Sophie Yacoub

New insights into the immunopathology and control of dengue virus infection

Dengue virus poses a major threat to global public health: two-thirds of the worlds population is now at risk from infection by this mosquito-borne virus. Dengue virus causes a range of diseases with a small proportion of infected patients developing severe plasma leakage that leads to dengue shock syndrome, organ impairment and bleeding. Infection with one of the four viral serotypes results in the development of homotypic immunity to that serotype. However, subsequent infection with a different serotype is associated with an increased risk of developing severe disease, which has led to the suggestion that severe disease is triggered by immunopathology. This Review outlines recent advances in the understanding of immunopathology, vaccine development and human monoclonal antibodies produced against dengue virus.

Acute lung injury and other serious complications of Plasmodium vivax malaria.

Plasmodium vivax infection is classified among the so-called benign malarias, but it is increasingly recognised that serious and even life-threatening complications may occur. We present the case of a returning traveller with P vivax infection who developed acute lung injury 3 days into treatment, and discuss the serious complications of this infection. The case highlights the fact that P vivax infection is benign by name but not always by nature.

Neglected tropical cardiomyopathies: II. Endomyocardial fibrosis

Endomyocardial fibrosis (EMF) was described as a distinct clinicopathological entity in 1948 in Uganda.w1 Initially several terms were used to describe the disease. These included tropical endomyocardial disease, endocarditis parietalis fibroplastica, endocardial fibrosis, constrictive endocarditis and endocardial fibroelastose. EMF is thought to be the most common type of restrictive cardiomyopathy worldwide.1 Although most studies have been reported from Uganda, Ivory Coast, Nigeria, Brazil and India, the disease has been occasionally encountered outside the tropics.2 Geographic distribution of EMF is not uniform both in Africa and Asia.3 4 In the endemic areas of Africa, EMF is the second cause of admission for acquired cardiovascular disease in children and young adults, after rheumatic heart disease,5 w2 accounting for up to 20% of all causes of heart failure. To date our knowledge of the prevalence of the disease is derived from hospital based studies with absence of data from systematic studies in the community. EMF affects predominantly children and adolescents, usually from low socioeconomic background. More than half the cases are seen in the first decade of life. Male preponderance was found in Kerala and Nigeria, while female preponderance has been described in Brazil and Uganda. A bimodal age distribution has been reported in some studies.5 w3 The aetiology of EMF remains unknown. Several hypotheses have been proposed and explored including cardiotoxicity of the eosinophil, infectious agents, autoimmune processes, genetic predisposition, ethnicity, diet, climate and poverty. ### Hypereosinophilia EMF appears to share some pathogenic mechanisms with the hypereosinophilic syndromes, which comprise a heterogenous group of disorders characterised by peripheral eosinophilia for at least 6 months and end organ damage related to eosinophil infiltrations. These syndromes have been classified as idiopathic, clonal and reactive. The similarity of mechanisms responsible for EMF and the hypereosinophilic syndromes could have exciting therapeutic implications. …

The pathogenesis of dengue

Purpose of review Dengue is one of the most rapidly spreading vector-borne diseases in the world, with the incidence increasing 30-fold in the past 50 years. There are currently no licensed treatments or vaccines for dengue. This review covers the recent advances in our understanding of dengue pathogenesis, including host and viral determinants. Recent findings The pathogenesis of severe dengue is thought to be immune-mediated due to the timing of the clinical manifestations and higher incidence in secondary infections with a heterologous serotype. Recent evidence has provided further information of neutralizing versus enhancing monoclonal antibodies and their target epitopes on the dengue virion, which has major implications for vaccine design. The role of T-cell immunopathology has also been advanced with recent evidence of cross-reactive high pro-inflammatory cytokine producing T cells predominating in severe dengue. Recent large genome-wide association studies have identified specific susceptibility loci associated with severe disease. Epidemiological studies have served to define certain at-risk groups and specific viral virulence factors have recently been described. Summary The pathogenesis of dengue is likely to be a complex interplay of host immunity and genetic predisposition combined with certain viral virulence factors. Better understanding of the underlying mechanisms leading to severe dengue is crucial if we are to develop prognostic markers, novel diagnostics and therapeutics and ultimately a balanced and safe vaccine.

Dengue Therapeutics, Chemoprophylaxis, and Allied Tools: State of the Art and Future Directions

Dengue is the most common arboviral disease of humans. There is an unmet need for a therapeutic intervention that reduces the duration and severity of dengue symptoms and diminishes the likelihood of severe complications. To this end, there are active discovery efforts in industry and academia to develop interventions, with a focus on small molecule inhibitors of dengue virus replication that are suitable for therapy or chemoprophylaxis. Advancements in animal models of dengue virus infection together with the possibility of a dengue human infection model have further enhanced the platform for dengue drug discovery. Whilst drug discovery efforts gestate, there are ongoing clinical research designed to benefit todays patients, including trials of supportive care interventions, and descriptive studies that should improve the ability of clinicians to make an accurate diagnosis early in the illness course and to identify patients most at risk of progression to severe disease. This review provides a state of the art summary of dengue drug discovery, clinical trials, and supportive allied research and reflects discussions at the 2nd International Dengue Therapeutics Workshop held in Ho Chi Minh City, Vietnam, in December 2013.

Cardiovascular manifestations of the emerging dengue pandemic

Dengue is one of the most important emerging viral diseases globally. The majority of symptomatic infections result in a relatively benign disease course. However, a small proportion of patients develop severe clinical manifestations, including bleeding, organ impairment, and endothelial dysfunction with increased capillary permeability causing hypovolaemic shock that can lead to cardiovascular collapse. Evidence is increasing that dengue can also cause myocardial impairment, arrhythmias and, occasionally, fulminant myocarditis. No antiviral agents or vaccines are licensed for dengue, and treatment remains supportive with judicious fluid replacement for patients with severe disease. Defining the role of cardiac dysfunction in the haemodynamic compromise of severe dengue has potentially important management implications. In this Review, we will outline the current understanding of the cardiovascular manifestations of dengue, including myocardial and vascular involvement, and conclude with a discussion of the available therapeutic options and potential future research directions.

Predicting outcome from dengue

Dengue is emerging as one of the most abundant vector-borne disease globally. Although the majority of infections are asymptomatic or result in only a brief systemic viral illness, a small proportion of patients develop potentially fatal complications. These severe manifestations, including a unique plasma leakage syndrome, a coagulopathy sometimes accompanied by bleeding, and organ impairment, occur relatively late in the disease course, presenting a window of opportunity to identify the group of patients likely to progress to these complications. However, as yet, differentiating this group from the thousands of milder cases seen each day during outbreaks remains challenging, and simple and inexpensive strategies are urgently needed in order to improve case management and to facilitate appropriate use of limited resources. This review will cover the current understanding of the risk factors associated with poor outcome in dengue. We focus particularly on the clinical features of the disease and on conventional investigations that are usually accessible in mid-level healthcare facilities in endemic areas, and then discuss a variety of viral, immunological and vascular biomarkers that have the potential to improve risk prediction. We conclude with a description of several novel methods of assessing vascular function and intravascular volume status non-invasively.

Neglected tropical cardiomyopathies: I. Chagas disease

Cardiomyopathies, defined as diseases of the myocardium associated with cardiac dysfunction, are classified into dilated, hypertrophic, restrictive and arrhythmogenic right ventricular cardiomyopathy, as well as unclassified.1 More recently, molecular classification has been suggested.2 Cardiomyopathies continue to be a significant cause of morbidity and mortality in the developed world.w1 In developing countries, however, there appears to be an increased incidence of the “usual” forms of cardiomyopathy, with a modified clinical course possibly due to genetic differences or environmental factors such as malnutrition, infections and pollution.w2 In addition, there are specific cardiomyopathies endemic to the tropics such as Chagas and endomyocardial fibrosis, which cause a considerable amount of death and suffering and have been classified as neglected diseases. We here describe what is known about these two diseases, their aetiologies, pathogenesis and management and outline directions for further research. The present article will discuss Chagas disease, and a subsequent article will address endomyocardial fibrosis. Chagas disease is the leading cause of cardiac disease in many countries in Latin America, and the World Health Organization has estimated that 16–18 million people are currently infected and 90 million are at risk of infection.3 Chagas disease has been classified as one of the most neglected diseases in the world,w3 with no new drug development in the past 30 years.w4 Yet there are still 200 000 new cases of Chagas disease reported each year and some rural communities in Latin America have seroprevalence rates as high as 40%. Chagas disease is caused by the protozoan parasite Trypanosoma cruzi (fig 1), which is spread by triatomine bugs (fig 2). The disease is mainly constrained geographically to countries where its vector is endemic, ranging from South America to Mexico and southern USA. Transmission has also been shown to occur via blood transfusions, …

Cardiac function and hemodynamics in Kenyan children with severe malaria.

Objectives:Mortality from severe malaria remains unacceptably high in sub-Saharan Africa. Several markers of cardiovascular compromise and metabolic acidosis correlate with mortality. The role of cardiac dysfunction in the pathogenesis of severe childhood malaria remains unknown. Design:We examined 30 children admitted with severe malaria by using portable echocardiography to assess their cardiac function and hemodynamic status on admission (day 0), day 1, and discharge. We compared hemodynamic parameters in two study groups: children presenting with metabolic acidosis (base deficit >8) and children without acidosis. Setting:High-dependency unit, Kilifi District Hospital, Kenya. Interventions:Acidotic patients received fluid resuscitation with either dextran 70 or starch at admission. Measurements and Main Results:Several markers of hemodynamic compromise were noted on admission, including severe tachycardia, low stroke volume index, and high inferior vena cava collapsibility index, which improved with subsequent readings. Overall, cardiac function assessed by ejection fraction (63.1% ± 5.2% vs. 71.9% ± 2.8%; p < .001) and left myocardial performance index (0.32 ± 0.16 vs. 0.25 ± 0.08; p = .03) was mildly abnormal on admission compared with discharge. Acidotic patients had worse hemodynamic indicators, with a significantly higher inferior vena cava collapsibility index on day 0 than nonacidotic patients (52.1 ± 21 .9 vs. 37.7 ± 15.4; p = .03), plus lower stroke volume index and worse cardiac function with higher left myocardial performance index (0.38 ± 0.18 vs. 0.26 ± 0.11; p = .05). Stroke volume index increased after first fluid bolus in 80% of children. Conclusions:Children with severe malaria and metabolic acidosis have evidence of hypovolemia and evidence of cardiac dysfunction.

A Case of Optic Neuropathy after Short-term Linezolid Use in a Patient with Acute Lymphocytic Leukemia

A patient undergoing chemotherapy for treatment of acute lymphocytic leukemia developed septicemia that was treated with linezolid for 16 days. The patient subsequently reported reduced vision in both eyes and was found to have bilateral optic neuropathy. After the discontinuation of linezolid treatment, both the optic neuropathy and visual impairment resolved without sequelae.