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

Wednesday, June 22, 2022

4:45 PM – 5:00 PM PT

Location: Salons 3/4

Authors: Joseph M. Rocco, MD (Presenting Author) - National Institute of Allergy and Infectious Disease; Maura Manion, MD (Co-Author) - National Institute of Allergy and Infectious Disease; Elizabeth Laidlaw, MSHS (Co-Author) - National Institute of Allergy and Infectious Disease; Adam Rupert, BS (Co-Author) - National Cancer Institute; Safia Kuriakose, PharmD (Co-Author) - National Institute of Allergy and Infectious Disease; Jeanette Higgins, PhD (Co-Author) - National Cancer Institute; Ornella Sortino, PhD (Co-Author) - National Institute of Allergy and Infectious Disease; Luxin Pei, PhD (Co-Author) - National Institute of Allergy and Infectious Disease; Silvia Lage, PhD (Co-Author) - National Institute of Allergy and Infectious Disease; Frances Galindo, RN (Co-Author) - National Institute of Allergy and Infectious Disease; Joseph Adelsberger, SCYM(ASCP) (Co-Author) - National Cancer Institute; Andrea Lisco, MD, PhD (Co-Author) - National Institute of Allergy and Infectious Disease; Irini Sereti, MD (Co-Author) - National Institute of Allergy and Infectious Disease

Presenting Author(s)

JR

Joseph M. Rocco, MD

Infectious Diseases Fellow
National Institute of Allergy and Infectious Disease
Silver Spring, Maryland, United States

Chair(s)

Marianna Rowlands, PhD

Associate Director
Novartis Institutes for Biomedical Research
Cambridge, Massachusetts, United States

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.