50 results on '"Plewes K"'
Search Results
2. The Effect of Regularly Dosed Acetaminophen vs No Acetaminophen on Renal Function in Plasmodium knowlesi Malaria (PACKNOW): A Randomized, Controlled Trial
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Cooper, DJ, Grigg, MJ, Plewes, K, Rajahram, GS, Piera, KA, William, T, Menon, J, Koleth, G, Edstein, MD, Birrell, GW, Wattanakul, T, Tarning, J, Patel, A, Yeo, TW, Dondorp, AM, Anstey, NM, Barber, BE, and Intensive Care Medicine
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Microbiology (medical) ,Malaysia ,Acute Kidney Injury ,Kidney ,Hemolysis ,Malaria ,Hemoglobins ,Infectious Diseases ,randomized controlled trial (RCT) ,Creatinine ,parasitic diseases ,Humans ,Plasmodium knowlesi ,acute kidney injury (AKI) ,Acetaminophen - Abstract
Background Acetaminophen inhibits cell-free hemoglobin-induced lipid peroxidation and improves renal function in severe falciparum malaria but has not been evaluated in other infections with prominent hemolysis, including Plasmodium knowlesi malaria. Methods PACKNOW was an open-label, randomized, controlled trial of acetaminophen (500 mg or 1000 mg every 6 hours for 72 hours) vs no acetaminophen in Malaysian patients aged ≥5 years with knowlesi malaria of any severity. The primary end point was change in creatinine at 72 hours. Secondary end points included longitudinal changes in creatinine in patients with severe malaria or acute kidney injury (AKI), stratified by hemolysis. Results During 2016–2018, 396 patients (aged 12–96 years) were randomized to acetaminophen (n = 199) or no acetaminophen (n = 197). Overall, creatinine fell by a mean (standard deviation) 14.9% (18.1) in the acetaminophen arm vs 14.6% (16.0) in the control arm (P = .81). In severe disease, creatinine fell by 31.0% (26.5) in the acetaminophen arm vs 20.4% (21.5) in the control arm (P = .12), and in those with hemolysis by 35.8% (26.7) and 19% (16.6), respectively (P = .07). No difference was seen overall in patients with AKI; however, in those with AKI and hemolysis, creatinine fell by 34.5% (20.7) in the acetaminophen arm vs 25.9% (15.8) in the control arm (P = .041). Mixed-effects modeling demonstrated a benefit of acetaminophen at 72 hours (P = .041) and 1 week (P = .002) in patients with severe malaria and with AKI and hemolysis (P = .027 and P = .002, respectively). Conclusions Acetaminophen did not improve creatinine among the entire cohort but may improve renal function in patients with severe knowlesi malaria and in those with AKI and hemolysis. Clinical Trials Registration NCT03056391.
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- 2021
3. Cell-free hemoglobin is associated with increased vascular resistance and reduced peripheral perfusion in severe malaria
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Kingston, HWF, Ghose, A, Rungpradubvong, V, Satitthummanid, S, Herdman, MT, Plewes, K, Ishioka, H, Leopold, SJ, Sinha, I, Intharabut, B, Piera, K, McNeil, Y, Mohanty, S, Maude, RJ, White, N, Day, NPJ, Yeo, TW, Hossain, MA, Anstey, NM, Dondorp, AM, and Lee Kong Chian School of Medicine (LKCMedicine)
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Adult ,Male ,Patient Acuity ,Hemodynamics ,Bacteremia ,Middle Aged ,Arginine ,Nitric Oxide ,Hemoglobins ,Young Adult ,Hematocrit ,Echocardiography ,Regional Blood Flow ,Case-Control Studies ,Severe Malaria ,parasitic diseases ,Humans ,Arterial Pressure ,Female ,Vascular Resistance ,Medicine [Science] ,Malaria, Falciparum - Abstract
Background In severe falciparum malaria, unlike sepsis, hypotension on admission is uncommon. We hypothesized that low nitric oxide bioavailability due to the presence of cell-free hemoglobin (CFH) increases vascular tone in severe malaria. Methods Patients with severe malaria (n = 119), uncomplicated malaria (n = 91), or suspected bacterial sepsis (n = 56), as well as healthy participants (n = 50), were recruited. The systemic vascular resistance index (SVRI) was estimated from the echocardiographic cardiac index and the mean arterial pressure. Results SVRI and hematocrit levels were lower and plasma CFH and asymmetric dimethylarginine levels were higher in patients with malaria, compared with healthy participants. In multivariate linear regression models for mean arterial pressure or SVRI in patients with severe malaria, hematocrit and CFH but not asymmetric dimethylarginine were significant predictors. The SVRI was lower in patients with suspected bacterial sepsis than in those with severe malaria, after adjustment for hematocrit and age. Plasma CFH levels correlated positively with the core-peripheral temperature gradient and plasma lactate levels and inversely with the perfusion index. Impaired peripheral perfusion, as reflected by a low perfusion index or a high core-peripheral temperature gradient, predicted mortality in patients with severe malaria. Conclusions CFH is associated with mean arterial pressure, SVRI, and peripheral perfusion in patients with severe malaria. This may be mediated through the nitric oxide scavenging potency of CFH, increasing basal vascular tone and impairing tissue perfusion.
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- 2019
4. Amino acid derangements in adults with severe falciparum malaria
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Leopold, S, Apinan, S, Ghose, A, Kingston, H, Plewes, K, Hossain, A, Dutta, A, Paul, S, Barua, A, Sattar, A, Day, N, Tarning, J, Winterberg, M, White, N, and Dondorp, A
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Adult ,Male ,Bangladesh ,Phenylalanine ,lcsh:R ,lcsh:Medicine ,Middle Aged ,Translational research ,Arginine ,Mass Spectrometry ,Article ,Young Adult ,Sepsis ,parasitic diseases ,Humans ,Female ,lcsh:Q ,Lactic Acid ,Amino Acids ,Malaria, Falciparum ,Acidosis ,Infection ,lcsh:Science - Abstract
Amino acid derangements are common in severe falciparum malaria and have been associated with endothelial dysfunction (L-arginine), metabolic acidosis (alanine and lactate), and disease severity (phenylalanine and tryptophan metabolites). Whether these amino acid perturbations reflect isolated pathogenic mechanisms or if they are part of overall changes in amino acid metabolism is unclear. To investigate this, we prospectively simultaneously quantified a broad range of plasma free amino acids (PFAA) using HPLC-MRM-Mass spectrometry in relation to presenting symptoms in adults with severe malaria (n = 88), septicaemia (n = 88), uncomplicated malaria (n = 71), and healthy controls (n = 48) from Bangladesh. The total plasma concentration of measured amino acids was significantly reduced in each of the patient groups when compared to normal levels observed in healthy local controls: uncomplicated malaria −54%, severe malaria −23%, and sepsis −32%, (p =
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- 2019
5. Does reduced oxygen delivery cause lactic acidosis in falciparum malaria? An observational study
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Kingston, H, Ghose, A, Rungpradubvong, V, Herdman, T, Plewes, K, Ishioka, H, Leopold, S, Maude, R, Intharabut, B, Mohanty, S, Day, N, White, N, Hossain, M, Anstey, N, and Dondorp, A
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Cardiac output ,Adult ,Male ,Bangladesh ,lcsh:Arctic medicine. Tropical medicine ,Haemodynamics ,lcsh:RC955-962 ,Acidosis, lactic ,Research ,Microcirculation ,India ,Oxygen consumption ,Middle Aged ,lcsh:Infectious and parasitic diseases ,Malaria ,Young Adult ,Sepsis ,parasitic diseases ,Humans ,lcsh:RC109-216 ,Female ,Malaria, Falciparum - Abstract
BACKGROUND: Lactic acidosis with an elevated lactate-pyruvate ratio suggesting anoxia is a common feature of severe falciparum malaria. High lactate levels are associated with parasitized erythrocyte sequestration in the microcirculation. To assess if there is an additional contribution to hyperlactataemia from relatively inadequate total oxygen delivery, oxygen consumption and delivery were investigated in patients with malaria. METHODS: Adult Bangladeshi and Indian patients with uncomplicated (N = 50) or severe (N = 46) falciparum malaria or suspected bacterial sepsis (N = 27) and healthy participants as controls (N = 26) were recruited at Chittagong Medical College Hospital, Chittagong, Bangladesh and Ispat General Hospital, Rourkela, India. Oxygen delivery (DO2I) was estimated from pulse oximetry, echocardiographic estimates of cardiac index and haematocrit. Oxygen consumption (VO2I) was estimated by expired gas collection. RESULTS: VO2I was elevated in uncomplicated median (IQR) 185.1 ml/min/m2 (135-215.9) and severe malaria 192 ml/min/m2 (140.7-227.9) relative to healthy persons 107.9 ml/min/m2 (69.9-138.1) (both p CONCLUSIONS: Reduced total oxygen delivery is not a major contributor to lactic acidosis in severe falciparum malaria.
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- 2019
6. Identifying the components of acidosis in patients with severe plasmodium falciparum malaria Using metabolomics
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Leopold, S, Ghose, A, Allman, E, Kingston, H, Hossain, A, Dutta, A, Plewes, K, Chotivanich, K, Day, N, Tarning, J, Winterberg, M, White, N, Llinás, M, and Dondorp, A
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Adult ,Male ,metabolic acidosis ,Plasmodium falciparum ,severe ,malaria ,Middle Aged ,gut-barrier integrity ,metabolomics ,Mass Spectrometry ,Young Adult ,Major Articles and Brief Reports ,parasitic diseases ,Humans ,Female ,Parasites ,Prospective Studies ,Intestinal Mucosa ,Malaria, Falciparum ,Acidosis ,Acids ,Biomarkers ,Chromatography, Liquid - Abstract
Background Acidosis in severe Plasmodium falciparum malaria is associated with high mortality, yet the pathogenesis remains incompletely understood. The aim of this study was to determine the nature and source of metabolic acids contributing to acidosis in patients with severe falciparum malaria. Methods A prospective observational study was conducted to characterize circulating acids in adults with P. falciparum malaria (n = 107) and healthy controls (n = 45) from Bangladesh using high-resolution liquid chromatography–mass spectrometry metabolomics. Additional in vitro P. falciparum culture studies were performed to determine if parasites release the acids detected in plasma from patients with severe malaria acidosis. Results We identified previously unmeasured plasma acids strongly associated with acidosis in severe malaria. Metabolomic analysis of P. falciparum parasites in vitro showed no evidence that these acids are released by the parasite during its life cycle. Instead, 10 of the plasma acids could be mapped to a gut microbial origin. Patients with malaria had low L-citrulline levels, a plasma marker indicating reduced gut barrier integrity. Longitudinal data showed the clearance of these newly identified acids was delayed in fatal cases. Conclusions These data suggest that a compromise in intestinal barrier function may contribute significantly to the pathogenesis of life-threatening acidosis in severe falciparum malaria. Clinical Trials Registration NCT02451904., Acidosis in severe falciparum malaria is associated with an accumulation of unidentified acids in blood plasma. Clinical and in vitro metabolomic studies identify a potential role for translocation of bacterial acids from the gut into the bloodstream.
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- 2019
7. Point-of-care lung ultrasound for the detection of pulmonary manifestations of malaria and sepsis: An observational study
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Leopold, S, Ghose, A, Plewes, K, Mazumder, S, Pisani, L, Kingston, H, Paul, S, Barua, A, Sattar, M, Huson, M, Walden, A, Henwood, P, Riviello, E, Schultz, M, Day, N, Kumar Dutta, A, White, N, Dondorp, A, AII - Infectious diseases, Graduate School, Intensive Care Medicine, ACS - Pulmonary hypertension & thrombosis, ACS - Diabetes & metabolism, and ACS - Microcirculation
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Adult ,Male ,Critical Care and Emergency Medicine ,Pulmonology ,Imaging Techniques ,Science ,Point-of-Care Systems ,Research and Analysis Methods ,Pathology and Laboratory Medicine ,Severity of Illness Index ,Diagnostic Radiology ,Signs and Symptoms ,Respiratory Failure ,Diagnostic Medicine ,Sepsis ,Ultrasound Imaging ,Medicine and Health Sciences ,Parasitic Diseases ,Edema ,Humans ,Prospective Studies ,Acute Respiratory Distress Syndrome ,Lung ,Ultrasonography ,Protozoans ,Bangladesh ,Respiratory Distress Syndrome ,Radiology and Imaging ,Organisms ,Malarial Parasites ,Biology and Life Sciences ,Eukaryota ,Tropical Diseases ,Pulmonary Imaging ,Parasitic Protozoans ,Malaria ,Oxygen ,Chemistry ,Physical Sciences ,Medicine ,Female ,Research Article ,Chemical Elements - Abstract
Introduction Patients with severe malaria or sepsis are at risk of developing life-threatening acute respiratory distress syndrome (ARDS). The objective of this study was to evaluate point-of-care lung ultrasound as a novel tool to determine the prevalence and early signs of ARDS in a resource-limited setting among patients with severe malaria or sepsis. Materials and methods Serial point-of-care lung ultrasound studies were performed on four consecutive days in a planned sub study of an observational cohort of patients with malaria or sepsis in Bangladesh. We quantified aeration patterns across 12 lung regions. ARDS was defined according to the Kigali Modification of the Berlin Definition. Results Of 102 patients enrolled, 71 had sepsis and 31 had malaria. Normal lung ultrasound findings were observed in 44 patients on enrolment and associated with 7% case fatality. ARDS was detected in 10 patients on enrolment and associated with 90% case fatality. All patients with ARDS had sepsis, 4 had underlying pneumonia. Two patients developing ARDS during hospitalisation already had reduced aeration patterns on enrolment. The SpO2/FiO2 ratio combined with the number of regions with reduced aeration was a strong prognosticator for mortality in patients with sepsis (AUROC 91.5% (95% Confidence Interval: 84.6%-98.4%)). Conclusions This study demonstrates the potential usefulness of point-of-care lung ultrasound to detect lung abnormalities in patients with malaria or sepsis in a resource-constrained hospital setting. LUS was highly feasible and allowed to accurately identify patients at risk of death in a resource limited setting.
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- 2018
8. Malaria in Canadian VFRs and migrants: surveillance report from CanTravBet, April 2013 — March 2018
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McCarthy, A., primary, Libman, M., additional, Yansouni, C., additional, Kuhn, S., additional, Geduld, J., additional, Hajek, J., additional, Ghesquiere, W., additional, Mirzanejad, Y., additional, Plewes, K., additional, Vincelette, J., additional, Barkati, S., additional, Ploude, P., additional, Greenaway, C., additional, Schwartz, K., additional, Thompson, C., additional, Kain, K., additional, and Boggild, A.K., additional
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- 2019
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9. Intravascular haemolysis, oxidative stress and acute kidney injury in severe falciparum malaria
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Plewes, K, White, N, and Dondorp, A
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Acute kidney injury (AKI) complicating severe falciparum malaria is an independent predictor of death in children and adults, however the magnitude of the problem in both populations is unclear due to divergent AKI definitions. Late recognition of this serious complication results in a mortality of up to 75% without renal replacement therapy, which is frequently unavailable. The aim of this thesis was to characterise malaria-associated AKI along the spectrum of this syndrome, evaluate the pathophysiology and assess the role of paracetamol as a renoprotective adjunctive therapy for the management of severe and moderately severe falciparum malaria. The main findings of the studies described here include: (1) The incidence of malaria-associated AKI is underrecognised as mild AKI is underreported. AKI defined by the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition identifies mild AKI and is strongly associated with mortality. (2) Sequestered parasite burden, immune activation, cell-free haemoglobin and lipid peroxidation contribute to the pathophysiology of AKI in severe malaria. The proposed mechanism of kidney injury mediated by cell-free haemoglobin is oxidative damage by ferryl (Fe4+)-haemoglobin, which can be reduced by paracetamol. (3) Paracetamol tablets administered at the maximum recommended adult dose (4 g/day) results in sub-therapeutic steady state concentrations for antipyresis in severe and moderately severe malaria in adults, and simulations suggest a loading dose might be indicated. (4) In a randomised controlled trial, it was shown that paracetamol reduces kidney dysfunction and the odds of developing AKI in severe and moderately severe malaria in adults. The protective effect was particularly prominent in patients with high plasma concentrations of cell-free haemoglobin resulting from pronounced intravascular haemolysis. In conclusion, this thesis shows that AKI defined by the harmonized KDIGO classification system is associated with mortality in falciparum malaria. Multiple mechanisms contribute to the pathophysiology of AKI in malaria and targeted preventative treatment with paracetamol reduces kidney dysfunction associated with high cell-free haemoglobin. The definition of AKI in the WHO malaria guidelines should be reconsidered. A larger trial of the use of paracetamol to reduce kidney dysfunction in severe malaria is warranted.
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- 2016
10. Low-cost portable fluorescein angiography
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Maude, R. J., primary, Plewes, K., additional, Dimock, J., additional, and Dondorp, A. M., additional
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- 2011
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11. Low seroprevalence of HIV and syphilis in pregnant women in refugee camps on the Thai-Burma border
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Plewes, K, primary, Lee, T, additional, Kajeechewa, L, additional, Thwin, M M, additional, Lee, S J, additional, Carrara, V I, additional, Nosten, F, additional, and Mcgready, R, additional
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- 2008
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12. New Delhi metallo-β-lactamase in Klebsiella pneumoniae and Escherichia coli, Canada.
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Mulvey MR, Grant JM, Plewes K, Roscoe D, Boyd DA, Mulvey, Michael R, Grant, Jennifer M, Plewes, Katherine, Roscoe, Diane, and Boyd, David A
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Multidrug-resistant Klebsiella pneumoniae and Escherichia coli isolates harboring New Delhi metallo-β-lactamase (NDM-1) were isolated from a patient who had returned to Canada from India. The NDM-1 gene was found on closely related incompatibility group A/C type plasmids. The occurrence of NDM-1 in North America is a major public health concern. [ABSTRACT FROM AUTHOR]
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- 2011
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13. Design for Airfreight Development - The Next Decade
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Hiatt, M. A., primary and Plewes, K. C., additional
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- 1965
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14. Plasmodium knowlesi Infection in Traveler Returning to Canada from the Philippines, 2023.
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Lo CK, Plewes K, Sharma S, Low A, Su LD, Belga S, Salazar FV, Hajek J, Morshed M, and Hogan CA
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- Male, Humans, Middle Aged, Philippines epidemiology, Canada epidemiology, Polymerase Chain Reaction, Plasmodium knowlesi genetics, Malaria diagnosis, Malaria drug therapy, Malaria epidemiology
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A 55-year-old man sought treatment for an uncomplicated febrile illness after returning to Canada from the Philippines. A suspected diagnosis of Plasmodium knowlesi infection was confirmed by PCR, and treatment with atovaquone/proguanil brought successful recovery. We review the evolving epidemiology of P. knowlesi malaria in the Philippines, specifically within Palawan Island.
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- 2023
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15. Healthcare seeking during travel: an analysis by the GeoSentinel surveillance network of travel medicine providers.
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Piyaphanee W, Stoney RJ, Asgeirsson H, Appiah GD, Díaz-Menéndez M, Barnett ED, Gautret P, Libman M, Schlagenhauf P, Leder K, Plewes K, Grobusch MP, Huits R, Mavunda K, Hamer DH, and Chen LH
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- Humans, Travel Medicine, Travel, Diarrhea, Delivery of Health Care, Rabies epidemiology, Rabies prevention & control
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Background: International travellers may seek care abroad to address health problems that arise during their trip or plan healthcare outside their country of residence as medical tourists., Methods: Data were collected on travellers evaluated at GeoSentinel Network sites who reported healthcare during travel. Both unplanned and planned healthcare were analysed, including the reason and nature of healthcare sought, characteristics of the treatment provided and outcomes. Travellers that presented for rabies post-exposure prophylaxis were described elsewhere and were excluded from detailed analysis., Results: From May 2017 through June 2020, after excluding travellers obtaining rabies post-exposure prophylaxis (n= 415), 1093 travellers reported care for a medical or dental issue that was an unanticipated part of the travellers' planned itinerary (unplanned healthcare). Travellers who sought unplanned healthcare abroad had frequent diagnoses of acute diarrhoea, dengue, falciparum malaria and unspecified viral syndrome, and obtained care in 131 countries. Thirty-four (3%) reported subsequent deterioration and 230 (21%) reported no change in condition; a third (n = 405; 37%) had a pre-travel health encounter. Forty-one travellers had sufficient data on planned healthcare abroad for analysis. The most common destinations were the US, France, Dominican Republic, Belgium and Mexico. The top reasons for their planned healthcare abroad were unavailability of procedure at home (n = 9; 19%), expertise abroad (n = 9; 19%), lower cost (n = 8; 17%) and convenience (n = 7; 15%); a third (n = 13; 32%) reported cosmetic or surgical procedures. Early and late complications occurred in 14 (33%) and 4 (10%) travellers, respectively. Four travellers (10%) had a pre-travel health encounter., Conclusions: International travellers encounter health problems during travel that often could be prevented by pre-travel consultation. Travellers obtaining planned healthcare abroad can experience negative health consequences associated with treatments abroad, for which pre-travel consultations could provide advice and potentially help to prevent complications., (© International Society of Travel Medicine 2023. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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16. Cost, health impacts and cost effectiveness of iceless refrigeration in India's last-mile vaccine cold chain delivery.
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Plewes K, Khonputsa P, Day NPJ, and Lubell Y
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- Child, Humans, Infant, Cost-Effectiveness Analysis, Refrigeration, Immunization Programs, Cost-Benefit Analysis, Health Care Costs, India epidemiology, Vaccination, Rotavirus Vaccines, Rotavirus Infections prevention & control
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Background: Compared with ice-based vaccine carriers (IBVCs), iceless vaccine carrier (ILVC) last-mile delivery could optimize vaccine effectiveness by reducing spoilage. We estimated ILVC-associated spoilage costs averted and cost effectiveness., Methods: IBVC vaccine spoilage costs were estimated for six vaccines. ILVC incremental costs were based on yearly ILVC cost over total doses. Cost effectiveness was estimated via Markov modeling of rotavirus vaccine., Results: The spoilage cost using IBVCs was US$9 603 294. Using ILVCs, the incremental cost per vaccine dose was US$0.026, the cost-benefit ratio was 0.28, the number of averted disability-adjusted life years was 0.03 per child and there was a saving of US$0.80 per child vaccinated., Conclusions: ILVCs may bring cost savings and health gains compared with IBVCs., (© The Author(s) 2022. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)
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- 2023
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17. The Effect of Regularly Dosed Acetaminophen vs No Acetaminophen on Renal Function in Plasmodium knowlesi Malaria (PACKNOW): A Randomized, Controlled Trial.
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Cooper DJ, Grigg MJ, Plewes K, Rajahram GS, Piera KA, William T, Menon J, Koleth G, Edstein MD, Birrell GW, Wattanakul T, Tarning J, Patel A, Wen Yeo T, Dondorp AM, Anstey NM, and Barber BE
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- Acetaminophen therapeutic use, Creatinine, Hemoglobins therapeutic use, Hemolysis, Humans, Kidney physiology, Malaysia, Acute Kidney Injury drug therapy, Malaria complications, Malaria drug therapy, Plasmodium knowlesi
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Background: Acetaminophen inhibits cell-free hemoglobin-induced lipid peroxidation and improves renal function in severe falciparum malaria but has not been evaluated in other infections with prominent hemolysis, including Plasmodium knowlesi malaria., Methods: PACKNOW was an open-label, randomized, controlled trial of acetaminophen (500 mg or 1000 mg every 6 hours for 72 hours) vs no acetaminophen in Malaysian patients aged ≥5 years with knowlesi malaria of any severity. The primary end point was change in creatinine at 72 hours. Secondary end points included longitudinal changes in creatinine in patients with severe malaria or acute kidney injury (AKI), stratified by hemolysis., Results: During 2016-2018, 396 patients (aged 12-96 years) were randomized to acetaminophen (n = 199) or no acetaminophen (n = 197). Overall, creatinine fell by a mean (standard deviation) 14.9% (18.1) in the acetaminophen arm vs 14.6% (16.0) in the control arm (P = .81). In severe disease, creatinine fell by 31.0% (26.5) in the acetaminophen arm vs 20.4% (21.5) in the control arm (P = .12), and in those with hemolysis by 35.8% (26.7) and 19% (16.6), respectively (P = .07). No difference was seen overall in patients with AKI; however, in those with AKI and hemolysis, creatinine fell by 34.5% (20.7) in the acetaminophen arm vs 25.9% (15.8) in the control arm (P = .041). Mixed-effects modeling demonstrated a benefit of acetaminophen at 72 hours (P = .041) and 1 week (P = .002) in patients with severe malaria and with AKI and hemolysis (P = .027 and P = .002, respectively)., Conclusions: Acetaminophen did not improve creatinine among the entire cohort but may improve renal function in patients with severe knowlesi malaria and in those with AKI and hemolysis., Clinical Trials Registration: NCT03056391., Competing Interests: Potential conflicts of interest. A. M. D. reports consulting fees paid to MORU by the Novartis Malaria Advisory Council; travel support provided by Gordon Malaria Conference organizers; is a member of the World Health Organization (WHO) Guidelines Development Group for antimalarial treatment, Scientific Advisory Board of the World-Wide Antimalarial Resistance Network, and Scientific Advisory Board of International Severe Acute Respiratory and Emerging Infection Consortium; and is the chair of the Artemisinin-resistance Initiative of the Global Fund Regional Steering Committee. G. S. R. reports grants from the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (award 1R01AI160457-01) and the Malaysian Ministry of Health (award NMRR-19-4109-52172) and reports a leadership or fiduciary role on the Infectious Disease Society of Kota Kinabalu. J. T. reports consulting fees paid to Mahidol Oxford Research Unit (MORU) by the Novartis Malaria Advisory Council, is a member of the WHO working group on weight-band dosing harmonization to support the WHO-initiated Global Accelerator for Paediatric Formulations, is chair of the Coronavirus Disease 2019 Clinical Research Coalition, Clinical Pharmacology Working Group, is a member of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) Infectious Diseases steering committee, and is a scientific advisor on the Drugs for Neglected Diseases initiative (DNDi) Programme: 21st Century Treatments for Sustainable Elimination of Leishmaniasis. T. W. Y. reports an international travel grant provided by the Pharmacometrics Japan Conference 2020. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)
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- 2022
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18. An Evaluation of Commonly Used Surrogate Baseline Creatinine Values to Classify AKI During Acute Infection.
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Cooper DJ, Plewes K, Grigg MJ, Patel A, Rajahram GS, William T, Hiemstra TF, Wang Z, Barber BE, and Anstey NM
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Introduction: Classification of acute kidney injury (AKI) requires a premorbid baseline creatinine, often unavailable in studies in acute infection., Methods: We evaluated commonly used surrogate and imputed baseline creatinine values against a "reference" creatinine measured during follow-up in an adult clinical trial cohort. Known AKI incidence (Kidney Disease: Improving Global Outcomes [KDIGO] criteria) was compared with AKI incidence classified by (1) back-calculation using the Modification of Diet in Renal Disease (MDRD) equation with and without a Chinese ethnicity correction coefficient; (2) back-calculation using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation; (3) assigning glomerular filtration rate (GFR) from age and sex-standardized reference tables; and (4) lowest measured creatinine during admission. Back-calculated distributions were performed using GFRs of 75 and 100 ml/min., Results: All equations using an assumed GFR of 75 ml/min underestimated AKI incidence by more than 50%. Back-calculation with CKD-EPI and GFR of 100 ml/min most accurately predicted AKI but misclassified all AKI stages and had low levels of agreement with true AKI diagnoses. Back-calculation using MDRD and assumed GFR of 100 ml/min, age and sex-reference GFR values adjusted for good health, and lowest creatinine during admission performed similarly, best predicting AKI incidence (area under the receiver operating characteristic curves [AUC ROCs] of 0.85, 0.87, and 0.85, respectively). MDRD back-calculation using a cohort mean GFR showed low total error (22%) and an AUC ROC of 0.85., Conclusion: Current methods for estimating baseline creatinine are large sources of potential error in acute infection studies. Preferred alternatives include MDRD equation back-calculation with a population mean GFR, age- and sex-specific GFR values corrected for "good health," or lowest measured creatinine. Studies using surrogate baseline creatinine values should report specific methodology., (© 2021 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.)
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- 2021
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19. Epidemiological and Clinical Characteristics of International Travelers with Enteric Fever and Antibiotic Resistance Profiles of Their Isolates: a GeoSentinel Analysis.
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Hagmann SHF, Angelo KM, Huits R, Plewes K, Eperon G, Grobusch MP, McCarthy A, Libman M, Caumes E, Leung DT, Asgeirsson H, Jensenius M, Schwartz E, Sánchez-Montalvá A, Kelly P, Pandey P, Leder K, Bourque DL, Yoshimura Y, Mockenhaupt FP, van Genderen PJJ, Odolini S, Schlagenhauf P, Connor BA, and Hamer DH
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- Adolescent, Anti-Bacterial Agents pharmacology, Asia, Child, Drug Resistance, Microbial, Humans, India, Salmonella paratyphi A, Salmonella typhi, Travel, Travel-Related Illness, Typhoid Fever drug therapy, Typhoid Fever epidemiology
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Enteric fever, caused by Salmonella enterica serovar Typhi ( S Typhi) and S. enterica serovar Paratyphi ( S Paratyphi), is a common travel-related illness. Limited data are available on the antimicrobial resistance (AMR) patterns of these serovars among travelers. Records of travelers with a culture-confirmed diagnosis seen during or after travel from January 2007 to December 2018 were obtained from GeoSentinel. Traveler demographics and antimicrobial susceptibility data were analyzed. Isolates were classified as nonsusceptible if intermediate or resistant or as susceptible in accordance with the participating site's national guidelines. A total of 889 travelers ( S Typhi infections, n = 474; S Paratyphi infections, n = 414; coinfection, n = 1) were included; 114 (13%) were children of <18 years old. Most individuals (41%) traveled to visit friends and relatives (VFRs) and acquired the infection in South Asia (71%). Child travelers with S Typhi infection were most frequently VFRs (77%). The median trip duration was 31 days (interquartile range, 18 to 61 days), and 448 of 691 travelers (65%) had no pretravel consultation. Of 143 S Typhi and 75 S Paratyphi isolates for which there were susceptibility data, nonsusceptibility to antibiotics varied (fluoroquinolones, 65% and 56%, respectively; co-trimoxazole, 13% and 0%; macrolides, 8% and 16%). Two S Typhi isolates (1.5%) from India were nonsusceptible to third-generation cephalosporins. S Typhi fluoroquinolone nonsusceptibility was highest when infection was acquired in South Asia (70 of 90 isolates; 78%) and sub-Saharan Africa (6 of 10 isolates; 60%). Enteric fever is an important travel-associated illness complicated by AMR. Our data contribute to a better understanding of region-specific AMR, helping to inform empirical treatment options. Prevention measures need to focus on high-risk travelers including VFRs and children., (Copyright © 2020 American Society for Microbiology.)
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- 2020
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20. Reduced Cardiac Index Reserve and Hypovolemia in Severe Falciparum Malaria.
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Kingston HWF, Ghose A, Rungpradubvong V, Satitthummanid S, Herdman MT, Plewes K, Leopold SJ, Ishioka H, Mohanty S, Maude RJ, Schultz MJ, Lagrand WK, Hossain MA, Day NPJ, White NJ, Anstey NM, and Dondorp AM
- Subjects
- Adult, Bangladesh, Case-Control Studies, Echocardiography, Female, Hemodynamics, Humans, Hypovolemia physiopathology, India, Linear Models, Logistic Models, Malaria, Falciparum diagnostic imaging, Malaria, Falciparum mortality, Male, Middle Aged, Multivariate Analysis, Ventricular Dysfunction, Left parasitology, Ventricular Function, Left, Young Adult, Hypovolemia parasitology, Malaria, Falciparum physiopathology, Ventricular Dysfunction, Left diagnostic imaging
- Abstract
Background: Impaired microvascular perfusion is central to the development of coma and lactic acidosis in severe falciparum malaria. Refractory hypotension is rare on admission but develops frequently in fatal cases. We assessed cardiac function and volume status in severe falciparum malaria and its prognostic significance., Methods: Patients with severe (N = 101) or acute uncomplicated falciparum malaria (N = 83) were recruited from 2 hospitals in India and Bangladesh, and healthy participants (N = 44) underwent echocardiography., Results: Patients with severe malaria had 38% shorter left ventricular (LV) filling times and 25% shorter LV ejection times than healthy participants because of tachycardia; however, stroke volume, LV internal diameter in diastole (LVIDd), and LV internal diameter in systole (LVIDs) indices were similar. A low endocardial fraction shortening (eFS) was present in 17% (9 of 52) of severe malaria patients. Adjusting for preload and afterload, eFS was similar in health and severe malaria. Fatal cases had smaller baseline LVIDd and LVIDs indices, more collapsible inferior vena cavae (IVC), and higher heart rates than survivors. The LVIDs and IVC collapsibility were independent predictors for mortality, together with base excess and Glasgow Coma Scale., Conclusions: Patients with severe malaria have rapid ejection of a normal stroke volume. Fatal cases had features of relative hypovolemia and reduced cardiac index reserve., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)
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- 2020
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21. Associations Between Restrictive Fluid Management and Renal Function and Tissue Perfusion in Adults With Severe Falciparum Malaria: A Prospective Observational Study.
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Ishioka H, Plewes K, Pattnaik R, Kingston HWF, Leopold SJ, Herdman MT, Mahanta K, Mohanty A, Dey C, Alam S, Srinamon K, Mohanty A, Maude RJ, White NJ, Day NPJ, Hossain MA, Faiz MA, Charunwatthana P, Mohanty S, Ghose A, and Dondorp AM
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- Acute Kidney Injury etiology, Adult, Female, Fluid Therapy adverse effects, Humans, Kidney Function Tests, Lactic Acid blood, Malaria, Falciparum mortality, Male, Prospective Studies, Pulmonary Edema etiology, Young Adult, Fluid Therapy methods, Malaria, Falciparum drug therapy
- Abstract
Background: Liberal fluid resuscitation has proved harmful in adults with severe malaria, but the level of restriction has not been defined., Methods: In a prospective observational study in adults with severe falciparum malaria, restrictive fluid management was provided at the discretion of the treating physician. The relationships between the volume of fluid and changes in renal function or tissue perfusion were evaluated., Results: A total of 154 patients were studied, 41 (26.6%) of whom died. Median total fluid intake during the first 6 and 24 hours from enrollment was 3.3 (interquartile range [IQR], 1.8-5.1) mL/kg per hour and 2.2 (IQR, 1.6-3.2) mL/kg per hour, respectively. Total fluid intake at 6 hours was not correlated with changes in plasma creatinine at 24 hours (n = 116; rs = 0.16; P = .089) or lactate at 6 hours (n = 94; rs = -0.05; P = .660). Development of hypotensive shock or pulmonary edema within 24 hours after enrollment were not related to the volume of fluid administration., Conclusions: Restrictive fluid management did not worsen kidney function and tissue perfusion in adult patients with severe falciparum malaria. We suggest crystalloid administration of 2-3 mL/kg per hour during the first 24 hours without bolus therapy, unless the patient is hypotensive., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)
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- 2020
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22. Cell-Free Hemoglobin Is Associated With Increased Vascular Resistance and Reduced Peripheral Perfusion in Severe Malaria.
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Kingston HWF, Ghose A, Rungpradubvong V, Satitthummanid S, Herdman MT, Plewes K, Ishioka H, Leopold SJ, Sinha I, Intharabut B, Piera K, McNeil Y, Mohanty S, Maude RJ, White NJ, Day NPJ, Yeo TW, Hossain MA, Anstey NM, and Dondorp AM
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- Adult, Arginine analogs & derivatives, Arginine blood, Bacteremia physiopathology, Case-Control Studies, Echocardiography, Female, Hematocrit, Humans, Male, Middle Aged, Nitric Oxide, Patient Acuity, Young Adult, Arterial Pressure, Hemoglobins metabolism, Malaria, Falciparum physiopathology, Regional Blood Flow, Vascular Resistance
- Abstract
Background: In severe falciparum malaria, unlike sepsis, hypotension on admission is uncommon. We hypothesized that low nitric oxide bioavailability due to the presence of cell-free hemoglobin (CFH) increases vascular tone in severe malaria., Methods: Patients with severe malaria (n = 119), uncomplicated malaria (n = 91), or suspected bacterial sepsis (n = 56), as well as healthy participants (n = 50), were recruited. The systemic vascular resistance index (SVRI) was estimated from the echocardiographic cardiac index and the mean arterial pressure., Results: SVRI and hematocrit levels were lower and plasma CFH and asymmetric dimethylarginine levels were higher in patients with malaria, compared with healthy participants. In multivariate linear regression models for mean arterial pressure or SVRI in patients with severe malaria, hematocrit and CFH but not asymmetric dimethylarginine were significant predictors. The SVRI was lower in patients with suspected bacterial sepsis than in those with severe malaria, after adjustment for hematocrit and age. Plasma CFH levels correlated positively with the core-peripheral temperature gradient and plasma lactate levels and inversely with the perfusion index. Impaired peripheral perfusion, as reflected by a low perfusion index or a high core-peripheral temperature gradient, predicted mortality in patients with severe malaria., Conclusions: CFH is associated with mean arterial pressure, SVRI, and peripheral perfusion in patients with severe malaria. This may be mediated through the nitric oxide scavenging potency of CFH, increasing basal vascular tone and impairing tissue perfusion., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)
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- 2020
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23. Identifying the Components of Acidosis in Patients With Severe Plasmodium falciparum Malaria Using Metabolomics.
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Leopold SJ, Ghose A, Allman EL, Kingston HWF, Hossain A, Dutta AK, Plewes K, Chotivanich K, Day NPJ, Tarning J, Winterberg M, White NJ, Llinás M, and Dondorp AM
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- Acidosis complications, Acidosis parasitology, Adult, Biomarkers blood, Chromatography, Liquid, Female, Humans, Intestinal Mucosa, Malaria, Falciparum complications, Malaria, Falciparum parasitology, Male, Mass Spectrometry, Middle Aged, Prospective Studies, Young Adult, Acidosis metabolism, Acids metabolism, Malaria, Falciparum metabolism, Metabolomics, Plasmodium falciparum physiology
- Abstract
Background: Acidosis in severe Plasmodium falciparum malaria is associated with high mortality, yet the pathogenesis remains incompletely understood. The aim of this study was to determine the nature and source of metabolic acids contributing to acidosis in patients with severe falciparum malaria., Methods: A prospective observational study was conducted to characterize circulating acids in adults with P. falciparum malaria (n = 107) and healthy controls (n = 45) from Bangladesh using high-resolution liquid chromatography-mass spectrometry metabolomics. Additional in vitro P. falciparum culture studies were performed to determine if parasites release the acids detected in plasma from patients with severe malaria acidosis., Results: We identified previously unmeasured plasma acids strongly associated with acidosis in severe malaria. Metabolomic analysis of P. falciparum parasites in vitro showed no evidence that these acids are released by the parasite during its life cycle. Instead, 10 of the plasma acids could be mapped to a gut microbial origin. Patients with malaria had low L-citrulline levels, a plasma marker indicating reduced gut barrier integrity. Longitudinal data showed the clearance of these newly identified acids was delayed in fatal cases., Conclusions: These data suggest that a compromise in intestinal barrier function may contribute significantly to the pathogenesis of life-threatening acidosis in severe falciparum malaria., Clinical Trials Registration: NCT02451904., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)
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- 2019
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24. Malaria: What's New in the Management of Malaria?
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Plewes K, Leopold SJ, Kingston HWF, and Dondorp AM
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- Drug Therapy, Combination, Humans, Malaria diagnosis, Plasmodium drug effects, Antimalarials therapeutic use, Disease Management, Drug Resistance, Malaria drug therapy, Malaria prevention & control
- Abstract
The global burden of malaria remains high, with 216 million cases causing 445,000 deaths in 2016 despite first-line treatment with artemisinin-based combination therapy. Decreasing transmission in Africa shifts the risk for severe malaria to older age groups as premunition wanes. Prompt diagnosis and treatment with intravenous artesunate in addition to appropriate supportive management are critical to reduce deaths from severe malaria. Effective individual management is challenging in settings with limited resources for higher-level care. Adjunctive therapies targeting the underlying pathophysiological pathways have the potential to reduce mortality. Resistance to artemisinin derivatives and their partner drugs threaten malaria management and control., (Copyright © 2018 Elsevier Inc. All rights reserved.)
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- 2019
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25. Acetaminophen as a Renoprotective Adjunctive Treatment in Patients With Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial.
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Plewes K, Kingston HWF, Ghose A, Wattanakul T, Hassan MMU, Haider MS, Dutta PK, Islam MA, Alam S, Jahangir SM, Zahed ASM, Sattar MA, Chowdhury MAH, Herdman MT, Leopold SJ, Ishioka H, Piera KA, Charunwatthana P, Silamut K, Yeo TW, Lee SJ, Mukaka M, Maude RJ, Turner GDH, Faiz MA, Tarning J, Oates JA, Anstey NM, White NJ, Day NPJ, Hossain MA, Roberts Ii LJ, and Dondorp AM
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- Acetaminophen administration & dosage, Acetaminophen pharmacokinetics, Adolescent, Adult, Analgesics, Non-Narcotic administration & dosage, Analgesics, Non-Narcotic pharmacokinetics, Analgesics, Non-Narcotic therapeutic use, Antimalarials adverse effects, Antimalarials therapeutic use, Area Under Curve, Female, Humans, Male, Young Adult, Acetaminophen therapeutic use, Acute Kidney Injury chemically induced, Acute Kidney Injury prevention & control, Artesunate adverse effects, Artesunate therapeutic use, Malaria, Falciparum drug therapy
- Abstract
Background: Acute kidney injury independently predicts mortality in falciparum malaria. It is unknown whether acetaminophen's capacity to inhibit plasma hemoglobin-mediated oxidation is renoprotective in severe malaria., Methods: This phase 2, open-label, randomized controlled trial conducted at two hospitals in Bangladesh assessed effects on renal function, safety, pharmacokinetic (PK) properties and pharmacodynamic (PD) effects of acetaminophen. Febrile patients (>12 years) with severe falciparum malaria were randomly assigned to receive acetaminophen (1 g 6-hourly for 72 hours) or no acetaminophen, in addition to intravenous artesunate. Primary outcome was the proportional change in creatinine after 72 hours stratified by median plasma hemoglobin., Results: Between 2012 and 2014, 62 patients were randomly assigned to receive acetaminophen (n = 31) or no acetaminophen (n = 31). Median (interquartile range) reduction in creatinine after 72 hours was 23% (37% to 18%) in patients assigned to acetaminophen, versus 14% (29% to 0%) in patients assigned to no acetaminophen (P = .043). This difference in reduction was 37% (48% to 22%) versus 14% (30% to -71%) in patients with hemoglobin ≥45000 ng/mL (P = .010). The proportion with progressing kidney injury was higher among controls (subdistribution hazard ratio, 3.0; 95% confidence interval, 1.1 to 8.5; P = .034). PK-PD analyses showed that higher exposure to acetaminophen increased the probability of creatinine improvement. No patient fulfilled Hy's law for hepatotoxicity., Conclusions: In this proof-of-principle study, acetaminophen showed renoprotection without evidence of safety concerns in patients with severe falciparum malaria, particularly in those with prominent intravascular hemolysis., Clinical Trials Registration: NCT01641289.
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- 2018
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26. Quantitation of paracetamol by liquid chromatography-mass spectrometry in human plasma in support of clinical trial.
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Kam RK, Chan MH, Wong HT, Ghose A, Dondorp AM, Plewes K, and Tarning J
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Aim: Paracetamol is a well-tolerated antipyretic widely used in severe malaria management. The study aimed to develop and validate a rapid LC-MS/MS assay to quantify paracetamol in plasma from patients with severe malaria., Materials & Methods: Plasma sample was precipitated by organic solvent containing isotope-labeled paracetamol internal standard. Supernatant was isolated, diluted with water, followed by LC-MS/MS analysis., Results: Plasma samples were extracted and assayed in less than 5.5 min. The assay response was linear (0.125-50 mg/l) with total intra- and interassay imprecision of <1.4%, which were considerably lower than most published reports., Conclusion: We developed, validated and applied a rapid and small volume LC-MS/MS assay with high precision and accuracy for plasma paracetamol quantitation in 989 samples from 62 patients with severe malaria. The simple and high-throughput quality could facilitate assay automation for future clinical studies., Competing Interests: Financial & competing interests disclosure This study was part of Mahidol-Oxford Tropical Medicine Research Unit (MORU), Bangkok, Thailand core malaria research supported by the Wellcome Trust of Great Britain [grant number A-15–0001]. RK-T Kam, H-T Wong and the LC–MS/MS instruments were financially supported by Phase I Clinical Trial Center, The Chinese University of Hong Kong. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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- 2018
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27. Intravascular haemolysis in severe Plasmodium knowlesi malaria: association with endothelial activation, microvascular dysfunction, and acute kidney injury.
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Barber BE, Grigg MJ, Piera KA, William T, Cooper DJ, Plewes K, Dondorp AM, Yeo TW, and Anstey NM
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- Acute Kidney Injury metabolism, Adult, Angiopoietin-2 metabolism, Creatinine metabolism, E-Selectin metabolism, Endothelial Cells metabolism, Erythrocytes metabolism, Erythrocytes parasitology, Female, Hemoglobins metabolism, Hemolysis, Humans, Intercellular Adhesion Molecule-1 metabolism, Interleukin-6 metabolism, Malaria, Falciparum complications, Malaria, Falciparum metabolism, Malaria, Falciparum parasitology, Malaysia, Male, Microvessels metabolism, Nitric Oxide metabolism, Osteoprotegerin metabolism, Young Adult, Acute Kidney Injury etiology, Malaria, Falciparum physiopathology, Microvessels physiopathology, Plasmodium knowlesi physiology
- Abstract
Plasmodium knowlesi occurs throughout Southeast Asia, and is the most common cause of human malaria in Malaysia. Severe disease in humans is characterised by high parasite biomass, reduced red blood cell deformability, endothelial activation and microvascular dysfunction. However, the roles of intravascular haemolysis and nitric oxide (NO)-dependent endothelial dysfunction, important features of severe falciparum malaria, have not been evaluated, nor their role in acute kidney injury (AKI). In hospitalised Malaysian adults with severe (n = 48) and non-severe (n = 154) knowlesi malaria, and in healthy controls (n = 50), we measured cell-free haemoglobin (CFHb) and assessed associations with the endothelial Weibel-Palade body (WPB) constituents, angiopoietin-2 and osteoprotegerin, endothelial and microvascular function, and other markers of disease severity. CFHb was increased in knowlesi malaria in proportion to disease severity, and to a greater extent than previously reported in severe falciparum malaria patients from the same study cohort. In knowlesi malaria, CFHb was associated with parasitaemia, and independently associated with angiopoietin-2 and osteoprotegerin. As with angiopoietin-2, osteoprotegerin was increased in proportion to disease severity, and independently associated with severity markers including creatinine, lactate, interleukin-6, endothelial cell adhesion molecules ICAM-1 and E-selectin, and impaired microvascular reactivity. Osteoprotegerin was also independently associated with NO-dependent endothelial dysfunction. AKI was found in 88% of those with severe knowlesi malaria. Angiopoietin-2 and osteoprotegerin were both independent risk factors for acute kidney injury. Our findings suggest that haemolysis-mediated endothelial activation and release of WPB constituents is likely a key contributor to end-organ dysfunction, including AKI, in severe knowlesi malaria.
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- 2018
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28. The effect of regularly dosed paracetamol versus no paracetamol on renal function in Plasmodium knowlesi malaria (PACKNOW): study protocol for a randomised controlled trial.
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Cooper DJ, Plewes K, Grigg MJ, Rajahram GS, Piera KA, William T, Chatfield MD, Yeo TW, Dondorp AM, Anstey NM, and Barber BE
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- Acetaminophen adverse effects, Acute Kidney Injury diagnosis, Acute Kidney Injury parasitology, Antioxidants adverse effects, Biomarkers blood, Biomarkers urine, Hemolysis drug effects, Humans, Malaria blood, Malaria diagnosis, Malaria parasitology, Malaysia, Multicenter Studies as Topic, Oxidative Stress drug effects, Randomized Controlled Trials as Topic, Risk Factors, Time Factors, Treatment Outcome, Acetaminophen administration & dosage, Acute Kidney Injury prevention & control, Antioxidants administration & dosage, Malaria drug therapy, Plasmodium knowlesi pathogenicity
- Abstract
Background: Plasmodium knowlesi is the most common cause of human malaria in Malaysia. Acute kidney injury (AKI) is a frequent complication. AKI of any cause can have long-term consequences, including increased risk of chronic kidney disease, adverse cardiovascular events and increased mortality. Additional management strategies are therefore needed to reduce the frequency and severity of AKI in malaria. In falciparum malaria, cell-free haemoglobin (CFHb)-mediated oxidative damage contributes to AKI. The inexpensive and widely available drug paracetamol inhibits CFHb-induced lipid peroxidation via reduction of ferryl haem to the less toxic Fe
3+ state, and has been shown to reduce oxidative damage and improve renal function in patients with sepsis complicated by haemolysis as well as in falciparum malaria. This study aims to assess the ability of regularly dosed paracetamol to reduce the incidence and severity of AKI in knowlesi malaria by attenuating haemolysis-induced oxidative damage., Methods: PACKNOW is a two-arm, open-label randomised controlled trial of adjunctive paracetamol versus no paracetamol in patients aged ≥ 5 years with knowlesi malaria, conducted over a 2-year period at four hospital sites in Sabah, Malaysia. The primary endpoint of change in creatinine from enrolment to 72 h will be evaluated by analysis of covariance (ANCOVA) using enrolment creatinine as a covariate. Secondary endpoints include longitudinal changes in markers of oxidative stress (plasma F2 -isoprostanes and isofurans) and markers of endothelial activation/Weibel-Palade body release (angiopoietin-2, von Willebrand Factor, P-selectin, osteoprotegerin) over 72 h, as well as blood and urine biomarkers of AKI. This study will be powered to detect a difference between the two treatment arms in a clinically relevant population including adults and children with knowlesi malaria of any severity., Discussion: Paracetamol is widely available and has an excellent safety profile; if a renoprotective effect is demonstrated, this trial will support the administration of regularly dosed paracetamol to all patients with knowlesi malaria. The secondary outcomes in this study will provide further insights into the pathophysiology of haemolysis-induced oxidative damage and acute kidney injury in knowlesi malaria and other haemolytic diseases., Trial Registration: Clinicaltrials.gov, NCT03056391 . Registered on 12 October 2016.- Published
- 2018
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29. Rickettsial Illnesses as Important Causes of Febrile Illness in Chittagong, Bangladesh.
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Kingston HW, Hossain M, Leopold S, Anantatat T, Tanganuchitcharnchai A, Sinha I, Plewes K, Maude RJ, Chowdhury MAH, Paul S, Uddin RAME, Siddiqui MAN, Zahed AS, Abu Sayeed A, Rahman MH, Barua A, Uddin MJ, Sattar MA, Dondorp AM, Blacksell SD, Day NPJ, Ghose A, Hossain A, and Paris DH
- Subjects
- Animals, Bangladesh epidemiology, Fever diagnosis, Humans, Mice, Phylogeny, Polymerase Chain Reaction, Population Surveillance, Prevalence, Rickettsia Infections diagnosis, Seasons, Serologic Tests, Fever epidemiology, Fever microbiology, Rickettsia classification, Rickettsia genetics, Rickettsia Infections epidemiology, Rickettsia Infections microbiology
- Abstract
We conducted a yearlong prospective study of febrile patients admitted to a tertiary referral hospital in Chittagong, Bangladesh, to assess the proportion of patients with rickettsial illnesses and identify the causative pathogens, strain genotypes, and associated seasonality patterns. We diagnosed scrub typhus in 16.8% (70/416) and murine typhus in 5.8% (24/416) of patients; 2 patients had infections attributable to undifferentiated Rickettsia spp. and 2 had DNA sequence-confirmed R. felis infection. Orientia tsutsugamushi genotypes included Karp, Gilliam, Kato, and TA763-like strains, with a prominence of Karp-like strains. Scrub typhus admissions peaked in a biphasic pattern before and after the rainy season, whereas murine typhus more frequently occurred before the rainy season. Death occurred in 4% (18/416) of cases; case-fatality rates were 4% each for scrub typhus (3/70) and murine typhus (1/28). Overall, 23.1% (96/416) of patients had evidence of treatable rickettsial illnesses, providing important evidence toward optimizing empirical treatment strategies.
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- 2018
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30. Acidosis and acute kidney injury in severe malaria.
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Sriboonvorakul N, Ghose A, Hassan MMU, Hossain MA, Faiz MA, Pukrittayakamee S, Chotivanich K, Sukthana Y, Leopold SJ, Plewes K, Day NPJ, White NJ, Tarning J, and Dondorp AM
- Subjects
- Acidosis parasitology, Acidosis physiopathology, Acids blood, Acids urine, Acute Kidney Injury parasitology, Acute Kidney Injury physiopathology, Adult, Bangladesh, Female, Humans, Male, Middle Aged, Young Adult, Acidosis metabolism, Acute Kidney Injury metabolism, Malaria, Falciparum complications, Phenylpropionates blood, Phenylpropionates urine, Sepsis complications
- Abstract
Background: In severe falciparum malaria metabolic acidosis and acute kidney injury (AKI) are independent predictors of a fatal outcome in all age groups. The relationship between plasma acids, urine acids and renal function was investigated in adult patients with acute falciparum malaria., Methods: Plasma and urinary acids which previously showed increased concentrations in proportion to disease severity in patients with severe falciparum malaria were quantified. Patients with uncomplicated malaria, sepsis and healthy volunteers served as comparator groups. Multiple regression and multivariate analysis were used to assess the relationship between organic acid concentrations and clinical syndromes, in particular AKI., Results: Patients with severe malaria (n = 90), uncomplicated malaria (n = 94), non-malaria sepsis (n = 19), and healthy volunteers (n = 61) were included. Univariate analysis showed that both plasma and creatinine-adjusted urine concentrations of p-hydroxyphenyllactic acid (pHPLA) were higher in severe malaria patients with AKI (p < 0.001). Multiple regression analysis, including plasma or creatinine-adjusted urinary acids, and PfHRP2 as parasite biomass marker as independent variables, showed that pHPLA was independently associated with plasma creatinine (β = 0.827) and urine creatinine (β = 0.226). Principal component analysis, including four plasma acids and seven urinary acids separated a group of patients with AKI, which was mainly driven by pHPLA concentrations., Conclusions: Both plasma and urine concentrations of pHPLA closely correlate with AKI in patients with severe falciparum malaria. Further studies will need to assess the potential nephrotoxic properties of pHPLA.
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- 2018
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31. Pathophysiology, clinical presentation, and treatment of coma and acute kidney injury complicating falciparum malaria.
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Plewes K, Turner GDH, and Dondorp AM
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- Acetaminophen administration & dosage, Acute Kidney Injury pathology, Animals, Anti-Inflammatory Agents administration & dosage, Antioxidants administration & dosage, Brain diagnostic imaging, Brain pathology, Coma pathology, Dexamethasone administration & dosage, Disease Models, Animal, Humans, Kidney pathology, Mannitol administration & dosage, Oxidative Stress, Treatment Outcome, Acute Kidney Injury physiopathology, Acute Kidney Injury therapy, Coma physiopathology, Coma therapy, Malaria, Falciparum complications
- Abstract
Purpose of Review: Cerebral impairment and acute kidney injury (AKI) are independent predictors of mortality in both adults and children with severe falciparum malaria. In this review, we present recent advances in understanding the pathophysiology, clinical features, and management of these complications of severe malaria, and discuss future areas of research., Recent Findings: Cerebral malaria and AKI are serious and well recognized complications of severe malaria. Common pathophysiological pathways include impaired microcirculation, due to sequestration of parasitized erythrocytes, systemic inflammatory responses, and endothelial activation. Recent MRI studies show significant brain swelling in both adults and children with evidence of posterior reversible encephalopathy syndrome-like syndrome although targeted interventions including mannitol and dexamethasone are not beneficial. Recent work shows association of cell-free hemoglobin oxidation stress involved in the pathophysiology of AKI in both adults and children. Paracetamol protected renal function likely by inhibiting cell-free-mediated oxidative stress. It is unclear if heme-mediated endothelial activation or oxidative stress is involved in cerebral malaria., Summary: The direct causes of cerebral and kidney dysfunction remain incompletely understood. Optimal treatment involves prompt diagnosis and effective antimalarial treatment with artesunate. Renal replacement therapy reduces mortality in AKI but delayed diagnosis is an issue.
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- 2018
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32. Disease Severity and Effective Parasite Multiplication Rate in Falciparum Malaria.
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Kingston HW, Ghose A, Plewes K, Ishioka H, Leopold SJ, Maude RJ, Paul S, Intharabut B, Silamut K, Woodrow C, Day NPJ, Chotivanich K, Anstey NM, Hossain A, White NJ, and Dondorp AM
- Abstract
Patients presenting with severe falciparum malaria in a Bangladeshi tertiary hospital had higher total parasite burden, estimated by parasitemia and plasma PfHRP2, than uncomplicated malaria patients despite shorter fever duration. This suggests that higher parasite multiplication rates (PMR) contribute to causing the higher biomass found in severe disease. Compared with patients without a history of previous malaria, patients with previous malaria carried a lower parasite biomass with similar fever duration at presentation, suggesting that host immunity reduces the PMR.
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- 2017
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33. Measuring the Plasmodium falciparum HRP2 protein in blood from artesunate-treated malaria patients predicts post-artesunate delayed hemolysis.
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Ndour PA, Larréché S, Mouri O, Argy N, Gay F, Roussel C, Jauréguiberry S, Perillaud C, Langui D, Biligui S, Chartrel N, Mérens A, Kendjo E, Ghose A, Hassan MMU, Hossain MA, Kingston HWF, Plewes K, Dondorp AM, Danis M, Houzé S, Bonnefoy S, Thellier M, Woodrow CJ, and Buffet PA
- Subjects
- Adolescent, Adult, Aged, Artemisinins pharmacology, Artesunate, Cytosol metabolism, Demography, Erythrocyte Membrane drug effects, Erythrocyte Membrane metabolism, Erythrocytes drug effects, Erythrocytes parasitology, Erythrocytes ultrastructure, Female, Humans, Malaria parasitology, Male, Middle Aged, Plasmodium falciparum drug effects, Plasmodium falciparum pathogenicity, Quinine pharmacology, Quinine therapeutic use, Young Adult, Antigens, Protozoan blood, Artemisinins therapeutic use, Hemolysis, Malaria blood, Malaria drug therapy, Plasmodium falciparum metabolism, Protozoan Proteins blood
- Abstract
Artesunate, the recommended drug for severe malaria, rapidly clears the malaria parasite from infected patients but frequently induces anemia-called post-artesunate delayed hemolysis (PADH)-for which a simple predictive test is urgently needed. The underlying event in PADH is the expulsion of artesunate-exposed parasites from their host erythrocytes by pitting. We show that the histidine-rich protein 2 (HRP2) of the malaria parasite Plasmodium falciparum persists in the circulation of artesunate-treated malaria patients in Bangladesh and in French travelers who became infected with malaria in Africa. HRP2 persisted in whole blood (not plasma) of artesunate-treated patients with malaria at higher levels compared to quinine-treated patients. Using an optimized membrane permeabilization method, HRP2 was observed by immunofluorescence, Western blotting, and electron microscopy to persist in once-infected red blood cells from artesunate-treated malaria patients. HRP2 was deposited at the membrane of once-infected red blood cells in a pattern similar to that for ring erythrocyte surface antigen (RESA), a parasite invasion marker. On the basis of these observations, we developed a semiquantitative titration method using a widely available HRP2-based rapid diagnostic dipstick test. Positivity on this test using a 1:500 dilution of whole blood from artesunate-treated patients with malaria collected shortly after parasite clearance predicted subsequent PADH with 89% sensitivity and 73% specificity. These results suggest that adapting an existing HRP2-based rapid diagnostic dipstick test may enable prediction of PADH several days before it occurs in artesunate-treated patients with malaria., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
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- 2017
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34. Cell-free hemoglobin mediated oxidative stress is associated with acute kidney injury and renal replacement therapy in severe falciparum malaria: an observational study.
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Plewes K, Kingston HWF, Ghose A, Maude RJ, Herdman MT, Leopold SJ, Ishioka H, Hasan MMU, Haider MS, Alam S, Piera KA, Charunwatthana P, Silamut K, Yeo TW, Faiz MA, Lee SJ, Mukaka M, Turner GDH, Anstey NM, Jackson Roberts L 2nd, White NJ, Day NPJ, Hossain MA, and Dondorp AM
- Subjects
- Acute Kidney Injury mortality, Acute Kidney Injury therapy, Adult, Antigens, Protozoan blood, Biomarkers blood, Creatinine blood, Erythrocytes pathology, F2-Isoprostanes blood, F2-Isoprostanes urine, Female, Humans, Lipid Peroxidation, Malaria, Falciparum complications, Malaria, Falciparum mortality, Male, Middle Aged, Prospective Studies, Protozoan Proteins blood, Renal Dialysis, Sepsis blood, Sepsis etiology, Acute Kidney Injury etiology, Hemoglobins metabolism, Malaria, Falciparum metabolism, Oxidative Stress
- Abstract
Background: Intravascular hemolysis is an intrinsic feature of severe malaria pathophysiology but the pathogenic role of cell-free hemoglobin-mediated oxidative stress in severe malaria associated acute kidney injury (AKI) is unknown., Methods: As part of a prospective observational study, enrolment plasma cell-free hemoglobin (CFH), lipid peroxidation markers (F
2 -isoprostanes (F2 -IsoPs) and isofurans (IsoFs)), red cell deformability, and serum creatinine were quantified in Bangladeshi patients with severe falciparum malaria (n = 107), uncomplicated malaria (n = 80) and sepsis (n = 28). The relationships between these indices and kidney function and clinical outcomes were examined., Results: AKI was diagnosed at enrolment in 58% (62/107) of consecutive patients with severe malaria, defined by an increase in creatinine ≥1.5 times expected baseline. Severe malaria patients with AKI had significantly higher plasma cell-free hemoglobin (geometric mean CFH: 8.8 μM; 95% CI, 6.2-12.3 μM), F2 -isoprostane (56.7 pg/ml; 95% CI, 45.3-71.0 pg/ml) and isofuran (109.2 pg/ml; 95% CI, 85.1-140.1 pg/ml) concentrations on enrolment compared to those without AKI (CFH: 5.1 μM; 95% CI, 4.0-6.6 μM; P = 0.018; F2 -IsoPs: 27.8 pg/ml; 95% CI, 23.7-32.7 pg/ml; P < 0.001; IsoFs: 41.7 pg/ml; 95% CI, 30.2-57.6 pg/ml; P < 0.001). Cell-free hemoglobin correlated with markers of hemolysis, parasite burden (P. falciparum histidine rich protein 2 (PfHRP2)), and F2 -IsoPs. Plasma F2 -IsoPs and IsoFs inversely correlated with pH, positively correlated with creatinine, PfHRP2 and fractional excretion of sodium, and were higher in patients later requiring hemodialysis. Plasma F2 -IsoP concentrations also inversely correlated with red cell deformability and were higher in fatal cases. Mixed effects modeling including an interaction term for CFH and time showed that F2 -IsoPs, IsoFs, PfHRP2, CFH, and red cell rigidity were independently associated with increasing creatinine over 72 h. Multivariable logistic regression showed that admission F2 -IsoPs, IsoFs and red cell deformability were associated with the need for subsequent hemodialysis., Conclusions: Cell-free hemoglobin and lipid peroxidation are associated with acute kidney injury and disease severity in falciparum malaria, suggesting a pathophysiological role in renal tubular injury. Evaluation of adjunctive therapies targeting cell-free hemoglobin-mediated oxidative stress is warranted.- Published
- 2017
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35. Genotypic and phenotypic characterization of G6PD deficiency in Bengali adults with severe and uncomplicated malaria.
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Plewes K, Soontarawirat I, Ghose A, Bancone G, Kingston HWF, Herdman MT, Leopold SJ, Ishioka H, Faiz MA, Anstey NM, Day NPJ, Hossain MA, Imwong M, Dondorp AM, and Woodrow CJ
- Subjects
- Adult, Bangladesh epidemiology, Diagnostic Tests, Routine, Ethnicity, Female, Genotyping Techniques, Glucosephosphate Dehydrogenase Deficiency genetics, Humans, Male, Middle Aged, Prospective Studies, Glucosephosphate Dehydrogenase Deficiency epidemiology, Glucosephosphate Dehydrogenase Deficiency pathology, Malaria, Falciparum complications
- Abstract
Background: Control of malaria increasingly involves administration of 8-aminoquinolines, with accompanying risk of haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Few data on the prevalence and genotypic basis of G6PD deficiency are available from Bangladesh, where malaria remains a major problem in the South (Chittagong Division). The aim of this study was to determine the prevalence of G6PD deficiency, and associated G6PD genotypes, in adults with falciparum malaria in southern Bangladesh., Methods: G6PD status was assessed via a combination of fluorescent spot testing (FST) and genotyping in 141 Bengali patients admitted with falciparum malaria to two centres in Chittagong Division from 2012 to 2014. In addition, an analysis of genomic data from 1000 Genomes Project was carried out among five healthy Indian subcontinent populations., Results: One male patient with uncomplicated malaria was found to have G6PD deficiency on FST and a genotype associated with deficiency (hemizygous Orissa variant). In addition, there were two female patients heterozygous for deficiency variants (Orissa and Kerala-Kalyan). These three patients had a relatively long duration of symptoms prior to admission compared to G6PD normal cases, possibly suggesting an interaction with parasite multiplication rate. In addition, one of 27 healthy local controls was deficient on FST and hemizygous for the Mahidol variant of G6PD deficiency. Examination of 1000 Genomes Project sequencing data across the Indian subcontinent showed that 19/723 chromosomes (2.63%) carried a variant associated with deficiency. In the Bengali from Bangladesh 1000 Genomes population, three of 130 chromosomes (2.31%) carried deficient alleles; this included single chromosomes carrying the Kerala-Kalyan and Orissa variants., Conclusions: In line with other recent work, G6PD deficiency is uncommon in Bengalis in Bangladesh. Further studies of particular ethnic groups are needed to evaluate the potential risk of wide deployment of primaquine in malaria control efforts in Bangladesh.
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- 2017
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36. Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria.
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Jeeyapant A, Kingston HW, Plewes K, Maude RJ, Hanson J, Herdman MT, Leopold SJ, Ngernseng T, Charunwatthana P, Phu NH, Ghose A, Hasan MM, Fanello CI, Faiz MA, Hien TT, Day NP, White NJ, and Dondorp AM
- Subjects
- Adult, Area Under Curve, Artemether, Artemisinins therapeutic use, Bangladesh, Child, Coma complications, Databases as Topic, Glasgow Coma Scale, Humans, Lactates blood, Malaria, Falciparum blood, Malaria, Falciparum drug therapy, Malaria, Falciparum mortality, Quinine therapeutic use, ROC Curve, Reproducibility of Results, Biomarkers, Clinical Trials as Topic, Malaria, Falciparum diagnosis
- Abstract
Background: Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria., Methods: Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African 'AQUAMAT' trial comparing artesunate and quinine (children), and the Vietnamese 'AQ' study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures., Results: Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the 'AQUAMAT' study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery., Conclusions: The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2017
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37. Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria.
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Wattanakul T, Teerapong P, Plewes K, Newton PN, Chierakul W, Silamut K, Chotivanich K, Ruengweerayut R, White NJ, Dondorp AM, and Tarning J
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- Administration, Oral, Adolescent, Adult, Antipyretics administration & dosage, Antipyretics pharmacokinetics, Biological Availability, Cross-Over Studies, Female, Half-Life, Humans, Injections, Intramuscular, Male, Middle Aged, Young Adult, Acetaminophen administration & dosage, Acetaminophen pharmacokinetics, Antimalarials administration & dosage, Antimalarials pharmacokinetics, Malaria, Falciparum drug therapy
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Background: Fever is an inherent symptom of malaria in both adults and children. Paracetamol (acetaminophen) is the recommended antipyretic as it is inexpensive, widely available and has a good safety profile, but patients may not be able to take the oral drug reliably. A comparison between the pharmacokinetics of oral syrup and intramuscular paracetamol given to patients with acute falciparum malaria and high body temperature was performed., Methods: A randomized, open-label, two-treatment, crossover, pharmacokinetic study of paracetamol dosed orally and intramuscularly was conducted. Twenty-one adult patients with uncomplicated falciparum malaria were randomized to receive a single 600 mg dose of paracetamol either as syrup or intramuscular injection on day 0 followed by a single dose administered by the alternative route on day 1. Paracetamol plasma concentrations were quantified frequently and modelled simultaneously using nonlinear mixed-effects modelling. The final population pharmacokinetic model was used for dose optimization simulations. Relationships between paracetamol concentrations with temperature and parasite half-life were investigated using linear and non-linear regression analyses., Results: The population pharmacokinetic properties of paracetamol were best described by a two-compartment disposition model, with zero-order and first-order absorption for intramuscular and oral syrup administration, respectively. The relative bioavailability of oral syrup was 84.4 % (95 % CI 68.2-95.1 %) compared to intramuscular administration. Dosing simulations showed that 1000 mg of intramuscular or oral syrup administered six-hourly reached therapeutic steady state concentrations for antipyresis, but more favourable concentration-time profiles were achieved with a loading dose of 1500 mg, followed by a 1000 mg maintenance dose. This ensured that maximum therapeutic concentrations were reached rapidly during the first 6 h. No significant relationships between paracetamol concentrations and temperature or parasite half-life were found., Conclusions: Paracetamol plasma concentrations after oral syrup and intramuscular administration in patients with acute falciparum malaria were described successfully by a two-compartment disposition model. Relative oral bioavailability compared to intramuscular dosing was estimated as 84.4 % (95 % CI 68.2-95.1 %). Dosing simulations showed that a loading dose followed by six-hourly dosing intervals reduced the time delay to reach therapeutic drug levels after both routes of administration. The safety and efficacy of loading dose paracetamol antipyretic regimens now needs to be established in larger studies.
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- 2016
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38. Sequestration and Red Cell Deformability as Determinants of Hyperlactatemia in Falciparum Malaria.
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Ishioka H, Ghose A, Charunwatthana P, Maude R, Plewes K, Kingston H, Intharabut B, Woodrow C, Chotivanich K, Sayeed AA, Hasan MU, Day NP, Faiz A, White NJ, Hossain A, and Dondorp AM
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- Adult, Bangladesh epidemiology, Female, Humans, Malaria, Falciparum epidemiology, Malaria, Falciparum mortality, Male, Middle Aged, Young Adult, Erythrocyte Deformability physiology, Lactates blood, Malaria, Falciparum pathology
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Background: Hyperlactatemia is a strong predictor of mortality in severe falciparum malaria. Sequestered parasitized erythrocytes and reduced uninfected red blood cell deformability (RCD) compromise microcirculatory flow, leading to anaerobic glycolysis., Methods: In a cohort of patients with falciparum malaria hospitalized in Chittagong, Bangladesh, bulk RCD was measured using a laser diffraction technique, and parasite biomass was estimated from plasma concentrations of Plasmodium falciparum histidine-rich protein 2 (PfHRP2). A multiple linear regression model was constructed to examine their associations with plasma lactate concentrations., Results: A total of 286 patients with falciparum malaria were studied, of whom 224 had severe malaria, and 70 died. Hyperlactatemia (lactate level, ≥ 4 mmol/L) was present in 111 cases. RCD at shear stresses of 1.7 Pa and 30 Pa was reduced significantly in patients who died, compared with survivors, individuals with uncomplicated malaria, or healthy individuals (P < .05, for all comparisons). Multiple linear regression analysis showed that the plasma PfHRP2 level, parasitemia level, total bilirubin level, and RCD at a shear stress of 1.7 Pa were each independently correlated with plasma lactate concentrations (n = 278; R(2) = 0.35)., Conclusions: Sequestration of parasitized red blood cells and reduced RCD both contribute to decreased microcirculatory flow in severe disease., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.)
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- 2016
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39. Severe falciparum malaria complicated by prolonged haemolysis and rhinomaxillary mucormycosis after parasite clearance: a case report.
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Plewes K, Maude RJ, Ghose A, and Dondorp AM
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- Adult, Anemia, Hemolytic pathology, Antimalarials therapeutic use, Ceftriaxone administration & dosage, Coinfection complications, Coinfection drug therapy, Humans, Malaria, Falciparum drug therapy, Malaria, Falciparum parasitology, Male, Maxillary Diseases microbiology, Mucormycosis drug therapy, Parasitemia drug therapy, Rhinitis microbiology, Severity of Illness Index, Anemia, Hemolytic chemically induced, Ceftriaxone adverse effects, Malaria, Falciparum complications, Maxillary Diseases complications, Mucormycosis complications, Opportunistic Infections complications, Rhinitis complications
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Background: Severe falciparum malaria may be complicated by prolonged haemolysis and recurrent fever after parasite clearance. However, their respective etiologies are unclear and challenging to diagnose. We report the first case of severe falciparum malaria followed by prolonged haemolytic anaemia and rhinomaxillary mucormycosis in a previously healthy adult male., Case Presentation: A 30-year old Bangladeshi man was admitted with severe falciparum malaria complicated by hyperlactataemia and haemoglobinuria. Prior to admission he was treated with intravenous quinine and upon admission received intravenous artesunate and empiric ceftriaxone. Thirty hours later the peripheral parasitaemia cleared with resolution of fever and haemoglobinuria. Despite parasite clearance, on day 3 the patient developed recurrent fever and acute haemolytic anaemia requiring seven blood transfusions over six days with no improvement of his haemoglobin or haemoglobinuria. On day 10, he was treated with high-dose dexamethasone and meropenem with discontinuation of the ceftriaxone. Two days later the haemoglobinuria resolved. Ceftriaxone-induced haemolysis was the suspected final diagnosis. On day 16, the patient had progressively worsening right-sided facial pain and swelling; a necrotic ulceration of the hard palate was observed. Rhinomaxillary mucormycosis was diagnosed supported by microscopy findings. The patient initially responded to treatment with urgent surgical debridement, itraconazole, followed by two weeks of amphotericin B deoxycholate, however was subsequently lost to follow up., Conclusions: This case highlights the range of potential alternative aetiologies of acute, prolonged haemolysis and recurrent fever following parasite clearance in severe falciparum malaria. It emphasizes the importance of a high degree of suspicion for alternative causes of haemolysis in order to avoid unnecessary treatments, including blood transfusion and steroids. It is critical to consider and identify common invasive bacterial and rare opportunistic co-infections as a cause of fever in severe malaria patients remaining febrile after parasite clearance to promote antimicrobial stewardship and prompt emergency care.
- Published
- 2015
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40. Erratum to: the role of previously unmeasured organic acids in the pathogenesis of severe malaria.
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Herdman MT, Sriboonvorakul N, Leopold SJ, Douthwaite S, Mohanty S, Hassan MM, Maude RJ, Kingston HW, Plewes K, Charunwatthana P, Silamut K, Woodrow CJ, Ghose A, Chotinavich K, Hossain MA, Faiz MA, Mishra S, Leepipatpiboon N, White NJ, Day NP, Tarning J, and Dondorp AM
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- 2015
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41. The role of previously unmeasured organic acids in the pathogenesis of severe malaria.
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Herdman MT, Sriboonvorakul N, Leopold SJ, Douthwaite S, Mohanty S, Hassan MM, Maude RJ, Kingston HW, Plewes K, Charunwatthana P, Silamut K, Woodrow CJ, Ghose A, Chotinavich K, Hossain MA, Faiz MA, Mishra S, Leepipatpiboon N, White NJ, Day NP, Tarning J, and Dondorp AM
- Subjects
- 3-Hydroxybutyric Acid blood, Acidosis complications, Adolescent, Adult, Aged, Chromatography, Liquid, Female, Humans, Hydroxybutyrates blood, Ketoglutaric Acids urine, Lactic Acid blood, Malaria, Falciparum blood, Malaria, Falciparum metabolism, Malaria, Falciparum mortality, Malaria, Falciparum urine, Male, Malonates urine, Mass Spectrometry, Methylmalonic Acid urine, Middle Aged, Phenylpropionates blood, Prospective Studies, Severity of Illness Index, Young Adult, Malaria, Falciparum etiology
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Introduction: Severe falciparum malaria is commonly complicated by metabolic acidosis. Together with lactic acid (LA), other previously unmeasured acids have been implicated in the pathogenesis of falciparum malaria., Methods: In this prospective study, we characterised organic acids in adults with severe falciparum malaria in India and Bangladesh. Liquid chromatography-mass spectrometry was used to measure organic acids in plasma and urine. Patients were followed until recovery or death., Results: Patients with severe malaria (n=138), uncomplicated malaria (n=102), sepsis (n=32) and febrile encephalopathy (n=35) were included. Strong ion gap (mean ± SD) was elevated in severe malaria (8.2 mEq/L ± 4.5) and severe sepsis (8.6 mEq/L ± 7.7) compared with uncomplicated malaria (6.0 mEq/L ± 5.1) and encephalopathy (6.6 mEq/L ± 4.7). Compared with uncomplicated malaria, severe malaria was characterised by elevated plasma LA, hydroxyphenyllactic acid (HPLA), α-hydroxybutyric acid and β-hydroxybutyric acid (all P<0.05). In urine, concentrations of methylmalonic, ethylmalonic and α-ketoglutaric acids were also elevated. Multivariate logistic regression showed that plasma HPLA was a strong independent predictor of death (odds ratio [OR] 3.5, 95 % confidence interval [CI] 1.6-7.5, P=0.001), comparable to LA (OR 3.5, 95 % CI 1.5-7.8, P=0.003) (combined area under the receiver operating characteristic curve 0.81)., Conclusions: Newly identified acids, in addition to LA, are elevated in patients with severe malaria and are highly predictive of fatal outcome. Further characterisation of their sources and metabolic pathways is now needed.
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- 2015
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42. Severe falciparum malaria treated with artesunate complicated by delayed onset haemolysis and acute kidney injury.
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Plewes K, Haider MS, Kingston HW, Yeo TW, Ghose A, Hossain MA, Dondorp AM, Turner GD, and Anstey NM
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- Acute Kidney Injury parasitology, Administration, Intravenous, Anemia, Hemolytic parasitology, Artesunate, Bangladesh, Humans, Malaria, Falciparum complications, Male, Middle Aged, Parasitemia complications, Treatment Outcome, Acute Kidney Injury drug therapy, Anemia, Hemolytic drug therapy, Artemisinins therapeutic use, Malaria, Falciparum drug therapy, Parasitemia drug therapy
- Abstract
Background: Severe falciparum malaria may be complicated by haemolysis after parasite clearance, however the mechanisms remain unclear. Recent reports describe a pattern of delayed onset haemolysis among non-immune travellers with hyperparasitaemia treated with intravenous artesunate, termed post-artesunate delayed haemolysis (PADH). The occurrence and clinical impact of PADH following severe malaria infections in areas of unstable transmission are unknown., Case: A 45-year-old Bangladeshi male was initially admitted to a local hospital with severe falciparum malaria complicated by hyperparasitaemia and treated with intravenous artesunate. Twenty days from his first presentation he was readmitted with delayed onset haemolytic anaemia and acute kidney injury. Multiple blood transfusions and haemodialysis were required. Renal biopsy revealed acute tubular injury and haem pigment nephropathy. His haemoglobin and renal function recovered to baseline after 62 days from his second admission., Discussion: This case highlights the differential diagnosis of post-malaria delayed onset haemolysis, including the recently described syndrome of post-artemisinin delayed haemolysis. The pathophysiology contributing to acute kidney injury in this patient and the limited treatment options are discussed., Conclusions: This report describes PADH complicated by acute kidney injury in an adult patient living in a malaria hypoendemic region who subsequently required blood transfusions and haemodialysis. This case emphasizes the importance of routine follow up of haemoglobin and renal function in artesunate-treated patients who have recovered from severe malaria.
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- 2015
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43. Microvascular obstruction and endothelial activation are independently associated with the clinical manifestations of severe falciparum malaria in adults: an observational study.
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Hanson J, Lee SJ, Hossain MA, Anstey NM, Charunwatthana P, Maude RJ, Kingston HW, Mishra SK, Mohanty S, Plewes K, Piera K, Hassan MU, Ghose A, Faiz MA, White NJ, Day NP, and Dondorp AM
- Subjects
- Adult, Endothelial Cells metabolism, Female, Humans, Male, Microcirculation, Middle Aged, Capillaries pathology, Endothelial Cells pathology, Malaria, Falciparum blood, Malaria, Falciparum complications, Malaria, Falciparum pathology
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Background: Microvascular obstruction and endothelial dysfunction have both been linked to tissue hypoperfusion in falciparum malaria, but their relative contributions to the disease's pathogenesis and outcome are unknown., Methods: Microvascular blood flow was quantified in adults with severe falciparum malaria on their admission to hospital; plasma biomarkers of endothelial function were measured simultaneously. The relationship between these indices and the patients' clinical findings and in-hospital course was examined., Results: Microvascular obstruction was observed in 119/142 (84 %) patients; a median (interquartile range (IQR)) of 14.9 % (6.6-34.9 %) of capillaries were obstructed in patients that died versus 8.3 % (1.7-26.6 %) in survivors (P = 0.039). The proportion of obstructed capillaries correlated with the estimated parasite biomass (rs = 0.25, P = 0.004) and with plasma lactate (rs = 0.38, P <0.0001), the strongest predictor of death in the series. Plasma angiopoietin-2 (Ang-2) concentrations were markedly elevated suggesting widespread endothelial activation; the median (IQR) Ang-2 concentration was 21.9 ng/mL (13.4-29.4 ng/mL) in patients that died versus 14.9 ng/mL (9.8-29.3 ng/mL) in survivors (P = 0.035). Ang-2 concentrations correlated with estimated parasite biomass (rs = 0.35, P <0.001) and plasma lactate (rs = 0.37, P <0.0001). Microvascular obstruction and Ang-2 concentrations were not significantly correlated with each other (rs = 0.17, P = 0.06), but were independently associated with plasma lactate (P <0.001 and P = 0.002, respectively)., Conclusions: Microvascular obstruction and systemic endothelial activation are independently associated with plasma lactate, the strongest predictor of death in adults with falciparum malaria. This supports the hypothesis that the two processes make an independent contribution to the pathogenesis and clinical manifestations of the disease.
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- 2015
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44. The clinical implications of thrombocytopenia in adults with severe falciparum malaria: a retrospective analysis.
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Hanson J, Phu NH, Hasan MU, Charunwatthana P, Plewes K, Maude RJ, Prapansilp P, Kingston HW, Mishra SK, Mohanty S, Price RN, Faiz MA, Dondorp AM, White NJ, Hien TT, and Day NP
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- Adult, Biomarkers blood, Female, Humans, Malaria, Falciparum mortality, Male, Middle Aged, Platelet Count, Prognosis, Retrospective Studies, Thrombocytopenia mortality, Young Adult, Malaria, Falciparum complications, Thrombocytopenia etiology
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Background: Thrombocytopenia is a common finding in adults with severe falciparum malaria, but its clinical and prognostic utility is incompletely defined., Methods: Clinical and laboratory data from 647 adults with severe falciparum malaria were analysed retrospectively to determine the relationship between a patient's platelet count on admission to hospital and their subsequent clinical course., Results: On admission, 614 patients (94.9%) were thrombocytopenic (platelet count <150 × 10(9)/L) and 328 (50.7%) had a platelet count <50 × 10(9)/L. The admission platelet count was inversely correlated with parasite biomass (estimated from plasma PfHRP2 concentrations, rs = -0.28, P = 0.003), the degree of microvascular sequestration (measured with orthogonal polarizing spectral imaging, rs = -0.31, P = 0.001) and disease severity (the number of World Health Organization severity criteria satisfied by the patient, rs = -0.21, P <0.001). Platelet counts were lower on admission in the patients who died (median: 30 (interquartile range 22 to 52) × 10(9)/L versus 50 (34 to 78) × 10(9)/L in survivors; P <0.001), but did not predict outcome independently from other established laboratory and clinical prognostic indices. The 39 patients (6%) with profound thrombocytopenia (platelet count <20 × 10(9)/L) were more likely to die (odds ratio: 5.00, 95% confidence interval: 2.56 to 9.75) than patients with higher platelet counts, but these high-risk patients could be identified more rapidly with simple bedside clinical assessment. The admission platelet count did not reliably identify the 50 patients (7.7%) with major bleeding during the study., Conclusions: Thrombocytopenia is a marker of disease severity in adults with falciparum malaria, but has limited utility in prognostication, triage and management.
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- 2015
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45. Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker.
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Tun KM, Imwong M, Lwin KM, Win AA, Hlaing TM, Hlaing T, Lin K, Kyaw MP, Plewes K, Faiz MA, Dhorda M, Cheah PY, Pukrittayakamee S, Ashley EA, Anderson TJ, Nair S, McDew-White M, Flegg JA, Grist EP, Guerin P, Maude RJ, Smithuis F, Dondorp AM, Day NP, Nosten F, White NJ, and Woodrow CJ
- Subjects
- Bangladesh epidemiology, Cross-Sectional Studies, DNA, Protozoan chemistry, DNA, Protozoan genetics, Genetic Markers, Genotype, Malaria, Falciparum epidemiology, Mutation, Myanmar epidemiology, Phylogeography, Prevalence, Sequence Analysis, DNA, Thailand epidemiology, Antimalarials pharmacology, Artemisinins pharmacology, Drug Resistance, Malaria, Falciparum parasitology, Plasmodium falciparum drug effects, Plasmodium falciparum genetics
- Abstract
Background: Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations., Methods: We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar., Findings: Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations., Interpretation: Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided., Funding: Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation., (Copyright © 2015 Tun et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.)
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- 2015
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46. Magnetic resonance imaging of the brain in adults with severe falciparum malaria.
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Maude RJ, Barkhof F, Hassan MU, Ghose A, Hossain A, Abul Faiz M, Choudhury E, Rashid R, Abu Sayeed A, Charunwatthana P, Plewes K, Kingston H, Maude RR, Silamut K, Day NP, White NJ, and Dondorp AM
- Subjects
- Adolescent, Adult, Aged, Bangladesh, Female, Humans, Male, Middle Aged, Optic Nerve diagnostic imaging, Optic Nerve pathology, Prospective Studies, Radiography, Retina pathology, Ultrasonography, Young Adult, Brain diagnostic imaging, Brain pathology, Magnetic Resonance Imaging, Malaria, Cerebral pathology
- Abstract
Background: Magnetic resonance imaging (MRI) allows detailed study of structural and functional changes in the brain in patients with cerebral malaria., Methods: In a prospective observational study in adult Bangladeshi patients with severe falciparum malaria, MRI findings in the brain were correlated with clinical and laboratory parameters, retinal photography and optic nerve sheath diameter (ONSD) ultrasound (a marker of intracranial pressure)., Results: Of 43 enrolled patients, 31 (72%) had coma and 12 (28%) died. MRI abnormalities were present in 79% overall with mostly mild changes in a wide range of anatomical sites. There were no differences in MRI findings between patients with cerebral and non-cerebral or fatal and non-fatal disease. Subtle diffuse cerebral swelling was common (n = 22/43), but mostly without vasogenic oedema or raised intracranial pressure (ONSD). Also seen were focal extracellular oedema (n = 11/43), cytotoxic oedema (n = 8/23) and mildly raised brain lactate on magnetic resonance spectroscopy (n = 5/14). Abnormalities were much less prominent than previously described in Malawian children. Retinal whitening was present in 36/43 (84%) patients and was more common and severe in patients with coma., Conclusion: Cerebral swelling is mild and not specific to coma or death in adult severe falciparum malaria. This differs markedly from African children. Retinal whitening, reflecting heterogeneous obstruction of the central nervous system microcirculation by sequestered parasites resulting in small patches of ischemia, is associated with coma and this process is likely important in the pathogenesis.
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- 2014
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47. Correlation of biomarkers for parasite burden and immune activation with acute kidney injury in severe falciparum malaria.
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Plewes K, Royakkers AA, Hanson J, Hasan MM, Alam S, Ghose A, Maude RJ, Stassen PM, Charunwatthana P, Lee SJ, Turner GD, Dondorp AM, and Schultz MJ
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- Acute Kidney Injury immunology, Adolescent, Adult, Animals, Female, Humans, Leukocytes, Mononuclear immunology, Malaria, Falciparum pathology, Male, Middle Aged, Parasite Load, Young Adult, Acute Kidney Injury pathology, Antigens, Protozoan blood, Biomarkers blood, Malaria, Falciparum complications, Malaria, Falciparum immunology, Protozoan Proteins blood, Receptors, Urokinase Plasminogen Activator blood
- Abstract
Background: Acute kidney injury (AKI) complicating severe Plasmodium falciparum malaria occurs in up to 40% of adult patients. The case fatality rate reaches 75% in the absence of renal replacement therapy (RRT). The precise pathophysiology of AKI in falciparum malaria remains unclear. Histopathology shows acute tubular necrosis with localization of host monocytes and parasitized red blood cells in the microvasculature. This study explored the relationship of plasma soluble urokinase-type plasminogen activator receptor (suPAR), as a proxy-measure of mononuclear cell activation, and plasma P. falciparum histidine rich protein 2 (PfHRP2), as a measure of sequestered parasite burden, with AKI in severe malaria., Methods: Admission plasma suPAR and PfHRP2 concentrations were assessed in Bangladeshi adults with severe falciparum malaria (n=137). Patients were stratified according to AKI severity based on admission creatinine clearance., Results: A total of 106 (77%) patients had AKI; 32 (23%), 42 (31%) and 32 (23%) were classified into 'mild, 'moderate' and 'severe' AKI groups, respectively. Plasma suPAR and PfHRP2 concentrations increased with AKI severity (test-for-trend P <0.0001) and correlated with other markers of renal dysfunction. Admission plasma suPAR and PfHRP2 concentrations were higher in patients who later required RRT (P <0.0001 and P=0.0004, respectively). In a multivariate analysis, both increasing suPAR and PfHRP2 were independently associated with increasing urine neutrophil gelatinase-associated lipocalin concentration, a marker of acute tubular necrosis (β=16.54 (95% CI 6.36-26.71) and β=0.07 (0.02-0.11), respectively)., Conclusions: Both sequestered parasite burden and immune activation contribute to the pathogenesis of AKI in severe falciparum malaria.
- Published
- 2014
- Full Text
- View/download PDF
48. Randomized controlled trial of levamisole hydrochloride as adjunctive therapy in severe falciparum malaria with high parasitemia.
- Author
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Maude RJ, Silamut K, Plewes K, Charunwatthana P, Ho M, Abul Faiz M, Rahman R, Hossain MA, Hassan MU, Bin Yunus E, Hoque G, Islam F, Ghose A, Hanson J, Schlatter J, Lacey R, Eastaugh A, Tarning J, Lee SJ, White NJ, Chotivanich K, Day NP, and Dondorp AM
- Subjects
- Adult, Antimalarials pharmacokinetics, Antimalarials pharmacology, Female, Humans, Kaplan-Meier Estimate, Lactic Acid blood, Levamisole pharmacokinetics, Levamisole pharmacology, Malaria, Falciparum metabolism, Malaria, Falciparum parasitology, Male, Microvessels drug effects, Middle Aged, Parasitemia parasitology, Plasmodium falciparum chemistry, Plasmodium falciparum isolation & purification, Regional Blood Flow, Antimalarials therapeutic use, Levamisole therapeutic use, Malaria, Falciparum drug therapy, Parasitemia drug therapy
- Abstract
Background: Cytoadherence and sequestration of erythrocytes containing mature stages of Plasmodium falciparum are central to the pathogenesis of severe malaria. The oral anthelminthic drug levamisole inhibits cytoadherence in vitro and reduces sequestration of late-stage parasites in uncomplicated falciparum malaria treated with quinine., Methods: Fifty-six adult patients with severe malaria and high parasitemia admitted to a referral hospital in Bangladesh were randomized to receive a single dose of levamisole hydrochloride (150 mg) or no adjuvant to antimalarial treatment with intravenous artesunate., Results: Circulating late-stage parasites measured as the median area under the parasite clearance curves were 2150 (interquartile range [IQR], 0-28 025) parasites/µL × hour in patients treated with levamisole and 5489 (IQR, 192-25 848) parasites/µL × hour in controls (P = .25). The "sequestration ratios" at 6 and 12 hours for all parasite stages and changes in microvascular blood flow did not differ between treatment groups (all P > .40). The median time to normalization of plasma lactate (<2 mmol/L) was 24 (IQR, 12-30) hours with levamisole vs 28 (IQR, 12-36) hours without levamisole (P = .15)., Conclusions: There was no benefit of a single-dose of levamisole hydrochloride as adjuvant to intravenous artesunate in the treatment of adults with severe falciparum malaria. Rapid parasite killing by intravenous artesunate might obscure the effects of levamisole.
- Published
- 2014
- Full Text
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49. Does artesunate prolong the electrocardiograph QT interval in patients with severe malaria?
- Author
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Maude RJ, Plewes K, Faiz MA, Hanson J, Charunwatthana P, Lee SJ, Tärning J, Yunus EB, Hoque MG, Hasan MU, Hossain A, Lindegardh N, Day NP, White NJ, and Dondorp AM
- Subjects
- Adult, Antimalarials blood, Antimalarials pharmacokinetics, Artemisinins blood, Artemisinins pharmacokinetics, Artesunate, Blood Pressure drug effects, Ethanolamines therapeutic use, Fluorenes therapeutic use, Glasgow Coma Scale, Heart Rate drug effects, Humans, Long QT Syndrome prevention & control, Lumefantrine, Male, Patient Selection, Antimalarials therapeutic use, Artemisinins therapeutic use, Electrocardiography drug effects, Long QT Syndrome chemically induced, Malaria drug therapy, Malaria physiopathology
- Abstract
Several antimalarials can cause significant prolongation of the electrocardiograph QT interval, which can be associated with an increased risk of potentially lethal ventricular arrhythmias. High doses of artemether and artemotil have been associated with QT prolongation in dogs, raising the possibility of a class effect with the artemisinin derivatives. Serial electrocardiograms were recorded, and QTc interval was calculated before and after administration of artesunate by intravenous injection in patients with severe falciparum malaria in Bangladesh. Of 21 adult patients with severe malaria enrolled, 8 (38%) died. The mean QTc interval was unaffected by bolus intravenous artesunate (2.4 mg/kg). In two patients, the QTc interval exceeded 0.5 seconds, but in both cases, an alternative explanation was plausible. No effect was observed on the JTc or PR interval, QRS width, blood pressure, or heart rate. Intravenous artesunate does not have significant cardiovascular effects in patients with severe falciparum malaria.
- Published
- 2009
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50. Use of molecular beacon probes for real-time PCR detection of Plasmodium falciparum and other plasmodium species in peripheral blood specimens.
- Author
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Elsayed S, Plewes K, Church D, Chow B, and Zhang K
- Subjects
- Animals, DNA Primers, Fluoresceins, Fluorescent Dyes, Humans, Malaria parasitology, Malaria, Falciparum diagnosis, Malaria, Falciparum parasitology, Parasitemia parasitology, Plasmodium classification, Plasmodium genetics, Plasmodium falciparum classification, Plasmodium falciparum genetics, Plasmodium falciparum isolation & purification, Sensitivity and Specificity, Time Factors, Malaria diagnosis, Molecular Probe Techniques, Parasitemia diagnosis, Plasmodium isolation & purification, Polymerase Chain Reaction methods
- Abstract
We describe the development and evaluation of a novel pair of real-time, fluorescence-based PCR assays using molecular beacon probes for rapid, sensitive, and specific detection and quantification of Plasmodium falciparum and other Plasmodium species organisms.
- Published
- 2006
- Full Text
- View/download PDF
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