Today we’ll be discussing Cytokine Storm, one of the major outcomes of the COVID-19 disease.

Inflammation is one of the body’s first lines of defense against potentially harmful stimuli, like invading pathogens or damaged or dying cells. Upon recognition of a stimulus, innate immune signaling pathways trigger an inflammatory response resulting in redness, heat, and swelling.

As part of this response, antigen-presenting cells and other supporting cells like epithelial or stromal cells release pro-inflammatory cytokines, like IL-1 and TNF-α and chemokines to attract other immune cells to the site of infection and activate them.

Upon recruitment of cytotoxic cells, anti-microbial and cytotoxic mediators are released, such as reactive oxygen species, to help destroy pathogens. This can result in local tissue damage, so repair processes are simultaneously initiated to help restore organ function.

In some cases, when cytokine release is uncontrolled it causes severe tissue damage, in a phenomenon known as cytokine storm syndrome.

Cytokine Storm Syndrome, also known as cytokine release syndrome, encompasses a wide variety of conditions, but can generally be defined as an uncontrolled release of pro-inflammatory cytokines. Hyper-production of these cytokines ultimately results in tissue damage or sepsis, and in some cases, can be fatal.

Genetic factors or chronic over-activation from a rampant viral infection like SARS-CoV-2 can cause the balance to tip from an appropriate response to an inappropriate one like a cytokine storm. The phrase cytokine storm was first described in 1993 in the context of graft-versus-host disease, but the term was popularized during the H5N1 Avian Flu outbreak in the early 2000s.

Cytokine Storm Syndrome has been associated with infectious diseases, including influenza, SARS, COVID-19, and non-infectious diseases including multiple sclerosis and pancreatitis. It has also been described as a potential adverse effect of treatment with some immunotherapies, including CAR-T cells. Because cytokine storm syndrome encompasses a variety of conditions, the exact cellular mechanisms and cytokines involved depend on the cell type and disease context.

To describe the pathology of cytokine storm, we’ll focus on commonalities seen in the context of infection with SARS or influenza viruses in the lung. While SARS and influenza viruses bind to different target cells in the lungs, they are both associated with a similar cytokine storm profile.

Initially, inflammation begins when the virus replicates within local macrophages resulting in apoptosis. This triggers acute inflammation and increased blood flow to the area so leukocytes can reach extra-vascular sites of infection. Pattern-recognition receptors expressed by newly recruited immune cells recognize the viral pathogen and release additional pro-inflammatory cytokines to recruit more immune cells, and the cytokine response is amplified.

As part of this inflammatory response in the lungs, there is a controlled balance between pro-inflammatory cytokine release and mechanisms to help dampen the response to preserve lung tissue. These include mechanisms to restrain macrophage activity, prevent aberrant toll-like receptor signaling, and produce anti-inflammatory cytokines, like IL-10. But in some circumstances, the inflammation may not be downregulated or suppressed.

When there is an overabundance of cytokines released and severe inflammation, the tissue repair processes are unable to keep up, resulting in major damage to lung tissue. This is often called acute lung injury. It is not well understood why this occurs and what makes some individuals more susceptible to cytokine storm as compared to others AND IS BEING ACTIVELY STUDIED, PARTICUARLY AROUND SARS.

Acute Lung Injury can progress into a more severe condition called acute respiratory distress syndrome. These severe lung infections are characterized by alveolar and capillary damage, increased collagen and fibrin deposition, increased cell permeability, and can ultimately be the cause of death for these patients.

In severe viral lung infections, local inflammatory cytokines can enter the bloodstream resulting in systemic inflammation in a condition that mimics sepsis and can result in multi-organ system failure.

Cytokines identified in the plasma follow relatively characteristic patterns of expression beginning with elevated levels of TNF, IL-1β, IL-8, MCP-1, and IP-10. This is followed by sustained elevation of IL-6 and high levels of IL-6 have been associated with more severe lung disease in SARS. As expected, there are also high levels of IL-10, an anti-inflammatory cytokine, as the body attempts to control the inflammation.

Given the complications and delicate balance of cytokines involved in pro- and anti-inflammatory responses, targeting and treating cytokine storm has proven to be extremely difficult. General anti-inflammatory treatments have not been effective, and in some cases, have worsened the outcome or made the individual more susceptible to secondary infections.

Other immunomodulatory treatments have been or are currently being investigated, but it is important that these treatments are specific enough to dampen the cytokine storm without causing harmful effects to normal immune function.

Current research into immunomodulatory therapies includes testing antibodies that can block or neutralize the effects of TNF or IL-6, two of the major pro-inflammatory cytokines associated with cytokine storm. For example, anti-IL-6 receptor antibodies are commonly used to treat inflammation associated with autoimmune diseases like rheumatoid arthritis. Their effectiveness in treating cytokine storm is being evaluated.

In summary, immune cell function and cytokine release is critical to respond to invading pathogens or other harmful stimuli. However, in some cases, the immune system can go into overdrive, creating a scenario in which the abundance of cytokines and other immune mediators results in damage of local tissues. This is called cytokine storm syndrome.

The exact mechanisms and signaling networks driving cytokine storm are not completely understood and are dependent on the tissue or disease context. In viral infections like SARS and influenza, cytokine storm in the lungs can result in severe lung damage and acute respiratory distress syndrome, which can be fatal.

We hope you’ve found today’s talk informative and check out our COVID-19 specific Cytokine Storm talk as well. Contact us if you have any comments here.