Research Article: Investigating causal pathways in severe falciparum malaria: A pooled retrospective analysis of clinical studies

Date Published: August 23, 2019

Publisher: Public Library of Science

Author(s): Stije J. Leopold, James A. Watson, Atthanee Jeeyapant, Julie A. Simpson, Nguyen H. Phu, Tran T. Hien, Nicholas P. J. Day, Arjen M. Dondorp, Nicholas J. White, James G. Beeson

Abstract: BackgroundSevere falciparum malaria is a medical emergency characterised by potentially lethal vital organ dysfunction. Patient fatality rates even with parenteral artesunate treatment remain high. Despite considerable research into adjuvant therapies targeting organ and tissue dysfunction, none have shown efficacy apart from renal replacement therapy. Understanding the causal contributions of clinical and laboratory abnormalities to mortality is essential for the design and evaluation of novel therapeutic interventions.Methods and findingsWe used a structural model causal inference approach to investigate causal relationships between epidemiological, laboratory, and clinical variables in patients with severe falciparum malaria enrolled in clinical trials and their in-hospital mortality. Under this causal model, we analysed records from 9,040 hospitalised children (0–12 years, n = 5,635) and adults (n = 3,405, 12–87 years) with severe falciparum malaria from 15 countries in Africa and Asia who were studied prospectively over the past 35 years. On admission, patient covariates associated with increased in-hospital mortality were severity of acidosis (odds ratio [OR] 2.10 for a 7-mEq/L increase in base deficit [95% CI 1.93–2.28]), renal impairment (OR 1.71 for a 2-fold increase in blood urea nitrogen [95% CI 1.58, 1.86]), coma (OR 3.59 [95% CI 3.07–4.21]), seizures (OR 1.40 [95% CI 1.16–1.68]), shock (OR 1.51 [95% CI 1.14–1.99]), and presumed pulmonary oedema (OR 1.58 [95% CI 1.04–2.39]). Lower in-hospital mortality was associated with moderate anaemia (OR 0.87 for a decrease of 10 percentage points in haematocrit [95% CI 0.80–0.95]). Circulating parasite density was not associated with mortality (OR 1.02 for a 6-fold increase [95% CI 0.94–1.11]), so the pathological effects of parasitaemia appear to be mediated entirely by the downstream effects of sequestration. Treatment with an artemisinin derivative decreased mortality compared with quinine (OR 0.64 [95% CI 0.56–0.74]). These estimates were consistent across children and adults (mainly representing African and Asian patients, respectively). Using inverse probability weighting, transfusion was not estimated to be beneficial in children with admission haematocrit values between 15% and 25% (OR 0.99 [95% CI 0.97–1.02]). Except for the effects of artemisinin treatment and transfusion, causal interpretations of these estimates could be biased by unmeasured confounding from severe bacterial sepsis, immunity, and duration of illness.ConclusionThese data suggest that moderate anaemia is associated with a reduced risk of death in severe falciparum malaria. This is possibly a direct causal association. The severe anaemia threshold criteria for a definition of severe falciparum malaria should be reconsidered.

Partial Text: Severe falciparum malaria remains an important cause of premature death in malaria-endemic countries [1,2]. The onset of life-threatening complications can be rapid, particularly in children, leaving little or no time to reach hospital [3]. The majority of in-hospital deaths occur within the first 24 hours following admission [4]. Patient fatality following treatment with parenteral artesunate is significantly lower than with quinine but still ranges between 10% and 30%, depending on the number and severity of complications present on admission [5–7].

In the absence of randomisation, causal inference is difficult and relies on nonstatistical assumptions supported by expert knowledge. Formalising these assumptions using causal diagrams (DAGs), which are readily understood and therefore readily challenged, improves transparency and facilitates investigation. Using a structural causal models framework [13], direct or total causal effects of the main features of severe malaria (anaemia, coma, acidosis, seizures, pulmonary oedema, AKI) on death in patients with severe falciparum malaria were examined, based on a pooled analysis of patient data from 9,040 prospectively studied children and adults in Southeast Asia and sub-Saharan Africa. This allowed for causal interpretation of factors that have been reported previously to be associated with increased risk, but it also suggested that moderate anaemia might confer some survival advantage in patients with severe falciparum malaria.



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