No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Cardiovascular manifestations of the emerging dengue pandemic
Abstract
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.
... The diagnosis is confirmed by endomyocardial biopsy or cardiac magnetic resonance, but both procedures are not widely available in dengue-endemic areas. [ 132 ] Moreover, the pericardium may be affected by dengue infection, and pericardial effusion is commonly observed in severe dengue patients due to systemic plasma leakage. [ 132 ] Some case reports of isolated dengue pericarditis have been described in the literature. ...
... [ 132 ] Moreover, the pericardium may be affected by dengue infection, and pericardial effusion is commonly observed in severe dengue patients due to systemic plasma leakage. [ 132 ] Some case reports of isolated dengue pericarditis have been described in the literature. [ 133 ] Several electrocardiographic (ECG) alterations are associated with dengue infection, such as bradycardia, atrioventricular block, and T-wave and ST-segment abnormalities. ...
... Therefore, there is a need for careful attention to fluid balance and hemodynamic instability in these patients. [ 132 ] Impaired myocardial function is expected in cases of severe dengue mainly because of the increased vascular permeability and the hypovolemic nature of the shock. However, adequate management of dengue-related hemodynamic instability requires, in addition to vigorous volume infusion, evaluation and treatment of associated ventricular dysfunction. ...
Dengue fever is considered the most prolific vector-borne disease in the world, with its transmission rate increasing more than eight times in the last two decades. While most cases present mild to moderate symptoms, 5% of patients can develop severe disease. Although the mechanisms are yet not fully comprehended, immune-mediated activation leading to excessive cytokine expression is suggested as a cause of the two main findings in critical patients: increased vascular permeability that may shock and thrombocytopenia, and coagulopathy that can induce hemorrhage. The risk factors of severe disease include previous infection by a different serotype, specific genotypes associated with more efficient replication, certain genetic polymorphisms, and comorbidities such as diabetes, obesity, and cardiovascular disease. The World Health Organization recommends careful monitoring and prompt hospitalization of patients with warning signs or propensity for severe disease to reduce mortality. This review aims to update the diagnosis and management of patients with severe dengue in the intensive care unit.
... A minority of patients develop severe disease and subsequent CV complications [9]. Risk factors for CV involvement include age >65 years and CV comorbidities such as hypertension, diabetes mellitus, and ischemic heart disease [57]. ...
... CV complications of DENV are seen in up to 12.5% of patients [9]. Manifestations of CV compromise include bradyarrhythmias, tachyarrhythmias, myocarditis, LV dysfunction, and pericarditis [9,57]. ...
... DENV infection may lead to three interrelated pathophysiological processes associated with SCD: LV systolic dysfunction, myocarditis, and arrhythmias ( Fig. 2) [57]. These processes act as triggers and modulators of cardiac electrical instability. ...
Sudden cardiac death (SCD) is responsible for approximately 6% of global mortality and 25% of cardiovascular (CV) deaths. SCD has been traditionally linked to coronary artery disease, valvular heart disease, cardiomyopathies, and genetic arrhythmia disorders. However, advancements in care for these diseases have not translated to a proportional reduction in SCD. This suggests an important role of underrecognized contributing pathologies. Neglected tropical diseases (NTDs) are a group of illnesses prevalent in tropical and sub-tropical regions which have been understudied partially due to their high prevalence in marginalized populations. The relationship between SCD and Chagas disease has been well-established, though emerging literature suggests that other NTDs with CV involvement may lead to fatal arrhythmias. Additionally, specific therapies for a subset of NTDs put patients at increased risk of malignant arrhythmias and other cardiac complications. This review aims to summarize the association between a group of selected NTDs and SCD.
... Dengue fever is a result of dengue virus (DENV) infection, which is a Flavivirus genus member and mosquito-borne disease [14]. The disease is prevalent in more than 100 countries of the world, highly affecting south and southeast Asia [14]. ...
... Dengue fever is a result of dengue virus (DENV) infection, which is a Flavivirus genus member and mosquito-borne disease [14]. The disease is prevalent in more than 100 countries of the world, highly affecting south and southeast Asia [14]. Myocardial depressant factor, subclinical myocarditis, altered calcium homeostasis, autonomic tone, and coronary hypo-perfusion are some important factors in the development of cardiac impairment. ...
... Commonly encountered acute abnormalities include sinus bradycardia, tachycardia, T wave, ST-segment changes, A-V block, and AF [14]. A 24 hours Holter monitoring study, including 35 children demonstrated ECG changes in 29% of the cases, including sinus pause (2.9%), first (5.7%) and second degree (8.6%) A-V block, atrial (11.4%), and ventricular ectopic beats (14.3%) [15]. ...
Cardiovascular manifestations and electrocardiographic abnormalities have been reported among some prevalent infections in tropical regions, which lead to a great amount of morbidity and mortality. The major infectious diseases include chikungunya, dengue fever, H1N1 influenza, and coronavirus disease-19 (COVID- 19) in the viral category, leptospirosis, salmonellosis, scrub typhus and tuberculosis in the bacterial category, and malaria in the protozoan parasite category. All these infirmities constitute a foremost infection burden worldwide and have been linked to the various cardiac rhythm aberrancies. So we aimed to identify and compile different studies on these infections and associated acute electrocardiographic (ECG) changes. The search was made in online international libraries like PubMed, Google Scholar, and EMBASE, and 38 most relevant articles, including original research, systematic reviews, and unique case reports were selected. All of them were evaluated thoroughly and information regarding ECG was collected. Myocarditis is the predominant underlying pathology for rhythm disturbance and can be affected either due to the direct pathogenic effect or the abnormal immune system activation. ECG variabilities in some infections like chikungunya, scrub typhus, and leptospirosis are associated with longer hospital stay and poor outcome. Tropical infective diseases are associated with prominent acute cardiac rhythm abnormalities due to myocarditis, which can be identified preliminarily by ECG changes.
... Vasoactive and proinflammatory cytokines increase capillary leakage, and endothelial dysfunction may also cause myocardial dysfunction. Altered intracellular calcium homeostasis potentially causes electrical abnormalities that cause arrythmia or desynchronized myocardial movement and eventually cause cardiovascular events [17]. ...
... The virus is taken in by macrophages, causing the activation of T cells and subsequent release vasoactive and pro-inflammatory cytokines. The release of these cytokines leads to capillary leakage and possible myocardial damage [17]. The interaction between NS1 protein and vascular endothelial glycocalyx layer is thought to increase capillary permeability. ...
... The resulting plasma leakage can result to myocardial interstitial edema and cause cardiac dysfunction by reducing preload and alteration of coronary microcirculation. Changes in intracellular calcium homeostasis in DENV-infected myotubes could lead to contractile dysfunction and ultimately to decompensation of heart failure [17]. ...
Background
Dengue virus (DENV) infection may be associated with increased risks of major adverse cardiovascular effect (MACE), but a large-scale study evaluating the association between DENV infection and MACEs is still lacking.
Methods and findings
All laboratory confirmed dengue cases in Taiwan during 2009 and 2015 were included by CDC notifiable database. The self-controlled case-series design was used to evaluate the association between DENV infection and MACE (including acute myocardial infarction [AMI], heart failure and stroke). The "risk interval" was defined as the first 7 days after the diagnosis of DENV infection and the "control interval" as 1 year before and 1 year after the risk interval. The incidence rate ratio (IRR) and 95% confidence interval (CI) for MACE were estimated by conditional Poisson regression. Finally, the primary outcome of the incidence of MACEs within one year of dengue was observed in 1,247 patients. The IRR of MACEs was 17.9 (95% CI 15.80–20.37) during the first week after the onset of DENV infection observed from 1,244 eligible patients. IRR were significantly higher for hemorrhagic stroke (10.9, 95% CI 6.80–17.49), ischemic stroke (15.56, 95% CI 12.44–19.47), AMI (13.53, 95% CI 10.13–18.06), and heart failure (27.24, 95% CI 22.67–32.73). No increased IRR was observed after day 14.
Conclusions
The risks for MACEs are significantly higher in the immediate time period after dengue infection. Since dengue infection is potentially preventable by early recognition and vaccination, the dengue-associated MACE should be taken into consideration when making public health management policies.
... This process disrupts the TNF-α/IL-10 and IL-6/IL-10 ratios, fostering localized inflammation and fibrosis [22]. Elevated TNF-a further inhibits l-type Ca 2+ channel currents, diminishing peak myocardial systolic Ca 2+ concentrations and adversely affecting cardiomyocyte contraction [23]. Moreover, high levels of inflammatory factors contribute to vascular dysfunction. ...
... The resultant release of inflammatory factors like IL-1β and TNF-a results in vascular endothelial cell lining inflammation and necrosis, increasing capillary permeability and vascular leakage [65]. Vascular leakage in myocyte interstitial spaces triggers myocardial interstitial edema, impairing myocardial contraction and overall function [23]. Endothelial dysfunction is another facet of DENV's impact on cardiovascular health. ...
Members of the Flaviviridae family, encompassing the Flavivirus and Hepacivirus genera, are implicated in a spectrum of severe human pathologies. These diseases span a diverse spectrum, including hepatitis, vascular shock syndrome, encephalitis, acute flaccid paralysis, and adverse fetal outcomes, such as congenital heart defects and increased mortality rates. Notably, infections by Flaviviridae viruses have been associated with substantial cardiovascular compromise, yet the exploration into the attendant cardiovascular sequelae and underlying mechanisms remains relatively underexplored. This review aims to explore the epidemiology of Flaviviridae virus infections and synthesize their cardiovascular morbidities. Leveraging current research trajectories and our investigative contributions, we aspire to construct a cogent theoretical framework elucidating the pathogenesis of Flaviviridae-induced cardiovascular injury and illuminate prospective therapeutic avenues.
... Among the male participants, 27.3% (21), and among the female participants, 72.7% (56), displayed symptomatic cardiac involvement. Considering the entire cohort, 26.9% (28) showed symptomatic cardiac involvement, while 73.1% (76) did not ( Table 2). ...
... Yacoub et al. observed that individuals experiencing severe dengue infection display more notable left ventricular (LV) systolic dysfunction compared to those with mild dengue fever [21]. Our study, wherein only 14 patients displayed ECHO abnormalities, does not align with this observation, considering that the majority of our dengue patients presented with mild dengue fever. ...
Introduction: Dengue fever (DF) arises from the dengue virus (DENV), a common viral illness transmitted by arthropods. This medical condition has the potential to result in severe complications, including but not limited to liver failure, disseminated intravascular coagulation, dengue encephalopathy, myocarditis, acute renal failure, and hemolytic uremic syndrome. Evaluating cardiac manifestations in dengue is crucial for timely intervention and intensive care to save patients' lives.
Materials and methods: A longitudinal study involved 104 dengue fever patients admitted to the Department of Medicine at New Civil Hospital, Surat, between May 2021 and October 2021, to identify potential cardiac involvement.
Results: The study found that out of the 104 patients, 28 (26.92%) showed cardiac involvement based on clinical manifestations. Among these patients, 28 (26.92%) exhibited abnormal ECG results, and 39 (37.50%) showed elevated creatine kinase-MB (CK-MB) levels. Of the 28 patients who showed ECG changes, 14 (50%) displayed abnormal 2D-echocardiography (ECHO) results. The most common electrocardiographic anomaly was a T-wave inversion in V1-V4. The predominant 2D-ECHO finding was mild pericardial effusion.
Conclusion: Cardiac involvement in dengue presents atypically and can lead to conditions like myocarditis, arrhythmias, cardiac failure, or shock. Assessing cardiac manifestations in dengue patients is pivotal for appropriate management.
... Myocarditis, pericarditis, functional abnormalities, arrhythmias, atrioventricular conduction disorders, and non-specific electrocardiographic (ECG) abnormalities are some of the cardiac problems observed in dengue patients. 3 Although few cases of myocarditis have been reported, AV blocks, particularly complete heart blocks (CHBs), have infrequently been described. 4,5 This article describes a rare occurrence of third-degree heart block and subclinical myocarditis in the context of dengue fever. ...
... Myocarditis, pericarditis, myocardial depression with heart failure, and shock are among these conditions. 3 Rhythm disturbances such as atrial fibrillation, ventricular tachyarrhythmias, ventricular ectopic beats, bundle branch blocks, sinus node dysfunction, first-and second-degree AV blocks, and rarely complete AV blocks have been described. 13 Nonspecific ECG changes, such as ST-T changes and abnormal Q waves, can occur in myocarditis. ...
Dengue is an endemic viral fever transmitted by mosquitoes that may be asymptomatic or cause a nonspecific flu-like illness. The disease’s most severe manifestations are dengue hemorrhagic fever and dengue shock syndrome. Various atypical manifestations have been observed that constitute the expanded dengue syndrome. Although uncommon, it is now known to cause cardiac complications that can be life-threatening and difficult to diagnose. We illustrate a case of a 16-year-old boy infected with dengue who experienced syncope, dizziness, and lethargy. His electrocardiogram showed third degree atrioventricular block which did not resolve with atropine and fluid resuscitation. After excluding all possible causes of complete heart block, transvenous pacing was done. A detailed workup was carried out that favored a diagnosis of subclinical myocarditis leading to complete heart block. The patient did not regain a normal rhythm and was considered for permanent pacemaker implantation. Myocarditis, pericarditis, rhythm disturbances, first- and second-degree atrioventricular blocks, and rarely third-degree heart blocks have been seen in dengue patients. However, a case of dengue illness associated complete heart blocks that is irreversible and necessitates a permanent pacemaker has never been described in the literature, and this is the first such case being reported. This article intends to increase clinicians’ awareness, particularly those in dengue-endemic regions, about better recognition and comprehension of cardiac problems associated with dengue fever.
... At the beginning of the critical stage (second stage), the fever decreases or disappears [17]. This is the phase of complications and usually lasts 24 to 48 hours. ...
... Plasma leakage Inflammatory response Viraemia Fig. 1 Clinical course of dengue. Adapted from [17] Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
Dengue is a viral infection widely distributed in tropical and subtropical regions of the world. Dengue is characterized by high fatality rates when the diagnosis is not made promptly and effectively. To aid in the diagnosis of dengue, we propose a clinical decision-support system that classifies the clinical picture based on its severity, and using causal relationships evaluates the behavior of the clinical and laboratory variables that describe the signs and symptoms related to dengue. The system is based on a fuzzy cognitive map that is defined by the signs, symptoms and laboratory tests used in the conventional diagnosis of dengue. The evaluation of the model was performed on datasets of patients diagnosed with dengue to compare the model with other approaches. The developed model showed a good classification performance with 89.4% accuracy and could evaluate the behaviour of clinical and laboratory variables related to dengue severity (it is an explainable method). This model serves as a diagnostic aid for dengue that can be used by medical professionals in clinical settings.
... Severe disease is characterized by endothelial dysfunction leading to vascular permeability and plasma leakage. This is thought to be mediated by the exacerbated production of circulating inflammatory mediators such as IL-1β and TNF-α [5,6]. Despite ongoing efforts, there are currently no methods available to predict and/or prevent disease progression, which demonstrates that elucidation of the mechanism(s) regulating the excessive inflammatory responses elicited by DENV is crucial for the understanding of its pathogenesis and the proper handling of the severe cases. ...
... PBMCs exposed to prM-DENV2 for 48h were treated with anti-TLR2 2h prior prM-DENV2 stimulation. TNF-α-depleted PBMCs supernatants were used to stimulate HUVEC for (D) 6 was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made ...
Severe dengue virus (DENV) infection is characterized by exacerbated inflammatory responses that lead to endothelial dysfunction and plasma leakage. We have recently demonstrated that Toll-like receptor 2 (TLR2) on blood monocytes senses DENV infection leading to endothelial activation. Here, we report that non-infectious immature DENV particles, which are released in large numbers by DENV-infected cells, drive endothelial activation via the TLR2 axis. We show that fully immature DENV particles induce a rapid, within 6 hours post-infection, inflammatory response in PBMCs. Furthermore, pharmacological blocking of TLR2/TLR6/CD14 and/or NF-kB prior to exposure of PBMCs to immature DENV reduces the initial production of inter alia TNF-α and IL-1β by monocytes and prevents endothelial activation. However, prolonged TLR2 block induces TNF-α production and leads to exacerbated endothelial activation, indicating that TLR2-mediated responses play an important role not only in the initiation but also the resolution of inflammation. Altogether, these data indicate that the maturation status of the virus has the potential to influence the kinetics and extent of inflammatory responses during DENV infection.
Author Summary
Severe dengue virus (DENV) infection is characterized by endothelial dysfunction leading to vascular permeability and plasma leakage. This is thought to be mediated by the exacerbated production of inflammatory mediators from cells of the innate immune system. We have previously demonstrated that Toll-like receptor 2 (TLR2), a pattern recognition receptor present on the surface of human monocytes, can sense DENV infection leading to the activation of the endothelium. Importantly, a large proportion of DENV particles is immature and are not readily infectious. Here we aimed to elucidate if and how these non-infectious immature DENV particles contribute to systemic inflammation. We evaluated if monocytes sense immature DENV and found that sensing of immature DENV induced early inflammatory responses in PBMCs. Pharmacological inhibition of TLR2/TLR6/CD14 and/or NF-κB prior to exposure to immature DENV demonstrates that this is the pathway leading to the early production inflammatory mediators and endothelial activation. However, prolonged inhibition of TLR2 induced the production of TNF-α and the subsequent activation of the endothelium, suggesting that TLR2-mediated responses play an important tole during both, initiation and resolution of inflammation. We propose that the maturation status of DENV in the human host can influence the extent and kinetics of the inflammatory responses during DENV infection.
... Overhydration may lead to fluid overload, resulting in respiratory distress in patients with dengue. In the present case, despite improvement in the serial hematocrit after fluid therapy, hypotension developed on the third day of treatment suggesting that this resulted from cardiac dysfunction rather than insufficient intravenous fluid replacement, thus indicating that the patient's pulmonary edema was cardiogenic due to impairment of left ventricular function [34,35]. ...
... Pathogenesis myocarditis in dengue infection virus[34]. ...
Dengue is a prevalent arthropod-borne viral disease in tropical and subtropical areas of the globe. Dengue clinical manifestations include asymptomatic infections; undifferentiated fever; dengue fever, which is characterized by fever, headache, retroorbital pain, myalgia, and arthralgia; and a severe form of the disease denominated dengue hemorrhagic fever/dengue shock syndrome, characterized by hemoconcentration, thrombocytopenia, and bleeding tendency. However, atypical manifestations, such as liver, central nervous system, and cardiac involvement, have been increasingly reported. Called expanded dengue syndrome. We report a 40 years old gentleman with atypical and rare presentation of dengue disease marked by a dramatic and fatal acute cardiac failure due to acute myocarditis. Condition improved after five days of conservative treatment. Cardiac complications in dengue are now increasingly observed with the most common case is myocarditis. The main mechanism of dengue myocarditis is still unknown though both direct viral infection and immune mediated damage have been suggested to be the cause of myocardial damage. The low incidence of dengue myocarditis is because it's asymptomatic and diagnosis is easily missed. Almost all cases of dengue myocarditis are self-limiting and severe myocarditis leading to dilated cardiomyopathy is extremely rare. To avoid otherwise preventable morbidity and mortality, physicians should have a high index of suspicion for cardiac complications in patients with dengue illness and should manage this accordingly.
... Dengue is a viral disease that can transmit to humans through the bites of an infected female Aedes genus mosquito [1]. Dengue can cause a wide range of symptoms from a mild febrile illness through to severe and life threatening manifestations such as shock, bleeding and organ dysfunction [2]. A hallmark feature of severe dengue is increased capillary permeability causing plasma leakage, which manifests as intravascular volume depletion and fluid accumulation such as pleural effusions, pulmonary edema and ascites [3]. ...
... (1) Conv (N = 16, K = 3, S = 1, P = 1, BN, Relu) (2) Conv (N = 8, K = 3, S = 1, P = 1, BN, Relu) (3) Conv (N = 1, K = 3, S = 1, P = 1, Sigmoid) ...
The presence of B-line artefacts, the main artefact reflecting lung abnormalities in dengue patients, is often assessed using lung ultrasound (LUS) imaging. Inspired by human visual attention that enables us to process videos efficiently by paying attention to where and when it is required, we propose a spatiotemporal attention mechanism for B-line detection in LUS videos. The spatial attention allows the model to focus on the most task relevant parts of the image by learning a saliency map. The temporal attention generates an attention score for each attended frame to identify the most relevant frames from an input video. Our model not only identifies videos where B-lines show, but also localizes, within those videos, B-line related features both spatially and temporally, despite being trained in a weakly-supervised manner. We evaluate our approach on a LUS video dataset collected from severe dengue patients in a resource-limited hospital, assessing the B-line detection rate and the model’s ability to localize discriminative B-line regions spatially and B-line frames temporally. Experimental results demonstrate the efficacy of our approach for classifying B-line videos with an F1 score of up to 83.2% and localizing the most salient B-line regions both spatially and temporally with a correlation coefficient of 0.67 and an IoU of 69.7%, respectively.
... During the course of admission, she was weaned off from mechanical ventilator. Serial ECG monitoring showed a decreased QT interval (using the Bazett formula) was 0.44 seconds ( Figure 4B) and is due to altered intracellular calcium homeostasis resulting from cytokines and inflammatory processes affecting myocytes and the interstitium [12]. This can be aggravated by various causes, one of which is severe electrolyte imbalance that alters cardiac tissue excitability and conduction. ...
... Si bien es cierto que no hubo estudio histopatológico o inmunohistoquímico que permitiera distinguir la afectación viral aguda del miocardio del compromiso crónico de origen parasitario, creemos poco probable que la infección viral por sí sola explicara las manifestaciones clínicas de este paciente. La identificación genómica del virus sólo se logra en 10-20% de los casos de miocarditis por dengue 19 . ...
A case is reported of a chronic chagasic cardiomyopathy in a two-years old child who was diagnosed after an acute dengue virus infection. The patient residing in an endemic area for Chagas disease, debuted with heart failure that improved with support treatment and after the complete resolution of the arbovirus, the changes of chronic cardiomyopathy persisted. The myocardial structural alteration was attributed to subclinical chagasic cardiomyopathy. The coexistence of infectious diseases in the tropics represents a diagnostic challenge, a situation to which are added problems such as poverty and lack of access to basic health services.
... Finally, the study aims to evaluate the overall outcome of patients based on the degree of thrombocytopenia and associated parameters. Thrombocytopenia can impact patient prognosis and may be associated with increased morbidity and mortality [11][12][13][14]. By examining the relationship between the degree of thrombocytopenia, clinical parameters, and patient outcomes, we aim to identify predictors of adverse outcomes and develop prognostic markers for risk stratification. ...
Introduction: Acute undifferentiated fever with thrombocytopenia is a common and challenging clinical presentation encountered in the emergency departments of tertiary care centers, particularly in tropical regions, often requiring prompt evaluation and management. The study aimed to explore the clinical and etiological profile of acute undifferentiated fever with thrombocytopenia in the Emergency Department of Indira Gandhi Institute of Medical Sciences, Patna. It investigates factors associated with patient outcomes and compares platelet transfusion requirements among different etiological groups.
Methods: In this cross-sectional observational study, 350 patients with acute undifferentiated fever with thrombocytopenia were analyzed for one year from October '21 to September '22. Pre-existing chronic infectious diseases, liver cirrhosis, and autoimmune conditions were excluded.
Results: Thrombocytopenia was observed in all patients, with 65% having platelet counts below 50,000/µL. Associations were found between the degree of thrombocytopenia and organ dysfunction, shock, and third space loss. Logistic regression analysis identified thrombocytopenia, organ dysfunction, and platelet transfusion requirement as significant predictors of the overall outcome. Etiological group comparisons revealed higher platelet transfusion requirements in the bacterial group.
Conclusion: Prompt recognition and management of thrombocytopenia in acute undifferentiated fever are vital. Thrombocytopenia, along with organ dysfunction and shock, significantly influence patient outcomes. Tailored interventions based on etiological factors are crucial. Further research should focus on specific viral aetiologies in acute undifferentiated fever with thrombocytopenia.
... The clinical course of dengue. (Image source:(Yacoub et al. 2014)) ...
Dengue fever is the most important emerging and persistently re-emerging arbovirosis that is transmitted via the bite of infected Aedes mosquitoes. Etiologically, it is caused by any of the four serotypes of the dengue virus, a prototype Flavivirus of the family Flaviviridae. The disease is widespread throughout the tropics and subtropics of the world, and can spread from countries of high endemicity to those of low endemicity by international travel. The illness can present asymptomatically or may result in uncharacterized fever, dengue fever or even its more severe form of Dengue Hemorrhagic Fever which causes plasma leakage resulting in hypovolemic shock or the Dengue Shock Syndrome. Classical dengue is self-limiting and presents with an abrupt and acute onset of high fever, followed by the development of headache, retro-orbital pain, myalgia and arthralgia due to which dengue is commonly referred to as ‘breakbone fever’, and patients may also develop a maculopapular rash and lymphadenopathy. There is no cross protectivity among the four serotypes, and secondary infection with a different serotype is often correlated with a marked risk of severe dengue. Virus isolation, nucleic acid detection using Polymerase Chain Reaction and serological detection of the viral NS1 antigen and dengue-specific IgM and IgG antibodies are all common diagnostic techniques for dengue. Other laboratory findings indicative of dengue are leukopenia, thrombocytopenia and metabolic acidosis. With no specific antiviral therapy, disease management essentially involves supportive care using antipyretics and fluid replacement. Lastly, there have been several efforts to develop adequate preventive measures against dengue in the form of mosquito control and the development of dengue vaccines. Several vaccine candidates are being studied for dengue, with Sanofi Pasteur’s live attenuated Dengvaxia being the only currently licensed dengue vaccine. Thus, this chapter aims to provide a detailed overview of dengue, its etiology, pathogenesis and clinical presentation, diagnosis, therapy and prevention.KeywordsDengue feverDengue hemorrhagic feverDengue shock syndromeBreakbone feverHemorrhagic diathesisArbovirusFlavivirus
... No antiviral agents are licensed for dengue and treatment remains supportive with judicious fluid replacement for patients with severe disease. 8 ECG abnormalities may be asymptomatic or go undetected. Clinical manifestations suggesting cardiac involvement in dengue are diverse and include chest pain, palpitations, pleurisy, and irregularities of pulse, bradycardia, hypotension, pulmonary edema, and features of shock. ...
Background: Dengue fever has emerged as one of the most common viral diseases in the world. The clinical manifestation ranges from mild febrile illness to severe disease such as dengue hemorrhagic fever and dengue shock syndrome. Dengue is known to affect various systems. So, different aspects of disease need to be explored. Cardiac involvement in dengue fever is not uncommon and has been reported in literature. ECG is widely used as a screening tool not only because it is easily available but also due to its ability to indicate cardiac involvement. Objective: The aim of the study was to determine the patterns of ECG changes and their frequency in a cohort of patients with dengue fever (DF) and dengue hemorrhagic fever (DHF) along with the association of ECG changes with severity of dengue infection and clinical manifestation of cardiac involvement. Method: We conducted a cross-sectional observational study involving 50 patients with dengue fever and dengue hemorrhagic fever, admitted in Medicine department of Dhaka Medical College Hospital, Dhaka from 1st October, 2017 to 31st March, 2018. Admitted patients with high grade fever and positive Dengue IgM, NS1 AG or RT-PCR were included. Patients with electrolyte abnormalities, preexisting heart disease, drugs interfering with heart rhythm were excluded from study. The Standard 12 lead ECG was carried out in study patients on 3rd day of disease onset and on the day of discharge after disease recovery. Frequency & pattern of ECG changes like heart rate, rhythm, P wave, T wave, ST segments and QRS complex were analyzed and recorded. Statistical analysis was done using SPSS 25 on windows 10. Categorical and numerical data’s were expressed as frequencies and percentage. Cross tabulation was done between DF and DHF with different ECG findings. To establish the significance of various findings and association in between variables chi-square analysis, Pearson correlations were done in all cases. P value < 0.05 considered significant Result: Total 50 patients with dengue fever were enrolled, 39 patients (78%) were diagnosed as dengue fever and 11 patients (22%) were diagnosed as dengue hemorrhagic fever (DHF). Mean age of the patient was 33.08 ± 9.79 years. Male – female ratio of 1.5:1 fever was noted in all 50 patients (100%), myalgia (94%), headache (84%), skin rash (82%), & retro-orbital pain(54%), vomiting (26%), only 3 patients (6%) complained about abdominal pain. Only 4 patients had cardiac symptoms. 3 patients complained about palpitation and only 1 patient had symptom of chest pain and dyspnea. In most of the patients, (34 in number, 68%) ECG was normal. Only 16 patients (32%) had abnormal findings in ECG. 9 patients (18%) had bradycardia, 3 patients (6%) had tachycardia, 2 Patient (4%) had T Inversion and 1 patient (2%) had ST elevation and 1 patient (2%) had ST depression. Among total 16 abnormal ECG, predominant finding was bradycardia (>50% of abnormal ECG). P value is <0.01. Correlation of ECGs with clinical severity (Dengue fever and Dengue Hemorrhagic fever) found no statistically significant association (P value is 0.725). J MEDICINE 2023; 24(2): 119-124
... Published reports vary widely on the incidence of these complications. As we observed in our case series, these manifestations are not systematically screened for in returning travelers with severe dengue and they are likely underdiagnosed (26)(27)(28)(29). Our findings warrant further study to determine the frequency, management, and outcomes of uncommon complications to improve timely recognition and decrease morbidity. ...
Background:
Dengue virus is a flavivirus transmitted by Aedes mosquitoes and is an important cause of illness worldwide. Data on the severity of travel-associated dengue illness are limited.
Objective:
To describe the epidemiology, clinical characteristics, and outcomes among international travelers with severe dengue or dengue with warning signs as defined by the 2009 World Health Organization classification (that is, complicated dengue).
Design:
Retrospective chart review and analysis of travelers with complicated dengue reported to GeoSentinel from January 2007 through July 2022.
Setting:
20 of 71 international GeoSentinel sites.
Patients:
Returning travelers with complicated dengue.
Measurements:
Routinely collected surveillance data plus chart review with abstraction of clinical information using predefined grading criteria to characterize the manifestations of complicated dengue.
Results:
Of 5958 patients with dengue, 95 (2%) had complicated dengue. Eighty-six (91%) patients had a supplemental questionnaire completed. Eighty-five of 86 (99%) patients had warning signs, and 27 (31%) were classified as severe. Median age was 34 years (range, 8 to 91 years); 48 (56%) were female. Patients acquired dengue most frequently in the Caribbean (n = 27 [31%]) and Southeast Asia (n = 21 [24%]). Frequent reasons for travel were tourism (46%) and visiting friends and relatives (32%). Twenty-one of 84 (25%) patients had comorbidities. Seventy-eight (91%) patients were hospitalized. One patient died of nondengue-related illnesses. Common laboratory findings and signs were thrombocytopenia (78%), elevated aminotransferase (62%), bleeding (52%), and plasma leakage (20%). Among severe cases, ophthalmologic pathology (n = 3), severe liver disease (n = 3), myocarditis (n = 2), and neurologic symptoms (n = 2) were reported. Of 44 patients with serologic data, 32 confirmed cases were classified as primary dengue (IgM+/IgG-) and 12 as secondary (IgM-/IgG+) dengue.
Limitations:
Data for some variables could not be retrieved by chart review for some patients. The generalizability of our observations may be limited.
Conclusion:
Complicated dengue is relatively rare in travelers. Clinicians should monitor patients with dengue closely for warning signs that may indicate progression to severe disease. Risk factors for developing complications of dengue in travelers need further prospective study.
Primary funding source:
Centers for Disease Control and Prevention, International Society of Travel Medicine, Public Health Agency of Canada, and GeoSentinel Foundation.
... 6 This increased vascular permeability is thought to be due to endothelial activation/ dysfunction, which results from decreased nitric oxide release, leading to impaired vascular relaxation. 7 Clinically, dengue hemorrhagic fever is a febrile illness which presents as plasma https://doi.org/10.29309/TPMJ/2023.30.04.7362 2 leakage (manifested by hemoconcentration, ascites and pleural effusion), bleeding tendency and liver involvement; some cases can result in hypovolemic shock and dengue shock syndrome. 8,9 Monitoring for the clinical signs of plasma leakage is imperative in dengue hemorrhagic fever, in order to effectively prevent the progression of the illness to shock syndrome. ...
Objective: To find the association between the patters of thrombocytopenia with the timings and patterns of plasma leakage in patients presenting with dengue hemorrhagic fever (DHF) during the dengue epidemic of 2019, in Rawalpindi city. Study Design: Cross-sectional study. Setting: Department of Medicine, District Headquarter Hospital, Rawalpindi, Pakistan. Period: August to November 2019. Material & Methods: In which patients who were labelled and managed as DHF on the basis of clinical presentation, positive serology and ultrasonic evidence of plasma leakage were included. Demographic profile, clinical features with duration of illness, laboratory investigations including serological markers (NS1, IgG and IgG) and ultrasonic findings were recorded on a self-structured performa and data was analyzed using SPSS v23.0. Results: Two hundred and ninety five patients with DHF were enrolled in the study. There were 2012 males and 83 females (male to female ration of 2.5:1). Mean age of all participants was 32.83 years. 50.5% of the cases were primary infection (based on serology), whereas 38.3% were secondary infection and 11.2% were triple negative infection. In 81.1% of the cases, plasma leakage occurred on the 4th to 7th day of illness. In these cases, platelet count was <40,000 cells/mm³ in 13.6% cases, between 40,000 cells/mm³ - 80,000 cells/mm³ in 50.8% cases and greater than 80,000 cells/mm³ in 35.5% cases. Amongst the 17.8% of cases where plasma leakage occurred between 8th to 10th days, 56.6% had platelet count greater than 80,000 cells/mm³, 22.6% has platelet count between 40,000 cells/mm³- 80,000 cells/mm³ and 20.8% had platelet count of less than 40,000 cells/mm³. Conclusion: Most people had plasma leakage at day 4-7 of illness, so needed more critical monitoring and admission at 4th to 7th day of illness, plasma leakage was observed more commonly in primary as compared to secondary infections and mostly at the day of leakage, platelet count was between 40,000 cells/mm³- 80,000 cells/mm³. Strict monitoring is required from the 4th day of illness to detect early signs of leakage to decrease the mortality and complications by dengue infection.
... Some viruses that do not directly infect cardiomyocytes can indirectly cause cardiac injury and negative inotropic effects by triggering an immune response or cytokine storm (Jensen and Marchant, 2016). These include Zika virus (Scatularo et al., 2022), Dengue virus (Yacoub et al., 2014), and Ebola virus (Chertow et al., 2017). In addition, coronaviruses, including Middle Eastern respiratory syndrome coronavirus, SARS-CoV, and SARS-CoV-2 can cause cardiac injury and myocarditis via angiotensin-converting enzyme 2 (ACE2) tropism, cytokine-mediated cardiotoxicity, or by triggering autoimmune responses to cardiac components . ...
Myocarditis is an inflammatory cardiac disease characterized by the destruction of myocardial cells, infiltration of interstitial inflammatory cells, and fibrosis, and is becoming a major public health concern. The aetiology of myocarditis continues to broaden as new pathogens and drugs emerge. The relationship between immune checkpoint inhibitors, severe acute respiratory syndrome coronavirus 2, vaccines against coronavirus disease-2019, and myocarditis has attracted increased attention. Immunopathological processes play an important role in the different phases of myocarditis, affecting disease occurrence, development, and prognosis. Excessive immune activation can induce severe myocardial injury and lead to fulminant myocarditis, whereas chronic inflammation can lead to cardiac remodelling and inflammatory dilated cardiomyopathy. The use of immunosuppressive treatments, particularly cytotoxic agents, for myocarditis, remains controversial. While reasonable and effective immunomodulatory therapy is the general trend. This review focuses on the current understanding of the aetiology and immunopathogenesis of myocarditis and offers new perspectives on immunomodulatory therapies.
... There are many hypotheses about dengue myocarditis; the most common is its involvement in vascular and cardiac through immune mechanisms. The dengue virus potentially infects myocytes and activates T cells and macrophages, leading to pro-inflammatory cytokines (especially tumor necrosis factor/TNF), endothelial dysfunction, and vasculopathy contributes to reduced preload for coronary microcirculation and myocardial edema (Yacoub et al. 2014). Increased activity in monocytes (especially CD14 + in the heart), complement system, and pro-inflammatory cytokines with decreased number of CD4 + CD25 for immune regulation during < 24 weeks gestation probably contributes to this patient's rapid progression to cardiac failure, possibly evolving to dilated cardiomyopathy (Abu-Raya et al. 2020;Schultheiss et al. 2021). ...
Background
Dengue fever is a mosquito-borne viral disease whose incidence has increased globally, with Indonesia as hyperendemic. In Indonesia, around 17.4% of febrile cases were due to dengue. Expanded dengue syndrome is a term for dengue fever with atypical manifestations in other organs such as renal, respiratory, and cardiac. Dengue myocarditis remains underdiagnosed and usually has a low risk of heart failure. However, pregnancy increases the risk of expanded dengue syndrome, with the incidence six times higher in pregnant women. Due to limited studies about myocarditis treatment during pregnancy, it is critical to understand the effects of heart drugs and the importance of treatment choices with limited selection during fulminant myocarditis.
Case presentation
We reported a case of an adult pregnant woman in her second trimester with fulminant myocarditis-associated expanded dengue syndrome based on criteria. The patient suddenly worsened with progressive cardiomegaly and lung edema accompanied by cardiogenic shock. Multidisciplinary treatment management has been given to improve cardiac function and other organs due to dengue by considering the risk and family consent. The patient recovered from myocarditis, and the cardiac size has reduced.
Conclusions
Fulminant myocarditis is a serious complication of expanded dengue syndrome, and aggressive therapy is required to prevent it. Further investigations and a multidisciplinary system are required to reduce or minimize fetal abnormalities.
... Dengue can be categorised into febrile (days 1-3), critical/defervescence, (days 4-6) and recovery phases (day 7 onwards), and one of the more prominent features of SD (often in the critical phase), is vascular leakage. Vascular leakage may then lead to severe bleeding, organfailure and potential fatal circulatory compromise causing shock [3,4]. The cause of dengue shock is multifactorial and cardiac impairment in clinical dengue, which may manifest as myocarditis, myocardial impairment and arrhythmias has been proposed to contribute to pathology [5][6][7][8]. ...
Background:
Dengue can be complicated by severe outcomes including cardiac impairment, and the lack of reliable prognostic biomarkers poses a challenge in managing febrile dengue patients. Here, we investigated the functionality of soluble suppressor of tumorigenicity (sST2) as a predictive marker of severe dengue and its association in dengue-associated cardiac impairment.
Methods:
Plasma samples, aged >16 years, collected from 36 dengue fever, 43 dengue with warning signs, 11 severe dengue (collected at febrile, critical and recovery phases) and 30 controls were assayed for plasma levels of sST2, troponin T and N-terminal (NT)-pro hormone brain natriuretic peptide (NT-proBNP) by ELISA. Cardiac parameters: stroke index (SI), cardiac index (CI) and Granov-Goor Index (GGI) were measured with a bioimpedance device during the different phases for dengue subjects and once for the controls.
Principal findings:
In the febrile, critical and early recovery phases, sST2 levels were significantly elevated in dengue participants and sST2 levels increased with increasing disease severity (P < 0.01 for all). sST2 concentrations were negatively correlated with SI (r = -0.48; P < 0.001, r = -0.55; P < 0.001), CI (r = -0.26; P = 0.02, r = -0.6: P < 0.001) and GGI (r = -0.44; P < 0.001, r = -0.57; P < 0.001) in the critical and early recovery phases. In contrast, sST2 levels in the febrile and critical phases, were positive correlated to troponin T (r = 0.44, P < 0.001; r = 0.22, P = 0.03, respectively) and NT-proBNP (r = 0.21, P = 0.03; r = 0.35, P < 0.001). ROC analysis demonstrated sST2 as a good biomarker of severe dengue in the critical phase, AUROC 0.79, P < 0.001.
Conclusion/significance:
sST2 levels were elevated in patients with dengue especially in cases of severe dengue. Furthermore, increased sST2 levels were associated with cardiac indicators suggesting lower cardiac performance. While further research is needed to demonstrate its clinical utility, sST2 may be a useful prognostic biomarker of severe dengue.
... Severe disease is characterized by endothelial dysfunction leading to vascular permeability and plasma leakage. This is thought to be mediated by the exacerbated production of circulating inflammatory mediators such as IL-1β and TNF-α [5,6]. Despite ongoing efforts, there are currently no methods available to predict and/or prevent disease progression, which demonstrates that elucidation of the mechanism(s) regulating the excessive inflammatory responses elicited by DENV is crucial for the understanding of its pathogenesis and the proper handling of the severe cases. ...
Severe dengue virus (DENV) infection is characterized by exacerbated inflammatory responses that lead to endothelial dysfunction and plasma leakage. We have recently demonstrated that Toll-like receptor 2 (TLR2) on blood monocytes senses DENV infection leading to endothelial activation. Here, we report that non-infectious immature DENV particles, which are released in large numbers by DENV-infected cells, drive endothelial activation via the TLR2 axis. We show that fully immature DENV particles induce a rapid, within 6 hours post-infection, inflammatory response in PBMCs. Furthermore, pharmacological blocking of TLR2/TLR6/CD14 and/or NF-kB prior to exposure of PBMCs to immature DENV reduces the initial production of inter alia TNF-α and IL-1β by monocytes and prevents endothelial activation. However, prolonged TLR2 block induces TNF-α production and leads to exacerbated endothelial activation, indicating that TLR2-mediated responses play an important role not only in the initiation but also the resolution of inflammation. Altogether, these data indicate that the maturation status of the virus has the potential to influence the kinetics and extent of inflammatory responses during DENV infection.
... In severe dengue (SD), an exaggerated host inflammatory response results in increased vascular permeability and plasma leakage and subsequent stepwise progression into intravascular hypovolemia, shock, and multiorgan dysfunction [2,5]. Cardiac function plays a major role in maintaining hemodynamic status, and cardiac complications in dengue have been reported [6]. Observational studies in pediatric patients with dengue have demonstrated transient cardiac impairment, which peaked during the critical phase of dengue in proportion with disease severity [7][8][9][10]. ...
Background
Cardiac impairment contributes to hypotension in severe dengue (SD). However, studies examining pathogenic factors affecting dengue-associated cardiac impairment are lacking. We examined the role of neutrophil mediators on cardiac impairment in clinical dengue.
Methods
We prospectively enrolled adult patients with dengue and controls. Cardiac parameters were measured using a bioimpedance device. Neutrophils mediators were measured, including myeloperoxidase (MPO) and citrullinated histone H3.
Results
We recruited 107 dengue patients and 30 controls. Patients with dengue were classified according to World Health Organization 2009 guidelines (44 with dengue fever [DF], 51 with DF with warning signs, and 12 with SD). During critical phase, stroke index (P < .001), cardiac index (P = .03), and Granov-Goor index (P < .001) were significantly lower in patients with dengue than in controls. During critical phase, MPO was significantly higher in patients with dengue than in controls (P < .001) and also significantly higher in patients with SD than in those with DF. In addition, MPO was inversely associated with the stroke, cardiac, and Granov-Goor indexes, during the critical phase, and longitudinally as well.
Conclusions
Cardiac function was decreased, and MPO increased, during with critical phase in patients SD compared with those with DF and controls. MPO may mediate dengue-associated cardiac impairment.
... When this is the case, cardiovascular involvement typically presents acutely with myocarditis and arrhythmia, which may progress to chronic dilated cardiomyopathy [147]. Similarly, most dengue infections are relatively benign; however, severe presentations include a dengue-associated vasculopathy with hemorrhage, endothelial dysfunction with capillary leak and hypovolemic shock, and organ dysfunction [148]. Direct effects of the dengue virus on the heart include myocardial impairment through circulating myocardial depressant factors, myocarditis, and arrhythmia, of which relative bradycardia is a notable feature [149,150]. ...
Climate change is a worsening global crisis that will continue negatively impacting population health and well-being unless adaptation and mitigation interventions are rapidly implemented. Climate change-related cardiovascular disease is mediated by air pollution, increased ambient temperatures, vector-borne disease and mental health disorders. Climate change-related cardiovascular disease can be modulated by climate change adaptation; however, this process could result in significant health inequity because persons and populations of lower socioeconomic status have fewer adaptation options. Clear scientific evidence for climate change and its impact on human health have not yet resulted in the national and international impetus and policies necessary to slow climate change. As respected members of society who regularly communicate scientific evidence to patients, clinicians are well-positioned to advocate on the importance of addressing climate change. This narrative review summarizes the links between climate change and cardiovascular health, proposes actionable items a cardiologist can execute both in their personal life and as an advocate of climate policies, and encourages communication of the health impacts of climate change when counseling patients. Our aim is to inspire the reader to invest more time in communicating the most crucial public health issue of the 21st century to their patients.
... Patients with DSS presented more frequently bleeding manifestations, elevated liver enzyme, and change in hematocrit leve.l [18][19][20] Regarding the hemodynamic outcome, the results showed that most children had an increased HR. The average HR was higher in aged group 1-2 years old. ...
The prevalence of dengue infection has increased markedly worldwide. Dengue shock syndrome (DSS) is a severe manifestation of dengue virus infection. Higher mortality of DSS was found in children. This study's aim was to portray prevalence and hemodynamic outcome in children attending the department of pediatric in Dr. Soetomo General Hospital. A Descriptive Retrospective study of children aged <15 years old with DSS was performed and evaluated from 2013-2016. The samples were divided into 5 groups, aged <1 years old, 1-2 years old, 3-5 years old 6-11 years old and 12-15 years old. Data were taken secondarily and calculated with Microsoft Excel 2010. The most common findings were prevalence of DSS in 6-11 years old group and mortality rate in <1 years old group. This can be seen as in the hemodynamic outcome; the average HR was higher in aged group 1-2 years old while RR was higher in group under 1-year-old. Meanwhile, the average blood pressure, PP, and MAP were lower in children under 2 years old. The hemodynamic outcome varies on each group based on age. Incidence of DSS remained high in older children but mortality rates were high in younger children.
... It has a vital role in recognising bacterial lipopolysaccharide (LPS) and activation of proinflammatory response during viral infections [24]. Furthermore, DENV NS1 produces the release of inflammatory cytokines (IL-6 and IL-8) which may lead to endothelial barrier dysfunction via TLR 4 dependent mechanism [25,26]. This indicates that dengue viral protein could enhance inflammatory burden by TLR4 activation-dependent mechanism. ...
The World Health Organization (WHO) recognizes dengue infection as a major public health concern in tropical and subtropical countries. Dengue infection is recognized as the second most deadly vector-borne disease in the world, based upon its incidence and mortality rate. Vascular dyshomeostasis and liver dysfunction are the major pathological manifestations in dengue patients. Vascular events in dengue patients include dropping of pulse rate, increased capillary leakage, hypotension, life-threatening hemorrhage due to release of inflammatory cytokines, growth factors, matrix metalloproteinase (MMP). The evident increase in cytokines, chemokines, and growth factors could further induce the release of pro- inflammatory cytokines and reactive oxygen species (ROS) by activating macrophages, monocytes, and T cells resulting in endothelial dysfunction and enhanced permeability in vessels. Moreover, the anti-dengue viral protein antibodies could target clotting cascades and endothelial cells, contributing to the vascular complications. Evidence has also indicated that infiltration of NK T cells and cytotoxic CD8⁺ cells during the early and late phases of dengue infection results in intra-hepatic damage. Several pieces of evidence have revealed that PAR-2 activation could regulate inflammatory cytokine release, immune cell activation, and endothelial cell damage. Thus, PAR-2 activation can be associated with vascular dyshomeostasis and hepatic dysfunction during critical phases of dengue infection. In this study, we correlate the pathological manifestations of dengue infection with PAR-2 activation and generate the proof-of-concept that targeting this receptor could abrogate these changes.
... Systolic dysfunction in the form of low ejection fraction (EF), diastolic dysfunction in the form of abnormal E/A ratio, and pericardial effusion was reported in the echocardiography. [6] The correlation of the inferior vena cava (IVC) collapsibility with hematocrit has also been documented as directly proportional. [7] The present study was planned to assess the ECG and 2D-ECHO findings of dengue infection and to correlate with the disease severity. ...
Background:
The mechanism of myocardial damage in dengue could be the release of inflammatory mediators or the direct action of the dengue virus on myocytes leading to myocarditis. The release of inflammatory mediators is more in a severe form of the disease that correlates to the higher incidence of cardiac manifestations in patients with severe dengue.
Aim:
To determine the electrocardiographic and two-dimensional (2D)-echocardiographic findings in children with dengue infection and to find a correlation with disease severity.
Materials and methods:
A total of 150 children between 1 month and 12 years of age seropositive for dengue Non-specific antigen 1 (NS1) Enzyme linked immunosorbent assay (ELISA) or dengue Immunoglobulin M (IgM) ELISA were studied in the Department of Pediatric Medicine of a tertiary care government hospital. The patients were undertaken for 12 lead electrocardiograms (ECGs) and echocardiograms.
Results:
Out of the 150 dengue seropositive cases, 61 cases were of mild dengue, 67 cases were of dengue with warning signs (DWSS), and 22 cases were severe dengue cases. Abnormal ECG was found in 78 cases (52%) in a total of 150 cases in terms of rate, prolonged PR interval (interval between atrial depolarization and ventricular activation), ST (ventricular repolarisation)-segment depression, and low-voltage complexes. Abnormal 2D- echocardiography (ECHO) was found in 70 (46.6%) out of 150 in terms of the ejection fraction (EF) <55%, Early diastole/atrial contraction (E/A) ratio <1, and the presence of pericardial effusion.
Conclusion:
Nearly 50% of the patients have abnormal ECG and ECHO findings, more so in the severe dengue group. There is a statistically significant association of the EF between mild dengue, DWWS with severe dengue (P =0.001).
... Consequently, there is a reduction in effective preload and myocardial tissue edema. This leads to a variety of cardiac manifestations of dengue fever ranging from an asymptomatic elevation of cardiac enzymes to cardiogenic shock and, arrhythmias [1]. ...
Background:
Myocarditis is a challenging diagnosis due to the heterogeneity of clinical presentations. Myocarditis can present with a mildly raised cardiac enzyme to severe myocarditis leading to congestive heart failure, arrhythmias, cardiogenic shock, and death. It is a predictor of morbidity and mortality in dengue-infected patients. The exact prevalence of dengue myocarditis and its outcomes are unknown in Pakistan.
Objectives:
We aim to study the prevalence and association of myocarditis with the length of stay in the hospital and mortality of dengue-infected patients.
Methods:
A retrospective observational study done at a tertiary care hospital. We reviewed hospital record files of 1008 consecutive patients with dengue viral infection admitted from November 2018 to November 2019.
Results:
Out of 1008 dengue-infected patients, 55.4% of patients were older than 35 years and 68.4% were males. Hypertension (HTN) was the most common comorbid condition. The prevalence of myocarditis in hospitalized dengue-infected patients was 4.2%. All (100%) of dengue myocarditis patients had raised cardiac troponin I (cTn-I), 59.5% of patients had at least one electrocardiography (ECG) change, and 24% had reduced ejection fraction (EF) (defined as EF < 55%). On multivariable analysis, patients with raised cTn-I levels (adjusted odds ratios = 5.29; [95% confidence interval (CI): 2.16-12.96]) and abnormal echocardiography (ECHO) [aOR = 4.38; 95% CI: 1.26-15.27)] had a prolonged hospital stay (>3 days). Raised cTn-I levels (aOR = 8.2; [95% CI: 1.83-36.84]) was significantly associated with in-hospital mortality.
Conclusions:
Raised cTn-I is the predictor of length of stay and in-hospital mortality in dengue-infected patients. Atrial fibrillation, diabetes mellitus, hypertension, low serum bicarbonate, high serum creatinine, and any abnormality on echocardiography were associated with adverse outcomes in dengue-infected patients.
... Although most of the dengue infections are asymptomatic or present with mild symptoms, a proportion of patients (1%-5%) develop complications, including organ shutdown, bleeding, and plasma leakage from capillaries [6]. Dengue is divided into three stages of the disease progression: a febrile stage, lasting up to 7 days, during which the patient can experience high-grade fever, myalgias, headache, malaise, and vomiting; a critical phase, lasting 2-3 days, during which severe clinical manifestations become apparent; and recovery phase, for 2-5 days, when there is clinical improvement associated with resorption of leaked extracellular fluid. ...
Background
Dengue is the most important viral disease globally and a majority of symptomatic infections result in a benign course. However, a small number of patients develop severe manifestations, including myocardial impairment, arrhythmias, and fulminant myocarditis.
Areas covered
This review outlines the incidence of cardiovascular (CV) manifestations of dengue. Electronic databases, including PubMed/MEDLINE, EMBASE, Scopus, and CINAHL were searched for articles incorporating cardiac manifestations of dengue fever (DF).
Expert opinion
Included studies involved 6,773 patients and 3,122 (46.1%) exhibited at least one cardiac manifestation with DF. Electrocardiogram (ECG) abnormalities (30.6%) included sinus bradycardia (8.8%), non-specific ST-T changes (8.6%), ST depression (7.9%), and T-wave inversion (2.3%). Mechanical sequelae were present in 10.4%, including left ventricular (LV) systolic dysfunction (5.7%), and myocarditis (2.9%). Pericardial involvement was noted as pericarditis (0.1%), pericardial effusion (1.3%), and pericardial tamponade (0.1%). Apart from that, the cardiac injury was depicted through a rise in cardiac enzymes (4.5%).
The spectrum of CV manifestations in dengue is broad, ranging from subtle ST-T changes to fulminant myocarditis. This can be a cause of hemodynamic collapse during the critical phase of capillary leakage. Use of contemporary techniques in diagnosing cardiac involvement should be employed for rapid diagnosis and treatment in DF.
... Pulse pressure (PP) was used as a secondary endpoint, because a narrowed PP is a key diagnostic criterion for DSS, according to the WHO classification [7]. Traditional vital sign monitoring such as heart rate is an indicator of hemodynamic status, but can be affected by many factors, including temperature, stress, arrhythmias, and pain [7,22], and the relative bradycardia observed in dengue patients could mask deterioration [23], so more robust ways of monitoring hemodynamic status are required. Other studies show that CRI is a more sensitive and specific indicator of decreased central blood volume status when compared to heart rate, blood pressure, SpO 2 , lactate, perfusion index, tissue oxygenation, etc. [8-10, 20, 24-29]. ...
Background
Dengue shock syndrome (DSS) is one of the major clinical phenotypes of severe dengue. It is defined by significant plasma leak, leading to intravascular volume depletion and eventually cardiovascular collapse. The compensatory reserve Index (CRI) is a new physiological parameter, derived from feature analysis of the pulse arterial waveform that tracks real-time changes in central volume. We investigated the utility of CRI to predict recurrent shock in severe dengue patients admitted to the ICU.
Methods
We performed a prospective observational study in the pediatric and adult intensive care units at the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. Patients were monitored with hourly clinical parameters and vital signs, in addition to continuous recording of the arterial waveform using pulse oximetry. The waveform data was wirelessly transmitted to a laptop where it was synchronized with the patient’s clinical data.
Results
One hundred three patients with suspected severe dengue were recruited to this study. Sixty-three patients had the minimum required dataset for analysis. Median age was 11 years (IQR 8–14 years). CRI had a negative correlation with heart rate and moderate negative association with blood pressure. CRI was found to predict recurrent shock within 12 h of being measured (OR 2.24, 95% CI 1.54–3.26), P < 0.001). The median duration from CRI measurement to the first recurrent shock was 5.4 h (IQR 2.9–6.8). A CRI cutoff of 0.4 provided the best combination of sensitivity and specificity for predicting recurrent shock (0.66 [95% CI 0.47–0.85] and 0.86 [95% CI 0.80–0.92] respectively).
Conclusion
CRI is a useful non-invasive method for monitoring intravascular volume status in patients with severe dengue.
... The management of DHF during the febrile phase is similar to that of DF [15]. Usually, significant plasma loss is seen in dengue patients, it leads to a rise in hematocrit value, to overcome this, parenteral fluid therapy is recommended [16,17]. Hospitalization is recommended in patients with any signs of bleeding and persistent high hematocrit. ...
Dengue virus (DENV) is the fastest re-emerging arbovirus existing in the tropical and subtropical regions today. It has become a worldwide major public health problem, especially affecting SouthEast Asian populations. Dengue is spread by Aedes mosquito bite. It has three phases based on severity termed as febrile, critical and recovery phases. As per the national survey data, the prevalence of dengue has been still rising consistently, and the burden of the disease is predominantly affecting the adults with progression towards the Dengue fever (DF), Dengue hemorrhagic fever (DHF) and Dengue shock syndrome (DSS). The key elements needed to achieve the dengue public health targets identified by the World health organization (WHO) global strategy are the diagnosis, care management, outbreak preparedness and integrated surveillance, sustainable vector control, future vaccine implementation. This review mainly describes the dengue treatment challenges, in addition to a brief discussion of dengue vaccine challenges and future outlook on dengue itself.
... 4 The case fatality rate in patients with severe dengue infection which consists of DHF and DSS can be as high as 44%. 2,5 The incubation period after the mosquito bite is 3-8 days. Infants and young children often have a non-specific febrile illness that can hardly be differentiated from other viral illnesses. ...
Background: Dengue is one of the most widespread arthropod borne diseases worldwide with an annual incidence of 50–100 million cases per year. The recent resurgence of dengue in the pediatric population has created concern among pediatricians, especially due to increased incidence of atypical features, leading to delayed diagnosis and increased mortality. There are few studies regarding this due to under reporting of the cases.
Aims and Objectives: This study aims to study the clinical profile and outcome of dengue patients between the age groups of 1 month and 12 years with special emphasis on patients with atypical features. Dengue patients with atypical presentation are easily misdiagnosed by physicians, especially in the pediatric age group which increases the morbidity and mortality.
Materials and Methods: This was a retrospective observational study conducted from May 2018 to September 2019 in the Department of Pediatrics, CNMCH. All pediatric patients who were dengue IgM or dengue NS1 positive were included in the study and their course of stay was followed through hospital records. The data were statistically analyzed through SPSS 16.0 software.
Results: Sixty-two dengue patients were included in the study. Thirty-two patients presented as mild febrile illness, classical dengue fever (DF), dengue hemorrhagic fever, or shock syndrome without atypical manifestations. Atypical manifestations were found in 30 patients (48.38%) of our study. Eleven (17.7%) patients had splenomegaly, 5 (8.1%) patients had hepatitis, 3 (4.8%) patients had diarrhea, 2 (3.2%) patients had acalculous cholecystitis, 1 (1.6%) patient had hepatitis with acalculous cholecystitis, 1 (1.6%) patient had hepatitis with diarrhea, 1 (1.6%) patient had myocarditis, 1 (1.6%) patient had paroxysmal supraventricular tachycardia, 1 (1.6%) patient had acute pancreatitis, 1 (1.6%) patient had acute kidney injury, 1 (1.6%) patient had ARDS, 1 (1.6%) patient had encephalitis, and 1 (1.6%) patient had myositis. Need of intensive care facility was more in patients with atypical manifestations due to mis or late diagnosis which prolonged course of stay.
Conclusion: Atypical manifestations of DF are more common than reported. Lack of awareness among physicians, especially in primary health center, leads to delayed diagnosis and increased mortality and morbidity.
... The analysis of gene-infection/disease interaction (infectome or diseasome network) help us to find out a-set-of new interactions which can clarify the molecular mechanism associated with viral infectious and non-infections diseases (Segura-Cabrera et al. 2013). The morbidity and mortality risk may increased significantly due to the infections/diseases associated with co-morbidity (Yacoub et al. 2014). ...
The chikungunya (CHIKV) viral infection is a global health burden characterized by the neurologic complications with CHIKV infection. CHIKV has relation with Ebola, Dengu, Semlikhi Forest Virus (SLFV) characterized by inflammations in these viral diseases. The present study aimed to discover molecular signatures for comorbidity of viral infections. So, in our study, we have analyzed transcriptome datasets related to viral diseases namely, CHIKV, Ebola, Dengu, SLFV, and inflammatory disorder “Pain” associated with these viral diseases. We built relationship networks based on the CHIKV virus after identifying shared genes among the illnesses mentioned above. After that we also constructed protein-protein interaction network (PPI) considering the differentially expressed genes (DEGs) of CHKIV and identified hub genes based on topological analysis. A total 500 DEGs was identified associated with CHIKV infections induced transcriptomic alterations. It was also found that 105 genes were common in both CHIKV and ebola infections. However, CHIKV shared under 24 significant transcripts with other alphaviruse infections. We also found that 49 genes shared with pain. In our analysis, we identified the relation of these viruses, common genes among them, comorbidities of CHIKV and Hub genes, significant pathways of CHIKV.
... The difference in the incidence of myocarditis in other reports may be related to dengue severity, which can vary year by year; this study was conducted during a year when severe dengue was not prevalent. Our results are compatible with those of a report of dengue cases in Southeast Asia [22][23][24] and a report from Sri Lanka [5]. Wichmann et al. [12] showed that 25% of patients with dengue had elevated levels of one or more cardiac biomarkers, such as myoglobin, CK-MB, troponin-T, N-terminal pro B-type natriuretic peptide, and hearttype fatty acid-binding protein. ...
Background
Dengue virus infection (DVI) is a major health problem in many parts of the world. Its manifestations range from asymptomatic infections to severe disease. Although cardiac involvement has been reported in DVI, its incidence has not yet been well established.
Methods
From July 2016 to January 2018, patients hospitalized at the Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Thailand, with dengue virus infection confirmed by positive NS1 or positive dengue immunoglobulin M findings, participated in the study. We characterized the incidence and change in cardiac function by serial echocardiography and levels of troponin-T and creatine kinase-myocardial band (CK-MB) on the day of admission, the day of defervescence, the first day of hypotension (if any), and at 2 week follow-up.
Results
Of the 81 patients evaluated, 6 (7.41%) exhibited elevated biomarker levels. There was no difference in clinical presentation amongst dengue fever, dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS), except for the amount of bleeding. Cardiac involvement was found in 22.2% of patients: 3 (3.70%) had left ventricular systolic dysfunction, 3 (3.70%) had transient diastolic dysfunction, 6 (7.41%) had increased levels of at least one cardiac biomarker (troponin-T or CK-MB), and 6 (7.41%) had small pericardial effusion. Myocarditis was suspected in only two patients (with DHF); thus, myocarditis was uncommon in patients with dengue virus infection. Three patients developed DSS during admission and were transferred to the intensive care unit.
Conclusion
Cardiac involvement in adults with dengue infection was common, ranging from elevated cardiac biomarker to myocarditis. Abnormalities in cardiac function had resolved spontaneously by the day of follow-up, without specific treatment. We found that DHF was a significant risk factor for cardiac involvement. Echocardiography is the investigation of choice for evaluating the haemodynamic status of patients with DVI, especially in severe dengue.
Dengue is often seen as an acute infection with fever and thrombocytopenia where complications such as shock and hemorrhage need to be averted while the patient recovers with supportive care. However, dengue can also be a differential diagnosis in the emergency care setting. Acute encephalopathy, acute renal failure, hepatitis, liver failure, acute pancreatitis, noncardiogenic pulmonary edema, acute respiratory distress syndrome, compartment syndrome, intracranial bleeds, hemophagocytic lymphohistiocytosis are few of the emergencies that may be seen in the course of dengue fever. These complications need prompt recognition and management to ensure better outcomes.
Abstract: Microvascular integrity is a critical factor in myocardial fluid homeostasis. The subtle equilibrium between capillary filtration and lymphatic fluid removal is disturbed during pathological processes leading to inflammation, but also in hypoxia or due to alterations in vascular perfusion and coagulability. The degradation of the glycocalyx as the main component of the endothelial filtration barrier as well as pericyte disintegration results in the accumulation of interstitial and intracellular water. Moreover, lymphatic dysfunction evokes an increase in metabolic waste products, cytokines and inflammatory cells in the interstitial space contributing to myocardial oedema formation. This leads to myocardial stiffness and impaired contractility, eventually resulting in cardiomyocyte apoptosis, myocardial remodelling and fibrosis. The following article reviews pathophysiological inflammatory processes leading to myocardial oedema including myocarditis, ischaemia-reperfusion injury and viral infections with a special focus on the pathomechanisms evoked by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In addition, clinical implications including potential long-term effects due to viral persistence (long COVID), as well as treatment options, are discussed.
Dengue fever may present with many cardiovascular manifestations contributing to death and disability. Acute Coronary Syndrome (ACS) during dengue is rare but poses important management dilemma. Here we present a series of 5 patients with dengue fever who developed different types of ACS during the ongoing dengue endemic in Bangladesh. Five patients admitted with dengue fever and who developed ACS between 1st July to 30th September 2023 at Medicine Department of Uttara Adhunik Medical College, Dhaka, Bangladesh were studied. All the patients had some co[1]morbidity like diabetes, hypertension, or both. Treatment of ACS was tailored according to their CBC report, most importantly, platelet count, and hematocrit. Four out of the 5 patients responded well to anti-ischemic therapy, even though anti-platelet and anti-coagulants could not be given in all cases. There was 1 fatality, but that was due to ARDS consequent due to severe bilateral pneumonia. Management of ACS in dengue is challenging. Physicians should have appropriate preparedness to deal with these cases. J Bangladesh Coll Phys Surg 2023; 41: 82-87
Background:
Major cardiovascular events (MACEs) have been described with dengue infection. Among these MACEs, heart failure (HF) is the most common but has not been thoroughly assessed. This study aimed to evaluate the association between dengue and HF.
Methods:
Under the self-controlled case-series study design, we used the Notifiable Infectious Disease dataset linkage with the National Health Insurance claims data to obtain the study subjects. All laboratory-confirmed dengue cases who were hospitalized for HF after dengue infection within one year between 2009 and 2015 in Taiwan were included. We identified the first 7 and 14 days after dengue infection as the risk intervals. The incidence rate ratio (IRR) and 95% confidence interval (CI) for HF were estimated by conditional Poisson regression.
Results:
Among the 65,906 dengue patients, 230 had admission for HF after dengue infection within one year. The IRR of HF admission within the first week after dengue infection was 27.2456.50 (95% C.I. 43.88-72.75). This risk was highest in >60 years (IRR = 59.32, 95% C.I. 45.43-77.43) and lower in 0-40 years (IRR = 25.82, 95% C.I. 2.89-231.02). The risk was nearly nine times higher among admission (for dengue infection) than among nonadmission cases (IRR 75.35 vs. 8.61, p < 0.0001). The risks increased slightly in the second week 8.55 and became less obvious after the third and fourth week.
Conclusions:
Patients with dengue infection have a risk of developing acute heart failure within one week, especially in >60 years, men, and dengue admission subjects. The findings emphasize the awareness of diagnosis and further appropriate treatment of HF.
Pericardial disease in the developing world is dominated primarily by effusive and constrictive syndromes and contributes to the acute and chronic heart failure burden in many regions. The confluence of geography (location in the tropics), a significant burden of diseases of poverty and neglect, and a significant contribution of communicable diseases to the general burden of disease, is reflected in the wide etiological spectrum of causes of pericardial disease. The prevalence of Mycobacterium tuberculosis (Mtb) in particular, is high throughout much of the developing world where it is the most frequent and important cause of pericarditis and is associated with significant morbidity and mortality. Acute viral/idiopathic pericarditis, which is the primary manifestation of pericardial disease in the developed world is believed to occur significantly less frequently in the developing world. Although diagnostic approaches and criteria to establish the diagnosis of pericardial disease are similar throughout the globe, resource constraints such as access to multimodality imaging and hemodynamic assessment are a major limitation in much of the developing world. These important considerations significantly influence the diagnostic and treatment approaches, and outcomes related to pericardial disease.
Importance:
Acute myocarditis, defined as a sudden inflammatory injury to the myocardium, affects approximately 4 to 14 people per 100 000 each year globally and is associated with a mortality rate of approximately 1% to 7%.
Observations:
The most common causes of myocarditis are viruses, such as influenza and coronavirus; systemic autoimmune disorders, such as systemic lupus erythematosus; drugs, such as immune checkpoint inhibitors; and vaccines, including smallpox and mRNA COVID-19 vaccines. Approximately 82% to 95% of adult patients with acute myocarditis present with chest pain, while 19% to 49% present with dyspnea, and 5% to 7% with syncope. The diagnosis of myocarditis can be suggested by presenting symptoms, elevated biomarkers such as troponins, electrocardiographic changes of ST segments, and echocardiographic wall motion abnormalities or wall thickening. Cardiac magnetic resonance imaging or endomyocardial biopsy are required for definitive diagnosis. Treatment depends on acuity, severity, clinical presentation, and etiology. Approximately 75% of patients admitted with myocarditis have an uncomplicated course, with a mortality rate of approximately 0%. In contrast, acute myocarditis that is complicated by acute heart failure or ventricular arrhythmias is associated with a 12% rate of either in-hospital mortality or need for heart transplant. Approximately 2% to 9% of patients have hemodynamic instability, characterized by inability to maintain adequate end-organ perfusion, and require inotropic agents, or mechanical circulatory devices, such as extracorporeal life support, to facilitate functional recovery. These patients have an approximately 28% rate of mortality or heart transplant at 60 days. Immunosuppression (eg, corticosteroids) is appropriate for patients who have myocarditis characterized by eosinophilic or giant cell myocardial infiltrations or due to systemic autoimmune disorders. However, the specific immune cells that should be targeted to improve outcomes in patients with myocarditis remain unclear.
Conclusions and relevance:
Acute myocarditis affects approximately 4 to 14 per 100 000 people per year. First-line therapy depends on acuity, severity, clinical presentation, and etiology and includes supportive care. While corticosteroids are often used for specific forms of myocarditis (eg, eosinophilic or giant cell infiltrations), this practice is based on anecdotal evidence, and randomized clinical trials of optimal therapeutic interventions for acute myocarditis are needed.
Dengue patients may experience some grade of severity. Cardiac involvement is common in severe dengue, therefore cardiac markers could be used to ensure the diagnosis of dengue myocarditis. However, information of the cardiac marker profiles in patients with milder severity of dengue infection is limited. The study aimed to evaluate creatinine kinase (CK), creatinine kinase-MB (CK-MB) and troponin I (TnI) in dengue myocarditis against the spectrum severity of dengue infection in children. This cross-sectional study was conducted using secondary data from medical records of dengue myocarditis patients aged 1-18 yr in Dr. Sardjito General Hospital, Yogyakarta. Fisher’s Exact tests were performed to compare the increase in cardiac markers to the dengue severity. The increase of CK was observed in dengue fever/DF (6 or 75% of patients), dengue hemorrhagic fever/DHF (6 or 67%) and dengue shock syndrome/DSS (16 or 73%). Furthermore, the increase of CK-MB was also observed in DF (6 or 75%), DHF (8 or 87%), and DSS (21 or 95%). No significant difference in the increase of CK and CK-MB proportions was observed in DF compared to DHF groups and in DF compared to DSS (p>0.05). The increase of Tn I was observed in DHF (2 or 22%) and DSS (10 or 45%) groups but not observed in DF group. Significant difference in the increase of Tn I proportion was observed in DF compared to DSS groups (p=0.022). In conclusion, cardiac involvement is common in all dengue severity level. The increment of Tn I corresponds to an increase in the dengue severity level. Further research by observing cardiac markers sequentially is needed.
Viral infections have been linked to a variety of cardiac pathology, which may include acute myocarditis, dilated cardiomyopathy, heart failure, cardiogenic shock, pericarditis, acute coronary syndromes, and arrhythmias. We performed a systematic review of literature focusing on the cardiovascular effects of various viral infections, as well as providing an update on the current understanding of the pathophysiology of Coronavirus disease-2019 (COVID-19). Cardiac manifestations of viral illnesses are usually self-limiting, have variable clinical presentations, and require sufficient clinical suspicion for diagnosis and optimal management.
The burden of cardiovascular diseases is sharply rising in low- and middle-income countries (LMICs). Along with the increasing rates of cardiovascular risk factors in these regions, there is a growing recognition of the contribution of neglected tropical diseases and other infections. Several cardiac implications of these infections have been reported but have not yet been validated by robust population data. This is in part due to limited access to health care and insufficient data collection infrastructure in many LMICs. Therefore, the true impact of these infections on the cardiovascular system may be underestimated, because of both underdiagnosis and underreporting bias. There is an urgent need to thoroughly delineate the cardiac impact of these conditions with elevated prevalence in LMICs and to propose strategies to reduce the negative consequences of these diseases in health systems with limited resources.
Dengue virus (DENV) poses a continuous threat to the public health of the global community with over 390 million infections and 25,000 deaths annually. The efficacy of the only licensed dengue vaccine, Dengvaxia, against all four DENV serotypes is less than desirable in real-world setting. In addition, there is a lack of clinically approved antiviral drugs against DENV. This drives an urgent need for the development of novel dengue therapeutics. Technological advancements in recent years have paved the way towards initiating an interest in the development of peptide drugs by the pharmaceutical industry. This chapter highlights the current status of the development of antiviral peptides targeting DENV, strategies that were utilized to design antiviral peptides, interactions that were identified between antiviral peptides and DENV host cell receptors or enzymes, advantages and disadvantages of antiviral peptides, as well as potential ways to overcome their limitations.
Despite a well-known association between gut barrier defect (leaky gut) and several diseases, data on translocation of pathogen molecules, including bacterial DNA (blood bacteriome), lipopolysaccharide (LPS), and serum (1→3)-β-D-glucan (BG), from the gut to the blood circulation (gut translocation) in dengue are still less studied. Perhaps, dengue infection might induce gut translocation of several pathogenic molecules that affect the disease severity. At the enrollment, there were 31 dengue cases in febrile and critical phases at 4.1 ± 0.3 days and 6.4 ± 1.1 days of illness, respectively, with the leaky gut as indicated by positive lactulose-to-mannitol excretion ratio. With blood bacteriome, the patients with critical phase (more severe dengue; n = 23) demonstrated more predominant abundance in Bacteroidetes and Escherichia spp. with the lower Bifidobacteria when compared with the healthy control (n = 5). Meanwhile, most of the blood bacteriome results in dengue with febrile stage (n = 8) were comparable to the control, except for the lower Bifidobacteria in dengue cases. Additionally, endotoxemia at the enrollment was demonstrated in five (62.5%) and 19 (82.6%) patients with febrile and critical phases, respectively, while serum BG was detectable in two (25%) and 20 (87%) patients with febrile and critical phases, respectively. There were higher peripheral blood non-classical monocytes and natural killer cells (NK cells) at the enrollment in patients with febrile phage than in the cases with critical stage. Then, non-classical monocytes (CD14-CD16+) and NK cells (CD56+CD16-) increased at 4 and 7 days of illness in the cases with critical and febrile stages, respectively, the elevation of LPS and/or BG in serum on day 7 was also associated with the increase in monocytes, NK cells, and cytotoxic T cells. In summary, enhanced Proteobacteria (pathogenic bacteria from blood bacteriomes) along with increased endotoxemia and serum BG (leaky gut syndrome) might be collaborated with the impaired microbial control (lower non-classical monocytes and NK cells) in the critical cases and causing more severe disease of dengue infection.
Background
As cardiac involvement can cause serious complications and death, understanding its role in acute dengue and influenza virus infections is important.
Methods
We provide a comparative evaluation of severe dengue and critically ill influenza patients with elevated cardiac troponin-I (cTnI) from 2014 to 2019. Inclusion criteria included patients in which cTnI test were ordered. Patient without cTnI test was excluded.
Results
During the study period, 82 (41 severe dengue and 41 critically ill influenza) patients had cTnI elevations, and 81 (35 severe dengue and 46 critically ill influenza) patients had a single normal cTnI test. Severe dengue patients with cTnI elevations had a significantly higher incidences of acute kidney injury, gastrointestinal bleeding, early mortality (≤7 after illness onset) and in-hospital mortality than those with severe dengue and single normal cTnI test. Significantly higher aspartate aminotransferase (AST) levels and higher incidence of gastrointestinal bleeding was observed in critically ill influenza patients with cTnI elevations compared to critically ill influenza patients with single normal cTnI measurement. Of the patients with cTnI elevations, the early and in-hospital mortality rates were 53.6% and 65.8%, respectively, in severe dengue patients, and 7.3% and 46.3%, respectively, in critically ill influenza patients. Significantly higher early mortality rates were observed in severe dengue patients with elevated cTnI levels than in critically ill influenza patients with cTnI elevations. Critically ill influenza patients with elevated cTnI levels had significantly higher incidences of pneumonia, pneumothorax, and bacteremia than severe dengue patients with cTnI elevations. Multivariate analysis revealed elevated AST (>1000U/L) (95% confidence interval [CI]: 1.690–143.174) was an independent risk factor for in-hospital mortality in severe dengue patients with elevated cTnI levels. Leukocytosis (95% CI: 1.079–1.124) and thrombocytopenia (95% CI: 2.739–5.821) were independently correlated with in-hospital mortality in critically ill influenza patients with cTnI elevations.
Conclusions
Differences in clinical features between severe dengue and critically ill influenza patients with cTnI elevations. High early mortality rate was observed in severe dengue patients with cardiac involvement. In contrast, most critically ill influenza patients died ≥2 weeks after the onset of illness, regardless of cTnI elevations. Our report has important clinical implications for the timely recognition and management of cardiac complication in patients with acute dengue and influenza virus infections.
Myocarditis is an inflammatory heart disease that can occur acutely, as in acute myocarditis, or persistently, as in chronic myocarditis or chronic inflammatory cardiomyopathy. Different agents can induce myocarditis, with viruses being the most common triggers. Generally, acute myocarditis affects relatively young people and men more than women. Myocarditis has a broad spectrum of clinical presentations and evolution trajectories, although most cases resolve spontaneously. Patients with reduced left ventricular ejection fraction, heart failure symptoms, advanced atrioventricular block, sustained ventricular arrhythmias or cardiogenic shock (the latter known as fulminant myocarditis) are at increased risk for death and heart transplantation. The presentation of chronic inflammatory cardiomyopathy may be more subtle, with progressive symptoms of heart failure or appearance of rhythm disturbance, not rarely preceded by an infective episode. Autoimmune disorder or systemic inflammatory conditions can be another significant predisposing substrate of myocarditis, especially in women. Emerging causes of myocarditis are drug-related like the new anticancer therapies, the immune checkpoint inhibitors. In this Italian Association of Hospital Cardiologists (ANMCO) and Italian Society of Cardiology (SIC) expert consensus document on myocarditis, we propose diagnostic strategies for identifying possible causes of the disease and factors associated with increased risk. Finally, we propose potential treatments and when referring patients to tertiary centers, especially for high-risk patients. Even if endomyocardial biopsy is the invasive diagnostic tool for making definitive diagnosis and differentiation of histological subtypes (i.e., lymphocytic vs eosinophilic vs giant cell myocarditis), it is not always readily available in all centers. Thus, we propose when this exam is mandatory or when it can be postponed or substituted by cardiac magnetic resonance imaging. This document reflects the Italian perspective on managing patients with myocarditis and their follow-up, considering also current US and European scientific position statements. © 2020 Il Pensiero Scientifico Editore s.r.l.. All rights reserved.
Purpose of Review
Dengue is an important public health problem in many parts of the world. This article consolidates the current knowledge about dengue myocarditis.
Recent Findings
Cardiac involvement in dengue is a common phenomenon. Myocarditis is the predominant manifestation. It can be subclinical with no impact on the outcome, or it can cause potentially fatal arrhythmias or cardiogenic shock and even lead to cardiomyopathy. Myocardial inflammation is elicited by direct viral invasion and production of inflammatory cytokines and free oxygen radicals. The manifestations can overlap with dengue shock syndrome resulting from capillary leakage. The diagnostic criterion is not well-defined and relies on evaluation of cardiac biomarkers and electrocardiographic and echocardiographic changes in the presence or absence of symptoms. There is an emerging role of cardiac magnetic resonance imaging and strain echocardiography. Treatment involves use of supportive therapies, and there is no evidence for use of antiviral drugs, corticosteroids, and immunosuppressants.
Summary
Physicians need to be wary of myocarditis in dengue. More research is needed for developing specific treatment.
Dysregulated immune responses may contribute to the clinical complications that occur in some patients with dengue.
In Vietnamese pediatric dengue cases randomized to early prednisolone therapy, 81 gene-transcripts (0.2% of the 47,231 evaluated) were differentially abundant in whole-blood between high-dose (2 mg/kg) prednisolone and placebo-treated patients two days after commencing therapy. Prominent among the 81 transcripts were those associated with T and NK cell cytolytic functions. Additionally, prednisolone therapy was not associated with changes in plasma cytokine levels.
The inability of prednisolone treatment to markedly attenuate the host immune response is instructive for planning future therapeutic strategies for dengue.
Dengue is a prevalent arthropod-borne viral disease in tropical and subtropical areas of the globe. Dengue clinical manifestations include asymptomatic infections; undifferentiated fever; dengue fever, which is characterized by fever, headache, retroorbital pain, myalgia, and arthralgia; and a severe form of the disease denominated dengue haemorrhagic fever/dengue shock syndrome, characterized by haemoconcentration, thrombocytopenia, and bleeding tendency. However, atypical manifestations, such as liver, central nervous system, and cardiac involvement, have been increasingly reported. We report an atypical and rare presentation of dengue disease marked by a dramatic and fatal cardiogenic shock due to acute myocarditis. Histopathological analysis of heart tissue showed several multifocal areas of muscle necrosis and intense interstitial oedema associated with clusters of virus particles inside the cardiomyocytes and in the interstitial space, providing evidence of a possible direct action of dengue virus on myocardium.
Background. Dengue shock syndrome (DSS) is a severe manifestation of dengue virus infection that particularly affects children and young adults. Despite its increasing global importance, there are no prospective studies describing the clinical characteristics, management, or outcomes of DSS.
Methods. We describe the findings at onset of shock and the clinical evolution until discharge or death, from a comprehensive prospective dataset of 1719 Vietnamese children with laboratory-confirmed DSS managed on a single intensive care unit between 1999 and 2009.
Results. The median age of patients was 10 years. Most cases had secondary immune responses, with only 6 clear primary infections, and all 4 dengue virus serotypes were represented during the 10-year study. Shock occurred commonly between days 4 and 6 of illness. Clinical signs and symptoms were generally consistent with empirical descriptions of DSS, although at presentation 153 (9%) were still febrile and almost one-third had no bleeding. Overall, 31 (2%) patients developed severe bleeding, primarily from the gastrointestinal tract, 26 of whom required blood transfusion. Only 8 patients died, although 123 of 1719 (7%) patients had unrecordable blood pressure at presentation and 417 of the remaining 1596 (26%) were hypotensive for age. The majority recovered well with standard crystalloid resuscitation or following a single colloid infusion. All cases were classified as severe dengue, while only 70% eventually fulfilled all 4 criteria for the 1997 World Health Organization classification of dengue hemorrhagic fever.
Conclusions. With prompt intervention and assiduous clinical care by experienced staff, the outcome of this potentially fatal condition can be excellent.
Dengue virus (DENV) infection can range in severity from mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Changes in host gene expression, temporally through the progression of DENV infection, especially during the early days, remains poorly characterized. Early diagnostic markers for DHF are also lacking.
In this study, we investigated host gene expression in a cohort of DENV-infected subjects clinically diagnosed as DF (n = 51) and DHF (n = 13) from Maracay, Venezuela. Blood specimens were collected daily from these subjects from enrollment to early defervescence and at one convalescent time-point. Using convalescent expression levels as baseline, two distinct groups of genes were identified: the "early" group, which included genes associated with innate immunity, type I interferon, cytokine-mediated signaling, chemotaxis, and complement activity peaked at day 0-1 and declined on day 3-4; the second "late" group, comprised of genes associated with cell cycle, emerged from day 4 and peaked at day 5-6. The up-regulation of innate immune response genes coincided with the down-regulation of genes associated with viral replication during day 0-3. Furthermore, DHF patients had lower expression of genes associated with antigen processing and presentation, MHC class II receptor, NK and T cell activities, compared to that of DF patients. These results suggested that the innate and adaptive immunity during the early days of the disease are vital in suppressing DENV replication and in affecting outcome of disease severity. Gene signatures of DHF were identified as early as day 1.
Our study reveals a broad and dynamic picture of host responses in DENV infected subjects. Host response to DENV infection can now be understood as two distinct phases with unique transcriptional markers. The DHF signatures identified during day 1-3 may have applications in developing early molecular diagnostics for DHF.
Background:
Dengue is a disease whose clinical manifestations range from asymptomatic infections to a severe disease. There have been some previous reports of myocardial involvement in dengue, but this association has not been completely established.
Methods:
From January to July of 2011, patients hospitalized with dengue, confirmed through dengue nonstructural protein 1 and/or immunoglobulin M detection, were included in this study and troponin I and N terminal fragment of B-type natriuretic peptide levels were determined. Patients with abnormal biomarkers underwent echocardiography and when any abnormality was detected, they underwent cardiac magnetic resonance imaging.
Results:
Eighty-one patients were evaluated and 12 patients (15%) presented with elevated biomarker levels. Compared to controls, they had higher leukocyte (P < .001) and platelet counts (P = .005); higher C-reactive protein (P = .02), and a lower viral load (P = .03). There was no difference according to clinical dengue classification; dengue hemorrhagic fever/dengue shock syndrome severity; duration of symptoms; or prevalence of secondary infection between the 2 groups. Two patients died secondary to cardiogenic shock before imaging studies. Necroscopic findings were compatible to myocarditis in both, and immunohistochemistry for dengue virus showed increased staining on mononuclear cells located in the myocardial tissue. Of the 10 patients who underwent echocardiography, depressed left ventricular ejection fraction (LVEF) was identified in 1, left ventricular segmental abnormalities with preserved LVEF in 2, and an important pericardial effusion with tamponade in another. Cardiac involvement was confirmed by CMR in these 4 patients.
Conclusions:
Dengue viruses were shown to cause cardiac disease with clinical manifestations ranging from mild elevation of biomarkers to myocarditis and/or pericarditis.
Dengue is a systemic viral infection transmitted between humans by Aedes mosquitoes. For some patients, dengue is a life-threatening illness. There are currently no licensed vaccines or specific therapeutics, and substantial vector control efforts have not stopped its rapid emergence and global spread. The contemporary worldwide distribution of the risk of dengue virus infection and its public health burden are poorly known. Here we undertake an exhaustive assembly of known records of dengue occurrence worldwide, and use a formal modelling framework to map the global distribution of dengue risk. We then pair the resulting risk map with detailed longitudinal information from dengue cohort studies and population surfaces to infer the public health burden of dengue in 2010. We predict dengue to be ubiquitous throughout the tropics, with local spatial variations in risk influenced strongly by rainfall, temperature and the degree of urbanization. Using cartographic approaches, we estimate there to be 390 million (95% credible interval 284-528) dengue infections per year, of which 96 million (67-136) manifest apparently (any level of clinical or subclinical severity). This infection total is more than three times the dengue burden estimate of the World Health Organization. Stratification of our estimates by country allows comparison with national dengue reporting, after taking into account the probability of an apparent infection being formally reported. The most notable differences are discussed. These new risk maps and infection estimates provide novel insights into the global, regional and national public health burden imposed by dengue. We anticipate that they will provide a starting point for a wider discussion about the global impact of this disease and will help to guide improvements in disease control strategies using vaccine, drug and vector control methods, and in their economic evaluation.
Background
Dengue is the most important vector-borne viral infection of man, with approximately 2 billion people living in areas at risk. Infection results in a range of manifestations from asymptomatic infection through to life-threatening shock and haemorrhage. One of the hallmarks of severe dengue is vascular endothelial disruption. There is currently no specific therapy and clinical management is limited to supportive care. Statins are a class of drug initially developed for lipid lowering. There has been considerable recent interest in their effects beyond lipid lowering. These include anti-inflammatory effects at the endothelium. In addition, it is possible that lovastatin may have an anti-viral effect against dengue. Observational data suggest that the use of statins may improve outcomes for such conditions as sepsis and pneumonia. This paper describes the protocol for a randomised controlled trial investigating a short course of lovastatin therapy in adult patients with dengue.
Methods/design
A randomised, double-blind, placebo-controlled trial will investigate the effects of lovastatin therapy in the treatment of dengue. The trial will be conducted in two phases with an escalation of dose between phases if an interim safety review is satisfactory. This is an exploratory study focusing on safety and there are no data on which to base a sample size calculation. A target sample size of 300 patients in the second phase, enrolled over two dengue seasons, was chosen based on clinical judgement and feasibility considerations. In a previous randomised trial in dengue, about 10% and 30% of patients experienced at least one serious adverse event or adverse event, respectively. With 300 patients, we will have 80% power to detect an increase of 12% (from 10% to 22%) or 16% (from 30% to 46%) in the frequency of adverse events. Furthermore, this sample size ensures some power to explore the efficacy of statins.
Discussion
The development of a dengue therapeutic that can attenuate disease would be an enormous advance in global health. The favourable effects of statins on the endothelium, their good safety profile and their low cost make lovastatin an attractive therapeutic candidate.
Trial registration
International Standard Randomised Controlled Trial Number ISRCTN03147572
Background:
Patients with dengue can experience a variety of serious complications including hypovolemic shock, thrombocytopenia, and bleeding. These problems occur as plasma viremia is resolving and are thought to be immunologically mediated. Early corticosteroid therapy may prevent the development of such complications but could also prolong viral clearance.
Methods:
We performed a randomized, placebo-controlled, blinded trial of low-dose (0.5 mg/kg) or high-dose (2 mg/kg) oral prednisolone therapy for 3 days in Vietnamese patients aged 5-20 years admitted with dengue and fever for ≤72 hours, aiming to assess potential harms from steroid use during the viremic phase. Intention-to-treat analysis was performed using linear trend tests with a range of clinical and virological endpoints specified in advance. In addition to recognized complications of dengue, we focused on the are under the curve for serial plasma viremia measurements and the number of days after enrollment to negative viremia and dengue nonstructural protein 1 status.
Results:
Between August 2009 and January 2011, 225 participants were randomized to 1 of the 3 treatment arms. Baseline characteristics were similar across the groups. All patients recovered fully and adverse events were infrequent. Aside from a trend toward hyperglycemia in the steroid recipients, we found no association between treatment allocation and any of the predefined clinical, hematological, or virological endpoints.
Conclusions:
Use of oral prednisolone during the early acute phase of dengue infection was not associated with prolongation of viremia or other adverse effects. Although not powered to assess efficacy, we found no reduction in the development of shock or other recognized complications of dengue virus infection in this study.
As dengue spreads to new geographical regions and the force of infection changes in existing endemic areas, a greater breadth of clinical presentations is being recognised. Clinical experience suggests that adults manifest a pattern of complications different from those observed in children, but few reports have described the age-related spectrum of disease in contemporaneous groups of patients recruited at the same geographical location.
Using detailed prospectively collected information from ongoing studies that encompass the full spectrum of hospitalised dengue cases admitted to a single hospital in southern Vietnam, we compared clinical and laboratory features, management, and outcome for 647 adults and 881 children with confirmed dengue. Signs of vascular leakage and shock were more frequent and more severe in children than adults, while bleeding manifestations and organ involvement were more common in adults. Additionally, adults experienced significantly more severe thrombocytopenia. Secondary infection but not serotype was independently associated with greater thrombocytopenia, although with a smaller effect than age-group. The effect of age-group on platelet count was also apparent in the values obtained several weeks after recovery, indicating that healthy adults have intrinsically lower counts compared to children.
There are clear distinctions between adults and children in the pattern of complications seen in association with dengue infection, and these depend partly on intrinsic age-dependent physiological differences. Knowledge of such differences is important to inform research on disease pathogenesis, as well as to encourage development of management guidelines that are appropriate to the age-groups at risk.
To evaluate 2-dimensional speckle tracking echocardiography as a diagnostic and prognostic tool in patients with acute myocarditis. In this retrospective cohort study, 45 patients (age, 39 ± 15 years; 32 male) with suspected acute myocarditis and 83 healthy controls (age, 39 ± 13 years; 27 male) underwent 2-dimensional speckle tracking echocardiography. Main outcome measures were circumferential and longitudinal strain and strain rate as prognostic and diagnostic markers. Patients with myocarditis had lower circumferential strain (-13.3 ± 5.6 % vs. -22.3 ± 4 %), circumferential strain rate (-0.9 ± 0.3 vs. -1.4 ± 0.3 s(-1)), longitudinal strain (-11.7 ± 4 % vs. -17.7 ± 1.9 %), and longitudinal strain rate (-0.7 ± 0.2 vs. -1.0 ± 0.1 s(-1)) (all P < .001). For diagnostic purposes, longitudinal strain had the greatest area under the curve, 0.93 (optimal cutoff value, -15.1 %; sensitivity, 78 %; specificity, 93 %). Future events were defined as cardiac death, heart transplant, placement of left ventricular assist device or implantable cardioverter-defibrillator, pulmonary edema-related respiratory failure, cardiogenic shock, and rehospitalization due to cardiac events. For every 1 % decline in longitudinal or circumferential strain, the hazard ratios (95 % CIs) were 1.26 (1.10-1.47) and 1.34 (1.14-1.63), respectively; for every 0.1 s(-1) decline in longitudinal or circumferential strain rate, the hazard ratios (95 % CIs) were 1.43 (1.09-1.89) and 1.52 (1.19-2.01), respectively (P < .01). Kaplan-Meier curve and log-rank test showed event-free survival significantly related to these 4 measurements. In acute myocarditis, left ventricular strain and strain rate may be promising diagnostic and prognostic tools, even in patients with preserved left ventricular ejection fraction. Most importantly, this imaging technique had a role in predicting deterioration and overall event-free survival.
Dengue hemorrhagic fever is characterized by the presence of a capillary leak syndrome. Its pathogenesis is presumed to differ from that of classical dengue fever (DF) and to be associated with secondary dengue infection. Returning travelers given a diagnosis of DF were evaluated for capillary leakage with abdominal sonography. Data were compared between travelers with primary/secondary infection defined by epidemiologic and serologic parameters. A total of 12 (34.3%) of 35 patients had sonographic signs of capillary leakage. Most (85%) patients with capillary leakage had classical DF. Capillary leak was diagnosed in 32% of primary dengue cases and in 40% of secondary dengue cases (P = 0.69). The two patients given a diagnosis of dengue hemorrhagic fever had primary infections. The high prevalence of capillary leakage among travelers, most of them with primary exposure to dengue, calls into question the importance of secondary infection in causing capillary leakage in dengue infection.
Myocarditis is an underdiagnosed cause of acute heart failure, sudden death, and chronic dilated cardiomyopathy. In developed countries, viral infections commonly cause myocarditis; however, in the developing world, rheumatic carditis, Trypanosoma cruzi, and bacterial infections such as diphtheria still contribute to the global burden of the disease. The short-term prognosis of acute myocarditis is usually good, but varies widely by cause. Those patients who initially recover might develop recurrent dilated cardiomyopathy and heart failure, sometimes years later. Because myocarditis presents with non-specific symptoms including chest pain, dyspnoea, and palpitations, it often mimics more common disorders such as coronary artery disease. In some patients, cardiac MRI and endomyocardial biopsy can help identify myocarditis, predict risk of cardiovascular events, and guide treatment. Finding effective therapies has been challenging because the pathogenesis of chronic dilated cardiomyopathy after viral myocarditis is complex and determined by host and viral genetics as well as environmental factors. Findings from recent clinical trials suggest that some patients with chronic inflammatory cardiomyopathy have a progressive clinical course despite standard medical care and might improve with a short course of immunosuppression.
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.
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
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.
None.
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.
Patients with severe dengue have evidence of systolic and diastolic cardiac impairment with septal and right ventricular wall being predominantly affected.
In 2009, an outbreak of dengue caused high fatality in Sri Lanka. We conducted 5 autopsies of clinically suspected myocarditis cases at the General Hospital, Peradeniya to describe the histopathology of the heart and other organs.
The diagnosis of dengue was confirmed with specific IgM and IgG ELISA, HAI and RT-PCR techniques. The histology was done in tissue sections stained with hematoxylin and eosin.
Of the 319 cases of dengue fever, 166(52%) had severe infection. Of them, 149 patients (90%) had secondary dengue infection and in 5 patients, DEN-1 was identified as the causative serotype. The clinical diagnosis of myocarditis was considered in 45(27%) patients. The autopsies were done in 5 patients who succumbed to shock (3 females and 2 males) aged 13- 31 years. All had pleural effusions, ascites, bleeding patches in tissue planes and histological evidence of myocarditis. The main histological findings of the heart were interstitial oedema with inflammatory cell infiltration and necrosis of myocardial fibers. One patient had pericarditis. The concurrent pulmonary abnormalities were septal congestion, pulmonary haemorrhage and diffuse alveolar damage; one case showed massive necrosis of liver.
The histology supports occurrence of myocarditis in dengue infection.
UNLABELLED: / BACKGROUND: Dengue is the most important arthropod borne viral disease worldwide in terms of morbidity and mortality and is caused by any of the four serotypes of dengue virus (DENV-1 to 4). Brazil is responsible for approximately 80% of dengue cases in the Americas, and since the introduction of dengue in 1986, a total of 5,944,270 cases have been reported including 21,596 dengue hemorrhagic fever and 874 fatal cases. DENV can infect many cell types and cause diverse clinical and pathological effects. The goal of the study was to investigate the usefulness of NS1 capture tests as an alternative tool to detect DENV in tissue specimens from previously confirmed dengue fatal cases (n = 23) that occurred in 2002 in Brazil. METHODOLOGY/PRINCIPAL FINDINGS: A total of 74 tissue specimens were available: liver (n = 23), lung (n = 14), kidney (n = 04), brain (n = 10), heart (n = 02), skin (n = 01), spleen (n = 15), thymus (n = 03) and lymph nodes (n = 02). We evaluated three tests for NS1 antigen capture: first generation Dengue Early ELISA (PanBio Diagnostics), Platelia NS1 (BioRad Laboratories) and the rapid test NS1 Ag Strip (BioRad Laboratories). The overall dengue fatal case diagnosis based on the tissues analyzed by Dengue Early ELISA, Platelia NS1 and the NS1 Ag Strip was 34.7% (08/23), 60.8% (14/23) and 91.3% (21/23), respectively. The Dengue Early ELISA detected NS1 in 22.9% (17/74) of the specimens analyzed and the Platelia NS1 in 45.9% (34/74). The highest sensitivity (78.3%; 58/74) was achieved by the NS1 Ag Strip, and the differences in the sensitivities were statistically significant (p
Most of the effects of statins can be explained by pleiotropic effects independent of their lowering of serum cholesterol; in some cases, these effects have been shown to be a result of the role of statins in the prenylation of cellular proteins, some of which are involved in the life cycle of animal viruses. This study evaluated the potential antiviral activity of lovastatin (LOV) against dengue virus (DENV) infection of epithelial and endothelial cells (VERO cells, epithelial cells derived from African green monkey kidney, and HMEC-1 cells, human dermal microvascular endothelial cells).
To evaluate its potential antiviral effects, LOV was used before, during and after inoculation of cell cultures with DENV.
Before and after viral inoculation, LOV caused a reduction in virus yield (80% for HMECs and 25% for VERO cells). However, with LOV treatment after inoculation induced a marked increase (2- to 9-fold) in viral-positive RNA while the amount of viral protein increased only by 13-23%. A moderate reduction (1 log unit) in viral titer occurred concurrent with the increase in DENV genomic RNA and protein within the cells.
According to our results, LOV appears to have a greater effect on viral assembly than on replication, resulting in the cellular presence of viral genomic RNA and proteins that fail to take the normal assembly pathway.
Dengue infections pose a huge burden to health care providers in most tropical countries. Careful clinical examination and history-taking supplemented by newer rapid diagnostic tests may lead to early etiological diagnosis. For severe dengue, early recognition of vascular permeability followed by rapid physiological replacement of fluids is life-saving. Prognosis of patients depends upon optimum management, an outcome that requires preparation via organization, training, and use of evidence-based practice guidelines.
Dengue infections are increasing at an alarming rate in many tropical and subtropical countries, where epidemics can put health care systems under extreme pressure. The more severe infections lead to dengue hemorrhagic fever (DHF), which can be life threatening. A variety of viral and host factors have been associated with the severity of dengue infections. Because secondary dengue infection is more commonly associated with DHF than primary infections, the acquired immune response to dengue, both B cells and T cells have been implicated. In this study, we set out to study T-cell responses across the entire dengue virus proteome and to see whether these were related to disease severity in a cohort of dengue-infected children from Thailand. Robust responses were observed in most infected individuals against most viral proteins. Responses to NS3 were the most frequent, and there was a very strong association between the magnitude of the response and disease severity. Furthermore, in DHF, cytokine-high CD107a-negative cells predominated.
There is currently no licensed antiviral drug for treatment of dengue. Chloroquine (CQ) inhibits the replication of dengue virus (DENV) in vitro.
A double-blind, randomized, placebo-controlled trial of CQ in 307 adults hospitalized for suspected DENV infection was conducted at the Hospital for Tropical Diseases (Ho Chi Minh City, Vietnam) between May 2007 and July 2008. Patients with illness histories of 72 hours or less were randomized to a 3-day course of CQ (n = 153) or placebo (n = 154). Laboratory-confirmation of DENV infection was made in 257 (84%) patients. The primary endpoints were time to resolution of DENV viraemia and time to resolution of DENV NS1 antigenaemia. In patients treated with CQ there was a trend toward a longer duration of DENV viraemia (hazard ratio (HR) = 0.80, 95% CI 0.62-1.05), but we did not find any difference for the time to resolution of NS1 antigenaemia (HR = 1.07, 95% CI 0.76-1.51). Interestingly, CQ was associated with a significant reduction in fever clearance time in the intention-to-treat population (HR = 1.37, 95% CI 1.08-1.74) but not in the per-protocol population. There was also a trend towards a lower incidence of dengue hemorrhagic fever (odds ratio = 0.60, PP 95% CI 0.34-1.04) in patients treated with CQ. Differences in levels of T cell activation or pro- or anti-inflammatory plasma cytokine concentrations between CQ- and placebo-treated patients did not explain the trend towards less dengue hemorrhagic fever in the CQ arm. CQ was associated with significantly more adverse events, primarily vomiting.
CQ does not reduce the durations of viraemia and NS1 antigenaemia in dengue patients. Further trials, with appropriate endpoints, would be required to determine if CQ treatment has any clinical benefit in dengue.
Current Controlled Trials number ISRCTN38002730.
To discuss the techniques currently available to evaluate the microcirculation in critically ill patients. In addition, the most clinically relevant microcirculatory alterations will be discussed.
Review of the literature on methods used to evaluate the microcirculation in humans and on microcirculatory alterations in critically ill patients.
In experimental conditions, shock states have been shown to be associated with a decrease in perfused capillary density and an increase in the heterogeneity of microcirculatory perfusion, with non-perfused capillaries in close vicinity to perfused capillaries. Techniques used to evaluate the microcirculation in humans should take into account the heterogeneity of microvascular perfusion. Microvideoscopic techniques, such as orthogonal polarization spectral (OPS) and sidestream dark field (SDF) imaging, directly evaluate microvascular networks covered by a thin epithelium, such as the sublingual microcirculation. Laser Doppler and tissue O(2) measurements satisfactorily detect global decreases in tissue perfusion but not heterogeneity of microvascular perfusion. These techniques, and in particular laser Doppler and near-infrared spectroscopy, may help to evaluate the dynamic response of the microcirculation to a stress test. In patients with severe sepsis and septic shock, the microcirculation is characterized by a decrease in capillary density and in the proportion of perfused capillaries, together with a blunted response to a vascular occlusion test.
The microcirculation in humans can be evaluated directly by videomicroscopy (OPS/SDF) or indirectly by vascular occlusion tests. Of note, direct videomicroscopic visualization evaluates the actual state of the microcirculation, whereas the vascular occlusion test evaluates microvascular reserve.
Microvascular fluid exchange (flow J(v)) underlies plasma/interstitial fluid (ISF) balance and oedematous swelling. The traditional form of Starling's principle has to be modified in light of insights into the role of ISF pressures and the recognition of the glycocalyx as the semipermeable layer of endothelium. Sum-of-forces evidence and direct observations show that microvascular absorption is transient in most tissues; slight filtration prevails in the steady state, even in venules. This is due in part to the inverse relation between filtration rate and ISF plasma protein concentration; ISF colloid osmotic pressure (COP) rises as J(v) falls. In some specialized regions (e.g. kidney, intestinal mucosa), fluid absorption is sustained by local epithelial secretions, which flush interstitial plasma proteins into the lymphatic system. The low rate of filtration and lymph formation in most tissues can be explained by standing plasma protein gradients within the intercellular cleft of continuous capillaries (glycocalyx model) and around fenestrations. Narrow breaks in the junctional strands of the cleft create high local outward fluid velocities, which cause a disequilibrium between the subglycocalyx space COP and ISF COP. Recent experiments confirm that the effect of ISF COP on J(v) is much less than predicted by the conventional Starling principle, in agreement with modern models. Using a two-pore system model, we also explore how relatively small increases in large pore numbers dramatically increase J(v) during acute inflammation.
Dengue fever is one of the most significant re-emerging tropical diseases, despite our expanding knowledge of the disease, viral tropism is still not known to target heart tissues or muscle.
A prospective pediatric clinical cohort of 102 dengue hemorrhagic fever patients from Colombia, South America, was followed for 1 year. Clinical diagnosis of myocarditis was routinely performed. Electrocardiograph and echocardiograph analysis were performed to confirm those cases. Immunohistochemistry for detection of dengue virus and inflammatory markers was performed on autopsied heart tissue. In vitro studies of human striated skeletal fibers (myotubes) infected with dengue virus were used as a model for myocyte infection. Measurements of intracellular Ca2+ concentration as well as immunodetection of dengue virus and inflammation markers in infected myotubes were performed.
Eleven children with dengue hemorrhagic fever presented with symptoms of myocarditis. Widespread viral infection of the heart, myocardial endothelium, and cardiomyocytes, accompanied by inflammation was observed in 1 fatal case. Immunofluorescence confocal microscopy showed that myotubes were infected by dengue virus and had increased expression of the inflammatory genes and protein IP-10. The infected myotubes also had increases in intracellular Ca2+ concentration.
Vigorous infection of heart tissues in vivo and striated skeletal cells in vitro are demonstrated. Derangements of Ca2+ storage in the infected cells may directly contribute to the presentation of myocarditis in pediatric patients.
The mechanisms underlying the bleeding manifestations and coagulopathy associated with dengue remain unclear, in part because of the focus of much previous work on severe disease without an appropriate comparison group. We describe detailed clinical and laboratory profiles for a large group of children with dengue of all severities, and a group with similar non-dengue febrile illnesses, all followed prospectively from early presentation through to recovery. Among the dengue-infected patients but not the controls, thrombocytopenia, increased partial thromboplastin times and reduced fibrinogen concentrations were apparent from an early stage, and these abnormalities correlated strongly with the severity and timing of vascular leakage but not bleeding. There was little evidence of procoagulant activation. The findings do not support a primary diagnosis of disseminated intravascular coagulation to explain the intrinsic coagulopathy. An alternative biologically plausible hypothesis is discussed.
Vascular leakage is the most serious complication of dengue infection. However, despite considerable progress in understanding the immunological derangements associated with dengue, the pathogenic mechanisms underlying the change in vascular permeability remain unclear. Lack of suitable model systems that manifest permeability characteristics similar to human vascular endothelium has seriously impeded research in this area. Similarly, limited knowledge of the factors regulating intrinsic microvascular permeability in health, together with limited understanding of the alterations seen in disease states in general, has also hampered progress. Fortunately considerable advances have been made in the field of endothelial biology in recent years, especially following appreciation of the crucial role played by the endothelial surface glycocalyx, acting in concert with underlying cellular structures, in regulating fluid flow across the microvasculature. We review what is known about vascular leakage during dengue infections, particularly in relation to current knowledge of vascular physiology, and discuss potential areas of research that may help to elucidate the complex nature of this singular phenomenon in the future.
Loss of vascular barrier function causes leak of fluid and proteins into tissues, extensive leak leads to shock and death. Barriers are largely formed by endothelial cell-cell contacts built up by VE-cadherin and are under the control of RhoGTPases. Here we show that a natural plasmin digest product of fibrin, peptide Bbeta15-42 (also called FX06), significantly reduces vascular leak and mortality in animal models for Dengue shock syndrome. The ability of Bbeta15-42 to preserve endothelial barriers is confirmed in rats i.v.-injected with LPS. In endothelial cells, Bbeta15-42 prevents thrombin-induced stress fiber formation, myosin light chain phosphorylation and RhoA activation. The molecular key for the protective effect of Bbeta15-42 is the src kinase Fyn, which associates with VE-cadherin-containing junctions. Following exposure to Bbeta15-42 Fyn dissociates from VE-cadherin and associates with p190RhoGAP, a known antagonists of RhoA activation. The role of Fyn in transducing effects of Bbeta15-42 is confirmed in Fyn(-/-) mice, where the peptide is unable to reduce LPS-induced lung edema, whereas in wild type littermates the peptide significantly reduces leak. Our results demonstrate a novel function for Bbeta15-42. Formerly mainly considered as a degradation product occurring after fibrin inactivation, it has now to be considered as a signaling molecule. It stabilizes endothelial barriers and thus could be an attractive adjuvant in the treatment of shock.
We performed a case-control study to assess the relationship between vascular endothelial growth factor (VEGF) and its soluble receptors (sVEGFR-1 and 2) in adult patients with dengue fever (DF) and dengue hemorrhagic fever (DHF).
We recruited 60 adult patients (34 DF and 26 DHF) with serologically-confirmed dengue infections, 10 patients with non-hemorrhagic infections, and 31 community-based healthy volunteers. The levels of VEGF, sVEGFR-1, and sVEGFR-2 were measured and the differences in these markers were compared using one-way analysis of variance (ANOVA), which was adjusted for multiple comparisons.
We observed lower VEGF levels in DF and DHF compared to study controls (p<0.01). sVEGFR-1 was higher in DHF than DF, whilst sVEGFR-2 was lower in DF and DHF compared to study controls (all p<0.01). In DHF, lower VEGF levels were observed in older patients. The use of a single marker, sVEGFR-1>350 pg/ml, was predictive of DHF.
The changes in VEGF and its soluble receptors highlight the importance of vascular permeability cytokines in the pathogenesis of DHF.
Cardiac rhythm abnormalities, including ventricular arrhythmia, atrial fibrillation and atrioventricular block, have been observed during the acute stage of dengue haemorrhagic fever. Atrioventricular or complete heart block can be fatal and may require a temporary pacemaker. We report a ten-year-old girl who presented with dengue haemorrhagic fever with sinoatrial block and atrioventricular dissociation that had a spontaneous resolution.
BACKGROUND: Although plasma leakage is the major cause of mortality and morbidity in patients with dengue hemorrhagic fever (DHF), a detailed assessment of the natural course of this process is still lacking. We employed serial ultrasound examination to delineate the locations and the timing of plasma leakage and to evaluate the usefulness of ultrasound in detecting plasma leakage in DHF. METHOD: Daily ultrasound examinations of the abdomen and right thorax were performed in 158 suspected dengue cases to detect ascites, thickened gall bladder wall and pleural effusions. Cases were classified into dengue fever (DF), DHF or other febrile illness (OFI) based on serology and evidence of plasma leakage including hemoconcentration and pleural effusion detected by chest radiograph. RESULTS: Ultrasonographic evidence of plasma leakage was detected in DHF cases starting from 2 days before defervescence and was detected in some cases within 3 days after fever onset. Pleural effusion was the most common ultrasonographic sign of plasma leakage (62% of DHF cases one day after defervescence). Thickening of the gallbladder wall and ascites were detected less frequently (43% and 52% of DHF cases respectively) and resolved more rapidly than pleural effusions. The size of pleural effusions, ascites and gall bladder wall thickness in DHF grade I and II were smaller than those of grade III patients. Ultrasound detected plasma leakage in 12 of 17 DHF cases who did not meet the criteria for significant hemoconcentration. CONCLUSIONS: Ultrasound examinations detected plasma leakage in multiple body compartments around the time of defervescence. Ultrasonographic signs of plasma leakage were detectable before changes in hematocrits. Ultrasound is a useful tool for detecting plasma leakage in dengue infection.
Vascular endothelial growth factor (VEGF) can be produced by monocytes and endothelial cells. It plays important role in angiogenesis and vascular permeability. The phenomenon of extensive plasma leakage into various serous cavities of the body is a cardinal symptom of dengue hemorrhagic fever (DHF). This study was performed to investigate the role of VEGF in patients with DHF. Plasma samples collected from the 53 dengue fever (DF) patients (including 14 patients with DHF), and 5 additional subjects with non-dengue febrile illness as controls were tested for VEGF levels using commercial enzyme-linked immunosorbent assay (ELISA) kits. The results showed that median plasma levels of VEGF in the patients with DHF (54.6 pg ml(-1)) were significantly higher than those of DF (14.6 pg ml(-1)) and control group (27.1 pg ml(-1)) (P < 0.05). In addition, VEGF levels in DF patients were not significantly different from those of control patients with non-dengue febrile illness (P = 0.17). Multiple regression analysis was used to analyze the clinical variables independently associated with VEGF levels. The data showed that D-dimer levels were significantly associated with VEGF levels. In this study, plasma VEGF levels in patients with DHF were significantly higher than values from DF patients. The association between increased plasma VEGF levels and increased plasma D-dimer levels in the patients with dengue illness suggests that activation of the fibrinolytic system may play a role in VEGF production in the patients with DF.
Alterations in microvascular perfusion have been identified in critically ill patients, especially in sepsis but also in cardiogenic shock, after cardiac arrest, and in high risk surgery patients. These alterations seem to be implicated in the development of organ dysfunction and are associated with outcome. Even though microvascular perfusion can sometimes be homogenously decreased as in acute hemorrhage or in non-resuscitated cardiogenic shock, heterogeneity of perfusion is observed in sepsis and in resuscitated hemorrhagic/cardiogenic shock. Heterogeneity of perfusion has major implications for monitoring, as many techniques cannot detect microcirculatory alterations when heterogeneity of flow is present in significant amount. Indeed, devices such as laser Doppler or O2 electrodes and near infrared spectroscopy have a relatively large sampling volume and measurements are affected by the highest values in the field. Using these techniques during a vascular occlusion test may help to characterize microvascular reactivity, however microvascular reactivity sometimes fail to represent actual microvascular perfusion. Videomicroscopic techniques can nowadays be applied at bedside but are still restricted to some selected patients (quiet or sedated patients). Tissue PCO2 is an elegant alternative but is not yet broadly used. In this manuscript we will discuss the main advantages and limitations of the techniques available for bedside evaluation of the microcirculation in critically ill patients.
Hemorrhage is a leading cause of traumatic death. We hypothesized that state-of-the-art feature extraction and machine learning techniques could be used to discover, detect, and continuously trend beat-to-beat changes in arterial pulse waveforms associated with the progression to hemodynamic decompensation.
We exposed 184 healthy humans to progressive central hypovolemia using lower-body negative pressure to the point of hemodynamic decompensation (systolic blood pressure > 80 mm Hg with or without bradycardia). Initial models were developed using continuous noninvasive blood pressure waveform data. The resulting algorithm calculates a compensatory reserve index (CRI), where 1 represents supine normovolemia and 0 represents the circulatory volume at which hemodynamic decompensation occurs (i.e., "running on empty"). Values between 1 and 0 indicate the proportion of reserve remaining before hemodynamic decompensation-much like the fuel gauge of a car indicates the amount of fuel remaining in the tank. A CRI estimate is produced after the first 30 heart beats, followed by a new CRI estimate after each subsequent beat.
The CRI model with a 30-beat window has an absolute difference between actual and expected time to decompensation of 0.1, with a SD of 0.09. The model distinguishes individuals with low tolerance to reduced central blood volume (i.e., those most likely to develop early shock) from those with high tolerance and are able to estimate how near or far an individual may be from hemodynamic decompensation.
Machine modeling can quickly and accurately detect and trend central blood volume reduction in real time during the compensatory phase of hemorrhage as well as estimate when an individual is "running on empty" and will decompensate (CRI, 0), well in advance of meaningful changes in traditional vital signs.
In Myanmar, dengue fever (DF)/dengue hemorrhagic fever (DHF) is one of the leading causes of morbidity and mortality among children. From Pyinmana Hospital in 2004 and Mandalay Children Hospital in 2006, 160 patients diagnosed clinically to have DHF/dengue shock syndrome (DSS) were examined for immunoglobulin M (IgM) and IgG levels. A focus reduction neutralization test was also used to determine primary or secondary dengue virus (DENV) infection. By using IgM-capture ELISA, 139 cases were confirmed as DENV infections. Of these IgM-positives, 94 samples were collected 7-24 days from the onset of illness, to which 13 (14%) and 81 (86%) were determined to be primary and secondary DENV infections, respectively. The 13 primary DENV infection cases were spread among the various severity groups (DHF grade I-IV and DSS) and represented age groups ranging from <1 year of age to 9 years of age. The patients in these primary infection cases showed a remarkably high IgM with a low IgG titer response compared with the secondary infection cases. No significant differences were observed in IgG titers with clinical severity. The data obtained in this study suggest that primary DENV infection cases exist certainly among DHF/DSS cases in Myanmar, and that additional mechanism(s) aside from the antibody-dependent enhancement mechanism could have influenced the clinical severity in DHF/DSS cases. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
Background
Dengue fever accounts for significant mortality in developing countries. Dengue fever serology takes a week at least to be reported positive, thus necessitating the need for other markers of diagnosis and prognosis.
Objective
The purpose of this study was to investigate the role of ultrasonography as a tool in diagnosing and predicting the severity of dengue fever in children.
Materials and methods
This was a prospective study conducted in a tertiary pediatric centre from September 2010 to July 2012. Three hundred twenty-four children with confirmed dengue fever were compared with 422 children of suspected dengue fever. Severity of illness was graded as per WHO criteria and sonography findings were correlated to the grade of illness.
Results
Gallbladder wall thickening was seen in 75% of the children with confirmed dengue fever. A significant difference was seen between survivors and non-survivors with respect to pericholecystic fluid collection (P = 0.002), hepatic intraparenchymal fluid (P < 0.001), splenomegaly (P = 0.002), splenic subcapsular fluid (P < 0.001), peripancreatic fluid (P < 0.001), perirenal fluid (P < 0.001) and pericardial fluid (P < 0.001). Other findings included ascites, pleural effusion, hepatomegaly and splenomegaly, which were present irrespective of grade of illness.
Conclusions
Ultrasonography can be used as a useful tool in developing countries to predict the severity of dengue fever in children.
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.
The authors report two cases of complicated dengue viral infection with acute myocarditis involving young male adults, of which one was fatal. The first case presented with typical signs of myocardial disease: chest pain and diaphoresis with myocardial depression in the electrocardiograph. The second case deteriorated rapidly and demised within the first day of admission. Histology of the heart muscles showed multiple small foci of myocyte necrosis surrounded by lymphocytes, in keeping with viral myocarditis. Both cases fulfilled the World Health Organization (WHO) diagnosis of probable dengue: the first case had positive dengue serology, both IgM and IgG at day six of illness, and the second case was polymerase chain reaction (PCR) positive for dengue and identified as serotype 2. Despite the severe outcome, both cases did not completely fulfil the criteria for dengue haemorrhagic fever (DHF). Although severe cardiac impairment is not commonly reported in dengue infection, it can be life threatening.
Dengue hemorrhagic fever is characterized by a unique vascular leakage syndrome. The mechanisms of endothelial barrier dysfunction in dengue hemorrhagic fever are not well understood. We examined the modulation of endothelial barrier function in dengue virus type 2 (DENV2) infections using primary human umbilical vein endothelial cells. We demonstrated that the increase in endothelial barrier function within 72ours after DENV2 infection is mediated by type I interferon-dependent CD73 up-regulation. After 72 hours, DENV2 slowed the recovery of endothelial barrier function in response to tumor necrosis factor-α or vascular endothelial growth factor. This phenomenon was likely caused by type I interferon receptor signaling inhibition and lower CD73 levels in DENV2-infected endothelial cells. Our findings suggest that during DENV2 infection, endothelial barrier homeostasis is maintained by a balance between pro-inflammatory and pro-angiogenic cytokines, and type I interferon-dependent CD73 expression and activity.
Adhesion molecules are essential for the immune response. They are involved in the regulation of cell-to-cell contact, thereby enabling leukocytes to communicate. Circulating forms of adhesion molecules are found in the serum of healthy individuals. Raised levels have been associated with disease severity in HCV and other infections and thus appear to be good markers of endothelial damage. The levels of soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) and of sP and sL-selectin in the plasma of children hospitalised for dengue in French Polynesia were monitored. Studies from the 1996/1997 dengue-2 outbreak, showed that levels of sVCAM-1 increase steadily during the febrile period, peak on day 7, and then decline relatively rapidly. Disregarding the time frame within the febrile period, sVCAM-1 levels were always higher compared to controls. There was a significant association between sVCAM-1 levels and dengue haemorrhagic fever, a severe manifestation of dengue virus infection characterised by plasma leakage. No association was apparent between sVCAM-1 levels and primary vs. secondary dengue virus infections. Levels of sP-selectin and sL-selectin were significantly higher in primary compared with secondary infection but were not different in patients presenting with plasma leakage. Lastly, sVCAM-1 levels were significantly higher in an outbreak of severe disease in 1989/1990 (dengue-3) when compared to a non-severe outbreak in 1988/1989 (dengue-1) and a mild outbreak in 1996/1997 (dengue-2). The results suggested that levels of sVCAM-1 production might prove to be a useful marker in the management of severe dengue. J. Med. Virol. 65:97–104, 2001. © 2001 Wiley-Liss, Inc.
To determine the frequency and spectrum of myocardial dysfunction in patients with severe sepsis and septic shock using transthoracic echocardiography and to evaluate the impact of the myocardial dysfunction types on mortality.
A prospective study of 106 patients with severe sepsis or septic shock was conducted from August 1, 2007, to January 31, 2009. All patients underwent transthoracic echocardiography within 24 hours of admission to the intensive care unit. Myocardial dysfunction was classified as left ventricular (LV) diastolic, LV systolic, and right ventricular (RV) dysfunction. Frequency of myocardial dysfunction was calculated, and demographic, hemodynamic, and physiologic variables and mortality were compared between the myocardial dysfunction types and patients without cardiac dysfunction.
The frequency of myocardial dysfunction in patients with severe sepsis or septic shock was 64% (n=68). Left ventricular diastolic dysfunction was present in 39 patients (37%), LV systolic dysfunction in 29 (27%), and RV dysfunction in 33 (31%). There was significant overlap. The 30-day and 1-year mortality rates were 36% and 57%, respectively. There was no difference in mortality between patients with normal myocardial function and those with left, right, or any ventricular dysfunction.
Myocardial dysfunction is frequent in patients with severe sepsis or septic shock and has a wide spectrum including LV diastolic, LV systolic, and RV dysfunction types. Although evaluation for the presence and type of myocardial dysfunction is important for tailoring specific therapy, its presence in patients with severe sepsis and septic shock was not associated with increased 30-day or 1-year mortality.
There are an estimated 50 million infections per year with the dengue virus, which is transmitted primarily by urban-adapted Aedes aegypti mosquitoes. This review summarizes pathophysiology and treatment as well as prospects for a vaccine and for vector-control approaches.
The current treatment for dengue hemorrhagic fever largely consists of supportive care. The drug pentoxifylline has been shown to blunt the proinflammatory actions of tumor necrosis factor-α, a key mediator of dengue hemorrhagic fever. We performed a pilot study evaluating pentoxifylline's effect on 55 children with dengue hemorrhagic fever. We believe our findings support the existing literature on its potential use in severe infection.
Myocarditis is an inflammatory disease of the heart frequently resulting from viral infections and/or post-viral immune-mediated responses. It is one of the important causes of dilated cardiomyopathy worldwide. The diagnosis is presumed on clinical presentation and noninvasive diagnostic methods such as cardiovascular magnetic resonance imaging. Endomyocardial biopsy remains the gold standard for in vivo diagnosis of myocarditis. The therapeutic and prognostic benefits of endomyocardial biopsy results have recently been demonstrated in several clinical trials. Although remarkable advances in diagnosis, understanding of pathophysiological mechanisms, and treatment of acute myocarditis were gained during the last years, no standard treatment strategies could be defined as yet, apart from standard heart failure therapy and physical rest. In severe cases, mechanical support or heart transplantation may become necessary. There is some evidence that immunosuppressive and immunomodulating therapy are effective for chronic, virus-negative inflammatory cardiomyopathy. Further investigations by controlled, randomized studies are needed to definitively determine their role in the treatment of myocarditis.
Endothelial cells are covered with a polysaccharide rich layer more than 400 nm thick, mechanical properties of which limit access of circulating plasma components to endothelial cell membranes. The barrier properties of this endothelial surface layer are deduced from the rate of tracer penetration into the layer and the mechanics of red and white cell movement through capillary microvessels. This review compares the mechanosensor and permeability properties of an inner layer (100-150 nm, close to the endothelial membrane) characterized as a quasi-periodic structure which accounts for key aspects of transvascular exchange and vascular permeability with those of the whole endothelial surface layers. We conclude that many of the barrier properties of the whole surface layer are not representative of the primary fiber matrix forming the molecular filter determining transvascular exchange. The differences between the properties of the whole layer and the inner glycocalyx structures likely reflect dynamic aspects of the endothelial surface layer including tracer binding to specific components, synthesis and degradation of key components, activation of signaling pathways in the endothelial cells when components of the surface layer are lost or degraded, and the spatial distribution of adhesion proteins in microdomains of the endothelial cell membrane.
A 63-year-old woman was admitted for acute chest pain and asthenia worsening for one week. Clinical examination was normal. ECG revealed widespread T waves depression. Echocardiography, cardiac MR-scan, biological examinations and coronary angiogram were normal except positive dengue fever serologies. She had suffered from dengue fever recently. Clinical and ECG outcomes were good under treatment. Cardiac complications are scarce in case of dengue fever. In this case report, clinical and especially ECG presentation are typical of acute pericarditis. This pericarditis is due to dengue fever.
Various minor cardiac rhythm abnormalities have been reported in patients with dengue virus infection. Previous studies have used only random electrocardiograms (ECG) to assess the incidence of cardiac arrhythmias, and the time when the ECGs were undertaken was not systematically defined.
To evaluate cardiac arrhythmias and heart rate variability in children with dengue virus infection during the convalescent stage using Holter monitoring.
Overnight 18-24-hour Holter monitoring was performed in 35 children [mean (SD) age 11·7 (2·3) y] at least 24 hours after defervescence (on the last day of admission). In 17 patients, time- and frequency-domain short-term (5 minutes) heart rate variability (HRV) during the convalescent stage was also compared with the value obtained during the follow-up visit (at least 14 days after defervescence).
During the convalescent stage, cardiac rhythm abnormalities were found in ten patients (29%), including sinus pause (1), first-degree (2) and Mobitz type I second-degree AV block (Wenckebach) (3) and atrial (4) and ventricular ectopic beats (5). There was no relationship between the clinical severity of dengue virus infection (DF, DHF without shock and DSS) and the incidence of cardiac arrhythmia. There was no significant difference in the averaged RR interval, the time-domain HRV (SDNN, RMSSD, pNN 50) or frequency-domain HRV (LF, HF, LF/HF ratio) between the convalescent stage and at follow-up.
Various benign bradyarrhythmias and ectopic beats are detected in patients with dengue virus infection during the convalescent stage.
The morbidity and mortality resulting from dengue hemorrhagic fever (DHF) are largely caused by endothelial barrier dysfunction and a unique vascular leakage syndrome. The mechanisms that lead to the location and timing of vascular leakage in DHF are poorly understood. We hypothesized that direct viral effects on endothelial responsiveness to inflammatory and angiogenesis mediators can explain the DHF vascular leakage syndrome.
We used an in vitro model of human endothelium to study the combined effects of dengue virus (DENV) type 2 (DENV2) infection and inflammatory mediators on paracellular macromolecule permeability over time.
Over the initial 72 h after infection, DENV2 suppressed tumor necrosis factor (TNF)-alpha-mediated hyperpermeability in human umbilical vein endothelial cell (HUVEC) monolayers. This suppressive effect was mediated by type I interferon (IFN). By 1 week, TNF-alpha stimulation of DENV2-infected HUVECs synergistically increased cell cycling, angiogenic changes, and macromolecule permeability. This late effect could be prevented by the addition of exogenous type I IFN.
DENV infection of primary human endothelial cells differentially modulates TNF-alpha-driven angiogenesis and hyperpermeability over time. Type I IFN plays a central role in this process. Our findings suggest a rational model for the DHF vascular leakage syndrome.
To compare the clinical and laboratory characteristics and disease severity between adults and children with dengue in Taiwan in 2002, we retrospectively studied 661 serologically confirmed dengue-infected patients (606 adults and 55 children) admitted between June and December 2002 to a single medical centre. The medical charts of the patients were reviewed for demographic, clinical, laboratory and imaging information. Compared with children, adult patients were found to have: higher incidences of arthralgia (P<0.001), myalgia (P=0.002), headache (P=0.028), abdominal pain (P=0.004) and upper gastrointestinal bleeding (P=0.013); lower platelet counts (P<0.001), prothrombin time (P=0.030) and serum albumin levels (P=0.037); a higher incidence of elevated alanine aminotransferase levels (P=0.001); and a higher prevalence of dengue haemorrhagic fever (DHF) (14.4% vs. 3.6%; P=0.026). The current data showed differences in clinical manifestations and laboratory characteristics between children and adults with dengue virus infection. Notably, a higher incidence of DHF was observed in adult patients compared with children in the 2002 dengue epidemic in Taiwan.
Dengue virus can infect many cell types from the vascular, muscular and hematological systems causing diverse clinical and pathological signs. The purpose of the present study was to investigate by different diagnostic methods dengue virus in human tissue specimens obtained from fatal cases (n=29) during a large-scale dengue fever epidemic in 2002 in the State of Rio de Janeiro, Brazil. The combination of four procedures provided diagnostic confirmation of DENV-3 infection in 26 (89.6%) out of the 29 suspected fatal cases. Dengue virus (DENV) was isolated from 2/74 (2.7%) tissue samples, inoculated into C6/36 cells and identified as DENV-3, nested RT-PCR accusing 22/72 (30.5%) samples as DENV-3. Real-time RT-PCR yielded the highest positivity rate, detecting viral RNA in 45/77 (58.4%) clinical specimens, including the liver (n=18), lung (n=8), spleen (n=8), brain (n=6), kidney (n=3), bone marrow (n=1) and heart (n=1). Immunohistochemical tests recognized the DENV antigen in 26/59 (44%) specimens. Given the accuracy and effectiveness of real-time RT-PCR in this investigation, this approach may play an important role for rapid diagnosis of dengue infections.