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\begin{document}

\title{Multiple organs failure in COVID-19 patients}



\author[1]{Rim Harfouch}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 17, 2024}


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\textbf{Rim M. Harfouch}

Department of microbiology and biochemistry, Faculty of pharmacy,
Al-Sham private university (ASPU), Latakia, Syria.

Correspondence Author's E-mail: r.h.foph.lat@aspu.edu.sy

\textbf{Abstract:}

The outbreak of severe acute respiratory syndrome coronavirus 2
(SARS-CoV2) in December 2019 form Wuhan, China leads to coronavirus
disease 2019 (COVID-19) pandemic. COVID-19 is accompanied by multi-organ
failure in severe patients. The involvement of different organs in
severe patients results in lengthening the hospitalization duration and
increasing the mortality rate. The multi-organ dysfunction is
characterized by acute lung failure, acute liver failure, acute kidney
injury, cardiovascular disease, and as well as a wide spectrum of
hematological abnormalities and neurological disorders. The most
important mechanisms are related to the direct and indirect pathogenic
features of SARS-CoV2. Although the presence of angiotensin-converting
enzyme 2, a receptor of SARS-CoV2 in the lung, heart, kidney, testis,
liver, lymphocytes, and nervous system was confirmed, there are
controversial findings to about the observation of SARS-CoV2 RNA in
these organs. Moreover, the organ failure may be induced by the cytokine
storm, a result of increased levels of inflammatory mediators,
endothelial dysfunction, coagulation abnormalities, and infiltration of
inflammatory cells into the organs. Therefore, further investigations
are needed to detect the exact mechanisms of pathogenesis. Since the
involvement of several organs in COVID-19 patients is important for
clinicians, increasing their knowledge may help to improve the outcomes
and decrease the rate of mortality and morbidity.

\textbf{Keywords:}

Multi-organ failure, coronavirus SARS-CoV-2, Characteristics.

\textbf{Introduction:}

The coronavirus SARS-CoV-2 has infected more than 250 million people and
caused death to over than 5 million, with a worldwide mortality rate of
2\%. Many patients who die from COVID-19 suffer from hyper-inflammation
caused by cytokine storm syndrome (CSS) and associated acute respiratory
distress syndrome {[}1, 2{]}. The antiviral Remdesivir was shown to
reduce the length of hospital stay for COVID-19 patients, but
anti-inflammatory agents have improved survival in these patients
{[}3{]}. The greatest survival rate has been found with glucocorticoids,
which play as immunosuppressive agents, when given to patients with an
oxygen requirement. However, patients treated with glucocorticoids may
fare worse than those who receive standard care in the absence of an
oxygen requirement or systemic inflammation. The selection of patients
and timing of glucocorticoids administration is critical for survival
benefit. Optimal treatment of targeted anti-cytokine therapy to prevent
CSS is suggested earlier without increasing viral replication {[}4{]}.

\textbf{Definition of Cytokine storm syndrome (CSS)}

Cytokine storm syndrome (CSS) is characterized by secretion of large
amounts of cytokines including IL-1\selectlanguage{greek}α, \selectlanguage{english}IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-6, IL-18 and TNF-\selectlanguage{greek}α,
\selectlanguage{english}continuous activation of lymphocytes and macrophages causing immune
dysregulation, and finally, overwhelming systemic inflammation and
multi-organ failure (MOF) with high mortality {[}5{]}.

The term CSS was first used after allogeneic stem cell transplant to
describe the hypercytokinemia (increased blood cytokines) in graft. Many
viral, bacterial and parasitic infections can cause CSS such as
Mycobacterium tuberculosis and Epstein-Barr virus (EBV), which cause
pathological immune activation characterized by elevated cytokines such
as interferon-\selectlanguage{greek}γ \selectlanguage{english}(IFN-\selectlanguage{greek}γ\selectlanguage{english}) in patients with immune defects {[}6{]}.

It has been found that SARS-CoV2 is related to the dysfunction or damage
of liver tissue, and after the lung, it seems to be the second organ.
Acute liver failure (ALF) in COVID-19 patients may result from the virus
invasion, which directly infects liver cells. Some infections of the
upper respiratory tract can influence the liver. The function of the
liver can be considered as a marker of disease progression, as the high
frequency of serious COVID-19 cases showed of liver injury than mild
cases. Several studies on COVID-19 patients primarily have demonstrated
various degrees of raised serum biochemistries of the liver, such as
irregular aspartate aminotransferase (AST), alanine aminotransferase
(ALT), and total bilirubin (TB) levels. In another study, the elevated
level of AST was identified in ICU admitted patients (62\%) more
frequently than other hospitalized patients (25\%). Therefore, the ALF
was predominant in critically ill cases than mild cases. Elevated GGT, a
diagnostic factor of cholangiocyte injury, and ALP levels were reported
in 30/56 (54\%) and 1/56 (1.8\%), respectively among COVID-19 patients
during hospitalization. The higher levels of ALF indicators, especially
AST, are strongly attributed to the higher mortality risk {[}7, 8{]}.

\textbf{Mechanisms of CSS in COVID-19}

The cytokine storm in COVID-19 may vary from the cytokine storms in
other clinical settings. It was revealed by autopsy findings, that the
lymphoid tissues were destroyed in COVID-19 patients, which is rare from
CSS in sepsis and CAR T-cell therapy. Spleen and lymph node atrophy are
observed in patients with COVID-19, while lymphadenopathy and
splenomegaly are more common in other CSS-related diseases. However, the
specific mechanisms for these differences remain unclear and need to be
further studied {[}9{]}.

Coronaviruses (CoVs) are enveloped single-stranded RNA viruses, which
have caused two marked pandemics SARS and MERS {[}9{]}. Spike (S)
proteins of coronaviruses, including the SARS-CoV, facilitate entry into
their target cells via the interaction with angiotensin-converting
enzyme 2 (ACE2), a functional cellular receptor, which is highly
expressed in vascular endothelial cells, alveolar epithelial cells,
intestinal epithelial cells and renal proximal tubular cells. ACE2
suppresses angiotensin II(AngII) and activates the formation of
angiotensin 1--7, a which is a vasodilator heptapeptide. The binding of
the coronavirus spike protein to ACE2 leads to the down-regulation of
ACE2, which in turn results in excessive production of vasoconstrictor
AngII and reduced production of vasodilator angiotensin 1--7.

Furthermore, AngII binds to the angiotensin receptor 1 (AT1R) and plays a
role of proinflammatory cytokine. The AngII-AT1R axis activates NF-\selectlanguage{greek}κ\selectlanguage{english}B and
metalloprotease 17 (ADAM17), which stimulates the production of the
epidermal growth factor receptor (EGFR) ligands and TNF-\selectlanguage{greek}α, \selectlanguage{english}which
activate the IL-6 amplifier (IL-6 Amp), and lead to a hyperinflammatory
status, resulting in increased vascular permeability of the lungs
{[}10{]}.

A retrospective study also found higher plasma concentrations of IL-2,
IL-7, IL-10, IP-10, MCP-1, and TNF-\selectlanguage{greek}α \selectlanguage{english}in intensive care unit (ICU)
patients compared with nonsevere patients, suggesting a cytokine storm
in severe patients {[}11{]}.

\textbf{Diagnosis of CSS in COVID-19}

There is no standard for the diagnosis of CSS related to COVID-19, so
further clinical and laboratory investigations are needed. The basic
principles for consideration of CSS in COVID-19 are the following
presentations:

\begin{enumerate}
\tightlist
\item
  A rapid or sudden regression of multiple organ functions (cardiac,
  liver or renal injury).
\item
  The elevation of systematic inflammatory biomarkers (such as CRP,
  erythrocyte sedimentation rate and serum ferritin).
\item
  A significant decrease of lymphocyte counts.
\item
  The elevation of cytokines, such as IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-2R, IL-6, IP-10, MCP-1,
  TNF-\selectlanguage{greek}α \selectlanguage{english}and IFN-\selectlanguage{greek}γ.
\selectlanguage{english}\end{enumerate}

Clinicians should keep highly alert on the possibility of CSS under
these circumstances. However, that CSS is highly heterogeneous and may
present with unspecific syndromes, the diagnosis of CSS in COVID-19 is
very challenging and the development of a specific diagnostic test that
helps to make the diagnosis of CSS earlier is a high priority for future
research {[}12{]}.

The inflammatory disorders in COVID-19 have been reported in many
studies. COVID-19 causes a decrease of lymphocyte count and an increase
of C reactive protein (CRP), especially in severely ill patients. The
major subtypes of T lymphocytes (T cell) (CD3+ CD4+ T cell and CD3+ CD8+
T cells) are reduced in the COVID-19 and are significantly lower in the
severe cases. Other immune cells, B cell and natural killer (NK) cell,
have more inconsistency in recent studies{[}13{]}.

\textbf{Conclusion:}

COVID-19 mainly in severe cases in addition to lung involves different
organs such as heart, liver, and kidney, as well as hematological and
nervous system, and induce multi-organ failure. SARS-COV2 may directly
invade the host cells of different organs through the ACE2 receptor due
to the presence of this receptor in these organs. On the other hand,
activation of the complement system, cytokine storm, dysregulated immune
responses, coagulation dysfunction, and infiltration of inflammatory
cells in SARS-CoV2 infection can induce the multi-organ failure in these
patients. Consequently, increasing the knowledge on the pathophysiology
of SARS-COV2-induced multi-organ failure may ultimately result in better
ways to treat COVID-19 patients and decrease the associated morbidity
and mortality.

\textbf{References:}

\begin{enumerate}
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