Two patients with cryptococcal meningitis and idiopathic CD4 lymphopenia: defective cytokine production and reversal by recombinant interferon- gamma therapy.

BACKGROUND Although Cryptococcus neoformans is a fungal pathogen that causes human disease predominantly in the immunocompromised host, severe cryptococcal infections are occasionally encountered in apparently immunocompetent individuals. Activation of cellular immunity by proinflammatory cytokines plays a central role in anticryptococcal defense. METHODS We describe 2 patients with severe cryptococcal meningitis who appeared to have idiopathic CD4 lymphopenia. For these patients and for 4 healthy volunteers, ex vivo stimulation of whole blood with microbial stimuli was used to investigate putative defects in cytokine production capacity. RESULTS Assessment of the cytokine released from the 2 patients with CD4 lymphopenia revealed a defective production of the proinflammatory cytokines interferon (IFN)- gamma and tumor necrosis factor (TNF) but not of the anti-inflammatory cytokine interleukin-10 (IL-10). One patient with disease progression despite receipt of antifungal treatment was administered immunotherapy with recombinant IFN- gamma . Administration of recombinant IFN- gamma resulted in both restoration of immunological parameters and a sustained clinical recovery. CONCLUSIONS Refractory meningitis may be due to defective TNF and IFN- gamma production, and IFN- gamma treatment may be useful in patients with an impaired cellular immune response and refractory cryptococcal meningitis.