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\begin{document}

\title{Hypothesis: Pentoxifylline is a potential cytokine modulator therapeutic
in COVID-19 patients}



\author[1]{Bruce Hendry}%
\author[2]{NIna Stafford}%
\author[3]{Ahran Arnold}%
\author[2]{Arvind Sangwaiya}%
\author[2]{Vijay Manglam}%
\author[3]{Stuart Rosen}%
\author[2]{Jayantha Arnold}%
\affil[1]{Kings College London}%
\affil[2]{London North West University Healthcare NHS Trust}%
\affil[3]{National Heart and Lung Institute}%


\vspace{-1em}



  
  \date{May 04, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
We propose a new hypothesis that the established drug pentoxifylline
deserves attention as a potential repurposed therapeutic for COVID-19.
Pentoxifylline is an anti-inflammatory agent that suppresses adenosine
responses, reduces Tumour Necrosis Factor alpha, Interleukin 1,
Interleukin 6 and Interferon gamma and may act to reduce tissue damage
during the cytokine storm response to SARS-CoV-2 infection. This agent
has been used clinically for many years and has a favourable profile of
safety and tolerability. Pre-clinical data support pentoxifylline as
effective in cytokine-driven lung damage. Clinical studies of
pentoxifylline in radiation and cytokine-induced lung damage in humans
are positive and consistent with anti-inflammatory efficacy.
Pentoxifylline is a readily available, off-patent, inexpensive drug
suitable for large scale use, including in resource-limited countries.
Current trials of therapeutics are largely focussed on the inhibition of
viral processes. We advocate urgent randomised trials of pentoxifylline
for COVID-19 as a complementary approach to target the host responses.%
\end{abstract}%



\sloppy


\textbf{Hypothesis: Pentoxifylline is a potential cytokine modulator
therapeutic in COVID-19 patients}

Prof Bruce M Hendry *

Dr Nina Stafford **

Dr Ahran D Arnold ***

Dr Arvind Sangwaiya **

Dr Vijay Manglam **

Prof Stuart D Rosen ***

Prof Jayantha Arnold **

* Renal Sciences, Department of Inflammation Biology, King's College
London, London SE5 9RJ, UK

** Department of Gastroenterology, Ealing Hospital, London North West
University Healthcare NHS Trust, Uxbridge Road, Southall, UB1 3HW, UK.

*** National Heart and Lung Institute, Imperial College London, London
W12 0HS.UK.

Corresponding Author: Professor Bruce Hendry KCL, 10 Cutcombe Road,
London, SE5 9RJ, UK

Email: bruce.hendry@kcl.ac.uk

Telephone: +44 7973 456 694



\textbf{Summary}

We propose a new hypothesis that the established drug pentoxifylline
deserves attention as a potential repurposed therapeutic for COVID-19.

Pentoxifylline is an anti-inflammatory agent that suppresses adenosine
responses, reduces tumour necrosis factor \selectlanguage{greek}α, \selectlanguage{english}interleukin 1, interleukin
6 and interferon \selectlanguage{greek}γ \selectlanguage{english}and may act to reduce tissue damage during the
cytokine storm response to SARS-CoV-2 infection. This agent has been
used clinically for many years and has a favourable profile of safety
and tolerability. Pre-clinical data support pentoxifylline as effective
in cytokine-driven lung damage. Clinical studies of pentoxifylline in
radiation and cytokine-induced lung damage in humans are positive and
consistent with anti-inflammatory efficacy.

Pentoxifylline is a readily available, off-patent, inexpensive drug
suitable for large scale use, including in resource-limited countries.

Current trials of therapeutics are largely focussed on the inhibition of
viral processes. We advocate urgent randomised trials of pentoxifylline
for COVID-19 as a complementary approach to target the host responses.

\textbf{Keywords}

COVID-19, cytokine, immunomodulation, pentoxifylline, pneumonia,
SARS-CoV-2, viral

\textbf{Running title}

Pentoxifylline and COVID-19

\textbf{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-1\selectlanguage{greek}β
\selectlanguage{english}(IL1\selectlanguage{greek}β\selectlanguage{english}), interleukin-6 (IL6), tumour necrosis factor-\selectlanguage{greek}α \selectlanguage{english}(TNF\selectlanguage{greek}α\selectlanguage{english}) and
interferon-\selectlanguage{greek}γ \selectlanguage{english}(IFN\selectlanguage{greek}γ\selectlanguage{english}) {[}3{]}. Several case series have reported increased
TNF\selectlanguage{greek}α \selectlanguage{english}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 TNF\selectlanguage{greek}α \selectlanguage{english}inducibility in macrophages, in the
presence of SARS-CoV-2 virus {[}4{]}. TNF\selectlanguage{greek}α, \selectlanguage{english}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.

\textbf{Description of hypothesis}

\textbf{Molecular and cellular actions of Pentoxifylline}

Pentoxifylline is a xanthine derivative drug with a wide range of
actions at the cellular and molecular level. pentoxifylline has
rheological actions increasing erythrocyte deformability and was
originally licensed for the treatment of peripheral vascular disease on
the basis of suggested improvement of microvascular and capillary blood
flow {[}7{]}. More recently pentoxifylline has been determined to have
extensive anti-inflammatory properties {[}8{]}. pentoxifylline inhibits
5'-nucleotidase and phosphodiesterases (PDE). PDE inhibition results in
increased cAMP levels, increased protein kinase A (PKA) activity and
altered transcriptional regulation of pro-inflammatory genes through
modulation of the NF\selectlanguage{greek}κ\selectlanguage{english}B/I\selectlanguage{greek}κ\selectlanguage{english}B pathway {[}8{]}. Pentoxifylline downregulates
transcription and expression levels of TNF\selectlanguage{greek}α, \selectlanguage{english}IL1b, IL6, IFN\selectlanguage{greek}γ, \selectlanguage{english}ICAM1 and
VCAM1. pentoxifylline 5'-nucleotidase inhibition reduces the production
of adenosine and inosine from adenosine monophosphate (AMP) and inosine
monophosphate (IMP) respectively. Pentofxyfilline appears able to
downregulate the pathologically important pro-inflammatory adenosine
receptor A2A pathway {[}9{]}. These effects contribute to the extensive
actions of pentoxifylline in reducing pro-inflammatory signals. For
example, pentoxifylline reduces cytokine release from pulmonary
macrophages derived from patients with sarcoidosis {[}10{]}. Lungs have
the highest proportion of total resident macrophages in the human body,
around 1 trillion.

\textbf{Pentoxifylline therapy in pre-clinical studies}

In rats pentoxifylline downregulates a range of inflammatory cytokines
in the context of sepsis and improves lung function {[}10{]}. In animal
studies pentoxifylline is effective as a therapeutic in a range of
models of lung injury including radiation-induced damage, cytotoxic
agent damage and aortic clamping {[}11{]}. The actions of pentoxifylline
in reducing lung damage appear to depend on a reduction of activity of
the adenosine receptor A2A {[}9{]}. The direct inhibition of 5'-
nucleotidase activity by pentoxifylline likely reduces adenosine
production and may therefore complement the actions on cytokine gene
transcription. Pentoxifylline improves glomerular damage and reduces
TNF\selectlanguage{greek}α \selectlanguage{english}in crescentic glomerulonephritis in rats {[}12{]}. Pentoxifylline
does not appear to alter the replication of SARS-CoV in mice and does
not show direct antiviral activity.

\textbf{Clinical studies of pentoxifylline}

The anti-inflammatory properties of pentoxifylline have been confirmed
in a range of clinical studies in diverse organ failure syndromes. In
severe renal disease patients exhibit resistance to erythropoietin
through a pro-inflammatory state characterised by increased TNF\selectlanguage{greek}α, \selectlanguage{english}IFN\selectlanguage{greek}γ
\selectlanguage{english}and IL6. pentoxifylline improves erythropoietin sensitivity in these
patients and this action is associated with reductions in serum TNF\selectlanguage{greek}α \selectlanguage{english}and
IFN\selectlanguage{greek}γ\selectlanguage{english} {[}13{]}. In diabetic nephropathy pentoxifylline reduces
proteinuria through inhibition of intraglomerular inflammatory signals.
Clinical studies have demonstrated pentoxifylline as effective in
reducing lung damage in the context of radiation damage, and
cardiopulmonary bypass {[}13,14{]}. Ustunsoy et al (2003) for example
found that pentoxifylline reduced levels of TNF\selectlanguage{greek}α \selectlanguage{english}and IL6 when given at
the time of bypass {[}14{]}.

One of the largest scale clinical trials of pentoxifylline
anti-inflammatory effects within the last decade, was the STOPAH trial
{[}15{]}. Examining potential benefit in acute alcoholic hepatitis, no
survival benefit was demonstrated, however no safety issues were
reported in an inherently vulnerable, immunocompromised patient cohort.
pentoxifylline preferential inhibition of macrophage function in
alveoli, as opposed to hepatocytes, potentially explains this outcome
{[}16{]}.

Rainsford (2006) reviewed possible treatments for the lung complications
associated with inflammatory cytokines in H5N1 ``bird flu'' and
suggested that pentoxifylline should be considered for clinical trials
in view of its pharmacology and safety profile {[}17{]}. These arguments
appear equally suited to the case of COVID-19. Although we cannot
describe the SARS-CoV-2 pulmonary syndrome as identical to that seen in
H5N1, there are certainly parallels.

TNF has a pivotal role in orchestrating the production of a
pro-inflammatory cytokine cascade. TNF\selectlanguage{greek}α \selectlanguage{english}is thus considered to be a
`master regulator' of pro-inflammatory cytokine production {[}18{]}.
Post mortem lung biopsies in COVID-19 showed interstitial oedema which
would normally be the result of TNF induced increased capillary
permeability {[}19,20{]}. This non cardiogenic pulmonary oedema (both
interstitial and intra-alveolar) is often the first stage of COVID-19
acute lung injury that progresses through the cytokine storm to ARDS
{[}20{]}. The recent description of thrombosis and endothelialitis in
COVID-19 {[}20{]} raises the possibility that the rheological actions of
pentoxifylline could have benefit in maintaining microvascular function.

Pentoxifylline has over 50 years safety record data of use in humans and
has an extensive evidence base for tolerability and safety.
Nevertheless, its safety in the context of COVID-19 has not been
established and this would need close monitoring in a clinical trial
setting. It is available in oral form with good bioavailability, and
also can be delivered by intravenous injection. The usual dose orally is
1.2g daily in 3 divided doses. An inhalational formulation has been
developed, originally for use in neonates. In COVID-19 the cytokine
storm appears to be strongly centred in lung tissue, and accordingly
inhaled pentoxifylline could be an optimum method for delivery at the
highest concentrations where it is most effective, with minimal systemic
exposure.

Use of a repurposed drug for COVID-19 may have multiple advantages in
addition to its safety and tolerability experience. It is widely
available as a generic agent, with multiple sources of supply and
therefore manageable cost. There should be no patent protection issues
in redirecting the agent to trials in COVID-19. This should be of acute
interest as limited-resource areas begin to amass cases of COVID-19.

\textbf{Design of studies of pentoxifylline in COVID-19}

Study of pentoxifylline in COVID-19 should be feasible and ethical given
the well-described adverse event profile of the drug. A randomised study
in COVID-19 patients presenting with, or at high risk of, pulmonary
complications could be designed with pentoxifylline versus a placebo or
comparator treatment, alongside standard of care. pentoxifylline has
been used at 400-1200 mg daily in 400mg doses. Initial study likely
should use 1200 mg daily in divided doses. If there is initial evidence
of benefit with oral pentoxifylline, then study of inhaled
pentoxifylline could be valuable in selected patients. In the future it
will also be logical to study the combination of cytokine-modifying
therapy with direct anti-viral therapeutics (such as the recently
favoured Remdesivir). The efficacy of pentoxifylline can be assessed by
randomised control trials with key endpoints including mortality, need
for ventilatory support, time on ventilatory support, measures of oxygen
exchange efficiency and time in hospital.

\textbf{Conclusions}

The full cellular, pre-clinical and clinical profile of pentoxifylline
suggests that pentoxifylline could be effective in reducing the severity
of lung injury in patients with COVID-19. These actions could reduce the
need for critical care interventions and reduce the burden and mortality
of COVID-19 in selected individuals.

If the theoretical and rheological 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 advocate urgent randomised trials of pentoxifylline for patients
infected with SARS CoV-2.

\textbf{List of Abbreviations}

AMP: adenosine monophosphate ARDS: adult respiratory distress syndrome
CRP: C-reactive protein ICAM1: intercellular adhesion molecule 1 IFN\selectlanguage{greek}γ:
\selectlanguage{english}interferon gamma IkB: Inhibitory factor kappa B IL: interleukin IMP:
inosine monophosphate NkB: nuclear factor kappa B PDE:
phosphodiesterases PKA: protein kinase A SARS: severe acute respiratory
syndrome TNF\selectlanguage{greek}α: \selectlanguage{english}tumour necrosis factor alpha

VCAM1: vascular cell adhesion molecule 1

\textbf{Declarations}

None of the authors have any relevant actual or potential conflicts of
interest.

BMH has received honoraria for speaking or consulting from AstraZeneca,
Gilead Sciences, Otsuka, Retrophin, Sanofi, UCB and ViiV Healthcare

\textbf{Contributions}

All authors contributed equally

\textbf{Ethics Approval} Not applicable

\textbf{Consent for Publication} Not applicable

\textbf{Availability of Data and Materials}

Not applicable

\textbf{Funding} Not applicable

\textbf{Acknowledgements}

Not applicable



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