ABSTRACT
Following a fatal case of Cryptococcus neoformans meningitis in a child with X-linked hyper-immunoglobulin M syndrome (XHIGM), we evaluated the fungal isolate in an experimental infection in a mouse model with respect to microbiology, epidemiology, virulence and response to therapy. The minimum inhibitory concentrations for antifungals in the susceptibility test were 0.5mg/L for amphotericin B, 4.0mg/L for fluconazole and 0.12mg/L for voriconazole. Evaluation of pathogenicity by means of an experimental infection in BALB/c mice showed that fungus isolated from the blood and cerebrospinal fluid of the child was able to disseminate, reaching the spleen, lungs and brain, where it caused significant macroscopic alterations in the size and texture of each organ. Treatment of infected mice with amphotericin B reduced the fungal load in the spleen and lungs, but not in the brain.
Subject(s)
Cryptococcus neoformans/isolation & purification , Cryptococcus neoformans/pathogenicity , Hyper-IgM Immunodeficiency Syndrome, Type 1/complications , Hyper-IgM Immunodeficiency Syndrome, Type 1/microbiology , Meningitis, Cryptococcal/diagnostic imaging , Meningitis, Cryptococcal/microbiology , Amphotericin B/pharmacology , Animals , Antifungal Agents/pharmacology , Child, Preschool , Cryptococcus neoformans/drug effects , Disease Models, Animal , Fatal Outcome , Humans , Hyper-IgM Immunodeficiency Syndrome, Type 1/diagnosis , Male , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Tomography, X-Ray ComputedABSTRACT
X-linked hyper-IgM syndrome (XHM) is a combined immune deficiency disorder caused by mutations in CD40 ligand. We tested CP-870,893, a human CD40 agonist monoclonal antibody, in the treatment of two XHM patients with biliary Cryptosporidiosis. CP-870,893 activated B cells and APCs in vitro, restoring class switch recombination in XHM B cells and inducing cytokine secretion by monocytes. CP-870,893 infusions were well tolerated and showed significant activity in vivo, decreasing leukocyte concentration in peripheral blood. Although specific antibody responses were lacking, frequent dosing in one subject primed T cells to secrete IFN-g and suppressed oocyst shedding in the stool. Nevertheless, relapse occurred after discontinuation of therapy. The CD40 receptor was rapidly internalized following binding with CP-870,893, potentially explaining the limited capacity of CP-870,893 to mediate immune reconstitution. This study demonstrates that CP-870,893 suppressed oocysts shedding in XHM patients with biliary cryptosporidiosis. The continued study of CD40 agonists in XHM is warranted.
