Search

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]

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 [...]

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]

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.

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]