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.