Persistent hypofibrinolysis in severe COVID-19 associated with elevated fibrinolysis inhibitors activity.

Hypercoagulability and reduced fibrinolysis are well-established complications associated with COVID-19. However, the timelines for the onset and resolution of these complications remain unclear. The aim of this study was to evaluate, in a cohort of COVID-19 patients, changes in coagulation and fibrinolytic activity through ROTEM assay at different time points during the initial 30 days following the onset of symptoms in both mild and severe cases. Blood samples were collected at five intervals after symptoms onset: 6-10 days, 11-15 days, 16-20 days, 21-25 days, and 26-30 days. In addition, fibrinogen, plasminogen, PAI-1, and alpha 2-antiplasmin activities were determined. Out of 85 participants, 71% had mild COVID-19. Twenty uninfected individuals were evaluated as controls. ROTEM parameters showed a hypercoagulable state among mild COVID-19 patients beginning in the second week of symptoms onset, with a trend towards reversal after the third week of symptoms. In severe COVID-19 cases, hypercoagulability was observed since the first few days of symptoms, with a tendency towards reversal after the fourth week of symptoms onset. A hypofibrinolytic state was identified in severe COVID-19 patients from early stages and persisted even after 30 days of symptoms. Elevated activity of PAI-1 and alpha 2-antiplasmin was also detected in severe COVID-19 patients. In conclusion, both mild and severe cases of COVID-19 exhibited transient hypercoagulability, reverted by the end of the first month. However, severe COVID-19 cases sustain hypofibrinolysis throughout the course of the disease, which is associated with elevated activity of fibrinolysis inhibitors. Persistent hypofibrinolysis could contribute to long COVID-19 manifestations.

Temporal trends of severity and outcomes of critically ill patients with COVID-19 after the emergence of variants of concern: A comparison of two waves.

BACKGROUND: The emergence of SARS-CoV-2 variants led to subsequent waves of COVID-19 worldwide. In many countries, the second wave of COVID-19 was marked by record deaths, raising the concern that variants associated with that wave might be more deadly. Our aim was to compare outcomes of critically-ill patients of the first two waves of COVID-19. METHODS: This retrospective cohort included critically-ill patients admitted between March-June 2020 and April-July 2021 in the largest academic hospital in Brazil, which has free-access universal health care system. We compared admission characteristics and hospital outcomes. The main outcome was 60-day survival and we built multivariable Cox model based on a conceptual causal diagram in the format of directed acyclic graph (DAG). RESULTS: We included 1583 patients (1315 in the first and 268 in the second wave). Patients in the second wave were younger, had lower severity scores, used prone and non-invasive ventilatory support more often, and fewer patients required mechanical ventilation (70% vs 80%, p<0.001), vasopressors (60 vs 74%, p<0.001), and dialysis (22% vs 37%, p<0.001). Survival was higher in the second wave (HR 0.61, 95%CI 0.50-0.76). In the multivariable model, admission during the second wave, adjusted for age, SAPS3 and vaccination, was not associated with survival (aHR 0.85, 95%CI 0.65-1.12). CONCLUSIONS: In this cohort study, patients with COVID-19 admitted to the ICU in the second wave were younger and had better prognostic scores. Adjusted survival was similar in the two waves, contrasting with record number of hospitalizations, daily deaths and health system collapse seen across the country in the second wave. Our findings suggest that the combination of the burden of severe cases and factors such as resource allocation and health disparities may have had an impact in the excess mortality found in many countries in the second wave.

Quantitative PCR as a marker for preemptive therapy and its role in therapeutic control in Trypanosoma cruzi/HIV coinfection.

BACKGROUND: Trypanosoma cruzi and HIV coinfection can evolve with depression of cellular immunity and increased parasitemia. We applied quantitative PCR (qPCR) as a marker for preemptive antiparasitic treatment to avoid fatal Chagas disease reactivation and analyzed the outcome of treated cases. METHODOLOGY: This mixed cross-sectional and longitudinal study included 171 Chagas disease patients, 60 coinfected with HIV. Of these 60 patients, ten showed Chagas disease reactivation, confirmed by parasites identified in the blood, cerebrospinal fluid, or tissues, 12 exhibited high parasitemia without reactivation, and 38 had low parasitemia and no reactivation. RESULTS: We showed, for the first time, the success of the timely introduction of benznidazole in the non-reactivated group with high levels of parasitemia detected by qPCR and the absence of parasites in reactivated cases with at least 58 days of benznidazole. All HIV+ patients with or without reactivation had a 4.0-5.1 higher chance of having parasitemia than HIV seronegative cases. A positive correlation was found between parasites and viral loads. Remarkably, treated T. cruzi/HIV-coinfected patients had 77.3% conversion from positive to negative parasitemia compared to 19.1% of untreated patients. Additionally, untreated patients showed ~13.6 times higher Odds Ratio of having positive parasitemia in the follow-up period compared with treated patients. Treated and untreated patients showed no differences regarding the evolution of Chagas disease. The main factors associated with all-cause mortality were higher parasitemia, lower CD4 counts/µL, higher viral load, and absence of antiretroviral therapy. CONCLUSION: We recommend qPCR prospective monitoring of T. cruzi parasitemia in HIV+ coinfected patients and point out the value of pre-emptive therapy for those with high parasitemia. In parallel, early antiretroviral therapy introduction is advisable, aiming at viral load control, immune response restoration, and increasing survival. We also suggest an early antiparasitic treatment for all coinfected patients, followed by effectiveness analysis alongside antiretroviral therapy.

Extracellular vesicles are a late marker of inflammation, hypercoagulability and COVID-19 severity.

Exacerbated inflammation and coagulation are a hallmark of COVID-19 severity. Extracellular vesicles (EVs) are intercellular transmitters involved in inflammatory conditions, which are capable of triggering prothrombotic mechanisms. Since the release of EVs is potentially associated with COVID-19-induced coagulopathy, the aim of this study was to evaluate changes in inflammation- and hypercoagulability-related EVs during the first month after symptom onset and to determine whether they are associated with disease severity. Blood samples of patients with mild or severe forms of the disease were collected on three occasions: in the second, third and fourth weeks after symptom onset for the quantification by flow cytometry of CD41A (platelet glycoprotein IIb/IIIa), CD162 (PSGL-1), CD31 (PECAM-1) and CD142 cells (tissue factor). Analysis of variance (ANOVA) with repeated measures, Kruskal-Wallis and correlation tests were used. Eighty-five patients were enrolled, 71% of whom had mild disease. Seventeen uninfected individuals served as controls. Compared to controls, both mild and severe COVID-19 were associated with higher EV-CD31+, EV-CD41+ and EV-CD142+ levels. All EV levels were higher in severe than in mild COVID-19 only after the third week from symptom onset, as opposed to C-reactive protein and D-dimer levels, which were higher in severe than in mild COVID-19 earlier during disease progression. EV levels were also associated with C-reactive protein and D-dimer levels only after the third week of symptoms. In conclusion, EVs expressing CD41A, CD31, TF, and CD162 appear as late markers of COVID-19 severity. This finding may contribute to the understanding of the pathogenesis of acute and possibly long COVID-19.

Severe dengue in the intensive care unit.

Dengue fever is considered the most prolific vector-borne disease in the world, with its transmission rate increasing more than eight times in the last two decades. While most cases present mild to moderate symptoms, 5% of patients can develop severe disease. Although the mechanisms are yet not fully comprehended, immune-mediated activation leading to excessive cytokine expression is suggested as a cause of the two main findings in critical patients: increased vascular permeability that may shock and thrombocytopenia, and coagulopathy that can induce hemorrhage. The risk factors of severe disease include previous infection by a different serotype, specific genotypes associated with more efficient replication, certain genetic polymorphisms, and comorbidities such as diabetes, obesity, and cardiovascular disease. The World Health Organization recommends careful monitoring and prompt hospitalization of patients with warning signs or propensity for severe disease to reduce mortality. This review aims to update the diagnosis and management of patients with severe dengue in the intensive care unit.

Investigation of etiology of community-acquired pneumonia in hospitalized patients in a tertiary hospital of São Paulo City, Brazil.

BACKGROUND: Community-Acquired Pneumonia (CAP) is the primary cause of hospitalization in the United States and the third leading cause of death in Brazil. The gold standard for diagnosing the etiology of CAP includes blood culture, Gram-stained sputum, and sputum culture. However, these methods have low sensitivity. No studies investigating the etiology of CAP have been conducted in Brazil in the last 20-years, and the empirical choice of antimicrobials is mainly based on the IDSA guidelines. This is the first national study with this aim, and as a result, there's potential for the Brazilian consensus to be impacted and possibly modify its guidelines rather than adhering strictly to the IDSA's recommendations. METHODS: The aim of this study is to identify the main microorganisms implicated in CAP by employing a multiplex Polymerase Chain Reaction (mPCR) at the foremost public hospital in Brazil. All patients who were admitted to the emergency department and diagnosed with severe CAP underwent an mPCR panel using nasopharyngeal and oropharyngeal swabs, with the aim of detecting 13 bacterial and 21 viral pathogens. RESULTS: A total of 169 patients were enrolled in the study. The mPCR panel identified an etiological agent in 61.5% of patients, with viruses being the most common (42.01%), led by Rhinovirus, followed by Influenza and Coronavirus (non-SARS-CoV-2). Bacterial agents were identified in 34.91% of patients, with S. pneumoniae being the most common, followed by H. influenzae, M. catarrhalis, and S. aureus. Additionally, we found that the prescription for 92.3% of patients could be modified, with most changes involving de-escalation of antibiotics and antiviral therapy. CONCLUSION: Our study revealed different etiological causes of CAP than those suggested by the Brazilian guidelines. Using molecular diagnostic tests, we were able to optimize treatment by using fewer antibiotics.

Understanding yellow fever-associated myocardial injury: an autopsy study.

BACKGROUND: Yellow fever (YF) is a viral hemorrhagic fever, endemic in parts of South America and Africa. There is scarce evidence about the pathogenesis of the myocardial injury. The objective of this study is to evaluate the cardiac pathology in fatal cases of YF. METHODS: This retrospective autopsy study included cases from the São Paulo (Brazil) epidemic of 2017-2019. We reviewed medical records and performed cardiac tissue histopathological evaluation, electron microscopy, immunohistochemical assays, RT-qPCR for YF virus (YFV)-RNA, and proteomics analysis on inflammatory and endothelial biomarkers. FINDINGS: Seventy-three confirmed YF cases with a median age of 48 (34-60) years were included. We observed myocardial fibrosis in 68 (93.2%) patients; cardiomyocyte hypertrophy in 68 (93.2%); endothelial alterations in 67 (91.8%); fiber necrosis in 50 (68.5%); viral myocarditis in 9 (12.3%); and secondary myocarditis in 5 (6.8%). Four out of five patients with 17DD vaccine-associated viscerotropic disease presented with myocarditis. The cardiac conduction system showed edema, hemorrhages and endothelial fibrinoid necrosis. Immunohistochemistry detected CD68-positive inflammatory interstitial cells and YFV antigens in endothelial and inflammatory cells. YFV-RNA was detected positive in 95.7% of the cardiac samples. The proteomics analysis demonstrated that YF patients had higher levels of multiple inflammatory and endothelial biomarkers in comparison to cardiovascular controls, and higher levels of interferon gamma-induced protein 10 (IP-10) in comparison to sepsis (p = 0.01) and cardiovascular controls (p < 0.001) in Dunn test. INTERPRETATION: Myocardial injury is frequent in severe YF, due to multifactorial mechanisms, including direct YFV-mediated damage, endothelial cell injury, and inflammatory response, with a possible prominent role for IP-10. FUNDING: This study was funded by Fundação de Amparo à Pesquisa do Estado de São Paulo, Bill and Melinda Gates Foundation, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior.

Yellow fever disease severity and endothelial dysfunction are associated with elevated serum levels of viral NS1 protein and syndecan-1.

Yellow fever virus (YFV) infections can cause severe disease manifestations, including hepatic injury, endothelial damage, coagulopathy, hemorrhage, systemic organ failure, and shock, and are associated with high mortality in humans. While nonstructural protein 1 (NS1) of the related dengue virus is implicated in contributing to vascular leak, little is known about the role of YFV NS1 in severe YF and mechanisms of vascular dysfunction in YFV infections. Here, using serum samples from qRT-PCR-confirmed YF patients with severe (n=39) or non-severe (n=18) disease in a well-defined hospital cohort in Brazil, plus samples from healthy uninfected controls (n=11), we investigated factors associated with disease severity. We developed a quantitative YFV NS1 capture ELISA and found significantly increased levels of NS1, as well as syndecan-1, a marker of vascular leak, in serum from severe YF as compared to non-severe YF or control groups. We also showed that hyperpermeability of endothelial cell monolayers treated with serum from severe YF patients was significantly higher compared to non-severe YF and control groups as measured by transendothelial electrical resistance (TEER). Further, we demonstrated that YFV NS1 induces shedding of syndecan-1 from the surface of human endothelial cells. Notably, YFV NS1 serum levels significantly correlated with syndecan-1 serum levels and TEER values. Syndecan-1 levels also significantly correlated with clinical laboratory parameters of disease severity, viral load, hospitalization, and death. In summary, this study points to a role for secreted NS1 in YF disease severity and provides evidence for endothelial dysfunction as a mechanism of YF pathogenesis in humans.

Investigation of etiology of community-acquired pneumonia in hospitalized patients in a tertiary hospital of São Paulo City, Brazil

Abstract Background Community-Acquired Pneumonia (CAP) is the primary cause of hospitalization in the United States and the third leading cause of death in Brazil. The gold standard for diagnosing the etiology of CAP includes blood culture, Gram-stained sputum, and sputum culture. However, these methods have low sensitivity. No studies investigating the etiology of CAP have been conducted in Brazil in the last 20-years, and the empirical choice of antimicrobials is mainly based on the IDSA guidelines. This is the first national study with this aim, and as a result, there's potential for the Brazilian consensus to be impacted and possibly modify its guidelines rather than adhering strictly to the IDSA's recommendations. Methods The aim of this study is to identify the main microorganisms implicated in CAP by employing a multiplex Polymerase Chain Reaction (mPCR) at the foremost public hospital in Brazil. All patients who were admitted to the emergency department and diagnosed with severe CAP underwent an mPCR panel using nasopharyngeal and oropharyngeal swabs, with the aim of detecting 13 bacterial and 21 viral pathogens. Results A total of 169 patients were enrolled in the study. The mPCR panel identified an etiological agent in 61.5% of patients, with viruses being the most common (42.01%), led by Rhinovirus, followed by Influenza and Coronavirus (non-SARS-CoV-2). Bacterial agents were identified in 34.91% of patients, with S. pneumoniae being the most common, followed by H. influenzae, M. catarrhalis, and S. aureus. Additionally, we found that the prescription for 92.3% of patients could be modified, with most changes involving de-escalation of antibiotics and antiviral therapy. Conclusion Our study revealed different etiological causes of CAP than those suggested by the Brazilian guidelines. Using molecular diagnostic tests, we were able to optimize treatment by using fewer antibiotics.

Hospital readmissions and emergency department re-presentation of COVID-19 patients: a systematic review.

Objective: To characterize the frequency, causes, and predictors of readmissions of COVID-19 patients after discharge from heath facilities or emergency departments, interventions used to reduce readmissions, and outcomes of COVID-19 patients discharged from such settings. Methods: We performed a systematic review for case series and observational studies published between January 2020 and April 2021 in PubMed, Embase, LILACS, and MedRxiv, reporting the frequency, causes, or risk factors for readmission of COVID-19 survivors/patients. We conducted a narrative synthesis and assessed the methodological quality using the JBI critical appraisal checklist. Results: We identified 44 studies including data from 10 countries. The overall 30-day median readmission rate was 7.1%. Readmissions varied with the length of follow-up, occurring <10.5%, <14.5%, <21.5%, and <30%, respectively, for 10, 30, 60, and 253 days following discharge. Among those followed up for 30 and 60 days, the median time from discharge to readmission was 3 days and 8-11 days, respectively. The significant risk factor associated with readmission was having shorter length of stay, and the important causes included respiratory or thromboembolic events and chronic illnesses. Emergency department re-presentation was >20% in four studies. Risk factors associated with mortality were male gender, advanced age, and comorbidities. Conclusions: Readmission of COVID-19 survivors is frequent, and post-discharge mortality is significant in specific populations. There is an urgent need to further examine underlying reasons for early readmission and to prevent additional readmissions and adverse outcomes in COVID-19 survivors.

Hospital readmissions and emergency department re-presentation of COVID-19 patients: a systematic review

[ABSTRACT]. Objective. To characterize the frequency, causes, and predictors of readmissions of COVID-19 patients after discharge from heath facilities or emergency departments, interventions used to reduce readmissions, and outcomes of COVID-19 patients discharged from such settings. Methods. We performed a systematic review for case series and observational studies published between January 2020 and April 2021 in PubMed, Embase, LILACS, and MedRxiv, reporting the frequency, causes, or risk factors for readmission of COVID-19 survivors/patients. We conducted a narrative synthesis and assessed the methodological quality using the JBI critical appraisal checklist. Results. We identified 44 studies including data from 10 countries. The overall 30-day median readmission rate was 7.1%. Readmissions varied with the length of follow-up, occurring <10.5%, <14.5%, <21.5%, and <30%, respectively, for 10, 30, 60, and 253 days following discharge. Among those followed up for 30 and 60 days, the median time from discharge to readmission was 3 days and 8–11 days, respectively. The sig- nificant risk factor associated with readmission was having shorter length of stay, and the important causes included respiratory or thromboembolic events and chronic illnesses. Emergency department re-presenta- tion was >20% in four studies. Risk factors associated with mortality were male gender, advanced age, and comorbidities. Conclusions. Readmission of COVID-19 survivors is frequent, and post-discharge mortality is significant in specific populations. There is an urgent need to further examine underlying reasons for early readmission and to prevent additional readmissions and adverse outcomes in COVID-19 survivors.

[RESUMEN]. Objetivo. Caracterizar la frecuencia, las causas y los factores predictores del reingreso de pacientes con COVID–19 tras haber recibido el alta de un centro de salud o un servicio de urgencias, las intervenciones utilizadas para reducir los reingresos y los resultados de los pacientes con COVID-19 dados de alta de dichos entornos. Métodos. Se realizó una revisión sistemática de estudios de serie de casos y estudios observacionales publi- cados entre enero del 2020 y abril del 2021 en PubMed, Embase, LILACS y MedRxiv en los cuales se informó sobre la frecuencia, las causas o los factores de riesgo relativos al reingreso de pacientes y sobrevivientes de COVID-19. Se realizó una síntesis narrativa y se evaluó la calidad metodológica utilizando la lista de verifi- cación de evaluación crítica de JBI. Resultados. Se encontraron 44 estudios con datos de 10 países. La tasa media general de reingreso a los 30 días fue de 7,1%. Los reingresos variaron con la duración del seguimiento, y tuvieron lugar en <10,5%, <14,5%, <21,5% y <30%, respectivamente, a los 10, 30, 60 y 253 días después del alta. Entre los que reci- bieron seguimiento por 30 y 60 días, el tiempo medio entre el alta y la readmisión fue de 3 y de 8 a 11 días, respectivamente. El factor de riesgo significativo asociado al reingreso fue una estancia más corta, y entre las causas importantes se encontraron episodios respiratorios o tromboembólicos y enfermedades crónicas. El reingreso en el servicio de urgencias fue de >20% en cuatro estudios. Los factores de riesgo asociados con la mortalidad fueron sexo masculino, edad avanzada y comorbilidades. Conclusión. El reingreso de sobrevivientes de COVID-19 es frecuente, y la mortalidad después del alta es significativa en grupos poblacionales específicos. Existe una necesidad urgente de seguir examinando las razones subyacentes del reingreso temprano, así como de prevenir reingresos adicionales y resultados adversos en los sobrevivientes de COVID–19.

[RESUMO]. Objetivo. Caracterizar a frequência, as causas e os preditores de reinternação de pacientes com COVID-19 após a alta do estabelecimento de saúde ou do pronto-socorro, intervenções usadas para reduzir reinter- nações e desfechos de pacientes com COVID-19 que receberam alta de tais instalações. Métodos. Revisão sistemática de séries de casos e estudos observacionais publicados entre janeiro de 2020 e abril de 2021, indexados nos bancos de dados PubMed, Embase, LILACS e MedRxiv, que relatassem a fre- quência, as causas ou os fatores de risco para a reinternação de sobreviventes da COVID-19/pacientes com COVID-19. Realizamos uma síntese narrativa das evidências e avaliamos a qualidade metodológica utilizando a checklist de avaliação crítica do Joanna Briggs Institute (JBI). Resultados. Foram identificados 44 estudos, incluindo dados de 10 países. O índice médio geral de reinter- nação em 30 dias foi de 7,1%. A frequência das reinternações variou com o tempo de acompanhamento, com <10,5%, <14,5%, <21,5% e <30%, respectivamente, ocorrendo nos primeiros 10, 30, 60 e 253 dias após a alta. Dentre aqueles seguidos por 30 e 60 dias, o tempo médio da alta até a reinternação foi de 3 dias e 8 a 11 dias, respectivamente. O único fator de risco significativamente associado à reinternação foi ter um tempo de permanência hospitalar mais curto, e as causas importantes incluíram eventos respiratórios ou tromboembóli- cos e doenças crônicas. Em quatro estudos, >20% dos pacientes retornaram ao pronto-socorro. Os fatores de risco associados à mortalidade foram sexo masculino, idade avançada e comorbidades. Conclusões. A reinternação hospitalar é frequente em sobreviventes da COVID-19 e a mortalidade pós-alta é significativa em populações específicas. Há uma necessidade urgente de examinar melhor as razões que levam à reinternação precoce e de evitar reinternações adicionais e desfechos adversos em sobreviventes da COVID-19.

Phylogeographic patterns of the yellow fever virus around the metropolitan region of São Paulo, Brazil, 2016-2019.

From 2016 to 2019, the largest outbreak caused by the Yellow Fever virus (YFV) in the 21st century in the Americas occurred in southeastern Brazil. A sylvatic cycle of transmission was reported near densely populated areas, such as the large metropolitan area of the city of São Paulo. Here, we describe the origin, spread, and movement of the YFV throughout the state of São Paulo. Whole-genome sequences were obtained from tissues of two patients who died due to severe yellow fever, during 2018-2019. Molecular analysis indicated that all analyzed tissues were positive for YFV RNA, with the liver being the organ with the highest amount of viral RNA. Sequence analysis indicates that genomes belonged to the South American genotype I and were grouped in the epidemic clade II, which includes sequences from the states of Goiás, Minas Gerais, and São Paulo of previous years. The analysis of viral dispersion indicates that the outbreak originated in Goiás at the end of 2014 and reached the state of São Paulo through the state of Minas Gerais after 2016. When the virus reached near the urban area, it spread towards both the east and south regions of the state, not establishing an urban transmission cycle in the metropolitan region of São Paulo. The virus that moved towards the east met with YFV coming from the south of the state of Rio de Janeiro, and the YFV that was carried to the south reached the Brazilian states located in the south region of the country.

Flexible broncoscopy in patients in supportive therapy with oxygenation by extracorporeal membrane.

OBJECTIVE: To report the experience of performing bronchoscopy in patients who underwent supportive therapy with extracorporeal membrane oxygenation in whom the bronchoscopy was performed. METHODS: This was a review of medical records of patients diagnosed with extracorporeal membrane oxygenation and who required diagnostic or therapeutic bronchoscopy. Records included were related to patients admitted to the intensive care unit of Hospital das Clínicas of Faculdade de Medicina of Universidade de São Paulo, between 2014 and 2020. RESULTS: During the study, 16 bronchoscopies were performed in 8 patients admitted to the intensive care unit and who underwent supportive therapy with extracorporeal membrane oxygenation. The mean age of patients was 28.37 years. Four patients were women (50%). A total of 5 (31.25%) therapeutic bronchoscopies and 11 (68.75%) diagnostics were performed. In 5 of patients, material was collected: 4 samples of bronchoalveolar lavage, three collections of transbronchial biopsies, and 1 of endobronchial biopsies. No patient had radiological worsening or hemodynamic complications. One patient (6.25%) had transient desaturation. There was moderate bleeding after transbronchial biopsy in 1 (6.25%) procedure, which was resolved endoscopically. CONCLUSION: Patients undergoing extracorporeal membrane oxygenation can safely perform diagnostic or therapeutic bronchoscopy provided that they have a detailed indication. Procedures were performed by a specialized bronchoscopy team in intensive care environment and with the assistance of a qualified multidisciplinary team in membrane oxygenation therapy extracorporeal.

Understanding Sabiá virus infections (Brazilian mammarenavirus).

BACKGROUND: Only two naturally occurring human Sabiá virus (SABV) infections have been reported, and those occurred over 20 years ago. METHODS: We diagnosed two new cases of SABV infection using metagenomics in patients thought to have severe yellow fever and described new features of histopathological findings. RESULTS: We characterized clinical manifestations, histopathology and analyzed possible nosocomial transmission. Patients presented with hepatitis, bleeding, neurological alterations and died. We traced twenty-nine hospital contacts and evaluated them clinically and by RT-PCR and neutralizing antibodies. Autopsies uncovered unique features on electron microscopy, such as hepatocyte "pinewood knot" lesions. Although previous reports with similar New-World arenavirus had nosocomial transmission, our data did not find any case in contact tracing. CONCLUSIONS: Although an apparent by rare, Brazilian mammarenavirus infection is an etiology for acute hemorrhagic fever syndrome. The two fatal cases had peculiar histopathological findings not previously described. The virological diagnosis was possible only by contemporary techniques such as metagenomic assays. We found no subsequent infections when we used serological and molecular tests to evaluate close contacts.

Updating the Phylodynamics of Yellow Fever Virus 2016-2019 Brazilian Outbreak With New 2018 and 2019 São Paulo Genomes.

The recent outbreak of yellow fever (YF) in São Paulo during 2016-2019 has been one of the most severe in the last decades, spreading to areas with low vaccine coverage. The aim of this study was to assess the genetic diversity of the yellow fever virus (YFV) from São Paulo 2016-2019 outbreak, integrating the available genomic data with new genomes from patients from the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP). Using phylodynamics, we proposed the existence of new IE subclades, described their sequence signatures, and determined their locations and time of origin. Plasma or urine samples from acute severe YF cases (n = 56) with polymerase chain reaction (PCR) positive to YFV were submitted to viral genome amplification using 12 sets of primers. Thirty-nine amplified genomes were subsequently sequenced using next-generation sequencing (NGS). These 39 sequences, together with all the complete genomes publicly available, were aligned and used to determine nucleotide/amino acids substitutions and perform phylogenetic and phylodynamic analysis. All YFV genomes generated in this study belonged to the genotype South American I subgroup E. Twenty-one non-synonymous substitutions were identified among the new generated genomes. We analyzed two major clades of the genotypes IE, IE1, and IE2 and proposed the existence of subclades based on their sequence signatures. Also, we described the location and time of origin of these subclades. Overall, our findings provide an overview of YFV genomic characterization and phylodynamics of the 2016-2019 outbreak contributing to future virological and epidemiological studies.

Phrenic Nerve Block and Respiratory Effort in Pigs and Critically Ill Patients with Acute Lung Injury.

BACKGROUND: Strong spontaneous inspiratory efforts can be difficult to control and prohibit protective mechanical ventilation. Instead of using deep sedation and neuromuscular blockade, the authors hypothesized that perineural administration of lidocaine around the phrenic nerve would reduce tidal volume (VT) and peak transpulmonary pressure in spontaneously breathing patients with acute respiratory distress syndrome. METHODS: An established animal model of acute respiratory distress syndrome with six female pigs was used in a proof-of-concept study. The authors then evaluated this technique in nine mechanically ventilated patients under pressure support exhibiting driving pressure greater than 15 cm H2O or VT greater than 10 ml/kg of predicted body weight. Esophageal and transpulmonary pressures, electrical activity of the diaphragm, and electrical impedance tomography were measured in pigs and patients. Ultrasound imaging and a nerve stimulator were used to identify the phrenic nerve, and perineural lidocaine was administered sequentially around the left and right phrenic nerves. RESULTS: Results are presented as median [interquartile range, 25th to 75th percentiles]. In pigs, VT decreased from 7.4 ml/kg [7.2 to 8.4] to 5.9 ml/kg [5.5 to 6.6] (P < 0.001), as did peak transpulmonary pressure (25.8 cm H2O [20.2 to 27.2] to 17.7 cm H2O [13.8 to 18.8]; P < 0.001) and driving pressure (28.7 cm H2O [20.4 to 30.8] to 19.4 cm H2O [15.2 to 22.9]; P < 0.001). Ventilation in the most dependent part decreased from 29.3% [26.4 to 29.5] to 20.1% [15.3 to 20.8] (P < 0.001). In patients, VT decreased (8.2 ml/ kg [7.9 to 11.1] to 6.0 ml/ kg [5.7 to 6.7]; P < 0.001), as did driving pressure (24.7 cm H2O [20.4 to 34.5] to 18.4 cm H2O [16.8 to 20.7]; P < 0.001). Esophageal pressure, peak transpulmonary pressure, and electrical activity of the diaphragm also decreased. Dependent ventilation only slightly decreased from 11.5% [8.5 to 12.6] to 7.9% [5.3 to 8.6] (P = 0.005). Respiratory rate did not vary. Variables recovered 1 to 12.7 h [6.7 to 13.7] after phrenic nerve block. CONCLUSIONS: Phrenic nerve block is feasible, lasts around 12 h, and reduces VT and driving pressure without changing respiratory rate in patients under assisted ventilation.

Flexible broncoscopy in patients in supportive therapy with oxygenation by extracorporeal membrane

ABSTRACT Objective: To report the experience of performing bronchoscopy in patients who underwent supportive therapy with extracorporeal membrane oxygenation in whom the bronchoscopy was performed. Methods: This was a review of medical records of patients diagnosed with extracorporeal membrane oxygenation and who required diagnostic or therapeutic bronchoscopy. Records included were related to patients admitted to the intensive care unit of Hospital das Clínicas of Faculdade de Medicina of Universidade de São Paulo, between 2014 and 2020. Results: During the study, 16 bronchoscopies were performed in 8 patients admitted to the intensive care unit and who underwent supportive therapy with extracorporeal membrane oxygenation. The mean age of patients was 28.37 years. Four patients were women (50%). A total of 5 (31.25%) therapeutic bronchoscopies and 11 (68.75%) diagnostics were performed. In 5 of patients, material was collected: 4 samples of bronchoalveolar lavage, three collections of transbronchial biopsies, and 1 of endobronchial biopsies. No patient had radiological worsening or hemodynamic complications. One patient (6.25%) had transient desaturation. There was moderate bleeding after transbronchial biopsy in 1 (6.25%) procedure, which was resolved endoscopically. Conclusion: Patients undergoing extracorporeal membrane oxygenation can safely perform diagnostic or therapeutic bronchoscopy provided that they have a detailed indication. Procedures were performed by a specialized bronchoscopy team in intensive care environment and with the assistance of a qualified multidisciplinary team in membrane oxygenation therapy extracorporeal.

Hospital readmissions and emergency department re-presentation of COVID-19 patients: a systematic review / Reingreso de pacientes con COVID-19 a salas de hospitalización y servicios de urgencias: una revisión sistemática / Reinternação hospitalar e retorno ao pronto-socorro de pacientes com COVID-19: revisão sistemática

ABSTRACT Objective. To characterize the frequency, causes, and predictors of readmissions of COVID-19 patients after discharge from heath facilities or emergency departments, interventions used to reduce readmissions, and outcomes of COVID-19 patients discharged from such settings. Methods. We performed a systematic review for case series and observational studies published between January 2020 and April 2021 in PubMed, Embase, LILACS, and MedRxiv, reporting the frequency, causes, or risk factors for readmission of COVID-19 survivors/patients. We conducted a narrative synthesis and assessed the methodological quality using the JBI critical appraisal checklist. Results. We identified 44 studies including data from 10 countries. The overall 30-day median readmission rate was 7.1%. Readmissions varied with the length of follow-up, occurring <10.5%, <14.5%, <21.5%, and <30%, respectively, for 10, 30, 60, and 253 days following discharge. Among those followed up for 30 and 60 days, the median time from discharge to readmission was 3 days and 8-11 days, respectively. The significant risk factor associated with readmission was having shorter length of stay, and the important causes included respiratory or thromboembolic events and chronic illnesses. Emergency department re-presentation was >20% in four studies. Risk factors associated with mortality were male gender, advanced age, and comorbidities. Conclusions. Readmission of COVID-19 survivors is frequent, and post-discharge mortality is significant in specific populations. There is an urgent need to further examine underlying reasons for early readmission and to prevent additional readmissions and adverse outcomes in COVID-19 survivors.

RESUMEN Objetivo. Caracterizar la frecuencia, las causas y los factores predictores del reingreso de pacientes con COVID-19 tras haber recibido el alta de un centro de salud o un servicio de urgencias, las intervenciones utilizadas para reducir los reingresos y los resultados de los pacientes con COVID-19 dados de alta de dichos entornos. Métodos. Se realizó una revisión sistemática de estudios de serie de casos y estudios observacionales publicados entre enero del 2020 y abril del 2021 en PubMed, Embase, LILACS y MedRxiv en los cuales se informó sobre la frecuencia, las causas o los factores de riesgo relativos al reingreso de pacientes y sobrevivientes de COVID-19. Se realizó una síntesis narrativa y se evaluó la calidad metodológica utilizando la lista de verificación de evaluación crítica de JBI. Resultados. Se encontraron 44 estudios con datos de 10 países. La tasa media general de reingreso a los 30 días fue de 7,1%. Los reingresos variaron con la duración del seguimiento, y tuvieron lugar en <10,5%, <14,5%, <21,5% y <30%, respectivamente, a los 10, 30, 60 y 253 días después del alta. Entre los que recibieron seguimiento por 30 y 60 días, el tiempo medio entre el alta y la readmisión fue de 3 y de 8 a 11 días, respectivamente. El factor de riesgo significativo asociado al reingreso fue una estancia más corta, y entre las causas importantes se encontraron episodios respiratorios o tromboembólicos y enfermedades crónicas. El reingreso en el servicio de urgencias fue de >20% en cuatro estudios. Los factores de riesgo asociados con la mortalidad fueron sexo masculino, edad avanzada y comorbilidades. Conclusión. El reingreso de sobrevivientes de COVID-19 es frecuente, y la mortalidad después del alta es significativa en grupos poblacionales específicos. Existe una necesidad urgente de seguir examinando las razones subyacentes del reingreso temprano, así como de prevenir reingresos adicionales y resultados adversos en los sobrevivientes de COVID-19.

RESUMO Objetivo. Caracterizar a frequência, as causas e os preditores de reinternação de pacientes com COVID-19 após a alta do estabelecimento de saúde ou do pronto-socorro, intervenções usadas para reduzir reinternações e desfechos de pacientes com COVID-19 que receberam alta de tais instalações. Métodos. Revisão sistemática de séries de casos e estudos observacionais publicados entre janeiro de 2020 e abril de 2021, indexados nos bancos de dados PubMed, Embase, LILACS e MedRxiv, que relatassem a frequência, as causas ou os fatores de risco para a reinternação de sobreviventes da COVID-19/pacientes com COVID-19. Realizamos uma síntese narrativa das evidências e avaliamos a qualidade metodológica utilizando a checklist de avaliação crítica do Joanna Briggs Institute (JBI). Resultados. Foram identificados 44 estudos, incluindo dados de 10 países. O índice médio geral de reinternação em 30 dias foi de 7,1%. A frequência das reinternações variou com o tempo de acompanhamento, com <10,5%, <14,5%, <21,5% e <30%, respectivamente, ocorrendo nos primeiros 10, 30, 60 e 253 dias após a alta. Dentre aqueles seguidos por 30 e 60 dias, o tempo médio da alta até a reinternação foi de 3 dias e 8 a 11 dias, respectivamente. O único fator de risco significativamente associado à reinternação foi ter um tempo de permanência hospitalar mais curto, e as causas importantes incluíram eventos respiratórios ou tromboembólicos e doenças crônicas. Em quatro estudos, >20% dos pacientes retornaram ao pronto-socorro. Os fatores de risco associados à mortalidade foram sexo masculino, idade avançada e comorbidades. Conclusões. A reinternação hospitalar é frequente em sobreviventes da COVID-19 e a mortalidade pós-alta é significativa em populações específicas. Há uma necessidade urgente de examinar melhor as razões que levam à reinternação precoce e de evitar reinternações adicionais e desfechos adversos em sobreviventes da COVID-19.

Staging liver fibrosis after severe yellow fever with ultrasound elastography in Brazil: A six-month follow-up study.

BACKGROUND: Yellow fever (YF) is a hemorrhagic disease caused by an arbovirus endemic in South America, with recent outbreaks in the last years. Severe cases exhibit fulminant hepatitis, but there are no studies regarding its late-term effects on liver parenchyma. Thus, the aim of this study was to determine the frequency and grade of liver fibrosis in patients who recovered from severe YF and to point out potential predictors of this outcome. METHODOLOGY/PRINCIPAL FINDINGS: We followed-up 18 patients who survived severe YF during a recent outbreak (January-April 2018) in Brazil using ultrasound (US) with shear-wave elastography (SWE) at 6 months after symptoms onset. No patient had previous history of liver disease. Median liver stiffness (LS) was 5.3 (4.6-6.4) kPa. 2 (11.1%) patients were classified as Metavir F2, 1 (8.3%) as F3 and 1 (8.3%) as F4; these two last patients had features of cardiogenic liver congestion on Doppler analysis. Age and cardiac failure were associated with increased LS (p = 0.036 and p = 0.024, respectively). SAPS-3 at ICU admission showed a tendency of association with significant fibrosis (≥ F2; p = 0.053). 7 patients used sofosbuvir in a research protocol, of which none showed liver fibrosis (p = 0.119). CONCLUSIONS/SIGNIFICANCE: We found a low frequency of liver fibrosis in severe YF survivors. US with SWE may have a role in the follow up of patients of age and / or with comorbidities after hospital discharge in severe YF, a rare but reemergent disease.