Microvascular obstruction and endothelial activation are independently associated with the clinical manifestations of severe falciparum malaria in adults

An observational study

Joshua Hanson, Sue J Lee, Md Amir Hossain, Nicholas M. Anstey, Prakaykaew Charunwatthana, Richard J. Maude, Hugh W. Kingston, Saroj K. Mishra, Sanjib Mohanty, Katherine Plewes, Kim Piera, M. Mahtab Uddin Hassan, Aniruddha Ghose, M. Aniruddha Faiz, Nicholas J White, Nicholas P J Day, Arjen M. Dondorp

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    Abstract

    Background: Microvascular obstruction and endothelial dysfunction have both been linked to tissue hypoperfusion in falciparum malaria, but their relative contributions to the disease's pathogenesis and outcome are unknown. 

    Methods: Microvascular blood flow was quantified in adults with severe falciparum malaria on their admission to hospital; plasma biomarkers of endothelial function were measured simultaneously. The relationship between these indices and the patients' clinical findings and in-hospital course was examined. 

    Results: Microvascular obstruction was observed in 119/142 (84 %) patients; a median (interquartile range (IQR)) of 14.9 % (6.6-34.9 %) of capillaries were obstructed in patients that died versus 8.3 % (1.7-26.6 %) in survivors (P = 0.039). The proportion of obstructed capillaries correlated with the estimated parasite biomass (rs = 0.25, P = 0.004) and with plasma lactate (rs = 0.38, P <0.0001), the strongest predictor of death in the series. Plasma angiopoietin-2 (Ang-2) concentrations were markedly elevated suggesting widespread endothelial activation; the median (IQR) Ang-2 concentration was 21.9 ng/mL (13.4-29.4 ng/mL) in patients that died versus 14.9 ng/mL (9.8-29.3 ng/mL) in survivors (P = 0.035). Ang-2 concentrations correlated with estimated parasite biomass (rs = 0.35, P <0.001) and plasma lactate (rs = 0.37, P <0.0001). Microvascular obstruction and Ang-2 concentrations were not significantly correlated with each other (rs = 0.17, P = 0.06), but were independently associated with plasma lactate (P <0.001 and P = 0.002, respectively). 

    Conclusions: Microvascular obstruction and systemic endothelial activation are independently associated with plasma lactate, the strongest predictor of death in adults with falciparum malaria. This supports the hypothesis that the two processes make an independent contribution to the pathogenesis and clinical manifestations of the disease.

    Original languageEnglish
    Article number122
    Pages (from-to)1-11
    Number of pages11
    JournalBMC Medicine
    Volume13
    DOIs
    Publication statusPublished - 27 May 2015

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    Falciparum Malaria
    Angiopoietin-2
    Observational Studies
    Lactic Acid
    Biomass
    Survivors
    Parasites
    Biomarkers

    Cite this

    Hanson, Joshua ; Lee, Sue J ; Hossain, Md Amir ; Anstey, Nicholas M. ; Charunwatthana, Prakaykaew ; Maude, Richard J. ; Kingston, Hugh W. ; Mishra, Saroj K. ; Mohanty, Sanjib ; Plewes, Katherine ; Piera, Kim ; Hassan, M. Mahtab Uddin ; Ghose, Aniruddha ; Faiz, M. Aniruddha ; White, Nicholas J ; Day, Nicholas P J ; Dondorp, Arjen M. / Microvascular obstruction and endothelial activation are independently associated with the clinical manifestations of severe falciparum malaria in adults : An observational study. In: BMC Medicine. 2015 ; Vol. 13. pp. 1-11.
    @article{de5889f35bca4b56a58ae6de9d71d9e0,
    title = "Microvascular obstruction and endothelial activation are independently associated with the clinical manifestations of severe falciparum malaria in adults: An observational study",
    abstract = "Background: Microvascular obstruction and endothelial dysfunction have both been linked to tissue hypoperfusion in falciparum malaria, but their relative contributions to the disease's pathogenesis and outcome are unknown. Methods: Microvascular blood flow was quantified in adults with severe falciparum malaria on their admission to hospital; plasma biomarkers of endothelial function were measured simultaneously. The relationship between these indices and the patients' clinical findings and in-hospital course was examined. Results: Microvascular obstruction was observed in 119/142 (84 {\%}) patients; a median (interquartile range (IQR)) of 14.9 {\%} (6.6-34.9 {\%}) of capillaries were obstructed in patients that died versus 8.3 {\%} (1.7-26.6 {\%}) in survivors (P = 0.039). The proportion of obstructed capillaries correlated with the estimated parasite biomass (rs = 0.25, P = 0.004) and with plasma lactate (rs = 0.38, P <0.0001), the strongest predictor of death in the series. Plasma angiopoietin-2 (Ang-2) concentrations were markedly elevated suggesting widespread endothelial activation; the median (IQR) Ang-2 concentration was 21.9 ng/mL (13.4-29.4 ng/mL) in patients that died versus 14.9 ng/mL (9.8-29.3 ng/mL) in survivors (P = 0.035). Ang-2 concentrations correlated with estimated parasite biomass (rs = 0.35, P <0.001) and plasma lactate (rs = 0.37, P <0.0001). Microvascular obstruction and Ang-2 concentrations were not significantly correlated with each other (rs = 0.17, P = 0.06), but were independently associated with plasma lactate (P <0.001 and P = 0.002, respectively). Conclusions: Microvascular obstruction and systemic endothelial activation are independently associated with plasma lactate, the strongest predictor of death in adults with falciparum malaria. This supports the hypothesis that the two processes make an independent contribution to the pathogenesis and clinical manifestations of the disease.",
    keywords = "Endothelial dysfunction, Falciparum malaria, Microcirculation, Pathophysiology",
    author = "Joshua Hanson and Lee, {Sue J} and Hossain, {Md Amir} and Anstey, {Nicholas M.} and Prakaykaew Charunwatthana and Maude, {Richard J.} and Kingston, {Hugh W.} and Mishra, {Saroj K.} and Sanjib Mohanty and Katherine Plewes and Kim Piera and Hassan, {M. Mahtab Uddin} and Aniruddha Ghose and Faiz, {M. Aniruddha} and White, {Nicholas J} and Day, {Nicholas P J} and Dondorp, {Arjen M.}",
    note = "JH (fellowship 1054195) and NMA (fellowship 1042072) are supported by the National Health and Medical Research Council of Australia.",
    year = "2015",
    month = "5",
    day = "27",
    doi = "10.1186/s12916-015-0365-9",
    language = "English",
    volume = "13",
    pages = "1--11",
    journal = "BMC Medicine",
    issn = "1741-7015",
    publisher = "BioMed Central",

    }

    Hanson, J, Lee, SJ, Hossain, MA, Anstey, NM, Charunwatthana, P, Maude, RJ, Kingston, HW, Mishra, SK, Mohanty, S, Plewes, K, Piera, K, Hassan, MMU, Ghose, A, Faiz, MA, White, NJ, Day, NPJ & Dondorp, AM 2015, 'Microvascular obstruction and endothelial activation are independently associated with the clinical manifestations of severe falciparum malaria in adults: An observational study', BMC Medicine, vol. 13, 122, pp. 1-11. https://doi.org/10.1186/s12916-015-0365-9

    Microvascular obstruction and endothelial activation are independently associated with the clinical manifestations of severe falciparum malaria in adults : An observational study. / Hanson, Joshua; Lee, Sue J; Hossain, Md Amir; Anstey, Nicholas M.; Charunwatthana, Prakaykaew; Maude, Richard J.; Kingston, Hugh W.; Mishra, Saroj K.; Mohanty, Sanjib; Plewes, Katherine; Piera, Kim; Hassan, M. Mahtab Uddin; Ghose, Aniruddha; Faiz, M. Aniruddha; White, Nicholas J; Day, Nicholas P J; Dondorp, Arjen M.

    In: BMC Medicine, Vol. 13, 122, 27.05.2015, p. 1-11.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Microvascular obstruction and endothelial activation are independently associated with the clinical manifestations of severe falciparum malaria in adults

    T2 - An observational study

    AU - Hanson, Joshua

    AU - Lee, Sue J

    AU - Hossain, Md Amir

    AU - Anstey, Nicholas M.

    AU - Charunwatthana, Prakaykaew

    AU - Maude, Richard J.

    AU - Kingston, Hugh W.

    AU - Mishra, Saroj K.

    AU - Mohanty, Sanjib

    AU - Plewes, Katherine

    AU - Piera, Kim

    AU - Hassan, M. Mahtab Uddin

    AU - Ghose, Aniruddha

    AU - Faiz, M. Aniruddha

    AU - White, Nicholas J

    AU - Day, Nicholas P J

    AU - Dondorp, Arjen M.

    N1 - JH (fellowship 1054195) and NMA (fellowship 1042072) are supported by the National Health and Medical Research Council of Australia.

    PY - 2015/5/27

    Y1 - 2015/5/27

    N2 - Background: Microvascular obstruction and endothelial dysfunction have both been linked to tissue hypoperfusion in falciparum malaria, but their relative contributions to the disease's pathogenesis and outcome are unknown. Methods: Microvascular blood flow was quantified in adults with severe falciparum malaria on their admission to hospital; plasma biomarkers of endothelial function were measured simultaneously. The relationship between these indices and the patients' clinical findings and in-hospital course was examined. Results: Microvascular obstruction was observed in 119/142 (84 %) patients; a median (interquartile range (IQR)) of 14.9 % (6.6-34.9 %) of capillaries were obstructed in patients that died versus 8.3 % (1.7-26.6 %) in survivors (P = 0.039). The proportion of obstructed capillaries correlated with the estimated parasite biomass (rs = 0.25, P = 0.004) and with plasma lactate (rs = 0.38, P <0.0001), the strongest predictor of death in the series. Plasma angiopoietin-2 (Ang-2) concentrations were markedly elevated suggesting widespread endothelial activation; the median (IQR) Ang-2 concentration was 21.9 ng/mL (13.4-29.4 ng/mL) in patients that died versus 14.9 ng/mL (9.8-29.3 ng/mL) in survivors (P = 0.035). Ang-2 concentrations correlated with estimated parasite biomass (rs = 0.35, P <0.001) and plasma lactate (rs = 0.37, P <0.0001). Microvascular obstruction and Ang-2 concentrations were not significantly correlated with each other (rs = 0.17, P = 0.06), but were independently associated with plasma lactate (P <0.001 and P = 0.002, respectively). Conclusions: Microvascular obstruction and systemic endothelial activation are independently associated with plasma lactate, the strongest predictor of death in adults with falciparum malaria. This supports the hypothesis that the two processes make an independent contribution to the pathogenesis and clinical manifestations of the disease.

    AB - Background: Microvascular obstruction and endothelial dysfunction have both been linked to tissue hypoperfusion in falciparum malaria, but their relative contributions to the disease's pathogenesis and outcome are unknown. Methods: Microvascular blood flow was quantified in adults with severe falciparum malaria on their admission to hospital; plasma biomarkers of endothelial function were measured simultaneously. The relationship between these indices and the patients' clinical findings and in-hospital course was examined. Results: Microvascular obstruction was observed in 119/142 (84 %) patients; a median (interquartile range (IQR)) of 14.9 % (6.6-34.9 %) of capillaries were obstructed in patients that died versus 8.3 % (1.7-26.6 %) in survivors (P = 0.039). The proportion of obstructed capillaries correlated with the estimated parasite biomass (rs = 0.25, P = 0.004) and with plasma lactate (rs = 0.38, P <0.0001), the strongest predictor of death in the series. Plasma angiopoietin-2 (Ang-2) concentrations were markedly elevated suggesting widespread endothelial activation; the median (IQR) Ang-2 concentration was 21.9 ng/mL (13.4-29.4 ng/mL) in patients that died versus 14.9 ng/mL (9.8-29.3 ng/mL) in survivors (P = 0.035). Ang-2 concentrations correlated with estimated parasite biomass (rs = 0.35, P <0.001) and plasma lactate (rs = 0.37, P <0.0001). Microvascular obstruction and Ang-2 concentrations were not significantly correlated with each other (rs = 0.17, P = 0.06), but were independently associated with plasma lactate (P <0.001 and P = 0.002, respectively). Conclusions: Microvascular obstruction and systemic endothelial activation are independently associated with plasma lactate, the strongest predictor of death in adults with falciparum malaria. This supports the hypothesis that the two processes make an independent contribution to the pathogenesis and clinical manifestations of the disease.

    KW - Endothelial dysfunction

    KW - Falciparum malaria

    KW - Microcirculation

    KW - Pathophysiology

    UR - http://www.scopus.com/inward/record.url?scp=84930627191&partnerID=8YFLogxK

    U2 - 10.1186/s12916-015-0365-9

    DO - 10.1186/s12916-015-0365-9

    M3 - Article

    VL - 13

    SP - 1

    EP - 11

    JO - BMC Medicine

    JF - BMC Medicine

    SN - 1741-7015

    M1 - 122

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