[Show abstract][Hide abstract] ABSTRACT: Although in the majority of cases dengue virus (DENV) infection results in a self-limiting febrile disease, it can cause severe plasma leakage in a minority of patients. The appearance of plasma leakage indicates an increased permeability of the vascular wall. In this study we investigated if DENV infection can lead to leakage of lipopolysaccharide (LPS) from the intestine into the blood of the patient, indicative of an increased permeability of the intestinal mucosal barrier.
The aim of this study was to investigate if LPS levels were elevated in DENV infected patients and if these levels correlated with disease severity.
LPS levels in the blood of DENV infected children were determined using the Limulus Amebocyte Lysate assay. To determine disease severity we used the 1997-WHO criteria, the expert physician's judgement and a score that focused on plasma leakage in particular. Furthermore, the modulatory factors LPS binding protein (LBP) and sCD14, as well as the immune activation marker neopterin were determined.
We showed significantly elevated LPS levels in plasma of DENV infected children compared to healthy controls. The plasma leakage severity score had the strongest correlation with levels of LPS. LBP, sCD14 and neopterin were elevated compared to healthy controls.
In this study we show evidence of elevated LPS levels during DENV infection. Moreover, a correlation between LPS levels and disease severity was found, especially when disease severity was determined in terms of plasma leakage.
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 01/2012; 53(1):38-42. DOI:10.1016/j.jcv.2011.09.028 · 3.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Platelet microparticles are the most abundant cell-derived microparticle subtype in the circulation. Yet the mechanism by which platelet microparticles are formed is poorly defined. This review highlights the concept of the generation of microparticles from platelets and their precursor cells, megakaryocytes. Special emphasis is placed on the mechanisms of microparticle formation and novel functions for microparticles in normal physiology and disease states.
Seminars in Thrombosis and Hemostasis 11/2010; 36(8):881-7. DOI:10.1055/s-0030-1267042 · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Platelet microparticles were identified more than 40 years ago and are the most abundant circulating microparticle subtype. Yet fundamental questions about their formation and role in human disease are just beginning to be understood at the cellular and molecular level. This review will address mechanisms of platelet microparticle generation and evaluate our current understanding of their clinical relevance.
New evidence indicates that the majority of CD41 microparticles circulating in healthy individuals derive directly from megakaryocytes. CD41 microparticles also form from activated platelets upon loss of cytoskeleton-membrane adhesion, which occurs in a multitude of disease states characterized by elevated platelet microparticle levels. More recent studies have demonstrated that platelet microparticles function as a transport and delivery system for bioactive molecules, participating in hemostasis and thrombosis, inflammation, malignancy infection transfer, angiogenesis, and immunity. The mechanism of platelet microparticle participation in specific disease entities such as rheumatoid arthritis has been elucidated.
Continued research into how platelet microparticles are generated and function as a transcellular delivery system will advance our basic understanding of microparticle physiology and may enable new strategies for treatment of select disease entities.
Current opinion in hematology 11/2010; 17(6):578-84. DOI:10.1097/MOH.0b013e32833e77ee · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inter-alpha inhibitor proteins (IaIp) belong to a family of protease inhibitors that are involved in the haemostatic and the vascular system. Dengue viruses (DENV) infections are characterized by coagulopathy and increased vascular permeability. In this study we measured the concentration of IaIp during DENV infections and evaluated its potential as a biomarker.
Concentrations of IaIp were measured in patients with acute DENV infections using a quantitative, competitive enzyme linked immunoassay. Concentrations of IaIp measured in pediatric patients suffering from severe DENV infections were significantly lower than in healthy controls.
This is the first report to demonstrate changes in concentration of IaIp during viral infections. The data also highlight the potential of IaIp as a biological marker for severity of DENV infections.
PLoS ONE 04/2010; 5(4):e9967. DOI:10.1371/journal.pone.0009967 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Inter-α inhibitor proteins (IaIp) belong to a family of protease inhibitors that are involved in the haemostatic and the vascular system. Dengue viruses (DENV) infections are characterized by coagulopathy and increased vascular permeability. In this study we measured the concentration of IaIp during DENV infections and evaluated its potential as a biomarker. Methods and Findings: Concentrations of IaIp were measured in patients with acute DENV infections using a quantitative, competitive enzyme linked immunoassay. Concentrations of IaIp measured in pediatric patients suffering from severe DENV infections were significantly lower than in healthy controls. Conclusions: This is the first report to demonstrate changes in concentration of IaIp during viral infections. The data also highlight the potential of IaIp as a biological marker for severity of DENV infections.
PLoS ONE 01/2010; 5(4). DOI:10.1371/journal.pone.0009967.t002 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dengue disease severity is usually classified using criteria set up by the World Health Organization (WHO). We aimed to assess the diagnostic accuracy of the WHO classification system and modifications to this system, and evaluated their potential practical usefulness.
Patients, admitted consecutively to the hospital with severe dengue, were classified using the WHO classification system and modifications to this system. Treating physicians were asked to classify patients immediately after discharge. We calculated the sensitivity of the various classification systems for the detection of shock and the agreement between the various classification systems and the treating physician's classification.
Of 152 patients with confirmed dengue, sixty-six (43%) had evidence of circulatory failure. The WHO classification system had a sensitivity of 86% (95%CI 76-94) for the detection of patients with shock. All modifications to the WHO classification system had a higher sensitivity than the WHO classification system (sensitivity ranging from 88% to 99%). The WHO classification system was in only modest agreement with the intuitive classification by treating physicians whereas several modified classification systems were in good agreement.
The use of the WHO classification system to classify dengue disease severity is to be questioned, because it is not accurate in correctly classifying dengue disease severity and it lacks sufficient agreement with clinical practice.
[Show abstract][Hide abstract] ABSTRACT: Leptospirosis is a zoonosis of worldwide distribution, spread by the urine of infected animals. It is a major public health problem, especially in developing countries, where circumstances for transmission are most favourable. The clinical picture varies from mild disease to a severe illness with haemostatic derangements and multiorgan failure eventually leading to death. Although the haemorrhagic complications of severe disease are serious, the pathophysiology is scarcely elucidated. The complex mechanisms involved in inflammation-induced coagulation activation are extensively studied in various infectious diseases, i.e. Gram-negative sepsis. Tissue factor-mediated coagulation activation, impairment of anticoagulant and fibrinolytic pathways in close concert with the cytokine network are thought to be important. But for human leptospirosis, data are limited. Because of the growing interest in this field, the impact of leptospirosis, and the availability of new therapeutic strategies, we reviewed the evidence regarding the role of coagulation in leptospirosis and provide suggestions for future research.
Tropical Medicine & International Health 02/2007; 12(1):111-22. DOI:10.1111/j.1365-3156.2006.01792.x · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dengue fever (DF)/dengue haemorrhagic fever (DHF) is a growing public health problem in the subtropics. Dengue was first reported in Indonesia in 1968 and since then the number of reports in the literature and the number of dengue virus (DENV)-infected cases reported by the Indonesian health authorities have increased. This review addresses the changing epidemiology of dengue in Indonesia by means of a chronological overview. Over time, the morbidity and mortality of dengue disease have increased and DHF epidemics occur throughout all the 29 provinces. The outbreak trend of DHF in the country has become irregular, with a high inter-epidemic background. All dengue serotypes are circulating, although severe disease is predominantly attributed to DENV-3. The case-fatality rate is dropping over time, probably reflecting increased awareness and improved treatment protocols. An increasing percentage of adolescents and adults develop DHF relatively earlier in the course of the disease, compared with the days when DHF was considered a primarily paediatric illness. Many inter-related factors such as environmental, biological and demographic issues influence dengue epidemiology and transmission.
[Show abstract][Hide abstract] ABSTRACT: Dengue virus infected patients have high plasminogen activator inhibitor type I (PAI-1) plasma concentrations. Whether the insertion/deletion (4G/5G) polymorphism in the promotor region of the PAI-1 gene is associated with increased PAI-1 plasma concentrations and with death from dengue is unknown. We, therefore, investigated the relationship between the 4G/5G polymorphism and PAI-1 plasma concentrations in dengue patients and risk of death from dengue.
A total of 194 patients admitted to the Dr. Kariadi Hospital in Semarang, Indonesia, with clinical suspected severe dengue virus infection were enrolled. Blood samples were obtained on day of admission, days 1, 2 and 7 after admission and at a 1-month follow-up visit. Plasma concentrations of PAI-1 were measured using a sandwich ELISA kit. The PAI-1 4G/5G polymorphism was typed by allele-specific PCR analysis.
Concentrations of PAI-1 on admission and peak values of PAI-1 during admission were higher than the values measured in healthy controls. Survival was significantly worse in patients with PAI-1 concentrations in the highest tertile (at admission: OR 4.7 [95% CI 0.9-23.8], peak value during admission: OR 6.3 [95%CI 1.3-30.8]). No association was found between the PAI-1 4G/5G polymorphism, and PAI-1 plasma concentrations, dengue disease severity and mortality from dengue.
These data suggest that the 4G/5G polymorphism has no significant influence on PAI-1 concentrations in dengue virus infected patients and is not associated with the risk of death from dengue. Other factors contributing to the variability of PAI-1 plasma concentrations in patients with dengue need to be explored.
[Show abstract][Hide abstract] ABSTRACT: To develop a population pharmacokinetic model for lopinavir in combination with ritonavir, in which the interaction between both drugs was characterized, and in which relationships between patient characteristics and pharmacokinetics were identified.
The pharmacokinetics of lopinavir in combination with ritonavir were described using NONMEM (version V, level 1.1). First, ritonavir data were fitted to a previously developed model to obtain individual Bayesian estimates of pharmacokinetic parameters. Hereafter, an integrated model for the description of the pharmacokinetics of lopinavir with ritonavir was designed.
From 122 outpatients 748 lopinavir and 748 ritonavir plasma concentrations were available for analysis. The interaction between the drugs was described by a time-independent inverse relationship between the exposure to ritonavir over a dosing-interval and the apparent clearance (CL/F) of lopinavir. The model parameters volume of distribution and absorption rate constant were 61.6 l (95% prediction interval (PI) 22.4, 83.7) and 0.564 h(-1) (95% PI 0.208, 0.947), respectively. The model yielded a theoretical value for the CL/F of lopinavir without ritonavir of 14.8 l h(-1) (95%PI 12.1, 20.1), which translates to a value of 5.73 l h(-1) in the presence of ritonavir. The only factor with significant effect on the pharmacokinetics was concurrent use of non-nucleoside reverse transcriptase inhibitors (NNRTI), which increased the CL/F of lopinavir by 39% (P < 0.001).
We have developed a model that has defined a time-independent inverse relationship between the exposure to ritonavir and the CL/F of lopinavir, and provided an adequate description of the pharmacokinetic parameters for the latter. Concomitant use of the NNRTIs efavirenz and nevirapine increased the CL/F of lopinavir.
British Journal of Clinical Pharmacology 10/2005; 60(4):378-89. DOI:10.1111/j.1365-2125.2005.02455.x · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have investigated the pharmacokinetics of nevirapine and paclitaxel in a patient who used both drugs concomitantly, as there are strong theoretical indications for a potential pharmacokinetic drug-drug interaction. Plasma concentrations of nevirapine (dose: 200 mg twice daily orally) and paclitaxel (dose: 100 mg/m(2) 3-h i.v. infusion) were determined in a HIV-1-infected patient with Kaposi's sarcoma. Since both drugs are metabolized via the same cytochrome P450 isoenzymes, investigation of a drug-drug interaction was considered important. We found that the plasma concentrations of nevirapine given together with paclitaxel were similar to those given without paclitaxel. The exposures to paclitaxel (AUC(0-infinity) = 3787 h.ng/ml) and its hydroxy metabolites when co-administered with nevirapine were comparable to the mean exposure to paclitaxel and its metabolites from eight historical controls (AUC(0-infinity) = 3614 h.ng/ml) treated with the same dose. No pharmacokinetic drug-drug interaction between nevirapine and paclitaxel could be demonstrated in our HIV-1-infected patient.
[Show abstract][Hide abstract] ABSTRACT: C-reactive protein is one of the most widely used indicators of the response of acute-phase proteins. The measurement of C-reactive protein in dengue, however, is clinically not useful, because of marginally elevated levels and absent association with disease severity. The prototypic long pentraxin, pentraxin 3, is an acute phase protein that is structurally related but distinct from C-reactive protein which has proven to correlate with the severity of bacterial infection in critically ill patients. The potential involvement of pentraxin 3 in dengue and its aptitude to predict more severe disease or poor clinical outcome has not been studied previously. We therefore measured pentraxin 3 plasma levels in 44 dengue virus infected patients. Pentraxin 3 levels were strikingly higher when compared to C-reactive protein levels, with highest pentraxin 3 values observed in the first 7 days after the onset of symptoms. Median pentraxin 3 levels at admission and peak levels during follow up were higher in patients suffering from dengue shock syndrome (at admission: 119.3 ng/ml [interquartile range 61.8--188.7], peak values during follow up: 147.9 ng/ml [interquartile range 85.7--204.3]) compared to levels found in patients with dengue fever and dengue hemorrhagic fever (at admission: 59.0 ng/ml [interquartile range 28.6--100.3], P=0.040; peak values during follow up: 80.8 ng/ml [interquartile range 36.1--168.1], P=0.020). Our results indicate that pentraxin 3 seems to be a marker of infection better than C-reactive protein in dengue. The role of pentraxin 3 in the pathogenesis of dengue and its potential as an early prognostic indicator of disease severity needs further assessment.
Journal of Medical Virology 08/2005; 76(4):547-52. DOI:10.1002/jmv.20397 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epidemiological research indicates a correlation between respiratory-tract infections and acute cardiovascular events. Chronic infections have been linked to the development of atherosclerosis. As a result of chronic infections a prolonged and elevated inflammatory activity arises. Inflammation and the associated vessel-wall damage play an important role in the pathophysiology of atherosclerosis. Acute infections have been linked to a transient increased risk of unstable angina pectoris and an acute myocardial infarct. The consequence of acute infections is a systemic inflammatory response which results in changes in the atherosclerotic plaque, thrombotic activation and a prothrombotic condition. The inflammatory response and prothrombotic condition reinforce each other. This can result in coagulation on ruptured atherosclerotic plaques and erosions in the vessel wall, which can give rise to the sudden constriction or blockage of coronary arteries.
Nederlands tijdschrift voor geneeskunde 07/2005; 149(23):1267-72.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to develop and validate a population pharmacokinetic model of ritonavir, used as an antiviral agent or as a booster, in a large patient population and to identify factors influencing its pharmacokinetics.
Ambulatory HIV-1-infected patients from the outpatient clinic of the Slotervaart Hospital, Amsterdam, the Netherlands, who were being treated with a ritonavir-containing regimen were included. During regular visits, blood samples were collected for the determination of ritonavir plasma concentrations and several clinical chemistry parameters. Furthermore, complete pharmacokinetic curves were available in some patients. Single and multiple compartment models with zero-order and first-order absorption, with and without absorption lag-time, with linear and nonlinear elimination were tested, using nonlinear mixed effect modelling (NONMEM). Pharmacokinetic parameters and interindividual, interoccasion and residual variability were estimated. In addition, the influence of several factors (e.g. patient characteristics, comedication) on the pharmacokinetics of ritonavir was explored.
From 186 patients 505 ritonavir plasma concentrations at a single time-point and 55 full pharmacokinetic profiles were available, resulting in a database of 1228 plasma ritonavir concentrations. In total 62% of the patients used ritonavir as a booster of their protease inhibitor containing antiretroviral regimen. First order absorption in combination with one-compartment disposition best described the pharmacokinetics of ritonavir. Clearance, volume of distribution and absorption rate constant were 10.5 l h−1 (95% prediction interval (95% PI) 9.38–11.7), 96.6 l (95% PI 67.2–121) and 0.871 h−1 (95% PI 0.429–1.47), respectively, with 38.3%, 80.0% and 169% interindividual variability, respectively. The interoccasion variability in the apparent bioavailability was 59.1%. The concomitant use of lopinavir resulted in a 2.7-fold increase in the clearance of ritonavir (P value < 0.001). No patients characteristics influenced the pharmacokinetics of ritonavir.
The pharmacokinetic parameters of ritonavir were adequately described by our population pharmacokinetic model. Concomitant use of the protease inhibitor lopinavir strongly influenced the pharmacokinetics of ritonavir. The model has been validated and can be used for further investigation of the interaction between ritonavir and other protease inhibitors.
British Journal of Clinical Pharmacology 03/2005; 59(2):174-82. DOI:10.1111/j.1365-2125.2004.02241.x · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dengue virus infections are an important cause of morbidity and mortality in the tropics, with 100 million people infected annually and an estimated 2.5 billion people at risk. Human infections can be asymptomatic or can manifest as the self-limited febrile dengue fever, or the more severe and life-threatening dengue haemorrhagic fever (DHF). There are several possible reasons why some infected individuals might develop a more severe form of the disease than others. Antibody enhancement and viral virulence have been implicated in the pathogenesis of DHF but host genetic factors may also be relevant and predispose some individuals to DHF. This review discusses the possible involvement of a variety of genetic polymorphisms on the course of dengue virus infections. It has been shown that several common genetic polymorphisms can influence the susceptibility to dengue haemorrhagic fever. Gene polymorphisms concerning human leucocyte antigens, antibody receptors, inflammatory mediators and other factors with immunoregulatory effects are described. The study of genetic polymorphisms might provide important insights into the pathogenesis of a more severe disease and could have an impact on the design of future vaccines.
[Show abstract][Hide abstract] ABSTRACT: Therapeutic drug monitoring of protease inhibitors (PIs) is usually performed on plasma samples although their antiretroviral effect takes place inside cells. Little is known, however, about the intracellular accumulation and related plasma pharmacokinetics of PIs such as lopinavir/ritonavir (LPV/RTV). Therefore, we studied the plasma and intracellular (cell-associated) steady-state pharmacokinetics of this PI combination in a dosage of 400/100 mg twice daily in a non-randomized cohort of HIV-1-infected individuals. Plasma (0-12 h) and peripheral blood mononuclear cell (PBMC; 0-8 h) samples were drawn during a 12-h dosing interval in 11 subjects. The plasma concentrations versus time curves of LPV and RTV were characterized by an irregular absorption phase showing double-peaks (Cmax) in most subjects and single-peaks in the remaining patients between 1 and 3 h after drug intake. Pre-dose concentrations of both agents in plasma were significantly higher than the concentrations at the end of the dosing interval indicating the presence of a circadian rhythm in their pharmacokinetics. The course of the intracellular concentrations versus time curves appeared to be similar to the plasma concentration curves, with the highest intracellular concentration measured 3 h after drug intake. The intracellular RTV concentrations were higher than reported in vitro EC50 values and might therefore contribute to the antiretroviral effect of LPV/RTV. The median intracellular-to-plasma concentration ratios (interquartile range) were 1.18 (0.74-2.06) and 4.59 (3.20-7.70) for LPV and RTV, respectively. In conclusion, both LPV and RTV accumulate to potential therapeutic concentrations in PBMCs. Irregular absorption and circadian plasma clearance patterns were observed for the PI combination LPV/RTV.
[Show abstract][Hide abstract] ABSTRACT: Clinicians often deviate from the recommended algorithm for the diagnosis of pulmonary embolism consisting of ventilation-perfusion scintigraphy and pulmonary angiography.
To assess the safety and feasibility of a diagnostic algorithm which reduces the need for lung scintigraphy and avoids the use of angiography.
Consecutive patients with a clinical suspicion of pulmonary embolism were prospectively investigated according to an algorithm in which the diagnosis of pulmonary embolism was excluded after a low clinical probability estimate and a normal d-dimer test result, a normal perfusion scintigraphy result, or a non-high probability scintigraphy result in combination with normal serial ultrasonography of the legs. In these patients anticoagulant treatment was withheld and they were followed up for 3 months to record possible thromboembolic events. During the study period, 923 consecutive patients were seen, of whom 292 were excluded because of predefined criteria.
Of the 631 included patients, the diagnosis was refuted on the basis of a low clinical probability estimate and a normal d-dimer test result (95 patients), normal perfusion scintigraphy (161 patients) and non-high probability lung scintigraphy followed by normal serial ultrasonography (210 patients). Of these 466 patients, venous thromboembolic complications during follow-up occurred in six (complication rate 1.3%, 95% confidence interval 0.5, 2.8). The diagnostic protocol was completed in 92% of all included patients.
The diagnosis of pulmonary embolism can be safely ruled out by a non-invasive algorithm consisting of d-dimer testing combined with a clinical probability estimate, lung scintigraphy, or serial ultrasonography of the legs (in case of non-diagnostic lung scintigraphy).
Journal of Thrombosis and Haemostasis 08/2004; 2(7):1110-7. DOI:10.1111/j.1538-7836.2004.00769.x · 5.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dengue viruses cause a variable spectrum of disease that ranges from an undifferentiated fever to dengue fever to the potentially fatal dengue shock syndrome. Due to the increased incidence and geographical distribution of dengue in the last 50 years, dengue is becoming increasingly recognised as one of the world's major infectious diseases. This article will review clinical and diagnostic aspects of dengue virus infections. It also presents our current knowledge of the pathophysiology of severe dengue and addresses the importance of dengue virus infections in those travelling to parts of the world where dengue is endemic.
European Journal of Clinical Microbiology 07/2004; 23(6):425-33. DOI:10.1007/s10096-004-1145-1 · 2.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the usefulness of intervention in drug interactions of antiretroviral drugs with coadministered agents by a clinical pharmacist in outpatient HIV-treatment.
The study design included two intervention arms (A and B), which were both preceded by a control observation period. In arm A, a complete list of the currently used drugs, extracted from pharmacy records was provided to the treating physician. In arm B the same list was provided but with a notification when a drug interaction was present and an advice how to handle this. The infectious disease specialist obtained the information before the patient's visit to the outpatient clinic (time point 0). Three months prior (time point -3) and 3 months after (time point +3) the intervention, pharmacy records were also screened for drug interactions. The number of drug interactions (total and per patient) was determined at the three different time points (-3, 0, +3). In addition, drug interactions encountered at time points -3 and 0 were checked for their presence at time points 0 and +3, respectively, for both intervention arms.
Arms A and B included 115 and 105 patients, respectively. Patient characteristics of both intervention arms were similar at time point 0. The number of interactions and the number of patients with interactions were similar in both intervention arms at time point 0. There were 42 and 40 potential drug interactions in 30 and 24 patients in arms A and B, respectively. The reduction in the number of interactions per patient over time and after intervention was small but significant, and was equal in both intervention arms. The advice of the clinical pharmacist had thus no additional value.
Both interventions were effective in reducing the number of drug interactions per patient. The advice of a clinical pharmacist was, however, redundant in the studied setting.
Journal of Clinical Pharmacy and Therapeutics 05/2004; 29(2):121-30. DOI:10.1111/j.1365-2710.2003.00541.x · 1.67 Impact Factor