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This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID-19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID-19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (C max ) and trough concentration (C trough ) were 2.32-fold (95% confidence interval [CI] 1.34-3.29), 2.31-fold (95% CI 1.33-3.29), and 2.32-fold (95% CI 1.11-3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID-19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1-acid glycoprotein (AAG) concentrations measured in patients with COVID-19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG-PK-Model) gave an estimated mean (SD) prediction error (PE) of -20% (31%) for total and -7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID-19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID-19.

BACKGROUND: Traditionally, during crises the number of new blood donors increases. However, the current coronavirus disease 2019 (COVID-19) pandemic created additional barriers to donate due to governmental prevention measures and increased personal health risks. In this report, we examined how the pandemic affected new donor registrations in the Netherlands, especially among groups with higher risk profiles for severe COVID-19. Additionally, we explored the role of media for blood donation and new donor registrations.STUDY DESIGN AND METHODS: We analyzed new donor registrations and attention for blood donation in newspapers and on social media from January until May 2020, in comparison to the same period in 2017 to 2019.RESULTS: After the introduction of nationwide prevention measures, several peaks in new donor registrations occurred, which coincided with peaks in media attention. Interestingly, people with a higher risk profile for COVID-19 (e.g., due to age or region of residence) were overrepresented among new registrants.DISCUSSION: In sum, the first peak of the current pandemic has led to increased new blood donor registrations, despite the associated increased health risks. Time and future studies will have to tell whether these new donors are one-off 'pandemic' donors or if they will become regular, loyal donors.

The persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies is a matter of importance regarding the coronavirus disease 19 (COVID-19) pandemic. To observe antibody dynamics, 105 blood donors, positive for SARS-CoV-2 antibodies by a lateral flow test within a seroprevalence study, were included in this study. Thirty-nine (37%) of 105 the donors were confirmed positive by a total Ig Wantai enzyme-linked immunosorbent assay (ELISA). Three (8%) in this group of 39 reported severe and 26/39 (67%) mild to moderate COVID-19 symptoms. By further ELISA-testing, 33/39 (85%) donors were initially positive for IgG antibodies, 31/39 (79%) for IgA, and 32/39 (82%) for IgM, while 27/39 (69%) were positive for all three isotypes. Persistence of IgG, IgA, and IgM was observed in 73%, 79%, and 32% of donors, respectively, after 6–9 months of observation. For IgM antibodies, the decline in the proportion of positive donors was statistically significant (p = 0.002) during 12 months observation, for IgG only the decline at 3 months was statistically significant (p = 0.042). Four donors exhibited notable increases in antibody levels. In conclusion, persistent SARS-CoV-2 IgA antibodies and IgG antibodies at 6–9 months are present in approximately three of four individuals with previous mild to moderate COVID-19.

BACKGROUND: In a randomized, placebo-controlled, clinical trial, bamlanivimab, a SARS-CoV-2-neutralizing monoclonal antibody, given in combination with remdesivir, did not improve outcomes among hospitalized patients with COVID-19 based on an early futility assessment.OBJECTIVE: To evaluate the a priori hypothesis that bamlanivimab has greater benefit in patients without detectable levels of endogenous neutralizing antibody (nAb) at study entry than in those with antibodies, especially if viral levels are high.DESIGN: Randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04501978).SETTING: Multicenter trial.PATIENTS: Hospitalized patients with COVID-19 without end-organ failure.INTERVENTION: Bamlanivimab (7000 mg) or placebo.MEASUREMENTS: Antibody, antigen, and viral RNA levels were centrally measured on stored specimens collected at baseline. Patients were followed for 90 days for sustained recovery (defined as discharge to home and remaining home for 14 consecutive days) and a composite safety outcome (death, serious adverse events, organ failure, or serious infections).RESULTS: Among 314 participants (163 receiving bamlanivimab and 151 placebo), the median time to sustained recovery was 19 days and did not differ between the bamlanivimab and placebo groups (subhazard ratio [sHR], 0.99 [95% CI, 0.79 to 1.22]; sHR > 1 favors bamlanivimab). At entry, 50% evidenced production of anti-spike nAbs; 50% had SARS-CoV-2 nucleocapsid plasma antigen levels of at least 1000 ng/L. Among those without and with nAbs at study entry, the sHRs were 1.24 (CI, 0.90 to 1.70) and 0.74 (CI, 0.54 to 1.00), respectively (nominal P for interaction = 0.018). The sHR (bamlanivimab vs. placebo) was also more than 1 for those with plasma antigen or nasal viral RNA levels above median level at entry and was greatest for those without antibodies and with elevated levels of antigen (sHR, 1.48 [CI, 0.99 to 2.23]) or viral RNA (sHR, 1.89 [CI, 1.23 to 2.91]). Hazard ratios for the composite safety outcome (LIMITATION: Subgroup analysis of a trial prematurely stopped because of futility; small sample size; multiple subgroups analyzed.CONCLUSION: Efficacy and safety of bamlanivimab may differ depending on whether an endogenous nAb response has been mounted. The limited sample size of the study does not allow firm conclusions based on these findings, and further independent trials are required that assess other types of passive immune therapies in the same patient setting.PRIMARY FUNDING SOURCE: U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

Background Studies presenting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) for healthy individuals are warranted. We estimate IFR by age and comorbidity status using data from a large serosurvey among Danish blood donors and nationwide data on coronavirus disease 2019 (COVID-19) mortality. Methods Danish blood donors aged 17–69 years donating blood October 2020–February 2021 were tested with a commercial SARS-CoV-2 total antibody assay. IFR was estimated for weeks 11 to 42, 2020 and week 43, 2020 to week 6, 2021, representing the first 2 waves of COVID-19 epidemic in Denmark. Results In total, 84944 blood donors were tested for antibodies. The seroprevalence was 2% in October 2020 and 7% in February 2021. Among 3898039 Danish residents aged 17–69 years, 249 deaths were recorded. The IFR was low for people, The COVID-19 infection fatality rate was low for citizens younger than 51 years without comorbidity (3.36 per 100000 infections). The infection fatality rate increased with age and comorbidity but declined from the first to second wave of the epidemic.

Coronavirus disease 2019 (COVID-19) is associated with an increased risk of thrombotic events. Ischemic stroke in COVID-19 patients entails high severity and mortality rates. Here we aimed to analyze cerebral thrombi of COVID-19 patients with large vessel occlusion (LVO) acute ischemic stroke to expose molecular evidence for SARS-CoV-2 in the thrombus and to unravel any peculiar immune-thrombotic features. We conducted a systematic pathological analysis of cerebral thrombi retrieved by endovascular thrombectomy in patients with LVO stroke infected with COVID-19 (n = 7 patients) and non-covid LVO controls (n = 23). In thrombi of COVID-19 patients, the SARS-CoV-2 docking receptor ACE2 was mainly expressed in monocytes/macrophages and showed higher expression levels compared to controls. Using polymerase chain reaction and sequencing, we detected SARS-CoV-2 Clade20A, in the thrombus of one COVID-19 patient. Comparing thrombus composition of COVID-19 and control patients, we noted no overt differences in terms of red blood cells, fibrin, neutrophil extracellular traps (NETs), von Willebrand Factor (vWF), platelets and complement complex C5b-9. However, thrombi of COVID-19 patients showed increased neutrophil density (MPO+ cells) and a three-fold higher Neutrophil-to-Lymphocyte Ratio (tNLR). In the ROC analysis both neutrophils and tNLR had a good discriminative ability to differentiate thrombi of COVID-19 patients from controls. In summary, cerebral thrombi of COVID-19 patients can harbor SARS-CoV2 and are characterized by an increased neutrophil number and tNLR and higher ACE2 expression. These findings suggest neutrophils as the possible culprit in COVID-19-related thrombosis. Graphical Abstract

Lateral flow device (LFD) rapid tests for SARS-CoV-2 antigens are used for asymptomatic testing (including for people who are presymptomatic or paucisymptomatic) in various settings, including in the UK. As of April 9, 2021, LFD tests were made available for twice per week rapid testing to the general population in England. News articles reported pressures within the UK Government to rescind asymptomatic testing due to concerns that, despite high specificity (estimated to be 99·9%),1 the proportion of people testing positive who had COVID-19 (ie, the positive predictive value) was falling in line with the reducing prevalence, leading to greater proportions of individuals having to unnecessarily isolate because of a false-positive test result.2 Asking people to isolate on the basis of what might be a false-positive result is associated with a perceived unfairness and, in some cases, moral indignation.\ud \ud The risk of people without COVID-19 self-isolating due to false-positive test results is a cost to the individual, their household, and their workplace that needs consideration and mitigation. However, this cost should be considered in the context of the costs of failing to identify true-positive results. In the UK, the epidemic control strategies implemented during the past year, including lockdowns, have all, to varying extents, required people who do not have COVID-19 to isolate or quarantine and to greatly restrict their social contacts, while shutting down entire economic sectors. These restrictions have had massive implications for the incomes, education, and wellbeing of many people, including children and young people.3 Any discussions concerning LFD testing policy should incorporate the trade-off between the negative effects of false positives and the onwards transmission prevented. This trade-off is particularly pertinent when considering the contribution of LFD testing to preventing the need for additional widespread restrictive measures.

The objective of the present study was to identify biological signatures of severe coronavirus disease 2019 (COVID-19) predictive of admission in the intensive care unit (ICU). Over 170 immunological markers were investigated in a ‘discovery’ cohort (n = 98 patients) of the Lausanne University Hospital (LUH-1). Here we report that 13 out of 49 cytokines were significantly associated with ICU admission in the three cohorts (P, Infection with SARS CoV2 results in the induction of multiple cytokine and inflammatory pathways. Here the authors demonstrate the association of HGF and CXCL13 production with increased severity and mortality in COVID-19 patients.

Background Coronavirus-19 (COVID-19) has been declared a global pandemic by the World Health Organisation. Severe disease typically presents with respiratory failure but Acute Kidney Injury (AKI) and a hypercoagulable state can also occur. Early reports suggest that thrombosis may be linked with AKI. We studied the development of AKI and outcomes of patients with COVID-19 taking chronic anticoagulation therapy. Methods Electronic records were reviewed for all adult patients admitted to Manchester University Foundation Trust Hospitals between March 10 and April 302,020 with a diagnosis of COVID-19. Patients with end-stage kidney disease were excluded. AKI was classified as per KDIGO criteria. Results Of the 1032 patients with COVID-19 studied,164 (15.9%) were taking anticoagulant therapy prior to admission. There were similar rates of AKI between those on anticoagulants and those not anticoagulated (23.8% versus 19.7%) with no difference in the severity of AKI or requirement of renal replacement therapy between groups (1.2% versus 3.5%). Risk factors for AKI included hypertension, pre-existing renal disease and male sex. There was a higher mortality in those taking anticoagulant therapy (40.2% versus 30%). Patients taking anticoagulants were less likely to be admitted to the Intensive Care Unit (8.5% versus 17.4%) and to receive mechanical ventilation (42.9% versus 78.1%). Conclusion Patients on chronic anticoagulant therapy did not have a reduced incidence or severity of AKI suggesting that AKI is unlikely to be thrombotic in nature. Therapeutic anticoagulation is currently still under investigation in randomised controlled studies to determine whether it has a potential role in COVID-19 treatment.

Background Venous thromboembolism (VTE) is a frequent complication of COVID-19, so that the importance of adequate in-hospital thromboprophylaxis in patients hospitalized with COVID-19 is well established. However, the incidence of VTE after discharge and whether postdischarge thromboprophylaxis is beneficial and safe are unclear. In this prospective observational single-center study, we report the incidence of VTE 6 weeks after hospitalization and the use of postdischarge thromboprophylaxis. Methods Patients hospitalized with confirmed COVID-19 were invited to a multidisciplinary follow-up clinic 6 weeks after discharge. D-dimer and C-reactive protein were measured, and all patients were screened for deep vein thrombosis with venous duplex-ultrasound. Additionally, selected high-risk patients received computed tomography pulmonary angiogram or ventilation–perfusion (V/Q) scan to screen for incidental pulmonary embolism. Results Of 485 consecutive patients hospitalized from March through June 2020, 146 patients were analyzed, of which 39% had been admitted to the intensive care unit (ICU). Postdischarge thromboprophylaxis was prescribed in 28% of patients, but was used more frequently after ICU stay (61%) and in patients with higher maximal D-dimer and C-reactive protein levels during hospitalization. Six weeks after discharge, elevated D-dimer values were present in 32% of ward and 42% of ICU patients. Only one asymptomatic deep vein thrombosis (0.7%) and one symptomatic pulmonary embolism (0.7%) were diagnosed with systematic screening. No bleedings were reported. Conclusion In patients who had been hospitalized with COVID-19, systematic screening for VTE 6 weeks after discharge revealed a low incidence of VTE. A strategy of selectively providing postdischarge thromboprophylaxis in high-risk patients seems safe and potentially effective.

In this nested case-control study, we evaluated haematological and morphological parameters of hospitalised patients with real-time polymerase chain reaction verified COVID-19 infection compared to patients with similar symptomatology but without COVID-19 infection. Seventy-four COVID-19 positive and 228 COVID-19 negative patients were evaluated with routine haematological parameters. Severe disease was defined as death and/or need of intensive care treatment. Twenty-seven COVID-19 positive and 18 COVID-19 negative patients were furthermore included for morphological evaluation using smear examination. Significant differences were found for platelet indices and white blood cell parameters. Thus, platelet count and plateletcrit was lower in COVID-19 patients, whilst mean platelet volume, platelet distribution width, and platelet large cell ratio was significantly higher than in non-COVID-19 patients. Leukocyte, neutrophil, immature granulocyte, lymphocyte, monocyte, eosinophil, and basophil count was lower in COVID-19 patients. No significant differences were found for red blood cell count, haemoglobin, haematocrit or mean corpuscular haemoglobin for COVID-19 versus non-COVID-19 patients. COVID-19 patients with a severe disease course had higher levels of immature granulocytes, but lower lymphocyte and platelet counts compared to patients with non-severe COVID-19. In terms of morphology, 14.8% of COVID-19 patients had a normal smear examination, compared to 83.3% of non-COVID-19 patients. Hypogranulated neutrophils were more frequent in COVID-19 patients (p

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here we report that elevated interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab had less severe disease. In SARS-CoV-2 infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, in the lung, hyaluronan synthase 1 (Has1) was the most downregulated gene and hyaluronan accumulation was decreased. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator, and indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases., Summary: IL-13 levels are elevated in patients with severe COVID-19. In a mouse model of disease, IL-13 neutralization results in reduced disease and lung hyaluronan deposition. Similarly, blockade of hyaluronan’s receptor, CD44, reduces disease, highlighting a novel mechanism for IL-13-mediated pathology.

The coronavirus disease 2019 (COVID-19) pandemic has led to surges of patients presenting to emergency departments (EDs) and potentially overwhelming health systems. We sought to assess the predictive accuracy of host biomarkers at clinical presentation to the ED for adverse outcome. Prospective observational study of PCR-confirmed COVID-19 patients in the ED of a Swiss hospital. Concentrations of inflammatory and endothelial dysfunction biomarkers were determined at clinical presentation. We evaluated the accuracy of clinical signs and these biomarkers in predicting 30-day intubation/mortality, and oxygen requirement by calculating the area under the receiver-operating characteristic curve and by classification and regression tree analysis. Of 76 included patients with COVID-19, 24 were outpatients or hospitalized without oxygen requirement, 35 hospitalized with oxygen requirement, and 17 intubated/died. We found that soluble triggering receptor expressed on myeloid cells had the best prognostic accuracy for 30-day intubation/mortality (area under the receiver-operating characteristic curve, 0.86; 95% CI, 0.77-0.95) and IL-6 measured at presentation to the ED had the best accuracy for 30-day oxygen requirement (area under the receiver-operating characteristic curve, 0.84; 95% CI, 0.74-0.94). An algorithm based on respiratory rate and sTREM-1 predicted 30-day intubation/mortality with 94% sensitivity and 0.1 negative likelihood ratio. An IL-6-based algorithm had 98% sensitivity and 0.04 negative likelihood ratio for 30-day oxygen requirement. sTREM-1 and IL-6 concentrations in COVID-19 in the ED have good predictive accuracy for intubation/mortality and oxygen requirement. sTREM-1- and IL-6-based algorithms are highly sensitive to identify patients with adverse outcome and could serve as early triage tools.

In the present study, we have determined SARS-CoV-2-specific antibody responses in sera of acute and postinfection phase subjects. Our results indicate that antibody responses against viral S and N proteins were equally sensitive in the acute phase of infection, but that responses against N appear to wane in the postinfection phase where those against the S protein persist over time. The most sensitive serological assay in both acute and postinfection phases used the native S protein trimer as the binding antigen, which has significantly greater conformational epitopes for antibody binding compared to the S1 monomer protein used in other assays. We believe these results are extremely important in order to generate correct estimates of SARS-CoV-2 infections in the general population. Furthermore, the assessment of antibody responses against the trimeric S protein will be critical to evaluate the durability of the antibody response and for the characterization of a vaccine-induced antibody response., Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses to the spike (S) protein monomer, S protein native trimeric form, or the nucleocapsid (N) proteins were evaluated in cohorts of individuals with acute infection (n = 93) and in individuals enrolled in a postinfection seroprevalence population study (n = 578) in Switzerland. Commercial assays specific for the S1 monomer, for the N protein, or within a newly developed Luminex assay using the S protein trimer were found to be equally sensitive in antibody detection in the acute-infection-phase samples. Interestingly, compared to anti-S antibody responses, those against the N protein appear to wane in the postinfection cohort. Seroprevalence in a “positive patient contacts” group (n = 177) was underestimated by N protein assays by 10.9 to 32.2%, while the “randomly selected” general population group (n = 311) was reduced by up to 45% relative to the S protein assays. The overall reduction in seroprevalence targeting only anti-N antibodies for the total cohort ranged from 9.4 to 31%. Of note, the use of the S protein in its native trimer form was significantly more sensitive compared to monomeric S proteins. These results indicate that the assessment of anti-S IgG antibody responses against the native trimeric S protein should be implemented to estimate SARS-CoV-2 infections in population-based seroprevalence studies. IMPORTANCE In the present study, we have determined SARS-CoV-2-specific antibody responses in sera of acute and postinfection phase subjects. Our results indicate that antibody responses against viral S and N proteins were equally sensitive in the acute phase of infection, but that responses against N appear to wane in the postinfection phase where those against the S protein persist over time. The most sensitive serological assay in both acute and postinfection phases used the native S protein trimer as the binding antigen, which has significantly greater conformational epitopes for antibody binding compared to the S1 monomer protein used in other assays. We believe these results are extremely important in order to generate correct estimates of SARS-CoV-2 infections in the general population. Furthermore, the assessment of antibody responses against the trimeric S protein will be critical to evaluate the durability of the antibody response and for the characterization of a vaccine-induced antibody response.

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Patients with severe mental illness (SMI) i.e. schizophrenia, schizoaffective disorder, and bipolar disorder are at increased risk of severe outcomes if infected with coronavirus disease 2019 (COVID-19). Whether patients with SMI are at increased risk of COVID-19 is, however, sparsely investigated. This important issue must be addressed as the current pandemic could have the potential to increase the existing gap in lifetime mortality between this group of patients and the background population. The objective of this study was to determine whether a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder is associated with an increased risk of COVID-19. A cross-sectional study was performed between January 18th and February 25th, 2021. Of 7071 eligible patients with schizophrenia, schizoaffective disorder, or bipolar disorder, 1355 patients from seven psychiatric centres in the Capital Region of Denmark were screened for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. A total of 1258 unvaccinated patients were included in the analysis. The mean age was 40.5 years (SD 14.6), 54.3% were female. Fifty-nine of the 1258 participants had a positive SARS-CoV-2 antibody test, corresponding to a adjusted seroprevalence of 4.96% (95% CI 3.87–6.35). No significant difference in SARS-CoV-2-risk was found between female and male participants (RR = 1.32; 95% CI 0.79–2.20; p = .290). No significant differences in seroprevalences between schizophrenia and bipolar disease were found (RR = 1.12; 95% CI 0.67–1.87; p = .667). Seroprevalence among 6088 unvaccinated blood donors from the same region and period was 12.24% (95% CI 11.41–13.11). SARS-CoV-2 seroprevalence among included patients with SMI was significantly lower than among blood donors (RR = 0.41; 95% CI 0.31–0.52; p < .001). Differences in seroprevalences remained significant when adjusting for gender and age, except for those aged 60 years or above. The study is registered at ClinicalTrails.gov (NCT04775407). https://clinicaltrials.gov/ct2/show/NCT04775407?term=NCT04775407&draw=2&rank=1.

Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10–15 d after the onset of COVID-19 symptoms. However, due to the recent emergence of SARS-CoV-2 in the human population, it is not known how long antibody responses will be maintained or whether they will provide protection from reinfection. Using sequential serum samples collected up to 94 d post onset of symptoms (POS) from 65 individuals with real-time quantitative PCR-confirmed SARS-CoV-2 infection, we show seroconversion (immunoglobulin (Ig)M, IgA, IgG) in >95% of cases and neutralizing antibody responses when sampled beyond 8 d POS. We show that the kinetics of the neutralizing antibody response is typical of an acute viral infection, with declining neutralizing antibody titres observed after an initial peak, and that the magnitude of this peak is dependent on disease severity. Although some individuals with high peak infective dose (ID50 > 10,000) maintained neutralizing antibody titres >1,000 at >60 d POS, some with lower peak ID50 had neutralizing antibody titres approaching baseline within the follow-up period. A similar decline in neutralizing antibody titres was observed in a cohort of 31 seropositive healthcare workers. The present study has important implications when considering widespread serological testing and antibody protection against reinfection with SARS-CoV-2, and may suggest that vaccine boosters are required to provide long-lasting protection.

Background. Coronavirus disease 2019 (COVID-19) can result in profound changes in blood coagulation. The aim of the study was to determine the incidence and predictors of venous thromboembolic events (VTE) among patients with COVID-19 requiring hospital admission. Subjects and Methods. We performed a retrospective study at the Lausanne University Hospital with patients admitted because of COVID-19 from February 28 to April 30, 2020. Results. Among 443 patients with COVID-19, VTE was diagnosed in 41 patients (9.3%; 27 pulmonary embolisms, 12 deep vein thrombosis, one pulmonary embolism and deep vein thrombosis, one portal vein thrombosis). VTE was diagnosed already upon admission in 14 (34.1%) patients and 27 (65.9%) during hospital stay (18 in ICU and nine in wards outside the ICU). Multivariate analysis revealed D-dimervalue>3,120 ng/ml(P<0.001; OR 15.8, 95% CI 4.7-52.9) and duration of 8 days or more from COVID-19 symptoms onset to presentation (P0.020; OR 4.8, 95% CI 1.3-18.3) to be independently associated with VTE upon admission. D-dimervalue≥3,000 ng/lcombined with a Wells score forPE≥2was highly specific (sensitivity 57.1%, specificity 91.6%) in detecting VTE upon admission. Development of VTE during hospitalization was independently associated with D-dimervalue>5,611 ng/ml(P<0.001; OR 6.3, 95% CI 2.4-16.2) and mechanical ventilation (P<0.001; OR 5.9, 95% CI 2.3-15.1). Conclusions. VTE seems to be a common COVID-19 complication upon admission and during hospitalization, especially in ICU. The combination ofWells≥2score andD−dimer≥3,000 ng/lis a good predictor of VTE at admission.

Background Specific diagnostic tests to detect severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and resulting COVID‐19 disease are not always available and take time to obtain results. Routine laboratory markers such as white blood cell count, measures of anticoagulation, C‐reactive protein (CRP) and procalcitonin, are used to assess the clinical status of a patient. These laboratory tests may be useful for the triage of people with potential COVID‐19 to prioritize them for different levels of treatment, especially in situations where time and resources are limited. Objectives To assess the diagnostic accuracy of routine laboratory testing as a triage test to determine if a person has COVID‐19. Search methods On 4 May 2020 we undertook electronic searches in the Cochrane COVID‐19 Study Register and the COVID‐19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID‐19 publications. We did not apply any language restrictions. Selection criteria We included both case‐control designs and consecutive series of patients that assessed the diagnostic accuracy of routine laboratory testing as a triage test to determine if a person has COVID‐19. The reference standard could be reverse transcriptase polymerase chain reaction (RT‐PCR) alone; RT‐PCR plus clinical expertise or and imaging; repeated RT‐PCR several days apart or from different samples; WHO and other case definitions; and any other reference standard used by the study authors. Data collection and analysis Two review authors independently extracted data from each included study. They also assessed the methodological quality of the studies, using QUADAS‐2. We used the 'NLMIXED' procedure in SAS 9.4 for the hierarchical summary receiver operating characteristic (HSROC) meta‐analyses of tests for which we included four or more studies. To facilitate interpretation of results, for each meta‐analysis we estimated summary sensitivity at the points on the SROC curve that corresponded to the median and interquartile range boundaries of specificities in the included studies. Main results We included 21 studies in this review, including 14,126 COVID‐19 patients and 56,585 non‐COVID‐19 patients in total. Studies evaluated a total of 67 different laboratory tests. Although we were interested in the diagnotic accuracy of routine tests for COVID‐19, the included studies used detection of SARS‐CoV‐2 infection through RT‐PCR as reference standard. There was considerable heterogeneity between tests, threshold values and the settings in which they were applied. For some tests a positive result was defined as a decrease compared to normal vaues, for other tests a positive result was defined as an increase, and for some tests both increase and decrease may have indicated test positivity. None of the studies had either low risk of bias on all domains or low concerns for applicability for all domains. Only three of the tests evaluated had a summary sensitivity and specificity over 50%. These were: increase in interleukin‐6, increase in C‐reactive protein and lymphocyte count decrease. Blood count Eleven studies evaluated a decrease in white blood cell count, with a median specificity of 93% and a summary sensitivity of 25% (95% CI 8.0% to 27%; very low‐certainty evidence). The 15 studies that evaluated an increase in white blood cell count had a lower median specificity and a lower corresponding sensitivity. Four studies evaluated a decrease in neutrophil count. Their median specificity was 93%, corresponding to a summary sensitivity of 10% (95% CI 1.0% to 56%; low‐certainty evidence). The 11 studies that evaluated an increase in neutrophil count had a lower median specificity and a lower corresponding sensitivity. The summary sensitivity of an increase in neutrophil percentage (4 studies) was 59% (95% CI 1.0% to 100%) at median specificity (38%; very low‐certainty evidence). The summary sensitivity of an increase in monocyte count (4 studies) was 13% (95% CI 6.0% to 26%) at median specificity (73%; very low‐certainty evidence). The summary sensitivity of a decrease in lymphocyte count (13 studies) was 64% (95% CI 28% to 89%) at median specificity (53%; low‐certainty evidence). Four studies that evaluated a decrease in lymphocyte percentage showed a lower median specificity and lower corresponding sensitivity. The summary sensitivity of a decrease in platelets (4 studies) was 19% (95% CI 10% to 32%) at median specificity (88%; low‐certainty evidence). Liver function tests The summary sensitivity of an increase in alanine aminotransferase (9 studies) was 12% (95% CI 3% to 34%) at median specificity (92%; low‐certainty evidence). The summary sensitivity of an increase in aspartate aminotransferase (7 studies) was 29% (95% CI 17% to 45%) at median specificity (81%) (low‐certainty evidence). The summary sensitivity of a decrease in albumin (4 studies) was 21% (95% CI 3% to 67%) at median specificity (66%; low‐certainty evidence). The summary sensitivity of an increase in total bilirubin (4 studies) was 12% (95% CI 3.0% to 34%) at median specificity (92%; very low‐certainty evidence). Markers of inflammation The summary sensitivity of an increase in CRP (14 studies) was 66% (95% CI 55% to 75%) at median specificity (44%; very low‐certainty evidence). The summary sensitivity of an increase in procalcitonin (6 studies) was 3% (95% CI 1% to 19%) at median specificity (86%; very low‐certainty evidence). The summary sensitivity of an increase in IL‐6 (four studies) was 73% (95% CI 36% to 93%) at median specificity (58%) (very low‐certainty evidence). Other biomarkers The summary sensitivity of an increase in creatine kinase (5 studies) was 11% (95% CI 6% to 19%) at median specificity (94%) (low‐certainty evidence). The summary sensitivity of an increase in serum creatinine (four studies) was 7% (95% CI 1% to 37%) at median specificity (91%; low‐certainty evidence). The summary sensitivity of an increase in lactate dehydrogenase (4 studies) was 25% (95% CI 15% to 38%) at median specificity (72%; very low‐certainty evidence). Authors' conclusions Although these tests give an indication about the general health status of patients and some tests may be specific indicators for inflammatory processes, none of the tests we investigated are useful for accurately ruling in or ruling out COVID‐19 on their own. Studies were done in specific hospitalized populations, and future studies should consider non‐hospital settings to evaluate how these tests would perform in people with milder symptoms., Plain language summary How accurate are routine laboratory tests for diagnosis of COVID‐19? What are routine laboratory tests? Routine laboratory tests are blood tests that assess the health status of a patient. Tests include counts of different types of white blood cells (these help the body fight infection), and detection of markers (proteins) that indicate organ damage, and general inflammation. These tests are widely available and in some places they may be the only tests available for diagnosis of COVID‐19. What did we want to find out? People with suspected COVID‐19 need to know quickly whether they are infected so that they can self‐isolate, receive treatment, and inform close contacts. Currently, the standard test for COVID‐19 is usually the RT‐PCR test. In the RT‐PCR, samples from the nose and throat are sent away for testing, usually to a large, central laboratory with specialist equipment. Other tests include imaging tests, like X‐rays, which also require specialist equipment. We wanted to know whether routine laboratory tests were sufficiently accurate to diagnose COVID‐19 in people with suspected COVID‐19. We also wanted to know whether they were accurate enough to prioritize patients for different levels of treatment. What did we do? We searched for studies that assessed the accuracy of routine laboratory tests to diagnose COVID‐19 compared with RT‐PCR or other tests. Studies could be of any design and be set anywhere in the world. Studies could include participants of any age or sex, with suspected COVID‐19, or use samples from people known to have – or not to have ‐ COVID‐19. What we found We found 21 studies that looked at 67 different routine laboratory tests for COVID‐19. Most of the studies looked at how accurately these tests diagnosed infection with the virus causing COVID‐19. Four studies included both children and adults, 16 included only adults and one study only children. Seventeen studies were done in China, and one each in Iran, Italy, Taiwan and the USA. All studies took place in hospitals, except one that used samples from a database. Most studies used RT‐PCR to confirm COVID‐19 diagnosis. Accuracy of tests is most often reported using ‘sensitivity’ and ‘specificity’. Sensitivity is the proportion of people with COVID‐19 correctly detected by the test; specificity is the proportion of people without COVID‐19 who are correctly identified by the test. The nearer sensitivity and specificity are to 100%, the better the test. A test to prioritize people for treatment would require a high sensitivity of more than 80%. Where four or more studies evaluated a particular test, we pooled their results and analyzed them together. Our analyses showed that only three of the tests had both sensitivity and specificity over 50%. Two of these were markers for general inflammation (increases in interleukin‐6 and C‐reactive protein). The third was for lymphocyte count decrease. Lymphocytes are a type of white blood cell where a low count might indicate infection. How reliable are the results? Our confidence in the evidence from this review is low because the studies were different from each other, which made them difficult to compare. For example, some included very sick people, while some included people with hardly any COVID‐19 symptoms. Also, the diagnosis of COVID‐19 was confirmed in different ways: RT‐PCR was sometimes used in combination with other tests. Who do the results of this review apply to? Routine laboratory tests can be issued by most healthcare facilities. However, our results are probably not representative of most clinical situations in which these tests are being used. Most studies included very sick people with high rates of COVID‐19 virus infection of between 27% and 76%. In most primary healthcare facilities, this percentage will be lower. What does this mean? Routine laboratory tests cannot distinguish between COVID‐19 and other diseases as the cause of infection, inflammation or tissue damage. None of the tests performed well enough to be a standalone diagnostic test for COVID‐19 nor to prioritize patients for treatment. They will mainly be used to provide an overall picture about the health status of the patient. The final COVID‐19 diagnosis has to be made based on other tests. How up‐to‐date is this review? We searched all COVID‐19 studies up to 4 May 2020.

Background COVID-19 is a new form of acute respiratory failure leading to multiorgan failure and ICU admission. Gathered evidence suggests that a 3-fold rise in D-dimer concentrations may be linked to poor prognosis and higher mortality. Purpose To describe D-dimer admission profile in severe ICU COVID19 patients and its predictive role in outcomes and mortality. Methods Single-center retrospective cohort study. All adult patients admitted to ICU with COVID19 were divided into 3 groups: (1) Lower-values group (D-dimer levels < 3-fold normal range value [NRV] [500ng/mL]), Intermediate-values group (D-dimer ≥3-fold and Results 118 patients (mean age 63 years, 73% males) were included (N = 73 Lower-values group, N = 31 Intermediate-values group; N = 11 Higher-values group). Mortality was not different between groups (p = 0.51). Kaplan-Meier survival curves revealed no differences (p = 0.52) between groups, nor it was verified even when gender, age, ICU length of stay, and SOFA score were considered as covariables. Conclusions In severe COVID19 patients, the D-dimer profile does not retain a predictive value regarding patients’ survivability and should not be used as a surrogate of disease severity.

Introduction Acute presentations of COVID-19 infection vary, ranging from asymptomatic carriage through to severe clinical manifestations including acute respiratory distress syndrome (ARDS). Longer term sequelae of COVID-19 infection includes lung fibrosis in a proportion of patients. Krebs von den Lungen 6 (KL-6) is a mucin like glycoprotein that has been proposed as a marker of pulmonary epithelial cell injury. We sought to determine whether KL-6 was a marker of 1) the severity of acute COVID-19 infection, or 2) the persistence of symptoms/radiological abnormalities at medium term follow up. Methods Prospective single centre observational study. Results Convalescent KL-6 levels were available for 93 patients (male 63%, mean age 55.8 years) who attended an 12-week follow up appointment after being admitted to hospital with COVID-19. For 67 patients a baseline KL-6 result was available for comparison. There was no significant correlations between baseline KL-6 and the admission CXR severity score or clinical severity NEWS score. Furthermore, there was no significant difference in the baseline KL-6 level and an initial requirement for oxygen on admission or the severity of acute infection as measured at 28 days. There was no significant difference in the 12-week KL-6 level and the presence or absence of subjective breathlessness but patients with abnormal CT scans at 12 weeks had significantly higher convalescent KL-6 levels compared to the remainder of the cohort (median 1101 IU/ml vs 409 IU/ml). Conclusions The association between high KL-6 levels at 12 weeks and persisting CT abnormalities (GGO/fibrosis), is a finding that requires further exploration. Whether KL-6 may help differentiate those patients with persisting dyspnoea due to complications rather than deconditioning or dysfunctional breathing alone, is an important future research question.