Dengue hemorrhagic fever - A systemic literature review of current perspectives on pathogenesis, prevention and control.

BACKGROUND: Dengue is an arboviral disease caused by dengue virus. Symptomatic dengue infection causes a wide range of clinical manifestations, from mild dengue fever (DF) to potentially fatal disease, such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). We conducted a literature review to analyze the risks of DHF and current perspectives for DHF prevention and control. METHODS: According to the PRISMA guidelines, the references were selected from PubMed, Web of Science and Google Scholar database using search strings containing a combination of terms that included dengue hemorrhagic fever, pathogenesis, prevention and control. Quality of references were evaluated by independent reviewers. RESULTS: DHF was first reported in the Philippines in 1953 and further transmitted to the countries in the region of South-East Asia and Western Pacific. Plasma leakages is the main pathophysiological hallmark that distinguishes DHF from DF. Severe plasma leakage can result in hypovolemic shock. Various factors are thought to impact disease presentation and severity. Virus virulence, preexisting dengue antibodies, immune dysregulation, lipid change and host genetic susceptibility are factors reported to be correlated with the development of DHF. However, the exact reasons and mechanisms that triggers DHF remains controversial. Currently, no specific drugs and licensed vaccines are available to treat dengue disease in any of its clinical presentations. CONCLUSION: This study concludes that antibody-dependent enhancement, cytokine dysregulation and variation of lipid profiles are correlated with DHF occurrence. Prompt diagnosis, appropriate treatment, active and continuous surveillance of cases and vectors are the essential determinants for dengue prevention and control.

Involvement of dual serotypes during a severe dengue outbreak in Wadi area, Nagpur district, Maharashtra 2017.

BACKGROUND & OBJECTIVES: An outbreak of dengue-like illness was reported from Wadi area within the Nagpur Municipal Corporation during September-October 2017 with five deaths. Major symptoms reported were high fever (103-106 oF), acute joint pains, myalgia, drowsiness, breathlessness, etc. An investigation was conducted to confirm the etiological agent, its characterization and the vectors involved in the outbreak. METHODS: Serological analysis was conducted to detect dengue (DEN)/chikungunya IgM antibodies in 158 sera samples. Nested-PCR was carried out to serotype eight ELISA positive samples. Adult and larval mosquito collections were conducted in the affected areas to determine species composition and mosquito density. RESULTS: Dengue IgM antibodies were detected in 44 sera samples. Molecular typing revealed involvement of DEN-2 and DEN-3 serotypes. Dengue hemorrhagic fever symptoms were observed in two patients. Aedes aegypti breeding was found rampant with Breteu index and house index ranging from 23 to 70 and 17 to 56, respectively. Major breeding habitats encountered were, used tyres, cement tanks and refrigerator trays. INTERPRETATION & CONCLUSION: Clinical symptoms, detection of anti-DEN IgM antibodies in high number of samples and heavy breeding of Ae. aegypti confirmed it was a dengue outbreak.

Assessment of benefits and risks associated with dengue vaccination at the individual and population levels: a dynamic modeling approach.

BACKGROUND: A case-cohort study, using a novel assay and data from three dengue vaccine efficacy trials, highlighted differences in vaccination outcomes according to baseline serostatus. Based on these results, we explored, with a model, the benefits and risks associated with vaccination. RESEARCH DESIGN AND METHODS: Parameters of a previously developed transmission model were estimated with subject-level data from a case-cohort study. The model was used to assess vaccination outcomes for a range of transmission settings over 5-30 years, with or without indirect protection. MAIN OUTCOME MEASURES: Symptomatic dengue cases, dengue hospitalizations, and severe dengue cases. RESULTS: The model is consistent with previous results indicating a transitory period at increased risk for dengue-seronegative vaccine recipients (setting-dependent duration) and long-term benefits for dengue-seropositive recipients. At the population level, benefits to seropositive individuals over 10 years outweighed the risk to those seronegative in moderate to high transmission settings (≥50% seropositivity at age 9), especially in high transmission settings (no excess hospitalizations in dengue-seronegative for ≥80% seropositivity at age 9). Results were more favorable when longer time horizons or indirect protection were considered. CONCLUSIONS: Results indicate a public health benefit associated with dengue vaccination especially in high-transmission settings, even with the initial excess risks to dengue-seronegative patients which diminish over time.

A case report of dengue haemorrhagic fever during the peripartum period: challenges in management and a case of vertical dengue transmission.

BACKGROUND: Incidence of Dengue infection is on the increase in Sri Lanka with it being associated with significant maternal and neonatal morbidity in pregnancy. CASE PRESENTATION: A 33-year-old pregnant woman at 38 weeks of gestation, presented with acute onset of fever, was later diagnosed with Dengue illness. Due to the emergence of warning symptoms and signs and rapidly dropping platelet count, the baby was delivered by urgent caesarian section. She went into the critical phase during the postoperative period and due to concealed bleeding, required blood transfusion. On the 5th day of life, the neonate was also diagnosed with possible dengue by vertical transmission and required blood and PLT transfusions for recovery. CONCLUSIONS: This case report illustrates how a high index of suspicion, early diagnosis, close monitoring, timely intervention and critical consideration of physiological changes of pregnancy when interpreting clinical situation, led to achieving a successful outcome.

Climate variability and dengue hemorrhagic fever in Southeast Sulawesi Province, Indonesia.

To determine the association of climatic factors and dengue hemorrhagic fever and to develop the prediction approach of future dengue transmission. The study used totally monthly dengue hemorrhagic fever cases at Health Office Kendari, Southeast Sulawesi, Indonesia. Monthly meteorological data, consisting of temperature, rainfall, and humidity, was obtained from the Meteorology, Climatology and Geophysics Agency in Kendari district. All data analysis, including Spearman and Poisson distribution, was carried out in R Studio (version 3.3.2) utilizing the R statistical language version 2.15. The highest rate of dengue hemorrhagic fever cases was found in January, February, and March. Temperature averages at lag 2 (p = 0.53, p < 0.0001), lag 3 (p = 0.59, p < 0.0001), and lag 4 (p = 0.41, p < 0.01)) correlated with the incident rate of DHF. The average temperature at lag 2 was found to have a positive impact on the incidence of DHF by Poisson function. This study provides preliminary evidence of the influence of climatic factors on dengue transmission.

Abundance and distribution of sylvatic dengue virus vectors in three different land cover types in Sarawak, Malaysian Borneo.

BACKGROUND: Mosquito-borne dengue virus (DENV) is maintained in a sylvatic, enzootic cycle of transmission between canopy-dwelling non-human primates and Aedes mosquitoes in Borneo. Sylvatic DENV can spill over into humans living in proximity to forest foci of transmission, in some cases resulting in severe dengue disease. The most likely vectors of such spillover (bridge vectors) in Borneo are Ae. albopictus and Ae. niveus. Borneo is currently experiencing extensive forest clearance. To gauge the effect of this change in forest cover on the likelihood of sylvatic DENV spillover, it is first necessary to characterize the distribution of bridge vectors in different land cover types. In the current study, we hypothesized that Ae. niveus and Ae. albopictus would show significantly different distributions in different land cover types; specifically, we predicted that Ae. niveus would be most abundant in forests whereas Ae. albopictus would have a more even distribution in the landscape. RESULTS: Mosquitoes were collected from a total of 15 sites using gravid traps and a backpack aspirator around Kampong Puruh Karu, Sarawak, Malaysian Borneo, where sylvatic DENV spillover has been documented. A total of 2447 mosquitoes comprising 10 genera and 4 species of Aedes, were collected over the three years, 2013, 2014 and 2016, in the three major land cover types in the area, homestead, agriculture and forest. Mosquitoes were identified morphologically, pooled by species and gender, homogenized, and subject to DNA barcoding of each Aedes species and to arbovirus screening. As predicted, Ae. niveus was found almost exclusively in forests whereas Ae. albopictus was collected in all land cover types. Aedes albopictus was significantly (P = 0.04) more abundant in agricultural fields than forests. Sylvatic DENV was not detected in any Aedes mosquito pools, however genomes of 14 viruses were detected using next generation sequencing. CONCLUSIONS: Land cover type affects the abundance and distribution of the most likely bridge vectors of sylvatic DENV in Malaysia Borneo. Conversion of forests to agriculture will likely decrease the range and abundance of Ae. niveus but enhance the abundance of Ae. albopictus.

An SIR-Dengue transmission model with seasonal effects and impulsive control.

In recent decades, Dengue fever and its deadly complications, such as Dengue hemorrhagic fever, have become one of the major mosquito-transmitted diseases, with an estimate of 390 million cases occurring annually in over 100 tropical and subtropical countries, most of which belonging to the developing world. Empirical evidence indicates that the most effective mechanism to reduce Dengue infections is to combat the disease-carrying vector, which is often implemented via chemical pesticides to destroy mosquitoes in their adult or larval stages. The present paper considers an SIR epidemiological model describing the vector-to-host and host-to-vector transmission dynamics. The model includes pesticide control represented in terms of periodic impulsive perturbations, as well as seasonal fluctuations of the vector growth and transmission rates of the disease. The effectiveness of the control strategy is studied numerically in detail by means of path-following techniques for non-smooth dynamical systems. Special attention is given to determining the optimal timing of the pesticide applications, in such a way that the number of infections and the required amount of pesticide are minimized.

Isolation of dengue virus from the upper respiratory tract of four patients with dengue fever.

BACKGROUND: Dengue fever is an important arboviral disease. The clinical manifestations vary from a mild non-specific febrile syndrome to severe life-threatening illness. The virus can usually be detected in the blood during the early stages of the disease. Dengue virus has also been found in isolated cases in the cerebrospinal fluid, urine, nasopharyngeal sections and saliva. In this report, we describe the isolation of dengue virus from the upper respiratory tract of four confirmed cases of dengue. METHODS: We reviewed all laboratory reports of the isolation of dengue virus from respiratory specimens at the clinical microbiology laboratory of the Kaohsiung Veterans General Hospital during 2007 to 2015. We then examined the medical records of the cases from whom the virus was isolated to determine their demographic characteristics, family contacts, clinical signs and symptoms, course of illness and laboratory findings. RESULTS: Dengue virus was identified in four patients from a nasopharyngeal or throat culture. Two were classified as group A dengue (dengue without warning signs), one as group B (dengue with warning signs) and one as group C (severe dengue). All had respiratory symptoms. Half had family members with similar respiratory symptoms during the period of their illnesses. All of the patients recovered uneventfully. CONCLUSIONS: The isolation of dengue virus from respiratory specimens of patients with cough, rhinorrhea and nasal congestion, although rare, raises the possibility that the virus is capable of transmission by the aerosol route among close contacts. This concept is supported by studies that show that the virus can replicate in cultures of respiratory epithelium and can be transmitted through mucocutaneous exposure to blood from infected patients. However, current evidence is insufficient to prove the hypothesis of transmission through the respiratory route. Further studies will be needed to determine the frequency of respiratory colonization, viable virus titers in respiratory secretions and molecular genetic evidence of transmission among close contacts.

Preventive and therapeutic challenges in combating Zika virus infection: are we getting any closer?

The neuroteratogenic nature of Zika Virus (ZIKV) infection has converted what would have been a tropical disease into a global threat. Zika is transmitted vertically via infected placental cells especially in the first and second trimesters. In the developing central nervous system (CNS), ZIKV can infect and induce apoptosis of neural progenitor cells subsequently causing microcephaly as well as other neuronal complications in infants. Its ability to infect multiple cell types (placental, dermal, and neural) and increased environmental stability as compared to other flaviviruses (FVs) has broadened the transmission routes for ZIKV infection from vector-mediated to transmitted via body fluids. To further complicate the matters, it is genetically similar (about 40%) with the four serotypes of dengue virus (DENV), so much so that it can almost be called a fifth DENV serotype. This homology poses the risk of causing cross-reactive immune responses and subsequent antibody-dependent enhancement (ADE) of infection in case of secondary infections or for immunized individuals. All of these factors complicate the development of a single preventive vaccine candidate or a pharmacological intervention that will completely eliminate or cure ZIKV infection. We discuss all of these factors in detail in this review and conclude that a combinatorial approach including immunization and treatment might prove to be the winning strategy.

¿Dengue, siempre una enfermedad importada en España? / Dengue? Always an imported disease in Spain?

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¿Es posible tener dengue autóctono en España? / Is it possible to have autochthonous dengue fever in Spain?

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Morbidity Rate Prediction of Dengue Hemorrhagic Fever (DHF) Using the Support Vector Machine and the Aedes aegypti Infection Rate in Similar Climates and Geographical Areas.

BACKGROUND: In the past few decades, several researchers have proposed highly accurate prediction models that have typically relied on climate parameters. However, climate factors can be unreliable and can lower the effectiveness of prediction when they are applied in locations where climate factors do not differ significantly. The purpose of this study was to improve a dengue surveillance system in areas with similar climate by exploiting the infection rate in the Aedes aegypti mosquito and using the support vector machine (SVM) technique for forecasting the dengue morbidity rate. METHODS AND FINDINGS: Areas with high incidence of dengue outbreaks in central Thailand were studied. The proposed framework consisted of the following three major parts: 1) data integration, 2) model construction, and 3) model evaluation. We discovered that the Ae. aegypti female and larvae mosquito infection rates were significantly positively associated with the morbidity rate. Thus, the increasing infection rate of female mosquitoes and larvae led to a higher number of dengue cases, and the prediction performance increased when those predictors were integrated into a predictive model. In this research, we applied the SVM with the radial basis function (RBF) kernel to forecast the high morbidity rate and take precautions to prevent the development of pervasive dengue epidemics. The experimental results showed that the introduced parameters significantly increased the prediction accuracy to 88.37% when used on the test set data, and these parameters led to the highest performance compared to state-of-the-art forecasting models. CONCLUSIONS: The infection rates of the Ae. aegypti female mosquitoes and larvae improved the morbidity rate forecasting efficiency better than the climate parameters used in classical frameworks. We demonstrated that the SVM-R-based model has high generalization performance and obtained the highest prediction performance compared to classical models as measured by the accuracy, sensitivity, specificity, and mean absolute error (MAE).

[Hemorrhagic dengue and vertical transmission to the newborn: a case report and literature review]. / Dengue materno de tipo hemorrágico con trasmisión vertical al neonato: reporte de un caso y revisión de la bibliografía.

OBJECTIVE: To describe the case of a patient with term pregnancy and infection with hemorrhagic dengue and vertical transmission to the newborn. CLINICAL CASE: Thirty-two year old patient with pregnancy at 38 weeks was admitted with fever 2 days earlier (38 degrees C). During her stay she continued with fever of 39 degrees C and platelets of 85,000/mm3. Serology for dengue NS1 antigen was reported positive. Labor was induced getting a new-born, male, 3,220 g, who breathed and cried at birth. During the postpartum period continued with fever, malaise, retro-ocular pain, generalized rash in upper and lower limbs, bleeding gums and petechial on the soft palate and thrombocytopenia of 5,000/mm3, later. At 8 days of stay, platelet concentration increased to 42,000/mm3 without requiring platelet concentrates and she was discharged after ten days in hospital with platelets of 94,000/mm3. The 4th day of extra-uterine live (EUL), neonate shows generalized rash over the trunk; The 5th day starts with 38 degrees C fever and thrombocytopenia (78,000/mm3). Dengue serological tests reported positive for Ag NS1 and negative for Abs IgM and IgG. Neonate was admitted to NICU, he continued with a decrease in platelet of 14,000/mm3- and ecchymotic areas by pressure and veno-punction sites. Four platelet concentrates were transfused. At 10th day of EUL platelet count was reported with 387,000/mm3. CONCLUSIONS: In an endemic area, such as Sinaloa state, in a pregnant woman with fever and thrombocytopenia, we should be alert to possibility of a DV infection and its complications. Although rare, such as this case, infection can be transmitted to fetus (vertical transmission) and produce a primary congenital dengue, even in its severe hemorrhagic types.

Lineage II of Southeast Asian/American DENV-2 is associated with a severe dengue outbreak in the Peruvian Amazon.

During 2010 and 2011, the Loreto region of Peru experienced a dengue outbreak of unprecedented magnitude and severity for the region. This outbreak coincided with the reappearance of dengue virus-2 (DENV-2) in Loreto after almost 8 years. Whole-genome sequence indicated that DENV-2 from the outbreak belonged to lineage II of the southeast Asian/American genotype and was most closely related to viruses circulating in Brazil during 2007 and 2008, whereas DENV-2 previously circulating in Loreto grouped with lineage I (DENV-2 strains circulating in South America since 1990). One amino acid substitution (NS5 A811V) in the 2010 and 2011 isolates resulted from positive selection. However, the 2010 and 2011 DENV-2 did not replicate to higher titers in monocyte-derived dendritic cells and did not infect or disseminate in a higher proportion of Aedes aegypti than DENV-2 isolates previously circulating in Loreto. These results suggest that factors other than enhanced viral replication played a role in the severity of this outbreak.

Phylogeography and molecular epidemiology of an epidemic strain of dengue virus type 1 in Sri Lanka.

In 2009, a severe epidemic of dengue disease occurred in Sri Lanka, with higher mortality and morbidity than any previously recorded epidemic in the country. It corresponded to a shift to dengue virus 1 as the major disease-causing serotype in Sri Lanka. Dengue disease reached epidemic levels in the next 3 years. We report phylogenetic evidence that the 2009 epidemic DENV-1 strain continued to circulate within the population and caused severe disease in the epidemic of 2012. Bayesian phylogeographic analyses suggest that the 2009 Sri Lankan epidemic DENV-1 strain may have traveled directly or indirectly from Thailand through China to Sri Lanka, and after spreading within the Sri Lankan population, it traveled to Pakistan and Singapore. Our findings delineate the dissemination route of a virulent DENV-1 strain in Asia. Understanding such routes will be of particular importance to global control efforts.

The complex relationship between weather and dengue virus transmission in Thailand.

Using a novel analytical approach, weather dynamics and seasonal dengue virus transmission cycles were profiled for each Thailand province, 1983-2001, using monthly assessments of cases, temperature, humidity, and rainfall. We observed systematic differences in the structure of seasonal transmission cycles of different magnitude, the role of weather in regulating seasonal cycles, necessary versus optimal transmission "weather-space," basis of large epidemics, and predictive indicators that estimate risk. Larger epidemics begin earlier, develop faster, and are predicted at Onset change-point when case counts are low. Temperature defines a viable range for transmission; humidity amplifies the potential within that range. This duality is central to transmission. Eighty percent of 1.2 million severe dengue cases occurred when mean temperature was 27-29.5°C and mean humidity was > 75%. Interventions are most effective when applied early. Most cases occur near Peak, yet small reductions at Onset can substantially reduce epidemic magnitude. Monitoring the Quiet-Phase is fundamental in effectively targeting interventions pre-emptively.

Comparing vector­host and SIR models for dengue transmission.

Various simple mathematical models have been used to investigate dengue transmission. Some of these models explicitly model the mosquito population, while others model the mosquitoes implicitly in the transmission term. We study the impact of modeling assumptions on the dynamics of dengue in Thailand by fitting dengue hemorrhagic fever (DHF) data to simple vector­host and SIR models using Bayesian Markov chain Monte Carlo estimation. The parameter estimates obtained for both models were consistent with previous studies. Most importantly, model selection found that the SIR model was substantially better than the vector­host model for the DHF data from Thailand. Therefore, explicitly incorporating the mosquito population may not be necessary in modeling dengue transmission for some populations.

Severe perinatal dengue hemorrhagic fever in a low birth weight infant.

A 31-year-old Hmong (Thai hilltribe) multiparous (G5P2) female with dengue hemorrhagic fever delivered a low birth weight male infant at 34 weeks estimated gestational age. The mother had fever for a total of 6 days, along with hepatomegaly, hepatic dysfunction and thrombocytopenia. Serology showed acute secondary dengue infection. She had no serious complications. The infant (birth weight 1,850 grams) developed a fever 140 hours postpartum of 37.8 degrees C for one day, then developed drowsiness, poor feeding and apnea. Hepatomegaly, thrombocytopenia, hepatic dysfunction and moderate coagulopathy were detected, with consequential shock and anemia due to gastrointestinal and pulmonary hemorrhage. Vigorous treatment with mechanical ventilation, packed red cells (PRC), fresh frozen plasma (FFP) and platelet concentrate transfusions were given and the child recovered successfully and commenced breast-feeding. At six months of age the child's growth and development were normal except for an impaired hearing screening test.