Consumptive coagulopathy of severe yellow fever occurs independently of hepatocellular tropism and massive hepatic injury.

Yellow fever (YF) is a mosquito-transmitted viral disease that causes tens of thousands of deaths each year despite the long-standing deployment of an effective vaccine. In its most severe form, YF manifests as a hemorrhagic fever that causes severe damage to visceral organs. Although coagulopathy is a defining feature of severe YF in humans, the mechanism by which it develops remains uncertain. Hepatocytes are a major target of yellow fever virus (YFV) infection, and the coagulopathy in severe YF has long been attributed to massive hepatocyte infection and destruction that results in a defect in clotting factor synthesis. However, when we analyzed blood from Brazilian patients with severe YF, we found high concentrations of plasma D-dimer, a fibrin split product, suggestive of a concurrent consumptive process. To define the relationship between coagulopathy and hepatocellular tropism, we compared infection and disease in Fah-/-, Rag2-/-, and Il2rɣ-/- mice engrafted with human hepatocytes (hFRG mice) and rhesus macaques using a highly pathogenic African YFV strain. YFV infection of macaques and hFRG mice caused substantial hepatocyte infection, liver damage, and coagulopathy as defined by virological, clinical, and pathological criteria. However, only macaques developed a consumptive coagulopathy whereas YFV-infected hFRG mice did not. Thus, infection of cell types other than hepatocytes likely contributes to the consumptive coagulopathy associated with severe YF in primates and humans. These findings expand our understanding of viral hemorrhagic disease and associated coagulopathy and suggest directions for clinical management of severe YF cases.

The response to re-emergence of yellow fever in Nigeria, 2017.

Yellow fever (YF) is an acute viral hemorrhagic disease caused by the YF virus (arbovirus) which continues to cause severe morbidity and mortality in Africa. A case of YF was confirmed in Nigeria on the 12th of September 2017, 21 years after the last confirmed case. The patient belongs to a nomadic population with a history of low YF vaccination uptake, in the Ifelodun Local Government Area (LGA) of Kwara State, Nigeria. An active case search in Ifelodun and its five contiguous LGAs led to the listing of 55 additional suspect cases of YF within the period of the outbreak investigation between September 18 to October 6, 2017. The median age of cases was 15 years, and 54.4% were males. Of these, blood samples were collected from 30 cases; nine tested positive in laboratories in Nigeria and six were confirmed positive for YF by the WHO reference laboratory in the region; Institut Pasteur, Dakar. A rapid YF vaccination coverage assessment was carried out, resulting in a coverage of 46% in the LGAs, with 25% of cases able to produce their vaccination cards. All stages of the yellow fever vector, Aedes mosquito were identified in the area, with high larval indices (House and Breteau) observed. In response to the outbreak, YF surveillance was intensified across all States in Nigeria, as well as reactive vaccination and social mobilisation campaigns carried out in the affected LGAs in Kwara State. A state-wide YF preventive campaign was also initiated.

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

Yellow fever.

Yellow fever, a mosquito-borne flavivirus disease occurs in tropical areas of South America and Africa. It is a disease of major historical importance, but remains a threat to travelers to and residents of endemic areas despite the availability of an effective vaccine for nearly 70 years. An important aspect is the receptivity of many non-endemic areas to introduction and spread of yellow fever. This paper reviews the clinical aspects, pathogenesis, and epidemiology of yellow fever, with an emphasis on recent changes in the distribution and incidence of the disease. Recent knowledge about yellow fever 17D vaccine mechanism of action and safety are discussed.

Pathophysiologic and transcriptomic analyses of viscerotropic yellow fever in a rhesus macaque model.

Infection with yellow fever virus (YFV), an explosively replicating flavivirus, results in viral hemorrhagic disease characterized by cardiovascular shock and multi-organ failure. Unvaccinated populations experience 20 to 50% fatality. Few studies have examined the pathophysiological changes that occur in humans during YFV infection due to the sporadic nature and remote locations of outbreaks. Rhesus macaques are highly susceptible to YFV infection, providing a robust animal model to investigate host-pathogen interactions. In this study, we characterized disease progression as well as alterations in immune system homeostasis, cytokine production and gene expression in rhesus macaques infected with the virulent YFV strain DakH1279 (YFV-DakH1279). Following infection, YFV-DakH1279 replicated to high titers resulting in viscerotropic disease with ∼72% mortality. Data presented in this manuscript demonstrate for the first time that lethal YFV infection results in profound lymphopenia that precedes the hallmark changes in liver enzymes and that although tissue damage was noted in liver, kidneys, and lymphoid tissues, viral antigen was only detected in the liver. These observations suggest that additional tissue damage could be due to indirect effects of viral replication. Indeed, circulating levels of several cytokines peaked shortly before euthanasia. Our study also includes the first description of YFV-DakH1279-induced changes in gene expression within peripheral blood mononuclear cells 3 days post-infection prior to any clinical signs. These data show that infection with wild type YFV-DakH1279 or live-attenuated vaccine strain YFV-17D, resulted in 765 and 46 differentially expressed genes (DEGs), respectively. DEGs detected after YFV-17D infection were mostly associated with innate immunity, whereas YFV-DakH1279 infection resulted in dysregulation of genes associated with the development of immune response, ion metabolism, and apoptosis. Therefore, WT-YFV infection is associated with significant changes in gene expression that are detectable before the onset of clinical symptoms and may influence disease progression and outcome of infection.

Timeliness of yellow fever surveillance, Central African Republic.

During January 2007-July 2012, a total of 3,220 suspected yellow fever cases were reported in the Central African Republic; 55 were confirmed and 11 case-patients died. Mean delay between onset of jaundice and case confirmation was 16.6 days. Delay between disease onset and blood collection could be reduced by increasing awareness of the population.

Epidemiological and laboratory characterization of a yellow fever outbreak in northern Uganda, October 2010-January 2011.

BACKGROUND: In November 2010, following reports of an outbreak of a fatal, febrile, hemorrhagic illness in northern Uganda, the Uganda Ministry of Health established multisector teams to respond to the outbreak. METHODS: This was a case-series investigation in which the response teams conducted epidemiological and laboratory investigations on suspect cases. The cases identified were line-listed and a data analysis was undertaken regularly to guide the outbreak response. RESULTS: Overall, 181 cases met the yellow fever (YF) suspected case definition; there were 45 deaths (case fatality rate 24.9%). Only 13 (7.5%) of the suspected YF cases were laboratory confirmed, and molecular sequencing revealed 92% homology to the YF virus strain Couma (Ethiopia), East African genotype. Suspected YF cases had fever (100%) and unexplained bleeding (97.8%), but jaundice was rare (11.6%). The overall attack rate was 13 cases/100000 population, and the attack rate was higher for males than females and increased with age. The index clusters were linked to economic activities undertaken by males around forests. CONCLUSIONS: This was the largest YF outbreak ever reported in Uganda. The wide geographical case dispersion as well as the male and older age preponderance suggests transmission during the outbreak was largely sylvatic and related to occupational activities around forests.

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.

A mouse model for studying viscerotropic disease caused by yellow fever virus infection.

Mosquito-borne yellow fever virus (YFV) causes highly lethal, viscerotropic disease in humans and non-human primates. Despite the availability of efficacious live-attenuated vaccine strains, 17D-204 and 17DD, derived by serial passage of pathogenic YFV strain Asibi, YFV continues to pose a significant threat to human health. Neither the disease caused by wild-type YFV, nor the molecular determinants of vaccine attenuation and immunogenicity, have been well characterized, in large part due to the lack of a small animal model for viscerotropic YFV infection. Here, we describe a small animal model for wild-type YFV that manifests clinical disease representative of that seen in primates without adaptation of the virus to the host, which was required for the current hamster YF model. Investigation of the role of type I interferon (IFN-alpha/beta) in protection of mice from viscerotropic YFV infection revealed that mice deficient in the IFN-alpha/beta receptor (A129) or the STAT1 signaling molecule (STAT129) were highly susceptible to infection and disease, succumbing within 6-7 days. Importantly, these animals developed viscerotropic disease reminiscent of human YF, instead of the encephalitic signs typically observed in mice. Rapid viremic dissemination and extensive replication in visceral organs, spleen and liver, was associated with severe pathologies in these tissues and dramatically elevated MCP-1 and IL-6 levels, suggestive of a cytokine storm. In striking contrast, infection of A129 and STAT129 mice with the 17D-204 vaccine virus was subclinical, similar to immunization in humans. Although, like wild-type YFV, 17D-204 virus amplified within regional lymph nodes and seeded a serum viremia in A129 mice, infection of visceral organs was rarely established and rapidly cleared, possibly by type II IFN-dependent mechanisms. The ability to establish systemic infection and cause viscerotropic disease in A129 mice correlated with infectivity for A129-derived, but not WT129-derived, macrophages and dendritic cells in vitro, suggesting a role for these cells in YFV pathogenesis. We conclude that the ability of wild-type YFV to evade and/or disable components of the IFN-alpha/beta response may be primate-specific such that infection of mice with a functional IFN-alpha/beta antiviral response is attenuated. Consequently, subcutaneous YFV infection of A129 mice represents a biologically relevant model for studying viscerotropic infection and disease development following wild-type virus inoculation, as well as mechanisms of 17D-204 vaccine attenuation, without a requirement for adaptation of the virus.

Serotonin-induced high intracellular pH aids in alkali secretion in the anterior midgut of larval yellow fever mosquito Aedes aegypti L.

The anterior midgut of the larval yellow fever mosquito Aedes aegypti generates a luminal pH in excess of 10 in vivo and similar values are attained by isolated and perfused anterior midgut segments after stimulation with submicromolar serotonin. In the present study we investigated the mechanisms of strong luminal alkalinization using the intracellular fluorescent indicator BCECF-AM. Following stimulation with serotonin, we observed that intracellular pH (pH(i)) of the anterior midgut increased from a mean of 6.89 to a mean of 7.62, whereas pH(i) of the posterior midgut did not change in response to serotonin. Moreover, a further increase of pH(i) to 8.58 occurred when the pH of the luminal perfusate was raised to an in vivo-like value of 10.0. Luminal Zn(2+) (10 micromol l(-1)), an inhibitor of conductive proton pathways, did not inhibit the increase in pH(i), the transepithelial voltage, or the capacity of the isolated tissue to alkalinize the lumen. Finally, the transapical voltage did not significantly respond to luminal pH changes induced either by perfusion with pH 10 or by stopping the luminal perfusion with unbuffered solution which results in spontaneous luminal alkalinization. Together, these results seem to rule out the involvement of conductive pathways for proton absorption across the apical membrane and suggest that a serotonin-induced alkaline pH(i) plays an important role in the generation of an alkaline lumen.

Viral hemorrhagic fever-induced acute kidney injury.

Viral hemorrhagic fevers (VHFs) are diseases caused by the RNA virus from 4 different families (Flaviridiae, Arenaviridae, Bunyaviridae, and Filoviridae) that are acquired through the bite of an infected arthropod or by the inhalation of particles of rodent excreta. Among the VHFs, dengue and yellow fever are the most prevalent in tropical regions worldwide. The clinical presentation is characterized by fever, malaise, increased vascular permeability, and coagulation defects that can result in bleeding. Acute kidney injury is an uncommon complication but renal dysfunction has been associated with various VHFs. In this article we review the renal manifestations of dengue and yellow fever infections.

Treatment of yellow fever.

Yellow fever (YF) is a life-threatening mosquito-borne flaviviral hemorrhagic fever (VHF) characterized by severe hepatitis, renal failure, hemorrhage, and rapid terminal events with shock and multi-organ failure. A live, attenuated vaccine (YF 17D), in wide use for over 60 years, causes a disease identical to wild-type virus at an incidence of 2.5x10(-6). Our current understanding of the pathogenesis and treatment of YF (described in this brief review) is derived from studies of animal models (macaques, hamsters) that reproduce the features of human YF and from descriptive studies of human cases of naturally acquired and vaccine-associated VHF. The least understood, but potentially most important terminal events appear to be due to 'cytokine storm' and represent a potential target for therapeutic interventions. Areas for future study include dissection of cytokine-mediated events in animal models, the pathogenic role of the profound neutrophilia that occurs pre-terminally, the (pathological) role of adaptive immune clearance in pathogenesis, and treatments directed at cytokine storm. Antibody, interferon-alpha, polyICLC and other immune modulators are highly effective when administered before or within a narrow time window after infection, but are ineffective when given after the infection is established. A few antivirals have been evaluated (ribavirin, tiazofurin, carboxamide, pyrazoline compounds). Ribavirin has been used successfully to treat hamsters when the drug is given at high doses up to 2 days after virus infection (shortly before liver infection), but has not shown promise in nonhuman primate models. Future work should focus on evaluating higher doses of ribavirin alone or in combinations with potentially synergistic drugs, including interferons. Also specific inhibitors against other flaviviruses such as dengue virus should be investigated for potential pan-flavivirus activity since recent studies have shown that specific targets such as the flavivirus proteases and helicases are very similar in structure.

Activation of the cytokine network and unfavorable outcome in patients with yellow fever.

To study the contribution of inflammatory mediators to the pathogenesis of yellow fever (YF), the serum levels of several cytokines and chemokines were measured in 7 patients with fatal YF (f-YF), 11 patients with nonfatal hemorrhagic YF (nf/h-YF), and 18 patients with nonfatal nonhemorrhagic YF (nf/nh-YF). The levels of interleukin (IL)-6, monocyte chemoattractant protein-1, interferon-inducible protein (IP)-10, tumor necrosis factor- alpha , and IL-1 receptor antagonist (IL-1RA) were all statistically significantly higher in the patients with f-YF than in those with nf/nh-YF. In patients with nf/h-YF, only levels of IP-10 and IL-1RA were significantly elevated. The high levels of pro- and anti-inflammatory cytokines and chemokines in serum from patients with f-YF are reminiscent of those seen in patients with bacterial sepsis. This finding has implications for the understanding of the pathophysiology of YF and the development of therapeutic strategies.

Yellow fever: the recurring plague.

Despite the availability of a safe and efficacious vaccine, yellow fever (YF) remains a disease of significant public health importance, with an estimated 200,000 cases and 30,000 deaths annually. The disease is endemic in tropical regions of Africa and South America; nearly 90% of YF cases and deaths occur in Africa. It is a significant hazard to unvaccinated travelers to these endemic areas. Virus transmission occurs between humans, mosquitoes, and monkeys. The mosquito, the true reservoir of YF, is infected throughout its life, and can transmit the virus transovarially through infected eggs. Man and monkeys, on the other hand, play the role of temporary amplifiers of the virus available for mosquito infection. Recent increases in the density and distribution of the urban mosquito vector, Aedes aegypti, as well as the rise in air travel increase the risk of introduction and spread of yellow fever to North and Central America, the Caribbean, the Middle East, Asia, Australia, and Oceania. It is an acute infectious disease characterized by sudden onset with a two-phase development, separated by a short period of remission. The clinical spectrum of yellow fever varies from very mild, nonspecific, febrile illness to a fulminating, sometimes fatal disease with pathognomic features. In severe cases, jaundice, bleeding diathesis, with hepatorenal involvement are common. The case fatality rate of severe yellow fever is 50% or higher. The pathogenesis and pathophysiology of the disease are poorly understood and have not been the subject of modern clinical research. There is no specific treatment for YF, making the management of YF patients extremely problematic. YF is a zoonotic disease that cannot be eradicated, therefore instituting preventive vaccination through routine childhood vaccination in endemic countries, can significantly reduce the burden of the disease. The distinctive properties of lifelong immunity after a single dose of yellow fever vaccination are the basis of the new applications of yellow fever 17D virus as a vector for foreign genes, "the chimeric vaccine,' and the promise of developing new vaccines against other viruses, and possibly against cancers.

Pathogenesis and pathophysiology of yellow fever.

It will be apparent to the reader that there is much to learn about the pathogenesis of YF. The role of specific genes and molecular determinants of neurotropism and viscerotropism has been defined only partially. The availability of infectious clones and a small animal (hamster) model should allow dissection of virulence factors, which can then be tested in the more difficult monkey model. The marked differences between wild-type YF strains should be evaluated by evaluating the relationships between virulence and genome sequence. The role of cytokine dysregulation and endothelial injury in YF will be elucidated as access to patients and of patients to more sophisticated medical care improves. The number of cases of YF in unvaccinated travelers hospitalized after return from the tropics has unfortunately increased, but such cases afford unique opportunities to study the pathogenesis of renal failure, coagulopathy, vascular instability, and shock, as well as new treatment modalities. At the cellular level, there are also important opportunities for research on YF virus-cell receptor interactions, the control of apoptotic cell death, and the predilection for cells of the midzone of the liver lobule. The role of dendritic cells in the early stage of YF infection is deserving of study. Finally, the role of the immune response to infection, particularly cellular immunity, is poorly characterized, and the suggestion that immune clearance may aggravate the condition of the host during the period of intoxication should be evaluated in appropriate animal models.