Activation of an Effective Immune Response after Yellow Fever Vaccination Is Associated with the Genetic Background and Early Response of IFN-γ and CLEC5A.

The yellow fever vaccine (YF17DD) is highly effective with a single injection conferring protection for at least 10 years. The YF17DD induces polyvalent responses, with a TH1/TH2 CD4+ profile, robust T CD8+ responses, and synthesis of interferon-gamma (IFN-γ), culminating in high titers of neutralizing antibodies. Furthermore, C-type lectin domain containing 5A (CLEC5A) has been implicated in innate outcomes in other flaviviral infections. Here, we conducted a follow-up study in volunteers immunized with YF17DD, investigating the humoral response, cellular phenotypes, gene expression, and single nucleotide polymorphisms (SNPs) of IFNG and CLEC5A, to clarify the role of these factors in early response after vaccination. Activation of CLEC5A+ monocytes occurred five days after vaccination (DAV). Following, seven DAV data showed activation of CD4+ and CD8+T cells together with early positive correlations between type II IFN and genes of innate antiviral response (STAT1, STAT2, IRF7, IRF9, OAS1, and RNASEL) as well as antibody levels. Furthermore, individuals with genotypes rs2430561 AT/AA, rs2069718 AG/AA (IFNG), and rs13237944 AC/AA (CLEC5A), exhibited higher expression of IFNG and CLEC5A, respectively. Together, we demonstrated that early IFN-γ and CLEC5A responses, associated with rs2430561, rs2069718, and rs13237944 genotypes, may be key mechanisms in the long-lasting immunity elicited by YF17DD.

Yellow fever disease in a renal transplant recipient: Case report and literature review.

Yellow fever (YF) is a viral disease, with clinical presentation among immunosuppressed patients not fully understood. YF vaccination (YFV), a live vaccine, is contraindicated in patients receiving immunosuppressive treatment due to the risk of developing the disease after vaccination. We report a case of a 50-year-old male recipient who presented wild-type YF five years after a deceased donor kidney transplant. He lived in a YF endemic area and inadvertently received YFV. One day after YFV, the patient presented nausea, vomiting, fever, diarrhea, polyarthralgia, thrombocytopenia, and increased levels of liver function enzymes. The serological test was compatible with YF disease, and quantitative viral load confirmed the diagnosis of wild-type YF. The patient received supportive care for twelve days, with hospital discharge in good clinical condition and stable renal function. One month after discharge, the patient developed de novo donor-specific anti-HLA antibodies (DSA) and histological evidence of endothelial lesion, with a diagnosis of acute antibody-mediated rejection (AMR), treated with plasmapheresis and human IVIg therapy. Six months after therapy, he presented normal renal function with a reduction of DSA MFI. In the reported case, we observed a clinical wild-type YF diagnosed even after YF vaccine administration, with good clinical outcome. De novo DSA and AMR occurred after the recovering of disease, with an adequate response to therapy and preserved allograft function. We reviewed the published literature on YF and YFV in solid organ transplantation.

Metabolic perturbations and cellular stress underpin susceptibility to symptomatic live-attenuated yellow fever infection.

Flaviviral infections result in a wide spectrum of clinical outcomes, ranging from asymptomatic infection to severe disease. Although the correlates of severe disease have been explored1-4, the pathophysiology that differentiates symptomatic from asymptomatic infection remains undefined. To understand the molecular underpinnings of symptomatic infection, the blood transcriptomic and metabolomic profiles of individuals were examined before and after inoculation with the live yellow fever viral vaccine (YF17D). It was found that individuals with adaptive endoplasmic reticulum (ER) stress and reduced tricarboxylic acid cycle activity at baseline showed increased susceptibility to symptomatic outcome. YF17D infection in these individuals induced maladaptive ER stress, triggering downstream proinflammatory responses that correlated with symptomatic outcome. The findings of the present study thus suggest that the ER stress response and immunometabolism underpin symptomatic yellow fever and possibly even other flaviviral infections. Modulating either ER stress or metabolism could be exploited for prophylaxis against symptomatic flaviviral infection outcome.

Transplante de fígado para insuficiência hepática hiperaguda relacionada à febre amarela / Liver transplant for yellow fever-related hyperacute liver failure

APRESENTAÇÃO: Algumas propostas de incorporação tecnológica no SUS são avaliadas pela CONITEC de forma simplificada, não sendo submetidas à consulta pública e/ou audiência pública. São propostas de relevante interesse público que tratam de ampliação de uso de tecnologias, nova apresentação de medicamentos ou incorporação de medicamentos com tradicionalidade de uso. Todas essas demandas envolvem tecnologias de baixo custo e baixo impacto orçamentário para o SUS e estão relacionadas à elaboração ou revisão de Protocolos Clínicos e Diretrizes Terapêuticas (PCDT). SOLICITAÇÃO DE INCORPORAÇÃO: Demandante: Secretaria de Atenção à Saúde ­ SAS. Demanda: incorporação do Transplante de Fígado para Insuficiência Hepática Hiperaguda relacionada à Febre Amarela. TRANSPLANTE DE FÍGADO: O transplante de fígado é um tipo de tratamento proposto para doenças que afetam o sistema hepatobiliar. Consiste na substituição do fígado doente por um enxerto saudável de um doador falecido, ou parte do fígado de um doador vivo. É o tratamento de escolha para um grupo de pacientes com doenças hepáticas ou biliares, para as quais as demais alternativas terapêuticas foram esgotadas e cujo uso tem potencial curativo ou de importante repercussão na qualidade de vida dos doentes. Esses transplantes estão indicados em casos de doenças hepáticas (como cirrose descompensada, polineuropatia amiloidótica familiar e câncer primário do fígado) ou biliares (como cirrose biliar primária ou secundária e atresia de vias biliares) e ainda em casos de algumas doenças metabólicas capazes de alterar gravemente a função hepatobiliar (como doença de Wilson, hemocromatose e deficiência de alfa-1-antitripsina). TRANSPLANTE DE FÍGADO EM FEBRE AMARELA: A partir do final do ano de 2017, a Coordenação-Geral do Sistema Nacional de Transplantes - CGSNT passou a observar um aumento relevante do número de inscrições em lista de espera por Insuficiência Hepática Hiperaguda - IHH. Simultaneamente, o diagnóstico de Febre Amarela ­ FA passou a ser relacionado a esse súbito crescimento, seguido da confirmação clínica e laboratorial dos casos de IHH diretamente provocados pelo agravamento da infecção pelo vírus da FA, notadamente nos mesmos estados brasileiros considerados regiões de surto epidêmico de Febre Amarela, quais sejam: Minas Gerais, Rio de Janeiro e São Paulo. Todos esses estados registraram casos de FA por meio dos sistemas de vigilância em saúde. CONSIDERAÇÕES FINAIS: De acordo com a Nota Informativa constante no processo 25000.042688/2018-63, a presente proposta de incorporação tem o objetivo de admitir temporariamente a indicação de transplante de fígado para casos de IHHFA dados os benefícios potenciais deste tratamento no restabelecimento da função hepática, a justificar sua realização de forma compassiva neste momento, e as ações para prover o estudo destes casos, com a criação do Grupo Técnico e dos procedimentos de Transplante de Fígado em Febre Amarela e Tratamento de Intercorrência em Transplante de Fígado por FA - Pós-transplante Crítico. Ressalte-se que a repercussão da insuficiência hepática no acometimento sistêmico da Febre Amarela não está bem estabelecida, e será um dos objetos do estudo multicêntrico proposto à tentativa de resposta a esta questão. Estima-se que, excluídas as contraindicações e os casos de êxito letal em lista, sejam realizados cerca de 48 (quarenta e oito) transplantes de fígado em IHHFA por ano, considerando a sazonalidade dos surtos de Febre Amarela (dezembro a maio). RECOMENDAÇÃO DA CONITEC: Os membros da CONITEC, presentes na 64ª reunião ordinária, realizada nos dias 07 e 08 de março de 2018, deliberaram, por unanimidade, recomendar a incorporação do Transplante de fígado para Insuficiência Hepática Hiperaguda ­ IHH relacionada à Febre Amarela ­ FA. Desse modo, foi assinado o Registro de Deliberação nº 346/2018. DECISÃO: PORTARIA Nº 23, DE 23 DE ABRIL DE 2019 Torna pública a decisão de incorporar o transplante de fígado para insuficiência hepática hiperaguda-IHH relacionada à febre amarela - FA, no âmbito do Sistema Único de Saúde - SUS.

Febre Amarela / Yellow Fever

A Febre Amarela é uma doença infecciosa aguda, caracterizada por febre. Não é transmissível e tem duração de no máximo 12 dias. As manifestações clínicas revelam as fases evolutivas da doença. Este trabalho consiste em um artigo de atualização, no qual foi realizado um estudo bibliográfico interpretativo e descritivo baseado na literatura atual sobre a Febre Amarela no Brasil. Esta doença é causada por um arbovírus que pertence à família Flaviviridae. A expansão da área de vacinação é muito discutida atualmente. Segundo o Ministério da Saúde, em 2016, foram confirmados seis casos de Febre Amarela no Brasil. Conforme a Sociedade Brasileira de Infectologia, a fisiopatologia desta doença é a mesma no ciclo urbano e no silvestre. O seu diagnóstico pode ser dividido em clínico e laboratorial, pois são as duas formas de confirmar a doença em indivíduos. As medidas preventivas consistem, principalmente, na imunização, medidas de proteção e no controle do vetor. Esta pesquisa fornece dados atuais em bases confiáveis, podendo ser utilizada para futuros trabalhos.

Yellow Fever is an acute infectious disease, characterized by fever. It is not transferable and lasts for a maximum of 12 days. The clinical manifestations reveal the evolutionary phases of the disease. This work consists of an update article, where an interpretative and descriptive bibliographic study was carried out based on the current literature on Yellow Fever in Brazil. This disease is caused by an arbovirus belonging to the family Flaviviridae. The expansion of the vaccination area is much discussed today. According to the Ministry of Health, in 2016, six cases of yellow fever were confirmed in Brazil. According to the Brazilian Society of Infectology, the pathophysiology of Yellow Fever is the same in the urban and wild cycle. The diagnosis of yellow fever can be divided into clinical and laboratory, as they are the two ways to confirm the disease in individuals. Preventive measures consist mainly of immunization, protective measures and vector control. This research provides current data on a reliable basis and can be used for future work

[Health risk zoning: yellow fever from a geographical perspective in La Macarena, Department of Meta, Colombia]. / La zonificación del riesgo en salud: la fiebre amarilla desde una perspectiva geográfica en La Macarena, departamento del Meta, Colombia.

This paper attempts to zone yellow fever risk in La Macarena (department of Meta, Colombia) in terms of environmental hazards and socio-economic vulnerabilities. An ecological study was carried out, in which data published from 2007 to 2013 on conditions of the municipality were integrated into a geographic information system. Through a superposition of map layers, magnitudes of hazard and vulnerability proportional to the degree of severity were obtained. As a result the spatial heterogeneity of the risk of yellow fever was described, suggesting that the areas surrounding populated centers, roads and rivers present the highest probability of transmission. It is concluded that the cartographic representation of the spatial distribution of risk in the municipality constitutes a methodological contribution to health risk zoning - in concrete geographical areas and based on hazards and vulnerabilities - which facilitates decision-making in public health.

En este trabajo se zonifica el riesgo de fiebre amarilla en La Macarena (departamento del Meta, Colombia), en función de amenazas ambientales y vulnerabilidades socioeconómicas. Se realizó un estudio ecológico en el que se integraron, en un sistema de información geográfica, datos publicados entre 2007 y 2013 sobre las condiciones del municipio. A través de superposición de capas cartográficas se obtuvieron magnitudes de amenaza y vulnerabilidad proporcionales al grado de severidad. Como resultado se describe la heterogeneidad espacial del riesgo de fiebre amarilla, la cual sugiere que las áreas circundantes a centros poblados, vías y ríos presentan la mayor probabilidad de transmisión. Se concluye que la representación cartográfica de la distribución espacial del riesgo en el municipio constituye un aporte metodológico a la zonificación de riesgos en salud, en espacios geográficos concretos y en función de amenazas y vulnerabilidades, lo cual facilita la toma de decisiones en salud pública.

La zonificación del riesgo en salud: la fiebre amarilla desde una perspectiva geográfica en La Macarena, departamento del Meta, Colombia / Health risk zoning: yellow fever from a geographical perspective in La Macarena, Department of Meta, Colombia

RESUMEN En este trabajo se zonifica el riesgo de fiebre amarilla en La Macarena (departamento del Meta, Colombia), en función de amenazas ambientales y vulnerabilidades socioeconómicas. Se realizó un estudio ecológico en el que se integraron, en un sistema de información geográfica, datos publicados entre 2007 y 2013 sobre las condiciones del municipio. A través de superposición de capas cartográficas se obtuvieron magnitudes de amenaza y vulnerabilidad proporcionales al grado de severidad. Como resultado se describe la heterogeneidad espacial del riesgo de fiebre amarilla, la cual sugiere que las áreas circundantes a centros poblados, vías y ríos presentan la mayor probabilidad de transmisión. Se concluye que la representación cartográfica de la distribución espacial del riesgo en el municipio constituye un aporte metodológico a la zonificación de riesgos en salud, en espacios geográficos concretos y en función de amenazas y vulnerabilidades, lo cual facilita la toma de decisiones en salud pública.

ABSTRACT This paper attempts to zone yellow fever risk in La Macarena (department of Meta, Colombia) in terms of environmental hazards and socio-economic vulnerabilities. An ecological study was carried out, in which data published from 2007 to 2013 on conditions of the municipality were integrated into a geographic information system. Through a superposition of map layers, magnitudes of hazard and vulnerability proportional to the degree of severity were obtained. As a result the spatial heterogeneity of the risk of yellow fever was described, suggesting that the areas surrounding populated centers, roads and rivers present the highest probability of transmission. It is concluded that the cartographic representation of the spatial distribution of risk in the municipality constitutes a methodological contribution to health risk zoning - in concrete geographical areas and based on hazards and vulnerabilities - which facilitates decision-making in public health.

What Controls the Acute Viral Infection Following Yellow Fever Vaccination?

Does target cell depletion, innate immunity, or adaptive immunity play the dominant role in controlling primary acute viral infections? Why do some individuals have higher peak virus titers than others? Answering these questions is a basic problem in immunology and can be particularly difficult in humans due to limited data, heterogeneity in responses in different individuals, and limited ability for experimental manipulation. We address these questions for infections following vaccination with the live attenuated yellow fever virus (YFV-17D) by analyzing viral load data from 80 volunteers. Using a mixed effects modeling approach, we find that target cell depletion models do not fit the data as well as innate or adaptive immunity models. Examination of the fits of the innate and adaptive immunity models to the data allows us to select a minimal model that gives improved fits by widely used model selection criteria (AICc and BIC) and explains why it is hard to distinguish between the innate and adaptive immunity models. We then ask why some individuals have over 1000-fold higher virus titers than others and find that most of the variation arises from differences in the initial/maximum growth rate of the virus in different individuals.

[Severe Yellow fever vaccine-associated disease: a case report and current overview]. / Schwere Gelbfieber-impfassoziierte Erkrankung: ein Fallbericht und aktuelle Übersicht.

History and physical examination A 56-year-old man developed high fever with severe headaches, fatigue, impaired concentration skills, and an exanthema 5 days after a yellow fever (YF) vaccination. Laboratory tests Liver enzymes and YF antibody titers were remarkably elevated. YF vaccine virus was detected in urine by PCR. Diagnosis and therapy Initially, severe YF vaccine-associated visceral disease was suspected and treated symptomatically. Clinical Course His fever ceased after 10 days in total, no organ failure developed. However, postencephalitic symptoms persisted with fatigue and impaired concentration, memory, and reading skills and partly incapability to work for over 3 months. A diagnosis was made of suspected YF vaccine-associated neurotropic disease. Conclusion Severe vaccine-derived adverse effects need to be considered in the indication process for YF vaccination.

Reemergence of yellow fever in Ethiopia after 50 years, 2013: epidemiological and entomological investigations.

BACKGROUND: Yellow Fever (YF) is a viral hemorrhagic disease transmitted by aedes mosquito species. Approximately, 200,000 cases and 30,000 deaths occur worldwide every year. In Ethiopia, the last outbreak was reported in 1966 with 2200 cases and 450 deaths. A number of cases with deaths from unknown febrile illness reported from South Ari district starting from November 2012. This investigation was conducted to identify the causative agent, source of the outbreak and recommend appropriate interventions. METHODS: Medical records were reviewed and Patients and clinicians involved in managing the case were interviewed. Descriptive data analysis was done by time, person and place. Serum samples were collected for serological analysis it was done using Enzyme-linked Immunosorbent Assay for initial screening and confirmatory tests were done using Plaque Reduction and Neutralization Test. Breteau and container indices were used for the entomological investigation to determine the risk of epidemic. RESULTS: A total of 141 Suspected YF cases with 43 deaths (CFR = 30.5%) were reported from November 2012 to October 2013 from South Omo Zone. All age groups were affected (mean 27.5, Range 1-75 Years). Of the total cases, 85.1% cases had jaundice and 56.7% cases had fever. Seven of the 21 samples were IgM positive for YF virus. Aedes bromeliae and Aedes aegypti were identified as responsible vectors of YF in affected area. The Breteau indices of Arkisha and Aykamer Kebeles were 44.4% and 33.3%, whereas the container indices were 12.9% and 22.2%, respectively. CONCLUSION: The investigation revealed that YF outbreak was reemerged after 50 years in Ethiopia. Vaccination should be given for the affected and neighboring districts and Case based surveillance should be initiated to detect every case.

[Control discourses and power relations of yellow fever: Philadelphia in 1793].

1793 Yellow fever in Philadelphia was the most severe epidemics in the late 18th century in the United States. More than 10% of the population in the city died and many people fled to other cities. The cause of yellow fever in the United States had close relationship with slaves and sugar in Philadelphia. Sugarcane plantation had needed many labors to produce sugar and lots of Africans had to move to America as slaves. In this process, Aëdes aegypti, the vector of yellow fever had migrated to America and the circumstances of ships or cities provided appropriate conditions for its breeding. In this period, the cause of yellow fever could not be established exactly, so suggestions of doctors became entangled in political and intellectual discourses in American society. There was a critical conflict between Jeffersonian Republicanism and Federalism about the origin and treatment of yellow fever. Benjamin Rush, a Jeffersonian Republican, suggested urban sanitation reform and bloodletting. He believed the infectious disease happened because of unsanitary city condition, so he thought the United States could be a healthy nation by improvement of the public health and sanitation. He would like to cope with national crisis and develop American society on the basis of republicanism. While Rush suggested the improvement of public health and sanitation, the city government of Philadelphia suggested isolation of yellow fever patients and quarantine. City government isolated the patients from healthy people and it reconstructed space of hospital. Also, it built orphanages to take care of children who lost their parents during the epidemic and implemented power to control people put in the state of exception. Of course, city government tried to protect the city and nation by quarantine of every ship to Philadelphia. Control policies of yellow fever in 1793 showed different conflicts and interactions. Through the yellow fever, Jeffersonian Republicanism and Federalism had conflicted in politically, but they had interactions for control of the infectious disease. And with these kinds of infectious diseases policies, we can see interactions in local, national and global level.

Entre o Carlo R. e o Orleannais: a saude publica e a profilaxia maritima no relato de dois casos de navios de imigrantes no porto do Rio de Janeiro, 1893-1907 / Between the Carlo R. and the Orleannais: public health and maritime prophylaxis in the description of two cases of ships transporting immigrants arriving in the port of Rio de Janeiro, 1893-1907

Aborda as mudanças ocorridas nas práticas da profilaxia marítima brasileira. Por meio de dois casos de navios de imigrantes, que chegaram ao porto do Rio de Janeiro com epidemias a bordo, são analisados a compreensão sobre a etiologia, a forma de prevenção e o combate às três doenças com regulamentação portuária internacional: febre amarela, peste bubônica e cólera. Até o final do século XIX, uma das principais práticas de profilaxia era a quarentena. No início do XX, identificamos a emergência do ideário da microbiologia e dos vetores no serviço sanitário dos portos. A quarentena, que já vinha sendo criticada como antiquada e ineficaz, é limitada a alguns casos, e novos métodos e tecnologias da higiene passam a ser aplicados na defesa sanitária dos portos.

We address the changes in Brazilian maritime prophylaxis by studying two cases of immigrant ships arriving at the port of Rio de Janeiro with epidemics onboard. The objective is to understand the etiology, means of prevention and methods used to combat the three diseases subject to international port regulations: yellow fever, bubonic plague and cholera. Until the late nineteenth century, quarantines were one of the main disease prevention practices. In the early twentieth century, microbiology and the concept of vectors in ports sanitation services emerged. Quarantines, which were already being criticized as antiquated and ineffective, were limited to a few cases, and new hygiene methods and technologies began to be applied in port sanitary defense.

Entre o Carlo R. e o Orleannais: a saúde pública e a profilaxia marítima no relato de dois casos de navios de imigrantes no porto do Rio de Janeiro, 1893-1907 / Between the Carlo R. and the Orleannais: public health and maritime prophylaxis in the description of two cases of ships transporting immigrants arriving in the port of Rio de Janeiro, 1893-1907

Aborda as mudanças ocorridas nas práticas da profilaxia marítima brasileira. Por meio de dois casos de navios de imigrantes, que chegaram ao porto do Rio de Janeiro com epidemias abordo, são analisados a compreensão sobre a etiologia, a forma de prevenção e o combate às três doenças com regulamentação portuária internacional: febre amarela, peste bubônica e cólera. Até o final do século XIX, uma das principais práticas de profilaxia era a quarentena. No início do XX, identificamos a emergência do ideário da microbiologia e dos vetores no serviço sanitário dos portos. A quarentena, que já vinha sendo criticada como antiquada e ineficaz, é limitada a alguns casos, e novos métodos e tecnologias da higiene passam a ser aplicados na defesa sanitária dos portos. (AU)

Yellow fever and dengue: a threat to Europe?

The introduction and rapidly expanding range of Aedes albopictus in Europe is an iconic example of the growing risk of the globalization of vectors and vector-borne diseases. The history of yellow fever and dengue in temperate regions confirms that transmission of both diseases could recur, particularly if Ae. aegypti, a more effective vector, were to be re-introduced. The article is a broad overview of the natural history and epidemiology of both diseases in the context of these risks.