Correction: Anti-prothrombin autoantibodies enriched after infection with SARS-CoV-2 and influenced by strength of antibody response against SARS-CoV-2 proteins.

[This corrects the article DOI: 10.1371/journal.ppat.1010118.].

Sonographic assessment of low muscle quantity identifies mortality risk during COVID-19: a prospective single-centre study.

BACKGROUND: Assessment of muscle quantity by sonographic muscle indices could help identify patients at risk for fatal outcome during coronavirus disease-2019 (COVID-19). The aim of this study was to explore sonographic muscle indices as predictors of COVID-19 outcome and to test the feasibility of sonographic muscle measurement in an isolation context. METHODS: Muscle indices, derived from the psoas muscle or thigh muscles, were quantified by sonography in a cohort of patients without COVID-19 to obtain reference values for low muscle quantity. Gender-specific median of different muscle indices were defined as threshold value for low muscle quantity. The prognostic relevance of low muscle quantity, was prospectively explored in two cohorts of hospitalized COVID-19 patients. Optimal muscle index cutoff values predictive for 30 day mortality during COVID-19 were determined by receiver operating characteristic-area under the curve and Youden index calculation. Muscle quantity and known prognostic factors of COVID-19 were analysed by multivariable log-regression. RESULTS: Compared with other muscle indices, the psoas muscle area index (PMAI) showed the most favourable characteristics to predict outcome of COVID-19 disease. Sonographic morphometry of patients without COVID-19 (n = 136) revealed a gender-specific median for PMAI (male: 291.1 mm2 /m2 , female 260.6 mm2 /m2 ) as threshold value of low muscle quantity. Subsequently, COVID-19 patients (Cohort I: n = 58; Cohort II: n = 55) were prospectively assessed by bedside sonography. The studied COVID-19 patients developed a critical course of disease in 22.4% (Cohort I: n = 13/58) and 34.5% (Cohort II: n = 20/55). Mortality rate reached 12.1% (Cohort I: n = 7/58) and 20.0% (Cohort I: n = 11/55) within 30 days of follow up. COVID-19 patients with a PMAI below the gender-specific median showed a higher 30 day mortality in both COVID-19 cohorts (log rank, P < 0.05). The optimal PMAI cutoff value (206 mm2 /m2 ) predicted 30 day mortality of hospitalized COVID-19 patients with a sensitivity of 72% and specificity of 78.5% (receiver operating characteristic-area under the curve: 0.793, 95% confidence interval 0.671-0.914, P = 0.008). Multivariable log-regression analysis of PMAI, age, gender, BMI and comorbidities confirmed an independent association of low PMAI with 30 day mortality of COVID-19 patients (P = 0.018). CONCLUSIONS: Sonographic morphometry provides reliable muscle quantification under hygienic precautions and allows risk stratification of patients with COVID-19.

Anti-prothrombin autoantibodies enriched after infection with SARS-CoV-2 and influenced by strength of antibody response against SARS-CoV-2 proteins.

Antiphospholipid antibodies (aPL), assumed to cause antiphospholipid syndrome (APS), are notorious for their heterogeneity in targeting phospholipids and phospholipid-binding proteins. The persistent presence of Lupus anticoagulant and/or aPL against cardiolipin and/or ß2-glycoprotein I have been shown to be independent risk factors for vascular thrombosis and pregnancy morbidity in APS. aPL production is thought to be triggered by-among other factors-viral infections, though infection-associated aPL have mostly been considered non-pathogenic. Recently, the potential pathogenicity of infection-associated aPL has gained momentum since an increasing number of patients infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been described with coagulation abnormalities and hyperinflammation, together with the presence of aPL. Here, we present data from a multicentric, mixed-severity study including three cohorts of individuals who contracted SARS-CoV-2 as well as non-infected blood donors. We simultaneously measured 10 different criteria and non-criteria aPL (IgM and IgG) by using a line immunoassay. Further, IgG antibody response against three SARS-CoV-2 proteins was investigated using tripartite automated blood immunoassay technology. Our analyses revealed that selected non-criteria aPL were enriched concomitant to or after an infection with SARS-CoV-2. Linear mixed-effects models suggest an association of aPL with prothrombin (PT). The strength of the antibody response against SARS-CoV-2 was further influenced by SARS-CoV-2 disease severity and sex of the individuals. In conclusion, our study is the first to report an association between disease severity, anti-SARS-CoV-2 immunoreactivity, and aPL against PT in patients with SARS-CoV-2.

Liver injury in patients with severe acute respiratory syndrome coronavirus-2 infection: a systematic review and meta-analysis.

OBJECTIVE: Coronavirus disease-19 (COVID-19) infection is a global health threat. To inform the liver community on the potential relevance of COVID-19, we performed a systematic review and meta-analysis of published data on liver injury in patients with COVID-19 infection. METHODS: We searched PubMed and Google Scholar through 22 March according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled data were analyzed by using random-effects meta-analyses. RESULTS: A total of 14 studies combining data from 2.871 patients were identified. The prevalence of pre-existing liver disease was reported at 3.1%. The pooled prevalence of elevated aspartate aminotransferase (AST) and alanine transaminase (ALT) levels were 26% [95% confidence interval (CI), 20-32%] and 19% (95% CI, 14-26%), respectively. Only two studies reported the prevalence of elevated liver function tests according to normal ward versus ICU and here the frequency of elevated levels of AST was 50% and 62% versus ALT 40.8% and thus quantitatively higher in ICU-treated patients. Mean levels of absolute AST levels were 33 U/L (95% CI, 30.21-36.09), while mean ALT levels were 31 U/L (95% CI, 27.52-34.57). Cholestatic liver function tests were only incompletely reported in 510 patients. Here, mean levels of alkaline phosphatase were 71 U/L across three studies, and mean levels of gamma-glutamyl transferase were 40.6 U/L across four studies. CONCLUSIONS: Emerging data on LFTs in COVID-19 are heterogeneous indicating mild LFTs involvement in every fourth to fifth patients with numerical more prevalent AST over ALT elevations. Prospective studies are needed to define the clinical relevance of liver injury in COVID-19.

COVID-19 as a Potential Trigger for Immune Thrombotic Thrombocytopenic Purpura and Reason for an Unusual Treatment: A Case Report.

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare autoimmune disorder characterized by severely reduced activity of the von Willebrand factor (VWF)-cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) due to autoantibodies. This leads to the development of pathogenic multimers of VWF, causing a thrombotic microangiopathy with decreased number of platelets, hemolysis, and life-threatening tissue ischemia of mostly brain, heart, and kidneys. Standard treatment of iTTP involves daily plasma exchange to remove ultra large multimers of VWF, inhibitors, substituting ADAMTS13, and the accompaniment of an immunosuppressive treatment with steroids. Recently, caplacizumab was approved for iTTP. Caplacizumab is a nanobody binding the A1 domain of VWF, blocking its interaction with glycoprotein Ib-IX-V platelet receptor and therefore preventing platelet aggregation. VWF activities may serve as therapeutic drug monitoring of caplacizumab, whereas ADAMTS13 activities may be used for biomarkers to guide caplacizumab treatment modalities and overall treatment duration. Additional immunosuppressive treatment by inhibiting autoantibody formation (e.g., the use of Rituximab, a chimeric monoclonal antibody directed against the B-cell antigen CD20) is a further treatment option. Infections are well-known causes for an acute episode for patients with iTTP. The novel SARS-CoV-2 virus is mainly associated with acute respiratory distress as well as diffuse endothelial inflammation and increased coagulopathy. However, little is known about an infection with SARS-CoV-2 virus triggering iTTP relapses. We herein report the case of an acute iTTP episode accompanying a SARS-CoV-2 infection.

Pathogenic lipid-binding antiphospholipid antibodies are associated with severity of COVID-19.

BACKGROUND: Coronavirus disease 19 (COVID-19)-associated coagulopathy is a hallmark of disease severity and poor prognosis. The key manifestations of this prothrombotic syndrome-microvascular thrombosis, stroke, and venous and pulmonary clots-are also observed in severe and catastrophic antiphospholipid syndrome. Antiphospholipid antibodies (aPL) are detectable in COVID-19 patients, but their association with the clinical course of COVID-19 remains unproven. OBJECTIVES: To analyze the presence and relevance of lipid-binding aPL in hospitalized COVID-19 patients. METHODS: Two cohorts of 53 and 121 patients from a single center hospitalized for PCR-proven severe acute respiratory syndrome-coronavirus 2 infection were analyzed for the presence of aPL and clinical severity of COVID-19. RESULTS: We here demonstrate that lipid-binding aPL are common in COVID-19. COVID-19 patients with lipid-binding aPL have higher median concentrations of C-reactive protein and D-dimer, and are more likely to have a critical clinical course and fatal outcome. Lipid-binding aPL isolated from COVID-19 patients target the recently described cell surface complex of lysobisphosphatidic acid (LBPA) with the protein C receptor (EPCR) to induce prothrombotic and inflammatory responses in monocytes and endothelial cells. We show that B1a cells producing lipid-reactive aPL of the IgG isotype circulate in the blood of COVID-19 patients. In vivo, COVID-19 aPL accelerate thrombus formation in an experimental mouse model dependent on the recently delineated signaling pathway involving EPCR-LBPA. CONCLUSIONS: COVID-19 patients rapidly expand B1a cells secreting pathogenic lipid-binding aPL with broad thrombotic and inflammatory effects. The association with markers of inflammation and coagulation, clinical severity, and mortality suggests a causal role of aPL in COVID-19-associated coagulopathy.

Evaluation of a laboratory-based high-throughput SARS-CoV-2 antigen assay for non-COVID-19 patient screening at hospital admission.

Several rapid antigen tests (RATs) for the detection of SARS-CoV-2 were evaluated recently. However, reliable performance data for laboratory-based, high-throughput antigen tests are lacking. Therefore and in response to a short-term shortage of PCR reagents, we evaluated DiaSorin's LIAISON SARS-CoV-2 antigen test in comparison to RT-qPCR, and concerning the application of screening non-COVID-19 patients on hospital admission. Applying the manufacturer-recommended cut-off of 200 arbitrary units (AU/mL) the specificity of the LIAISON Test was 100%, the overall analytical sensitivity 40.2%. Lowering the cut-off to 100 AU/mL increased the sensitivity to 49.7% and decreased the specificity to 98.3%. Confining the analysis to samples with an RT-qPCR result < 25 Ct resulted in a sensitivity of 91.2%. The quality of the LIAISON test is very similar to that of good RATs described in the literature with the advantage of high throughput and the disadvantage of relatively long analysis time. It passes the WHO quality criteria for rapid antigen tests and is characterized by particularly high specificity. The LIAISON test can therefore be used for the same applications as recommended for RATs by the WHO. Due to limited sensitivity, the LIAISON test should only be used for screening, if PCR-based assays are not available.

No Evidence for Classic Thrombotic Microangiopathy in COVID-19.

BACKGROUND: Coronavirus disease-2019 (COVID-19) triggers systemic infection with involvement of the respiratory tract. There are some patients developing haemostatic abnormalities during their infection with a considerably increased risk of death. MATERIALS AND METHODS: Patients (n = 85) with SARS-CoV-2 infection attending the University Medical Center, Mainz, from 3 March to 15 May 2020 were retrospectively included in this study. Data regarding demography, clinical features, treatment and laboratory parameters were analyzed. Twenty patients were excluded for assessment of disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) due to lack of laboratory data. RESULTS: COVID-19 patients (n = 65) were investigated, 19 with uncomplicated, 29 with complicated, and 17 with critical course; nine (13.8%) died. Seven patients showed overt DIC according to the ISTH criteria. The fibrinogen levels dropped significantly in these patients, although not below 100 mg/dl. Hallmarks of TMA, such as thrombocytopenia and microangiopathic haemolytic anaemia, were not detected in any of our COVID-19 patients. ADAMTS13 activity was mildly to moderately reduced in 4/22 patients, all having strongly elevated procalcitonin levels. CONCLUSION: DIC occurred in 7/65 COVID-19 patients but fibrinogen and platelet consumption were compensated in almost all. ADAMTS13 assays excluded TTP and hallmarks of classic TMA were absent in all investigated patients. We hypothesize that the lacking erythrocyte fragmentation and only mild platelet consumption in severe COVID-19 are due to a microangiopathy predominantly localized to the alveolar microcirculation with a low blood pressure gradient.

Clinical Frailty Scale for risk stratification in patients with SARS-CoV-2 infection.

Predictive factors for adverse outcomes in patients with COVID-19 are urgently needed. Data related to the applicability of the Clinical Frailty Scale (CFS) for risk stratification in patients with COVID-19 are currently lacking. We investigated the ability of CFS to predict need for mechanical ventilation and the duration of hospital stays in European patients with COVID-19. In total, 42 patients with confirmed COVID-19 infection admitted to the University Medical Center Mainz between March 3 and April 15 2020 were included into this validation study and data were retrospectively analyzed. CFS was assessed at admission in all patients. Patients were followed for need for mechanical ventilation and time to hospital discharge. At admission, the median CFS was 3 (range: 1-7) and 14 (33.3%) patients were considered as at least pre-frail (CFS >3). 24 (57.1%) patients were discharged from hospital after a median time of 7 days (IQR 4-8). 12 (28.6%) patients developed acute respiratory distress syndrome and required mechanical ventilation. In multivariable Cox regression analyses, higher CFS scores (HR 1.659, 95% CI 1.090 to 2.525, p=0.018) were an independent predictor for a higher risk of mechanical ventilation after adjusting for age, Charlson Comorbidity Index and quick sepsis-related organ failure score. Additionally, lower CFS scores (HR 0.554, 95% CI 0.312 to 0.983, p=0.043) were associated with earlier discharge from hospital. In conclusion, this report demonstrates the usefulness of the CFS for risk stratification at hospital admission in patients with COVID-19.

Patterns of liver injury in COVID-19 - a German case series.

BACKGROUND: Reports of liver injury in patients with novel coronavirus disease 2019 (COVID-19) are emerging from China and the USA. A wide variety of liver function test abnormalities and few cases of severe liver failure have been reported. No data on the hepatic phenotype from Europe are available at current. METHODS: We report a case series of 44 consecutive patients hospitalized for COVID-19 in Germany. RESULTS: At the time of admission, aspartate aminotransferase greater than the upper limit of normal was present in 70%, while alanine aminotransferase was elevated in 15.8%. Markers of cholestatic liver injury were altered only in a minority of patients. During hospitalization, 31% and 22% experienced increasing aspartate aminotransferase and alanine aminotransferase, respectively, when transaminases were normal at admission. Severe liver injury defined by 3×> upper limit of normal was observed in 9.1% over a mean time of 10.5 days. Importantly, patients exhibited cytotoxicity including lactate dehydrogenase and creatinine kinase elevations, but no signs of relevant liver function impairment. CONCLUSION: In summary, in a case series of hospitalized patients in Germany, cytotoxicity in the absence of severe liver dysfunction at admission and only few cases suggestive of severe liver injury during hospital were observed.