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A cytokine storm means a violent inflammatory reaction that gets out of control of our body. Normally, the inflammatory response to a viral infection, for example, is self-limiting, but in some people the activation of the immune system is so strong that it can damage many organs and eventually even die. Recent studies have proven that cytokine storm is one of the major causes of death in people suffering from COVID-19.


  1. Cytokine storm - what is it?
  2. Cytokine storm - mechanism of formation
  3. Cytokine storm - causes
  4. Cytokine storm - consequences
  5. Cytokine storm - symptoms
  6. Cytokine storm - treatment
  7. Cytokine storm - COVID-19 and other pandemics

Cytokine storm - what is it?

Cytokine stormakahypercytokineemia , or cytokine cascade, is an excessive and uncontrolled immune system response that releases massive amounts of pro-inflammatory substances. Untreated cytokine storms can lead to serious complications such as sepsis, shock, tissue damage, and multi-organ failure, with subsequent death.

Cytokine storm is not classified as a disease entity, but as a complex of immune responses that may appear in the course of various clinical conditions, e.g. infectious diseases.

The term "cytokine storm" was first used in 1993 to describe the effects of graft versus host disease that can occur in the recipient's body after organ transplantation. In 2003, it was also shown that a cytokine storm may be related to the body's response to infection by viruses, bacteria or fungi.

The term "cytokine storm" seems to be used for the first time in the context of infection with the H5N1 avian influenza virus in 2005. Then it began to be used more and more commonly in the scientific literature.

Cytokine storm - mechanism of formation

The initiation of a cytokine storm may occur, for example, during an infection with an influenza virus. After infection, the virus enters the epithelial cells of the upper and lower respiratory tract through the process of endocytosis. Then the viral genetic material is recognized by the so-called pathogen-related molecular patterns (PAMP for short), which in turn can initiate a system responseimmune system, including a cytokine storm.

During a cytokine storm, the cells of the immune system are rapidly activated. Rapid division of T lymphocytes and B lymphocytes, monocytes, macrophages, dendritic cells and NK cells and their overproduction of over 150 different cytokines.

A feature of the cytokine storm is the loss of negative feedback by the immune system, which physiologically inhibits the excessive production of pro-inflammatory cytokines. Release of cytokines induces the release of further cytokines, which initiates an unstoppable chain reaction. It comes to a kind of self-propelling vicious circle.

Cytokines are a diverse group of small molecules that are mainly secreted by cells in the immune system to communicate with each other. The most important functions of cytokines are the control of division and differentiation of immune cells and the regulation of the inflammatory response.

Cytokines include proteins such as:

  • Interferons (IFNs) which play a major role in innate immunity to viruses and other microbes
  • Interleukins (IL), which primarily regulate the differentiation and activation of immune cells. They can be pro-inflammatory (activating the inflammatory response) or anti-inflammatory (inhibiting the inflammatory response)
  • Chemokines act as substances that "attract" cells of the immune system and thus control their movement to the sites of inflammatory reaction
  • Colony stimulating factors (CSF) control hematopoiesis, the process of producing mature immune cells from blood stem cells
  • Tumor necrosis factor (TNF) is perhaps the most studied pro-inflammatory cytokine that plays a central role in the cytokine storm

Cytokine storm - causes

Factors leading to a cytokine storm are associated with a wide variety of infectious and non-communicable diseases. Infectious agents include:

  • group A streptococci
  • cytomegalovirus
  • Epstein-Barr virus
  • Ebola virus
  • flu virus
  • pox virus
  • coronaviruses e.g. SARS-CoV, MERS-CoV

Non-infectious factors include:

  • graft versus host disease
  • multiple sclerosis
  • juvenile idiopathic arthritis
  • pancreatitis
  • cancer e.g. lymphoma
  • biological therapies e.g. rituximab
  • hemophagocytic syndrome
  • macrophage activation syndrome

One of the biggest mysteries surrounding the cytokine storm iswhy some people appear to be particularly vulnerable and others resistant to the development of a cytokine storm. This is probably related to the genetic variability of the immune response in the human population.

Cytokine storm - consequences

Cytokine storm is an important cause of death in patients infected with viruses such as Ebola, Marburg, coronaviruses, and pandemic flu. Acute lung injury (ALI) is a common consequence of a cytokine storm in viruses affecting the lungs, such as SARS-CoV and influenza viruses.

ALI is characterized by an acute inflammatory response from lung tissue followed by a chronic phase of lung collagen deposition and fibrosis. Over time, ALI may develop into its more severe form, i.e. acute respiratory distress syndrome (ARDS).

Local pneumonia can spread through the circulatory system to the rest of the body, wreaking havoc in other organs. Eventually one can observe a severe clinical syndrome in the form of sepsis.

People with severe infection-related sepsis show characteristic blood cytokine profiles that change over time. The acute response cytokines are TNF, interleukin-1 and 8, which appear early minutes or hours after infection followed by a marked increase in interleukin-6 levels. The anti-inflammatory interleukin-10 appears slightly later as the body tries to control the acute systemic inflammatory response.

In addition to lung infections, cytokine storm is a consequence of severe infections of the gastrointestinal tract, urinary tract, central nervous system, skin and joint spaces.

Cytokine storm - symptoms

  • fever
  • fatigue
  • loss of appetite
  • muscle and joint pain
  • nausea and vomiting
  • diarrhea
  • drop in blood pressure
  • accelerated heartbeat
  • convulsions
  • headache
  • delirium and hallucinations
  • entanglement
  • rash

On the other hand, high levels are found in laboratory tests:

  • nitrogen compounds in the blood
  • D-dimers
  • aminotransferaz
  • ferritin
  • CRP proteins
  • interleukins-6
  • lactate dehydrogenase
  • extended prothrombin time
  • decreased platelet count

Cytokine storm - treatment

Currently, there is no single cytokine storm therapy and drugs specifically designed to treat it. The main approach in treating this syndrome is to induce immunosuppression, i.e.a decrease in the reactivity of the immune system. For this purpose, drugs such as:

  • corticosteroids
  • cytokine inhibitors e.g. tocilizumab

Cytokine storm - COVID-19 and other pandemics

Accumulating clinical evidence suggests that a subset of severe COVID-19 patients due to SARS-CoV-2 virus infection may exhibit cytokine storm syndrome.

A multicenter retrospective study published by Ruan et al. That analyzed 150 confirmed COVID-19 cases found that COVID-19 mortality may be due to a virus-activated cytokine storm. In these patients, increased levels of ferritin and interleukin-6 in the blood were observed. This may have important implications for the treatment of the disease, as currently COVID-19 treatment is supportive.

Therefore, it is suggested that patients with severe COVID-19 should be screened for cytokine storms (e.g. by measuring ferritin) to identify a subset of patients for whom immunosuppressive treatment would be effective. This new therapeutic approach is being tested at the Department of Infectious Diseases of the Independent Public Clinical Hospital No. 1 in Lublin.

A cytokine storm may explain the death rate among young people from COVID-19, as a similar situation was observed in 1918 during the Spanish flu pandemic. Back then, more than half of the deaths occurred in he althy people between the ages of 18 and 40 and were caused by the cytokine storm that led to the acute respiratory distress syndrome.

On the other hand, the phenomenon of the cytokine storm explains why children experience a milder infection with the SARS-CoV-2 virus. Their immune system is just underdeveloped and does not react as violently to the presence of the virus.

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About the authorKarolina Karabin, MD, PhD, molecular biologist, laboratory diagnostician, Cambridge Diagnostics Polska A biologist by profession, specializing in microbiology, and a laboratory diagnostician with over 10 years of experience in laboratory work. A graduate of the College of Molecular Medicine and a member of the Polish Society of Human Genetics. Head of research grants at the LaboratoryMolecular Diagnostics at the Department of Hematology, Oncology and Internal Diseases of the Medical University of Warsaw. She defended the title of doctor of medical sciences in the field of medical biology at the 1st Faculty of Medicine of the Medical University of Warsaw. Author of many scientific and popular science works in the field of laboratory diagnostics, molecular biology and nutrition. On a daily basis, as a specialist in the field of laboratory diagnostics, he runs the content department at Cambridge Diagnostics Polska and cooperates with a team of nutritionists at the CD Dietary Clinic. He shares his practical knowledge on diagnostics and diet therapy of diseases with specialists at conferences, training sessions, and in magazines and websites. She is particularly interested in the influence of modern lifestyle on molecular processes in the body.

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