Browsing by Author "Verburgh, Estelle"
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- ItemOpen AccessA comparative cost analysis of the pathway to diagnosing lymphoma in a tertiary hospital, Western Cape, South Africa(2022) Fareed-Brey, Waarisa; Cunnama, Lucy; Verburgh, Estelle; Antel, KatherineCancer is one of the leading causes of death before the age of 70 in 91 countries (out of 172) with a noted increasing incidence of cancer and mortality (Bray et al., 2018). In tuberculosis (TB) endemic areas, a fine needle aspirate (FNA) is often used as the diagnostic tool of choice when trying to understand the underlying cause of lymphadenopathy (LAP), which can lead to delayed diagnosis of lymphoma (Antel et al., 2019). A significant gap exists in the lack of costing of the diagnostic pathway to diagnosing lymphoma. The study aimed to cost the diagnostic pathways, namely FNA, core-needle biopsy (CNB), and surgical excision biopsy (SEB) using secondary data collected in 2018 (February until October) at Groote Schuur Hospital (GSH), within the tertiary level hospital outpatient clinics to informed the patient pathways. The overall purpose of the study was to inform policy-making decisions and process guidelines. A cost analysis study was conducted using a combination of ingredients-based costing and top-down costing from a provider's perspective. Annual costs were calculated and inflated to 2021 South African Rands using the consumer price index (CPI) and converted to United States American Dollars. More CNBs are currently being performed than SEBs at GSH, and when pathways were followed, CNB initiated pathways (US $567) were less costly compared to FNA initiated pathways (US$ 877). The cost of the CNB procedure varied with the use of a single-use biopsy gun and the multi-use Magnum BARD gun. CNB provides an alternate choice to SEB and based on the study conducted, CNB pathways are less costly. The main cost driver for all three procedures was personnel and this could be decreased by task shifting and training of medical officers and interns.
- ItemOpen AccessCD68-positive tumour associated macrophages, PD-L1 expression, and EBV latent infection in a high HIV-prevalent South African cohort of Hodgkin lymphoma patients(2021) Antel, Katherine Rae; Verburgh, EstelleBackground and aims A higher proportion of CD68-positive tumour associated macrophages (TAMs) has been associated with poorer outcomes in HIV-negative patients with Hodgkin lymphoma (HL), but whether this is true in HIV positive patients with HL is not known. In this study, we investigated the number of CD68-positive TAMs and expression of programmed cell death-ligand 1 (PD-L1) in lymph node specimens from HL patients and correlated expression with clinical features (HIV status, disease severity and survival) and histopathological features (EBV latent positivity and subtype of HL). Methods We stained archived lymph node specimens from 77 patients diagnosed with HL for CD68 and PD-L1. Stains were graded as: CD68 low (≤25%), CD68 high (>25%), PD-L1 low (≤50%), and PD-L1 high (>50%). Expression levels were correlated with the clinical and histopathological features using bivariate and multivariate analyses. Survival was analysed by overall and progression-free survival. Results Thirty-four of the 77 included patients (44%) were HIV-positive. EBV latency was detected in 97% of HIV positive HL patients and in 14% of HIV-negative HL patients. A high CD68 score was associated with lower median haemoglobin levels (9.4 vs 11.4 g/dL; p=0.02), platelet numbers (262 vs 424 cells ×109 /L; p=0.01), and lymphocyte numbers (0.99 vs 1.70 cells ×109 /L, p=0.01) and a trend towards advanced disease (international prognostic score ≥4; hazard ratio 2.4; confidence interval 0.89–6.47; p=0.08). HIV status did not affect CD68 or PD-L1 expression. A higher proportion of CD68-positive TAMs was found in samples that were EBV-positive. HIV positivity and EBV negativity correlated with poorer survival. CD68 and PD-L1 expression were not predictive of survival. Conclusions High CD68 expression was associated with EBV positivity but not HIV positivity and did not predict adverse outcomes. PD-L1 expression was unaffected by HIV status or EBV positivity and did predict adverse outcomes.
- ItemOpen AccessCorrection to: Diagnostic accuracy of the Xpert MTB/Rif Ultra for tuberculosis adenitis(2020-03-02) Antel, Katherine; Oosthuizen, Jenna; Malherbe, Francois; Louw, Vernon J; Nicol, Mark P; Maartens, Gary; Verburgh, EstelleAfter publication of the original article [1], we were notified that there is a mistake in the article note.
- ItemOpen AccessDiagnostic accuracy of the Xpert MTB/Rif Ultra for tuberculosis adenitis(2020-01-13) Antel, Katherine; Oosthuizen, Jenna; Malherbe, Francois; Louw, Vernon J; Nicol, Mark P; Maartens, Gary; Verburgh, EstelleAbstract Background The WHO recently recommended the new Xpert MTB/RIF Ultra assay (Ultra) instead of the Xpert MTB/RIF assay because Ultra has improved sensitivity. We report the diagnostic accuracy of Ultra for tuberculous adenitis in a tuberculosis and HIV endemic setting. Methods We obtained fine-needle aspirates (FNA) and lymph node tissue by core-needle biopsy in adult patients with peripheral lymphadenopathy of >20 mm. Ultra and mycobacterial culture were performed on FNA and tissue specimens, with histological examination of tissue specimens. We assessed the diagnostic accuracy of Ultra against a composite reference standard of ‘definite tuberculosis’ (microbiological criteria) or ‘probable tuberculosis’ (histological and clinical criteria). Results We prospectively evaluated 99 participants of whom 50 were HIV positive: 21 had ‘definite tuberculosis’, 15 ‘probable tuberculosis’ and 63 did not have tuberculosis (of whom 38% had lymphoma and 19% disseminated malignancy). Using the composite reference standard the Ultra sensitivity on FNA was 70% (95% CI 51–85; 21 of 30), and on tissue was 67% (45–84; 16/24) these were far superior to the detection of acid-fast bacilli on an FNA (26%; 7/27); AFB on tissue (33%; 8/24); or tissue culture (39%; 9/23). The detection of granulomas on histology had high senstivity (83%) but the lowest specficity. When compared with culture the Ultra on FNA had a sensitvity of 78% (40-97; 7/9) and tissue 90% (55-100; 9/10). Conclusions Ultra performed on FNA or tissue of a lymph node had good sensitivity and high specificity. Ultra had a higher yield than culture and has the advantage of being a rapid test. Ultra on FNA would be an appropriate initial investigation for lymphadenopathy in tuberculosis endemic areas followed by a core biopsy for histopathology with a repeat Ultra on tissue if granulomas are present.
- ItemOpen AccessFeature detection in ultrasound images for computer aided diagnosis of Hodgkin's Lymphoma(2021) Dawood, Tareen; Mutsvangwa, Tinashe; Verburgh, EstelleThe varying clinical presentation of Hodgkin's lymphoma (HL) poses a diagnostic challenge in South Africa, as the clinical picture of this lymphoma overlaps with prevalent comorbidities such as tuberculosis (TB) and the Human Immuno-Deficiency Virus (HIV). HIV infection additionally increases the risk of developing HL. These factors motivate for the need to investigate the role of imaging modalities in the diagnostic pathway of HL. The goal of this project was to develop and evaluate an automated framework for improving diagnostic imaging interpretability of ultrasound for HL diagnosis in a HIV TB endemic environment. To achieve this, a precise abdominal ultrasound protocol was developed with clinical guidance. The specific frames in the protocol were used to detect several image biomarkers of clinical interest: splenic enlargement (splenomegaly), splenic lesions, splenic microabscesses, abdominal lymph node enlargement, ascites, and effusions (pleural and pericardial). The developed protocol provided a novel guideline to identify an abnormality from the available ultrasound images. A secondary outcome of the protocol was the development of a prospective guide to image Hodgkin's lymphoma patients using ultrasound, however further testing and evaluation is required to validate its use. Image processing techniques were then applied to identified frames, and geometrical and textural features extracted, to develop an automated abnormality characterisation framework. A total of 36 features were extracted and used to characterise each abnormality. Thereafter, an automated algorithm was used to characterise and classify Hodgkin's lymphoma. A support vector machine model was built, with two experiments performed to evaluate the model. The model achieved a maximum training accuracy of 83%, similar in performance to support vector machine classification models used in medical applications. Noticeably the classification accuracy increased favourably when specific abnormalities were assessed: an enlarged spleen, splenic micro abscesses, ascites, pleural effusions, and pericardial effusions. This may indicate that these specific abnormalities are sufficient to differentiate patients with and without Hodgkin's lymphoma but understanding the reasoning for the decision taken by the system requires further investigation. In this study we show how image processing and automated classification techniques when applied to ultrasound images, have the potential to improve the differential diagnostic pathway of HL. Further evaluation using a larger dataset is planned, to validate and implement these findings in a strained healthcare setting.
- ItemOpen AccessImplementation of the JAK2V617F mutation analysis in the pathway of suspected myeloproliferative neoplasms in Groote Schuur Hospital(2016) Poulet, Erma; Verburgh, EstelleWe studied the implementation of JAK2 mutation analysis in conjunction with the World Health Organisation (WHO) guidelines in the pathway to MPN diagnosis in 279 patients presenting with one of three clinical scenarios: erythrocytosis, OR leukocytosis and/or thrombocytosis and/or splenomegaly; OR patients with thrombosis without cytoses. Patients were investigated for MPN and managed in the haematology clinic of Groote Schuur Hospital. We studied the association of clinical and laboratory variables with clonal vs non-clonal diagnoses. In 120/297 patients MPN was confirmed: Polycythemia vera (PV), (n=51, 100% JAK2 mutated); essential thrombocytosis, (n=41, 42% JAK2 mutated); primary myelofibrosis (n=28, 57% JAK2 mutated). The 2016 WHO haemoglobin/haematocrit thresholds in PV were validated. Idiopathic erythrocytosis (IE) found in 44 patients. Bone marrow histology, but not serum EPO level, was essential to differentiate between clonal and non-clonal erythrocytosis. Both PV and IE patients complied with the criteria of absolute erythrocytosis on peripheral blood, yet nuclear red cell mass identified critical differences between clonal and non-clonal erythrocytosis. No patient venesected for nonclonal erythropoiesis developed thrombocytosis. JAK2 mutation analysis applied with the WHO diagnostic algorithm efficiently differentiated true clonal myeloproliferation from reactive cytoses. Lifestyle and metabolic factors such as smoking and thrombosis were not associated with either clonal or non-clonal erythrocytosis, and were equally present in mutated and unmutated essential thrombocytosis.
- ItemOpen AccessLymphoma: Understanding the diagnostic challenges and improving outcomes in a TBand HIV-endemic area(2021) Antel, Katherine Rae; Verburgh, Estelle; Maartens, Gary; Louw, VernonBackground and aims Diagnosing lymphoma can be challenging: even in the best-resourced settings, lymphoma diagnosis may be delayed owing to the insidious onset of symptoms and/or difficulties in obtaining lymph node biopsy for diagnosis. In TB-endemic countries the diagnostic challenges in lymphoma may be further compounded by symptoms overlapping with those of TB and by resource limitations that may impede obtaining a diagnostic biopsy. New lymphoma diagnostic modalities, including the use of nextgeneration sequencing, are evolving rapidly and informing both prognosis and therapy in the field of lymphoma. These modalities of testing are likely to mean that less tissue is needed for assessment, or even that diagnosis can be made from peripheral blood. In this thesis we identify and describe local barriers in the diagnosis of lymphoma; and describe methods used to decrease the time-to-diagnosis of lymphoma and to subtype the most common lymphoma, diffuse large B-cell lymphoma (DLBCL). Our four main aims have been to: (i) Describe the pathway to a diagnosis of lymphoma in South Africa, with emphasis on the examination of local barriers to diagnosis (including overlapping symptomatology with TB) by retrospectively studying a cohort of patients with lymphoma. (ii) Investigate the diagnostic utility of the newest TB diagnostic test (the Xpert MTB/RIF Ultra); and apply this test in a diagnostic algorithm for lymphadenopathy of unknown aetiology, both on a fine-needle aspirate (FNA) from a lymph node and on tissue obtained by corebiopsy. (iii) Investigate whether a rapid-access lymph node biopsy clinic that used a core-biopsy method for lymph node biopsy was able to reduce the time-to-diagnosis of lymphoma, and to subtype accurately lymphomas for which subtyping is clinically relevant. (iv) Describe the subtype of DLBCL by HIV status using an immunohistochemical algorithm, in order both to describe the pattern of DLBCL by the most current diagnostic classification and to lay the foundations for further genetic work potentially capable of identifying mutations that could be used for genetic testing in DLBCL locally. Methods Four cohorts were analysed: (i) In the first, a group of 163 patients with lymphoma, the time-to-diagnosis and factors causing a delay in diagnosis were analysed. (ii) In the second, 99 patients with lymphadenopathy of unknown cause were recruited and the sensitivity and specificity of the Ultra were analysed using both fine-needle aspirate (FNA) and a core-biopsy technique. (iii) In the third cohort (n = 130), which included the second cohort of n = 99), outcomes from a rapid-access lymph node biopsy clinic – which used the core-biopsy method for the diagnosis of lymphoma – were analysed. (iv) In the fourth cohort (n = 182), the tissue of patients with DLBCL was analysed based on further immunohistochemical stains using the Hans algorithm in order to determine the molecular subtypes of DLBCL and determine their effect on prognosis. Results (i) In the first cohort ((n = 163), 29% HIV-infected), which was studied retrospectively, it took a median of 7 weeks for the diagnosis of lymphoma to be made from the time the patient sought medical attention. The longest time delay was in the healthcare practitioner interval (time from first healthcare visit to diagnostic biopsy). On multivariable logistic regression analysis, diagnostic delay > 6 weeks was associated with late-stage disease at presentation (odds ratio (OR) 2.3, 95% confidence interval (CI) 1.1–5.2) and a diagnosis of Hodgkin lymphoma (OR 3.0, 95% CI 1.1–8.0). HIV status was not associated with diagnostic delay (OR 0.9, 95% CI 0.3–2.2). The median time to diagnosis for patients on TB treatment was a month longer than for patients not on TB treatment. However, this was not statistically significant owing likely to a small sample size (n = 16, p = 0.28). (ii) In the second cohort, the diagnostic utility of the Ultra on lymph node aspirate and tissue were prospectively evaluated. The Ultra was found to be a sensitive and specific test for diagnosing TB of the lymph node. When compared with culture, the Ultra on aspirate had a sensitivity of 78% (40–97; 7/9) and on tissue 90% (55–100; 9/10). When using a composite reference score that combined both ‘definite TB' (culture positive) and ‘probable TB' (histological and clinical criteria), the Ultra was superior to currently used methods of diagnosing TB of the lymph node, including the detection of AFBs from an aspirate or on tissue biopsy or tissue culture (which had sensitivities of 26%, 33% and 39% respectively). The detection of granulomas on histology had high sensitivity (83%) but the lowest specificity. (iii) In the third cohort, which was studied prospectively, we obtained two important outcomes. Firstly, we showed that a rapid-access lymph node biopsy clinic was able to decrease the time-to-diagnosis of lymphoma when compared with that of cohort one (the historical cohort) to a diagnostic interval of 13.5 days compared with 48 days (p = 0.002). Secondly, the core-biopsy was able to detect lymphoma with a high rate of accuracy. The first-attempt core-biopsy was able to diagnose lymphoma in 84% of cases, and provided sufficient tissue to subtype lymphoma in a high proportion of the lymphoma cases (27/30, 90%). (iv) In the fourth, retrospectively evaluated cohort of patients with DLBCL (n = 181, 51 HIVpositive), there was a similar distribution of germinal centre (GC) and activated B cell (ABC) subtypes in the HIV-infected and HIV-uninfected groups. In contrast to what is reported in HIV-negative DLBCL literature, there were no statistically significant differences in overall survival by DLBCL subtype. Moreover, no significant difference in 5-year overall survival was demonstrated between the GCB and ABC subtypes (HR 1.2, 95% CI 0.8–1.9). Patients with HIV infection with a CD4 count of < 150 CD4 cells/mm3 had significantly poorer survival than those with no HIV infection (HR 2.4, 95% CI 1.3–4.1). Conclusions Making a diagnosis of lymphoma in South Africa is challenging. Two of the greatest challenges are overlapping symptomatology with TB and obtaining an adequate lymph node sample. The Ultra test on lymph node tissue is rapid, sensitive and specific; and can be performed on both FNA and tissue obtained through core-biopsy. Making an accurate diagnosis of TB is of critical importance, as TB is the most common cause for enlarged lymph nodes in TB-endemic areas. A reliable TB test on lymph node tissue will enable both an accurate TB diagnosis and the identification of patients who are negative for TB. The latter will require further investigation with a lymph node biopsy (via core needle or excision). As diagnostic testing and methods evolve in the direction of next-generation platforms, it is important to understand the tumour biology in our local setting, and in HIV-lymphoma, in order to be able to apply these new methods. This thesis describes the subtypes and outcomes seen in HIV DLBCL – knowledge that will be important in developing genetic next-generation sequencing methods that are specific to the type of lymphoma to be found in our context (and which may include genetic mutations induced by the Epstein–Barr virus). A clear diagnostic algorithm for the investigation of lymphadenopathy is presented, pulling together the four aims presented at the start of this section. Considering the prevalence of TB in South Africa, the goal is, in the first instance, to diagnose or exclude TB adenitis. In patients who test negative for TB, the goal then becomes to proceed with a diagnostic biopsy and, from our findings, to support the use of core-biopsy. This method, we have demonstrated, is able to provide sufficient tissue for the diagnosis and subtyping of lymphoma.
- ItemOpen AccessThe determinants and impact of diagnostic delay in lymphoma in a TB and HIV endemic setting(2019-04-25) Antel, Katherine; Levetan, Carly; Mohamed, Zainab; Louw, Vernon J; Oosthuizen, Jenna; Maartens, Gary; Verburgh, EstelleBackground Little is known about the pathway to diagnosis of lymphoma in Sub-Saharan Africa, despite the increased risk of lymphoma in people living with HIV (PLHIV). The challenges of diagnosis in this setting include diagnostic confusion with extrapulmonary tuberculosis (EPTB), which commonly causes lymphadenopathy in PLHIV. Methods We analysed the time to diagnosis and treatment in patients using predetermined time intervals. Univariate and multivariable analyses were performed to determine the relationship between patient and disease-specific variables with delays to diagnosis. We were particularly interested in the impact of HIV, empiric tuberculosis therapy and fine-needle aspirate for cytology (FNAC) in contributing to delay. Results Patients (n = 163), 29% HIV-infected, waited a median of 4 weeks before seeking medical attention. It took a median of 7 weeks for the diagnosis of lymphoma to be made from the time the patient sought medical attention, termed the healthcare practitioner interval. In multivariable logistic regression analysis, diagnostic delay > 6 weeks was associated with late-stage disease (OR 2.3, 95% CI 1.1–5.2) and Hodgkin lymphoma (HL) (OR 3.0, 95% CI 1.1–8.0). HIV status was not associated with diagnostic delay (OR 0.9, 95% CI 0.3–2.2). The median time to diagnosis was a median of 4 weeks longer for patients on tuberculous (TB) therapy (n = 16, p = 0.28) and patients who underwent an FNAC (n = 63, p = 0.04). Where FNAC was performed, it was diagnostic for lymphoma in only 11%. Diagnostic delay was not associated with overall survival. Conclusions Time-to-diagnosis of lymphoma in South Africa was similar to that reported from high-income countries and shows significant periods of delay between the onset of symptoms to diagnosis and treatment. The longest period of delay was in the health practitioner interval. Education regarding the significance of lymphadenopathy for both patients and health care practitioners and appropriate investigative steps preferably by best-practice algorithms specific to TB-endemic areas are needed to shorten the time-to-diagnosis of lymphoma.
- ItemOpen AccessThe diagnostic accuracy of abdominal ultrasound findings in patients evaluated for peripheral lymphadenopathy in a high HIV TB endemic population(2023) Adams, Ellouise; Verburgh, Estelle; Antel KatherineBackground: Extrapulmonary tuberculosis (EPTB) is common among people living with HIV (PLWH). The abdominal ultrasound is an accessible investigation frequently employed to support the diagnosis of EPTB but may lead to misdiagnoses of diseases with overlapping clinical features, such as lymphoma. Objectives: To describe the abdominal ultrasound features and confirmed diagnoses of patients referred to a biopsy clinic with unexplained lymphadenopathy. Method: This was a retrospective descriptive study of patients attending the peripheral lymph node biopsy clinic at Groote Schuur Hospital (GSH) between 2017 and 2020 who had abdominal ultrasound examination while being investigated for unexplained lymphadenopathy. Ultrasound features were compared to the final diagnosis made on the lymph node biopsy. Results: Thirty-four patients were included, most of whom were HIV-infected (59.0%). Approximately one third had a confirmed diagnosis of lymphoma (29%) and approximately one third had a confirmed diagnosis of tuberculosis (32%). Splenic hypoechoic lesions were more common in patients with lymphoma (63.6%) than patients with tuberculosis (45.5%) and malignancy (16.7%). Ascites was equally distributed between patients with tuberculosis (36.4%) and lymphoma (36.4%). The ultrasound report and confirmed diagnoses were in agreement in 40.0% of patients with tuberculosis. Additionally, 36.4% of patients with confirmed lymphoma were suspected to have tuberculosis based on the abdominal ultrasound. Conclusion: Abdominal ultrasound detection of abnormalities such as splenic hypoechoic lesions, lymphadenopathy and ascites/pleural effusion have a differential diagnosis including both tuberculosis and lymphoma, and should be interpreted in conjunction with equally focused diagnostic tests.
- ItemOpen AccessTrends in clinical presentation and treatment outcomes in a South African TTP cohort(2024) Vundla, Nokubonga; Verburgh, Estelle; Bailly, JeniqueBackground: HIV is the most common cause of secondary thrombotic thrombocytopenic purpura (TTP) in South Africa. Objectives: To assess the clinical presentations and outcomes of patients treated for HIV-associated and idiopathic TTP. Methods: We conducted a retrospective cohort study of patients consecutively diagnosed with TTP from 2010 to 2020 at Groote Schuur Hospital. Study participants were identified by reviewing patient files and Western Cape Blood Services records. Kaplan-Meier curves and log-rank tests were used to evaluate remission rates overall and, by HIV status and treatment group. Logistic regression models were used to identify predictors of remission and relapse. Results: 139 patients were included, 85.6% of whom were HIV positive. There were no significant differences in the TTP pentad features by HIV status. Most patients achieved remission (71.9%) with an overall median time of 8 days. Remission occurred significantly earlier in those treated with FFPs only, suggesting less severe disease (median=8 days [IQR 6-10]), compared to those requiring the addition of plasma exchange suggesting more severe disease (median=12 days [IQR 8-22]). The overall mortality in the 10-year period was 38.9%, with 10.8% of the surviving patients relapsing after a median of 169 days (IQR 146-281) following the initial TTP event. There were no significant differences in remission status, time to remission, mortality or relapse by HIV status. All HIV positive patients who relapsed had defaulted their antiretroviral therapy (ART). Conclusion: HIV status did not affect patient outcomes in our cohort. ART is important in preventing HIV-associated TTP and relapse. What this study adds: A well-defined demographic of patients with TTP in the ART era in South Africa. Key words: Thrombotic thrombocytopenic purpura, haemolytic anaemia, thrombotic microangiopathy, HIV-associated TTP, ADAMTS13, treatment outcomes, plasma infusion, plasma exchange.