Dexamethasone: A Dual Role
The researchers explored how dexamethasone influences immune cells in patients with COVID-19. In patients with moderate disease severity who received dexamethasone, there was a significant increase in leukocyte counts.
This increase in leukocytes was linked to changes in B-cells and neutrophils in patients with moderate COVID-19—those who were hospitalized and required oxygen supplementation but did not need mechanical ventilation. However, in severely ill patients who received dexamethasone, these changes were not observed. Additionally, in patients with moderate COVID-19 treated with dexamethasone, the number of monocytes decreased. These changes in immune cell composition indicate the immunomodulatory effect of dexamethasone.
Dexamethasone treatment affected gene activity in immune cells, with the most significant changes occurring in monocytes, followed by B-cells and CD4+ T-cells. These changes were most noticeable in patients with moderate and severe COVID-19.
Dexamethasone Shifts Monocytes into a Unique State
Dexamethasone suppressed the activity of several genes responsible for inflammation (IL1B, CCL3, CCL4, CCL3L3, and CCL4L2) and activated genes associated with anti-inflammatory effects (IL1R2, TSC22D3, CD163, SAP30, PER1, and ZFP36L2). These changes occurred regardless of the severity of COVID-19.
The researchers identified a specific state of monocytes in which they responded most effectively to dexamethasone. The genes responsible for the drug’s anti-inflammatory action were most active in this state.
Gene Activity Changes in Monocytes Correlate with Treatment Outcomes
In patients with moderate COVID-19, dexamethasone effectively regulated inflammatory responses in monocytes. In these patients, 80% of monocytes transitioned into the state most conducive to responding to dexamethasone, which was associated with better clinical outcomes, including survival. However, in some patients with severe COVID-19, monocytes did not respond to treatment, which correlated with poorer outcomes. These patients had significantly fewer monocytes that responded to dexamethasone. In patients who ultimately succumbed to COVID-19, the levels of monocytes responsive to dexamethasone were very low or undetectable.
The researchers also examined other changes induced by dexamethasone in the monocytes of surviving patients. Beyond suppressing pro-inflammatory genes, dexamethasone reduced the expression of alarmins, cytokines, and chemokines that signal danger and enhance inflammation while restoring the activity of genes such as HLA-DRB1, HLA-DRA, HLA-DPA1, and CD74, which are crucial for proper immune system function. Alarmin activity depended on the duration of dexamethasone treatment, with lower activity observed on day seven than on day three.
Predicting Dexamethasone Treatment Success through Early Gene Activity Changes in Monocytes
The scientists compared the genetic profiles of blood samples from patients at different stages of treatment. They found that changes in gene activity within monocytes could predict how a patient would respond to dexamethasone treatment. These changes became apparent as early as 2-4 days after the start of therapy. In patients who later died, these changes were less pronounced or absent, correlating with the ineffectiveness of the treatment. Therefore, early changes in gene activity in monocytes can be used to diagnose the effectiveness of dexamethasone treatment and to select the best therapy for patients with COVID-19.
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