Investigating the association between IL-6 antagonist therapy and blood coagulation in critically ill patients with COVID-19: a protocol for a prospective, observational, multicentre study.

INTRODUCTION: Hypercoagulation is one the main features of COVID-19. It is induced by the hyperinflammatory response that shifts the balance of haemostasis towards pro-coagulation. Interleukin-6 (IL-6) antagonist therapy has been recommended in certain subgroups of critically ill patients with COVID-19 to modulate inflammatory response. The interaction between immune response and haemostasis is well recognised. Therefore, our objective is to evaluate whether the modulation of the inflammatory response by IL-6 antagonist inflicts any changes in whole blood coagulation as assessed by viscoelastic methods in critically ill patients with COVID-19. METHODS AND ANALYSIS: In this prospective observational study, we are going to collect data on inflammatory parameters and blood coagulation using the ClotPro^® device. The primary outcome is the change of the fibrinolytic system measured by the Lysis Time and Lysis onset time before and after immunomodulation therapy. Data will be collected before the IL-6 antagonist administration at baseline (T₀) then after 24, 48 hours, then on day 5 and 7 (T_1-4, respectively). Secondary outcomes include changes in other parameters related to inflammation, blood coagulation and biomarkers of endothelial injury. ETHICS AND DISSEMINATION: Ethical approval was given by the Medical Research Council of Hungary (1405-3/2022/EÜG). All participants provided written consent. The results of the study will be disseminated through peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05218369; Clinicaltrials.gov.

Effectiveness and safety of fibrinolytic therapy in critically ill patients with COVID-19 with ARDS: protocol for a prospective meta-analysis.

INTRODUCTION: The use of fibrinolytic therapy has been proposed in severe acute respiratory distress syndrome (ARDS). During the COVID-19 pandemic, anticoagulation has received special attention due to the frequent findings of microthrombi and fibrin deposits in the lungs and other organs. Therefore, the use of fibrinolysis has been regarded as a potential rescue therapy in these patients. In this prospective meta-analysis, we plan to synthesise evidence from ongoing clinical trials and thus assess whether fibrinolytic therapy can improve the ventilation/perfusion ratio in patients with severe COVID-19-caused ARDS as compared with standard of care. METHODS AND ANALYSIS: This protocol was registered in PROSPERO. All randomised controlled trials and prospective observational trials that compare fibrinolytic therapy with standard of care in adult patients with COVID-19 and define their primary or secondary outcome as improvement in oxygenation and/or gas exchange, or mortality will be considered eligible. Safety outcomes will include bleeding event rate and requirement for transfusion. Our search on 25 January 2022 identified five eligible ongoing clinical trials. A formal search of MEDLINE (via PubMed), Embase, CENTRAL will be performed every month to identify published results and to search for further trials that meet our eligibility criteria. DISSEMINATION: This could be the first qualitative and quantitative synthesis summarising evidence of the efficacy and safety of fibrinolytic therapy in critically ill patients with COVID-19. We plan to publish our results in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42021285281.

An Analysis of Serological Response and Infection Outcomes Following Oxford-AstraZeneca (AZD1222) and Pfizer-BioNTech (mRNA BNT162b2) SARS-CoV-2 Vaccines in Kidney and Kidney-pancreas Transplants.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 is associated with high mortality among transplant recipients. Comparative data that define humoral responses to the Oxford-AstraZeneca (AZ) and BNT162b2 (Pfizer-BioNTech) vaccines are limited. METHODS: We recruited 920 kidney transplant patients receiving at least 1 dose of severe acute respiratory syndrome coronavirus 2 vaccine, excluding patients with virus pre-exposure. Serological status was determined with the COVID-SeroKlir ELISA (Kantaro-EKF Diagnostics). Patients with a corrected antibody level of <0.7 AU/mL were considered seronegative. RESULTS: Four hundred ninety-five AZ and 141 Pfizer patients had a sample analyzed after first dose and 593 after second dose (346 AZ versus 247 Pfizer). After first dose, 25.7% of patients seroconverted (26.6% AZ, 22.8% Pfizer). After second dose, 148 (42.8%) of AZ seroconverted compared with 130 (52.6%) of Pfizer (P = 0.02; hazard ratio, 1.48; 95% confidence interval, 1.07-2.06). When negative responders were excluded, Pfizer patients were shown to have significantly higher response than AZ patients (median 2.6 versus 1.78 AU/mL, P = 0.005).Patients on mycophenolate had a reduced seroconversion rate (42.2% versus 61.4%; P < 0.001; hazard ratio, 2.17) and reduced antibody levels (0.47 versus 1.22 AU/mL, P = 0.001), and this effect was dose dependent (P = 0.05). Prednisolone reduced the seroconversion from 58.2% to 43.6% (P = 0.03) among Pfizer but not AZ recipients. Regression analysis showed that antibody levels were reduced by older age (P = 0.002), mycophenolate (P < 0.001), AZ vaccine (versus Pfizer, P = 0.001), and male gender (P = 0.02). Sixteen of 17 serious postvaccine infections occurred to patients who did not seroconvert. CONCLUSIONS: Both seroconversion and antibody levels are lower in AZ compared with Pfizer vaccinated recipients following 2 vaccine doses. Mycophenolate was associated with lower antibody responses in a dose-dependent manner. Serious postvaccine infections occurred among seronegative recipients.

Higher Dose Anticoagulation Cannot Prevent Disease Progression in COVID-19 Patients: A Systematic Review and Meta-Analysis.

Implementation of higher dose (HD) thromboprophylaxis has been considered in patients infected with coronavirus disease 2019 (COVID-19). Our aim was to compare HD to standard dose (SD) thromboprophylaxis in COVID-19 patients. The protocol is registered on PROSPERO (CRD42021284808). We searched for randomised controlled studies (CENTRAL, Embase, Medline and medRxviv) that compared HD to SD anticoagulation in COVID-19 and analysed outcomes such as mortality, thrombotic events, bleedings, and disease progression. The statistical analyses were made using the random effects model. Fourteen articles were included (6253 patients). HD compared with SD showed no difference in mortality (OR 0.83 [95% CI 0.54-1.28]). The use of HD was associated with a decreased risk of thrombosis (OR 0.58 [95% CI 0.44-0.76]), although with an increased risk of major bleeding (OR 1.64 [95% CI 1.25-2.16]). The cohort with D-dimer < 1 mg/mL showed no effect (OR 1.19 [95% CI 0.67-2.11]), but in the case of D-dimer > 1 mg/mL, a tendency of lower risk in the HD group was observed (OR 0.56 [95% CI 0.31-1.00]). The need for intubation in moderately ill patients showed a nonsignificant lower likelihood in the HD group (OR 0.82 [95% CI 0.63-1.08]). We cannot advocate for HD in all COVID-19 patients, although it shows some nonsignificant benefits on disease progression in those with elevated D-dimer who do not need ICU admission.

Differential Diagnostic Challenges in the COVID-19 Pandemic: Renal Abscess After SARS-CoV-2 Infection in a Young Adolescent.

BACKGROUND Prolonged fever in pediatric patients is often a diagnostic challenge. Clinicians tend to associate prolonged fever with COVID-19-related diseases in patients with a history of SARS-CoV-2 infection. Here we present a patient who was admitted with a clinical suspicion of multi-inflammatory syndrome in children (MIS-C) and was finally diagnosed with a renal abscess. CASE REPORT A 16-year-old girl with prolonged fever, bilateral non-purulent conjunctivitis, weight loss, muscle pain, general malaise, cough, and yellow sputum was admitted to Heim Pál National Pediatric Institute, Budapest, Hungary. She had proven SARS-CoV-2 infection 3 weeks prior to admission. Although inflammatory markers were elevated, repeated urine analyses, aerobic and anaerobic urine cultures, hemoculture, chest X-ray, and otorhinolaryngology examinations were negative. Based on clinical and laboratory criteria, the diagnosis of MIS-C was eventually ruled out. Abdominal ultrasound revealed a 17×20×15 mm simplex cyst at the edge of the parenchyma in the upper third of the left kidney. Magnetic resonance imaging was performed, showing a multi-compartment, septated, thick-walled parenchymal lesion of 50×40×52 mm in the upper pole of the right kidney, which showed signal characteristics of an abscess, and 20×16 mm and 8 mm lesions in the upper pole of the left kidney, which appeared to be cysts. After being unresponsive to intravenous wide-spectrum antibiotic therapy (meropenem 2 g tid for 5 days), surgical intervention was needed to remove the abscess. CONCLUSIONS This case demonstrates that during the COVID-19 pandemic, besides the obvious post-COVID etiology, other life-threatening conditions should be investigated in the first line.