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BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1573 (Published 20 April 2020) Cite this as: BMJ 2020;369:m1573

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Pentoxifylline Is An Inexpensive And Widely Available Oral Anti-Tumour Necrosis Factor Agent For Prevention Or Treatment Of Cytokine Storm In COVID-19 COVID-19

Dear Editor

Pentoxifylline Is An Inexpensive And Widely Available Oral Anti-Tumour Necrosis Factor Agent For Prevention Or Treatment Of Cytokine Storm In COVID-19 COVID-19

We were interested to see this update on the large RECOVERY trial in the UK.

We wish to highlight the need to trial Pentoxifylline, which is an oral anti-tumour necrosis factor alpha (TNFα) , to prevent/treat cytokine storm in COVID-19. Pentoxifylline is readily available as an inexpensive, oral drug and its potential therapeutic benefits could therefore be extended to large numbers of patients, including in resource-limited countries.

Several case series have reported increased TNFα levels in patients with COVID-19, and particularly high levels appear to be associated with so in severe disease course [1,2]. One series has described increased TNFα inducibility in macrophages, in the presence of SARS-CoV-2 virus [3].

Whilst it is critical to find anti-viral based strategies to fight SARS-CoV-2 infections, it may be equally important to find therapeutic agents to deal directly with the cytokine storm that appears to be the main pathophysiology in severe COVID-19.

TNFα is considered to be the master regulator of cytokines, giving rise to both immune pneumonitis and acute myocardial injury in COVID-19. This may be prevented by anti-TNFα agents in light of the evidence from studies on renal ischaemia-reperfusion and TNFα. [4].

We and other colleagues have called for randomised clinical trials of intravenous anti-TNF agents, such as Infliximab, to treat the cytokine storm induced by SARS-CoV-2 [5,6].

We propose that re-purposing an oral anti-TNFα agent, Pentoxifylline, which has a safety record of more than 50 years, should also be trialled in COVID-19. Pentoxifylline is a non-specific phosphodiesterase inhibitor and operates through the cyclic AMP pathway to inhibit TNFα production in macrophages [7]. Pentoxifylline can dose dependently suppress TNFα production at both the mRNA and bioactivity levels [8].

Several studies have confirmed that Pentoxifylline is an effective TNF inhibitor, and within the last decade, was most notably studied as a potential treatment for alcoholic hepatitis [9]. At Ealing Hospital, we had enrolled patients in the STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial [9].

While no survival benefit was demonstrated in this population, there were no reported safety issues, in this large-scale trial. Pentoxifylline is known to preferentially inhibit macrophage function in alveoli, and therefore potentially carries even higher promise in the COVID-19 cohort [10].

It is known that the therapeutic window for methyl-xanthines, such as Pentoxifylline, is narrow. Pentoxifylline is safe to use with patients with many comorbidities with the exception of acute myocardial infarction; cerebral haemorrhage; extensive retinal haemorrhage; and severe cardiac arrhythmias.

If the theoretical therapeutic benefit of Pentoxifylline for COVID-19 is clinically demonstrable, it may prove to be an inexpensive, and readily available, treatment strategy to target harmful cytokine excess in this disease. We therefore advocate urgent randomised trials of Pentoxifylline for patients infected with SARS CoV-2.

Dr Nina Stafford*
Specialty Registrar in Gastroenterology

Dr Ahran Arnold**
Clinical Research Fellow in Cardiology

Dr Arvind Sangwaiya*
Consultant Gastroenterologist

Dr Vijay Manglam*
Consultant Gastroenterologist

Professor Jayantha Arnold*
Consultant Physician and Gastroenterologist

*Ealing Hospital, London North West University Healthcare Trust, Uxbridge Road, Southall, London UB1 3HW, United Kingdom.

**National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0HS, United Kingdom.

References

1. Diao B, Wang C, Tan Y, Chen X, Liu Y, Nings L, Chen L et al. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19). MedRxiv. doi: 10.1101/2020.02.18.20024364

2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet Jan 2020; 395: 497–506. Doi: 10.1016/S0140-6736(20)30183-5

3. Giamarellos-Bourboulis et al., Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure, Cell Host & Microbe (2020), doi: 10.1016/j.chom.2020.04.009.

4. Kanagasundaram NS. Pathophysiology of ischaemic acute kidney injury. Annals of Clinical Biochemistry 2015, 42(2) 193-205. doi: 10.1177/0004563214556820

5. Feldman M, Maini RN, Woody JN, Holgate GW, Rowland M et al. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. Lancet published online on 9 April 2020. Doi: 10.1016/S0140-6736(20)30858-8

6. Arnold AD, Scurr A, Arnold JD. Tumour Necrosis Factor May Be The Central Regulator Of Covid-19 Protection Produced By BCG Vaccination. BMJ Rapid Response published online on 9 April 2020, available at: https://www.bmj.com/content/369/bmj.m1439/rr.

7. Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R. Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition. Clinics 2008: 63: 321–8. doi:10.1590/S1807-59322008000300006.

8. Strieter RM, Remick DG, Ward PA et al. Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. 1988 Sep 30;155(3):1230-6. Doi: 0.1016/s0006-291x(88)81271-3.

9. Thursz M, Richardson P, Allison M et al. Prednisolone or Pentoxifylline for alcoholic hepatitis. N Eng J Med 2015;372:1619-1628. doi:10.1056/NEJMoa1412278.

10. Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U. Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages. Am J Respir Crit Care Med. 1999;159(2):508-11. doi:10.1164/ajrccm.159.2.9804085.

Competing interests: No competing interests

26 April 2020
Jayantha Arnold
Consultant Physician and Gastroenterologist
Dr Nina Stafford, Dr Ahran Arnold, Dr Arvind Sangwaiya, Dr Vijay Manglam
Ealing Hospital, London Northwest Healthcare NHS Trust
Uxbridge Road, Southall, London UB1 3HW