Complement Depletion in Cryptococcal Sepsis

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Abstract
Marked depletion of serum opsonins and complement (C) components was documented during cryptococcal septicemia in three patients. Phagocytic indices (PI) obtained with normal (nl) neutrophils and sera from these patients were <0.2 (nl 1.8 to 2.3). Serum total hemolytic C (CH50) was <10% of normal; C3 levels by immunoassay were depressed in all three patients (values were 23, 37, and 24 mg%; nl 80 to 140). Serum C4 levels by bioassay were normal in two patients and depressed in a single patient whose serum contained IgG antibody to Cryptococcus neoformans (CN) (C4 level 2956; nl 70,000 to 193,000). Cleavage products of factor B in serum were demonstrated in the three patients by immunoelectrophoresis. Ability of these sera to mediate C3 binding to CN was severely impaired. Direct immunofluorescence assay detected no C3 fixation to CN. Radioimmunoassay (RIA) of two patients' sera diluted 1/20 detected 36 and 26% normal binding of C3 to CN. Fluorescent and RIA assays with CN-absorbed sera and MgEGTA sera suggest an important role for the alternative C pathway in fixation of opsonic C3 fragments to the CN surface. No depletion of serum opsonins or C components was found in six other patients with cryptococcosis who were not fungemic at time of study. Guinea pigs given 6 × 108 CN developed fungemia and died within 2 weeks. Their sera revealed depletion of serum opsonins and hypocomplementemia. Mean serum PI was 1.0 (nl 2.2 to 3.3) and mean CH50 was 99 (nl 150 to 300 units/ml). Heat-killed CN in intracardiac doses of 2 × 109 and 5 × 109 cells produced the same phenomenon acutely. Sera obtained at 60 min had PI of 0.7 and 1.1 and CH50 of 119 and 103. Depletion of serum C components accompanied CN fungemia in both man and experimentally infected guinea pigs. Yeast within the bloodstream may be the direct cause of hypocomplementemia. The resulting loss of serum opsonins may further impair the host's ability to contain the infection.