Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia

Abstract

Background: In hospitalized patients with coronavirus disease 2019 (COVID-19) pneumonia, progression to acute respiratory failure requiring invasive mechanical ventilation (MV) is associated with significant morbidity and mortality. Severe dysregulated systemic inflammation is the putative mechanism. We hypothesize that early prolonged methylprednisolone (MP) treatment could accelerate disease resolution, decreasing the need for intensive care unit (ICU) admission and mortality.

Methods: We conducted a multicenter observational study to explore the association between exposure to prolonged, low-dose MP treatment and need for ICU referral, intubation, or death within 28 days (composite primary end point) in patients with severe COVID-19 pneumonia admitted to Italian respiratory high-dependency units. Secondary outcomes were invasive MV-free days and changes in C-reactive protein (CRP) levels.

Results: Findings are reported as MP (n = 83) vs control (n = 90). The composite primary end point was met by 19 vs 40 (adjusted hazard ratio [aHR], 0.41; 95% CI, 0.24-0.72). Transfer to ICU and invasive MV were necessary in 15 vs 27 (P = .07) and 14 vs 26 (P = .10), respectively. By day 28, the MP group had fewer deaths (6 vs 21; aHR, 0.29; 95% CI, 0.12-0.73) and more days off invasive MV (24.0 ± 9.0 vs 17.5 ± 12.8; P = .001). Study treatment was associated with rapid improvement in PaO₂:FiO₂ and CRP levels. The complication rate was similar for the 2 groups (P = .84).

Conclusion: In patients with severe COVID-19 pneumonia, early administration of prolonged MP treatment was associated with a significantly lower hazard of death (71%) and decreased ventilator dependence. Treatment was safe and did not impact viral clearance. A large randomized controlled trial (RECOVERY trial) has been performed that validates these findings. Clinical trial registration. ClinicalTrials.gov NCT04323592.

Keywords: ARDS; COVID-19; SARS-CoV-2; methylprednisolone; pneumonia.

Figure 1.

Flowchart of the study population. Failed to meet inclusion criteria (n = 72): age >80 years (n = 9), criteria for PaO₂:FiO₂, C-reactive protein level, or acute respiratory distress syndrome (n = 63). Met exclusion criteria (n = 35): heart failure as main cause of acute respiratory failure (n = 2), decompensated liver cirrhosis (n = 3), on long-term oxygen therapy and/or home ventilation (n = 2), dementia or severe neurodegenerative condition (n = 14), active cancer (n = 3), on chronic steroid therapy (n = 4), use of tocilizumab or other experimental treatment (n = 7). Twenty-eight patients who reached the primary end point before admission to a respiratory high-dependency unit (RHDU) or within 24 hours of admission to an RHDU were excluded from the analysis; 20 out of these 28 patients did not start methylprednisolone treatment.

Figure 2.

Kaplan-Meier estimates of survival probability. Abbreviations: CTR, control; MP, methylprednisolone.

Figure 3.

Time course of C-reactive protein and PaO₂:FiO₂ variation. Upper panel: time course of C-reactive protein levels (mean ± SE). The differences between groups were significant at days 3 and 7. Middle panel: time course of mean PaO₂:FiO₂. The differences between groups were significant at day 3. Lower panel: time course of the mean lymphocyte count showing no significant differences between groups.