PMID- 36048425 OWN - NLM STAT- MEDLINE DCOM- 20230210 LR - 20230513 IS - 1537-6591 (Electronic) IS - 1058-4838 (Print) IS - 1058-4838 (Linking) VI - 76 IP - 3 DP - 2023 Feb 8 TI - Severe Mycobacterial Immune Reconstitution Inflammatory Syndrome (IRIS) in Advanced Human Immunodeficiency Virus (HIV) Has Features of Hemophagocytic Lymphohistiocytosis and Requires Prolonged Immune Suppression. PG - e561-e570 LID - 10.1093/cid/ciac717 [doi] AB - BACKGROUND: People with HIV and mycobacterial infections can develop immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy (ART). Severe mycobacterial IRIS has an overlapping clinical phenotype with hemophagocytic lymphohistiocytosis (HLH). We evaluated the pathophysiologic similarities between mycobacterial IRIS and HLH to identify clinical and immune predictors of mycobacterial IRIS severity. METHODS: HLH criteria were applied to a longitudinal cohort of 80 patients with HIV (CD4 <100 cells/microL) 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 subsets were assessed at baseline and IRIS-equivalent time points. RESULTS: HLH-IRIS patients required corticosteroids more frequently (OR: 21.5; 95%CI: 5.6-114.8) and for longer duration (21.2; 95%CI: 10.7-31.7 weeks) than those not meeting HLH criteria. Utilizing decision tree analyses, hemoglobin <9.2 g/dL was the best predictor of HLH-IRIS before ART, whereas ferritin, CXCL9 and sCD25 were most diagnostic for HLH at IRIS onset. At the IRIS timepoint, but not baseline, HLH-IRIS patients had lower regulatory and higher activated T cells along with greater production of IFNgamma-IL-18 axis biomarkers compared with both IRIS and non-IRIS groups. Principal component analysis corroborated the distinct clustering of HLH-IRIS patients. CONCLUSIONS: Severe mycobacterial IRIS and HLH have an overlapping pathogenesis involving IFNgamma and unopposed T-cell activation causing severe inflammatory disease clinically distinguished by hyperferritinemia (hyperferritinemic IRIS [FIRIS]). Hemoglobin, ferritin, CXCL9, and sCD25 identify high-risk patients and may improve risk stratification and therapeutic strategies for mycobacterial IRIS. CI - Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022. FAU - Rocco, Joseph M AU - Rocco JM AUID- ORCID: 0000-0003-4307-4934 AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Laidlaw, Elizabeth AU - Laidlaw E AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Galindo, Frances AU - Galindo F AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Anderson, Megan AU - Anderson M AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Rupert, Adam AU - Rupert A AD - Leidos Biomedical Research, Inc, Frederick, Maryland, USA. FAU - Higgins, Jeanette AU - Higgins J AD - Leidos Biomedical Research, Inc, Frederick, Maryland, USA. FAU - Sortino, Ornella AU - Sortino O AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Ortega-Villa, Ana M AU - Ortega-Villa AM AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Sheikh, Virginia AU - Sheikh V AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Roby, Gregg AU - Roby G AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Kuriakose, Safia AU - Kuriakose S AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Lisco, Andrea AU - Lisco A AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Manion, Maura AU - Manion M AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Sereti, Irini AU - Sereti I AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. LA - eng GR - HH/HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural PL - United States TA - Clin Infect Dis JT - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America JID - 9203213 RN - 0 (Biomarkers) SB - IM MH - Humans MH - HIV MH - *Immune Reconstitution Inflammatory Syndrome MH - *Lymphohistiocytosis, Hemophagocytic/complications/diagnosis MH - *HIV Infections/complications/drug therapy MH - Biomarkers PMC - PMC10169423 OTO - NOTNLM OT - human immunodeficiency virus OT - immune reconstitution inflammatory syndrome OT - macrophage activation syndrome OT - mycobacteria OT - tuberculosis COIS- Potential conflicts of interest. I. S. reports a patent, unrelated to this work, "Methods for the treatment of Kaposi's sarcoma or KSHV-induced lymphoma using immunomodulatory compounds, and uses of biomarkers (WO 2016210262 A1)". All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. EDAT- 2022/09/02 06:00 MHDA- 2023/02/11 06:00 PMCR- 2022/09/01 CRDT- 2022/09/01 11:23 PHST- 2022/06/28 00:00 [received] PHST- 2022/09/02 06:00 [pubmed] PHST- 2023/02/11 06:00 [medline] PHST- 2022/09/01 11:23 [entrez] PHST- 2022/09/01 00:00 [pmc-release] AID - 6681110 [pii] AID - ciac717 [pii] AID - 10.1093/cid/ciac717 [doi] PST - ppublish SO - Clin Infect Dis. 2023 Feb 8;76(3):e561-e570. doi: 10.1093/cid/ciac717.