Early Corticosteroids Decrease Mortality in Critically Ill Patients with COVID-19: A Cohort Study

Background: Critically ill patients with coronavirus disease 19 (COVID-19) have a high fatality rate likely due to a dysregulated immune response. Corticosteroids could attenuate this inappropriate response, although there are still some concerns regarding its use, timing, and dose. Methods: This is a nationwide, prospective, multicenter, observational, cohort study in critically ill adult patients with COVID-19 admitted into Intensive Care Units (ICU) in Spain from March 12 th to June 29 th , 2020. Using a multivariable Cox model with inverse probability weighting, we compared relevant outcomes between patients treated with early corticosteroids (before or within the �rst 48h of ICU admission) with those who did not receive early corticosteroids or any corticosteroids at all. Primary endpoint was ICU mortality. Secondary endpoints included 7-day mortality, ventilator-free days, and complications. Results: A total of 691 patients out of 882 (78.3%) received corticosteroid during their hospital stay. Patients treated with early-corticosteroids (n=485) had a lower ICU mortality (30.3% vs 40.6%, HR 0.71, 95% CI 0.57-0.89) and higher number of ventilator-free days (mean difference 2.5 days, 95% CI 1.3-3.8) compared to non-early treated patients. There were no differences in 7-day mortality (HR 0.76, 95% CI 0.48-1.2), medical complications (OR 2.18, 95% CI 0.91-5.25) or secondary infections (OR 0.88, 95% CI 0.67-1.15) between both groups. Of note, early use of moderate-to-high doses was associated with better outcomes than low dose regimens. Conclusion: Early use of corticosteroids in critically ill patients with COVID-19 is associated with lower mortality (10.3% absolute risk reduction) and shorter duration of mechanical ventilation.


Background
Coronavirus disease 2019 (COVID- 19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was rst recognized in Wuhan, China, in December 2019 [1].The anti-viral immune response is crucial to eliminate the invading virus.However, an inappropriate response may cause a systemic hyperin ammatory state, producing complications such as acute respiratory distress syndrome (ARDS) and multisystem organ failure [2].Early treatment of this hyperin ammation may be important for reducing mortality in COVID-19 patients.
Corticosteroids are used to treat several hyperin ammatory syndromes [3].Early after the outbreak, the World Health Organization (WHO) recommended against the routine use of systemic corticosteroids for treating COVID-19 patients, due to their known side effects and a potential slowing of viral clearance [1].However, the RECOVERY trial has shown improved outcomes in COVID-19 patients treated with corticosteroids [4].Consequently, the US National Institutes of Health (NIH) is recommending now the use of dexamethasone to treat COVID-19 patients requiring supplemental oxygen [5].
Spain is one of the European countries most affected by the COVID-19 pandemic with a broad experience in the use of corticosteroids in Intensive Care Units (ICU) for patients with ARDS [6].In a large COVID-19 registry of patients admitted into a network of ICUs, we examined whether early use of corticosteroids decreases all-cause mortality and improves clinically relevant outcomes.

Study design
This is a multicentre, observational study with retrospective analysis of prospectively collected data in consecutive critically ill COVID-19 patients admitted from March 12 th to June 29 th , 2020 into a network of ICUs in 36 hospitals from Spain and Andorra.The study was approved by a referral Ethics Committee (Ethics Committee of Euskadi, Spain) and by all participating hospitals.Data source and study population Following a standardized protocol, site investigators collected data from electronic medical records.We recorded pre-admission and daily data from ICU admission to ICU discharge.Before data analysis, two independent investigators and a statistician screened the database for errors against standardized ranges and contacted site investigators with queries.
All consecutive COVID-19 patients admitted to participating ICUs, were considered for study entry if they had: age >18 years and con rmed SARS-CoV-2 infection from a respiratory tract sample using RT-PCR assay.Exclusion criteria were non-con rmed SARS-CoV-2 infection, patients with no data at baseline, patients with do-not-resuscitate orders, and patients who did not meet the outcomes of death or ICU discharge by June 29 th , 2020.

Variables, Exposures, and Endpoints
We recorded data on demographics and comorbidities according to established de nitions (See Additional File), laboratory ndings, vital signs, severity scores at ICU admission, supportive therapies, and relevant outcomes reported by June 29 th , 2020.We collected pre-ICU-admission and full data set on the rst day of ICU (baseline), and the "worst" values during ICU stay (maximum or minimum, depending on the parameter).
For this study, we established a post-hoc cut-off at 48 hours after ICU admission, and classi ed patients in two groups: (i) patients receiving corticosteroids within the rst 48 hours (early-treated group); (ii) patients receiving corticosteroids after 48 hours or never (non-early group).Other exploratory exposures included the administration of corticosteroids at any time during hospital stay (ever-treated group = early plus delayed use) and no administration at all (never-treated group).We also examined patients receiving low dose of corticosteroids (de ned as methylprednisolone < 1 mg/kg/d or dexamethasone < 0.12 mg/kg/d or prednisone < 0.5 mg/kg/d) or receiving moderate-to-high doses (any dose higher than low dose).
The primary endpoint was ICU mortality.We excluded from the analysis patients who died or were discharged within the rst 48 hours.Secondary endpoints were medical and infectious complications, ventilator-free days, ICU length of stay (LOS), and 7-day mortality.

Statistical analysis
We aimed to enrol as many patients as possible, with no pre-de ned sample size.
We report the values of variables as percentages, mean and standard deviation (SD), or median and interquartile range (IQR), as appropriate.To compare variables among groups, we used Student t-test or Mann-Whitney test and one-way ANOVA or Kruskal-Wallis test for numerical variables, and Chi-squared test or Fisher exact test for categorical variables.
To assess the relationship between corticosteroids treatment and endpoints, time-to-event curves were plotted using the Kaplan-Meier method and analysed with Cox regression analysis.For the Kaplan-Meier curves, patients with complementary outcomes were right-censored at the longest recorded LOS.We used inverse probability of treatment weighting (IPW) for baseline differences between treatment groups.We tted logistic models using the following baseline variables: age, gender, comorbidities (diabetes mellitus and arterial hypertension), APACHE II and SOFA scores, and PaO 2 /FiO 2 at admission.Weights were calculated following the methodology described elsewhere [7], and a pseudo-population (adjusted sample) was built subsequently.The 95% con dence intervals (CI) were the 2.5 th and 97.5 th percentiles of the distribution obtained from a nonparametric bootstrap with 1,000 samples.To test the robustness of results, we rerun the primary analysis under several assumptions and scenarios (See Additional File).
Missing data were not imputed.Analyses were performed in a complete case analysis basis.All tests were two-sided, and a p-value <0.05 was considered statistically signi cant.Analyses were performed using STATA version 16.

Results
From 1,102 consecutive patients with COVID-19, we analysed 882 patients (Fig. 1).Baseline characteristics are reported in Table 1.Acute hypoxemic respiratory failure was the main reason for ICU admission.1).During ICU stay, corticosteroid early-treated patients developed less organ dysfunction, had less requirement for renal replacement therapy (RRT), and less systemic in ammation than non-early treated patients (Table 2).S2).The reduction in mortality with corticosteroids was independent of treatment with tocilizumab, initiation of steroids before ICU admission, need of invasive mechanical ventilation (MV), lymphocytes count, duration of corticosteroids treatment, or the admitting hospital (Table S2).This reduction in mortality was also observed when including the 149 patients not discharged from ICU or when including "missing" as a category in the IPW cohort.S3-S4, Figure S1).

Secondary outcomes
Patients treated with early corticosteroids had shorter ICU LOS (Table 3), lower rate of acute renal failure (HR 0.64; 95%CI, 0.48-0.84),higher rates of hyperglycaemia, and higher levels of aspartate transaminases.There were no differences in the rate of secondary infections between groups.
Regarding corticosteroids doses, early use of moderate-to-high doses, compared with low doses, was associated with a shorter ICU LOS, lower organ dysfunction, less requirement of MV or RRT, and no increase in medical or infectious complications (Table S3-S4).
Patients who never corticosteroids were a less severe population: younger, with fewer signs of organ damage and in ammation, and lower requirement for MV.Nonetheless, compared with earlytreated patients, they had higher ICU mortality (36.6% vs. 30.3%,HR 0.55, 95% CI 0.35-0.93)(Tables S5-6, Figure S2).In contrast, compared with ever-treated patients, they had no difference in ICU survival, but lower LOS, less requirement for mechanical ventilation and vasopressors, better disease progression, and a lower number of infectious complications (Tables S7-S8, Figure S3).

Discussion
The major ndings of our study are that early use of corticosteroids in critically ill patients with COVID-19 was associated with: (i) lower ICU mortality when compared to delayed or no use of corticosteroids; (ii) shorter ICU LOS; (iii) decreased organ dysfunction, and (iv) fewer days on MV, with no increase in medical or infectious complications.These ndings remained statistically signi cant after adjusting for age, gender, comorbidities, severity, and PaO 2 /FiO 2 at admission.
To study the in uence of corticosteroids on mortality in our cohort we set a cut-off point of 48 hours after admission to ICU.We consider this period long enough for an experienced clinician to assess patients' response to initial support and therapy and modify them accordingly.We have tried to solve the question placed by many clinicians: shall I start corticosteroids in this patient?Like an intention-to-treat analysis, patients receiving corticosteroids after 48 h of ICU admission were not excluded because the decision to start therapy in this group was probably guided by other uncontrolled factors.
Two recent publications support the early and selective use of corticosteroids in symptomatic patients infected with SARS-COV-2.The RECOVERY trial found a reduction in 28-day mortality in hospitalized COVID-19 patients treated with dexamethasone if they required oxygen or MV [4].The study by Fadel et al. [8] found that an early short of methylprednisolone in moderate-to-severe COVID-19 reduced escalation of ICU care, need for MV, and hospital mortality.Our study reinforces those results, especially in critically ill COVID-19 patients.Of note, these ndings are in contrast with previous reports on corticosteroid therapy in past outbreaks of other coronaviruses (SARS-CoV, MERS-CoV), or other viral pneumonia (In uenza, Respiratory Syncytial Virus) [9][10][11][12][13].
Our sensitivity analysis showed that early use of corticosteroids was not as effective in women, in those with lower risk of death -younger patients with good oxygenation and less in ammation-and neither in those with greater risk or severity -cancer, diabetics, D-Dimer > 1500 ng/mL, APACHE score > 14-.These ndings suggest that patient characteristics should be assessed before prescribing corticosteroids.
In clinical practice, corticosteroids are used in most critically ill patients [13].The extensive use of corticosteroids in our cohort re ects the severity of our patients (almost 60% directly admitted to ICU upon arrival to the hospital, 81.9% with invasive mechanical ventilation in the rst 48 hours after ICU admission, and with a mean PaO2/FiO2 = 150).Since observational studies are prone to selection bias, we used inverse probability of treatment weighting to tackle this problem.Corticosteroid therapy is further entangled by other factors that merit discussion, including timing, type of corticosteroids, duration of treatment, and dosing.
Our average time to corticosteroids administration was 12 days after symptom onset (Table S1), like the 13 days in the RECOVERY study for mechanically ventilated patients [4].The decision to initiate corticosteroid therapy in our patients was guided when signs of hyperin ammation and severity of respiratory failure were evident.The delay or non-use of corticosteroids in 45% of our patients may re ect the controversy on their bene t/harm pro le, WHO recommendations [1], or signi cant changes in clinical evolution.Ideally, we should start corticosteroid therapy in the initial phases of the hyperin ammatory state.Early use in the absence of hyperin ammation could be harmful, especially in the initial stage of viral replication [4,[14][15].Similar to the RECOVERY trial, we have also found that corticosteroids were not associated with a reduction in mortality among those patients with symptoms duration under 7 days.
One possible explanation is that corticosteroids may slow viral clearance in such an early phase.
Interestingly, patients who never received corticosteroids had higher mortality than early-treated patients, a difference that was not observed when we compare them with ever-treated patients, that includes early plus delayed treatment.Delayed corticosteroids, when advanced organ damage already exists, might be ineffective and even detrimental, as previously described in ARDS [20], with increased infectious complications and mortality, counteracting the positive effect of early treatment.The absence of bene t with too early use of corticosteroids (within 7 days of symptom onset), together with the bene cial effect of early use, and the worst results with delayed use, reveals a U-shaped time-outcome relationship.
Although we do not know the optimal time to start corticosteroids, probably patients with elevated in ammatory markers after seven days of symptoms, requiring oxygen or ventilatory support may bene t the most, whereas those who have not received corticosteroids in early phases, probably will not bene t afterwards.
To the best of our knowledge, recommendations about dose and duration of corticosteroid treatment are empiric.With large doses and long treatments, the potential for adverse effects increases, and the possible bene t is lost [21].The Italian National Institute for Infectious Diseases recommends a 10-day regimen: 5-days full dose of methylprednisolone 1 mg/Kg daily or dexamethasone 20 mg daily, and ve days for tapering [22].In general, most regimens for acute hyperin ammatory states recommend treatments shorter than two weeks [22,23].Most common dose regimens range between 0.5-2 mg/kg/day of methylprednisolone, equivalent to 0.1-0.4mg/kg/day of dexamethasone, de ned in our study as moderate-to-high doses.The cut-off points were de ned before the publication of the RECOVERY trial that used a xed dexamethasone dose (6 mg) lower than described in the literature for ARDS [6].We observed a greater mortality reduction with a moderate-to-high dose regimen, similar to other studies [6,24].Although our classi cation is arti cial, it favours a higher dose of corticosteroids.As a result of RECOVERY trial, the NIH recommend a low xed dose of daily dexamethasone [4][5], but future comparative studies with higher doses are warranted [6].Also, the bene cial effects of early corticosteroids in our patients expand beyond an absolute reduction in all-cause mortality, including a shorter ICU LOS, less organ dysfunction, and an increase in ventilator-free days.
This study has several strengths.First, this multicentre nationwide prospective data collection with over 1,000 patients from 36 ICUs provides a very detailed description of all gathered data from ICU admission to death or ICU discharge.Second, to the best of our knowledge, this is the rst observational study that prospectively explores the association between different doses and timings of corticosteroid therapy in COVID-19 patients and ICU mortality.Third, we have used IPW to control for confounding with prespeci ed demographic, comorbidities, and severity parameters.However, we acknowledge some limitations of our study.First, the observational nature of our study design.Although we adjusted for likely confounders, some unmeasured confounding is still possible.Second, we cannot exclude missing data for some variables and potential for inaccuracies in the electronic health records due to the burden of care experienced by participating clinicians during the pandemic.However, due to the nature of our registry, we consider that selection bias was not favoured, and our analyses are valid.Third, although moderate-to-high doses of dexamethasone were most effective, no rm conclusions can be drawn on the drug or the dose, as our hypothesis and the de nition of variables in the protocol preclude to do so, and doses prede ned as low are not completely equivalent and could be controversial.Finally, at the time of the analysis, 149 (13.5%) patients did not have a de nitive outcome regarding status at ICU discharge and were not included in the main analysis, although included in the sensitivity analyses.

Conclusions
In conclusion, in critically ill COVID-19 patients with acute respiratory failure, the use of corticosteroids within the rst 48 h of ICU admission was associated with a marked reduction in ICU mortality and ICU LOS.We also found a clear relationship between exposure and a bene cial effect on organ dysfunction.
Further research is needed to characterize the optimal drug, onset, dose, and duration of corticosteroids therapy in this patient population.VERSIÓN 5 -5 de mayo-2020).The procedures used in this study adhere to the tenets of the Declaration of Helsinki.
Consent to participate: The need for written informed consent from participants was considered by each participating centre Consent for publication: Not applicable Availability of data and materials: After publication, data will be made available to other investigators on reasonable requests to the corresponding author.A proposal with a detailed description of study objectives and statistical analysis plan will be needed for evaluation of the reasonability of requests.
Additional materials might also be required during the process of evaluation.Deidenti ed participant data will be provided after approval from the corresponding author.
Competing interests: We declare no competing interests.Supplementary Files

Abbreviations COVID- 19 :
Abbreviations COVID-19: Coronavirus disease 2019 Funding: NoneAuthors' contributions: PM, PC, ACT, MH, CF, and the COVID-19 Spanish ICU Network collected the clinical data.AG, EA, and CF performed the initial data analysis and interpretation.PM and PC summarised all data.ACT, AG, CF, PM, and JV drafted the manuscript.JV, MH, and PC contributed to data interpretation and revised the nal manuscript.All authors contributed to critical revision of the manuscript for intellectual content, and all are responsible for the content of this paper.

Figures
Figures

Figure 1 Flow
Figure 1

Table S1 )
. Corticosteroid exposure did not differ according to age, sex, body-mass index, severity scores, and main comorbidities (Table

Table 2
Evolution of organ failure, vital signs, and laboratory ndings during ICU stay according to the use of early corticosteroids in the rst 48 h of ICU admission.

Table 3
Outcomes according to early corticosteroids use in the rst 48 h of ICU admission.IPW subcohort, n = 455