Could SARS-CoV-2-Induced Hyperinflammation Magnify the Severity of Coronavirus Disease (CoViD-19) Leading to Acute Respiratory Distress Syndrome?

Abstract

An exaggerated immune response induced in the lower respiratory tract against coronaviruses (CoV’s) including CoViD-19 (2019-nCoV) appears to contribute to the overwhelming lung damage in comparison to the direct viral invasion and replication in the host. While it has resulted in high global rates of morbidity (3,672,238 infected cases), a sizeable number of individuals have already succumbed (254,045 deaths) (1) (case fatality rate of 1-10% ) to severe pathological manifestations involving the lower respiratory tract (2) as of May 7, 2020) as reported by the World Health Organization (1), although this has been documented to be of less severity as compared to influenza (3).

CoViD-19 reportedly has four stages; a pre-symptomatic phase of fever, cough and generalised malaise heralded by high viral loads in severely affected cases. After about a week, the second stage manifests with viral pneumonia that involves the lower respiratory tract (when viral loads in the upper respiratory tract decreases exponentially). A vast majority of patients show clinical improvement as protective humoral responses are developed at this stage of the disease. A minor proportion of individuals progress to the third phase of CoViD-19 by developing symptoms of hypercytokinemia (cytokine release syndrome (CRS)/cytokine storm) characterized by exaggerated levels of pro-inflammatory cytokines and other pathognomonic biomarkers of inflammation leading to rapid onset of acute respiratory distress syndrome (ARDS) and multi-organ failure (Stage 4). It is also intriguing to know that many individuals with CoViD-19 have refrained from developing ARDS. The median time from development of symptomatic disease to death from CoViD-19 is ~2-8 weeks (4). The crown-shaped peplomers of SARS-CoV-2 appear to trigger a prolonged phase of hypercytokinemia that encompasses a broad array of pro-inflammatory mediators like IL-6, IL-1β, TNF-α, CXCL8 (IL-8) together with the infiltration of inflammatory and degranulating cells into the lungs, usually 7-10 days following the onset of symptoms during the second stage of CoViD-19 (4). Variations in human genetic make-up have been shown to affect disease progression and prognosis of infectious diseases. A more recent emergence of interest surrounds individuals harboring mutations in the Mediterranean fever gene (mefv), which likely could predispose the onset of severe CoViD-19 disease manifestations resulting from cytokine storm (5).

Cytokine storm refers to a systemic acute inflammatory manifestation triggered during viral infections characterized by an upsurge in immune cells and cytokine levels (6). It occurs when leukocytes become activated leading to abrupt release of TNF-α, IL-6, IL-1β, IL-10, which at times can be life-threatening due to acute onset of hypotensive shock, and multi-organ failure (6) as reported in CoViD-19 (1, 4). Cytokine storm likely could dampen innate and adaptive immune responses against SARS-CoV-2 infection. Cytokine storm pathophysiology in CoViD-19 is often reported to be due to high levels of IL-6 in individuals (6) although this could synergize with TNF-α and IL-1β levels. A similar kind of hyperactive inflammatory response also appears to have occurred in SARS-CoV and MERS-CoV infections culminating in severe lung fibrosis, often with poor disease prognosis (7). Recent reports suggest that CoViD-19 disease is characterized by exaggerated release of acute phase reactants that includes C-reactive protein (CRP), serum amyloid A, and ferritin, suggesting a rapid activation of the innate immune response (8, 9). Individuals with CoViD-19 reportedly possess elevated levels of circulating TNF-α, IL-1β, IL-1Rα, sIL-2Rα, IL-6, IL-10, IL-17, IL-18, IFN-γ, MCP-3, M-CSF, MIP-1α, G-CSF, IP-10 and MCP-1 (10). Reports suggest that IL-6, IL-8 and TNF-α attributes to SARS-related ARDS. Further, development of lung damage is likely due to elevation of inflammatory cytokine levels and CRP in SARS patients. Importantly, high levels of serum TNF-α tends to become high in patients who die of SARS-CoV-1 than in those who survive (11). However, emerging reports of SARS-CoV-2 suggests the predominance of IL-6 to TNF-α although this requires to be confirmed from multiple findings (12).

IL-6 is predominantly produced by lung epithelial cells in response to stimulatory factors similar to what has been shown for several other respiratory viruses including SARS-CoV and MERS-CoV. IL-6 is produced in a constitutive manner only upon stimuli and not by resident immune cells of the lungs, thus portraying its pleotropic and immuno-regulatory role in the respiratory mucosa. Although IL-6 is regarded as a marker of pneumonia in CoV infections, it has now become evident that abrupt release of IL-1β and TNF-α could contribute to severity of CoViD-19 pathogenesis. The onset of cytokine storm in the lung compartment likely occurs prior to recruitment of inflammatory cells, especially in allergic patients and those with other co-morbidities, leading to an exorbitant rise in mortality rates (13). A similar cytokine storm that led to severe lung injury resulting from release of 18 inflammatory mediators has been demonstrated in SARS-CoV-infected patients (14). Immune-mediated damage to the lungs and other organs, and subsequent development of multi-organ dysfunction is explained by hypercytokinemia resulting from cytokine release largely by SARS-CoV-infected ACE2-expressing cells, but not by uninfected cells (15). More recent experimental investigation has reported dramatically high levels of CXCL10, CCL5 and IL-1β in human lung epithelial cells and in the lung tissues of SARS-CoV-infected mice. The report has established that pulmonary inflammation was modulated via NLRP3 providing key clues to development of potential antiviral targets (16).

It has also been reported that individuals admitted into intensive care units have significantly elevated levels of IL-6, IL-10 and TNF-α and fewer T cells in the circulation (17). Interestingly, it has also been reported that CoViD-19 disease severity correlates positively with concomitant rise in inflammatory cytokine levels that also drive the depletion and exhaustion of SARS-CoV-2-specific CD8+ T cells (17). It has also become evident that the frequency of circulating CD4+ and CD8+ T cells are exponentially reduced, and show signs of hyperactivation i.e. elevated expression of HLA-DR and CD38. Interestingly, the hyperactive CD8+ T cells were also enriched with perforin and granulysin that potentially adds to the reported lung injury (18). More recent findings points to consistently elevated levels of CXCL10, CCL7 and IL-1 receptor antagonist and their association with increased viral load, exacerbated lung injury and a fatal prognosis.

Published data from SARS-CoV-infected patients points to an increase inuf6 TNF-α levels enhancing the migration of inflammatory cells, viz. eosinophils and neutrophils (19). A cohort of 41 laboratory-confirmed CoViD-19 patients in Wuhan, China, subjected to serological evaluation revealed high levels of IL-1β, IFN-γ, IP-10, and MCP-1, of all the 22 cytokines tested among both ICU as well as non-ICU cases. It has also become evident that in moribund cases, cytokine storm was highly associated with the magnitude of disease severity (9). Subsequent experimental data also suggests that production of TNF is mediated via NF-κB through degradation of I-κBα by CoV spike proteins (20). CoVs being predominantly zoonotic, a similar up-regulation of TNF-α has also been documented in feline CoV infection (21).

More recently, the direct involvement of the NOD-like receptor family protein (NLRp-3) inflammasome has come to light in SARS-CoV 3a culminating in the release of IL-1β via ion channel proteins called viroporins (22). In addition to the classical cytokine storm, CCL2, CXCL10, CXCL9 and CXCL8 upregulation has also been reported in uncomplicated SARS-CoV infection (22). The underlying rationale behind the far-reaching prognosis of CoViD-19 in Wuhan, China is believed to involve virus-activated cytokine storm syndrome or fulminant myocarditis, which could be related to secondary haemo-phagocytic lympho-histiocytosis (sHLH), an under-recognized ailment most commonly triggered by viral infections and sepsis, and is co-related with CoViD-19 disease (23).

The proposed cytokine storm in the pathogenesis of CoV’s could result in deleterious consequences with varying degrees of immunopathology (Figure 1). As an initial step, infiltration of airway by IFN-αβ and IFN-µ mediated by Fas-FasL-/TRAIL-DR5-dependent mechanisms leads to endothelial cell apoptosis and vascular leakage, which will be followed by TNF-mediated T-cell apoptosis resulting in suboptimal responses of T cells. Through the abrogation of STAT-1 signaling specifically in myeloid cells, activated macrophages can accumulate and alter the homeostasis of lung tissues. The final phase of cytokine assault by IL-6, CXCL8, IL-1β, and GM-CSF, CCL2, CCL5, IP-10 and CCL3 reportedly results in ARDS (24).

It must be considered that an ongoing phase of immunosenescence in the mucosa of elderly individuals deteriorates CoV severity leading to poor levels of functional T-cell subsets, antigen-specific IgA and immunological remodeling. CoVs also display neuro-virulence attributes, differentially inducing the production of pro-inflammatory mediators by astrocytes and microglial cells as shown in experimental mice (25). Intriguingly, the onset of cytokine storm in CoViD-19 disease can be hypothesized to be gender-biased as closely related MERS-CoV infection exhibited a high incidence in males than females (26). Gender-based variations in the expression of ACE2 likely could have implications in severe disease progression resulting from cytokine storm. Coding variants at specific amino acid sites are likely to be a genetic risk factor for development of severe CoViD-19, and could affect human males and females differently. Surveys conducted on the follow-up of patients SARS-CoV suggest a strong role for the involvement of cytokine storm (27).

Together, to control the askew and flared cytokine assault, and to likely alleviate lung pathology and increased survival rates, the efficacy of immuno-suppressants like actemra, IL-1β antagonists like anakinra could be investigated. Tocilizumab (a recombinant humanized anti-human IL-6 receptor monoclonal antibody) specifically binds sIL-6R and mIL-6R to inhibit signal transduction, and has been well-tolerated as established in animal drug trials (28, 29). A recently published CoViD-19 research has shown encouraging results with no evidence of any serious adverse events (30). A multicentric randomized-controlled trial of tocilizumab has been approved for CoViD-19 pneumonia (ChiCTR2000029765) (31). Application of artificial liver purification systems in addition to the rapid detection of cytokine index should be considered for implementation. Recently, an in silico docking analysis has documented curcumin, a known anti-inflammatory blockade strategy can potentially inhibit the main protease (M-Pro) of CoViD-19 (32). The importance of studies on the association between specific HLA loci/haplotypes, genetic predispositions and development of anti-SARS-CoV-2 immune responses also is urgently warranted. As a measure of restraint, it is indeed the need of the hour to discover or repurpose improved concepts for disease control as well as for alleviating the magnitude of cytokine storm syndrome in the ongoing CoViD-19 pandemic.

Full text

OPINION
published: 27 May 2020
doi: 10.3389/fimmu.2020.01206
Frontiers in Immunology | www.frontiersin.org 1May 2020 | Volume 11 | Article 1206
Edited by:
Linda F. Van Dyk,
University of Colorado Denver,
United States
Reviewed by:
Eirini Moysi,
Vaccine Research Center (NIAID),
United States
Ashraf Siddig Yousif,
Ragon Institute of MGH, United States
*Correspondence:
Esaki M. Shankar
shankarem@cutn.ac.in
A. S. Smiline Girija
smilinejames25@gmail.com
Specialty section:
This article was submitted to
Viral Immunology,
a section of the journal
Frontiers in Immunology
Received: 28 March 2020
Accepted: 14 May 2020
Published: 27 May 2020
Citation:
Girija ASS, Shankar EM and
Larsson M (2020) Could
SARS-CoV-2-Induced
Hyperinflammation Magnify the
Severity of Coronavirus Disease
(CoViD-19) Leading to Acute
Respiratory Distress Syndrome?
Front. Immunol. 11:1206.
doi: 10.3389/fimmu.2020.01206
Could SARS-CoV-2-Induced
Hyperinflammation Magnify the
Severity of Coronavirus Disease
(CoViD-19) Leading to Acute
Respiratory Distress Syndrome?
A. S. Smiline Girija 1
*, Esaki M. Shankar 2
*and Marie Larsson 3
1Department of Microbiology, Saveetha Dental College and Hospitals, Chennai, India, 2Infection Biology, Department of Life
Sciences, Central University of Tamil Nadu, Thiruvarur, India, 3Molecular Medicine and Virology, Department of Biomedicine
and Clinical Sciences, Linköping University, Linköping, Sweden
Keywords: cytokine storm, corona virus disease 2019, IL-6, TNF-α, IL-1β
The exaggerated immune response induced in the lower respiratory tract against coronaviruses
(CoVs), including CoViD-19 (2019-nCoV), appears to contribute to the overwhelming lung
damage caused by the disease in comparison to the effect of the direct viral invasion and replication
in the host. While it has resulted in high global rates of morbidity (4,618,821 infected cases), a
sizeable number of individuals have already succumbed (311,847 deaths)1(case fatality rate of 1–
10%) to severe pathological manifestations involving the lower respiratory tract (1) as of May 18,
2020, as reported by the World Health Organization1. This has, however, been documented to be
less severe when compared to influenza (2).
CoViD-19 reportedly has four stages: a pre-symptomatic phase of fever, cough, and generalized
malaise heralded by high viral loads in severely affected cases. After about a week, the second
stage manifests with viral pneumonia that involves the lower respiratory tract (while viral loads
in the upper respiratory tract decrease exponentially). A vast majority of patients show clinical
improvement as protective humoral responses are developed at this stage of the disease. A minor
proportion of individuals progress to the third phase of CoViD-19 by developing symptoms of
hypercytokinemia (cytokine release syndrome (CRS)/cytokine storm) characterized by exaggerated
levels of pro-inflammatory cytokines and other pathognomonic biomarkers of inflammation,
leading to the rapid onset of acute respiratory distress syndrome (ARDS) and multi-organ failure
(Stage 4). It is also intriguing to know that many individuals with CoViD-19 have not developed
ARDS. The median time from development of symptomatic disease to death from CoViD-19 is
∼2–8 weeks (3). SARS-CoV-2 appears to trigger a prolonged phase of hypercytokinemia (also
called as macrophage activation syndrome) that encompasses a broad array of pro-inflammatory
mediators like IL-6, IL-1β, TNF-α, and CXCL8 (IL-8) together with the infiltration of inflammatory
and degranulating cells into the lungs, usually 7–10 days following the onset of symptoms during
the second stage of CoViD-19 (3–7). Variations in human genetic make-up have been shown to
affect disease progression and prognosis of infectious diseases. A more recent emergence of interest
surrounds individuals harboring mutations in the Mediterranean fever gene (mefv), which likely
could predispose the onset of severe CoViD-19 disease manifestations resulting from local and
systemic cytokine storm (8).
Cytokine storm refers to a systemic acute inflammatory manifestation triggered during viral
infections characterized by an upsurge in immune cells and cytokine levels (9). It occurs when
leukocytes become activated leading to an abrupt release of TNF-α, IL-6, IL-1β, and IL-10, which
at times can be life-threatening due to the acute onset of hypotensive shock and multi-organ failure
(9), as reported in CoViD-191(3). Cytokine storm likely could dampen innate and adaptive
1https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/

Girija et al. Cytokine Storm and Severity of CoViD-19 Disease
immune responses against SARS-CoV-2 infection. Cytokine
storm pathophysiology in CoViD-19 is often reported to be
due to high levels of IL-6 in individuals (9), although this, we
believe, could synergize with TNF-αand IL-1βlevels. A similar
kind of hyperactive inflammatory response also appears to have
occurred in SARS-CoV and MERS-CoV infections culminating
in severe lung fibrosis, often with poor disease prognosis (10).
Recent reports suggest that CoViD-19 disease is characterized by
an exaggerated release of acute phase reactants that includes C-
reactive protein (CRP), serum amyloid A, and ferritin, suggesting
a rapid activation of the innate immune response (11,12).
Individuals with CoViD-19 reportedly possess elevated levels of
circulating TNF-α, IL-1β, IL-1Rα, sIL-2Rα, IL-6, IL-10, IL-17,
IL-18, IFN-γ, MCP-3, M-CSF, MIP-1α, G-CSF, IP-10, and MCP-
1 (13). Reports suggest that IL-6, IL-8, and TNF-αattributes
to SARS-related ARDS. Further, development of lung damage
is likely due to the elevation of inflammatory cytokine levels
and CRP in SARS patients. Importantly, high levels of serum
TNF-αtends to be seen more prevalently in patients who die of
SARS-CoV-1 than in those who survive (14). However, emerging
reports of SARS-CoV-2 suggests the predominance of IL-6 over
TNF-αalthough this is yet to be confirmed from multiple
findings (15).
IL-6 is predominantly produced by lung epithelial cells in
response to stimulatory factors similar to what has been shown
for several other respiratory viruses, including SARS-CoV and
MERS-CoV. IL-6 is produced in a constitutive manner only
upon stimuli and not by resident immune cells of the lungs,
thus portraying its pleotropic and immuno-regulatory role in
the respiratory mucosa. Although IL-6 is regarded as a marker
of pneumonia in CoV infections, it has now become evident
that abrupt release of IL-1βand TNF-αcould contribute to
the severity of CoViD-19 pathogenesis. The onset of cytokine
storm in the lungs likely occurs prior to the recruitment of
inflammatory cells, especially in allergic patients and those with
other co-morbidities, leading to an exorbitant rise in mortality
rates (16). A similar cytokine storm that led to severe lung
injury resulting from the release of 18 inflammatory mediators
has been demonstrated in SARS-CoV-infected patients (17).
Immune-mediated damage to the lungs and other organs,
and subsequent development of multi-organ dysfunction, is
explained by hypercytokinemia resulting from cytokine release
largely by SARS-CoV-infected ACE2-expressing cells, but not by
uninfected cells (18). More recent experimental investigation has
reported dramatically high levels of CXCL10, CCL5, and IL-1β
in human lung epithelial cells and in the lung tissues of SARS-
CoV-infected mice. The report has established that pulmonary
inflammation was modulated via NLRP3, providing key clues to
the development of potential antiviral targets (19).
It has also been reported that individuals admitted into
intensive care units have significantly elevated levels of IL-6, IL-
10, and TNF-αand fewer T cells in circulation (20). Interestingly,
it has also been reported that CoViD-19 disease severity
correlates positively with a concomitant rise in inflammatory
cytokine levels that also drives the depletion and exhaustion
of SARS-CoV-2-specific CD8+T cells (20). It has also become
evident that the frequency of circulating CD4+and CD8+T cells
are exponentially reduced and show signs of hyperactivation,
i.e., an elevated expression of HLA-DR and CD38. Interestingly,
the hyperactive CD8+T cells were also enriched with perforin
and granulysin that potentially adds to the reported lung injury
(21). More recent findings point to the consistently elevated
levels of CXCL10, CCL7, and IL-1 receptor antagonist and their
association with an increased viral load, exacerbated lung injury,
and a fatal prognosis.
Published data from SARS-CoV-infected patients points to
an increase in inuf6 TNF-αlevels, enhancing the migration
of inflammatory cells viz. eosinophils and neutrophils (22). A
cohort of 41 laboratory-confirmed CoViD-19 patients in Wuhan,
China, subjected to serological evaluation, revealed high levels
of IL-1β, IFN-γ, IP-10, and MCP-1, of all the 22 cytokines
tested among both ICU as well as non-ICU cases. It has also
become evident that in moribund cases, cytokine storm was
highly associated with the magnitude of disease severity (12).
Subsequent experimental data also suggests that production of
TNF-αis mediated via NF-κB through the degradation of I-κBα
by CoV spike proteins (23). CoVs being predominantly zoonotic,
a similar up-regulation of TNF-αhas also been documented in
feline CoV infection (24).
More recently, the direct involvement of the NOD-like
receptor family protein (NLRp-3) inflammasome has come
to light in SARS-CoV 3a culminating in the release of
IL-1βvia ion channel proteins called viroporins (25). In
addition to the classical cytokine storm, CCL2, CXCL10,
CXCL9, and CXCL8 upregulation has also been reported
in uncomplicated SARS-CoV infections (25). The underlying
rationale behind the far-reaching prognosis of CoViD-19 in
Wuhan, China, is believed to involve virus-activated cytokine
storm syndrome or fulminant myocarditis, which could be
related to secondary haemo-phagocytic lympho-histiocytosis
(sHLH), an under-recognized ailment most commonly triggered
by viral infections and sepsis, and is co-related with CoViD-19
disease (1).
The proposed cytokine storm in the pathogenesis of CoV
could result in deleterious consequences with varying degrees
of immunopathology (Figure 1). As an initial step, infiltration
of the airway by IFN-αβ and IFN-µmediated by Fas-
FasL-/TRAIL-DR5-dependent mechanisms leads to endothelial
cell apoptosis and vascular leakage, which will be followed
by TNF-mediated T-cell apoptosis resulting in suboptimal
responses of T cells. Through the abrogation of STAT-1
signaling specifically in myeloid cells, activated macrophages
can accumulate and alter the homeostasis of lung tissue. The
final phase of the cytokine assault by IL-6, CXCL8, IL-1β, and
GM-CSF, CCL2, CCL5, IP-10, and CCL3 reportedly results in
ARDS (26).
It must be considered that an ongoing phase of
immunosenescence in the mucosa of elderly individuals
deteriorates CoV severity, leading to poor levels of functional
T-cell subsets, antigen-specific IgA, and immunological
remodeling. CoV also display neuro-virulence attributes,
differentially inducing the production of pro-inflammatory
mediators by astrocytes and microglial cells, as shown in
experimental mice (27). Intriguingly, the onset of cytokine storm
Frontiers in Immunology | www.frontiersin.org 2May 2020 | Volume 11 | Article 1206

Girija et al. Cytokine Storm and Severity of CoViD-19 Disease
FIGURE 1 | Proposed mechanism of induction of cytokine storm in coronavirus disease (CoViD-19). Following entry of SARS-CoV-2 into a susceptible host, the virus
employs its spike protein to invade the respiratory airway epithelial cells via ACE2 receptors expressed on the cells causing damage to the upper respiratory
epithelium. Several danger-associated molecular patterns, cellular stress factors (IL-1a, IL-33, HMGB1) and pro-inflammatory chemokines and chemoattractants (eg.,
CXCL8, CXCL10, C3a, C5a) are released that recruit several types of inflammatory cells (monocytes/macrophages, granulocytes and NK cells) that release IL-1β, IL-6,
IL-18, TNF-α, IFN-γand several other factors that can further trigger inflammation (also via NLRP3 and AIM2 inflammasome assembly and caspase-1 activation)
especially in the lower respiratory tract. Mast cell, macrophage and endothelial activation also takes place to exaggerate the inflammatory cascade resulting in
cytokine storm syndrome (or hypercytokinemia). Excessive cytokine release and binding to cytokine receptors lead to massive cytokine signaling that culminates in
Fas-FasL/TRAIL-DR5-dependent signaling in endothelial cells causing their death, which erodes the blood vessel walls that results in vascular leakage. Intravascular
coagulation also ensues leading to widespread damage of blood capillaries in the lungs. T cell death/depletion ensues via TNF-αand also expression of exhaustion
molecules (PD-1) on CD4+and CD8+T cells (not shown) can result in poor anti-viral immune responses. Onset of acute respiratory distress syndrome can be fatal
characterized by pneumonitis, pyrexia, myalgia, dyspnoea, loss of smell/taste and can lead to high mortality rates.
in CoViD-19 disease can be hypothesized to be gender-biased,
as the closely related MERS-CoV infection exhibited a higher
incidence in males than females (28). Gender-based variations
in the expression of ACE2 could likely have implications in
severe disease progression resulting from cytokine storm.
Coding variants at specific amino acid sites are likely to be
a genetic risk factor for the development of severe CoViD-
19 and could affect human males and females differently.
Surveys conducted on the follow-up of patients with SARS-
CoV suggest a strong role for the involvement of cytokine
storm (29).
Together, to control the askew and flared cytokine assault, and
to likely alleviate lung pathology and increased survival rates,
the efficacy of immuno-suppressants like actemra and IL-1β
antagonists like anakinra could be investigated. Tocilizumab (a
recombinant humanized anti-human IL-6 receptor monoclonal
antibody) specifically binds sIL-6R and mIL-6R to inhibit signal
transduction and has been well-tolerated as established in
animal drug trials (30,31). A recently published CoViD-19
research has shown encouraging results with no evidence of
any serious adverse events (32). A multicentric randomized-
controlled trial of tocilizumab has been approved for CoViD-19
pneumonia (ChiCTR2000029765) (33). Application of artificial
liver purification systems in addition to the rapid detection
of cytokine index should be considered for implementation.
Recently, an in silico docking analysis has documented how
curcumin, a known anti-inflammatory blockade strategy, can
potentially inhibit the main protease (M-Pro) of CoViD-19
Frontiers in Immunology | www.frontiersin.org 3May 2020 | Volume 11 | Article 1206

Girija et al. Cytokine Storm and Severity of CoViD-19 Disease
(34). The importance of studies on the association between
specific HLA loci/haplotypes, genetic predispositions, and the
development of anti-SARS-CoV-2 immune responses also is
urgently warranted. As a measure of restraint, it is indeed
the need of the hour to discover or repurpose improved
concepts for disease control as well as for alleviating the
magnitude of cytokine storm syndrome in the ongoing
CoViD-19 pandemic.
AUTHOR CONTRIBUTIONS
AG: conception or design of the work, the acquisition, analysis or
interpretation of data for the work, drafting the work or revising
it critically for important intellectual content, provide approval
for publication of the content, and agreed to be accountable for
all aspects of the work in ensuring that questions related to the
accuracy or integrity of any part of the work are appropriately
investigated and resolved. ES: conception or design of the work,
the acquisition, analysis or interpretation of data for the work,
provide approval for publication of the content, and agreed to be
accountable for all aspects of the work in ensuring that questions
related to the accuracy or integrity of any part of the work are
appropriately investigated and resolved. ML: provided approval
for publication of the content and agreed to be accountable for
all aspects of the work in ensuring that questions related to the
accuracy or integrity of any part of the work are appropriately
investigated and resolved.
FUNDING
This work has been supported by: AI52731, The Swedish
Research Council, The Swedish Physicians against AIDS
Research Foundation, The Swedish International Development
Cooperation Agency, SIDA SARC, VINNMER for Vinnova,
Linköping University Hospital Research Fund, CALF, The
Swedish Society of Medicine, and Medical Research Council
of Southeast Sweden for ML. ES is funded by the Department
of Science and Technology-Science and Engineering Research
Board, Government of India (Grant Number CRG/2019/006096).
ACKNOWLEDGMENTS
The authors gratefully thank Prof. A. P. Dash, Central University
of Tamil Nadu, India, Dr. Vijayakumar Velu, Emory University,
Prof. Rajaraman Eri, University of Tasmania, Australia, Dr.
Yean K. Yong, Xiamen University, Malaysia, Dr. Siva Sundara
Kumar, Central University of Tamil Nadu, India, Dr. Pachamuthu
Balakrishnan and Dr. Syed H. Iqbal, YRG CARE, India, and
Dr. Amudhan Murugesan, Government Theni Medical College,
India, for thoughtful and critical discussions on cytokine
storm and CoViD-19 that helped in collating and compiling
the concepts discussed in the manuscript. All clinical, non-
clinical, technical and academic staff and research scholars of
diagnostic and research laboratories of the above institutions
are gratefully acknowledged for the gracious support and
insightful discussions.
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Conflict of Interest: ES is the Associate Editor of Frontiers in Immunology.
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conflict of interest.
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