CLINICAL STUDIES OF ABNORMAL HOST DEFENSE

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The purpose of this project is to study patients with abnormal host defense. In FY '94 studies focussed on patients with abnormal phagocyte function. These include patients with chronic granulomatous disease of childhood (CGD), Hyperimmunoglobulin E-recurrent infection sydrome (Job's), specific granule deficiency, leukocyte adhesion deficiency and other patients with recurrent infections who do not fall into a specifically defined disease category. Currently we follow 77 patients with CGD, 18 patients with the hyperimmunoglobulin-E recurrent infection syndrome, and 18 patients with other phagocyte dysfunction syndromes. In addition, 12 patients are followed with disseminated multiple drug resistant-atypical mycobacteria infections, some of whom appear to have abnormalities of phagocytic cells. A phase IV study of the effect of interferon-gamma for infection prophylaxis in CGD has continued at NIH at the specific request of the FDA. No unexpected toxicities have been seen with interferon-gamma. The reduction in infections observed in the initial study has been sustained and of note is that the incidence of fungal infections in CGD patients receiving interferon-gamma is half that for those patients not receiving the drug. In view of the high incidence of fungal infections in CGD patients, we have also initiated a study designed to assess the efficacy of itraconazole in CGD. Several long term studies were completed related to specific management issues of CGD patients. These included comprehensive reviews of skeletal involvement in CGD, special anesthetic considerations in CGD, unique urologic manifestations in CGD, the surgical management of pulmonary infections in CGD, and the surgical pathology of the lung in CGD. Each of these clinical studies could only be compiled at NIH where a large cohort of CGD patients could be followed for a long time. Several unique infections and their successful management were described in CGD. These include reports of the successful treatment of Sarcinosporon inkin, Exophiala dermatitidis, and Paecilomyces varioti. The encouraging findings in CGD patients prompted consideration of the use of interferon- gamma in other infectious diseases.As part of our long term objective of evaluating interferon-gamma in tuberculosis, we initiated studies of its use in an unusual patient population with disseminated atypical mycobacteria infection resistant to conventional therapy. Twelve patients have been studied to date. Dramatic clinical benefit with eradication of the infection was seen in the patients treated.