One of the lingering mysteries surrounding the coronavirus is why some people get so much sicker than others.

Scientists have found that older people and those with preexisting health problems are more likely to develop severe cases. But infants can acquire serious infections and young, otherwise healthy adults have been hospitalized and died from coronavirus complications, too.

An emerging body of research suggests that the reason for this might be related to the very mechanism designed to protect our bodies from infection.  

A new review from researchers at Zunyi Medical University in Wuhan, China, found that many immune systems straddle a fine line by aggressively fighting the coronavirus without going haywire. But among patients who develop severe outcomes, immune systems can overreact by producing a “cytokine storm” — a release of chemical signals that instruct the body to attack its own cells. This response was also characteristic of patients who died of H1N1, SARS, MERS, and the 1918 flu.

“If the virus replicates very quickly, before your body has a chance to try and prevent it with an immune response, or if the immune response comes in too late, then it can’t control the virus and starts going berserk,” Anthony Fehr, a virologist at the University of Kansas, told the Washington Post.

According to the Wuhan researchers, that aggressive immune response causes coronavirus cases to go from mild to severe.

Cytokine storms cause inflammation and organ failure

The Wuhan study outlines a step-by-step path for how the coronavirus invades the body.

First, the virus’ spiky proteins latch onto cell receptors found throughout the body called ACE2. Japanese immunologists recently determined that a specific enzyme, TMPRSS2, helps facilitate that process. The enzyme is highly expressed in the alveoli (tiny air sacs in the lungs), which may explain why the virus enters the lungs first. 

When the immune system senses a threat, it responds by activating white blood cells. Among certain patients, these white blood cells release too many cytokines – proteins that further activate the immune response and trigger inflammation in the body.

This “cytokine storm” prompts white blood cells to attack healthy lung tissue. 


Coronavirus particles.

Corona Borealis Studio/Shutterstock

The reaction may cause milder coronavirus symptoms like fever, fatigue, muscle aches, or swollen toes. But it can also lead to severe symptoms including blood clots, excessive leaking in the blood vessels, fluid in the lungs, depleted oxygen in the blood, and low blood pressure.

The New York Times reported that cytokine storms become obvious a few days after a person is infected. Some of the main signs include an abnormally fast heart rate, fever, and drop in blood pressure.

The Japanese immunologists found that, under extreme circumstances, cytokine storms can lead to acute respiratory distress syndrome (ARDS), the life-threatening lung injury behind most coronavirus deaths. This occurs when proteins and dead cells form a membrane around the alveoli, making it difficult to absorb oxygen. An aggressive immune response can also damage the lungs, heart, kidneys, intestines, and liver. 

“No one knows why some people — and not others — develop this response, but there are likely host risk factors, including genetic mutations in genes that contribute to a familial form of this disease,” Dr. Randy Cron, a rheumatologist at the University of Alabama at Birmingham, told his university.

He estimated that up to 15% of people carry a mutation that’s linked to a higher risk of cytokine storms.

Cytokine storms could also be part of the reason that infants tend to get more severe infections than older kids. Children represent just 1% to 2% of coronavirus cases in countries like China, Spain, and the US, but a study from the US Centers for Disease Control and Prevention found that up to 62% of infants with the coronavirus were hospitalized, whereas the rate for children between 1 and 17 was no greater than 14%. 

Some scientists believe that’s because infants haven’t developed a strong immune response yet. But others suggest that infants actually present a more aggressive inflammatory response than older children do: A 2012 study found that infants younger than 3 months produced more of an inflammatory cytokine called interleukin-1 (IL-1) compared to children between 3 and 18 months. 

wuhan coronavirus infant

A baby wearing a protective face mask in Hong Kong on February 3, 2020.

Anthony Wallace/AFP/Getty

Researchers around the world are searching for antiviral drugs that could treat coronavirus symptoms. Some of these directly target cytokine storms.

Two companies, Regeneron and Sanofi, are running trials of an anti-inflammatory drug called Kevzara, which inhibits a key cytokine called interleukin-6 (IL-6). The drug has already been approved to treat rheumatoid arthritis in the US. Studies have discovered elevated levels of IL-6 among some critically ill coronavirus patients — and significantly higher levels of IL-6 in severe cases than mild ones.

Swiss pharma company Roche is also testing an IL-6 inhibitor called Actemra that was approved in 2017 to treat cytokine storms. Some physicians worry that anti-inflammatory drugs may also suppress the body’s natural immune response, but the Japanese immunologists found that drugs targeting IL-6 could impede a life-threatening inflammatory response.

If these anti-inflammatory treatments are proven to work for coronavirus patients, researchers would need to time them appropriately. Once a cytokine storm is set in motion, a patient’s chances of survival go down. The Chinese Academy of Medical Sciences recently determined that knowing precisely when to block that storm is critical to reducing the death rate among coronavirus patients.

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