Multi-level tuberculosis of the spine identified by 18 F-FDG-PET/CT and concomitant urogenital tuberculosis: a case report from the spinal TB X cohort.

BACKGROUND: Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and typically infects the lungs. However, extrapulmonary forms of TB can be found in approximately 20% of cases. It is suggested, that up to 10% of extrapulmonary TB affects the musculoskeletal system, in which spinal elements (spinal tuberculosis, STB) are involved in approximately 50% of the cases. STB is a debilitating disease with nonspecific symptoms and diagnosis is often delayed for months to years. In our Spinal TB X Cohort, we aim to describe the clinical phenotype of STB using whole-body 18 F-fluorodeoxyglucose positron emission tomography computed tomography (PET/CT) and to identify a specific gene expression profile for the different stages of dissemination on PET/CT. Here we report on the first patient recruited into our cohort who underwent PET/CT before treatment initiation, at 6-months and at 12-months - time of TB treatment completion. CASE PRESENTATION: A 27-year-old immunocompetent male presented with severe thoracolumbar back pain for 9 months with severe antalgic gait and night sweats. Magnetic resonance imaging (MRI) of the whole spine revealed multilevel spinal disease (T5/6, T11/12, L3/4) in keeping with STB. After informed consent and recruitment into the Spinal TB X Cohort, the patient underwent PET/CT as per protocol, which revealed isolated multilevel STB (T4-7, T11/12, L3/4) with no concomitant lung or urogenital lesion. However, sputum and urine were Xpert MTB/RIF Ultra positive and Mtb was cultured from the urine sample. CT-guided biopsy of the T11/12 lesion confirmed drug-sensitive Mtb on Xpert MTB/RIF Ultra and the patient was started on TB treatment according to local guidelines for 12 months. The 6-month follow-up PET/CT revealed new and existing spinal lesions with increased FDG-uptake despite significant improvement of clinical features and laboratory markers. After 9 months of treatment, the patient developed an acute urethral stricture, most likely due to urogenital TB, and a suprapubic catheter was inserted. The 12-month PET/CT showed significantly decreased PET/CT values of all lesions, however, significant persistent spinal inflammation was present at the end of TB treatment. Clinically, the patient was considered cured by the TB control program and currently awaits urethroplasty. CONCLUSIONS: In our case, PET/CT emerged as a valuable imaging modality for the initial assessment, surpassing MRI by revealing more comprehensive extensive disease. Subsequent PET/CT scans at 6-month uncovered new lesions and increased inflammation in existing ones, while by the end of TB treatment, all lesions exhibited improvement. However, the interpretation of FDG avidity remains ambiguous, whether it correlates with active infection and viable Mtb. or fibro- and osteoblast activity indicative of the healing process. Additionally, the absence of extraspinal TB lesions on PET/CT despite positive microbiology from sputum and urine maybe explained by paucibacillary, subclinical infection of extraspinal organs. The Spinal TB X Cohort endeavours to shed light on whole-body imaging patterns at diagnosis, their evolution midway through TB treatment, and upon treatment completion. Ultimately, this study aims to advance our understanding of the biology of this complex disease.

Health Sciences students' experience of COVID-19 case management and contact tracing in Cape Town, South Africa.

BACKGROUND: COVID-19 has challenged health and higher education systems globally. Managing the epidemic in Cape Town, South Africa (SA), required partnerships with universities and setting up of de novo systems for mass case and contact tracing (C&CT). Health sciences, predominantly medical students, as well as social work and psychology students formed the core of this telephone-based work over the 18 months when SARS-CoV-2 caused severe disease. METHODS: This qualitative study aimed to elicit students' motivations for becoming involved in C&CT, their experiences, and recommendations for C&CT and curricula. After Cape Town's first COVID-19 wave, six on-line focus groups comprising 23 students were conducted, and a further four were conducted with 13 students after the second wave. As the researchers were predominantly educators previously involved in undergraduate health sciences education, the study's purpose was to reflect on students' experiences to make educational and health system recommendations. RESULTS: Students were largely motivated to mitigate the impact of the epidemic on society and support people affected by COVID-19, as well as hone their professional skills. While these motivations were realised, students also needed to learn new skills - to autonomously work remotely, using novel communication strategies to engage those affected and use virtual groups to connect with colleagues. They managed responsibilities within the healthcare systems that did not always work smoothly, distressed cases who were financially insecure, difficult employers, and language barriers. They were prepared through training, and supported by virtual, yet effective teamwork and debriefing opportunities. Although the work was sometimes physically and emotionally exhausting, students found the work personally meaningful. They embraced public health's role to protect population and individuals' health. CONCLUSION: New teaching and learning practices adopted due to Covid-19 lockdowns enabled this digital C&CT project. It facilitated students to become confident, work autonomously and navigate challenges they will encounter as young professionals. The programme demonstrated that novel opportunities for rich student learning, such as in telehealth, can be embedded into public health and clinical functions of health services in contexts such as in SA, deepening partnerships between the health services and universities, to mutual benefit.

Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town.

OBJECTIVE: Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor (LDLR) mutations account for >90% of cases, apolipoprotein B (APOB) mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 (PCSK9) gain of function mutations are rare (<1% of cases). We aimed to evaluate the functional impact of several novel PCSK9 variants in a cohort of patients with FH by genetic cascade screening and in vitro functionality assays. Approach and Results: Patients with clinically diagnosed FH underwent genetic analysis of LDLR, and if negative, sequential testing of APOB and PCSK9. We analyzed cosegregation of hypercholesterolemia with novel PCSK9 variants. Gain of function status was determined by in silico analyses and validated by in vitro functionality assays. Among 1055 persons with clinical FH, we identified nonsynonymous PCSK9 variants in 27 (2.6%) patients and 7 of these carried one of the 4 previously reported gain of function variants. In the remaining 20 patients with FH, we identified 7 novel PCSK9 variants. The G516V variant (c.1547G>T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL; P<0.001). In vitro studies demonstrated the pathogenicity of the G516V variant. CONCLUSIONS: In our study, 1.14% of cases with clinical FH were clearly attributable to pathogenic variants in PCSK9. Pathogenicity is established beyond doubt for the G516V variant.

Comparing gene expression profiles of adults with isolated spinal tuberculosis to disseminated spinal tuberculosis identified by 18FDG-PET/CT at time of diagnosis, 6- and 12-months follow-up: classifying clinical stages of spinal tuberculosis and monitoring treatment response (Spinal TB X cohort study).

BACKGROUND: Tuberculosis (TB) is one of the top ten causes of death worldwide, with approximately 10 million cases annually. Focus has been on pulmonary TB, while extrapulmonary TB (EPTB) has received little attention. Diagnosis of EPTB remains challenging due to the invasive procedures required for sample collection. Spinal TB (STB) accounts for 10% of EPTB and often leads to lifelong debilitating disease due to devastating spinal deformation and compression of neural structures. Little is known about the extent of disease, although both isolated STB and a disseminated form of STB have been described. In our Spinal TB X cohort study, we aim to describe the clinical phenotype of STB using whole-body 18FDG-PET/CT, identify a specific gene expression profile for different stages of dissemination and compare findings to previously described gene expression signatures for latent and active pulmonary TB. METHODS: A single-centre, prospective cohort study will be established to describe the distributional pattern of STB detected by whole-body 18FDG-PET/CT and gene expression profile of patients with suspected STB on magnetic resonance imaging (MRI) at point of diagnosis, six months, and 12 months. Blood biobanking will be performed at these time points. Specimens for microbiology will be obtained from sputum/urine, from easily accessible sites of disease (e.g., lymph nodes, abscess) identified in the first 18FDG-PET/CT, from CT-guided biopsy and/or surgery. Clinical parameters and functional scores will be collected at every physical visit. Data will be entered into RedCap® database; data cleaning, validation and analysis will be performed by the study team. The University of Cape Town Ethics Committee approved the protocol (243/2022). DISCUSSION: The Spinal TB X cohort study is the first prospective cohort study using whole-body 18FDG-PET/CT scans in patients with microbiologically confirmed spinal tuberculosis. Dual imaging techniques of the spine using 18FDG-PET/CT and magnetic resonance imaging as well as tissue diagnosis (microbiology and histopathology) will allow us to develop a virtual biopsy model. If successful, a distinct gene-expression profile will aid in blood-based diagnosis (point of care testing) as well as treatment monitoring and would lead to earlier diagnosis of this devastating disease. TRIAL REGISTRATION: The study has been registered on ClinicalTrials.gov (NCT05610098).

To treat or not to treat tuberculosis -clinical decision making in patients with previous pulmonary tuberculosis using 18F-FDG PET/CT.

Post-tuberculosis (TB) radiological changes and symptoms can mimic TB. PCR-based diagnostic tests can show positive results, suggesting the presence of Mycobacterium tuberculosis DNA in the absence of viable bacteria. We present a case with two episodes of previous TB. Despite workup including trace to low positive PCR results, after performing sputum analysis, bronchoalveolar lavage analysis, cyto-brush and 18F-FDG PET/CT guided transthoracic biopsy, no culturable mycobacteria were detected. 18F-FDG PET/CT showed a high metabolic activity of the biopsied lesions. More accurate strategies and tools in patients with previous TB and positive PCR results are required to make appropriate treatment decisions.

Statins and other lipid-lowering therapy and pregnancy outcomes in homozygous familial hypercholesterolaemia: A retrospective review of 39 pregnancies.

BACKGROUND AND AIMS: Pregnancy in HoFH females is associated with further elevation of already markedly elevated low density lipoprotein cholesterol (LDL-C) levels, particularly if lipid-lowering therapy is discontinued, placing the mother and fetus at increased cardiovascular risk. Lipoprotein apheresis is the current recommended treatment for pregnant HoFH patients. However, this is costly, time consuming, and is not available in many countries. Alternative treatment strategies to control hypercholesterolaemia during pregnancy in HoFH patients are necessary. METHODS: This study was a retrospective review of 39 pregnancies from a cohort of 20 genotypically confirmed female HoFH patients. RESULTS: No maternal cardiac complications or deaths occurred during the pregnancies or during the first year postpartum. Twenty five pregnancies were exposed to lipid-lowering therapy, of which 18 were exposed to statin therapy, just prior to or during the pregnancy. Thirty three (84%) pregnancies carried to term, 3 (8%) premature deliveries and 3 (8%) miscarriages were observed. Complications associated with pregnancy in these HoFH patients, did not differ from those reported during pregnancies of otherwise healthy woman. CONCLUSIONS: HoFH is a severe disease impacting significantly on life expectancy. However, for many females with HoFH, despite the high cardiovascular risk, pregnancy is not uncommon. In resource poor settings and when LA is not available, lipid lowering therapy, particularly statin therapy during pregnancy, appears to be safe for both mother and fetus and is an acceptable alternative for LDL-C reduction in these high risk patients.

LDL-cholesterol target achievement in patients with heterozygous familial hypercholesterolemia at Groote Schuur Hospital: Minority at target despite large reductions in LDL-C.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is characterized by markedly increased LDL-cholesterol (LDL-C) and premature cardiovascular disease (CVD). LDL-C lowering is the cornerstone of therapy. The aim of our study was to evaluate LDL-C target achievement and explore reasons for not reaching target in FH patients attending a public-sector lipid clinic at Groote Schuur Hospital in Cape Town, South Africa. METHODS: We reviewed clinical records of patients with genetically confirmed heterozygous FH (heFH) retrospectively. For patients seen after 2013, when new guidelines were published, we determined reasons for use of submaximal therapy. RESULTS: Our study population consisted of 776 adult heFH patients. A substantial proportion (41%) of those younger than 50 years of age had already experienced a cardiovascular event. The mean (±SD) untreated and best achieved LDL-C values during follow up were 8.1 ±â€¯2.1 and 4.0 ±â€¯1.5 mmol/l, respectively. Despite a mean LDL-C reduction of 50%, only 140 (25%) achieved an LDL-C ≤ 3.0 mmol/l. Of the 164 participants with follow up after 2013, 42 did not reach LDL-C < 3.0 mmol/l and did not use maximal therapy (26%). The commonest reasons for not using maximum therapy were statin side-effects (n = 15, 36%) and acceptance by the patient (n = 9, 22%) or the physician (n = 8, 19%) of the control achieved. CONCLUSIONS: The heFH population in Cape Town is characterized by high baseline LDL-C, a high prevalence of CVD at presentation and low rates of achieving an LDL-C target of 3.0 mmol/l.

Efficacy and safety of fluvastatin in children and adolescents with heterozygous familial hypercholesterolaemia.

AIM: To assess whether early initiation of statin therapy for heterozygous familial hypercholesterolaemia favourably affects lipid profiles or vascular morphological changes. METHODS: Children and adolescents aged 10-16 y with heterozygous familial hypercholesterolaemia were administered fluvastatin (80 mg/d) for 2 y in a single-arm two-centre study. Carotid B-mode intima-media thickness (IMT) and M-mode arterial wall stiffness (beta) were recorded. Eighty of the 85 enrolled subjects completed the trial. RESULTS: The median decrease in low-density lipoprotein (LDL) cholesterol from baseline at last study visit was 33.9%; median decreases in total cholesterol, triglycerides and apolipoprotein B were 27.1%, 5.3% and 24.2%, respectively; the median increase in high-density lipoprotein (HDL) cholesterol was 5.3%. Changes in carotid arterial wall thickness and stiffness versus baseline were fractional and statistically non-significant (delta IMT -0.005 mm, 95% CI -0.018 to +0.007 mm, n=83; and delta beta = 0.017, 95% CI -0.219 to +0.253, n=79). Adverse events, all non-serious, were reported by 58 subjects (68.2%); four were suspected to be drug-related. Change in hormone levels and sexual maturation were appropriate for this age group. CONCLUSION: Fluvastatin lowered LDL cholesterol, total cholesterol and apolipoprotein B levels effectively over a prolonged period in children and adolescents with heterozygous familial hypercholesterolaemia. Carotid IMT and wall stiffness remained largely unchanged.