As new cases of COVID-19 continue to grow worldwide, in addition to developing anti-viral treatments, there has also been a focus on how to combat cytokine storm syndrome associated with the disease. A subgroup of patients exhibits characteristic signs of cytokine storm including elevated cytokine profiles and respiratory failure from acute respiratory distress syndrome. If you haven’t seen it yet, be sure to watch our talk on cytokine storm, where we introduced some of the basic concepts on the topic. Today, we’ll cover what we know about cytokine storm syndrome in COVID-19 so far.

Early studies suggest that the immune response in COVID-19 patients is two-phased. Initially, when the disease is moderate, immune cells work to eliminate the virus, in part, by producing inflammatory cytokines. During this stage, it may be beneficial to use treatments that stimulate the immune response.

During severe cases of COVID-19, patients exhibit very high cytokine levels or hyper inflammation. In some cases, the lungs become damaged. Patients in this stage develop acute respiratory distress syndrome or ARDS. Reversing damage to the lungs is a major hurdle in treating COVID-19, and ARDS is one of the leading causes of mortality in these patients. Some patients with severe respiratory symptoms retain a high viral load in the lungs and further studies are required to understand the dynamics between the viral load kinetics and an effective immune response.

Extreme inflammation can release large amounts of cytokine into circulation and start affecting secondary organs, even as the viral load begins to decrease. In addition to the lungs, the heart may also be affected by systemic inflammation during SARS-CoV-2 infection, as some patients experience myocarditis without any presence of the virus in the heart.

The origin of the cytokines involved in SARS-CoV-2 related cytokine storm syndrome have not yet been determined as the complete immune response has not been fully assessed. However, current studies give us a glimpse into what may ultimately be causing the cytokine storm.

Severe SARS-CoV-2 infection is associated with lymphocytopenia, the severe loss of lymphocytes in the blood. This suggests that cytokines are being released by non-T cell leukocytes, like inflammatory macrophages. In fact, levels of some cytokines, like IL-6, IL-10, and TNF-α, are inversely correlated with T cell counts. High levels of IL-6 can suppress T cell activation, so the cytokine storm may help explain the low T cell counts in these patients.

One theory as to what drives the massive release of cytokines involves rapid viral replication that leads to wide-scale cell pyroptosis, an inflammatory form of apoptosis. This recruits macrophages to the lungs that in turn will amplify the inflammatory response. Though we’re beginning to gain insight into the cytokine storm, important questions still remain to determine the main causes of such large scale release of cytokines.

Initial studies have begun to give us an idea of specific cytokines involved in the COVID-19 immune response. Studies comparing serum cytokine levels in uninfected individuals, patients exhibiting moderate symptoms, and those with severe symptoms have found that increased levels of IL-6, IL-10, TNF-α, and soluble IL-2R are correlated with disease severity.

Another study examined patients with pneumonia, comparing cytokines and chemokines in patients in the intensive care unit (or ICU) as compared to those that were not. They found that IL-2, IL-7, G-CSF, IP-10 MCP-1, and MIP-1α were all elevated in patients in the ICU. Additional studies with larger sample sizes will be required to fully understand cytokines involved and most importantly, time kinetics of their expression levels to help guide treatment strategies.

In addition to elevated serum cytokines, studies have shown that there is a decreased production of a key anti-viral cytokine by T cells known as IFN-γ*. This suggests that the cytokine storm may be dampening the T cell adaptive immune response.

As cytokine storm syndrome is a disease and cell-type specific response, it is important to profile the cytokines to help us understand which pathways are involved. This can ultimately help us develop specific therapies to combat cytokine storm.

To fully understand the cytokine profiles of COVID-19 patients, we can quantify inflammatory cytokines in serum or bronchoalveolar lavage fluid. Typically, these tests must be performed with small sample volumes and with a short turnaround time. For this, screening multiple cytokines in a single assay is critical.

Our LEGENDplex™ kits allow researchers to measure up to 13 targets simultaneously using only a flow cytometer. This provides a clear picture of the inflammatory status without the need to run multiple assays. We offer a number of pre-defined panels relevant to cytokine storm and SARS-CoV-2 research, including anti-virus response panels, inflammation panels, and other immune response panels.

Each of the panels has been carefully designed to include relevant soluble mediators to specific pathways or areas of interest. In addition, we offer custom assay capabilities for research that may require a specific set of cytokines.

While the patient’s own immune system may cause lung disease and multi-organ failure and lead to death for some COVID-19 patients, treatment may not be as simple as using a broad anti-inflammatory drug. In early stages of the disease, the immune system helps to protect against the virus and reduce the viral load. Applying broad anti-inflammatory treatments may dampen the immune response and impair the patient’s ability to eliminate the viral pathogen. Broad anti-inflammatories may also make the patient susceptible to secondary infection and could even worsen the outcome.

Understanding the exact cytokines involved in cytokine storm, is important for developing treatments. For example, since we know that IL-6 is elevated in patients with severe lung disease, using a specific IL-6 inhibitor may help to fight off the cytokine storm without widespread effects on the immune system. IL-6 inhibitors are currently being used in autoimmune disease and many studies and clinical trials are working to determine the efficacy of this drug in COVID-19. In addition to IL-6 inhibitors, other similar treatment strategies such as TNF-α blockade are being studied.

Understanding SARS-CoV-2 associated cytokine storm syndrome is a major hurdle in treating the disease. Because cytokine storm varies between disease, we must first characterize the cytokines involved and at what stage of the disease blocking them may be effective.

Today, we discussed how a subset of COVID-19 patients experience cytokine storm syndrome. They have elevated levels of inflammatory cytokines in the lungs, leading to tissue damage. To assess these cytokines, researchers can use multiplex assays, like LEGENDplex™, to quantitate the factors made in response to SARS-CoV-2 infection. Current studies have found that elevated levels of IL-6, IL-10, TNF-α, and soluble IL-2 receptor in patients with severe symptoms. For additional comments or questions, please contact us here.