Uncoupling of platelet granule release and integrin activation suggests GPIIb/IIIa as therapeutic target in COVID-19.

Thromboembolic events are frequent and life-threating complications of COVID 19, but are also observed in patients with sepsis. Disseminated thrombosis can occur despite anticoagulation, suggesting that platelets play a direct, but yet incompletely understood role. Several studies demonstrated altered platelet function in COVID 19 with in part controversial findings, while underlying disease-specific mechanisms remain ill-defined. We performed a comprehensive cohort study with 111 patients, comprising 37 with COVID-19, 46 with sepsis, and 28 with infection, compared to controls. Platelet phenotype and function were assessed under static and flow conditions, revealing unexpected disease-specific differences. From hospital admission on, platelets in COVID-19 failed to activate integrin GPIIb/IIIa in response to multiple agonists. Dense granule release was markedly impaired due to virtually missing granules, also demonstrated by whole mount electron microscopy. In contrast, alpha-granule marker CD62P exposure was only mildly affected, revealing a subpopulation of PAC-1-/CD62P+ platelets, independently confirmed by automated clustering. This uncoupling of alpha-granule release was not observed in sepsis patients, despite a similar disease severity. We found overall unaltered thrombus formation in COVID 19 and sepsis samples under venous shear rates, which was dependent on the presence of tissue factor. Unexpectedly, under arterial shear rates thrombus formation was virtually abrogated in sepsis, while we detected overall normal-sized and stable thrombi in blood from COVID-19 patients. These thrombi were susceptible to subthreshold levels of GPIIb/IIIa blockers eptifibatide or tirofiban that had only a minor effect in control blood. We provide evidence that low dose GPIIb/IIIa blockade could be a therapeutic approach in COVID-19.

Virus variant-specific clinical performance of SARS coronavirus two rapid antigen tests in point-of-care use, from November 2020 to January 2022.

OBJECTIVES: Antigen rapid diagnostic tests (RDTs) for SARS coronavirus 2 (SARS-CoV-2) are quick, widely available, and inexpensive. Consequently, RDTs have been established as an alternative and additional diagnostic strategy to quantitative reverse transcription polymerase chain reaction (RT-qPCR). However, reliable clinical and large-scale performance data specific to a SARS-CoV-2 virus variant of concern (VOC) are limited, especially for the Omicron VOC. The aim of this study was to compare RDT performance among different VOCs. METHODS: This single-centre prospective performance assessment compared RDTs from three manufacturers (NADAL, Panbio, MEDsan) with RT-qPCR including deduced standardized viral load from oropharyngeal swabs for detection of SARS-CoV-2 in a clinical point-of-care setting from November 2020 to January 2022. RESULTS: Among 35 479 RDT/RT-qPCR tandems taken from 26 940 individuals, 164 of the 426 SARS-CoV-2 positive samples tested true positive with an RDT corresponding to an RDT sensitivity of 38.50% (95% CI, 34.00-43.20%), with an overall specificity of 99.67% (95% CI, 99.60-99.72%). RDT sensitivity depended on viral load, with decreasing sensitivity accompanied by descending viral load. VOC-dependent sensitivity assessment showed a sensitivity of 42.86% (95% CI, 32.82-53.52%) for the wild-type SARS-CoV-2, 43.42% (95% CI, 32.86-54.61%) for the Alpha VOC, 37.67% (95% CI, 30.22-45.75%) for the Delta VOC, and 33.67% (95% CI, 25.09-43.49%) for the Omicron VOC. Sensitivity in samples with high viral loads of ≥106 SARS-CoV-2 RNA copies per mL was significantly lower in the Omicron VOC (50.00%; 95% CI, 36.12-63.88%) than in the wild-type SARS-CoV-2 (79.31%; 95% CI, 61.61-90.15%; p 0.015). DISCUSSION: RDT sensitivity for detection of the Omicron VOC is reduced in individuals infected with a high viral load, which curtails the effectiveness of RDTs. This aspect furthert: limits the use of RDTs, although RDTs are still an irreplaceable diagnostic tool for rapid, economic point-of-care and extensive SARS-CoV-2 screening.

Medical and cardio-vascular emergency department visits during the COVID-19 pandemic in 2020: is there a collateral damage? A retrospective routine data analysis.

BACKGROUND: In this retrospective routine data analysis, we investigate the number of emergency department (ED) consultations during the COVID-19 pandemic of 2020 in Germany compared to the previous year with a special focus on numbers of myocardial infarction and acute heart failure. METHODS: Aggregated case numbers for the two consecutive years 2019 and 2020 were obtained from 24 university hospitals and 9 non-university hospitals in Germany and assessed by age, gender, triage scores, disposition, care level and by ICD-10 codes including the tracer diagnoses myocardial infarction (I21) and heart failure (I50). RESULTS: A total of 2,216,627 ED consultations were analyzed, of which 1,178,470 occurred in 2019 and 1,038,157 in 2020. The median deviation in case numbers between 2019 and 2020 was - 14% [CI (- 11)-(- 16)]. After a marked drop in all cases in the first COVID-19 wave in spring 2020, case numbers normalized during the summer. Thereafter starting in calendar week 39 case numbers constantly declined until the end of the year 2020. The decline in case numbers predominantly concerned younger [- 16%; CI (- 13)-(- 19)], less urgent [- 18%; CI (- 12)-(- 22)] and non-admitted cases [- 17%; CI (- 13)-(- 20)] in particular during the second wave. During the entire observation period admissions for chest pain [- 13%; CI (- 21)-2], myocardial infarction [- 2%; CI (- 9)-11] and heart failure [- 2%; CI (- 10)-6] were less affected and remained comparable to the previous year. CONCLUSIONS: ED visits were noticeably reduced during both SARS-CoV-2 pandemic waves in Germany but cardiovascular diagnoses were less affected and no refractory increase was noted. However, long-term effects cannot be ruled out and need to be analysed in future studies.

Clinical performance evaluation of SARS-CoV-2 rapid antigen testing in point of care usage in comparison to RT-qPCR.

BACKGROUND: Antigen rapid diagnostic tests (RDT) for SARS-CoV-2 are fast, broadly available, and inexpensive. Despite this, reliable clinical performance data from large field studies is sparse. METHODS: In a prospective performance evaluation study, RDT from three manufacturers (NADAL®, Panbio™, MEDsan®, conducted on different samples) were compared to quantitative reverse transcription polymerase chain reaction (RT-qPCR) in 5 068 oropharyngeal swabs for detection of SARS-CoV-2 in a hospital setting. Viral load was derived from standardised RT-qPCR Cycle threshold (Ct) values. The data collection period ranged from November 12, 2020 to February 28, 2021. FINDINGS: The sensitivity of RDT compared to RT-qPCR was 42·57% (95% CI 33·38%-52·31%). The specificity was 99·68% (95% CI 99·48%-99·80%). Sensitivity declined with decreasing viral load from 100% in samples with a deduced viral load of ≥108 SARS-CoV-2 RNA copies per ml to 8·82% in samples with a viral load lower than 104 SARS-CoV-2 RNA copies per ml. No significant differences in sensitivity or specificity could be observed between samples with and without spike protein variant B.1.1.7. The NPV in the study cohort was 98·84%; the PPV in persons with typical COVID-19 symptoms was 97·37%, and 28·57% in persons without or with atypical symptoms. INTERPRETATION: RDT are a reliable method to diagnose SARS-CoV-2 infection in persons with high viral load. RDT are a valuable addition to RT-qPCR testing, as they reliably detect infectious persons with high viral loads before RT-qPCR results are available. FUNDING: German Federal Ministry for Education and Science (BMBF), Free State of Bavaria.

COVID-19 and the kidney: A retrospective analysis of 37 critically ill patients using machine learning.

INTRODUCTION: There is evidence that SARS-CoV2 has a particular affinity for kidney tissue and is often associated with kidney failure. METHODS: We assessed whether proteinuria can be predictive of kidney failure, the development of chronic kidney disease, and mortality in 37 critically ill COVID-19 patients. We used machine learning (ML) methods as decision trees and cut-off points created by the OneR package to add new aspects, even in smaller cohorts. RESULTS: Among a total of 37 patients, 24 suffered higher-grade renal failure, 20 of whom required kidney replacement therapy. More than 40% of patients remained on hemodialysis after intensive care unit discharge or died (27%). Due to frequent anuria proteinuria measured in two-thirds of the patients, it was not predictive for the investigated endpoints; albuminuria was higher in patients with AKI 3, but the difference was not significant. ML found cut-off points of >31.4 kg/m2 for BMI and >69 years for age, constructed decision trees with great accuracy, and identified highly predictive variables for outcome and remaining chronic kidney disease. CONCLUSIONS: Different ML methods and their clinical application, especially decision trees, can provide valuable support for clinical decisions. Presence of proteinuria was not predictive of CKD or AKI and should be confirmed in a larger cohort.

COVID-19 Induced Acute Respiratory Distress Syndrome-A Multicenter Observational Study.

Background: Proportions of patients dying from the coronavirus disease-19 (COVID-19) vary between different countries. We report the characteristics; clinical course and outcome of patients requiring intensive care due to COVID-19 induced acute respiratory distress syndrome (ARDS). Methods: This is a retrospective, observational multicentre study in five German secondary or tertiary care hospitals. All patients consecutively admitted to the intensive care unit (ICU) in any of the participating hospitals between March 12 and May 4, 2020 with a COVID-19 induced ARDS were included. Results: A total of 106 ICU patients were treated for COVID-19 induced ARDS, whereas severe ARDS was present in the majority of cases. Survival of ICU treatment was 65.0%. Median duration of ICU treatment was 11 days; median duration of mechanical ventilation was 9 days. The majority of ICU treated patients (75.5%) did not receive any antiviral or anti-inflammatory therapies. Venovenous (vv) ECMO was utilized in 16.3%. ICU triage with population-level decision making was not necessary at any time. Univariate analysis associated older age, diabetes mellitus or a higher SOFA score on admission with non-survival during ICU stay. Conclusions: A high level of care adhering to standard ARDS treatments lead to a good outcome in critically ill COVID-19 patients.

Pro- and Anti-Inflammatory Responses in Severe COVID-19-Induced Acute Respiratory Distress Syndrome-An Observational Pilot Study.

Objectives: The severity of Coronavirus Disease 2019 (COVID-19) is largely determined by the immune response. First studies indicate altered lymphocyte counts and function. However, interactions of pro- and anti-inflammatory mechanisms remain elusive. In the current study we characterized the immune responses in patients suffering from severe COVID-19-induced acute respiratory distress syndrome (ARDS). Methods: This was a single-center retrospective study in patients admitted to the intensive care unit (ICU) with confirmed COVID-19 between March 14th and May 28th 2020 (n = 39). Longitudinal data were collected within routine clinical care, including flow-cytometry of lymphocyte subsets, cytokine analysis and growth differentiation factor 15 (GDF-15). Antibody responses against the receptor binding domain (RBD) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein were analyzed. Results: All patients suffered from severe ARDS, 30.8% died. Interleukin (IL)-6 was massively elevated at every time-point. The anti-inflammatory cytokine IL-10 was concomitantly upregulated with IL-6. The cellular response was characterized by lymphocytopenia with low counts of CD8+ T cells, natural killer (NK) and naïve T helper cells. CD8+ T and NK cells recovered after 8 to 14 days. The B cell system was largely unimpeded. This coincided with a slight increase in anti-SARS-CoV-2-Spike-RBD immunoglobulin (Ig) G and a decrease in anti-SARS-CoV-2-Spike-RBD IgM. GDF-15 levels were elevated throughout ICU treatment. Conclusions: Massively elevated levels of IL-6 and a delayed cytotoxic immune defense characterized severe COVID-19-induced ARDS. The B cell response and antibody production were largely unimpeded. No obvious imbalance of pro- and anti-inflammatory mechanisms was observed, with elevated GDF-15 levels suggesting increased tissue resilience.

Medical Emergencies During the COVID-19 Pandemic.

BACKGROUND: In this study, we investigate the number of emergency room consultations during the COVID-19 pandemic of 2020 in Germany compared to figures from the previous year. METHODS: Case numbers from calendar weeks 1 through 22 of the two consecutive years 2019 and 2020 were obtained from 29 university hospitals and 7 non-university hospitals in Germany. Information was also obtained on the patients' age, sex, and urgency, along with the type of case (outpatient/inpatient), admitting ward, and a small number of tracer diagnoses (I21, myocardial infarction; J44, COPD; and I61, I63, I64, G45, stroke /TIA), as well as on the number of COVID-19 cases and of tests performed for SARS-CoV-2, as a measure of the number of cases in which COVID-19 was suspected or at least included in the differential diagnoses. RESULTS: A total of 1 022 007 emergency room consultations were analyzed, of which 546 940 took place in 2019 and 475 067 in 2020. The number of consultations with a positive test for the COVID-19 pathogen was 3122. The total number of emergency room consultations in the observation period was 13% lower in 2020 than in 2019, with a maximum drop by 38% coinciding with the highest number of COVID-19 cases (calendar week 14; 572 cases). After the initiation of interpersonal contact restrictions in 2020, there was a marked drop in COVID-19 case numbers, by a mean of -240 cases per week per emergency room (95% confidence interval [-284; -128]). There was a rise in case numbers thereafter, by a mean of 17 patients per week [14; 19], and the number of cases of myocardial infarction returned fully to the level seen in 2019. CONCLUSION: In Germany, the COVID-19 pandemic led to a significant drop in medical emergencies of all kinds presenting to the nation's emergency departments. A recovery effect began to be seen as early as calendar week 15, but the levels seen in 2019 were not yet reached overall by calendar week 22; only the prevalence of myocardial infarction had renormalized by then. The reasons for this require further investigation.