract. 2019;7:2309‐2318.e4. https://doi.org/10.1016/j.jaip. 1. 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