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

Background Severe 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 findings We 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. Conclusion These 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. Author summaryWhy was this study done? Severe falciparum malaria is a medical emergency with high patient fatality, even following treatment with parenteral artesunate. No adjunctive treatments have proved effective despite considerable research, except renal replacement therapy in patients with acute renal failure. Understanding the causal contributions of the different key patient variables at presentation could improve the definition of severe falciparum malaria, patient triage, and the prioritisation of future trials aimed to assess novel treatments. What did the researchers do and find? We pooled data from 9,040 case records from prospective studies in patients with strictly defined severe falciparum malaria conducted across Asia and Africa. We constructed causal diagrams based on expert knowledge showing what we consider to be the best description of the causal pathways leading to death in severe malaria. This model was used to obtain generalisable estimates of the causal contributions to a fatal outcome of coma and increases in base deficit, shock, renal impairment, seizures, presumed pulmonary oedema, and anaemia. We found that patients with lower haematocrits were at a lower risk of death and that there was no strong evidence for a beneficial effect of transfusion in moderately anaemic children (15%-25% haematocrit). What do these findings mean? In the context of severe falciparum malaria, moderate anaemia may protect against death, and a conservative approach to blood transfusion might be warranted. The current haemoglobin threshold of 5 g/dL used to define severe malarial anaemia may be too high and should be reconsidered. In order to refute or confirm these findings, randomised studies are needed to assess optimal transfusion thresholds.