Steroids

Mechanism of action: Serious outcomes (hospitalization, end-organ damage, mechanical ventilation, death) are driven by the host’s inflammatory response. Steroids act by modifying the host response.

The RECOVERY Collaborative Group found that dexamethasone (6 mg IV Q24) improved 28-day mortality in patients requiring invasive mechanical ventilation (NNT = 8.5) and in those patients requiring any supplemental oxygen (NNT = 29).⁸ As a result of these robust data, systemic corticosteroids have become standard care in COVID-19 patients with hypoxemia.

COVID Steroid 2 sought to determine whether a higher dose of steroids would be beneficial in those with severe hypoxemia. Though there was no statistically significant difference in days alive without life support (the primary outcome) between the 12-mg and 6-mg dexamethasone groups, 28- and 90-day mortality were numerically better in the higher-dose arm.⁹ A study powered for mortality may show a benefit to a higher dose in severely hypoxemic patients. 

More recently, inhaled budesonide has been investigated for use in outpatients with COVID-19. Though the PRINCIPLE study demonstrated a benefit in time to symptom resolution, it suffered from a number of methodological issues (open-label, subjective outcome, co-primary endpoints) that bring the results into question.¹⁰Additionally, budesonide remains an expensive treatment, limiting patient access.

Bottom line: Dexamethasone should be given to all patients with hypoxemia due to COVID. More data are needed regarding the optimal dose in those with critical illness. Inhaled budesonide appears promising but will require higher-quality data prior to widespread use.

Inflammatory Modulators: Baricitinib

and Tocilizumab

Mechanism of action: Both agents work by suppressing the hyperactive host inflammatory response that occurs as COVID-19 progresses. Tocilizumab is an anti-interleukin-6 receptor monoclonal antibody that inhibits interleukin-6 binding and thus suppresses the pro-inflammatory cytokine cascade. Baricitinib is a Janus kinase inhibitor that suppresses the cytokine pathway.

Initial studies on tocilizumab failed to show consistent benefits. This may have been a result of corticosteroids not being used routinely in either the control group or treatment arm. The RECOVERY Collaborative remedied that situation with its large high-quality study where the majority of patients received steroids. It found that in hypoxemic COVID patients with signs of systemic inflammation (C-reactive protein >75 mg/L), tocilizumab, when added to dexamethasone, improved 28-day mortality by 4 percent (NNT = 25).¹¹ Additionally, the tocilizumab group performed better in terms of their secondary endpoints of mechanical ventilation and discharge home.

Studies on baricitinib have been less straightforward. Early studies showed suggestions of benefit but, as with tocilizumab, did not have widespread use of systemic steroids. Most patients in the COV-BARRIER trial did receive steroids as standard care. The trial fell short in showing a statistically significant benefit for its primary outcome of disease progression in patients with hypoxemia and signs of systemic inflammation (elevated C-reactive protein, D-dimer, lactate dehydrogenase or ferritin).¹² There was a significant improvement in mortality (secondary outcome) that was more pronounced in patients with hypoxemia (9.5 percent reduction).