Seasonal patterns of mortality in medical admissions at Groote Schuur Hospital, Cape Town: 2002-2009

Includes bibliographical references.Across the world, studies have shown that hospital mortality may be influenced by seasonal factors. Very few studies examining this phenomenon have been conducted in South Africa. This study aimed to determine whether there are seasonal patterns of mortality associated with medical causes of admission to a hospital in Cape Town, and to identify demographic risk factors and specific disease categories that are associated with increased susceptibility to seasonal mortality. Part A is the protocol that was developed for the study. It begins with a summary of key aspects of the literature review. The aim, hypotheses and objectives of the study are then described, followed by a detailed account of the study methodology, ethical issues, plans for communication of the study findings and logistics. The protocol was approved by the Research Ethics Committee at University of Cape Town. Part B is the structured literature review, in which studies describing trends in seasonal mortality, and associated risk factors and determinants of excess seasonal mortality, are discussed. International and local studies were included, in order to provide an appropriated background for this study. Part C is a presentation of the study findings in the form of a journal-ready manuscript for the South African Medical Journal. Graphs have been used to illustrate the trends in mortality for each year of the study period, and the relationship between mortality and average temperatures and precipitation. Interactions with seasonal mortality and gender, socioeconomic status, ethnicity and age-groups have also been illustrated. Results have been quantified with the calculation of mortality rate ratios with 95% confidence intervals. Patterns of mortality for circulatory, respiratory and gastrointestinal diseases, and cancer, are analysed. There is a brief discussion of the findings with suggestions for further research and public health interventions to reduce excess seasonal mortality in this setting. Part D is comprised of appendices containing relevant analyses that were not be included in the article, as well as other documents pertaining to the study. Tables and graphs have been annotated, and reference is made to these appendices in the article

Adverse drug reactions in South African patients receiving bedaquiline-containing tuberculosis treatment: an evaluation of spontaneously reported cases

Background Bedaquiline was recently introduced into World Health Organization (WHO)-recommended regimens for treatment of drug resistant tuberculosis. There is limited data on the long-term safety of bedaquiline. Because bedaquiline prolongs the QT interval, there are concerns regarding cardiovascular safety. The Western Cape Province in South Africa has an established pharmacovigilance programme: a targeted spontaneous reporting system which solicits reports of suspected adverse drug reactions (ADRs) in patients with HIV-1 and/or tuberculosis infection. Since 2015, bedaquiline has been included in the treatment regimens recommended for resistant tuberculosis in South Africa. We describe ADRs in patients on bedaquiline-containing tuberculosis treatment that were reported to the Western Cape Pharmacovigilance programme. Methods We reviewed reports of suspected ADRs and deaths received between March 2015 and June 2016 involving patients receiving bedaquiline-containing tuberculosis treatment. A multidisciplinary panel assessed causality, and categorised suspected ADRs using World Health Organisation-Uppsala Monitoring Centre system categories. “Confirmed ADRs” included all ADRs categorised as definite, probable or possible. Preventability was assessed using Schumock and Thornton criteria. Where a confirmed ADR occurred in a patient who died, the panel categorised the extent to which the ADR contributed to the patient’s death as follows: major contributor, contributor or non-contributor. Results Thirty-five suspected ADRs were reported in 32 patients, including 13 deaths. There were 30 confirmed ADRs, of which 23 were classified as “possible” and seven as “probable”. Bedaquiline was implicated in 22 confirmed ADRs in 22 patients. The most common confirmed ADR in patients receiving bedaquiline was QT prolongation (8 cases, 7 of which were severe). A fatal arrhythmia was suspected in 4 sudden deaths. These 4 patients were all taking bedaquiline together with other QT-prolonging drugs. There were 8 non-bedaquiline-associated ADRs, of which 7 contributed to deaths. Conclusions Confirmed ADRs in patients receiving bedaquiline reflect the known safety profile of bedaquiline. Quantifying the incidence and clinical consequences of severe QT-prolongation in patients receiving bedaquiline-containing regimens is a research priority to inform recommendations for patient monitoring in treatment programmes for drug resistant tuberculosis. Pharmacovigilance systems within tuberculosis treatment programmes should be supported and encouraged, to provide ongoing monitoring of treatment-limiting drug toxicity

A decline in tuberculosis diagnosis, treatment initiation and success during the COVID-19 pandemic, using routine health data in Cape Town, South Africa

Background Coronavirus disease (COVID-19) negatively impacted tuberculosis (TB) programs which were already struggling to meet End-TB targets globally. We aimed to quantify and compare diagnosis, treatment initiation, treatment success, and losses along this TB care cascade for drug-susceptible TB in Cape Town, South Africa, prior to and during COVID-19. Methods This observational study used routine TB data within two predefined cohorts: pre-COVID-19 (1 October 2018–30 September 2019) and during-COVID-19 (1 April 2020–31 March 2021). The numbers of people diagnosed, treated for TB and successfully treated were received from the Western Cape Provincial Health Data Centre. Pre and post treatment loss to follow up and cascade success rates (proportion of individuals diagnosed with an outcome of treatment success) were calculated and compared across cohorts, disaggregated by sex, age, HIV status, TB treatment history and mode of diagnosis. Results There were 27,481 and 19,800 individuals diagnosed with drug-susceptible TB in the pre- and during-COVID-19 cohorts respectively, a relative reduction of 28% (95% CI [27.4% - 28.5%]). Initial loss to follow up increased from 13.4% to 15.2% (p<0.001), while post treatment loss increased from 25.2% to 26.1% (p < 0.033). The overall cascade success rate dropped by 2.1%, from 64.8% to 62.7% (p< 0.001). Pre- and during-COVID-19 cascade success rates were negatively associated with living with HIV and having recurrent TB. Conclusions An already poorly performing TB program in Cape Town was negatively impacted by the COVID-19 pandemic. There was a substantial reduction in the number of individuals diagnosed with drug-susceptible. Increases in pre-and post-treatment losses resulted in a decline in TB cascade success rates. Strengthened implementation of TB recovery plans is vital, as health services now face an even greater gap between achievements and targets and will need to become more resilient to possible future public health disruptions

Reducing initial loss to follow up among people with bacteriologically confirmed tuberculosis: LINKEDin, a quasi-experimental study in South Africa

Every person diagnosed with tuberculosis (TB) needs to initiate treatment. The WHO estimated 61% of people who developed TB in 2021 were included in a TB treatment registration system. Initial loss to follow up (ILTFU) is the loss of persons to care between diagnosis and treatment initiation/registration. LINKEDin, a quasi-experimental study, evaluated the effect of two interventions (hospital-recording and an alert-and-response patient management intervention) in six sub-districts across three high-TB burden provinces of South Africa. Using integrated electronic reports, we identified all persons diagnosed with TB (Xpert MTB/RIF positive) in hospital and at primary healthcare facilities. We prospectively determined linkage to care at 30 days after TB diagnosis. We calculated the risk of ILTFU during the baseline and intervention periods and the relative risk reduction in ILTFU between these periods. We found a relative reduction in ILTFU of 42.4% (95%CI:28.5,53.7) in KwaZulu Natal (KZN) and 22.3% (95%CI:13.3,30.4) in the Western Cape (WC) with no significant change in Gauteng. In KZN and the WC, the relative reduction in ILTFU appeared greater in sub-districts where the alert-and-response patient management intervention was implemented; KZN (49.3% (95%CI:32.4,62) vs 32.2% (95%CI:5.4,51.4)); and WC (34.2% (95%CI:20.9,45.3) vs 13.4% (95%CI:0.7,24.4)). We reported a notable reduction in ILTFU in two provinces using existing routine health service data and applying a simple intervention to trace and recall those not linked to care. TB programs need to consider ILTFU as a priority and develop interventions specific to their context to ensure improved linkage to care

Risk factors for Coronavirus disease 2019 (Covid-19) death in a population cohort study from the Western Cape province, South Africa

Risk factors for coronavirus disease 2019 (COVID-19) death in sub-Saharan Africa and the effects of human immunodeficiency virus (HIV) and tuberculosis on COVID-19 outcomes are unknown. We conducted a population cohort study using linked data from adults attending public-sector health facilities in the Western Cape, South Africa. We used Cox proportional hazards models, adjusted for age, sex, location, and comorbidities, to examine the associations between HIV, tuberculosis, and COVID-19 death from 1 March to 9 June 2020 among (1) public-sector “active patients” (≥1 visit in the 3 years before March 2020); (2) laboratory-diagnosed COVID-19 cases; and (3) hospitalized COVID-19 cases. We calculated the standardized mortality ratio (SMR) for COVID-19, comparing adults living with and without HIV using modeled population estimates.Among 3 460 932 patients (16% living with HIV), 22 308 were diagnosed with COVID-19, of whom 625 died. COVID19 death was associated with male sex, increasing age, diabetes, hypertension, and chronic kidney disease. HIV was associated with COVID-19 mortality (adjusted hazard ratio [aHR], 2.14; 95% confidence interval [CI], 1.70–2.70), with similar risks across strata of viral loads and immunosuppression. Current and previous diagnoses of tuberculosis were associated with COVID-19 death (aHR, 2.70 [95% CI, 1.81–4.04] and 1.51 [95% CI, 1.18–1.93], respectively). The SMR for COVID-19 death associated with HIV was 2.39 (95% CI, 1.96–2.86); population attributable fraction 8.5% (95% CI, 6.1–11.1)

Virologic outcomes with tenofovir-lamivudine-dolutegravir in adults failing PI-based second-line ART

Background: In South African antiretroviral guidelines, selected patients failing second-line protease inhibitor (PI)-based therapy qualify for genotypic resistance testing – those with PI resistance receive darunavir-based third-line regimens; those without PI resistance continue current regimen with adherence support. The Western Cape province, from September 2020, implemented a strategy of tenofovir-lamivudine-dolutegravir (TLD) for patients, provided there was no tenofovir resistance, irrespective of PI resistance. Objectives: To evaluate virologic outcomes with TLD among adults failing second-line PI regimens with no tenofovir resistance. Method: An observational cohort study comparing outcomes in patients switched to TLD with those continuing the same PI or switched to darunavir-based regimens. Follow-up was until virologic suppression (HIV-1 RNA 400 copies/mL), or at the point of censoring. Results: One hundred and thirty-three patients switched to TLD, 101 to darunavir-based regimens, and 121 continued with the same PI. By 12 months, among patients with PI resistance, 42/47 (89%) in the TLD group had HIV-1 RNA 400 copies/mL compared to 91/99 (92%) in the darunavir group (hazard ratio, 1.11; 95% confidence interval, 0.77–1.60). In patients without PI resistance, 66/86 (77%) in the TLD group had HIV-1 RNA 400 copies/mL compared to 42/120 (35%) in those continuing with the same PI (hazard ratio, 4.03; 95% confidence interval, 2.71–5.98). Two patients receiving TLD developed virologic failure with high-level dolutegravir resistance. Conclusion: Amongst patients failing second-line PI with no PI resistance, switching to TLD was associated with higher virologic suppression, likely due to improved adherence. Virologic outcomes were similar in patients with PI resistance switched to darunavir-based regimens or TLD

Evaluation of radiological capacity and usage in paediatric TB diagnosis: A mixed-method protocol of a comparative study in Mozambique, South Africa and Spain.

IntroductionTuberculosis remains one of the top ten causes of mortality globally. Children accounted for 12% of all TB cases and 18% of all TB deaths in 2022. Paediatric TB is difficult to diagnose with conventional laboratory tests, and chest radiographs remain crucial. However, in low-and middle-income countries with high TB burden, the capacity for radiological diagnosis of paediatric TB is rarely documented and data on the associated radiation exposure limited.MethodsA multicentre, mixed-methods study is proposed in three countries, Mozambique, South Africa and Spain. At the national level, official registry databases will be utilised to retrospectively compile an inventory of licensed imaging resources (mainly X-ray and Computed Tomography (CT) scan equipment) for the year 2021. At the selected health facility level, three descriptive cross-sectional standardised surveys will be conducted to assess radiology capacity, radiological imaging diagnostic use for paediatric TB diagnosis, and radiation protection optimization: a site survey, a clinician-targeted survey, and a radiology staff-targeted survey, respectively. At the patient level, potential dose optimisation will be assessed for children under 16 years of age who were diagnosed and treated for TB in selected sites in each country. For this component, a retrospective analysis of dosimetry will be performed on TB and radiology data routinely collected at the respective sites. National inventory data will be presented as the number of units per million people by modality, region and country. Descriptive analyses will be conducted on survey data, including the demographic, clinical and programmatic characteristics of children treated for TB who had imaging examinations (chest X-ray (CXR) and/or CT scan). Dose exposure analysis will be performed by children's age, gender and disease spectrum.DiscussionAs far as we know, this is the first multicentre and multi-national study to compare radiological capacity, radiation protection optimization and practices between high and low TB burden settings in the context of childhood TB management. The planned comparative analyses will inform policy-makers of existing radiological capacity and deficiencies, allowing better resource prioritisation. It will inform clinicians and radiologists on best practices and means to optimise the use of radiological technology in paediatric TB management

The study-specific objectives.

IntroductionTuberculosis remains one of the top ten causes of mortality globally. Children accounted for 12% of all TB cases and 18% of all TB deaths in 2022. Paediatric TB is difficult to diagnose with conventional laboratory tests, and chest radiographs remain crucial. However, in low-and middle-income countries with high TB burden, the capacity for radiological diagnosis of paediatric TB is rarely documented and data on the associated radiation exposure limited.MethodsA multicentre, mixed-methods study is proposed in three countries, Mozambique, South Africa and Spain. At the national level, official registry databases will be utilised to retrospectively compile an inventory of licensed imaging resources (mainly X-ray and Computed Tomography (CT) scan equipment) for the year 2021. At the selected health facility level, three descriptive cross-sectional standardised surveys will be conducted to assess radiology capacity, radiological imaging diagnostic use for paediatric TB diagnosis, and radiation protection optimization: a site survey, a clinician-targeted survey, and a radiology staff-targeted survey, respectively. At the patient level, potential dose optimisation will be assessed for children under 16 years of age who were diagnosed and treated for TB in selected sites in each country. For this component, a retrospective analysis of dosimetry will be performed on TB and radiology data routinely collected at the respective sites. National inventory data will be presented as the number of units per million people by modality, region and country. Descriptive analyses will be conducted on survey data, including the demographic, clinical and programmatic characteristics of children treated for TB who had imaging examinations (chest X-ray (CXR) and/or CT scan). Dose exposure analysis will be performed by children’s age, gender and disease spectrum.DiscussionAs far as we know, this is the first multicentre and multi-national study to compare radiological capacity, radiation protection optimization and practices between high and low TB burden settings in the context of childhood TB management. The planned comparative analyses will inform policy-makers of existing radiological capacity and deficiencies, allowing better resource prioritisation. It will inform clinicians and radiologists on best practices and means to optimise the use of radiological technology in paediatric TB management.</div

Dosimetry chart.

In this figure, we describe the procedures for obtaining the dosimetry data in each country and the calculation of the cumulative organ dose to the lungs (PACS: Picture Archiving and Communications System; TB: tuberculosis; CXR: chest x-ray; CT: computed tomography scan; kVp: kilovoltage peak; mA: milliamperes; CTDI: computed tomography dose index; HVL: half-value layer; DAP: dose area product; SA: South Africa; NCIRF: National Cancer Institute dosimetry system for Radiography and Fluoroscopy; NCICT: National Cancer Institute dosimetry system for Computed Tomography; mGy: milligray).</p

Study components and methodologies.

In the figure, we describe the different study methodologies applied to answer each study objective (CT: computed tomography scan; TB: tuberculosis; PACS: Picture Archiving and Communications System; CXR: chest x-ray).</p