key: cord-0812394-17o9qrbb
authors: Kumar, Gagan; Patel, Dhaval; Hererra, Martin; Jefferies, David; Sakhuja, Ankit; Meersman, Mark; Dalton, Drew; Nanchal, Rahul; Guddati, Achuta Kumar
title: Do high‐dose corticosteroids improve outcomes in hospitalized COVID‐19 patients?
date: 2021-10-08
journal: J Med Virol
DOI: 10.1002/jmv.27357
sha: b72b0b995001107ccdf862bae82e58d5c99b2d4f
doc_id: 812394
cord_uid: 17o9qrbb

Coronavirus disease 2019 (COVID‐19) is characterized by dysregulated hyperimmune response and steroids have been shown to decrease mortality. However, whether higher dosing of steroids results in better outcomes has been debated. This was a retrospective observation of COVID‐19 admissions between March 1, 2020, and March 10, 2021. Adult patients (≥18 years) who received more than 10 mg daily methylprednisolone equivalent dosing (MED) within the first 14 days were included. We excluded patients who were discharged or died within 7 days of admission. We compared the standard dose of steroids (<40 mg MED) versus the high dose of steroids (>40 mg MED). Inverse probability weighted regression adjustment (IPWRA) was used to examine whether higher dose steroids resulted in improved outcomes. The outcomes studied were in‐hospital mortality, rate of acute kidney injury (AKI) requiring hemodialysis, invasive mechanical ventilation (IMV), hospital‐associated infections (HAI), and readmissions. Of the 1379 patients meeting study criteria, 506 received less than 40 mg of MED (median dose 30 mg MED) and 873 received more than or equal to 40 mg of MED (median dose 78 mg MED). Unadjusted in‐hospital mortality was higher in patients who received high‐dose corticosteroids (40.7% vs. 18.6%, p < 0.001). On IPWRA, the use of high‐dose corticosteroids was associated with higher odds of death (odds ratio [OR] 2.14; 95% confidence interval [CI] 1.45–3.14, p < 0.001) but not with the development of HAI, readmissions, or requirement of IMV. High‐dose corticosteroids were associated with lower rates of AKI requiring hemodialysis (OR 0.33; 95% CI 0.18–0.63). In COVID‐19, corticosteroids more than or equal to 40 mg MED were associated with higher in‐hospital mortality.

Recently, the Society of Critical Care Medicine has made a strong recommendation to use a short course of systemic corticosteroids. 1 This was based on metanalysis by the REACT working group, which showed a significant reduction in 28-day mortality in patients receiving steroids. 2 The reduction in mortality was observed for dexamethasone and hydrocortisone treatments. The RECOVERY trial comprised the largest study in the metanalysis and used dexamethasone 6 mg daily for 10 days. 3 At the point of writing this manuscript, steroids have been shown to be useful in moderate to severe coronavirus disease 2019 (COVID-19)-those requiring high flow oxygen and those requiring noninvasive or invasive mechanical ventilation (IMV). The dose of the steroids has been debated.

Researchers have observed dose-dependent activation of corticosteroid receptors without an increase in adverse effects. 4 Whether this effect results in improved outcomes is currently unknown. A few randomized controlled trials (RCTs) used high-dose methylprednisolone for short periods [5] [6] [7] [8] and have reported conflicting results. Some researchers have proposed a higher dose of steroids, including pulse dosing with good results. 9, 10 In a nonviral acute respiratory distress syndrome (ARDS), high dose steroids followed by tapering dose was shown to improve mortality and ventilator-free days without increased risk of serious side effects. 11 In other viral illnesses such as the Middle East respiratory syndrome, high dose steroids were beneficial in severe cases while in H1N1 pneumonia, mild to moderate dose improved outcomes, and higher dose did not. 12, 13 In an observational study of 447 COVID-19 patients, high dose steroids improved mortality and progression to mechanical ventilation. 9 However, the optimal dose of corticosteroids in COVID-19 is still unknown. RCTs are ongoing to answer this question. 14, 15 The objectives of this retrospective study were to determine if a higher dose of corticosteroids was associated with improvement in outcomes of hospitalized COVID-19 patients. We used inverse probability weighted regression adjustment, a statistical method that has been shown to minimize bias among propensity score methods. 16 2 | METHODS 

We obtained the type and dose of corticosteroids used for the COVID19 patient. The selection method for the study is shown in Figure S1 . We excluded those who did not receive any corticosteroids. We also excluded those patients who either were discharged within 7 days of admission or died within 7 days of admission to exclude nonsick and extremely sick patients who would have either survived or died with or without corticosteroids. We used methylprednisolone equivalent dosing (MED) for comparison. 1 mg of dexamethasone was equivalent to 5 mg of methylprednisolone. We calculated the total amount of MED received within the first 14 days of admission. An average daily dose of steroids was calculated by dividing the total dose received in the first 14 days by the total number of days of corticosteroids were received within the first 14 days. We excluded patients whose daily average dose was less than 10 mg and those who received the first dose of corticosteroids after 14 days of admission.

We used restricted cubic splines to examine the probability of (remedesivir, corticosteroids, tocilizumab, convalescent plasma, hydroxychloroquine, and ivermectin). We collected data for hospitalacquired infections (HAI), IMV acute kidney injury (AKI), acute kidney injury requiring hemodialysis, venous thromboembolism (VTE), acute strokes, blood transfusions, and pneumothorax. The severity of illness was defined by Sequential Organ Failure Assessment (SOFA) score and 4C score. 17 

Our primary dependent variable was in-hospital mortality. Other outcomes studied were the rate of AKI requiring hemodialysis, IMV, HAI, readmission, and duration of IMV.

We obtained the highest inflammatory marker level within the first 5 days of admission and compared it with the lowest inflammatory marker during the subsequent 3 weeks. We only compared those KUMAR ET AL. | 373 patients who had both sets of values. We compared changes in the level of ferritin, CRP, LDH, and fibrinogen in standard and high dose steroid groups using t-test (after log transformation of the inflammatory markers) and Wilcoxon rank test for D-dimer.

We described the categorical data using frequency count and percentages. We report means and standard deviation or medians and interquartile ranges (IQRs) for continuous variables as appropriate for their distribution. We compared demographical and clinical characteristics using the χ 2 test and the Wilcoxon rank test for categorical and continuous variables, respectively. For all analyses, we deemed statistical significance a p-value less than 0.05.

To compare the two regimens of corticosteroids (high dose vs. standard dose), we used inverse probability weighted regression adjustment (IPWRA) to correct for potential bias brought about by higher doses of steroids in sicker patients. We calculated the probability of receiving high dose corticosteroids (propensity score model) by fitting a multivariable logistic regression model with high dose steroid as the dependent variable and patient demographics, comorbidities, use of anticoagulants and antiplatelet agents before hospitalization, SOFA score, and 4C score on admission, IMV, intensive care unit (ICU) transfer, use of vasopressors, medications related to COVID-19 (remedesivir, ivermectin, hydroxychloroquine, tocilizumab, ad convalescent plasma), and initial inflammatory markers (ferritin, D-dimer, fibrinogen, LDH, and CRP). These predictors were chosen based on clinical judgment and model fit. We log-transformed (natural logs) markers of inflammation as they were not normally distributed. For D-dimer, we used deciles as we were unable to normalize its distribution. We imputed missing values of inflammatory markers using median values. Inverse probability weights were obtained by using an inverse of the predicted probability of anticoagulation from the propensity score model. Next, we fitted our outcome model (in-hospital mortality) using the inverse probability weights and adjusted this regression model for patient demographics, comorbidities, SOFA and 4C score, IMV, ICU transfer, use of vasopressors, COVID-19 medications received, initial inflammatory markers (ferritin, D-dimer, fibrinogen, LDH, and CRP) and complications such as VTE, acute stroke, AKI requiring hemodialysis, HAI, pneumothorax, and blood transfusion.

We used a similar approach for other outcomes such as AKI requiring hemodialysis, mechanical ventilation, hospital-acquired infections, and rates of readmission. For our secondary analysis, we excluded patients who developed respective outcomes before initiation of corticosteroids. For example, for analysis of the risk of IMV, we excluded patients who received corticosteroids after they were intubated.

As an exploratory analysis, we compared a daily dose of MED more than or equal to 80 mg per day with those who received less than 80 mg per day to examine if an extremely high dose of corticosteroids were associated with reduced in-hospital mortality and other secondary outcomes. We used similar statistical methods as described above. We performed all statistical analyses using STATA MP 16.0 (Stata-Corp).

There were 5204 COVID-19 admissions during the study period. Of (Table 1 ).

Patients who received high-dose corticosteroids were younger but other demographical and comorbidities were similar in both steroid groups (Table 1) . Patients who received high-dose corticosteroids more often received other possible therapies for COVID-19 (tocilizumab, remdesivir, and higher dose anticoagulation). The severity of illness as observed by SOFA score and 4C score were not statistically different on admission between the two groups (Table 1) .

A patient who received high dose corticosteroids were/became sicker than their counterparts as adjudicated by higher rates of ICU admissions (67.8% vs. 42.3%, p < 0.001), ventilator use (28.1% vs. 11%, p < 0.001), lower PF ratio on a ventilator (52 vs. 58, p = 0.006), and vasopressor requirements (14.7% vs. 9%, p = 0.003) ( Table 2) .

Also, In the cohort that received high dose corticosteroids, both AKI and AKI requiring hemodialysis, HAIs (including candidemia), VTE, and blood transfusions were more common than in the cohort receiving standard-dose corticosteroids (Table 3) .

Unadjusted in-hospital mortality was higher in patients who received high-dose corticosteroids (40.7% vs. 18.6%, p < 0.001). However, the rate of discharges to home and with home health was significantly higher in patients who received high-dose corticosteroids. Readmission rates (15.1% vs. 18.9%, p = 0.11) and death during the readmissions (30.7% vs.

26.4%, p = 0.51) were not significantly different in the two groups.

Patients who received higher dose corticosteroids, with exception of D-dimer, had higher levels of ferritin, CRP, LDH, and fibrinogen (Table S2 ). The improvement in levels of inflammatory markers over 

In this retrospective study, we report that corticosteroids at more than or equal to 40 mg MED were associated with higher in-hospital mortality after adjusting for multiple covariates including severity.

A dose more than or equal to 40 mg MED did not decrease the rate or duration of mechanical ventilation. Similarly, dosages more than or equal to 80 mg MED were also associated with higher in-hospital mortality and did not improve rates or duration of mechanical ventilation. Dosage more than or equal to 80 mg MED was also associated with higher rates of HAIs. The use of high-dose corticosteroids did not improve readmissions. To our knowledge, this is the largest retrospective observational study examining this question. This study is designed to be hypothesis-generating and providing data for future RCTs. We have attempted to provide answers for multiple outcomes of interest.

We started using corticosteroids universally for our patients who required oxygen after initial reports from the RECOVERY trial.

We have only used methylprednisolone and dexamethasone in COVID-19 patients. As there was no consensus over the dosing Figure S2 ).

RCTs. 11, [18] [19] [20] In COVID-19, there is sufficient data to recommend its use in patients requiring oxygen and those on IMV. However, the answer to optimal steroid dosing is still elusive. The higher dose of corticosteroids has been used in a few RCTs and the outcomes have been mixed. CoDEX trial used 20 mg of dexamethasone (approximately 100 mg of methylprednisolone) for 5 days followed by 10 mg for 5 days or until ICU discharge and found a decrease in ventilatorfree days but not mortality. 7 Using the same regimen, Jamaati et al. 8 did not find any differences in outcomes. In a smaller RCT, pulse dose steroid (250 mg × 3 days) was shown to improve mortality. 5, 21 In propensity-matched observational studies, there are reports of improved survival 22 but not by others. 23, 24 We found significantly higher odds of death with higher dose steroids. With mortality averaging 32.6% in our study, this results in one excess death for every six patients receiving high-dose steroids.

Lower dose corticosteroids apart from the RECOVERY trial have failed to show any significant differences in mortality. In the MET-COVID study, there were no differences in mortality at 28 days when 0.5 mg/kg of methylprednisolone was given twice for 5 days. 6 differences in death or respiratory support. 25 Similarly, REMAP-CAP did not show any improvement in mortality, but better odds of organ support-free days. 26 Glucocorticoid's mechanism of action is mediated by the glucocorticoid receptor. Glucocorticoid receptor binds with glucocorticoids in the cytoplasm and is then translocated to the nucleus where it inhibits transcription of genes involved in leucocyte and endothelial/ epithelial cell activation and subsequent reduction of proinflammatory cytokines, chemokines, and adhesion molecules. We examined changes in inflammatory markers with standard and higher doses of corticosteroids but did not observe significant changes in rates of improvement in the two groups (Appendix). This may suggest that a lower dosage is possibly sufficient to reduce inflammation and a higher dosage may not be needed.

We have reported earlier that corticosteroids are associated with increased risk of HAI in COVID19. 30 In particular, at a higher dose (≥80 mg MED), we found significantly higher rates of HAI in this group. Corticosteroids have been shown to increase rates of readmissions in small studies, but we did not observe this in our patient population. 31 Subsequent mortality during readmission was also similar in the two groups. precision of our estimates. We could not ascertain whether the steroid regimen-both dosing and type, changed during hospitalization depending on HAIs and changing severity of illness, and inflammatory markers.

Corticosteroids more than or equal to 40 mg MED were associated with higher in-hospital mortality. Higher dosages more than or equal to 80 mg MED were also associated with increased mortality and development of HAI. High-dose corticosteroids were not associated with decreased rates or duration of mechanical ventilation or readmissions.

The use of the standard dose of steroids is suggested till further answers from RCTs are obtained. We suggest adding the risk of venous thromboembolism and acute kidney injury as secondary endpoints.

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The authors declare that there are no conflicts of interest.

The study was reviewed and found exempt by the Northeast Georgia Health System IRB board. 

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

https://orcid.org/0000-0002-6024-1055