W166 - Severe Mycobacterial Immune Reconstitution Inflammatory Syndrome can cause Secondary Hemophagocytic Lymphohistiocytosis with a Unique Immune and Genetic Profile

People with HIV/AIDS and mycobacterial infections can develop immune reconstitution inflammatory syndrome (IRIS) after starting antiretrovirals. Mycobacterial-IRIS has an overlapping clinical phenotype with hemophagocytic lymphohistiocytosis (HLH). We applied HLH-criteria to 80-patients with AIDS and mycobacterial infections followed at NIH and evaluated clinical outcomes, biomarkers, immunophenotypes, and genetics.  

Overall, 32.5% developed IRIS and met HLH-criteria (HLH-IRIS group, n=26), whereas 35% had IRIS without meeting HLH-criteria (IRIS group, n=28). IRIS did not occur in 32.5% (Non-IRIS group, n=26). Clinical outcomes were evaluated by logistic/linear regression. We measured 23-biomarkers at baseline and IRIS-timepoints. Flow cytometry was performed for activated and regulatory T-cells. Protein-altering variants in cytotoxicity and immunoregulatory genes were evaluated for with next generation sequencing.

HLH-IRIS patients required more steroids (OR 24.4 [CI_95%6.0-138.5]) for a duration 24.9-weeks (CI_95%14.0-35.8-weeks) longer than those not meeting HLH-criteria. At the IRIS-timepoint, but not baseline, HLH-IRIS patients had greater production of IFNγ-IL18 axis biomarkers (IFNγ, CXCL9, IL18, IL18BP) when compared to IRIS and Non-IRIS groups. Soluble CD25 and percentage of activated T-cells were increased in HLH-IRIS with decreased regulatory T-cells. Rare, protein-altering variants in cytotoxicity genes were found in 11/54-patients (20.4%) that developed IRIS compared to 1/26 (3.8%) without IRIS. HLH-IRIS patients had additional rare, protein-altering variants in other immunoregulatory genes including LRBA, RLTPR, and TREX1.

Severe mycobacterial-IRIS and HLH have overlapping pathogeneses involving the IFNγ-IL18 axis and a dysregulated T-cell immunophenotype. Rare variants in cytotoxicity and immunoregulatory genes could impact mycobacterial-IRIS risk. This shared pathophysiology could be used to improve the diagnosis and management of mycobacterial-IRIS.