Luis Villar - Academia.edu (original) (raw)

Papers by Luis Villar

Memórias do Instituto Oswaldo Cruz, 2006

We have investigated the temporal distribution of dengue (DEN) virus serotypes in the department ... more We have investigated the temporal distribution of dengue (DEN) virus serotypes in the department (state) of Santander, Colombia, in relation to dengue incidence, infection pattern, and severity of disease. Viral isolation was attended on a total of 1452 acute serum samples collected each week from 1998 to 2004. The infection pattern was evaluated in 596 laboratory-positive dengue cases using an IgG ELISA, and PRNT test. The dengue incidence was documented by the local health authority.

Severe dengue (SD) is a major cause of morbidity and mortality impacting approximately 5 million ... more Severe dengue (SD) is a major cause of morbidity and mortality impacting approximately 5 million of the 400 million people infected with dengue virus (DENV) annually. To define DENV target cells and immunological hallmarks of SD progression in children’s blood, we integrated virus-inclusive single cell RNA-Seq 2 (viscRNA-Seq 2) with functional assays. Beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells. Alterations in cell type abundance, gene and protein expression and secretion, and cell-cell communications point towards increased migration and inflammation in SD progressors (SDp). Concurrently, antigen presenting cells from SDp demonstrate intact uptake, yet impaired interferon responses and antigen presentation, in part DENV-modulated. Increased activation, regulation, and exhaustion of effector responses and expansion of HLA-DR-expressing, possibly compensatory, adaptive-like NK cells also characterize SDp. These fin...

Genome Medicine

Background Each year 3–6 million people develop life-threatening severe dengue (SD). Clinical war... more Background Each year 3–6 million people develop life-threatening severe dengue (SD). Clinical warning signs for SD manifest late in the disease course and are nonspecific, leading to missed cases and excess hospital burden. Better SD prognostics are urgently needed. Methods We integrated 11 public datasets profiling the blood transcriptome of 365 dengue patients of all ages and from seven countries, encompassing biological, clinical, and technical heterogeneity. We performed an iterative multi-cohort analysis to identify differentially expressed genes (DEGs) between non-severe patients and SD progressors. Using only these DEGs, we trained an XGBoost machine learning model on public data to predict progression to SD. All model parameters were “locked” prior to validation in an independent, prospectively enrolled cohort of 377 dengue patients in Colombia. We measured expression of the DEGs in whole blood samples collected upon presentation, prior to SD progression. We then compared th...

Biomédica, 2006

tiene alta sensibilidad, pero es muy inespecífica. Objetivo. Formular una escala diagnóstica de m... more tiene alta sensibilidad, pero es muy inespecífica. Objetivo. Formular una escala diagnóstica de mayor exactitud que la definición de la OMS para la identificación clínica temprana del dengue en áreas endémicas. Materiales y métodos. En una cohorte de adultos (>12 años) con síndrome febril agudo sin causa aparente en Bucaramanga, Colombia, compuesta por 125 casos de dengue (confirmados serológica o virológicamente) y 126 de síndrome febril de otra etiología, se determinaron las manifestaciones clínicas tempranas (en los primeros cuatro días de la enfermedad) asociadas al dengue y con ellas se formularon y evaluaron diversas combinaciones diagnósticas. Resultados. La escala compuesta por exantema, prueba de torniquete positiva, ausencia de rinorrea, artralgias, ausencia de diarrea (1 punto por cada hallazgo), recuentos de leucocitos <4.000/mm 3 (3 puntos) y plaquetas <180.000/mm 3 (2 puntos) exhibió un área bajo la curva de características operador-receptor de 81,04%, superior a la observada con los criterios de la OMS de 69,96% (p=0,0003). Con ≥3 puntos se obtuvo una sensibilidad de 95,2%; una especificidad de 27,8%; un valor diagnóstico positivo de 56,7%; un valor diagnóstico negativo de 85,4%. Con ≥6 puntos se obtuvo una sensibilidad de 70,4%; una especificidad de 78,6%; un valor diagnóstico positivo de 76,5%; un valor diagnóstico negativo de 72,8%. Con ≥8 puntos se obtuvo una sensibilidad de 42,4%; una especificidad de 96%; un valor diagnóstico positivo de 91,4%; un valor diagnóstico negativo de 62,7%. Con 9 o 10 puntos, la especificidad y el valor diagnóstico positivo fueron de 100%. Conclusión. La escala descrita puede ser útil para el diagnóstico clínico temprano del dengue en áreas endémicas. Palabras clave: dengue, diagnóstico clínico, Organización Mundial de la Salud, recuento de leucocitos, recuento de plaquetas. Clinical criteria to diagnose dengue in its early stages Introduction. Clinical differentiation of dengue from other diseases with similar symptoms is difficult. The case definition of the World Health Organization (WHO) has high sensitivity but its specificity is very low. Objective. A diagnostic scale was formulated for early clinical diagnosis of dengue that provided greater accuracy than that of the WHO definition. Materials and methods. A cohort of 251 adults (>12 years of age) with unspecific acute febrile syndrome was selected from clinics located in Bucaramanga, Colombia. They consisted of 125 cases of dengue (serologically and/or virologically confirmed) and 126 with other febrile diseases. Clinical manifestations encountered during the first four days of dengue disease were determined, along with the diverse diagnostic combinations that were presented. Results: The scale consisted of the following criteria: presence of rash, positive tourniquet test, absence of nasal discharge, arthralgias, absence of diarrhea (1 point for each finding), leukocyte count < 4,000/mm3 (3 points) and platelet count <180.000/mm3 (2 points). In a receiver-operating-characteristic curve, the predictive area of 81.0% was significantly superior to the one produced with WHO criteria, (70.0%, p<0.001). Febrile syndrome with at least a 3 point score obtained the following values: sensitivity= 95.2%; specificity=27.8%; positive predictive value=56.7%; negative predicative value=85.4%. With a 6-point score,

Emerging Infectious Diseases, 2022

PLOS Neglected Tropical Diseases, 2020

Population based serological surveys are the gold-standard to quantify dengue (DENV) transmission... more Population based serological surveys are the gold-standard to quantify dengue (DENV) transmission. The purpose of this study was to estimate the age-specific seroprevalence and the force of infection of DENV in an endemic area of Colombia. Between July and October 2014, we conducted a household based cross-sectional survey among 1.037 individuals aged 2 to 40 years living in 40 randomly selected locations in urban Piedecuesta, Santander, Colombia. In addition, we also enrolled 246 indviduals living in rural "veredas". Participants were asked to answer a questionnaire that included demographic, socioeconomic and environmental questions and to provide a 5 ml blood sample. Sera were tested using the IgG indirect ELISA (Panbio) kit to determine past DENV infection. The overall DENV seroprevalence was 70% (95% CI = 67%-71%), but was significantly higher in urban (81%, 95% CI = 78%-83%) as compared to rural (21%, 95% CI = 17%-27%) locations. Age was a major predictor of seropositivity, consistent with endemic circulation of the virus. Using catalytic models we estimated that on average, 12% (95%CI = 11%-13%) of susceptible individuals living in the city are infected by DENV each year. Beyond age, the only predictor of seropositivity in urban locations was prior history of dengue diagnosed by a physician (aPR 1.15, 95% CI = 0.98-1.35). Among participants living in rural settings, those that reported traveling outside of their vereda were more likely to be seropositive (aPR 3.60, 95%CI = 1.54-8.42) as well as those who were born outside of Santander department (aPR = 2.77, 95%CI = 1.20-6.37). These results are consistent with long term endemic circulation of DENV in Piedecuesta, with large heterogeneities between urban and rural areas located just a few kilometers apart. Design of DENV control interventions, including vaccination, will need to consider this fine scale spatial heterogeneity.

Since its 2013 emergence in the Americas, chikungunya virus (CHIKV) has posed a serious threat to... more Since its 2013 emergence in the Americas, chikungunya virus (CHIKV) has posed a serious threat to public health. Early and accurate diagnosis of the disease, though currently lacking in clinics, is integral to enable timely care and epidemiological response. We developed a dual detection system: a CHIKV antigen E1/E2-based enzyme-linked immunosorbent assay (ELISA) and a lateral flow test using high-affinity anti-CHIKV antibodies. The ELISA was validated with 100 PCR-tested acute Chikungunya fever samples from Honduras. The assay had an overall sensitivity and specificity of 51% and 96.67%, respectively, with accuracy reaching 95.45% sensitivity and 92.03% specificity at a Ct cutoff of 22. As the Ct value increased from 22, ELISA sensitivity decreased. We then developed and validated two lateral flow tests using independent antibody pairs. The sensitivity and specificity reached 100% for both lateral flow tests using 39 samples from Colombia and Honduras at Ct cutoffs of 20 and 27, r...

The British journal of nutrition, Jan 14, 2018

PUFA might modulate inflammatory responses involved in the development of severe dengue. We aimed... more PUFA might modulate inflammatory responses involved in the development of severe dengue. We aimed to examine whether serum PUFA concentrations in patients diagnosed with dengue fever (DF) were related to the risk of progression to dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS). A secondary aim was to assess correlations between fatty acids (FA) and inflammatory biomarkers in patients with DF. We conducted a prospective case-control study nested within a cohort of patients who were diagnosed with DF and followed during the acute episode. We compared the distribution of individual FA (% of total FA) at onset of fever between 109 cases who progressed to DHF/DSS and 235 DF non-progressing controls using unconditional logistic regression. We estimated correlations between baseline FA and cytokine concentrations and compared FA concentrations between the acute episode and >1 year post-convalescence in a subgroup. DHA was positively related to progression to DHF/DSS (multivar...

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 30, 2017

We previously reported that vaccination with the tetravalent dengue vaccine (CYD-TDV; Dengvaxia) ... more We previously reported that vaccination with the tetravalent dengue vaccine (CYD-TDV; Dengvaxia) may bias the diagnosis of dengue based on immunoglobulin M (IgM) and immunoglobulin G (IgG) assessments. We undertook a post hoc pooled analysis of febrile episodes that occurred during the active surveillance phase (the 25 months after the first study injection) of 2 pivotal phase III, placebo-controlled CYD-TDV efficacy studies that involved ≥31000 children aged 2-16 years across 10 countries in Asia and Latin America. Virologically confirmed dengue (VCD) episode was defined with a positive test for dengue nonstructural protein 1 antigen or dengue polymerase chain reaction. Probable dengue episode was serologically defined as (1) IgM-positive acute- or convalescent-phase sample, or (2) IgG-positive acute-phase sample and ≥4-fold IgG increase between acute- and convalescent-phase samples. There were 1284 VCD episodes (575 and 709 in the CYD-TDV and placebo groups, respectively) and 1767...

PLoS neglected tropical diseases, 2017

Dengue fever is a major public health concern in many parts of the tropics and subtropics. The fi... more Dengue fever is a major public health concern in many parts of the tropics and subtropics. The first dengue vaccine has already been licensed in six countries. Given the growing interests in the effective use of the vaccine, it is critical to understand the economic burden of dengue fever to guide decision-makers in setting health policy priorities. A standardized cost-of-illness study was conducted in three dengue endemic countries: Vietnam, Thailand, and Colombia. In order to capture all costs during the entire period of illness, patients were tested with rapid diagnostic tests on the first day of their clinical visits, and multiple interviews were scheduled until the patients recovered from the current illness. Various cost items were collected such as direct medical and non-medical costs, indirect costs, and non-out-of-pocket costs. In addition, socio-economic factors affecting disease severity were also identified by adopting a logit model. We found that total cost per episode ...

BMC infectious diseases, Jul 10, 2017

Dengue has been prevalent in Colombia with high risk of outbreaks in various locations. While the... more Dengue has been prevalent in Colombia with high risk of outbreaks in various locations. While the prediction of dengue epidemics will bring significant benefits to the society, accurate forecasts have been a challenge. Given competing health demands in Colombia, it is critical to consider the effective use of the limited healthcare resources by identifying high risk areas for dengue fever. The Climate Risk Factor (CRF) index was constructed based upon temperature, precipitation, and humidity. Considering the conditions necessary for vector survival and transmission behavior, elevation and population density were taken into account. An Early Warning Signal (EWS) model was developed by estimating the elasticity of the climate risk factor function to detect dengue epidemics. The climate risk factor index was further estimated at the smaller geographical unit (5 km by 5 km resolution) to identify populations at high risk. From January 2007 to December 2015, the Early Warning Signal mode...

Nature, Jun 24, 2017

Although the recent Zika virus (ZIKV) epidemic in the Americas and its link to birth defects have... more Although the recent Zika virus (ZIKV) epidemic in the Americas and its link to birth defects have attracted a great deal of attention, much remains unknown about ZIKV disease epidemiology and ZIKV evolution, in part owing to a lack of genomic data. Here we address this gap in knowledge by using multiple sequencing approaches to generate 110 ZIKV genomes from clinical and mosquito samples from 10 countries and territories, greatly expanding the observed viral genetic diversity from this outbreak. We analysed the timing and patterns of introductions into distinct geographic regions; our phylogenetic evidence suggests rapid expansion of the outbreak in Brazil and multiple introductions of outbreak strains into Puerto Rico, Honduras, Colombia, other Caribbean islands, and the continental United States. We find that ZIKV circulated undetected in multiple regions for many months before the first locally transmitted cases were confirmed, highlighting the importance of surveillance of viral...

Biomédica, 2015

Introducción. El dengue y sus manifestaciones agudas se han descrito ampliamente en la literatura... more Introducción. El dengue y sus manifestaciones agudas se han descrito ampliamente en la literatura, sin embargo, los síntomas en la fase de convalecencia se han estudiado poco.Objetivo. Describir las manifestaciones clínicas de una población durante su periodo de convalecencia de un episodio de dengue.Materiales y métodos. Se hizo un estudio observacional en sujetos que estuvieron hospitalizados con dengue diagnosticado por serología. Después del alta se les visitó para evaluar la persistencia de la sintomatología clínica, la fatiga (evaluada mediante el Fatigue Questionnaire de Chalder) y la calidad de vida (evaluada mediante el cuestionario EuroQoL-5D). Se determinó como fatiga significativa aquella con un puntaje igual o superior a cuatro en la escala empleada. Se hizo seguimiento telefónico y domiciliario de los participantes con fatiga hasta tres meses después del alta hospitalaria.Resultados. La prevalencia de fatiga en los 32 sujetos seleccionados (edad media: 35 años, sexo fe...

The New England journal of medicine, Jan 24, 2016

The control groups in two phase 3 trials of dengue vaccine efficacy included two large regional c... more The control groups in two phase 3 trials of dengue vaccine efficacy included two large regional cohorts that were followed up for dengue infection. These cohorts provided a sample for epidemiologic analyses of symptomatic dengue in children across 10 countries in Southeast Asia and Latin America in which dengue is endemic. We monitored acute febrile illness and virologically confirmed dengue (VCD) in 3424 healthy children, 2 to 16 years of age, in Asia (Indonesia, Malaysia, the Philippines, Thailand, and Vietnam) from June 2011 through December 2013 and in 6939 children, 9 to 18 years of age, in Latin America (Brazil, Colombia, Honduras, Mexico, and Puerto Rico) from June 2011 through April 2014. Acute febrile episodes were determined to be VCD by means of a nonstructural protein 1 antigen immunoassay and reverse-transcriptase-polymerase-chain-reaction assays. Dengue hemorrhagic fever was defined according to 1997 World Health Organization criteria. Approximately 10% of the febrile ...

International Journal of Infectious Diseases, 2015

Background Dengue is an emerging infectious disease of global importance with 2.5 to almost 4 bil... more Background Dengue is an emerging infectious disease of global importance with 2.5 to almost 4 billion people residing in dengue endemic countries in which an estimated 50-100 million infections occur annually. 1,2 Historically, the highest risk areas for dengue fever were in Southeast Asia and the western Pacific (where approximately 75% of the global disease burden is located). However, the risk of dengue, and severe dengue, is increasing in the Americas following disease re-emergence after lapsed vector control programs. 3 Between 2000 and 2006, the majority of cases reported (68%) were registered in this region. 4 Cyclical outbreaks of dengue in the Caribbean, and Central and South America have resulted in considerable morbidity and mortality. In 2013, 2.35 million cases of dengue were reported in the Americas, of which 37,687 cases were classified as severe dengue, with Brazil and Colombia recording the highest incidence. Dengue is an important consideration in the differential diagnosis of fever in endemic countries and in travelers returning from these regions. 5 Dengue infection presents with a wide spectrum of signs and symptoms, including rapid onset of fever that may be accompanied by myalgia, arthralgia, retro-orbital pain, facial flushing, erythema, nausea, vomiting, cutaneous

BMC Infectious Diseases, 2015

Background: Dengue is a viral disease whose clinical spectrum ranges from unapparent to severe fo... more Background: Dengue is a viral disease whose clinical spectrum ranges from unapparent to severe forms and fatal outcomes. Although dengue death is 99 % avoidable, every year around 20,000 deaths are estimated to occur in more than 100 countries. We consider that, along with biological factors, social determinants of health (SDHs) are related to dengue deaths as well. Methods: A scoping review was conducted to explore what has been written about the role of SDHs in dengue mortality. The inclusion criteria were that documents (grey or peer-reviewed) had to include information about dengue fatal cases in humans and be published between 1997 and 2013 and written in English, Spanish, Portuguese or French. The search was conducted using a set of key words related to dengue mortality in several electronic databases: PubMed, LILACS, COCHRANE, Scielo, Science Direct, WHOLIS, OpenGrey, OpenSingle and Google Scholar. Information on SDHs was categorized under individual, social and environmental, and health systems dimensions. A summative content analysis using QDA Miner was conducted to assess the frequency of information on SDHs and its contextual meaning in the reviewed literature. The role of each SDH in dengue mortality was assessed using content analysis results. Results: From a total of 971 documents retrieved, 78 met the criteria. Those documents were published in the Americas region (50.0 %), Asia (38.4 %), Europe (9.0 %) and Africa (2.6 %). The described SDHs related to dengue deaths included, in the individual dimension: age, ethnicity, education, type of infection and immunological status; and in the social dimension: poverty and care-seeking behavior. The health systems dimension included access, opportunity, and quality of care, as well as health staff knowledge. Ethnicity was considered a determinant that depends on cultural and socioeconomic conditions. Conclusions: Along with biological factors, there are several SDHs related to dengue mortality. However, only a few of these have been systematically analyzed, suggesting the need for more studies on this subject to inform the design and implementation of sustainable interventions to decrease dengue mortality. These findings nevertheless provide a better understanding of the non-biological factors involved in dengue mortality.

PLOS Neglected Tropical Diseases, 2015

A systematic literature review was conducted to describe the epidemiology of dengue disease in Co... more A systematic literature review was conducted to describe the epidemiology of dengue disease in Colombia. Searches of published literature in epidemiological studies of dengue disease encompassing the terms "dengue", "epidemiology," and "Colombia" were conducted. Studies in English or Spanish published between 1 January 2000 and 23 February 2012 were included. The searches identified 225 relevant citations, 30 of which fulfilled the inclusion criteria defined in the review protocol. The epidemiology of dengue disease in Colombia was characterized by a stable "baseline" annual number of dengue fever cases, with major outbreaks in 2001-2003 and 2010. The geographical spread of dengue disease cases showed a steady increase, with most of the country affected by the 2010 outbreak. The majority of dengue disease recorded during the review period was among those <15 years of age. Gaps identified in epidemiological knowledge regarding dengue disease in Colombia may provide several avenues for future research, namely studies of asymptomatic dengue virus infection, primary versus secondary infections, and under-reporting of the disease. Improved understanding of the factors that determine disease expression and enable improvement in disease control and management is also important.