Criteria to predict cytokine storm in COVID-19 patients identified

Like a cold front that moves in, setting the stage for severe weather, coronavirus infection triggers showers of infection-fighting immune molecules—showers that sometimes escalate into a chaotic immune response known as a cytokine storm. About 20 to 30 percent of patients hospitalized with COVID-19 develop severe immune manifestations, in some instances leading to cytokine storm, with life-threatening organ damage and high risk of death.

Predicting which COVID-19 patients will develop cytokine storm is challenging, owing to the many variables that influence immune function. But now, in breakthrough work, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) have developed and validated predictive criteria for early identification of COVID-19 patients who are developing hyperimmune responses, raising the possibility for early therapeutic intervention.

“If we can anticipate cytokine storm, we can apply treatment sooner and possibly decrease mortality,” explained Roberto Caricchio, MD, Chief of the Section of Rheumatology, Director of the Temple Lupus Program, Professor of Medicine and Microbiology and Immunology at LKSOM, and lead author on the new report.

The report, published online in the Annals of the Rheumatic Diseases, is the first to identify criteria that can be readily used in clinical practice to potentially head off the worst of the hyperimmune attack against COVID-19.

The breakthrough is the result of an extensive collaboration between researchers and clinicians across multiple departments in the Lewis Katz School of Medicine and Temple University Hospital, constituting the Temple University COVID-19 Research Group.

According to Dr. Caricchio, large numbers of COVID-19 patients have been treated at Temple since the pandemic emerged in the United States. “We have a significant amount of data in terms of variables to predict cytokine storm,” he said.

Since early March, every patient admitted to Temple University Hospital (TUH) has had data on more than 60 different laboratory variables collected daily until the time of recovery or time of death. Among variables measured every day are factors like white blood cell count, metabolic enzyme activity, and markers of inflammation and respiratory function. Importantly these markers are commonly used in hospitals across the globe and therefore are readily available.

The research group carried out statistical analyses on laboratory data for 513 COVID-19 patients hospitalized at TUH in March and April, 64 of whom developed cytokine storm. A genetic algorithm was used to identify cut-off values for each individual laboratory variable to define the predictive requirements for cytokine storm. Genetic algorithms mimic the processes of natural selection and evolution in analyzing the data, and in this case, over multiple iterations, the algorithm turned up variables indicating which patients are most likely to develop cytokine storm.

Overall, the analyses yielded six predictive criteria comprising three clusters of laboratory results relating to inflammation, cell death and tissue damage, and electrolyte imbalance. In particular, patients in cytokine storm exhibited a proinflammatory status and elevated levels of enzymes indicating significant systemic tissue damage. Moreover, patients who met the criteria had extended hospital stays and were at increased risk of death from COVID-19, with almost half of patients who experienced cytokine storm meeting all criteria within the first day of hospitalization.

The researchers validated the criteria in a subsequent cohort of 258 patients admitted to TUH for COVID-19 infection. “The algorithm correctly predicted cytokine storm in almost 70 percent of patients,” Dr. Caricchio said.

“The ability to reproduce our results in a second cohort of patients means that our group of variables are effective criteria for cytokine storm diagnosis in COVID-19 patients,” he added. The final step now is to have the criteria validated by other centers where COVID-19 patients are admitted for care.

Dr. Caricchio noted that the criteria could be applied to COVID-19 patients at any hospital or level of hospitalization anywhere in the world. “This makes the criteria very valuable for guiding decisions about how to treat COVID-19 patients worldwide,” he said. Applied more broadly, the criteria could greatly facilitate early diagnosis and intervention, helping save many lives.

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STAT3 identified as important factor in emotional reactivity

Numerous scientific studies indicate that inflammatory processes play a key role in the development of psychiatric disorders. One of the areas of particular interest is the interleukin 6/STAT3 signal transduction pathway, which is associated with depression, schizophrenia, and bipolar disorder. In a study published in Molecular Psychiatry, MedUni Vienna researchers led by Daniela Pollak from the Division of Neurophysiology and Neuropharmacology showed that STAT3 plays an important role in the serotonergic system as a molecular mediator for controlling emotional reactivity, thereby establishing a mechanistic link between the immune system, serotonergic transmission and affective disorders such as depression.

The STAT3 signal transduction pathway is activated in response to a series of immunogenic and non-immunogenic stimuli, i.e. those that can and those that cannot trigger an immune response. “It was found that STAT3 is involved in nervous system functions that are important for controlling behavior in physiological and pathological situations. In an earlier study, we had managed to show that STAT3 also regulates the expression of the serotonin transporter gene (Note: SERT),” explains Pollak.

Changes in serotonergic transmission, that is to say the transmission of information from one neuron to another using serotonin as a messenger substance, correlate closely with pathological changes in depression or other affective disorders. However, the interaction between the STAT3 signal transduction pathway and the neuronal information flow in the brain and its importance in regulating emotional behavior has not yet been explored.

STAT3 deficiency reduces emotional reactivity

The published work therefore specifically investigated the significance of the STAT3 signal transduction pathway in the serotonergic system of the midbrain—an emotional regulation center—by targeted inhibition of STAT3 in a mouse model. Says Pollak: “Where STAT3 was selectively absent from the serotonergic system of the midbrain, the mice displayed reduced, negative emotional reactivity in their behavior and a diminished response to the effects of amphetamine in the brain. These effects could be detected in mice with reduced STAT3 expression both in a genetic and in a viral model, so that it was possible to rule out developmental changes and to show that an acute manipulation of STAT3 in the adult organism impacts on emotional behavior.”

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Potential target identified for migraine therapy

Migraines affect millions of people worldwide, often lasting days and severely disrupting lives. More than simply super-intense headaches, some migraines actually result from pathological excitation of neurons in the brain. A new study in mice led by Kohichi Tanaka at Tokyo Medical and Dental University (TMDU) shows that susceptibility to migraines could be related to a molecular transporter that normally works to prevent excessive excitation of neurons.

Neurons in the brain communicate with each other by passing along molecules called neurotransmitters. After a neurotransmitter takes care of business, it is transported away from the synapse—the space between two neurons—so that it cannot be used over and over again. This process is called reuptake, and is one of many ways in which over-excitation of neurons in the brain is prevented. Migraines are related to a condition called cortical depression, in which a large wave of hyperactivity spreads across the brain, followed by a wave of inhibition, or depressed brain activity. Tanaka and his team hypothesized that susceptibility to cortical spreading depression is related to disrupted transport of glutamate, the most common excitatory neurotransmitter.

In turns out that mammals have four molecules that transport glutamate, and three of them are in the cerebral cortex. To determine which of these, if any, is related to cortical spreading depression, the researchers created three strains of knockout mice, each of which lacked one of the three cortical glutamate-transporter genes. They found that when mice lacked the GLT-1 transporter, cortical spreading depression occurred more frequently and spread more quickly than in control mice or in the other knockout mice.

“We know that 90% of glutamate is transported by GLT-1 back into astrocytes, not neurons,” says Tanaka. “Our findings thus highlight another important function of glial cells in the brain as they support neuronal function.”

To confirm their findings, the team then measured the amount of glutamate outside of cells using a platinum-iridium electrode coated with glutamate oxidase. When glutamate oxidase interacts with glutamate, it creates a negative current that can be detected by the electrode very quickly, allowing almost real-time measurements of glutamate concentration in the region.

“A fast biosensor is critical,” explains Tanaka, “because cortical spreading depression only lasts about 5 minutes, and the changes in glutamate concentration could never be found using conventional methods that take minutes to hours of sampling.” When testing the three knockout mice, only the GLT-1 knockout mice produced current that differed from that of the control mice. This means that the greater and faster accumulation of glutamate outside of neurons resulted from impaired uptake by astrocytes.

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