Introduction

To date, the most serious symptoms from COVID-19 are pulmonary complications. An overwhelming number of patients with COVID-19 present with pneumonia and acute respiratory failure. Acute respiratory distress syndrome (ARDS) involves accumulation of pro- and anti-inflammatory cytokines in the lung parenchyma that is associated with severe injury to lung epithelium and endothelium [1]. Common risk factors for the development of ARDS relevant to COVID-19 infection include pneumonia, pulmonary vasculitis, and non-pulmonary sepsis [2]. Progression to ARDS is characterized by chest imaging (positive for bilateral opacities not fully explained by pleural effusions), respiratory failure not fully explained by cardiac failure or fluid overload, and oxygen requirement. In the Berlin definition [2], ARDS is characterized as mild, moderate, or severe according to the extent of hypoxemia.
Cytokine expression shifts in patients with ARDS and those at risk for ARDS. Changes in interleukin-6 (IL‑6) and IL-8, for example, have been used to predict clinical outcome (mortality) in ARDS patients [3]. IL-6 plays multiple roles in the immune response. IL-6 signaling mediates effects in the vascular wall such as vascular permeability, activation of the endothelium, recruitment of immune cells, and endothelial dysfunction. The result is often vascular hypertrophy and fibrosis [4]. In one study, individual cytokines increased in patients before and after the onset of ARDS, yet greater increases occurred in cognate receptors and/or antagonists, so that the molar ratios of agonists to antagonists declined dramatically at the onset of ARDS and remained low for at least 7 days. In this study, IL-6 increased an average 400-fold (mean peak 1230 pg mL-1) over normal in 53 patients on the first day of ARDS, while sIL-6R increased only 2-3 fold. IL-6 steadily declined in these patients from Day 1-21 of ARDS, but remained elevated compared with normal levels. Importantly, the molar ratios of IL-6 and its cognate receptor sIL-6R (a specific agonist) increased more than 10-fold in patients at risk for ARDS and approximately 100-fold in patients with ARDS [5]. In another study, plasma IL-6 levels > 400 pg mL-1 on any day in the first week of ARDS was associated with a low likelihood of survival [6]. In a third study, serum IL-6 and IL-8 levels on day 1 were significantly higher in all the ARDS patients as compared to healthy controls. As compared to survivors, the IL-6 and IL-8 levels were significantly higher in non-survivors measured on day 1. By using acute physiology and chronic health evaluation (APACHE) II score, IL-6, and IL-8, the receiver operating characteristic curve was plotted, and the provided predictable accuracy of mortality (outcome) was 94% [3].
IL-6 pathway blockade has been used to successfully treat rheumatoid arthritis and Castleman’s disease [7, 8] and to prevent cytokine release syndrome (CRS) arising from chimeric antigen receptor T-cell therapy [9, 10]. The rationale for exploring drugs that target the IL-6 pathway in the treatment of COVID-19 is based on their utility in managing CRS. Clinically, both TCZ (which binds the IL-6 receptor and is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for management of CRS) and SIL (which binds IL-6) are used to control CRS [9].
In the context of the COVID-19 pandemic, several countries have issued emergency use guidelines for TCZ in the treatment of severe COVID-19 pneumonia, and EUSA Pharma has instituted a compassionate use program with SIL to treat patients with COVID-19 who have developed serious respiratory complications. Additionally, there are 48 studies of TCZ and 3 studies investigating SIL for COVID-19 treatment as of June 1, 2020 (clinicaltrials.gov).

Siltuximab Clinical Experience

SIL (SYLVANT®) is an IL-6 antagonist indicated for the treatment of patients with multicentric Castleman’s disease who are HIV negative and HHV-8 negative, approved in 2014 by the FDA. SIL is administered as an 11 mg kg-1 IV dose given over 1 hour every 3 weeks. SIL is not approved for the treatment of CRS, but has been administered as a single intravenous (IV) dose of 11 mg kg-1 IV for this indication. Researchers in Belgium will compare the time to clinical improvement in adult patients with acute hypoxic respiratory failure and systemic CRS receiving SYLVANT 11 mg kg-1 IV (COV-AID trial; NCT04330638; Treatment of COVID-19 Patients with Anti-interleukin Drugs) versus other therapies (standard of care, anakinra, TCZ, TCZ + anakinra, SIL + anakinra). Primary completion of the trial is estimated as September 2020, with study completion estimated December 2020.

Tocilizumab Clinical Experience

TCZ (ACTEMRA®) is an IL-6 receptor inhibitor with several indications (rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, cytokine release syndrome), approved in 2018 by the FDA. For the management of CRS, the recommended dose is 8 mg kg-1 IV over 1 hour for patients at or above 30 kg and 12 mg kg-1 for patients less than 30 kg in weight. Doses exceeding 800 mg per infusion are not recommended in CRS patients. In the COV-AID trial (NCT04330638), TCZ will be administered as a single IV infusion at a dose of 8 mg kg-1 with a maximum infusion of 800 mg per injection.