Cytokine storm

A cytokine storm is an excessive or uncontrolled release of proinflammatory cytokines. Cytokines associated with cytokine storm include interferons (IFNs), interleukins, chemokines, colony-stimulating factors (CSFs) and tumor necrosis factor (TNF). Cytokine storms are associated with infectious and non-infectious diseases.Cytokine storm is also known as cytokine storm syndrome (CSS), cytokine release syndrome, macrophage activation syndrome and hemophagocytic lymphohistiocytosis.

The term cytokine storm was first used in 1993 to describe the effects of graft-versus-host disease (GVHD), a condition that may occur after an organ or cell transplant, if donor cells have an immune response against the cells of the recipient. Cytokine storm is associated with the host reaction to influenza and various viral, bacterial or fungal infections. A cytokine storm occurs during sepsis, which is characterized by systemic inflammatory response to infection. As of 2016 the definition of sepsis states the “Sepsis is a life-threatening organ dysfunction due to a dysregulated host response to infection”. Cytokine storm is a consequence of severe infections in the lung, gastrointestinal tract, urinary tract, central nervous system, skin, joint spaces and other sites. Cytokine storms are a common complication of respiratory diseases caused by influenza viruses such as H5N1 and coronavirus diseases such as SARS, MERS and COVID-19. Non-infectious diseases associated with cytokine storm include multiple sclerosis and pancreatitis.

Cytokine storms cause inflammation at a local site that spreads throughout the body via the circulation. Inflammatory responses include increased blood flow to allow vascular leukocytes and plasma proteins to reach sites of injury. Increase in local temperature and swelling can be advantageous in host defense but can cause tissue damage, which is normally repaired. With severe inflammation, healing occurs through a process called fibrosis, which results in organ dysfunction. Cytokine storm in the alveoli of the lung can lead to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In ALI an acute mononuclear/neutrophilic inflammatory response is followed by a phase of progressive collagen deposition in the lung.

It is thought that risk factors in the host, such as genetic mutations, contribute to the likelihood that some patients but not others develop a cytokine storm response to infection. Cytokine storm syndrome (CSS) can be screened using an elevated serum ferritin test. CSS is treated with immunosuppressive approaches such as high-dose corticosteroids or by targeting inflammatory cytokine proteins including interleukins IL-1 and IL-6 and interferon-gamma.

The cytokine storm associated with severe COVID-19 includes substantially elevated serum levels of pro-inflammatory cytokines IL-6 and IL-1β, as well as IL-2, IL-8, IL-17, G-CSF, GM-CSF, IP10, MCP1, MIP1α (also known as CCL3) and TNF. In COVID-19 the cytokine storm leads to shock and tissue damage in the heart, liver, kidney, lungs or multiple organ failure.

Elevated levels of IL-6 has been shown to be an indicator of poor outcome. A Wuhan study that analysed 150 cases found higher levels of IL-6, C-reactive protein (CRP) and ferritin associated with COVID-19 patients that died. Tocilizumab is an IL-6 receptor-targeted antibody used in a clinical trial to treat COVID-19 that was reported to control fever and improve respiratory function. Tocilizumab and sarilumab (Kevzara), another antibody to the IL-6 receptor used to treat rheumatoid arthritis are in clinical trials in Denmark. Anakinra (Kineret), a modified version of a human protein that blocks cytokine IL-1 receptors, is FDA approved for rheumatoid arthritis and a multisystem inflammatory disease in infants. This drug along with emapalumab (Gamifant), an antibody that inhibits cytokine interferon-gamma and is approved for cytokine storm caused by a genetic predisposition, are in clinical trials in Italy for COVID-19.

Potential targets to treat the cytokine storm associated with severe COVID-19 include neutralizing antibodies (mAbs) against inflammatory cytokines and their targets and small-molecule inhibitors of downstream components of cytokine storm-related immunopathology. Mesenchymal stem cells (MSCs) are being tested in COVID-19 clinical trials due to their anti-inflammatory and anti-apoptotic effects.