The immunopathogenic mechanism of severe cutaneous adverse reactions to first line anti-tuberculosis drugs

Choshi, Phuti

The immunopathogenic mechanism of severe cutaneous adverse reactions to first line anti-tuberculosis drugs

Thesis / Dissertation

2024

Abstract

Background and hypothesis In HIV-TB endemic settings like South Africa, first line anti-tuberculosis drugs (FLTD) are the commonest cause of severe immune mediated adverse drug reactions, including Stevens Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). The mechanisms of these treatment-limiting, life-threatening reactions, particular in persons living with HIV (PLHV) is poorly understood, making diagnosis and treatment challenging in patients who can ill-afford suboptimal and prolonged anti-TB treatment interruptions. We hypothesize that polymorphisms in Human Leukocyte Antigen (HLA), Endoplasmic Reticulum Aminopeptidase (ERAP) and Killer Immunoglobulin Receptor (KIR) genes along with HIV-related immune dysregulation during drug exposure might confer susceptibility. In this thesis, we aimed to identify genetic markers in African populations for FLTD-induced SJS/TEN and DRESS, and using single-cell proteomic and transcriptomic analyses, we aimed to immunophenotype different stages of the reactions. Methods We selected three groups of participants from the IMARI in Africa registry: i) HIV+ FLTD SCAR cases, ii) HIV- FLTD SCAR cases and iii) HIV+/- FLTD tolerant controls (>8 weeks on treatment without any adverse events). We collected saliva and blood at baseline and in SCAR cases, we collected blood at different stages of the reaction including pre sequential drug challenge (SDC), on positive reaction to any FLTD (post SDC) and during recovery (at least three months from an acute reaction). We used RegiSCAR phenotype validation, Naranjo drug causality and ELISpot assay to identify offending drugs and precision phenotype cases. We isolated DNA from saliva for HLA, ERAP and KIR typing. In a well-defined subset of patients, we used an integrated single-cell approach involving: i) mass cytometry by time of flight (n=8), and ii) single cell RNA sequencing (scRNA-seq) (n=3) to characterise immune cells activated by drug. Results Forty-one RegiSCAR validated SCAR cases that reacted to one or more FLTD on rechallenge were included, Rifampicin-associated DRESS was commonest (n=18). IFN-gamma ELISpot, optimised for FLTDs, was most sensitive (75%) for Rifampicin-DRESS cases. Rifampicin-DRESS/SJS/TEN (with positive ELISpot) was associated with HLA-B*44:03 (OR:28.8; 95%CI: 5.6-107.7; P=

Keywords

Medicine

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Collections

PhD / Doctoral

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