Deloris E. Koziol

BACKGROUND: Chronic granulomatous disease is a rare disorder in which the phagocytes fail to produce hydrogen peroxide. The patients are predisposed to bacterial and fungal infections. Prophylactic antibiotics and interferon gamma have reduced bacterial infections, but there is also the danger of life-threatening fungal infections. We assessed the efficacy of itraconazole as prophylaxis against serious fungal infections in chronic granulomatous disease. METHODS: Thirty-nine patients at least 5 years old (6 female and 33 male; mean age, 14.9 years) were enrolled in a randomized, double-blind, placebo-controlled study. After the initially assigned treatment, each patient alternated between itraconazole and placebo annually. Patients 13 years of age or older and all patients weighing at least 50 kg received a single dose of 200 mg of itraconazole per day; those less than 13 years old or weighing less than 50 kg received a single dose of 100 mg per day. The primary end point was severe fungal infection, as determined by histologic results or culture. RESULTS: One patient (who had not been compliant with the treatment) had a serious fungal infection while receiving itraconazole, as compared with seven who had a serious fungal infection while receiving placebo (P=0.10). No patient receiving itraconazole but five patients receiving placebo had a superficial fungal infection. No serious toxic effects were noted, although one patient had a rash and another had elevated results on liver-function tests; both of these effects resolved with the discontinuation of itraconazole. CONCLUSIONS: Itraconazole prophylaxis appears to be an effective and well-tolerated treatment that reduces the frequency of fungal infections in chronic granulomatous disease, but monitoring for long-term toxic effects is warranted.

BACKGROUND: Genetic variations in cytokine genes are thought to regulate cytokine protein production. However, studies using T cell mitogens have not always demonstrated a significant relationship between cytokine polymorphisms and in vitro protein production. Furthermore, the functional consequence of a polymorphism at position -330 in the IL-2 gene has not been described. We associated in vitro protein production with cytokine gene polymorphic genotypes after costimulation of cultured peripheral blood lymphocytes. METHODS: PBL were isolated from forty healthy volunteers. Cytokine protein production was assessed by enzyme-linked immunosorbent assay. Polymorphisms in interleukin- (IL) 2, IL-6, IL-10, tumor necrosis factor (TNF-alpha), tumor growth factor (TGF-beta), and interferon (IFN-gamma) were determined by polymerase chain reaction (PCR). RESULTS: Statistical difference between protein production and cytokine polymorphic variants in the IL-10, IFN-gamma, and TNF-alpha genes was not evident after 48-hour stimulation with concanavalin-A. In contrast, after anti-CD3/CD28 stimulation significant differences (P<0.05) were found among high and low producers for IL-2, IL-6, and among high, intermediate, and low producers for IFN-gamma, and IL-10. Augmented levels of IL-2 in individuals that were homozygous for the polymorphic IL-2 allele were due to an early and sustained enhancement of IL-2 production. No association was found among TNF-alpha and TGF-beta genotypes and protein production. CONCLUSION: Polymorphisms in IL-2, IL-6, IL-10, and IFN-gamma genes are associated with their protein production after anti-CD3/CD28 stimulation. The profound effect of the IL-2 gene polymorphism in homozygous individuals may serve as a marker for those that could mount the most vigorous allo- or autoimmune responses, or perhaps become tolerant more easily.

The relationship between the presence of antibody to hepatitis B core antigen (anti-HBc) in donor blood and the development of hepatitis in recipients of that blood was studied in 6293 blood donors and 481 recipients who were followed for 6 to 9 months after transfusion. Of 193 recipients of at least 1 unit of blood positive for anti-HBc, 23 (11.9%) developed non-A, non-B hepatitis compared with 12 (4.2%) of 288 recipients of only anti-HBc-negative blood (p less than 0.001). Donor anti-HBc status was not significantly associated with the development of hepatitis B in the recipient and was negatively associated with the development of cytomegalovirus hepatitis. The relationship of donor anti-HBc status and the development of non-A, non-B hepatitis in the recipient was independent of transfusion volume and elevated donor transaminase level. Although 88% of anti-HBc-positive blood units were not associated with recipient non-A, non-B hepatitis, calculation of maximal corrected efficacy predicted that exclusion of anti-HBc-positive donors might have prevented 43% of the cases of non-A, non-B hepatitis with a donor loss of 4%. Because of the serious chronic consequences of non-A, non-B hepatitis, surrogate tests for non-A, non-B virus carriers must be seriously considered.

OBJECTIVE: To validate manual muscle testing (MMT) for strength assessment in juvenile and adult dermatomyositis (DM) and polymyositis (PM). METHODS: Patients with PM/DM (73 children and 45 adults) were assessed at baseline and reevaluated 6-9 months later. We compared Total MMT (a group of 24 proximal, distal, and axial muscles) and Proximal MMT (7 proximal muscle groups) tested bilaterally on a 0-10 scale with 144 subsets of 6 and 96 subsets of 8 muscle groups tested unilaterally. Expert consensus was used to rank the best abbreviated MMT subsets for face validity and ease of assessment. RESULTS: The Total, Proximal, and best MMT subsets had excellent internal reliability (Total MMT r(s) = 0.91-0.98), and consistency (Cronbach's alpha = 0.78-0.97). Inter- and intrarater reliability were acceptable (Kendall's W 0.68-0.76, r(s) = 0.84-0.95). MMT subset scores correlated highly with Total and Proximal MMT scores and with the Childhood Myositis Assessment Scale, and correlated moderately with physician global activity, functional disability, magnetic resonance imaging, and axial and distal MMT scores, and, in adults, with creatine kinase level. The standardized response mean for Total MMT was 0.56 in juveniles and 0.75 in adults. Consensus was reached to use a subset of 8 muscles (neck flexors, deltoids, biceps, wrist extensors, gluteus maximus and medius, quadriceps, and ankle dorsiflexors) that performed as well as the Total and Proximal MMT, and had good face validity and ease of assessment. CONCLUSION: These findings aid in standardizing the use of MMT for assessing strength as an outcome measure for myositis.