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\begin{document}

\title{Hypothesis Article: The Potential Therapeutic Effects of Colchicine for
Prevention of Cytokine Storms Consequences in COVID-19 Patients}



\author[1]{mohammad hablolvarid}%
\affil[1]{Razi vaccine and serum research institute}%


\vspace{-1em}



  
  \date{June 14, 2024}


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\selectlanguage{english}
\begin{abstract}
Background and Purpose. Since the onset of COVID-19 many clinical trials
of drugs and/or vaccines are continuing and new ones are introduce
daily. Yet the international research process failed to develop a
preventative vaccine or potent therapeutic drugs for relieving the
severity of the disease. Therefore, at present the best recommendation
to people to slow the spread of the disease is; please stay at home and
maintain social distancing! Experimental approach. Many aspects of
pharmacotherapeutic mechanism of action of some previously approved
drugs with anti-inflammatory effects, such as colchicine, in various
disorders is not fully understood. Therefore, many potential therapeutic
uses for these drugs and its analogues can be imagined. In this
hypothesis article, an attempt has been made to evaluate some potential
therapeutic effects of colchicine that may be benefit against COVID-19.
Key Results. Prophylactic therapy with colchicine regulates the innate
inflammatory response by blocking intracellular signaling pathways. This
can inhibit respiratory alveolar destruction following COVID-19
pneumonia, which is the main cause of ARDS and death in these patients.
Conclusion and Implications Since the macrophage and granulocytes are
the main pro-inflammatory mediators in the lung, it seems application of
therapeutic doses of colchicine, before the onset of respiratory
problems, will protect the lung against severe damages and respiratory
failure in COVID-19 patients. Obviously, many clinical trials are
required to prove the validity of this claim.%
\end{abstract}%



\sloppy


\textbf{Conclusion and Implications}

Since the macrophage and granulocytes are the main pro-inflammatory
mediators in the lung, it seems application of therapeutic doses of
colchicine, before the onset of respiratory problems, will protect the
lung against severe damages and respiratory failure in COVID-19
patients. Obviously, many clinical trials are required to prove the
validity of this claim.

Before December 2019, no one in the world could have imagined that a
novel severe pathogenic corona virus (CoV) which later designated as
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will soon
cause a deep crisis in the whole world (Ren et al., 2020). In February
2020 the disease caused by this virus defined as coronavirus disease
2019 (COVID-19). Rapid spread of the disease in China followed by other
countries caused the World Health Organization (WHO) in 11 Mar 2020
announced the disease a pandemic. Meanwhile, a consistent international
work for development of potential vaccines and drugs with different
mechanisms of action has been started. But, despite the fact that many
clinical trials of COVID-19 drugs or vaccines are continuing and new
ones are being added daily, scientists have been unable to find
effective ways to slow the spread of the SARS-CoV-2 and treatment of
COVID-19. Therefore, at present the best recommendation to people to
slow the spread of the SARS-CoV-2 is, please stay at home and maintain
social distancing!

Although most COVID-19 patients will develop mild to moderate symptoms
of sickness, but, researchers argued that in minority of COVID-19
patients the oversecretion of pro-inflammatory cytokines and chemokines,
often termed cytokine storm, play a crucial role in the fatal pneumonia
observed after SARS-CoV-2 infections (Rahmati and mosavi., 2020; Zhang
et al., 2020; Ruan et al., 2020). Different cytokine profiles in
patients with severe COVID-19 have been reported but elevated levels of
several cytokines/ chemokine such as interleukin 6 (IL-6), interleukin
10 (IL-10), interferon (IFN)-?, tumor necrosis factor (TNF) and
Interferon gamma-inducible protein 10 (IP-10) have been greater
emphasized in seriously ill patients, hospitalized in intensive care
unit (ICU), than patient with mild to moderate symptoms ( Rahmati and
Mosavi., 2020; Han et al., 2020; Li et al., 2020; Zhou et al., 2020; Liu
et al, 2020; Marietta et al., 2020). However, some researcher reiterate
that most cytokines measured in COVID-19 patients were not elevated
above the upper limit of normal and few slightly above normal levels are
indication of an infection related inflammatory response rather than
hypercytokinemia (Liu et al., 2020). In other words these
proinflammatory markers may be a consequence of the organ damage caused
by the infection rather than the driver of acute respiratory distress
syndrome (ARDS) caused by this infectious agent (Ruan et al., 2020). it
is very important to understand that magnitude of the elevation of
inflammatory cytokines in COVID-19 patient is truly a unique phenomenon
or simply one that results in many similar conditions that cause severe
damage to multiple organs such as in secondary haemophagocytic
lymphohistiocytosis (sHLH), severe sepsis or in ARDS (Gu et al., 2019).
Until now, the cytokine profile of COVID-19 patients with different
disease severity is not clear (Han et al., 2020) and patients with
severe COVID-19 represent different cytokine patterns. Therefore,
multiple trials of immunosuppressive therapies has been used to test
this hypothesis, so, more care should be taken before immunosuppressive
therapy by cytokine blockers. Several approaches including total
targeting of the inflammation or neutralizing a single key inflammatory
mediator such as interleukin-6 (IL-6) are employed to manage cytokine
storm in COVID-19 patients (Zhang et al., 2020). Though the results of a
recent report provides further evidence that IL-6 in not elevated in
COVID-19 patients. It should be emphasized that, computed tomography
(CT) images taken from patients with SARS-CoV-2 infected pneumonia
revealed characteristic white patches containing fluid in the lungs
(Wang et al., 2020). The predominant histological pattern of lung
injuries in 38 patients who died from COVID-19 in Italy was reported as:
capillary congestion, interstitial and intraalveolar edema, dilated
alveolar ducts and collapsed alveoli, hyaline membranes composed of
serum proteins and condensed fibrin, and loss of pneumocytes. In fact
following pulmonary injury, elevated levels of hyaluronan (HA) matrices
accumulate within the airway submucosa, pulmonary vasculature walls,
and, to a lesser extent, the alveoli and in respiratory secretions,
correlating with the extent of injury (Lauer et al., 2015). A review of
the literature reveals that HA has been associated with the
pathophysiology of acute respiratory distress syndrome (ARDS). However,
its key role in driving the morbidity and mortality of the condition has
not yet been fully recognized (Hallgren et al., 1989). HA can absorb
vast amounts of water, therefore, accumulation of this matrics in the
pulmonary alveoli disrupt oxygen exchanges and leads the patient to ARDS
(Hallgren et al., 1989; Shi et al., 2020; Xu et al., 2020). High level
of inflammatory cytokines such as IL-1 and TNF was detected in the lung
of COVID-19 infected patients. These cytokines have key role in
induction of HA-synthase-2 (HAS2) in CD31+ endothelium cells; lung
alveolar epithelial cell adhesion molecule positive (EPCAM+) cells and
fibroblasts (Bell et al., 2020; Shi et al., 2020). It must be emphasized
that there is much to be yet understood about various cytokines in the
genesis of acute respiratory distress and pneumonia. However, every
action for reduction or inhibition of production of HA, such as decrease
IL-1 and TNF levels, is very useful for easier breathing of COVID-19
patients and suppressing the inflammation must be performed as the main
efforts to manage the disease, hence it is wise to screen all patients
with severe COVID-19 for hyperinflammation and determining the subgroups
of patients for whom immunosuppression therapy may play a therapeutic
role in combating disease and decreasing mortality. To quiet such
pro-inflammatory factors production, researcher are now trying to find
effective immunosuppressant therapeutic agents for COVID-19 patients.
For instance, anakinra (human IL-1 receptor antagonist); tocilizumab
(humanized monoclonal antibody against the IL-6 receptor) and Janus
kinase (JAK) inhibitors that have therapeutic application in the
treatment of inflammatory diseases such as rheumatoid arthritis, showed
significant survival benefit in patients with hyperinflammation and some
has been approved in patients with COVID-19 pneumonia (Gonz\selectlanguage{ngerman}ález-Gay et
al., 2020) But, corticosteroids because of exacerbation of lung injury,
are not recommended (Russel et al., 2020) It is important to remember
that the pharmacotherapeutic mechanism of action of some previously
approved drugs with proven anti-inflammatory effects, such as
colchicine, in various disorders is not fully understood. Therefore,
many potential therapeutic uses for colchicine and its analogues such as
COVID-19 treatment could be expected. A Persian proverb says: water is
in a jar and we are thirsty for lips!

Colchicine has been one of the first line therapy for the treatment of
acute gouty arthritis and familial Mediterranean fever (FMF), but, due
to the anti-inflammatory and anti-fibrotic activities, other therapeutic
benefits of colchicine such as Behcet's disease (BD) has been determined
(Leung et al., 2015). In the following paragraphs, some therapeutic
effects of colchicine that are in consistent with this suggestion, are
described:

Actually, colchicine down regulates multiple inflammatory pathways and
modulates innate immunity. The main inhibitory mechanisms of actions of
colchicine are inhibition of neutrophil chemotaxis, adhesion,
mobilization and also blockage of superoxide production. Moreover,
colchicine inhibit NACHT-LRRPYD-containing protein 3 (NALP3)
inflammasomes activation and interleukin (IL) 1\selectlanguage{greek}β \selectlanguage{english}processing and release.
Through microtubule depolymerisation, colchicine interferes with
neutrophil adhesion and recruitment to inflamed tissue Furthermore,
Colchicine has been shown to reduce oxidative stress by reducing calcium
(Ca) influx into neutrophils (Leung et al., 2015). It has been shown
that, even at nano concentrations (3 nanomolar) colchicine as a
prophylactic drug can be used for elimination of adhesiveness of
neutrophils to endothelial cells and at higher concentrations (300
nanomolar) it prevents further neutrophil recruitment (Cronstein et al.,
1995). Moreover, at higher concentrations (5 micromolar), colchicine
suppresses monosodium urate (MSU) induced NALP3 inflammasomes,
responsible for caspase-1 activation and subsequent IL1\selectlanguage{greek}β \selectlanguage{english}and IL18
processing and release (Martinon et al., 2006). Therefore, low
prophylactic dose of colchicine could achieve a high enough
intracellular concentration in macrophages to inhibit NALP3 inflammasome
activation. Colchicine may also increase the threshold for initiation of
complete NALP3 inflammasome activation to some extent by reducing
subclinical inflammation (Pascual and Castellano., 1992). Prophylactic
therapy with colchicine also regulates the innate inflammatory response
by blocking intracellular signaling pathways by targeting nuclear factor
kB (NF-kB) or caspase-1. Colchicine was also shown to modulate
lipopolysaccharide-induced secretion of tumor necrosis factor (TNF) by
liver macrophages in a rat model. Furthermore, colchicine is a potent
inhibitor of pore formation induced by activation of both purinergic
receptors P2X7 and P2X2 both in vitro and in vivo. The formation of P2X7
pores is a necessary step in the innate immune response for triggering
ATP-induced NALP3 inflammasome activation (Leung et al., 2015;
Marques-da-Silva et al., 2011)

In the cases of COVID-19 pneumonia, the epithelium of respiratory
alveoli are destroyed and filled with fluid and inflammatory cells, so
the lung unable to take on oxygen and get rid of carbon dioxide.
Actually, this is the main cause of ARDS and death in these patients.
Therefore, suppressing the inflammation must be performed as the main
efforts to manage the disease. Since the macrophage and granulocytes are
the main pro-inflammatory mediators in the lung, it seems application of
therapeutic doses of colchicine, before the onset of respiratory
problems, will protect the lung against severe damages and respiratory
failure in COVID-19 patients. Obviously, many clinical trials are
required to prove the validity of this claim. However, narrow
therapeutic index of colchicine with no clear cut off distinction
between nontoxic, toxic, and lethal doses as well as unique route of,
oral, administration are the main disadvantages of this drug
(Finkelstein et al., 2010). Nevertheless, the benefits of
intratracheally application of hyaluronidase for inhibition of
hyaluronan synthase 2 (HAS2) enzyme and fluid accumulation in the lungs
has already been recommended (Shi et al., 2020; Xu et al., 2020).

\textbf{Competing interests:}

The author declare no competing interest.

\textbf{Author information:}

Mohammad Hassan Hablolvarid, Department of Animal Pathology and
Epidemiology, Razi vaccine and serum research institute, Agricultural
Research, Education and Extension Organization (AREEO), Karaj-Iran.

\textbf{Corresponding author:}

Dr. Mohammad Hassan Hablolvarid, Veterinary Pathologist, Department of
Animal Pathology and Epidemiology, Razi vaccine and serum research
institute, Agricultural Research, Education and Extension Organization
(AREEO), Karaj-Iran.

hablolvarid@yahoo.com

h.hablolvarid@rvsri.ac.ir

\begin{enumerate}
\tightlist
\item
  Bell, T. J., Brand, O. J., Morgan, D. J, et al (2018). Defective lung
  function following influenza virus is due to prolonged, reversible
  hyaluronan synthesis. \emph{Matrix Biol} . \textbf{80} , 14--28.
\item
  Cronstein, B. N., Molad, Y., Reibman, J., et al (1995). Colchicine
  alters the quantitative and qualitative display of selectins on
  endothelial cells and neutrophils. \emph{J Clin Invest} .\textbf{96}
  (2), 994--1002.
\item
  Finkelstein, T., Aks, S., Hutson, J. R., Juurlink, D. R, et al (2010).
  Colchicine poisoning: the dark side of an ancient drug. \emph{Clin
  Toxicol} \emph{(Phila)} . \textbf{48} (5), 407-14. doi:
  10.3109/15563650.2010.495348.
\item
  Gonz\selectlanguage{ngerman}ález-Gay, M. A., Mayo, J., Castañeda, S., Cifrián, J. M and
  Hernández-Rodríguez, J (2020). Tocilizumab: from the rheumatology
  practice to the fight against COVID-19, a virus infection with
  multiple faces, \emph{Expert Opinion on Biological Therapy}
  ,\textbf{20} (7), 717-723 doi: 10.1080/14712598.2020.1770222
\item
  Gu, Y., Hsu, A. C., Pang, Z., et al (2019). Role of the innate
  cytokine storm induced by the influenza A virus. \emph{Viral Immunol}
  .\textbf{32} (6), 244--251. doi:10.1089/ vim.2019.0032.
\item
  Hallgren, R., Samuelsson, T., Laurent, T.C., and Modig, J (1989).
  Accumulation of hyaluronan (hyaluronic acid) in the lung in adult
  respiratory distress syndrome. \emph{Am Rev Respir Dis} . \textbf{139}
  , 682--7. doi: org/10.1164/ajrccm/139.3.682
\item
  Han, H., Ma, Q., Li, C., Liu, R., et al (2020). Profiling serum
  cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease
  severity predictors. \emph{Emerging Microbes \& Infections}
  ,\textbf{9} (1), 1123-1130. doi: 10.1080/22221751.2020.1770129
\item
  Lauer, M. E.,~Dweik, R. A.,~Garantziotis, S.,~and~Aronica, M. A
  (2015). The rise and fall of hyaluronan in respiratory
  diseases.\emph{Int J Cell Biol} . 2015: 712507. doi:
  org/10.1155/2015/712507
\item
  Leung, Y. Y., Hui, L. L. Y., and Kraus, V. B (2015). Colchicine ---
  update on mechanisms of action and therapeutic uses.\emph{Semin
  Arthritis Rheum} . \textbf{45} (3), 341--350.
  doi:10.1016/j.semarthrit.2015.06.013.
\item
  Li, B., Feng, F., Yang, G., Liu, A., et al (2020). Immunoglobulin G/M
  and Cytokines Detections in Continuous Sera from Patients with Novel
  Coronaviruses (2019-nCoV) Infection. Available at:
  SSRN:~\emph{https://ssrn.com/abstract=3543609}~or~\emph{http://dx.doi.org/10.2139/ssrn.3543609}
\item
  Liu, Y., Zhang, C.,~Huang, F.,~Yang, Y.,~Wang, F., et al (2020).
  Elevated plasma level of selective cytokines in COVID-19 patients
  reflect viral load and lung injury. \emph{National Science Review} .
  \textbf{7} (6), 1003--1011, doi.org/10.1093/nsr/nwaa037
\item
  Marietta, M., Ageno, W., Artoni, A., De Candia, E., et al (2020).
  COVID-19 and haemostasis: a position paper from Italian Society on
  Thrombosis and Haemostasis (SISET). \emph{Blood Transfusion} =
  Trasfusione del Sangue. \textbf{18} (3), 167-169. doi:
  10.2450/2020.0083-20
\item
  Marques-da-Silva, C., Chaves, M. M., Castro, N. G., et al (2011).
  Colchicine inhibits cationic dye uptake induced by ATP in P2X2 and
  P2X7 receptor-expressing cells: implications for its therapeutic
  action. \emph{Br J Pharmacol} . \textbf{163} (5), 912--926.
\item
  Martinon, F., Pétrilli, V., Mayor, A., et al (2006). Gout-associated
  uric acid crystals activate the NALP3 inflammasome. \emph{Nature}
  .\textbf{440} (7081), 237--241.
\item
  Pascual, E., and Castellano, J. A (1992). Treatment with colchicine
  decreases white cell counts in synovial fluid of asymptomatic knees
  that contain monosodium urate crystals. \emph{J Rheumatol}
  .\textbf{19,} 600--603.
\item
  Rahmati, M., and Moosavi, MA (2020). Cytokine-targeted therapy in
  severely ill COVID-19 patients: Options and Cautions. \emph{EJMO}
  .\textbf{4} (2): 179-181. doi: 10.14744/ejmo.2020.72142
\item
  Ren, L. L., Wang, Y. M., Wu, Z. Q., et al (2020). Identification of a
  novel coronavirus causing severe pneumonia in human: a descriptive
  study. \emph{Chin Med J} . \textbf{133} (9), 1015-1024.
  doi:10.1097/CM9.0000000000000722
\item
  Ruan, Q., Yang, K., Wang, W., Jiang, L., Song, J (2020). Clinical
  predictors of mortality due to COVID-19 based on an analysis of data
  of 150 patients from Wuhan, China. \emph{Intensive Care Med}
  .\textbf{46} (5), 846-848. doi: 10.1007/s00134-020-05991-x.
\item
  Russell, C. D., Millar, J. E., and Baillie, J. K (2020). Clinical
  evidence does not support corticosteroid treatment for 2019-nCoV lung
  injury. \emph{The Lancet} . \textbf{395} (10223), 473-75. doi:
  10.1016/S0140-6736(20)30317-2.
\item
  Shi, Y., Wang, Y., Shao, C., et al (2020). COVID-19 infection: the
  perspectives on immune responses. \emph{Cell Death \& Differentiation}
  . \textbf{27} , 1451--1454. doi:org/10.1038/s41418-020-0530-3
\item
  Wang, D., Hu, B., Hu, C., Zhu, F., Liu, X., Zhang, J., et al (2020).
  Clinical characteristics of 138 hospitalized patients with 2019 novel
  coronavirus-infected pneumonia in Wuhan, China. \emph{JAMA.} {[}Epub
  ahead of print{]}. doi: org/10.1001/jama.2020.1585.
\item
  Xu, Z., Shi, L., Wang, Y., et al (2020). Pathological findings of
  COVID-19 associated with acute respiratory distress
  syndrome.\emph{Lancet Respir Med} . \textbf{8} (4), 420-422. doi:
  10.1016/S2213-2600(20)30076X
\item
  Zhang, C., Wu, Z., Li, J. W., Zhao, H., Wang, G. Q (2020). The
  cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6
  receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the
  mortality. \emph{International Journal of Antimicrobial Agents}
  .\textbf{55} (5), 05954 doi:~10.1016/j.ijantimicag.2020.105954
\item
  Zhou, Y., Fu, B., Zheng, X., Wang, D., Zhao, C., Sun, R., et al
  (2020). Pathogenic T cells and inflammatory monocytes incite
  inflammatory storm in severe COVID-19 patients. \emph{National Science
  Review} . \textbf{7} (6), 998--1002, doi.org/10.1093/nsr/nwaa041
\end{enumerate}

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