Yellow fever and orthotopic liver transplantation: new insights from the autopsy room for an old but re-emerging disease.

AIMS: The clinical spectrum of yellow fever (YF) ranges from asymptomatic to fulminant hepatitis. During the sylvatic YF epidemic in the metropolitan area of São Paulo, Brazil in 2018, seven orthotopic liver transplantations (OLTs) were performed in our institution to treat fulminant YF hepatitis. Three patients recovered, while four patients died following OLT. The autopsy findings of all these cases are presented herein as the first description of YF in transplanted patients. METHODS AND RESULTS: All patients were men, aged 16-40 years, without vaccination to YF virus (YFV). All organs were examined, with tissue sampling for histopathological analysis. Detection of YF virus antigens (YFV Ag) was performed with two primary antibodies (mouse polyclonal anti-YFV antibody directed to wild strain and a goat anti-YF virus antibody), and RT-PCR assays were utilised to detect YFV-RNA. All the cases depicted typical findings of YF hepatitis in the engrafted liver. The main extrahepatic findings were cerebral oedema, pulmonary haemorrhage, pneumonia, acute tubular necrosis and ischaemic/reperfusion pancreatitis. Of the four cases, the YVF Ag was detected in the heart in one case, liver and testis in three cases, and the kidney and spleen in all four cases. All four cases had YF virus RNA detected by RT-PCR in the liver and in other organs. CONCLUSIONS: Infection of the engrafted liver and other organs by YFV, possibly combined with major ischaemic systemic lesions, may have led to the death of four of the seven patients undergoing OLT.

Development of an algorithm to aid triage decisions for intensive care unit admission: a clinical vignette and retrospective cohort study.

BACKGROUND: Intensive care unit (ICU) admission triage is performed routinely and is often based solely on clinical judgment, which could mask biases. A computerized algorithm to aid ICU triage decisions was developed to classify patients into the Society of Critical Care Medicine's prioritization system. In this study, we sought to evaluate the reliability and validity of this algorithm. METHODS: Nine senior physicians evaluated forty clinical vignettes based on real patients. The reference standard was defined as the priorities ascribed by two investigators with full access to patients' records. Agreement of algorithm-based priorities with the reference standard and with intuitive priorities provided by the physicians were evaluated. Correlations between algorithm prioritization and physicians' judgment of the appropriateness of ICU admissions in scarcity and nonscarcity settings were also evaluated. Validity was further assessed by retrospectively applying this algorithm to 603 patients with requests for ICU admission for association with clinical outcomes. RESULTS: Agreement between algorithm-based priorities and the reference standard was substantial, with a median κ of 0.72 (interquartile range [IQR] 0.52-0.77). Algorithm-based priorities demonstrated higher interrater reliability (overall κ 0.61, 95% confidence interval [CI] 0.57-0.65; median percentage agreement 0.64, IQR 0.59-0.70) than physicians' intuitive prioritization (overall κ 0.51, 95% CI 0.47-0.55; median percentage agreement 0.49, IQR 0.44-0.56) (p = 0.001). Algorithm-based priorities were also associated with physicians' judgment of appropriateness of ICU admission (priorities 1, 2, 3, and 4 vignettes would be admitted to the last ICU bed in 83.7%, 61.2%, 45.2%, and 16.8% of the scenarios, respectively; p < 0.001) and with actual ICU admission, palliative care consultation, and hospital mortality in the retrospective cohort. CONCLUSIONS: This ICU admission triage algorithm demonstrated good reliability and validity. However, more studies are needed to evaluate a difference in benefit of ICU admission justifying the admission of one priority stratum over the others.

Discrepancies Between Clinical and Autopsy Diagnoses in Rapid Response Team-Assisted Patients: What Are We Missing?

OBJECTIVES: The rapid response team (RRT) assists hospitalized patients with sudden clinical deterioration. There is scarce evidence of diagnostic accuracy in this scenario, but it is possible that a considerable rate of misdiagnosis exists. Autopsy remains a valuable tool for assessing such question. This study aimed to compare clinical (premortem) and autopsy (postmortem) diagnoses in patients assisted by the RRT and describe major discrepancies. METHODS: We reviewed 104 clinical data and autopsies from patients assisted by the RRT during a cardiac arrest event in a tertiary care hospital in Brazil. Clinical and autopsy diagnostic discrepancies were classified using the Goldman criteria. Other clinical and pathological data were described, and the group with major diagnostic discrepancies was further analyzed. RESULTS: We found 39 (37.5%) patients with major diagnostic discrepancies. Most frequent immediate causes of death in this group determined by autopsy were sepsis (36%), pulmonary embolism (23%) and hemorrhagic shock (21%). Pulmonary embolism was the cause of death significantly more frequent in the major discrepancy group than in the minor discrepancy group (23% versus 3%, P = 0.002). We individually described all major diagnostic discrepancies. CONCLUSIONS: We found a high rate (37.5%) of major misdiagnosis in autopsies from patients assisted by the RRT in a tertiary teaching hospital. Pulmonary embolism was the most inaccurate fatal diagnosis detected by autopsy.

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.

Use and misuse of biomarkers and the role of D-dimer and C-reactive protein in the management of COVID-19: A post-hoc analysis of a prospective cohort study.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is associated with high mortality among hospitalized patients and incurs high costs. Severe acute respiratory syndrome coronavirus 2 infection can trigger both inflammatory and thrombotic processes, and these complications can lead to a poorer prognosis. This study aimed to evaluate the association and temporal trends of D-dimer and C-reactive protein (CRP) levels with the incidence of venous thromboembolism (VTE), hospital mortality, and costs among inpatients with COVID-19. METHODS: Data were extracted from electronic patient records and laboratory databases. Crude and adjusted associations for age, sex, number of comorbidities, Sequential Organ Failure Assessment score at admission, and D-dimer or CRP logistic regression models were used to evaluate associations. RESULTS: Between March and June 2020, COVID-19 was documented in 3,254 inpatients. The D-dimer level ≥4,000 ng/mL fibrinogen equivalent unit (FEU) mortality odds ratio (OR) was 4.48 (adjusted OR: 1.97). The CRP level ≥220 mg/dL OR for death was 7.73 (adjusted OR: 3.93). The D-dimer level ≥4,000 ng/mL FEU VTE OR was 3.96 (adjusted OR: 3.26). The CRP level ≥220 mg/dL OR for VTE was 2.71 (adjusted OR: 1.92). All these analyses were statistically significant (p<0.001). Stratified hospital costs demonstrated a dose-response pattern. Adjusted D-dimer and CRP levels were associated with higher mortality and doubled hospital costs. In the first week, elevated D-dimer levels predicted VTE occurrence and systemic inflammatory harm, while CRP was a hospital mortality predictor. CONCLUSION: D-dimer and CRP levels were associated with higher hospital mortality and a higher incidence of VTE. D-dimer was more strongly associated with VTE, although its discriminative ability was poor, while CRP was a stronger predictor of hospital mortality. Their use outside the usual indications should not be modified and should be discouraged.

Setting up hospital care provision to patients with COVID-19: lessons learnt at a 2400-bed academic tertiary center in São Paulo, Brazil.

As of August 30, 2020, Brazil ranked second among countries with the highest number of COVID-19 cases, with the city of São Paulo as the national epidemic epicenter. Local public healthcare institutions were challenged to respond to a fast-growing hospital demand, reengineering care provision to optimize clinical outcomes and minimize intra-hospital coronavirus infection. In this paper we describe how the largest public hospital complex in Latin America faced this unprecedented burden, managing severe COVID-19 cases while sustaining specialized care to patients with other conditions. In our strategic plan a 900-bed hospital was exclusively designated for COVID-19 care and continuity of care to those not infected with coronavirus ensured in other inpatient facilities. After 152 days, 4241 patients with severe COVID-19 were hospitalized, 70% of whom have already been discharged, whereas the remaining Institutes of the complex successfully maintained high complexity inpatient and urgent/emergency care to non-COVID-19 patients.

A decision-aid tool for ICU admission triage is associated with a reduction in potentially inappropriate intensive care unit admissions.

PURPOSE: Intensive care unit (ICU) admission triage occurs frequently and often involves highly subjective decisions that may lead to potentially inappropriate ICU admissions. In this study, we evaluated the effect of implementing a decision-aid tool for ICU triage on ICU admission decisions. METHODS: This was a prospective, before-after study. Urgent ICU referrals to ten ICUs in a tertiary hospital in Brazil were assessed before and after the implementation of the decision-aid tool. Our primary outcome was the proportion of potentially inappropriate ICU referrals (defined as priority 4B or 5 referrals, accordingly to the Society of Critical Care Medicine guidelines of 1999 and 2016, respectively) admitted to the ICU within 48 h. We conducted multivariate analyses to adjust for potential confounders and evaluated the interaction between phase and triage priority. RESULTS: Of the 2201 patients analyzed, 1184 (53.8%) patients were admitted to the ICU. After adjustment for confounders, implementation of the decision-aid tool was associated with a reduction in potentially inappropriate ICU admissions using either the 1999 [adjOR (95% CI) = 0.36 (0.13-0.97)] or 2016 [adjOR (95%CI) = 0.35 (0.13-0.96)] definitions. CONCLUSION: Implementation of a decision-aid tool for ICU triage was associated with a reduction in potentially inappropriate ICU admissions.

Severe yellow fever in Brazil: clinical characteristics and management.

BACKGROUND: Little is known about clinical characteristics and management of severe yellow fever as previous yellow fever epidemics often occurred in times or areas with little access to intensive care units (ICU). We aim to describe the clinical characteristics of severe yellow fever cases requiring admission to the ICU during the 2018 yellow fever outbreak in São Paulo, Brazil. Furthermore, we report on preliminary lessons learnt regarding clinical management of severe yellow fever. METHODS: Retrospective descriptive cohort study. Demographic data, laboratory test results on admission, clinical follow-up, and clinical outcomes were evaluated. RESULTS: From 10 January to 11 March 2018, 79 patients with laboratory confirmed yellow fever were admitted to the ICU in a tertiary hospital in Sao Paolo because of rapid clinical deterioration. On admission, the median AST was 7,000 IU/L, ALT 3,936 IU/L, total bilirubin 5.3 ml/dL, platelet 74 × 103/mm3, INR 2.24 and factor V 37%. Seizures occurred in 24% of patients, even without substantial intracranial hypertension. The high frequency of pancreatitis and rapidly progressive severe metabolic acidosis were notable findings. 73% of patients required renal replacement therapy. The in-hospital fatality rate was 67%. Patients with diabetes mellitus had a higher case fatality rate (CFR) of 80%, while patients without diabetes had a CFR of 65%. Leading causes of death were severe gastrointestinal bleeding, epileptic status, severe metabolic acidosis, necrohemorrhagic pancreatitis, and multi-organ failure. CONCLUSIONS: Severe yellow fever is associated with a high CFR. The following management lessons were learnt: Anticonvulsant drugs in patients with any symptoms of hepatic encephalopathy or arterial ammonia levels >70 µmol/L was commenced which reduced the frequency of seizures from 28% to 17%. Other new therapy strategies included early institution of plasma exchange. Due to the high frequency of gastric bleeding, therapeutic doses of intravenous proton pump inhibitors should be administered.

Origin of the São Paulo Yellow Fever epidemic of 2017-2018 revealed through molecular epidemiological analysis of fatal cases.

The largest outbreak of yellow fever of the 21st century in the Americas began in 2016, with intense circulation in the southeastern states of Brazil, particularly in sylvatic environments near densely populated areas including the metropolitan region of São Paulo city (MRSP) during 2017-2018. Herein, we describe the origin and molecular epidemiology of yellow fever virus (YFV) during this outbreak inferred from 36 full genome sequences taken from individuals who died following infection with zoonotic YFV. Our analysis revealed that these deaths were due to three genetic variants of sylvatic YFV that belong the South American I genotype and that were related to viruses previously isolated in 2017 from other locations in Brazil (Minas Gerais, Espírito Santo, Bahia and Rio de Janeiro states). Each variant represented an independent virus introduction into the MRSP. Phylogeographic and geopositioning analyses suggested that the virus moved around the peri-urban area without detectable human-to-human transmission, and towards the Atlantic rain forest causing human spill-over in nearby cities, yet in the absence of sustained viral transmission in the urban environment.

Use and misuse of biomarkers and the role of D-dimer and C-reactive protein in the management of COVID-19: A post-hoc analysis of a prospective cohort study

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is associated with high mortality among hospitalized patients and incurs high costs. Severe acute respiratory syndrome coronavirus 2 infection can trigger both inflammatory and thrombotic processes, and these complications can lead to a poorer prognosis. This study aimed to evaluate the association and temporal trends of D-dimer and C-reactive protein (CRP) levels with the incidence of venous thromboembolism (VTE), hospital mortality, and costs among inpatients with COVID-19. METHODS: Data were extracted from electronic patient records and laboratory databases. Crude and adjusted associations for age, sex, number of comorbidities, Sequential Organ Failure Assessment score at admission, and D-dimer or CRP logistic regression models were used to evaluate associations. RESULTS: Between March and June 2020, COVID-19 was documented in 3,254 inpatients. The D-dimer level ≥4,000 ng/mL fibrinogen equivalent unit (FEU) mortality odds ratio (OR) was 4.48 (adjusted OR: 1.97). The CRP level ≥220 mg/dL OR for death was 7.73 (adjusted OR: 3.93). The D-dimer level ≥4,000 ng/mL FEU VTE OR was 3.96 (adjusted OR: 3.26). The CRP level ≥220 mg/dL OR for VTE was 2.71 (adjusted OR: 1.92). All these analyses were statistically significant (p<0.001). Stratified hospital costs demonstrated a dose-response pattern. Adjusted D-dimer and CRP levels were associated with higher mortality and doubled hospital costs. In the first week, elevated D-dimer levels predicted VTE occurrence and systemic inflammatory harm, while CRP was a hospital mortality predictor. CONCLUSION: D-dimer and CRP levels were associated with higher hospital mortality and a higher incidence of VTE. D-dimer was more strongly associated with VTE, although its discriminative ability was poor, while CRP was a stronger predictor of hospital mortality. Their use outside the usual indications should not be modified and should be discouraged.

Setting up hospital care provision to patients with COVID-19: lessons learnt at a 2400-bed academic tertiary center in São Paulo, Brazil

ABSTRACT As of August 30, 2020, Brazil ranked second among countries with the highest number of COVID-19 cases, with the city of São Paulo as the national epidemic epicenter. Local public healthcare institutions were challenged to respond to a fast-growing hospital demand, reengineering care provision to optimize clinical outcomes and minimize intra-hospital coronavirus infection. In this paper we describe how the largest public hospital complex in Latin America faced this unprecedented burden, managing severe COVID-19 cases while sustaining specialized care to patients with other conditions. In our strategic plan a 900-bed hospital was exclusively designated for COVID-19 care and continuity of care to those not infected with coronavirus ensured in other inpatient facilities. After 152 days, 4241 patients with severe COVID-19 were hospitalized, 70% of whom have already been discharged, whereas the remaining Institutes of the complex successfully maintained high complexity inpatient and urgent/emergency care to non-COVID-19 patients.

Evidence for prescribing exercise as treatment in pediatric rheumatic diseases.

There has been an increasing recognition of adverse short-, mid-, or long-term effects associated with the treatment as well as the disease itself that impair the health-related quality of life and functional capacity of children and adolescents with rheumatic diseases. Interestingly, cumulative evidence has suggested that exercise training may benefit patients with juvenile idiopathic arthritis, juvenile systemic lupus erythematosus, juvenile dermatomyositis and juvenile fibromyalgia, attenuating several clinical symptoms related to physical disability. Remarkably, recent evidence also suggests that exercise may have direct effects on the pathogenesis of autoimmune diseases by attenuating chronic low-grade systemic inflammation. It is also important to emphasize that no exercise-related adverse effects have been reported. This short review provides the evidence for physical training as a treatment of pediatric rheumatic diseases, introducing a novel concept that exercise is a treatment for these populations.