July 13, 2024

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Cytokine storm: COVID-19 and deadly diseases

Cytokine storm: COVID-19 and deadly diseases


Cytokine storm: COVID-19 and deadly diseases.

NEJM | A melee of the immune system! How the cytokine storm became the “life-threatening accomplice” of the disease?


As we all know, the immune system is the security guard of our human body.

This guard holds an immune network composed of many immune cells.

When it is invaded or its own cells undergo abnormal changes, the immune system will activate its immune network and immunity The initiation of the network depends on the “correspondents” between the various immune cells-cytokines.


Immune cells release a large number of pro-inflammatory cytokines, such as our common interleukins and tumor necrosis factor, when they resist foreign invasion or clear their own abnormalities.

These cytokines will contact more immune cells to participate in this battle. When the immune system wins, it will reduce the release of cytokines and keep the body stable.


However, when the immune system is over-activated in the process of resistance, which prompts immune cells to produce too many cytokines, it will cause a cytokine storm to occur.

The excessive growth of the “cytokine” team makes it no longer controlled by the immune system. Begin to attack all cells of the body at will, causing systemic inflammation, organ failure, and death.


The rapid spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), also known as the Coronavirus 2019 (COVID-19), reminds us that a cytokine storm may ultimately lead to severe illness or death.

Excessive force of immune cells leads to the occurrence of a cytokine storm, which eventually becomes the deadly accomplice of the virus.

In clinic, cytokine storm has important prognostic and therapeutic significance, so how to correctly evaluate and recognize cytokine storm is very important for clinicians. It is also urgent to find a way to deal with the cytokine storm.



 Cytokine storm, COVID-19 and deadly diseases



Published on December 15, 2020, David C. Fajgenbaum and Carl H. June from the University of Pennsylvania published a review titled “Cytokine Storm” in The New England Journal of Medicine, systematically discussing the definition of cytokine storm,

The pathophysiological characteristics, clinical manifestations and treatment of the syndrome caused by cytokine storm, and the influence of iatrogenic factors on the cytokine storm are described.

In addition, the key cytokines such as tumor necrosis factor are discussed in detail. It plays an important role in the process of storm, and proposes treatment strategies for different cytokines.

Finally, the cytokine storm related to COVID-19 is reviewed.

It provides clinicians with clearer ideas, such as concepts, definitions, staging, evaluation, and treatment tools to help doctors better manage cytokine storms.


Cytokine storm, COVID-19 and deadly diseases




Cytokine storm clinical and laboratory testing


Cytokine storm is characterized by systemic symptoms, systemic inflammation, and multiple organ dysfunction.

If not treated in time, it may lead to multiple organ failure.

The complexity of the immune system and the interdependence of inflammatory mediators make the clinical distinction between normal and abnormal reactions more complicated.


The occurrence and duration of cytokine storms vary with the cause and treatment.

Although the triggers are different, the late clinical manifestations of cytokine storm are similar. Almost all patients with cytokine storm have fever.

In addition, patients may experience fatigue, anorexia, headache, skin rash, diarrhea, arthralgia, myalgia, and neuropsychiatric symptoms.

These symptoms may be directly caused by tissue damage or physiological changes in the acute phase, or may be immune cell-mediated reactions.

Patients can quickly develop diffuse intravascular coagulation, accompanied by vascular occlusion or hemorrhage, dyspnea, hypoxemia, hypotension, vasodilatory shock, and death.


Many patients have respiratory symptoms, including coughing and shortness of breath, and can develop acute respiratory distress syndrome (ARDS), accompanied by hypoxemia, and may require mechanical ventilation.

Excessive inflammation, coagulopathy, and low platelets increase the risk of spontaneous bleeding in patients with cytokine storm.

In severe cases of cytokine storm, renal failure, acute liver injury or cholestasis, stress cardiomyopathy can also develop.


When a cytokine storm occurs, non-specific inflammatory markers such as C-reactive protein (CRP) generally increase.

Many patients have hypertriglyceridemia and various abnormal blood cell counts, such as white blood cell changes, anemia, thrombocytopenia, and elevated levels of ferritin and D-dimer.

Normally, the level of serum inflammatory cytokines will be significantly increased, such as interferon-γ, interleukin-6, interleukin-10 and soluble interleukin-2 receptor alpha (a marker of T cell activation).


For all suspected cases of cytokine storm, a comprehensive infection examination and laboratory evaluation of renal function and liver function should be performed.

Biomarkers of the acute phase of inflammation, such as CRP and ferritin, and blood cell counts should also be measured because they are related to disease activity.

Respiratory assessment is required if necessary.


Because patients may also suffer from diseases other than cytokine storms, such as sepsis, it is more complicated to accurately distinguish cytokine storms.

The most important thing is to distinguish the difference between iatrogenic and systemic infections caused by cytokine storms, because for different The triggers and treatment strategies are very different, so the determination of serum cytokines combined with infection exclusion testing can help determine the cause of the cytokine storm.


Diseases that should be excluded when considering cytokine storms also include allergic reactions and physiological reactions to microbial infections.

Based on the complexity and systemic nature of immune cells, an effective and effective immune status assessment must not only assess the proportion of multiple immune cells, but also assess whether the systemic mode of action among various immune cells is in a normal dynamic equilibrium state.


Serum biomarkers, such as glycoprotein 130 (gp130), interferon-γ and interleukin-1 receptor antagonist (IL1RA), can be used to predict the severity of cytokine storm induced by CAR-T cell therapy.

HScore and MS scores can be used to classify HLH-2004-related cytokine storms and guide treatment.

For the classification of cytokine storm caused by other reasons, the immune system disorder part of CTCAE can be used. The following is the link:


https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ CTCAE_v5_Quick_Reference_5x7.pdf

Cytokine storm, COVID-19 and deadly diseases

Figure 1: Clinical manifestations of cytokine storm





Definition and pathological characteristics of cytokine storm


Distinguishing between protective inflammatory response and pathological cytokine storm is of great significance to treatment, and it is quite challenging.

At present, there is no unified definition of cytokine storm.

There are big differences as to what the definition should be and whether specific circumstances such as COVID-2019 should be included in the scope of cytokine storm disease.

The authors suggest a unified definition of cytokine storm based on the following three criteria: elevated circulating cytokine levels, acute systemic inflammatory symptoms, and any secondary organ dysfunction.

However, no single manifestation of cytokine storm can be judged alone. In view of its complexity, comprehensive consideration is recommended when judging.


The cells of the innate immune system are the first line of defense against pathogens.

Neutrophils, monocytes and macrophages recognize pathogens, produce cytokines, and engulf pathogens and cells through phagocytosis.

There are many other innate immune cells, such as dendritic cells and natural killer cells (NK).

Innate immune cells use pattern recognition receptors to recognize and respond to various microbial invaders by producing cytokines that activate cells of the adaptive immune system.


Neutrophils, macrophages and NK cells are most commonly involved in the pathogenesis of cytokine storm. Neutrophils help thrombus formation and promote the production of cytokines during cytokine storms.

Macrophages have multiple functions, can remove senescent cells through phagocytosis, and have tissue repair, immune regulation and antigen presentation effects.

Macrophages are over-activated and secrete excessive cytokines, which eventually leads to severe tissue damage, which may lead to organ failure.

Certain functions of NK cells are weakened in certain forms of cytokine storm.


The adaptive immune system is composed of B cells and T cells.

T cells differentiate into a series of subgroups with unique effector cell functions, and may participate in cytokine storms. Iatrogenic causes of cytokine storms involving excessive activation of T cells, such as CAR-T cells and anti-CD28 antibody therapy, indicate that activated T cells have the ability to trigger cytokine storms.

B cells are not often involved in the pathogenesis of cytokine storms.

However, B cell depletion is effective in the treatment of certain cytokine storm diseases, such as human herpes virus 8 (HHV-8)-related multicentric Castleman disease.


The cytokine storm disorder is related to the complex and interconnected network between cell types, signal pathways and cytokines. Interferon-γ, interleukin-1, interleukin-6, TNF, and interleukin-18 are key cytokines that are often elevated in the cytokine storm, and are considered to have central immunopathological effects.

The specific immune cells that secrete various cytokines are not yet fully understood, and there are likely to be differences in cytokine storm disorders.






At present, some immunosuppressants are often used clinically to regulate the cytokine storm, so that the immune response in the body is in the normal range, which can eliminate the virus without overly killing normal tissue cells.

Therefore, in the process of clinical treatment for cytokine storm, attention should be paid to controlling and slowing down the cytokine storm response, and at the same time, the dosage should be accurately controlled to avoid excessive suppression of immune response caused by excessive drug dose.

It can be seen that the most important thing about immunity is balance. If immunity is too weak, it is vulnerable to external viruses and bacteria.

If it is too strong, it is easy to “kill 800 enemies and self-destruct one thousand.”


Interleukin-1 receptor antagonist Anakinra is effective against cytokine storm when used alone or in combination with other drugs.


Interleukin-6 is an important mediator of acute inflammatory response and is the pathophysiological characteristic of cytokine storm.

Its level is highly elevated in various potential immunopathological lesions and in mouse models of cytokine storm. .

Tocilizumab is a monoclonal antibody that targets the interleukin-6 receptor and is one of the first targeted therapies to remove the cytokine storm.

Stuximab directly neutralizes interleukin-6 and has been shown to be effective for many cytokine storm diseases.

Therefore, tocilizumab and stuximab have been developed and approved by regulatory agencies in Japan, the United States and dozens of other countries for the treatment of Castleman disease.


TNF is a powerful, multifunctional, and pro-inflammatory cytokine. In addition to inducing fever, enhancing systemic inflammation and activating interleukin-6, TNF can also induce apoptosis and regulate immunity.


Plasma proteins such as complement proteins and other inflammatory mediators can participate in the pathogenesis of cytokine storm.

In the cytokine storm, hypocomplementemia caused by increased consumption of immune complexes can be observed.

Several complement inhibitors are being evaluated for the treatment of cytokine storm diseases.



Figure 2: Pathological characteristics of cytokine storm



Figure 3: T cell effector groups involved in cytokine storm



Figure 4: Soluble mediators in the cytokine storm.





Causes of cytokine storm


Cytokine storm and cytokine release syndrome are life-threatening systemic inflammatory syndromes that can be caused by various therapies, pathogens, cancer, autoimmune conditions, and single-gene diseases.


The iatrogenic causes of the cytokine storm include: CAR-T cells that can recognize and eliminate CD19+ lymphoma cells, Bonatumumab, and others including rituximab, gene therapy, immune checkpoint inhibitors, and heart bypass Surgery, allogeneic stem cell transplantation, and Staphylococcal enterotoxin B and Francis bacteria.


Cytokine storms can also be caused by natural microbial infections. For example, bacterial infections that cause sepsis can induce the production of many cytokines, which can cause fever, cell death, coagulation, and multiple organ dysfunction.

When trying to eliminate pathogens, the collateral damage caused by the immune response may be more deadly than the pathogen itself.

Patients who have hyper-inflammatory response to microorganisms usually have defects in pathogen detection, effector and regulatory mechanisms, or inflammation resolution.


Other microorganisms can trigger a cytokine storm, including herpes virus, and some influenza viruses, such as H5N1 avian influenza virus.

Intravenous immunoglobulin and convalescent plasma injections are sometimes used to help control pathogens.

For some viral infections, treating patients with pro-inflammatory cytokines in the early stages of infection can help control the virus before the immune response has harmful effects.


In addition, interleukin-6 is the driving factor for most patients.


Figure 5: Clinical causes, pathological drivers and treatment methods of cytokine storm





Cytokine storm and COVID-19


Cytokine storms have also been reported in COVID-2019 patients, and they are associated with poor prognosis.

Reports of increased cytokine levels in COVID-2019 patients and the therapeutic effectiveness of immunosuppressant drugs, especially for severely ill patients, indicate that cytokine storm may be the pathogenesis of COVID-19.


In COVID-19 patients, CD4 + and CD8 + T cells are activated at high frequency and plasma cells are increased.

In addition to the increase in systemic cytokine levels and activation of immune cells, there are also some clinical and laboratory abnormal data showing that, such as C-reactive protein increase High and pulmonary embolism levels, hypoalbuminemia, renal dysfunction, and pleural effusion indicate the occurrence of cytokine storm disorder.


Laboratory test results also reflect the occurrence of excessive inflammation and tissue damage. However, it is unclear whether the cytokine storm is a driver of COVID-19 or a secondary process.

Two large, randomized, controlled trials of anti-interleukin-6 receptor antibody therapy have not shown that it is beneficial to the survival of COVID-19 hospitalized patients.


Lymphopenia is not common in cytokine storm disease, but it is a sign of severe COVID-19.

It is unclear whether the lymphopenia observed in COVID-19 is due to tissue infiltration or lymphocyte destruction.


The choice of treatment time when using immunosuppressants can also have an important impact on the results.

Although the role of immune disorders and cytokines in the treatment of COVID-19 is unclear, hundreds of immunomodulatory drugs are being studied.

Kanazumab, an anti-interleukin-1 beta monoclonal antibody, and anakinra have been used to study acute respiratory distress syndrome caused by COVID-19.



Sum up:


Under the cytokine storm, there are more drugs that may be effective for many diseases, but research has not yet been conducted.

Considering that there are more and more new therapies targeting the immune system, further research should focus on the identification of drugs and precise medication for different patients.

In addition, the predictive role of biomarkers cannot be ignored.


The various treatments mentioned in this article have their specific side effects and risks.

All targeted drugs have targeted specific risks, and combination therapy has greater potential risks than single-agent therapy.

In addition, pathological excessive inflammation itself is a kind of immunodeficiency, which can expose patients to the risk of infection, and immunosuppressants are very likely to further increase the risk.


In this era of accurate cytokine analysis and individualized treatment, the author suggests that when empirical treatment is carried out, patients must be monitored and appropriate preventive measures should be given, and randomized controlled trials should be conducted to assess efficacy and safety.


The advancement of research and treatment of cytokine storms requires the collection of samples for omics research and the cooperation of experts with different expertise.

It is expected that a scientific breakthrough will be made in the personalized treatment of cytokine storms guided by biomarkers.






Cytokine storm: COVID-19 and deadly diseases

(sourceinternet, reference only)

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