Cohort Study Protocol of the Brazilian Collaborative Research Network on COVID-19: strengthening WHO global data (preprint)

Introduction With the COVID-19 pandemic, hospitals in low-income countries were faced with a triple challenge. First, a large number of patients required hospitalization because of the infection’s more severe symptoms. Second, there was a lack of systematic and broad testing policies for early identification of cases. Third, there were weaknesses in the integration of information systems, which led to the need to search for available information from the hospital information systems. Accordingly, it is also important to state that relevant aspects of COVID-19’s natural history had not yet been fully clarified. The aim of this research protocol is to present the strategies of a Brazilian network of hospitals to perform systematized data collection on COVID-19 through the World Health Organization (WHO) Platform. Methods and Analysis This is a multicenter project among Brazilian hospitals to provide data on COVID-19 through the WHO global platform, which integrates patient care information from different countries. From October 2020 to March 2021, a committee worked on defining a flowchart for this platform, specifying the variables of interest, data extraction standardization and analysis. Ethics and Dissemination This protocol was approved by the Research Ethics Committee (CEP) of the Research Coordinating Center of Brazil (CEP of the Hospital Nossa Senhora da Conceição), on January 29, 2021, under approval No. 4.515.519 and by the National Research Ethics Commission (CONEP), on February 5, 2021, under approval No. 4.526.456. The project results will be explained in WHO reports and published in international peer-reviewed journals, and summaries will be provided to the funders of the study. Strengths and limitations of this study As the study involves a convenience and non-probabilistic sample of patients hospitalized in health units, it may not represent the population of patients with COVID-19 hospitalized in the country. However, the information generated by this research can serve as a basis for the development of maps of the evolution of SARS-CoV-2 infection and public policies to face pandemics. It is a study that uses secondary data, and therefore, information bias may occur, but on the other hand, it has a low cost and facilitates a population-based study with national coverage. Article Summary This is a multicenter project among Brazilian hospitals to provide data on COVID-19 through the WHO global platform. It is expected to deepen knowledge about the pandemic scenario and help hospital institutions to develop preventive measures, health service protocols and strengthen the training of teams in the existing complications.

Effectiveness, Explainability and Reliability of Machine Meta-Learning Methods for Predicting Mortality in Patients with COVID-19: Results of the Brazilian COVID-19 Registry (preprint)

The majority prognostic scores proposed for early assessment of coronavirus disease 19 (COVID-19) patients are bounded by methodological flaws. Our group recently developed a new risk score - ABC 2 SPH - using traditional statistical methods (least absolute shrinkage and selection operator logistic regression - LASSO). In this article, we provide a thorough comparative study between modern machine learning (ML) methods and state-of-the-art statistical methods, represented by ABC 2 SPH, in the task of predicting in-hospital mortality in COVID-19 patients using data upon hospital admission. We overcome methodological and technological issues found in previous similar studies, while exploring a large sample (5,032 patients). Additionally, we take advantage of a large and diverse set of methods and investigate the effectiveness of applying meta-learning, more specifically Stacking, in order to combine the methods' strengths and overcome their limitations. In our experiments, our Stacking solutions improved over previous state-of-the-art by more than 26% in predicting death, achieving 87.1% of AUROC and MacroF1 of 73.9%. We also investigated issues related to the interpretability and reliability of the predictions produced by the most effective ML methods. Finally, we discuss the adequacy of AUROC as an evaluation metric for highly imbalanced and skewed datasets commonly found in health-related problems.

Frequency and burden of neurological manifestations in hospitalized patients with COVID-19: findings from a large Brazilian cohort (preprint)

Background: Scientific data regarding the prevalence of COVID-19 neurological manifestations and prognosis in Latin America countries is still lacking. Therefore, the study aims to understand neurological manifestations of SARS-CoV 2 infection in the Brazilian population and its association with patient outcomes, such as in-hospital mortality. Methods This study is part of the Brazilian COVID-19 Registry, a multicentric COVID-19 cohort, including data from 37 Brazilian hospitals. For the analysis, patients were grouped according to the presence of self-reported vs. clinically-diagnosed neurological manifestations and matched with patients without neurological manifestations by age, sex, number of comorbidities, hospital, and whether or not patients ha neurological underlying disease. Results From 7,232 hospitalized patients with COVID-19, 27.8% presented self-reported neurological manifestations, 9.9% were diagnosed with a clinically-defined neurological syndrome and 1.2% did not show any neurological symptoms. In patients with self-reported symptoms, the most common ones were headache (19.3%), ageusia (10.4%) and anosmia (7.4%). Meanwhile, in the group with clinically-defined neurological syndromes, acute encephalopathy was the most common diagnosis (10.5%), followed by coma (0.6%1) and seizures (0.4%). Men and younger patients were more likely to self-report neurological symptoms, while women and older patients were more likely to develop a neurological syndrome. Patients with clinically-defined neurological syndromes presented a higher prevalence of comorbidities, as well as lower oxygen saturation and blood pressure at hospital admission. In the paired analysis, it was observed that patients with clinically-defined neurological syndromes were more likely to require ICU admission (46.9 vs. 37.9%), mechanical ventilation (33.4 vs. 28.2%), to develop acute heart failure (5.1 vs. 3.0%, p=0.037) and to die (40.7 vs. 32.3%, p<0.001) when compared to controls. Conclusion Neurological manifestations are an important cause of morbidity in COVID-19 patients. More specifically, patients with clinically defined neurological syndromes presented a poorer prognosis for the disease when compared to matched controls.

Hypothyroidism does not lead to worse prognosis in COVID-19: findings from the Brazilian COVID-19 registry (preprint)

Background: It is not clear whether previous thyroid diseases influence the course and outcomes of COVID-19. The study aims to compare clinical characteristics and outcomes of COVID-19 patients with and without hypothyroidism. Methods: The study is a part of a multicentric cohort of patients with confirmed COVID-19 diagnosis, including data collected from 37 hospitals. Matching for age, sex, number of comorbidities and hospital was performed to select the patients without hypothyroidism for the paired analysis. Results: From 7,762 COVID-19 patients, 526 had previously diagnosed hypothyroidism (50%) and 526 were selected as matched controls. The median age was 70 (interquartile range 59.0-80.0) years-old and 68.3% were females. The prevalence of underlying comorbidities were similar between groups, except for coronary and chronic kidney diseases, that had a higher prevalence in the hypothyroidism group (9.7% vs. 5.7%, p=0.015 and 9.9% vs. 4.8%, p=0.001, respectively). At hospital presentation, patients with hypothyroidism had a lower frequency of respiratory rate > 24 breaths per minute (36.1% vs 42.0%; p=0.050) and need of mechanical ventilation (4.0% vs 7.4%; p=0.016). D-dimer levels were slightly lower in hypothyroid patients (2.3 times higher than the reference value vs 2.9 times higher; p=0.037). In-hospital management was similar between groups, but hospital length-of-stay (8 vs 9 days; p=0.029) and mechanical ventilation requirement (25.4% vs. 33.1%; p=0.006) were lower for patients with hypothyroidism. There was a trend of lower in-hospital mortality in patients with hypothyroidism (22.1% vs. 27.0%; p=0.062). Conclusion: In this large Brazilian COVID-19 Registry, patients with hypothyroidism had a lower requirement of mechanical ventilation, and showed a trend of lower in-hospital mortality. Therefore, hypothyroidism does not seem to be associated with a worse prognosis, and should not be considered among the comorbidities that indicate a risk factor for COVID-19 severity.

Effectiveness, Explainability and Reliability of Machine Meta-Learning Methods for Predicting Mortality in Patients with COVID-19: Results of the Brazilian COVID-19 Registry (preprint)

Objective: To provide a thorough comparative study among state ofthe art machine learning methods and statistical methods for determining in-hospital mortality in COVID 19 patients using data upon hospital admission; to study the reliability of the predictions of the most effective methods by correlating the probability of the outcome and the accuracy of the methods; to investigate how explainable are the predictions produced by the most effective methods. Materials and Methods: De-identified data were obtained from COVID 19 positive patients in 36 participating hospitals, from March 1 to September 30, 2020. Demographic, comorbidity, clinical presentation and laboratory data were used as training data to develop COVID 19 mortality prediction models. Multiple machine learning and traditional statistics models were trained on this prediction task using a folded cross validation procedure, from which we assessed performance and interpretability metrics. Results: The Stacking of machine learning models improved over the previous state of the art results by more than 26% in predicting the class of interest (death), achieving 87.1% of AUROC and macroF1 of 73.9%. We also show that some machine learning models can be very interpretable and reliable, yielding more accurate predictions while providing a good explanation for the why. Conclusion: The best results were obtained using the meta learning ensemble model Stacking. State of the art explainability techniques such as SHAP values can be used to draw useful insights into the patterns learned by machine-learning algorithms. Machine learning models can be more explainable than traditional statistics models while also yielding highly reliable predictions. Key words: COVID-19; prognosis; prediction model; machine learning

Chagas disease and SARS-CoV-2 coinfection does not lead to worse in-hospital outcomes (preprint)

Chagas disease (CD) continues to be a major public health burden in Latina America. Information on the interplay between COVID-19 and CD is lacking. Our aim was to assess clinical characteristics and in-hospital outcomes of patients with CD and COVID-19, and to compare it to non-CD patients. Consecutive patients with confirmed COVID-19 were included from March to September 2020. Genetic matching for sex, age, hypertension, diabetes mellitus and hospital was performed in a 4:1 ratio. Of the 7,018 patients who had confirmed COVID-19, 31 patients with CD and 124 matched controls were included (median age 72 (64.-80) years-old, 44.5% were male). At baseline, heart failure (25.8% vs. 9.7%) and atrial fibrillation (29.0% vs. 5.6%) were more frequent in CD patients than in the controls (p 

Chagas disease and SARS-CoV-2 coinfection does not lead to worse in-hospital outcomes: results from the Brazilian COVID-19 Registry (preprint)

Objective: Chagas disease (CD) continues to be a major public health burden in Latina America, where co-infection with SARS-CoV-2 can occur. However, information on the interplay between COVID-19 and Chagas disease is lacking. Our aim was to assess clinical characteristics and in-hospital outcomes of patients with CD and COVID-19, and to compare it to non-CD patients. Methods: Patients with COVID-19 diagnosis were selected from the Brazilian COVID-19 Registry, a prospective multicenter cohort, from March to September, 2020. CD diagnosis was based on hospital record at the time of admission. Study data were collected by trained hospital staff using Research Electronic Data Capture (REDCap) tools. Genetic matching for sex, age, hypertension, DM and hospital was performed in a 4:1 ratio. Results: Of the 7,018 patients who had confirmed infection with SARS-CoV-2 in the registry, 31 patients with CD and 124 matched controls were included. Overall, the median age was 72 (64.-80) years-old and 44.5% were male. At baseline, heart failure (25.8% vs. 9.7%) and atrial fibrillation (29.0% vs. 5.6%) were more frequent in CD patients than in the controls (p<0.05 for both). C-reactive protein levels were lower in CD patients compared with the controls (55.5 [35.7, 85.0] vs. 94.3 [50.7, 167.5] mg/dL). Seventy-two (46.5%) patients required admission to the intensive care unit. In-hospital management, outcomes and complications were similar between the groups. Conclusions: In this large Brazilian COVID-19 Registry, CD patients had a higher prevalence of atrial fibrillation and chronic heart failure compared with non-CD controls, with no differences in-hospital outcomes. The lower C-reactive protein levels in CD patients require further investigation.

Smart Check - COVID-19 triage system: evaluation of the impact on the screening time and identification of clinical manifestations of SARS-CoV-2 infection in a public health service. (preprint)

Introduction: Most patients with COVID-19 have mild or moderate manifestations, however, there is a wide spectrum of clinical presentations and even more severe repercussions that require high diagnostic suspicion. Vital sign acquisition and monitoring are crucial for detecting and responding to patients with COVID-19. Objective: Thus, we conducted this study to demonstrate the impact of using a tool called Smart Check on the triage time of patients with suspected COVID-19 and to identify the main initial clinical manifestations in these cases. Methodology: We assessed triage times before and after the use of Smart Check in 11,466 patients. In this group, we identified 211 patients for the identification of COVID-19 clinical manifestations in a case-control analysis. Results: Smart Check was able to decrease the triage time by 33 seconds on average, with 75% of the exams being performed within 5 minutes, whereas with the usual protocol these steps were performed within 6 minutes. A range of clinical presentations made up the COVID-19 initial manifestations. Those with the highest frequency were dry cough (46.8%), fever (41.3%), dyspnea (35.8%), and headache (32.1%). Loss of appetite, fever, and ageusia were the manifestations that had a statistically significant association with the SARS-CoV-2 presence. Conclusions: Smart Check, a simple clinical evaluation tool, along with the targeted use of rapid PCR testing, can optimize triage time for patients with and without COVID-19. In triage centers, a number of initial signs and symptoms should be cause for SARS-CoV-2 infection suspicion, in particular the association of respiratory, neurological, and gastrointestinal manifestations. Keywords: new coronavirus, COVID-19, triage, clinical manifestations

ABC2-SPH risk score for in-hospital mortality in COVID-19 patients: development, external validation and comparison with other available scores (preprint)

Objective: To develop and validate a rapid scoring system at hospital admission for predicting in-hospital mortality in patients hospitalized with coronavirus disease 19 (COVID-19), and to compare this score with other existing ones. Design: Cohort study Setting: The Brazilian COVID-19 Registry has been conducted in 36 Brazilian hospitals in 17 cities. Logistic regression analysis was performed to develop a prediction model for in-hospital mortality, based on the 3978 patients that were admitted between March-July, 2020. The model was then validated in the 1054 patients admitted during August-September, as well as in an external cohort of 474 Spanish patients. Participants: Consecutive symptomatic patients ([≥]18 years old) with laboratory confirmed COVID-19 admitted to participating hospitals. Patients who were transferred between hospitals and in whom admission data from the first hospital or the last hospital were not available were excluded, as well those who were admitted for other reasons and developed COVID-19 symptoms during their stay. Main outcome measures: In-hospital mortality Results: Median (25th-75th percentile) age of the model-derivation cohort was 60 (48-72) years, 53.8% were men, in-hospital mortality was 20.3%. The validation cohorts had similar age distribution and in-hospital mortality. From 20 potential predictors, seven significant variables were included in the in-hospital mortality risk score: age, blood urea nitrogen, number of comorbidities, C-reactive protein, SpO2/FiO2 ratio, platelet count and heart rate. The model had high discriminatory value (AUROC 0.844, 95% CI 0.829 to 0.859), which was confirmed in the Brazilian (0.859) and Spanish (0.899) validation cohorts. Our ABC2-SPH score showed good calibration in both Brazilian cohorts, but, in the Spanish cohort, mortality was somewhat underestimated in patients with very high (>25%) risk. The ABC2-SPH score is implemented in a freely available online risk calculator (https://abc2sph.com/). Conclusions: We designed and validated an easy-to-use rapid scoring system based on characteristics of COVID-19 patients commonly available at hospital presentation, for early stratification for in-hospital mortality risk of patients with COVID-19.