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

doi: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

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

Global and Tropical Health

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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 (r_s = 0.25, P = 0.004) and with plasma lactate (r_s = 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 (r_s = 0.35, P <0.001) and plasma lactate (r_s = 0.37, P <0.0001). Microvascular obstruction and Ang-2 concentrations were not significantly correlated with each other (r_s = 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 language	English
Article number	122
Pages (from-to)	1-11
Number of pages	11
Journal	BMC Medicine
Volume	13
DOIs	https://doi.org/10.1186/s12916-015-0365-9
Publication status	Published - 27 May 2015

Bibliographical note

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

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Hanson, J., Lee, S. J., Hossain, M. A., Anstey, N. M., Charunwatthana, P., Maude, R. J., Kingston, H. W., Mishra, S. K., Mohanty, S., Plewes, K., Piera, K., Hassan, M. M. U., Ghose, A., Faiz, M. A., White, N. J., Day, N. P. J., & Dondorp, A. M. (2015). Microvascular obstruction and endothelial activation are independently associated with the clinical manifestations of severe falciparum malaria in adults: An observational study. BMC Medicine, 13, 1-11. Article 122. https://doi.org/10.1186/s12916-015-0365-9

@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 = may,

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

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

C2 - 26018532

SN - 1741-7015

VL - 13

SP - 1

EP - 11

JO - BMC Medicine

JF - BMC Medicine

M1 - 122

ER -

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

Abstract

Bibliographical note

UN SDGs

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