key: cord-0781618-stuqdpjk
authors: Climente‐Martí, Mónica; Ruiz‐Millo, Oreto; López‐Cruz, Ian; Atienza‐García, Ángel; Martínez‐Moragón, Eva; Garijo‐Gómez, Emilio; López‐Grima, María Luisa; Zaragoza‐Crespo, Rafael; Llau‐Pitarch, Juan Vicente; Bautista‐Rentero, Daniel; Nogueira‐Coito, José Miguel; Ripollés‐González, Tomás; Marco‐Artal, María Antonia; Romero‐Serrano, Ramón; Dolz‐Sinisterra, Francisco; López‐Estudillo, Rosario
title: Impact of intermediate to high doses of methylprednisolone on mortality rate in patients with COVID‐19 pneumonia‐induced severe systemic inflammation
date: 2021-06-28
journal: Int J Clin Pract
DOI: 10.1111/ijcp.14479
sha: 78ddadccee17a7b64bfcaf2f51833645065af37f
doc_id: 781618
cord_uid: stuqdpjk

INTRODUCTION: In addition to respiratory support needs, patients' characteristics to guide indication or timing of corticosteroid treatment in COVID‐19 patients are not completely established. This study aimed to evaluate the impact of methylprednisolone on mortality rate in patients with COVID‐19 pneumonia‐induced severe systemic inflammation (PI‐SSI). METHODS: Between 9 March and 5 May 2020 (final follow‐up on 2 July 2020), a retrospective cohort study was conducted in hospitalised patients with COVID‐19 PI‐SSI (≥2 inflammatory biomarkers [IBs]: temperature ≥38℃, lymphocyte ≤800 cell/µL, C‐reactive protein ≥100 mg/L, lactate dehydrogenase ≥300 units/L, ferritin ≥1000 mcg/L, D‐dimer ≥500 ng/mL). Patients received 0.5‐1.0 mg/kg of methylprednisolone for 5‐10 days or standard of care. The primary outcome was 28‐day all‐cause mortality. Secondary outcomes included ≥2 points improvement on a 7‐item WHO‐scale (Day 14), transfer to intensive care unit (ICU) (Day 28) and adverse effects. Kaplan–Meier method and Cox proportional hazard regression were implemented to analyse the time to event outcomes. RESULTS: A total of 142 patients (corticosteroid group n = 72, control group n = 70) were included. A significant reduction in 28‐day all‐cause mortality was shown with methylprednisolone in patients with respiratory support (HR: 0.15; 95% CI 0.03‐0.71), with ≥3 (HR: 0.17; 95% CI 0.05‐0.61) or ≥4 altered IB (HR: 0.15; 95% CI 0.04‐0.54) and in patients with both respiratory support and ≥3 (HR: 0.11; 95% CI 0.02‐0.53] or ≥4 altered IB (HR: 0.14; 95% CI 0.04‐0.51). No significant differences were found in secondary outcomes. CONCLUSION: Intermediate to high doses of methylprednisolone, initiated between 5 and 12 days after symptom onset, was associated with a significant reduction in 28‐day all‐cause mortality in patients with COVID‐19 pneumonia and ≥3 o ≥ 4 altered IB, independently of the need of respiratory support.

Clinical manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated disease, COVID-19, range from asymptomatic, mild pneumonia to acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome, and death. 1, 2 It is clear that the host immune response plays a key role in the pathophysiological effects of organ injury. 2 In severe COVID-19 pneumonia, patients' symptoms worsen and become more hypoxic 4-7 days after the onset of symptoms and can progress to ARDS between 8 and 12 days. 3, 4 A macrophage activation syndrome with hyperinflammation and cytokine storm appear to be the ultimate cause of tissue damage and organ failure in these patients. [5] [6] [7] The similarity of SARS-CoV-2-induced hyperinflammation to hyperferritinemic syndromes supported the use of anti-inflammatory and immunomodulatory agents such as corticosteroids. 8, 9 Initially, corticosteroids were restricted to patients with SARS-COV-2 pneumonia and ARDS by the World Health Organization (WHO) due to their potential effects on delayed viral clearance and the increased risk of secondary infections or death. 10, 11 Later, the RECOVERY clinical trial 12 has demonstrated the benefit of low dose of dexamethasone in reducing 28-day mortality risk among patients hospitalised with SARS-CoV-2 pneumonia. This evidence has led the WHO and scientific societies to recommend the use of dexamethasone, at a dose of 6 mg orally or intravenously once daily, or 50 mg of hydrocortisone intravenously every 8 hours, for 7-10 days, in patients with severe and critical COVID-19 and in patients who require oxygen therapy with and without invasive mechanical ventilation, advising against the routine use of corticosteroids for mild clinical conditions. [13] [14] [15] Data on the efficacy of other corticosteroids are limited to smaller trials, and not all of them have reproduced similar results.

all-cause mortality. Secondary outcomes included ≥2 points improvement on a 7item WHO-scale (Day 14), transfer to intensive care unit (ICU) (Day 28) and adverse effects. Kaplan-Meier method and Cox proportional hazard regression were implemented to analyse the time to event outcomes.

Results: A total of 142 patients (corticosteroid group n = 72, control group n = 70) were included. A significant reduction in 28-day all-cause mortality was shown with methylprednisolone in patients with respiratory support (HR: 0.15; 95% CI 0.03-0.71), with ≥3 (HR: 0.17; 95% CI 0.05-0.61) or ≥4 altered IB (HR: 0.15; 95% CI 0.04-0.54) and in patients with both respiratory support and ≥3 (HR: 0.11; 95% CI 0.02-0.53] or ≥4 altered IB (HR: 0.14; 95% CI 0.04-0.51). No significant differences were found in secondary outcomes.

Intermediate to high doses of methylprednisolone, initiated between 5 and 12 days after symptom onset, was associated with a significant reduction in 28day all-cause mortality in patients with COVID-19 pneumonia and ≥3 o ≥ 4 altered IB, independently of the need of respiratory support.

• Systemic corticosteroids are one of the few interventions that have succeeded in demonstrating its effect in mortality risk reduction in critical and severe COVID-19 patients who require respiratory support.

• WHO and scientific societies recommend the use of dexamethasone, at a dose of 6 mg orally or intravenously once daily, or 50 mg of hydrocortisone intravenously every 8 hours, for 7-10 days, in patients with severe and critical COVID-19 and in patients who require respiratory support, and it is now recognised as standard of care for these patients. Nevertheless, some uncertainties still remain about their optimal use in COVID-19 patients.

• This study shows that intermediate to high-doses of methylprednisolone, initiated between 5-12 days after symptoms onset, decreases mortality risk in hospitalised patients with COVID-19 pneumonia-induced severe systemic inflammation.

• It suggests that the corticosteroid treatment effect in mortality risk reduction may be a function of hyperinflammation's degree, independently of the needs of respiratory support.

• Identify the profile of patients who might benefit most from corticosteroid therapy, defining inflammatory biomarkers and cut-off values that will allow clinicians to tailor treatment strategies in hospitalised COVID-19 patients, to reduce mortality.

While some failed to demonstrate efficacy, 15, 16 others showed beneficial effects over the course of the disease regarding the duration of the need of mechanical ventilation and admission to the intensive care unit (ICU). 3, 17, 18 Therefore, other corticosteroids such as methylprednisolone or prednisone are reserved in case of not having dexamethasone, using them at equivalent doses. [13] [14] [15] Despite the growing evidence supporting the corticosteroid use, some uncertainties still remain regarding their optimal use in SARS-CoV-2 pneumonia. It is known that, in addition to developing respiratory failure, a subgroup of patients will progress into a severe systemic inflammation (SSI) syndrome and several inflammatory biomarkers (IBs) have been associated with severity and a worse prognosis. [19] [20] [21] [22] Hence, in order to better define the profile of patients who might benefit most from corticosteroid therapy, we conducted this study with the aim of assessing the impact of intermediate to high doses of methylprednisolone on mortality rate in patients with COVID-19 pneumonia-induced SSI.

A single-centre, observational, longitudinal, retrospective study was conducted at a 539-bed general teaching hospital in Valencia (Spain), between 9 March 2020 and 5 May 2020. The recruitment period extended from 9 March to 17 April 2020 and final follow-up was completed on 2 July 2020.

Patients eligible were aged 18 years or older with severe COVID-19 pneumonia, confirmed by the reverse transcription polymerase chain reaction (RT-PCR) test, and had progressed into SSI, defined as at least two out of six IB raised over the predefined cut-off points [19] [20] [21] [22] : fever (body temperature ≥38℃), absolute lymphocyte count ≤800 cell/µL, C-reactive protein (CRP) ≥100 mg/L, lactate dehydrogenase (LDH) ≥300 units/L, ferritin ≥1000 mcg/L and D-dimer ≥500 ng/mL. Exclusion criteria were: previous long-term systemic corticosteroid therapy (more than 6 months), methylprednisolone or equivalent treatment at doses out of range 0.5-1.0 mg/kg or duration less than 5 days and sepsis or ARDS according to Berlin criteria 23 at the beginning of corticosteroid use or progression into SSI. Pregnant or breast-feeding women, patients transferred to an ICU or who died within the first 48 hours of admission were also excluded.

A sample-size calculation was performed to detect a 20% difference in 28-day all-cause mortality assuming a test power of 0.80, a 95% confidence level and no drop-out rate. Seventy patients in each group were required.

Every patient was fully informed about the off-label character of the treatment strategy and the potential side effects, and informed consent was obtained before initiating any treatment following the national protocol for treating hospitalised patients with COVID-19 developed by the Ministry of Health, Consumer Affairs and Social Welfare. 24 The study was conducted in accordance with 

Electronic health records, including laboratory results, prescribed medication, respiratory support received (oxygen with or without non-invasive or invasive ventilation) and information on vital status were reviewed for all admitted patients with laboratory-confirmed 

The primary outcome was 28-day all-cause mortality in overall population (≥2 IB altered) and subgroups of patients classified according to respiratory support needs at the progression into SSI and/or the number of altered IB (≥3 or ≥4). For a clearer understanding of risk, the outcomes were also modelled separately. A secondary outcome was ≥2 stages of improvement at Day 14 on a 7-item WHO-endorsed ordinal scale (ranging from 1 to 2, not hospitalised to 7, death). 26 The two outpatient strata (points 1 and 2) were combined into one, due to was not possible to know whether discharged patients were able to resume or not their normal activities. Other secondary outcomes were transfer to ICU, progression into ARDS and severe adverse effects (hyperglycaemia defined as glycaemia >200 mg/dL for two consecutive tests, nosocomial infection and sepsis).

The demographic and clinical variables were described using univariate analysis. Distribution normality was assessed using the Kolmogorov-Smirnov test. Categorical variables were reported as frequencies (%); normally distributed quantitative variables, as mean and standard deviation (SD); and non-normally distributed, as median and interquartile range (IQR). Chi-square or Fisher's exact tests and t test for two independent samples or Mann-Whitney U test were used for descriptive statistics, as appropriate.

For the primary outcome of 28-day all-cause mortality, Kaplan-Meier survival plots were constructed, and survival curves for both groups were compared by use of log-rank test. Survival data were censored when the patient died or on Day 28 for survived patients.

Hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained from Cox proportional hazard univariate and multivariate models to assess the relationship of corticosteroid treatment and 28-day mortality in overall population and subgroups of patients classified as previously stated. Adjusted multivariate Cox models incorporated covariates including number of comorbidities, previous neurological antecedents, oxygen supplementation needed at the beginning of corticosteroid or progression to SSI, azithromycin therapy, lopinavir/ritonavir therapy, tocilizumab therapy and low-molecular weight heparin (LMWH) therapeutic dosage use.

Statistical analysis was performed using PASW version 19.0 for Windows (SPSS™, Inc, Chicago, IL, USA). All statistical tests were two sided, and a P < .05 was considered statistically significant.

During the recruitment period, a total of 327 possible candidates were admitted to the hospital (Figure 1 ). Of the 142 patients included, the mean (SD) age was 67. 6 

Mortality analyses are reported in Table 2 Treatment effect of corticosteroids in reduction of 28-day all-cause mortality was independent of the number of comorbidities, previous neurological antecedents, oxygen supplementation needs at the beginning of corticosteroid or progression to SSI, azithromycin therapy, lopinavir/ritonavir therapy, tocilizumab therapy and LMWH therapeutic dosage use.

Methylprednisolone ( LMWH as therapeutic dosage use (P = .002). Table 3 shows therapy received during hospitalisation. 

In this study, including 142 patients with COVID-19 pneumoniainduced SSI, we found that intermediate to high-dose (0.5-1.0 mg/ kg/day) methylprednisolone therapy, initiated between 5 and 12 days after symptom onset, was associated with a significant reduction in the risk of 28-day all-cause mortality in patients with has reported IL-6 receptor antagonists such as tocilizumab seem to improve survival outcomes in critically ill patients with COVID-19.

In our study population, 28-day all-cause mortality was up to four times lower than previous published studies. 12, 29 However, mortality in the control group for patients with ≥3 o ≥ 4 altered IB, alone or combined with respiratory support, was similar (between 20% and Note: Data are median (IQR) or n (%), unless otherwise indicated.

Abbreviation: LMWH, low-molecular weight heparin.

TA B L E 3 Therapy received during hospitalisation 30%) to other studies. 12, 29 Also, as can be seen in The clinical benefit of dexamethasone, 11,12,17 hydrocortisone 3,16 or methylprednisolone 18, 30 has been evaluated in previous studies.

In different trials, the corticosteroid dosing extended from low to high doses 3, 11, 12, [16] [17] [18] 30 and total duration of treatment varied between 3 and 14 days. 3, 11, 12, [16] [17] [18] 30 Studies comparing the efficacy of methylprednisolone and dexamethasone have obtained heterogeneous results. [31] [32] [33] Clinical outcomes have also been very unequal between studies, and it is uncertain whether these apparent differences are related to the corticosteroid formulation and dose, the severity of illness or issues related to statistical power. 3, 11, 12, 14, [16] [17] [18] 30 Hence, in order to identify which patients benefit the most from corticosteroid therapy, we conducted this study focusing on a subgroup of patients with COVID-19 pneumonia-induced SSI and analysed the effect of methylprednisolone depending on respiratory support needs and the number of altered IB. [19] [20] [21] [22] Interestingly, we found significant benefit in 28-day all-cause mortality among patients receiving methylprednisolone who had ≥3 and ≥4 altered IB, suggesting that the magnitude of the benefit seems to be closely related to the degree of hyperinflammation (see Table 2 , Figure 2 ). In these patients, benefit was even higher if, in addition to the elevation in IB, they also needed respiratory support.

Nevertheless, the results of this post hoc subgroup analysis should be confirmed in a randomised clinical trial with risk stratification based on the level of hyperinflammation.

Our study has other limitations as it is a single-centre study with an observational and retrospective nature. Prognostic similarity at baseline cannot be assumed. Despite being included in the institutional protocol from 29 March 2020, the prescription of corticosteroids was at the discretion of the treating physician and variability cannot be completely ruled out. Lastly, the selection of the IB to determine the progression into SSI was based on the outcomes from different observational studies, but the prognostic value and optimal clinical use of some of them are still uncertain. [19] [20] [21] [22] This study is unique in terms of the subset of patients included, since it focuses on a subgroup of patients progressing into a severe inflammatory syndrome. To our knowledge, there are no studies comparing the effect of corticosteroid therapy according to the inflammation degree, and our findings suggest that in this subgroup of patients, corticosteroids may be even more beneficial than shown in the RECOVERY trial. 12

Intermediate or high dose (0.5-1.0 mg/kg/day) of methylprednisolone was associated with a significant reduction in the risk of 28-day all-cause mortality in hospitalised patients with COVID-19

pneumonia-induced SSI, independently of the need of respiratory support. Benefits in mortality were higher in patients with both respiratory support and ≥3 or ≥4 altered IB.

We are grateful to Prof. Alberto Ferrer-Riquelme, Multivariate Statistical Engineering, from the Department of Applied Statistics,

OR and Quality at Universitat Politecnica de Valencia, Spain, for his critical review of the statistical analyses. We also thank Veronica

Chorro-Mari, PharmD, PhD, at Barts Health NHS Trust for her English language review.

We declare a different version of this paper is available as preprint publication at: https://papers.ssrn.com/sol3/papers.cfm?abstr act_id=3756801.

None.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Mónica Climente-Martí https://orcid.org/0000-0002-4387-1987

Oreto Ruiz-Millo https://orcid.org/0000-0001-5829-6957

Ian López-Cruz https://orcid.org/0000-0001-7252-8961

Eva Martínez-Moragón https://orcid.org/0000-0001-8986-9463

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Impact of intermediate to high doses of methylprednisolone on mortality rate in patients with COVID-19 pneumonia-induced severe systemic inflammation

The Doctor Peset COVID-19 Working Group members (alphabetical order): Marta Acosta-Dávila

Affiliations of the COVID-19 Working Group: Doctor Peset University Hospital. Gaspar Aguilar