immune attack

What makes the flu so severe for some is linked to Covid-19 outcomes — study

Scientists examine what causes immune overreactions linked to potentially deadly consequences.

When the human body fights an infection — whether the attacker is the flu or Covid-19 — the immune system can spiral out of control, creating an outsized reaction called a cytokine storm.

When a cytokine storm hits, the immune system overproduces immune cells and cytokines, small proteins involved in cell-to-cell communication that cause inflammation. These storms can overburden the body, cause organ failure, and even lead to death. Physicians suspect they may even contribute to Covid-19 patients’ sudden crash when a case rapidly transitions from mild to severe.

It's not clear exactly what triggers cytokine storms, but recent research on patients with influenza A, a type of the seasonal flu, hints at a critical factor. According to the new study, influenza A triggers cytokine storms by elevating blood glucose and speeding up glucose metabolism.

This finding was published Wednesday in the journal Science Advances.

This study specifically focused on the link between glucose metabolism and influenza A. However, the researchers argue it could explain why people with diabetes seem to experience worsened outcomes from the novel coronavirus.

“We believe that glucose metabolism contributes to various Covid-19 outcomes since both influenza and Covid-19 can induce a cytokine storm, and since Covid-19 patients with diabetes have shown higher mortality,” co-author Shi Liu, a researcher at Wuhan University, announced on Wednesday.

Other scientists are more cautious about the connection.

“This is not proof,” Robert Eckel, an endocrinologist at the University of Colorado Hospital who was not involved in the study, tells Inverse.

Still, this may be an indication that clinicians who treat patients with Covid-19 and diabetes need to keep careful watch over their patient's glucose levels, Eckel says.

“The team has not proven cause and effect, but it's highly suggestive that having better glucose control would be associated with fewer cytokines, and potentially better outcomes," he explains.

In the study, researchers aimed to determine how glucose metabolism influenced the cytokine storms brought on by influenza A.

Between 2017 and 2019, they analyzed blood samples of 119 patients with influenza A who visited two hospitals in Wuhan, China. As a control, they also analyzed 119 healthy people's blood samples from a local blood donation center. The team examined both groups' cytokine production and blood glucose levels.

In infected patients, the researchers discovered that higher levels of proinflammatory cytokines correlated with higher levels of blood glucose. This suggested that influenza A sent glucose metabolism into overdrive.

In turn, the team realized that people with higher blood sugar — a hallmark of diabetes and overall issues with glucose metabolism — were more likely to experience deadly cytokine storms.

Upon further investigation, the team determined that one pathway, called the hexosamine biosynthesis pathway (HBP), was likely driving this effect.

The HBP typically helps metabolize glucose in the body. However, when someone is sick with influenza A, the HPV goes into overdrive and produces a metabolite called glucosamine. The team found that, in people with higher blood sugar, this metabolite appears in increased levels alongside cytokine storms. The scientists can't say if the glucosamine caused the storms, but say the two are correlated.

The researchers also experimented on mice infected with the flu and found that when they injected the mice with the glucosamine, they produced significantly higher levels of inflammatory cytokines and chemokines than mice that did not receive glucosamine.

They replicated their experiment in cell cultures, too, and found that disrupting the HBP's production of glucosamine impaired cytokine storms — a reverse effect.

Taken together, these findings suggest elevated blood sugar could be a sign of a cytokine storm during an influenza A infection.

"We would strongly encourage optimal glucose control of the range of 110 to 180 milligrams per deciliter."

Keeping glucose levels in balance may help prevent cytokine production from spinning out of control, and ultimately, improve a patient's course of illness. It's another reason to keep glucose levels within a healthy range, in addition to protecting against cardiovascular, eye, and kidney disease.

“Good glucose control is always recommended, but particularly now,” Eckel stresses. “If someone were infected with COVID-19 — either with symptoms and not tested or with symptoms and tested to be showing to be positive — we would strongly encourage optimal glucose control of the range of 110 to 180 milligrams per deciliter.”

Eckel's advice echoes the blood sugar target ranges outlined by the American Diabetes Association.

Based on data from other viral infections like Covid-1 and SARS, we know that glucose probably impairs the immune system, Eckel says.

"Diabetes modifies the ability to fight infection," he explains. "It may not be putting people with diabetes that increase risk, but once infection sets in, it has a tendency to be more likely to result in hospitalization with a more complicated and difficult course."

People with diabetes typically take longer to clear infections and the severity of the disease is notably increased. According to other recent reports published in the New England Journal of Medicine and The Lancet, patients with diabetes and hypertension make up a high proportion of severe and deadly Covid-19 cases.

But the cause behind this effect is still unclear. Scientists aren't sure whether it's glucose metabolism itself that's responsible for bad outcomes, or whether confounding factors like age or comorbidities are influencing these results.

At this stage, the Centers for Disease Control recommends people with diabetes deal with Covid-19 like those without the condition: Watch for fever, coughing, and shortness of breath, and call a healthcare provider if you experience symptoms.

Abstract: In this study, we demonstrated an essential function of the hexosamine biosynthesis pathway (HBP)–associated O-linked b-N-acetylglucosamine (O-GlcNAc) signaling in influenza A virus (IAV)–induced cytokine storm. O-GlcNAc transferase (OGT), a key enzyme for protein O-GlcNAcylation, mediated IAV-induced cytokine production. Upon investigating the mechanisms driving this event, we determined that IAV induced OGT to bind to interferon regulatory factor–5 (IRF5), leading to O-GlcNAcylation of IRF5 on serine-430. O-GlcNAcylation of IRF5 is required for K63-linked ubiquitination of IRF5 and subsequent cytokine production. Analysis of clinical samples revealed that IRF5 is O-GlcNAcylated, and higher levels of proinflammatory cytokines correlated with higher levels of blood glucose in IAV-infected patients. We identified a molecular mechanism by which HBP-mediated O-GlcNAcylation regulates IRF5 function during IAV infection, highlighting the importance of glucose metabolism in IAV-induced cytokine storm.
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