Background:  Cryptococcal meningitis (CM) is the second most frequent AIDS-defining illness in Sub-Saharan Africa. Paradoxical inflammatory reactions known as HIV immune reconstitution inflammatory syndrome (IRIS) occur frequently in patients with recent CM after they initiate ART.

Methods:  We prospectively evaluated 115 ART-naïve Ugandan subjects with AIDS for 12 months after initiation of ART; 65 subjects had recent CM and 50 control subjects had no known active opportunistic infection. Serum cytokines (n = 27) were measured serially over 24 weeks of ART using Luminex multiplex assays.

Results:  In subjects with recent CM, IRIS manifest as paradoxical worsening occurred in 45% (29 of 65) during the first year of ART. The median time of CM-IRIS was 6 weeks (IQR 4 to 19, maximum 29); 17 CM subjects died (26% of CM). CM-IRIS was independently associated with death (OR 6.7, 95%CI 1.8 to 24.0, p = 0.004) in a multivariate analysis including CM-status and CD4 count. At the time of IRIS events, levels of C-reactive protein (CRP), D-dimer, interleukin (IL) -6), granulocyte-macrophage colony-stimulation factor (GM-CSF), and IL-1ra were increased in cryptococcal-IRIS subjects compared to time-matched controls (p <0.05). Elevated pre-ART CRP levels of >33 mg/L (highest-quartile) were independently associated with future death (OR 10.4, 95%CI 2.5 to 42, p = 0.001) or CM-IRIS (OR 4.8, 95%CI 1.3 to 18.4, p = 0.02). Higher pre-ART levels of IL-12, lower IP-10 levels, or undetectable GM-CSF levels were associated with future IRIS (p <0.05). The combination of a pre-ART elevation of CRP (>33 mg/L), and IL-4 (>7 pg/mL) together predicted IRIS (100%) and death (80%).

Conclusions:  Serum inflammatory biomarkers predict risk for development of cryptococcal-IRIS after the initiation of ART. Our results suggest that a cytokine imbalance pre-ART, characterized by elevated serum IL-4 and CRP, in combination with decreased IP-10 and GM-CSF levels, is associated with the subsequent development of IRIS.