Immunotherapy of COVID-19: Inside and Beyond IL-6 Signalling

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.

Dysregulated Immune Responses in SARS-CoV-2-Infected Patients: A Comprehensive Overview

“…The authors suggested that the level of CD3+CD4+ T cells could have a predictive value for the early detection of severe COVID-19 forms and the selection of patients requiring rapid aggressive treatment with corticosteroids or IL-6 inhibitors. However, IL-6 blockade may not be effective in some severe COVID-19 [ 83 ], and largely depended on many factors including baseline IL-6 levels, PaO 2 /FIO 2 , requirement of HFO or NIV, levels of CRP, ferritin, D-dimer, and LDH [ 84 , 85 ].…”

Sarilumab Administration in COVID-19 Patients: Literature Review and Considerations

“…Critical and severe COVID-19 forms, constituting 2–5% and 15% of cases, respectively, are assumed to occur from SARS-CoV-2-induced autoinflammatory syndrome, both at systemic and pulmonary levels, in which a dysregulated immune response, due to overflowing cytokine production and release, leads to widespread tissue and vascular damages [ 30 ]. Viral infections and autoimmune pathologies are known to be correlated to an abnormal immune response known as a “cytokine storm”, characterized by an excessive release of pro-inflammatory cytokines [ 31 , 32 ].…”

“…In conclusion, therapeutic blockade of IL-6 pathways should not be performed in critically ill patients, in whom IL-6 cis-signaling is predominant with favorable homeostatic roles, nor in the early (viral) phase of SARS-CoV-2 infection, in which IL-6 signaling may be useful to block viral replication and dissemination [ 30 ]. The proven benefits of anti-IL-6 treatment in COVID-19 patients could be achieved by disrupting only pro-inflammatory IL-6 trans-presentation and trans-signaling, prevalent and pathogenic in severe disease, by acting no later than the second week of symptom onset (or within seven days of hospitalization) [ 30 ].…”

“…Although it is often cumbersome to stratify and recognize the right patients to treat with anti-IL-6 agents within the right time of COVID-19 pathophysiology, some important inflammatory and respiratory parameters have been suggested to help clinicians manage the decision. Along these lines, Zizzo et al proposed that IL-6 levels between 35 and 90 pg/mL, as well as C-reactive protein (CRP) levels between 120 and 160 mg/L, may help to identify those severe patients who would benefit from the cytokine cascade interruption within 6 days of hospitalization [ 30 ]. In the same way, COVID-19 patients with serum LDH levels > 550 U/L, ferritin levels > 1600–2000 ng/mL, and D-dimer levels > 3000–5000 ng/mL represent critically ill patients who would not respond to anti-IL-6 treatments [ 30 ].…”

“…Along these lines, Zizzo et al proposed that IL-6 levels between 35 and 90 pg/mL, as well as C-reactive protein (CRP) levels between 120 and 160 mg/L, may help to identify those severe patients who would benefit from the cytokine cascade interruption within 6 days of hospitalization [ 30 ]. In the same way, COVID-19 patients with serum LDH levels > 550 U/L, ferritin levels > 1600–2000 ng/mL, and D-dimer levels > 3000–5000 ng/mL represent critically ill patients who would not respond to anti-IL-6 treatments [ 30 ].…”