Cytokine storm

Inflammation is a process that is necessary in the body’s defense against harmful microorganisms (pathogens) and tissue repair, and is triggered by the activation of innate and adaptive immune cells. Inflammation is a strictly regulated process that provides adequate activation of immune cells and the release of sufficient amounts of cytokines and other mediators to remove pathogens, but it is a process in which regulatory mechanisms of negative feedback mechanisms prevent overactivation (hyperactivation) of immune cells, stop inflammation and restore homeostasis.

The term cytokine storm was first used in the literature three decades ago to describe an inflammatory syndrome during a graft-versus-host reaction following allogeneic hematopoietic stem cell transplantation. The term “cytokine release syndrome” was coined to describe a similar systemic inflammatory syndrome following infusions of anti-CD3 antibodies (muromonab). One decade ago, a cytokine storm was first described that developed after the treatment of oncological diseases with T cells with a chimeric antigen receptor (T cells therapy-CAR therapy).

1. What is a cytokine storm?

Cytokine storm is a systemic inflammatory syndrome that is life-threatening and is characterized by excessive activation of immune cells and elevated levels of cytokines in the blood. A cytokine storm occurs when there is a disorder in the regulation of immune cell activity that results in excessive cytokine release.

Three criteria determine the diagnosis of a cytokine storm:

  1. elevated levels of cytokines in the blood,
  2. symptoms of acute systemic inflammation
  3. secondary disorders of the organs (kidneys, liver, lungs)

Disorders of the function of several organ systems can lead to organ failure and death if adequate treatment is not taken.

2. What are cytokines?

Cytokines are low-molecular-weight proteins that regulate various processes in the body, including the immune response and inflammation. Cytokines are regulatory molecules necessary in the body’s defense against harmful microorganisms because they enable communication between the cells of the immune system, direct, strengthen or stop the immune response and inflammation.

The large family of cytokines includes interleukins, interferons, chemokines, growth factors, the tumor necrosis factor family, and adipokines. They are formed in T and B lymphocytes, macrophages, dendritic cells, neutrophils and other cells outside the immune system and bind to specific receptors on the membranes of target cells.

Some cytokines trigger, maintain and enhance inflammation, while others have anti-inflammatory properties. In addition to their role in regulating the functions of innate and adaptive immune cells during infection, cytokines play an important role in tissue repair, wound healing, angiogenesis, tumorigenesis, and neurobiological processes.

3. What are the causes of cytokine storm?

Cytokine storm can occur for several reasons. It can develop during bacterial (sepsis) and viral infections (SARS-CoV-2, EBV infections in predisposed individuals), but infectious agents are not the only causes of this systemic inflammatory syndrome. Cytokine storm can be iatrogenic induced, ie after the use of some biological drugs (anti-CD19 and anti-CD3 antibodies, CAR T cell therapy of malignant diseases), as part of autoimmune and malignant diseases, as well as congenital disorders of the immune system in which due to mutations in certain genes inflammation occurs in the absence of pathogens (autoinflammatory diseases).

4. How does a cytokine storm form?

Cytokine storm occurs due to dysregulation of immune processes, which results in excessive and continuous release of cytokines and their increased levels in the circulation when they can have systemic effects and cause damage to vital organs.

Immune cell hyperactivation and cytokine storm can occur as a result of:

  • Inappropriate activation of immune cells in the absence of pathogens (eg in genetic disorders involving inappropriate activation of inflammasome (autoinflammatory diseases) or as part of idiopathic multicentric Castleman’s disease)
  • Inadequate or ineffective immune response characterized by overactivity of effector immune cells, such as CAR T-cell therapy, sepsis, or uncontrolled infection with prolonged immune cell activation (eg, haemophagocytic lymphohistiocytosis (HLH) associated with Barr virus infection). EBV)
  • Failure to resolve the immune response and return to homeostasis (eg in primary HLH)

In each of these conditions, there are failures in negative feedback mechanisms that prevent hyperinflammation and excessive production of inflammatory cytokines. Immunosuppressive effects that antagonize proinflammatory cells and cytokines are exerted by regulatory immune cells (e.g., regulatory T and B lymphocytes), as well as anti-inflammatory cytokines such as IL-10 or receptor antagonists for proinflammatory cytokines such as IL-1 receptor antagonist (IL-1RA ) and other anti-inflammatory cytokines.

5. Which cells and cytokines participate in the cytokine storm?

The cells of the innate immune system are the first line of defense against pathogens. Neutrophils, monocytes and macrophages recognize pathogens, produce cytokines, and destroy pathogens by phagocytosis. Other cells of the innate immune system, such as dendritic cells, gamma-delta T cells and natural killer-NK cells, also participate in the body’s defense against pathogens. Innate immune cells use pattern recognition receptors (PRRs) to recognize a wide range of microbes.

The innate cells in which they are most commonly involved in the pathogenesis of the cytokine storm are neutrophils, macrophages and NK cells. In a cytokine storm, neutrophils and macrophages are activated and secrete excessive amounts of cytokines, causing serious tissue damage that can lead to organ failure. Hemophagocyte macrophages are often observed in the bone marrow of patients with cytokine storm. Interferon-gamma (IFN-γ) can induce macrophage hemophagocytosis, which contributes to the development of cytopenia observed in some patients with cytokine storm. The cytolytic function of NK cells is reduced in some forms of cytokine storm, which can lead to prolonged antigenic stimulation and excessive inflammatory process. High concentrations of IL-6 can impair NK cell function by reducing the production of cytolytic molecules of perforin and granzyme.

The cells of the adaptive immune system are T and B lymphocytes. Helper T (Th1) lymphocytes of type 1 and cytotoxic T lymphocytes (CTL) are primarily responsible for defending the host from viral infections. Th1 cells regulate macrophage recruitment, while Th2 cells recruit eosinophils and basophils, Th9 cells recruit mast cells, and Th17 cells recruit neutrophils. Excessive inflammatory response of Th1 cells often occurs during a cytokine storm. Th1 cells produce large amounts of IFN-γ, induce late hypersensitivity reactions, activate macrophages, and are necessary for defense against intracellular pathogens. Iatrogenic causes of cytokine storm involving excessive T-cell activation, such as CAR T-cell therapy, administration of anti-CD28 antibodies, indicate the ability of activated T cells to trigger a cytokine storm. CTLs are key cells in some forms of cytokine storm. In conditions in which there are disorders of CTL to effectively kill pathogens, there is a prolonged activation of T cells, which triggers a cascade of inflammatory reactions and tissue damage. Th17 cells play a major role in the body’s defense, especially against fungal infections, and altered Th17 cell function can mediate autoimmunity. Th17 with its cytokines can be the triggers of a cytokine storm that is independent of IFN-γ. B cells are not often associated with the pathogenesis of the cytokine storm, but human herpes virus 8 (HHV-8) – associated multicentric Castleman disease, suggests that B lymphocytes are capable of triggering a cytokine storm especially when there is a viral infection.

The cytokines IFN-γ, IL-1, IL-6, tumor necrosis factor (TNF) and IL-18 play a central role in tissue and organ damage in a cytokine storm.

cytokine storm

6. Clinical features and laboratory abnormalities of cytokine storm

Cytokine storm is a term that encompasses several disorders of immune regulation which is characterized by systemic inflammation and multiorgan dysfunction which can lead to organ failure and death if adequate treatment is not undertaken. The onset and duration of cytokine storm varies depending on the cause and the treatment applied. Although the initial the causes can vary, the clinical manifestations in the late phase of the cytokine storm are similar and often overlap.

Clinically, almost all patients with cytokine storm have fever. Fatigue, anorexia, headache, rash, diarrhea, arthralgia, myalgia, and neuropsychiatric disorders are present.

These symptoms can be directly caused by cytokines and activated immune cells.

The development of a cytokine storm can be rapid, causing disseminated intravascular coagulation (DIC), either with vascular occlusion or catastrophic bleeding, and dyspnea, hypoxemia, hypotension, vasodilatory shock, and death may occur. Many patients have respiratory symptoms, including cough and rapid breathing, which can progress to acute respiratory distress syndrome (ARDS), with low blood oxygen levels (hypoxemia) that may require mechanical ventilation. In severe cases of cytokine storm, renal failure, liver dysfunction and cardiomyopathy may develop, and in a later phase, encephalopathy.

Assessing the condition of patients with cytokine storm has three main objectives:

  1. identification of the underlying disorder (and exclusion of disorders that may mimic a cytokine storm),
  2. determining the severity of the cytokine storm and
  3. determination of clinical characteristics

Laboratory findings in a cytokine storm are variable and depend on the underlying cause.

Microbiological analysis is performed to determine the existence of infection, then analysis to assess kidney and liver function, as well as measurement of arterial blood gases to assess the function of the respiratory system should be performed.

Nonspecific inflammatory markers such as C-reactive proteins (CRP) and ferritin are elevated and correlate with disease severity. Many patients have hypertriglyceridemia and various abnormalities in the blood count, such as leukocytosis, leukopenia, anemia, thrombocytopenia, and elevated ferritin and d-dimer levels. Changes in blood cells are a consequence of a complex mutual cytokine-induced interactions, such as bone marrow cell mobilization, cytokine-induced cell destruction, and chemokine-mediated cell migration. There are elevated serum concentrations of inflammatory cytokines, such as IFN-γ, (or CXCL9 and CXCL10, chemokines induced by IFN-γ), IL-6, IL-10, soluble IL-2 receptor alpha (marker of T-cell activation).

High elevated serum IL-6 levels are present in the cytokine storm induced by CAR T-cell therapy with storm T-cells and in several other cytokine storms caused by other causes.

cytokine storm

7. What is cytokine storm therapy?

The general strategy for the treatment of cytokine storm includes therapy to maintain the function of vital organs, control the underlying disease and, when possible, eliminate the triggers of abnormal activation of immune cells. Depending on the causes that led to the cytokine storm, targeted immunomodulatory therapy (blockade of certain inflammatory cytokines, eg blockade of IL-6) or non-specific immunosuppressive therapy (corticosteroids) is used.

The development of the cytokine storm is thought to be influenced by underlying causes, associated chronic diseases (especially autoimmune and malignant diseases), and congenital genetic disorders of the immune system.

Covid-19, caused by SARS-CoV-2, is characterized by symptoms ranging from mild fatigue to life-threatening pneumonia, a cytokine storm and multi-organ dysfunction.

The cytokine storm is thought to be fatal in patients with severe Covid-19. The mechanisms of damage to the lungs and other organs in Covid-19 are not fully known and are the subject of ongoing research. Elevated blood cytokine levels and beneficial effects of immunosuppressive therapy (IL-6 blockade, corticosteroids) in patients with severe Covid-19 suggest that the cytokine storm may contribute to the pathogenesis of severe Covid-19.

If you have questions, comments and suggestions for topics I will be happy to answer.

Literature and images from: Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med. 2020 Dec 3;383(23):2255-2273. doi: 10.1056/NEJMra2026131. PMID: 33264547; PMCID: PMC7727315.

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