With over 100,000 deaths worldwide from coronavirus disease 2019 (COVID-19), it is incumbent on researchers to accelerate clinical trials of any readily available and potentially acceptably safe therapies that could reduce the rising death toll, writes researchers led by Marc Feldmann at Oxford University Botnar Research Centre, in The Lancet.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gains access to host cells via angiotensin-converting enzyme 2, which is expressed in the type II surfactant-secreting alveolar cells of the lungs. Severe COVID-19 is associated with a major immune inflammatory response with abundant neutrophils, lymphocytes, macrophages, and immune mediators. Which mediators are most important in driving the immune pathology remains to be elucidated. Deaths from COVID-19 are chiefly due to diffuse alveolar damage with pulmonary oedema, hyaline membrane formation, and interstitial mononuclear inflammatory infiltrate compatible with early-phase adult respiratory distress syndrome (ARDS). Prevention of ARDS and death in patients with COVID-19 is a pressing health emergency.
Anti-tumour necrosis factor (TNF) antibodies have been used for more than 20 years in severe cases of autoimmune inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, or ankylosing spondylitis. There are ten (as reported on Sept 29, 2019) US Food and Drug Administration approved and four off-label indications for anti-TNF therapy, indicating that TNF is a valid target in many inflammatory diseases. TNF is present in blood and disease tissues of patients with COVID-19 and TNF is important in nearly all acute inflammatory reactions, acting as an amplifier of inflammation. We propose that anti-TNF therapy should be evaluated in patients with COVID-19 on hospital admission to prevent progression to needing intensive care support.
There is evidence of an inflammatory excess in patients with COVID-19. Lung pathology in COVID-19 is characterised by capillary leakage of fluid and recruitment of immune-inflammatory lymphocytes, neutrophils, and macrophages, implying a role for adhesion molecules, chemokines, and cytokines targeting vascular endothelium.
Cytokine upregulation is documented in COVID-19. In patients with COVID-19, there is upregulation of pro-inflammatory cytokines in the blood, including interleukin (IL)-1, IL-6, TNF, and interferon γ,, and patients in intensive care units have increased concentrations of many cytokines. Preliminary data from Salford Royal Hospital and the University of Manchester in the UK document the presence of proliferating excess monocytes expressing TNF by intracellular staining in patients with COVID-19 in intensive care (Hussell T, Grainger J, Menon M, Mann E, University of Manchester, Manchester, UK, personal communication). Available cytokine data on immunology and inflammation in COVID-19 are summarised in the appendix.
Initial reports comprising a trial of 21 severe and critical COVID-19 patients in China (ChiCTR2000029765) and a case study from France of clinical benefit with the anti-IL6 receptor antibody tocilizumab in COVID-19 suggest that cytokines are of importance in the “cytokine storm” and further controlled clinical trials are in progress. Although there are many potential drug candidates for reducing inflammation in COVID-19, only a few drugs such as the anti-TNF antibodies infliximab or adalimumab are potentially effective, widely available, and have a well-established safety profile.
The potential role of anti-TNF therapy thus warrants consideration. Preclinical studies suggest that the response to severe respiratory syncytial virus (RSV) and influenza in mice is ameliorated by anti-TNF therapy, which reduces weight loss, disease duration, and cell and fluid infiltrate. This research suggests a potential rationale for use of anti-TNF therapy in viral pneumonia, especially given the known mechanism of action of TNF and the reversal of TNF-induced immunopathology by TNF blockade in multiple diseases. It is known TNF is produced in most types of inflammation, especially in the acute phase, and is important in the coordination and development of the inflammatory response. However, too much production of TNF for too long becomes immune suppressive.
Blockade of TNF alone is clinically effective in many circumstances and diseases, despite the presence of many other pro-inflammatory cytokines and mediators. There is evidence of a “TNF dependent cytokine cascade” in rheumatoid arthritis tissue and upon bacterial challenge in baboons., Thus, if TNF is blocked, there is a rapid (<12 h) decrease of IL-6 and IL-1 concentrations in patients with active rheumatoid arthritis and, importantly, a reduction of adhesion molecules and vascular endothelial growth factor, which is also known as vascular permeability factor, denoting its importance in capillary leak.
Furthermore, a reduction in leucocyte trafficking occurs in inflamed tissues of joints due to reduction in adhesion molecules and chemokines with reduction in cell content and exudate. Finally, after anti-TNF infusion tissue TNF is reduced as it passes into the blood bound to the anti-TNF antibody. Blood concentrations of immunoreactive, but biologically inactive, TNF increase more than ten times after infusion. For these reasons it is possible that a single infusion of anti-TNF antibody might reduce some of the processes that occur during COVID-19 lung inflammation, reducing TNF and other inflammatory mediators, cellularity, and exudate.
Authors
Marc Feldmann, Ravinder N Maini, James N Woody, Stephen T Holgate, Gregory Winter, Matthew Rowland, Duncan Richards, Tracy Hussell
[link url="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2820%2930858-8/fulltext?dgcid=raven_jbs_etoc_email"]The Lancet comment[/link]