Maladies induites par les mastocytes (MCDD): Epidémiologie mondiale et aspects de la gestion dans la région du Moyen-Orient.

par Samah Tawil (Samah)

Projet de thèse en Santé publique - épidémiologie

Sous la direction de Khaled Ezzedine.

Thèses en préparation à Paris Est , dans le cadre de École doctorale Santé Publique , en partenariat avec Epidemiology in Dermatology and Evaluation of therapeutics (laboratoire) et de Faculté de médecine (établissement opérateur d'inscription) depuis le 01-10-2018 .


  • Résumé

    This project will be divided into 2 phases. The first phase will focus on the validation of a diagnostic tool for epidemiological studies. The second phase will assess the prevalence using the previously validated tools as well as the estimation of risk factors associated with MCDD as well as its impact on the quality of life of affected patients.  Phase 1: An appropriately validated diagnostic tool for epidemiological studies in the general population is lacking. Such a tool will be generated in a clinical setting on physician-diagnosed urticaria patients (multicenter study) and validated later on. The use of a composite tool (questionnaire plus a pictorial aid) will be assessed, compared with the physician diagnosis considered as the golden standard. The value of pictorial aids for epidemiological studies has been demonstrated for HS [8], psoriasis [10], vitiligo [11], and atopic dermatitis [12], and has shown an increase in sensitivity and specificity in regards to the Gold standard diagnosis, which is the specialized physician diagnosis. In fact, the dermatology center of Henri –Mondor represented by Dr. Ezzedine has similar projects on many skin diseases and worked on the validation of auto-diagnostic tools [6,8]. A similar value for MCDD should be hypothesized in this project. In several centers from Lebanon and France (listed below), patients consulting for MCDD (cases) and for other non-related dermatological diseases (controls) will be asked to make their own diagnosis (in waiting rooms before encountering the physician): they would have to select their symptoms according to a list of symptoms and definitions, and to identify their skin lesions from the pictorial album. Specialized physicians participating in the study will dermatologists or immuno-allergists, part of a specific network for easy accessibility. The disease will then have to be confirmed or infirmed by the specialized physician, after applying the latest diagnosis criteria (and laboratory testing if necessary). This will allow the selection of the best diagnosing combination of symptom(s) and picture(s). Cases will be patients aged 12 years and older, with the most commonly encountered MCDD, namely acute and chronic urticaria, whether spontaneous or induced, in addition to mastocytosis. In case children lower than 12 years of age are to be included, parents of children will have to participate to the study as surrogate respondents. Patients of same age brackets with eczematous and exanthematic skin lesions, pruritus and angioedema, such as atopic dermatitis, psoriasis, prurigo, rosacae, hereditary or ACE-inhibitor-induced angioedema, and chronic pruritus with secondary skin lesions will be used as controls. Moreover, patients with viral infections presenting with non-urticarial rashes may also be included. In a similar setting to the tool generation study, the right combination identified above will be offered to patients for self diagnosis, before they consult the physician for confirmation. Validity criteria of the composite tool will be confirmed. A questionnaire, translated to different languages, will be used, including the following sections: - Socio-demographic and health characteristics - Previous dermatological diagnosis - Chief complaint - Final diagnosis - Severity scales such as: o Angioedema Activity Score (AAS) o Urticaria Activity Score (UAS) o Scoring Index of Mastocytosis (SCORMA) The expected outcome is an article about the validity of the composite epidemiological tool with an expected duration of one year for data collection and implementation. Statistical analysis: The Statistical Package for Social Sciences (SPSS) version 22.0 will be used to analyze data. Comparing cases and controls for severity scales will be considered using the Chi Square test for cross tabulation of qualitative variables and the student t-test for quantitative variables. Kappa coefficient for agreement will be also used with different appropriate scales to assess the severity of the disease. The use of continuous/scale variables would compel us to compute an Intra-Class Correlation coefficient, predictive values, receiver operating characteristic (ROC) curve to measure specificity and sensitivity. In all cases, a p-value <0.05 will be considered significant. Estimation of Sample size Based on previous study data (3,13) and taking into consideration high Cronbach alpha values for urticaria diagnostic tools (UAS and UCT) ranging from 0.84 to 0.937, and based on the fact that the questionnaire to be used for the validation of diagnosis combines 40 items, we assumed that a minimum number of 400 patients are required to participate in the study. List of dermatology/immunolgy centers participating in the study : - Centre d'allergie et d'immunologie. Hôpital de Hotel-Dieu de France. Lebanon - LAU Medical Center - Risk hospital. Lebanon - Hamra Medical Center, Dermatology Clinic. Lebanon - Trad Medical Center, Clemenceau. Lebanon - Elie Melhem Clinics (EMC), Sin El Fil. Lebanon - Geitaoui Medical Center, Achrafieh. Lebanon - G&G (Gerbeka's) Dermatology Center, Sioufi. Lebanon - Centre Hospitalier Universitaire Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, FR-94010 Créteil. France  Phase 2 Because of the paucity of the global epidemiological information [7], a second phase of the study is to assess the prevalence of MCDD in adults using the previously validated tools. Assessing risk/triggering factors and the existence of interactions between personal and environmental factors in the exacerbation of these diseases will be a secondary objective. Evaluating the impact of MCDD on the quality of life of the affected patients using previously validated tools such as Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Dermatology Life Quality Index (DLQI), and Urticaria Control Test (UCT) and their cross-validation will be a tertiary objetive [14, 15, 16]. A cross-sectional study in the adult community will be conducted for this purpose. Using Epi-infoTM 7 for calculation of the sample size for cross-sectional studies (cluster sampling) in which the primary endpoint is the prevalence of urticaria worldwide, around 684 adults are required to enter the study (taking into account a lifetime prevalence rates of urticaria of 8.8% in adults [14] and a precision measure of 3%). A total sample size of 700 adults will be adopted to account for missing or confusing values and to have a generalizable sample size. A multistage stratified and cluster sampling will be conducted from the lists of random communities within the country. In every community, a random sample of adults will be interviewed. The composite tool validated in Phase 1 will be used to calculate the prevalence of MCDD after the preparation of the questionnaire including questions about urticaria risk factors and quality of life indicators based on previously validated tools. This estimation will be made using age brackets specific incidences. Adjustment over a World Health Organization (WHO) standardized population is a possibility to obtain a worldwide figure and to be able to compare among countries. Stratified cluster sampling will be adopted to divide the Lebanese population into regions (mainly eight governorates), then an equal number of adults will be chosen to be taken from each governorate that is divided into smaller communities (private dermatology clinics, universities, pharmacies, etc.). The expected outcome is the generation of two articles; the first is about the prevalence and estimation of risk factors of MCDD and the second is about its impact on the quality of life in the adult community with an expected duration of one year for implementation (networking, training …) and data collection and one more year for results analysis. Statistical analysis: For the statistical tests that will be used: the Chi Square test will be used for cross tabulation of qualitative variables and the student t-test or ANOVA for quantitative variables in bivariate analysis, and prevalence and incidence ratios will be calculated. A backward stepwise likelihood ratio logistic regression will be performed for multivariate analysis where urticaria will be the dependent variable. For the quality of life scores, results will presented as mean scores. Correlations will be calculated using Pearson correlation. Faisabilité: This PhD research will be able to validate a diagnostic tool for epidemiological studies as well as providing a strong evidence of the prevalence of the MCDD in the global population especially in the Middle-East and its impact on the quality of life. At the same time, the project will benefit from the logistics the program offers and the extensive experience of leaders in research in the field of dermatology under their supervision. The needed resources for phase 1 will be a network of dermatologists; trained research assistants; questionnaire for interview, pictorial aids; and usual diagnosis criteria. Random communities and pictorial aids are the needed resources for phase 2 as well as trained research assistants' teams (field workers) for interviews.

  • Titre traduit

    Mast-cell driven diseases (MCDD): Global epidemiology and management aspects in the Middle Eastern region.


  • Résumé

    This project will be divided into 2 phases. The first phase will focus on the validation of a diagnostic tool for epidemiological studies. The second phase will assess the prevalence using the previously validated tools as well as the estimation of risk factors associated with MCDD as well as its impact on the quality of life of affected patients.  Phase 1: An appropriately validated diagnostic tool for epidemiological studies in the general population is lacking. Such a tool will be generated in a clinical setting on physician-diagnosed urticaria patients (multicenter study) and validated later on. The use of a composite tool (questionnaire plus a pictorial aid) will be assessed, compared with the physician diagnosis considered as the golden standard. The value of pictorial aids for epidemiological studies has been demonstrated for HS [8], psoriasis [10], vitiligo [11], and atopic dermatitis [12], and has shown an increase in sensitivity and specificity in regards to the Gold standard diagnosis, which is the specialized physician diagnosis. In fact, the dermatology center of Henri –Mondor represented by Dr. Ezzedine has similar projects on many skin diseases and worked on the validation of auto-diagnostic tools [6,8]. A similar value for MCDD should be hypothesized in this project. In several centers from Lebanon and France (listed below), patients consulting for MCDD (cases) and for other non-related dermatological diseases (controls) will be asked to make their own diagnosis (in waiting rooms before encountering the physician): they would have to select their symptoms according to a list of symptoms and definitions, and to identify their skin lesions from the pictorial album. Specialized physicians participating in the study will dermatologists or immuno-allergists, part of a specific network for easy accessibility. The disease will then have to be confirmed or infirmed by the specialized physician, after applying the latest diagnosis criteria (and laboratory testing if necessary). This will allow the selection of the best diagnosing combination of symptom(s) and picture(s). Cases will be patients aged 12 years and older, with the most commonly encountered MCDD, namely acute and chronic urticaria, whether spontaneous or induced, in addition to mastocytosis. In case children lower than 12 years of age are to be included, parents of children will have to participate to the study as surrogate respondents. Patients of same age brackets with eczematous and exanthematic skin lesions, pruritus and angioedema, such as atopic dermatitis, psoriasis, prurigo, rosacae, hereditary or ACE-inhibitor-induced angioedema, and chronic pruritus with secondary skin lesions will be used as controls. Moreover, patients with viral infections presenting with non-urticarial rashes may also be included. In a similar setting to the tool generation study, the right combination identified above will be offered to patients for self diagnosis, before they consult the physician for confirmation. Validity criteria of the composite tool will be confirmed. A questionnaire, translated to different languages, will be used, including the following sections: - Socio-demographic and health characteristics - Previous dermatological diagnosis - Chief complaint - Final diagnosis - Severity scales such as: o Angioedema Activity Score (AAS) o Urticaria Activity Score (UAS) o Scoring Index of Mastocytosis (SCORMA) The expected outcome is an article about the validity of the composite epidemiological tool with an expected duration of one year for data collection and implementation. Statistical analysis: The Statistical Package for Social Sciences (SPSS) version 22.0 will be used to analyze data. Comparing cases and controls for severity scales will be considered using the Chi Square test for cross tabulation of qualitative variables and the student t-test for quantitative variables. Kappa coefficient for agreement will be also used with different appropriate scales to assess the severity of the disease. The use of continuous/scale variables would compel us to compute an Intra-Class Correlation coefficient, predictive values, receiver operating characteristic (ROC) curve to measure specificity and sensitivity. In all cases, a p-value <0.05 will be considered significant. Estimation of Sample size Based on previous study data (3,13) and taking into consideration high Cronbach alpha values for urticaria diagnostic tools (UAS and UCT) ranging from 0.84 to 0.937, and based on the fact that the questionnaire to be used for the validation of diagnosis combines 40 items, we assumed that a minimum number of 400 patients are required to participate in the study. List of dermatology/immunolgy centers participating in the study : - Centre d'allergie et d'immunologie. Hôpital de Hotel-Dieu de France. Lebanon - LAU Medical Center - Risk hospital. Lebanon - Hamra Medical Center, Dermatology Clinic. Lebanon - Trad Medical Center, Clemenceau. Lebanon - Elie Melhem Clinics (EMC), Sin El Fil. Lebanon - Geitaoui Medical Center, Achrafieh. Lebanon - G&G (Gerbeka's) Dermatology Center, Sioufi. Lebanon - Centre Hospitalier Universitaire Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, FR-94010 Créteil. France  Phase 2 Because of the paucity of the global epidemiological information [7], a second phase of the study is to assess the prevalence of MCDD in adults using the previously validated tools. Assessing risk/triggering factors and the existence of interactions between personal and environmental factors in the exacerbation of these diseases will be a secondary objective. Evaluating the impact of MCDD on the quality of life of the affected patients using previously validated tools such as Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Dermatology Life Quality Index (DLQI), and Urticaria Control Test (UCT) and their cross-validation will be a tertiary objetive [14, 15, 16]. A cross-sectional study in the adult community will be conducted for this purpose. Using Epi-infoTM 7 for calculation of the sample size for cross-sectional studies (cluster sampling) in which the primary endpoint is the prevalence of urticaria worldwide, around 684 adults are required to enter the study (taking into account a lifetime prevalence rates of urticaria of 8.8% in adults [14] and a precision measure of 3%). A total sample size of 700 adults will be adopted to account for missing or confusing values and to have a generalizable sample size. A multistage stratified and cluster sampling will be conducted from the lists of random communities within the country. In every community, a random sample of adults will be interviewed. The composite tool validated in Phase 1 will be used to calculate the prevalence of MCDD after the preparation of the questionnaire including questions about urticaria risk factors and quality of life indicators based on previously validated tools. This estimation will be made using age brackets specific incidences. Adjustment over a World Health Organization (WHO) standardized population is a possibility to obtain a worldwide figure and to be able to compare among countries. Stratified cluster sampling will be adopted to divide the Lebanese population into regions (mainly eight governorates), then an equal number of adults will be chosen to be taken from each governorate that is divided into smaller communities (private dermatology clinics, universities, pharmacies, etc.). The expected outcome is the generation of two articles; the first is about the prevalence and estimation of risk factors of MCDD and the second is about its impact on the quality of life in the adult community with an expected duration of one year for implementation (networking, training …) and data collection and one more year for results analysis. Statistical analysis: For the statistical tests that will be used: the Chi Square test will be used for cross tabulation of qualitative variables and the student t-test or ANOVA for quantitative variables in bivariate analysis, and prevalence and incidence ratios will be calculated. A backward stepwise likelihood ratio logistic regression will be performed for multivariate analysis where urticaria will be the dependent variable. For the quality of life scores, results will presented as mean scores. Correlations will be calculated using Pearson correlation. Faisabilité: This PhD research will be able to validate a diagnostic tool for epidemiological studies as well as providing a strong evidence of the prevalence of the MCDD in the global population especially in the Middle-East and its impact on the quality of life. At the same time, the project will benefit from the logistics the program offers and the extensive experience of leaders in research in the field of dermatology under their supervision. The needed resources for phase 1 will be a network of dermatologists; trained research assistants; questionnaire for interview, pictorial aids; and usual diagnosis criteria. Random communities and pictorial aids are the needed resources for phase 2 as well as trained research assistants' teams (field workers) for interviews.