The association of obesity and severe dengue:possible pathophysiological mechanisms

Dengue virus (DENV) is a medically important flavivirus and the aetiological agent of Dengue, a normally self-resolving febrile illness that, in some individuals, can progress into Severe Dengue (SD), a life-threatening disorder that manifests as organ impairment, bleeding and shock. Many different risk factors have been associated with the development of SD, one of which is obesity. In many countries where DENV is endemic, obesity is becoming more prevalent, therefore SD is becoming an increased public health concern. However, there is a paucity of research on the mechanistic links between obesity and SD. This is a narrative review based on original research and reviews sourced from PubMed and Google Scholar. Four key areas could possibly explain how obesity can promote viral pathogenesis. Firstly, obesity downregulates AMP-Protein Kinase (AMPK), which leads to an accumulation of lipids in the endoplasmic reticulum (ER) that facilitates viral replication. Secondly, the long-term production of pro-inflammatory adipokines found in obese individuals can cause endothelial and platelet dysfunction and can facilitate SD. Thirdly, obesity could also cause endothelial dysfunction in addition to chronic inflammation, through the production of reactive oxygen species (ROS) and possible damage to the glycocalyx found in the endothelium. Finally, obesity has several effects on immunomodulation that reduces NK cell function, B and T cell response and increased pre-disposition to stronger pro-inflammatory cytokine responses after viral infection. Together, these effects can lead to greater viral proliferation and greater tissue damage both of which could contribute to SD. The four mechanisms outlined in this review can be taken as reference starting points for investigating the link between obesity and SD, and to discover potential therapeutic strategies that can potentially reduce disease severity

Digital and technological innovation in vector-borne disease surveillance to predict, detect, and control climate-driven outbreaks.

Vector-borne diseases are particularly sensitive to changes in weather and climate. Timely warnings from surveillance systems can help to detect and control outbreaks of infectious disease, facilitate effective management of finite resources, and contribute to knowledge generation, response planning, and resource prioritisation in the long term, which can mitigate future outbreaks. Technological and digital innovations have enabled the incorporation of climatic data into surveillance systems, enhancing their capacity to predict trends in outbreak prevalence and location. Advance notice of the risk of an outbreak empowers decision makers and communities to scale up prevention and preparedness interventions and redirect resources for outbreak responses. In this Viewpoint, we outline important considerations in the advent of new technologies in disease surveillance, including the sustainability of innovation in the long term and the fundamental obligation to ensure that the communities that are affected by the disease are involved in the design of the technology and directly benefit from its application

Automatic Detection of B-lines in Lung Ultrasound Videos From Severe Dengue Patients

Lung ultrasound (LUS) imaging is used to assess lung abnormalities, including the presence of B-line artefacts due to fluid leakage into the lungs caused by a variety of diseases. However, manual detection of these artefacts is challenging. In this paper, we propose a novel methodology to automatically detect and localize B-lines in LUS videos using deep neural networks trained with weak labels. To this end, we combine a convolutional neural network (CNN) with a long short-term memory (LSTM) network and a temporal attention mechanism. Four different models are compared using data from 60 patients. Results show that our best model can determine whether one-second clips contain B-lines or not with an F1 score of 0.81, and extracts a representative frame with B-lines with an accuracy of 87.5%.Comment: 5 pages, 2 figures, 2 table

Microvascular dysfunction in septic and dengue shock: pathophysiology and implications for clinical management

The microcirculation comprising of arterioles, capillaries and post-capillary venules is the terminal vascular network of the systemic circulation. Microvascular homeostasis, comprising of a balance between vasoconstriction, vasodilation and endothelial permeability in healthy states, regulates tissue perfusion. In severe infections, systemic inflammation occurs irrespective of the infecting microorganism(s), resulting in microcirculatory dysregulation and dysfunction, which impairs tissue perfusion and often precedes end-organ failure. The common hallmarks of microvascular dysfunction in both septic shock and dengue shock, are endothelial cell activation, glycocalyx degradation and plasma leak through a disrupted endothelial barrier. Microvascular tone is also impaired by a reduced bioavailability of nitric oxide. In vitro and in vivo studies have however demonstrated that the nature and extent of microvascular dysfunction as well as responses to volume expansion resuscitation differ in these two clinical syndromes. This review compares and contrasts the pathophysiology of microcirculatory dysfunction in septic versus dengue shock and the attendant effects of fluid administration during resuscitation

Chagas disease in the United Kingdom: A review of cases at the hospital for Tropical Diseases London 1995-2018. The current state of detection of Chagas disease in the UK

Background: Chagas disease (CD), is a parasitic disease endemic in Latin America. Presentation in non-endemic areas is either in the asymptomatic indeterminate phase or the chronic phase with cardiac and/or gastrointestinal complications. Methods: The Hospital for Tropical Diseases (HTD) based in central London, provides tertiary care for the management of CD. We reviewed all cases managed at this centre between 1995 and 2018. Results: Sixty patients with serologically proven CD were identified. Most were female (70%), with a median age at diagnosis of 41 years. Three quarters of the patients were originally from Bolivia. 62% of all patients were referred to the HTD by their GP. Nearly half of the patients were asymptomatic (47%). Twelve patients had signs of cardiac involvement secondary to CD. Evidence of gastrointestinal damage was established in three patients. Treatment was provided at HTD for 31 patients (47%). Most patients (29) received benznidazole, five of them did not tolerate the course and were switched to nifurtimox. Of the seven patients receiving this second line drug, five completed treatment, whilst two interrupted it due to side effects. Conclusions: Despite the UK health system having all the resources required to diagnose, treat and follow up cases, there is lack of awareness of CD, such that the vast majority of cases remain undiagnosed and therefore do not receive treatment. We propose key interventions to improve the detection and management of this condition in the UK, especially in pregnant women and neonates

Visual and biochemical evidence of glycocalyx disruption in human dengue infection, and association with plasma leakage severity

Background: Dengue is the most common arboviral infection globally; a minority of patients develop shock due to profound plasma leak through a disrupted endothelial barrier. Understanding of the pathophysiology underlying plasma leak is incomplete, but emerging evidence indicates a key role for degradation of the endothelial glycocalyx. Methods: We conducted an observational study in Vietnam to evaluate the sublingual microcirculation using sidestream darkfield imaging in (1) outpatients with confirmed dengue (2) patients hospitalized with dengue and (3) outpatients with other febrile illness (OFI). We estimated the glycocalyx degradation by measuring the perfused boundary region (PBR hf) and an overall microvascular health score (MVHS) with the software application GlycoCheckTM at enrolment, 48 h later and hospital discharge/defervescence. We measured plasma syndecan1 and endocan at the same time-points. We compared PBR hf, MVHS, syndecan1 and endocan, between (1) outpatients with confirmed dengue vs. OFI and (2) patients with dengue subdivided by clinical severity of plasma leak. Results: We included 75 patients with dengue (41 outpatients, 15 inpatients, 19 in intensive care) and 12 outpatients with OFI. Images from 45 patients were analyzed using GlycoCheckTM. There was no significant difference in PBR hf or MVHS between outpatients with dengue and OFI. Median plasma syndecan1 was not significantly different in outpatients with dengue vs. OFI, while median plasma endocan was significantly lower among patients with dengue vs. OFI during the critical phase. In patients with dengue, PBR hf was higher in patients with Grade 2 vs. Grade 0 plasma leakage during the critical phase (PBR hf 1.96 vs. 1.36 μm for Grade 2 vs. Grade 0 plasma leakage on days 4–6, respectively, p < 0.001). Median levels of plasma syndecan1 and endocan were higher in Grade 2 vs. Grade 0 plasma leakage, especially during the critical phase (Syndecan1 2,613.8 vs. 125.9 ng/ml for Grade 2 vs. Grade 0 plasma leakage on days 4–6, respectively, p < 0.001, and endocan 3.21 vs. 0.16 ng/ml for Grade 2 vs. Grade 0 plasma leakage on days 4–6, respectively). Conclusions: We present the first human in vivo evidence of glycocalyx disruption in dengue, with worse visual glycocalyx damage and higher plasma degradation products associated with more severe plasma leak

Studying the endothelial glycocalyx in vitro: what is missing?

All human cells are coated by a surface layer of proteoglycans, glycosaminoglycans (GAGs) and plasma proteins, called the glycocalyx. The glycocalyx transmits shear stress to the cytoskeleton of endothelial cells, maintains a selective permeability barrier, and modulates adhesion of blood leukocytes and platelets. Major components of the glycocalyx, including syndecans, heparan sulfate, and hyaluronan, are shed from the endothelial surface layer during conditions including ischaemia and hypoxia, sepsis, atherosclerosis, diabetes, renal disease, and some viral infections. Studying mechanisms of glycocalyx damage in vivo can be challenging due to the complexity of immuno-inflammatory responses which are inextricably involved. Previously, both static as well as perfused in vitro models have studied the glycocalyx, and have reported either imaging data, assessment of barrier function, or interactions of blood components with the endothelial monolayer. To date, no model has simultaneously incorporated all these features at once, however such a model would arguably enhance the study of vasculopathic processes. This review compiles a series of current in vitro models described in the literature that have targeted the glycocalyx layer, their limitations, and potential opportunities for further developments in this field