The Experts below are selected from a list of 3597 Experts worldwide ranked by ideXlab platform

Timothy William - One of the best experts on this subject based on the ideXlab platform.

  • Intravascular haemolysis in severe Plasmodium Knowlesi Malaria: association with endothelial activation, microvascular dysfunction, and acute kidney injury
    2019
    Co-Authors: Bridget E Barber, Timothy William, Matthew J Grigg, Arjen M Dondorp, Kim A. Piera, Daniel J. Cooper, Katherine Plewes, Tsin W. Yeo, Nicholas M Anstey
    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.

  • reduced red blood cell deformability in Plasmodium Knowlesi Malaria
    Blood Advances, 2018
    Co-Authors: Bridget E Barber, Timothy William, Matthew J Grigg, Bruce Russell, Rou Zhang, Amirah Amir, Mark D Chatfield, Arjen M Dondorp, Nicholas M Anstey
    Abstract:

    The simian parasite Plasmodium Knowlesi can cause severe and fatal human Malaria. However, little is known about the pathogenesis of this disease. In falciparum Malaria, reduced red blood cell deformability (RBC-D) contributes to microvascular obstruction and impaired organ perfusion. In P Knowlesi infection, impaired microcirculatory flow has been observed in Macaca mulatta (rhesus macaques), unnatural hosts who develop severe and fatal disease. However, RBC-D has not been measured in human infection or in the natural host M fascicularis (long-tailed macaques). Using ektacytometry, we measured RBC-D in adults with severe and non-severe Knowlesi and falciparum Malaria and in healthy controls. In addition, we used micropipette aspiration to determine the relative stiffness of infected RBCs (iRBCs) and uninfected RBCs (uRBCs) in P Knowlesi-infected humans and M fascicularis. Ektacytometry demonstrated that RBC-D overall was reduced in human Knowlesi Malaria in proportion to disease severity, and in severe Knowlesi Malaria, it was comparable to that of severe falciparum Malaria. RBC-D correlated inversely with parasitemia and lactate in Knowlesi Malaria and HRP2 in falciparum Malaria, and it correlated with hemoglobin nadir in Knowlesi Malaria. Micropipette aspiration confirmed that in humans, P Knowlesi infection increased stiffness of both iRBCs and uRBCs, with the latter mostly the result of echinocytosis. In contrast, in the natural host M fascicularis, echinocyte formation was not observed, and the RBC-D of uRBCs was unaffected. In unnatural primate hosts of P Knowlesi, including humans, reduced deformability of iRBCs and uRBCs may represent a key pathogenic mechanism leading to microvascular accumulation, impaired organ perfusion, and anemia.

  • artemether lumefantrine versus chloroquine for the treatment of uncomplicated Plasmodium Knowlesi Malaria an open label randomized controlled trial can know
    Clinical Infectious Diseases, 2018
    Co-Authors: Matthew J Grigg, Timothy William, Jayaram Menon, Bridget E Barber, Giri Shan Rajahram, Emma Schimann, Christopher S Wilkes, Kaajal Patel, Arjun Chandna, Ric N Price
    Abstract:

    Background Plasmodium Knowlesi is reported increasingly across Southeast Asia and is the most common cause of Malaria in Malaysia. No randomized trials have assessed the comparative efficacy of artemether-lumefantrine (AL) for Knowlesi Malaria. Methods A randomized controlled trial was conducted in 3 district hospitals in Sabah, Malaysia to compare the efficacy of AL against chloroquine (CQ) for uncomplicated Knowlesi Malaria. Participants were included if they weighed >10 kg, had a parasitemia count <20000/μL, and had a negative rapid diagnostic test result for Plasmodium falciparum histidine-rich protein 2. Diagnosis was confirmed by means of polymerase chain reaction. Patients were block randomized to AL (total target dose, 12 mg/kg for artemether and 60 mg/kg for lumefantrine) or CQ (25 mg/kg). The primary outcome was parasite clearance at 24 hours in a modified intention-to-treat analysis. Results From November 2014 to January 2016, a total of 123 patients (including 18 children) were enrolled. At 24 hours after treatment 76% of patients administered AL (95% confidence interval [CI], 63%-86%; 44 of 58) were aparasitemic, compared with 60% administered CQ (47%-72%; 39 of 65; risk ratio, 1.3 [95% CI, 1.0-1.6]; P = .06). Overall parasite clearance was shorter after AL than after CQ (median, 18 vs 24 hours, respectively; P = .02), with all patients aparasitemic by 48 hours. By day 42 there were no treatment failures. The risk of anemia during follow-up was similar between arms. Patients treated with AL would require lower bed occupancy than those treated with CQ (2414 vs 2800 days per 1000 patients; incidence rate ratio, 0.86 [95% CI, .82-.91]; P < .001). There were no serious adverse events. Conclusions AL is highly efficacious for treating uncomplicated Knowlesi Malaria; its excellent tolerability and rapid therapeutic response allow earlier hospital discharge, and support its use as a first-line artemisinin-combination treatment policy for all Plasmodium species in Malaysia. Clinical trials registration NCT02001012.

  • The effect of regularly dosed paracetamol versus no paracetamol on renal function in Plasmodium Knowlesi Malaria (PACKNOW): study protocol for a randomised controlled trial
    BMC, 2018
    Co-Authors: Daniel J. Cooper, Timothy William, Matthew J Grigg, Mark D Chatfield, Arjen M Dondorp, Kim A. Piera, Katherine Plewes, Giri Shan Rajahram, Tsin Wen Yeo, Nicholas M Anstey
    Abstract:

    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 Fe3+ 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

  • artesunate mefloquine versus chloroquine for treatment of uncomplicated Plasmodium Knowlesi Malaria in malaysia act know an open label randomised controlled trial
    Lancet Infectious Diseases, 2016
    Co-Authors: Matthew J Grigg, Timothy William, Jayaram Menon, Bridget E Barber, Giri Shan Rajahram, Christopher S Wilkes, Prabakaran Dhanaraj, Lorenz Von Seidlein, Cielo Pasay, James S Mccarthy
    Abstract:

    Summary Background The zoonotic parasite Plasmodium Knowlesi has become the most common cause of human Malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate–mefloquine with chloroquine to define the optimum treatment for uncomplicated P Knowlesi Malaria in adults and children. Methods We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P Knowlesi Malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate–mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876. Findings Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate–mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76–91]) of 115 patients in the artesunate–mefloquine group versus 61 (55% [45–64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0–40·8]; p vs 24·0 h [6·0–60·0]; p vs 13·8 h [12·1–15·4]; p pks25 was present in 44 (86%) of 51 patients in the artesunate–mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate–mefloquine group (mean 11·5 h [95% CI 8·3–14·6]) than in the chloroquine group (14·8 h [11·7–17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate–mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812–0·906]; p Interpretation Artesunate–mefloquine is highly efficacious for treatment of uncomplicated P Knowlesi Malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas. Funding Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network.

Giri Shan Rajahram - One of the best experts on this subject based on the ideXlab platform.

  • artemether lumefantrine versus chloroquine for the treatment of uncomplicated Plasmodium Knowlesi Malaria an open label randomized controlled trial can know
    Clinical Infectious Diseases, 2018
    Co-Authors: Matthew J Grigg, Timothy William, Jayaram Menon, Bridget E Barber, Giri Shan Rajahram, Emma Schimann, Christopher S Wilkes, Kaajal Patel, Arjun Chandna, Ric N Price
    Abstract:

    Background Plasmodium Knowlesi is reported increasingly across Southeast Asia and is the most common cause of Malaria in Malaysia. No randomized trials have assessed the comparative efficacy of artemether-lumefantrine (AL) for Knowlesi Malaria. Methods A randomized controlled trial was conducted in 3 district hospitals in Sabah, Malaysia to compare the efficacy of AL against chloroquine (CQ) for uncomplicated Knowlesi Malaria. Participants were included if they weighed >10 kg, had a parasitemia count <20000/μL, and had a negative rapid diagnostic test result for Plasmodium falciparum histidine-rich protein 2. Diagnosis was confirmed by means of polymerase chain reaction. Patients were block randomized to AL (total target dose, 12 mg/kg for artemether and 60 mg/kg for lumefantrine) or CQ (25 mg/kg). The primary outcome was parasite clearance at 24 hours in a modified intention-to-treat analysis. Results From November 2014 to January 2016, a total of 123 patients (including 18 children) were enrolled. At 24 hours after treatment 76% of patients administered AL (95% confidence interval [CI], 63%-86%; 44 of 58) were aparasitemic, compared with 60% administered CQ (47%-72%; 39 of 65; risk ratio, 1.3 [95% CI, 1.0-1.6]; P = .06). Overall parasite clearance was shorter after AL than after CQ (median, 18 vs 24 hours, respectively; P = .02), with all patients aparasitemic by 48 hours. By day 42 there were no treatment failures. The risk of anemia during follow-up was similar between arms. Patients treated with AL would require lower bed occupancy than those treated with CQ (2414 vs 2800 days per 1000 patients; incidence rate ratio, 0.86 [95% CI, .82-.91]; P < .001). There were no serious adverse events. Conclusions AL is highly efficacious for treating uncomplicated Knowlesi Malaria; its excellent tolerability and rapid therapeutic response allow earlier hospital discharge, and support its use as a first-line artemisinin-combination treatment policy for all Plasmodium species in Malaysia. Clinical trials registration NCT02001012.

  • The effect of regularly dosed paracetamol versus no paracetamol on renal function in Plasmodium Knowlesi Malaria (PACKNOW): study protocol for a randomised controlled trial
    BMC, 2018
    Co-Authors: Daniel J. Cooper, Timothy William, Matthew J Grigg, Mark D Chatfield, Arjen M Dondorp, Kim A. Piera, Katherine Plewes, Giri Shan Rajahram, Tsin Wen Yeo, Nicholas M Anstey
    Abstract:

    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 Fe3+ 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

  • artesunate mefloquine versus chloroquine for treatment of uncomplicated Plasmodium Knowlesi Malaria in malaysia act know an open label randomised controlled trial
    Lancet Infectious Diseases, 2016
    Co-Authors: Matthew J Grigg, Timothy William, Jayaram Menon, Bridget E Barber, Giri Shan Rajahram, Christopher S Wilkes, Prabakaran Dhanaraj, Lorenz Von Seidlein, Cielo Pasay, James S Mccarthy
    Abstract:

    Summary Background The zoonotic parasite Plasmodium Knowlesi has become the most common cause of human Malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate–mefloquine with chloroquine to define the optimum treatment for uncomplicated P Knowlesi Malaria in adults and children. Methods We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P Knowlesi Malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate–mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876. Findings Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate–mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76–91]) of 115 patients in the artesunate–mefloquine group versus 61 (55% [45–64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0–40·8]; p vs 24·0 h [6·0–60·0]; p vs 13·8 h [12·1–15·4]; p pks25 was present in 44 (86%) of 51 patients in the artesunate–mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate–mefloquine group (mean 11·5 h [95% CI 8·3–14·6]) than in the chloroquine group (14·8 h [11·7–17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate–mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812–0·906]; p Interpretation Artesunate–mefloquine is highly efficacious for treatment of uncomplicated P Knowlesi Malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas. Funding Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network.

  • deaths due to Plasmodium Knowlesi Malaria in sabah malaysia association with reporting as Plasmodium Malariae and delayed parenteral artesunate
    Malaria Journal, 2012
    Co-Authors: Giri Shan Rajahram, Nicholas M Anstey, Timothy William, Jayaram Menon, Bridget E Barber, Tsin W. Yeo
    Abstract:

    Background: The simian parasite Plasmodium Knowlesi is recognized as a common cause of severe and fatal human Malaria in Sabah, Malaysia, but is morphologically indistinguishable from and still commonly reported as Plasmodium Malariae, despite the paucity of this species in Sabah. Since December 2008 Sabah Department of Health has recommended intravenous artesunate and referral to a general hospital for all severe Malaria cases of any species. This paper reviews all Malaria deaths in Sabah subsequent to the introduction of these measures. Reporting of Malaria deaths in Malaysia is mandatory. Methods: Details of reported Malaria deaths during 2010-2011 were reviewed to determine the proportion of each Plasmodium species. Demographics, clinical presentations and management of severe Malaria caused by each species were compared. Results: Fourteen Malaria deaths were reported, comprising seven Plasmodium falciparum, six P. Knowlesi and one Plasmodium vivax (all PCR-confirmed). Of the six P. Knowlesi deaths, five were attributable to Knowlesi Malaria and one was attributable to P. Knowlesi-associated enterobacter sepsis. Patients with directly attributable P. Knowlesi deaths (N=5) were older than those with P. falciparum (median age 51 [IQR 50-65] vs 22 [IQR 9-55] years, p=0.06). Complications in fatal P. Knowlesi included respiratory distress (N=5, 100%), hypotension (N=4, 80%), and renal failure (N=4, 80%). All patients with P. Knowlesi were reported as P. Malariae by microscopy. Only two of five patients with severe Knowlesi Malaria on presentation received immediate parenteral anti-Malarial treatment. The patient with P. vivax-associated severe illness did not receive parenteral treatment. In contrast six of seven patients with severe falciparum Malaria received immediate parenteral treatment. Conclusion: Plasmodium Knowlesi was responsible, either directly or through gram-negative bacteraemia, for almost half of Malaria deaths in Sabah. Patients with severe non-falciparum Malaria were less likely to receive immediate parenteral therapy. This highlights the need in Sabah for microscopically diagnosed P. Malariae to be reported as P. Knowlesi to improve recognition and management of this potentially fatal species. Clinicians need to be better informed of the potential for severe and fatal Malaria from non-falciparum species, and the need to treat all severe Malaria with immediate intravenous artesunate.

  • severe Plasmodium Knowlesi Malaria in a tertiary care hospital sabah malaysia
    Emerging Infectious Diseases, 2011
    Co-Authors: Timothy William, Nicholas M Anstey, Jenarun Jelip, Jayaram Menon, Giri Shan Rajahram, Leslie Chan, Samantha Donaldson, Serena Khoo, Charlie Fredrick, Tsin W. Yeo
    Abstract:

    The simian parasite Plasmodium Knowlesi causes severe human Malaria; the optimal treatment remains unknown. We describe the clinical features, disease spectrum, and response to antiMalarial chemotherapy, including artemether-lumefantrine and artesunate, in patients with P. Knowlesi Malaria diagnosed by PCR during December 2007–November 2009 at a tertiary care hospital in Sabah, Malaysia. Fifty-six patients had PCR-confirmed P. Knowlesi monoinfection and clinical records available for review. Twenty-two (39%) had severe Malaria; of these, 6 (27%) died. Thirteen (59%) had respiratory distress; 12 (55%), acute renal failure; and 12, shock. None experienced coma. Patients with uncomplicated disease received chloroquine, quinine, or artemether-lumefantrine, and those with severe disease received intravenous quinine or artesunate. Parasite clearance times were 1–2 days shorter with either artemether-lumefantrine or artesunate treatment. P. Knowlesi is a major cause of severe and fatal Malaria in Sabah. Artemisinin derivatives rapidly clear parasitemia and are efficacious in treating uncomplicated and severe Knowlesi Malaria.

Matthew J Grigg - One of the best experts on this subject based on the ideXlab platform.

  • Intravascular haemolysis in severe Plasmodium Knowlesi Malaria: association with endothelial activation, microvascular dysfunction, and acute kidney injury
    2019
    Co-Authors: Bridget E Barber, Timothy William, Matthew J Grigg, Arjen M Dondorp, Kim A. Piera, Daniel J. Cooper, Katherine Plewes, Tsin W. Yeo, Nicholas M Anstey
    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.

  • reduced red blood cell deformability in Plasmodium Knowlesi Malaria
    Blood Advances, 2018
    Co-Authors: Bridget E Barber, Timothy William, Matthew J Grigg, Bruce Russell, Rou Zhang, Amirah Amir, Mark D Chatfield, Arjen M Dondorp, Nicholas M Anstey
    Abstract:

    The simian parasite Plasmodium Knowlesi can cause severe and fatal human Malaria. However, little is known about the pathogenesis of this disease. In falciparum Malaria, reduced red blood cell deformability (RBC-D) contributes to microvascular obstruction and impaired organ perfusion. In P Knowlesi infection, impaired microcirculatory flow has been observed in Macaca mulatta (rhesus macaques), unnatural hosts who develop severe and fatal disease. However, RBC-D has not been measured in human infection or in the natural host M fascicularis (long-tailed macaques). Using ektacytometry, we measured RBC-D in adults with severe and non-severe Knowlesi and falciparum Malaria and in healthy controls. In addition, we used micropipette aspiration to determine the relative stiffness of infected RBCs (iRBCs) and uninfected RBCs (uRBCs) in P Knowlesi-infected humans and M fascicularis. Ektacytometry demonstrated that RBC-D overall was reduced in human Knowlesi Malaria in proportion to disease severity, and in severe Knowlesi Malaria, it was comparable to that of severe falciparum Malaria. RBC-D correlated inversely with parasitemia and lactate in Knowlesi Malaria and HRP2 in falciparum Malaria, and it correlated with hemoglobin nadir in Knowlesi Malaria. Micropipette aspiration confirmed that in humans, P Knowlesi infection increased stiffness of both iRBCs and uRBCs, with the latter mostly the result of echinocytosis. In contrast, in the natural host M fascicularis, echinocyte formation was not observed, and the RBC-D of uRBCs was unaffected. In unnatural primate hosts of P Knowlesi, including humans, reduced deformability of iRBCs and uRBCs may represent a key pathogenic mechanism leading to microvascular accumulation, impaired organ perfusion, and anemia.

  • artemether lumefantrine versus chloroquine for the treatment of uncomplicated Plasmodium Knowlesi Malaria an open label randomized controlled trial can know
    Clinical Infectious Diseases, 2018
    Co-Authors: Matthew J Grigg, Timothy William, Jayaram Menon, Bridget E Barber, Giri Shan Rajahram, Emma Schimann, Christopher S Wilkes, Kaajal Patel, Arjun Chandna, Ric N Price
    Abstract:

    Background Plasmodium Knowlesi is reported increasingly across Southeast Asia and is the most common cause of Malaria in Malaysia. No randomized trials have assessed the comparative efficacy of artemether-lumefantrine (AL) for Knowlesi Malaria. Methods A randomized controlled trial was conducted in 3 district hospitals in Sabah, Malaysia to compare the efficacy of AL against chloroquine (CQ) for uncomplicated Knowlesi Malaria. Participants were included if they weighed >10 kg, had a parasitemia count <20000/μL, and had a negative rapid diagnostic test result for Plasmodium falciparum histidine-rich protein 2. Diagnosis was confirmed by means of polymerase chain reaction. Patients were block randomized to AL (total target dose, 12 mg/kg for artemether and 60 mg/kg for lumefantrine) or CQ (25 mg/kg). The primary outcome was parasite clearance at 24 hours in a modified intention-to-treat analysis. Results From November 2014 to January 2016, a total of 123 patients (including 18 children) were enrolled. At 24 hours after treatment 76% of patients administered AL (95% confidence interval [CI], 63%-86%; 44 of 58) were aparasitemic, compared with 60% administered CQ (47%-72%; 39 of 65; risk ratio, 1.3 [95% CI, 1.0-1.6]; P = .06). Overall parasite clearance was shorter after AL than after CQ (median, 18 vs 24 hours, respectively; P = .02), with all patients aparasitemic by 48 hours. By day 42 there were no treatment failures. The risk of anemia during follow-up was similar between arms. Patients treated with AL would require lower bed occupancy than those treated with CQ (2414 vs 2800 days per 1000 patients; incidence rate ratio, 0.86 [95% CI, .82-.91]; P < .001). There were no serious adverse events. Conclusions AL is highly efficacious for treating uncomplicated Knowlesi Malaria; its excellent tolerability and rapid therapeutic response allow earlier hospital discharge, and support its use as a first-line artemisinin-combination treatment policy for all Plasmodium species in Malaysia. Clinical trials registration NCT02001012.

  • The effect of regularly dosed paracetamol versus no paracetamol on renal function in Plasmodium Knowlesi Malaria (PACKNOW): study protocol for a randomised controlled trial
    BMC, 2018
    Co-Authors: Daniel J. Cooper, Timothy William, Matthew J Grigg, Mark D Chatfield, Arjen M Dondorp, Kim A. Piera, Katherine Plewes, Giri Shan Rajahram, Tsin Wen Yeo, Nicholas M Anstey
    Abstract:

    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 Fe3+ 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

  • artesunate mefloquine versus chloroquine for treatment of uncomplicated Plasmodium Knowlesi Malaria in malaysia act know an open label randomised controlled trial
    Lancet Infectious Diseases, 2016
    Co-Authors: Matthew J Grigg, Timothy William, Jayaram Menon, Bridget E Barber, Giri Shan Rajahram, Christopher S Wilkes, Prabakaran Dhanaraj, Lorenz Von Seidlein, Cielo Pasay, James S Mccarthy
    Abstract:

    Summary Background The zoonotic parasite Plasmodium Knowlesi has become the most common cause of human Malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate–mefloquine with chloroquine to define the optimum treatment for uncomplicated P Knowlesi Malaria in adults and children. Methods We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P Knowlesi Malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate–mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876. Findings Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate–mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76–91]) of 115 patients in the artesunate–mefloquine group versus 61 (55% [45–64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0–40·8]; p vs 24·0 h [6·0–60·0]; p vs 13·8 h [12·1–15·4]; p pks25 was present in 44 (86%) of 51 patients in the artesunate–mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate–mefloquine group (mean 11·5 h [95% CI 8·3–14·6]) than in the chloroquine group (14·8 h [11·7–17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate–mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812–0·906]; p Interpretation Artesunate–mefloquine is highly efficacious for treatment of uncomplicated P Knowlesi Malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas. Funding Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network.

Jayaram Menon - One of the best experts on this subject based on the ideXlab platform.

  • artemether lumefantrine versus chloroquine for the treatment of uncomplicated Plasmodium Knowlesi Malaria an open label randomized controlled trial can know
    Clinical Infectious Diseases, 2018
    Co-Authors: Matthew J Grigg, Timothy William, Jayaram Menon, Bridget E Barber, Giri Shan Rajahram, Emma Schimann, Christopher S Wilkes, Kaajal Patel, Arjun Chandna, Ric N Price
    Abstract:

    Background Plasmodium Knowlesi is reported increasingly across Southeast Asia and is the most common cause of Malaria in Malaysia. No randomized trials have assessed the comparative efficacy of artemether-lumefantrine (AL) for Knowlesi Malaria. Methods A randomized controlled trial was conducted in 3 district hospitals in Sabah, Malaysia to compare the efficacy of AL against chloroquine (CQ) for uncomplicated Knowlesi Malaria. Participants were included if they weighed >10 kg, had a parasitemia count <20000/μL, and had a negative rapid diagnostic test result for Plasmodium falciparum histidine-rich protein 2. Diagnosis was confirmed by means of polymerase chain reaction. Patients were block randomized to AL (total target dose, 12 mg/kg for artemether and 60 mg/kg for lumefantrine) or CQ (25 mg/kg). The primary outcome was parasite clearance at 24 hours in a modified intention-to-treat analysis. Results From November 2014 to January 2016, a total of 123 patients (including 18 children) were enrolled. At 24 hours after treatment 76% of patients administered AL (95% confidence interval [CI], 63%-86%; 44 of 58) were aparasitemic, compared with 60% administered CQ (47%-72%; 39 of 65; risk ratio, 1.3 [95% CI, 1.0-1.6]; P = .06). Overall parasite clearance was shorter after AL than after CQ (median, 18 vs 24 hours, respectively; P = .02), with all patients aparasitemic by 48 hours. By day 42 there were no treatment failures. The risk of anemia during follow-up was similar between arms. Patients treated with AL would require lower bed occupancy than those treated with CQ (2414 vs 2800 days per 1000 patients; incidence rate ratio, 0.86 [95% CI, .82-.91]; P < .001). There were no serious adverse events. Conclusions AL is highly efficacious for treating uncomplicated Knowlesi Malaria; its excellent tolerability and rapid therapeutic response allow earlier hospital discharge, and support its use as a first-line artemisinin-combination treatment policy for all Plasmodium species in Malaysia. Clinical trials registration NCT02001012.

  • artesunate mefloquine versus chloroquine for treatment of uncomplicated Plasmodium Knowlesi Malaria in malaysia act know an open label randomised controlled trial
    Lancet Infectious Diseases, 2016
    Co-Authors: Matthew J Grigg, Timothy William, Jayaram Menon, Bridget E Barber, Giri Shan Rajahram, Christopher S Wilkes, Prabakaran Dhanaraj, Lorenz Von Seidlein, Cielo Pasay, James S Mccarthy
    Abstract:

    Summary Background The zoonotic parasite Plasmodium Knowlesi has become the most common cause of human Malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate–mefloquine with chloroquine to define the optimum treatment for uncomplicated P Knowlesi Malaria in adults and children. Methods We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P Knowlesi Malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate–mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876. Findings Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate–mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76–91]) of 115 patients in the artesunate–mefloquine group versus 61 (55% [45–64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0–40·8]; p vs 24·0 h [6·0–60·0]; p vs 13·8 h [12·1–15·4]; p pks25 was present in 44 (86%) of 51 patients in the artesunate–mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate–mefloquine group (mean 11·5 h [95% CI 8·3–14·6]) than in the chloroquine group (14·8 h [11·7–17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate–mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812–0·906]; p Interpretation Artesunate–mefloquine is highly efficacious for treatment of uncomplicated P Knowlesi Malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas. Funding Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network.

  • increasing incidence of Plasmodium Knowlesi Malaria following control of p falciparum and p vivax Malaria in sabah malaysia
    PLOS Neglected Tropical Diseases, 2013
    Co-Authors: Timothy William, Hasan A Rahman, Nicholas M Anstey, Jenarun Jelip, Mohammad Y Ibrahim, Jayaram Menon, Matthew J Grigg, Bridget E Barber
    Abstract:

    Background The simian parasite Plasmodium Knowlesi is a common cause of human Malaria in Malaysian Borneo and threatens the prospect of Malaria elimination. However, little is known about the emergence of P. Knowlesi, particularly in Sabah. We reviewed Sabah Department of Health records to investigate the trend of each Malaria species over time. Methods Reporting of microscopy-diagnosed Malaria cases in Sabah is mandatory. We reviewed all available Department of Health Malaria notification records from 1992–2011. Notifications of P. Malariae and P. Knowlesi were considered as a single group due to microscopic near-identity. Results From 1992–2011 total Malaria notifications decreased dramatically, with P. falciparum peaking at 33,153 in 1994 and decreasing 55-fold to 605 in 2011, and P. vivax peaking at 15,857 in 1995 and decreasing 25-fold to 628 in 2011. Notifications of P. Malariae/P. Knowlesi also demonstrated a peak in the mid-1990s (614 in 1994) before decreasing to ≈100/year in the late 1990s/early 2000s. However, P. Malariae/P. Knowlesi notifications increased >10-fold between 2004 (n = 59) and 2011 (n = 703). In 1992 P. falciparum, P. vivax and P. Malariae/P. Knowlesi monoinfections accounted for 70%, 24% and 1% respectively of Malaria notifications, compared to 30%, 31% and 35% in 2011. The increase in P. Malariae/P. Knowlesi notifications occurred state-wide, appearing to have begun in the southwest and progressed north-easterly. Conclusions A significant recent increase has occurred in P. Knowlesi notifications following reduced transmission of the human Plasmodium species, and this trend threatens Malaria elimination. Determination of transmission dynamics and risk factors for Knowlesi Malaria is required to guide measures to control this rising incidence.

  • deaths due to Plasmodium Knowlesi Malaria in sabah malaysia association with reporting as Plasmodium Malariae and delayed parenteral artesunate
    Malaria Journal, 2012
    Co-Authors: Giri Shan Rajahram, Nicholas M Anstey, Timothy William, Jayaram Menon, Bridget E Barber, Tsin W. Yeo
    Abstract:

    Background: The simian parasite Plasmodium Knowlesi is recognized as a common cause of severe and fatal human Malaria in Sabah, Malaysia, but is morphologically indistinguishable from and still commonly reported as Plasmodium Malariae, despite the paucity of this species in Sabah. Since December 2008 Sabah Department of Health has recommended intravenous artesunate and referral to a general hospital for all severe Malaria cases of any species. This paper reviews all Malaria deaths in Sabah subsequent to the introduction of these measures. Reporting of Malaria deaths in Malaysia is mandatory. Methods: Details of reported Malaria deaths during 2010-2011 were reviewed to determine the proportion of each Plasmodium species. Demographics, clinical presentations and management of severe Malaria caused by each species were compared. Results: Fourteen Malaria deaths were reported, comprising seven Plasmodium falciparum, six P. Knowlesi and one Plasmodium vivax (all PCR-confirmed). Of the six P. Knowlesi deaths, five were attributable to Knowlesi Malaria and one was attributable to P. Knowlesi-associated enterobacter sepsis. Patients with directly attributable P. Knowlesi deaths (N=5) were older than those with P. falciparum (median age 51 [IQR 50-65] vs 22 [IQR 9-55] years, p=0.06). Complications in fatal P. Knowlesi included respiratory distress (N=5, 100%), hypotension (N=4, 80%), and renal failure (N=4, 80%). All patients with P. Knowlesi were reported as P. Malariae by microscopy. Only two of five patients with severe Knowlesi Malaria on presentation received immediate parenteral anti-Malarial treatment. The patient with P. vivax-associated severe illness did not receive parenteral treatment. In contrast six of seven patients with severe falciparum Malaria received immediate parenteral treatment. Conclusion: Plasmodium Knowlesi was responsible, either directly or through gram-negative bacteraemia, for almost half of Malaria deaths in Sabah. Patients with severe non-falciparum Malaria were less likely to receive immediate parenteral therapy. This highlights the need in Sabah for microscopically diagnosed P. Malariae to be reported as P. Knowlesi to improve recognition and management of this potentially fatal species. Clinicians need to be better informed of the potential for severe and fatal Malaria from non-falciparum species, and the need to treat all severe Malaria with immediate intravenous artesunate.

  • severe Plasmodium Knowlesi Malaria in a tertiary care hospital sabah malaysia
    Emerging Infectious Diseases, 2011
    Co-Authors: Timothy William, Nicholas M Anstey, Jenarun Jelip, Jayaram Menon, Giri Shan Rajahram, Leslie Chan, Samantha Donaldson, Serena Khoo, Charlie Fredrick, Tsin W. Yeo
    Abstract:

    The simian parasite Plasmodium Knowlesi causes severe human Malaria; the optimal treatment remains unknown. We describe the clinical features, disease spectrum, and response to antiMalarial chemotherapy, including artemether-lumefantrine and artesunate, in patients with P. Knowlesi Malaria diagnosed by PCR during December 2007–November 2009 at a tertiary care hospital in Sabah, Malaysia. Fifty-six patients had PCR-confirmed P. Knowlesi monoinfection and clinical records available for review. Twenty-two (39%) had severe Malaria; of these, 6 (27%) died. Thirteen (59%) had respiratory distress; 12 (55%), acute renal failure; and 12, shock. None experienced coma. Patients with uncomplicated disease received chloroquine, quinine, or artemether-lumefantrine, and those with severe disease received intravenous quinine or artesunate. Parasite clearance times were 1–2 days shorter with either artemether-lumefantrine or artesunate treatment. P. Knowlesi is a major cause of severe and fatal Malaria in Sabah. Artemisinin derivatives rapidly clear parasitemia and are efficacious in treating uncomplicated and severe Knowlesi Malaria.

Bridget E Barber - One of the best experts on this subject based on the ideXlab platform.

  • Intravascular haemolysis in severe Plasmodium Knowlesi Malaria: association with endothelial activation, microvascular dysfunction, and acute kidney injury
    2019
    Co-Authors: Bridget E Barber, Timothy William, Matthew J Grigg, Arjen M Dondorp, Kim A. Piera, Daniel J. Cooper, Katherine Plewes, Tsin W. Yeo, Nicholas M Anstey
    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.

  • reduced red blood cell deformability in Plasmodium Knowlesi Malaria
    Blood Advances, 2018
    Co-Authors: Bridget E Barber, Timothy William, Matthew J Grigg, Bruce Russell, Rou Zhang, Amirah Amir, Mark D Chatfield, Arjen M Dondorp, Nicholas M Anstey
    Abstract:

    The simian parasite Plasmodium Knowlesi can cause severe and fatal human Malaria. However, little is known about the pathogenesis of this disease. In falciparum Malaria, reduced red blood cell deformability (RBC-D) contributes to microvascular obstruction and impaired organ perfusion. In P Knowlesi infection, impaired microcirculatory flow has been observed in Macaca mulatta (rhesus macaques), unnatural hosts who develop severe and fatal disease. However, RBC-D has not been measured in human infection or in the natural host M fascicularis (long-tailed macaques). Using ektacytometry, we measured RBC-D in adults with severe and non-severe Knowlesi and falciparum Malaria and in healthy controls. In addition, we used micropipette aspiration to determine the relative stiffness of infected RBCs (iRBCs) and uninfected RBCs (uRBCs) in P Knowlesi-infected humans and M fascicularis. Ektacytometry demonstrated that RBC-D overall was reduced in human Knowlesi Malaria in proportion to disease severity, and in severe Knowlesi Malaria, it was comparable to that of severe falciparum Malaria. RBC-D correlated inversely with parasitemia and lactate in Knowlesi Malaria and HRP2 in falciparum Malaria, and it correlated with hemoglobin nadir in Knowlesi Malaria. Micropipette aspiration confirmed that in humans, P Knowlesi infection increased stiffness of both iRBCs and uRBCs, with the latter mostly the result of echinocytosis. In contrast, in the natural host M fascicularis, echinocyte formation was not observed, and the RBC-D of uRBCs was unaffected. In unnatural primate hosts of P Knowlesi, including humans, reduced deformability of iRBCs and uRBCs may represent a key pathogenic mechanism leading to microvascular accumulation, impaired organ perfusion, and anemia.

  • artemether lumefantrine versus chloroquine for the treatment of uncomplicated Plasmodium Knowlesi Malaria an open label randomized controlled trial can know
    Clinical Infectious Diseases, 2018
    Co-Authors: Matthew J Grigg, Timothy William, Jayaram Menon, Bridget E Barber, Giri Shan Rajahram, Emma Schimann, Christopher S Wilkes, Kaajal Patel, Arjun Chandna, Ric N Price
    Abstract:

    Background Plasmodium Knowlesi is reported increasingly across Southeast Asia and is the most common cause of Malaria in Malaysia. No randomized trials have assessed the comparative efficacy of artemether-lumefantrine (AL) for Knowlesi Malaria. Methods A randomized controlled trial was conducted in 3 district hospitals in Sabah, Malaysia to compare the efficacy of AL against chloroquine (CQ) for uncomplicated Knowlesi Malaria. Participants were included if they weighed >10 kg, had a parasitemia count <20000/μL, and had a negative rapid diagnostic test result for Plasmodium falciparum histidine-rich protein 2. Diagnosis was confirmed by means of polymerase chain reaction. Patients were block randomized to AL (total target dose, 12 mg/kg for artemether and 60 mg/kg for lumefantrine) or CQ (25 mg/kg). The primary outcome was parasite clearance at 24 hours in a modified intention-to-treat analysis. Results From November 2014 to January 2016, a total of 123 patients (including 18 children) were enrolled. At 24 hours after treatment 76% of patients administered AL (95% confidence interval [CI], 63%-86%; 44 of 58) were aparasitemic, compared with 60% administered CQ (47%-72%; 39 of 65; risk ratio, 1.3 [95% CI, 1.0-1.6]; P = .06). Overall parasite clearance was shorter after AL than after CQ (median, 18 vs 24 hours, respectively; P = .02), with all patients aparasitemic by 48 hours. By day 42 there were no treatment failures. The risk of anemia during follow-up was similar between arms. Patients treated with AL would require lower bed occupancy than those treated with CQ (2414 vs 2800 days per 1000 patients; incidence rate ratio, 0.86 [95% CI, .82-.91]; P < .001). There were no serious adverse events. Conclusions AL is highly efficacious for treating uncomplicated Knowlesi Malaria; its excellent tolerability and rapid therapeutic response allow earlier hospital discharge, and support its use as a first-line artemisinin-combination treatment policy for all Plasmodium species in Malaysia. Clinical trials registration NCT02001012.

  • artesunate mefloquine versus chloroquine for treatment of uncomplicated Plasmodium Knowlesi Malaria in malaysia act know an open label randomised controlled trial
    Lancet Infectious Diseases, 2016
    Co-Authors: Matthew J Grigg, Timothy William, Jayaram Menon, Bridget E Barber, Giri Shan Rajahram, Christopher S Wilkes, Prabakaran Dhanaraj, Lorenz Von Seidlein, Cielo Pasay, James S Mccarthy
    Abstract:

    Summary Background The zoonotic parasite Plasmodium Knowlesi has become the most common cause of human Malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate–mefloquine with chloroquine to define the optimum treatment for uncomplicated P Knowlesi Malaria in adults and children. Methods We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P Knowlesi Malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate–mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876. Findings Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate–mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76–91]) of 115 patients in the artesunate–mefloquine group versus 61 (55% [45–64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0–40·8]; p vs 24·0 h [6·0–60·0]; p vs 13·8 h [12·1–15·4]; p pks25 was present in 44 (86%) of 51 patients in the artesunate–mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate–mefloquine group (mean 11·5 h [95% CI 8·3–14·6]) than in the chloroquine group (14·8 h [11·7–17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate–mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812–0·906]; p Interpretation Artesunate–mefloquine is highly efficacious for treatment of uncomplicated P Knowlesi Malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas. Funding Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network.

  • increasing incidence of Plasmodium Knowlesi Malaria following control of p falciparum and p vivax Malaria in sabah malaysia
    PLOS Neglected Tropical Diseases, 2013
    Co-Authors: Timothy William, Hasan A Rahman, Nicholas M Anstey, Jenarun Jelip, Mohammad Y Ibrahim, Jayaram Menon, Matthew J Grigg, Bridget E Barber
    Abstract:

    Background The simian parasite Plasmodium Knowlesi is a common cause of human Malaria in Malaysian Borneo and threatens the prospect of Malaria elimination. However, little is known about the emergence of P. Knowlesi, particularly in Sabah. We reviewed Sabah Department of Health records to investigate the trend of each Malaria species over time. Methods Reporting of microscopy-diagnosed Malaria cases in Sabah is mandatory. We reviewed all available Department of Health Malaria notification records from 1992–2011. Notifications of P. Malariae and P. Knowlesi were considered as a single group due to microscopic near-identity. Results From 1992–2011 total Malaria notifications decreased dramatically, with P. falciparum peaking at 33,153 in 1994 and decreasing 55-fold to 605 in 2011, and P. vivax peaking at 15,857 in 1995 and decreasing 25-fold to 628 in 2011. Notifications of P. Malariae/P. Knowlesi also demonstrated a peak in the mid-1990s (614 in 1994) before decreasing to ≈100/year in the late 1990s/early 2000s. However, P. Malariae/P. Knowlesi notifications increased >10-fold between 2004 (n = 59) and 2011 (n = 703). In 1992 P. falciparum, P. vivax and P. Malariae/P. Knowlesi monoinfections accounted for 70%, 24% and 1% respectively of Malaria notifications, compared to 30%, 31% and 35% in 2011. The increase in P. Malariae/P. Knowlesi notifications occurred state-wide, appearing to have begun in the southwest and progressed north-easterly. Conclusions A significant recent increase has occurred in P. Knowlesi notifications following reduced transmission of the human Plasmodium species, and this trend threatens Malaria elimination. Determination of transmission dynamics and risk factors for Knowlesi Malaria is required to guide measures to control this rising incidence.