High Levels of IL-6 and TNF-α Proteins in Blood Predict Worse COVID-19 Outcomes

High Levels of IL-6 and TNF-α Proteins in Blood Predict Worse COVID-19 Outcomes
Female caucasian doctor checking on Covid-19 infected patient while connected to a ventilator at a hospital room

Researchers at Icahn School of Medicine at Mount Sinai in New York showed that having high levels of the cytokine proteins interleukin (IL)-6 and tumor necrosis factor (TNF)-α on admission to hospital with COVID-19 predicted a worse outcome than having lower levels.

This finding was independent of age, gender and underlying medical conditions, among other factors, although levels of two other cytokines—IL-1β and IL-8—did not significantly impact patient outcomes, according to the team.

“We propose that serum IL-6 and TNF-α levels should be considered in the management and treatment of COVID-19 patients to stratify prospective clinical trials, guide resource allocation, and inform therapeutic options,” said lead researcher Sacha Gnjatic, PhD, an associate professor at Mount Sinai.

As drugs to block both these cytokines are already on the market and approved to treat various autoimmune diseases, Gnjatic and colleagues also believe that serious COVID-19 patients should be assessed for potential treatment with these drugs.

From the beginning of the pandemic, one notable difference between severe and mild-moderate cases of COVID-19 is the onset of excessive inflammation or a ‘cytokine storm’ in severe patients leading to multiple organ damage and a high mortality rate. As reported by the researchers in the journal Nature Medicine, a cytokine test was initiated for over 1000 patients admitted to Mount Sinai hospital during March and April with suspected or confirmed SARS-CoV-2.

The cytokines TNF-α, IL-6, IL-8 and IL-1β are all known to promote inflammation in the body. For example, high levels are found in people with autoimmune conditions such as rheumatoid arthritis. As they were suspected to be markers of COVID-19 severity, levels of these four proteins were tested in patients with the virus on admission to hospital. The patients were then followed-up for up to 41 days.

Levels of the interleukin proteins were considered high if 2-3 times higher than the upper limit of normal levels, whereas the cutoff for TNF-α being high was at the 99th percentile of normal levels or above. When the scientists had corrected for a large number of possible factors that could influence measures of these proteins in the blood, such as age, comorbidities, gender, blood oxygen levels and so on, they found that people with high levels of IL-6 and TNF-α had a risk of dying that was at least twice as high as other COVID-19 patients.

High IL-8 levels also seemed to be predictive of a bad outcome, but this association did not remain significant after correcting for all the possible confounding factors. The team checked their results in a further group of 231 COVID-19 patients and saw the same links with IL-6 and TNF-α levels.

As the test was quick, with results in a couple of hours, and fairly easy to implement, the researchers believe it should be implemented more widely to help treat these patients and predict who is likely to need the most care.

They also believe more research is needed on the impact of treating patients with drugs to lower the levels of these proteins. For example, remdesivir – shown to be beneficial for COVID-19 patients – lowers IL-6 levels.