A tromboelastometria identifica coagulopatia associada à insuficiência hepática e coagulação intravascular disseminada causadas por febre amarela, orientando a terapia hemostática específica: um relato de caso / Thromboelastometry identifies coagulopathy associated with liver failure and disseminated intravascular coagulation caused by yellow fever, guiding specific hemostatic therapy: a case report

RESUMO Este relato de caso detalha um caso grave de febre amarela complicada por insuficiência hepática e coagulação intravascular disseminada. A tromboelastometria foi capaz de identificar os distúrbios da coagulação e orientar o tratamento hemostático. Relatamos o caso de um homem com 23 anos de idade admitido na unidade de terapia intensiva com quadro com início abrupto de febre e dor muscular generalizada associados a insuficiência hepática e coagulação intravascular disseminada. Os resultados dos exames laboratoriais convencionais revelaram trombocitopenia, enquanto a tromboelastometria sugeriu coagulopatia com discreta hipofibrinogenemia, consumo de fatores de coagulação e, consequentemente, aumento do risco de sangramento. Diferentemente dos exames laboratoriais convencionais, a tromboelastometria identificou o distúrbio de coagulação específico e, assim, orientou o tratamento hemostático. Administraram-se concentrados de fibrinogênio e vitamina K, não sendo necessária a transfusão de qualquer componente do sangue, mesmo na presença de trombocitopenia. A tromboelastometria permitiu a identificação precoce da coagulopatia e ajudou a orientar a terapêutica hemostática. A administração de fármacos hemostáticos, incluindo concentrados de fibrinogênio e vitamina K, melhorou os parâmetros tromboelastométricos, com correção do transtorno da coagulação. Não se realizou transfusão de hemocomponentes, e não ocorreu qualquer sangramento.

Abstract This case report a severe case of yellow fever complicated by liver failure and disseminated intravascular coagulation. Thromboelastometry was capable of identifying clotting disorders and guiding hemostatic therapy. We report the case of a 23-year-old male admitted to the Intensive Care Unit with sudden onset of fever, generalized muscle pain associated with liver failure, and disseminated intravascular coagulation. The results of conventional laboratory tests showed thrombocytopenia, whereas thromboelastometry suggested coagulopathy with slight hypofibrinogenemia, clotting factor consumption, and, consequently, an increased risk of bleeding. Unlike conventional laboratory tests, thromboelastometry identified the specific coagulation disorder and thereby guided hemostatic therapy. Both fibrinogen concentrates and vitamin K were administered, and no blood component transfusion was required, even in the presence of thrombocytopenia. Administration of hemostatic drugs, including fibrinogen concentrate and vitamin K, improved thromboelastometric parameters, correcting the complex coagulation disorder. Blood component transfusion was not performed, and there was no bleeding.

Late-Relapsing Hepatitis after Yellow Fever.

One patient presented hyporexia, asthenia, adynamia, and jaundice two months after acute yellow fever (YF) onset; plus laboratory tests indicating hepatic cytolysis and a rebound of alanine and aspartate transaminases, and total and direct bilirubin levels. Laboratory tests discarded autoimmune hepatitis, inflammatory or metabolic liver disease, and new infections caused by hepatotropic agents. Anti-YFV IgM, IgG and neutralizing antibodies were detected in different times, but no viremia. A liver biopsy was collected three months after YF onset and tested positive for YFV antigens and wild-type YFV-RNA (364 RNA-copies/gram/liver). Transaminases and bilirubin levels remained elevated for five months, and the arresting of symptoms persisted for six months after the acute YF onset. Several serum chemokines, cytokines, and growth factors were measured. A similar immune response profile was observed in the earlier phases of the disease, followed by more pronounced changes in the later stages, when transaminases levels returned to normal. The results indicated viral persistence in the liver and continual liver cell damage three months after YF onset and reinforced the need for extended follow-ups of YF patients. Further studies to investigate the role of possible viral persistence and the immune response causing relapsing hepatitis following YF are also necessary.

Hepatitis Relapse after Yellow Fever Infection: Is There Another Wave?

Abstract During the yellow fever (YF) outbreak in Brazil, many cases of fulminant hepatitis were seen, although mild to moderate hepatitis was mostly observed with complete recovery. This report presents a case of late-onset hepatitis due to YF relapse. The patient sought medical attention after jaundice recurrence 40 days after the first YF hepatitis episode. This case highlights the importance of patient follow-up after the complete resolution of YF symptoms and discharge.

Canine visceral leishmaniasis in area with recent Leishmania transmission: prevalence, diagnosis, and molecular identification of the infecting species

Abstract INTRODUCTION: Canine visceral leishmaniasis (CVL) is an endemic disease in Brazil, and integrated control actions have been adopted by the Brazilian Ministry of Health to control its spread. However, the transmission profile is unknown in areas with recent CVL cases, including Itaúna, located in the Brazilian state of Minas Gerais, where the present study was carried out. METHODS: A total of 2,302 dogs from 12 neighborhoods were serologically tested for canine VL using the current diagnostic protocol adopted by the Brazilian Ministry of Health. Test positivity rate (TPR) and CVL prevalence were determined for each neighborhood. The presence of Leishmania was assessed in 60 seropositive dogs which had been recommended for euthanasia. Twenty-two of them (37%) were asymptomatic, and 38 (63%) were symptomatic for CVL. Parasitological (myeloculture and smear/imprint) and molecular (PCR) methods were employed for Leishmania detection in bone marrow, spleen, mesenteric lymph nodes, and ear skin. The infecting Leishmania species was identified by DNA sequencing. RESULTS: CVL prevalence (per 1,000 dogs) varied from 0.0-166.67, depending on the neighborhood, with a mean of 68.96 (SD 51.38). Leishmania DNA was detected in at least one tissue from all seropositive dogs, with comparable TPR among tissues. Leishmania parasites were identified in most (54/60) seropositive dogs, and the infecting parasite was identified as Leishmania infantum in all of these. CONCLUSIONS: Prevalence of CVL is a contributor to the spread of visceral leishmaniasis in Itaúna.

Sofosbuvir inhibits yellow fever virus in vitro and in patients with acute liver failure.

INTRODUCTION AND OBJECTIVES: Direct antiviral agents (DAAs) are very efficient in inhibiting hepatitis C virus and might be used to treat infections caused by other flaviviruses whose worldwide detection has recently increased. The aim of this study was to verify the efficacy of DAAs in inhibiting yellow fever virus (YFV) by using drug repositioning (a methodology applied in the pharmaceutical industry to identify new uses for approved drugs). MATERIALS AND METHODS: Three DAAs were evaluated: daclatasvir, sofosbuvir and ledipasvir or their combinations. For in vitro assays, the drugs were diluted in 100% dimethyl sulfoxide. Vaccine strain 17D and a 17D strain expressing the reporter fluorescent protein were used in the assays. A fast and reliable cell-based screening assay using Vero cells or Huh-7 cells (a hepatocyte-derived carcinoma ell line) was carried out. Two patients who acquired yellow fever virus with acute liver failure were treated with sofosbuvir for one week as a compassionate use. RESULTS: Using a high-content screening assay, we verified that sofosbuvir presented the best antiviral activity against YFV. Moreover, after an off-label treatment with sofosbuvir, the two female patients diagnosed with yellow fever infection displayed a reduction in blood viremia and an improvement in the course of the disease, which was observed in the laboratory medical parameters related to disease evolution. CONCLUSIONS: Sofosbuvir may be used as an option for treatment against YFV until other drugs are identified and approved for human use. These results offer insights into the role of nonstructural protein 5 (NS5) in YFV inhibition and suggest that nonstructural proteins may be explored as drug targets for YFV treatment.

Liver Transplantation for Acute Liver Failure due to Yellow Fever: A Case Report.

Yellow fever is a noncontagious disease caused by an arbovirus in the Flaviviridae family. It is an endemic disease in the tropical forests of Africa and South America, with the mosquito as a vector. Approximately half of those infected will be asymptomatic, while 15% will develop the severe/malignant form of the disease that includes renal and hepatic failure, bleeding, and neurological impairment as the principal symptoms. The lethality of the severe form reaches up to 70%. The objective of this study was to report on the case of a patient who was transferred to the hepatobiliary unit of our service due to acute liver failure due to yellow fever. He was treated with liver transplantation. The patient progressed satisfactorily, being discharged from the intensive care unit in 10 days and discharged from the hospital within 19 days after transplantation. Despite the encouraging result of our team, this has not been applied to other centers that have also performed this modality of treatment; therefore, the question remains as to whether and when to recommend liver transplantation for treatment of severe yellow fever.

Disseminated mycosis in a patient with yellow fever

Disseminated mycosis (DM)­with cardiac involvement and shock­is an unexpected and severe opportunistic infection in patients with yellow fever. DM can mimic bacterial sepsis and should be considered in the differential diagnosis of causes of systemic inflammatory response syndrome in this group of patients, especially in areas where an outbreak of yellow fever is ongoing. We report the case of a 53-year-old male patient who presented to the emergency department with fever, myalgia, headache, and low back pain. The laboratory investigation revealed a positive molecular test for yellow fever, hepatic injury, and renal failure. During hospitalization, the patient developed hepatic encephalopathy, ascending leukocytosis, and ascites, with signs consistent with peritonitis. On the 11th day of hospitalization, the patient developed atrioventricular block, shock and died. At autopsy, angioinvasive mycosis was evidenced mainly in the heart, lungs, kidneys, and adrenals.

Fiebre amarilla / Yellow fever

La fiebre amarilla representa a una de las fiebres hemorrágicas que adquieren en Venezuela y a una de las cuatro arbovirosis endémicas que tenemos. Revisando la literatura médica nacional e internacional, se actualizan aspectos relevantes de esta endemia rural. Se mencionan en la etiología las características del agente viral, que tiene ARN como componente primordial de su genoma. En la epidemiología, se menciona su prevalencia en el continente americano y africano y se evalúa su modo de transmisión. En la patogenia y la anatomía patológica se describe al hígado como órgano blanco de la infección. Se destacan en las manifestaciones clínicas los trastornos hemorrágicos y de la coagulación sanguínea. El diagnóstico como en Medicina Tropical, corresponde a un diagnóstico integral: la clínica, en primer lugar, asociada a la epidemiología y a la etiología de la enfermedad. Se establece diagnóstico diferencial con otras entidades relacionadas. El tratamiento es de soporte y en terapia intensiva. Se concluye con la profilaxis, evaluando la utilidad que sigue teniendo la vacunación.

The yelow fever represents one of the hemorrhagic fever that can be acquired in Venezuela and one of the four endemic arbovirosis we have. By reviewing the national and international medical literature. Relevant aspects of this endemic rural disease have been updated. In the etiology, several characterictics of the virus are mentioned; including the RNA as a primordial component of its genome. In the epidemiology, its prevalence on the African and American continents is mentioned, and the transmission mode es evaluated. In the pathogenesis and pathological anatomy, the liver is described as the primary organ of infection. Bleeding and blood clotting disorders are the essential clinical manifestations. Like in Tropical Medicina, The corresponding integral diagnosis is required. In the first instance, the clinical aspects, associated to the epidemiology and to the etiology of the disease are analyzed a diffential diagnosis is made with other related entities. The treatment consists of support measures and Intensive Care in the Intensive Care Unit (ICU). For the prophylaxis, we discuss the advantages of vaccination.

Hepatopatias fulminantes/febres hemorrágicas na Amazônia: revisão histórica, padrões de lesão hepática e diagnóstico etiológico / Fulminant hepatic failure/hemorrhagic fevers in Amazon Basin: historical review, hepatic damage patterns and etiological diagnosis

Esta análise morfológica e imuno-histoquímica de hepatopatias fulminantes da Amazônia incluindo a série histórica original de Hepatite de Lábrea (HL) e casos de Febre Amarela (FA) concentrou-se em padrões de lesão . Mostraram-se características da FA: morte celular por apoptose medio-zonal, balonização hepatocelular, elevado índice de proliferação celular avaliado pelo PCNA e flebite portal. Os casos de HL mostraram extensa necrose hepatocelular lítica, células “em mórula”, regeneração hepatocelular com multinucleações e transformação pseudo-acinar, flebite portal e centro-lobular, com extinção parenquimatosa, depósitos portais de fibras elásticas e colágeno tipo I e depósitos lobulares de colágeno III / This morphologic and immunohistochemical analysis of fulminant hepatic failure from Amazon Basin, including the original historical series of Labrea Hepatitis (LH) and of Yellow fever (YF) cases was concentrated on lesion patterns. Midzonal apoptotic cellular death, hepatocellular ballooning degeneration, high cellular proliferation index assessed by PCNA and portal phlebitis were shown to be characteristics of YF. LH cases showed extensive lytic hepatocellular necrosis, “morula cells”, hepatocellular regeneration with multinucleation and pseudo-acinar transformation, portal and hepatic vein phlebitis, with parenchymal extinction, portal elastic fibers and type I collagen fibers and lobular type III collagen fiber deposition...

Adiaspiromicose pulmonar: achado casual em paciente falecido de febre amarela / Pulmonary adiaspiromycosis: casual finding in a patient who died of yellow fever

During an outbreak of yellow fever (rural form of the infection) occurred recently in the State of Goiás, Brazil, a patient, with clinical manifestations suggestive of the infection, died in the University Hospital of Brasilia, DF, on the fifth day from admission. Postmortem examination revealed, microscopically, the characteristic alterations of the infection, and discovered in the lungs and hilar lymph nodes round microrganisms identified as adiaconidia of Emmonsia parva var. crescens.

Durante um surto de febre amarela (forma rural da infecção) instalado, em fins de 1999, no Estado de Goiás, Brasil, um enfermo, com sintomatologia suspeita, faleceu no Hospital Universitário de Brasília, DF, cinco dias após a admissão. À necropsia, microscopicamente, além das alterações hepáticas características da infecção, encontraram-se nos pulmões e linfonodos hilares, estruturas arredondadas, reconhecidas como adiaconídios de Emmonsia parva var. crescens.

Mechanisms of dengue virus-induced bone marrow suppression.

Infection with many flaviviruses is associated with transient suppression of haematopoiesis. Of the flaviviruses of man, none are more accessible to clinical and laboratory study than dengue. Consequently, the clinical syndrome of dengue-associated bone marrow suppression has been well documented. A review of experimental dengue infections of volunteers and histopathological studies of bone marrow from patients with severe dengue virus infection suggests that marrow suppression evolves rapidly through several phases: (1) onset of marrow suppression within 3-4 days of infection; (2) onset of host inflammatory responses in the marrow and of fever shortly thereafter; (3) occurrence of a neutrophil nadir on the fourth to fifth day after onset of fever; (4) almost simultaneously, immune activation sufficient to neutralize viraemia and accelerate elimination of infected cells; (5) remission of symptoms; and (6) resolution of cytopenias. Clinical observations and experimental data bear on possible mechanisms of dengue virus-mediated marrow suppression. Work from the authors' laboratory in which long-term bone marrow cultures were used to investigate interactions between dengue virus and bone marrow cells (stromal elements and haematopoietic progenitors) is also reviewed. Long-term marrow culture (LTMC) was a useful experimental system. In vitro, early blast cells as well as the more differentiated haematopoietic elements were abortively infected, killed and eliminated by phagocytosis by specialized marrow macrophages called dendritic cells. Moreover, the ARC from stroma rather than haematopoietic precursors were productively infected. When ARC were infected, stroma failed to support haematopoiesis. Cytokine production by virus-infected stromal cells was altered. A hypothesis is proposed to account for dengue virus-induced marrow suppression. Down-regulation of haematopoiesis is probably a protective mechanism of the microenvironment that limits injury to the marrow stem/progenitor cell compartment during the subsequent process of elimination of infected cells.

Vacunación en la fiebre amarilla / Vaccination in the yellow fever

Actualmente, la vacuna contra la fiebre amarilla es preparada exclusivamente con la cepa 17D del virus atenuado. Esta vacuna tiene un excelente registro de inocuidad y su poder inmunogénico es elevado. En el pasado se utilizó ampliamente en Africa la cepa "French neurotropic", desarrollada por el Instituto Pasteur de Dakar, a través de múltiples pases en cerebro de ratón. Entre 1940 y 1960 se aplicaron más de 80 millones de dosis por medio de escarificación; sin embargo, se comprobó que la vacuna ocasionaba encefalitis en una proporción pequeña, pero importante, de niños menores de 12 años. Esto dió por resultado que al inicio de la década de los 80 se interrumpiera su producción. Producción mundial de la vacuna: una encuesta realizada en la década de los años ochenta indicó que la producción mundial de la vacuna contra la fiebre amarilla se acercaba a los 19 millones de dosis por año, de las cuales aproximadamente 12 millones fueron producidas por la Fundación Oswaldo Cruz, Brasil. También se estimó que la reserva mundial de la vacuna era de 4.5 millones de dosis, cantidad considerada insuficiente para combatir epidemias extensas, o prevenir la propagación de las mismas a otras áreas. Actualmente hay once laboratorios aprobados por la OMS para la producción de vacunas contra la fiebre amarilla, dos de los cuales están situados en países del Continente Americano

[The other types of viral hepatitis]. / Les autres hépatites à virus.

Hepatitis due to viruses other than A, B, C, D, E are numerous but uncommon in adults. Among the group of Herpesviridae (HSV, CMV, EBV, VZV), clinical hepatitis is usually suggestive of disseminated viral infection. Fulminant hepatitis occasionally observed in immunocompromised hosts are due to HSV, and VZV, but exceptionally to EBV. Many new techniques using specific monoclonal antibodies permit an accurate and fast diagnosis. Three drugs (vidarabine, acyclovir, ribavirine) have been shown to be efficient in the treatment of severe forms of the disease. Hepatitis due to exotic viruses (Amaril, Ebola, Lassa) are exceptional in France, but require specific prophylactic measures.

Fulminant hepatitis: a clinical review of 11 years

Vinte e quatro casos de hepatite fulminante (HF), internados na Clínica de Doenças Infecciosas e Parasitárias do Hospital das Clínicas da Faculdade de Medicina da Universidade de Säo Paulo durante o período de janeiro de 1976 a dezembro de 1986, foram revistos para a obtençäo de dados clínicos, epidemiológicos e laboratoriais. 88% dos pacientes morreram. Vinte (83%) dos pacientes apresentaram hemorragias, dentre os quais 19 morreram (95%). Infecçöes bacterianas secundárias ocorreram em 14 pacientes (58%) todos os quais faleceram. Ascite foi notada em 3 casos e edema cerebral em 16 casos. Os valores máximos de ALT obtidos para cada paciente durante a internaçäo variaram de 81 a 40460 UI/l. Treze pacientes tiveram elevaçäo de creatinina (54%). A atividade do tempo de protrombina variou de 2,1% a 67%. A febre esteve presente em 20 casos (83%). A encefalopatia surgiu durante as 2 primeiras semanas de doenças em 72% dos casos. Em 7 casos havia doenças associadas à hepatite. A etiologia näo pode ser determinada em 13 casos; 3 casos foram por febre amarela; e 6 casos por outros vírus. Em 1 caso a causa foi drogas e em um caso, possivelmente, foi álcool. Os autores acreditam que a definiçäo de HF merece discussäo antes de ser totalmente aceita. Neste estudo, a HF foi uma doença que acometeu principalmente jovens. A letadade encontrada foi semelhante a de outros estudos. Fatores que contribuiram para o óbito foram hemorragias e infecçöes bacterianas secundárias. Fatores de piora do prognóstico de hepatite foram a presença de outras doenças associadas e de procedimento cirurgico. Os níveis de ALT durante a internaçäo näo refletiram a gravidade da hepatite. Os autores acreditam que a febre amarela deve ser considerada um agente etiológico de HF quando o seu quadro clínico seja compatível com tal, embora os mecanismos fisiopatológicos da encefalopatia sejam ainda obscuros. Os dados clínicos dos 3 casos de febre amarela säo apresentados à parte