The spectrum of clinical biomarkers in severe malaria and new avenues for exploration

Globally, malaria is a public health concern, with severe malaria (SM) contributing a major share of the disease burden in malaria endemic countries. In this context, identification and validation of SM biomarkers are essential in clinical practice. Some biomarkers (C-reactive protein, angiopoietin 2, angiopoietin-2/1 ratio, platelet count, histidine-rich protein 2) have yielded interesting results in the prognosis of <i>Plasmodium falciparum</i> severe malaria, but for severe <i>P. vivax</i> and <i>P. knowlesi</i> malaria, similar evidence is missing. The validation of these biomarkers is hindered by several factors such as low sample size, paucity of evidence-evaluating studies, suboptimal values of sensitivity/specificity, poor clinical practicality of measurement methods, mixed <i>Plasmodium</i> infections, and good clinical value of the biomarkers for concurrent infections (pneumonia and current COVID-19 pandemic). Most of these biomarkers are non-specific to pathogens as they are related to host response and hence should be regarded as prognostic/predictive biomarkers that complement but do not replace pathogen biomarkers for clinical evaluation of SM patients. This review highlights the importance of research on diagnostic/predictive/therapeutic biomarkers, neglected malaria species, and clinical practicality of measurement methods in future studies. Finally, the importance of omics technologies for faster identification/validation of SM biomarkers is also included.

疟疾是全球性公共卫生问题，在疟疾流行国家中，重症疟疾（severe malaria, SM）占据了疾病负担的主要份额。在此背景下，重症疟疾生物标志物的鉴定与验证在临床实践中至关重要。部分生物标志物（C反应蛋白、血管生成素2、血管生成素2/1比值、血小板计数、组氨酸丰富蛋白2）在恶性疟原虫（*Plasmodium falciparum*）重症疟疾的预后评估中已取得颇具价值的研究结果，但针对间日疟原虫（*P. vivax*）和诺氏疟原虫（*P. knowlesi*）引发的重症疟疾，目前仍缺乏同类佐证数据。上述生物标志物的验证工作受限于多重因素：样本量偏小、相关验证研究证据匮乏、灵敏度/特异度数值未达最优、检测方法临床实用性欠佳、存在混合疟原虫感染，以及当合并存在肺炎与当前新型冠状病毒肺炎（COVID-19）大流行相关感染时，此类生物标志物的临床解读易受干扰。此类生物标志物大多并非病原体特异性标志物，而是与宿主应答相关，因此在重症疟疾患者的临床评估中，它们应被视为可辅助而非替代病原体标志物的预后/预测性生物标志物。本综述着重强调了未来研究需关注的若干方向：诊断/预测/治疗性生物标志物的相关研究、被忽视的疟原虫虫种，以及检测方法的临床实用性。最后，本综述还探讨了组学（omics）技术在加速重症疟疾生物标志物鉴定与验证进程中的重要价值。