Asymptomatic Dengue Infection Research Articles

An epidemiological study of dengue in Delhi, India

Delhi, the capital of India, is an important metropolitan hub for major financial and sociocultural exchanges, offering challenging threats to current public health infrastructure. In recent past, an upsurge of dengue cases in Delhi posed a significant menace to the existing dengue control policies. To reform the control strategies and take timely intervention to prevent future epidemics, an epidemiological study on the proportion of both asymptomatic and symptomatic dengue infections in selected population was conducted. The aim of the study was to investigate and assess the epidemiology of dengue infection and to estimate the proportion of asymptomatic and symptomatic dengue infections in Delhi. In this study, around 50 confirmed dengue cases, a total of 2125 individuals as household and neighbourhood contacts, with or without dengue febrile illness, were finger pricked and serologically detected as dengue positive or negative using SD Duo Bioline Rapid Diagnostic Test (SD Inc, Korea) with NS1, IgM & IgG combo test, which detected dengue virus antigen and antibodies to dengue virus in human blood. Out of 2125 individuals, 768 (36.1%) individuals showed positive dengue test with past (25.5%), primary (1.88%) or secondary (8.8%) dengue infections. Higher percentage of IgG was found in age groups 15–24 years and 25–50 years (36% each). Infants (<1 year) presented higher incidence of new infections (22% of NS1+IgM positives) as compared to adults. Further analysis revealed that out of the 226 newly infected cases (including NS1 and IgM positives), 142 (63%) were asymptomatic and 84 (37%) were symptomatic, as per WHO guidelines. Our findings also suggest that out of the total population screened, 10.6% dengue infection was either primary or secondary. On the basis of these results, it may be hypothesized that there are large number of asymptomatic dengue infections in the community as compared to reported symptomatic cases in Delhi. For the effective control of dengue transmission in such community like Delhi where dengue epidemics have frequently been encountered, it is essential to ascertain the proportion of asymptomatic dengue infections which may act as a reservoir for dengue transmission, as well as threat for developing dengue haemorrhagic fever (DHF).

Association of FcγRIIa Polymorphism with Clinical Outcome of Dengue Infection: First Insight from Pakistan.

Dengue illness has been a major health concern in Pakistan during the last decade. Dengue infection can result in a spectrum of clinically distinct outcomes, ranging from asymptomatic infection to potentially life-threatening forms of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). A single-nucleotide polymorphism in FcγRIIa (rs1801274) results in altered affinity of the receptor for different subclasses of immunoglobulin G, and is a key player in determining the susceptibility to or protection from severe clinical infection of dengue. In this study, we analyzed the allelic and genotypic distribution of rs1801274 in subjects of Pakistani origin with subclinical dengue infection (n = 40), dengue fever (DF) (n = 40), and DHF/DSS (n = 30). We found that HH homozygotes and heterozygotes were significantly more likely to develop clinical dengue (odds ratio [OR] = 3.21, 95% confidence interval [CI] = 1.29-7.97, P = 0.009), either DF (OR = 2.82, 95% CI = 1.00-7.97, P = 0.045) or DHF/DSS (OR = 3.90, 95% CI = 1.13-13.07, P = 0.024) than the asymptomatic dengue infection. Results of allelic distribution comparisons and logistic regression analysis also supported the same relationship. The results suggest complex nature of interacting factors in determining the course for severe dengue illness.

Epidemiological trends of dengue disease in Colombia (2000-2011): a systematic review.

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.

Contrasting associations of polymorphisms in FcγRIIa and DC-SIGN with the clinical presentation of dengue infection in a Mexican population

Dengue virus (DENV) causes a spectrum of illness from asymptomatic infection, to a mild febrile illness, to occasional more severe complications including hemorrhage and shock. Dengue is endemic in the state of Morelos, Mexico. Two single nucleotide polymorphisms (SNPs), rs1801274 of FcγRIIa and rs4804803 of DC-SIGN, have been associated with protection from or susceptibility to severe dengue infection. Both of these polymorphisms are located in genes for receptors with important roles in dengue pathogenesis, and their relationship with the clinical presentation of dengue infection in Mexican populations is unknown. In this study, real-time PCR was used to characterize the distribution of rs1801274 and rs4804803 in subjects with asymptomatic dengue infection (n=145), uncomplicated dengue (n=67), and severe dengue (n=36) in Morelos. In contrast with previous studies, the histidine (A) variant of rs1801274 was associated with more mild infection: carrying the histidine allele (either homozygous or heterozygous) was associated with protection from symptomatic infection compared with asymptomatic (OR 0.51, p=0.038). Histidine homozygotes were also less likely to present severe dengue (OR 0.34, p=0.05). Logistic regression models confirm this association (OR 0.48, p=0.04) and also indicate that the G allele of rs4804803 is associated with symptomatic dengue (OR 2.3, p=0.08), after accounting for other biological factors including history of infection. This variant was rare in this study population, with a frequency of 5.4%. These findings reflect the complexity of influences on the development of severe dengue infection. The inclusion of asymptomatic infections and adjusted case definitions likely do not explain the entire disparity with previous findings. Interactions with other polymorphisms may explain why the association of rs1801274 is reversed in this population compared to others. This study demonstrates the importance of genetic association studies in multiple genetically distinct populations.

Lack of Clinical Manifestations in Asymptomatic Dengue Infection Is Attributed to Broad Down-Regulation and Selective Up-Regulation of Host Defence Response Genes

ObjectivesDengue represents one of the most serious life-threatening vector-borne infectious diseases that afflicts approximately 50 million people across the globe annually. Whilst symptomatic infections are frequently reported, asymptomatic dengue remains largely unnoticed. Therefore, we sought to investigate the immune correlates conferring protection to individuals that remain clinically asymptomatic.MethodsWe determined the levels of neutralizing antibodies (nAbs) and gene expression profiles of host immune factors in individuals with asymptomatic infections, and whose cognate household members showed symptoms consistent to clinical dengue infection.ResultsWe observed broad down-regulation of host defense response (innate, adaptive and matrix metalloprotease) genes in asymptomatic individuals as against symptomatic patients, with selective up-regulation of distinct genes that have been associated with protection. Selected down-regulated genes include: TNF α (TNF), IL8, C1S, factor B (CFB), IL2, IL3, IL4, IL5, IL8, IL9, IL10 and IL13, CD80, CD28, and IL18, MMP8, MMP10, MMP12, MMP15, MMP16, and MMP24. Selected up-regulated genes include: RANTES (CCL5), MIP-1α (CCL3L1/CCL3L3), MIP-1β (CCL4L1), TGFβ (TGFB), and TIMP1.ConclusionOur findings highlight the potential association of certain host genes conferring protection against clinical dengue. These data are valuable to better explore the mysteries behind the hitherto poorly understood immunopathogenesis of subclinical dengue infection.

Dengue Fever in South Korea, 2006–2010

To the Editor: Dengue fever is an acute, febrile disease caused by a flavivirus and is transmitted by Aedes spp. mosquitoes (1). South Korea is not considered as a region to which dengue virus is endemic because it is located above 35°N latitude and has an isotherm of 10°C in winter, which potentially limits year-round survival of Aedes aegypti mosquitoes (1,2). Thus, dengue fever was seldom recognized as a public health concern in South Korea. However, the first case of dengue fever in South Korea was reported in 1995 in a woman who had traveled to Sri Lanka (3). A second case was found in a sailor who had worked in countries in Africa in 2000 (4). Since 2001, dengue fever has been a notifiable infectious disease in South Korea because of concerns about increasing international travel as a source of infection and because the less efficient potential dengue vector, Ae. albopictus mosquitoes, were found in this country. All cases reported through the surveillance system should be complemented by thorough epidemiologic investigations to determine whether a case was imported or originated in South Korea. Thus, we analyzed dengue fever–associated data from the Korea Centers for Disease Control and Prevention. During 2006–2010, a total of 367 suspected cases were reported by physicians through the National Infectious Disease Surveillance System. IgM ELISA and reverse transcription PCR results identified 324 cases as dengue fever. Investigation of 34 cases could not be completed because some cases were in foreigners and in Korean persons who resided in foreign countries, left South Korea after diagnosis, or could not be reached by the contact information that was provided. Investigation of 290 cases was completed by reviewing medical records and by interviews. Interviews were conducted by provincial and Korea Centers for Disease Control and Prevention Epidemic Intelligence Service officers, who used a standardized investigation form. All 290 case-patients had a history of international travel before onset of dengue fever symptoms. Destination information was available for all 290 case-patients; 17 countries were identified. Visitors to the Philippines (34.1%) contributed the largest number of cases, followed by visitors to Indonesia, India, Thailand, Vietnam, Cambodia, Laos, Malaysia, Myanmar, Bangladesh, China, East Timor, Maldives, Palau, Sri Lanka, Brazil, and Nigeria (Table). These countries are in areas to which dengue fever is endemic or have reported cases (1). Table Presumptive country of origin of imported dengue fever cases, South Korea, 2006–2010 The time interval between the last day of travel and symptom onset was known for 272 (93.8%) of the 290 case-patients. A total of 271 case-patients had traveled within 14 days before symptom onset, and 89 (32.7%) had symptom onset or were given a diagnosis of dengue fever during travel. Symptoms developed within 7 days after travel in 171 (62.9%) persons and 8–14 days after travel in 11 (4.0%) persons. Mean ± SD duration from the last day of travel to symptom onset among 182 case-patients who had symptom onset after travel was 3.20 ± 2.61 days. Our results indicate that all investigated case-patients had a history of international travel and times of symptom onset during or after travel but within the incubation period for dengue infection. One case-patient had a time to symptom onset of <34 days. This person was eventually given a diagnosis of infection with Epstein-Barr virus but was tested for dengue virus. Because the incubation period exceeded that for dengue virus incubation, this case was classified as an asymptomatic dengue virus infection and an Epstein-Barr virus infection. Most dengue cases in South Korea are likely imported, and most presumptive countries from which dengue fever originated are in Southeast and southern Asia. These countries are popular holiday destinations for persons from South Korea. Because of distances, few tourists from South Korea travel to Africa and South America (5). China is the most popular destination for travelers from South Korea. However, the proportion of persons who acquired dengue infection in China was low (0.7%) because most persons who traveled to China went to Beijing or Shanghai, not to areas in southern China where dengue epidemics have occurred (5,6). We report that all dengue fever cases in South Korea during 2006–2010 were imported by persons who had traveled abroad. Global expansion of dengue virus and an increase in international travelers have increased the likelihood of additional cases of dengue fever. In addition, Ae. albopictus mosquitoes have been detected in South Korea and can potentially transmit autochthonous dengue infection, as reported in Croatia, France, and Hawaii, USA (7–9). Thus, more intensified surveillance and investigations should be focused on dengue transmission by Ae. albopictus mosquitoes in South Korea.

Eventual Role of Asymptomatic Cases of Dengue for the Introduction and Spread of Dengue Viruses in Non-Endemic Regions

In dengue virus infections the asymptomatic cases are much more frequent than the symptomatic ones, but their true role in the introduction and subsequent spread of dengue viruses in non-endemic regions remains to de clarified. We analyzed data from English and French literatures to assess if viremia in asymptomatic dengue infections might be sufficient to represent a true risk. During outbreaks of dengue a large number of individuals are infected and since viremia levels in symptomatic patients are known to vary by many orders of magnitude, it is reasonable to augur that a proportion of asymptomatic cases might reach levels of viremia sufficient to infect competent mosquitoes. In addition, a number of new ways of contamination in man by dengue viruses were recently described such as blood transfusion, bone marrow transplantation, and nosocomial infections that may be worth considering.

Infeksi Virus Dengue Tanpa Gejala pada Keluarga Penderita DBD di Provinsi Jawa Barat

Background: Dengue Hemorrhagic Fever (DHF) in Indonesia shows an increasing trend since it was first reported in 1968. Based on data from 2003 to 2007, all districts in West Java province had reported outbreak of DHF. Dengue virus transmission iS. kept up by the presence of virus in the infective host in human and/or mosquitoes. Methods: A cross-sectional research was conducted to obtain the incidence of asymptomatic dengue infections in family members of the individual infected. Data was extracted from respondents . who were family members of patients that showed immunological response to dengue virus infection. Result: Out of 979 family members of patients tested, 183 (18.7%) individual showed asymptomatic positive immunological response of dengue virus infection. Respondents who leave in a district have risk to be infected 1.35 fold greater than those who leave in a city (p= 0,043; 95% CI=l, 004-1, 805). There is no significant risk to be infected among gender (female and male respondent) and age groups c: 15 years and> 15 years). Conclusion: There is a latent potential problem of sustainable dengue virus transmission in West Java Province. This condition requires attention because the existence of positive individuaIs without symptoms and their mobility play a role as a reservoir of dengue virus . Keywords: dengue viorus infection, asymptomatic, immunological responses

Association of MICA and MICB alleles with symptomatic dengue infection

Dengue viruses (DV) are one of the most important arthropod-borne viral diseases in the developing world. DV can cause syndromes that are either self-limiting or severe. Allelic variants of human leukocyte antigen (HLA) genes have been demonstrated to be associated with disease susceptibility. Here we report the association of nonclassical HLA class I MICA–MICB genes with disease outcome during DV infection. A sequencing-based typing method and genotyping of MICA and MICB in a well-characterized group of Cuban individuals with dengue hemorrhagic fever (DHF), dengue fever (DF), or asymptomatic dengue infection (ADI) was performed. Statistical analysis revealed a tendency for MICA*008 and MICB*008 to associate with susceptibility to illness when symptomatic versus asymptomatic cases (odds ratio [OR] = 2.1, p v = 0.03, and OR = 10.4, p = 0.0096, respectively) were compared. Surprisingly, a stronger association of both allelic forms was observed for the DF patients compared with the ADI group (MICA*008, OR = 5.2, p = 0.0001; and MICB*008, OR = 13.2, p = 0.0025) rather than the severe cases. Major histocompatibility class I-related gene-related natural killer cells and/or γδ and αβ T-cell activation might regulate the development of symptomatic DF and DHF.

Asymptomatic Dengue Infection in a Cuban Population Confirms the Protective Role of the RR Variant of the FcγRIIa Polymorphism

The role of human Fcgamma receptors (FcgammaR) has been recognized considerably over the last years. These receptors vary in their affinity for IgG subclasses and the intracellular signals elicited by them. Allelic variants of FcgammaR genes may influence the biological phagocyte activity, accounting for an inherited pre-disposition to disease. The specific FcgammaRIIa (CD32) contains a polymorphic variant (H/R131) that has been associated to a reduced risk for developing dengue hemorrhagic fever (DHF). Here, we investigated the role of this polymorphism in a very well-characterized group of Cuban individuals with antecedents of DHF, dengue fever (DF), or subclinical dengue infection. The HH131 genotype was significantly associated with dengue disease, either DF (*P = 0.016; odds ratio = 4.425; 95% confidence interval = 1.10-20.52) or DHF (P = 0.00018; odds ratio = 10.56; 95% confidence interval = 2.33-54.64) with respect to the subclinical infection.

Laboratory assays and field dengue vaccine evaluation at Ratchaburi province, Thailand: a preliminary result

Laboratory-based epidemiological studies have been initiated in a cohort of school-aged children in Ratchaburi province, Thailand in preparation for imminent dengue vaccine field trials. In these studies, levels of neutralising antibodies were determined by the plaque reduction neutralisation test (PRNT) while virological confirmation was performed using RT-PCR or mosquito inoculation. Serological confirmation was performed using IgM and IgG ELISA. The incidence rate of dengue in the Ratchaburi cohort was 1635 per 100,000 during 2005–2006. Among 3547 patients in this cohort, 331 were classified with febrile disease and 58 with dengue. All four dengue serotypes were observed in Ratchaburi province. Efforts to identify the infecting serotype in symptomatic patients, based solely upon the neutralising antibody response, were complicated by cross- neutralising antibodies. In addition, 20 symptomatic and 49 asymptomatic cases were identified among 897 subjects investigated during 2005–2006, a ratio of 1:2.5. Serological analysis of asymptomatic dengue infections demonstrated boosting of immune responses due to subclinical infections with dengue or Japanese encephalitis. These results demonstrate that laboratory-confirmed dengue disease in areas of high transmission can be established. Epidemiological data of this kind are critical to dengue vaccine efficacy trials.

Seroepidemiology of Dengue Virus Infection Among Adults in Singapore

To determine the seroepidemiology of dengue virus infection in a representative sample of the adult resident population aged 18 years old to 74 years old in Singapore and to estimate the proportion of asymptomatic dengue infection during the 2004 epidemic. The study was based on 4152 stored blood samples collected between September and December 2004 from participants aged 18 years old to 74 years old during the 2004 National Health Survey. Sera were tested for IgG and IgM antibodies using a commercial test kit (PanBio Capture/Indirect ELISA). Of the study population, 59.0% and 2.6% tested positive for dengue IgG (past infection) and IgM/high-titre IgG (recent infection), respectively. Only 17.2% of young adults aged 18 years old to 24 years old were dengue IgG positive. Multivariate analyses showed that older age, Indian ethnicity and male gender were significantly associated with past infection, whereas only age was significantly associated with recent dengue infection. Based on the dengue cases notified during the period of survey, it was estimated that for every 23 individuals recently infected with dengue, only 1 was reported to the health authority as a clinical case. The Singapore population is highly susceptible to dengue epidemics despite its aggressive Aedes prevention and control programme. The finding of a high proportion of unreported cases due to asymptomatic and subclinical infection poses a challenge for dengue control.

IgG Subclass and the FcG Receptor Iia Polymorphism Associate to Dengue Fever, Dengue Hemorrhagic Fever and Asymptomatic Dengue Infection in Cuba

Background: FcG Receptors II (FcGRII) mediate a variety of biological response, including Antibodies Dependent Enhancement (ADE). The ADE theory shows that the presence of circulating dengue-specific IgG antibodies can enhance the viral entry trough FcGR and constitutes the largest risk factor for the individuals to develop of Dengue Hemorrhagic Fiver (DHF). An Arginine (R) to Histidine (H) substitution at position 131 of the FcGRIIa gene change the IgG binding affinity of the receptor with reduced opsonization of IgG2 associated with the arginine variant. The exceptional epidemiological circumstances in Cuba allow us to maintain a homogeneous sample with a similar history of natural dengue virus infections. In this work we investigate whether homozygosity for the arginine variant might be associated with a reduced risk of DHF caused by ADE and the subclass of IgG in the acute serum samples from individuals who suffered secondary infection to dengue 2 virus in the epidemic of Santiago de Cuba in 1997 with different clinical pictures. Methods: The Subclass of IgG were detected using Dot Blot in the soluble fraction and the immunocomplex fraction of the dengue acute serum samples kinetically collected. The DNA samples were studied to determine the polymorphism associated to Fc gamma receptor IIa. The FcGRIIa genotypes (R/R131, H/H131 and R/H131) and allelic frequencies were compared. Results: IgG1 are the predominant IgG subclass during the dengue acute infection even as a part of the immunocomplex or free in the serum. On the other hand IgG3 levels, only detected in the immunocomplex fraction, were observed in DF cases. The distribution of FcGRIIa genotype frequencies in Santiago de Cuba population showed the predominant RH genotype and the homozygocity for arginine variant did not found any protective effect associate to dengue infection in our population. Conclusion: The IgG subclass involved in dengue infection are IgG1 and IgG3 and the ADE phenomenon probably take place by the FcGRIIIa and FcGRIIIb associate with these IgG.

Incidence of primary dengue virus infections in Southern Vietnamese children and reactivity against other flaviviruses

To study the incidence of asymptomatic primary dengue infections among children and reactivity against other flaviviruses. A total of 216 children, who had no dengue-specific IgG antibodies during a serosurvey in 2003 were re-examined 23 months later to determine if seroconversion had occurred. Dengue-specific IgG was demonstrated with enzyme-linked immunosorbent assay (ELISA) and reactivity patterns against other flaviviruses were assessed by using immunofluorescence assay (IFA). Sixty-six children had seroconverted for dengue virus-specific IgG; the true annual incidence of primary dengue was thus 17.3% (95% CI: 13.8-21.4). Japanese Encephalitis virus (JEV)-specific IgG antibodies were detected by IFA among three (4.6%) samples that showed seroconversion in the dengue ELISA, because of cross-reactivity. Our findings highlight the high incidence of dengue among Vietnamese children; JEV infections are rare. The true annual incidence of dengue can be estimated with a single cross-sectional seroprevalence survey.

Multi-level analyses of spatial and temporal determinants for dengue infection

BackgroundDengue is a mosquito-borne viral infection that is now endemic in most tropical countries. In Thailand, dengue fever/dengue hemorrhagic fever is a leading cause of hospitalization and death among children. A longitudinal study among 1750 people in two rural and one urban sites in northern Thailand from 2001 to 2003 studied spatial and temporal determinants for recent dengue infection at three levels (time, individual and household).MethodsDeterminants for dengue infection were measured by questionnaire, land-cover maps and GIS. IgM antibodies against dengue were detected by ELISA. Three-level multi-level analysis was used to study the risk determinants of recent dengue infection.ResultsRates of recent dengue infection varied substantially in time from 4 to 30%, peaking in 2002. Determinants for recent dengue infection differed per site. Spatial clustering was observed, demonstrating variation in local infection patterns. Most of the variation in recent dengue infection was explained at the time-period level. Location of a person and the environment around the house (including irrigated fields and orchards) were important determinants for recent dengue infection.ConclusionWe showed the focal nature of asymptomatic dengue infections. The great variation of determinants for recent dengue infection in space and time should be taken into account when designing local dengue control programs.

Antibody-dependent enhancement of dengue virus growth in human monocytes as a risk factor for dengue hemorrhagic fever.

Serum specimens collected during a prospective study of dengue infections among schoolchildren in Bangkok were tested for their ability to enhance dengue 2 (DEN-2) virus growth in human monocytes in vitro. Two groups of dengue-immune sera were compared: 32 dengue antibody positive serum specimens from children who subsequently developed asymptomatic secondary dengue infections; and 9 dengue antibody positive serum specimens from children who subsequently developed severe symptomatic secondary dengue infections, 8 of which were clinically diagnosed as dengue hemorrhagic fever. Antibody-dependent enhancement of virus growth was quantitated by measurement of virus yields in supernatant fluids of normal human monocyte cultures that were infected with DEN-2 virus in the presence of undiluted test serum. Only 4 of 32 (12%) preinfection sera from asymptomatic children, but 6 of 9 (67%) preinfection sera from symptomatic children, had significant enhancing activity (P less than 0.001). High serum DEN-2 antibody dependent enhancing activity is a significant (relative risk = 6.2) risk factor for severe illness among children in a dengue hemorrhagic fever endemic region. Dengue antibodies can be neutralizing and therefore protective, or they can be enhancing and increase the risk of dengue hemorrhagic fever.