When Immune Systems Turn Against Sick Patients
Discovery
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Rhiannon Jenkinson, PhD

When Immune Systems Turn Against Sick Patients

How a relentless storm of molecules is waging war with COVID-19 patients

Usually our immune cells release molecules called cytokines that set off a cascade of signals to cells to marshal a response. In most cases, the stronger this immune response, the stronger the chance of vanquishing the infection. But in some cases the storm rages on, unleashing a relentless downpour of cytokines long after the virus has waned, and leaving the exhausted immune system on high alert. In these instances, the cytokine storm causes more harm than good, attacking lungs, kidneys and other organs. Cytokine storms are a devastating event in a small percentage of patients critically ill with COVID-19, and likely contributing to their death.

Q: What exactly is a cytokine storm?

A: Cytokines are small proteins made and released by cells to communicate with each other. During infection by a virus or bacteria our cells produce cytokines to communicate danger and to co-ordinate an appropriate immune response, drive inflammation and fight the infection. Critically, this process normally occurs in a controlled and time-restricted manner and is resolved once the infection is cleared and the tissue returns to its normal state.

Sometimes this process can go wrong and result in what we call a cytokine storm. This is where immune and other cells are triggered by bacteria or a virus to produce cytokines in an excessive and uncontrolled manner. This in turn can recruit more immune cells, lead to more cytokines and inflammation, resulting in damage to the tissue locally. Sometimes the cytokines spread throughout the blood, altering cell behaviour throughout the body. Such uncontrolled production of cytokines and immuno-pathology can seriously affect the ability of organs, such as the lung, to function normally - and in the worst case can be fatal.

Q: What conditions trigger it? 

A: Many of us have now heard the term ‘cytokine storm’ in the media and know that a SARS-COV2 infection can trigger this; but cytokine storms are not unique to this virus. Other examples of viruses that can result in a cytokine storm are influenza, dengue, and respiratory syncytial virus. Bacteria can also drive uncontrolled cytokine release, as can bone marrow transplantation, where the graft reacts against the host.

Q: Who is at risk for this cytokine storm?

A: The demographic of who is at risk of a cytokine storm varies depending on which viral infection is driving this process. It can be hard to predict which individuals will mount an over-zealous immune response to an infection towards a particular pathogen. For some infections this appears to be more prevalent within certain age groups and for people with pre-existing conditions, including those with diseases that affect lung function, such as asthma or people with compromised immune systems. In addition, evidence suggests that genetics plays a role in our immune response to infection as does our past history of infection, immune set points and ability to resolve the inflammation. For the current SARS-COV2 pandemic those most at risk appear to be the elderly, whereas in the influenza H1N1 pandemic of 1918 and more recently with avian H5N1 viruses young adults between 20-40 years of age were most at risk. The exact reasons for this are largely unknown.

Q: How do you treat it and what treatments should be avoided?

A: We still don’t know the best way for treating a cytokine storm. Many scientists are trying to find drugs or therapies that can control and dampen it down in order to limit tissue damage. Strategies aimed at immuno-modulation may be the answer, but it is likely that these will need to be administered at the right time during the course of infection to prevent uncontrolled viral replication and infection, as normally our immune system keeps this in check. Therefore a combination of antiviral drugs to inhibit viral replication and entry into new cells, alongside immuno-modulators that prevent excessive cytokine production, may provide a solution.

Q: Is there a way to test for cytokine storms?

A: The disease mechanisms and predicting or testing for which patients who when infected with COVID19 infection will go on to develop immuno-pathology and a cytokine storm is under intense investigation.  It appears there are several correlates with disease severity. One is sustained decreases in lymphocyte counts in the peripheral blood and evidence that neutrophil counts in the blood go up. The other is higher levels of cytokines such as IL-6 and TNFa in the peripheral blood in severe compared to mild cases.

So in a high percentage (but not all) patients that progress to a more severe disease increased levels of IL-6 can be measured in the blood and decreases in the number of their lymphocytes, so identification of early markers that indicate progression towards the production of a cytokine storm may be more extremely helpful in allowing appropriate clinical care for patients that may be at risk of going on to develop severe disease.

Q: Is a cytokine storm a systemic reaction or does it mainly attack the lungs?

A: The cytokine storm is often initiated in the tissue where there is active infection, so in the case of respiratory viruses such as influenza and COVID-19 this hyper-inflammatory state with excessive and uncontrolled cytokine production occurs in the lungs. However, viruses can infect other epithelial tissues and cytokines can disseminate through the blood causing vascular hyper-permeability and multi-organ damage and failure.

Q: Lastly, we are learning a lot about this novel coronavirus. What can we learn about cytokine storms that might be useful in controlling them?

A: In order to design drugs that target the cytokine storm and the cells that produce them we need to understand the science behind what drives the damaging inflammatory response to COVID-19. By understanding the mechanisms we can design therapies that target the immune system at the right time in the right way. While we are working to gain this knowledge, there is much we can learn from information gathered from previous viral outbreaks such as H1N5 influenza, SARS and MERS and also from bacterial infections that drive a similar hyper-inflammatory immune response and result in cytokine storms.

Existing immuno-modulating therapies are being tested for their efficacy at controlling damaging inflammation and the cytokine storm. These will provide a stop gap until custom drugs can progress through the drug development pipeline and are proved safe for use in humans. Alongside the development of safe and efficacious vaccines, scientists are working hard to provide us a toolbox to treat and prevent COVID-19 and other emerging viruses.

(Rhiannon Jenkinson, PhD, is a Director of Science in Discovery Services at Charles River. She is an expert in immunology and oncology.)