A new approach to treating COVID-19: IL-6 antagonists target cytokine storm – treating different diseases: severe COVID and tumor immunotherapy-associated pneumonia

introduction

Academician Zhou Qi, academician of the Chinese Academy of Sciences, said that cytokine storm (CS) is an important node for the transition of mild disease to severe and critical disease in patients with new crown infection, and it is also an important cause of
death from severe and critical illness 。 At present, the new crown virus infection is still in the pandemic stage, and the "immune war" between the human body and the new crown virus has aroused the public's attention to the autoimmune system, so how should this "storm" caused by the overreaction of the immune system be stopped? In this issue, we will explore the mechanism of cytokine storm and IL-6 in patients infected with new coronavirus infection, and provide the latest interpretation
of the clinical results of related treatment options.

Director Zhou Chengzhi, a respiratory oncologist at the National Center for Respiratory Medicine, said: IL-6 antagonist, which has been used in the treatment of tumor by immune checkpoint inhibitors, caused by severe immune adverse reactions, especially drugs often used during immune pneumonia, in some severe patients caused by COVID-19, for cytokine storm, clinical practice has proved to be a good treatment
.

Cytokine storm - the "deadly accomplice" of the new crown virus

By hijacking the immune system, the new coronavirus causes an imbalance in the body's immune regulatory network, excessive release and accumulation of pro-inflammatory factors, and a cytokine storm, causing immune damage to tissues and organs ^[1].

➤ At present, the pathogenesis of cytokine storm caused by the new coronavirus is not clear, and previous studies of cytokine storms caused by viral infection have shown that the pathological process is as follows (Figure 1):

• First, viral RNA is sensed by the innate immune system, initiating a rapid antiviral signaling cascade pathway, and infected lung epithelium, endothelium, and other immune cells produce primary cytokines (type I and III IFN, IL-1β, IL-18, TNF-α, IL-6, IL-33, etc.
  ), mainly limiting viral replication and spread, and initiating downstream immune responses ^[2].
  
  

• Subsequently, primary cytokines recruit and activate CD8+ T cells, NK cells, Treg cells, and Th2 cells, and secrete secondary cytokines (IFN-γ, IL-10, bitonin and IL-5) to eliminate viral and viral infections, inhibit inflammation, and promote recovery of lung function^[2].
  
  

Figure 1: Cytokine storm after viral infection^[2].

➤ During the new crown virus infection, the role played by inflammatory cytokines is also changing
.

• In the early stages of infection, cytokines act only on cells that the virus invades and play a protective role: the virus enters the upper respiratory tract (nasa, pharynx), releases RNA, and replicates in the lower respiratory tract and enters the bloodstream
  .
  Dendritic cells, macrophages, and respiratory epithelial cells secrete cytokines and chemokines to generate an immune response and eliminate pathogens
  .
  As a result, patients are usually asymptomatic at this stage ^[3].
  
  

• Subsequently, the inflammatory pathway is activated, producing a cytokine storm: at this stage, the immune system is overactivated, cytokines are overproduced, vascular permeability increases, blood is hypercoagulable, and host cells are damaged, leading to hypoxia, shock, and even death ^[3] (Figure 2).
  
  

Figure 2: Coronavirus and cytokine storm^[3].

IL-6 – one of the "key factors" of the cytokine storm

IL-6 is one of the key cytokines involved in infection-induced cytokine storms and has complex
manifestations in cytokine storms.

➤ IL-6 is an important pro-inflammatory cytokine that is released during infection or tissue damage, promoting innate and acquired immune responses
.

➤ IL-6 is involved in the progression of viral diseases, ultimately favoring the persistence of the virus in infected hosts (Figure 3):

Figure 3 Role of IL-6 in respiratory viral infections^[4].

• Th1 cell-derived IFNγ is essential
  for an effective antiviral immune response.
  However, IL-6 may inhibit Th1 polarization by stimulating CD4+ cells to differentiate into Th2 cells or inhibiting IFNγ expression, thereby blocking CD8⁺ and NK cell-mediated cytolysis^[4].
  
  

• IL-6 works synergistically with IL-1b and TNF to upregulate the expression of trypsin, thereby activating matrix metalloproteinases (eg, mmp-9), causing the breakdown of the basement membrane and extracellular matrix, which in turn leads to increased tissue permeability and edema^[4].
  
  

• IL-6 can promote Th17 cell differentiation and IL-17A secretion, and activate the expression of anti-apoptotic molecules (such as Bcl-XL), thereby favoring the survival of virus-infected cells^[4].
  
  

• IL-17 promotes neutrophil migration and survival while promoting the onset of COVID-19-driven acute respiratory distress syndrome ^[4].
  
  

Sttuximab – one of the "drug candidates" to improve the inflammatory phase

➤ Study Design: Studies involving a variety of participants and treatment interventions were analysed by searching the clinical trial literature for siltuximab in MEDLINE, PubMed, ClinicalTrials.
gov, and other official databases
.
All adult patients included were critically ill with severe respiratory disease due to COVID-19 ^[5].

➤ Research results:

• IL-6 signal transduction pathway :(1) Classical signal transduction pathway, IL-6 binds to a complex composed of membrane-bound IL-6 receptors and gp130, followed by activation of the JAK-STAT3 pathway transduction signaling
  .
  (2) Trans signal transduction pathway, IL-6 binds to soluble IL-6 receptors present in serum and interstitial fluid^[5].
  
  

• Strategies to block the IL-6 pathway: can be achieved by different mechanisms, inhibiting IL-6 itself (stuximab), through its receptors (tocilizumab, sarilumab) or kinases (such as JAK/STAT), etc.
  ^[5].
  
  

• Sttuximab, which specifically binds to IL-6 and thereby inactivates IL-6-induced signal transduction, has been approved by the FDA and EMA (Figure 4).
  
  In Spain, stuximab has been used as an off-label and special-use treatment for severe respiratory infections with COVID-19 ^[5].
  
  

Fig.
4 Mechanism of action of stuximab^[5].

• Results from a retrospective, single-center, observational, cohort study suggest that stuximab reduces excessive inflammatory response and mortality in patients with severe COVID-19 ^[5].
  
  

➤ Conclusion: Sttuximab can reduce the level of IL-6, thereby reducing the inflammatory process in patients with severe new coronary pneumonia, and can be used to prevent cytokine release syndrome and death caused by this cause ^[5].

brief summary

Cytokine storm plays an important role in the new crown virus infection and is one of
the "accomplices" behind the death of severely ill patients.
IL-6, as a key factor in cytokine storm, promotes inflammation and participates in disease progression
after novel coronavirus infection.
There is growing evidence that inhibition of IL-6 signaling is a favorable clinical strategy
for the treatment of various inflammatory diseases.
Recent clinical studies have also demonstrated that the IL-6 inhibitor stuximab can bring significant clinical benefits
to patients with severe new coronavirus infection.
Therefore, in clinical work, the level of cytokines such as IL-6 should be closely monitored, the cytokine storm should be correctly identified, evaluated, and targeted treatment should be given in time to prevent disease progression and reduce mortality
.

Expert profiles

Professor Zhou Chengzhi

Chief physician, doctoral supervisor

Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Director of Clinical Diagnosis and Treatment Department, Deputy Director of Respiratory and Critical Care Department, Director of Oncology District 1, Assistant Director of Cancer Center
, Director of Cancer Center.

He took the lead in proposing the concept of "severe lung cancer" in the world, and led the publication of the first version of the "International Consensus on Severe Lung Cancer"
.
The whole management concepts
of lung cancer such as "cancer lung treatment", "PS score is reversible and fluctuating", and "anti-tumor drug upgrading" were proposed.

Academic Appointments:

• Deputy leader of the lung cancer group of the respiratory branch of the Chinese Medical Association

• Member of the Lung Cancer Working Group of the Respiratory Branch of the Chinese Medical Doctor Association

• Secretary-General of the China Respiratory Oncology Collaborative Group (CROC) and Vice Chairman of the Youth Committee

• Member of the Youth Committee and Patient Education Committee of the Chinese Society of Clinical Oncology (CSCO).
  

• Chairman of the Tumor Critical Care Committee of Guangdong Thoracic Oncology Society

• Chairman of the Lung Cancer Branch of Guangdong Precision Medicine Application Society

• Deputy leader of the Lung Cancer Group of the Respiratory Disease Branch of Guangdong Medical Association

• Vice Chairman of the Lung Oncology Branch of Guangdong Medical Association

• Vice Chairman of Medical Oncology Branch of Guangdong Medical Doctor Association

• Vice Chairman of Lung Cancer Branch and Real World Research Branch of Guangdong Clinical Medical Association

References:

[1] Shi Hao, et al.
Research progress of traditional Chinese medicine in the prevention and treatment of COVID-19 cytokine storm[J].
Liaoning Journal of Traditional Chinese Medicine,2022,49(12):216-220+226.
)

[2] Guo XJ et al.
Semin Immunopathol.
2017 Jul; 39(5):541-550.

[3] Zhu Sheng, et al.
Understanding severe new coronary pneumonia from excessive inflammatory response[J].
Journal of Practical Shock(Chinese-English),2020,4(06):331-333.
)

[4] Gubernatorova EO, et al.
IL-6：Relevance for immunopathology of SARS-CoV-2.
Cytokine Growth Factor Rev.
2020 Jun; 53：13-24.

[5] Villaescusa L,et al.
A New Approach to the Management of COVID-19.
Antagonists of IL-6: Siltuximab.
Adv Ther.
2022 Mar; 39(3):1126-1148.

Edit: Smile

Revised: Tessie

Typesetting: Uni

Execution: Yuna

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