Cerebrospinal Fluid Cytokine Profiles Predict Risk of Early Mortality and Immune Reconstitution Inflammatory Syndrome in HIV-Associated Cryptococcal Meningitis

Author Summary Cryptococcal meningitis is a severe opportunistic infection, estimated to kill several hundred thousand HIV-infected individuals each year. One of the factors contributing to this high death toll is the inadequacy of antifungal treatments. As few novel antifungal drugs are being developed, several groups have started to investigate the potential of immune modulation, with treatments designed to change the patient's immune response to infection. However, our understanding of the immune response to cryptococcal infection in HIV-infected patients, and how these responses impact on clinical outcomes, is limited. In this study, we took advantage of the fact that we can sample cerebrospinal fluid (CSF) from the site of the infection in patients when they develop cryptococcal meningitis. We undertook a detailed analysis measuring levels of immune response parameters in the CSF of these patients, and demonstrated that there were several distinct components of the immune response. Variations in these responses were associated with both the rate at which patients cleared their infection during treatment, and with mortality. Our results provide a basis for the development of future immunomodulatory therapies, and may allow identification of patients most at risk of dying, enabling more intensive treatments to be given to those at highest risk.