Contexte - Concernant l'histoire naturelle de l'asthme professionnel (AP), les évidences s'accumulent sur le fait que le processus inflammatoire menant à l'asthme clinique se développe tôt dans le cursus des travailleurs. L'étude ABCD - Asthme en Boulangerie et Coiffure Débutant - poursuit deux objectifs : 1) décrire l'évolution temporelle de l'incidence de l'AP au cours des premières années d'exposition de boulangers/pâtissiers (BP) et coiffeurs - secteurs reconnus à risque d'AP - et 2) identifier les facteurs de risque personnels, professionnels et nutritionnels influençant cette incidence. Méthode - L'étude ABCD repose sur deux facettes intriquées : (i) une cohorte longitudinale rétrospective d'anciens apprentis d'ancienneté croissante permettant l'estimation de l'incidence précoce de l'AP, et (ii) une étude de type cas-témoin nichée dans la cohorte explorant certains facteurs de risque de l'AP. Résultats - 866 sujets participèrent à l'étude qui mit en évidence une incidence cumulée de l'AP élevée lors des 4 premières années d'exposition chez les BP, et dans un moindre degré chez les coiffeurs. Le risque d'AP dépend du statut atopique chez les BP ; il est positivement associé, chez les coiffeurs, à l'intensité de l'exposition et, dans une moindre mesure, à l'indice de masse corporelle et à certains facteurs nutritionnels. Conclusions - Cette étude a permis de produire des données originales sur l'incidence précoce de l'asthme professionnel. Ces données constituent un support pour le développement de campagnes de prévention, notamment pour la détection précoce de la maladie dès les premières années d'exposition. / Context - Regarding the natural history of occupational asthma (OA), there is increasing evidence that the inflammatory process leading to clinical asthma appears early after inception of exposure. The ABCD study (French acronym for early asthma in bakery and hairdressing) aims to answer two objectives: 1) describe the temporal evolution of the OA incidence in the early years of exposure of bakers/pastry-makers (BP) and hairdressers - occupations known at risk of OA - and 2) identify personal, occupational and nutritional risk factors. Method - The ABCD study has two intertwined facets: (i) a retrospective longitudinal cohort of past apprentices of increasing seniority allowing to estimate the early incidence of OA, and (ii) a nested case-control study allowing to explore some risk factors of OA. Results - 866 subjects participated to the study. The ABCD study shows a high cumulative incidence of OA during the first 4 years of exposure among BP, and in a lesser extent, among hairdressers. While the OA risk depends on atopic status for BP, it is positively associated, for hairdressers, with exposure intensity and, to a lesser extent, to body mass index and with a variety of nutritioal factors. Conclusions - This study produced original data on early incidence of OA. These data may provide support for the development of preventive action, in particular for the detection of OA in the early years of exposure.

INTRODUÇÃO: Há evidências consistentes a partir de estudos epidemiológicos de que os profissionais de limpeza têm um risco elevado de desenvolver asma. Os determinantes deste risco não são totalmente conhecidos. Esses trabalhadores estão expostos a agentes ocupacionais de baixo e alto peso molecular, tanto a agentes sensibilizantes, como a irritantes. É importante produzir evidências de que este risco está relacionado ao trabalho e não às condições sociais ou outros fatores concorrentes, conhecer a anormalidade patológica subjacente, e investigar os possíveis agentes. O acúmulo deste conhecimento permitirá a proposição de medidas para substituição ou controle do uso dos agentes envolvidos e prevenção da ocorrência de novos casos desnecessariamente. Além disso, o uso de novas técnicas não invasivas, como a citologia do escarro e A FeNO, poderá facilitar o diagnóstico precoce dos casos. Desta maneira, este estudo pretende avaliar se o ambiente de trabalho induz inflamação pulmonar em trabalhadores assintomáticos, antes da alteração das provas funcionais e a eficácia do escarro induzido e da FeNO NO como marcadores de inflamação pulmonar precoce entre trabalhadores de limpeza profissional não doméstica. MÉTODO: Os trabalhadores foram avaliados através da comparação da citologia do escarro, valores da FeNO, espirometria e PFE, realizados durante o período de trabalho e após as férias. A amostra foi caracterizada através do questionário de triagem do estudo de saúde respiratória da Comunidade Européia, questionário de sintomas respiratórios e a pontuação no ISAAC. RESULTADOS: Em nosso estudo, encontramos um aumento significativo dos valores do VEF1 após o período de férias, (pré 2,76 ± 0,57 e pós 2,94 ± 0,61; p < 0,05) apesar de estar dentro da normalidade, em ambos os períodos. A média das medidas do PFE também mostrou-se maior durante o período de férias em comparação ao período de trabalho, embora não estatisticamente significante (pré 366,6 ± 54,1 e pós 386,4 ± 62,9 e p > 0,05). Encontramos uma redução dos valores da medida da FeNO após as férias (pré 16,3 ± 9,7 e pós 13,8 ± 7,8 p < 0,05) e redução de eosinófilos (pré 0,019 ± 0,05 e pós 0,003 ± 0,01 p < 0,05), linfócitos (pré 0,16 ± 0,35 e pós 0,01 ± 0,09 p < 0,05) e macrófagos (pré 0,421 ± 0,47 e pós 0,235 ± 0,30 p < 0,05) na citologia do escarro induzido, realizada após o período de férias. CONCLUSÃO: Demonstramos que o ambiente ocupacional ao qual são expostos os trabalhadores de limpeza profissional não doméstica provoca inflamação nas vias aéreas de trabalhadores assintomáticos. Esta inflamação pode ser aferida por métodos não invasivos como escarro induzido e FeNo, antes do aparecimento de alterações nas provas funcionais, embora estes métodos ainda necessitem de padronização. São necessários novos estudos para quantificar a exposição ao cloro e sua relação com inflamação, assim como para padronizar o uso do escarro induzido e da FeNO no diagnóstico de doenças ocupacionais entre trabalhadores de limpeza, além de medidas preventivas e educativas nesta população / There is consistent evidence from epidemiological studies that the cleaning professionals have a high risk of developing asthma. The determinants of this risk are not fully known. These workers are exposed to occupational agents of low and high molecular weight, both the sensitizing agents, such as irritant. It is important to produce evidence that this risk is related to work and not social conditions or other competitive factors, know the underlying pathological abnormality, and investigate possible agents. The accumulation of this knowledge will allow proposing measures to replace or control the use of the agents involved and preventing the occurrence of new cases unnecessarily. In addition, the use of new non-invasive techniques, such as sputum cytology and the FeNO may facilitate early diagnosis of cases. Thus, this study aims to assess if the work environment induces lung inflammation in asymptomatic workers, before the change of functional tests and the effectiveness of induced sputum and exhaled NO as early lung inflammation markers between professional cleaning workers. METHOD: Workers were evaluated by comparing the sputum cytology, FeNO values, spirometry and PEF, made during the work period and after the holidays. The sample was characterized by screening questionnaire of respiratory health study of the European Community, questionnaire of respiratory symptoms and a score in ISAAC. RESULTS: In our study, we found a significant increase in FEV1 values after the vacational period, (pre 2.76 ± 0.57 and 2.94 ± 0.61; post; p < 0.05) despite of being within the normal range in both periods. The average peak flow measurements also was higher during the vacational period compared to the period of work, although not statistically significant (366.6 ± 54.1 pre and post 386.4 ± 62.9; p > 0.05). We found a reduction of the exhaled measured values of NO after the holidays (pre and post 16.3 ± 9.7, 13.8 ± 7.8; p < 0.05), reduction of eosinophils (pre and post 0.05 ± 0.019, 0.003 ± 0.01; p < 0.05), lymphocytes (pre and post 0.16 ± 0.35, 0.01 ± 0.09; p < 0.05) and macrophages (pre and post 0.421 ± 0.47 0.235 ± 0 30 p < 0.05) in induced sputum cytology, performed after the holiday period. CONCLUSION: We demonstrate that the occupational environment to which professional cleaning non-domestic workers are exposed causes inflammation in the airways of asymptomatic workers. This inflammation can be measured by non-invasive methods such as induced sputum and FeNo, before the onset of changes in functional tests, although these methods still require standardization. Further studies are needed to quantify the exposure to chlorine and its relation to inflammation, as well as to standardize the use of induced sputum and exhaled nitric oxide in the diagnosis of occupational diseases among cleaning workers, and preventive and educational measures in this population

L’asthme professionnel est une maladie fréquente, qui coûte cher, qui touche des travailleurs jeunes, dont le diagnostic est difficile et avec d’importantes conséquences socio-économiques. La prévention occupe une place centrale dans la gestion de l’asthme professionnel, d’un point de vue de santé publique. Ce mémoire de maîtrise présente trois articles rapportant des développements récents en matière de prévention de l’asthme professionnel. Tout d’abord, une revue de la littérature sur les agents sensibilisants de bas poids moléculaire dans l’asthme professionnel entre 2000 et 2010 recense 41 nouveaux agents et insiste sur l’importance de mettre à jour régulièrement les bases de données afin d’améliorer la prévention primaire. Ensuite, basé sur un cas clinique, la deuxième publication présente l’utilité potentielle du modèle d’analyse de risque QSAR (Quantitative Structure-Activity Relationship) dans le processus diagnostique de l’asthme professionnel, notamment lors d’une exposition multiple à des agents sensibilisants. Enfin, le troisième article présente la performance en milieu clinique du premier questionnaire de dépistage spécifique à l’asthme professionnel. Un modèle simple associant 8 items du questionnaire, l’âge des travailleurs et leur durée d’exposition professionnelle permet de discriminer 80% des 169 sujets adressés pour suspicion d’asthme professionnel. Un tel modèle pourrait être intégré dans les programmes de surveillance médicale qui constituent la base de la prévention secondaire. Ces trois publications insistent sur les possibilités d’explorer de nouveaux outils préventifs dans le domaine de l’asthme professionnel, outils qui ouvrent des perspectives de développements futurs dont les implications cliniques et socio-économiques peuvent être importantes. / Occupational asthma is a common disease, which affects young workers and is difficult to diagnose. It is a major financial burden and has important socioeconomic consequences. Prevention is central in the management of occupational asthma, in terms of public health. This thesis presents three articles reporting on recent developments in the prevention of occupational asthma. First, a review of the literature on sensitizing low-molecular- weight agents in occupational asthma between 2000 and 2010 reports 41 new agents and emphasizes the importance of regularly updating databases to improve primary prevention. Then, based on a clinical case, the second publication presents the potential utility of the model of risk analysis QSAR (Quantitative Structure-Activity Relationship) in the diagnostic workup for occupational asthma, especially in the case of multiple exposure to sensitizing agents. The third article presents the clinical performance of the first screening questionnaire specific to occupational asthma. A simple model consisting of 8 items of the questionnaire, age and exposure duration could discriminate 80% of the 169 subjects with and without OA in a clinical setting. Such a model could be integrated into medical surveillance programs, which are the basis of secondary prevention. These three publications emphasize the possibilities to explore new prevention tools in the field of occupational asthma, tools that provide opportunities for future developments, which could have major clinical and socio-economic implications.

In a large population-based study among adults in northern Europe the relation between occupational exposure and new-onset asthma was studied. The study comprised 13 284 subjects born between 1945 and 1973, who answered a questionnaire 19891992 and again 19992001. Asthma was defined as Asthma diagnosed by a physician with reported year of diagnose. Hazard ratios (HR), for new-onset adult asthma during 19802000, were calculated using a modified job-exposure matrix as well as high-risk occupations in Cox regression models. The analyses were made separately for men and women and were also stratified for atopy. During the observation period there were 429 subjects with new-onset asthma with an asthma incidence of 1.3 cases per 1000 person-years for men and 2.4 for women. A significant increase in new-onset asthma was seen for men exposed to plant-associated antigens (HR 3.6; 95% CI [confidence interval] 1.49.0), epoxy (HR 2.4; 95% CI 1.34.5), diisocyanates (HR 2.1; 95% CI 1.23.7) and accidental peak exposures to irritants (HR 2.4; 95% CI 1.34.7). Both men and women exposed to cleaning agents had an increased asthma risk. When stratifying for atopy an increased asthma risk were seen in non-atopic men exposed to acrylates (HR 3.3; 95% CI 1.47.5), epoxy compounds (HR 3.6; 95% CI 1.67.9), diisocyanates and accidental peak exposures to irritants (HR 3.0; 95% CI 1.27.2). Population attributable risk for occupational asthma was 14% for men and 7% for women. This population-based study showed that men exposed to epoxy, diisocyanates and acrylates had an increased risk of new-onset asthma. Non-atopics seemed to be at higher risk than atopics, except for exposure to high molecular weight agents. Increased asthma risks among cleaners, spray painters, plumbers, and hairdressers were confirmed.

Es va determinar el risc d'asma i la seva associació amb les exposicions laborals, així com la càrrega d'asma relacionat amb el treball, entre professionals sanitaris. Després de validar un qüestionari nou, es va administrar una enquesta a 5600 metges, infermers, i tècnics en teràpia respiratòria i ocupacional a Texas (tasa de resposta-66%). S'evidencia un risc elevat d'asma desprès d'haver començat a treballar per tasques de neteja general, desinfecció d'instruments mèdics, l'ús de guants de làtex i l'administració de medicaments en aerosol. També s'evidencien associacions significatives entre símptomes de hiperreactivitat bronquial i l'ús de productes generals de neteja, l'administració de medicaments en aerosol, l'aplicació de productes adhesius/dissolvents, i en persones amb antecedents d'exposició a un vessament químic. El risc per làtex desaparegué desprès de l'any 2000. Les exposicions laborals contribueixen de manera important a l'asma en el personal sanitari, justificant tant la implementació de controls adequats com la recerca addicional. / The magnitude of asthma risk, its associations with occupational exposures, and the burden of work-related asthma was estimated in healthcare professionals. After validating a new asthma questionnaire, a cross-sectional survey was conducted among 5600 Texas physicians, nurses, respiratory therapists and occupational therapists (response rate, 66%). Elevated risks of asthma after entry into the profession were found for general cleaning tasks, medical instrument cleaning, use of powdered latex gloves, and administration of aerosolized medications. Significant associations were also found between bronchial hyperresponsiveness-related symptoms and use of general cleaning products, administration of aerosolized medications, use of adhesives or solvents as products in patient care, and with a history of acute exposure to a chemical spill. The risk associated with latex disappeared after the year 2000. Occupational exposures contribute importantly to asthma among healthcare professionals and are not trivial, meriting both further study and implementation of appropriate controls.

Les asthmes en relation avec le travail (ART) incluent l’asthme professionnel (AP), dû à des causes et conditions attribuables à un environnement professionnel particulier, et l’asthme aggravé par le travail (AAT), qui est une forme pré-existante ou coïncidente d’asthme, aggravée par l’environnement professionnel. Le diagnostic des ART constitue un véritable enjeu. Le premier chapitre est une revue de la littérature, mettant en évidence les points discutés et notamment la place éventuelle des marqueurs de l’inflammation. Le deuxième chapitre présente une analyse de données épidémiologiques chez 417 apprentis coiffeurs et boulangers, des filières à risques d’AP. Des modèles mixtes montrent une association entre le degré de sensibilisation à douze allergènes communs et l’hyperréactivité bronchique (HBR) ainsi que les niveaux de FeNO expiré. Ce dernier est plus élevé de 83% (p<0,01) chez les sujets fortement sensibilisés et de 30% chez les sujets faiblement sensibilisés (p<0,01) comparé au groupe des sujets non sensibilisés. Le troisième chapitre relate l’élaboration d’un protocole de recherche (ARPEIGE) visant à acquérir des connaissances cliniques, épidémiologiques et économiques sur les ART, et aux développement et choix des outils et algorithmes décisionnels. L’analyse des questionnaires de repérage montre qu’en visite de routine en médecine du travail, une part non négligeable de salariés déclare des symptômes respiratoires évoquant un asthme actif, dont certains pourraient être en lien avec le travail. Ce protocole met en évidence la difficulté d’effectuer un dépistage des ART par le faible taux de retours des questionnaires approfondis. Malgré l’importance du diagnostic des ART, les stratégies diagnostiques restent discutées. Si les données chez les apprentis ont montré une association entre certains marqueurs de l’inflammation bronchique (FeNO) et des marqueurs d’atopie (tests cutanés), leur place dans le diagnostic clinique de l’asthme reste discutée. Au-delà des stratégies visant au diagnostic individuel, se pose également la question des stratégies diagnostiques utilisables en population professionnelle. Dans l’étude ARPEIGE, un questionnaire de repérage des symptômes fournit des données relatives à la prévalence des symptômes évocateurs d’asthme. Cependant, peu de sujets repérés acceptent de poursuivre les investigations, d’où l’importance de réfléchir à des stratégies qui permettraient un dépistage des ART au-delà de l’étape de repérage. / Work-related asthma (WRA) includes work aggravation of preexisting asthma (WEA) and new-onset asthma induced by occupational exposure (OA). Making an accurate diagnosis of WRA is important, the condition having significant health consequences and substantial socio-economic impacts. The first part is based on a literature review including data on prevalence, risk factors and diagnosis procedures of WRA. The issues in diagnosing WRA are also discussed, as well as the use of airway inflammation markers (FeNO levels and sputum eosinophils). The second part shows an analysis of epidemiological data in 417 apprentices in baking, pastry-cooking and hairdressing, which are populations at risk of OA. Mixed-effect models were applied and showed that the degree of sensitization was related to bronchial hyperresponsiveness (BHR) and FeNO levels. Compared to non-sensitized subjects, FeNO levels were 83% higher (p>0,01) in highly sensitized subjects and 30% higher (p<0,01) in weakly sensitized subjects. The third part describes the protocol of a field study aiming to collect new data on clinical, epidemiological and economical aspects of WRA. It focuses especially on the design of tools and decision algorithms, such as a screening questionnaire, and more advanced questionnaires on control, quality of life, expositions and socio-economic consequences, and a peak-flow journal. Screening results show that a substantial number of workers declare asthma-like respiratory symptoms, some of which being possibly related to work. Despite the importance of WRA diagnosis, diagnostic procedures are still being discussed. Although the apprentice study showed an association between airway inflammation markers (FeNO levels) and atopy markers (prick-tests), their use in the diagnostic procedure is still under discussion. Diagnostic procedures that could be used in populations at work are also subject to think about, in particular in epidemiological study, with the difficulty of differentiating OA from WEA. Thus, in the ARPEIGE study, a screening questionnaire was useful to collect data on asthma-like respiratory symptoms. Nevertheless, few screened workers agreed to go further and fill in the peak flow journal. Similarly, in the literature asthma and COPD screening campaigns using spirometry seemed difficult to implement. There is a lack of strategies that would enable a more accurate screening of WRA.

Le diagnostic de l'asthme professionnel (AP) est toujours un défi. Le test de provocation bronchique spécifique (TPS), comme une méthode de diagnostic de référence, n’est pas aisément accessible. Cette étude diagnostique rétrospective vise à évaluer des outils diagnostiques actuels et à développer des scores cliniques pour AP (définis comme ayant le résultat positif en TPS). Les données concernant les travailleurs soupçonnés d'avoir de l’AP qui, d’une part, ont été exposés aux agents de haut-poids-moléculaire élevé (HPM) (n=139) et à bas-poids-moléculaire (BPM) (n=285), et d’autre part, ont travaillé encore un mois avant de l’évaluation de TPS. Par ailleurs, les modèles de régression logistique sont développés dans chaque groupe d'exposition. Ainsi, concernant des tests objectifs, les valeurs de différents tests distinctifs sont ajoutées aux caractéristiques cliniques, et enfin, le résultat a été évalué. Les modèles ont été testés pour l’exactitude, et pour la validation interne par la procédure bootstrapping. Suite à cela, les modèles finaux sont traduits en scores cliniques et le score total est stratifié en groupes à risque. Chez les travailleurs exposés à des agents BPM, si le test de la méthacholine est fait isolément, le modèle prédictif n'a pas montré de meilleures valeurs diagnostiques que le test de provocation. Cependant, dans le groupe HPM, le modèle final, y compris le sexe, l'âge> 40 ans, la durée des symptômes ≥1 an, la rhinoconjonctivite, l'utilisation de corticostéroïdes inhalés, le test de provocation à la méthacholine, et le test de la piqûre épidermique spécifique, avait un bon calibrage et une validation interne raisonnable. Par ailleurs, la catégorie de sujets avec une probabilité élevée d’avoir AP avait une meilleure spécificité et une meilleure valeur prédite positive par rapport à la combinaison de test de provocation à la méthacholine et de la piqûre épidermique spécifique dans la détection de l'AP, cependant n'avait pas de signification statistique. En conclusion, ce modèle quantifie la probabilité individuelle d'AP. Dans les centres où l'accès à TPS est difficile ou impossible, notre modèle serait utile dans le diagnostic d’OA, néanmoins, la validation externe du modèle reste nécessaire. Mots-clés : asthme professionnel, modèle diagnostique, prévention, score clinique. / The diagnosis of occupational asthma (OA) is challenging since the use of specific inhalation challenge (SIC) as the reference test is not widely accessible. This retrospective diagnostic study is aimed to evaluate current diagnostic tools and to develop clinical scores for OA (defined as positive SIC). Data from workers with suspected OA who were exposed to high-molecular-weight (HMW) (n=139) and low-molecular-weight (LMW) agents (n=285) and still working one month before the SIC were evaluated. Logistic regression models were developed in each exposure group. The added values of different objective tests to clinical and exposure characteristics were evaluated. The models were tested for accuracy, and, validated internally by the bootstrapping procedure. The final models were translated into clinical score and the sum scores were stratified into risk groups. In workers exposed to LMW agents, the predictive model did not perform better diagnostically than the methacholine challenge test alone. In the HMW group, the final model including sex, age >40 years, symptom duration ≥1 year, rhinoconjunctivitis, inhaled corticosteroid use, the methacholine challenge test, and specific SPT had a good accuracy and reasonable internal validation. The high probability category of the predictive model had a better specificity and positive predicted value compared to the combination of methacholine challenge test and specific SPT in detecting OA but did not reach the statistical significance. Our results suggest that this model could quantify an individual’s probability of OA. This model emphasizes the necessity of performing both tests in order to have a more accurate diagnosis in workers exposed to HMW agents. In centers where access to SIC is difficult or impossible, our model might be of benefit in diagnosing OA. Nevertheless, external validation of the model is necessary. Key words: occupational asthma, diagnostic model, prevention, clinical score.

A asma ocupacional é a forma mais comum de doença pulmonar relacionada ao trabalho e vários dos casos reportados estão correlacionados à exposição de proteases. A serino protease subtilisina foi bastante utilizada na década de 60 e foi a principal responsável pela alta incidência de asma na indústria de detergente. Este projeto visou a desenvolver um modelo murino de inflamação alérgica pulmonar à subtilisina e caracterizar os mecanismos principais envolvidos nessa resposta. A sensibilização e desafio com subtilisina induziu doença alérgica pulmonar, verificada pela eosinofilia às vias aéreas, produção de muco, IgE total, hiper reatividade brônquica e produção de citocinas tipo II no pulmão. Estas respostas foram dependentes da atividade enzimática da subtilisina, PAR-2, receptor de IL-33 ST2, IL-1R e da sinalização via MyD88. Em conjunto, nossos resultados estabelecem um novo modelo experimental de asma ocupacional induzida por subtilisina e fornece os principais mecanismos moleculares responsáveis pela inflamação alérgica. / Occupational asthma is the most common form of pulmonary disease related to work. Most of occupational asthma cases reported are strictly correlated with proteases exposure. Serine protease subtilisin was widely used in the detergent industry during the 60s, which resulted in increased incidence of occupational asthma. We aimed to develop and characterize a murine model of occupational asthma using subtilisin as allergen. Briefly, sensitization and challenge with subtilisin triggered lung allergic inflammation, as accessed by eosinophilic influx to the airways, mucus production, and increased levels of type II cytokines. Subtilisin induced total IgE and airway hyperactivity. Allergic responses to subtilisin were dependent on its serine protease activity, protease-activated receptor (PAR)-2, IL-33 receptor ST2, IL-1R, and Myd88 signaling. Together, these data establish a new murine model of occupational asthma induced by subtilisin and provide the main molecular mechanisms responsible for allergic inflammation.

A asma ocupacional é a forma mais comum de doença pulmonar relacionada ao trabalho e vários dos casos reportados estão correlacionados à exposição de proteases. A serino protease subtilisina foi bastante utilizada na década de 60 e foi a principal responsável pela alta incidência de asma na indústria de detergente. Este projeto visou a desenvolver um modelo murino de inflamação alérgica pulmonar à subtilisina e caracterizar os mecanismos principais envolvidos nessa resposta. A sensibilização e desafio com subtilisina induziu doença alérgica pulmonar, verificada pela eosinofilia às vias aéreas, produção de muco, IgE total, hiper reatividade brônquica e produção de citocinas tipo II no pulmão. Estas respostas foram dependentes da atividade enzimática da subtilisina, PAR-2, receptor de IL-33 ST2, IL-1R e da sinalização via MyD88. Em conjunto, nossos resultados estabelecem um novo modelo experimental de asma ocupacional induzida por subtilisina e fornece os principais mecanismos moleculares responsáveis pela inflamação alérgica. / Occupational asthma is the most common form of pulmonary disease related to work. Most of occupational asthma cases reported are strictly correlated with proteases exposure. Serine protease subtilisin was widely used in the detergent industry during the 60s, which resulted in increased incidence of occupational asthma. We aimed to develop and characterize a murine model of occupational asthma using subtilisin as allergen. Briefly, sensitization and challenge with subtilisin triggered lung allergic inflammation, as accessed by eosinophilic influx to the airways, mucus production, and increased levels of type II cytokines. Subtilisin induced total IgE and airway hyperactivity. Allergic responses to subtilisin were dependent on its serine protease activity, protease-activated receptor (PAR)-2, IL-33 receptor ST2, IL-1R, and Myd88 signaling. Together, these data establish a new murine model of occupational asthma induced by subtilisin and provide the main molecular mechanisms responsible for allergic inflammation.

Le facteur le plus important de pronostic de l'asthme professionnel (AP) est la durée des symptômes avant le retrait de lʼexposition à lʼagent causant lʼAP. La qualité de vie réduite, la détresse psychologique et les maladies psychiatriques sont des conditions souvent associées à l'AP. Notre objectif était d'identifier les facteurs, incluant le statut socioéconomique, qui ont une influence sur lʼintervalle de temps nécessaire pour présenter une requête à une agence médicolégale à la suite de lʼapparition de symptômes dʼasthme et de confirmer qu'un tel délai est associé à un moins bon pronostic respiratoire et à des coûts directs plus élevés. En outre, nous avons examiné la relation entre les variables cliniques et socio-économiques dʼune part et leur influence sur les facteurs psychologiques et économiques dʼautre part chez des travailleurs atteints d'AP. Ensuite, nous avons voulu évaluer si les individus souffrant de détresse psychologique (DP) et de morbidité psychiatrique pourraient être identifiés en utilisant un instrument mesurant la qualité de vie (QV). Lʼétude a été effectuée auprès dʼindividus ayant déposé des demandes d'indemnisation pourʼAP auprès du Commission de la sécurité et de la santé du travail du Québec (CSST). Les données ont été recueillies au moment de la réévaluation, soit environ deux ans et demi après le diagnostic. Outre la collecte des marqueurs cliniques de l'asthme, les individus ont été soumis à une évaluation générale de leur histoire sociodémographique et médicale, à une brève entrevue psychiatrique (évaluation des soins primaires des troubles mentaux, PRIME-MD) et à un ensemble de questionnaires, incluant le Questionnaire sur la qualité de vie - AQLQ(S), le Questionnaire respiratoire de St. George (SGRQ) et le Psychiatric Symptom Index (PSI).Soixante personnes ont été incluses dans l'étude. Etre plus âgé, avoir un revenu supérieur à 30 000$ CA etêtre atteint dʼAP dû à un allergène de haut poids moléculaire ont une association positive avec le nombre dʼannées dʼexposition avec symptômes avant le retrait. Au cours de la période de suivi, le nombre dʼannées dʼexposition avec symptômes était plus grand chez les individus ayant une hyperréactivité bronchique persistante. Par ailleurs, la présence de symptômes au poste de travail pendant moins d'un an est associée à une réduction des coûts directs. Les paramètres de QV et de DP avaient des corrélations modérées avec les marqueurs cliniques de lʼAP. Les plus fortes associations avec ces variables ont pu être observées dans les cas de la sévérité de l'asthme, des statuts dʼemploi et matrimonial, du revenu et de la durée de la période de travail avec l'employeur. Un seuil de 5,1 au niveau de la sous-échelle de la fonction émotionnelle de lʼAQLQ(S) sʼest avéré avoir la meilleure valeur discriminante pour distinguer les individus avec ou sans détresse psychiatrique cliniquement significative selon le PSI. Nous avons été en mesure d'identifier les variables socio-économiques associées à un intervalle plus long dʼexposition professionnelle en présence de symptômes dʼasthme. De même, une plus longue période d'exposition a été associée à un moins bon pronostic de la maladie et à des coûts de compensation plus élevés. Ces résultats s'avèrent utiles pour la surveillance de lʼAP qui pourrait cibler ces sous-groupes d'individus. La QV et la PS sont fréquemment réduites chez les individus atteints d'AP qui perçoivent une compensation. Elles sont associées à des marqueurs cliniques de lʼasthme et à des facteurs socio-économiques. En outre, nos résultats suggèrent que le questionnaire de lʼAQLQ(S) peut être utilisé pour identifier les individus avec un niveau de détresse psychologique potentiellement significatif. / The most important factor in the prognosis of occupational asthma (OA) is the length of exposure with symptoms prior to removal from exposure. Impaired quality of life, psychological distress and psychiatric disease are conditions frequently associated with OA. Our goal was to identify factors, including socio-economic status, that can influence the delay in submitting a claim to a medicolegal agency after the onset of asthmatic symptoms, and to confirm that such a delay is associated with a worse respiratory prognosis and higher direct costs. Further, we examined the association between clinical and socio-economic variables and their influence on psychological and cost outcomes in individuals with OA. Next, we wanted to evaluate whether individuals with clinically significant psychological distress (PD) and psychiatric morbidity could be identified by using a quality of life (QOL) measurement instrument. This is a study of individuals who filed claims for compensation for occupational asthma from the Workersʼ Compensation Board of Quebec (the CSST). Data were collected at re-evaluation, approximately two and a half years after diagnosis. Besides collecting clinical markers of asthma, individuals underwent a general socio-demographic and medical history evaluation, a brief psychiatric interview (Primary Care Evaluation of Mental Disorders, PRIME-MD) and completed a battery of questionnaires, including the Asthma Quality of Life Questionnaire - AQLQ(S), the St. Georgeʼs Respiratory Questionnaire (SGRQ), and the Psychiatric Symptoms Index (PSI). Sixty individuals were included in the study. Being older, having a revenue of >$30,000 Can. (CAD$) and having OA due to high- molecular- weight agents were all positively associated with the number of years of exposure with symptoms before removal from exposure. Individuals with persistent airway hyperresponsiveness at follow-up had a higher number of years with symptoms. Experiencing symptoms in the workplace for less than one year generated lower direct costs. QOL and PD parameters had moderate correlations with clinical markers of OA. Asthma severity, employment and marital status, income and length of employment with the employer showed the strongest associations with QOL and PD. More impaired QOL was associated with higher direct costs for compensation. A cut-off of 5.1 on the AQLQ(S) emotional function subscale had the best discriminative value to distinguish individuals with or without clinically significant psychological distress according to the PSI. We were able to identify socio-economic variables that were associated with a longer interval during which individuals remained symptomatic in the workplace before being removed from exposure. This longer exposure time was associated with worse disease outcomes and higher compensation costs. These findings could prove to be useful in surveillance programs that could be preferentially targeted for these subgroups of individuals. Impaired QOL and PD are frequent among individuals with OA receiving compensation and are associated with clinical markers of OA and socio-economic factors. Further, our findings suggest that the AQLQ(S) questionnaire could be used to identify individuals with potentially clinically significant levels of psychological distress.