CYTOKINE IS RESPONSIBLE FOR YOUR SERVIVAL IN COVID-19 INFECTION


COVID-19 is a rapidly spreading

global threat that has been

declared as a pandemic by the

WHO. COVID-19 is transmitted

via droplets or direct contact

and infects the respiratory

tract resulting in pneumonia in

most of the cases and acute

respiratory distress syndrome

(ARDS) in about 15 % of the

cases. Mortality in COVID-19

patients has been linked to the

presence of the so-called

“cytokine storm” induced by

the virus. Excessive production

of proinflammatory cytokines

leads to ARDS aggravation and

widespread tissue damage

resulting in multi-organ failure

and death. Targeting cytokines

during the management of

COVID-19 patients could

improve survival rates and

reduce mortality.

Introduction


In December 2019, an outbreak

of pneumonia cases was

reported in Wuhan, China. The

outbreak was linked to the

Huanan food Market. The new

virus, 2019-nCoV, so called

then, was isolated on 7 January

2020 and identified as the

cause of the outbreak (1). The

2019-nCoV virus rapidly

spread across China and many

other countries and caused a

rapidly growing global

outbreak. On 11 February

2020, the WHO has named the

disease COVID-19, short for

“coronavirus disease 2019” (2)

and on 12 March 2020 the total

number of COVID-19

confirmed cases reached

125,260 globally with 80,981

cases in China and 44,279

outside of China and the

COVID-19 was declared to be a

pandemic by the WHO (3). As

of 26 May 2020, COVID-19 has

been confirmed in 5,404,512

individuals globally with

deaths reaching 343,514 with a

morality of 6.4%, The United

States had the highest number

of confirmed cases (1,618,757

cases) (4).

Transmission and Clinical

Manifestations of COVID-19


COVID-19 is caused by the

SARS-CoV-2 that belongs to the

beta-coronaviruses subfamily.

Coronaviruses are enveloped,

positive single stranded large

RNA viruses. Although the first

data available about COVID-19

indicates possible

animal-to-human transmission

via wild animals in Huanan

seafood Market in Wuhan (5,

6), epidemiological data and

studies, after that, have

increasingly demonstrated that

the virus transmits

human-to-human, through

droplets or direct contact, with

the reporting that individuals

who did not have direct

contact with the Huanan

seafood market were

diagnosed with COVID-19 and

with secondary cases

occurring at hospitals among

health care workers who had

extensive contact with

COVID-19 patients. The virus

was confirmed to spread

through respiratory droplets

from coughs or sneezes (7–9)

with the ability of the host to

shed the infection while

asymptomatic (10). Studies are

now also proposing the

possible feco-oral transmission

of the virus (11).

COVID-19 patients are mainly

adults older than 18 years old

with a male predominance, the

preconceived notion that

pediatrics are not subjected to

infection later changed with

confirmed cases occurring in

pediatrics in China and

worldwide (12, 13), however,

mortality is still much more in

the adult group above the age

of 65 years. Adults with

pre-existing cardiovascular

diseases, respiratory diseases,

endocrine diseases, diabetics,

or immunocompromised

adults remain the most

exposed to serious

complication of COVID-19 (14).

Although many patients of

COVID-19 remain

asymptomatic, some patients

get pneumonia and 10% of

cases require mechanical

ventilation and ICU admission.

Patients usually present with

fever, dry cough, shortness of

breath, headache, malaise,

muscle, and bony aches. Less

common symptoms include

sore throat, confusion,

productive cough, hemoptysis,

diarrhea, nausea, and chest

pain (15). Progression to

pneumonia is documented by

radiological findings and

usually occurs 1–2 weeks after

the beginning of the symptoms.

Signs of pneumonia include

decreased oxygen saturation,

deterioration of blood gas,

multi-focal glass ground

opacities, or patchy/segmental

consolidation in chest X-ray or

CT. Patients presenting late or

deteriorating hospitalized

patients usually suffer from

acute respiratory distress

syndrome (ARDS), acute

respiratory failure, acute renal

injury, and multi-organ failure (15–17).

Laboratory Findings of

COVID-19


Complete blood picture of

COVID-19 patients usually

shows lymphopenia with or

without total leukopenia. A

lymphocyte count <1.0 × 109/L

has been associated with

severe disease (18). A recent

research has reported that

severe cases of COVID-19 tend

to have higher neutrophil to

lymphocyte ratio (NLR). NLR is

calculated from a routine

blood picture by dividing the

absolute neutrophil count by

the absolute lymphocyte count

and indicates a patient’s

overall inflammatory status.

Increasing NLR is a risk factor

of mortality not only in

infectious diseases but also in

malignancy, acute coronary

syndrome, intracerebral

hemorrhage, polymyositis, and

dermatomyostis (19). Platelet

count is usually normal or

mildly decreased. C-reaction

protein and erythrocyte

sedimentation rate are usually

increased while procalcitonin

levels are normal and

elevation of procalcitonin

usually indicates secondary

bacterial infection. Lactate

dehydrogenase, ferritin,

D-dimer, and creatine kinase

elevation is associated with

severe disease. Elevation in

creatinine or liver enzyme

levels (ALT and AST) occurs in

complicated cases progressing

to multi-organ failure (18).



Cytokine Profile and The

Cytokine Storm


The newly emerging COVID-19

is continuing to challenge

medical health systems all over

the world and the scenario is

still getting worse. The

COVID-19 poses an increasing

threat to humans with a

fatality rate of 6.4 % so far (4).

COVID-19 infection is

accompanied by an aggressive

inflammatory response with

the release of a large amount

of pro-inflammatory cytokines

in an event known as

“cytokine storm.” The host

immune response to the

SARS-CoV-2 virus is

hyperactive resulting in an

excessive inflammatory

reaction. Several studies

analyzing cytokine profiles

from COVID-19 patients

suggested that the cytokine

storm correlated directly with

lung injury, multi-organ

failure, and unfavorable

prognosis of severe COVID-19 (16, 20–24).

The immune system has an

exquisite mechanism capable

of responding to various

pathogens. Normal anti-viral

immune response requires the

activation of the inflammatory

pathways of the immune

system; however, aberrant or

exaggerated response of the

host’s immune system can

cause severe disease if remains

uncontrolled (25). Cytokines

are an essential part of the

inflammatory process.

Cytokines are produced by

several immune cells including

the innate macrophages,

dendritic cells, natural killer

cells and the adaptive T and B

lymphocytes. During an innate

immune response to a viral

infection, pattern recognition

receptors (PRRs) recognize

different molecular structures

that are characteristic to the

invading virus. These

molecular structures are

referred to as pathogen

associated molecular patterns

(PAMPs). Binding of PAMPs to

PRRs triggers the start of the

inflammatory response against

the invading virus resulting in

the activation of several

signaling pathways and

subsequently transcription

factors which induce the

expression of genes

responsible for production of

several products involved in

the host’s immune response to

the virus, among which are the

genes encoding several

pro-inflammatory cytokines.

The major transcription

factors that are activated by

PRRs are nuclear factor kB,

activation protein 1, interferon

response factors three and

seven. These transcription

factors induce the expression

of genes encoding

inflammatory cytokines,

chemokines and adhesion

molecules. This sequence of

events results in recruitment

of leukocytes and plasma proteins to site of infection where they perform various effector functions that serve to combat the triggering infection (26).

Three of the most important pro-inflammatory cytokines of the innate immune response are IL-1, TNF- α, and IL-6. Tissue macrophages, mast cells, endothelial, and epithelial cells are the major source of these cytokines during innate immune response. The “cytokine storm” results from a sudden acute increase in circulating levels of different pro-inflammatory cytokines including IL-6, IL-1, TNF- α, and interferon. This increase in cytokines results in influx of various immune cells such as macrophages, neutrophils, and T cells from the circulation into the site of infection with destructive effects on human tissue resulting from destabilization of endothelial cell to cell interactions, damage of vascular barrier, capillary damage, diffuse alveolar damage, multiorgan failure, and ultimately death. Lung injury is one consequence of the cytokine storm that can progress into acute lung injury or its more severe form ARDS (27). ARDS leading to low oxygen saturation levels is a major cause of mortality in COVID-19. Although the exact mechanism of ARDS in COVID-19 patients is not fully understood, the excessive production of pro-inflammatory cytokines is considered to be one of the major contributing factors (15–17).

Accumulating evidence suggests that some patients with severe COVID-19 suffer from a “cytokine storm.” Analysis of cytokine levels in plasma of 41 COVID-19 confirmed cases in China revealed elevated levels of IL-1β, IL-7, IL-8, IL-9, IL-10, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1A, MIP1-B, PDGF, TNF-α, and VEGF in both patients admitted to the ICU and non-ICU patients compared to healthy adults. All patients included in the study had pneumonia and 1/3 of the patients were admitted to ICU and six of these patients died (16).

A multicenter retrospective study of 150 COVID-19 patients in China evaluated predictors of mortality for COVID-19. The study analyzed data from 82 cases who resolved from COVID-19 and 68 cases who died from COVID-19 and reported significantly higher levels of IL-6 in mortality cases than resolving cases (20). Another study analyzing data from 21 patients in China reported increased levels of IL-10, IL-6, and TNF-α in severe cases (n = 11 patients) compared to moderate cases (n = 10 patients) (21). A similar study by Gao et al. assessed 43 patients in China and reported that levels of IL-6 were significantly higher in severe cases (n = 15) than in mild cases (n = 28) (22). Similarly, Chen et al. studied a total of 29 COVID-19 patients, divided into three groups according to relevant diagnostic criteria, and found that IL-6 was higher in critical cases (n = 5 patients) than in severe cases (n = 9 patients) and that IL-6 was higher in severe cases than in mild cases (n = 15 cases) (23).

No much data is available yet regarding severe pediatric COVID-19 patients. A study that evaluated eight critically ill Chinese pediatric COVID-19 patients treated in the ICU, with ages ranging from 2 months to 15 years, reported increased levels of IL-6, IL-10, and IFN-γ among other laboratory findings (24).

Cytokine storm (CS) is a critical life-threating condition requiring intensive care admission and having a quite high mortality. CS is characterized by a clinical presentation of overwhelming systemic inflammation, hyperferritinemia, hemodynamic instability, and multi-organ failure, and if left untreated, it leads to death. The trigger for CS is an uncontrolled immune response resulting in continuous activation and expansion of immune cells, lymphocytes, and macrophages, which produce immense amounts of cytokines, resulting in a cytokine storm. The CS clinical findings are attributed to the action of the proinflammatory cytokines like IL-1, IL-6, IL-18, IFN-γ, and TNF-α (27).

CS has been reported in several viral infections including influenza H5N1 virus (28, 29), influenza H1N1 virus (30), and the two coronaviruses highly related to COVID-19; “SARS-CoV” and “MERS-CoV” (31, 32). Both pro-inflammatory cytokines (e.g., IL-1, IL-6, and TNF-α) and anti-inflammatory cytokines (e.g., IL-10 and IL-1 receptor antagonist) are elevated in the serum of CS patients. The main contributors to the interplay of the cytokine storm are IL-6 and TNF-α. In the absence of an immediate and appropriate therapeutic intervention, patients develop ARDS as a result of acute lung damage followed by multi-organ failure and resulting in death. Hence, the CS should be treated immediately, otherwise mortality can result (28). In addition to anti-viral therapies that can directly target the virus, anti-inflammatory therapies that diminish the cytokine responses are suggested to decrease both the morbidity and mortality in COVID-19 patients.

The early recognition of CS and the prompt treatment can lead to better outcome. Several biological agents targeting cytokines have been proposed for treating CS. IL-1 receptor antagonist, anakinra, which is used in treatment of rheumatoid arthritis, was proven to be helpful in cytophagic histiocytic panniculitis with secondary hemophagocytic lymphohistiocytosis, a disease associated with severe CS (33). Tocilizumab is a recombinant humanized IL-6 receptor antagonist that interferes with IL-6 binding to its receptor and blocks signaling. Tocilizumab is used in treatment of rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, and has proven valuable in treatment of CS triggered by CAR-T cell therapy for hematological malignancies (34). Downstream inhibitors of cytokines, e.g., JAK inhibitors, are also being explored in treating CS.

As IL-6 is the most frequently reported cytokine to be increased in COVID-19 patients and as IL-6 elevated levels have been associated to higher mortalities, tocilizumab is a candidate drug to be used in managing the cytokine storm accompanying COVID-19. Encouraging results have been reported in China where tocilizumab was used in treatment of 21 patients with severe and critical COVID-19. Clinical data showed that the symptoms, hypoxygenmia, and CT opacity changes were improved immediately after the treatment with tocilizumab in most of the patients, suggesting that tocilizumab could be an efficient therapeutic agent for treatment of the cytokine storm associated with COVID-19 (35). The US Food and Drug Administration (FDA) has approved Roche’s Phase III clinical trial of the use of tocilizumab in hospitalized patients with severe COVID-19 pneumonia. The trial is planned to include 330 patients with severe COVID-19 pneumonia (36).

Cytokine storm appears to be one of the common causes of mortality in the recently declared pandemic of COVID-19. Therapeutic approaches to manage the COVID-19 cytokine storm might provide an avenue to decrease the COVID-19 associated morbidity and mortality and is the focus of upcoming studies.

Author Contributions
All authors contributed to gathering of data, writing, editing, and revising of the manuscript.

Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: COVID-19, cytokine, storm, ARDS, IL-6

Citation: Ragab D, Salah Eldin H, Taeimah M, Khattab R and Salem R (2020) The COVID-19 Cytokine Storm; What We Know So Far. Front. Immunol. 11:1446. doi: 10.3389/fimmu.2020.01446

Received: 14 April 2020; Accepted: 04 June 2020;
Published: 16 June 2020.

Edited by:

Laura Maggi, University of Florence, Italy
Reviewed by:

Remo Castro Russo, Federal University of Minas Gerais, Brazil
Paul Proost, KU Leuven, Belgium
Copyright © 2020 Ragab, Salah Eldin, Taeimah, Khattab and Salem. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Dina Ragab, dinaragab@med.asu.edu.eg

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