High levels of a protein called calprotectin in cells infected with SARS-CoV-2 are linked to worse outcomes for patients.

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Forecasting a (cytokine) storm

29 Mar 2021

These novel immune signatures identify patients most at risk for developing severe COVID-19 symptoms.

The influx of COVID-19 patients has overwhelmed hospitals around the globe. Managing resources is particularly challenging, considering the course of infection differs significantly between patients. Some present with relatively mild symptoms, while others can quickly enter a downward spiral, ending up in the intensive care unit (ICU) battling life-threatening respiratory distress.

Early interventions can help, but the question is, which patients need them? In general, older patients and those with underlying medical conditions are known to be more vulnerable. However, the biological mechanisms controlling infection severity are still poorly understood and screening protocols to more accurately categorize patients are not yet available.

Measurable inflammatory biomarkers are key pieces of this puzzle, said Florent Ginhoux, a Senior Principal Investigator at A*STAR’s Singapore Immunology Network (SIgN). An exaggerated immune response is a hallmark feature of severe COVID-19, in which inflammatory proteins flood the body—a process known as the cytokine storm.

In collaboration with Eric Solary and Michaela Fontenay from Gustave Roussy and Institut Cochin respectively, Ginhoux tested whether specific immune molecules could represent early warning signs that such a storm is brewing. Their study, published in Cell, suggests that the presence of a specific type of white blood cell and elevated levels of an inflammatory protein called calprotectin were tightly linked to greater disease severity.

Ginhoux and his team first obtained blood samples from a cohort of COVID-19 patients experiencing the full spectrum of infection severity: from a mild fever and cough to respiratory distress requiring ventilation. Using high-throughput flow cytometry and single-cell sequencing, they found that immune cells from patients with severe infections appeared to be out of place—their blood contained markedly elevated levels of neutrophils at the very early stages of their maturation. This was a red flag, considering that these cells are typically found only in the bone marrow.

Additionally, the team observed striking differences in the levels of calprotectin in the blood of patients with severe COVID-19. “Calprotectin is a very well-known marker of inflammation,” explained Ginhoux, adding that its levels also spike in the case of other infectious diseases. “It stood out as one of the most upregulated markers in severe patients.”

“The detection of these markers would allow patients to receive earlier treatment such as oxygen, corticosteroids and anticoagulants, which may slow down disease evolution and prevent critical situations requiring hospitalization in the ICU,” said Ginhoux. Follow-up studies will focus on more in-depth statistical and mechanistic analyses of these newfound predictive biomarkers, he added.

The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN).

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Silvin, A., Chapuis, N., Dunsmore, G., Goubet, A.G., Dubuisson, A., et al. Elevated calprotectin and abnormal myeloid cell subsets discriminate severe from mild COVID-19. Cell 182(6), 1401-1418.E18 (2020) | article

About the Researcher

Florent Ginhoux

Senior Principal Investigator

Singapore Immunology Network
Florent Ginhoux completed his undergraduate studies at the University Pierre et Marie Curie (UPMC), Paris VI. He subsequently obtained a Master’s degree from the Pasteur Institute in 2000 and his PhD from UPMC, Paris VI, in 2004. He is currently a Senior Principal Investigator at A*STAR’s Singapore Immunology Network (SIgN) and an EMBO Young Investigator. His laboratory focuses on the ontogeny and differentiation of macrophages and dendritic cells in both humans and mice. He was listed as a highly cited researcher on Web of Science in 2016, 2017 and 2018.

This article was made for A*STAR Research by Wildtype Media Group