Severe mycobacterial IRIS in advanced HIV has features of hemophagocytic lymphohistiocytosis and requires prolonged immune suppression

People with HIV and mycobacterial infections can develop immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy. Severe mycobacterial-IRIS has an overlapping clinical phenotype with hemophagocytic lymphohistiocytosis (HLH). To evaluate the pathophysiologic similarities between mycobacterial-IRIS and HLH and identify clinical and immune predictors of mycobacterial-IRIS severity. HLH-criteria were applied to a longitudinal cohort of 80-patients with HIV (CD4?< ?100 cells/µL) and mycobacterial infections. Participants were subdivided into IRIS meeting HLH-criteria (HLH-IRIS), IRIS without HLH (IRIS), and those without IRIS (Non-IRIS). Clinical outcomes were evaluated by regression analyses. Soluble biomarkers and T-cell immune phenotypes were assessed at baseline and IRIS-equivalent timepoints. HLH-IRIS patients required corticosteroids more frequently (OR 21.5 [CI95% 5.6-114.8]) and for longer duration (21.2-weeks [CI95% 10.7-31.7]) than those not meeting HLH-criteria. Utilizing decision tree analyses, hemoglobin < 9.2 g/dL was the best predictor of HLH-IRIS before antiretroviral treatment, whereas ferritin and immune markers (CXCL-9, sCD25) were most diagnostic for HLH at onset of IRIS. At the IRIS-timepoint, but not baseline, HLH-IRIS patients had lower regulatory and higher activated T-cells along with greater production of IFN?-IL18 axis biomarkers compared to both IRIS and Non-IRIS groups. Principal component analysis corroborated the distinct clustering of HLH-IRIS patients. Severe mycobacterial-IRIS and HLH have an overlapping pathogenesis involving IFN? and unopposed T-cell activation causing severe inflammatory disease clinically distinguished by hyperferritinemia (hyperferritinemic IRIS or FIRIS). Hemoglobin, ferritin, CXCL-9, and sCD25 identify this high-risk population and may improve risk stratification and therapeutic strategies for mycobacterial-IRIS. Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.

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