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REVIEW ARTICLE
Interleukin-6 Perpetrator of the COVID-19 Cytokine Storm
Jyoti Shekhawat
1
•Kavya Gauba
1
•Shruti Gupta
1
•Purvi Purohit
1
•
Prasenjit Mitra
1
•Mahendra Garg
2
•Sanjeev Misra
3
•Praveen Sharma
1
•
Mithu Banerjee
1
Received: 19 January 2021 / Accepted: 8 June 2021
ÓAssociation of Clinical Biochemists of India 2021
Abstract COVID-19 has emerged as a global pandemic. It
is mainly manifested as pneumonia which may deteriorate
into severe respiratory failure. The major hallmark of the
disease is the systemic inflammatory immune response
characterized by Cytokine Storm (CS). CS is marked by
elevated levels of inflammatory cytokines, mainly inter-
leukin-6 (IL-6), IL-8, IL-10, tumour necrosis factor-a
(TNF-a) and interferon-c(IFN-c). Of these, IL-6 is found
to be significantly associated with higher mortality. IL-6 is
also a robust marker for predicting disease prognosis and
deterioration of clinical profile. In this review, the pivotal
role played by IL-6 in the immuno-pathology of COVID-
19 has been illustrated. The role of IL-6 as a pleiotropic
cytokine executing both pro and anti-inflammatory activi-
ties has been reviewed. ADAM 10, a metalloproteinase
switches the anti-inflammatory pathway of IL-6 to pro
inflammatory hence blocking the action of ADAM 10
could be a new therapeutic strategy to mitigate the proin-
flammatory action of IL-6. Furthermore, we explore the
role of anti-IL6 agents, IL-6 receptor antibodies which
were being used for autoimmune diseases but now are
being repurposed for the therapy of COVID-19.
Keywords Interleukin-6 SARS-CoV-2 Cytokine storm
ACE2 Receptor Monoclonal antibodies
Introduction
Coronavirus Disease 2019 (COVID-19) was first reported
in Wuhan, China, as a cluster of pneumonia cases with
unknown etiology [1]. Since then, it has emerged as an
outbreak and caused global havoc. On 30th January 2020,
the disease had been declared as a Public Health Emer-
gency of International Concern (PHEIC) by the World
Health Organization (WHO) [2]. The etiological agent of
the disease was soon identified as a member of the coro-
navirus family called Severe Acute Respiratory Syndrome
Coronavirus 2 (SARS-CoV-2). Preceding the COVID-19
pandemic, two other outbreaks were witnessed in the
twenty-first century, namely the Severe Acute Respiratory
Syndrome (SARS) and the Middle East Respiratory Syn-
drome (MERS) caused by different pathogenic members of
the coronavirus family (SARS-CoV and MERS-CoV) [3].
&Mithu Banerjee
mithu.banerjee.3@gmail.com
Jyoti Shekhawat
jyotikanwar1000@gmail.com
Kavya Gauba
kavyagauba17@gmail.com
Shruti Gupta
drshrutiga@gmail.com
Purvi Purohit
dr.purvipurohit@gmail.com
Prasenjit Mitra
prasy4u@gmail.com
Mahendra Garg
mkgargs@gmail.com
Sanjeev Misra
misralko@gmail.com
Praveen Sharma
praveensharma55@gmail.com
1
Department of Biochemistry, All India Institute of Medical
Sciences, Jodhpur 342005, India
2
Department of Endocrinology, All India Institute of Medical
Sciences, Jodhpur 342005, India
3
Department of Surgical Oncology, All India Institute of
Medical Sciences, Jodhpur 342005, India
123
Ind J Clin Biochem
https://doi.org/10.1007/s12291-021-00989-8
The immune pathogenesis, genome sequences and evolu-
tionary phylogenetic relationship of SARS-CoV-2 with
other coronaviruses have been fully elucidated [4]. The
mortality rate of COVID-19 infection is 6.7% which is
comparatively lower than for both SARS (10%) and MERS
(35%) [5]. The disease presents itself similar to common
flu with symptoms including fever, cough, nausea, head-
ache, myalgia, dyspnea, pneumonia etc., some are
asymptomatic while others may experience ARDS (actute
respiratory distress syndrome) [6]. However, individuals
with co-morbidities such as diabetes, hypertension or old
age may experience exacerbated symptoms [7]. Inter-
leukin-6 is a multifactorial cytokine which plays role in
both pro-inflammatory pathways as well as anti-inflam-
matory pathways. In COVID-19 it has been reported to be
elevated in from mild to critically ill patients. It is also
correlated with disease patheogenesis and its progression
[8].
COVID-19 Pathogenesis
The transmission of SARS-CoV-2 is primarily via aerosol
droplets or contact with an infected person. Upon entry of
the viral particle inside the lungs, it attaches itself to cells
of the respiratory tract after which it is endocytosed into the
host pulmonary cell. The crystallised structure of SARS-
CoV-2 shows the presence of surface spike (S) proteins,
similar to those found in SARS-CoV, which binds to the
Angiotensin-converting enzyme-2 (ACE-2) receptor pre-
sent on the alveolar epithelial cells and it is responsible for
conversion of Ang-II (angiotensin-II) to angiotensin 1–7
(Ang 1–7) in the renin angiotensin system [9]. The ACE2
receptor is crucial for the virulence of the virus as cells
lacking them are found to be resistant to infection by
SARS-CoV-2 infection [10]. ACE2 are not only expressed
in both upper and lower respiratory tract but also in cell of
small intestine, pancreas, kidneys, heart, oesophagus,
bladder and brain making them all vulnerable to infection
by SARS-CoV-2 [11]. It is noteworthy that normal ACE2
expression is not very high in upper respiratory tract and is
only transiently enhanced in response to infection with
SARS-CoV-2 for increased transmissibility of the virus
[12]. Also, ACE2 expression in other tissues explains the
development of multi-organ failure that often accompanies
severe COVID-19 infection [13,14]. After viral entry,
spike protein is cleaved by transmembrane serine protease
2 (TMPRSS2) and then released by another protease called
Furin, thus promoting viral entry through endosomal
pathway as depicted in Fig. 1[15]. The spike fusion pep-
tide released by Furin then executes the virus-cell fusion
contributing to viral spread and persistence. The low pH of
the endosomal vesicle favours the delivery of viral genome
into the cytoplasm allowing it to replicate and assemble
into virions which are then released from the cell [16]. The
infected cells are then subjected to apoptosis or necrosis,
triggering an inflammatory response which is characterised
by production of pro-inflammatory cytokines and simulta-
neous recruitment of macrophages and Th cells. Th1
(CD4 ?) cells regulate antigen presentation and Interferon-
cproduction while Th17 cells induce secretion of IL-17,
IL-21 and IL-22. This leads to further recruitment of other
inflammatory cells such as neutrophils and CD8 cells [17].
Spread of infection into circulating immune cells causing
their apoptosis, results in lymphocytopenia. A reduction in
the total number of T cells results in a hyperinflammatory
state in the body due to over secretion of cytokines and
chemokines, termed as CS. CS, if untreated, may aggra-
vated to other life-threatening scenarios such as Acute
Respiratory Distress Syndrome (ARDS), Macrophage
Activation Syndrome (MAS) and Secondary Hemophago-
cytic Lymphohistiocytosis (sHLH).
Cytokine Storm Associated with SARS-CoV-2
Infection
Hyper-cytokinemia or ‘‘Cytokine storm (CS)’’ in COVID-
19 is marked by an aggressive hyperinflammatory immune
response and is the major hallmark of the disease [18]. It is
a conglomeration of inflammatory symptoms induced by
the activation of T-cells, macrophages and subsequent
release of cytokines, which further potentiates recruitment
and activation of other immune cells [19]. It is hypothe-
sised that immune responses associated with MAS/HLH
might be the driving force for COVID-19 related CS (20).
CS is characterised by elevated serum levels of pro-in-
flammatory cytokines and chemokines, namely, IL-1, IL-6,
IL-12, IFN-cand TNF-a[8,20,21]. Elevated levels of
these pro-inflammatory cytokines in severe patients might
be useful as biomarkers of the disease prognosis and can be
used as potential targets for therapy [22]. Several studies
have suggested that CS, directly or indirectly, correlates
with lung injury, ARDS, multi-organ failure, need for
mechanical ventilation and unfavourable disease prognosis
in COVID-19 [22,23].
Along with cytokines, elevated levels of serum crea-
tinine, lactate dehydrogenase, C-reactive protein, procal-
citonin, ferritin, D-dimer and White Blood Cell count are
the lab parameters that portend impending respiratory
failure and need for supplementary oxygen in COVID-19
patients [23].
Of all the cytokines mediating the CS, IL-6 has been
proposed as the most accurate predictor of disease course
as well as mortality in SARS-CoV-2 infected patients.
Moreover, therapeutic implications targeting IL-6 or its
Ind J Clin Biochem
123
signalling have shown success in treatment of COVID-19
patients.
IL-6 in Viral Immunity: A Double-Edged Sword
Interleukin-6 is a pleiotropic cytokine produced in response
to tissue damage by viral infections. The IL-6 signaling
cascade is a highly regulated and dynamic process with
well-defined pro and anti-inflammatory effects mediated by
the Trans and Classical signal transduction respectively
[24]. IL-6 homeostasis governs the outcomes of immuno-
protection versus immunopathology of viral infections.
As a part of pro-inflammatory functions, Th17 activation
and differentiation are dependent on IL-6. Rapid induction
of granzyme B and perforin expression in CD8
?
T cells
which eliminates the viral pathogen is also dependant on
IL-6 trans-signalling along with IL-15 [25]. The activation
of these Cytotoxic T Lymphocytes (CTLs) then stimulates
the release of TNF-aand IFN-cwhich modulates
neutrophil migration [26]. Furthermore, IL-6 serves as an
endogenous pyrogenic cytokine serving as a thermoregu-
lator and amplifying the immune surveillance in viral
infections [27]. Early IL-6 signalling is known to promote
IL-27 dependant maturation of regulatory T cells in lungs
and limit viral immunopathology. Removal of either IL-6
or IL-27 is known to enhance viral infection. During res-
piratory viral infections, IL-6 acts as a driver of virus-
induced immunopathology by inducing the production of
IL-27 by monocytes and macrophages in the respiratory
tract, promoting the local maturation of T cells [28].
Studies on IL-6 deficient mice infected with H1N1 influ-
enza virus have shown that IL-6 is required to heal acute
lung injury caused by influenza A virus [29]. Mice lacking
IL-6 displayed reduced ability to mount an anti-viral
immune response which was further associated with
enhanced proliferation and migration of lung fibroblasts.
These mice exhibited a compromised recruitment of mac-
rophages in the lungs leading to reduced phagocytosis of
viruses in lung macrophages [30].
Fig. 1 SARS-CoV-2 entry into target cell. The virus binds to ACE2
receptor followed by cleavage of spike protein by a serine protease,
TRMPSS2. This cleavage triggers the internalization of the virion
particle through endocytosis. Then another protease called Furin acts
to release the spike fusion peptide facilitating viral entry into host.s
Ind J Clin Biochem
123
On the other hand, as part of anti-inflammatory func-
tions, IL-6 is involved in the progression of viral diseases,
ultimately favouring viral persistence in infected hosts. IL-
6 promotes Th2 response while inhibiting Th1 cell prolif-
eration [31]. It does so by two mechanisms: Firstly, by
stimulating CD4 ?T cells to secrete IL-4 thus directing
response to Th2 and secondly, by suppressing IFN-c
expression by CD4 ?T cells which normally promotes
Th1 polarization and is essential for an effective antiviral
response [32]. IL-6 promotes Th17 cell differentiation
leading to the production of IL-17 which upregulates the
expression of anti-apoptotic molecules enhancing the sur-
vival of the virus in infected cells. IL-17 also blocks the
destruction of target cells by CTLs. Neutralization of IL-17
augments virus clearance and enhances lysis by CTLs
leading to elimination of virus-infected cells [33]. IL-17
also promotes migration of neutrophils to the lungs leading
to tissue damage during inflammation (35). This infiltration
by neutrophils leads to the development of Neutrophil
Extracellular Traps (NETs) in the lungs which contributes
to organ damage and COVID-19 related ARDS [34]. IL-6
produced by TLR-mediated signalling counter-regulates
the CD8 ?T cell responses leading to T-cell dysfunction
in chronic viral infections [35]. It works synergistically
with IL-1band TNFato induce trypsin upregulation in
influenza virus-cytokine-trypsin cycle and this helps virus
to replicate by activating matrix metalloproteinases that
causes degradation of extracellular matrix. This IL-6
mediated trypsin upregulation may account for multi-organ
failure in influenza virus infection [36].
IL-6 binds to its membrane-bound receptor to initiate the
classic-type signalling which adds to anti-inflammatory
processes as illustrated in Fig. 2. Cells lacking expression
of membrane-bound IL-6 receptors are part of trans-sig-
nalling, mediated by soluble type receptor of IL-6 (sIL-6R)
and gp130, responsible for pro-inflammatory functions of
IL-6 [38]. sIL-6R is generated by the action of metallo-
proteinases known as ADAM10 and ADAM17 and alter-
native splicing mechanism [37]. Thus, therapeutic
approaches need to be designed in a way that would
attenuate the pro-inflammatory response without affecting
the classic (anti-inflammatory) signalling process of IL-6
[38,39]. Since ADAM10 plays a key role in switching
from the classical (anti-inflammatory) to trans signalling
pathway (pro-inflammatory), strategies to block its action
holds a lot of promise in preventing the cytokine storm
[37]. A fusion protein Sgp130-Fc has been developed from
the conjugation of sgp130, a natural inhibitor of trans
signalling cascade, and Fc region of IgG human antibody
[40,41]. This molecule specifically blocks trans signalling
without effecting classic signalling pathway [42].
Therefore, the debatable role of IL-6 as an anti- and pro-
inflammatory cytokine requires vigilant evaluation for it to
be considered as an effective therapeutic target in SARS-
CoV-2 infection.
Fig. 2 The classic and the
trans-signalling pathways are
mediated by the membrane-
bound form of IL-6 receptor
(mIL6R) and soluble form of
IL-6 receptor (sIL6-R)
respectively. Monoclonal
antibodies against IL-6 and IL-
6R can inhibit these pathways.
Similarly, Janus Kinase
Inhibitors (JAKinibs) inhibit
phosphorylation of STAT (a
transcription factor), thus
blocking the downstream
signalling of IL-6. ADAM10
plays a key role in switching
from the classical to trans
signalling pathway by
converting sIL-6R to mIL-6R
Ind J Clin Biochem
123
IL-6: The Sidekick to ACE -2 Immunopathology
in SARS-CoV-2 Infection
There is evidence that suggests a strong association
between circulating IL-6 levels and blood pressure. An
increased IL-6 expression directly correlates with hyper-
tension [43]. Therefore, hypertensive patients with
COVID-19 who have elevated levels of IL-6 are highly
susceptible to severe respiratory failure [44]. The Renin-
Angiotenstin Aldosterone System (RAAS) maintains the
blood pressure and electrolyte balance by two major
mechanisms which are in a state of dynamic equilibrium.
These are the Angiotensin II–Angiotensin 1 Receptor axis
and the Angiotensin 1–7-Mas receptor axis as illustrated in
Fig. 3a. The former causes an inflammatory response and
vasoconstriction while the latter suppresses inflammatory
responses and supports vasodilation [45]. Disruption of the
equilibrium between these two axes disturbs the home-
ostasis maintained by RAAS thus regulating systemic
inflammation.
As already discussed, sars cov2 gains entry into the host
lungs via ACE2 receptor binding, thus rendering the
receptor unavailable for maintenance of RAAS. An
imbalance between the two axes of RAAS results in a shift
in equilibrium towards the pro-inflammatory pathway
mediated by Angiotensin 1 receptor axis, as depicted in
Fig. 3b[46]. Many studies have also reported increased
levels of angiotensin II in covid 19 patients when compared
to healthy individuals, and is found to be in linear associ-
ation with viral load and lung injury [47]. Also, angiotensin
Fig. 3 a In healthy state, the
Angiotensin II–Angiotensin 1
Receptor axis and the
Angiotensin 1–7-Mas receptor
axis are in a state of dynamic
equilibrium to maintain the
blood pressure. The former
causes an inflammatory
response while the latter
suppresses inflammatory
responses. bIn SARS-CoV-2
infected state, viral binding to
ACE2 renders it unavailable to
bind to Angiotensin II causing
an imbalance between the two
axes and a shift towards the pro-
inflammatory functions
Ind J Clin Biochem
123
II is known to significantly increase the expression of IL-6
mRNA and protein in a dose-dependent manner [48].
Angiotensin II binds to angiotensin I receptor which
then initiates a downstream signaling that leads to oxida-
tive stress, formation of reactive oxygen species (ROS) and
upregulated expression of IL-6 [49]. Conversely, IL-6
released by macrophages promotes enhanced expression of
Angiotensin 1 receptor, which attaches itself to walls of
endothelial cells leading to cell and vascular inflammation
[50]. This, in turn, creates a redox imbalance, causing an
increase in oxidative burden and IL-6 expression. Hence,
IL-6 and Angiotensin II activate each other by exerting a
positive feedback control. Treatment of COVID-19
patients with RAAS inhibitors such as ACE inhibitors
(ACEIs) and angiotensin II type 1 receptor blockers
(ARBs) led to attenuation of the inflammatory response, as
observed through the inhibition of IL-6 levels, increased
CD3 and CD8 T cell counts in peripheral blood and
decreased viral load [46,51].
IL-6: Predictor of Disease Prognosis
and Associated Risk Factors in COVID-19 Patients
Elevated IL-6 serum levels are linked to poorer prognosis
and deteriorating clinical outcomes in COVID-19 patients.
It has been indicated that moderately elevated levels of IL-
6 above 80 pg/ml were adequate to identify COVID-19
patients with a high risk of respiratory failure [23]. Fur-
thermore, RNAaemia (SARS CoV2 nucleic acid) in serum
was strongly associated with cytokine storm and an
immensely high IL-6 serum levels [52]. Old age, high
SOFA score (Sequential Organ Failure Assessment), high
BMI, elevated D-dimers and high IL-6 levels were proven
risk factors for increase in mortality & poor prognosis in
adult patients [53]. A retrospective study conducted on ICU
patients revealed significantly high levels of IL-6 in non-
survivor group compared to survivor with AUROC of 0.73
[54]. Another, two hospital based retrospective study also
revealed higher baseline IL-6 levels in severe cases [55]. A
study generated two predictive models based on high flow
oxygen requirement which also demonstrated that patients
with higher IL-6 values are early identification markers of
COVID-19 severity [56]. It was also significantly related
with elevated levels of AST, ALT and GGT during hos-
pitalization of COVID-19 patients [57]. Higher IL-6 levels
has also been linked to long term care need in elderly
patients and in-hospital mortality rates [61]. A study con-
ducted on 225 COVID-19 patients in Southwest quaternary
United states hospital found that elevated levels of IL-6
positively correlates with adverse cardiac events or deaths
[58].
Among the predisposing conditions, diabetes emerged
as the most important association in COVID-19 patients
with mortality rate of 16–35% [59]. Recent data from
COVID-19 patients with diabetes have shown elevated
levels of systemic IL-6 compared to patients without dia-
betes [60]. SARS-CoV-2 infection may exacerbate pre-
existing diabetes, as ACE2 expression in pancreatic cells
contributes to impaired insulin secretion as well as insulin
resistance [61]. Thus, IL-6 may govern COVID-19 disease
severity in diabetics. Similarly, obese patients with
COVID-19 are more likely to develop severe respiratory
distress syndrome [62]. They have higher concentration of
pro-inflammatory cytokines both in steady state and in
diseases [63]. Further, obese patients tend to have height-
ened IL-6 production in adipocytes leading to decreased
anti-viral immune response by neutrophils and hence,
uncontrolled viral replication at early stages of infection
[63]. Age is another risk factor for poorer prognosis in
COVID-19 [53]. This age-associated vulnerability is
probably due to increased expression of ACE2 with age
accounting for higher mortality in elderly patients [64].
Smoking has also been identified as a risk factor for
SARS-CoV-2 infection. It has already been stated that
active smokers are more susceptible to influenza virus
infections and are more likely to develop chronic
obstructive pulmonary disease (COPD) [65]. They have
increased ACE2 expression in the lungs, which may
potentially explain a fourfold increased risk of develop-
ment of severe COVID-19 in smokers [66,67]. During
evaluation of risk factors associated with COVID-19 in a
Chinese cohort, it was found that 19.2% of patients were
smokers [68].
COVID-19 mortality rates in males are twice that of
females [69]. Similar data on association of male gender
with poorer prognosis were obtained earlier for SARS-CoV
and MERS-CoV infections [70,71]. The reason behind this
gender difference lies in the ACE2 gene which is an
X-linked gene. During X-chromosome inactivation, a sig-
nificant number of genes undergo dosage compensation.
However, ACE2, escapes X chromosome inactivation, thus
contributing to gender disparity in disease susceptibility
[72]. Endocrine factors may further contribute to gender
disparity in immune responses [73,74]. Viral load in
COVID-19 females is lower in comparison to males, with
concomitant higher CD4
?
T cells [79]. A comparative
analysis depicted that course of COVID-19 is more severe
in males. The number of men who died from COVID-19 is
2.4 times that of females (70.3% vs. 29.7%). This sug-
gested that male patients are at increased risk of worse
outcomes and death compared to female patients, inde-
pendent of age [75]. A study also concluded that levels of
IL-6 were significantly elevated in males compared to
females. Also, a higher number of males were reported to
Ind J Clin Biochem
123
experience lymphopenia [76]. Therefore, immune-modu-
latory effects of hormones such as estrogens contribute to
decrease susceptibility and better prognosis in women
infected with SARS-CoV-2.
Anti-IL-6 Agents: Therapeutic Targets
for COVID-19 Infection
A diverse spectrum of pharmaceutical agents is presently
being employed for the treatment and management of
COVID-19 infection. Monoclonal antibody Tocilizumab
an IL-6 receptor antibody has been advocated for treatment
[77–79].
While antivirals like remdesivir specifically target the
viral replication by inhibiting the RNA-dependant-RNA
polymerase [80], other drugs like Hydroxychloroquine
inhibit the CS but have adverse effects like gastrointestinal
complications, retinopathy and QT interval prolongation in
treated COVID-19 patients [81]. Thus, in addition to
antiviral drugs, ameliorating the CS would prove to be an
efficient treatment strategy to successfully combat the
disease.
Plant-derived natural immunosuppressant compounds,
such as curcumin, luteolin, piperine, resveratrol, allicin,
colchicines, eugenol etc. have been known to inhibit the
pro-inflammatory cytokines and chemokines. This specific
targeting of cytokines is achieved by the inhibitory action
on specific signalling cascades like NF-jB, JAK/STAT,
MAPK/ERK [82]. Use of these plants sources with
enhanced bioavailability and safety profiles is a ray of hope
and opens up a novel approach to mitigate the CS in
COVID-19.
The latest treatment molecules for combating the CS
have been the monoclonal antibodies (MoAbs) emerging as
the versatile class of biotherapeutics for passive
immunotherapy. The use of monoclonal antibodies against
viral infections like influenza and rheumatoid arthritis have
already shown promising results [83]. Since IL-6 is found
to be significantly upregulated in COVID-19 infection,
MoAbs that can neutralize its effects may serve as a
potential treatment option as depicted in Fig. 2.
Tocilizumab is a recombinant humanised monoclonal
antibody of the IgG1 class, which is directed against both
the soluble and membrane-bound forms of the interleukin-
6 (IL-6) receptor.
Small retrospective cohort studies on patients affected
by severe COVID-19 demonstrated that treatment with
Tocilizumab improved the clinical profile of COVID-19
patients [84]. Patients with severe respiratory failure dis-
playing macrophage activation syndrome (MAS) showed
decreased expression of human leucocyte antigen-D (HLA-
DR) which was mediated by IL-6 expression. Treatment of
these patients with Tocilizumab partially restored HLA-DR
expression [85]. A case study of 64 year old male treated
with tocilizumab for hemophagocytic lymphohistocytosis
syndrome and COVID-19 has also shown decreased levels
of inflammatory markers including IL-6 [86]. Tocilizumab
has been recommended for use in severe or critically ill
patients with confirmed elevated levels of IL-6 in the
‘‘Diagnosis and Treatment Protocol for Novel Coronavirus
Pneumonia (Trial Version 7)’’ issued by the National
Health Commission of China [87]. Several clinical trials on
the use of Tocilizumab have been attempted in different
COVID-19 population groups ranging from patients with
pneumonia to life-threatening CS associated condition
(available on ClinicalTrials.gov.in).
Sarilumab, a human MoAb against IL-6 receptor, is
presently in use for the treatment of RA patients [88].
Addition of Sarilumab in the treatment regimen of eight
patients diagnosed positive for SARS-CoV-2 was done and
a significant improvement in respiratory function (30%
reduction in oxygen requirement compared to baseline)
was observed leading to an early discharge, merely 14 days
after hospital admission to hospital [89].
Siltuximab, an anti-IL-6 antibody, has been evaluated in
the Siltuximab in Severe COVID-19 (SISCO) study.
Mortality rates were compared in two cohorts consisting of
patients on treatment regimen with or without siltuximab
and it was found that siltuximab receiving patients exhib-
ited a decreased mortality rate. Another anti- IL-6 MoAb
which is presently suggested as an effective treatment
option for RA and psoriatic arthritis is Clazakizumab
[90,91]. Significant improvement has been observed in
respiratory functions, inflammatory markers and oxygen
requirements in COVID-19 patients with significantly
raised levels of CRP and IL-6 after treatment with Claza-
kizumab [92].
The effects of cytokines involved in COVID-19 induced
CS are mediated via the JAK/STAT cascade as illustrated
in Fig. 2. Thus, CS in SARS-CoV-2 can also be alleviated
using JAK inhibitors (JAKi). Ruxolitinib is the first FDA
approved JAK inhibitor that inhibits both JAK1 and 2 [93].
It was observed that patients who received Ruxolitinib had
a faster clinical and chest CT improvement and displayed
significantly decreased levels of cytokines compared to
control group. Moreover, no deaths were recorded in the
Ruxolitinib receiving group (n = 20) while three patients
died due to respiratory failure in the control group (n = 21)
[94]. Another JAKi, Baricitinib has been suggested to be of
therapeutic use against SARS-CoV-2 [95]. Baricitinib-
treated COVID-19 patients achieve greater improvements
in all clinical characteristics (fever, cough and dyspnea)
and respiratory function parameters compared to baseline.
A substantial number of trials on anti-IL6 agents that have
Ind J Clin Biochem
123
been presently undertaken will pave the path for treatment
strategies in the days to come.
Conclusion and Future Perspectives
In conclusion, the role of IL-6 in the immunopathology of
COVID-19 is pivotal. IL-6 occupies the centre stage in
initiating and potentiating the dreaded CS. It also helps in
predicting disease severity & mortality in COVID-19.
Raised IL-6 levels were associated with ARDS, increased
requirement of mechanical ventilation, prolonged hospital
stay, worse SOFA score, multiple organ impairment and
intensive care unit admission. This review elaborated IL-6
levels in preference to other cytokines raised in cytokine
storm because anti IL-6 antibodies and IL-6 receptor
inhibitors have already been in vogue for the treatment of
autoimmune diseases and now have been repurposed for
the treatment of COVID-19 with some success. In addition,
JAK inhibitors are also being tried in clinical trials for the
treatment of COVID-19.
Molecules that block ADAM 10 hold a lot of promise
since they tilt the inflammatory balance from pro-inflam-
matory to anti-inflammatory pathway thus abetting the
cytokine storm which is the main pathological event that
propels SARS-COVID-19 patients into a downhill course.
Further studies on genetic polymorphisms in various ethnic
groups which affect IL-6 levels need to be conducted for
stratification of COVID patients into mild, moderate and
severe. Delineating such genetic polymorphisms may also
pave the path for pharmacogenomic database for the
exhibition of anti-IL-6 antibodies.
Author contributions JS: Data acquisition, original draft, Editing.
KG: Data creation, resources, writing, original draft. SG: Review and
editing, data creation. PP: Review and editing. MR: Review and
editing. PM: Review and editing. MG: Data creation, review and
editing. SM: Supervision. PS: Review and editing, supervision. MB:
Conceptualization, supervision, review and editing.
Funding This review article did not receive any specific grant from
funding agencies in the public, commercial sectors.
Declarations
Conflict of interest The authors declare that they have no conflict of
interest to disclose.
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