Sophie Yacoub

Research Area: Global Health
Scientific Themes: Tropical Medicine & Global Health and Clinical Trials & Epidemiology

The Dengue Group at OUCRU consists of 28 staff including clinicians, scientists, post-doctoral and PhD students as well as research assistants and study nurses. The group has a strong international focus with expanding collaborative research networks across Southeast Asia, as well as in the UK, Australia and the USA. The group’s primary objectives are to improve diagnosis and management of dengue at a global level, and to facilitate/enhance disease prevention strategies.

We have established a coordinated program of clinical research focused on novel therapeutic trials, monitoring studies of critically ill patients, development of innovative technology, and clinical entomology studies, all supported by laboratory science focused on immunology, pathogenesis and physiology studies.

There are no collaborations listed for this principal investigator.

Gan P, Yacoub S. 2019. Picturing health: dengue in Vietnam LANCET, 394 (10214), pp. 2059-2066. | Read more

Hung TM, Wills B, Clapham HE, Yacoub S, Turner HC. 2019. The Uncertainty Surrounding the Burden of Post-acute Consequences of Dengue Infection. Trends Parasitol, 35 (9), pp. 673-676. | Show Abstract | Read more

Post-acute consequences currently form a significant component of the dengue disability-adjusted life year (DALY) burden estimates. However, there is considerable uncertainty regarding the incidence, duration, and severity of these symptoms. Further research is needed to more accurately estimate the health and economic burden of these dengue manifestations.

Turner HC, Hao NV, Yacoub S, Hoang VMT, Clifton DA, Thwaites GE, Dondorp AM, Thwaites CL, Chau NVV. 2019. Achieving affordable critical care in low-income and middle-income countries. BMJ Glob Health, 4 (3), pp. e001675. | Read more

Whitehorn J, Yacoub S. 2019. Global warming and arboviral infections. Clin Med (Lond), 19 (2), pp. 149-152. | Show Abstract | Read more

Climate change is already expanding the geographic footprint of arboviral infections. In this article we consider the impact of climate change on three arboviruses with particular consideration of the effect on Europe.

Morra ME, Altibi AMA, Iqtadar S, Minh LHN, Elawady SS, Hallab A, Elshafay A, Omer OA, Iraqi A, Adhikari P et al. 2018. Definitions for warning signs and signs of severe dengue according to the WHO 2009 classification: Systematic review of literature. Rev Med Virol, 28 (4), pp. e1979. | Show Abstract | Read more

Since warning signs and signs of severe dengue are defined differently between studies, we conducted a systematic review on how researchers defined these signs. We conducted an electronic search in Scopus to identify relevant articles, using key words including dengue, "warning signs," "severe dengue," and "classification." A total of 491 articles were identified through this search strategy and were subsequently screened by 2 independent reviewers for definitions of any of the warning or severe signs in the 2009 WHO dengue classification. We included all original articles published in English after 2009, classifying dengue by the 2009 WHO classification or providing the additional definition or criterion of warning signs and severity (besides the information of 2009 WHO). Analysis of the extracted data from 44 articles showed wide variations among definitions and cutoff values used by physicians to classify patients diagnosed with dengue infection. The establishment of clear definitions for warning signs and severity is essential to prevent unnecessary hospitalization and harmonizing the interpretation and comparability of epidemiological studies dedicated to dengue infection.

Rodriguez-Manzano J, Chia PY, Yeo TW, Holmes A, Georgiou P, Yacoub S. 2018. Correction to: Improving Dengue Diagnostics and Management Through Innovative Technology. Curr Infect Dis Rep, 20 (8), pp. 28. | Show Abstract | Read more

In the original publication, the Table 2 contains an error. The original article has been corrected.

Rodriguez-Manzano J, Chia PY, Yeo TW, Holmes A, Georgiou P, Yacoub S. 2018. Improving Dengue Diagnostics and Management Through Innovative Technology. Curr Infect Dis Rep, 20 (8), pp. 25. | Show Abstract | Read more

PURPOSE OF REVIEW: Dengue continues to be a major global public health threat. Symptomatic infections can cause a spectrum of disease ranging from a mild febrile illness to severe and potentially life-threatening manifestations. Management relies on supportive treatment with careful fluid replacement. The purpose of this review is to define the unmet needs and challenges in current dengue diagnostics and patient monitoring and outline potential novel technologies to address these needs. RECENT FINDINGS: There have been recent advances in molecular and point-of-care (POC) diagnostics as well as technologies including wireless communication, low-power microelectronics, and wearable sensors that have opened up new possibilities for management, clinical monitoring, and real-time surveillance of dengue. Novel platforms utilizing innovative technologies for POC dengue diagnostics and wearable patient monitors have the potential to revolutionize dengue surveillance, outbreak response, and management at population and individual levels. Validation studies of these technologies are urgently required in dengue-endemic areas.

Mai NTH, Phu NH, Nghia HDT, Phuong TM, Duc DT, Chau NVV, Wills B, Lim CCT, Thwaites G, Simmons CP, Yacoub S. 2018. Dengue-Associated Posterior Reversible Encephalopathy Syndrome, Vietnam. Emerg Infect Dis, 24 (2), pp. 402-404. | Show Abstract | Read more

Dengue can cause neurologic complications in addition to the more common manifestations of plasma leakage and coagulopathy. Posterior reversible encephalopathy syndrome has rarely been described in dengue, although the pathophysiology of endothelial dysfunction likely underlies both. We describe a case of dengue-associated posterior reversible encephalopathy syndrome and discuss diagnosis and management.

Yacoub S, Trung TH, Lam PK, Thien VHN, Hai DHT, Phan TQ, Nguyet OPK, Quyen NTH, Simmons CP, Broyd C et al. 2017. Cardio-haemodynamic assessment and venous lactate in severe dengue: Relationship with recurrent shock and respiratory distress. PLoS Negl Trop Dis, 11 (7), pp. e0005740. | Show Abstract | Read more

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.

Yacoub S, Lam PK, Huynh TT, Nguyen Ho HH, Dong Thi HT, Van NT, Lien LT, Ha QNT, Le DHT, Mongkolspaya J et al. 2017. Endothelial Nitric Oxide Pathways in the Pathophysiology of Dengue: A Prospective Observational Study. Clin Infect Dis, 65 (9), pp. 1453-1461. | Show Abstract | Read more

Background: Dengue can cause increased vascular permeability that may lead to hypovolemic shock. Endothelial dysfunction may underlie this; however, the association of endothelial nitric oxide (NO) pathways with disease severity is unknown. Methods: We performed a prospective observational study in 2 Vietnamese hospitals, assessing patients presenting early (<72 hours of fever) and patients hospitalized with warning signs or severe dengue. The reactive hyperemic index (RHI), which measures endothelium-dependent vasodilation and is a surrogate marker of endothelial function and NO bioavailability, was evaluated using peripheral artery tonometry (EndoPAT), and plasma levels of l-arginine, arginase-1, and asymmetric dimethylarginine were measured at serial time-points. The main outcome of interest was plasma leakage severity. Results: Three hundred fourteen patients were enrolled; median age of the participants was 21(interquartile range, 13-30) years. No difference was found in the endothelial parameters between dengue and other febrile illness. Considering dengue patients, the RHI was significantly lower for patients with severe plasma leakage compared to those with no leakage (1.46 vs 2.00; P < .001), over acute time-points, apparent already in the early febrile phase (1.29 vs 1.75; P = .012). RHI correlated negatively with arginase-1 and positively with l-arginine (P = .001). Conclusions: Endothelial dysfunction/NO bioavailability is associated with worse plasma leakage, occurs early in dengue illness and correlates with hypoargininemia and high arginase-1 levels.

Yacoub S, Lam PK, Vu LHM, Le TL, Ha NT, Toan TT, Van NT, Quyen NTH, Le Duyen HT, Van Kinh N et al. 2016. Association of Microvascular Function and Endothelial Biomarkers With Clinical Outcome in Dengue: An Observational Study. J Infect Dis, 214 (5), pp. 697-706. | Show Abstract | Read more

BACKGROUND: The hallmark of severe dengue is increased microvascular permeability, but alterations in the microcirculation and their evolution over the course of dengue are unknown. METHODS: We conducted a prospective observational study to evaluate the sublingual microcirculation using side-stream dark-field imaging in patients presenting early (<72 hours after fever onset) and patients hospitalized with warning signs or severe dengue in Vietnam. Clinical findings, microvascular function, global hemodynamics assessed with echocardiography, and serological markers of endothelial activation were determined at 4 time points. RESULTS: A total of 165 patients were enrolled. No difference was found between the microcirculatory parameters comparing dengue with other febrile illnesses. The proportion of perfused vessels (PPV) and the mean flow index (MFI) were lower in patients with dengue with plasma than those without leakage (PPV, 88.1% vs 90.6% [P = .01]; MFI, 2.1 vs 2.4 [P = .007]), most markedly during the critical phase. PPV and MFI were correlated with the endothelial activation markers vascular cell adhesion molecule 1 (P < .001 for both) and angiopoietin 2 (P < .001 for both), negatively correlated. CONCLUSIONS: Modest microcirculatory alterations occur in dengue, are associated with plasma leakage, and are correlate with molecules of endothelial activation, angiopoietin 2 and vascular cell adhesion molecule 1.

Jaenisch T, Tam DTH, Kieu NTT, Van Ngoc T, Nam NT, Van Kinh N, Yacoub S, Chanpheaktra N, Kumar V, See LLC et al. 2016. Clinical evaluation of dengue and identification of risk factors for severe disease: protocol for a multicentre study in 8 countries. BMC Infect Dis, 16 (1), pp. 120. | Show Abstract | Read more

BACKGROUND: The burden of dengue continues to increase globally, with an estimated 100 million clinically apparent infections occurring each year. Although most dengue infections are asymptomatic, patients can present with a wide spectrum of clinical symptoms ranging from mild febrile illness through to severe manifestations of bleeding, organ impairment, and hypovolaemic shock due to a systemic vascular leak syndrome. Clinical diagnosis of dengue and identification of which patients are likely to develop severe disease remain challenging. This study aims to improve diagnosis and clinical management through approaches designed a) to differentiate between dengue and other common febrile illness within 72 h of fever onset, and b) among patients with dengue to identify markers that are predictive of the likelihood of evolving to a more severe disease course. METHOD/DESIGN: This is a prospective multi-centre observational study aiming to enrol 7-8000 participants aged ≥ 5 years presenting with a febrile illness consistent with dengue to outpatient health facilities in 8 countries across Asia and Latin America. Patients presenting within 72 h of fever onset who do not exhibit signs of severe disease are eligible for the study. A broad range of clinical and laboratory parameters are assessed daily for up to 6 days during the acute illness, and also at a follow up visit 1 week later. DISCUSSION: Data from this large cohort of patients, enrolled early with undifferentiated fever, will be used to develop a practical diagnostic algorithm and a robust clinical case definition for dengue. Additionally, among patients with confirmed dengue we aim to identify simple clinical and laboratory parameters associated with progression to a more severe disease course. We will also investigate early virological and serological correlates of severe disease, and examine genetic associations in this large heterogeneous cohort. In addition the results will be used to assess the new World Health Organization classification scheme for dengue in practice, and to update the guidelines for "Integrated Management of Childhood Illness" used in dengue-endemic countries. TRIAL REGISTRATION: NCT01550016. Registration Date: March 7, 2012.

Van Vinh Chau N, Buu Chau L, Desquesnes M, Herder S, Phu Huong Lan N, Campbell JI, Van Cuong N, Yimming B, Chalermwong P, Jittapalapong S et al. 2016. A Clinical and Epidemiological Investigation of the First Reported Human Infection With the Zoonotic Parasite Trypanosoma evansi in Southeast Asia. Clin Infect Dis, 62 (8), pp. 1002-1008. | Show Abstract | Read more

BACKGROUND: Trypanosomais a genus of unicellular parasitic flagellate protozoa.Trypanosoma bruceispecies and Trypanosoma cruziare the major agents of human trypanosomiasis; other Trypanosomaspecies can cause human disease, but are rare. In March 2015, a 38-year-old woman presented to a healthcare facility in southern Vietnam with fever, headache, and arthralgia. Microscopic examination of blood revealed infection with Trypanosoma METHODS: Microscopic observation, polymerase chain reaction (PCR) amplification of blood samples, and serological testing were performed to identify the infecting species. The patient's blood was screened for the trypanocidal protein apolipoprotein L1 (APOL1), and a field investigation was performed to identify the zoonotic source. RESULTS: PCR amplification and serological testing identified the infecting species as Trypanosoma evansi.Despite relapsing 6 weeks after completing amphotericin B therapy, the patient made a complete recovery after 5 weeks of suramin. The patient was found to have 2 wild-type APOL1 alleles and a normal serum APOL1 concentration. After responsive animal sampling in the presumed location of exposure, cattle and/or buffalo were determined to be the most likely source of the infection, with 14 of 30 (47%) animal blood samples testing PCR positive forT. evansi. CONCLUSIONS: We report the first laboratory-confirmed case ofT. evansiin a previously healthy individual without APOL1 deficiency, potentially contracted via a wound while butchering raw beef, and successfully treated with suramin. A linked epidemiological investigation revealed widespread and previously unidentified burden ofT. evansiin local cattle, highlighting the need for surveillance of this infection in animals and the possibility of further human cases.

Yacoub S, Mongkolsapaya J, Screaton G. 2016. Recent advances in understanding dengue. F1000Res, 5 pp. 78-78. | Show Abstract | Read more

Dengue is an emerging threat to billions of people worldwide. In the last 20 years, the incidence has increased four-fold and this trend appears to be continuing. Caused by one of four viral serotypes, dengue can present as a wide range of clinical phenotypes with the severe end of the spectrum being defined by a syndrome of capillary leak, coagulopathy, and organ impairment. The pathogenesis of severe disease is thought to be in part immune mediated, but the exact mechanisms remain to be defined. The current treatment of dengue relies on supportive measures with no licensed therapeutics available to date. There have been recent advances in our understanding of a number of areas of dengue research, of which the following will be discussed in this review: the drivers behind the global dengue pandemic, viral structure and epitope binding, risk factors for severe disease and its pathogenesis, as well as the findings of recent clinical trials including therapeutics and vaccines. We conclude with current and future dengue control measures and key areas for future research.

Screaton G, Mongkolsapaya J, Yacoub S, Roberts C. 2015. New insights into the immunopathology and control of dengue virus infection. Nat Rev Immunol, 15 (12), pp. 745-759. | Show Abstract | Read more

Dengue virus poses a major threat to global public health: two-thirds of the world's 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.

Vannucchi V, Tomberli B, Zammarchi L, Fornaro A, Castelli G, Pieralli F, Berni A, Yacoub S, Bartoloni A, Olivotto I. 2015. Chagas disease as a cause of heart failure and ventricular arrhythmias in patients long removed from endemic areas: an emerging problem in Europe. J Cardiovasc Med (Hagerstown), 16 (12), pp. 817-823. | Show Abstract | Read more

Chagas disease is a parasitic disease caused by the protozoan Trypanosoma cruzi. In endemic areas (South and Central America), Chagas disease represents a relevant public health issue, and is the most frequent cause of cardiomyopathy. In nonendemic areas, such as Europe, Chagas disease represents an emerging problem following the establishment of sizeable communities from Brazil and Bolivia. Chagas cardiomyopathy represents the most frequent and serious complication of chronic Chagas disease, affecting about 20-30% of patients, potentially leading to heart failure, arrhythmias, thromboembolism, stroke and sudden death. Because late complications of Chagas disease may develop several years or even decades after the acute infection, it may be extremely challenging to reach the correct diagnosis in patients long removed from the countries of origin. We report two examples of Chagas cardiomyopathy in South American women permanently residing in Italy for more than 20 years, presenting with cardiac manifestations ranging from left ventricular dysfunction and heart failure to isolated ventricular arrhythmias. The present review emphasizes that Chagas disease should be considered as a potential diagnosis in patients from endemic areas presenting with 'idiopathic' cardiac manifestations, even when long removed from their country of origin, with potential implications for treatment and control of Chagas disease transmission.

Taylor WR, Fox A, Pham KT, Le HNM, Tran NTH, Tran GV, Nguyen BT, Nguyen MV, Nguyen LT, Yacoub S et al. 2015. Dengue in adults admitted to a referral hospital in Hanoi, Vietnam. Am J Trop Med Hyg, 92 (6), pp. 1141-1149. | Show Abstract | Read more

Knowledge of adult dengue virus (DENV) infection from Hanoi, Vietnam, is limited. In 2008, we prospectively studied 143 (77 male) confirmed (nonstructural 1 antigen enzyme-linked immunosorbent assay [ELISA], DENV polymerase chain reaction, paired serology) adult dengue patients of median age 23.5 (range 16-72) years. They were admitted to the National Hospital for Tropical Diseases, Hanoi, on median illness day (D) 5 (range 1-8). By D8, 141 (98.6%) were afebrile. Platelet counts and hematocrit (median, interquartile range [IQR]) nadired and peaked on D5 and D4, respectively: 40,000/μL (10,000-109,000/μL), 43.4% (34.9-49.7%). Four (2.8%) patients had severe dengue: 1) D10 shock (N = 1) and 2) aspartate aminotransferase (AST) ≥ 1,000 IU/L (N = 3, D5 and D7). Of 143 patients, 118 (82.5%) had ≥ 1 warning sign (World Health Organization [WHO] 2009 criteria): mucosal bleeding 66/143 (46.1%), soft tissue edema 54/143 (37.7%), and ultrasound detected plasma leakage (pleural effusions/ascites) 30/129 (23.25%). 138 (96.5%) patients received intravenous (IV) fluids: 3 L (IQR: 0.5-8.5 L). Most patients had non-severe dengue with warning signs. High rates of edema and plasma leakage may be explained partly by liberal use of IV fluids. Studies are needed on optimizing fluid management in non-severe adult dengue.

Bich TD, Pham OKN, Hai DHT, Nguyen NM, Van HN, The TD, Wills B, Yacoub S. 2015. A pregnant woman with acute cardiorespiratory failure: dengue myocarditis. Lancet, 385 (9974), pp. 1260. | Read more

Yacoub S, Wertheim H, Simmons CP, Screaton G, Wills B. 2015. Microvascular and endothelial function for risk prediction in dengue: an observational study. Lancet, 385 Suppl 1 pp. S102. | Show Abstract | Read more

BACKGROUND: Dengue infection can result in a wide spectrum of disease. The defining feature of severe disease is increased capillary permeability, which can lead to hypovolaemic shock. Microvascular and endothelial dysfunction might underlie hypovolaemic shock, but they have not been assessed clinically. We aimed to investigate the use of microvascular assessment as a prognostic method in dengue. METHODS: This is an ongoing prospective observational study that aims to recruit 300 participants: children over the age of 3 years and adults presenting to two outpatient departments in Vietnam with fever of less than 72 h duration and suspected dengue, and patients admitted to hospital with warning signs or severe disease. Participants are being clinically assessed daily for 6 days, and 2 weeks later. Microvascular imaging using sublingual sidestream darkfield imaging (SDF) and endothelial function testing using peripheral artery tonometry are being performed at enrolment, defervescence, and follow-up FINDINGS: To date, 167 patients have been recruited (92 outpatient arm, 75 inpatient arm, median age 27 years [IQR 21-33], 78 male [47%]). Dengue has been confirmed in 67 individuals in the outpatient arm, of whom 29 (43%) developed warning signs, three (4%) developed severe disease, and 35 had uncomplicated dengue; the other 25 outpatients (27%) were diagnosed as other febrile illness. At enrolment, the reactive hyperaemic index, a marker of endothelial function, was lowest in the patients who went on to develop severe dengue (median 1·54, IQR 1·36-1·77) followed by those who developed warning signs (1·78, 1·43-2·36) and then uncomplicated dengue (2·18, 1·65-2·24). Initial SDF results showed a lower proportion of perfused vessels and mean flow index during the febrile phase of dengue compared with follow-up, and were worst in the severe group at defervescence. INTERPRETATION: This study of vascular function at serial timepoints in dengue is, to our knowledge, the first and most comprehensive. Our preliminary results suggest that microvascular and endothelial dysfunction are associated with severity of dengue, and occur before the appearance of severe clinical manifestations. These techniques might be useful in risk prediction in dengue. A limitation is that a formal sample size could not be calculated because no previous microvascular data in dengue exist. FUNDING: Wellcome Trust.

Yacoub S, Wills B. 2015. Dengue: an update for clinicians working in non-endemic areas. Clin Med (Lond), 15 (1), pp. 82-85. | Show Abstract | Read more

Dengue is one of the most rapidly emerging viral infections globally, with 2.5 billion people now thought to live in dengue-endemic areas. In addition, reports of travel-related and autochthonous infections are increasing in non-endemic areas. Most patients with dengue experience a self-limiting febrile illness, but a proportion develop potentially life threatening complications around the time of fever clearance, including plasma leakage occasionally leading to shock, bleeding, and organ impairment. As dengue can present with non-specific symptoms of fever, headache and myalgias, the potential for misdiagnosis and inappropriate management by medical staff inexperienced with the disease is a concern. This short review will outline the latest World Health Organisation disease classification, potential complications, clinical assessment and management for clinicians working in non-endemic areas.

Yacoub S, Wills B. 2014. Predicting outcome from dengue. BMC Med, 12 (1), pp. 147. | Show Abstract | Read more

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.

Whitehorn J, Yacoub S, Anders KL, Macareo LR, Cassetti MC, Nguyen Van VC, Shi P-Y, Wills B, Simmons CP. 2014. Dengue therapeutics, chemoprophylaxis, and allied tools: state of the art and future directions. PLoS Negl Trop Dis, 8 (8), pp. e3025. | Show Abstract | Read more

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 today's 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.

Yacoub S, Wertheim H, Simmons CP, Screaton G, Wills B. 2014. Cardiovascular manifestations of the emerging dengue pandemic. Nat Rev Cardiol, 11 (6), pp. 335-345. | Show Abstract | Read more

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.

Yacoub S, Mongkolsapaya J, Screaton G. 2013. The pathogenesis of dengue. Curr Opin Infect Dis, 26 (3), pp. 284-289. | Show Abstract | Read more

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.

Yacoub S, Grifiths A, Chau TTH, Simmons C, Wills B, Hien TT, Henein M, Farrar J. 2012. Cardiac function and haemodynamics in Vietnemese patients with different dengue severity grades INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E119-E119. | Read more

Yacoub S, Griffiths A, Chau TTH, Simmons CP, Wills B, Hien TT, Henein M, Farrar J. 2012. Cardiac function in Vietnamese patients with different dengue severity grades. Crit Care Med, 40 (2), pp. 477-483. | Show Abstract | Read more

OBJECTIVE: Dengue continues to cause significant global morbidity and mortality. Severe disease is characterized by cardiovascular compromise from capillary leakage. Cardiac involvement in dengue has also been reported but has not been adequately studied. SETTING: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. SUBJECTS AND DESIGN: Seventy-nine patients aged 8-6 yrs with different dengue severity grades were studied using echocardiography including tissue Doppler imaging. The patients were split into severity grades: dengue, dengue with warning signs, and severe dengue. Changes in cardiac functional parameters and hemodynamic indices were monitored over the hospital stay. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Patients with severe dengue had worse cardiac function compared with dengue in the form of left ventricular systolic dysfunction with increased left myocardial performance index (0.58 [0.26-0.80] vs. 0.38 [0.22-0.70], p = .006). Septal myocardial systolic velocities were reduced (6.4 [4.8-10] vs. 8.1 [6-13] cm/s, p = .01) as well as right ventricular systolic (11.4 [7.5-17] vs. 13.5 [10-17] cm/s, p = .016) and diastolic velocities (13 [8-23] vs. 17 [12-25] cm/s, p = .0026). In the severe group, these parameters improved from hospital admission to discharge; septal myocardial systolic velocities to 8.8 (7-11) cm/s (p = .002), right ventricular myocardial systolic velocities to 15.0 (11.8-23) cm/s, (p = .003), and diastolic velocity to 21 (11-25) cm/s (p = .002). Patients with cardiac impairment were more likely to have significant pleural effusions. CONCLUSIONS: Patients with severe dengue have evidence of systolic and diastolic cardiac impairment with septal and right ventricular wall being predominantly affected.

Yacoub S, Kotit S, Yacoub MH. 2011. Disease appearance and evolution against a background of climate change and reduced resources. Philos Trans A Math Phys Eng Sci, 369 (1942), pp. 1719-1729. | Show Abstract | Read more

Global health continues to face increasing challenges owing to a variety of reasons that include the almost constant changes in disease appearance and evolution. Most, but not all, of these changes affect low-income countries and are influenced by climate change. Tracking the recent and anticipated changes in the demographics and global distribution of these changes is essential for evolving effective new methods for dealing with the problems. The recent recognition by the United Nations of the importance of non-communicable diseases is a major positive step. For the sake of this paper, the following diseases were chosen: dengue and malaria, to highlight the role of climate change on vector-borne diseases. Drug-resistant tuberculosis illustrates the role of globalization and reduced resources on disease evolution. The continuing rise in cardiovascular mortality and morbidity, particularly in resource-poor countries is largely attributed to lack of preventive and therapeutic measures against such conditions as hypertension, diabetes, atherosclerosis and congenital heart disease as well as neglected diseases, of which Chagas and rheumatic heart disease will be discussed further.

Yacoub S, Lang H-J, Shebbe M, Timbwa M, Ohuma E, Tulloh R, Maitland K. 2010. Cardiac function and hemodynamics in Kenyan children with severe malaria. Crit Care Med, 38 (3), pp. 940-945. | Show Abstract | Read more

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.

Joshi L, Taylor SRJ, Large O, Yacoub S, Lightman S. 2009. A case of optic neuropathy after short-term linezolid use in a patient with acute lymphocytic leukemia. Clin Infect Dis, 48 (7), pp. e73-e74. | Show Abstract | Read more

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.

Tan LKK, Yacoub S, Scott S, Bhagani S, Jacobs M. 2008. Acute lung injury and other serious complications of Plasmodium vivax malaria. Lancet Infect Dis, 8 (7), pp. 449-454. | Show Abstract | Read more

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.

Yacoub S, Kotit S, Mocumbi AO, Yacoub MH. 2008. Neglected diseases in cardiology: a call for urgent action. Nat Clin Pract Cardiovasc Med, 5 (4), pp. 176-177. | Read more

Mocumbi AO, Yacoub S, Yacoub MH. 2008. Neglected tropical cardiomyopathies: II. Endomyocardial fibrosis: myocardial disease. Heart, 94 (3), pp. 384-390. | Read more

Yacoub S, Mocumbi AO, Yacoub MH. 2008. Neglected tropical cardiomyopathies: I. Chagas disease: myocardial disease. Heart, 94 (2), pp. 244-248. | Read more

Yacoub S, Arellano S, Padgett-Moncada D. 2006. Violence related injuries, deaths and disabilities in the capital of Honduras. Injury, 37 (5), pp. 428-434. | Show Abstract | Read more

BACKGROUND: Honduras has the second highest incidence of violence in the Americas. The aim of this study is to explore the number and mechanism of fatal injuries, non-fatal injuries and the sequelae of these injuries due to violence. This is compared with unintentional injuries, in the capital of Honduras for 2001, with a view to better-targeted prevention. METHODS: Data for non-fatal injuries was retrospectively obtained from medical records of all admissions from the public Emergency Department in Tegucigalpa for 2001. Data on fatal injuries were obtained from the national forensic department. All injuries were reviewed for intention, mechanism and age group. RESULTS: There were 1631 (rate 138/100,000) fatal injuries recorded for 2001 in Tegucigalpa. Of these, 1149 (70.4%) were due to violence, compared to 355 (21.8%) due to unintentional injuries and 127 (7.8%) of unknown intent. Homicides accounted for 1044 (64%), suicides 105 (6.4%) and unintentional deaths 355 (22%). Firearms were the leading cause of death in the homicide group (84.3%). In addition 1592 (rate 235/100,000) non-fatal injuries were documented for people 15 years and above, with 1228 (77.1%) caused by violence, of which 640 (52.1%) were caused by firearms. The age group 15-24 years had the highest rates of fatal and non-fatal injuries due to violence. Twenty percent had permanent sequelae as a result of their injuries. Firearm injuries had the highest proportion of sequelae (28.8%). CONCLUSION: Violence in Tegucigalpa is a major cause of injury resulting in substantial morbidity, mortality and disability, particularly in young individuals. Firearms are the most common form of violence related injury mechanism and carry the highest associated mortality and permanent disability. Prevention programs are urgently needed to address this devastating problem.

Yacoub S, Mohammed MJ, Ramsan M, Albonico M. 2005. Clinical predictors of malaria and other febrile illnesses in children under five on Pemba Island, Tanzania. Trop Doct, 35 (2), pp. 78-81. | Show Abstract | Read more

Under the current guidelines of presumptive treatment of all children with reported fever, the risk of over-prescribing antimalarial drugs and missing other important causes of fever, like acute respiratory tract infection (ARI), is substantial. Clinical algorithms have been shown to be useful in diagnosing malaria, but often with differing results, due to regional variations. We set out to explore the clinical features associated with malaria compared with other febrile illnesses and specifically severe malaria with ARI in children under five in Pemba. Two hundred and seven children aged six months to five years presenting to a hospital clinic with fever were studied in Pemba. Clinical findings were related to the presence of malaria parasitaemia. Malaria accounted for 67.7% of the febrile episodes investigated. Five symptoms and signs, including pallor, drowsiness, splenomegaly, fever duration and no chest crackles, could accurately predict a case of malaria with a sensitivity of 91.3% and specificity of 53% and positive predictive value of 80.3%. Several clinical features were found to differentiate severe malaria from ARI. These results confirm that clinical algorithms can increase the diagnostic accuracy of malaria, although not sufficiently to replace microscopy, and by promoting the use of clinical skills other treatable causes of febrile illnesses may be identified. These findings could have implications in optimizing treatment and malaria control in children on Pemba.

Yacoub S, Birks EJ, Slavik Z, Henein M. 2003. Early detection of myocardial dysfunction in Chagas disease using novel echocardiographic indices. Trans R Soc Trop Med Hyg, 97 (5), pp. 528-534. | Show Abstract | Read more

The first manifestation of cardiac involvement in Chagas disease could be sudden death or rapid deterioration in cardiac function. The aim of this study was to identify a non-invasive method for early detection of cardiac involvement in patients with Chagas disease. During a 6-month period in 2001, 133 people were studied using echocardiography and electrocardiography in Honduras; 88 were seropositive for Trypanosoma cruzi, of which 31 were asymptomatic, and 45 were seronegative controls. The echocardiographic assessment included geometrical and time interval derived indices. Patients with asymptomatic Chagas disease had increased left and right myocardial performance index (MPI) when compared with seronegative controls (P= 0.003 and P= 0.023, respectively) with 36% having a left MPI above the upper limit of the normal range. They also had a reduced diastolic posterior wall thickness (P= 0.005) and lower posterior wall thickness to left ventricular cavity (PWT:LVC) ratio (P= 0.002). Our results show that the MPI, a simple Doppler parameter, and the PWT:LVC ratio are useful in the early detection of myocardial involvement in asymptomatic patients with Chagas disease. These parameters could serve as useful screening tools and monitor the disease progression in these patients.

Understanding pathways leading to severe dengue and predicting outcomes using biomarkers and physiological data from innovative wearable devices.

The incidence of dengue infections has increased seven-fold over the last 50 years, to around 100 million per year. Although most infections are either asymptomatic or result in a self-limiting febrile illness, more severe manifestations such as bleeding, organ impairment and shock do occur. Patients admitted to ICU with severe dengue have a 1-10% chance of dying. There is currently neither specific therapeutics, nor a highly effective vaccine. Therefore, it is important to increase our ...

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