key: cord-0894464-qgsquo4f authors: Moreno, A.; Vargas, C.; Azocar, F.; Villarroel, F.; Cofré, M.; Oppliger, H.; Ríos, F.; Raijmakers, M.; Silva, I.; Beltrán, C.; Zamora, F. title: STEROIDS AND MORTALITY IN NON-CRITICALLY ILL COVID-19 PATIENTS: A PROPENSITY SCORE WEIGHTED STUDY IN A CHILEAN COHORT date: 2021-09-20 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2021.09.038 sha: 87000b794e539d8d30964beec442383f4dc62dd8 doc_id: 894464 cord_uid: qgsquo4f Objectives Evaluate the impact on 30-day mortality of early use of corticosteroids in patients with COVID-19 with supplementary oxygen requirements and without invasive mechanical ventilation at the initiation of therapy. Methods Between April 15th and July 15th, 2020, all hospitalized patients with COVID-19 and oxygen requirements were prospectively included in a database. Patients who died or required intubation within the first 48 hours were excluded. Patients who received corticoids within the first 5 days of hospitalization and at least 24 hours prior to intubation were considered as in “early corticosteroids group.” To compare both populations and adjust for non-random treatment assignment bias a weight adjusted propensity score model was used. Results 571 patients met the inclusion criteria, 520 had sufficient information for the analysis. Of these, 233 received early corticosteroids and 287 did not. After the analysis, a reduction of 8.5% (p = 0.038) in 30 -day mortality was observed in the early corticosteroid group. The reduction in mortality was nonsignificant when patients with corticosteroid initiation between day 5 and day 8 of hospitalization were included. Conclusion Early corticosteroid use in patients with pneumonia due to COVID-19 and supplementary oxygen requirements without invasive mechanical ventilation reduces mortality. In Chile, the first patient with COVID-19 was diagnosed in March 2020. The disease spread rapidly, causing a first wave of infections that had its peak on epidemiological week 27, corresponding to the week of July 3 rd , 2020, mainly affecting the capital, Santiago. Our hospital is in Santiago and is one of the main adult care centers in the country, which provides care to 1.5 million people. Before the first wave, it had 22 critical beds enabled to provide mechanical ventilation and after the conversion of beds, it reached a total of 85 beds with invasive ventilation capacity. The use of corticosteroids in patients with COVID-19 is supported by several studies and meta-analysis (Van Paassen et al., 2020; Sai Pulakurthi et al., 2021) , who show a reduction in mortality with the use of corticosteroids. Most of the included studies were on critically ill patients and only two of the 44 studies are on the Latin American population (Jeronimo et al., 2020; Tomazini et al., 2020) , both studies are randomized but only one evaluates non critically ill patients and no reduction in mortality with the use of corticosteroid was observed. Of the studies included in the meta-analysis, only a minority managed to establish the benefit with statistical significance and the estimators are highly influenced by the weight of RECOVERY trial (The RECOVERY Collaborative Group et al., 2021) . In this study. A reduction in mortality of 12.3% was observed for patients on mechanical ventilation and 4.2%, for those with oxygen requirements without invasive ventilation. The RECOVERY study was carried out in the United Kingdom where the epidemiological characteristics and conditions of care are not comparable with those of Latin America. For this reason, it is necessary to establish whether this small margin of benefit in the population without invasive mechanical ventilation is maintained, despite the demographic differences observed in different populations. Between April 15 th and July 15 th , 2020, data were prospectively recorded for all adult hospitalized patients with a diagnosis of COVID-19 and oxygen requirements. Infection was documented by positive PCR test for SARS-CoV-2 through nasopharyngeal swab performed on admission. Patients who died or required intubation within the first 48 hours of hospitalization were excluded. The information collected included days of symptoms, date of hospital admission, and their demographic characteristics such as age, sex, and comorbidities (hypertension (HT), diabetes (DM2), chronic kidney disease (CKD), chronic liver disease, solid or hematological cancer, HIV infection, pharmacological immunosuppression, and chronic lung disease). Laboratory results were recorded for the first 5 days of hospitalization, including leukocyte cell counts, lymphocytes, neutrophils, platelets, lactate dehydrogenase (LDH), C-reactive protein (CRP), D-dimer, ferritin, blood urea nitrogen (BUN), creatinine, aspartate transaminase (AST), alanine aminotransferase (ALT), and lactic acid. The worst of each variable found within the first five days of hospitalization was used for the analysis. The worst value was the lowest lymphocyte and platelet count and the highest value, for the rest of the laboratory studies. Follow-up data on 30-day mortality, was extracted from national registries. The last search was performed 4 months after the recruitment of the last patient to avoid loss of deceased due to delays in the registry. The date of intubation was obtained from the registry of our intensive care unit. The correlative variable "day of admission" was created with the date of admission, considering April 15 th as "day 0" and July 15 th as "day 91." On June 15 th , 2020, a local management guideline was published, it protocolized the use of corticosteroids in patients with COVID-19. The protocol was based on a study demonstrating the benefit of early use of short courses of corticosteroids (Fadel et al., 2020) and stated the use of 8-16 mg/day of Dexamethasone for three days or 40-80 mg/day Methylprednisolone for three days, final doses were defined by the treating physician according to the patient's weight and comorbidities, no need for progressive reduction of corticosteroids was specifically stablished. Use was indicated in patients who met all the following criteria: having more than seven days of symptoms, having acute respiratory failure, and having inflammatory markers in the lab profile. The protocol is described in full in Table 1 . This guide was widely distributed in the hospital, especially within the emergency department to achieve early indication from the moment the patient was admitted. Corticosteroid use was established based on pharmacy and clinical records. Early corticosteroid use was defined as the indication of at least one dose of methylprednisolone or dexamethasone, within the first 5 days of hospitalization and at least one day before the start of invasive mechanical ventilation The total corticosteroid dose was calculated by adding the doses of Methylprednisolone and/or Dexamethasone administered to each patient during the observation period considering an equivalence of 6.7 and 1.3 mg of prednisone for each mg of dexamethasone and methylprednisolone, respectively. None of the patients received any other type of antiviral, immunomodulatory treatments, or vaccination against COVID-19 during the period of observation. Continuous variables were reported as median and interquartile range, and the difference between treated and untreated groups was assessed using the Mann-Whitney Test. Categorical variables were reported as percentages and the difference between treated and untreated groups was assessed using a chi square test. We tested two different propensity score weighting models to adjust for bias due to non-random treatment assignment. One was the Overlap Weights (Overlap) and the other, Inverse Probability Weights (IPW), both of which were evaluated according to the balance of variables achieved by each model (Li et al., 2018; Li and Thomas, 2019; . Propensity scores were estimated by logistic regression using the following variables: age, correlative day of admission, days of symptoms, sex, pharmacological immunosuppression, HT, DM2, CKD, chronic liver disease, platelets, LDH, CRP, and lymphocytes. Age and correlated day of admission were included in this study using natural cubic spline with four degrees of freedom and laboratory variables were included by quintiles. To compare the difference in treatment effect between the two groups, the average treatment in the overlap population (ATO) was used with the Overlap model and the average treatment effect (ATE) was used in the IPW model, both estimated with the R package PS weight (Li and Thomas, 2019; Thomas et al., 2020) . The primary endpoint was the mortality rate at 30 days from admission into the hospital. A total of 571 patients were recruited, of whom 520 provided sufficient data for propensity score analysis. Of these, 233 were in the early corticosteroid group and 287, in the no early corticosteroid group. The median age was 64 years and 55% were male. The prevalence of comorbidities was 55.2% for HT, 37.9% for DM2, 6.5% for CKD, 2.5% for chronic liver disease, 2.7% for solid or hematologic cancer, 0.2% for HIV, and 8.9% for chronic lung disease. There were no differences between the two groups, except for the history of pharmacological immunosuppression in which only 1 of the 15 patients was included in the early corticosteroid group (p = 0.003). Mortality was similar in both groups, close to 28%, the analysis on the crude data showed a risk difference of 0.012 (CI -0.065 -0.90), against the use of early corticosteroid. Intubation rate was 3.6 times higher in patients who used early corticosteroids compared to those who did not (6.62% vs. 24%, p = <0.001). It is also noteworthy that early corticosteroid use increased as the observation period progressed, being prescribed in 2%, 42%, and 75% of total admissions for each 30-day observation period. The clinical and demographic characteristics are shown in Table 2 . Patients in the early corticosteroid group had significantly more lymphopenia and higher leukocyte counts, LDH, neutrophils, BUN, CRP, D-dimer, ferritin, and ALT values (Table 3) . Patients were admitted with a median of 7 days of symptoms and received steroids between days 7 and 12 from symptoms onset, with a median of 9 days. Fifty-seven patients in the non-early corticosteroid group received corticosteroids during their hospitalization with a median of 13 days of symptoms and 7 days of hospitalization (Table 4) . Of the early corticosteroid users, 96% received Dexamethasone and 3.7% received Methylprednisolone. Patients without information correspond mostly to patients who received treatment in the emergency room and therefore do not appear in the pharmacy register. The median duration of treatment was 3 days (IQR 2-4), and the median total dose in milligrams of Prednisone was 293 mg (RIQ 160-453), equivalent to 15 mg/day of Dexamethasone for 3 days. (Table 5) Results of the statistical analysis The logistical model was selected, whose equation was able to predict steroid use with a discriminate value of 0.90 (Area under the Curve) and a pseudo R2 of 0.42. Figure 1 shows the standardized mean differences of the variables included in the model. In the crude data analysis, most of the variables show differences above 10%, reflecting allocation bias, after adjustment by the Overlap Weights model, all variables reduced their difference below 10%, allowing the evaluation of the effect of corticosteroids. After comparing the IPW and overlap methods, it was decided to select the latter because it represented considerably better balance, especially of the variables that determine the severity of this disease ( Figure 1 ). Considering the best model (Overlap), for those in the group without early corticosteroid use, the probability of death was 34.1%, and for those in the early corticosteroid use group, it was 25.6%. Thus, a reduction in the mortality of 8.5% (p = 0.038) was observed. If we expand the criteria for corticosteroid use from the first 5 days of admission to the first 8, a 5.9% (p=0.125) decrease in mortality is observed but with no significant difference between the two groups. The use of corticosteroids in COVID-19 is mainly supported by studies conducted in Asian and European cohorts. In our study, we can observe important differences between our population and that of these cohorts. For example, two diseases significantly influenced by the use of corticosteroids, such as diabetes and chronic lung disease have respectively double and half of the incidence, than those in the population of the RECOVERY trial. Additionally, in patients without mechanical ventilation, the margins of benefit on corticosteroids use are narrow and therefore differences in prevalence of comorbidities, availability of critical beds, and the use of other therapies may reduce or reverse the reported risk-benefit relation. This is one of the largest cohorts in the region evaluating the benefit of steroids in COVID-19 patients without initial mechanical ventilation. No other antiviral therapies or immunomodulators were used for patient management, nor was there vaccination or outbreaks of variants other than the one that caused the initial outbreak, allowing a pure analysis of the benefit of corticosteroids. Our results showed that the early use of steroids during hospitalization in COVID-19 patients with supplemental O2 requirements reduces mortality by 8.5%, a finding that consolidates the use of corticosteroids in COVID-19, despite the epidemiological difference observed in our population. The differences observed in the crude laboratory analysis between the two groups reflects a more severe inflammatory profile and a higher probability of death in the early corticosteroid group. This is consistent with the 1,2% risk difference against the early use of corticosteroids observed on the crude data analysis. These differences however were correctly compensated by the model selected. Difference in the intubation rate reflects a more severe respiratory failure in the early corticosteroids group, since we do not have a respiratory function parameter in our model, this was not fully compensated, and therefore a bias is still present in our analysis. However, this bias tends to locate the most severe patients in the early corticosteroid group and therefore it is possible that the benefit of corticosteroids would be even greater. The results show that as the use of corticosteroids during hospitalization is delayed, the benefit in mortality decreases and loses its statistical significance. This could suggest that there is a window of opportunity for the use of corticosteroids (Siddiqi and Mehra, 2020) , which would be in the period between overcoming the replicative phase of the virus and prior to the onset of the hyper inflammatory phase. Although this period is not well defined, our suggestion is to start the treatment as soon as the patient begins to require supplementary oxygen. The median total dose of corticosteroid used, measured in milligrams of Prednisone, coincides with the protocol indication of 8-16 mg/day of Dexamethasone for 3 days, which demonstrates, in general, good adherence to the protocol. One day after the launch of our guide, the preliminary RECOVERY study was published, which caused some doctors to change the indication to 6 mg of Dexamethasone for up to 10 days. However, in general, the tendency was to use therapies more adjusted to the local protocol. In our hospital, the only oral corticosteroid available is Prednisone, which has traditionally been used for the management of stable patients who are chronic corticosteroid users, and not to manage acute decompensations. To evaluate the impact of its use in our patients with COVID-19, a search was conducted in pharmacy records, and statistical analysis was performed including this third corticosteroid. Only 17 patients changed from non-users to users of early corticosteroids. Most of them were patients with a history of pharmacological immunosuppression or chronic lung disease, and the median total dose was 100 mg Prednisone (25mg/day), more consistent with maintenance doses of pharmacological immunosuppression, and far from the 320 mg suggested in our management protocol. For this reason, it was decided to keep these patients in the usual management group. Most of the high-quality evidence demonstrating the benefits of steroid use comes from studies in Working Group et al., 2020) . It should be considered that the severity of patients cannot be defined according to the ventilatory support received in the context of over demand of critical beds. The same patient with the same degree of respiratory failure may receive different levels of ventilatory support, depending on the availability of this resource throughout the evolution of the pandemic. Several efforts have been made to evaluate risk scoring systems and predictors of mortality that allow stratification of the patients with COVID-19. (Knight et al., 2020; Wynants et al., 2020) . It would be interesting to define the use of corticosteroids according to the category of risk or severity, rather than the ventilatory support received since the latter is conditioned by the availability of the resource rather than the patient's condition. Adjustment for severity in our population was based primarily on the inclusion of risk factors and laboratory parameters that have been described in the literature as related to severity or mortality (Liao et al., 2020; Wu et al., 2020; . It would have been desirable to include some parameters reflecting the level of respiratory failure as recommended by current stratification systems (Knight et al., 2020) . The risk factor of obesity is an important factor that could not be collected in all patients because of the lack of a reliable way to calculate BMI in the context of over demand during the first wave. The use of corticosteroids in patients with COVID-19 with supplementary oxygen requirements without initial invasive mechanical ventilation reduces mortality by 8.5%. This reduction in mortality decreases as the start of the treatment is delayed during hospitalization. We recommend that corticosteroid treatment be initiated as soon as possible in all patients with confirmed COVID-19 and supplementary oxygen requirements. Balance of variables between the Inverse Probability (IPW) and the Overlap (overlap) propensity score weighting models compared with the unweighted population Differences between the early and non-early corticosteroids use groups are represented through the standardized mean differences for each variable included in the model. The crude analysis (unweighted) shows important differences between the two groups in most of the variables included. After adjusting for the Overlap weight model, these differences are reduced below 10%. With this, it is possible to clear the influence of these variables on mortality, allowing the analysis of the role of corticosteroids Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With Coronavirus Disease A Randomized, Double-blind, Phase IIb, Placebocontrolled Trial Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score Balancing Covariates via Propensity Score Weighting Addressing Extreme Propensity Scores via the Overlap Weights Haematological characteristics and risk factors in the classification and prognosis evaluation of COVID-19: a retrospective cohort study Corticosteroid use in COVID-19 patients: a systematic review and meta-analysis on clinical outcomes 2020 Corticosteroid therapy for COVID-19 A systematic review and meta-analysis of randomized controlled trials Systematic Review and Meta COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal Dexamethasone in Hospitalized Patients with Covid-19 Overlap Weighting: A Propensity Score Method That Mimics Attributes of a Randomized Clinical Trial Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients with Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis Risk Factors Associated with Acute Respiratory Distress Syndrome and Death in Patients with Coronavirus Disease Prediction models for diagnosis and prognosis of covid-19: Systematic review and critical appraisal Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study PSweight: An R Package for Propensity Score Weighting Analysis We would like to acknowledge. MD. Carla Araya and MD. Ronald Pairumani for facilitating the Intensive Care Unit database. Mariana Miguieles, Pre-Medical student from Universidad de Chile, Jose Tapia, Eileen Shulz, Ignacio Perez, and Paulo Contador Pre-Medical students from the Universidad de Santiago de Chile, who helped us to collect the data. Lastly, Sergio Mayorga, software engineer from Universidad Catolica de Chile, who helped on the database construction.