key: cord-0809785-jljmd8hn
authors: Albani, F.; Fusina, F.; Granato, E.; Capotosto, C.; Ceracchi, C.; Gargaruti, R.; Santangelo, G.; Schiavone, L.; Taranto, M. S.; Tosati, C.; Vavassori, E.; Natalini, G.
title: Effect of corticosteroid treatment on 1376 hospitalized COVID-19 patients. A cohort study.
date: 2020-07-18
journal: nan
DOI: 10.1101/2020.07.17.20155994
sha: d16e9fe142ca7979f40cc830d44a8d7d9cdf9768
doc_id: 809785
cord_uid: jljmd8hn

Background: Since the start of the novel coronavirus 2019 (COVID-19) pandemic, corticosteroid use has been the subject of debate. The available evidence is uncertain, and knowledge on the subject is evolving. The aim of our cohort study was to evaluate the association between corticosteroid therapy and hospital mortality, in patients hospitalized with COVID-19 after balancing for possible confounders. Results: One thousand four hundred forty four patients were admitted to our hospital with a positive RT-PCR test for SARS-CoV-2, 559 patients (39%) were exposed to corticosteroids during hospital stay, 844 (61%) were not exposed to corticosteroids.In the cohort of patients exposed to corticosteroids, 171 (30.6%) died. In the cohort of patients not exposed to corticosteroids, 183 (21.7%) died (unadjusted p <0.001). Nonetheless, exposure to corticosteroids was not associated with in-hospital mortality after balancing with overlap weight propensity score (adjusted p = 0.25). Patients in the corticosteroids cohort had reduced risk of ICU admission (adjusted p <0.001). Conclusions: Treatment with corticosteroids did not affect hospital mortality in patients with COVID-19 after balancing for confounders. A possible advantage of corticosteroid therapy was to reduce Intensive Care Unit admission, which could be useful in reducing pressure on the Intensive Care Units in times of limited resources, as during the COVID-19 pandemic.

In December 2019 a cluster of atypical pneumonia was observed in Wuhan, China. A new coronavirus, later called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV 2), was identified as responsible for the disease, 1 which subsequently spread to the rest of the world. More than two thousand patients presented to our Emergency Department with a positive RT-PCR test for SARS-CoV 2 during the novel coronavirus disease (COVID- 19) pandemic, from 20 th February to 10 th May. One thousand four hundred and forty three of them were admitted to the hospital.

Many pharmacological therapies have been attempted despite the absence of evidence supporting their efficacy, among them corticosteroids.

Initially the World Health organization discouraged the use of corticosteroids for the treatment of COVID-19 because their administration to patients with SARS had shown no survival benefit and possible harms (avascular necrosis, psychosis, diabetes, and delayed viral clearance). [2] [3] [4] The interest in corticosteroids was renewed by the observation that their use was associated with a mortality reduction in COVID-19 patients in China, 5 and recommendations after this report included the use of steroids in patients with and ARDS as a weak recommendation. 6 This uncertain and evolving evidence concerning the use of corticosteroids had, as a consequence, their inconstant use in COVID-19 patients. In our hospital they were used in about 40% of patients.

Gathering evidence on the effect of corticosteroids treatment in COVID-19 is crucial, because the infection rates of other human coronaviruses have a typical wave pattern with the pick in autumn\winter 7 and a second surge of the disease could be possible.

The aim of our cohort study was to evaluate the association between corticosteroid therapy and hospital mortality in patients hospitalized with COVID-19 after balancing for possible confounders.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) was realized on identified a priori variables with Fisher test for factorial variable and t-test and Mann-Whitney test for continuous ones.

A overlap weight propensity score for treatment allocation was estimated from a multivariable model containing patient age, sex, PaO2/FiO2, lactate, C Reactive Protein, Platelets, ICU admission and treatment with corticosteroids, enoxaparin, azithromycin or hydroxychloroquine. Dose of hydrocortisone and methylprednisolone were converted to equivalent doses of dexamethasone. 9

The overlap weight propensity score was then applied to a logistic regression modelling the primary outcome (in-hospital mortality) 10 . Odds Ratio with 95% Confidence Interval (OR, 95%CI) are reported. The same was performed for OR of ICU admission, considering only corticosteroids treatment received on the wards. Missing values were assessed and replaced by mean substitution. If a statistical significant association was found, the Evalues for the point estimate and the confidence interval limit closer to the null were computed, to assess the possible effect of unmeasured confounder. 11 Three sensitivity analyses were planned: one taking into account the quartiles of timing of hospital admission, one excluding patients admitted to intensive care, another analyzing complete cases. Significance was evaluated at α = 0.05 and all testing was 2-sided.

Statistical analysis was performed using R Studio software version 4.0.0 (R Core Team, 2014) and packages 'psw' and 'E-value' for overlap weight propensity score and calculation of E-value. Recorded data from this cohort has been used to evaluate effect of other pharmacological intervention in COVID 19, manuscripts at present are undergoing peer-review.

One thousand four hundred and forty three patients were admitted to our hospital with a positive RT-PCR test for SARS-CoV-2. Five hundred and fifty nine patients (39%) were . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 18, 2020. . https://doi.org/10.1101/2020.07.17.20155994 doi: medRxiv preprint exposed to corticosteroids during hospital stay, 844 (61%) were not exposed to corticosteroids. Twentyseven patients were excluded from the analysis (one patient was younger than 18 years, and 26 patients were still hospitalized at the time of the analysis).

Median equivalent doses of dexamethasone dose (cumulative dose/days of therapy) was 10 mg (1st-3rd quartile 4.5-20). Patients who were never admitted to ICU received equivalent doses of dexamethasone of 8 mg (4-16.1). Duration of corticosteroid therapy was longer in survivors than in patients who died: 6 (4-10) days vs 4 (1-7), respectively (p <0.001).

Clinical and laboratory characteristics in the cohort of patients exposed and not exposed to corticosteroids are shown in Table 1 . Age was not significantly different between the two cohorts, while Body Mass Index was higher in patients treated with corticosteroids. Arterial hypertension was more frequent in the corticosteroid group, while diabetes mellitus was not significantly different between the two groups. Patients in the corticosteroids cohort were more hypoxic and the inflammation markers (CRP and LDH) were higher, moreover lymphocytopenia was more severe. PaCO2 was not different in the two cohorts. One hundred seventy one patients died (30.6%) in the cohort of patients exposed to corticosteroids, and 183 (21.7%) died in the cohort of patients not exposed to corticosteroids (unadjusted p <0.001). Fifty six patients (11.5%) were admitted to ICU in the cohort of patients exposed to corticosteroids on the ward vs 131 (14.4%) who were not treated with corticosteroids in the ward (unadjusted p =0.15).

All the recorded variables were associated with mortality in the bivariate analysis except for Body Mass Index, history of arterial hypertension or diabetes mellitus and PaCO2, as shown in Table 2 .

Covariate balancing with overlap weight propensity score is shown in Figure 1 expressed as standardized mean difference which became zero after balancing.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 18, 2020. . Table 3 shows that the exposure to corticosteroids was not associated with in-hospital mortality after balancing with overlap weight propensity score. Patients in the corticosteroids cohort had reduced risk of ICU admission and E-value of 2.26 (1.76 upper limit of C.I.). Planned sensitivity analyses were in agreement with these findings.

Treatment with corticosteroids did not affect hospital mortality in patients with COVID-19 after balancing for confounders. Since their use was first proposed as a treatment strategy for ARDS, 12,13 corticosteroids have been at the center of controversy in the scientific community.

Some evidence points towards a beneficial effect of corticosteroids in ARDS. 12, [14] [15] [16] Recently Villar et al. 17 showed that early therapy with dexamethasone could reduce the duration of mechanical ventilation and the overall mortality in patients with established moderate-to-severe ARDS, possibly because early administration could have an effect on the systemic immune response involved in ARDS pathophysiology. Some evidence casts doubts on the appropriateness of corticosteroid therapy: a large multicenter randomized clinical trial 18 showed no benefit in ARDS and found an increased risk of mortality when treatment began late in the course of the disease. Moreover, corticosteroid use has been associated with complications such as increased infection rate, 19 hyperglycemia, 20,21 hypernatremia 22 and ICU acquired weakness. 23 At the beginning of the COVID-19 pandemic, caution was advised when prescribing corticosteroids, due to the possibility of a more prolonged viral shredding and reduced viral clearance. 24 The off-label use of steroids became increasingly popular after the first study about a possible decrease of mortality in COVID-19 ARDS with the use of corticosteroids was published. 5 Nevertheless, this study suffered some relevant limitations.

Corticosteroids therapy was assessed in a small cohort of ARDS patients (84 patients), . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 18, 2020. . https://doi.org/10.1101/2020.07.17.20155994 doi: medRxiv preprint and 50 out of them (60%) received methylprednisolone. More relevantly, data were shown without any balancing for possible confounders.

The crude mortality in our study was higher in patients treated with corticosteroids than in patients who did not receive them. The risk of in-hospital death did not differ between treated and non treated patients when adjusted for patients' characteristics, which were similar to the ones described in previous studies. 25 -27 The lack of effect of steroids on crude mortality has been previously reported in COVID-19 patients. 28, 29 Recently a preprint, not peer-reviewed manuscript of a randomized clinical trial (RCT) called RECOVERY trial was made available. This trial reports a 3% reduction of hospital mortality with the use of corticosteroids in COVID-19 patients. We hope that the peer reviewed results and conclusions of this study will be made available as soon as possible, so as to have a better understanding of the effects of corticosteroids in COVID-19. 30 Nonetheless data from randomized clinical trials should always be compared to data from observational studies, because it might suffer from limited external validity. In many occasions, randomized trials on septic patients were not subsequently confirmed and their importance was reduced with time, including what concerned the use of steroids. [31] [32] [33] [34] A positive finding associated with the use of steroids was a reduced ICU admission rate compared to patients not receiving them. Corticosteroids can improve compliance and hypoxemia in ARDS patients, 18 reducing the indication for ICU admission in our hospital during the COVID-19 pandemic, which was triggered by hypoxemia severity and dyspnea.

In this sense, therapy with corticosteroids could be useful in reducing pressure on the Intensive Care Units in times of limited resources, as during the COVID-19 pandemic, when ICU bed occupancy had to be rationalized.

The impact of steroid therapy cannot be assessed without considering the used dose. In our patients the median equivalent dose of dexamethasone was 10 mg/die. Recent data showed that a low dose corticosteroids, defined ad lower than 1 mg•kg -1 •day -1 of . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 18, 2020. . https://doi.org/10.1101/2020.07.17.20155994 doi: medRxiv preprint prednisone (equivalent to 0.15 mg•kg -1 •day -1 of dexamethasone), 9 had no effect on mortality, whereas higher doses were independently associated with and increase risk of death in patients with severe COVID-19. 35 The weight in our patients was 77 (17) kg, which means that the average daily dose was about 0.13 mg•kg -1 •day -1 . Therefore the finding that low doses of steroids have no impact on mortality is confirmed by our data.

The study suffers three main limitations. First, it is a retrospective analysis of prospectively collected data. Second, it is a single center study and the findings might be valid for centers with a similar setting and volume of COVID-19 admissions. Finally, propensity score with overlap method was used to balance covariate across the two treatment cohorts, so the effect of known covariate associated with mortality was taken into account and more robust conclusions could be drawn. 36 Nevertheless the effect of unmeasured confounders or could not be excluded. In light of this limitation, meta-analyses taking into account data from this and other observational studies are needed.

In conclusion, treatment with corticosteroids was not associated with in-hospital mortality in patients admitted for COVID-19, when balancing for possible confounders. A possible advantage of corticosteroids was to reduce ICU admission, which could be useful in reducing pressure on the Intensive Care Units in times of limited resources, as during the COVID-19 pandemic.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 18, 2020. . https://doi.org/10.1101/2020.07.17.20155994 doi: medRxiv preprint

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

The referral Ethics Committee (Comitato Etico di Brescia) approved the study and waived the need for informed consent from individual patients, due to the retrospective nature of the study. All research was conducted in accordance with Declaration of Helsinki.

Not applicable.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 18, 2020. . https://doi.org/10.1101/2020.07.17.20155994 doi: medRxiv preprint Leukocytes 10 9 *L -1 8.0 (4.1) 8.6 (4.4) 0.009 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 18, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 18, 2020. . https://doi.org/10.1101/2020.07.17.20155994 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 18, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 18, 2020. . https://doi.org/10.1101/2020.07.17.20155994 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 18, 2020. . https://doi.org/10.1101/2020.07.17.20155994 doi: medRxiv preprint Figure 1 Covariance balance plot before and after overlap weights propensity matching for patients treated with corticosteroids and patients not treated with corticosteroid, expressed with standardized mean difference for comparability. ICU, Intensive Care Unit admission; RCP ,Reactive C Protein; HDC, treatment with Hydroxychloroquine; AZT, treatment with Azithromycin; PF, PaO2/FiO2 ratio.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 18, 2020. . https://doi.org/10.1101/2020.07.17.20155994 doi: medRxiv preprint

A novel coronavirus outbreak of global health concern

Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome

SARS: systematic review of treatment effects

Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. Interim guidance 13

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease

Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Distress Syndrome: A Randomized Controlled Trial

High-Dose Corticosteroids in Patients with the Adult Respiratory Distress Syndrome

Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial

Effects of methyl prednisolone in early ARDS

Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial

Efficacy and Safety of Corticosteroids for Persistent Acute Respiratory Distress Syndrome

Bloodstream infections in critically ill patients with COVID-19

Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Clinical course and predictors of 60-day mortality in 239 critically ill patients with COVID-19: a multicenter retrospective study from Wuhan

Effect of Dexamethasone in Hospitalized Patients with COVID-19

Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With Septic Shock

Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock

Intensive Insulin Therapy in Critically Ill Patients

Efficacy and Safety of Recombinant Human Activated