Diagnosing Severe Falciparum Malaria in Parasitaemic African Children

A Prospective Evaluation of Plasma PfHRP2 Measurement

Ilse Hendriksen, Juliet Mwanga-Amumpaire, Lorenz Von Seidlein, George Mtove, Lisa White, Rasaq Olaosebikan, Sue J Lee, Antoinette K Tshefu, Charles Woodrow, Ben Amos, Corine Karema, s Saiwaew, Kathryn Maitland, Ermelinda Gomes, W Pan-Ngum, Samwel Gesase, Kamolrat Silamut, Hugh Reyburn, S Joseph, Chotivanich & 4 others Caterina Fanello, N Day, Nicholas J White, Arjen Dondorp

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    Abstract

    Background: In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria. 

    Methods and Findings: Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350-1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991-1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log10 plasma PfHRP2 and risk of death. Mortality increased 20% per log10 increase in PfHRP2 above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95%CI 1.05-1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50% with plasma PfHRP2?174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95%CI 0.44-0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95%CI 0.69-1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings. 

    Conclusions: Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of "true" severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children. 
    Original languageEnglish
    Article numbere1001297
    Pages (from-to)1-10
    Number of pages10
    JournalPLoS Medicine
    Volume9
    Issue number8
    DOIs
    Publication statusPublished - 2012

    Fingerprint

    Falciparum Malaria
    Malaria
    Quinine
    Parasitemia
    Odds Ratio
    Plasmodium falciparum
    Parasites
    Plasmodium falciparum HRP-2 antigen
    Fever
    Rwanda
    Gambia
    Mozambique
    Democratic Republic of the Congo
    Uganda
    Tanzania
    Mortality
    Kenya
    Coma
    Acidosis
    L-Lactate Dehydrogenase

    Cite this

    Hendriksen, I., Mwanga-Amumpaire, J., Von Seidlein, L., Mtove, G., White, L., Olaosebikan, R., ... Dondorp, A. (2012). Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement. PLoS Medicine, 9(8), 1-10. [e1001297]. https://doi.org/10.1371/journal.pmed.1001297
    Hendriksen, Ilse ; Mwanga-Amumpaire, Juliet ; Von Seidlein, Lorenz ; Mtove, George ; White, Lisa ; Olaosebikan, Rasaq ; Lee, Sue J ; Tshefu, Antoinette K ; Woodrow, Charles ; Amos, Ben ; Karema, Corine ; Saiwaew, s ; Maitland, Kathryn ; Gomes, Ermelinda ; Pan-Ngum, W ; Gesase, Samwel ; Silamut, Kamolrat ; Reyburn, Hugh ; Joseph, S ; Chotivanich ; Fanello, Caterina ; Day, N ; White, Nicholas J ; Dondorp, Arjen. / Diagnosing Severe Falciparum Malaria in Parasitaemic African Children : A Prospective Evaluation of Plasma PfHRP2 Measurement. In: PLoS Medicine. 2012 ; Vol. 9, No. 8. pp. 1-10.
    @article{a6315e3f0f0746f1a7370e431947a290,
    title = "Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement",
    abstract = "Background: In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria. Methods and Findings: Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95{\%}CI) plasma PfHRP2 was 1,611 (1,350-1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991-1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log10 plasma PfHRP2 and risk of death. Mortality increased 20{\%} per log10 increase in PfHRP2 above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95{\%}CI 1.05-1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50{\%} with plasma PfHRP2?174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95{\%}CI 0.44-0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95{\%}CI 0.69-1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings. Conclusions: Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of {"}true{"} severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children. ",
    keywords = "artesunate, Plasmodium falciparum histidine rich protein 2, protozoal protein, quinine, unclassified drug, acidosis, adolescent, Africa, anemia, article, child, clinical trial, coma, death, disease severity, enzyme linked immunosorbent assay, female, human, infant, major clinical study, malaria falciparum, male, microscopy, morbidity, mortality, newborn, parasite load, parasitemia, preschool child, prognosis, prospective study, school child, sensitivity analysis, shock, Adolescent, Antigens, Protozoan, Artemisinins, Child, Child, Preschool, Demography, Female, Humans, Infant, Malaria, Falciparum, Male, Models, Biological, Odds Ratio, Parasitemia, Prospective Studies, Protozoan Proteins, Quinine, Risk Factors, Severity of Illness Index",
    author = "Ilse Hendriksen and Juliet Mwanga-Amumpaire and {Von Seidlein}, Lorenz and George Mtove and Lisa White and Rasaq Olaosebikan and Lee, {Sue J} and Tshefu, {Antoinette K} and Charles Woodrow and Ben Amos and Corine Karema and s Saiwaew and Kathryn Maitland and Ermelinda Gomes and W Pan-Ngum and Samwel Gesase and Kamolrat Silamut and Hugh Reyburn and S Joseph and Chotivanich and Caterina Fanello and N Day and White, {Nicholas J} and Arjen Dondorp",
    year = "2012",
    doi = "10.1371/journal.pmed.1001297",
    language = "English",
    volume = "9",
    pages = "1--10",
    journal = "PLoS Medicine",
    issn = "1549-1277",
    publisher = "Public Library of Science (PLoS)",
    number = "8",

    }

    Hendriksen, I, Mwanga-Amumpaire, J, Von Seidlein, L, Mtove, G, White, L, Olaosebikan, R, Lee, SJ, Tshefu, AK, Woodrow, C, Amos, B, Karema, C, Saiwaew, S, Maitland, K, Gomes, E, Pan-Ngum, W, Gesase, S, Silamut, K, Reyburn, H, Joseph, S, Chotivanich, Fanello, C, Day, N, White, NJ & Dondorp, A 2012, 'Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement', PLoS Medicine, vol. 9, no. 8, e1001297, pp. 1-10. https://doi.org/10.1371/journal.pmed.1001297

    Diagnosing Severe Falciparum Malaria in Parasitaemic African Children : A Prospective Evaluation of Plasma PfHRP2 Measurement. / Hendriksen, Ilse; Mwanga-Amumpaire, Juliet; Von Seidlein, Lorenz; Mtove, George; White, Lisa; Olaosebikan, Rasaq; Lee, Sue J; Tshefu, Antoinette K; Woodrow, Charles; Amos, Ben; Karema, Corine; Saiwaew, s; Maitland, Kathryn; Gomes, Ermelinda; Pan-Ngum, W; Gesase, Samwel; Silamut, Kamolrat; Reyburn, Hugh; Joseph, S; Chotivanich; Fanello, Caterina; Day, N; White, Nicholas J; Dondorp, Arjen.

    In: PLoS Medicine, Vol. 9, No. 8, e1001297, 2012, p. 1-10.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Diagnosing Severe Falciparum Malaria in Parasitaemic African Children

    T2 - A Prospective Evaluation of Plasma PfHRP2 Measurement

    AU - Hendriksen, Ilse

    AU - Mwanga-Amumpaire, Juliet

    AU - Von Seidlein, Lorenz

    AU - Mtove, George

    AU - White, Lisa

    AU - Olaosebikan, Rasaq

    AU - Lee, Sue J

    AU - Tshefu, Antoinette K

    AU - Woodrow, Charles

    AU - Amos, Ben

    AU - Karema, Corine

    AU - Saiwaew, s

    AU - Maitland, Kathryn

    AU - Gomes, Ermelinda

    AU - Pan-Ngum, W

    AU - Gesase, Samwel

    AU - Silamut, Kamolrat

    AU - Reyburn, Hugh

    AU - Joseph, S

    AU - Chotivanich, null

    AU - Fanello, Caterina

    AU - Day, N

    AU - White, Nicholas J

    AU - Dondorp, Arjen

    PY - 2012

    Y1 - 2012

    N2 - Background: In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria. Methods and Findings: Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350-1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991-1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log10 plasma PfHRP2 and risk of death. Mortality increased 20% per log10 increase in PfHRP2 above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95%CI 1.05-1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50% with plasma PfHRP2?174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95%CI 0.44-0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95%CI 0.69-1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings. Conclusions: Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of "true" severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children. 

    AB - Background: In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria. Methods and Findings: Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350-1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991-1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log10 plasma PfHRP2 and risk of death. Mortality increased 20% per log10 increase in PfHRP2 above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95%CI 1.05-1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50% with plasma PfHRP2?174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95%CI 0.44-0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95%CI 0.69-1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings. Conclusions: Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of "true" severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children. 

    KW - artesunate

    KW - Plasmodium falciparum histidine rich protein 2

    KW - protozoal protein

    KW - quinine

    KW - unclassified drug

    KW - acidosis

    KW - adolescent

    KW - Africa

    KW - anemia

    KW - article

    KW - child

    KW - clinical trial

    KW - coma

    KW - death

    KW - disease severity

    KW - enzyme linked immunosorbent assay

    KW - female

    KW - human

    KW - infant

    KW - major clinical study

    KW - malaria falciparum

    KW - male

    KW - microscopy

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    KW - mortality

    KW - newborn

    KW - parasite load

    KW - parasitemia

    KW - preschool child

    KW - prognosis

    KW - prospective study

    KW - school child

    KW - sensitivity analysis

    KW - shock

    KW - Adolescent

    KW - Antigens, Protozoan

    KW - Artemisinins

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    KW - Child, Preschool

    KW - Demography

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    KW - Humans

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    KW - Malaria, Falciparum

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    KW - Risk Factors

    KW - Severity of Illness Index

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