key: cord-0798409-zv1dgbnh
authors: Pagnesi, Matteo; Inciardi, Riccardo M.; Lombardi, Carlo Mario; Agostoni, Piergiuseppe; Ameri, Pietro; Barbieri, Lucia; Bellasi, Antonio; Camporotondo, Rita; Canale, Claudia; Carubelli, Valentina; Carugo, Stefano; Catagnano, Francesco; Vecchia, Laura A. Dalla; Danzi, Gian Battista; Di Pasquale, Mattia; Gaudenzi, Margherita; Giovinazzo, Stefano; Gnecchi, Massimiliano; Guazzi, Marco; Iorio, Annamaria; La Rovere, Maria Teresa; Leonardi, Sergio; Maccagni, Gloria; Mapelli, Massimo; Margonato, Davide; Merlo, Marco; Monzo, Luca; Mortara, Andrea; Nuzzi, Vincenzo; Piepoli, Massimo; Porto, Italo; Pozzi, Andrea; Sarullo, Filippo; Sinagra, Gianfranco; Tedino, Chiara; Tomasoni, Daniela; Volterrani, Maurizio; Zaccone, Gregorio; Senni, Michele; Metra, Marco
title: Determinants of the protective effect of glucocorticoids on mortality in hospitalized patients with COVID-19: Insights from the Cardio-COVID-Italy multicenter study
date: 2021-05-28
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.05.056
sha: d01a9b9ea0e753e0f2c31d63128d54d0ce6ad2af
doc_id: 798409
cord_uid: zv1dgbnh

BACKGROUND: Glucocorticoid therapy has emerged as an effective therapeutic option in hospitalized patients with coronavirus disease 2019 (COVID-19). Our aim was to focus on the impact of relevant clinical and laboratory factors on the protective effect of glucocorticoids on mortality. METHODS: We performed a sub-analysis of the multicenter Cardio-COVID-Italy registry, enrolling consecutive patients with COVID-19 admitted to 13 Italian cardiology units between March 1(st), 2020, and April 9(th), 2020. The primary endpoint was in-hospital mortality. RESULTS: A total of 706 COVID-19 patients were included (n = 349 treated with glucocorticoids, n = 357 not treated with glucocorticoids). After adjustment for relevant covariates, use of glucocorticoids was associated with a lower risk of in-hospital mortality (adjusted HR 0.44, 95% CI 0.26-0.72, p = 0.001). A significant interaction was observed between the protective effect of glucocorticoids on mortality and PaO(2)/FiO(2) ratio on admission (p = 0.042), oxygen saturation on admission (p = 0.017), and peak CRP (0.023). Such protective effect of glucocorticoids was mainly observed in patients with lower PaO(2)/FiO(2) ratio (<300), lower oxygen saturation (<90%), and higher CRP (>100 mg/L). CONCLUSIONS: The protective effects of glucocorticoids on mortality in COVID-19 was more evident among patients of worse respiratory parameters and higher systemic inflammation.

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and represents a major cause of morbidity and mortality worldwide (Wiersinga et al., 2020) . Systemic glucocorticoids have emerged as an effective therapeutic option in hospitalized patients with COVID-19, especially in case of moderatesevere acute respiratory distress syndrome or need of respiratory support (RECOVERY Collaborative Group et al., 2021; Tomazini et al., 2020 ; WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group et al., 2020) . However, their use may be associated with drug-related adverse events (e.g., potential pro-thrombotic effect, increased susceptibility to infection, neuro-psychiatric symptoms, etc.), that could be detrimental in patients with COVID-19 (Mishra and Mulani, 2021) . Hence, further assessment of the subset of patients most responsive to glucocorticoids could be useful to refine the use of these drugs in hospitalized patients with J o u r n a l P r e -p r o o f COVID-19. Our aim was to confirm the protective effect of glucocorticoid use on mortality in a real-world, inpatient COVID-19 population, and to focus on the impact of relevant clinical and laboratory factors on such protective effect.

We analyzed a multicenter registry of consecutive patients with laboratory-confirmed COVID-19 admitted to 13 Italian cardiology units between March 1 st , 2020, and April 9 th , 2020.

Details on study design and study population have already been described Tomasoni et al., 2020) . Baseline characteristics, laboratory data, and details on clinical presentation, in-hospital management, and in-hospital outcomes were compared between patients who received vs. those who did not receive systemic glucocorticoids during hospital stay. The association between glucocorticoid use and in-hospital mortality was assessed by means of univariate and multivariate Cox regression analysis; results are presented as hazard ratio (HR) and 95% confidence interval (CI). Kaplan-Meier analysis was also performed to report the estimated rate of in-hospital mortality and to compare mortality between groups (log-rank test). The interaction between glucocorticoid use and several variables of interest with respect to in-hospital mortality was tested by means of formal interaction testing analysis; the relationship between the levels of continuous variables of interest and the treatment effect of glucocorticoids (HR for in-hospital mortality) was displayed using restricted cubic spline models. A p-value <0.05 (two-tailed) was considered statistically significant. All statistical analyses were performed using Stata version 14 (Stata Corp., College Station, Texas).

A total of 706 patients were included in the present analysis (n=349 treated with glucocorticoids, n=357 not treated with glucocorticoids). Mean age was 68 ± 13 years, and 69.4% of patients were males. As shown in Table 1 , patients treated with glucocorticoids had higher body J o u r n a l P r e -p r o o f mass index (BMI) and less frequently reported a history of heart failure (HF) or atrial fibrillation (AF), as compared to patients not treated with glucocorticoids. At clinical presentation, oxygen saturation and PaO2/FiO2 ratio were significantly lower and the presence of fever and respiratory rate ≥22 bpm was more frequent in the glucocorticoids group. Regarding laboratory findings at hospital admission, patients treated with glucocorticoids had significantly lower levels of lymphocytes and higher levels of hemoglobin, C-reactive protein (CRP), and D-dimer; furthermore, peak CRP during hospital stay was significantly higher in the glucocorticoids group. During hospital stay, oxygen support with FiO2 ≥50%, non-invasive ventilation, and intubation were more frequent in the glucocorticoids group, whereas patients not treated with glucocorticoids more frequently did not receive oxygen support ( Table 1) . Median hospital stay in the overall population was 14 [interquartile range 9-24] days, and a total of 166 patients (23.5%) died during hospital stay (78 in the glucocorticoid group, 88 in the no glucocorticoid group). Glucocorticoid use was associated with lower in-hospital all-cause mortality (HR 0.61, 95% CI 0.45-0.83, p=0.002).

Kaplan-Meier estimated rates of cumulative 28-day mortality were 38.0% and 45.2% in the glucocorticoids and no glucocorticoids groups, respectively (log-rank p=0.001; Supplementary   Figure 1 ). After adjustment for age, participating center, hypertension, AF, coronary artery disease, history of HF, chronic kidney disease, PaO2/FiO2 ratio, increased troponin, peak CRP, lymphocyte count, and hemoglobin values, glucocorticoid use remained independently associated with lower inhospital mortality (adjusted HR 0.44, 95% CI 0.26-0.72, p=0.001). The Harrel's C-index for the multivariable model was 0.80 (95% CI 0.75-0.85). With respect to in-hospital mortality, a significant interaction was observed between glucocorticoid use and PaO2/FiO2 ratio on admission (p=0.042), oxygen saturation on admission (p=0.017), and peak CRP (p=0.023), but not BMI Unfortunately, details on type and doses of glucocorticoids and duration of therapy were not available in our registry, and data on glucocorticoid therapy prior to hospital admission, pre-existing autoimmune or rheumatological diseases, and time from symptom onset to hospital admission was not collected. Considering the potential glucocorticoid-related adverse events, a detailed assessment of risk-benefit ratio and the identification of patients most responsive to such therapy are fundamental. Future, larger studies are needed to further refine the use of glucocorticoids in patients with COVID-19. 

No funding was provided for this study.

This study complied with the edicts of the Declaration of Helsinki and was approved by the ethical committee of Civil Hospitals of Brescia Italy (no. NP 4105) and of each recruiting centre.

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: PaO2/FiO2 ratio on admission, oxygen saturation on admission, and peak C-reactive protein (CRP).

The hazard ratio (HR) and 95% confidence interval (CI) is shown across the spectrum of the continuous variables of interest (PaO2/FiO2 ratio on admission, oxygen saturation on admission, and peak CRP); p-value for interaction between glucocorticoid use and the continuous variables of interest is also reported.

J o u r n a l P r e -p r o o f Table 1 -Baseline clinical characteristics, clinical presentation, laboratory data, and in-hospital management.

Data are presented as n/N (%), mean standard deviation or median [Q25, Q75]. ARDS = acute respiratory distress syndrome; BMI = body mass index; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRP = C-reactive protein; eGFR = estimated glomerular filtration rate; HF = heart failure; NT-proBNP = N-terminal pro-B-type natriuretic peptide; SOFA = Sequential Organ Failure Assessment; WBC = white blood cell. 

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Association of Troponin Levels With Mortality in Italian Patients Hospitalized With Coronavirus Disease 2019: Results of a Multicenter Study

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Dexamethasone in Hospitalized Patients with Covid-19

Impact of heart failure on the clinical course and outcomes of patients hospitalized for COVID-19. Results of the Cardio-COVID-Italy multicentre study

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

Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Metaanalysis

Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review

None.J o u r n a l P r e -p r o o f