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.