The effects of tertiary and quaternary infections on the epidemiology of dengue

This is the final version of the article. Available from Public Library of Science via the DOI in this record.The epidemiology of dengue is characterised by irregular epidemic outbreaks and desynchronised dynamics of its four co-circulating virus serotypes. Whilst infection by one serotype appears to convey life-long protection to homologous infection, it is believed to be a risk factor for severe disease manifestations upon secondary, heterologous infection due to the phenomenon of Antibody-Dependent Enhancement (ADE). Subsequent clinical infections are rarely reported and, since the majority of dengue infections are generally asymptomatic, it is not clear if and to what degree tertiary or quaternary infections contribute to dengue epidemiology. Here we investigate the effect of third and subsequent infections on the transmission dynamics of dengue and show that although the qualitative patterns are largely equivalent, the system more readily exhibits the desynchronised serotype oscillations and multi-annual epidemic outbreaks upon their inclusion. More importantly, permitting third and fourth infections significantly increases the force of infection without resorting to high basic reproductive numbers. Realistic age-prevalent patterns and seroconversion rates are therefore easier reconciled with a low value of dengue's transmission potential if allowing for more than two infections; this should have important consequences for dengue control and intervention measures.This work was funded by the BBSRC (PSW) and the Royal Society (MR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Assessing dengue vaccination impact: Model challenges and future directions.

In response to the sharp rise in the global burden caused by dengue virus (DENV) over the last few decades, the WHO has set out three specific key objectives in its disease control strategy: (i) to estimate the true burden of dengue by 2015; (ii) a reduction in dengue mortality by at least 50% by 2020 (used as a baseline); and (iii) a reduction in dengue morbidity by at least 25% by 2020. Although various elements will all play crucial parts in achieving this goal, from diagnosis and case management to integrated surveillance and outbreak response, sustainable vector control, vaccine implementation and finally operational and implementation research, it seems clear that new tools (e.g. a safe and effective vaccine and/or effective vector control) are key to success. The first dengue vaccine was licensed in December 2015, Dengvaxia® (CYD-TDV) developed by Sanofi Pasteur. The WHO has provided guidance on the use of CYD-TDV in endemic countries, for which there are a variety of considerations beyond the risk-benefit evaluation done by regulatory authorities, including public health impact and cost-effectiveness. Population-level vaccine impact and economic and financial aspects are two issues that can potentially be considered by means of mathematical modelling, especially for new products for which empirical data are still lacking. In December 2014 a meeting was convened by the WHO in order to revisit the current status of dengue transmission models and their utility for public health decision-making. Here, we report on the main points of discussion and the conclusions of this meeting, as well as next steps for maximising the use of mathematical models for vaccine decision-making

An economic evaluation of Wolbachia deployments for dengue control in Vietnam

INTRODUCTION: Dengue is a major public health challenge and a growing problem due to climate change. The release of Aedes aegypti mosquitoes infected with the intracellular bacterium Wolbachia is a novel form of vector control against dengue. However, there remains a need to evaluate the benefits of such an intervention at a large scale. In this paper, we evaluate the potential economic impact and cost-effectiveness of scaled Wolbachia deployments as a form of dengue control in Vietnam-targeted at the highest burden urban areas. METHODS: Ten settings within Vietnam were identified as priority locations for potential future Wolbachia deployments (using a population replacement strategy). The effectiveness of Wolbachia deployments in reducing the incidence of symptomatic dengue cases was assumed to be 75%. We assumed that the intervention would maintain this effectiveness for at least 20 years (but tested this assumption in the sensitivity analysis). A cost-utility analysis and cost-benefit analysis were conducted. RESULTS: From the health sector perspective, the Wolbachia intervention was projected to cost US$420 per disability-adjusted life year (DALY) averted. From the societal perspective, the overall cost-effectiveness ratio was negative, i.e. the economic benefits outweighed the costs. These results are contingent on the long-term effectiveness of Wolbachia releases being sustained for 20 years. However, the intervention was still classed as cost-effective across the majority of the settings when assuming only 10 years of benefits. CONCLUSION: Overall, we found that targeting high burden cities with Wolbachia deployments would be a cost-effective intervention in Vietnam and generate notable broader benefits besides health gains

Cluster randomized test-negative design (CR-TND) trials: a novel and efficient method to assess the efficacy of community level dengue interventions

Cluster randomized trials are the gold standard for assessing efficacy of community-level interventions, such as vector control strategies against dengue. We describe a novel cluster randomized trial methodology with a test-negative design, which offers advantages over traditional approaches. It utilizes outcome-based sampling of patients presenting with a syndrome consistent with the disease of interest, who are subsequently classified as test-positive cases or test-negative controls on the basis of diagnostic testing. We use simulations of a cluster trial to demonstrate validity of efficacy estimates under the test-negative approach. This demonstrates that, provided study arms are balanced for both test-negative and test-positive illness at baseline and that other test-negative design assumptions are met, the efficacy estimates closely match true efficacy. We also briefly discuss analytical considerations for an odds ratio-based effect estimate arising from clustered data, and outline potential approaches to analysis. We conclude that application of the test-negative design to certain cluster randomized trials could increase their efficiency and ease of implementation

Renal angiomyolipoma presenting with massive retroperitoneal haemorrhage due to deranged clotting factors: a case report

BACKGROUND: Angiomyolipomata of the kidney are unusual lesions composed of abnormal vasculature, smooth muscle, and adipose elements. They may be associated with tuberous sclerosis and occasionally present with flank pain, a palpable mass, and gross haematuria. As angiomyolipomata grow their risk of bleeding increases, with a greater than 50% chance of significant bleeding in lesions > 4 cm; anticoagulant therapy accentuates this risk. CASE PRESENTATION: A case of massive retroperitoneal haemorrhage in a patient on warfarin is presented. The underlying diagnosis of renal angiomyolipoma was diagnosed based on CT findings. Emergency resuscitation and selective interpolar arterial embolization was performed which saved the patient's life as well as his kidney. CONCLUSION: This case illustrates the clinical scenario of massive retroperitoneal haemorrhage in an anticoagulated patient with renal angiomyolipomata. In the emergent situation, adequate resuscitation along ABC principles, as well as control of haemorrhage with either nephrectomy (partial or radical), non-selective renal arterial embolization, or selective embolization of the feeding vessel(s), is necessary. For this to occur, it is imperative to consider the diagnosis early in warfarinized patients (and others at risk of bleeding) who present with abdominal pain. The authors hope this case report highlights to readers the clinical scenario of massive retroperitoneal haemorrhage in anticoagulated patients with renal angiomyolipomata so that they can deal appropriately with such presentations

The diagnosis of dengue in patients presenting with acute febrile illness using supervised machine learning and impact of seasonality

Background: Symptomatic dengue infection can result in a life-threatening shock syndrome and timely diagnosis is essential. Point-of-care tests for non-structural protein 1 and IgM are used widely but performance can be limited. We developed a supervised machine learning model to predict whether patients with acute febrile illnesses had a diagnosis of dengue or other febrile illnesses (OFI). The impact of seasonality on model performance over time was examined. Methods: We analysed data from a prospective observational clinical study in Vietnam. Enrolled patients presented with an acute febrile illness of 90%). Conclusion: Supervised machine learning models are able to discriminate between dengue and OFI diagnoses in patients presenting with an early undifferentiated febrile illness. These models could be of clinical utility in supporting healthcare decision-making and provide passive surveillance across dengue endemic regions. Effects of seasonality and changing disease prevalence must however be taken into account—this is of significant importance given unpredictable effects of human-induced climate change and the impact on health

Burden of postinfectious symptoms after acute Dengue, Vietnam.

We assessed predominantly pediatric patients in Vietnam with dengue and other febrile illness 3 months after acute illness. Among dengue patients, 47% reported >1 postacute symptom. Most resolved by 3 months, but alopecia and vision problems often persisted. Our findings provide additional evidence on postacute dengue burden and confirm children are affected

Clinical and Virological Features of Dengue in Vietnamese Infants

Dengue is a major public health problem in tropical and subtropical countries, including Vietnam. Dengue cases occur in children and young adults; however, severe dengue also occurs in infants less than 1 year of age. Prompt recognition of dengue is important for appropriate case management, particularly in infants in whom febrile illness from other causes is common. We describe the clinical picture, virological and immunological characteristics of infants with dengue admitted to three hospitals in southern Vietnam, compared with infants admitted with fever not due to dengue. We show that infants with dengue are difficult to distinguish from those with other febrile illnesses based on signs and symptoms at presentation, and so laboratory tests to confirm dengue virus infection may be useful for diagnosis and management. Conventional diagnostic methods for dengue have low sensitivity early in infection, and we show that an alternative antigen-detection assay that has demonstrated good sensitivity and specificity in older age groups also performs well in infants. This study will help to inform the diagnosis and management of dengue in infants