Exposing and Overcoming Limitations of Clinical Laboratory Tests in COVID-19 by Adding Immunological Parameters (preprint)

Background: Almost two years since the onset of the COVID-19 pandemic no predictive algorithm has been generally adopted, nor new tests identified to improve the prediction and management of SARS-CoV-2 infection. Methods: Retrospective observational analysis of the predictive performance of clinical parameters and laboratory tests in hospitalised patients with COVID-19. Outcomes were 28-day survival and maximal severity in a cohort of 1,579 patients and two validation cohorts of 598 and 434 patients. A pilot study conducted in a patient subgroup measured 17 cytokines and 27 lymphocyte phenotypes to explore additional predictive laboratory tests. Findings: 1) Despite a strong association of 22 clinical and laboratory variables with the outcomes, their joint prediction power was limited due to redundancy. 2) Eight variables: age, comorbidity index, oxygen saturation to fraction of inspired oxygen ratio, neutrophil-lymphocyte ratio, C-reactive protein, aspartate aminotransferase/alanine aminotransferase ratio, fibrinogen, and glomerular filtration rate captured most of the statistical predictive power. 3) The interpretation of clinical and laboratory variables was improved by grouping them in categories. 4) Age and organ damage-related tests were the best predictors of survival, and inflammatory-related tests were the best predictors of severity. 5) The pilot study identified several immunological tests (including chemokine ligand 10, chemokine ligand 2, and interleukin 1 receptor antagonist), that performed better than currently used tests. Conclusions: Currently used tests for clinical management of COVID 19 patients are of limited value due to redundancy, as all measure aspects of two major processes: inflammation, and organ damage. There are no independent predictors based on the quality of the nascent adaptive immune response. Understanding the limitations of current tests would improve their interpretation and simplify clinical management protocols. A systematic search for better biomarkers is urgent and feasible.

Anakinra as rescue therapy to treat patients with severe COVID-19 refractory to tocilizumab (preprint)

Objective. To evaluate the role played by anakinra in the treatment of patients with severe COVID-19 who fail to “accepted” standard of care and tocilizumab.Methods. We conducted a retrospective cohort study assessed in Althaia Health Network University and Vall d’Hebrón University Hospital, in Barcelona, Spain. We included patients with confirmed RT-PCR for SARS-CoV-2, moderate-to-severe acute respiratory distress syndrome [PaO2:FiO2] (PAFI) ≤200 mmHg, and hyperinflammation. All of them were primarily managed with non-invasive ventilation outside of the ICU and received standard of care with hydroxychloroquine, lopinavir/ritonavir, azithromycin, and enoxaparin supplemented with tocilizumab. These patients received an additional administration of 100 mg subcutaneous anakinra twice a day (low-dose) or every 6-8 hours (medium-dose). Mechanical ventilation-free survival, ICU admission, respiratory function changes (PAFI), inflammatory markers, and survival were analyzed.Results. Clinical and respiratory improvements were already present at 48 hours post-anakinra. PAFI increased 105.2% at 48 hours over anakinra administration and 166.9% at day 7. Respiratory function improvement was significant at day 7 (p<0.0001) with 10/12 (83%) responders having a PAFI ≥ 200 mm Hg. Despite of this improvement, inflammatory markers lasted to decrease. Two patients required ICU and temporary mechanical ventilation. No patients died and no adverse effects related to anakinra appeared. Short-time follow-up showed no relapses.Conclusions. In severe ARDS related to SARS-CoV-2 refractory to standard of care plus tocilizumab, low-to-moderate doses of anakinra as a rescue therapy showed effectiveness and safety, avoiding mechanical ventilation and deaths.