Point of care ultrasound findings in critically ill SARS-COV2 patients in an HIV endemic, resourced constrained setting.

Objectives: To describe the incidence of venous thromboembolism (VTE) in mechanically ventilated COVID-19 patients in an HIV endemic, resourced constrained setting. To describe the incidence of VTE in relation to HIV status and anticoagulant therapy, and to evaluate VTE-associated cardio-respiratory changes. To establish the contribution of HIV, anticoagulation therapy and other risk factors to mortality. Design: Prospective descriptive study. Setting: Single-center tertiary teaching hospital. Participants: One hundred and one consecutively admitted critically ill adult patients with COVID-19 acute respiratory distress syndrome. Interventions: Point of care ultrasound (POCUS) assessment of the lower limbs and the cardio-respiratory system was performed on intensive care unit (ICU) admission and repeated if clinically indicated. Measurements and main results: DVT was diagnosed by POCUS, whilst pulmonary embolism was diagnosed using a combination of clinical criteria and POCUS (echocardiography and chest wall ultrasound). VTE was diagnosed in 16/101 (16%) patients, despite 14/16 (88%) receiving prior therapeutic dosage of low molecular weight heparin. Clinically significant PE was diagnosed in 5/16 (31%) with 11/16 (69%) having DVT only. The majority of VTE patients, 12/16 (75%), demised 16/101 (16%) patients had HIV co-infection, and 4/16 (25%) with HIV had VTE. Valvular abnormalities were the most common cardiac abnormality with marked tricuspid regurgitation detected in 51/101 (51%). The absence of right atrial enlargement had a 93% negative predictive value for the absence of VTE. Univariate analysis did not demonstrate statistically significant individual risk factors for mortality. Conclusions: Mechanically ventilated COVID- 19 patients at ICU admission had a low incidence of VTE (16%). Therapeutic dose anticoagulation did not reduce mortality compared to prophylactic dosage. In contrast to findings from other studies, no individual risk factor contributed significantly to mortality, likely due to small sample size. POCUS is an ideal screening tool to aid in the assessment of critically ill patients.

The International Prognostic Score and HIV status predict red cell concentrate transfusion needs in Hodgkin lymphoma.

Despite the burden of anemia among Hodgkin lymphoma (HL) patients, data evaluating red cell concentrate transfusion are limited. We retrospectively studied 285 newly diagnosed HL patients who received first-line adriamycin, bleomycin sulfate, vinblastine sulfate, and dacarbazine (ABVD) treatment at Groote Schuur Hospital, Cape Town. HIV prevalence in the cohort was 39.5% and 74.2% of patients had advanced stage HL. Patient prognosis was scored using the HL International Prognostic Score (IPS-7) and HL IPS-3. Seventy (24.6%) patients were transfused with a median of 2 (IQR 1-5) units per patient. Compared to HIV-negative patients, more HIV-positive patients were transfused (14.1% vs. 40.4%, p < .001) and received more units, median 2 (IQR 1-3) vs. 3 (IQR 2-5), p = .035. HL IPS-7 (OR 2.1, p < .001) and HL IPS-3 (OR 2.6, p < .001) were independently associated with transfusion. HL IPS-7, HL IPS-3, and HIV positivity remained associated with transfusion after adjusting for covariates. For patients with newly diagnosed HL, HL IPS-7, HL IPS-3, and HIV status predicted transfusion.

Focused investigations to expedite cancer diagnosis among patients with lymphadenopathy in a tuberculosis and HIV-endemic region.

PURPOSE: In tuberculosis (TB)-endemic areas, lymphadenopathy is frequently due to TB adenitis, but lymphoma and cancers are important differential diagnoses and critical to diagnose at the earliest opportunity. Key obstacles to lymphoma diagnosis include empiric TB treatment and difficulty accessing a biopsy. We report on a specialized clinic utilizing high-yield investigations for patients with lymphadenopathy. METHODS: This prospective interventional study investigated the utility of a core biopsy and the Xpert MTB/RIF Ultra (Ultra) on fine-needle aspirate (FNA) and tissue in a newly established lymph node biopsy clinic over 4 years. Electronic referral facilitated patient assessment within a week. Hematology fellows without specialist surgical or radiological expertise performed the biopsy on the first visit. RESULTS: In 277 patients, including 43% people with HIV, TB was the most frequent diagnosis (34%), followed by lymphoma (27%) and other cancers (17%). Patients were seen a median of 5 days [interquartile range (IQR) 2-8.5 days] from referral. Core biopsy provided sufficient tissue for diagnosis in 96% of patients with lymphoma (72/75) and 94% of patients with cancer (44/47). FNA Ultra had a sensitivity of 73.9% [34/46; 95% confidence interval (CI) 58.9-85.7], and tissue Ultra 73% (46/63; 95% CI 60.3-83.4). There were six false-positive Ultra tests, highlighting the value of histology to either support TB or make an alternative diagnosis. CONCLUSION: Core biopsies collected under the conditions described are safe and sensitive and can yield a rapid diagnosis. Combining Ultra and a core biopsy can accurately diagnose TB and cancer. This clinic provides an implementation model for resource-constrained and TB-endemic areas.

CD68-positive tumour associated macrophages, PD-L1 expression, and EBV latent infection in a high HIV-prevalent South African cohort of Hodgkin lymphoma patients.

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). 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. 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. 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.

Diagnosing lymphoma in the shadow of an epidemic: lessons learned from the diagnostic challenges posed by the dual tuberculosis and HIV epidemics.

Infectious disease epidemics may overshadow and exacerbate existing challenges in diagnosing lymphoma. We describe pragmatic strategies we have implemented to overcome diagnostic obstacles caused by the local tuberculosis (TB) and HIV epidemics in South Africa, which may serve as a guide to minimize diagnostic delay during the COVID-19 pandemic. We report on the diagnostic utility of a rapid-access lymph node core-biopsy clinic, where lymph node biopsies are taken from outpatients at their first visit. Analysis of tissue biopsies (n = 110) revealed the three most common conditions diagnosed were TB adenitis (34%), lymphoma (29%), and disseminated malignancy (20%). A first-attempt core-biopsy was able to diagnose lymphoma in 27/32 (84%) of cases. Compared with a historical cohort, the diagnostic interval (time from first health visit to diagnostic biopsy) for patients with lymphoma was significantly shorter, 13.5 vs 48 days (p = 0.002).

Diffuse large B-cell lymphoma in a South African cohort with a high HIV prevalence: an analysis by cell-of-origin, Epstein-Barr virus infection and survival.

Diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS) is subdivided according to the cell-of-origin (COO) classification into germinal centre B-cell (GCB) and activated B-cell (ABC) subtypes, each with different molecular profiles and clinical behaviour. This study aims to describe the pattern of the COO subtypes, the proportion of Epstein-Barr virus (EBV) co-infection, and their influence on survival outcomes in a setting of high HIV prevalence. This retrospective cohort study included patients diagnosed with de novo DLBCL NOS at our tertiary academic centre in Cape Town, South Africa over a 14-year period. Immunohistochemical stains were performed for COO classification, according to the Hans algorithm. Tumour EBV co-infection was established by EBV-encoded ribonucleic acid in situ hybridisation (EBER-ISH) staining. The effect of the COO subtypes and EBV co-infection on overall survival were described by means of univariate, bivariate and multivariate analyses. A total of 181 patients with DLBCL NOS were included, which comprised 131 HIV-uninfected and 50 HIV-infected patients. There was an equal distribution of GCB and ABC subtypes in the HIV-infected and HIV-uninfected groups. EBV co-infection was detected in 16% of the HIV-infected cases and in 7% of the HIV-uninfected cases (p=0.09). There was no significant difference in the incidence of EBV co-infection between the GCB and ABC subtypes (p=0.67). HIV-infected patients with CD4 ≥150 cells/mm3 had similar survival to HIV-uninfected patients (p=0.005). Multivariate regression analysis showed that in the HIV-infected group with marked immunosuppression (CD4 <150 cells/mm3), there was significantly poorer overall survival compared to the HIV-uninfected group (HR 2.4, 95% CI 1.3-4.1). There were no statistically significant differences in overall survival by DLBCL COO subtype. There was no difference in the proportion of DLBCL COO subtypes, regardless of HIV status. EBV co-infection was more common in the HIV-infected group, but less than described in the literature. Unexpectedly, there were no significant differences in survival outcomes between the GCB and ABC subtypes. Higher CD4 counts in the HIV-infected group had good survival outcomes, while lower CD4 counts predicted adverse survival outcomes. Further research is needed to explore the genetic mutational landscape of HIV-associated DLBCL.

Correction to: Diagnostic accuracy of the Xpert MTB/Rif Ultra for tuberculosis adenitis.

After publication of the original article [1], we were notified that there is a mistake in the article note.

Correction to: In the South African setting, HIV-associated Burkitt lymphoma is associated with frequent leukaemic presentation, complex cytogenetic karyotypes, and adverse clinical outcomes.

The article "In the South African setting, HIV-associated Burkitt lymphoma is associated with frequent leukaemic presentation, complex cytogenetic karyotypes, and adverse clinical outcomes".

Diagnostic accuracy of the Xpert MTB/Rif Ultra for tuberculosis adenitis.

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.

In the South African setting, HIV-associated Burkitt lymphoma is associated with frequent leukaemic presentation, complex cytogenetic karyotypes, and adverse clinical outcomes.

South Africa (SA) has a high prevalence of human immunodeficiency virus (HIV) infection. People living with HIV are at markedly increased risk of developing Burkitt lymphoma (BL), which is characterized by the MYC translocation. There is a paucity of survival data of HIV-associated Burkitt lymphoma/leukaemia (HIV-BL) cases from SA, and the relationship between karyotype and outcomes has not been widely reported. Here we report the clinico-pathological characteristics of a cohort of cytogenetically confirmed HIV-BL cases. A retrospective, descriptive review was conducted of clinico-pathological features of HIV-BL patients newly diagnosed and treated between 2005 and 2014 at our tertiary academic institution in Cape Town. Only HIV-BL patients with cytogenetic evidence of a MYC translocation were included for analysis. A multivariable Cox proportional hazards model assessed the impact of variables on overall survival (OS). Forty-nine patients met inclusion criteria. Their median age was 37 years (IQR 30-43 years) and 57% (n = 28) were females. Their median CD4 count was 240 cells/µl (IQR 103-423 cells/µl). The majority, 61% (n = 30), had leukaemic presentation, and 20% (n = 10) had a complex karyotype on conventional karyotyping. Seventy-seven percent (n = 36) received various protocols of combination intensive chemotherapy, excluding rituximab. Their OS was 64% (95% CI 45-77%) at 6 months, and 34% (95% CI 17-51%) at 5 years. Leukaemic presentation and a complex karyotype gave a 2.7-fold (95% CI 1.0-6.7) and 2.6-fold (95% CI 1.1-6.6) increased risk of mortality respectively, which were statistical significant (p < 0.05). We report 49 newly diagnosed, cytogenetically confirmed HIV-BL patients at our institution over a 10-year period. There was a high proportion of complex karyotypes and leukaemic presentation, which both independently adversely affected survival. This may be due to differences in the pathobiology of HIV-BL that requires further study and could lead to therapeutic advances in this patient group.

The determinants and impact of diagnostic delay in lymphoma in a TB and HIV endemic setting.

BACKGROUND: 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.

Role of splenectomy for immune thrombocytopenic purpura (ITP) in the era of new second-line therapies and in the setting of a high prevalence of HIV-associated ITP.

BACKGROUND: New agents are being used as second-line treatment for immune thrombocytopenia (ITP) and have brought into question the relevance of splenectomy for steroid-resistant ITP. METHODS: We retrospectively analysed 73 patients who underwent splenectomy for ITP at our institution over an 11-year period. The median follow-up period was 25 months; patients with follow-up of <1 month were excluded. The outcomes of splenectomy were compared in HIV-positive v. HIV-negative patients. RESULTS: The rate of complete response was 83%, and response was sustained for at least 1 year or until latest follow-up in 80% of patients. Twelve patients were HIV-positive. Splenectomy was laparoscopic in 43 patients (62%) with an overall 16% complication rate. The 90-day mortality rate was 1.38%. There was no statistically significant difference in response or complication rate in the HIV-positive patients. There was a statistically significant (p=0.003) poorer response to splenectomy in the patients with steroid-resistant ITP. CONCLUSION: Splenectomy is effective and safe irrespective of HIV status and remains an appropriate second-line treatment for ITP. Further research is needed to corroborate our finding of lower response in patients who are steroid-resistant, as this might be a subgroup of patients who may benefit from thrombopoietin agonists as second line therapy.