Abstract
Combined immunodeficiencies (CIDs) are a clinically and genetically heterogeneous group of primary immunodeficiencies (PIDs) that affect T-lymphocyte immunity with abnormal development or function. As compared to severe combined immune deficiencies (SCID), these patients are usually diagnosed later. They display a broad infectious susceptibility; immune dysregulation manifestations and chronic lymphoproliferation are also frequent. These complications and their specific treatments can lead to persistent damage to several organs. Prognosis of CIDs is worse as compared to other PIDs. The curative treatment is usually hematopoietic stem cell transplantation (HSCT), but difficult questions remain regarding the definitive indication of HSCT and its timing; the final decision depends on a conjunction of factors such as immunological parameters, severity of clinical manifestations, and natural history of the disease, when molecular diagnosis is known. CD40L deficiency, a CID caused by mutations in CD40LG gene, well illustrates the dilemma between HSCT vs. long-term supportive treatment. This disease leads to higher risk of developing infections from bacterial and intracellular pathogens, especially Pneumocystis and Cryptosporidium spp. While supportive care allows improved survival during childhood, organ damages may develop with increasing age, mainly chronic lung disease and biliary tract disease (secondary to Cryptosporidium spp. infection) that may evolve later to sclerosing cholangitis, a severe complication associated with increased mortality. Early HSCT before organ damage development is associated with best survival and cure rate, while HSCT remains a risky therapeutic option for older patients, for those with organ damage, especially severe liver disease, and/or for those with limited or no donor availability. Prospective studies are needed to analyze risks of HSCT compared to those of life-long supportive therapy, including quality of life measures.
Highlights
Reviewed by: Kohsuke Imai, Tokyo Medical and Dental University, Japan Antonio Condino-Neto, University of São Paulo, Brazil
The curative treatment is usually hematopoietic stem cell transplantation (HSCT), but difficult questions remain regarding the definitive indication of HSCT and its timing; the final decision depends on a conjunction of factors such as immunological parameters, severity of clinical manifestations, and natural history of the disease, when molecular diagnosis is known
CD40 ligand (CD40L) deficiency, a Combined immunodeficiencies (CIDs) caused by mutations in CD40LG gene, well illustrates the dilemma between HSCT vs. long-term supportive treatment
Summary
Combined immunodeficiencies (CIDs) are a clinically and genetically heterogeneous group of primary immunodeficiencies (PIDs) that affect T-lymphocyte immunity with abnormal development or function. Defects of immune regulation are frequent and can lead to autoimmune and immune dysregulation manifestations that in some circumstances can be the predominant features. They occur in up to 40% of patients with CIDs, autoimmune cytopenia and inflammatory bowel diseases being the most frequent [2]. Lymphoma is observed [4] This can be due to impaired immunosurveillance to viral or tumoral antigens; chronic inflammation and infection with oncogenic viruses such as Epstein Barr Virus (EBV) can promote lymphoproliferation. A proportion of patients with CIDs remains without molecular diagnosis [37]
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