37 results on '"Rajahram, Giri S"'
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2. 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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- 2023
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3. Quantification of parasite clearance in Plasmodium knowlesi infections
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T. Thurai Rathnam, Jeyamalar, Grigg, Matthew J., Dini, Saber, William, Timothy, Sakam, Sitti Saimah, Cooper, Daniel J., Rajahram, Giri S., Barber, Bridget E., Anstey, Nicholas M., Haghiri, Ali, Rajasekhar, Megha, and Simpson, Julie A.
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- 2023
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4. Is the rise of simian zoonotic malarias a public health problem caused by humans? A review of simian malaria in humans
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Woolley, Stephen D., Beeching, Nicholas J., Lalloo, David G., and Rajahram, Giri S.
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- 2023
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5. Plasmodium vivax malaria 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
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- 2022
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6. 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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7. An Evaluation of Commonly Used Surrogate Baseline Creatinine Values to Classify AKI During Acute Infection
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Cooper, Daniel J., Plewes, Katherine, Grigg, Matthew J., Patel, Aatish, Rajahram, Giri S., William, Timothy, Hiemstra, Thomas F., Wang, Zhiqiang, Barber, Bridget E., and Anstey, Nicholas M.
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- 2021
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8. 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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9. Age-Related Clinical Spectrum of Plasmodium knowlesi Malaria and Predictors of Severity
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Grigg, Matthew J., William, Timothy, Barber, Bridget E., Rajahram, Giri S., Menon, Jayaram, Schimann, Emma, Piera, Kim, Wilkes, Christopher S., Patel, Kaajal, Chandna, Arjun, Drakeley, Christopher J., Yeo, Tsin W., and Anstey, Nicholas M.
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- 2018
10. Artemether-Lumefantrine Versus Chloroquine for the Treatment of Uncomplicated Plasmodium knowlesi Malaria : An Open-Label Randomized Controlled Trial CAN KNOW
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Grigg, Matthew J., William, Timothy, Barber, Bridget E., Rajahram, Giri S., Menon, Jayaram, Schimann, Emma, Wilkes, Christopher S., Patel, Kaajal, Chandna, Arjun, Price, Ric N., Yeo, Tsin W., and Anstey, Nicholas M.
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- 2018
11. Comparative evaluation of two commercial real-time PCR kits (QuantiFast™ and abTES™) for the detection of Plasmodium knowlesi and other Plasmodium species in Sabah, Malaysia
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Nuin, Nor Afizah, Tan, Angelica F., Lew, Yao Long, Piera, Kim A., William, Timothy, Rajahram, Giri S., Jelip, Jenarun, Dony, Jiloris F., Mohammad, Rashidah, Cooper, Daniel J., Barber, Bridget E., Anstey, Nicholas M., Chua, Tock H., and Grigg, Matthew J.
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- 2020
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12. Efficacy of Artesunate-mefloquine for Chloroquine-resistant 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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- 2016
13. Plasmodium falciparum artemisinin resistance monitoring in Sabah, Malaysia: in vivo therapeutic efficacy and kelch13 molecular marker surveillance
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Grigg, Matthew J., William, Timothy, Piera, Kim A., Rajahram, Giri S., Jelip, Jenarun, Aziz, Ammar, Menon, Jayaram, Marfurt, Jutta, Price, Ric N., Auburn, Sarah, Barber, Bridget E., Yeo, Tsin W., and Anstey, Nicholas M.
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- 2018
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14. 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 Wen, Dondorp, Arjen M., Anstey, Nicholas M., and Barber, Bridget E.
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- 2018
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15. Falling Plasmodium knowlesi malaria death rate among adults despite rising incidence, Sabah, Malaysia, 2010-2014
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Rajahram, Giri S., Barber, Bridget E., William, Timothy, Grigg, Matthew J., Menon, Jayaram, Yeo, Tsin W., and Anstey, Nicholas M.
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Malaria -- Causes of -- Control -- Research ,Plasmodium -- Physiological aspects -- Research ,Health - Abstract
Plasmodium knowlesi is the most common cause of malaria in East Malaysia, and the incidence of disease is increasing despite intensive control efforts that have substantially reduced the incidence of [...]
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- 2016
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16. Quantifcation of parasite clearance in Plasmodium knowlesi infections.
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Thurai Rathnam, Jeyamalar T., Grigg, Matthew J., Dini, Saber, William, Timothy, Sakam, Sitti Saimah, Cooper, Daniel J., Rajahram, Giri S., Barber, Bridget E., Anstey, Nicholas M., Haghiri, Ali, Rajasekhar, Megha, and Simpson, Julie A.
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Background The incidence of zoonotic Plasmodium knowlesi infections in humans is rising in Southeast Asia, leading to clinical studies to monitor the efficacy of anti-malarial treatments for knowlesi malaria. One of the key outcomes of anti-malarial drug efficacy is parasite clearance. For Plasmodium falciparum, parasite clearance is typically estimated using a two-stage method, that involves estimating parasite clearance for individual patients followed by pooling of individual estimates to derive population estimates. An alternative approach is Bayesian hierarchical modelling which simultaneously analyses all parasite-time patient profiles to determine parasite clearance. This study compared these methods for estimating parasite clearance in P. knowlesi treatment efficacy studies, with typically fewer parasite measurements per patient due to high susceptibility to anti-malarials. Methods Using parasite clearance data from 714 patients with knowlesi malaria and enrolled in three trials, the Worldwide Antimalarial Resistance Network (WWARN) Parasite Clearance Estimator (PCE) standard two-stage approach and Bayesian hierarchical modelling were compared. Both methods estimate the parasite clearance rate from a model that incorporates a lag phase, slope, and tail phase for the parasitaemia profiles. Results The standard two-stage approach successfully estimated the parasite clearance rate for 678 patients, with 36 (5%) patients excluded due to an insufficient number of available parasitaemia measurements. The Bayesian hierarchical estimation method was applied to the parasitaemia data of all 714 patients. Overall, the Bayesian method estimated a faster population mean parasite clearance (0.36/h, 95% credible interval [0.18, 0.65]) compared to the standard two-stage method (0.26/h, 95% confidence interval [0.11, 0.46]), with better model fits (compared visually). Artemisinin-based combination therapy (ACT) is more effective in treating P. knowlesi than chloroquine, as confirmed by both methods, with a mean estimated parasite clearance half-life of 2.5 and 3.6 h, respectively using the standard two-stage method, and 1.8 and 2.9 h using the Bayesian method. Conclusion For clinical studies of P. knowlesi with frequent parasite measurements, the standard two-stage approach (WWARN’s PCE) is recommended as this method is straightforward to implement. For studies with fewer parasite measurements per patient, the Bayesian approach should be considered. Regardless of method used, ACT is more efficacious than chloroquine, confirming the findings of the original trials. [ABSTRACT FROM AUTHOR]
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- 2023
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17. Diagnostic accuracy and limit of detection of ten malaria parasite lactate dehydrogenase-based rapid tests for Plasmodium knowlesi and P. falciparum.
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Tan, Angelica F., Sakam, Sitti Saimah binti, Rajahram, Giri S., William, Timothy, Abd Rachman Isnadi, Mohammad Faruq, Daim, Sylvia, Barber, Bridget E., Kho, Steven, Sutherland, Colin J., Anstey, Nicholas M., Yerlikaya, Seda, van Schalkwyk, Donelly A., and Grigg, Matthew J.
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PLASMODIUM ,DETECTION limit ,LACTATE dehydrogenase ,LACTATES ,INVERSE relationships (Mathematics) ,DIAGNOSIS methods - Abstract
Background: Plasmodium knowlesi causes zoonotic malaria across Southeast Asia. First-line diagnostic microscopy cannot reliably differentiate P. knowlesi from other human malaria species. Rapid diagnostic tests (RDTs) designed for P. falciparum and P. vivax are used routinely in P. knowlesi co-endemic areas despite potential cross-reactivity for species-specific antibody targets. Methods: Ten RDTs were evaluated: nine to detect clinical P. knowlesi infections from Malaysia, and nine assessing limit of detection (LoD) for P. knowlesi (PkA1-H.1) and P. falciparum (Pf3D7) cultures. Targets included Plasmodium-genus parasite lactate dehydrogenase (pan-pLDH) and P. vivax (Pv)-pLDH. Results: Samples were collected prior to antimalarial treatment from 127 patients with microscopy-positive PCR-confirmed P. knowlesi monoinfections. Median parasitaemia was 788/µL (IQR 247-5,565/µL). Pan-pLDH sensitivities ranged from 50.6% (95% CI 39.6-61.5) (SD BIOLINE) to 87.0% (95% CI 75.1-94.6) (First Response® and CareStart™ PAN) compared to reference PCR. Pv-pLDH RDTs detected P. knowlesi with up to 92.0% (95% CI 84.3-96.7%) sensitivity (Biocredit™). For parasite counts =200/µL, pan-pLDH (Standard Q) and Pv-pLDH RDTs exceeded 95% sensitivity. Specificity of RDTs against 26 PCR-confirmed negative controls was 100%. Sensitivity of six highest performing RDTs were not significantly different when comparing samples taken before and after (median 3 hours) antimalarial treatment. Parasite ring stages were present in 30% of pre-treatment samples, with ring stage proportions (mean 1.9%) demonstrating inverse correlation with test positivity of Biocredit™ and two CareStart™ RDTs. For cultured P. knowlesi, CareStart™ PAN demonstrated the lowest LoD at 25 parasites/µL; LoDs of other pan-pLDH ranged from 98 to >2000 parasites/µL. Pv-pLDH LoD for P. knowlesi was 49 parasites/µL. No false-positive results were observed in either P. falciparum-pLDH or histidine-rich-protein-2 channels. Conclusion: Selected RDTs demonstrate sufficient performance for detection of major human malaria species including P. knowlesi in co-endemic areas where microscopy is not available, particularly for higher parasite counts, although cannot reliably differentiate among non-falciparum malaria. [ABSTRACT FROM AUTHOR]
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- 2022
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18. Effect of Regularly Dosed Acetaminophen vs No Acetaminophen on Renal Function in Plasmodium knowlesi Malaria (PACKNOW): A Randomized, Controlled Trial.
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Cooper, Daniel J, Grigg, Matthew J, Plewes, Katherine, Rajahram, Giri S, Piera, Kim A, William, Timothy, Menon, Jayaram, Koleth, Glenn, Edstein, Michael D, Birrell, Geoffrey W, Wattanakul, Thanaporn, Tarning, Joel, Patel, Aatish, Yeo, Tsin Wen, Dondorp, Arjen M, Anstey, Nicholas M, and Barber, Bridget E
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DRUG therapy for malaria ,ACUTE kidney failure prevention ,GLOMERULAR filtration rate ,ACETAMINOPHEN ,HEMOLYSIS & hemolysins ,OXIDATIVE stress ,TREATMENT effectiveness ,DESCRIPTIVE statistics ,LONGITUDINAL method ,CREATININE - Abstract
Background Acetaminophen inhibits cell-free hemoglobin-induced lipid peroxidation and improves renal function in severe falciparum malaria but has not been evaluated in other infections with prominent hemolysis, including Plasmodium knowlesi malaria. Methods PACKNOW was an open-label, randomized, controlled trial of acetaminophen (500 mg or 1000 mg every 6 hours for 72 hours) vs no acetaminophen in Malaysian patients aged ≥5 years with knowlesi malaria of any severity. The primary end point was change in creatinine at 72 hours. Secondary end points included longitudinal changes in creatinine in patients with severe malaria or acute kidney injury (AKI), stratified by hemolysis. Results During 2016–2018, 396 patients (aged 12–96 years) were randomized to acetaminophen (n = 199) or no acetaminophen (n = 197). Overall, creatinine fell by a mean (standard deviation) 14.9% (18.1) in the acetaminophen arm vs 14.6% (16.0) in the control arm (P = .81). In severe disease, creatinine fell by 31.0% (26.5) in the acetaminophen arm vs 20.4% (21.5) in the control arm (P = .12), and in those with hemolysis by 35.8% (26.7) and 19% (16.6), respectively (P = .07). No difference was seen overall in patients with AKI; however, in those with AKI and hemolysis, creatinine fell by 34.5% (20.7) in the acetaminophen arm vs 25.9% (15.8) in the control arm (P = .041). Mixed-effects modeling demonstrated a benefit of acetaminophen at 72 hours (P = .041) and 1 week (P = .002) in patients with severe malaria and with AKI and hemolysis (P = .027 and P = .002, respectively). Conclusions Acetaminophen did not improve creatinine among the entire cohort but may improve renal function in patients with severe knowlesi malaria and in those with AKI and hemolysis. Clinical Trials Registration NCT03056391. [ABSTRACT FROM AUTHOR]
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- 2022
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19. Deaths due to Plasmodium knowlesi malaria in Sabah, Malaysia: association with reporting as Plasmodium malariae and delayed parenteral artesunate
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Rajahram Giri S, Barber Bridget E, William Timothy, Menon Jayaram, Anstey Nicholas M, and Yeo Tsin W
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Malaria ,Plasmodium knowlesi ,Arctic medicine. Tropical medicine ,RC955-962 ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background The simian parasite Plasmodium knowlesi is recognized as a common cause of severe and fatal human malaria in Sabah, Malaysia, but is morphologically indistinguishable from and still commonly reported as Plasmodium malariae, despite the paucity of this species in Sabah. Since December 2008 Sabah Department of Health has recommended intravenous artesunate and referral to a general hospital for all severe malaria cases of any species. This paper reviews all malaria deaths in Sabah subsequent to the introduction of these measures. Reporting of malaria deaths in Malaysia is mandatory. Methods Details of reported malaria deaths during 2010-2011 were reviewed to determine the proportion of each Plasmodium species. Demographics, clinical presentations and management of severe malaria caused by each species were compared. Results Fourteen malaria deaths were reported, comprising seven Plasmodium falciparum, six P. knowlesi and one Plasmodium vivax (all PCR-confirmed). Of the six P. knowlesi deaths, five were attributable to knowlesi malaria and one was attributable to P. knowlesi-associated enterobacter sepsis. Patients with directly attributable P. knowlesi deaths (N = 5) were older than those with P. falciparum (median age 51 [IQR 50-65] vs 22 [IQR 9-55] years, p = 0.06). Complications in fatal P. knowlesi included respiratory distress (N = 5, 100%), hypotension (N = 4, 80%), and renal failure (N = 4, 80%). All patients with P. knowlesi were reported as P. malariae by microscopy. Only two of five patients with severe knowlesi malaria on presentation received immediate parenteral anti-malarial treatment. The patient with P. vivax-associated severe illness did not receive parenteral treatment. In contrast six of seven patients with severe falciparum malaria received immediate parenteral treatment. Conclusion Plasmodium knowlesi was responsible, either directly or through gram-negative bacteraemia, for almost half of malaria deaths in Sabah. Patients with severe non-falciparum malaria were less likely to receive immediate parenteral therapy. This highlights the need in Sabah for microscopically diagnosed P. malariae to be reported as P. knowlesi to improve recognition and management of this potentially fatal species. Clinicians need to be better informed of the potential for severe and fatal malaria from non-falciparum species, and the need to treat all severe malaria with immediate intravenous artesunate.
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- 2012
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20. Plasmodium knowlesi Malaria in Sabah, Malaysia, 2015–2017: Ongoing Increase in Incidence Despite Near-elimination of the Human-only Plasmodium Species.
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Cooper, Daniel J, Rajahram, Giri S, William, Timothy, Jelip, Jenarun, Mohammad, Rashidah, Benedict, Joseph, Alaza, Danshy A, Malacova, Eva, Yeo, Tsin W, Grigg, Matthew J, Anstey, Nicholas M, and Barber, Bridget E
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MALARIA prevention , *CONFIDENCE intervals , *MALARIA , *MICROSCOPY , *POLYMERASE chain reaction , *PROTOZOA , *DESCRIPTIVE statistics - Abstract
Background Malaysia aims to eliminate malaria by 2020. However, while cases of Plasmodium falciparum and Plasmodium vivax have decreased substantially, the incidence of zoonotic malaria from Plasmodium knowlesi continues to increase, presenting a major challenge to regional malaria control efforts. Here we report incidence of all Plasmodium species in Sabah, including zoonotic P. knowlesi , during 2015–2017. Methods Microscopy-based malaria notification data and polymerase chain reaction (PCR) results were obtained from the Sabah Department of Health and State Public Health Laboratory, respectively, from January 2015 to December 2017. From January 2016 this was complemented by a statewide prospective hospital surveillance study. Databases were matched, and species was determined by PCR, or microscopy if PCR was not available. Results A total of 3867 malaria cases were recorded between 2015 and 2017, with PCR performed in 93%. Using PCR results, and microscopy if PCR was unavailable, P. knowlesi accounted for 817 (80%), 677 (88%), and 2030 (98%) malaria cases in 2015, 2016, and 2017, respectively. P. falciparum accounted for 110 (11%), 45 (6%), and 23 (1%) cases and P. vivax accounted for 61 (6%), 17 (2%), and 8 (0.4%) cases, respectively. Of those with P. knowlesi , the median age was 35 (interquartile range: 24–47) years, and 85% were male. Conclusions Malaysia is approaching elimination of the human-only Plasmodium species. However, the ongoing increase in P. knowlesi incidence presents a major challenge to malaria control and warrants increased focus on knowlesi-specific prevention activities. Wider molecular surveillance in surrounding countries is required. [ABSTRACT FROM AUTHOR]
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- 2020
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21. Deaths From Plasmodium knowlesi Malaria: Case Series and Systematic Review.
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Rajahram, Giri S, Cooper, Daniel J, William, Timothy, Grigg, Matthew J, Anstey, Nicholas M, and Barber, Bridget E
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DRUG therapy for malaria , *MALARIA diagnosis , *CARDIOVASCULAR diseases , *DIAGNOSTIC errors , *INTRAVENOUS therapy , *MALARIA , *METABOLIC disorders , *PUBLIC health laws , *SYSTEMATIC reviews , *COMORBIDITY , *DISEASE incidence , *ODDS ratio ,RISK of malaria - Abstract
Background Plasmodium knowlesi causes severe and fatal malaria, and incidence in Southeast Asia is increasing. Factors associated with death are not clearly defined. Methods All malaria deaths in Sabah, Malaysia, from 2015 to 2017 were identified from mandatory reporting to the Sabah Department of Health. Case notes were reviewed, and a systematic review of these and all previously reported fatal P. knowlesi cases was conducted. Case fatality rates (CFRs) during 2010–2017 were calculated using incidence data from the Sabah Department of Health. Results Six malaria deaths occurred in Sabah during 2015–2017, all from P. knowlesi. Median age was 40 (range, 23–58) years; 4 cases (67%) were male. Three (50%) had significant cardiovascular comorbidities and 1 was pregnant. Delays in administering appropriate therapy contributed to 3 (50%) deaths. An additional 26 fatal cases were included in the systematic review. Among all 32 cases, 18 (56%) were male; median age was 56 (range, 23–84) years. Cardiovascular-metabolic disease, microscopic misdiagnosis, and delay in commencing intravenous treatment were identified in 11 of 32 (34%), 26 of 29 (90%), and 11 of 31 (36%) cases, respectively. The overall CFR during 2010–2017 was 2.5/1000: 6.0/1000 for women and 1.7/1000 for men (P =.01). Independent risk factors for death included female sex (odds ratio, 2.6; P =.04), and age ≥45 years (odds ratio, 4.7; P <.01). Conclusions Earlier presentation, more rapid diagnosis, and administration of intravenous artesunate may avoid fatal outcomes, particularly in females, older adults, and patients with cardiovascular comorbidities. [ABSTRACT FROM AUTHOR]
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- 2019
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22. Haemophagocytic lymphohistiocytosis secondary to dengue fever: a case report.
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Cheo, S. W., Rashid, W. N. F. A. Abdul, Ho, C. V., Akhbar, Rosdina Z. Ahmad, Low, Q. J., and Rajahram, Giri S.
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- 2021
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23. 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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24. World Malaria Report: time to acknowledge Plasmodium knowlesi malaria.
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Barber, Bridget E., Rajahram, Giri S., Grigg, Matthew J., William, Timothy, and Anstey, Nicholas M.
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MALARIA prevention , *PLASMODIUM falciparum , *PLASMODIUM vivax , *PREVENTIVE medicine ,MALARIA transmission - Abstract
Background: The 2016 World Health Organization (WHO) World Malaria Report documents substantial progress towards control and elimination of malaria. However, major challenges remain. In some regions of Southeast Asia, the simian parasite Plasmodium knowlesi has emerged as an important cause of human malaria, and the authors believe this species warrants regular inclusion in the World Malaria Report. Main text: Plasmodium knowlesi is the most common cause of malaria in Malaysia, and cases have also been reported in nearly all countries of Southeast Asia. Outside of Malaysia, P. knowlesi is frequently misdiagnosed by microscopy as Plasmodium falciparum or Plasmodium vivax. Thus, P. knowlesi may be underdiagnosed in affected regions and its true incidence underestimated. Acknowledgement in the World Malaria Report of the regional importance of P. knowlesi will facilitate efforts to improve surveillance of this emerging parasite. Furthermore, increased recognition will likely lead to improved delivery of effective treatment for this potentially fatal infection, as has occurred in Malaysia where P. knowlesi case-fatality rates have fallen despite rising incidence. In a number of knowlesi-endemic countries, substantial progress has been made towards the elimination of P. vivax and P. falciparum. However, efforts to eliminate these human-only species should not preclude efforts to reduce human malaria from P. knowlesi. The regional importance of knowlesi malaria was recognized by the WHO with its recent Evidence Review Group meeting on knowlesi malaria to address strategies for prevention and mitigation. Conclusion: The WHO World Malaria Report has an appropriate focus on falciparum and vivax malaria, the major causes of global mortality and morbidity. However, the authors hope that in future years this important publication will also incorporate data on the progress and challenges in reducing knowlesi malaria in regions where transmission occurs. [ABSTRACT FROM AUTHOR]
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- 2017
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25. Chapter One - Knowlesi malaria: Human risk factors, clinical spectrum, and pathophysiology.
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Anstey, Nicholas M., Grigg, Matthew J., Rajahram, Giri S., Cooper, Daniel J., William, Timothy, Kho, Steven, and Barber, Bridget E.
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ERYTHROCYTE deformability , *HUMAN life cycle , *MALARIA , *ERYTHROCYTES , *DISEASE risk factors , *ACUTE kidney failure - Abstract
Plasmodium knowlesi is endemic across Southeast Asia, and is the commonest cause of zoonotic malaria. The spectrum of clinical disease from P. knowlesi infection ranges from asymptomatic infection, through to severe malaria and death. Over 90% of clinical disease occurs in adults, mostly living in forest edge areas undergoing intensive land use change. With a 24-h asexual life cycle in humans, high parasite counts are possible, but most clinical cases of knowlesi malaria are uncomplicated with low parasitaemia. In co-endemic areas, median parasitaemia in knowlesi malaria is lower than that seen in vivax and falciparum malaria, suggesting a lower fever threshold. Severe malaria occurs in 6-9% of symptomatic adults. Manifestations of severe malaria from P. knowlesi are similar to those seen with falciparum malaria, with the notable absence of coma. Age, parasitaemia, cardiovascular comorbidities and delayed diagnosis are risk factors for severe disease and death, which are only seen in adults. Thrombocytopenia is near-universal in adults, likely related to platelet-red cell binding and clearance. Mechanisms underlying the microvascular sludging seen in fatal disease in non-natural primate hosts and the microvascular accumulation of parasites in fatal human disease are not clear. Marked reductions in deformability of both infected and uninfected red blood cells are associated with disease severity in both humans and other non-natural primate hosts, likely contributing to impaired microvascular perfusion and organ dysfunction. Endothelial activation, endothelial dysfunction, glycocalyx degradation and haemolysis are also associated with, and likely contribute to, severe disease and organ dysfunction, particularly acute kidney injury. [ABSTRACT FROM AUTHOR]
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- 2021
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26. 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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27. Chapter Three - Plasmodium knowlesi detection methods for human infections--Diagnosis and surveillance.
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Grigg, Matthew J., Lubis, Inke N., Tetteh, Kevin K. A., Barber, Bridget E., William, Timothy, Rajahram, Giri S., Tan, Angelica F., Sutherland, Colin J., Noviyanti, Rintis, Drakeley, Chris J., Britton, Sumudu, and Anstey, Nicholas M.
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PLASMODIUM , *DIAGNOSIS , *TREATMENT delay (Medicine) , *DIAGNOSIS methods , *MALARIA prevention , *INFECTION - Abstract
Within the overlapping geographical ranges of P. knowlesi monkey hosts and vectors in Southeast Asia, an estimated 1.5 billion people are considered at risk of infection. P. knowlesi can cause severe disease and death, the latter associated with delayed treatment occurring from misdiagnosis. Although microscopy is a sufficiently sensitive first-line tool for P. knowlesi detection for most low-level symptomatic infections, misdiagnosis as other Plasmodium species is common, and the majority of asymptomatic infections remain undetected. Current point-of-care rapid diagnostic tests demonstrate insufficient sensitivity and poor specificity for differentiating P. knowlesi from other Plasmodium species. Molecular tools including nested, real-time, and single-step PCR, and loop-mediated isothermal amplification (LAMP), are sensitive for P. knowlesi detection. However, higher cost and inability to provide the timely point-of-care diagnosis needed to guide appropriate clinical management has limited their routine use in most endemic clinical settings. P. knowlesi is likely underdiagnosed across the region, and improved diagnostic and surveillance tools are required. Reference laboratory molecular testing of malaria cases for both zoonotic and non-zoonotic Plasmodium species needs to be more widely implemented by National Malaria Control Programs across Southeast Asia to accurately identify the burden of zoonotic malaria and more precisely monitor the success of human-only malaria elimination programs. The implementation of specific serological tools for P. knowlesi would assist in determining the prevalence and distribution of asymptomatic and submicroscopic infections, the absence of transmission in certain areas, and associations with underlying land use change for future spatially targeted interventions. [ABSTRACT FROM AUTHOR]
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- 2021
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28. Chapter Two - Clinical management of Plasmodium knowlesi malaria.
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Barber, Bridget E., Grigg, Matthew J., Cooper, Daniel J., van Schalkwyk, Donelly A., William, Timothy, Rajahram, Giri S., and Anstey, Nicholas M.
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PLASMODIUM , *MALARIA , *ACUTE kidney failure , *MULTIPLE organ failure - Abstract
The zoonotic parasite Plasmodium knowlesi has emerged as an important cause of human malaria in parts of Southeast Asia. The parasite is indistinguishable by microscopy from the more benign P. malariae, but can result in high parasitaemias with multiorgan failure, and deaths have been reported. Recognition of severe knowlesi malaria, and prompt initiation of effective therapy is therefore essential to prevent adverse outcomes. Here we review all studies reporting treatment of uncomplicated and severe knowlesi malaria. We report that although chloroquine is effective for the treatment of uncomplicated knowlesi malaria, artemisinin combination treatment is associated with faster parasite clearance times and lower rates of anaemia during follow-up, and should be considered the treatment of choice, particularly given the risk of administering chloroquine to drug-resistant P. vivax or P. falciparum misdiagnosed as P. knowlesi malaria in co-endemic areas. For severe knowlesi malaria, intravenous artesunate has been shown to be highly effective and associated with reduced case-fatality rates, and should be commenced without delay. Regular paracetamol may also be considered for patients with severe knowlesi malaria or for those with acute kidney injury, to attenuate the renal damage resulting from haemolysis-induced lipid peroxidation. [ABSTRACT FROM AUTHOR]
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- 2021
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29. 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, William, Timothy, Menon, Jayaram, Dhanaraj, Prabakaran, Barber, Bridget E, Wilkes, Christopher S, von Seidlein, Lorenz, Rajahram, Giri S, Pasay, Cielo, McCarthy, James S, Price, Ric N, Anstey, Nicholas M, and Yeo, Tsin W
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MALARIA treatment , *ARTEMISININ , *PLASMODIUM , *MEFLOQUINE , *CHLOROQUINE , *RANDOMIZED controlled trials , *DRUG therapy for malaria , *ANTIMALARIALS , *COMBINATION drug therapy , *COMPARATIVE studies , *RESEARCH methodology , *MEDICAL cooperation , *ORAL drug administration , *PROTOZOA , *RESEARCH , *RESEARCH funding , *EVALUATION research , *THERAPEUTICS - Abstract
Background: The zoonotic parasite Plasmodium knowlesi has become the most common cause of human malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate-mefloquine with chloroquine to define the optimum treatment for uncomplicated P knowlesi malaria in adults and children.Methods: We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P knowlesi malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate-mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876.Findings: Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate-mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76-91]) of 115 patients in the artesunate-mefloquine group versus 61 (55% [45-64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0-40·8]; p<0·0001). Parasite clearance was faster in patients given artesunate-mefloquine than in those given chloroquine (18·0 h [range 6·0-48·0] vs 24·0 h [6·0-60·0]; p<0·0001), with faster clearance of ring stages in the artesunate-mefloquine group (mean time to 50% clearance of baseline parasites 8·6 h [95% CI 7·9-9·4] vs 13·8 h [12·1-15·4]; p<0·0001). Risk of anaemia within 28 days was lower in patients in the artesunate-mefloquine group (71 [62%; 95% CI 52·2-70·6]) than in those in the chloroquine group (83 [75%; 65·6-82·5]; p=0·035). Gametocytaemia as detected by PCR for pks25 was present in 44 (86%) of 51 patients in the artesunate-mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate-mefloquine group (mean 11·5 h [95% CI 8·3-14·6]) than in the chloroquine group (14·8 h [11·7-17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate-mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812-0·906]; p<0·0001). One (<1%) patient in the artesunate-mefloquine group had a serious neuropsychiatric event regarded as probably related to study drug.Interpretation: Artesunate-mefloquine is highly efficacious for treatment of uncomplicated P knowlesi malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas.Funding: Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network. [ABSTRACT FROM AUTHOR]- Published
- 2016
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30. 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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31. 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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32. Longitudinal changes in iron homeostasis in human experimental and clinical malaria.
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Woolley SD, Grigg MJ, Marquart L, Gower J, 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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Background: The interaction between iron deficiency 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 samples and associated data from 55 participants enrolled in malaria VIS, and 171 malaria patients and 30 healthy controls enrolled in clinical studies in Malaysia. Ferritin, hepcidin, erythropoietin, and soluble transferrin receptor (sTfR) were measured by ELISA., Results: 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 iron status (ferritin) was associated with post-treatment increases in liver transaminase levels. In Malaysian malaria patients, hepcidin and ferritin were elevated on admission compared to healthy controls, while sTfR increased following admission. Hepcidin normalised by day 28; however, ferritin and sTfR both remained elevated 4 weeks following admission., Conclusion: 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., Competing Interests: Declaration of interests None of the authors have conflicts of interests to declare.
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- 2023
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33. Updating estimates of Plasmodium knowlesi malaria risk in response to changing land use patterns across Southeast Asia.
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Tobin RJ, Harrison LE, Tully MK, Lubis IND, Noviyanti R, Anstey NM, Rajahram GS, Grigg MJ, Flegg JA, Price DJ, and Shearer FM
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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.
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- 2023
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34. Quantifying human-animal contact rates in Malaysian Borneo: Influence of agricultural landscapes on contact with potential zoonotic disease reservoirs.
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Klim H, William T, Chua TH, Rajahram GS, Drakeley CJ, Carroll MW, and Fornace KM
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Changing landscapes across the globe, but particularly in Southeast Asia, are pushing humans and animals closer together and may increase the likelihood of zoonotic spillover events. Malaysian Borneo is hypothesized to be at high risk of spillover events due to proximity between reservoir species and humans caused by recent deforestation in the region. However, the relationship between landscape and human-animal contact rates has yet to be quantified. An environmentally stratified cross-sectional survey was conducted in Sabah, Malaysia in 2015, collecting geolocated questionnaire data on potential risk factors for contact with animals for 10,100 individuals. 51% of individuals reported contact with poultry, 46% with NHPs, 30% with bats, and 2% with swine. Generalised linear mixed models identified occupational and demographic factors associated with increased contact with these species, which varied when comparing wildlife to domesticated animals. Reported contact rates with each animal group were integrated with remote sensing-derived environmental data within a Bayesian framework to identify regions with high probabilities of contact with animal reservoirs. We have identified high spatial heterogeneity of contact with animals and clear associations between agricultural practices and high animal rates. This approach will help inform public health campaigns in at-risk populations and can improve pathogen surveillance efforts on Malaysian Borneo. This method can additionally serve as a framework for researchers looking to identify targets for future pathogen detection in a chosen region of study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Klim, William, Chua, Rajahram, Drakeley, Carroll and Fornace.)
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- 2023
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35. The Effect of Regularly Dosed Acetaminophen vs No Acetaminophen on Renal Function in Plasmodium knowlesi Malaria (PACKNOW): A Randomized, Controlled Trial.
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Cooper DJ, Grigg MJ, Plewes K, Rajahram GS, Piera KA, William T, Menon J, Koleth G, Edstein MD, Birrell GW, Wattanakul T, Tarning J, Patel A, Wen Yeo T, Dondorp AM, Anstey NM, and Barber BE
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- Acetaminophen therapeutic use, Creatinine, Hemoglobins therapeutic use, Hemolysis, Humans, Kidney physiology, Malaysia, Acute Kidney Injury drug therapy, Malaria complications, Malaria drug therapy, Plasmodium knowlesi
- Abstract
Background: Acetaminophen inhibits cell-free hemoglobin-induced lipid peroxidation and improves renal function in severe falciparum malaria but has not been evaluated in other infections with prominent hemolysis, including Plasmodium knowlesi malaria., Methods: PACKNOW was an open-label, randomized, controlled trial of acetaminophen (500 mg or 1000 mg every 6 hours for 72 hours) vs no acetaminophen in Malaysian patients aged ≥5 years with knowlesi malaria of any severity. The primary end point was change in creatinine at 72 hours. Secondary end points included longitudinal changes in creatinine in patients with severe malaria or acute kidney injury (AKI), stratified by hemolysis., Results: During 2016-2018, 396 patients (aged 12-96 years) were randomized to acetaminophen (n = 199) or no acetaminophen (n = 197). Overall, creatinine fell by a mean (standard deviation) 14.9% (18.1) in the acetaminophen arm vs 14.6% (16.0) in the control arm (P = .81). In severe disease, creatinine fell by 31.0% (26.5) in the acetaminophen arm vs 20.4% (21.5) in the control arm (P = .12), and in those with hemolysis by 35.8% (26.7) and 19% (16.6), respectively (P = .07). No difference was seen overall in patients with AKI; however, in those with AKI and hemolysis, creatinine fell by 34.5% (20.7) in the acetaminophen arm vs 25.9% (15.8) in the control arm (P = .041). Mixed-effects modeling demonstrated a benefit of acetaminophen at 72 hours (P = .041) and 1 week (P = .002) in patients with severe malaria and with AKI and hemolysis (P = .027 and P = .002, respectively)., Conclusions: Acetaminophen did not improve creatinine among the entire cohort but may improve renal function in patients with severe knowlesi malaria and in those with AKI and hemolysis., Clinical Trials Registration: NCT03056391., Competing Interests: Potential conflicts of interest. A. M. D. reports consulting fees paid to MORU by the Novartis Malaria Advisory Council; travel support provided by Gordon Malaria Conference organizers; is a member of the World Health Organization (WHO) Guidelines Development Group for antimalarial treatment, Scientific Advisory Board of the World-Wide Antimalarial Resistance Network, and Scientific Advisory Board of International Severe Acute Respiratory and Emerging Infection Consortium; and is the chair of the Artemisinin-resistance Initiative of the Global Fund Regional Steering Committee. G. S. R. reports grants from the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (award 1R01AI160457-01) and the Malaysian Ministry of Health (award NMRR-19-4109-52172) and reports a leadership or fiduciary role on the Infectious Disease Society of Kota Kinabalu. J. T. reports consulting fees paid to Mahidol Oxford Research Unit (MORU) by the Novartis Malaria Advisory Council, is a member of the WHO working group on weight-band dosing harmonization to support the WHO-initiated Global Accelerator for Paediatric Formulations, is chair of the Coronavirus Disease 2019 Clinical Research Coalition, Clinical Pharmacology Working Group, is a member of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) Infectious Diseases steering committee, and is a scientific advisor on the Drugs for Neglected Diseases initiative (DNDi) Programme: 21st Century Treatments for Sustainable Elimination of Leishmaniasis. T. W. Y. reports an international travel grant provided by the Pharmacometrics Japan Conference 2020. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)
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- 2022
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36. Plasmodium knowlesi detection methods for human infections-Diagnosis and surveillance.
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Grigg MJ, Lubis IN, Tetteh KKA, Barber BE, William T, Rajahram GS, Tan AF, Sutherland CJ, Noviyanti R, Drakeley CJ, Britton S, and Anstey NM
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- Humans, Molecular Diagnostic Techniques, Nucleic Acid Amplification Techniques, Malaria diagnosis, Malaria epidemiology, Plasmodium knowlesi genetics
- Abstract
Within the overlapping geographical ranges of P. knowlesi monkey hosts and vectors in Southeast Asia, an estimated 1.5 billion people are considered at risk of infection. P. knowlesi can cause severe disease and death, the latter associated with delayed treatment occurring from misdiagnosis. Although microscopy is a sufficiently sensitive first-line tool for P. knowlesi detection for most low-level symptomatic infections, misdiagnosis as other Plasmodium species is common, and the majority of asymptomatic infections remain undetected. Current point-of-care rapid diagnostic tests demonstrate insufficient sensitivity and poor specificity for differentiating P. knowlesi from other Plasmodium species. Molecular tools including nested, real-time, and single-step PCR, and loop-mediated isothermal amplification (LAMP), are sensitive for P. knowlesi detection. However, higher cost and inability to provide the timely point-of-care diagnosis needed to guide appropriate clinical management has limited their routine use in most endemic clinical settings. P. knowlesi is likely underdiagnosed across the region, and improved diagnostic and surveillance tools are required. Reference laboratory molecular testing of malaria cases for both zoonotic and non-zoonotic Plasmodium species needs to be more widely implemented by National Malaria Control Programs across Southeast Asia to accurately identify the burden of zoonotic malaria and more precisely monitor the success of human-only malaria elimination programs. The implementation of specific serological tools for P. knowlesi would assist in determining the prevalence and distribution of asymptomatic and submicroscopic infections, the absence of transmission in certain areas, and associations with underlying land use change for future spatially targeted interventions., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
37. Knowlesi malaria: Human risk factors, clinical spectrum, and pathophysiology.
- Author
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Anstey NM, Grigg MJ, Rajahram GS, Cooper DJ, William T, Kho S, and Barber BE
- Subjects
- Animals, Humans, Parasitemia, Risk Factors, Malaria complications, Malaria epidemiology, Malaria, Falciparum, Plasmodium knowlesi
- Abstract
Plasmodium knowlesi is endemic across Southeast Asia, and is the commonest cause of zoonotic malaria. The spectrum of clinical disease from P. knowlesi infection ranges from asymptomatic infection, through to severe malaria and death. Over 90% of clinical disease occurs in adults, mostly living in forest edge areas undergoing intensive land use change. With a 24-h asexual life cycle in humans, high parasite counts are possible, but most clinical cases of knowlesi malaria are uncomplicated with low parasitaemia. In co-endemic areas, median parasitaemia in knowlesi malaria is lower than that seen in vivax and falciparum malaria, suggesting a lower fever threshold. Severe malaria occurs in 6-9% of symptomatic adults. Manifestations of severe malaria from P. knowlesi are similar to those seen with falciparum malaria, with the notable absence of coma. Age, parasitaemia, cardiovascular comorbidities and delayed diagnosis are risk factors for severe disease and death, which are only seen in adults. Thrombocytopenia is near-universal in adults, likely related to platelet-red cell binding and clearance. Mechanisms underlying the microvascular sludging seen in fatal disease in non-natural primate hosts and the microvascular accumulation of parasites in fatal human disease are not clear. Marked reductions in deformability of both infected and uninfected red blood cells are associated with disease severity in both humans and other non-natural primate hosts, likely contributing to impaired microvascular perfusion and organ dysfunction. Endothelial activation, endothelial dysfunction, glycocalyx degradation and haemolysis are also associated with, and likely contribute to, severe disease and organ dysfunction, particularly acute kidney injury., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
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