Sixty seconds on . . . the RECOVERY trial
BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1573 (Published 20 April 2020) Cite this as: BMJ 2020;369:m1573Read our latest coverage of the coronavirus pandemic
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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
Dear Editor:
While I understand that the question of these drugs effectiveness has been raised, given that they have pretty well already been demonstrated to be unhelpful or marginally beneficial at best, would it not make more sense to put our research efforts into other treatments that might make sense?
An rct of anticoagulants or one of diuretics, aldosterone blockers, surfactant or immune modulators, the effectiveness of which we don’t know, would be nice to nest into the design of these large trials. Even steroids such as dexamethasone (cheap and simple) would be worth studying, despite the association with increased mortality (not surprising, given that one would go for “bigger guns” in critically ill patients who are more likely to die, making mortality with steroids look universally high).
This trial is a bit of a missed opportunity, but, given we have over 2 million cases in the world, there should be no shortage of patients to recruit to any trials.
Competing interests: No competing interests
Use of Antacid Drugs -- Another factor the Recovery Trial should investigate
Children may be protected from the respiratory viruses in the sputum that they usually swallow (rather than spit out) by the presence of good levels of hydrochloric acid in their stomach gastric acid. One reason for the rapid spread of the SARS-Co-2 virus in older age groups might be the vast overuse in this age group of antacid liquids and tablets, such as proton pump inhibitors. (One oral dose of omeprazole can increase the stomach pH from around 2 to over 6.0 [1].)
Could the lack of protective stomach acid be the reason that the SARS-Co-2 virus is mainly affecting the older age groups and not children and young people?
If SARS-Co-2 viruses are not killed in the stomach because of low gastric acid levels, they pass into the small intestine where there are large numbers of ACE2 receptors, important for the development of COVID-19 disease. [2] Gastrointestinal involvement has been reported for infection with the SARS- Co-2 virus. [3,4] It may result in viral translocation and viraemia with subsequent secondary involvement of organs, such as the lungs. [4]
Severe infections might result from the lungs being attacked at the same time both directly from the upper respiratory tract and also from the gastrointestinal tract.
If this is correct, people with normal protective stomach acid will be less susceptible to COVID-19. A method of protecting susceptible people would then be stopping unnecessary antacid medication, followed by methods of augmenting stomach acid where possible.
It would be of value if the Recovery Trial would compare the amount and frequency of antacid drug use in patients with severe infections with the amount used by patients with mild disease. Both the antacid drugs obtained on prescription and also those purchased over-the-counter must be listed, as many antacids are just used occasionally for episodes of abdominal discomfort or pain. Such pain can occur with gastrointestinal involvement in potentially severe infections with COVID-19. [4]
References
1. Freedberg DE, Lebwohl B, Abrams JA The impact of proton pump inhibitors on the human gastrointestinal microbiome. Clin Lab Med. 2014 Dec;34(4):771-85. doi: 0.1016/j.cll.2014.08.008.
2. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004 Jun;203(2):631-7.
3. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology. 2020 Mar 3. pii: S0016-5085(20)30282-1. doi:10.1053/j.gastro.2020.02.055
4. Henry BM, de Oliveira MHS, Benoit J, Lippi G. Gastrointestinal symptoms associated with severity of coronavirus disease 2019 (COVID-19): a pooled analysis. Intern Emerg Med. 2020 Apr 17. doi: 10.1007/s11739-020-02329-9.
Competing interests: No competing interests