At the onset of the pandemic, hospitals and healthcare workers were unsure how to treat the novel coronavirus. It was trial and error in the beginning, with some failures, like hydroxychloroquine, and some triumphs, like monoclonal antibodies.
Although controversial for “standard” acute respiratory distress syndrome, steroids—specifically dexamethasone—were quickly proven to reduce mortality in those with severe COVID-19 lung infections. However, the unexpected effectiveness of dexamethasone comes with a downside—the steroid seems to only help men.
“We found that while males derived benefit from the steroids, females—at both the cellular level and at the population level—received limited benefit,” said Bryan Yipp, MD, professor of medicine at the University of Calgary and co-author of a new study. “The mainstay therapy for severe COVID-19 that we’re giving everybody is only benefiting half the population. This is a big problem.”
To further understand respiratory stress in COVID-19 patients and the effects of dexamethasone, Yipp and collaborator Jeff Biernaskie collected blood samples from both COVID-19 and non-COVID-19 patients admitted to Calgary ICUs in severe respiratory distress.
Using single cell RNA sequencing and bioinformatics techniques to analyze the functional states of thousands of immune cells, the researchers singled out the interaction between COVID-19 and neutrophils, the most abundant type of white blood cells in the human body. Typically, neutrophils are the key drivers of acute respiratory distress syndrome (ARDS). But, neutrophils appear to present differently in COVID-19 patients. In fact, the researchers discovered that—despite similar severity—the numbers of circulating neutrophils are higher in COVID-19 lung infections than regular bacterial-induced respiratory distress.
What’s more, dexamethasone, specifically, interacts in an unexpected way with neutrophils. According to the researchers’ study, published in Nature Medicine, dexamethasone was associated with suppressed neutrophil numbers in circulation compared with untreated COVID-19 controls (13% versus 41%). Additionally, plasma proteomics from the same patient cohort revealed that dexamethasone suppressed 10 host proteins that previous literature has identified as biomarkers distinguishing severe COVID-19.
Both COVID-19 and dexamethasone also appear to affect interferons, the protein group in charge of clearing a virus quickly. Rather than working fast, the interferon response in COVID-19 trickles along, which worsens inflammation, ultimately causing organ damage. However, the interferon response presents differently between the sexes.
“What we found was that specifically in males, we see an exaggerated neutrophil interferon response, that is significantly restrained when a patient is given dexamethasone,” said Biernaskie. “But with females, relative to males, their neutrophil interferon response was much more tempered, so dexamethasone had little effect.”
In females, dexamethasone also induced the emergence of immature neutrophils expressing two genes known for encoding immunosuppressive molecules—both of which were absent in healthy controls of either sex.
The researchers conclude that several avenues of study remain, including where neutrophil polarization occurs in response to both dexamethasone and COVID-19 infection. But, in light of dexamethasone treatment presenting as sexually dimorphic, the scientists say a focus on personalized medicine may be the best step forward.