Background
COVID-19 is a disease caused by the SARS-CoV-2 virus, characterised by
an early mild- moderate viral syndrome of fever, tiredness, cough and
headache [1]. Over 80% of patients have a self-limiting illness not
requiring hospital admission and show clear improvement in two weeks. A
minority of COVID-19 patients progress through a transition phase around
days 7-11 of worsening pulmonary complications [1]. These manifest
as breathlessness, acute lung injury and respiratory failure, and often
progress to require mechanical ventilation with subsequent high
mortality. This deterioration appears to be driven by lung host
responses including a cytokine storm of inflammation leading to severe
tissue damage and irreversible organ failure likened to adult
respiratory distress syndrome (ARDS) [2]. Patients who develop ARDS
are at very high risk of death.
The cytokine storm phase of COVID-19 is associated with increased
production of a range of inflammatory cytokines including interleukin-1β
(IL1β), interleukin-6 (IL6), tumour necrosis factor-α (TNFα) and
interferon-γ (IFNγ) [3]. Several case series have reported increased
TNFα levels in patients with COVID-19 and particularly high levels
appear to be associated with a severe disease course [3,4]. One
series has described increased TNFα inducibility in macrophages, in the
presence of SARS-CoV-2 virus [4]. TNFα, as the master regulator of
cytokines, is considered key in both immune pneumonitis and acute
myocardial injury witnessed in COVID-19.
Current COVID-19 therapeutic studies are mainly focused on agents
designed to target viral processes or virus-host interactions, for
example with Remdesivir. We note that Remdesvir has recently been
approved by the UK government, after “numerical reduction in time to
clinical improvement”, but failing to meet statistical significance on
the primary clinical endpoint of mortality [5].
An alternative therapeutic approach is to target the host responses that
underlie the cytokine storm and associated inflammation [3]. We, and
other colleagues [6], have called for randomised clinical trials of
anti-TNF agents, such as Infliximab, to treat the cytokine storm induced
by SARS-CoV-2 - see our BMJ Rapid Response published online on 9 April
2020, available at: https://www.bmj.com/content/369/bmj.m1439/rr.
Pentoxifylline is a cytokine-modulating anti-inflammatory agent with
many actions that might reasonably be expected to be therapeutic in the
transition phase of COVID-19.