Background Cryptococcal meningitis (CM)-related immune reconstitution inflammatory syndrome (IRIS) complicates antiretroviral therapy (ART) in 20–40% of ART-naïve persons with AIDS and prior CM. Pathogenesis is unknown. Methods We compared initial CSF cultures, inflammatory markers and cytokine profiles in ART-naïve AIDS patients 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-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 (IFN-g), interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha (TNF-a) compared with subjects not developing IRIS (P<.05). Initial CSF WBCs ≤25 cells/μL and protein ≤50 mg/dL were associated with development of IRIS (OR=7.2, 95%CI: 2.7 to 18.7, P<.001). Compared to baseline levels, we identified CSF elevations of IFN-g, TNF-a, G-CSF, VEGF, and eotaxin (CCL11) (P<.05) at IRIS but minimal inflammatory changes in those with CM relapse. Conclusions Patients who subsequently develop CM-IRIS exhibit less initial CSF inflammation at the time of CM diagnosis compared to those who do not develop IRIS. The inflammatory CSF cytokine profiles observed at time of IRIS can distinguish IRIS from CM-relapse.

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