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.

Septic shock, hyperferritinemic syndrome, and multiple organ dysfunction without respiratory failure in a patient with disseminated histoplasmosis and advanced HIV disease.

AIDS-related disseminated histoplasmosis (DH) can cause septic shock and multiorgan dysfunction with mortality rates of up to 80%. A 41-year-old male presented with fever, fatigue, weight loss, disseminated skin lesions, low urine output, and mental confusion. Three weeks before admission, the patient was diagnosed with HIV infection, but antiretroviral therapy (ART) was not initiated. On day 1 of admission, sepsis with multiorgan dysfunction (acute renal failure, metabolic acidosis, hepatic failure, and coagulopathy) was identified. A chest computed tomography showed unspecific findings. Yeasts suggestive of Histoplasma spp. were observed in a routine peripheral blood smear. On day 2, the patient was transferred to the ICU, where his clinical condition progressed with reduced level of consciousness, hyperferritinemia, and refractory septic shock, requiring high doses of vasopressors, corticosteroids, mechanical ventilation, and hemodialysis. Amphotericin B deoxycholate was initiated. On day 3, yeasts suggestive of Histoplasma spp. were observed in the bone marrow. On day 10, ART was initiated. On day 28, samples of peripheral blood and bone marrow cultures revealed Histoplasma spp. The patient stayed in the ICU for 32 days, completing three weeks of intravenous antifungal therapy. After progressive clinical and laboratory improvement, the patient was discharged from the hospital on oral itraconazole, trimethoprim-sulfamethoxazole, and ART. This case highlights the inclusion of DH in the differential diagnosis of patients with advanced HIV disease, septic shock and multiorgan dysfunction but without respiratory failure. In addition, it provides early in-hospital diagnosis and treatment and comprehensive management in the ICU as determining factors for a good outcome.

Optimization of Antimicrobial Stewardship Programs Using Therapeutic Drug Monitoring and Pharmacokinetics-Pharmacodynamics Protocols: A Cost-Benefit Review.

PURPOSE: Antimicrobial stewardship programs are important for reducing antimicrobial resistance because they can readjust antibiotic prescriptions to local guidelines, switch intravenous to oral administration, and reduce hospitalization times. Pharmacokinetics-pharmacodynamics (PK-PD) empirically based prescriptions and therapeutic drug monitoring (TDM) programs are essential for antimicrobial stewardship, but there is a need to fit protocols according to cost benefits. The cost benefits can be demonstrated by reducing toxicity and hospital stay, decreasing the amount of drug used per day, and preventing relapses in infection. Our aim was to review the data available on whether PK-PD empirically based prescriptions and TDM could improve the cost benefits of an antimicrobial stewardship program to decrease global hospital expenditures. METHODS: A narrative review based on PubMed search with the relevant studies of vancomycin, aminoglycosides, beta-lactams, and voriconazole. RESULTS: TDM protocols demonstrated important cost benefit for patients treated with vancomycin, aminoglycosides, and voriconazole mainly due to reduce toxicities and decreasing the hospital length of stay. In addition, PK-PD strategies that used infusion modifications to meropenem, piperacillin-tazobactam, ceftazidime, and cefepime, such as extended or continuous infusion, demonstrated important cost benefits, mainly due to reducing daily drug needs and lengths of hospital stays. CONCLUSIONS: TDM protocols and PK-PD empirically based prescriptions improve the cost-benefits and decrease the global hospital expenditures.

Septic shock, hyperferritinemic syndrome, and multiple organ dysfunction without respiratory failure in a patient with disseminated histoplasmosis and advanced HIV disease

ABSTRACT AIDS-related disseminated histoplasmosis (DH) can cause septic shock and multiorgan dysfunction with mortality rates of up to 80%. A 41-year-old male presented with fever, fatigue, weight loss, disseminated skin lesions, low urine output, and mental confusion. Three weeks before admission, the patient was diagnosed with HIV infection, but antiretroviral therapy (ART) was not initiated. On day 1 of admission, sepsis with multiorgan dysfunction (acute renal failure, metabolic acidosis, hepatic failure, and coagulopathy) was identified. A chest computed tomography showed unspecific findings. Yeasts suggestive of Histoplasma spp. were observed in a routine peripheral blood smear. On day 2, the patient was transferred to the ICU, where his clinical condition progressed with reduced level of consciousness, hyperferritinemia, and refractory septic shock, requiring high doses of vasopressors, corticosteroids, mechanical ventilation, and hemodialysis. Amphotericin B deoxycholate was initiated. On day 3, yeasts suggestive of Histoplasma spp. were observed in the bone marrow. On day 10, ART was initiated. On day 28, samples of peripheral blood and bone marrow cultures revealed Histoplasma spp. The patient stayed in the ICU for 32 days, completing three weeks of intravenous antifungal therapy. After progressive clinical and laboratory improvement, the patient was discharged from the hospital on oral itraconazole, trimethoprim-sulfamethoxazole, and ART. This case highlights the inclusion of DH in the differential diagnosis of patients with advanced HIV disease, septic shock and multiorgan dysfunction but without respiratory failure. In addition, it provides early in-hospital diagnosis and treatment and comprehensive management in the ICU as determining factors for a good outcome.

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.

Intensive care unit staff preparedness as an independent factor for death of patients during COVID-19 pandemic: An observational cohort study.

The pandemic of COVID-19 brought to the world an unprecedented challenge. This single center observational study aimed to evaluate the impact of staff preparedness by comparing the outcomes between two intensive care units (ICUs) from a hospital that had to expand ICU beds to deal with an incremented volume of critical patients. Patients consecutively admitted to these ICUs with suspected COVID-19, from March 1st until April 30th, 2020, were included. Both ICUs attended a similar population and had the same facilities, what differed was the staff: one previously well-established (ICU-1) and another recently assembled (ICU-2). 114 patients with severe respiratory syndrome were included. In-hospital mortality was 40%. Compared with patients in the well-established ICU-1, patients in the recently assembled ICU-2 were older (54 versus 61.5, p=0.045), received more antibiotics (93% versus 98%, p=0.001) and chloroquine/hydroxychloroquine 6% versus 30%, p=0.001), had a higher proportion of invasive mechanical ventilation (44% versus 52%, p=0.008) and had greater in-hospital mortality (30% versus 50%, p=0.017). The proportion of patients considered at high risk for death according to PSI was similar between the two ICU populations. Age ≥ 60 years (adjusted OR 2.33; 95% CI 1.02-5.31), need of invasive mechanical ventilation (adjusted OR 2.79; 95% CI 1.22-6.37), and ICU type (recently assembled) (adjusted OR 2.38; 95% CI 1.04-5.44) were independently associated with in-hospital mortality . This finding highlights the importance of developing support strategies to improve preparedness of staff recently assembled to deal with emergencies.

Splenic Infarction with Aortic Thrombosis in COVID-19.

Coronavirus disease 2019 (COVID-19) has been associated with an increased risk of venous and arterial thrombotic disease. Although pulmonary embolism has been the most common thrombotic complication, there have been recent reports of COVID-19-associated large-vessel ischemic stroke, acute upper- and lower-limb ischemia, as well as infarctions of the abdominal viscera, including renal, splenic, and small bowel infarctions. Here, we describe a case of splenic infarction (SI) associated with aortic thrombosis, which evolved despite the prophylactic use of low-molecular-weight heparin (LMWH), in a 60-year-old female patient with COVID-19. The patient was treated clinically with a therapeutic dose of LMWH, followed by warfarin, and eventually presented a favorable outcome. We also present a review of the literature regarding SI in patients with COVID-19.

Epidemiology, clinical aspects, outcomes and prognostic factors associated with Trichosporon fungaemia: results of an international multicentre study carried out at 23 medical centres.

BACKGROUND: Trichosporon fungaemia (TF) episodes have increased in recent years and mortality rates remain high despite the advances in the management of sepsis. New concepts about its clinical course, treatment and microbiology need to be investigated for the better management of this infection. OBJECTIVES: To describe the aetiology, natural history, clinical management and prognostic factors of TF. METHODS: TF episodes documented between 2005 and 2018 in 23 South American centres were retrospectively investigated by using a standard clinical form. Molecular identification, antifungal susceptibility testing and biofilm production were also performed. RESULTS: Eighty-eight TF episodes were studied. Patients had several underlying conditions, including haematological diseases (47.7%), post-operative status (34%), solid organ transplants (n = 7, 7.9%), among others. Seventy-three (82.9%) patients had a central venous catheter (CVC) at TF diagnosis. The 30 day mortality rate was 51.1%. Voriconazole-based therapy was given to 34 patients (38.6%), with a 30 day mortality rate of 38.2%. Multivariate predictors of 30 day mortality were age (OR 1.036), mechanical ventilation (OR 8.25) and persistent neutropenia (OR 9.299). CVC removal was associated with over 75% decreased risk of 30 day mortality (OR 0.241). Microbiological analyses revealed that 77.7% of the strains were identified as Trichosporon asahii, and voriconazole showed the strongest in vitro activity against Trichosporon spp. Most of the strains (63%) were considered medium or high biofilm producers. CONCLUSIONS: Older age, mechanical ventilation and persistent neutropenia were associated with poor prognosis. CVC may play a role in the pathogenicity of TF and its removal was associated with a better prognosis.

Potential autoimmune encephalitis following yellow fever vaccination: A report of three cases.

Meningoencephalitis following yellow fever vaccination is considered a viral neuroinvasive disease. We describe three patients with typical autoimmune encephalitis syndromes that developed 1-27 days following yellow fever vaccination. Anti-N-methyl-d-aspartate-r antibodies were identified in the CSF and serum of two patients and the other case was associated with anti-neurexin-3 antibodies. One case was confirmed as vaccine-associated neurotropic disease due to reactive CSF yellow fever IgM, which suggested an infectious-autoimmune overlap mechanism. Two aditional cases of Anti-N-methyl-d-aspartate-r encephalitis were identified in the literature review. Antibody-positive autoimmune encephalitis should be included in the differential diagnosis of neurologic adverse events following yellow fever vaccination.

Awake Proning as an Adjunctive Therapy for Refractory Hypoxemia in Non-Intubated Patients with COVID-19 Acute Respiratory Failure: Guidance from an International Group of Healthcare Workers.

Non-intubated patients with acute respiratory failure due to COVID-19 could benefit from awake proning. Awake proning is an attractive intervention in settings with limited resources, as it comes with no additional costs. However, awake proning remains poorly used probably because of unfamiliarity and uncertainties regarding potential benefits and practical application. To summarize evidence for benefit and to develop a set of pragmatic recommendations for awake proning in patients with COVID-19 pneumonia, focusing on settings where resources are limited, international healthcare professionals from high and low- and middle-income countries (LMICs) with known expertise in awake proning were invited to contribute expert advice. A growing number of observational studies describe the effects of awake proning in patients with COVID-19 pneumonia in whom hypoxemia is refractory to simple measures of supplementary oxygen. Awake proning improves oxygenation in most patients, usually within minutes, and reduces dyspnea and work of breathing. The effects are maintained for up to 1 hour after turning back to supine, and mostly disappear after 6-12 hours. In available studies, awake proning was not associated with a reduction in the rate of intubation for invasive ventilation. Awake proning comes with little complications if properly implemented and monitored. Pragmatic recommendations including indications and contraindications were formulated and adjusted for resource-limited settings. Awake proning, an adjunctive treatment for hypoxemia refractory to supplemental oxygen, seems safe in non-intubated patients with COVID-19 acute respiratory failure. We provide pragmatic recommendations including indications and contraindications for the use of awake proning in LMICs.

Severe gastrintestinal bleeding as an unusual presentation of pediatric tuberculosis: a situation for injectable antituberculous drugs use?

Disseminated tuberculosis is a severe disease with high-mortality that requires early diagnosis and treatment. Intestinal tuberculosis accounts for only 2% of tuberculosis cases worldwide and is extremely rare in children. We report a case of a 4-year-old girl admitted due to disseminated tuberculosis with extensive intestinal involvement characterized by massive intestinal bleeding and hemorrhagic shock. The severity of the intestinal involvement precluded the exclusive use of oral anti-tuberculosis drugs and the patient was successfully treated with a combination of injectable and oral anti-tuberculosis agents. We discuss the importance of a regimen with injectable drugs for treating severe forms of tuberculosis in which the intestinal involvement impaired the use of oral drugs.

Prone positioning to improve oxygenation and relieve respiratory symptoms in awake, spontaneously breathing non-intubated patients with COVID-19 pneumonia.

Emergency departments are facing an unprecedented challenge in dealing with patients who have coronavirus disease 2019 (COVID-19). The massive number of cases evolving to respiratory failure are leading to a rapid depletion of medical resources such as respiratory support equipment, which is more critical in low- and middle-income countries. In this context, any therapeutic and oxygenation support strategy that conserves medical resources should be welcomed. Prone positioning is a well-known ventilatory support strategy to improve oxygenation levels. Self-proning can be used in the management of selected patients with COVID-19 pneumonia. Here, we describe our experience with two COVID-19-positive patients who were admitted with respiratory failure. The patients were successfully managed with self-proning and noninvasive oxygenation without the need for intubation.

Disseminated Mycobacterium avium on HIV/AIDS: Historical and Current Literature Review.

Combination antiretroviral therapy (cART) has changed Mycobacterium avium epidemiology. A significant decrease in the incidence of disseminated M. avium complex: (DMAC) infection was observed between pre-cART and post-cART periods. In contrast, diagnoses of DMAC more than doubled from 1990 to 1996. During this time, DMAC prevalence in people living with AIDS (PLHA) in developed countries reached 20-23% overall and >40% in groups with CD4 cell counts <10 cells/mm3. At present, DMAC in PLHA has an incidence of two events per 1000 patient years. Recently, the centers for disease control changed the criteria for MAC primary prophylaxis, where only patients without immediate cART and CD4 cell counts <50 cells/mm3 are prescribed 1200 mg of azithromycin weekly. Treatment is discontinued when patients initiate effective cART. Diagnosing a disseminated M. avium infection is difficult due to the low accuracy of fluid cultures and a lack of diagnostic processes. However, the usefulness of newer molecular techniques such as whole-genome sequencing has not been evaluated for DMAC and HIV/AIDS. As DMAC has a high mortality rate if not properly diagnosed and treated, we performed a literature review of HIV/AIDS and DMAC epidemiology, risk factors, prophylaxis, clinical manifestation, diagnosis, prognosis, and treatment.

Detection of Wild-type Yellow Fever Virus in Breast Milk.

Yellow fever is an endemic disease in tropical areas in America and Africa. We report a case where the wild-type yellow fever virus was detected in a breast milk sample of a 33-year-old woman, from a rural area in the municipality of São Paulo, thus highlighting a potential risk for transmission of yellow fever virus through breast-feeding.

Efficacy of sofosbuvir as treatment for yellow fever: protocol for a randomised controlled trial in Brazil (SOFFA study).

INTRODUCTION: An ongoing outbreak of yellow fever (YF) has been reported in Brazil with 1261 confirmed cases and 409 deaths since July 2017. To date, there is no specific treatment available for YF. Recently published papers describing in vitro and animal models suggest a potential effect of antiviral drugs (approved for the treatment of hepatitis virus) against flaviviruses, including YF. The primary aim of this study is to analyse the effect of sofosbuvir on viral kinetics and clinical outcomes among patients presenting with YF. This is a multicentre open-label randomised controlled trial with 1:1 individual allocation, stratified by severity and by recruiting centre. METHODS AND ANALYSIS: Adults with suspected or confirmed YF infection and symptoms lasting up to 15 days are screened. Eligible and consenting patients are randomised to receive oral sofosbuvir 400 mg daily for 10 days or to receive standard clinical care. Viral kinetics are measured daily and the reduction in YF plasma viral load from the sample at inclusion to 72 hours after randomisation will be compared between active and control groups. Clinical outcomes include severity meeting criteria for intensive care support, liver transplantation, in-hospital mortality and mortality within 60 days. ETHICS AND DISSEMINATION: Ethics approval was obtained at the participating sites and at the national research ethics committee (CAAE 82673018.6.1001.0068). The trial has been submitted for ethical approval at additional potential recruiting centres. Results of the study will be published in journals and presented at scientific meetings. TRIAL REGISTRATION: Brazilian Clinical Trials Registry (RBR-93dp9n).

Severe Yellow Fever and Extreme Hyperferritinemia Managed with Therapeutic Plasma Exchange.

A 43-year-old man was admitted to the intensive care unit and diagnosed with yellow fever. He presented with refractory bleeding, extreme hyperferritinemia, and multiple organ dysfunction syndrome, requiring renal replacement therapy, mechanical ventilation, and treatment with vasoactive drugs. Because the bleeding did not respond to fresh-frozen plasma administration, the patient received therapeutic plasma exchange, which was accompanied by a marked improvement of the clinical and biochemical parameters, including a significant decline in serum ferritin levels.

Yellow Fever: Factors Associated with Death in a Hospital of Reference in Infectious Diseases, São Paulo, Brazil, 2018.

Faced with the reemergence of yellow fever (YF) in the metropolitan region of São Paulo, Brazil, we developed a retrospective study to describe the cases of YF attended at the Institute of Infectology Emilio Ribas from January to March 2018 and analyze the factors associated with death, from the information obtained in the hospital epidemiological investigation. A total of 72 cases of sylvatic YF were confirmed, with 21 deaths (29.2% lethality rate). Cases were concentrated in males (80.6%) and in the age group of 30 to 59 years (56.9%). Two logistic regression models were performed, with continuous variables adjusted for the time between onset of symptoms and hospitalization. The first model indicated age (odds ratiosadjusted [ORadj]: 1.038; CI 95%: 1.008-1.212), aspartate aminotransferase (AST) (ORadj: 1.038; CI 95%: 1.005-1.072), and creatinine (ORadj: 2.343; CI 95%: 1.205-4.553) were independent factors associated with mortality. The second model indicated age (ORadj: 1.136; CI 95%: 1.013-1.275), alanine aminotransferase (ALT) (ORadj: 1.118; CI 95%: 1.018-1.228), and creatinine (ORadj: 2.835; CI 95%: 1.352-5,941). The risk of death in the model with continuous variables was calculated from the increase of 1 year (age), 1 mg/dL (creatinine), and 100 U/L for AST and ALT. Another logistic regression analysis with dichotomous variables indicated AST > 1,841 IU/L (ORadj: 12.92; CI 95%: 1.50-111.37) and creatinine > 1.2 mg/dL (ORadj: 81.47; CI 95%: 11.33-585.71) as independent factors associated with death. These results may contribute to the appropriate clinical management of patients with YF in health-care services and improve the response to outbreaks and public health emergencies.

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.

Lomentospora prolificans fungemia in hematopoietic stem cell transplant patients: First report in South America and literature review.

Lomentospora prolificans is a filamentous fungus and an emerging pathogen in immunocompromised patients. It is encountered most commonly in Australia, Spain, and USA. We described the first case of Lomentospora prolificans fungemia in South America. The patient was a hematopoietic stem cell transplantation (HSCT) recipient who developed the infection 37 days after stem cells infusion. In addition, we performed a literature review of invasive lomentosporiosis in HSCT patients.