Review Article

SARS-CoV-2: Cytokine Storm and Therapy

1 2 3 4 5
Mir Ibrahim Sajid , Javeria Tariq , Shehar Bano Awais , Zehra Naseem , Samira Shabbir Balouch ,
Sajid Abaidullah6
1 2
Student, Medical College, Aga Khan University, Stadium Road, Karachi, Pakistan; Student, Medical College, Aga
Khan University, Stadium Road, Karachi, Pakistan; 3Student, Medical College, Aga Khan University, Stadium Road,
4 5
Karachi, Pakistan; Student, Medical College, Aga Khan University, Stadium Road, Karachi, Pakistan; Assistant
Professor, Oral & Maxillofacial Surgery, Neela Gumbad, Lahore, Pakistan; 6Professor & Head of North Medicine
Department, KEMU/ Mayo Hospital, Lahore

Abstract
SARS-CoV-2 can vary on a spectrum of an asymptomatic disease process, to a severe stage characterized by a
“Cytokine Storm”. This phenomenon is a pro-inflammatory state marked by an intricate interplay of a
cocktail of chemokines and cytokines. An excessively raised serum levels of cytokines and chemokines can
lead to the development of acute respiratory distress syndrome. This article highlights the pathophysiologic
mechanisms responsible for creating this cytokine havoc and delves into potential therapeutic interventions
Corresponding Author | Prof. Dr. Sajid Abaidullah, Professor & Head of North Medicine Department, KEMU/ Mayo Hospital,
Lahore Email: [email protected]
Keywords | SARS-CoV-2, Cytokine Storm, Cytokines, Chemokines, Therapy, Anti-Viral Therapies, Anti-Inflammatory
Therapies, Review

Introduction SARS-CoV-1 was too identified as a respiratory

pathogen in China in the province of Guangdong, in

T he novel coronavirus (n-CoV) stemmed as a

local epidemic in the Wuhan City of China and
presented as viral pneumonia of unknown etiology.
2002.3 Even though SARS-CoV-1 was a fatal virus,
resulting in a case fatality ratio of 11%, almost double
to that SARS-CoV-2,4 the transmission rate (Ro) was
Once the nasopharyngeal samples were utilized to do significantly lower. This decreased infection poten-
a reverse transcriptase-polymerase chain reaction tial prevented the major spread of the virus, and the
(RT-PCR) testing, it became evident, that this was a viral illness was successfully managed at homes and
mutated version of the notorious Coronavirus family.1 hospitals, without taking a toll on the healthcare
What started as a Wuhan endemic disease, soon systems.
spread to other parts of the world and was declared as
‘pandemic’ by the World Health Organization on 12th MERS was isolated in 2012, when people in the
March 2020.2 To date, 16th July 2020, this virus Middle East started developing respiratory symp-
5
infected more than 8.1 million people with >440,000 toms, especially in Saudi Arabia. This particular
deaths (mortality rate: 5.3%). virus was expected to be a mutated version of the
human coronavirus, with dromedary camels being
Before SARS-CoV-2 was the talk of the town, the the primary zoonotic reserve. MERS reported a
Coronavirus family has been responsible for two significantly higher mortality rate of approximately
major epidemics and several minors. The major ones 50% in 2012; however, it was effectively contained
being, the SARS-CoV-1 and the Middle Eastern by the end of 2013.
Respiratory Syndrome (MERS). Surprisingly, the

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The SARS-CoV-2 infection has resulted in symptoms the diseases, requiring intensive care support and
which vary considerably, from asymptomatic forms mechanical ventilation. The presence of these media-
to acute bilateral pneumonias that requires hospitali- tors suggests activation of Th1 subset of T-Helper
zation. The milder version of the disease presents as Cells, however, it’s of interest to note that as opposed
fatigue, fever and dry cough, with characteristic to the SARS-CoV-1 infection, in addition to Th-1
13
lymphopenia and elevated levels of lactate dehydro- cells, Th-2 Cells are also upregulated. This subset of
genase.6 Computed Tomography (CT) scan of the T-Helper Cells entails IL-4 and IL-10, which are
lung field displays distinctive patterns of bilateral responsible for suppressing an inflammatory
2
homogenous, ground-glass opacities. Patients who response.
lie on the severe spectrum of the disease process may
develop acute respiratory syndrome (ARDS) and This intricate interplay between these families of
require intensive care support with mechanical venti- C&C has dictated the severity of the disease process
lation. A subset of these patients would experience a in SARS-CoV-2. In this review, we highlight the
‘cytokine storm’, whereby an elevated level of pro- critical role of these pro-inflammatory mediators and
inflammatory cytokines, render the patient prone to a discuss various immune-modulating therapies which
rapidly progressive and fatal multiorgan failure.7 have either shown to or hypothesized to, play a vital
role in attenuating this storm.
Cytokine Storm
Chemokines: Chemokines- as their namesake, hold
Cytokine storm refers to a hyper exaggerated, uncont- the ability to strongly attract immune cells- by
rolled, and generalized inflammatory response to a creating an effective chemical gradient,14 and aid
foreign antigen.8 This term was coined after a vigo- immune cells migration from intravascular compart-
rous immune response was generated in hosts who ments into the site of inflammation. Apart from this
underwent graft surgery.9 The cytokine storm has role in immunology, the chemokines are a key player
since been used to describe immensely powerful in the generation of innate and adaptive immunity and
15
immune responses to both infectious and non-infec- cancer metastasis. In response to viral or microbial
tious diseases, especially the respiratory infection infections, they are promptly secreted by a variety of
10 16
caused by the H5N1 influenza virus. cells.

The presence of cytokine storm can be responsible for An example here is of CXCL10, whose role has been
the development of life-endangering ARDS, which illustrated in human and animal models. In these
can account for up to 40% of mortalities, in the setting experimental models, it has shown to play an essen-
17
of induced hypoxemia and interstitial lung infiltra- tial part in the onset of ARDS. In vitro, following
tes.11. ARDS can occur in clinical vignettes of severe experimental infection of the subject, levels of
sepsis, pneumonia of multiple etiologies, and incom- CXCL10 have shown to increase exponentially,
patible blood transfusions. ARDS pathogenesis followed by microvascular damage and ARDS-
entails inflammatory disruption to the alveolo-capi- typical pulmonary edema.18 This rise in CXCL10
llary membrane, leading to greater permeability of levels, in part, have been attributed to the increase in
the lung and deposition of protein-rich pulmonary neutrophils, who release this particular cytokine,
edema fluid into the airspace, resulting in respiratory which in turn recruits more neutrophils- thereby
failure. creating an autocrine loop leading to the development
of severe inflammation of the lungs. Mice models
As shown in the pathogenesis and immune response predict that once CXCL10 levels are neutralized with
studies of SARS-CoV-1 and MERS,12 a higher circu- their respective antibodies, the chances of developing
lating level of cytokines and chemokines (C&C) are extensive lung damage can decline.
19

responsible for inflammation of the lungs. Similarly,

studies1 have shown that SARS-CoV-2 also exhibits Apart from CXCL10, the vital role of CXCL8 in the
20
an exaggerated pro-inflammatory milieu of C&C, development of ARDS has been explored. In the
such as CCL 2, IL-1B, CXCL 10 and IFNγ, rendering settings of ARDS, this chemokine’s elevated levels in
patient more prone to developing the severe form of the blood(21,22) and broncho-alveolar lavage(23) are

Vol 26 | Special Issue | 2020 | Page 244

evidence of its involvement in the pathogenesis of the multiple sclerosis.
respiratory distress syndrome.
Therapeutic Interventions
Interleukins: Interleukins play an essential role in
activating immunomodulatory cytokines and driving Interferon-λ: Interferon- λ (IFN- λ) belongs to the
differentiation between various cell types. These family of interferons (alpha, beta and gamma) and is
mediators, especially IL-6, direct immune cells to the involved in both antiviral and immunomodulatory
locus of infection, especially during the acute phase actions. IF N- λ is known to have a wide range of
of inflammation- stimulating the epithelial cells and effects on both cancerous and non-cancerous cells,
facilitating the production of secondary cytokines.24 and hence considered as a pleiotropic cytokine. It
IL-1β and tumor necrosis factor (TNF-α) facilitate the binds to its receptor on target cells and mediates its
25
increase in production of IL-6, from cells such as actions via JAK-STAT signaling pathway.
B&T lymphocytes, mast cells and fibroblasts,26
27 SARS-CoV-2 primarily targets the epithelial cells of
among others, which in turn activates Th-17. In
the alveolus. IFN- λ is beneficial in immune respon-
patients tested positive for SARS-CoV-2, higher Th-
ses against viruses, tumors and other pathogens; and
17 levels have been visualized,28,29 which can be a
recently has proved effective in “Cytokine storm”
possible stimulant for an increase in IL-6, thereby
when given earlier in the course of infection. IFN- λ
accounting for higher IL-6 levels in these patients.30
mediates the following actions preventing the over-
Given the ability of IL-6 to stimulate multiple genes
activation of humoral immune response and thus
and activate a cocktail of C&C; the plasma levels of
improving symptoms in a COVID patient:
this interleukin have shown to be directly related to
the severity of the disease. 1. It regulates the action of mononuclear phago-
cytes inhibiting the inflammatory action of IFN-
Colony Stimulating Factors (CSF): These proteins
αβ, which is mediated by macrophages.
are associated with inflammatory conditions and are
components of an amplification cascade that ultima- 2. It exerts its antiviral actions on alveolar epithelial
tely increases the production of cytokines by macro- cells via the JAK-STAT pathway leading to acti-
phages at inflammatory sites. Studies in animal vation of several antiviral genes
models have demonstrated that depletion of CSF’s 3. Inhibits the recruitment of neutrophils at the
can provide a therapeutic advantage in inflammatory inflammatory site
conditions, such as SARS-CoV-2.
However it isn’t known to reduce the mortality and is
Tumor Necrosis Factor α (TNF-α): Tumor necrosis only used to reduce viral load during the early
factor is a cytokine released from immune cells in the manifestation of the disease since its usage in a later
acute inflammation and infection phase and remains a course isn’t beneficial as high serum levels of IFN- λ
central cytokine in viral diseases. It's relation to the are associated with severe ARDS;
pathogenesis of several chronic inflammatory, and
1. It increases the production of IL-6 by monocytes
autoimmune diseases have been expressed over the
years. 2. It up-regulates the expression of MHC class I and
II on various leukocytes and epithelial cells.
Interferons: Interferons belong to a class of immune
mediators which have shown to play a pivotal role in Corticosteroid Therapies: Corticosteroids (particu-
the generation of innate immunity following a viral larly glucocorticoids) are steroid hormones used
infection. This phenomenon entailsbinding to speci- mainly to suppress inflammation in several diseases
fic host receptors and expressing genes which encode like asthma, allergy, septic shock rheumatoid arthri-
for proteins responsible for the production of anti- tis, inflammatory bowel disease, and multiple sclero-
viral and immune-modulating responses. Perhaps for sis. They are widely used to alleviate lung injury
this very reason, interferons have been used over the caused by severe community-acquired pneumonia
years in the treatment of viral (e.g. chronic hepatitis) because of their anti-inflammatory actions, and hence
and non-viral infections such as lymphoma and also administered in COVID patients presenting with
associated pneumonia leading to ARDS.

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However the therapeutic role of glucocorticoids for critically ill SARS-CoV2 infected patients during the
viral pneumonia caused by H1N1, MERS, SARS30 earlier course of the disease. Chen and colleagues
remains controversial due to their adverse effects such found that 27% of 99 Wuhan patients who recovered
as; (osteoporosis, skin atrophy, diabetes, abdominal from SARS-CoV-2 received IVIG treatment(30).
obesity, glaucoma, cataracts, avascular necrosis and Experiments conducted by Jawhara in Wuhan sugges-
secondary infection, growth retardation, and hyper- ted the effective usage of IVIG which neutralizes
tension); which seemingly outweigh the potential SARS-CoV-2 virus; with a much greater efficacy if
beneficial effects. Although corticosteroids served as IgG pool is collected from the plasma of donors who
the prime immunomodulator during the SARS-CoV-1 are residents of the same city and are previously
epidemic in 2003 where it markedly reduced the infected by COVID to yield a specific immune res-
mortality rate; its usage is based on dosage, duration ponse. In an experiment conducted by Diez using
and timing of intervention of glucocorticoid therapy. IVIG products, significant cross-reactivity was noted
to S1 protein of SARS-CoV2, which is responsible for
When used earlier in the course of SARS-CoV-2 the binding of the SARS virus to host cell.
infection, Corticosteroids (CS) enhance the viral load
in plasma by decreasing the clearance of virus due to IVIG mediates its immune response via multiple
early immune-suppression; thus leading to worsening mechanisms:
of the disease. Hence, CS is used in critically ill
patients trapped in a cytokine storm (such as ARDS, 1) It blocks the cocktail of pro-inflammatory cyto-
acute cardiac injury, renal failure, and patients with kines and leukocyte adhesion molecules, thereby
higher serum levels of D-Dimer); whereby it prevents ameliorating the Th1 and Th17 T-Helper subsets
pulmonary fibrosis and occurrence of severe ARDS and suppressing the levels of autoantibodies.
via its anti-inflammatory effects. Therefore appro- 2) It induces COX-2 dependent PG-E2 production
priate use of low-dose CS administered timely and in the dendritic cells
given for short duration, is known to increase the 3) Reduction of IL-6 levels and promotion of anti-
survival rate of severely ill patients with SARS- inflammatory cytokines such as IL-10
CoV2, shortens the stay in ICU and minimizes the 4) Upregulating the expressions of PPARγ, which
need for ventilator support. mediates anti-inflammatory responses in degra-
ding inflammation in the body. Similarly, TLR-4
Recently conducted randomized clinical trials didn’t
expression, which mediates the inflammatory
yield a conclusive positive effect, and hence WHO
response, was found to be reduced.
did not recommend the usage of systemic glucocor-
ticoids in SARS-CoV-2 patients. However, evidence Given the ability of CS in amplifying passive
suggests that methylprednisolone 1–2 mg/kg per day immunity and altering systemic inflammatory
no more than 7 days, along with to TCZ treatment, responses, a high dose IVIG may be considered an
proved beneficial during cytokine storm. excellent choice in patients who worsening in the
initial stages of SARS-CoV-2.
Intravenous Immunoglobulins:IVIG consists of a pool
of IgG obtained from the blood of thousands of The IVIG was widely used as an alternative in the
healthy donors and is not only used to treat several treatment of serious influenza-related pneumonia,
autoimmune and inflammatory diseases such as although there are concerns about its therapeutic
dermatomyositis, Kawasaki disease, multiple sclero- effect on SARS-CoV-2 pneumonia, given the
sis, lupus, chronic lymphocytic leukemia, and idiopa- inclusion of the seventh version of the guidelines
thic thrombocytopenic purpura; but also used to specifying that it can be recommended for use in
(21)
suppress several viral and bacterial infections . The patients with acute illness and critical condition.
immunomodulatory role of IVIG in immunosupp- Clinical intravenous immunoglobulin administration
ressed individuals led to several studies and interven- has enabled rapid clinical improvement, as demons-
tions on SARS-CoV-2 patients yielding positive trated by the need for short respiratory support with
results with good tolerance. Hence it’s suggested to CPAP, improved blood &gas levels and radiological
use a high dose of IVIG (0, 3– 0, 5 g/kg) for 5 days in imaging.

Vol 26 | Special Issue | 2020 | Page 246

Briefly, following IVIG treatment, the health and IL-6 Antagonists: IL-6 receptor antagonist,
respiratory status of all patients enhanced, and the Tocilizumab (TCZ) is a monoclonal antibody that
oxygen saturation levels increased, resulting in the inhibits the inflammatory response mediated by IL-6
patients being extubated earlier with noticeably better via binding to soluble and membrane-bound IL-6
chest radiographs(50). Eventually, immunotherapy receptors (sIL-6R and mIL-6R). It is not only used for
combined with resistant IgG and antiviral therapies autoimmune rheumatic diseases (e.g., Rheumatoid
may provide effective treatment against SARS-CoV- arthritis) but also for treating Cytokine release synd-
2. By enhancing the immune response in newly rome (CRS) induced by chimericantigen receptor T-
infected patients, these antibody IgG antibodies cell (CART) therapy(13). Since serum IL-6 levels are
obtained from recovering patients should help treat markedly elevated in critically ill SARS-CoV-2
patients with SARS-CoV-2(24). patients suffering from cytokine storm and ARDS;
TCZ has potential therapeutic effects in SARS-CoV2
IL-1 Family Antagonists:IL-1 family consists of IL- infection. Retrospective studies conducted by Wei
1β, IL-18, and IL-33 that play a key role in favoring Haiming in China demonstrated that usage of TCZ
inflammation during the cytokine storm(51). IL-1 enhanced oxygenation, reduced fever, resolved lung
signaling is involved in the acute phase of infection lesions and improved blood lymphocytes and serum
and also affects the differentiation of lymphocytes, CRP levels(21). Hence, TCZ is used to treat critical
particularly Th17 cells. The isoform IL-1β is known cases of SARS-CoV2 because of its high efficacy in
to play a role in SARS-CoV2 infection, particularly CRS. However, it could also lead to several adverse
aggravating lung-related pathology, i.e. ARDS and effects like hepatotoxicity, hypertriglyceridemia and
cause pyroptosis via IL-1β(28). opportunistic bacterial or fungal infections. To treat
CRS associated with SARS-CoV-2, a dosage of 8
Hence IL-1β antagonists can be used to treat the
mg/kg IV is recommended per day.
cytokine storm, thereby increasing survival in SARS-
CoV2 patients, especially those suffering from severe TNF-α Blockers:TNF-α is a key inflammatory cyto-
sepsis. Anti- IL-1β therapy is based on the inhibition kine obtained mainly from the monocytes, fibroblasts
of different mechanisms that mediate IL-1β signa- and endothelial cells. TNF mediated immune response
ling. These include: is vital for several viral infections like influenza,
smallpox; however, markedly raised levels as seen in
1) Anakinra: A modified IL-1 receptor antagonist
SARS-CoV-2 patients have been associated with lung
with a half-life of 4-6 hours, used especially in
injury or ARDS. TNF-α blockers are often used for the
COVID patients with sepsis. Anakinra’s pres-
treatment of rheumatoid arthritis, ankylosing spondy-
cribed adult dosage ranges from 100 to 200 mg
litis, and psoriatic arthritis(21). Multiple TNF-α inhibi-
daily to 100 mg three days a week; whereas, in
tors used in studies involving animal models showed
the pediatric population, the drug dosage is
the potential role of Anti-TNF therapy in lung injury
recommended at 1 mg/kg daily. Empirical infor-
and ARDS, thus reducing SARS associated mortality
mation has demonstrated that tocilizumab-
in mice; however, its efficacy in humans is still not
refractory CRS with clinical characteristics
conclusive. Evidence supporting the success of TNF-α
similar to HLH / MAS secondary to CAR T cell
receptor trap (Etanercept) in treatment of CRS
therapy is effectively modulated by Anakinra.
secondary to CART is also documented; however,
2) Rilonacept*: A receptor trap trials regarding its use in SARS-CoV-2 associated
3) Canakinumab*: An anti-IL-1β antibody cytokine storm didn’t yield positive results yet. TNF-α
inhibitors are also used for TEN (Toxic epidermal
*Use of Rilonacept and Canakinumab so far haven’t
necrolysis) and due to similarities of TEN with severe
been seen in the treatment of SARS-CoV-2.
SARS-CoV-2 infection, in terms of the pathogenesis
Anti-IL-1β treatment is safe and is strongly correlated and clinical features; usage of TNF-α inhibitors is
with a reduction in neutrophils count that can be clini- suggested for SARS-CoV-2 infection.
cally significant as a high NLR (neutrophil to leuko-
Janus Kinase (JAK) Inhibitors: SARS-CoV-2 is
cyte ratio) predicts poor SARS-CoV-2 prognosis.
known to mediate its effects by binding to an ACE-2

Vol 26 | Special Issue | 2020 | Page 247

receptor present on cell-surface in heart, alveoli of Interferon αβ-inhibitors may not be as straight-
lungs, kidneys and blood vessels. It thenenters the cell forward and is highly dependent on the time it is
via endocytosis which is regulated by AP2-associated given. If used early on in the disease process, it may
protein kinase I (AAK1). Baricitinib (a JAK/STAT decrease the body’s immune response to the viral
inhibitor) is also an AAK1 inhibitor and hence can load, which may be harmful instead of beneficial.
suppress the COVID symptoms by hindering the Therefore, the use of INF- αβ inhibitors may only be
entry of the virus into the cell. However, JAK inhibi- helpful if used later in the disease timeline.
tors also inhibit the production of IFN, which is nee-
ded for anti-viral actions, thus suppressing immunity. Chloroquine: Chloroquine-an orally administered
Therefore, further investigation is required regarding antiviral drug, previously used for infections such as
the safe usage of JAK inhibitors in SARS-CoV-2 Malaria, has been recently suggested as a possible
infected patients.22 treatment for SARS-CoV-2. The drug has significant
infiltration into various organs of the body, including
Neutrophil-Elastase Inhibitors (NES): Patients the lungs. It works by:
severely infected with SARS-CoV-2 usually suffer
from CRS and ARDS. The infection has shown to 1. Inhibiting virus-endosome fusion by increasing
induce lymphocytopenia; however, due to increased the endosomal pH
inflammatory response, a simultaneous increase in 2. Inhibiting the production of pro-inflammatory
neutrophils resulting in a high Neutrophil-to-Lym- cytokines (IL-6 and TNF α)
22
phocyte ratio has been observed. Neutrophils 3. Interfering with the glycosylation of certain
produce ROS (Reactive oxygen species) and protea- cellular receptors.
ses (mainly Elastase which activates the S protein on
SARS-CoV-2), leading to ARDS. Hence NES would All of these processes may prevent the development of
result in inhibition of Neutrophil Elastase production, ARDS, which has shown to occur in SARS-CoV-2
preventing damage to alveoli and thus preventing patients. The use of Chloroquine stems from studies
ARDS. Also, it inhibits the activation of S protein and done on cells infected with SARS-CoV-1. These stu-
hence hindering the binding of SARS-CoV-2 on the dies have demonstrated a prophylactic and therapeutic
(23)
host cell. However, clinical trials are needed to role of Chloroquine in the viral disease .
provide supportive evidence for the usage of NES as a
Multiple clinical trials in China have led to an expert
potential therapeutic agent in SARS-CoV-2 infection.
consensus on the use of Chloroquine in individuals
Interferon- αβ inhibitors: Interferon- αβ works as aged 18-65. However, this drug is contraindicated in
an immune modulator via the JAK/STAT pathway, by combination with other drugs that have shown to
inducing interferon production- which leads to the prolong the QT interval and in pregnant women.
recruitment of macrophages and other cells of the Overall, Chloroquine is a safe, old and well-resear-
innate immune system,leading to an anti-viral host ched drug which can potentially be used to treat
response. However, studies on Influenza virus have patients with SARS-CoV-2.
shown that an excessive release of Interferon αβ
Ulinastatin: Ulinastatin (Urinary trypsin inhibitor) is
further into the disease process, leads to apoptosis of
a naturally occurring protease inhibitor which is
T cellsand alveolar epithelial cells through Fas-Fas
present in our bodies and works by phosphorylating
ligand and Death receptor-5- thereby preventing viral
the nuclear factor-NF-kB. In this manner, it helps
clearance. In addition to the inability of generating
remove oxygen free radicals from the body and play
effective viral clearance, the apoptosis of epithelial
an anti-apoptotic role necessary to treat infections
cells may damage the tissues and vessels of the
22 such as acute pancreatitis. This drug has also shown to
lungs.
aid in the release of IL 10- helping generate an anti-
Early release and moderate levels of Interferon- αβ inflammatory response.23
are shown to be effective against viruses. Conversely,
In hospitalized patients with SARS-CoV-2 infection;
high levels of INF αβ enhance apoptosis but do not
a treatment regimen consisting of high dose Ulinas-
have any other anti-viral effects. Hence, the use of

Vol 26 | Special Issue | 2020 | Page 248

tatin has shown it be a safe-to-use drug with multiple therapies for SARS-CoV-2.
advantages. All of these patients have shown a
various degree of resolution in terms of primary lung Stem Cell Therapy: Mesenchymal stem cells
lesions, with approximately 66.7% of them no longer (MSCs) although preferred from the bone marrow,
requiring oxygen therapy. With no adverse effects can be acquired from different human tissues, for
reported, Ulinastatin can potentially be a likely treat- example, peripheral blood, adipose tissues and birth
ment option for SARS-CoV-2. associated tissues (placenta, umbilical cord, amniotic
fluid).
Oxidized Phospholipids (OxPL): During infec-
tions, the local production of reactive oxygen species MSCs are capable of secreting Keratinocyte growth
can lead to oxidation of phospholipids in the lungs, factor, Hepatocyte growth factor, epidermal growth
including unsaturated phosphatidylcholine (present factor, angiopoietin-1, IL-1 receptor antagonist (IL-
in the surfactant) and the subsequent formation of 1RA), and prostaglandin E2. These factors have
oxidized phospholipids (OxPL). OxPL have been shown to heal injured lung tissue, resist fibrosis and
shown to increase the production of pro-inflamma- cause an increased surfactant production. MSCs also
tory cytokines through increased activation of the bring about the release of IL-10 by activating Th-2
TLR-4-TRIF-TRAF6 signaling cascade, leading to subset, which has anti-inflammatory properties.24
cytokine storm and subsequently, an acute lung
Studies have assessed the therapeutic use of MSCs in
injury. This phenomenon was seen in individuals
acute lung injury. Laboratory tests and imaging of a
infected with SARS-CoV-1 and H1N1, whereby an
woman infected with SARS-CoV-2 has showed very
accumulation of OxPL has been seen in the lungs, in
effective results after 21 days of treatment with stem
the setting of a cytokine storm.23
cell therapy. Another study in Beijing in February
Etirovan, a TLR -4 inhibitor has been revealed to 2020 was successful in improving the clinical symp-
block not only the cytokine storm but also the further toms of all patients after only two days of the inter-
production of OxPL, decreasing the rate of acute lung vention. While stem cell therapy looks promising,
injury and mortality in mice infected with Influenza more clinical trials on humans will be necessary to
virus. Similarly, the accumulation of OxPL in patients determine the optimal dose and route of delivery as
with SARS-CoV-2 may be a plausible mechanism in well as the patients who can be selected for this
causing acute lung injury. Therefore, the use of TLR- therapy.25
4 inhibitors or OxPL can prove to be beneficial in
Plasma Therapy: Treatments aiming at the reduc-
preventing lung injury in those infected with SARS-
tion of the inflammatory cascade and its associated
CoV-2.
mediators have also been initiated, primarily during
Sphingosine-1-phosphate receptor 1 agonist the initial period of this disease’s pathogenesis. The
therapy: Sphingosine-1-phosphate-receptor 1 primary aim of such treatment regimens involves
(S1P1) after binding to its receptor on pulmonary cleansing the serum via interchanging a person’s
endothelial cells, inhibits the release of excessive pro- plasma or by blood filtration to control uncontrolled
inflammatory C&C, preventing the damage that inflammation by inhibiting the ‘cytokine storm’ by
results from a cytokine storm. The use of Sphingosine changing the levels of pro and anti-inflammatory
25,26
-1-phosphate receptor agonists in mice has shown to cytokines. Moreover, patients suffering from
shield the lung against injury caused by the Influenza coronavirus experience imbalances in their fluid
Virus. They do so by inhibiting cytokine storm, homeostasis, involving ionic and acid-base imba-
migration of dendritic cells and T cell proliferation. lance. Thus, performing plasma exchange proved to
be efficacious in improving the fluid balance,
On that account, since the same cells of the lung are particularly among those having a severe illness.26
involved in SARS-CoV-2, and the same pro-infla-
mmatory cytokines are released (IL-6, TNF- α) which Sepsis and its associated system-wide inflammatory
cause lung injury, Sphingosine-1 phosphate receptor cascade, negatively alters the blood flow through
1 agonists may be further studied as potential capillary beds, resulting in organ ischemia and
26
failure. Thus, patients experiencing sepsis or septic

Vol 26 | Special Issue | 2020 | Page 249

shock can receive renal replacement therapy through and childbirth: a systematic review of recent evi-
adsorption of inflammatory cytokines and pathogenic dence. Biomedica2020;36:145-57.
proteins via sorbents composed of polystyrene copo-
27 Table 1: Comparison of Predictive Values (Bishop Score
lymer beads. Studying this treatment modality, a
vs. Cervical Length)
study by Zuccari and colleagues28 demonstrated that
Stage of Characteristic
IL-8 decreased considerably in the first day following Treatment options
disease Features
a plasma exchange, while procalcitonin reaches Initial Marked by viremia Mild disease: IFN- λ,
lower levels after the first day. In addition to this small acute NES inhibitors,
phase Chloroquine
vessel circulation with regards to vascular density Severe disease:
and blood flow in the sublingual region also Intravenous
improved. Immunoglobulins
(IVIG), Stem cell
A prior meta-analysis on plasma therapy in corona- therapy, Plasma cell
therapy
virus patients has shown promising results as it leads Prevent Cytokine storm:
to early discharged and decreased case fatality rates if S1P1 antagonists,
initiated during the period of initial symptoms. More- Oxidized Phospholipids
over, viral burden decreases significantly post plasma Accelerat Inflammation and In cytokine storm:
ion phase involvement of other IFN- αβ inhibitors, IL 1β
-

therapy. Further benefits of this treatment include the organs like heart, antagonists,
low risk of severe complications, with fever and lung, Gastrointestinal IL-6 antagonists, TNF- α
shivering being the currently reported consequen- tract progressing to blockers, JAK inhibitors
ces.28 In addition to this, plasma from treated complications such as Ulnistatin
“Cytokine storm” In severely ill patients
coronavirus patients and plasma therapy can be used marked by with ARDS:
to provide passive immunity to currently infected progressive Corticosteroids
symptomatic patients or serve as post-exposure pro- lymphocytopenia and
elevated serum
phylaxis.29 Shen and colleagues30 also demonstrated
cytokines
an increase in coronavirus-specific immunoglobulin Final Resolution of Continuation of the
levels and resolution of ARDS among patients, while Recovery symptoms therapy with dose
Bloch and colleagues also included evidence of phase adjustments
disease termination in imaging. 3. J.S. Peiris KYY, A.D. Osterhaus, K. Stöhr. The severe
acute respiratory syndrome. N Engl J Med. 2003;
Concluding Remarks 349(25):2431-41.
Clinical and laboratory findings have led to thera- 4. Chan‐Yeung M, Xu R. SARS: epidemiology. Respi-
peutic interventions based on the course of the rology 2003;8(9):14.
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