High-dose corticosteroid pulse therapy increases the survival rate in COVID-19 patients at risk of hyper-inflammatory response

Abstract

Objective: Test whether high dose corticosteroid pulse therapy (HDCPT) with either methylprednisolone or dexamethasone is associated with increased survival in COVID-19 patients at risk of hyper-inflammatory response. Provide some initial diagnostic criteria using laboratory markers to stratify these patients.

Methods: This is a prospective observational study, 318 met the inclusion criteria. 64 patients (20.1%) were treated with HDCPT by using at least 1.5mg/kg/24h of methylprednisolone or dexamethasone equivalent. A multivariate Cox regression (controlling for co-morbidities and other therapies) was carried out to determine whether HDCPT (among other interventions) was associated with decreased mortality. We also carried out a 30-day time course analysis of laboratory markers between survivors and non-survivors, to identify potential markers for patient stratification.

Results: HDCPT showed a statistically significant decrease in mortality (HR = 0.087 [95% CI 0.021-0.36]; P < 0.001). 30-day time course analysis of laboratory marker tests showed marked differences in pro-inflammatory markers between survivors and non-survivors. As diagnostic criteria to define the patients at risk of developing a COVID-19 hyper-inflammatory response, we propose the following parameters (IL-6 > = 40 pg/ml, and/or two of the following: C-reactive protein > = 100 mg/L, D-dimer > = 1000 ng/ml, ferritin > = 500 ng/ml and lactate dehydrogenase > = 300 U/L).

Conclusions: HDCPT can be an effective intervention to increase COVID-19 survival rates in patients at risk of developing a COVID-19 hyper-inflammatory response, laboratory marker tests can be used to stratify these patients who should be given HDCPT. This study is not a randomized clinical trial (RCT). Future RCTs should be carried out to confirm the efficacy of HDCPT to increase the survival rates of COVID-19.

Fig 1. Multivariate Cox regression analysis, n = 318.

Pre-Corticosteroids^¶ refers to whether the patient was under any oral or inhaled corticosteroid therapy upon entering the hospital. COPD (Chronic Obstructive Pulmonary Disease). ACE inhibitors / ARBs, angiotensin-converting enzyme inhibitors / angiotensin receptor blockers. qSOFA (quick Sequential Organ Failure Assessment). High Dose Corticosteroids PT, high-dose corticosteroids pulse therapy. AC, anticoagulation therapy. See Methods for a full description of all of these variables. Highlighted in green are the interventions with p-value < 0.01 (**/***).

Fig 2. Time course analysis of survivors/non-survivors all laboratory tests carried out during the first month from COVID-19 illness onset.

Median and interquartile range are presented in each timepoint. The data is showed in a linear scale except in the case of IL-6, ferritin, D-dimer and procalcitonin, which are shown in a Log10 scale (see S1 Table for the measurement unit of all markers and rest of the time course analyses). The false discovery rate (FDR) of the overall time-differences is shown for each marker (see the results of all the tests carried out in S1 Table). a. Inflammatory markers: IL-6, Ferritin, Lactate dehydrogenase (LDH), D-dimer and C-reactive protein (CRP). Marked with a red line are suggestive cut-offs that could potentially be used to select patients at risk of developing a hyper-inflammatory response IL-6 > = 40 pg/ml, C-reactive protein > = 100 mg/L, D-dimer > = 1000 ng/ml, ferritin > = 500 ng/ml and lactate dehydrogenase > = 300 U/L). b. Other clinically relevant markers: platelets, total neutrophils, troponin T, total lymphocytes, procalcitonin, glomerular filtration rate (GFR) and triglycerides.