School of Pathology (ETDs)

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    Analysis of Whole Exome Sequence Data from African Patients with HD-Like Features and No Known HDPhenocopy Syndrome
    (University of the Witwatersrand, Johannesburg, 2023) Naicker, Racilya; Krause, Amanda; Baine-Savanhu, Fiona
    Huntington disease (HD) is a rare progressive neurodegenerative disorder that results from a CAG repeat expansion within the huntingtin gene (HTT). Several syndromes present with HD- like features in the absence of the HTT expansion and are termed HD phenocopies. Huntington disease-like 2 (HDL2), a known phenocopy, is most commonly observed in individuals with African, or probable African, ancestry. Therefore, previous diagnostic testing in the Division of Human Genetics, National Health Laboratory Service (Johannesburg, South Africa) screened for both HD and HDL2 in patients with HD-like phenotypes and an indication of African ancestry. Patients who tested negative for both syndromes remain undiagnosed, highlighting the need for further testing strategies. This study aimed to identify variants implicated in the HD-like phenotype of these patients. In a group of nine undiagnosed patients with Black African ancestry, a virtual gene panel was analysed through a whole exome sequencing (WES) approach. The data was filtered, and candidate variants were prioritised according to the frequency, type, and location of the variants as well as in-silico pathogenicity prediction scores. A total of 20 candidate variants in 15 genes were shortlisted and classified according to ACMG/AMP guidelines. Notably, variants in the mitochondrial DNA polymerase subunit gamma (POLG; c.2246T>C; p.Phe749Ser) and the glutaryl-CoA dehydrogenase (GCDH; c.877G>A; p.Ala293Thr) genes were classified as likely pathogenic and pathogenic, respectively. Genotype-phenotype correlation indicated a potential diagnosis of autosomal dominant progressive external ophthalmoplegia in the patient carrying the POLG variant, whereas the GCDH variant was considered an incidental finding due to a lack of correlation with the characteristics of glutaric aciduria type 1. These findings highlight the diagnostic challenges faced in the African context for patients with HD-like clinical features and call for further validation studies and re-analysis of the WES data using alternative gene panels for the patients for whom no putative pathogenic variants were identified
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    Comparison between lupus nephritis in HIV positive patients and HIV associated immune complex glomerulonephritis with “lupus–like” features: a clinicopathologic study
    (2024) Mathaba, Margaret Masala
    Background: Systemic lupus erythematosus (SLE) is an autoimmune disease seen commonly in black females of childbearing age. More than half of the patients present with renal disease or lupus nephritis complications. Coinfection with HIV in patients with lupus nephritis is rare. Despite Africa having the highest rate of HIV infection in the world, and there is no available data on the coexistence of HIV and Lupus nephritis. HIV is associated with a wide spectrum of renal diseases, including “lupus-like” HIV-Associated Immune Complex Kidney Disease (HIVICK). The most prevalent renal lesions in “lupus-like” HIVICK is diffuse proliferative lupus nephritis Objectives: This study aimed to compare and correlate the demographics, epidemiology, pathological and clinical findings of HIV positive patients with lupus nephritis and those with “lupus-like” HIVICK. Methods: This retrospective chart review study was conducted at the Charlotte Maxeke Johannesburg Academic Hospital in 5 years (2014-2018). We reviewed case reports that met our criteria for cases with lupus nephritis and cases with “lupus-like” HIVICK and allocated a lupus class according to the report findings. Results: Out of 2174 renal reports, 25(1.14%) patients were diagnosed with lupus nephritis and nine (0.41%) with “lupus-like” HIVICK. There were significant differences in age, serology (urea and creatinine), clinical presentation and lupus class. Conclusion: The occurrence of both HIV associated lupus nephritis and ‘lupus like’ HIVICK is rare. In our setting, the former is more common than the latter. We observed clinical and pathological differences which may be used to diagnose these disease entities.
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    Maternal vaccination in South Africa: timing and completeness
    (2024) Bourne, Julia
    Maternal immunisation is an invaluable public health measure that protects not only the mother, but also the foetus and new-born infant against a host of diseases; and is recommended by both the World Health Organisation (WHO) and South African national health authorities. Pregnancy induces a heightened state of immune system vulnerability, leaving women more susceptible to severe influenza outcomes, whilst neonatal tetanus has a fatality rate of between 80-100% in the absence of medical intervention. Maternal immunisation against influenza and tetanus has been successfully utilised as a public health strategy across the globe to uphold maternal and neonatal health. Maintaining coverage is imperative for both diseases as influenza strains change seasonally and tetanus cannot be eliminated, highlighting the importance of continued maternal immunisation. This study aimed to describe the uptake of both influenza and tetanus vaccinations during pregnancy, the completion of the tetanus vaccination schedule and the timing of both influenza and tetanus immunisation within South African antenatal care facilities. In addition, this study described clinical and demographic factors affecting maternal immunisation uptake. Clinical and demographic data were collected in a parent study and were retrospectively analysed in this study using the statistical software Stata. Influenza vaccination uptake within the sampled population was found to be 16.62% (806/4851). The odds of influenza vaccination were significantly higher in women aged 21-30 years, and women with six or more ANC visits. Metro East Cape Town site in the Western Cape outperformed Gauteng sites, with significantly increased odds of influenza vaccination amongst women frequenting that site. Appropriate influenza immunisation: defined as immunisation occurring during the period of either 01/04/2017-31/07/2017 or 01/04/2018-30/06/2018, occurred in 74.86% (530/708) of the cohort. Women who were alcohol users were significantly more likely to receive an influenza vaccine – yet this may be explained by the Metro East site which had the higher influenza coverage having the highest prevalence of alcohol use during pregnancy. Of 7105 women, 7031 (98.96%) received at least one dose of tetanus toxoid vaccine (TTV). Of these women, 39.24% (2759) received one dose; 51.06% (3590) received two doses and 9.70% (682) received the recommended three doses of TTV in their index pregnancy. Tetanus schedule completion was significantly more likely in women ≤20 years, and those who presented for their booking antenatal care (ANC) visit in the first trimester. In addition, women with more than three visits had an increased likelihood of TTV schedule completion. The odds of TTV schedule completion were decreased by negatively parity and gravidity, values over one and less than six, and greater than one respectively. Women with hypertension were significantly less likely to receive three TTV doses compared to women without hypertension. Julia Bourne MSc(Vaccinology) Research Report: Version 2.0 v Tetanus immunisation schedule adherence prevalence was 0.60% (4/670) in women with three doses and 90.34% (3209/3552) in women with two. Improvements may be made in South African maternal immunisation coverage, with this study supporting the idea of targeted educational campaigns and a revision of the maternal immunisation schedule to include the tetanus, diphtheria & acellular pertussis vaccine instead of the tetanus toxoid vaccine.
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    Molecular characterization of invasive Streptococcus agalactiae in South Africa, 2019 – 2020
    (2024) Ntozini, Buhle
    Background: Group B streptococcus (GBS) is a leading cause of neonatal meningitis and sepsis. Capsular polysaccharide and protein-based GBS vaccines are currently in development. Therefore, it is important to understand the serotype and antigen distribution of GBS to assess potential vaccine coverage. We aimed to use whole genome sequencing (WGS) and phenotypic methods to assess the serotype and antigen distribution, antimicrobial susceptibility patterns, and the phylogeny of invasive GBS isolates in South Africa (SA). Methods: As part of national laboratory-based surveillance, 661 invasive GBS isolates cultured from normally sterile-site specimens (e.g. blood and cerebrospinal fluid) from patients of all ages, were collected from 2019-2020. Phenotypic identification was based on colony morphology and β-hemolysis. Serotyping was performed using latex agglutination. Antimicrobial susceptibility testing was based on disc diffusion and broth microdilution methods. Whole genome sequencing (WGS) was performed using the NextSeq 550 System and the 2 x 100-bp paired-end mode. WGS based prediction of serotypes, surface protein genes, and resistance gene detection was performed using a validated GBS bioinformatics pipeline developed by the US Centers for Disease Control and Prevention (CDC). Results: A total of 658/661 isolates yielded good quality sequences from WGS and three isolates poor quality sequences. The isolates belonged to 6 major clonal complexes (CCs): CC1 (37/658, 5.6%), CC8/10 (69/658, 10.5%), CC17 (272/658, 41.3%), CC19 (45/658, 6.8%), CC23 (188/658, 28.6%) and CC24 (37/658, 5.6%). Five singletons (10/658, 1.5%) were identified. Excluding phenotypically and genotypically non-typeable isolates, concordance for serotyping using latex agglutination and WGS was 99.7% (647/649). Overall, 6 serotypes were detected: III (281/656, 42.8%), Ia (183/656, 27.9%), V (78/656, 11.9%), II (955/656, 8.4%), Ib (44/656, 6.7%), and IV (15/656, 2.3%). Three percent (20/658) of the isolates were non-susceptible to penicillin. Erythromycin and clindamycin resistance was detected in 16.1% (106/658) and 3.8% (25/657) of the isolates respectively. Majority (91.5%, 625/657) of the isolates were resistant to tetracycline. Fifty-five percent (11/20) of penicillin non-susceptible isolates had mutations in the PBP2x gene known to confer resistance, while no PBP2x resistance mutation were detected in the remaining resistant isolates. ermTR (34.9%, 37/106) and mefA/E (29.2%, 31/106) resistance genes were the most common determinants of erythromycin resistance. Clindamycin resistance was mediated by the erm (ermB, T, and TR) genes. Tetracycline resistance was driven by the presence of the tet genes (tetM, tetO, and tetL), with tetM being the most common (95.8%, 599/625). Nearly all the isolates carried at least one of the 3 main pilus gene clusters (657/658, 99.8%), 1 of the 4 homologous alpha/Rib family determinants (656/658, 99.7%) and 1 of the serine-rich repeat (Srr) protein genes (626/658, 95.1%). The hvgA virulence gene was found exclusively in CC17 isolates. Conclusion: Our results show that the majority of isolates circulating in SA belong to the 5 major GBS CCs (CC1, CC8/10, CC17, CC19, and CC23). This study suggests that vaccines currently under development should provide good coverage in our setting. We show that the GBS6 vaccine that targets serotypes Ia, Ib, II, III, IV, and V has the potential to cover 100% of invasive GBS disease in SA. A pilus protein-based vaccine has a potential coverage of 99.8% and the GBS-NN and the latch peptide vaccines have a potential coverage of 68.5% and 95.3% respectively. Βeta-lactams remain appropriate for treatment and intrapartum antibiotic prophylaxis (IAP). However, detecting the emergence of non-susceptibility requires ongoing surveillance.