The purpose of this project is to study patients with abnormal host defense; to determine the cause of their abnormality; and to devise effective therapies for their underlying disorder and the life-threatening infections associated with their disease processes. The LHD has a long tradition of investigating patients with abnormalities of phagocytic cell function. These studies include early delineation of the clinical, functional, and in some cases, the molecular defects of patients with neutrophil specific granule deficiency, chronic granulomatous disease of childhood (CGD), leukocyte adhesion deficiency and the syndrome of hyperimmunoglobulin-E and recurrent infections and IRAK-4 deficiency. Cohorts of patients have been collected over the years which we continue to follow at NIH. Currently we follow over 150 patients with CGD, about 40 patients with the hyperimmunoglobulin-E recurrent infection syndrome, and 30 patients with other phagocyte dysfunction syndromes, including leukocyte adhesion deficiency, cyclic neutropenia, neutrophil specific granule deficiency and Chediak-Higashi syndrome and IRAK-4 deficiency. All these patients serve as a national resource for investigators desiring samples from patients and are available for clinical research protocols involving intramural or extramural scientists. We now have EB virus transformed B cells from most of our patients and we have been pleased to share these B cell lines with other intramural or extramural colleagues. We continue to monitor and expand these cohorts of patients who serve as models for long term studies of the immunological manipulation of the abnormal host defenses. This year we completed a long term study in 76 CGD patients enrolled in an uncontrolled, open label follow-up study to assess the long-term clinical safety and efficacy of interferon-?. We followed patients for up to 9 years (328 patient years). Serious infections were 0.3 per patient year (bacterial 0.18; fungal 0.12). Mild adverse events were common but tolerable in most patients (fever in 38% of patients. But some patients withdrew because of the adverse events (3) or patient preference (15), or for transfer to another trial (8). Children born to patients during the trial were healthy. There were no life-threatening interferon-? adverse events and no discernable effect on growth and development. The overall mortality was 6.6% over 9 years. Thus, interferon-? prophylaxis for CGD appears effective and well tolerated over a prolonged period of time.
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