Actualización sobre fiebre amarilla en el contexto de la reemergencia de la enfermedad / Update on Yellow Fever in the Context of the Re-emergence of the Disease

Introducción: La fiebre amarilla se ha convertido en una enfermedad reemergente y un problema para la salud pública. Se estima que afecta a más de 200 000 personas anualmente en las regiones tropicales de África, América del Sur y Centroamérica, con al menos 30 000 defunciones. Existen 47 países endémicos, de ellos 34 en el continente africano, que contribuyen con más del 90 por ciento de la morbilidad y mortalidad por fiebre amarilla en el planeta. Quienes viajan a lugares donde la enfermedad es endémica pueden importarla a otros países. Objetivo: Recopilar información científica actualizada sobre la fiebre amarilla en el contexto de su reemergencia. Métodos: Se realizó una síntesis de la información científica disponible en la literatura médica sobre la enfermedad. Se consultaron diferentes buscadores y bases de datos, como PubMed, Ebsco, Scielo, ClinicalKey y Google Académico. El periodo de búsqueda estuvo comprendido entre enero y mayo de 2019. Conclusiones: La circulación del virus de la fiebre amarilla continúa aumentando de una manera desconcertante en poblaciones humanas, tanto en África como en América del Sur y Centroamérica. En el ámbito de su reemergencia, no resulta suficiente la sostenibilidad de sistemas de vigilancia confiables, combinados con programas de control de la enfermedad. La divulgación de los conocimientos científicos alcanzados, puede contribuir a la actualización permanente del personal de salud en aras de lograr un accionar eficaz que conduzca a la disminución de la morbilidad y mortalidad por esta enfermedad en la población mundial(AU)

Introduction: Yellow fever has become a reemerging disease and a public health problem. It is estimated that it affects more than 200,000 people annually in the tropical regions of Africa, South America and Central America, with at least 30,000 deaths. There are 47 endemic countries, 34 of them on the African continent, which contribute more than 90percent of morbidity and mortality from yellow fever on the planet. Those who travel to places where the disease is endemic can import it to other countries. Objective: To collect up-to-date scientific information on yellow fever in the context of its re-emergence. Methods: A synthesis of the scientific information available in the medical literature on the disease was carried out. Different search engines and databases were consulted, such as PubMed, Ebsco, Scielo, ClinicalKey and Google Scholar. The search period was from January to May 2019. Conclusions: The circulation of the yellow fever virus continues to increase in a disconcerting way in human populations, both in Africa and in South and Central America. In the field of its re-emergence, the sustainability of reliable surveillance systems, combined with disease control programs, is not enough. The dissemination of the scientific knowledge achieved can contribute to the permanent updating of health personnel in order to achieve an effective action that leads to the reduction of morbidity and mortality from this disease in the world population(AU)

Estimating case fatality risk of severe Yellow Fever cases: systematic literature review and meta-analysis.

BACKGROUND: Case fatality risk (CFR), commonly referred to as a case fatality ratio or rate, represents the probability of a disease case being fatal. It is often estimated for various diseases through analysis of surveillance data, case reports, or record examinations. Reported CFR values for Yellow Fever vary, offering wide ranges. Estimates have not been found through systematic literature review, which has been used to estimate CFR of other diseases. This study aims to estimate the case fatality risk of severe Yellow Fever cases through a systematic literature review and meta-analysis. METHODS: A search strategy was implemented in PubMed and Ovid Medline in June 2019 and updated in March 2021, seeking reported severe case counts, defined by fever and either jaundice or hemorrhaging, and the number of those that were fatal. The searches yielded 1,133 studies, and title/abstract review followed by full text review produced 14 articles reporting 32 proportions of fatal cases, 26 of which were suitable for meta-analysis. Four studies with one proportion each were added to include clinical case data from the recent outbreak in Brazil. Data were analyzed through an intercept-only logistic meta-regression with random effects for study. Values of the I2 statistic measured heterogeneity across studies. RESULTS: The estimated CFR was 39 % (95 % CI: 31 %, 47 %). Stratifying by continent showed that South America observed a higher CFR than Africa, though fewer studies reported estimates for South America. No difference was seen between studies reporting surveillance data and studies investigating outbreaks, and no difference was seen among different symptom definitions. High heterogeneity was observed across studies. CONCLUSIONS: Approximately 39 % of severe Yellow Fever cases are estimated to be fatal. This study provides the first systematic literature review to estimate the CFR of Yellow Fever, which can provide insight into outbreak preparedness and estimating underreporting.

Ultrasound Findings and Laboratory Predictors of Early Mortality in Patients With Severe Yellow Fever.

OBJECTIVE. Yellow fever is a hemorrhagic disease caused by an arbovirus endemic in South America; outbreaks have occurred in recent years. The purpose of this study was to describe abdominal ultrasound findings in patients with severe yellow fever and correlate them with clinical and laboratory data. MATERIALS AND METHODS. A retrospective cohort study was performed between January and April 2018. The subjects were patients admitted to an ICU with polymerase chain reaction-confirmed yellow fever. Bedside sonography was performed within 48 hours of admission. Images were independently analyzed by two board-certified radiologists. Laboratory test samples were collected within 12 hours of image acquisition. Multivariable logistic regression analysis was performed to identify 30-day mortality predictors; p < .05 was considered statistically significant. RESULTS. Forty-six patients (40 [87%] men, six [13%] women; mean age, 47.5 ± 15.2 years) were evaluated with bedside sonography. Laboratory tests showed high serum levels of aspartate aminotransferase (5319 U/L), total bilirubin (6.2 mg/dL), and creati-nine (4.3 mg/dL). Twenty-six (56.5%) patients died within 30 days of admission (median time to death, 5 days [interquartile range, 2-9 days]). The most frequent ultrasound findings were gallbladder wall thickening (80.4%), increased renal cortex echogenicity (71.7%), increased liver parenchyma echogenicity (65.2%), perirenal fluid (52.2%), and ascites (30.4%). Increased renal echogenicity was associated with 30-day mortality (84.6% versus 55.0%; p = .046) and was an independent predictor of this outcome after multivariate analysis (odds ratio, 10.89; p = .048). CONCLUSION. Reproducible abdominal ultrasound findings in patients with severe yellow fever may be associated with severity of disease and prognosis among patients treated in the ICU.

Re-Emergence of Yellow Fever in Brazil during 2016-2019: Challenges, Lessons Learned, and Perspectives.

Yellow fever (YF) is a re-emerging viral zoonosis caused by the Yellow Fever virus (YFV), affecting humans and non-human primates (NHP). YF is endemic in South America and Africa, being considered a burden for public health worldwide despite the availability of an effective vaccine. Acute infectious disease can progress to severe hemorrhagic conditions and has high rates of morbidity and mortality in endemic countries. In 2016, Brazil started experiencing one of the most significant YF epidemics in its history, with lots of deaths being reported in regions that were previously considered free of the disease. Here, we reviewed the historical aspects of YF in Brazil, the epidemiology of the disease, the challenges that remain in Brazil's public health context, the main lessons learned from the recent outbreaks, and our perspective for facing future YF epidemics.

Clinical profiles and factors associated with mortality in adults with yellow fever admitted to an intensive care unit in Minas Gerais, Brazil.

BACKGROUND: Yellow fever (YF) is a viral hemorrhagic disease caused by an arbovirus from the Flaviviridae family. Data on the clinical profile of severe YF in intensive care units (ICUs) are scarce. This study aimed to evaluate factors associated with YF mortality in patients admitted to a Brazilian ICU during the YF outbreaks of 2017 and 2018. METHODS: This was a longitudinal cohort case series study that included YF patients admitted to the ICU. Demographics, clinical and laboratory data were analyzed. Cox regression identified independent predictors of death risk. RESULTS: A total of 114 patients were studied. The median age was 48 years, and 92.1% were males. In univariate analysis, jaundice, leukopenia, bradycardia, prothrombin time, expressed as a ratio to the international normalized ratio-(PT-INR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, lactate, arterial pH and bicarbonate, Acute Physiology and Chronic Health Evaluation II (APACHE II) and Simplified Acute Physiology Score 3 (SAPS 3) severity scores, transfusion of fresh frozen plasma, acute renal failure (Acute Kidney Injury Network stage III (AKIN III)), hemodialysis, cumulative fluid balance at 72 h of ICU, vasopressor use, seizures and grade IV encephalopathy were significantly associated with mortality. In multivariate analysis, factors independently associated with YF mortality were PT-INR, APACHE II, and grade IV hepatic encephalopathy. CONCLUSIONS: In the large outbreak in Brazil, factors independently associated with death risk in YF were: PT-INR, APACHE II, and grade IV hepatic encephalopathy. Early identification of patients with YF mortality risk factors may be very useful. Once these patients with a poor prognosis have been identified, proper management should be promptly implemented.

Yellow fever: profile of cases and factors associated with death in a hospital in the State of Rio de Janeiro, 2017-2018.

OBJECTIVE: Describe the clinical and epidemiological profile of confirmed cases of yellow fever whose patients were hospitalized in a general hospital for infectious diseases in the State of Rio de Janeiro, Brazil, from March 11, 2017 to June 15, 2018, during a recent outbreak and factors associated with death. METHODS: This is a retrospective observational study with analysis of secondary databases of local epidemiological surveillance system, and complementary data collection from epidemiological investigation records and clinical records. Study variables included demographic, epidemiological, clinical, and laboratory data. A descriptive statistical analysis and a bivariate and multivariate analysis by logistic regression were performed to analyze factors associated with death. RESULTS: Fifty-two patients diagnosed with yellow fever were hospitalized, 86.5% male patients, median age 49.5 years, 40.4% rural workers. The most frequent signs and symptoms were fever (90.4%), jaundice (86.5%), nausea and/or vomiting (69.2%), changes in renal excretion (53.8%), bleeding (50%), and abdominal pain (48.1%), with comorbidity in 38.5% of all cases. The lethality rate was 40.4%. Factors significantly associated with a higher chance of death in the bivariate analysis were: bleeding, changes in renal excretion, and maximum values of direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine. In the multivariate analysis by logistic regression, only changes in renal excretion and ALT remained significant predictors of higher chance of death. A threshold effect was also observed for AST. The cutoff points identified as high risk for death were ALT > 4,000 U/L and AST > 6,000 U/L. CONCLUSIONS: This study contributed to the knowledge on the profile of confirmed cases of high severity yellow fever. The main factors associated with death were changes in renal excretion and elevated serum transaminases, especially ALT. High lethality emphasizes the need for early diagnosis and treatment, and the importance of increasing vaccination coverage.

Predictors of mortality in patients with yellow fever: an observational cohort study

BACKGROUND: Yellow fever virus infection results in death in around 30% of symptomatic individuals. The aim of this study was to identify predictors of death measured at hospital admission in a cohort of patients admitted to hospital during the 2018 outbreak of yellow fever in the outskirts of São Paulo city, Brazil. METHODS: In this observational cohort study, we enrolled patients with yellow fever virus from two hospitals in São Paolo­the Hospital das Clínicas, University of São Paulo and the Infectious Diseases Institute "Emilio Ribas". Patients older than 18 years admitted to hospital with fever or myalgia, headache, arthralgia, oedema, rash, or conjunctivitis were consecutively screened for inclusion in the present study. Consenting patients were included if they had travelled to geographical areas in which yellow fever virus cases had been previously confirmed. Yellow fever infection was confirmed by real-time PCR in blood collected at admission or tissues at autopsy. We sequenced the complete genomes of yellow fever virus from infected individuals and evaluated demographic, clinical, and laboratory findings at admission and investigated whether any of these measurements correlated with patient outcome (death). FINDINGS: Between Jan 11, 2018, and May 10, 2018, 118 patients with suspected yellow fever were admitted to Hospital das Clínicas, and 113 patients with suspected yellow fever were admitted to Infectious Diseases Institute "Emilio Ribas". 95 patients with suspected yellow fever were included in the study, and 136 patients were excluded. Three (3%) of 95 patients with suspected yellow fever who were included in the study were excluded because they received a different diagnosis, and 16 patients with undetectable yellow fever virus RNA were excluded. Therefore, 76 patients with confirmed yellow fever virus infection, based on detectable yellow fever virus RNA in blood (74 patients) or yellow fever virus confirmed only at the autopsy report (two patients), were included in our analysis. 27 (36%) of 76 patients died during the 60 day period after hospital admission. We generated 14 complete yellow fever virus genomes from the first 15 viral load-detectable samples. The genomes belonged to a single monophyletic clade of the South America I genotype, sub-genotype E. Older age, male sex, higher leukocyte and neutrophil counts, higher alanine aminotransferase, aspartate transaminase (AST), bilirubin, and creatinine, prolonged prothrombin time, and higher yellow fever virus RNA plasma viral load were associated with higher mortality. In a multivariate regression model, older age, elevated neutrophil count, increased AST, and higher viral load remained independently associated with death. All 11 (100%) patients with neutrophil counts of 4000 cells per mL or greater and viral loads of 5·1 log10 copies/mL or greater died (95% CI 72­100), compared with only three (11%) of 27 (95% CI 2­29) among patients with neutrophil counts of less than 4000 cells per mL and viral loads of less than 5·1 log10 copies/mL. INTERPRETATION: We identified clinical and laboratory predictors of mortality at hospital admission that could aid in the care of patients with yellow fever virus. Identification of these prognostic markers in patients could help clinicians prioritise admission to the intensive care unit, as patients often deteriorate rapidly. Moreover, resource allocation could be improved to prioritise key laboratory examinations that might be more useful in determining whether a patient could have a better outcome. Our findings support the important role of the virus in disease pathogenesis, suggesting that an effective antiviral could alter the clinical course for patients with the most severe forms of yellow fever

Severe yellow fever in Brazil: clinical characteristics and management.

BACKGROUND: Little is known about clinical characteristics and management of severe yellow fever as previous yellow fever epidemics often occurred in times or areas with little access to intensive care units (ICU). We aim to describe the clinical characteristics of severe yellow fever cases requiring admission to the ICU during the 2018 yellow fever outbreak in São Paulo, Brazil. Furthermore, we report on preliminary lessons learnt regarding clinical management of severe yellow fever. METHODS: Retrospective descriptive cohort study. Demographic data, laboratory test results on admission, clinical follow-up, and clinical outcomes were evaluated. RESULTS: From 10 January to 11 March 2018, 79 patients with laboratory confirmed yellow fever were admitted to the ICU in a tertiary hospital in Sao Paolo because of rapid clinical deterioration. On admission, the median AST was 7,000 IU/L, ALT 3,936 IU/L, total bilirubin 5.3 ml/dL, platelet 74 × 103/mm3, INR 2.24 and factor V 37%. Seizures occurred in 24% of patients, even without substantial intracranial hypertension. The high frequency of pancreatitis and rapidly progressive severe metabolic acidosis were notable findings. 73% of patients required renal replacement therapy. The in-hospital fatality rate was 67%. Patients with diabetes mellitus had a higher case fatality rate (CFR) of 80%, while patients without diabetes had a CFR of 65%. Leading causes of death were severe gastrointestinal bleeding, epileptic status, severe metabolic acidosis, necrohemorrhagic pancreatitis, and multi-organ failure. CONCLUSIONS: Severe yellow fever is associated with a high CFR. The following management lessons were learnt: Anticonvulsant drugs in patients with any symptoms of hepatic encephalopathy or arterial ammonia levels >70 µmol/L was commenced which reduced the frequency of seizures from 28% to 17%. Other new therapy strategies included early institution of plasma exchange. Due to the high frequency of gastric bleeding, therapeutic doses of intravenous proton pump inhibitors should be administered.

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

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

Predictors of mortality in patients with yellow fever: an observational cohort study.

BACKGROUND: Yellow fever virus infection results in death in around 30% of symptomatic individuals. The aim of this study was to identify predictors of death measured at hospital admission in a cohort of patients admitted to hospital during the 2018 outbreak of yellow fever in the outskirts of São Paulo city, Brazil. METHODS: In this observational cohort study, we enrolled patients with yellow fever virus from two hospitals in São Paolo-the Hospital das Clínicas, University of São Paulo and the Infectious Diseases Institute "Emilio Ribas". Patients older than 18 years admitted to hospital with fever or myalgia, headache, arthralgia, oedema, rash, or conjunctivitis were consecutively screened for inclusion in the present study. Consenting patients were included if they had travelled to geographical areas in which yellow fever virus cases had been previously confirmed. Yellow fever infection was confirmed by real-time PCR in blood collected at admission or tissues at autopsy. We sequenced the complete genomes of yellow fever virus from infected individuals and evaluated demographic, clinical, and laboratory findings at admission and investigated whether any of these measurements correlated with patient outcome (death). FINDINGS: Between Jan 11, 2018, and May 10, 2018, 118 patients with suspected yellow fever were admitted to Hospital das Clínicas, and 113 patients with suspected yellow fever were admitted to Infectious Diseases Institute "Emilio Ribas". 95 patients with suspected yellow fever were included in the study, and 136 patients were excluded. Three (3%) of 95 patients with suspected yellow fever who were included in the study were excluded because they received a different diagnosis, and 16 patients with undetectable yellow fever virus RNA were excluded. Therefore, 76 patients with confirmed yellow fever virus infection, based on detectable yellow fever virus RNA in blood (74 patients) or yellow fever virus confirmed only at the autopsy report (two patients), were included in our analysis. 27 (36%) of 76 patients died during the 60 day period after hospital admission. We generated 14 complete yellow fever virus genomes from the first 15 viral load-detectable samples. The genomes belonged to a single monophyletic clade of the South America I genotype, sub-genotype E. Older age, male sex, higher leukocyte and neutrophil counts, higher alanine aminotransferase, aspartate transaminase (AST), bilirubin, and creatinine, prolonged prothrombin time, and higher yellow fever virus RNA plasma viral load were associated with higher mortality. In a multivariate regression model, older age, elevated neutrophil count, increased AST, and higher viral load remained independently associated with death. All 11 (100%) patients with neutrophil counts of 4000 cells per mL or greater and viral loads of 5·1 log10 copies/mL or greater died (95% CI 72-100), compared with only three (11%) of 27 (95% CI 2-29) among patients with neutrophil counts of less than 4000 cells per mL and viral loads of less than 5·1 log10 copies/mL. INTERPRETATION: We identified clinical and laboratory predictors of mortality at hospital admission that could aid in the care of patients with yellow fever virus. Identification of these prognostic markers in patients could help clinicians prioritise admission to the intensive care unit, as patients often deteriorate rapidly. Moreover, resource allocation could be improved to prioritise key laboratory examinations that might be more useful in determining whether a patient could have a better outcome. Our findings support the important role of the virus in disease pathogenesis, suggesting that an effective antiviral could alter the clinical course for patients with the most severe forms of yellow fever. FUNDING: São Paulo Research Foundation (FAPESP).

Yellow fever: profile of cases and factors associated with death in a hospital in the State of Rio de Janeiro, 2017-2018 / Febre amarela: perfil dos casos e fatores associados ao óbito em hospital referência no estado do Rio de Janeiro, 2017-2018

ABSTRACT OBJECTIVE Describe the clinical and epidemiological profile of confirmed cases of yellow fever whose patients were hospitalized in a general hospital for infectious diseases in the State of Rio de Janeiro, Brazil, from March 11, 2017 to June 15, 2018, during a recent outbreak and factors associated with death. METHODS This is a retrospective observational study with analysis of secondary databases of local epidemiological surveillance system, and complementary data collection from epidemiological investigation records and clinical records. Study variables included demographic, epidemiological, clinical, and laboratory data. A descriptive statistical analysis and a bivariate and multivariate analysis by logistic regression were performed to analyze factors associated with death. RESULTS Fifty-two patients diagnosed with yellow fever were hospitalized, 86.5% male patients, median age 49.5 years, 40.4% rural workers. The most frequent signs and symptoms were fever (90.4%), jaundice (86.5%), nausea and/or vomiting (69.2%), changes in renal excretion (53.8%), bleeding (50%), and abdominal pain (48.1%), with comorbidity in 38.5% of all cases. The lethality rate was 40.4%. Factors significantly associated with a higher chance of death in the bivariate analysis were: bleeding, changes in renal excretion, and maximum values of direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine. In the multivariate analysis by logistic regression, only changes in renal excretion and ALT remained significant predictors of higher chance of death. A threshold effect was also observed for AST. The cutoff points identified as high risk for death were ALT > 4,000 U/L and AST > 6,000 U/L. CONCLUSIONS This study contributed to the knowledge on the profile of confirmed cases of high severity yellow fever. The main factors associated with death were changes in renal excretion and elevated serum transaminases, especially ALT. High lethality emphasizes the need for early diagnosis and treatment, and the importance of increasing vaccination coverage.

RESUMO OBJETIVO Descrever o perfil clínico-epidemiológico dos casos confirmados de febre amarela internados em hospital geral de referência para doenças infecciosas no estado do Rio de Janeiro, Brasil, de 11 de março de 2017 a 15 de junho de 2018, durante recente surto e fatores associados ao óbito. MÉTODOS Estudo observacional retrospectivo, com análise de bases de dados secundários da vigilância epidemiológica local e coleta complementar de dados nas fichas de investigação epidemiológica e prontuários clínicos. As variáveis analisadas incluíram dados demográficos, epidemiológicos, clínicos e laboratoriais. Foi conduzida análise estatística descritiva bivariada e múltipla por regressão logística para estudo de fatores associados ao óbito. RESULTADOS Foram internados 52 casos confirmados, 86,5% deles homens, com mediana de idade de 49,5 anos e 40,4% trabalhadores rurais. Os sinais e sintomas mais frequentes foram: febre (90,4%), icterícia (86,5%), náuseas e/ou vômitos (69,2%), alterações de excreção renal (53,8%), hemorragias (50%) e dor abdominal (48,1%), com comorbidade em 38,5% dos casos. A letalidade foi de 40,4%. Os fatores associados significativamente à maior chance de óbito na análise bivariada foram: hemorragia, alterações de excreção renal e valores máximos de bilirrubina direta, aspartato aminotransferase (AST), alanina aminotransferase (ALT), ureia e creatinina. Na análise múltipla por regressão logística, apenas alterações de excreção renal e ALT permaneceram como preditores significativos de maior chance de óbito. Observou-se ainda efeito limítrofe para AST. Os pontos de corte identificados como de alto risco para óbito foram ALT > 4.000 U/L e AST > 6.000 U/L. CONCLUSÕES O estudo contribuiu para o conhecimento do perfil de casos confirmados de febre amarela com gravidade alta. Os principais fatores associados ao óbito foram a alteração da excreção renal e a elevação sérica de transaminases, sobretudo a ALT. A letalidade elevada reforça a necessidade de diagnóstico e tratamento precoces, e a importância do incremento da cobertura vacinal.

Epidemiological monitoring of the last outbreak of yellow fever in Brazil - An outlook from Portugal.

BACKGROUND: Yellow Fever (YF) is a high fatality rate disease (30-50%) caused by Flavivirus, present in some African and South American countries. In order to determine the magnitude and epidemiological distribution of YF cases, vaccination coverage and most affected regions in Brazil, a descriptive epidemiological study monitoring the last outbreak was undertaken in Portugal. METHOD: The Brazilian database "Portal da Saude" was used to collect data on cases of YF. We used Microsoft Excel on a weekly basis to update the suspected, confirmed and mortality cases as well as the case fatality rate and epizootics in non-human primates. RESULTS: Case Fatality Rate was 33.6%. A total and 82% of confirmed cases were males. The outbreak predominantly affected two south-eastern states, Minas Gerais and Espírito Santo, both with a very low vaccination coverage. CONCLUSIONS: The last outbreak of YF was by far the largest observed over the last few decades! Until the emergence of this outbreak, Espírito Santo, Bahia and Rio de Janeiro were states of low risk for YF and the vaccine not previously recommended. The World Health Organization's "Global Strategy to Eliminate Yellow Fever Epidemic" (EYE) should be on the way, to prevent YF outbreaks in Brazil and other countries in Africa and South America.

Management and control of yellow fever virus: Brazilian outbreak January-April, 2018.

Yellow fever virus (YFV) has a long history of causing human disease. Today, YFV is persevered in jungle environments with occasional sporadic human outbreaks in South America and periodic intermediate human transmissions with occasional urban outbreaks in sub-Saharan Africa. The ever-present risk of outbreak is primarily controlled for via vaccination coverage to vulnerable human populations. Global vaccine supplies have been strained in the setting of recent outbreaks in Africa and Brazil. The increasingly global community of today has placed an ever-growing tension on the management and control of YFV. A historic outbreak of YFV in Brazil is tracked from January to April 2018 using the International Society for Infectious Diseases' (ISID) Program for Monitoring Emerging Diseases (ProMed). A narrative summary is generated from the review of 29 ProMed reports pertaining to the key words yellow fever and Brazil. Significant topics addressed include urban proximity, vaccination dose sparing with 1/5th standard dose, international travellers, epizootic trends, vaccine hesitancy, and mass immunisation campaigns. These topics are reviewed in detail for the current outbreak in comparison to previous outbreaks. Through close attention to these topics the degree and extent of the current outbreak was attenuated.

Non-specific effects of childhood vaccinations - A case control study nested into a Health and Demographic Surveillance System in rural Burkina Faso.

INTRODUCTION: Previous studies in African countries have been suggestive of non-specific effects (NSE) of vaccination on child survival. Live vaccines (e.g. measles, MV) have been found to reduce child mortality while inactivated vaccines (e.g. diphtheria-tetanus-pertussis, DTP) have been associated with increased mortality; NSE were often found to be sex-specific. METHODS: A case-control study nested into the Health and Demographic Surveillance System (HDSS) cohort of the Centre de Recherche en Santé de Nouna (CRSN) was conducted in northwestern Burkina Faso. A total of 3,010 children born in 2009-11, were included in the study, 375 cases and 2635 age and village matched controls. The main outcome measures were the mortality odds ratios for vaccinated versus unvaccinated children by antigen. The main outcome measures were the mortality odds ratios for vaccinated versus unvaccinated children by antigen. RESULTS: Most deaths occurred in late infancy, and there were significantly more deaths in males as compared to females (OR 1.29, CI 1.04-1.60). Overall, there was no statistically significant association between vaccine status and mortality. However, among children in the age group 2-8 months, there was a consistent sex-differential pattern for all doses of oral polio vaccine combined with pentavalent vaccine (OPV + Penta), with the vaccines being associated with lower mortality in boys, but not in girls. Routine MV + yellow fever vaccine was associated with reduced mortality, but only before mass vaccination campaigns with meningitis and measles vaccines took place. CONCLUSIONS: The findings of this study provide further support on the existence of NSE of childhood vaccinations in a large population of rural Burkina Faso. More randomized controlled trials are needed to confirm these observations.

Is the absence or intermittent YF vaccination the major contributor to its persistent outbreaks in eastern Africa?

Despite the availability of a safe and efficacious yellow fever vaccine since 1937, yellow fever remains a public health threat as a re-emerging disease in Africa and South America. We reviewed the trend of reported yellow fever outbreaks in eastern African countries, identified the risk epidemiological factors associated with the outbreaks and assessed the current situation of Yellow Fever vaccination in Africa. Surveillance and case finding for yellow fever in Africa are insufficient primarily due to lack of appropriate diagnostic capabilities, poor health infrastructure resulting in under-recognition, underreporting and underestimation of the disease. Despite these challenges, Ethiopia reported 302,614 cases (30,505 deaths) in 1943-2015, Kenya had 207 cases (38 deaths) in 1992-2016, Sudan experienced 31,750 suspected cases (1855 deaths) from 1940 to 2012 and Uganda had 452 cases (65 deaths) in 1941-2016. Major risk factors associated with past yellow fever outbreaks include climate, human practices and virus genetics. Comparisons between isolates from different outbreaks after 45 years have revealed the genetic stability of the structural proteins of YFV which are the primary targets of the host immune cells. This probably explains why yellow fever 17D vaccine is considered as outstandingly efficacious and safe after being used for 75 years. However, the 14 amino-acid changes among these isolates may have a greater impact on the changing disease epidemiology, virulence and transmission rate. Low population immunity against YF influences outbreak frequency especially in countries where the incorporation of YF vaccination is not combined with mass vaccination campaigns or vaccination is limited to international travellers. Understanding Yellow fever virus epidemiology as determined by its evolution underscores appropriate disease mitigation strategies and immunization policies. Mobilizing scarce resources to enhance population immunity through sufficient vaccination, promoting environmental sanitation/hygienic practices, driving behavioral change and community-based vector control are significant to preventing future epidemics.

Spread of yellow fever virus outbreak in Angola and the Democratic Republic of the Congo 2015-16: a modelling study.

BACKGROUND: Since late 2015, an epidemic of yellow fever has caused more than 7334 suspected cases in Angola and the Democratic Republic of the Congo, including 393 deaths. We sought to understand the spatial spread of this outbreak to optimise the use of the limited available vaccine stock. METHODS: We jointly analysed datasets describing the epidemic of yellow fever, vector suitability, human demography, and mobility in central Africa to understand and predict the spread of yellow fever virus. We used a standard logistic model to infer the district-specific yellow fever virus infection risk during the course of the epidemic in the region. FINDINGS: The early spread of yellow fever virus was characterised by fast exponential growth (doubling time of 5-7 days) and fast spatial expansion (49 districts reported cases after only 3 months) from Luanda, the capital of Angola. Early invasion was positively correlated with high population density (Pearson's r 0·52, 95% CI 0·34-0·66). The further away locations were from Luanda, the later the date of invasion (Pearson's r 0·60, 95% CI 0·52-0·66). In a Cox model, we noted that districts with higher population densities also had higher risks of sustained transmission (the hazard ratio for cases ceasing was 0·74, 95% CI 0·13-0·92 per log-unit increase in the population size of a district). A model that captured human mobility and vector suitability successfully discriminated districts with high risk of invasion from others with a lower risk (area under the curve 0·94, 95% CI 0·92-0·97). If at the start of the epidemic, sufficient vaccines had been available to target 50 out of 313 districts in the area, our model would have correctly identified 27 (84%) of the 32 districts that were eventually affected. INTERPRETATION: Our findings show the contributions of ecological and demographic factors to the ongoing spread of the yellow fever outbreak and provide estimates of the areas that could be prioritised for vaccination, although other constraints such as vaccine supply and delivery need to be accounted for before such insights can be translated into policy. FUNDING: Wellcome Trust.

Epidemiological characteristics of yellow fever in Brazil, 2000-2012. / Características epidemiológicas da febre amarela no Brasil, 2000-2012.

OBJECTIVE: this study aims to describe the epidemiological characteristics of yellow fever in Brazil in the period 2000-2012. METHODS: this is a descriptive ecological epidemiological study, using information from Ministry of Health databases. RESULTS: 326 cases of yellow fever were confirmed in Brazil during this period, with 156 deaths and an average case fatality rate of 47.8%; the young male adult age group was the most affected; in epizootic terms, 2,856 suspected cases of yellow fever in non-human primates were reported and 31.1% of these were confirmed by laboratory tests; during the study period the area in which sylvatic transmission of the disease occurs was found to have expanded to densely population regions, such as South, Southeast and Midwest Brazil. CONCLUSION: the risk of urban yellow fever transmission persists, as sylvatic incidence of the disease has expanded to regions with high Aedes aegypti infestation, this being the mosquito responsible for urban transmission of the disease.