Viscerotropic Disease Research Articles

Defining Risk Groups to Yellow Fever Vaccine-Associated Viscerotropic Disease in the Absence of Denominator Data

Several risk groups are known for the rare but serious, frequently fatal, viscerotropic reactions following live yellow fever virus vaccine (YEL-AVD). Establishing additional risk groups is hampered by ignorance of the numbers of vaccinees in factor-specific risk groups thus preventing their use as denominators in odds ratios (ORs). Here, we use an equation to calculate ORs using the prevalence of the factor-specific risk group in the population who remain well. The 95% confidence limits and P values can also be calculated. Moreover, if the estimate of the prevalence is imprecise, discrimination analysis can indicate the prevalence at which the confidence interval results in an OR of ∼1 revealing if the prevalence might be higher without yielding a non-significant result. These methods confirm some potential risk groups for YEL-AVD and cast doubt on another. They should prove useful in situations in which factor-specific risk group denominator data are not available.

Immunization with a Thermostable Newcastle Disease Virus K148/08 Strain Originated from Wild Mallard Duck Confers Protection against Lethal Viscerotropic Velogenic Newcastle Disease Virus Infection in Chickens

Newcastle disease (ND) is one of the most devastating poultry infections because of its worldwide distribution and accompanying economical threat. In the present study, we characterized the ND virus (NDV) K148/08 strain from wild mallard duck, with regard to safety, thermostability, immunogenicity, and protective efficacy against velogenic ND viral infection. The NDV K148/08 strain offered enhanced immunogenicity and safety relative to commercially available vaccine strains. The NDV K148/08 strain was safe in 1-day-old SPF chicks after vaccination using a coarse or cabinet-type fine sprayer. We demonstrated that the NDV K148/08 strain elicited high levels of antibody responses and provided protective efficacy against lethal NDV challenge. In addition, the thermostability of the NDV K148/08 strain was as high as that of the thermostable V4 strain. Therefore, the NDV K148/08 strain may be useful to ensure NDV vaccine performance and effectiveness in developing countries, especially in remote areas without cold chains.

Safety of the Yellow Fever Vaccine: A Retrospective Study

Yellow fever (YF) vaccine is considered safe; however, severe illness and death following vaccination have been reported. Vaccine Safety Datalink (VSD) and US Department of Defense (DoD) data were used to identify adverse reactions following YF vaccination. Within the VSD, YF-vaccine-exposed subjects were compared to age-, site-, and gender-matched unexposed subjects. YF-vaccine-exposed DoD subjects were studied using a risk-interval design. For both cohorts, ICD-9 codes were analyzed for allergic and local reactions, mild systemic reactions, and possible visceral and neurologic adverse events (AEs). The VSD cohort received 47,159 doses from 1991 through 2006. The DoD cohort received 1.12 million doses from 1999 through 2007. Most subjects received other vaccines simultaneously. In the VSD cohort, rates of allergic, local, and mild systemic reactions were not statistically different between YF-vaccine-exposed and -unexposed subjects. In the DoD, there was an increased risk for outpatient allergic events in the period following vaccination with YF and other vaccines rate ratios [RR 3.85, 95% confidence interval (CI) 3.35-4.41] but with no increased risk for inpatient allergic reactions. In both cohorts, inpatient ICD-9 codes for visceral events were significantly less common following vaccination; inpatient codes for neurologic events were less common in the VSD YF-vaccine-exposed adult cohort, but did not differ between exposed and unexposed periods in the DoD. In the DoD, one fatal case of YF-vaccine-associated viscerotropic disease (YF-vaccine-AVD) was detected. The estimated death rate was 0.89 for 1,000,000 YF vaccine doses (95% CI 0.12-6.31/1,000,000 doses). No YF vaccine-associated deaths occurred in the VSD. In these closed cohorts we did not detect increased risk for visceral or neurologic events following YF vaccination. The death rate following YF vaccine was consistent with previous reports. These data support current recommendations for use of YF vaccine in young healthy individuals. These data are inadequate to judge safety of YF vaccines in elderly patients.

Yellow Fever Vaccine Attenuation Revealed: Loss of Diversity

Live attenuated vaccines against diseases caused by RNA viruses, such as polio, measles, mumps, and yellow fever, are among the most efficient and safest human vaccines. They induce lifelong protective immunity after 1 or 2 administrations in 90%–95% of immunized individuals and are easily manufactured at large scale and low cost. Despite their amazing clinical success in the global control of these diseases and despite the very low number of adverse events observed over decades of use in billions of individuals, these vaccines still raise worry of possible reversion to the original pathogenicity. Live attenuated vaccines have all been empirically derived from pathogenic clinical isolates by serial cultivation in vitro, and our understanding of the molecular basis of their attenuation is still limited. In this issue of the Journal, Beck et al [1] report results of deep sequencing analysis of the genome in of the yellow fever 17D (YF-17D) vaccine strain and its comparison to the parental strain Asibi from which it was originally derived in 1937 [2]. This first comparison of a live RNA virus vaccine to its wild-type parental strain by deep sequencing provides biologically significant observations on attenuation and critical information on the stability of live vaccines and the risk of reversion to virulence. Yellow fever is a viral hemorrhagic fever endemic in tropical and subtropical regions of sub-Saharan Africa and South America caused by the mosquito-borne yellow fever flavivirus (YFV). In the African rainforest, the zoonotic transmission cycle of YFV in great apes involves Aedes species mosquitoes, whereas the urban cycle in humans occurs through Aedes aegypti. The World HealthOrganization (WHO)estimates that there are 200 000 cases of and 30 000 deaths due to yellow fever annually. YFV infection may progress to multiorgan failure of the liver, kidneys, and myocardial tissues, resulting in hemorrhagic shock with a case-fatality varying from 20% to 50%. The infectious origin of yellow fever was proven by Walter Reed in 1901, and the virus was isolated in 1927 by Adrian Stokes from a Ghanaian patient named Asibi [3]. A few years later, Max Theiler managed to attenuate this virus while maintaining its immunogenicity, paving the way to the vaccine. He was awarded the Nobel Prize in Medicine in 1951 for this work. The YF-17D vaccine was empirically attenuated after 204 serial passages of the Asibi YFV strain in mouse and chicken embryo tissues. Variants were assessed for their ability to raise neutralizing antibodies and to protect monkeys from a challenge with the virulent Asibi strain. In 1945, the WHO granted the use of 2 substrain seed lots of this vaccine in humans: 17DD, which was used in South America, and 17D204, which is currently used in the rest of the world. Both substrains in the vaccine are manufactured in embryonic chicken eggs. Currently, 6 manufacturers produce YF-17D vaccine, using a seed lot system that has not changed since 1945 to ensure genetic stability and safety of the vaccine seeds. Another live yellow fever vaccine was developed in France in 1934 by attenuation in mouse brain tissue, and the French neurotropic vaccine (FNV) was widely used in Africa until 1982, when its production was stopped as a result of a high incidence of neurological complications. Vaccine seeds are now assessed for neurotropism and viscerotropism in primates before the production process is finalized. A single administration of YF17D vaccine induces long-lasting protection; however, the WHO recommends booster immunizations every 10 years. YF17D has an excellent safety record over years of massive use. Yet, rare adverse events are identified, occurring between 2 and 30 days after vaccination, comprising either neurotropic or viscerotropic diseases with a >50% fatality rate (0.05–1.5 cases per 100 000 vaccinations) [4]. The mechanisms underlying these rare complications remain largely unknown. Molecular and animal studies performed to date provide no evidence that mutations Received and accepted 4 October 2013. Correspondence: Frederic Tangy, PhD, Unite de Genomique Virale et Vaccination, CNRS, UMR 3569, Institut Pasteur, 28 rue du Dr Roux, Paris 75015, France (ftangy@pasteur.fr). The Journal of Infectious Diseases © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/infdis/jit551

Antiviral Immune Response After Live Yellow Fever Vaccination of a Kidney Transplant Recipient Treated With IVIG

Despite the serious risk that live yellow fever virus (YFV) vaccination poses for immunocompromised individuals, inadvertent immunization does occur (1–3). We present a case study in which we measured the antiviral immune response of a kidney transplant recipient who received intravenous immunoglobulin (IVIG) as a precautionary step to reduce the risk of vaccine-associated viscerotropic disease following YFV vaccination.

Deconvoluting protective immune responses elicited by the live-attenuated 17D yellow fever virus vaccine (P6324)

Abstract The safe and efficacious live-attenuated 17D yellow fever virus (YFV) vaccines provide a benchmark for immunization. The contribution of 17D elicited humoral and cell-mediated responses to protection from challenge with wtYFV remains unknown due to a lack of tractable animal models of immunization and disease. By artificially reproducing the primate-specific phenotype of wtYFV to circumvent type I IFN control, we developed a murine model in which challenge with an otherwise lethal wtYFV is limited to low-level replication in the draining lymph nodes following 17D immunization. Moreover, the fatal viscerotropic disease and cytokine storm afflicting naive animals is completely abrogated. Similar to humans, 17D immunization in our model elicits neutralizing antibodies as well as robust YFV-specific CD4+ and CD8+ T cell accumulation with polyfunctional cytokine profiles and markers of early memory differentiation. Transfer of immune sera, CD4+/CD8+ T cells and/or B cell populations from 17D-immunized mice into naïve mice prior to challenge with wtYFV indicates that antibodies are not solely responsible for protection. However, YFV-specific T cells elicited in naive mice infected with wtYFV accumulate to higher numbers than in 17D vaccinated mice, yet fail to protect. We are currently comparing 17D and wtYFV infections to deconvolute mechanisms of 17D-induced immunogenicity and wild-type YFV immune evasion.

Adverse events following yellow fever preventive vaccination campaigns in eight African countries from 2007 to 2010

BackgroundSerious, but rare adverse events following immunization (AEFI) have been reported with yellow fever (YF) 17D vaccine, including severe allergic reactions, YF vaccine-associated neurologic disease (YEL-AND) and YF vaccine-associated viscerotropic disease (YEL-AVD). The frequency with which YEL-AND and YEL-AVD occur in YF endemic countries is mostly unknown. MethodsFrom 2007 to 2010, eight African countries – Benin, Cameroon, Guinea, Liberia, Mali, Senegal, Sierra Leone, and Togo- implemented large-scale YF preventive vaccination campaigns. Each country established vaccine pharmacovigilance systems that included standard case definitions, procedures to collect and transport biological specimens, and National Expert Committees to review data and classify cases. Staff in all countries received training and laboratory capacity expanded. ResultsIn total, just over 38 million people were vaccinated against YF and 3116 AEFIs were reported of which 164 (5%) were classified as serious. Of these, 22 (13%) were classified as YF vaccine reactions, including 11 (50%) hypersensitivity reactions, six (27%) suspected YEL-AND, and five (23%) suspected YEL-AVD. The incidence per 100,000 vaccine doses administered was 8.2 for all reported AEFIs, 0.43 for any serious AEFI, 0.058 for YF vaccine related AEFIs, 0.029 for hypersensitivity reactions, 0.016 for YEL-AND, and 0.013 for YEL-AVD. Our findings were limited by operational challenges, including difficulties in obtaining recommended biological specimens leading to incomplete laboratory evaluation, unknown case ascertainment, and variable levels of staff training and experience. ConclusionsDespite limitations, active case-finding in the eight different countries did not find an incidence of YF vaccine associated AEFIs that was higher than previous reports. These data reinforce the safety profile of YF vaccine and support the continued use of attenuated YF vaccine during preventive mass vaccination campaigns in YF endemic areas.

Characterization and comparison of the pathogenicity of viscerotropic velogenic Newcastle disease virus isolates in Korea

Characterization and comparison of the pathogenicity of viscerotropic velogenic Newcastle disease virus isolates in Korea

Viscerotropic disease: Case definition and guidelines for collection, analysis, and presentation of immunization safety data

Viscerotropic disease: Case definition and guidelines for collection, analysis, and presentation of immunization safety data

Review of the risks and benefits of yellow fever vaccination including some new analyses

The live, attenuated yellow fever (YF) 17D vaccine provides highly effective and durable immunity and is widely used for travelers to and residents of endemic areas of South America and Africa. Neurotropic and viscerotropic serious adverse events associated with these vaccines occur rarely, but YF 17D vaccine-associated viscerotropic disease (YEL-AVD) is notable for its lethality. There appear to be two distinct patterns of risk for YEL-AVD: the first in younger persons, particularly women, with defects in innate immunity, in whom the case-fatality rate is higher; and the second in elderly persons, particularly men with age-related immune senescence and a lower case-fatality rate. From 1990 to the present, the number of cases (n = 31) and deaths (n = 12) from YEL-AVD in travelers has exceeded the reports of YF (n = 6) acquired by natural infection, raising the question whether the risk of vaccination exceeds the benefit in travelers. To provide some guidance on this point, the rate of vaccine-related injury is compared with the rate of naturally acquired disease in a new analysis that estimates the immunologically susceptible denominator population in YF endemic and epidemic areas. For many years, the risk of vaccine-related illness and death was similar to the risk of illness and death from natural infection with YF in South America. Africa posed a substantially higher estimated risk of wild-type YF than vaccine-related injury. Multiple factors should be considered in making decisions about YF vaccination, including specific destination, season of the year, local evidence for YF transmission, likelihood of exposure to vector mosquitoes and individual risk factors for YEL-AVD, with the goal of increasing vaccine coverage for travel to high-risk areas and reducing unnecessary vaccination. Prospects for future, safer vaccines are also described.

Yellow Fever Vaccine-Associated Viscerotropic Disease

Yellow fever is a mosquito-transmitted hemorrhagic viral disease that is endemic to tropical regions in South America and Africa. It remains a significant health concern for deploying military personnel, accordingly vaccination is frequently performed on troops. Although the vaccine is generally administered with only minor complications, rare severe complications are also reported. Herein, we report a mild case of yellow fever vaccine-associated viscerotropic disease 4 days after administration of the vaccine. The various complications of the vaccine and their pathogenesis are also reviewed.

The safety of yellow fever vaccine 17D or 17DD in children, pregnant women, HIV+ individuals, and older persons: systematic review.

Yellow fever vaccine provides long-lasting immunity. Rare serious adverse events after vaccination include neurologic or viscerotropic syndromes or anaphylaxis. We conducted a systematic review of adverse events associated with yellow fever vaccination in vulnerable populations. Nine electronic bibliographic databases and reference lists of included articles were searched. Electronic databases identified 2,415 abstracts for review, and 32 abstracts were included in this review. We identified nine studies of adverse events in infants and children, eight studies of adverse events in pregnant women, nine studies of adverse events in human immunodeficiency virus-positive patients, five studies of adverse events in persons 60 years and older, and one study of adverse events in individuals taking immunosuppressive medications. Two case studies of maternal-neonate transmission resulted in serious adverse events, and the five passive surveillance databases identified very small numbers of cases of yellow fever vaccine-associated viscerotropic disease, yellow fever vaccine-associated neurotropic disease, and anaphylaxis in persons ≥ 60 years. No other serious adverse events were identified in the other studies of vulnerable groups.

Characterization of avian paramyxovirus type 1 from migratory wild birds in chickens

Newcastle disease virus (NDV) is one of the most important infectious agents in the poultry industry, and vaccines against it have been widely used for prevention and control. Live vaccines, which can replicate in the respiratory and digestive systems, have been especially needed in areas with outbreaks of viscerotropic velogenic Newcastle disease. Towards the goal of searching for a new live vaccine candidate, avian paramyxovirus type 1 (APMV-1) was isolated from the faeces of wild birds. Three APMV-1 strains thus isolated were characterized in terms of phylogeny, pathogenicity, immunogenicity and tissue tropism, and on the basis of these analyses were classified as lentogenic genotype I NDV. CBU2179, one of the three APMV-1 strains, was selected and was evaluated in terms of its efficacy and safety in specific pathogen-free chickens and commercial broilers. The manufactured trial vaccine from this strain, also called CBU2179, induced similar immune responses to those of VG/GA and B1 commercial vaccines, and provided 100% protection against challenge from viscerotropic velogenic NDV, KJW/49 strain (the official challenge strain in Korea). Also, the CBU2179 virus was re-isolated and persisted as long as or longer than other vaccine strains in both the respiratory and alimentary tracts. Therefore, the CBU2179 strain may represent a good candidate for a live Newcastle disease vaccine to protect chickens against viscerotropic velogenic NDV.

Yellow Fever Virus Vaccine–associated Deaths in Young Women1

Yellow fever vaccine–associated viscerotropic disease is a rare sequela of live-attenuated virus vaccine. Elderly persons and persons who have had thymectomies have increased susceptibility. A review of published and other data suggested a higher than expected number of deaths from yellow fever vaccine–associated viscerotropic disease among women 19–34 years of age without known immunodeficiency.

An Inactivated Cell-Culture Vaccine against Yellow Fever

Yellow fever is a lethal viral hemorrhagic fever occurring in Africa and South America. A highly effective live vaccine (17D) is widely used for travelers to and residents of areas in which yellow fever is endemic, but the vaccine can cause serious adverse events, including viscerotropic disease, which is associated with a high rate of death. A safer, nonreplicating vaccine is needed. In a double-blind, placebo-controlled, dose-escalation, phase 1 study of 60 healthy subjects between 18 and 49 years of age, we investigated the safety and immunogenicity of XRX-001 purified whole-virus, β-propiolactone-inactivated yellow fever vaccine produced in Vero cell cultures and adsorbed to aluminum hydroxide (alum) adjuvant. On two visits 21 days apart, subjects received intramuscular injections of vaccine that contained 0.48 μg or 4.8 μg of antigen. Levels of neutralizing antibodies were measured at baseline and on days 21, 31, and 42. The vaccine induced the development of neutralizing antibodies in 100% of subjects receiving 4.8 μg of antigen in each injection and in 88% of subjects receiving 0.48 μg of antigen in each injection. Antibody levels increased by day 10 after the second injection, at which time levels were significantly higher with the 4.8-μg formulation than with the 0.48-μg formulation (geometric mean titer, 146 vs. 39; P<0.001). Three adverse events occurred at a higher incidence in the two vaccine groups than in the placebo group: mild pain, tenderness, and (much less frequently) itching at the injection site. One case of urticaria was observed on day 3 after the second dose of 4.8 μg of vaccine. A two-dose regimen of the XRX-001 vaccine, containing inactivated yellow fever antigen with an alum adjuvant, induced neutralizing antibodies in a high percentage of subjects. XRX-001 has the potential to be a safer alternative to live attenuated 17D vaccine. (Funded by Xcellerex; ClinicalTrials.gov number, NCT00995865.).

A Case of Yellow Fever Vaccine–Associated Viscerotropic Disease in Ecuador

We report the first case of viscerotropic syndrome in Ecuador. Because of similarities between yellow fever and viscerotropic syndrome, the incidence of this recently described complication of vaccination with the 17D yellow fever vaccine is not known. There is a large population in South America that is considered at risk for possible reemergence of urban yellow fever. Knowledge of potentially fatal complications of yellow fever vaccine should temper decisions to vaccinate populations where the disease is not endemic.

Yellow Fever transmission in Brazil

Yellow fever (YF) is an arboviral disease caused by a virus from Flaviviridae family and genus Flavivirus endemic in tropical regions of Africa and South America. Transmission occurs after infected mosquito bite, genera Aedes and Haemogogus. Urban YF was eradicated in Brazil in 1942, since than sporadic wild transmission has been maintained in country endemic area. From 1989 to 2008, 546 human confirmed cases YF were reported including 241 deaths (case fatality rate 44, 1%) in Brazil. During this period north and midwestern region were responsible for the highest number of cases registering human cases almost every year. Beginning in 1999, YF virus underwent a geographic expansion into southeast, south and midwestern region - Federal District, Goias, Sao Paulo, Minas Gerais, Parana and Rio Grande do Sul states – related to outbreaks in areas that were silent for several decades and outside Amazon area. This study describes the re-emergence of YF virus in enzootic cycles involving mosquitoes, primates and humans cases in midwestern, southeast and south region during 2008 and 2009. During this period and explosive recording of monkey's death was registry by health authorities with laboratory confirmed epizootics. Human cases were associated with leisure and work activities in rural areas and occurred among unvaccinated person. Brazilian Ministry of Health considered it as a public health event of national concern according to the International Health Regulations (2005). Epidemiological control measures were adopted including entomologic control and assessments, monkey deaths surveillance investigation and mass vaccination campaigns were implemented. YF vaccine-associated viscerotropic and neurotropic disease were reported. Those activities were important to establish an effective intervention to control and prevent future outbreaks. Public health authority's interest has been awakened by reporting early identification of YF virus circulation to understand the potential geographic virus expansion and reemergence. Abstracts for SupplementInternational Journal of Infectious DiseasesVol. 14Preview Full-Text PDF Open Archive

Clinical and Immunological Insights on Severe, Adverse Neurotropic and Viscerotropic Disease following 17D Yellow Fever Vaccination

Yellow fever (YF) vaccines (17D-204 and 17DD) are well tolerated and cause very low rates of severe adverse events (YEL-SAE), such as serious allergic reactions, neurotropic adverse diseases (YEL-AND), and viscerotropic diseases (YEL-AVD). Viral and host factors have been postulated to explain the basis of YEL-SAE. However, the mechanisms underlying the occurrence of YEL-SAE remain unknown. The present report provides a detailed immunological analysis of a 23-year-old female patient. The patient developed a suspected case of severe YEL-AVD with encephalitis, as well as with pancreatitis and myositis, following receipt of a 17D-204 YF vaccination. The patient exhibited a decreased level of expression of Fc-gammaR in monocytes (CD16, CD32, and CD64), along with increased levels of NK T cells (an increased CD3(+) CD16(+/-) CD56(+/-)/CD3(+) ratio), activated T cells (CD4(+) and CD8(+) cells), and B lymphocytes. Enhanced levels of plasmatic cytokines (interleukin-6 [IL-6], IL-17, IL-4, IL-5, and IL-10) as well as an exacerbated ex vivo intracytoplasmic cytokine pattern, mainly observed within NK cells (gamma interferon positive [IFN-gamma(+)], tumor necrosis factor alpha positive [TNF-alpha(+)], and IL-4 positive [IL-4(+)]), CD8(+) T cells (IL-4(+) and IL-5(+)), and B lymphocytes (TNF-alpha(+), IL-4(+), and IL-10(+)). The analysis of CD4(+) T cells revealed a complex profile that consisted of an increased frequency of IL-12(+) and IFN-gamma(+) cells and a decreased percentage of TNF-alpha(+), IL-4(+), and IL-5(+) cells. Depressed cytokine synthesis was observed in monocytes (TNF-alpha(+)) following the provision of antigenic stimuli in vitro. These results support the hypothesis that a strong adaptive response and abnormalities in the innate immune system may be involved in the establishment of YEL-AND and YEL-AVD.

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-α/β) in protection of mice from viscerotropic YFV infection revealed that mice deficient in the IFN-α/β 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-α/β response may be primate-specific such that infection of mice with a functional IFN-α/β 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.

Leishmania tropica–Induced Cutaneous and Presumptive Concomitant Viscerotropic Leishmaniasis With Prolonged Incubation

Leishmaniasis includes a spectrum of diseases caused by protozoan parasites belonging to the genus Leishmania. The disease is traditionally classified into visceral, cutaneous, or mucocutaneous leishmaniasis, depending on clinical characteristics as well as the species involved. Leishmania tropica is one of the causative agents of cutaneous leishmaniasis, with a typical incubation period of weeks to months. Observation We describe a 17-year-old Afghani girl who had lived in the United States for 4 years and who presented with a 6-month history of pretibial ulcerations, 9.1-kg weight loss, abdominal pain, splenomegaly, and extreme fatigue. Histopathologic examination and culture with isoenzyme electrophoresis speciation of her skin lesions confirmed the presence of L tropica. In addition, results of serum laboratory and serological studies were highly suggestive of concomitant visceral involvement. The patient was treated with a 28-day course of intravenous pentavalent antimonial compound sodium stibogluconate with complete resolution of her systemic signs and symptoms and improvement of her pretibial ulcerations. This is an exceptional case in that our patient presented with disease after an incubation period of years rather than the more typical weeks to months. In addition, this patient had confirmed cutaneous involvement, as well as strong evidence of viscerotropic disease caused by L tropica, a species that characteristically displays dermotropism, not viscerotropism.