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.
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. drjoshhanson@gmail.com.|Global Health Division, Menzies School of Health Research, Darwin, Australia. drjoshhanson@gmail.com.
authors.forename: Josh
authors.initials: J
authors.lastname: Hanson
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. sue@tropmedres.ac.|Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. sue@tropmedres.ac.
authors.forename: Sue J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Medicine, Chittagong Medical College Hospital, Chittagong, Bangladesh. amir_hossain_ctg@yahoo.com.
authors.forename: Md Amir
authors.initials: MA
authors.lastname: Hossain
authors.affiliation: Global Health Division, Menzies School of Health Research, Darwin, Australia. Nicholas.Anstey@menzies.edu.au.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Anstey
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Jib@tropmedres.ac.
authors.forename: Prakaykaew
authors.initials: P
authors.lastname: Charunwatthana
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Richard@tropmedres.ac.|Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Richard@tropmedres.ac.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Maude
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. hwfkingston@googlemail.com.|Global Health Division, Menzies School of Health Research, Darwin, Australia. hwfkingston@googlemail.com.
authors.forename: Hugh W F
authors.initials: HW
authors.lastname: Kingston
authors.affiliation: Department of Medicine, Ispat Hospital, Rourkela, Orissa, India. sarojrkl@gmail.com.
authors.forename: Saroj K
authors.initials: SK
authors.lastname: Mishra
authors.affiliation: Department of Medicine, Ispat Hospital, Rourkela, Orissa, India. sanjibmalaria@rediffmail.com.
authors.forename: Sanjib
authors.initials: S
authors.lastname: Mohanty
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. kaplewes@gmail.com.
authors.forename: Katherine
authors.initials: K
authors.lastname: Plewes
authors.affiliation: Global Health Division, Menzies School of Health Research, Darwin, Australia. Kim.Piera@menzies.edu.au.
authors.forename: Kim
authors.initials: K
authors.lastname: Piera
authors.affiliation: Department of Medicine, Chittagong Medical College Hospital, Chittagong, Bangladesh. mahtabnipu@yahoo.com.
authors.forename: Mahtab U
authors.initials: MU
authors.lastname: Hassan
authors.affiliation: Department of Medicine, Chittagong Medical College Hospital, Chittagong, Bangladesh. anrdghs@yahoo.com.
authors.forename: Aniruddha
authors.initials: A
authors.lastname: Ghose
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. drmafaiz@gmail.com.|Centre for Specialized Care and Research, Chittagong, Bangladesh. drmafaiz@gmail.com.|Dev Care Foundation, Dhaka, Bangladesh. drmafaiz@gmail.com.
authors.forename: M Abul
authors.initials: MA
authors.lastname: Faiz
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. nickwdt@tropmedres.ac.|Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. nickwdt@tropmedres.ac.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Nickd@tropmedres.ac.|Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Nickd@tropmedres.ac.
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. arjen@tropmedres.ac.|Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. arjen@tropmedres.ac.
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
mesh_terms: D000328:Adult; D002196:Capillaries / Q000473:pathology*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood* / Q000150:complications* / Q000473:pathology*; D008297:Male; D008833:Microcirculation; D008875:Middle Aged