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

Abstract

BackgroundMicrovascular 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.MethodsMicrovascular 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.ResultsMicrovascular 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).ConclusionsMicrovascular 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.

Systematic review of the role of angiopoietin-1 and angiopoietin-2 in Plasmodium species infections: biomarkers or therapeutic targets?

“…In ten out of eleven studies comparing healthy controls with either uncomplicated [25, 32, 34, 35, 37, 43–45], severe [34, 35, 43, 45, 46] or cerebral falciparum malaria [25, 32, 37, 44, 45] or uncomplicated [43, 47] or severe [43] vivax malaria, a similar pattern in changes was observed for Ang-1 and Ang-2 levels: a decrease of Ang-1 [25, 32], an increase of Ang-2 [25, 32, 34, 35, 37, 43–47] and consequently an increase of the Ang-2/Ang-1 ratio [25, 32] (see Additional files 3, 4, 5). Adults and children, living either in endemic areas or travellers in non-endemic areas all showed these similar changes.…”

“…Differences in the absolute Ang-1 and Ang-2 concentrations were also found between disease severity states: lower Ang-1 and higher Ang-2 concentrations were observed in severe disease compared to uncomplicated disease in both falciparum [25, 28–30, 32, 34, 43–45] and vivax malaria [31, 43] and in non-survivors compared to survivors infected with P. falciparum [25, 27, 30, 32–35, 41, 46] (see Additional files 3, 4, 5, 6). …”

“…Furthermore, an elevated Ang-2 concentration was associated with respiratory distress [49], impaired consciousness [49], acute kidney injury [33, 46], multi-organ failure [46], anaemia [33], jaundice [33], hypoglycaemia [33], pure cerebral malaria (cerebral malaria patients without the other complications of severe malaria according to WHO 2000 criteria) [33] and higher Ang-1 levels were associated with a higher platelet count in P. falciparum and P. vivax infections [31, 33, 50]. …”

“…However, no correlation was found between concentrations of Ang-1 and Ang-2 or Ang-2/Ang-1 ratio and sequestration in cerebral malaria in brain autopsies [33], microvascular obstruction measured with an Orthogonal Polarization Spectral device in the rectal mucosa [46] or rosetting as determined by IgG antibody levels to the infected erythrocyte surface of ex vivo isolates and corrected for disease severity [49]. Parasite biomass, as measured by Pf HRP2, was correlated with Ang-2 in P. falciparum [34, 43, 46], but not as measured by PvLDH and pLDH in P. vivax. [43].…”

Urinalysis as a diagnostic tool in severe malaria

“…En este sentido, Hanson, et al, no encontraron relación entre la concentración de creatinina en san-gre y la mortalidad en pacientes con malaria, pero sí evidenciaron mayores valores de nitrógeno ureico en sangre entre los pacientes que murieron (74).…”