The predictive capacity of biomarkers for clinical pulmonary oedema in patients with severe falciparum malaria is low: a prospective observational study

Background: Pulmonary oedema is a feared and difficult to predict complication of severe malaria that can emerge after start of antimalarial treatment. Proinflammatory mediators are thought to play a central role in its pathogenesis. Methods: An exploratory study was conducted to evaluate the predictive capacity of biomarkers for development of clinical pulmonary oedema in patients with severe falciparum malaria at two hospitals in Bangladesh. Plasma concentrations of interleukin-6 (IL-6), IL-8, tumour necrosis factor (TNF), soluble Receptor of Advanced Glycation End-products (sRAGE), surfactant protein-D (SP-D), club cell secretory protein (CC16), and Krebs von den Lungen-6 (KL-6) on admission were compared with healthy controls. Correlations between these biomarker and plasma lactate and Plasmodium falciparum histidine-rich protein 2 (PfHRP2) levels were evaluated. Receiver Operating Characteristic (ROC) curves were constructed to assess the predictive capacity for clinical pulmonary oedema of the biomarkers of interest. Results: Of 106 screened patients with falciparum malaria, 56 were classified as having severe malaria with a mortality rate of 29%. Nine (16%) patients developed clinical pulmonary oedema after admission. Plasma levels of the biomarkers of interest were higher in patients compared to healthy controls. IL-6, IL-8, TNF, sRAGE, and CC16 levels correlated well with plasma PfHRP2 levels (r_s = 0.39; P = 0.004, r_s = 0.43; P = 0.001, r_s = 0.54; P < 0.001, r_s = 0.44; P < 0.001, r_s = 0.43; P = 0.001, respectively). Furthermore, IL-6 and IL-8 levels correlated well with plasma lactate levels (r_s = 0.37; P = 0.005, r_s = 0.47; P < 0.001, respectively). None of the biomarkers of interest had predictive capacity for development of clinical pulmonary oedema. Conclusions: IL-6, IL-8, TNF, sRAGE, SP-D, CC16 and KL-6 cannot be used in predicting clinical pulmonary oedema in severe malaria patients.