Developing a molecular tool to stratify the acute joint presentation: facilitating early diagnosis of septic arthritis.

摘要：非创伤性急性关节肿胀、儿童跛行或儿童因疼痛而不愿负重/移动关节是急诊科常见的症状。关键的诊断区别在于脓毒性关节炎（定义为继发于细菌感染的关节炎症）和非感染性炎症（如痛风和短暂性滑膜炎）之间的区别。然而，区分感染性和非感染性关节炎是一项诊断挑战，因为两组之间的临床症状和体征可能很微妙，有相当大的重叠，而筛查实验室/影像学检查和滑液/血液培养相对不敏感。先前的研究表明，细菌及其毒素对骨骼和软骨等关节组织具有高度破坏性，因此，延迟诊断和开始治疗（通常包括静脉注射抗生素和关节冲洗的组合）可能会产生严重的临床后果。然而，脓毒性关节炎仅占急性关节症状的一小部分，但几乎所有此类患者都要住院，接受潜在的侵入性手术，并普遍接受抗感染治疗，这伴随着抗生素耐药性扩大、过度使用和费用增加的风险。因此，对急性关节表现的快速准确的临床分层是非常可取的。这可以通过鉴定感染性关节炎特有的新型血液、滑液和尿液生物标志物来实现。此外，对于那些微生物学证实患有脓毒性关节炎的患者，分离细菌的基因组测序可能会识别出与不良结构或全身性预后相关的独特分子特征，这可能最终用于开发新的抗菌治疗方法，以改善此类患者的临床结果。因此，该学生计划利用已建立的代谢组学、蛋白质组学和转录组学技术，结合先进的生物信息学方法进行数据分析，分析疑似脓毒性关节炎患者的血液、滑液和尿液样本。本研究招募的患者样本将在常规调查和治疗（关节抽吸/手术冲洗）期间收集，因此没有患者仅为研究目的而接受侵入性手术。将对从常规滑液和血液培养中分离的所有细菌进行基因组测序。此外，学生将提供细胞培养和体外感染模型开发方面的实践培训，以提高培训的技能和广度。

Keywords: Sepsis, biomarker, arthritis, diagnosisAbstract:Atraumatic acute joint swelling, a limping child or a child unwilling to weight-bear/move a joint due to pain are common presentations to the Emergency Department. The key diagnostic differential is between septic arthritis, which is defined as inflammation of a joint secondary to bacterial infection, and non-infectious causes of inflammation e.g. gout and transient synovitis. However, distinguishing between infectious and non-infectious arthritis represents a diagnostic challenge as clinical signs and symptoms may be subtle with considerable overlap between the two groups and screening laboratory/imaging studies and synovial fluid/blood cultures are relatively insensitive. Previous work has demonstrated that bacteria and their toxins are highly destructive to joint tissues such as bone and cartilage and therefore a delay in diagnosis and initiation of treatment, which typically involves a combination of intravenous antibiotics coupled with joint irrigation, may have severe clinical consequences. Septic arthritis however comprises only a minority of acute joint presentations, yet almost all such patients are admitted to hospital, undergo potentially invasive procedures and universally receive anti-infective therapeutics, with their attendant risks in the context of expanding antibiotic resistance, overuse and expense. The rapid and accurate clinical stratification of the acute joint presentation would thus be extremely desirable. This may be achieved through the identification of novel blood, synovial fluid and urinary biomarkers unique to infectious arthritis. In addition, for those patients with microbiologically confirmed septic arthritis, genome sequencing of isolated bacteria may identify unique molecular signatures associated with poor structural or systemic prognosis, which could be utilised ultimately to develop novel antimicrobial treatments to improve clinical outcome in such patients. This studentship therefore proposes to analyse blood, synovial fluid and urine samples of patients presenting with suspected septic arthritis utilising established metabolomic, proteomic and transcriptomic techniques coupled with advanced bioinformatic approaches for dataset analysis. Samples from patients recruited to this study will be collected during routine investigations and treatments (joint aspiration/surgical washout) and thus no patients will undergo invasive procedures solely for the purpose of the study. Genome sequencing will be conducted on all bacteria isolated from routine synovial fluid and blood cultures. In addition the studentship will provide hands on training in cell culture and ex vivo infection model development to enhance the skill set and breadth of training on offer.