Paucity of Initial Cerebrospinal Fluid Inflammation in Cryptococcal Meningitis Is Associated with Subsequent Immune Reconstitution Inflammatory Syndrome

Background. Cryptococcal meningitis (CM)-related immune reconstitution inflammatory syndrome (IRIS) complicates antiretroviral therapy (ART) in 20%-40% of ART-naive persons with AIDS and prior CM. Pathogenesis is unknown. Methods. We compared initial cerebrospinal fluid (CSF) cultures, inflammatory markers, and cytokine profiles in ART-naive patients with AIDS who did or did not subsequently develop IRIS after starting ART. We also compared results obtained at IRIS events or CM relapse. Results. Of 85 subjects with CM, 33 (39%) developed CM-related IRIS and 5 (6%) developed culture-positive CM relapse. At CM diagnosis, subjects subsequently developing IRIS had less inflammation, with decreased CSF leukocytes, protein, interferon-gamma, interleukin-6, interleukin-8, and tumor necrosis factor-alpha, compared with subjects not developing IRIS (P<.05, for each). Initial CSF white blood cell counts <= 25 cells/mu L and protein levels <= 50 mg/dL were associated with development of IRIS (odds ratio, 7.2 [95% confidence interval, 2.7-18.7]; P<.001). Compared with baseline levels, we identified CSF elevations of interferon-gamma, tumor necrosis factor-alpha, granulocyte colony-stimulating factor, vascular-endothelial growth factor, and eotaxin (CCL11) (P<.05, for each) at the time of IRIS but minimal inflammatory changes in those with CM relapse. Conclusions. Patients who subsequently develop CM-related IRIS exhibit less initial CSF inflammation at the time of CM diagnosis, compared with those who do not develop IRIS. The inflammatory CSF cytokine profiles observed at time of IRIS can distinguish IRIS from CM relapse.