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The immunopathogenic mechanism of severe cutaneous adverse reactions to first line anti-tuberculosis drugs
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 a...
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| Format: | Thesis |
| Language: | Eng |
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Department of Medicine
2024
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| _version_ | 1867613335111860224 |
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| access_status_str | Open Access |
| author | Choshi, Phuti |
| author2 | Peter, Jonathan |
| author_browse | Choshi, Phuti Peter, Jonathan |
| author_facet | Peter, Jonathan Choshi, Phuti |
| author_sort | Choshi, Phuti |
| collection | Thesis |
| description | 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= |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/40346 |
| institution | University of Cape Town (South Africa) |
| language | Eng |
| last_indexed | 2026-06-10T12:34:28.941Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2024 |
| publishDateRange | 2024 |
| publishDateSort | 2024 |
| publisher | Department of Medicine |
| publisherStr | Department of Medicine |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/40346 The immunopathogenic mechanism of severe cutaneous adverse reactions to first line anti-tuberculosis drugs Choshi, Phuti Peter, Jonathan Medicine 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= 2024-07-04T14:09:08Z 2024-07-04T14:09:08Z 2024 2024-07-02T14:12:09Z Thesis / Dissertation Doctoral PhD http://hdl.handle.net/11427/40346 Eng application/pdf Department of Medicine Faculty of Health Sciences |
| spellingShingle | Medicine Choshi, Phuti The immunopathogenic mechanism of severe cutaneous adverse reactions to first line anti-tuberculosis drugs |
| thesis_degree_str | Doctoral |
| title | The immunopathogenic mechanism of severe cutaneous adverse reactions to first line anti-tuberculosis drugs |
| title_full | The immunopathogenic mechanism of severe cutaneous adverse reactions to first line anti-tuberculosis drugs |
| title_fullStr | The immunopathogenic mechanism of severe cutaneous adverse reactions to first line anti-tuberculosis drugs |
| title_full_unstemmed | The immunopathogenic mechanism of severe cutaneous adverse reactions to first line anti-tuberculosis drugs |
| title_short | The immunopathogenic mechanism of severe cutaneous adverse reactions to first line anti-tuberculosis drugs |
| title_sort | immunopathogenic mechanism of severe cutaneous adverse reactions to first line anti tuberculosis drugs |
| topic | Medicine |
| url | http://hdl.handle.net/11427/40346 |
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