Abstract
Primary immunodeficiency diseases (PID) result from defects in genes affecting the immune and other systems in many and varied ways (1, 2). Until the last few years, treatments have been largely supportive, with the exception of bone marrow transplantation. However, recent advances in immunobiology, genetics, and the explosion of discovery and commercialization of biologic modifiers have drastically altered the landscape and opportunities in clinical immunology. Therapeutic options and life expectancy of PID patients have also improved dramatically, in large part as a result of better prevention and treatment of infections as well as better understanding and treatment of autoimmune complications (3). As early-life infection-related mortality declines we should anticipate the emergence of other conditions that were previously not appreciated, including malignancies and degenerative disorders unmasked by increasing longevity (4). The genomic revolution has identified literally hundreds of new genetic etiologies of immune dysfunction, many of which are or will soon be eligible for targeted therapies. These emerging immunomodulatory agents represent new therapeutic options in PIDs (5).
Highlights
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States
chronic granulomatous disease (CGD) served as the first Primary immunodeficiency diseases (PID) for which cytokine therapy with interferon gamma (IFNγ) [8] and antifungal prophylaxis was indicated and approved [9]
The reasons that CGD played such a prominent role in the development and study of prophylaxis were that it was relatively survivable with medical management and bone marrow transplantation was relatively infrequent until recently
Summary
Fungal, viral, and mycobacterial infections carry a high morbidity and mortality in the immunocompromised, and enormous effort has been directed at prevention. A relatively large population of patients was able to participate in clinical trials, which markedly assisted the exploration and development of therapeutics This paradigm has been missing from several other diseases, either because they are not as survivable or because bone marrow transplantation has been more aggressively practiced [e.g., severe combined immune deficiency, Wiskott–Aldrich syndrome (WAS), hyper-IgM syndrome]. For these reasons, many of the approaches discussed below will not have significant prospective clinical validation, making it necessary to rely upon mechanistic explanations and anecdotal reports. While it is likely that in the relatively near future treatments to replace (transplantation) or repair (gene therapy) the underlying
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