398 results on '"Grigg, Matthew J."'
Search Results
102. Association between Landscape Factors and Spatial Patterns ofPlasmodium knowlesiInfections in Sabah, Malaysia
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Fornace, Kimberly M., primary, Abidin, Tommy Rowel, additional, Alexander, Neal, additional, Brock, Paddy, additional, Grigg, Matthew J., additional, Murphy, Amanda, additional, William, Timothy, additional, Menon, Jayaram, additional, Drakeley, Chris J., additional, and Cox, Jonathan, additional
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- 2016
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103. Artesunate–mefloquine versus chloroquine for treatment of uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT KNOW): an open-label, randomised controlled trial
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Grigg, Matthew J, primary, William, Timothy, additional, Menon, Jayaram, additional, Dhanaraj, Prabakaran, additional, Barber, Bridget E, additional, Wilkes, Christopher S, additional, von Seidlein, Lorenz, additional, Rajahram, Giri S, additional, Pasay, Cielo, additional, McCarthy, James S, additional, Price, Ric N, additional, Anstey, Nicholas M, additional, and Yeo, Tsin W, additional
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- 2016
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104. Asymmetric Dimethylarginine in Adult Falciparum Malaria: Relationships With Disease Severity, Antimalarial Treatment, Hemolysis, and Inflammation
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Barber, Bridget E., primary, William, Timothy, additional, Grigg, Matthew J., additional, Parameswaran, Uma, additional, Piera, Kim A., additional, Yeo, Tsin W., additional, and Anstey, Nicholas M., additional
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- 2016
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105. FallingPlasmodium knowlesiMalaria Death Rate among Adults despite Rising Incidence, Sabah, Malaysia, 2010–2014
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Rajahram, Giri S., primary, Barber, Bridget E., additional, William, Timothy, additional, Grigg, Matthew J., additional, Menon, Jayaram, additional, Yeo, Tsin W., additional, and Anstey, Nicholas M., additional
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- 2016
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106. Parasite Biomass-Related Inflammation, Endothelial Activation, Microvascular Dysfunction and Disease Severity in Vivax Malaria
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Barber, Bridget E., William, Timothy, Grigg, Matthew J., Parameswaran, Uma, Piera, Kim A., Price, Ric N., Yeo, Tsin W., Anstey, Nicholas M., Barber, Bridget E., William, Timothy, Grigg, Matthew J., Parameswaran, Uma, Piera, Kim A., Price, Ric N., Yeo, Tsin W., and Anstey, Nicholas M.
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Plasmodium vivax can cause severe malaria, however its pathogenesis is poorly understood. In contrast to P. falciparum, circulating vivax parasitemia is low, with minimal apparent sequestration in endothelium-lined microvasculature, and pathogenesis thought unrelated to parasite biomass. However, the relationships between vivax disease-severity and total parasite biomass, endothelial autocrine activation and microvascular dysfunction are unknown. We measured circulating parasitemia and markers of total parasite biomass (plasma parasite lactate dehydrogenase [pLDH] and PvLDH) in adults with severe (n = 9) and non-severe (n = 53) vivax malaria, and examined relationships with disease-severity, endothelial activation, and microvascular function. Healthy controls and adults with non-severe and severe falciparum malaria were enrolled for comparison. Median peripheral parasitemia, PvLDH and pLDH were 2.4-fold, 3.7-fold and 6.9-fold higher in severe compared to non-severe vivax malaria (p = 0.02, p = 0.02 and p = 0.015, respectively), suggesting that, as in falciparum malaria, peripheral P. vivax parasitemia underestimates total parasite biomass, particularly in severe disease. P. vivax schizonts were under-represented in peripheral blood. Severe vivax malaria was associated with increased angiopoietin-2 and impaired microvascular reactivity. Peripheral vivax parasitemia correlated with endothelial activation (angiopoietin-2, von-Willebrand-Factor [VWF], E-selectin), whereas markers of total vivax biomass correlated only with systemic inflammation (IL-6, IL-10). Activity of the VWF-cleaving-protease, ADAMTS13, was deficient in proportion to endothelial activation, IL-6, thrombocytopenia and vivax disease-severity, and associated with impaired microvascular reactivity in severe disease. Impaired microvascular reactivity correlated with lactate in severe vivax malaria. Findings suggest that tissue accumulation of P. vivax may occur, with the hidden biomass greatest in severe
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- 2015
107. Retinal Changes in Uncomplicated and SeverePlasmodium knowlesiMalaria
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Govindasamy, Gayathri, primary, Barber, Bridget E., additional, Ghani, Shuaibah A., additional, William, Timothy, additional, Grigg, Matthew J., additional, Borooah, Shyamanga, additional, Dhillon, Bal, additional, Dondorp, Arjen M., additional, Yeo, Tsin W., additional, Anstey, Nicholas M., additional, and Maude, Richard J., additional
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- 2015
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108. Asymptomatic and Submicroscopic Carriage ofPlasmodium knowlesiMalaria in Household and Community Members of Clinical Cases in Sabah, Malaysia
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Fornace, Kimberly M., primary, Nuin, Nor Afizah, additional, Betson, Martha, additional, Grigg, Matthew J., additional, William, Timothy, additional, Anstey, Nicholas M., additional, Yeo, Tsin W., additional, Cox, Jonathan, additional, Ying, Lau Tiek, additional, and Drakeley, Chris J., additional
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- 2015
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109. Parasite Biomass-Related Inflammation, Endothelial Activation, Microvascular Dysfunction and Disease Severity in Vivax Malaria
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Barber, Bridget E., primary, William, Timothy, additional, Grigg, Matthew J., additional, Parameswaran, Uma, additional, Piera, Kim A., additional, Price, Ric N., additional, Yeo, Tsin W., additional, and Anstey, Nicholas M., additional
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- 2015
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110. Combining Parasite Lactate Dehydrogenase-Based and Histidine-Rich Protein 2-Based Rapid Tests To Improve Specificity for Diagnosis of Malaria Due to Plasmodium knowlesi and Other Plasmodium Species in Sabah, Malaysia
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Grigg, Matthew J., William, Timothy, Barber, Bridget E., Parameswaran, Uma, Bird, Elspeth, Piera, Kim, Aziz, Ammar, Dhanaraj, Prabakaran, Yeo, Tsin W., Anstey, Nicholas M., Grigg, Matthew J., William, Timothy, Barber, Bridget E., Parameswaran, Uma, Bird, Elspeth, Piera, Kim, Aziz, Ammar, Dhanaraj, Prabakaran, Yeo, Tsin W., and Anstey, Nicholas M.
- Abstract
Plasmodium knowlesi causes severe and fatal malaria in Malaysia. Microscopic misdiagnosis is common and may delay appropriate treatment. P. knowlesi can cross-react with “species-specific” parasite lactate dehydrogenase (pLDH) monoclonal antibodies used in rapid diagnostic tests (RDTs) to detect P. falciparum and P. vivax. At one tertiary-care hospital and two district hospitals in Sabah, we prospectively evaluated two combination RDTs for malaria diagnosis by using both a pan-Plasmodium-pLDH (pan-pLDH)/P. falciparum-specific-pLDH (Pf-pLDH) RDT (OptiMAL-IT) and a non-P. falciparum VOM-pLDH/Pf-HRP2 RDT (CareStart). Differential cross-reactivity among these combinations was hypothesized to differentiate P. knowlesi from other Plasmodium monoinfections. Among 323 patients with PCR-confirmed P. knowlesi (n = 193), P. falciparum (n = 93), and P. vivax (n = 37) monoinfections, the VOM-pLDH individual component had the highest sensitivity for nonsevere (35%; 95% confidence interval [CI], 27 to 43%) and severe (92%; CI, 81 to 100%) P. knowlesi malaria. CareStart demonstrated a P. knowlesi sensitivity of 42% (CI, 34 to 49%) and specificity of 74% (CI, 65 to 82%), a P. vivax sensitivity of 83% (CI, 66 to 93%) and specificity of 71% (CI, 65 to 76%), and a P. falciparum sensitivity of 97% (CI, 90 to 99%) and specificity of 99% (CI, 97 to 100%). OptiMAL-IT demonstrated a P. knowlesi sensitivity of 32% (CI, 25 to 39%) and specificity of 21% (CI, 15 to 29%), a P. vivax sensitivity of 60% (CI, 42 to 75%) and specificity of 97% (CI, 94 to 99%), and a P. falciparum sensitivity of 82% (CI, 72 to 89%) and specificity of 39% (CI, 33 to 46%). The combination of CareStart plus OptiMAL-IT for P. knowlesi using predefined criteria gave a sensitivity of 25% (CI, 19 to 32%) and specificity of 97% (CI, 92 to 99%). Combining two RDT combinations was highly specific for P. knowlesi malaria diagnosis; however, sensitivity was poor. The specificity of pLDH RDTs was decreased for P. viv
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- 2014
111. A study protocol for a randomised open-label clinical trial of artesunate-mefloquine versus chloroquine in patients with non-severe Plasmodium knowlesi malaria in Sabah, Malaysia (ACT KNOW trial)
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Grigg, Matthew J., William, Timothy, Dhanaraj, Prabakaran, Menon, Jayaram, Barber, Bridget E., von Seidlein, Lorenz, Rajahram, Giri, Price, Ric N., Anstey, Nicholas M., Yeo, Tsin W., Grigg, Matthew J., William, Timothy, Dhanaraj, Prabakaran, Menon, Jayaram, Barber, Bridget E., von Seidlein, Lorenz, Rajahram, Giri, Price, Ric N., Anstey, Nicholas M., and Yeo, Tsin W.
- Abstract
Introduction Malaria due to Plasmodium knowlesi is reported throughout South-East Asia, and is the commonest cause of it in Malaysia. P. knowlesi replicates every 24 h and can cause severe disease and death. Current 2010 WHO Malaria Treatment Guidelines have no recommendations for the optimal treatment of non-severe knowlesi malaria. Artemisinin-combination therapies (ACT) and chloroquine have each been successfully used to treat knowlesi malaria; however, the rapidity of parasite clearance has not been prospectively compared. Malaysia's national policy for malaria pre-elimination involves mandatory hospital admission for confirmed malaria cases with discharge only after two negative blood films; use of a more rapidly acting antimalarial agent would have health cost benefits. P. knowlesi is commonly microscopically misreported as P. malariae, P. falciparum or P. vivax, with a high proportion of the latter two species being chloroquine-resistant in Malaysia. A unified ACT-treatment protocol would provide effective blood stage malaria treatment for all Plasmodium species.Methods and analysis ACT KNOW, the first randomised controlled trial ever performed in knowlesi malaria, is a two-arm open-label trial with enrolments over a 2-year period at three district sites in Sabah, powered to show a difference in proportion of patients negative for malaria by microscopy at 24 h between treatment arms (clinicaltrials.gov #NCT01708876). Enrolments started in December 2012, with completion expected by September 2014. A total sample size of 228 is required to give 90% power (α 0.05) to determine the primary end point using intention-to-treat analysis. Secondary end points include parasite clearance time, rates of recurrent infection/treatment failure to day 42, gametocyte carriage throughout follow-up and rates of anaemia at day 28, as determined by survival analysis.Ethics and dissemination This study has been approved by relevant institutional ethics committees in Malaysia
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- 2014
112. Factors that are associated with the risk of acquiring Plasmodium knowlesi malaria in Sabah, Malaysia: a case-control study protocol
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Grigg, Matthew J., William, Timothy, Drakeley, Chris J., Jelip, Jenarun, von Seidlein, Lorenz, Barber, Bridget, Fornace, K. M., Anstey, Nicholas M., Yeo, Tsin W., Cox, J., Grigg, Matthew J., William, Timothy, Drakeley, Chris J., Jelip, Jenarun, von Seidlein, Lorenz, Barber, Bridget, Fornace, K. M., Anstey, Nicholas M., Yeo, Tsin W., and Cox, J.
- Abstract
Introduction Plasmodium knowlesi has long been present in Malaysia, and is now an emerging cause of zoonotic human malaria. Cases have been confirmed throughout South-East Asia where the ranges of its natural macaque hosts and Anopheles leucosphyrus group vectors overlap. The majority of cases are from Eastern Malaysia, with increasing total public health notifications despite a concurrent reduction in Plasmodium falciparum and P. vivax malaria. The public health implications are concerning given P. knowlesi has the highest risk of severe and fatal disease of all Plasmodium spp in Malaysia. Current patterns of risk and disease vary based on vector type and competence, with individual exposure risks related to forest and forest-edge activities still poorly defined. Clustering of cases has not yet been systematically evaluated despite reports of peri-domestic transmission and known vector competence for human-to-human transmission.Methods and analysis A population-based case–control study will be conducted over a 2-year period at two adjacent districts in north-west Sabah, Malaysia. Confirmed malaria cases presenting to the district hospital sites meeting relevant inclusion criteria will be requested to enrol. Three community controls matched to the same village as the case will be selected randomly. Study procedures will include blood sampling and administration of household and individual questionnaires to evaluate potential exposure risks associated with acquisition of P. knowlesi malaria. Secondary outcomes will include differences in exposure variables between P. knowlesi and other Plasmodium spp, risk of severe P. knowlesi malaria, and evaluation of P. knowlesi case clustering. Primary analysis will be per protocol, with adjusted ORs for exposure risks between cases and controls calculated using conditional multiple logistic regression models.Ethics This study has been approved by the human research ethics committees of Malaysia, the Menzies School of Heal
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- 2014
113. Plasmodium knowlesiMalaria During Pregnancy
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Barber, Bridget E., primary, Bird, Elspeth, additional, Wilkes, Christopher S., additional, William, Timothy, additional, Grigg, Matthew J., additional, Paramaswaran, Uma, additional, Menon, Jayaram, additional, Jelip, Jenarun, additional, Yeo, Tsin W., additional, and Anstey, Nicholas M., additional
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- 2014
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114. Changing epidemiology of malaria in Sabah, Malaysia: increasing incidence of Plasmodium knowlesi
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William, Timothy, primary, Jelip, Jenarun, additional, Menon, Jayaram, additional, Anderios, Fread, additional, Mohammad, Rashidah, additional, Awang Mohammad, Tajul A, additional, Grigg, Matthew J, additional, Yeo, Tsin W, additional, Anstey, Nicholas M, additional, and Barber, Bridget E, additional
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- 2014
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115. Zoonotic Malaria: The Better You Look, the More You Find.
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Anstey, Nicholas M and Grigg, Matthew J
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MALARIA , *HUMAN behavior , *PLASMODIUM vivax - Abstract
The article presents an editorial on the disease called zoonic malaria. Topics discussed include an overview of zoonotic malaria, its diagnosis, its treatment options, the methodology, the bacteria from the disease, its medical history, its risk factors, its management, and its molecualr surveillance.
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- 2019
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116. Combining Parasite Lactate Dehydrogenase-Based and Histidine-Rich Protein 2-Based Rapid Tests To Improve Specificity for Diagnosis of Malaria Due to Plasmodium knowlesi and Other Plasmodium Species in Sabah, Malaysia
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Grigg, Matthew J., primary, William, Timothy, additional, Barber, Bridget E., additional, Parameswaran, Uma, additional, Bird, Elspeth, additional, Piera, Kim, additional, Aziz, Ammar, additional, Dhanaraj, Prabakaran, additional, Yeo, Tsin W., additional, and Anstey, Nicholas M., additional
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- 2014
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117. Increasing Incidence of Plasmodium knowlesi Malaria following Control of P. falciparum and P. vivax Malaria in Sabah Malaysia
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William, Timothy, Rahman, Hasan A., Jelip, Jenarun, Ibrahim, Mohammad Y., Menon, Jayaram, Grigg, Matthew J., Yeo, Tsin W., Anstey, Nicholas M., Barber, Bridget E., William, Timothy, Rahman, Hasan A., Jelip, Jenarun, Ibrahim, Mohammad Y., Menon, Jayaram, Grigg, Matthew J., Yeo, Tsin W., Anstey, Nicholas M., and Barber, Bridget E.
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BackgroundThe 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.MethodsReporting 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.ResultsFrom 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.ConclusionsA 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.
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- 2013
118. Limitations of microscopy to differentiate Plasmodium species in a region co-endemic for Plasmodium falciparum, Plasmodium vivax and Plasmodium knowlesi
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Barber, Bridget E., William, Timothy, Grigg, Matthew J., Yeo, Tsin W., Anstey, Nicholas M., Barber, Bridget E., William, Timothy, Grigg, Matthew J., Yeo, Tsin W., and Anstey, Nicholas M.
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BackgroundIn areas co-endemic for multiple Plasmodium species, correct diagnosis is crucial for appropriate treatment and surveillance. Species misidentification by microscopy has been reported in areas co-endemic for vivax and falciparum malaria, and may be more frequent in regions where Plasmodium knowlesi also commonly occurs. MethodsThis prospective study in Sabah, Malaysia, evaluated the accuracy of routine district and referral hospital-based microscopy, and microscopy performed by an experienced research microscopist, for the diagnosis of PCR-confirmed Plasmodium falciparum, P. knowlesi, and Plasmodium vivax malaria. ResultsA total of 304 patients with PCR-confirmed Plasmodium infection were enrolled, including 130 with P. knowlesi, 122 with P. falciparum, 43 with P. vivax, one with Plasmodium malariae and eight with mixed species infections. Among patients with P. knowlesi mono-infection, routine and cross-check microscopy both identified 94 (72%) patients as “P. malariae/P. knowlesi”; 17 (13%) and 28 (22%) respectively were identified as P. falciparum, and 13 (10%) and two (1.5%) as P. vivax. Among patients with PCR-confirmed P. falciparum, routine and cross-check microscopy identified 110/122 (90%) and 112/118 (95%) patients respectively as P. falciparum, and 8/122 (6.6%) and 5/118 (4.2%) as “P. malariae/P. knowlesi”. Among those with P. vivax, 23/43 (53%) and 34/40 (85%) were correctly diagnosed by routine and cross-check microscopy respectively, while 13/43 (30%) and 3/40 (7.5%) patients were diagnosed as “P. malariae/P. knowlesi”. Four of 13 patients with PCR-confirmed P. vivax and misdiagnosed by routine microscopy as “P. malariae/P. knowlesi” were subsequently re-admitted with P. vivax malaria. ConclusionsMicroscopy does not reliably distinguish between P. falciparum, P. vivax and P. knowlesi in a region where all three species frequently occur. Misdiagnosis of P. knowlesi as both P. vivax and P. falcipa
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- 2013
119. Evaluation of the Sensitivity of a pLDH-Based and an Aldolase-Based Rapid Diagnostic Test for Diagnosis of Uncomplicated and Severe Malaria Caused by PCR-Confirmed Plasmodium knowlesi, Plasmodium falciparum, and Plasmodium vivax
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Barber, Bridget E, William, Timothy, Grigg, Matthew J., Piera, Kim, Yeo, Tsin W., Anstey, Nicholas M., Barber, Bridget E, William, Timothy, Grigg, Matthew J., Piera, Kim, Yeo, Tsin W., and Anstey, Nicholas M.
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Plasmodium knowlesi can cause severe and fatal human malaria in Southeast Asia. Rapid diagnosis of all Plasmodium species is essential for initiation of effective treatment. Rapid diagnostic tests (RDTs) are sensitive for detection of uncomplicated and severe falciparum malaria but have not been systematically evaluated in knowlesi malaria. At a tertiary referral hospital in Sabah, Malaysia, we prospectively evaluated the sensitivity of two combination RDTs for the diagnosis of uncomplicated and severe malaria from all three potentially fatal Plasmodium species, using a pan-Plasmodium lactate dehydrogenase (pLDH)-P. falciparum histidine-rich protein 2 (PfHRP2) RDT (First Response) and a pan-Plasmodium aldolase-PfHRP2 RDT (ParaHIT). Among 293 hospitalized adults with PCR-confirmed Plasmodium monoinfection, the sensitivity of the pLDH component of the pLDH-PfHRP2 RDT was 74% (95/129; 95% confidence interval [CI], 65 to 80%), 91% (110/121; 95% CI, 84 to 95%), and 95% (41/43; 95% CI, 85 to 99%) for PCR-confirmed P. knowlesi, P. falciparum, and P. vivax infections, respectively, and 88% (30/34; 95% CI, 73 to 95%), 90% (38/42; 95% CI, 78 to 96%), and 100% (12/12; 95% CI, 76 to 100%) among patients tested before antimalarial treatment was begun. Sensitivity in severe malaria was 95% (36/38; 95% CI, 83 to 99), 100% (13/13; 95% CI, 77 to 100), and 100% (7/7; 95% CI, 65 to 100%), respectively. The aldolase component of the aldolase-PfHRP2 RDT performed poorly in all Plasmodium species. The pLDH-based RDT was highly sensitive for the diagnosis of severe malaria from all species; however, neither the pLDH- nor aldolase-based RDT demonstrated sufficiently high overall sensitivity for P. knowlesi. More sensitive RDTs are needed in regions of P. knowlesi endemicity.
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- 2013
120. Plasmodium vivax Population Structure and Transmission Dynamics in Sabah Malaysia
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Abdullah, Noor Rain, Barber, Bridget E., William, Timothy, Norahmad, Nor Azrina, Satsu, Umi Rubiah, Muniandy, Prem Kumar, Ismail, Zakiah, Grigg, Matthew J., Jelip, Jenarun, Piera, Kim, von Seidlein, Lorenz, Yeo, Tsin, Anstey, Nicholas M., Price, Ric N., Auburn, Sarah, Abdullah, Noor Rain, Barber, Bridget E., William, Timothy, Norahmad, Nor Azrina, Satsu, Umi Rubiah, Muniandy, Prem Kumar, Ismail, Zakiah, Grigg, Matthew J., Jelip, Jenarun, Piera, Kim, von Seidlein, Lorenz, Yeo, Tsin, Anstey, Nicholas M., Price, Ric N., and Auburn, Sarah
- Abstract
Despite significant progress in the control of malaria in Malaysia, the complex transmission dynamics of P. vivax continue to challenge national efforts to achieve elimination. To assess the impact of ongoing interventions on P. vivax transmission dynamics in Sabah, we genotyped 9 short tandem repeat markers in a total of 97 isolates (8 recurrences) from across Sabah, with a focus on two districts, Kota Marudu (KM, n = 24) and Kota Kinabalu (KK, n = 21), over a 2 year period. STRUCTURE analysis on the Sabah-wide dataset demonstrated multiple sub-populations. Significant differentiation (FST = 0.243) was observed between KM and KK, located just 130 Km apart. Consistent with low endemic transmission, infection complexity was modest in both KM (mean MOI = 1.38) and KK (mean MOI = 1.19). However, population diversity remained moderate (HE = 0.583 in KM and HE = 0.667 in KK). Temporal trends revealed clonal expansions reflecting epidemic transmission dynamics. The haplotypes of these isolates declined in frequency over time, but persisted at low frequency throughout the study duration. A diverse array of low frequency isolates were detected in both KM and KK, some likely reflecting remnants of previous expansions. In accordance with clonal expansions, high levels of Linkage Disequilibrium (IAS >0.5 [P<0.0001] in KK and KM) declined sharply when identical haplotypes were represented once (IAS = 0.07 [P = 0.0076] in KM, and IAS = -0.003 [P = 0.606] in KK). All 8 recurrences, likely to be relapses, were homologous to the prior infection. These recurrences may promote the persistence of parasite lineages, sustaining local diversity. In summary, Sabah's shrinking P. vivax population appears to have rendered this low endemic setting vulnerable to epidemic expansions. Migration may play an important role in the introduction of new parasite strains leading to epidemic expansions, with important implications for malaria elimination.
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- 2013
121. Platelets kill circulating parasites of all major Plasmodiumspecies in human malaria
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Kho, Steven, Barber, Bridget E., Johar, Edison, Andries, Benediktus, Poespoprodjo, Jeanne R., Kenangalem, Enny, Piera, Kim A., Ehmann, Anna, Price, Ric N., William, Timothy, Woodberry, Tonia, Foote, Simon, Minigo, Gabriela, Yeo, Tsin W., Grigg, Matthew J., Anstey, Nicholas M., and McMorran, Brendan J.
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Platelets are understood to assist host innate immune responses against infection, although direct evidence of this function in any human disease, including malaria, is unknown. Here we characterized platelet–erythrocyte interactions by microscopy and flow cytometry in patients with malaria naturally infected with Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, or Plasmodium knowlesi. Blood samples from 376 participants were collected from malaria-endemic areas of Papua, Indonesia, and Sabah, Malaysia. Platelets were observed binding directly with and killing intraerythrocytic parasites of each of the Plasmodiumspecies studied, particularly mature stages, and was greatest in P vivaxpatients. Platelets preferentially bound to the infected more than to the uninfected erythrocytes in the bloodstream. Analysis of intraerythrocytic parasites indicated the frequent occurrence of platelet-associated parasite killing, characterized by the intraerythrocytic accumulation of platelet factor-4 and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling of parasite nuclei (PF4+TUNEL+parasites). These PF4+TUNEL+parasites were not associated with measures of systemic platelet activation. Importantly, patient platelet counts, infected erythrocyte-platelet complexes, and platelet-associated parasite killing correlated inversely with patient parasite loads. These relationships, taken together with the frequency of platelet-associated parasite killing observed among the different patients and Plasmodiumspecies, suggest that platelets may control the growth of between 5% and 60% of circulating parasites. Platelet–erythrocyte complexes made up a major proportion of the total platelet pool in patients with malaria and may therefore contribute considerably to malarial thrombocytopenia. Parasite killing was demonstrated to be platelet factor-4-mediated in P knowlesiculture. Collectively, our results indicate that platelets directly contribute to innate control of Plasmodiuminfection in human malaria.
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- 2018
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122. Plasmodium vivax Population Structure and Transmission Dynamics in Sabah Malaysia
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Abdullah, Noor Rain, primary, Barber, Bridget E., additional, William, Timothy, additional, Norahmad, Nor Azrina, additional, Satsu, Umi Rubiah, additional, Muniandy, Prem Kumar, additional, Ismail, Zakiah, additional, Grigg, Matthew J., additional, Jelip, Jenarun, additional, Piera, Kim, additional, von Seidlein, Lorenz, additional, Yeo, Tsin W., additional, Anstey, Nicholas M., additional, Price, Ric N., additional, and Auburn, Sarah, additional
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- 2013
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123. Epidemiology of Plasmodium knowlesi malaria in north-east Sabah, Malaysia: family clusters and wide age distribution
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Barber, Bridget E., William, Timothy, Dhararaj, Prabakaran, Anderios, Fread, Grigg, Matthew J., Yeo, Tsin W., Anstey, Nicholas M., Barber, Bridget E., William, Timothy, Dhararaj, Prabakaran, Anderios, Fread, Grigg, Matthew J., Yeo, Tsin W., and Anstey, Nicholas M.
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BackgroundThe simian parasite Plasmodium knowlesi is a common cause of human malaria in Malaysian Borneo, with a particularly high incidence in Kudat, Sabah. Little is known however about the epidemiology in this substantially deforested region. MethodsMalaria microscopy records at Kudat District Hospital were retrospectively reviewed from January 2009-November 2011. Demographics, and PCR results if available, were recorded for each positive result. Medical records were reviewed for patients suspected of representing family clusters, and families contacted for further information. Rainfall data were obtained from the Malaysian Meteorological Department. Results“Plasmodium malariae” mixed or mono-infection was diagnosed by microscopy in 517/653 (79%) patients. Of these, PCR was performed in 445 (86%) and was positive for P. knowlesi mono-infection in 339 (76%). Patients with knowlesi malaria demonstrated a wide age distribution (median 33, IQR 20–50, range 0.7-89 years) with P. knowlesi predominating in all age groups except those <5 years old, where numbers approximated those of Plasmodium falciparum and Plasmodium vivax. Two contemporaneous family clusters were identified: a father with two children (aged 10–11 years); and three brothers (aged one-11 years), all with PCR-confirmed knowlesi malaria. Cases of P. knowlesi demonstrated significant seasonal variation, and correlated with rainfall in the preceding three to five months. ConclusionsPlasmodium knowlesi is the most common cause of malaria admissions to Kudat District Hospital. The wide age distribution and presence of family clusters suggest that transmission may be occurring close to or inside people’s homes, in contrast to previous reports from densely forested areas of Sarawak. These findings have significant implications for malaria control. Prospective studies of risk factors, vectors and transmission dynamics of P. knowlesi in Sabah, including potential for human-to-hum
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- 2012
124. Evaluation of the Sensitivity of a pLDH-Based and an Aldolase-Based Rapid Diagnostic Test for Diagnosis of Uncomplicated and Severe Malaria Caused by PCR-Confirmed Plasmodium knowlesi, Plasmodium falciparum, and Plasmodium vivax
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Barber, Bridget E., primary, William, Timothy, additional, Grigg, Matthew J., additional, Piera, Kim, additional, Yeo, Tsin W., additional, and Anstey, Nicholas M., additional
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- 2013
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125. Increasing Incidence of Plasmodium knowlesi Malaria following Control of P. falciparum and P. vivax Malaria in Sabah, Malaysia
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William, Timothy, primary, Rahman, Hasan A., additional, Jelip, Jenarun, additional, Ibrahim, Mohammad Y., additional, Menon, Jayaram, additional, Grigg, Matthew J., additional, Yeo, Tsin W., additional, Anstey, Nicholas M., additional, and Barber, Bridget E., additional
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- 2013
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126. Efficacy of Artesunate-mefloquine for Chloroquineresistant Plasmodium vivax Malaria in Malaysia: An Open-label, Randomized, Controlled Trial.
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Grigg, Matthew J., William, Timothy, Menon, Jayaram, Barber, Bridget E., Wilkes, Christopher S., Rajahram, Giri S., Edstein, Michael D., Auburn, Sarah, Price, Ric N., Yeo, Tsin W., and Anstey, Nicholas M.
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MEFLOQUINE , *PLASMODIUM vivax , *MALARIA treatment , *ARTEMISININ , *DRUG efficacy , *THERAPEUTICS - Abstract
Background. Chloroquine (CQ)-resistant Plasmodium vivax is increasingly reported throughout southeast Asia. The efficacy of CQ and alternative artemisinin combination therapies (ACTs) for vivax malaria in Malaysia is unknown. Methods. A randomized, controlled trial of CQ vs artesunate-mefloquine (AS-MQ) for uncomplicated vivax malaria was conducted in 3 district hospitals in Sabah, Malaysia. Primaquine was administered on day 28. The primary outcome was the cumulative risk of treatment failure by day 28 by Kaplan-Meier analysis. Results. From 2012 to 2014, 103 adults and children were enrolled. Treatment failure by day 28 was 61.1% (95% confidence interval [CI], 46.8-75.6) after CQ and 0% (95% CI, 0-.08) following AS-MQ (P < .001), of which 8.2% (95% CI, 2.5-9.6) were early treatment failures. All patients with treatment failure had therapeutic plasma CQ concentrations at day 7. Compared with CQ, AS-MQ was associated with faster parasite clearance (normalized clearance slope, 0.311 vs 0.127; P < .001) and fever clearance (mean, 19.0 vs 37.7 hours; P = .001) and with lower risk of anemia at day 28 (odds ratio = 3.7; 95% CI, 1.5-9.3; P = .005). Gametocytes were present at day 28 in 23.8% (10/42) of patients following CQ vs none with AS-MQ (P < .001). AS-MQ resulted in lower bed occupancy: 4037 vs 6510 days/1000 patients (incidence rate ratio 0.62; 95% CI, .60-.65; P < .001). One patient developed severe anemia not regarded as related to their AS-MQ treatment. Conclusions. High-grade CQ-resistant P. vivax is prevalent in eastern Malaysia. AS-MQ is an efficacious ACT for all malaria species. Wider CQ-efficacy surveillance is needed in vivax-endemic regions with earlier replacement with ACT when treatment failure is detected. [ABSTRACT FROM AUTHOR]
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- 2016
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127. A Prospective Comparative Study of Knowlesi, Falciparum, and Vivax Malaria in Sabah, Malaysia: High Proportion With Severe Disease From Plasmodium Knowlesi and Plasmodium Vivax But No Mortality With Early Referral and Artesunate Therapy
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Barber, Bridget E., primary, William, Timothy, additional, Grigg, Matthew J., additional, Menon, Jayaram, additional, Auburn, Sarah, additional, Marfurt, Jutta, additional, Anstey, Nicholas M., additional, and Yeo, Tsin W., additional
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- 2012
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128. Individual-level factors associated with the risk of acquiring human Plasmodium knowlesimalaria in Malaysia: a case-control study
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Grigg, Matthew J, Cox, Jonathan, William, Timothy, Jelip, Jenarun, Fornace, Kimberly M, Brock, Patrick M, von Seidlein, Lorenz, Barber, Bridget E, Anstey, Nicholas M, Yeo, Tsin W, and Drakeley, Christopher J
- Abstract
The emergence of human malaria due to the monkey parasite Plasmodium knowlesithreatens elimination efforts in southeast Asia. Changes in land use are thought to be driving the rise in reported P knowlesicases, but the role of individual-level factors is unclear. To address this knowledge gap we assessed human and environmental factors associated with zoonotic knowlesi malaria risk.
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- 2017
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129. Plasmodium vivax Population Structure and Transmission Dynamics in Sabah Malaysia.
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Abdullah, Noor Rain, Barber, Bridget E., William, Timothy, Norahmad, Nor Azrina, Satsu, Umi Rubiah, Muniandy, Prem Kumar, Ismail, Zakiah, Grigg, Matthew J., Jelip, Jenarun, Piera, Kim, von Seidlein, Lorenz, Yeo, Tsin W., Anstey, Nicholas M., Price, Ric N., and Auburn, Sarah
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PLASMODIUM vivax ,PROTOZOAN populations ,MALARIA prevention ,MALARIA transmission ,MOLECULAR cloning - Abstract
Despite significant progress in the control of malaria in Malaysia, the complex transmission dynamics of P. vivax continue to challenge national efforts to achieve elimination. To assess the impact of ongoing interventions on P. vivax transmission dynamics in Sabah, we genotyped 9 short tandem repeat markers in a total of 97 isolates (8 recurrences) from across Sabah, with a focus on two districts, Kota Marudu (KM, n = 24) and Kota Kinabalu (KK, n = 21), over a 2 year period. STRUCTURE analysis on the Sabah-wide dataset demonstrated multiple sub-populations. Significant differentiation (F
ST = 0.243) was observed between KM and KK, located just 130 Km apart. Consistent with low endemic transmission, infection complexity was modest in both KM (mean MOI = 1.38) and KK (mean MOI = 1.19). However, population diversity remained moderate (HE = 0.583 in KM and HE = 0.667 in KK). Temporal trends revealed clonal expansions reflecting epidemic transmission dynamics. The haplotypes of these isolates declined in frequency over time, but persisted at low frequency throughout the study duration. A diverse array of low frequency isolates were detected in both KM and KK, some likely reflecting remnants of previous expansions. In accordance with clonal expansions, high levels of Linkage Disequilibrium (IA S >0.5 [P<0.0001] in KK and KM) declined sharply when identical haplotypes were represented once (IA S = 0.07 [P = 0.0076] in KM, and IA S = -0.003 [P = 0.606] in KK). All 8 recurrences, likely to be relapses, were homologous to the prior infection. These recurrences may promote the persistence of parasite lineages, sustaining local diversity. In summary, Sabah's shrinking P. vivax population appears to have rendered this low endemic setting vulnerable to epidemic expansions. Migration may play an important role in the introduction of new parasite strains leading to epidemic expansions, with important implications for malaria elimination. [ABSTRACT FROM AUTHOR]- Published
- 2013
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130. Plasmodium vivaxmalaria serological exposure markers: Assessing the degree and implications of cross-reactivity with P. knowlesi
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Longley, Rhea J., Grigg, Matthew J., Schoffer, Kael, Obadia, Thomas, Hyslop, Stephanie, Piera, Kim A., Nekkab, Narimane, Mazhari, Ramin, Takashima, Eizo, Tsuboi, Takafumi, Harbers, Matthias, Tetteh, Kevin, Drakeley, Chris, Chitnis, Chetan E., Healer, Julie, Tham, Wai-Hong, Sattabongkot, Jetsumon, White, Michael T., Cooper, Daniel J., Rajahram, Giri S., Barber, Bridget E., William, Timothy, Anstey, Nicholas M., and Mueller, Ivo
- Abstract
Serological markers are a promising tool for surveillance and targeted interventions for Plasmodium vivaxmalaria. P. vivaxis closely related to the zoonotic parasite P. knowlesi, which also infects humans. P. vivaxand P. knowlesiare co-endemic across much of South East Asia, making it important to design serological markers that minimize cross-reactivity in this region. To determine the degree of IgG cross-reactivity against a panel of P. vivaxserological markers, we assayed samples from human patients with P. knowlesimalaria. IgG antibody reactivity is high against P. vivaxproteins with high sequence identity with their P. knowlesiortholog. IgG reactivity peaks at 7 days post-P. knowlesiinfection and is short-lived, with minimal responses 1 year post-infection. We designed a panel of eight P. vivaxproteins with low levels of cross-reactivity with P. knowlesi. This panel can accurately classify recent P. vivaxinfections while reducing misclassification of recent P. knowlesiinfections.
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- 2022
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131. Combining Parasite Lactate Dehydrogenase-Based and Histidine-Rich Protein 2-Based Rapid Tests To Improve Specificity for Diagnosis of Malaria Due to Plasmodium knowlesiand Other PlasmodiumSpecies in Sabah, Malaysia
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Grigg, Matthew J., William, Timothy, Barber, Bridget E., Parameswaran, Uma, Bird, Elspeth, Piera, Kim, Aziz, Ammar, Dhanaraj, Prabakaran, Yeo, Tsin W., and Anstey, Nicholas M.
- Abstract
ABSTRACTPlasmodium knowlesicauses severe and fatal malaria in Malaysia. Microscopic misdiagnosis is common and may delay appropriate treatment. P. knowlesican cross-react with “species-specific” parasite lactate dehydrogenase (pLDH) monoclonal antibodies used in rapid diagnostic tests (RDTs) to detect P. falciparumand P. vivax. At one tertiary-care hospital and two district hospitals in Sabah, we prospectively evaluated two combination RDTs for malaria diagnosis by using both a pan-Plasmodium-pLDH (pan-pLDH)/P. falciparum-specific-pLDH (Pf-pLDH) RDT (OptiMAL-IT) and a non-P. falciparumVOM-pLDH/Pf-HRP2 RDT (CareStart). Differential cross-reactivity among these combinations was hypothesized to differentiate P. knowlesifrom other Plasmodiummonoinfections. Among 323 patients with PCR-confirmed P. knowlesi(n= 193), P. falciparum(n= 93), and P. vivax(n= 37) monoinfections, the VOM-pLDH individual component had the highest sensitivity for nonsevere (35%; 95% confidence interval [CI], 27 to 43%) and severe (92%; CI, 81 to 100%) P. knowlesimalaria. CareStart demonstrated a P. knowlesisensitivity of 42% (CI, 34 to 49%) and specificity of 74% (CI, 65 to 82%), a P. vivaxsensitivity of 83% (CI, 66 to 93%) and specificity of 71% (CI, 65 to 76%), and a P. falciparumsensitivity of 97% (CI, 90 to 99%) and specificity of 99% (CI, 97 to 100%). OptiMAL-IT demonstrated a P. knowlesisensitivity of 32% (CI, 25 to 39%) and specificity of 21% (CI, 15 to 29%), a P. vivaxsensitivity of 60% (CI, 42 to 75%) and specificity of 97% (CI, 94 to 99%), and a P. falciparumsensitivity of 82% (CI, 72 to 89%) and specificity of 39% (CI, 33 to 46%). The combination of CareStart plus OptiMAL-IT for P. knowlesiusing predefined criteria gave a sensitivity of 25% (CI, 19 to 32%) and specificity of 97% (CI, 92 to 99%). Combining two RDT combinations was highly specific for P. knowlesimalaria diagnosis; however, sensitivity was poor. The specificity of pLDH RDTs was decreased for P. vivaxand P. falciparumbecause of P. knowlesicross-reactivity and cautions against their use alone in areas where P. knowlesimalaria is endemic. Sensitive P. knowlesi-specific RDTs and/or alternative molecular diagnostic tools are needed in areas where P. knowlesimalaria is endemic.
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- 2014
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132. Neutrophil activation, acute lung injury and disease severity in Plasmodium knowlesi malaria.
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Tan, Angelica F., Sakam, Sitti Saimah binti, Piera, Kim, Rajahram, Giri S., William, Timothy, Barber, Bridget E., Anstey, Nicholas M., Grigg, Matthew J., and Kho, Steven
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LEUCOCYTES , *LEUCOCYTE elastase , *HOSPITAL admission & discharge , *MALARIA , *NEUTROPHILS - Abstract
The risk of severe malaria from the zoonotic parasite Plasmodium knowlesi approximates that from P. falciparum. In severe falciparum malaria, neutrophil activation contributes to inflammatory pathogenesis, including acute lung injury. The role of neutrophil activation in the pathogenesis of severe knowlesi malaria has not been examined. We evaluated 213 patients with P. knowlesi mono-infection (138 non-severe, 75 severe) and 49 Plasmodium-negative controls from Malaysia. Markers of neutrophil activation (soluble neutrophil elastase [NE], citrullinated histone [CitH3] and circulating neutrophil extracellular traps [NETs]) were quantified in peripheral blood by microscopy and immunoassays. Findings were correlated with malaria severity, ALI clinical criteria, biomarkers of parasite biomass, haemolysis, and endothelial activation. Neutrophil activation increased with disease severity, with median levels higher in severe than non-severe malaria and controls for NE (380[IQR:210–930]ng/mL, 236[139–448]ng/mL, 218[134–307]ng/mL, respectively) and CitH3 (8.72[IQR:3.0–23.1]ng/mL, 4.29[1.46–9.49]ng/mL, 1.53[0.6–2.59]ng/mL, respectively)[all p<0.01]. NETs were higher in severe malaria compared to controls (126/μL[IQR:49–323] vs 51[20–75]/μL, p<0.001). In non-severe malaria, neutrophil activation fell significantly upon discharge from hospital (p<0.03). In severe disease, NETs, NE, and CitH3 were correlated with parasitaemia, cell-free haemoglobin and angiopoietin-2 (all Pearson's r>0.24, p<0.05). Plasma NE and angiopoietin-2 were higher in knowlesi patients with ALI than those without (p<0.008); neutrophilia was associated with an increased risk of ALI (aOR 3.27, p<0.01). In conclusion, neutrophil activation is increased in ALI and in proportion to disease severity in knowlesi malaria, is associated with endothelial activation, and may contribute to disease pathogenesis. Trials of adjunctive therapies to regulate neutrophil activation are warranted in severe knowlesi malaria. Author summary: The most common malaria in Malaysia is caused by animal-to-human transmission of Plasmodium knowlesi from its natural monkey hosts to humans via mosquito bites. As the human immune system responds to such infection, white blood cells such as neutrophils are recruited, activated and release products with pathogen-killing activity. There is increasing evidence that neutrophil products cause damage to the host and contribute to severe disease. While this has been studied in human-only malaria, the role of neutrophils in zoonotic P. knowlesi malaria is poorly understood. In this study, we examined three markers of neutrophil activation (neutrophil elastase, citrullinated histone H3 and neutrophil extracellular traps) in hospital patients with severe and non-severe knowlesi malaria from Sabah, East Malaysia. Compared to healthy controls, neutrophil activation was increased in patients with knowlesi malaria in proportion to disease severity. The increase in neutrophil activation was also linked to different types of severe malaria manifestations, especially acute lung injury. These findings have implications for development of new strategies to prevent host organ damage for better treatment of severe knowlesi malaria. [ABSTRACT FROM AUTHOR]
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- 2024
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133. Zoonotic malaria transmission and land use change in Southeast Asia: what is known about the vectors.
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van de Straat, Bram, Sebayang, Boni, Grigg, Matthew J., Staunton, Kyran, Garjito, Triwibowo Ambar, Vythilingam, Indra, Russell, Tanya L., and Burkot, Thomas R.
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MALARIA , *KRA , *LAND use , *MOSQUITO vectors , *NUMBERS of species - Abstract
Zoonotic Plasmodium infections in humans in many Southeast Asian countries have been increasing, including in countries approaching elimination of human-only malaria transmission. Most simian malarias in humans are caused by Plasmodium knowlesi, but recent research shows that humans are at risk of many different simian Plasmodium species. In Southeast Asia, simian Plasmodium species are mainly transmitted by mosquitoes in the Anopheles leucosphyrus and Anopheles dirus complexes. Although there is some evidence of species outside the Leucosphyrus Group transmitting simian Plasmodium species, these await confirmation of transmission to humans. The vectors of monkey malarias are mostly found in forests and forest fringes, where they readily bite long-tailed and pig-tailed macaques (the natural reservoir hosts) and humans. How changing land-uses influence zoonotic malaria vectors is still poorly understood. Fragmentation of forests from logging, agriculture and other human activities is associated with increased zoonotic Plasmodium vector exposure. This is thought to occur through altered macaque and mosquito distributions and behaviours, and importantly, increased proximity of humans, macaques, and mosquito vectors. Underlying the increase in vector densities is the issue that the land-use change and human activities create more oviposition sites and, in correlation, increases availably of human blood hosts. The current understanding of zoonotic malaria vector species is largely based on a small number of studies in geographically restricted areas. What is known about the vectors is limited: the data is strongest for distribution and density with only weak evidence for a limited number of species in the Leucosphyrus Group for resting habits, insecticide resistance, blood feeding habits and larval habitats. More data are needed on vector diversity and bionomics in additional geographic areas to understand both the impacts on transmission of anthropogenic land-use change and how this significant disease in humans might be controlled. [ABSTRACT FROM AUTHOR]
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- 2022
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134. Supplementary information from Predictive analysis across spatial scales links zoonotic malaria to deforestation
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Brock, Patrick M., Fornace, Kimberly M., Grigg, Matthew J., Anstey, Nicholas M., William, Timothy, Cox, Jon, Drakeley, Chris J., Ferguson, Heather M., and Kao, Rowland R.
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parasitic diseases ,15. Life on land - Abstract
The complex transmission ecologies of vector-borne and zoonotic diseases pose challenges to their control, especially in changing landscapes. Human incidence of zoonotic malaria (Plasmodium knowlesi) is associated with deforestation although mechanisms are unknown. Here, a novel application of a method for predicting disease occurrence that combines machine learning and statistics is used to identify the key spatial scales that define the relationship between zoonotic malaria cases and environmental change. Using data from satellite imagery, a case–control study, and a cross-sectional survey, predictive models of household-level occurrence of P. knowlesi were fitted with 16 variables summarized at 11 spatial scales simultaneously. The method identified a strong and well-defined peak of predictive influence of the proportion of cleared land within 1 km of households on P. knowlesi occurrence. Aspect (1 and 2 km), slope (0.5 km) and canopy regrowth (0.5 km) were important at small scales. In contrast, fragmentation of deforested areas influenced P. knowlesi occurrence probability most strongly at large scales (4 and 5 km). The identification of these spatial scales narrows the field of plausible mechanisms that connect land use change and P. knowlesi, allowing for the refinement of disease occurrence predictions and the design of spatially-targeted interventions.
135. 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, Daniel J, Plewes, Katherine, Grigg, Matthew J, Rajahram, Giri S, Piera, Kim A, William, Timothy, Chatfield, Mark D, Yeo, Tsin W, Dondorp, Arjen M, Anstey, Nicholas M, and Barber, Bridget E
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parasitic diseases ,3. Good health - 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.
136. Supplementary information from Predictive analysis across spatial scales links zoonotic malaria to deforestation
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Brock, Patrick M., Fornace, Kimberly M., Grigg, Matthew J., Anstey, Nicholas M., William, Timothy, Cox, Jon, Drakeley, Chris J., Ferguson, Heather M., and Kao, Rowland R.
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parasitic diseases ,15. Life on land - Abstract
The complex transmission ecologies of vector-borne and zoonotic diseases pose challenges to their control, especially in changing landscapes. Human incidence of zoonotic malaria (Plasmodium knowlesi) is associated with deforestation although mechanisms are unknown. Here, a novel application of a method for predicting disease occurrence that combines machine learning and statistics is used to identify the key spatial scales that define the relationship between zoonotic malaria cases and environmental change. Using data from satellite imagery, a case–control study, and a cross-sectional survey, predictive models of household-level occurrence of P. knowlesi were fitted with 16 variables summarized at 11 spatial scales simultaneously. The method identified a strong and well-defined peak of predictive influence of the proportion of cleared land within 1 km of households on P. knowlesi occurrence. Aspect (1 and 2 km), slope (0.5 km) and canopy regrowth (0.5 km) were important at small scales. In contrast, fragmentation of deforested areas influenced P. knowlesi occurrence probability most strongly at large scales (4 and 5 km). The identification of these spatial scales narrows the field of plausible mechanisms that connect land use change and P. knowlesi, allowing for the refinement of disease occurrence predictions and the design of spatially-targeted interventions.
137. Primaquine dose and the risk of haemolysis in patients with uncomplicated Plasmodium vivax malaria: a systematic review and individual patient data meta-analysis.
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Rajasekhar, Megha, Simpson, Julie A, Ley, Benedikt, Edler, Peta, Chu, Cindy S, Abreha, Tesfay, Awab, Ghulam R, Baird, J Kevin, Bancone, Germana, Barber, Bridget E, Grigg, Matthew J, Hwang, Jimee, Karunajeewa, Harin, Lacerda, Marcus V G, Ladeia-Andrade, Simone, Llanos-Cuentas, Alejandro, Pukrittayakamee, Sasithon, Rijal, Komal R, Saravu, Kavitha, and Sutanto, Inge
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PLASMODIUM vivax , *PRIMAQUINE , *GLUCOSE-6-phosphate dehydrogenase , *MALARIA , *MEDICAL records - Abstract
Primaquine radical cure is used to treat dormant liver-stage parasites and prevent relapsing Plasmodium vivax malaria but is limited by concerns of haemolysis. We undertook a systematic review and individual patient data meta-analysis to investigate the haematological safety of different primaquine regimens for P vivax radical cure. For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, if they included a treatment group with daily primaquine given over multiple days where primaquine was commenced within 3 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether–lumefantrine, artesunate–mefloquine, artesunate–amodiaquine, or dihydroartemisinin–piperaquine), and if they recorded haemoglobin or haematocrit concentrations on day 0. We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. The main outcome was haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL by day 14. Haemoglobin concentration changes between day 0 and days 2–3 and between day 0 and days 5–7 were assessed by mixed-effects linear regression for patients with glucose-6-phosphate dehydrogenase (G6PD) activity of (1) 30% or higher and (2) between 30% and less than 70%. The study was registered with PROSPERO, CRD42019154470 and CRD42022303680. Of 226 identified studies, 18 studies with patient-level data from 5462 patients from 15 countries were included in the analysis. A haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL occurred in one (0·1%) of 1208 patients treated without primaquine, none of 893 patients treated with a low daily dose of primaquine (<0·375 mg/kg per day), five (0·3%) of 1464 patients treated with an intermediate daily dose (0·375 mg/kg per day to <0·75 mg/kg per day), and six (0·5%) of 1269 patients treated with a high daily dose (≥0·75 mg/kg per day). The covariate-adjusted mean estimated haemoglobin changes at days 2–3 were –0·6 g/dL (95% CI –0·7 to –0·5), –0·7 g/dL (–0·8 to –0·5), –0·6 g/dL (–0·7 to –0·4), and –0·5 g/dL (–0·7 to –0·4), respectively. In 51 patients with G6PD activity between 30% and less than 70%, the adjusted mean haemoglobin concentration on days 2–3 decreased as G6PD activity decreased; two patients in this group who were treated with a high daily dose of primaquine had a reduction of more than 25% to a concentration of less than 7 g/dL. 17 of 18 included studies had a low or unclear risk of bias. Treatment of patients with G6PD activity of 30% or higher with 0·25–0·5 mg/kg per day primaquine regimens and patients with G6PD activity of 70% or higher with 0·25–1 mg/kg per day regimens were associated with similar risks of haemolysis to those in patients treated without primaquine, supporting the safe use of primaquine radical cure at these doses. Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture. [ABSTRACT FROM AUTHOR]
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- 2024
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138. Effect of primaquine dose on the risk of recurrence in patients with uncomplicated Plasmodium vivax: a systematic review and individual patient data meta-analysis.
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Commons, Robert J, Rajasekhar, Megha, Edler, Peta, Abreha, Tesfay, Awab, Ghulam R, Baird, J Kevin, Barber, Bridget E, Chu, Cindy S, Cui, Liwang, Daher, André, Gonzalez-Ceron, Lilia, Grigg, Matthew J, Hwang, Jimee, Karunajeewa, Harin, Lacerda, Marcus V G, Ladeia-Andrade, Simone, Lidia, Kartini, Llanos-Cuentas, Alejandro, Longley, Rhea J, and Pereira, Dhelio B
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PLASMODIUM vivax , *PRIMAQUINE , *DISEASE relapse , *POISSON regression , *MEDICAL research - Abstract
Primaquine is used to eliminate Plasmodium vivax hypnozoites, but its optimal dosing regimen remains unclear. We undertook a systematic review and individual patient data meta-analysis to investigate the efficacy and tolerability of different primaquine dosing regimens to prevent P vivax recurrence. For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, and if they included a treatment group with daily primaquine given over multiple days, where primaquine was commenced within 7 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether–lumefantrine, artesunate–mefloquine, artesunate–amodiaquine, or dihydroartemisinin–piperaquine). We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. We assessed the effects of total dose and duration of primaquine regimens on the rate of first P vivax recurrence between day 7 and day 180 by Cox's proportional hazards regression (efficacy analysis). The effect of primaquine daily dose on gastrointestinal symptoms on days 5–7 was assessed by modified Poisson regression (tolerability analysis). The study was registered with PROSPERO, CRD42019154470. Of 226 identified studies, 23 studies with patient-level data from 6879 patients from 16 countries were included in the efficacy analysis. At day 180, the risk of recurrence was 51·0% (95% CI 48·2–53·9) in 1470 patients treated without primaquine, 19·3% (16·9–21·9) in 2569 patients treated with a low total dose of primaquine (approximately 3·5 mg/kg), and 8·1% (7·0–9·4) in 2811 patients treated with a high total dose of primaquine (approximately 7 mg/kg), regardless of primaquine treatment duration. Compared with treatment without primaquine, the rate of P vivax recurrence was lower after treatment with low-dose primaquine (adjusted hazard ratio 0·21, 95% CI 0·17–0·27; p<0·0001) and high-dose primaquine (0·10, 0·08–0·12; p<0·0001). High-dose primaquine had greater efficacy than low-dose primaquine in regions with high and low relapse periodicity (ie, the time from initial infection to vivax relapse). 16 studies with patient-level data from 5609 patients from ten countries were included in the tolerability analysis. Gastrointestinal symptoms on days 5–7 were reported by 4·0% (95% CI 0·0–8·7) of 893 patients treated without primaquine, 6·2% (0·5–12·0) of 737 patients treated with a low daily dose of primaquine (approximately 0·25 mg/kg per day), 5·9% (1·8–10·1) of 1123 patients treated with an intermediate daily dose (approximately 0·5 mg/kg per day) and 10·9% (5·7–16·1) of 1178 patients treated with a high daily dose (approximately 1 mg/kg per day). 20 of 23 studies included in the efficacy analysis and 15 of 16 in the tolerability analysis had a low or unclear risk of bias. Increasing the total dose of primaquine from 3·5 mg/kg to 7 mg/kg can reduce P vivax recurrences by more than 50% in most endemic regions, with a small associated increase in gastrointestinal symptoms. Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture. [ABSTRACT FROM AUTHOR]
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- 2024
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139. Updating estimates of Plasmodium knowlesi malaria risk in response to changing land use patterns across Southeast Asia.
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Tobin, Ruarai J., Harrison, Lucinda E., Tully, Meg K., Lubis, Inke N. D., Noviyanti, Rintis, Anstey, Nicholas M., Rajahram, Giri S., Grigg, Matthew J., Flegg, Jennifer A., Price, David J., and Shearer, Freya M.
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MALARIA , *PLASMODIUM , *LAND use , *ENVIRONMENTAL risk , *SPATIAL variation , *Q fever , *ALPHAVIRUSES - Abstract
Background: Plasmodium knowlesi is a zoonotic parasite that causes malaria in humans. The pathogen has a natural host reservoir in certain macaque species and is transmitted to humans via mosquitoes of the Anopheles Leucosphyrus Group. The risk of human P. knowlesi infection varies across Southeast Asia and is dependent upon environmental factors. Understanding this geographic variation in risk is important both for enabling appropriate diagnosis and treatment of the disease and for improving the planning and evaluation of malaria elimination. However, the data available on P. knowlesi occurrence are biased towards regions with greater surveillance and sampling effort. Predicting the spatial variation in risk of P. knowlesi malaria requires methods that can both incorporate environmental risk factors and account for spatial bias in detection. Methods & results: We extend and apply an environmental niche modelling framework as implemented by a previous mapping study of P. knowlesi transmission risk which included data up to 2015. We reviewed the literature from October 2015 through to March 2020 and identified 264 new records of P. knowlesi, with a total of 524 occurrences included in the current study following consolidation with the 2015 study. The modelling framework used in the 2015 study was extended, with changes including the addition of new covariates to capture the effect of deforestation and urbanisation on P. knowlesi transmission. Discussion: Our map of P. knowlesi relative transmission suitability estimates that the risk posed by the pathogen is highest in Malaysia and Indonesia, with localised areas of high risk also predicted in the Greater Mekong Subregion, The Philippines and Northeast India. These results highlight areas of priority for P. knowlesi surveillance and prospective sampling to address the challenge the disease poses to malaria elimination planning. Author summary: Plasmodium knowlesi is a parasite that can cause malaria when it infects humans. Although most people do not experience severe illness from Plasmodium knowlesi infection, a small number will develop serious or even fatal disease. The parasite is found naturally in some monkeys throughout Southeast Asia, and spreads from these monkeys to humans through mosquitoes. Previous research predicted where the risk of being infected is highest according to what we know about the environment across Southeast Asia, such as if there are forests in an area or if the altitude is high. In this work, we extend this previous research with more up-to-date data on environmental conditions and infections to predict the risk of being infected with Plasmodium knowlesi. We show that the risk Plasmodium knowlesi poses to humans is high across much of Southeast Asia, and that the disease will continue to challenge national goals to eliminate malaria. [ABSTRACT FROM AUTHOR]
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- 2024
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140. The effect of regularly dosed paracetamol versus no paracetamol on renal function in <italic>Plasmodium knowlesi</italic> malaria (PACKNOW): study protocol for a randomised controlled trial.
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Cooper, Daniel J., Plewes, Katherine, Grigg, Matthew J., Rajahram, Giri S., Piera, Kim A., William, Timothy, Chatfield, Mark D., Yeo, Tsin Wen, Dondorp, Arjen M., Anstey, Nicholas M., and Barber, Bridget E.
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ACETAMINOPHEN ,MALARIA ,ACUTE kidney failure ,CHRONIC kidney failure ,CARDIOVASCULAR diseases - 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. [ABSTRACT FROM AUTHOR]- Published
- 2018
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141. Malaria Parasite Clearance: What Are We Really Measuring?
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Khoury, David S., Zaloumis, Sophie G., Grigg, Matthew J., Haque, Ashraful, and Davenport, Miles P.
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DRUG development , *DRUG efficacy , *PARASITES , *PLASMODIUM - Abstract
Antimalarial drugs are vital for treating malaria and controlling transmission. Measuring drug efficacy in the field requires large clinical trials and thus we have identified proxy measures of drug efficacy such as the parasite clearance curve. This is often assumed to measure the rate of drug activity against parasites and is used to predict optimal treatment regimens required to completely clear a blood-stage infection. We discuss evidence that the clearance curve is not measuring the rate of drug killing. This has major implications for how we assess optimal treatment regimens, as well as how we prioritise new drugs in the drug development pipeline. The parasite clearance half-life is used to assess the efficacy of antimalarial drugs. It is usually assumed that a parasite will be rapidly removed by the host after it is killed by a drug. This shapes our interpretation of the parasite clearance half-life. The parasite clearance curve is not always measuring how quickly a drug kills parasites, because parasites that are killed may remain in circulation for some time. Experimental approaches can be used to determine whether circulating parasites are viable or nonviable after treatment. These approaches allow us to assess how quickly parasites are killed. Approaches that distinguish between viable and nonviable parasites would assist in better assessing the efficacy of antimalarials in vivo. [ABSTRACT FROM AUTHOR]
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- 2020
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142. Evaluation of a point-of-care haemozoin assay (Gazelle device) for rapid detection of Plasmodium knowlesi malaria.
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Tan, Angelica F., Thota, Priyaleela, Sakam, Sitti Saimah Binti, Lew, Yao Long, Rajahram, Giri S., William, Timothy, Barber, Bridget E., Kho, Steven, Anstey, Nicholas M., Bell, David, and Grigg, Matthew J.
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PLASMODIUM , *GAZELLES , *MALARIA , *ENDEMIC diseases , *POINT-of-care testing , *HEME , *INSECTICIDE resistance - Abstract
Plasmodium knowlesi is the major cause of zoonotic malaria in Southeast Asia. Rapid and accurate diagnosis enables effective clinical management. A novel malaria diagnostic tool, Gazelle (Hemex Health, USA) detects haemozoin, a by-product of haem metabolism found in all Plasmodium infections. A pilot phase refined the Gazelle haemozoin identification algorithm, with the algorithm then tested against reference PCR in a larger cohort of patients with P. knowlesi mono-infections and febrile malaria-negative controls. Limit-of-detection analysis was conducted on a subset of P. knowlesi samples serially diluted with non-infected whole blood. The pilot phase of 40 P. knowlesi samples demonstrated 92.5% test sensitivity. P. knowlesi-infected patients (n = 203) and febrile controls (n = 44) were subsequently enrolled. Sensitivity and specificity of the Gazelle against reference PCR were 94.6% (95% CI 90.5–97.3%) and 100% (95% CI 92.0–100%) respectively. Positive and negative predictive values were 100% and 98.8%, respectively. In those tested before antimalarial treatment (n = 143), test sensitivity was 96.5% (95% CI 92.0–98.9%). Sensitivity for samples with ≤ 200 parasites/µL (n = 26) was 84.6% (95% CI 65.1–95.6%), with the lowest parasitaemia detected at 18/µL. Limit-of-detection (n = 20) was 33 parasites/µL (95% CI 16–65%). The Gazelle device has the potential for rapid, sensitive detection of P. knowlesi infections in endemic areas. [ABSTRACT FROM AUTHOR]
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- 2023
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143. Diagnostic performance of a 5-plex malaria immunoassay in regions co-endemic for Plasmodium falciparum, P. vivax, P. knowlesi, P. malariae and P. ovale.
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Kho, Steven, Anstey, Nicholas M., Barber, Bridget E., Piera, Kim, William, Timothy, Kenangalem, Enny, McCarthy, James S., Jang, Ihn Kyung, Domingo, Gonzalo J., Britton, Sumudu, and Grigg, Matthew J.
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MALARIA , *PLASMODIUM falciparum , *IMMUNOASSAY , *CHEMILUMINESCENCE assay , *LACTATE dehydrogenase , *C-reactive protein - Abstract
Commercial point-of-care tests remain insufficient for accurately detecting and differentiating low-level malaria infections in regions co-endemic with multiple non-falciparum species, including zoonotic Plasmodium knowlesi (Pk). A 5-plex chemiluminescent assay simultaneously measures pan-Plasmodium lactate dehydrogenase (pLDH), P. falciparum (Pf)-LDH, P. vivax (Pv)-LDH, Pf-histidine-rich protein-2 (HRP2), and C-reactive protein. We assessed its diagnostic performance on whole blood (WB) samples from 102 healthy controls and 306 PCR-confirmed clinical cases of Pf, Pv, Pk, P. malariae (Pm) and P. ovale (Po) mono-infections from Southeast-Asia. We confirm its excellent HRP2-based detection of Pf. Cross-reactivity of Pf-LDH with all non-falciparum species tested was observed (specificity 57.3%). Pv-LDH performance was suboptimal for Pv (93.9% sensitivity and 73.9% specificity). Poor specificity was driven by strong Pk cross-reactivity, with Pv-LDH detecting 93.9% of Pk infections. The pan-LDH-to-Pf-LDH ratio was capable of discerning Pv from Pk, and robustly differentiated Pf from Pm or Po infection, useful in regions with hrp2/3 deletions. We tested the platform's performance in plasma for the first time, with WB outperforming plasma for all analytes except Pv-LDH for Pk. The platform is a promising tool for WB malaria diagnosis, although further development is warranted to improve its utility in regions co-endemic for multiple non-falciparum species. [ABSTRACT FROM AUTHOR]
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- 2022
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144. Predictive analysis across spatial scales links zoonotic malaria to deforestation.
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Brock, Patrick M., Ferguson, Heather M., Kao, Rowland R., Fornace, Kimberly M., Cox, Jon, Drakeley, Chris J., Grigg, Matthew J., Anstey, Nicholas M., and William, Timothy
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ZOONOSES , *MALARIA , *DEFORESTATION , *MACHINE learning , *COMMUNICABLE diseases - Abstract
The complex transmission ecologies of vector-borne and zoonotic diseases pose challenges to their control, especially in changing landscapes. Human incidence of zoonotic malaria (Plasmodium knowlesi) is associated with deforestation although mechanisms are unknown. Here, a novel application of a method for predicting disease occurrence that combines machine learning and statistics is used to identify the key spatial scales that define the relationship between zoonotic malaria cases and environmental change. Using data from satellite imagery, a case-control study, and a cross-sectional survey, predictive models of household-level occurrence of P. knowlesi were fitted with 16 variables summarized at 11 spatial scales simultaneously. The method identified a strong and well-defined peak of predictive influence of the proportion of cleared land within 1 km of households on P. knowlesi occurrence. Aspect (1 and 2 km), slope (0.5 km) and canopy regrowth (0.5 km) were important at small scales. By contrast, fragmentation of deforested areas influenced P. knowlesi occurrence probability most strongly at large scales (4 and 5 km). The identification of these spatial scales narrows the field of plausible mechanisms that connect land use change and P. knowlesi, allowing for the refinement of disease occurrence predictions and the design of spatially-targeted interventions. [ABSTRACT FROM AUTHOR]
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- 2019
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145. A molecular barcode and web-based data analysis tool to identify imported Plasmodium vivax malaria
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Hidayat Trimarsanto, Roberto Amato, Richard D. Pearson, Edwin Sutanto, Rintis Noviyanti, Leily Trianty, Jutta Marfurt, Zuleima Pava, Diego F. Echeverry, Tatiana M. Lopera-Mesa, Lidia M. Montenegro, Alberto Tobón-Castaño, Matthew J. Grigg, Bridget Barber, Timothy William, Nicholas M. Anstey, Sisay Getachew, Beyene Petros, Abraham Aseffa, Ashenafi Assefa, Awab G. Rahim, Nguyen H. Chau, Tran T. Hien, Mohammad S. Alam, Wasif A. Khan, Benedikt Ley, Kamala Thriemer, Sonam Wangchuck, Yaghoob Hamedi, Ishag Adam, Yaobao Liu, Qi Gao, Kanlaya Sriprawat, Marcelo U. Ferreira, Moses Laman, Alyssa Barry, Ivo Mueller, Marcus V. G. Lacerda, Alejandro Llanos-Cuentas, Srivicha Krudsood, Chanthap Lon, Rezika Mohammed, Daniel Yilma, Dhelio B. Pereira, Fe E. J. Espino, Cindy S. Chu, Iván D. Vélez, Chayadol Namaik-larp, Maria F. Villegas, Justin A. Green, Gavin Koh, Julian C. Rayner, Eleanor Drury, Sónia Gonçalves, Victoria Simpson, Olivo Miotto, Alistair Miles, Nicholas J. White, Francois Nosten, Dominic P. Kwiatkowski, Ric N. Price, Sarah Auburn, Pearson, Richard D [0000-0002-7386-3566], Sutanto, Edwin [0000-0002-2997-4648], Marfurt, Jutta [0000-0002-3846-0825], Echeverry, Diego F [0000-0003-0301-4478], Tobón-Castaño, Alberto [0000-0002-1671-2649], Grigg, Matthew J [0000-0001-9914-8352], Alam, Mohammad S [0000-0001-8330-5499], Khan, Wasif A [0000-0002-7650-8068], Ley, Benedikt [0000-0002-5734-0845], Mueller, Ivo [0000-0001-6554-6889], Lacerda, Marcus VG [0000-0003-3374-9985], Pereira, Dhelio B [0000-0002-7761-5498], Espino, Fe EJ [0000-0003-1690-1711], Koh, Gavin [0000-0002-7336-1566], Rayner, Julian C [0000-0002-9835-1014], Drury, Eleanor [0000-0002-9887-6961], Miotto, Olivo [0000-0001-8060-6771], Nosten, Francois [0000-0002-7951-0745], Kwiatkowski, Dominic P [0000-0002-5023-0176], Price, Ric N [0000-0003-2000-2874], Auburn, Sarah [0000-0002-4638-536X], and Apollo - University of Cambridge Repository
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Likelihood Functions ,Internet ,Molecular medicine ,45 ,Epidemiology ,692/308/2056 ,article ,Medicine (miscellaneous) ,631/114/1305 ,General Biochemistry, Genetics and Molecular Biology ,692/4017 ,Malaria ,Genetics research ,Machine learning ,Malaria, Vivax ,692/699/255/1629 ,Humans ,PLASMODIUM ,692/308/174 ,Plasmodium vivax ,General Agricultural and Biological Sciences - Abstract
Funder: HT was supported by a Charles Darwin University International PhD Scholarship (CDIPS), Funder: Malaysian Ministry of Health (BP00500420), Traditionally, patient travel history has been used to distinguish imported from autochthonous malaria cases, but the dormant liver stages of Plasmodium vivax confound this approach. Molecular tools offer an alternative method to identify, and map imported cases. Using machine learning approaches incorporating hierarchical fixation index and decision tree analyses applied to 799 P. vivax genomes from 21 countries, we identified 33-SNP, 50-SNP and 55-SNP barcodes (GEO33, GEO50 and GEO55), with high capacity to predict the infection's country of origin. The Matthews correlation coefficient (MCC) for an existing, commonly applied 38-SNP barcode (BR38) exceeded 0.80 in 62% countries. The GEO panels outperformed BR38, with median MCCs > 0.80 in 90% countries at GEO33, and 95% at GEO50 and GEO55. An online, open-access, likelihood-based classifier framework was established to support data analysis (vivaxGEN-geo). The SNP selection and classifier methods can be readily amended for other use cases to support malaria control programs.
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- 2022
146. Primaquine for uncomplicated Plasmodium vivax malaria in children younger than 15 years: a systematic review and individual patient data meta-analysis.
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Commons RJ, Rajasekhar M, Allen EN, Yilma D, Chotsiri P, Abreha T, Adam I, Awab GR, Barber BE, Brasil LW, Chu CS, Cui L, Edler P, Gomes MDSM, Gonzalez-Ceron L, Grigg MJ, Hamid MMA, Hwang J, Karunajeewa H, Lacerda MVG, Ladeia-Andrade S, Leslie T, Longley RJ, Monteiro WM, Pasaribu AP, Poespoprodjo JR, Richmond CL, Rijal KR, Taylor WRJ, Thanh PV, Thriemer K, Vieira JLF, White NJ, Zuluaga-Idarraga LM, Workman LJ, Tarning J, Stepniewska K, Guerin PJ, Simpson JA, Barnes KI, and Price RN
- Abstract
Background: Primaquine, the only widely available treatment to prevent relapsing Plasmodium vivax malaria, is produced as 15 mg tablets, and new paediatric formulations are being developed. To inform the optimal primaquine dosing regimen for children, we aimed to determine the efficacy and safety of different primaquine dose strategies in children younger than 15 years., Methods: We undertook a systematic review (Jan 1, 2000-July 26, 2024) for P vivax efficacy studies with at least one treatment group that was administered primaquine over multiple days, that enrolled children younger than 15 years, that followed up patients for at least 28 days, and that had data available for inclusion by June 30, 2022. Patients were excluded if they were aged 15 years or older, presented with severe malaria, received adjunctive antimalarials within 14 days of diagnosis, commenced primaquine more than 7 days after starting schizontocidal treatment, had a protocol violation in the original study, or were missing data on age, sex, or primaquine dose. Available individual patient data were collated and standardised. To evaluate efficacy, the risk of recurrent P vivax parasitaemia between days 7 and 180 was assessed by time-to-event analysis for different total mg/kg primaquine doses (low total dose of ∼3·5 mg/kg and high total dose of ∼7 mg/kg). To evaluate tolerability and safety, the following were assessed by daily mg/kg primaquine dose (low daily dose of ∼0·25 mg/kg, intermediate daily dose of ∼0·5 mg/kg, and high daily dose of ∼1 mg/kg): gastrointestinal symptoms (vomiting, anorexia, or diarrhoea) on days 5-7, haemoglobin decrease of at least 25% to less than 7g/dL (severe haemolysis), absolute change in haemoglobin from day 0 to days 2-3 or days 5-7, and any serious adverse events within 28 days. This study is registered with PROSPERO, CRD42021278085., Findings: In total, 3514 children from 27 studies and 15 countries were included. The cumulative incidence of recurrence by day 180 was 51·4% (95% CI 47·0-55·9) following treatment without primaquine, 16·0% (12·4-20·3) following a low total dose of primaquine, and 10·2% (8·4-12·3) following a high total dose of primaquine. The hazard of recurrent P vivax parasitaemia in children younger than 15 years was reduced following primaquine at low total doses (adjusted hazard ratio [HR] 0·17, 95% CI 0·11-0·25) and high total doses (0·09, 0·07-0·12), compared with no primaquine. In 525 children younger than 5 years, the relative rates of recurrence were also reduced, with an adjusted HR of 0·33 (95% CI 0·18-0·59) for a low total dose and 0·13 (0·08-0·21) for a high total dose of primaquine compared with no primaquine. The rate of recurrence following a high total dose was reduced compared with a low dose in children younger than 15 years (adjusted HR 0·54, 95% CI 0·35-0·85) and children younger than 5 years (0·41, 0·21-0·78). Compared with no primaquine, children treated with any dose of primaquine had a greater risk of gastrointestinal symptoms on days 5-7 after adjustment for confounders, with adjusted risks of 3·9% (95% CI 0-8·6) in children not treated with primaquine, 9·2% (0-18·7) with a low daily dose of primaquine, 6·8% (1·7-12·0) with an intermediate daily dose of primaquine, and 9·6% (4·8-14·3) with a high daily dose of primaquine. In children with 30% or higher glucose-6-phosphate dehydrogenase (G6PD) activity, there were few episodes of severe haemolysis following no primaquine (0·4%, 95% CI 0·1-1·5), a low daily dose (0·0%, 0·0-1·6), an intermediate daily dose (0·5%, 0·1-1·4), or a high daily dose (0·7%, 0·2-1·9). Of 15 possibly drug-related serious adverse events in children, two occurred following a low, four following an intermediate, and nine following a high daily dose of primaquine., Interpretation: A high total dose of primaquine was highly efficacious in reducing recurrent P vivax parasitaemia in children compared with a low dose, particularly in children younger than 5 years. In children treated with high and intermediate daily primaquine doses compared with low daily doses, there was no increase in gastrointestinal symptoms or haemolysis (in children with 30% or higher G6PD activity), but there were more serious adverse events., Funding: Medicines for Malaria Venture, Bill & Melinda Gates Foundation, and Australian National Health and Medical Research Council., Competing Interests: Declaration of interests JKB reports institutional research funding from MMV, GSK, Wellcome Trust, and Sanaria; participation on the US National Institutes of Health data safety monitoring board; and membership of the editorial board of Travel Medicine and Infectious Disease and the guidelines development group for malaria control and elimination, Global Malaria Programme, WHO. RJC, JKB, and RNP report contributions to Up-to-Date. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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147. Osteoprotegerin (OPG) and its ligands RANKL and TRAIL in falciparum, vivax and knowlesi malaria: correlations with disease severity, and B cell production of OPG.
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Nair AS, Woodford J, Loughland J, Andrew D, Piera K, Amante F, William T, Grigg MJ, McCarthy JS, Anstey NM, Boyle MJ, and Barber BE
- Abstract
Osteoprotegerin (OPG) is a soluble decoy receptor for receptor activator of NF-ƙB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL), and is increasingly recognised as a marker of poor prognosis in a number of diseases. Here we demonstrate that in Malaysian adults with falciparum and vivax malaria, OPG is increased, and its ligands TRAIL and RANKL decreased, in proportion to disease severity. In volunteers experimentally infected with P. falciparum and P. vivax , RANKL was suppressed, while TRAIL was unexpectedly increased, suggesting binding of OPG to RANKL prior to TRAIL. We also demonstrate that P. falciparum stimulates B cells to produce OPG in vitro , and that B cell OPG production is increased ex vivo in patients with falciparum, vivax and knowlesi malaria. Our findings provide further evidence of the importance of the OPG/RANKL/TRAIL pathway in pathogenesis of diseases involving systemic inflammation, and may have implications for adjunctive therapies. Further evaluation of the role of B cell production of OPG in host responses to malaria and other inflammatory diseases is warranted., Competing Interests: Declaration of Interests None of the authors have conflicts of interest to declare.
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- 2024
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148. Longitudinal changes in iron homeostasis in human experimental and clinical malaria.
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Woolley SD, Grigg MJ, Marquart L, Gower JSE, Piera K, Nair AS, Amante FM, Rajahram GS, William T, Frazer DM, Chalon S, McCarthy JS, Anstey NM, and Barber BE
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- Humans, Female, Male, Adult, Receptors, Transferrin metabolism, Receptors, Transferrin blood, Middle Aged, Malaysia epidemiology, Young Adult, Longitudinal Studies, Malaria, Falciparum parasitology, Malaria, Falciparum blood, Malaria, Falciparum metabolism, Erythropoietin metabolism, Erythropoietin blood, Biomarkers, Parasitemia blood, Iron metabolism, Iron blood, Homeostasis, Hepcidins blood, Hepcidins metabolism, Malaria blood, Malaria parasitology, Malaria metabolism, Ferritins blood
- Abstract
Background: The interaction between iron status and malaria is incompletely understood. We evaluated longitudinal changes in iron homeostasis in volunteers enrolled in malaria volunteer infection studies (VIS) and in Malaysian patients with falciparum and vivax malaria., Methods: We retrieved data and samples from 55 participants (19 female) enrolled in malaria VIS, and 171 patients (45 female) with malaria and 30 healthy controls (13 female) enrolled in clinical studies in Malaysia. Ferritin, hepcidin, erythropoietin, and soluble transferrin receptor (sTfR) were measured by ELISA., Findings: In the VIS, participants' parasitaemia was correlated with baseline mean corpuscular volume (MCV), but not iron status (ferritin, hepcidin or sTfR). Ferritin, hepcidin and sTfR all increased during the VIS. Ferritin and hepcidin normalised by day 28, while sTfR remained elevated. In VIS participants, baseline ferritin was associated with post-treatment increases in liver transaminase levels. In Malaysian patients with malaria, hepcidin and ferritin were elevated on admission compared to healthy controls, while sTfR increased following admission. By day 28, hepcidin had normalised; however, ferritin and sTfR both remained elevated., Interpretation: Our findings demonstrate that parasitaemia is associated with an individual's MCV rather than iron status. The persistent elevation in sTfR 4 weeks post-infection in both malaria VIS and clinical malaria may reflect a causal link between malaria and iron deficiency., Funding: National Health and Medical Research Council (Program Grant 1037304, Project Grants 1045156 and 1156809; Investigator Grants 2016792 to BEB, 2016396 to JCM, 2017436 to MJG); US National Institute of Health (R01-AI116472-03); Malaysian Ministry of Health (BP00500420)., Competing Interests: Declaration of interests None of the authors have conflicts of interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2024
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149. The economic burden of zoonotic Plasmodium knowlesi malaria on households in Sabah, Malaysia compared to malaria from human-only Plasmodium species.
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Abraham P, McMullin C, William T, Rajahram GS, Jelip J, Teo R, Drakeley C, Manah AM, Anstey NM, Grigg MJ, and Devine A
- Abstract
Background: The emergence of the zoonotic monkey parasite Plasmodium knowlesi as the dominant cause of malaria in Malaysia has disrupted current national WHO elimination goals. Malaysia has free universal access to malaria care; however, out-of-pocket costs are unknown. This study estimated household costs of illness attributable to malaria due to P. knowlesi against other non-zoonotic Plasmodium species infections in Sabah, Malaysia., Methodology/principal Findings: Household costs were estimated from patient-level surveys collected from four hospitals between 2013 and 2016. Direct costs including medical and associated travel costs, and indirect costs due to lost productivity were included. One hundred and fifty-two malaria cases were enrolled: P. knowlesi (n=108), P. vivax (n=22), P. falciparum (n=16), and P. malariae (n=6). Costs were inflated to 2022 Malaysian Ringgits and reported in United States dollars (US$). Across all cases, the mean total costs were US$138 (SD=108), with productivity losses accounting for 58% of costs (US$80; SD=73). P. vivax had the highest mean total household cost at US$210, followed by P. knowlesi (US$127), P. falciparum (US$126), and P. malariae (US$105). Most patients (80%) experienced direct health costs above 10% of monthly income, with 58 (38%) patients experiencing health spending over 25% of monthly income, consistent with catastrophic health expenditure., Conclusions/significance: Despite Malaysia's free health-system care for malaria, patients and families face other related medical, travel, and indirect costs. Household out-of-pocket costs were driven by productivity losses; primarily attributed to infections in working-aged males in rural agricultural-based occupations. Costs for P. knowlesi were comparable to P. falciparum and lower than P. vivax. The higher P. vivax costs related to direct health facility costs for repeat monitoring visits given the liver-stage treatment required., Author Summary: Knowlesi malaria is due to infection with a parasite transmitted by mosquitos from monkeys to humans. Most people who are infected work or live near the forest. It is now the major type of malaria affecting humans in Malaysia. The recent increase of knowlesi malaria cases in humans has impacted individuals, families, and health systems in Southeast Asia. Although the region has made substantial progress towards eliminating human-only malaria species, knowlesi malaria threatens elimination targets as traditional control measures do not address the parasite reservoir in monkeys. The economic burden of illness due to knowlesi malaria has not previously been estimated or subsequently compared with other malaria species. We collected data on the cost of illness to households in Sabah, Malaysia, to estimate their related total economic burden. Medical costs and time off work and usual activities were substantial in patients with the four species of malaria diagnosed during the time of this study. This research highlights the financial burden which households face when seeking care for malaria in Malaysia, despite the free treatment provided by the government.
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- 2024
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150. Improved limit of detection for zoonotic Plasmodium knowlesi and P. cynomolgi surveillance using reverse transcription for total nucleic acid preserved samples or dried blood spots.
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Braima KA, Piera KA, Lubis IN, Noviyanti R, Rajahram GS, Kariodimedjo P, Nainggolan IR, Permatasari R, Trianty L, Amalia R, Sakam SSB, Tan AF, William T, Westaway JA, Lee P, Daim S, Surendra H, Christy N, Letizia AG, Peatey CL, Moideen MA, Barber BE, Sutherland CJ, Anstey NM, and Grigg MJ
- Abstract
Background: Zoonotic P. knowlesi and P. cynomolgi symptomatic and asymptomatic infections occur across endemic areas of Southeast Asia. Most infections are low-parasitemia, with an unknown proportion below routine microscopy detection thresholds. Molecular surveillance tools optimizing the limit of detection (LOD) would allow more accurate estimates of zoonotic malaria prevalence., Methods: An established ultra-sensitive Plasmodium genus quantitative-PCR (qPCR) assay targeting the 18S rRNA gene underwent LOD evaluation with and without reverse transcription (RT) for P. knowlesi , P. cynomolgi and P. vivax using total nucleic acid preserved (DNA/RNA Shield
™ ) isolates and archived dried blood spots (DBS). LODs for selected P. knowlesi- specific assays, and reference P. vivax- and P. cynomolgi -specific assays were determined with RT. Assay specificities were assessed using clinical malaria samples and malaria-negative controls., Results: The use of reverse transcription improved Plasmodium species detection by up to 10,000-fold ( Plasmodium genus), 2759-fold ( P. knowlesi ), 1000-fold ( P. vivax ) and 10-fold ( P. cynomolgi ). The median LOD with RT for the Kamau et al. Plasmodium genus RT-qPCR assay was ≤0.0002 parasites/μL for P. knowlesi and 0.002 parasites/μL for both P. cynomolgi and P. vivax . The LODs with RT for P. knowlesi -specific PCRs were: Imwong et al. 18S rRNA (0.0007 parasites/μL); Divis et al. real-time 18S rRNA (0.0002 parasites/μL); Lubis et al. hemi-nested SICAvar (1.1 parasites/μL) and Lee et al. nested 18S rRNA (11 parasites/μL). The LOD for P. vivax- and P. cynomolgi- specific assays with RT were 0.02 and 0.20 parasites/μL respectively. For DBS P. knowlesi samples the median LOD for the Plasmodium genus qPCR with RT was 0.08, and without RT was 19.89 parasites/uL (249-fold change); no LOD improvement was demonstrated in DBS archived beyond 6 years. The Plasmodium genus and P. knowlesi -assays were 100% specific for Plasmodium species and P. knowlesi detection, respectively, from 190 clinical infections and 48 healthy controls. Reference P. vivax- specific primers demonstrated known cross-reactivity with P. cynomolgi ., Conclusion: Our findings support the use of an 18S rRNA Plasmodium genus qPCR and species-specific nested PCR protocol with RT for highly-sensitive surveillance of zoonotic and human Plasmodium species infections.- Published
- 2024
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