Potential for medical error: Incorrectly completed request forms for thyroid function tests limit pathologists’ advice to clinicians

Background. Various publications have highlighted the significance of laboratory errors in the pre- and post-analytical phases and their impact on results. Thyroid-stimulating hormone (TSH) is a first-line thyroid function test and, if abnormal, reflex thyroxine (T4) or tri-iodothyronine (T3) testing is requested, depending on clinical and medication data provided. Interpretative comments are added to all TFTresults.Objectives. In view of the paucity of articles describing such errors, we audited laboratory request forms requesting thyroid function tests (TFT), received from primary care clinics and regional hospitals at our laboratory.Design. We assessed 482 laboratory request forms for TFT from primary health care clinics for specific parameters. Results. A total of 482 forms were analysed. Medication/s used by the patient (74.5%) and doctor’s contact number (65.1%) were the most commonly incomplete parameters. Of the 123 patients with medication details, 62 (50.4%) were on thyroxine.Conclusions. There are few studies examining the frequencyand impact of incomplete laboratory forms on laboratory errors, and even fewer studies examining interpretative comments accompanying clinical biochemistry results. We studied how pre-analytical errors in completing request forms may lead to incorrect interpretative comments and inappropriate reflex testing, and so influence the quality of the post-analytical phase

Latent class analysis: an innovative approach for identification of clinical and laboratory markers of disease severity among COVID-19 patients admitted to the intensive care unit

Objective: The aim of this study was to identify clinical and laboratory phenotype distribution patterns and their usefulness as prognostic markers in COVID-19 patients admitted to the intensive care unit (ICU) at Tygerberg Hospital, Cape Town. Methods and results: A latent class analysis (LCA) model was applied in a prospective, observational cohort study. Data from 343 COVID-19 patients were analysed. Two distinct phenotypes (1 and 2) were identified, comprising 68.46% and 31.54% of patients, respectively. The phenotype 2 patients were characterized by increased coagulopathy markers (D-dimer, median value 1.73 ng/L vs 0.94 ng/L; p < 0.001), end-organ dysfunction (creatinine, median value 79 µmol/L vs 69.5 µmol/L; p < 0.003), under-perfusion markers (lactate, median value 1.60 mmol/L vs 1.20 mmol/L; p < 0.001), abnormal cardiac function markers (median N‐terminal pro‐brain natriuretic peptide (NT-proBNP) 314 pg/ml vs 63.5 pg/ml; p < 0.001 and median high‐sensitivity cardiac troponin (Hs-TropT) 39 ng/L vs 12 ng/L; p < 0.001), and acute inflammatory syndrome (median neutrophil-to-lymphocyte ratio 15.08 vs 8.68; p < 0.001 and median monocyte value 0.68 × 109/L vs 0.45 × 109/L; p < 0.001). Conclusion: The identification of COVID-19 phenotypes and sub-phenotypes in ICU patients could help as a prognostic marker in the day-to-day management of COVID-19 patients admitted to the ICU

Predicting COVID-19 outcomes from clinical and laboratory parameters in an intensive care facility during the second wave of the pandemic in South Africa

Background: The second wave of coronavirus disease 2019 (COVID-19) in South Africa was caused by the Beta variant of severe acute respiratory syndrome coronavirurus-2. This study aimed to explore clinical and biochemical parameters that could predict outcome in patients with COVID-19. Methods: A prospective study was conducted between 5 November 2020 and 30 April 2021 among patients with confirmed COVID-19 admitted to the intensive care unit (ICU) of a tertiary hospital. The Cox proportional hazards model in Stata 16 was used to assess risk factors associated with survival or death. Factors with P<0.05 were considered significant. Results: Patients who died were found to have significantly lower median pH (P<0.001), higher median arterial partial pressure of carbon dioxide (P<0.001), higher D-dimer levels (P=0.001), higher troponin T levels (P=0.001), higher N-terminal-prohormone B-type natriuretic peptide levels (P=0.007) and higher C-reactive protein levels (P=0.010) compared with patients who survived. Increased standard bicarbonate (HCO3std) was associated with lower risk of death (hazard ratio 0.96, 95% confidence interval 0.93–0.99). Conclusions: The mortality of patients with COVID-19 admitted to the ICU was associated with elevated D-dimer and a low HCO3std level. Large studies are warranted to increase the identification of patients at risk of poor prognosis, and to improve the clinical approach

Comparison of patients with severe COVID-19 admitted to an intensive care unit in South Africa during the first and second wave of the COVID-19 pandemic

BACKGROUND: The second wave of coronavirus disease 2019 (COVID‑19), dominated by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Beta variant, has been reported to be associated with increased severity in South Africa (SA). OBJECTIVES: To describe and compare clinical characteristics, management and outcomes of COVID‑19 patients admitted to an intensive care unit (ICU) in SA during the first and second waves. METHODS: In a prospective, single-centre, descriptive study, we compared all patients with severe COVID‑19 admitted to ICU during the first and second waves. The primary outcomes assessed were ICU mortality and ICU length of stay (LOS). RESULTS: In 490 patients with comparable ages and comorbidities, no difference in mortality was demonstrated during the second compared with the first wave (65.9% v. 62.5%, p=0.57). ICU LOS was longer in the second wave (10 v. 6 days, p<0.001). More female admissions (67.1% v. 44.6%, p<0.001) and a greater proportion of patients were managed with invasive mechanical ventilation than with non-invasive respiratory support (39.0% v. 14%, p<0.001) in the second wave. CONCLUSIONS: While clinical characteristics were comparable between the two waves, a higher proportion of patients was invasively ventilated and ICU stay was longer in the second. ICU mortality was unchanged

Prognostic value of biochemical parameters among severe COVID-19 patients admitted to an intensive care unit of a tertiary hospital in South Africa

Background: Data on biochemical markers and their association with mortality rates in patients with severe coronavirus disease 2019 (COVID-19) admitted to intensive care units (ICUs) in sub-Saharan Africa are scarce. An evaluation of baseline routine biochemical parameters was performed in COVID-19 patients admitted to the ICU, in order to identify prognostic biomarkers. Methods: Demographic, clinical, and laboratory data were collected prospectively from patients with PCR-confirmed COVID-19 admitted to the adult ICU of a tertiary hospital in Cape Town, South Africa, between October 2020 and February 2021. Robust Poisson regression methods and the receiver operating characteristic (ROC) curve were used to explore the association of biochemical parameters with severity and mortality. Results: A total of 82 patients (median age 53.8 years, interquartile range 46.4–59.7 years) were enrolled, of whom 55 (67%) were female and 27 (33%) were male. The median duration of ICU stay was 10 days (interquartile range 5–14 days); 54/82 patients died (66% case fatality rate). Baseline lactate dehydrogenase (LDH) (adjusted relative risk 1.002, 95% confidence interval 1.0004–1.004; P = 0.016) and N-terminal pro B-type natriuretic peptide (NT-proBNP) (adjusted relative risk 1.0004, 95% confidence interval 1.0001–1.0007; P = 0.014) were both found to be independent risk factors of a poor prognosis, with optimal cut-off values of 449.5 U/l (sensitivity 100%, specificity 43%) and 551 pg/ml (sensitivity 49%, specificity 86%), respectively. Conclusions: LDH and NT-proBNP appear to be promising predictors of a poor prognosis in COVID-19 patients in the ICU. Studies with a larger sample size are required to confirm the validity of this combination of biomarkers

Immunologic and vascular biomarkers of mortality in critical COVID-19 in a South African cohort

Introduction: Biomarkers predicting mortality among critical Coronavirus disease 2019 (COVID-19) patients provide insight into the underlying pathophysiology of fatal disease and assist with triaging of cases in overburdened settings. However, data describing these biomarkers in Sub-Saharan African populations are sparse. Methods: We collected serum samples and corresponding clinical data from 87 patients with critical COVID-19 on day 1 of admission to the intensive care unit (ICU) of a tertiary hospital in Cape Town, South Africa, during the second wave of the COVID-19 pandemic. A second sample from the same patients was collected on day 7 of ICU admission. Patients were followed up until in-hospital death or hospital discharge. A custom-designed 52 biomarker panel was performed on the Luminex® platform. Data were analyzed for any association between biomarkers and mortality based on pre-determined functional groups, and individual analytes. Results: Of 87 patients, 55 (63.2%) died and 32 (36.8%) survived. We found a dysregulated cytokine response in patients who died, with elevated levels of type-1 and type-2 cytokines, chemokines, and acute phase reactants, as well as reduced levels of regulatory T cell cytokines. Interleukin (IL)-15 and IL-18 were elevated in those who died, and levels reduced over time in those who survived. Procalcitonin (PCT), C-reactive protein, Endothelin-1 and vascular cell adhesion molecule-1 were elevated in those who died. Discussion: These results show the pattern of dysregulation in critical COVID-19 in a Sub-Saharan African cohort. They suggest that fatal COVID-19 involved excessive activation of cytotoxic cells and the NLRP3 (nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3) inflammasome. Furthermore, superinfection and endothelial dysfunction with thrombosis might have contributed to mortality. HIV infection did not affect the outcome. A clinically relevant biosignature including PCT, pH and lymphocyte percentage on differential count, had an 84.8% sensitivity for mortality, and outperformed the Luminex-derived biosignature

Haematological predictors of poor outcome among COVID-19 patients admitted to an intensive care unit of a tertiary hospital in South Africa

BACKGROUND: Studies from Asia, Europe and the USA indicate that widely available haematological parameters could be used to determine the clinical severity of Coronavirus disease 2019 (COVID-19) and predict management outcome. There is limited data from Africa on their usefulness in patients admitted to Intensive Care Units (ICUs). We performed an evaluation of baseline haematological parameters as prognostic biomarkers in ICU COVID-19 patients. METHODS: Demographic, clinical and laboratory data were collected prospectively on patients with confirmed COVID-19, admitted to the adult ICU in a tertiary hospital in Cape Town, South Africa, between March 2020 and February 2021. Robust Poisson regression methods and receiver operating characteristic (ROC) curves were used to explore the association of haematological parameters with COVID-19 severity and mortality. RESULTS: A total of 490 patients (median age 54.1 years) were included, of whom 237 (48%) were female. The median duration of ICU stay was 6 days and 309/490 (63%) patients died. Raised neutrophil count and neutrophil/lymphocyte ratio (NLR) were associated with worse outcome. Independent risk factors associated with mortality were age (ARR 1.01, 95%CI 1.0–1.02; p = 0.002); female sex (ARR 1.23, 95%CI 1.05–1.42; p = 0.008) and D-dimer levels (ARR 1.01, 95%CI 1.002–1.03; p = 0.016). CONCLUSIONS: Our study showed that raised neutrophil count, NLR and D-dimer at the time of ICU admission were associated with higher mortality. Contrary to what has previously been reported, our study revealed females admitted to the ICU had a higher risk of mortality

Diagnostic Accuracy of Adenosine Deaminase and Lymphocyte Proportion in Pleural Fluid for Tuberculous Pleurisy in Different Prevalence Scenarios

BACKGROUND: Tuberculous pleural effusion (TPE) is a paucibacillary manifestation of tuberculosis, so isolation of Mycobacterium tuberculosis is difficult, biomarkers being an alternative for diagnosis. Adenosine deaminase (ADA) is the most cost-effective pleural fluid marker and is routinely used in high prevalence settings, whereas its value is questioned in areas with low prevalence. The lymphocyte proportion (LP) is known to increase the specificity of ADA for this diagnosis. We analyse the diagnostic usefulness of ADA alone and the combination of ADA ≥ 40 U/l (ADA(40)) and LP ≥ 50% (LP(50)) in three different prevalence scenarios over 11 years in our area. MATERIALS AND METHODS: Biochemistry, cytology and microbiology studies from 472 consecutive pleural fluid samples were retrospectively analyzed. ADA and differential cell count were determined in all samples. We established three different prevalence periods, based on percentage of pleural effusion cases diagnosed as tuberculosis: 1998-2000 (31.3%), 2001-2004 (11.8%), and 2005-2008 (7.4%). ROC curves, dispersion diagrams and pre/post-test probability graphs were produced. TPE accounted for 73 episodes (mean prevalence: 15.5%). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for ADA(40) were 89%, 92.7%, 69.2% and 97.9%, respectively. For ADA(40)+LP(50) the specificity and PPV increased (98.3% and 90%) with hardly any decrease in the sensitivity or NPV (86.3% and 97.5%). No relevant differences were observed between the three study periods. CONCLUSIONS/SIGNIFICANCE: ADA remains useful for the diagnosis of TPE even in low-to-intermediate prevalence scenarios when combined with the lymphocyte proportion

Antibody Repertoires in Humanized NOD-scid-IL2Rγnull Mice and Human B Cells Reveals Human-Like Diversification and Tolerance Checkpoints in the Mouse

Immunodeficient mice reconstituted with human hematopoietic stem cells enable the in vivo study of human hematopoiesis. In particular, NOD-scid-IL2Rγnull engrafted mice have been shown to have reasonable levels of T and B cell repopulation and can mount T-cell dependent responses; however, antigen-specific B-cell responses in this model are generally poor. We explored whether developmental defects in the immunoglobulin gene repertoire might be partly responsible for the low level of antibody responses in this model. Roche 454 sequencing was used to obtain over 685,000 reads from cDNA encoding immunoglobulin heavy (IGH) and light (IGK and IGL) genes isolated from immature, naïve, or total splenic B cells in engrafted NOD-scid-IL2Rγnull mice, and compared with over 940,000 reads from peripheral B cells of two healthy volunteers. We find that while naïve B-cell repertoires in humanized mice are chiefly indistinguishable from those in human blood B cells, and display highly correlated patterns of immunoglobulin gene segment use, the complementarity-determining region H3 (CDR-H3) repertoires are nevertheless extremely diverse and are specific for each individual. Despite this diversity, preferential DH-JH pairings repeatedly occur within the CDR-H3 interval that are strikingly similar across all repertoires examined, implying a genetic constraint imposed on repertoire generation. Moreover, CDR-H3 length, charged amino-acid content, and hydropathy are indistinguishable between humans and humanized mice, with no evidence of global autoimmune signatures. Importantly, however, a statistically greater usage of the inherently autoreactive IGHV4-34 and IGKV4-1 genes was observed in the newly formed immature B cells relative to naïve B or total splenic B cells in the humanized mice, a finding consistent with the deletion of autoreactive B cells in humans. Overall, our results provide evidence that key features of the primary repertoire are shaped by genetic factors intrinsic to human B cells and are principally unaltered by differences between mouse and human stromal microenvironments

A narrative review of the potential pharmacological influence and safety of ibuprofen on coronavirus disease 19 (COVID-19), ACE2, and the immune system: a dichotomy of expectation and reality

The coronavirus disease 19 (COVID-19) pandemic is currently the most acute healthcare challenge in the world. Despite growing knowledge of the nature of Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), treatment options are still poorly defined. The safety of non-steroidal anti-inflammatory drugs (NSAIDs), specifically ibuprofen, has been openly questioned without any supporting evidence or clarity over dose, duration, or temporality of administration. This has been further conflicted by the initiation of studies to assess the efficacy of ibuprofen in improving outcomes in severe COVID-19 patients. To clarify the scientific reality, a literature search was conducted alongside considerations of the pharmacological properties of ibuprofen in order to construct this narrative review. The literature suggests that double-blind, placebo-controlled study results must be reported and carefully analysed for safety and efficacy in patients with COVID-19 before any recommendations can be made regarding the use of ibuprofen in such patients. Limited studies have suggested: (i) no direct interactions between ibuprofen and SARS-CoV-2 and (ii) there is no evidence to suggest ibuprofen affects the regulation of angiotensin-converting-enzyme 2 (ACE2), the receptor for COVID-19, in human studies. Furthermore, in vitro studies suggest ibuprofen may facilitate cleavage of ACE2 from the membrane, preventing membrane-dependent viral entry into the cell, the clinical significance of which is uncertain. Additionally, in vitro evidence suggests that inhibition of the transcription factor nuclear factor-κB (NF-kB) by ibuprofen may have a role in reducing excess inflammation or cytokine release in COVID-19 patients. Finally, there is no evidence that ibuprofen will aggravate or increase the chance of infection of COVID-19