Professor Shakir, director of the Drug Safety Research Unit, explains the cytokine storm, a major killer in patients with severe COVID-19 infection

What are cytokines?

Cytokines are a group of proteins that are secreted by cells in the immune system.

They act as chemical messengers to regulate other immune cells, exerting their effects in tissues locally or further afield by circulating in the blood and lymph.

Essentially, cytokines are released from one immune cell to affect the actions of another cell in the immune system by binding to receptors on its surface. They include interferons, interleukins, lymphokines and tumour necrosis factors.

Cells which release cytokines include macrophages, lymphocytes (both B and T lymphocytes) and other immune cells.

Cytokines exert their functions by allowing immune cells to communicate; they can activate or inhibit immune cells, control their development or direct immune cell movement.

In systemic viral infections, cytokines can induce an inflammatory response which is beneficial until their production becomes uncontrolled.

What is a cytokine storm?

This is the condition which happens in viral infections where a huge amount of cytokines are produced. It can make the patients far sicker by causing multi-organ failure, which is frequently fatal.

Simply put, a cytokine storm or surge is an uncontrollable flood of cytokines which tends to worsen respiratory function and produce multi-organ failure. Cardinal features of a cytokine storm include unremitting fever, cytopenia, massive increase in ferritin, high ESR (erythrocyte sedimentation rate) and Adult Respiratory Distress Syndrome (ARDS).

In COVID-19 this cytokine storm is associated with increased levels of interleukins IL2-2, IL-7 and other cytokines. A mortality predictor in a cytokine storm is the level of ferritin, while thrombocytopenia is also a marker of a fatal outcome.

Cytokine storms can be more severe in young patients who have more efficient immune systems and responses than older patients. Usually it occurs a few days after the onset of the illness and was the major killer with the Asian Influenza in 1959.

What is the current treatment approach?

Treatment is supportive including management of ARDS.

According to a Lancet paper: 'As during previous pandemics (Severe Acute Respiratory Syndrome and Middle East Respiratory Syndrome), corticosteroids are not routinely recommended and might exacerbate COVID-19-associated lung injury'. However, in hyperinflammation, immunosuppression is likely to be beneficial. Re-analysis of data from a Phase III randomised controlled trial of IL-1 blockade (anakinra) in sepsis showed significant survival benefit in patients with hyperinflammation, without increased adverse events. A multicentre, randomised controlled trial of tocilizumab (IL-6 receptor blockade, licensed for cytokine release syndrome), has been approved in patients with COVID-19 pneumonia and elevated IL-6 in China (ChiCTR2000029765). Janus kinase (JAK) inhibition could affect both inflammation and cellular viral entry in COVID-19.'

Other suggested therapies are tacrolimus and mycophenolate, both of which are immunosuppressants inhibiting IL-2 and other cytokines, which are used in patients with solid organ transplants. However, there are no double blind randomised clinical trials that assessed their benefit in this indication.

Professor Shakir is director of the Drug Safety Research Unit