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Mathematical modeling on T-cell mediated adaptive immunity in primary dengue infections.

J Theor Biol; 429: 229-240, 2017 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-28684293


At present, dengue is the most common mosquito-borne viral disease in the world, and the global dengue incidence is increasing day by day due to climate changing. Here, we present a mathematical model of dengue viruses (DENVs) dynamics in micro-environment (cellular level) consisting of healthy cells, infected cells, virus particles and T-cell mediated adaptive immunity. We have considered the explicit role of cytokines and antibody in our model. We find that the virus load goes down to zero within 6 days as it is common for DENV infection. From our analysis, we have identified the important model parameters and done the numerical simulation with respect to such important parameters. We have shown that the cytokine mediated virus clearance plays a very important role in dengue dynamics. It can change the dynamical behavior of the system and causes essential extinction of the virus. Finally, we have incorporated the antiviral treatment for dengue in our model and shown that the basic reproduction number is directly proportional to the antiviral treatment effects.

Cardio-haemodynamic assessment and venous lactate in severe dengue: Relationship with recurrent shock and respiratory distress.

PLoS Negl Trop Dis; 11(7): e0005740, 2017 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-28692675


BACKGROUND: Dengue can cause plasma leakage that may lead to dengue shock syndrome (DSS). In approximately 30% of DSS cases, recurrent episodes of shock occur. These patients have a higher risk of fluid overload, respiratory distress and poor outcomes. We investigated the association of echocardiographically-derived cardiac function and intravascular volume parameters plus lactate levels, with the outcomes of recurrent shock and respiratory distress in severe dengue. METHODS/PRINCIPLE FINDINGS: We performed a prospective observational study in Paediatric and adult ICU, at the Hospital for Tropical Diseases (HTD), Ho Chi Minh City, Vietnam. Patients with dengue were enrolled within 12 hours of admission to paediatric or adult ICU. A haemodynamic assessment and portable echocardiograms were carried out daily for 5 days from enrolment and all interventions recorded. 102 patients were enrolled; 22 patients did not develop DSS, 48 had a single episode of shock and 32 had recurrent shock. Patients with recurrent shock had a higher enrolment pulse than those with 1 episode or no shock (median: 114 vs. 100 vs. 100 b/min, P = 0.002), significantly lower Stroke Volume Index (SVI), (median: 21.6 vs. 22.8 vs. 26.8mls/m2, P<0.001) and higher lactate levels (4.2 vs. 2.9 vs. 2.2 mmol/l, P = 0.001). Higher SVI and worse left ventricular function (higher Left Myocardial Performance Index) on study days 3-5 was associated with the secondary endpoint of respiratory distress. There was an association between the total IV fluid administered during the ICU admission and respiratory distress (OR: 1.03, 95% CI 1.01-1.06, P = 0.001). Admission lactate levels predicted patients who subsequently developed recurrent shock (P = 0.004), and correlated positively with the total IV fluid volume received (rho: 0.323, P = 0.001) and also with admission ALT (rho: 0.764, P<0.001) and AST (rho: 0.773, P<0.001). CONCLUSIONS/SIGNIFICANCE: Echo-derived intravascular volume assessment and venous lactate levels can help identify dengue patients at high risk of recurrent shock and respiratory distress in ICU. These findings may serve to, not only assist in the management of DSS patients, but also these haemodynamic endpoints could be used in future dengue fluid intervention trials.

Disruption of predicted dengue virus type 3 major outbreak cycle coincided with switching of the dominant circulating virus genotype.

Infect Genet Evol; 2017 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-28698156


Dengue is hyperendemic in most of Southeast Asia. In this region, all four dengue virus serotypes are persistently present. Major dengue outbreak cycle occurs in a cyclical pattern involving the different dengue virus serotypes. In Malaysia, since the 1980s, the major outbreak cycles have involved dengue virus type 3 (DENV3), dengue virus type 1 (DENV1) and dengue virus type 2 (DENV2), occurring in that order (DENV3/DENV1/DENV2). Only limited information on the DENV3 cycles, however, have been described. In the current study, we examined the major outbreak cycle involving DENV3 using data from 1981 to 2016. We examined the genetic diversity of DENV3 isolates obtained during the period when DENV3 was the dominant serotype and during the inter-dominant transmission period. Results obtained suggest that the typical DENV3/DENV1/DENV2 cyclical outbreak cycle in Malaysia has recently been disrupted. The last recorded major outbreak cycle involving DENV3 occurred in 2002, and the expected major outbreak cycle involving DENV3 in 2008-2012 did not materialize. DENV genome analyses revealed that DENV3 genotype II (DENV3/II) was the predominant DENV3 genotype (67%-100%) recovered between 1987 and 2002. DENV3 genotype I (DENV3/I) emerged in 2002 followed by the introduction of DENV3 genotype III (DENV3/III) in 2008. These newly emerged DENV3 genotypes replaced DENV3/II, but there was no major upsurge of DENV3 cases that accompanied the emergence of these viruses. DENV3 remained in the background of DENV1 and DENV2 until now. Virus genome sequence analysis suggested that intrinsic differences within the different dengue virus genotypes could have influenced the transmission efficiency of DENV3. Further studies and continuous monitoring of the virus are needed for better understanding of the DENV transmission dynamics in hyperendemic regions.

Determinants of mortality and prolonged hospital stay among dengue patients attending tertiary care hospital: a cross-sectional retrospective analysis.

BMJ Open; 7(7): e016805, 2017 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-28698348


OBJECTIVES: Dengue imposes substantial economic, societal and personal burden in terms of hospital stay, morbidity and mortality. Early identification of dengue cases with high propensity of increased hospital stay and death could be of value in isolating patients in need of early interventions. The current study was aimed to determine the significant factors associated with dengue-related prolonged hospitalisation and death. DESIGN: Cross-sectional retrospective study. SETTING: Tertiary care teaching hospital. PARTICIPANTS: Patients with confirmed dengue diagnosis were stratified into two categories on the basis of prolonged hospitalisation (≤3 days and >3 days) and mortality (fatal cases and non-fatal cases). Clinico-laboratory characteristics between these categories were compared by using appropriate statistical methods. RESULTS: Of 667 patients enrolled, 328 (49.2%) had prolonged hospitalisation. The mean hospital stay was 4.88±2.74 days. Multivariate analysis showed that dengue haemorrhagic fever (OR 2.3), elevated alkaline phosphatase (ALP) (OR 2.3), prolonged prothrombin time (PT) (OR 1.7), activated partial thromboplastin time (aPTT) (OR 1.9) and multiple-organ dysfunctions (OR 2.1) were independently associated with prolonged hospitalisation. Overall case fatality rate was 1.1%. Factors associated with dengue mortality were age >40 years (p=0.004), secondary infection (p=0.040), comorbidities (p<0.05), acute kidney injury (p<0.001), prolonged PT (p=0.022), multiple-organ dysfunctions (p<0.001), haematocrit >20% (p=0.001), rhabdomyolosis (p<0.001) and respiratory failure (p=0.007). Approximately half of the fatal cases in our study had prolonged hospital stay of greater than three days. CONCLUSIONS: The results underscore the high proportion of dengue patients with prolonged hospital stay. Early identification of factors relating to prolonged hospitalisation and death will have obvious advantages in terms of appropriate decisions about treatment and management in high dependency units.

Informed community mobilization for dengue prevention in households with and without a regular water supply: Secondary analysis from the Camino Verde trial in Nicaragua.

BMC Public Health; 17(Suppl 1): 395, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28699544


BACKGROUND: Studies in different countries have identified irregular water supply as a risk factor for dengue virus transmission. In 2013, Camino Verde, a cluster-randomised controlled trial in Managua, Nicaragua, and Mexico's Guerrero State, demonstrated impact of evidence-based community mobilisation on recent dengue infection and entomological indexes of infestation by Aedes aegypti mosquitoes. This secondary analysis of data from the trial impact survey asks: (1) what is the importance of regular water supply in neighbourhoods with and without the trial intervention and (2) can community interventions like Camino Verde reasonably exclude households with adequate water supply? METHODS: Entomological data collected in the dry season of 2013 in intervention and control communities allow contrasts between households with regular and irregular water supplies. Indicators of entomological risk included the House Index and pupa positive household index. Generalised linear mixed models with cluster as a random effect compared households with and without regular water, and households in intervention and control communities. RESULTS: For the House Index, regular water supply was associated with a protection in both intervention households (OR 0.7, 95%CI 0.6-0.9) and control households (OR 0.6, 95%CI 0.5-0.8). For the pupa positive household index, we found a similar protection from regular water supply in intervention households (OR 0.6, 95%CI 0.4-0.8) and control households (OR 0.7, 95%CI 0.5-0.9). The Camino Verde intervention had a similar impact on House Index in households with regular water supply (OR 0.7, 95%CI 0.5-1.0) and irregular water supply (OR 0.6, 95%CI 0.4-0.8); for the pupa positive household index, the effect of the intervention was very similar in households with regular (OR0.5, 95%CI 0.3-0.8) and irregular (OR 0.5, 95%CI 0.3-0.9) water supply. CONCLUSION: While Aedes aegypti control efforts based on informed community mobilisation had a strong impact on households without a regular water supply, this intervention also impacted entomological indices in households with a regular water supply. These households should not be excluded from community mobilisation efforts to reduce the Aedes aegypti vector. TRIAL REGISTRATION: ISRCTN27581154 .

When communities are really in control: ethical issues surrounding community mobilisation for dengue prevention in Mexico and Nicaragua.

BMC Public Health; 17(Suppl 1): 410, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28699548


We discuss two ethical issues raised by Camino Verde, a 2011-2012 cluster-randomised controlled trial in Mexico and Nicaragua, that reduced dengue risk though community mobilisation. The issues arise from the approach adopted by the intervention, one called Socialisation of Evidence for Participatory Action. Community volunteer teams informed householders of evidence about dengue, its costs and the life-cycle of Aedes aegypti mosquitoes, while showing them the mosquito larvae in their own water receptacles, without prescribing solutions. Each community responded in an informed manner but on its own terms. The approach involves partnerships with communities, presenting evidence in a way that brings conflicting views and interests to the surface and encourages communities themselves to deal with the resulting tensions.One such tension is that between individual and community rights. This tension can be resolved creatively in concrete day-to-day circumstances provided those seeking to persuade their neighbours to join in efforts to benefit community health do so in an atmosphere of dialogue and with respect for personal autonomy.A second tension arises between researchers' responsibilities for ethical conduct of research and community autonomy in the conduct of an intervention. An ethic of respect for individual and community autonomy must infuse community intervention research from its inception, because as researchers succeed in fostering community self-determination their direct influence in ethical matters diminishes. TRIAL REGISTRATION: ISRCTN 27581154.

Household costs for personal protection against mosquitoes: secondary outcomes from a randomised controlled trial of dengue prevention in Guerrero state, Mexico.

BMC Public Health; 17(Suppl 1): 399, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28699550


BACKGROUND: Dengue is a serious public health issue that affects households in endemic areas in terms of health and also economically, imposing costs for prevention and treatment of cases. The Camino Verde cluster-randomised controlled trial in Mexico and Nicaragua assessed the impact of evidence-based community engagement in dengue prevention. The Mexican arm of the trial was conducted in 90 randomly selected communities in three coastal regions of Guerrero State. This study reports an analysis of a secondary outcome of the trial: household use of and expenditure on anti-mosquito products. We examined whether the education and mobilisation activities of the trial motivated people to spend less on anti-mosquito products. METHODS: We carried out a household questionnaire survey in the trial communities in 2010 (12,312 households) and 2012 (5349 households in intervention clusters, 5142 households in control clusters), including questions about socio-economic status, self-reported dengue illness, and purchase of and expenditure on insecticide anti-mosquito products in the previous month. We examined expenditures on anti-mosquito products at baseline in relation to social vulnerability and we compared use of and expenditures on these products between intervention and control clusters in 2012. RESULTS: In 2010, 44.2% of 12,312 households reported using anti-mosquito products, with a mean expenditure of USD4.61 per month among those who used them. Socially vulnerable households spent less on the products. In 2012, after the intervention, the proportion of households who purchased anti-mosquito products in the last month was significantly lower in intervention clusters (47.8%; 2503/5293) than in control clusters (53.3%; 2707/5079) (difference - 0.05, 95% CIca -0.100 to -0.010). The mean expenditure on the products, among those households who bought them, was USD6.43; 30.4% in the intervention clusters and 36.7% in the control clusters spent more than this (difference - 0.06, 95% CIca -0.12 to -0.01). These expenditures on anti-mosquito products represent 3.3% and 3.8% respectively of monthly household income for the poorest 10% of the population in 2012. CONCLUSIONS: The Camino Verde community mobilisation intervention, as well as being effective in reducing dengue infections, was effective in reducing household use of and expenditure on insecticide anti-mosquito products. TRIAL REGISTRATION: ( ISRCTN27581154 ).

Coverage and beliefs about temephos application for control of dengue vectors and impact of a community-based prevention intervention: secondary analysis from the Camino Verde trial in Mexico.

BMC Public Health; 17(Suppl 1): 426, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28699554


BACKGROUND: Temephos in domestic water containers remains a mainstay of Latin American government programmes for control of Aedes aegypti and associated illnesses, including dengue. There is little published evidence about coverage of routine temephos programmes. A cluster randomised controlled trial of community mobilisation in Mexico and Nicaragua reduced vector indices, dengue infection, and clinical dengue cases. Secondary analysis from the Mexican arm of the trial examined temephos coverage and beliefs, and the impact of the trial on these outcomes. METHODS: The trial impact survey in December 2012, in 10,491 households in 45 intervention and 45 control clusters, asked about visits from the temephos programme, retention of applied temephos, and views about temephos and mosquito control. Fieldworkers noted if temephos was present in water containers. RESULTS: Some 42.4% of rural and 20.7% of urban households reported no temephos programme visits within the last 12 months. Overall, 42.0% reported they had temephos placed in their water containers less than 3 months previously. Fieldworkers observed temephos in at least one container in 21.1% of households. Recent temephos application and observed temephos were both significantly more common in urban households, when other household variables were taken into account; in rural areas, smaller households were more likely to have temephos present. Most households (74.4%) did not think bathing with water containing temephos carried any health risk. Half (51%) believed drinking or cooking with such water could be harmful and 17.6% were unsure. Significantly fewer households in intervention sites (16.5%) than in control sites (26.0%) (Risk Difference - 0.095, 95% confidence interval - 0.182 to -0.009) had temephos observed in their water; more households in intervention clusters (41.8%) than in control clusters (31.6%) removed the applied temephos quickly. Although fewer households in intervention sites (82.7%) compared with control sites (86.7%) (RD -0.04, 95% CI -0.067 to -0.013) agreed temephos and fumigation was the best way to avoid mosquitoes, the proportion believing this remained very high. CONCLUSION: Coverage with the government temephos programme was low, especially in rural areas. Despite an intervention encouraging non-chemical mosquito control, most households continued to believe that chemicals are the best control method. TRIAL REGISTRATION: ISRCTN: 27581154 .

Pupal productivity in rainy and dry seasons: findings from the impact survey of a randomised controlled trial of dengue prevention in Guerrero, Mexico.

BMC Public Health; 17(Suppl 1): 428, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28699555


BACKGROUND: The follow-up survey of a cluster-randomised controlled trial of evidence-based community mobilisation for dengue control in Nicaragua and Mexico included entomological information from the 2012 rainy and dry seasons. We used data from the Mexican arm of the trial to assess the impact of the community action on pupal production of the dengue vector Aedes aegypti in both rainy and dry seasons. METHODS: Trained field workers inspected household water containers in 90 clusters and collected any pupae or larvae present for entomological examination. We calculated indices of pupae per person and pupae per household, and traditional entomological indices of container index, household index and Breteau index, and compared these between rainy and dry seasons and between intervention and control clusters, using a cluster t-test to test significance of differences. RESULTS: In 11,933 houses in the rainy season, we inspected 40,323 containers and found 7070 Aedes aegypti pupae. In the dry season, we inspected 43,461 containers and counted 6552 pupae. All pupae and entomological indices were lower in the intervention clusters (IC) than in control clusters (CC) in both the rainy season (RS) and the dry season (DS): pupae per container 0.12 IC and 0.24 CC in RS, and 0.10 IC and 0.20 CC in DS; pupae per household 0.46 IC and 0.82 CC in RS, and 0.41 IC and 0.83 CC in DS; pupae per person 0.11 IC and 0.19 CC in RS, and 0.10 IC and 0.20 CC in DS; household index 16% IC and 21% CC in RS, and 12.1% IC and 17.9% CC in DS; container index 7.5% IC and 11.5% CC in RS, and 4.6% IC and 7.1% CC in DS; Breteau index 27% IC and 36% CC in RS, and 19% IC and 29% CC in DS. All differences between the intervention and control clusters were statistically significant, taking into account clustering. CONCLUSIONS: The trial intervention led to significant decreases in pupal and conventional entomological indices in both rainy and dry seasons. TRIAL REGISTRATION: ISRCTN27581154 .

Dengue occurrence relations and serology: cross-sectional analysis of results from the Guerrero State, Mexico, baseline for a cluster-randomised controlled trial of community mobilisation for dengue prevention.

BMC Public Health; 17(Suppl 1): 435, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28699560


BACKGROUND: The Mexican arm of the Camino Verde trial of community mobilisation for dengue prevention covered three coastal regions of Guerrero state: Acapulco, Costa Grande and Costa Chica. A baseline cross-sectional survey provided data for community mobilisation and for adapting the intervention design to concrete conditions in the intervention areas. METHODS: Trained field teams constructed community profiles in randomly selected clusters, based on observation and key informant interviews. In each household they carried out an entomological inspection of water containers, collected information on socio-demographic variables and cases of dengue illness among household members in the last year, and gathered paired saliva samples from children aged 3-9 years, which were subjected to ELISA testing to detect recent dengue infection. We examined associations with dengue illness and recent dengue infection in bivariate and then multivariate analysis. RESULTS: In 70/90 clusters, key informants were unable to identify any organized community groups. Some 1.9% (1029/55,723) of the household population reported dengue illness in the past year, with a higher rate in Acapulco region. Among children 3-9 years old, 6.1% (392/6382) had serological evidence of recent dengue infection. In all three regions, household use of anti-mosquito products, household heads working, and households having less than 5 members were associated with self-reported dengue illness. In Acapulco region, people aged less than 25 years, those with a more educated household head and those from urban sites were also more likely to report dengue illness, while in Costa Chica and Costa Grande, females were more likely to report dengue illness. Among children aged 3-9 years, those aged 3-4 years and those living in Acapulco were more likely to have evidence of recent dengue infection. CONCLUSIONS: The evidence from the baseline survey provided important support for the design and implementation of the trial intervention. The weakness of community leadership and the relatively low rates of self-reported dengue illness were challenges that the Mexican intervention team had to overcome. The higher dengue illness occurrence among women in Costa Grande and Costa Chica may help explain why women participated more than men in activities during the Camino Verde trial.

The women made it work: fuzzy transitive closure of the results chain in a dengue prevention trial in Mexico.

BMC Public Health; 17(Suppl 1): 408, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28699563


BACKGROUND: A modified theory of planned behaviour (acronym CASCADA) proposes that Conscious knowledge precedes a change in Attitude, which in turn precedes positive deviations from negative Subjective norms, intention to Change, perception of Agency to change, Discussion of possible action, and Action itself. We used this as a results chain to investigate gender-specific behaviour dynamics in chemical-free dengue prevention. METHODS: Secondary analysis of the Mexican arm of a cluster randomised controlled trial used household survey data on intermediate outcomes of dengue prevention behaviour. We used a matrix of odds ratios between outcomes, transformed to a symmetrical range (-1, 1), to compute fuzzy transitive closure of the results chain for control and intervention clusters, then for male and female respondents separately in each group. Transitive closure of a map computes the influence of each factor on each other factor, taking account of all influences in the system. Cumulative net influence was the sum of influences across the results chain. RESULTS: Responses of 5042 women and 1143 men in 45 intervention clusters contrasted with those of 5025 women and 1179 men in 45 control clusters. Control clusters showed a distal block (negative influence) in the results chain with a cumulative net influence of 0.88; intervention clusters showed no such block and a cumulative net influence of 1.92. Female control respondents, like the overall control picture, showed a distal block, whereas female intervention responses showed no such blocks (cumulative net influence 0.78 and 1.73 respectively). Male control respondents showed weak distal blocks. Male intervention responses showed several new negative influences and a reduction of cumulative net influence (1.38 in control and 1.11 in intervention clusters). CONCLUSIONS: The overall influence of the intervention across the results chain fits with the trial findings, but is different for women and men. Among women, the intervention overcame blocks and increased the cumulative net influence of knowledge on action. Among men, the intervention did not reinforce prevention behaviour. This might be related to emphasis, during the intervention, on women's participation and empowerment. The fuzzy transitive closure of the CASCADA map usefully highlights the differences between gender-specific results chains. TRIAL REGISTRATION: ISRCTN27581154 .

Household costs of dengue illness: secondary outcomes from a randomised controlled trial of dengue prevention in Guerrero state, Mexico.

BMC Public Health; 17(Suppl 1): 411, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28699565


BACKGROUND: Dengue is a serious public health problem with an important economic impact. This study used data from a cluster randomised controlled trial of community mobilisation for dengue prevention to estimate the household costs of treatment of dengue illness. It examined the economic impact of the trial intervention in the three coastal regions of Mexico's Guerrero State. METHODS: The 2010 baseline survey covered households in a random sample of 90 clusters in the coastal regions; the clusters were randomly allocated to intervention or control and re-surveyed in 2012. The surveys asked about dengue cases in the last 12 months, expenditures on their treatment, and work or school days lost by patients and care givers. We did not assign monetary value to days lost, since a lost day to a person of low earning power is of equal or higher value to that person than to one who earns more. RESULTS: The 12,312 households in 2010 reported 1020 dengue cases in the last 12 months (1.9% of the sample population). Most (78%) were ambulatory cases, with a mean cost of USD 51 and 10.8 work/school days, rising to USD 96 and 11.4 work/school days if treated by a private physician. Hospitalised cases cost USD 28-94 in government institutions and USD 392 in private hospitals (excluding additional inpatient charges), as well as 9.6-17.3 work/school days. Dengue cases cost households an estimated 412,825 work/school days throughout the three coastal regions. In the follow up survey, 6.1% (326/5349) of households in intervention clusters and 7.9% (405/5139) in control clusters reported at least one dengue case. The mean of days lost per case was similar in intervention and control clusters, but the number of days lost from dengue and all elements of costs for dengue cases per 1000 population were lower in intervention clusters. If the total population of the three coastal regions had received the intervention, some 149,401 work or school days lost per year could have been prevented. CONCLUSION: The economic effect of dengue on households, including lost work days, is substantial. The Camino Verde trial intervention reduced household costs for treatment of dengue cases. TRIAL REGISTRATION: The trial was registered as ISRCTN:27,581,154 .

Camino Verde (The Green Way): evidence-based community mobilisation for dengue control in Nicaragua and Mexico: feasibility study and study protocol for a randomised controlled trial.

BMC Public Health; 17(Suppl 1): 407, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28699570


BACKGROUND: Since the Aedes aegypti mosquitoes that transmit dengue virus can breed in clean water, WHO-endorsed vector control strategies place sachets of organophosphate pesticide, temephos (Abate), in household water storage containers. These and other pesticide-dependent approaches have failed to curb the spread of dengue and multiple dengue virus serotypes continue to spread throughout tropical and subtropical regions worldwide. A feasibility study in Managua, Nicaragua, generated instruments, intervention protocols, training schedules and impact assessment tools for a cluster randomised controlled trial of community-based approaches to vector control comprising an alternative strategy for dengue prevention and control in Nicaragua and Mexico. METHODS/DESIGN: The Camino Verde (Green Way) is a pragmatic parallel group trial of pesticide-free dengue vector control, adding effectiveness to the standard government dengue control. A random sample from the most recent census in three coastal regions of Guerrero state in Mexico will generate 90 study clusters and the equivalent sampling frame in Managua, Nicaragua will generate 60 clusters, making a total of 150 clusters each of 137-140 households. After a baseline study, computer-driven randomisation will allocate to intervention one half of the sites, stratified by country, evidence of recent dengue virus infection in children aged 3-9 years and, in Nicaragua, level of community organisation. Following a common evidence-based education protocol, each cluster will develop and implement its own collective interventions including house-to-house visits, school-based programmes and inter-community visits. After 18 months, a follow-up study will compare dengue history, serological evidence of recent dengue virus infection (via measurement of anti-dengue virus antibodies in saliva samples) and entomological indices between intervention and control sites. DISCUSSION: Our hypothesis is that informed community mobilisation adds effectiveness in controlling dengue. TRIAL REGISTRATION: ISRCTN27581154 .

Influence of meteorological variables on dengue incidence in the municipality of Arapiraca, Alagoas, Brazil.

Rev Soc Bras Med Trop; 50(3): 309-314, 2017 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28700047


INTRODUCTION:: Meteorological influences along with the lack of basic sanitation has contributed to disease outbreaks, resulting in large socio-economic losses, especially in terms of dengue. This study aimed to evaluate the meteorological influences on the monthly incidence of dengue in Arapiraca-AL, Brazil during 2008-2015. METHODS:: We used generalized linear models constructed via logistic regression to assess the association between the monthly incidence of dengue (MID) of and 8 meteorological variables [rainfall (R), air temperature (AT), dew point temperature (DPT), relative humidity (RH), pressure surface, wind speed (WS), wind direction (WD), and gust], based on data obtained from DATASUS and meteorological station databases, respectively. The dengue-1 model included R, AT, DPT, and RH and the dengue-2 model included AT, DPT, RH, WS, and WD. A MID >100 (classified as moderate incidence) indicated an abnormal month. RESULTS:: Based on the dengue-1 model, variables with the highest odds ratio included R-lag1, DPT-lag1, and AT-lag1 with a 10.1, 18.3, and 26.7 times greater probability of a moderate MID, respectively. Based on the dengue-2 model, variables with the highest odds ratio were AT-lag1 and RH-lag0 indicating an 8.9 and 18.1 times greater probability of a moderate MID, respectively. CONCLUSIONS:: AT, DPT, R, RH and WS influenced the occurrence of a moderate MID.

Neurological manifestations of dengue in Central Brazil.

Rev Soc Bras Med Trop; 50(3): 379-382, 2017 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28700057


INTRODUCTION: : The incidence of dengue has increased throughout the 2000s with a consequent global increase in atypical clinical forms. METHODS: : This study reports a series of cases of neurological dengue out of 498 confirmed cases of laboratory dengue in Goiânia, Brazil. Cases were confirmed based on viral RNA detection via polymerase chain reaction or IgM antibody capture. RESULTS: : Neurological symptoms occurred in 5.6% of cases, including paresthesia (3.8%), encephalitis (2%), encephalopathy (1%), seizure (0.8%), meningoencephalitis (0.4%), and paresis (0.4%). DENV-3 was the predominant circulating serotype (93%). CONCLUSIONS: : We reported dengue cases with neurological manifestations in endemic area.

RNA-Seq analysis of peripheral blood mononuclear cells reveals unique transcriptional signatures associated with disease progression in dengue patients.

Transl Res; 2017 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-28683259


Patients infected with Dengue virus usually present a mild, self-limiting febrile dengue infection (DI) that occasionally leads to a potentially lethal complication, called the severe dengue (DS). The ability to identify the prognostic markers of DS could allow an improved disease intervention and management. To identify the transcriptional signatures associated with the dengue disease progression, we carried out the high-throughput sequencing of the RNA isolated from the peripheral blood mononuclear cells (PBMCs) of the dengue patients of varying severity and compared with that in the patients with other febrile illnesses (OFIs) or the healthy controls. The transcriptional signatures that discriminated the DS patients from OFI and DI patients were broadly related to the pathways involving glycine, serine, and threonine metabolisms, extracellular matrix organization, ubiquitination, and cytokines and inflammatory response. Several upregulated genes in the inflammatory process (MPO, DEFA4, ELANE, AUZ1, CTSG, OLFM4, SLC16A14, and CRISP3) that were associated with the dengue disease progression are known to facilitate leukocyte-mediated migration, and neutrophil activation and degranulation process. High activity of MPO and ELANE in the plasma samples of the follow-up and recovered dengue patients, as well as and the presence of a larger amount of cell-free dsDNA in the DS patients, suggested an association of neutrophil-mediated immunity with dengue disease progression. Careful monitoring of some of these gene transcripts, and control of the activity of proteins encoded by them, may have a great translational significance for the prognosis and management of the dengue patients.

Dengue virus specific IgY provides protection following lethal dengue virus challenge and is neutralizing in the absence of inducing antibody dependent enhancement.

PLoS Negl Trop Dis; 11(7): e0005721, 2017 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-28686617


Dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) are severe disease manifestations that can occur following sequential infection with different dengue virus serotypes (DENV1-4). At present, there are no licensed therapies to treat DENV-induced disease. DHF and DSS are thought to be mediated by serotype cross-reactive antibodies that facilitate antibody-dependent enhancement (ADE) by binding to viral antigens and then Fcγ receptors (FcγR) on target myeloid cells. Using genetically engineered DENV-specific antibodies, it has been shown that the interaction between the Fc portion of serotype cross-reactive antibodies and FcγR is required to induce ADE. Additionally, it was demonstrated that these antibodies were as neutralizing as their non-modified variants, were incapable of inducing ADE, and were therapeutic following a lethal, antibody-enhanced infection. Therefore, we hypothesized that avian IgY, which do not interact with mammalian FcγR, would provide a novel therapy for DENV-induced disease. We demonstrate here that goose-derived anti-DENV2 IgY neutralized DENV2 and did not induce ADE in vitro. Anti-DENV2 IgY was also protective in vivo when administered 24 hours following a lethal DENV2 infection. We were also able to demonstrate via epitope mapping that both full-length and alternatively spliced anti-DENV2 IgY recognized different epitopes, including epitopes that have not been previously identified. These observations provide evidence for the potential therapeutic applications of goose-derived anti-DENV2 IgY.

In Vitro Assembly and Stabilization of Dengue and Zika Virus Envelope Protein Homo-Dimers.

Sci Rep; 7(1): 4524, 2017 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-28674411


Zika virus (ZIKV) and the 4 dengue virus (DENV) serotypes are mosquito-borne Flaviviruses that are associated with severe neuronal and hemorrhagic syndromes. The mature flavivirus infectious virion has 90 envelope (E) protein homo-dimers that pack tightly to form a smooth protein coat with icosahedral symmetry. Human antibodies that strongly neutralize ZIKV and DENVs recognize complex quaternary structure epitopes displayed on E-homo-dimers and higher order structures. The ZIKV and DENV E protein expressed as a soluble protein is mainly a monomer that does not display quaternary epitopes, which may explain the modest success with soluble recombinant E (sRecE) as a vaccine and diagnostic antigen. New strategies are needed to design recombinant immunogens that display these critical immune targets. Here we present two novel methods for building or stabilizing in vitro E-protein homo-dimers that display quaternary epitopes. In the first approach we immobilize sRecE to enable subsequent dimer generation. As an alternate method, we describe the use of human mAbs to stabilize homo-dimers in solution. The ability to produce recombinant E protein dimers displaying quaternary structure epitopes is an important advance with applications in flavivirus diagnostics and vaccine development.
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