Primary immunodeficiency disorders in Southeast Asia : needs, priorities and opportunities

Primary immunodeficiency disorders (PID) are rare inborn errors of the immune system. Patients with PID are susceptible to infections, autoimmunity, lymphoproliferation, allergy and cancer as a result of immune aberrations. The field of PID is marked by rapid discovery in genetic etiologies, disease mechanisms and novel treatments. However, the gap between cutting-edge scientific research and its translation to clinical practice is widening, as the lack of resources and expertise in PID remains the critical bottle-neck in many countries. In 2009, The Asian Primary Immunodeficiency (APID) Network was established by the Department of Paediatrics and Adolescent Medicine, The University of Hong Kong with the mission to promote awareness of PID among clinicians in mainland China and Southeast Asia by means of a consultative platform, and to offer genetic tests for patients with suspected PID for diagnostic confirmation. This thesis provides a comprehensive review of the clinical characteristics and genetic findings of patients referred to the APID Network. The trend and current status of PID service development in Asia was analyzed, with an aim to identify the needs and priorities in improving the standard of care for PID. Data supported a major improvement PID care in terms of the age of diagnosis, particularly in X-linked agammaglobulinemia and Wiskott-Aldrich syndrome. However, treatment remained a major issue for severe combined immunodeficiency due to disease severity and the lack of expertise and resources, limiting the availability of hematopoietic stem cell transplantation which is the life-saving procedure to these children. Long-term follow-up and outcome data are largely unavailable for PID in Asia. All these are imminent issues to be tackled. The close collaboration among immunology centers and systematic data analysis constitute the foundation for research on PID. This provides insights into the phenotypic and genetic diversities, as well as unique disease presentations in Asia which are not otherwise described in the literature. This study highlights the susceptibility to BCG-osis, tuberculosis, melioidosis and Chromobacterium violaceum infection in patients with chronic granulomatous disease. By performing a detailed systematic literature review of Penicillium marneffei infection, a form of endemic mycosis in Southeast Asia, penicilliosis was first advocated as an indicator for PID in HIV-negative individuals. This was followed by the discovery of autosomal dominant STAT1 defect as a genetic predisposition for this fatal infectious disease. The collaborative network also provides exciting opportunities for discovering novel PID. Our work demonstrated that whole exome sequencing is readily applicable to the clinical setting for identifying monogenic cause of well-defined phenotypes, and is particularly valuable in multi-centered studies involving patients from diverse ethnic background. Our findings also revealed how whole exome sequencing could uncover atypical phenotypes of classical PID, which would otherwise be missed by adopting an algorithmic diagnostic approach. The continuous efforts of the APID Network will not only directly benefit more patients and their families, but will undoubtedly contribute to the advancement of knowledge in PID.published_or_final_versionPaediatrics and Adolescent MedicineMasterDoctor of Medicin