A case of pulmonary melioidosis in Germany: a rare differential diagnosis in returning travelers from South-East Asia.

BACKGROUND: Melioidosis is a bacterial infection associated with high mortality. The diagnostic approach to this rare disease in Europe is challenging, especially because pulmonary manifestation of melioidosis can mimic pulmonary tuberculosis (TB). Antibiotic therapy of melioidosis consists of an initial intensive phase of 2-8 weeks followed by an eradication therapy of 3-6 months. CASE PRESENTATION: We present the case of a 46-year-old female patient with pulmonary melioidosis in Germany. The patient showed chronic cough, a pulmonary mass and a cavitary lesion, which led to the initial suspicion of pulmonary TB. Melioidosis was considered due to a long-term stay in Thailand with recurrent exposure to rice fields. RESULTS: Microbiologic results were negative for TB. Histopathology of an endobronchial tumor showed marked chronic granulation tissue and fibrinous inflammation. Melioidosis was diagnosed via polymerase chain reaction by detection of Burkholderia pseudomallei/mallei target from mediastinal lymph-node tissue. CONCLUSION: This case report emphasizes that melioidosis is an important differential diagnosis in patients with suspected pulmonary tuberculosis and recent travel to South-East Asia.

Accuracy and ease-of-use of seven point-of-care SARS-CoV-2 antigen-detecting tests: A multi-centre clinical evaluation.

BACKGROUND: Antigen-detecting rapid diagnostic tests (Ag-RDTs) for SARS-CoV-2 are important diagnostic tools. We assessed clinical performance and ease-of-use of seven Ag-RDTs in a prospective, manufacturer-independent, multi-centre cross-sectional diagnostic accuracy study to inform global decision makers. METHODS: Unvaccinated participants suspected of a first SARS-CoV-2 infection were recruited at six sites (Germany, Brazil). Ag-RDTs were evaluated sequentially, with collection of paired swabs for routine reverse transcription polymerase chain reaction (RT-PCR) testing and Ag-RDT testing. Performance was compared to RT-PCR overall and in sub-group analyses (viral load, symptoms, symptoms duration). To understandusability a System Usability Scale (SUS) questionnaire and ease-of-use (EoU) assessment were performed. FINDINGS: 7471 participants were included in the analysis. Sensitivities across Ag-RDTs ranged from 70·4%-90·1%, specificities were above 97·2% for all Ag-RDTs but one (93·1%).Ag-RDTs, Mologic, Bionote, Standard Q, showed diagnostic accuracy in line with WHO targets (> 80% sensitivity, > 97% specificity). All tests showed high sensitivity in the first three days after symptom onset (≥87·1%) and in individuals with viral loads≥ 6 log10SARS-CoV2 RNA copies/mL (≥ 88·7%). Usability varied, with Rapigen, Bionote and Standard Q reaching very good scores; 90, 88 and 84/100, respectively. INTERPRETATION: Variability in test performance is partially explained by variable viral loads in population evaluated over the course of the pandemic. All Ag-RDTs reach high sensitivity early in the disease and in individuals with high viral loads, supporting their role in identifying transmission relevant infections. For easy-to-use tests, performance shown will likely be maintained in routine implementation. FUNDING: Ministry of Science, Research and Arts, State of Baden-Wuerttemberg, Germany, internal funds from Heidelberg University Hospital, University Hospital Charité - Universitätsmedizin Berlin, UK Department of International Development, WHO, Unitaid.

Can we predict the severe course of COVID-19 - a systematic review and meta-analysis of indicators of clinical outcome?

BACKGROUND: COVID-19 has been reported in over 40million people globally with variable clinical outcomes. In this systematic review and meta-analysis, we assessed demographic, laboratory and clinical indicators as predictors for severe courses of COVID-19. METHODS: This systematic review was registered at PROSPERO under CRD42020177154. We systematically searched multiple databases (PubMed, Web of Science Core Collection, MedRvix and bioRvix) for publications from December 2019 to May 31st 2020. Random-effects meta-analyses were used to calculate pooled odds ratios and differences of medians between (1) patients admitted to ICU versus non-ICU patients and (2) patients who died versus those who survived. We adapted an existing Cochrane risk-of-bias assessment tool for outcome studies. RESULTS: Of 6,702 unique citations, we included 88 articles with 69,762 patients. There was concern for bias across all articles included. Age was strongly associated with mortality with a difference of medians (DoM) of 13.15 years (95% confidence interval (CI) 11.37 to 14.94) between those who died and those who survived. We found a clinically relevant difference between non-survivors and survivors for C-reactive protein (CRP; DoM 69.10 mg/L, CI 50.43 to 87.77), lactate dehydrogenase (LDH; DoM 189.49 U/L, CI 155.00 to 223.98), cardiac troponin I (cTnI; DoM 21.88 pg/mL, CI 9.78 to 33.99) and D-Dimer (DoM 1.29mg/L, CI 0.9 to 1.69). Furthermore, cerebrovascular disease was the co-morbidity most strongly associated with mortality (Odds Ratio 3.45, CI 2.42 to 4.91) and ICU admission (Odds Ratio 5.88, CI 2.35 to 14.73). DISCUSSION: This comprehensive meta-analysis found age, cerebrovascular disease, CRP, LDH and cTnI to be the most important risk-factors that predict severe COVID-19 outcomes and will inform clinical scores to support early decision-making.

The Abbott PanBio WHO emergency use listed, rapid, antigen-detecting point-of-care diagnostic test for SARS-CoV-2-Evaluation of the accuracy and ease-of-use.

OBJECTIVES: Diagnostics are essential for controlling the pandemic. Identifying a reliable and fast diagnostic device is needed for effective testing. We assessed performance and ease-of-use of the Abbott PanBio antigen-detecting rapid diagnostic test (Ag-RDT). METHODS: This prospective, multi-centre diagnostic accuracy study enrolled at two sites in Germany. Following routine testing with reverse-transcriptase polymerase chain reaction (RT-PCR), a second study-exclusive swab was performed for Ag-RDT testing. Routine swabs were nasopharyngeal (NP) or combined NP/oropharyngeal (OP) whereas the study-exclusive swabs were NP. To evaluate performance, sensitivity and specificity were assessed overall and in predefined sub-analyses accordingly to cycle-threshold values, days after symptom onset, disease severity and study site. Additionally, an ease-of-use assessment (EoU) and System Usability Scale (SUS) were performed. RESULTS: 1108 participants were enrolled between Sept 28 and Oct 30, 2020. Of these, 106 (9.6%) were PCR-positive. The Abbott PanBio detected 92/106 PCR-positive participants with a sensitivity of 86.8% (95% CI: 79.0% - 92.0%) and a specificity of 99.9% (95% CI: 99.4%-100%). The sub-analyses indicated that sensitivity was 95.8% in Ct-values <25 and within the first seven days from symptom onset. The test was characterized as easy to use (SUS: 86/100) and considered suitable for point-of-care settings. CONCLUSION: The Abbott PanBio Ag-RDT performs well for SARS-CoV-2 testing in this large manufacturer independent study, confirming its WHO recommendation for Emergency Use in settings with limited resources.

The onset of active disease in systemic lupus erythematosus patients is characterised by excessive regulatory CD4+-T-cell differentiation.

OBJECTIVES: An imbalance between CD4+-regulatory T-cells (Tregs) and CD4+-responder T-cells (Tresps) correlates with active disease flares in systemic lupus erythematosus (SLE) patients. Both cell subsets consist of highly proliferating Tregs/Tresps expressing inducible T-cell co-stimulatory molecule (ICOS) and less proliferating ICOS--Tregs/Tresps. METHODS: Six-colour-flow-cytometric analysis was used to examine the effect of ICOS+- and ICOS--Treg/Tresp cell differentiation on the composition of the total CD4+-T-helper cell pool with ICOS+- and ICOS--Tregs/Tresps. Functionality of Tregs was examined using suppression assays. RESULTS: In 83 healthy volunteers, the ratio of ICOS+-Tregs/ICOS+-Tresps increased significantly with age, while that of ICOS--Tregs/ICOS--Tresps did not change. In 86 SLE patients (SLEDAI <7), disease activity was associated with an age-independently increased ratio of both ICOS+-Tregs/ICOS+-Tresps and ICOS--Tregs/ICOS--Tresps. In these patients, the functional activity of ICOS+-Tregs, but not of ICOS--Tregs, was preserved. In 13 markedly active disease patients (SLEDAI >7), the percentage of both ICOS+-Tregs and ICOS+-Tresps, was strongly increased within total CD4+-T-helper cells. However, the increased ratio of ICOS+-Tregs/ICOS+-Tresps was not maintained in these patients, due to terminal differentiation and accumulation of naïve cells within total ICOS+-Tregs. Despite increased differentiation of both ICOS--Tregs and ICOS--Tresps, the percentage of ICOS--Tregs increased within CD4+-T-helper cells, while that of ICOS--Tresps decreased, resulting in a significantly increased ratio of ICOS--Tregs/ICOS--Tresps independent of age. CONCLUSIONS: Our data reveal a crucial role of Treg immune senescence for the occurrence of disease flares in SLE patients, with ICOS+-Treg cells being most affected.

Can we predict the severe course of COVID-19 - a systematic review and meta-analysis of indicators of clinical outcome?

Background: COVID-19 has been reported in over 40million people globally with variable clinical outcomes. In this systematic review and meta-analysis, we assessed demographic, laboratory and clinical indicators as predictors for severe courses of COVID-19. Methods: We systematically searched multiple databases (PubMed, Web of Science Core Collection, MedRvix and bioRvix) for publications from December 2019 to May 31st 2020. Random-effects meta-analyses were used to calculate pooled odds ratios and differences of medians between (1) patients admitted to ICU versus non-ICU patients and (2) patients who died versus those who survived. We adapted an existing Cochrane risk-of-bias assessment tool for outcome studies. Results: Of 6,702 unique citations, we included 88 articles with 69,762 patients. There was concern for bias across all articles included. Age was strongly associated with mortality with a difference of medians (DoM) of 13.15 years (95% confidence interval (CI) 11.37 to 14.94) between those who died and those who survived. We found a clinically relevant difference between non-survivors and survivors for C-reactive protein (CRP; DoM 69.10, CI 50.43 to 87.77), lactate dehydrogenase (LDH; DoM 189.49, CI 155.00 to 223.98), cardiac troponin I (cTnI; DoM 21.88, CI 9.78 to 33.99) and D-Dimer (DoM 1.29mg/L, CI 0.9 - 1.69). Furthermore, cerebrovascular disease was the co-morbidity most strongly associated with mortality (Odds Ratio 3.45, CI 2.42 to 4.91) and ICU admission (Odds Ratio 5.88, CI 2.35 to 14.73). Discussion: This comprehensive meta-analysis found age, cerebrovascular disease, CRP, LDH and cTnI to be the most important risk-factors in predicting severe COVID-19 outcomes and will inform decision analytical tools to support clinical decision-making.

Prediction of local COVID-19 spread in Heidelberg.

Since the first identified case of COVID-19 in Wuhan, China, the disease has developed into a pandemic, imposing a major challenge for health authorities and hospitals worldwide. Mathematical transmission models can help hospitals to anticipate and prepare for an upcoming wave of patients by forecasting the time and severity of infections. Taking the city of Heidelberg as an example, we predict the ongoing spread of the disease for the next months including hospital and ventilator capacity and consider the possible impact of currently imposed countermeasures.

Immunosuppressive therapy influences the accelerated age-dependent T-helper cell differentiation in systemic lupus erythematosus remission patients.

BACKGROUND: CD4+ T cells are of great importance in the pathogenesis of systemic lupus erythematosus (SLE), as an imbalance between CD4+ regulatory T cells (Tregs) and CD4+ responder T cells (Tresps) causes flares of active disease in SLE patients. In this study, we aimed to find the role of aberrant Treg/Tresp cell differentiation for maintaining Treg/Tresp cell balance and Treg functionality. METHODS: To determine differences in the differentiation of Tregs/Tresps we calculated the percentages of CD45RA+CD31+ recent thymic emigrant (RTE) Tregs/Tresps and CD45RA+CD31- mature naive (MN) Tregs/Tresps, as well as CD45RA-CD31+ and CD45RA-CD31- memory Tregs/Tresps (CD31+ and CD31- memory Tregs/Tresps) within the total Treg/Tresp pool of 78 SLE remission patients compared with 94 healthy controls of different ages. The proliferation capacity of each Treg/Tresp subset was determined by staining the cells with anti-Ki67 monoclonal antibodies. Differences in the autologous or allogeneic Treg function between SLE remission patients and healthy controls were determined using suppression assays. RESULTS: With age, we found an increased differentiation of RTE Tregs via CD31+ memory Tregs and of RTE Tresps via MN Tresps into CD31- memory Tregs/Tresp in healthy volunteers. This opposite differentiation of RTE Tregs and Tresps was associated with an age-dependent increase in the suppressive activity of both naive and memory Tregs. SLE patients showed similar age-dependent Treg cell differentiation. However, in these patients RTE Tresps differentiated increasingly via CD31+ memory Tresps, whereby CD31- memory Tresps arose that were much more difficult to inhibit for Tregs than those that emerged through differentiation via MN Tresps. Consequently, the increase in the suppressive activity of Tregs with age could not be maintained in SLE patients. Testing the Tregs of healthy volunteers and SLE patients with autologous and nonautologous Tresps revealed that the significantly decreased Treg function in SLE patients was not exclusively attributed to an age-dependent diminished sensitivity of the Tresps for Treg suppression. The immunosuppressive therapy reduced the accelerated age-dependent Tresp cell proliferation to normal levels, but simultaneously inhibited Treg cell proliferation below normal levels. CONCLUSIONS: Our data reveal that the currently used immunosuppressive therapy has a favorable effect on the differentiation and proliferation of Tresps but has a rather unfavorable effect on the proliferation of Tregs. Newer substances with more specific effects on the immune system would be desirable.