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.

在全球范围内，疟疾始终是备受关注的公共卫生问题，其中重症疟疾（severe malaria, SM）在疟疾流行国家的疾病负担中占据了主要份额。在此背景下，重症疟疾生物标志物（biomarker）的鉴定与验证工作在临床实践中至关重要。部分生物标志物（如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、富组氨酸蛋白2）在恶性疟原虫（*Plasmodium falciparum*）引发的重症疟疾预后评估中已获得令人瞩目的研究成果，但针对间日疟原虫（*P. vivax*）与诺氏疟原虫（*P. knowlesi*）引发的重症疟疾，此类相关证据仍存在空白。上述生物标志物的验证工作受多重因素制约，包括样本量不足、相关验证研究匮乏、灵敏度与特异度未达最优水平、检测方法临床实用性欠佳、混合疟原虫感染，以及该类生物标志物在合并感染（肺炎与当前新型冠状病毒肺炎（COVID-19）大流行）场景下具备良好临床价值等问题。由于多数此类生物标志物与宿主免疫应答相关，而非针对特定病原体，因此在重症疟疾患者的临床评估中，它们应被视为可辅助但无法替代病原体标志物的预后/预测性生物标志物。本综述强调了未来研究需重点关注诊断、预测与治疗性生物标志物、被忽视的疟疾虫种，以及检测方法的临床实用性等方向的重要意义。此外，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流程中的核心价值。