Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement

Hendriksen, Ilse C. E.; Mwanga-Amumpaire, Juliet; Seidlein, Lorenz von; Mtove, George; White, Lisa J.; Olaosebikan, Rasaq; Lee, Sue J.; Tshefu, Antoinette; Woodrow, Charles J.; Amos, Ben; Karema, Corine; Saiwaew, Somporn; Maitland, Kathryn; Gomes, Ermelinda; Pan-ngum, Wirichada; Gesase, Samwel; Silamut, Kamolrat; Reyburn, Hugh; Joseph, Sarah; Chotivanich, Kesinee; Fanello, Caterina; Day, Nicholas P. J.; White, Nicholas J.; Dondorp, Arjen M.

doi:10.1371/journal.pmed.1001297

Cited by 126 publications

(192 citation statements)

References 48 publications

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“…Plasma PfHRP2 concentration presents a close correlation with disease severity in both children and adults (31,32). To better understand the interplay between parasite biomass and parasite adhesion types in adult SM, we performed correlation analysis.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, restoration of EPCR functions may be a key target for adjunctive malaria drug treatments. protein 2 (PfHRP2), a surrogate of parasite biomass, can predict disease severity and fatality rates in both children and adults (31,32), the probability of disease deterioration (33), retinopathy-positive cerebral malaria (34), and whether a fever is caused by malaria (35). Nevertheless, a recent longitudinal study in Tanzanian children showed that high PfHRP2 levels did not necessitate severe disease (36), suggesting severe disease requires additional factors.…”

Section: Significancementioning

confidence: 99%

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Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass

Bernabeu

Danziger

Avril

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

127

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The interplay between cellular and molecular determinants that lead to severe malaria in adults is unexplored. Here, we analyzed parasite virulence factors in an infected adult population in India and investigated whether severe malaria isolates impair endothelial protein C receptor (EPCR), a protein involved in coagulation and endothelial barrier permeability. Severe malaria isolates overexpressed specific members of the Plasmodium falciparum var gene/ PfEMP1 (P. falciparum erythrocyte membrane protein 1) family that bind EPCR, including DC8 var genes that have previously been linked to severe pediatric malaria. Machine learning analysis revealed that DC6-and DC8-encoding var transcripts in combination with high parasite biomass were the strongest indicators of patient hospitalization and disease severity. We found that DC8 CIDRα1 domains from severe malaria isolates had substantial differences in EPCR binding affinity and blockade activity for its ligand activated protein C. Additionally, even a low level of inhibition exhibited by domains from two cerebral malaria isolates was sufficient to interfere with activated protein C-barrier protective activities in human brain endothelial cells. Our findings demonstrate an interplay between parasite biomass and specific PfEMP1 adhesion types in the development of adult severe malaria, and indicate that low impairment of EPCR function may contribute to parasite virulence. malaria | Plasmodium falciparum | var | PfEMP1 | EPCR

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Section: Resultsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass

Bernabeu

Danziger

Avril

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

127

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“…A physical examination was performed at admission, and a venous blood sample was taken for an assessment of peripheral blood parasitemia, quantitative assessment of plasma Plasmodium falciparum histidine-rich protein 2 (PfHRP2) (a marker of the total-body parasite burden) (27) , gamma-glutamyl transpeptidase, total bilirubin, creatinine, and urea) (Reflotron; Roche Diagnostics), hematocrit (Hct), biochemistry, and acid-base parameters (EC8ϩ cartridge for an i-STAT handheld blood analyzer). Hematocrit was reported by the i-STAT instrument or, when not available, derived from hemoglobin (Hb) measured by a Haemocue instrument (n ϭ 5).…”

Section: Methodsmentioning

confidence: 99%

“…A P value of 0.05 was used in the forward step and a P value of 0.001 was used in the backward step to compensate for the relatively small population studied. The following admission covariates were investigated by using the stepwise approach: age (years), weight-for-age Z score (37,38), temperature (°C), heart rate (beats/min), coma (continuous variable based on the GCS/BCS coma score), cerebral malaria (coma and/or convulsions), blood urea nitrogen (mg/dl), hemoglobin (g/dl), base excess (mmol/liter), parasitemia (parasites/l), plasma PfHRP2 (ng/ml) as a marker of the total parasite burden (27), total bilirubin (mol/liter), creatinine (high, Ն44.2 mol/liter at Ͻ1 year of age and Ն62 mol/liter at Ն1 year of age; low, Ͻ44.2 mol/ liter at Ͻ1 year of age and Ͻ62 mol/liter at Ն1 year of age), HIV coinfection, shock (compensated or decompensated), fluid bolus treatment, and/or blood transfusion.…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic and Pharmacodynamic Properties of Intramuscular Quinine in Tanzanian Children with Severe Falciparum Malaria

Hendriksen

Maiga

Lemnge

et al. 2013

Antimicrob Agents Chemother

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f Although artesunate is clearly superior, parenteral quinine is still used widely for the treatment of severe malaria. A loading-dose regimen has been recommended for 30 years but is still often not used. A population pharmacokinetic study was conducted with 75 Tanzanian children aged 4 months to 8 years with severe malaria who received quinine intramuscularly; 69 patients received a loading dose of 20 mg quinine dihydrochloride (salt)/kg of body weight. Twenty-one patients had plasma quinine concentrations detectable at baseline. A zero-order absorption model with one-compartment disposition pharmacokinetics described the data adequately. Body weight was the only significant covariate and was implemented as an allometric function on clearance and volume parameters. Population pharmacokinetic parameter estimates (and percent relative standard errors [%RSE]) of elimination clearance, central volume of distribution, and duration of zero-order absorption were 0.977 liters/h (6.50%), 16.7 liters (6.39%), and 1.42 h (21.5%), respectively, for a typical patient weighing 11 kg. Quinine exposure was reduced at lower body weights after standard weight-based dosing; there was 18% less exposure over 24 h in patients weighing 5 kg than in those weighing 25 kg. Maximum plasma concentrations after the loading dose were unaffected by body weight. There was no evidence of dose-related drug toxicity with the loading dosing regimen. Intramuscular quinine is rapidly and reliably absorbed in children with severe falciparum malaria. Based on these pharmacokinetic data, a loading dose of 20 mg salt/kg is recommended, provided that no loading dose was administered within 24 h and no routine dose was administered within 12 h of admission. (This study has been registered with Current Controlled Trials under registration number ISRCTN 50258054.)

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“…Some factors that predict multiple organ involvement include parasite virulence, host immune status, infection with Plasmodium falciparum, and plasma concentration of histidine-rich protein (HRP)-2 antigen. 4,9,[12][13][14] Nevertheless, whether a combination of easy-to-obtain, inexpensive markers of risk could predict the outcome of patients admitted to hospital with malaria has not been determined. The aim of this study was to examine risk factors for multiple organ dysfunction in patients admitted to hospital with malaria.…”

Section: Introductionmentioning

confidence: 99%

Hemoglobin Concentration and Parasitemia on Hospital Admission Predict Risk of Multiple Organ Dysfunction Syndrome among Adults with Malaria

Walton

Oliveros

Villamor

2014

The American Journal of Tropical Medicine and Hygiene

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Abstract. Risk factors for progression from acute malaria to multiple organ dysfunction syndrome (MODS) are poorly understood. The MODS is commonly diagnosed with the sequential organ failure assessment (SOFA) scale, but this scale has been understudied in patients with severe malaria. We conducted a cohort study among 426 adult males admitted to hospital with malaria in Bogotá, Colombia. We estimated SOFA scores and relative risks (RRs) for MODS during hospitalization according to patients' characteristics on admission. Risk of MODS was 7.3% over a median 6.0 days in hospital. Baseline hemoglobin was strongly, inversely associated with MODS (adjusted RR for hemoglobin 8.5 g/dL versus hemoglobin 11 g/dL = 9.5, 95% confidence interval [CI]: 3.6, 25.3). Plasmodium falciparum malaria and parasitemia were positively associated with MODS. There was a strong interaction between baseline parasitemia and hemoglobin on MODS risk. In conclusion, the use of parasitemia and hemoglobin on admission to identify high-risk patients deserves consideration.

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Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement

Abstract: Arjen Dondorp and colleagues investigate whether the plasma level of Plasmodium falciparum histidine-rich protein 2 can be used to distinguish between severe malaria and other severe febrile illness in African children with malaria.

Cited by 126 publications

References 48 publications

Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass

Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass

Population Pharmacokinetic and Pharmacodynamic Properties of Intramuscular Quinine in Tanzanian Children with Severe Falciparum Malaria

Hemoglobin Concentration and Parasitemia on Hospital Admission Predict Risk of Multiple Organ Dysfunction Syndrome among Adults with Malaria

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