Allergic and respiratory diseases affect a relevant segment of the population resulting in significant social and economic burden and their prevalence is increasing. For over 30 years, the prevalence of asthma has increased worldwide, especially among children and adolescents. According to the World Health Organization (WHO), there are now at least 300 million people suffering from asthma and over 200 million people suffering from COPD that includes chronic bronchitis and emphysema. In terms of mortality, each year in the world there are almost 250,000 asthma-related deaths and COPD ranks at the 5th leading cause of death. In addition, a WHO/World Bank projection to 2020 brings COPD to the 3rd leading cause of death with 4.7 million deaths. Although other allergic and respiratory diseases like rhinitis, drug allergy, pulmonary interstitial diseases … are also very common at the population level, their burden has still to be estimated.

 

a. “Historique”

EPAR (Equipe of Epidemiology of allergic and respiratory diseases) (E5) (www.epar.fr) has begun its research activities on allergic and respiratory disease within the “Unité Mixte de Recherche en Santé (UMR-S)” 707 (Epidemiology, Information Systems, Modelling) of INSERM and Université Pierre et Marie Curie (UPMC) Paris Sorbonne Universités, led by Professor Guy THOMAS, since 2006. Between 2007 and 2012, research work at EPAR generated a total of almost 300 scientific publications (papers, books chapters…), 200 of listed in PUBMED. The most important publications include articles in The New England Journal of Medicine, J Allergy and Clinical Immunology, Thorax, Amer J Crit Care Resp Med, Allergy, Eur Respir J, Health Env Perspective. Our main research focus has consisted in the identification of allergic and respiratory phenotypes and the determination of the role of environmental risk factors in the aggravation and the development of these phenotypes. This in view of explaining the augmentation of the prevalence of these conditions observed in the past decades worldwide. These research themes have been developed by Dr Isabella Annesi-­Maesano (DR2 INSERM) and Prof. Jocelyne Just (PU-PHUPMC). The central hypothesis of EPAR has been that in order to explain the increase of allergic and respiratory diseases observed in the past decades it is essential to take into account that these are heterogeneous conditions displaying different phenotypes and that the role of risk factors varies according to the type of phenotype. Important steps were achieved in the identification of phenotypes of asthma in early childhood when these diseases develop and in the comprehension of the impact of indoor and outdoor air pollution on asthma and COPD in susceptible populations, young children and elderly respectively. In the next 4 years, the work on the comprehension of the increase of allergic and respiratory diseases will expand to cover more allergic and respiratory diseases and to take into account other etiological factors. Clinical epidemiology of allergic and respiratory diseases that has been absent so far in EPAR activities will be newly developed by Prof. Pascal Démoly and his collaborators (University of Montpellier) that will join EPAR in order to investigate the fate of subjects with allergic and respiratory diseases and the influence of medical treatment (including immunotherapy) on evolution of these diseases, which has been done in a piecemeal fashion to date. In particular, drug allergy will be taken into account with the implementation of a registry. Another registry is starting for severe sarcoïdosis, one of the commonest pulmonary interstitial diseases (PID). Presently, PID are being screened successfully in the 93 department were they are very common. From the etiological point of view, the interactions of type gene (both genetic and epigenetic factors) - environment will be considered. In addition, the prevention component will be consolidated thanks to the arrival of the Department of General Practice of UPMC Paris Sorbonne Universités (Prof Anne-­‐Marie Magnier), who works on the respiratory effects of indoor air pollution at the primary care level. The project progression will be based on the development of novel methods for assessing human exposure (expology) (Dr. JF Bertholon, MCU-­‐PH at UPMC already associated with EPAR) and statistics applied to the case of allergy and respiratory disease (P. Saint Pierre, MCU, that will join EPAR) (Figure 1). The proposed EPAR structure will bring together researchers that have been working together already since several years and will thus provide the conditions for an even better promotion of the comprehension of allergic and respiratory diseases. Indeed, IAM, JJ, PD, AMM, JFB, PSP… already work together since several years as shown by mutual publications. Of note, the continuity of EPAR projects and activities is ensured by the presence of several young researchers that either have already permanent positions at UPMC (Dr Gladys Ibanez) or will try the INSERM “concours for CR” (Nour Baïz).

 
b. Caracterisation of the research

Despite the efforts, the increase in allergic and respiratory disease remains unexplained. This results partly from the approaches and methods that were used which have proved to be inappropriate and insufficient. On the one hand, the used approach did not take into account the heterogeneity of these diseases, which include several phenotypes; on the other hand, they inadequately measured environmental exposures and were limited to the physicochemical environment. To understand allergic and respiratory diseases that are complex diseases, a multidisciplinary approach is necessary. EPAR research work has to be positioned in this context. In terms of health indicators the work already started since 2007 to identify phenotypes and to introduce endotypes1  of allergy, asthma, and COPD and other pathologies through lifespan will continue. In terms of exposure, this will be estimated through quantitative and representative measures and will include the phenomenon of multi-­‐pollution exposure. In addition, a broader (other than exclusively physicochemical and biological) definition of environment will be taken into account. The interactions of type gene -­‐ environment, which are highly informative for understanding the mechanisms in the case of diseases with a genetic component as asthma, allergies, COPD…. will be investigated. Interaction studies of gene-­‐environmental type, including epigenetics and appropriate assessments of biological and chemical agents, are in their infancy. Yet, it is the consideration of these interactions that may lead to identify epigenetic and genetic determinants of asthma and COPD and their associated phenotypes/endotypes, and to elucidate the interactions of these determinants with environmental factors and hence their impact on the diseases through the entire life. In order to answer the research questions outlined above, EPAR will consist of 3 thematic poles corresponding to 3 separate objectives (Figure 1):

  1. Origins of Asthma and Allergies (ORAAL)
  2. Environment and allergic and respiratory health
  3. Clinical epidemiology of allergic and respiratory diseases and of a transversal research methodological axis developping “Expology and statistics applied to allergic and respiratory diseases”. All thematic poles will interact among them and share findings.

 

c. Collaborations

 

EPAR members and EPAR itself are known worldwide for their work in the field of the investigation of allergy and respiratory disease. They have participated and still participate in several research, education and advocacy initiatives. From the point of view of research, EPAR is involved in the following international and national ongoing collaborative scientific projects (as Work Package Leader), which allow EPAR to be included in the most updated research projects on allergic and respiratory diseases and to exchange with outstanding experts in the field. Findings from such studies will be published in peer-­review journals At the international level: -­ SINPHONIE (Schools Indoor Pollution and Health: Observatory Network in Europe) (DG-SANCO) (WP Leadership) -­ PHASE (Public Health Adaptation Strategies to extreme weather events) (DG-­SANCO) (WP Leadership). -­ MeDALL (Mechanisms of the Development of Allergy) (FP7 project) and its ancillary projects (CHICOS…) -­ ESCAPE (European Study of Cohorts for Air Pollution Effects) -­ ECRHS III (European Community Respiratory Health Survey-­Phase III) - ITCH (Genetics of drug allergy) -­ PROTECT (IMI, EMA project, drug allergy) At the national level, major ongoing funded projects include: EDEN ((WP Leadership), EGEA ((Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy) and Asthm’child), FERMA, TAP, ELFE… In addition, EPAR will promote research, knowledge and advocacy on allergic and respiratory diseases through its partnership with national and international networks (GA²LEN, Global Allergy and Asthma European Network, funded by the European Union, WHO GARD Global Alliance against Respiratory Diseases), WHO ARIA (Allergic rhinitis initiative in asthma)…) and collaborations with national and international agencies, medical societies, and scientific programming communities (European respiratory Society (ERS): Clinical Assembly, Occupation and Epidemiology Assembly and Paediatric Assembly, European Academy of Allergy and Clinical Immunology (EAACI): Paediatrics section and Aerobiology and air pollution Interest Group), American Thoracic Society (ATS), International Union against Tuberculosis and Lung Diseases (IUATLD), International Respiratory Clinical Research network, Society of Pneumology of French Language (SPLF), National Committee to Fight against Lung Disease (CNMRT), French Office for the fight against Smoking, French Society of Allergology and Clinical Immunology (SFAIC), French Society of Pediatrics….). EPAR will continue to contribute to the annual meetings of the European Respiratory Society (ERS), the European Academy of Allergy and Clinical Immunology (EAACI) (since 2010) and the American Thoracic Society (ATS) (since 2011), Congrès de Pneumologie de Langue Française (CPLF), Congrès Francophone d’Allergologie (CFA), J2R (Respiratory Days). EPAR educational activities will continue besides teaching at various University degrees (Medical School, Master degrees, Specialty School, EAACI and ERS Schools…) by proposing Master and PhD projects in France and abroad.

 

d. Tools

 

 

1 «An endotype is a subtype of a condition, which is defined by a distinct functional or pathobiological mechanism. This is distinct from a phenotype, which is any observable characteristic or trait of a disease, such as morphology, development, biochemical or physiological properties, or behavior, without any implication of a mechanism. It is envisaged that patients with a specific endotype present themselves within phenotypic clusters of diseases». (Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008 Sep 20;372(9643):1107-19)