Abstract
Acting on the cytokine cascade is key to preventing disease progression and death in hospitalised patients with COVID-19. Among anti-cytokine therapies, interleukin (IL)-6 inhibitors have been the most used and studied since the beginning of the pandemic. Going through previous observational studies, subsequent randomised controlled trials, and meta-analyses, we focused on the baseline characteristics of the patients recruited, identifying the most favourable features in the light of positive or negative study outcomes; taking into account the biological significance and predictivity of IL-6 and other biomarkers according to specific thresholds, we ultimately attempted to delineate precise windows for therapeutic intervention. By stimulating scavenger macrophages and T-cell responsivity, IL-6 seems protective against viral replication during asymptomatic infection; still protective on early tissue damage by modulating the release of granzymes and lymphokines in mild-moderate disease; importantly pathogenic in severe disease by inducing the proinflammatory activation of immune and endothelial cells (through trans-signalling and trans-presentation); and again protective in critical disease by exerting homeostatic roles for tissue repair (through cis-signalling), while IL-1 still drives hyperinflammation. IL-6 inhibitors, particularly anti-IL-6R monoclonal antibodies (e.g., tocilizumab, sarilumab), are effective in severe disease, characterised by baseline IL-6 concentrations ranging from 35 to 90 ng/mL (reached in the circulation within 6 days of hospital admission), a ratio of partial pressure arterial oxygen (PaO2) and fraction of inspired oxygen (FiO2) between 100 and 200 mmHg, requirement of high-flow oxygen or non-invasive ventilation, C-reactive protein levels between 120 and 160 mg/L, ferritin levels between 800 and 1600 ng/mL, D-dimer levels between 750 and 3000 ng/mL, and lactate dehydrogenase levels between 350 and 500 U/L. Granulocyte-macrophage colony-stimulating factor inhibitors might have similar windows of opportunity but different age preferences compared to IL-6 inhibitors (over or under 70 years old, respectively). Janus kinase inhibitors (e.g., baricitinib) may also be effective in moderate disease, whereas IL-1 inhibitors (e.g., anakinra) may also be effective in critical disease. Correct use of biologics based on therapeutic windows is essential for successful outcomes and could inform future new trials with more appropriate recruiting criteria.
Highlights
As of October 1, 2021, the Coronavirus Disease 2019 (COVID19) pandemic has caused over 200,000,000 cases and more than 4,500,000 deaths [1]
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is more often asymptomatic, on the other hand healthy carriers importantly contribute to the spread of the virus, and COVID-19 can manifest itself in different forms of severity, namely mild, moderate, severe and critical
The beneficial effects of tocilizumab and other biologics in the management of COVID-19 have long been debated owing to large discrepancies in study results, possibly due to differences in sample size, patient series composition, and treatment protocols
Summary
As of October 1, 2021, the Coronavirus Disease 2019 (COVID19) pandemic has caused over 200,000,000 cases and more than 4,500,000 deaths [1]. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is more often asymptomatic, on the other hand healthy carriers importantly contribute to the spread of the virus, and COVID-19 can manifest itself in different forms of severity, namely mild, moderate, severe and critical. Mild forms affect patients with respiratory symptoms who are generally not hospitalised and do not require supplemental oxygen. Moderate forms affect patients with viral pneumonia who require low-flow supplemental oxygen (LFO, ≤ 5 liters per minute). Severe forms affect patients with bilateral interstitial pneumonia and acute respiratory distress syndrome (ARDS) requiring high-flow oxygen (HFO) or non-invasive ventilation (NIV). Critical forms affect patients admitted to intensive care unit (ICU) with severe ARDS, shock, and/or multiple organ failure, requiring invasive mechanical ventilation (IMV) with or without other organ support therapies, such as vasopressors, extracorporeal membrane oxygenation (ECMO), or dyalisis [2]
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