Differing Causes of Lactic Acidosis and Deep Breathing in Cerebral Malaria and Severe Malarial Anemia May Explain Differences in Acidosis-Related Mortality.

Nathan R. Brand,Chandy C. John,Karen E. S. Hamre,Robert O. Opoka,Georges Snounou

doi:10.1371/journal.pone.0163728

Abstract

Lactic acidosis (LA) is a marker for mortality in severe malaria, but the mechanisms that lead to LA in the different types of severe malaria and the extent to which LA-associated mortality differs by type of severe malaria are not well described. We assessed the frequency of LA in children admitted to Mulago Hospital, Kampala, Uganda with cerebral malaria (CM, n = 193) or severe malarial anemia (SMA, n = 216). LA was compared to mortality and measures of parasite biomass and sequestration (P. falciparum histidine-rich protein-2 (PfHRP2) concentration, platelet count), and to a measure of systemic tissue oxygen delivery (hemoglobin level). LA was more frequent in children with SMA than CM (SMA, 47.7%, CM, 34.2%, P = 0.006), but mortality was higher in children with CM (13.0%) than SMA (0.5%, P<0.0001). In CM, LA was associated with increased PfHRP2 concentration and decreased platelet count but was not associated with hemoglobin level. In contrast, in SMA, LA was associated with a decreased hemoglobin level, but was not associated with PfHRP2 concentration or platelet count. LA was related to mortality only in CM. In multivariable regression analysis of the effect PfHRP2 and hemoglobin levels on LA and DB, only PfHRP2 level increased risk of LA and DB in CM, while in SMA, elevated hemoglobin strongly decreased risk of LA and DB, and PfHRP2 level modestly increased risk of LA. The study findings suggest that LA in CM is due primarily to parasite sequestration, which currently has no effective adjunctive therapy, while LA in SMA is due primarily to anemia, which is rapidly corrected with blood transfusion. Differing etiologies of LA in CM and SMA may explain why LA is associated with mortality in CM but not SMA.

Highlights

The World Health Organization estimates that in 2015 there were 214 million new cases of malaria and 438,000 deaths [1]. 90% of these deaths occurred in sub-Saharan Africa, 77% were children under the age of 5, and 66% occurred within 24 hours of hospital admission[1, 2]
The observation was confirmed by the Severe Malaria in African Children (SMAC) network, a network comprising more than 14,000 children in 3 countries, which found deep breathing (DB) to be one of three clinical signs used in the Lambaréné organ dysfunction score to predict mortality in hospitalized patients with malaria [10]
We show that the pathophysiologic correlates of Lactic acidosis (LA) are Demographic, clinical and laboratory findings children with cerebral malaria (CM) who survived vs. died

Summary

Introduction

The World Health Organization estimates that in 2015 there were 214 million new cases of malaria and 438,000 deaths [1]. 90% of these deaths occurred in sub-Saharan Africa, 77% were children under the age of 5, and 66% occurred within 24 hours of hospital admission[1, 2]. Studies to date on the associations between LA, DB or RD and mortality have assessed children with severe malaria as a single clinical entity and have not assessed risks in the different types of severe malaria independently. Severe malarial anemia (SMA) is among the most common forms of severe malaria, with an estimated 1.5 to 5 million children affected annually [11]. Diverse etiologies can lead to acidosis in children suffering from different forms of severe malaria, so the reversal of LA requires knowledge of what is causing the LA. Potential contributors to LA in children include local tissue parasite sequestration, with resulting localized ischemia, which may occur in any form of severe malaria, but is likely most pronounced in CM, and systemic impairment of oxygen delivery due to low hemoglobin levels, which is most common in SMA

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