key: cord-0698748-oa5mrob8
authors: Perazzo, Hugo; Cardoso, Sandra W.; Ribeiro, Maria Pia D.; Moreira, Rodrigo; Coelho, Lara E.; Jalil, Emilia M.; Japiassú, André Miguel; Gouvêa, Elias Pimentel; Nunes, Estevão Portela; Andrade, Hugo Boechat; Gouvêa, Luciano Barros; Ferreira, Marcel Treptow; Rodrigues, Pedro Mendes de Azambuja; Moreira, Ronaldo; Geraldo, Kim; Freitas, Lucilene; Pacheco, Vinicius V.; João, Esau Custódio; Fuller, Trevon; Rocha, Verônica Diniz; Nunes, Ceuci de Lima Xavier; Souza, Tâmara Newman Lobato; Toscano, Ana Luiza Castro Conde; Schwarzbold, Alexandre Vargas; Noal, Helena Carolina; Pinto, Gustavo de Araujo; Lemos, Paula Macedo de Oliveira; Santos, Carla; Mello, Fernanda Carvalho de Queiroz; Veloso, Valdilea G.; Grinsztejn, Beatriz
title: In-hospital mortality and severe outcomes after hospital discharge due to COVID-19: A prospective multicenter study from Brazil
date: 2022-07-31
journal: The Lancet Regional Health - Americas
DOI: 10.1016/j.lana.2022.100244
sha: 5ed0a9f0cbaa4af4683d9343f4d1ad2f86612a5b
doc_id: 698748
cord_uid: oa5mrob8

Background We evaluated in-hospital mortality and outcomes incidence after hospital discharge due to COVID-19 in a Brazilian multicenter cohort. Methods This prospective multicenter study (RECOVER-SUS, NCT04807699) included COVID-19 patients hospitalized in public tertiary hospitals in Brazil from June 2020 to March 2021. Clinical assessment and blood samples were performed at hospital admission, with post-hospital discharge remote visits. Hospitalized participants were followed-up until March 31, 2021. The outcomes were in-hospital mortality and incidence of rehospitalization or death after hospital discharge. Kaplan–Meier curves and Cox proportional-hazard models were performed. Findings 1589 participants [54.5% male, age=62 (IQR 50-70) years; BMI=28.4 (IQR,24.9–32.9) Kg/m² and 51.9% with diabetes] were included. A total of 429 individuals [27.0% (95%CI,24.8–29.2)] died during hospitalization (median time 14 (IQR,9–24) days). Older age [vs<40 years; age=60–69 years-aHR=1.89 (95%CI,1.08–3.32); age=70–79 years-aHR=2.52 (95%CI,1.42–4.45); age≥80-aHR=2.90 (95%CI 1.54–5.47)]; noninvasive or mechanical ventilation at admission [vs facial-mask or none; aHR=1.69 (95%CI 1.30–2.19)]; SAPS-III score≥57 [vs<57; aHR=1.47 (95%CI 1.13–1.92)] and SOFA score≥10 [vs <10; aHR=1.51 (95%CI 1.08–2.10)] were independently associated with in-hospital mortality. A total of 65 individuals [6.7% (95%CI 5.3–8.4)] had a rehospitalization or death [rate=323 (95%CI 250–417) per 1000 person-years] in a median time of 52 (range 1–280) days post-hospital discharge. Age ≥ 60 years [vs <60, aHR=2.13 (95%CI 1.15–3.94)] and SAPS-III ≥57 at admission [vs <57, aHR=2.37 (95%CI 1.22–4.59)] were independently associated with rehospitalization or death after hospital discharge. Interpretation High in-hospital mortality rates due to COVID-19 were observed and elderly people remained at high risk of rehospitalization and death after hospital discharge. Funding Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Programa INOVA-FIOCRUZ.

Background We evaluated in-hospital mortality and outcomes incidence after hospital discharge due to COVID-19 in a Brazilian multicenter cohort.

Methods This prospective multicenter study (RECOVER-SUS, NCT04807699) included COVID-19 patients hospitalized in public tertiary hospitals in Brazil from June 2020 to March 2021. Clinical assessment and blood samples were performed at hospital admission, with post-hospital discharge remote visits. Hospitalized participants were followed-up until March 31, 2021. The outcomes were in-hospital mortality and incidence of rehospitalization or death after hospital discharge. Kaplan−Meier curves and Cox proportional-hazard models were performed.

Findings 1589 participants [54.5% male, age=62 (IQR 50-70) years; BMI=28.4 (IQR,24.9−32.9) Kg/m 2 Interpretation High in-hospital mortality rates due to COVID-19 were observed and elderly people remained at high risk of rehospitalization and death after hospital discharge.

Although risk factors of COVID-19 in-hospital mortality have been reported, most studies from Brazil have been based on retrospective cohorts and dataset analyses. More recently, long-term post-COVID-19 syndrome has been described as a potential complication. However, there is a paucity of data available regarding severe complications after hospital discharge in people hospitalized with COVID-19 in Latin America.

In this study, we prospectively analyzed data from 1589 individuals hospitalized with COVID-19 and followed until hospital discharge, death, or a censured date (March 31, 2021) in seven centres in Brazil [RECOVER-SUS study; NCT04807699]. In addition, participants who were discharged from hospital were visited to follow-up on incidence, rehospitalization or death after hospital discharge. We identified factors associated with in-hospital mortality and incidence of severe outcomes posthospital discharge due to COVID-19. In-hospital mortality rate was high; older age, substantial ventilation support and high severity scores (SAPS-III and SOFA scores) at hospital admission were significantly associated with in-hospital mortality. The incidence of severe outcomes after hospital discharge was also high. Even after hospital discharge, people aged ≥ 60 years and/or those with high SAPS-III score ≥ 57 at hospital admission had a 2-fold higher risk of death or rehospitalization during outpatient follow-up.

Globally, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that caused the Coronavirus disease 2019 (COVID-19) pandemic has overwhelmed health systems due to high rates of hospitalization and intensive care unit (ICU) admissions. 1 Brazil, the largest country in Latin America, is characterized by deep social and economic inequalities. 2 As of March 2022, Brazil, an epicenter of the COVID-19 pandemic, ranks second in number of deaths (more than 650,000 since March 2020). 3 Relatively high intra-hospital mortality rates due to COVID-19 have been reported worldwide (from 17 to 38%). 4−7 Estimates of hospital admission and mortality rates in Brazil have been based on retrospective studies and dataset analyses. 7−9 However, prospective data evaluating risk factors associated with overall mortality in Brazil are still scarce. More recently, long-term post-COVID-19 syndrome has been described as a potential complication after COVID-19. 10 However, there is a paucity of available data regarding severe complications after hospital discharge in people hospitalized with COVID-19 worldwide. The RECOVER-SUS study was a collaboration among universities/research institutions and/or tertiary centers from the Brazilian Public Health System ("Sistema Unico de Sa ude") to tackle COVID-19 pandemic in Brazil. This analysis aimed to evaluate the incidence of in-hospital mortality and severe outcomes (rehospitalization or death) after hospital discharge due to COVID-19 in a multicenter prospective cohort from Brazil. 

Socio-demographic characteristics, comorbidities, comedications, COVID-19 symptoms and vital signs and anthropometric measures (weight and height) were recorded at hospital admission (baseline). Clinical data and blood samples were collected by trained investigators at baseline and days 3 (D3), 7 (D7) and 14 (D14) of hospitalization. Additionally, clinical data were recorded at days 10 (D10), 21 (D21), 25 (D25), 30 (D30) and every 5 days thereafter if hospital stay was longer than 30 days. Laboratory tests included red and white bloodcells count, platelets count, international normalized ratio (INR), creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, procalcitonin, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Severity of COVID-19 was defined according to the WHO severity classification. 12 Simplified Acute Physiology Score III (SAPS-III) and Sequential Organ Failure Assessment (SOFA) Score were calculated at baseline. Study data were collected and managed using REDCap electronic data capture tools hosted at INI-FIOCRUZ 13 All participants were followed from hospital admission until transfer to other institution, hospital discharge, death, or censured date on March 31, 2021, whichever occurred first. The primary outcome was in-hospital mortality.

A remote visit (telephone call) at least 2 weeks after hospital discharge was performed by trained investigators for all discharged participants included in the RECOVER-SUS study. Participants (or authorized relatives/household members) were interviewed to assess participant's health status. The outcomes assessed during remote visits were any episode of rehospitalization (defined as minimum length of stay of 24 h in any hospital/institution) and post discharge death. If more than one hospitalization episode occurred during this postdischarge follow-up, the first one was considered for the analysis. Therefore, the secondary outcome of this study was rehospitalization or death.

Continuous variables were reported as median (interquartile range, IQR) and categorical variables were reported as absolute (n) and relative frequencies (%). Missing data were reported in Tables. Chi-squared and Mann-Whitney/Kruskal-Wallis tests were used for between groups comparisons. In-hospital follow-up started at the first day of hospitalization and ended at the earliest of death, hospital transfer or discharge, or March 31, 2021, whichever occurred first. The primary and secondary outcomes for this analysis were overall in-hospital mortality and rehospitalization or death after hospital discharge. Post-discharge follow-up started at day of discharge and ended at the earliest of death, rehospitalization or day of contact for those who were alive and did not have any rehospitalization. The incidence outcomes rates [per 1000 person-days (PD) for in-hospital mortality and per 1000 person-years (PY) for post-discharge outcomes] were calculated considering individuals who experienced and those who did not experience an outcome event. Kaplan−Meier curves were plotted, and the log-rank tests were calculated. We used the time to event Cox proportional-hazard model for uni-and multivariate analyses after checking that the main variables verified the proportional-hazard assumption using the Schoenfeld residuals. All continuous variables were categorized in Cox models to mitigate a potential influence of outliers on the estimate of risk for primary and secondary outcomes (hazardratios). All Cox models were adjusted for the variable "center" to minimize the risk of center-specific bias clustering effect due to an imbalance among centers of the RECOVER-SUS study. Variables associated with each outcome (p ≤ 0.05) were entered into multivariate models adjusted for age and sex at birth. The severity of multicollinearity among variables entered in each multivariate Cox model was quantified by the variance inflation factor (VIF). Age was stratified into four group categories for analysis of in-hospital mortality: 18−39 years; 40−59 years; 60−69 years; 70−79 years and ≥80 years. Sensitivity analyses were performed considering hospital admission in different periods: from June to December 2020 and from January to March 2021. The analysis was performed using STATA-package, version 15, 2017 (StataCorp LP, College Station, TX, USA). Significance level was determined when p ≤ 0.05 assuming two-tailed tests.

The study was approved by the Ethical Committee from Instituto Nacional de Infectologia Evandro Chagas − Fundação Oswaldo Cruz (IRB n°32449420. 4 

A total of 1649 individuals hospitalized with COVID-19 symptoms from June 7, 2020, to March 31, 2021 were included in the RECOVER-SUS study. From those, 60 subjects not classified as suspected, probable, or confirmed case by the WHO definition were excluded from analysis. Thus, 1589 participants [54.5% male, median age=62 (IQR, 50−70), median body mass index (BMI) of 28.4 (IQR, 24.9−32.9) Kg/m 2 ; 51.9% with type-2 diabetes and 33.9% with systemic arterial hypertension] were included in the study ( Figure 1 ). Table 1 Table 2 ). (Table 3) . Type-2 diabetes and systemic arterial hypertension were reported in 50.0% and 35.3% of participants, respectively. Most individuals had confirmed COVID-19 (83.3%) and had been admitted with non-significant respiratory support (none or nasal can-nula=70%). The median length of hospital stay of those individuals was 9 (range, 1−116) days. A total of 65 individuals [6.7% (95%CI 5.3−8.4)] had a rehospitalization or death in a median time of 52 (range, 1−280) days post-hospital discharge. Of those 65 participants with a severe outcome, 9 died without hospitalization, 42 were rehospitalized but remained alive, and 14 died during rehospitalization. Among those who died (n = 23), 57% were female, had a median age of 73 (IQR 70−82) years 

This prospective study, the first to our knowledge describing incidence and risk factors associated with severe COVID-19 outcomes after hospital discharge in [12] . Missing (n): time form onset of symptoms (n = 77); pulse (n = 74); respiratory rate (n = 98), systolic and diastolic blood pressure (n = 75), leucocytes levels (n = 28); lymphocytes levels (n = 35), platelet count (n = 29); INR (n = 213); creatinine levels (n = 38), ALT (n = 134), AST (n = 131), procalcitonin levels (n = 372), c-reactive protein (n = 73), ESR (n = 374).

Brazil, revealed factors associated with in-hospital mortality and incidence of severe outcomes, including rehospitalization or death, in a large multicentric cohort. The main strengths of the study were the prospective study design, the structured data collection in electronic forms by trained abstractors and the follow-up after hospital discharge of a large reallife cohort in Brazil. Most studies reporting in-hospital mortality due to COVID-19 to date in Brazil have been retrospective analyses. Our findings have important implications for optimizing the management during hospitalization due to COVID-19 and after hospital discharge in low-to-middle income countries. We observed high mortality rates during hospitalization; older age, substantial ventilation support and high severity scores at hospital admission were significantly associated with in-hospital mortality. Even after hospital discharge, people aged more than 60 years and with high SAPS-III scores at hospital admission remained at relatively high risk of complications during outpatient follow-up. Several studies have reported risk factors associated with in-hospital mortality due to COVID-19. Our findings were aligned with a previous multicenter study performed in Greece that analyzed in-hospital mortality in a cohort enrolling 3062 individuals with similar demographic and clinical characteristics. 4 On the other hand, a U.S. multicentric, retrospective study, which analyzed data from 2491 patients with similar median age (62 years) and higher proportion of individuals under mechanical ventilation at admission (19%) compared to our sample, reported lower in-hospital mortality rate (17%). 5 Additionally, a retrospective study that analyzed data from 10,021 patients from 920 hospitals in Germany reported that 22.3% of individuals died during hospitalization due to COVID-19. 6 Our study identified that older people needing substantial ventilation support are at higher risk of in-hospital mortality, as previously described. The effect of age on mortality of patients hospitalized with COVID-19 with or without association with comorbidities or medical conditions remain unclear. 14 Zeiser et al. reported that in-hospital mortality subsequently increased in sub-groups of patients aged ≥60 years in a retrospective analysis of a nationwide Brazilian database. 15 Our prospective study confirmed this finding, as we observed an increased age-related risk of in-hospital mortality in patients hospitalized with COVID-19 adjusted for confounding factors. Our findings highlight the importance of stratifying patients with COVID-19 with SAPS-III and SOFA scores at hospital admission to predict in-hospital mortality. 16 Interestingly, metabolic features or co-morbidities were not associated with in-hospital mortality. This finding might be explained by collinearity with severity scores (SAPS-III and/or SOFA) that include parameters related with multiple organs/systems dysfunctions. A retrospective study from the Brazilian COVID-19 Registry (data from 25 hospitals) reported that in-hospital mortality was 22%, but this can be up to 48% for patients treated in ICU. 8 Another retrospective analysis of a nationwide Brazilian database with more than 250,000 hospitalizations reported a high proportion of deaths (38%) that dramatically increased when people were admitted under mechanical ventilation (up to 80%). These contradictory findings might be explained because Brazil is the fifth largest country in the world, with different climates and ethnically and culturally diverse, which might comprise different epidemiological stages of COVID-19 pandemic in different regions at the same time. A recent study retrospective analysis of a dataset that characterizes the COVID-19 pandemic in Brazil (n = 11,321) reported different mortality rates according to geographic distribution and ethnical characteristics. 17 We observed that in-hospital survival increased throughout the pandemic, as the mortality rate was significantly higher in individuals hospitalized in 2020 compared to those admitted since January 2021. This finding was also reported in a systematic review and meta-analysis that identified a significant reduction in ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; COPD, chronic obstructive pulmonary disease; COVID-19, NIV, noninvasive ventilation; Simplified Acute Physiology Score (SAPS) III; Sequential Organ Failure Assessment (SOFA). Variables found be associated (p ≤ 0.05) with the analyzed outcome were entered into multivariate models adjusted for age and sex at birth. Procalcitonin level was not entered in the Cox analysis since this variable was not available in all centers. Variables from uni-and multivariate analysis were controlled by center in all Cox analyses. The severity of multicollinearity among variables entered in the multivariate model was quantified by the variance inflation factor (VIF . Survival without severe outcomes after hospital discharge. Survival for COVID-19 patients without rehospitalization or death outcomes in the RECOVER-SUS study is shown for age groups ≤60 and ≥60 years from day of discharge until 9 months after hospital discharge.

mortality rates during the pandemic in patients admitted into ICUs after adjusted for geographic location. 18 This might be explained by a better knowledge of the disease and its clinical management through the COVID-19 pandemic and/or changes in patients' profile due to the emergence of new variants with different severity. We observed that people admitted in 2021 were younger and seemed to have less severe disease at hospital admission compared to those hospitalized in 2020 (Supplementary Table 4 ). However, other factors might be related to the difference of in-hospital mortality observed between both periods, such as different virus lineages and a seasonal effect due to potential coinfections with other respiratory viruses in winter. In addition, a better survival might be associated with a lower level of occupation of hospital beds in the second period. Protection from vaccination was probably minimal if any, as a very low proportion (2.0%) of people in Brazil were fully vaccinated by this study's censure date (March 31, 2021). 19 Importantly, we described relatively high incidence of severe outcomes (rehospitalization or death) after hospital discharge. To the best of our knowledge, this was one of the first studies conducted in Brazil, epicenter of the COVID-19 pandemic in South America, that described incidence of post-discharge outcomes. After hospitalization, 6.7% of the study participants initially discharged were readmitted for any cause or died after hospital discharge. This finding was aligned with previous multicentric studies that reported readmission rates from 4.5 to 7%. 20−22 Our study highlighted that older individuals and those admitted with severe COVID-19 disease remain at risk of complications after discharge. The higher mortality and rehospitalization rates in the elderly could be due to a lower avidity in mounting a humoral response in those individuals. 23 These results can help policymakers to reduce the burden of COVID-19 rehospitalizations in a short-term follow-up. However, it should be noted that hospital readmission is only one of multiple impacts of critical illness due to COVID-19. In the long term, patients recovering from severe COVID-19 may require lengthy rehabilitation before resuming work and other daily activities. 24 Therefore, the healthcare system will need to develop best practices and clinical recommendations for the management of COVID-19 patients after initial hospital discharge.

This study has some limitations. First, there was a considerable imbalance among the seven centers that ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; COPD, chronic obstructive pulmonary disease; COVID-19, NIV, noninvasive ventilation; Simplified Acute Physiology Score (SAPS) III. Variables found be associated (p ≤ 0.05) with the analyzed outcome were entered into multivariate models adjusted for age and sex at birth. Procalcitonin level was not entered in the Cox analysis since this variable was not available in all centers. Variables from uni-and multivariate analysis were controlled by center in all Cox analyses. The severity of multicollinearity among variables entered in the multivariate model was quantified by the variance inflation factor (VIF recruited participants for the RECOVER-SUS study (Supplementary Table 1 ), since 87% of participants were from Rio de Janeiro, mainly at INI-FIOCRUZ (n = 1325). However, we minimized a potential withincenter clustering effect by adjusting all analyses by the variable "center". The variable age could be stratified in five sub-groups to evaluate the effect of different age strata on in-hospital mortality. However, this was unfeasible for analysis of incidence of outcomes post-hospital discharge due to a relatively low number of events (n = 65). Second, the COVID-19 vaccination status of participants at hospital admission was lacking. However, participants included in 2020 were not vaccinated, and COVID-19 vaccination officially started in 2021 (end of January) exclusively for elderly people (> 80 years) and healthcare workers. Moreover, only 2.0% of the Brazilian population were fully vaccinated on the date of censure for this analysis (March 31, 2021). 19 Third, the SARS-CoV-2 genetic lineages were available for a limited sub-sample of participants. Finally, despite repeated contact attempts, 12% of the participants discharged were not evaluated at and hence not included in the post discharge outcomes analysis. However, most clinical and laboratorial characteristics were similar between those participants included and excluded in this analysis (Supplementary Table 5 ). In addition, causes of death for those who died after discharge were unknown, which is a limitation of the present study.

In conclusion, this prospective study reported high inhospital mortality rates in a multicentric, well characterized cohort of individuals hospitalized in Brazil. Older age, need of substantial ventilation support, especially mechanical ventilation, and high severity scores were independently associated with in-hospital mortality. Additionally, individuals aged ≥ 60 years and those with high SAPS-III score at hospital admission remained at high risk of rehospitalization and death after hospital discharge. This study underscores the need to monitor critically ill patients with COVID-19 after hospital discharge. Further studies are needed to understand the long-term impact of post-COVID-19 syndrome. 

Estevão Portela Nunes has received payment for lectures by Gilead; Alexandre Vargas Schwarzbold has received grants from AZ, MSD and Clover Biopharm; Fernanda Carvalho de Queiroz Mello has been acting as the President of the Society of Pneumonology and Tisiology fo the State of Rio de Janeiro (no payment) and Beatriz Grinsztejn has been participating in Advisory Board of Merck; GSK/ViiV and Janssen; The other authors declare no conflicts of interest.

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The authors thank the investigators and members of Instituto Nacional de Infectologia Evandro Chagas/ Fundação Oswaldo Cruz, Hospital Federal Servidores do Estado do Rio de Janeiro, Hospital Universit ario Clementino Fraga Filho/Universidade Federal do Rio de Janeiro, Instituto de Infectologia Emilio Ribas, Instituto Couto Maia, Hospital Regional São Jos e and Universidade Federal de Santa Maria, Santa Maria for their dedication to the RECOVER-SUS study. In addition, we express our most sincere appreciation to all patients and their family for volunteering to participate in the RECOVER-SUS study. We thank "Vice-Presidência de Produção e Inovação em Sa ude" from Oswaldo Cruz Foundation (FIOCRUZ) for their support to the RECOVER-SUS study.

All data from the current study are reported in the manuscript, tables and supplementary material. In addition, data are available upon a reasonable request to Hugo Perazzo, the corresponding author, from The Evandro Chagas National Institute of Infectious Disease, Oswaldo Cruz Foundation, Rio de Janeiro (RJ), Brazil y The RECOVER-SUS Brasil Group is comprised of the following contributors 

Supplementary material associated with this article can be found in the online version at doi:10.1016/j. lana.2022.100244.