CCL19 as a Chemokine Risk Factor for Posttreatment Lyme Disease

Approximately 10% to 20% of patients optimally treated for early Lyme disease develop persistent symptoms of unknown pathophysiology termed posttreatment Lyme disease syndrome (PTLDS). The objective of this study was to investigate associations between PTLDS and immune mediator levels during acute illness and at several time points following treatment. Seventy-six participants with physician-documented erythema migrans and 26 healthy controls with no history of Lyme disease were enrolled. Sixty-four cytokines, chemokines, and inflammatory markers were measured at each visit for a total of 6 visits over 1 year. An operationalized definition of PTLDS incorporating symptoms and functional impact was applied at 6 months and 1 year following treatment completion, and clinical outcome groups were defined as the return-to-health, symptoms-only, and PTLDS groups. Significance analysis of microarrays identified 7 of the 64 immune mediators to be differentially regulated by group. Generalized logit regressions controlling for potential confounders identified posttreatment levels of the T-cell chemokine CCL19 to be independently associated with clinical outcome group. Receiver operating characteristic analysis identified a CCL19 cutoff of >111.67 pg/ml at 1 month following treatment completion to be 82% sensitive and 83% specific for later PTLDS. We speculate that persistently elevated CCL19 levels among participants with PTLDS may reflect ongoing, immune-driven reactions at sites distal to secondary lymphoid tissue. Our findings suggest the relevance of CCL19 both during acute infection and as an immunologic risk factor for PTLDS during the posttreatment phase. Identification of a potential biomarker predictor for PTLDS provides the opportunity to better understand its pathophysiology and to develop early interventions in the context of appropriate and specific clinical information. A total of 65 immune and inflammatory mediators were profiled in serum samples derived from early Lyme disease patients and age- and sex-matched controls. These samples have been generated as part of a prospective cohort study that includes a well-defined cohort of patients with acute Lyme disease enrolled from a Lyme endemic area of the mid-Atlantic United States. Only patients with untreated, confirmed early Lyme disease manifesting an active EM skin lesion at the time of enrollment, as defined by CDC case criteria are eligible. Patients with a history of prior Lyme disease or the presence of confounding preexisting medical conditions associated with prolonged fatigue, pain or neurocognitive symptoms are excluded. Controls are nonhospitalized age- and sex-matched and have no prior history of Lyme disease or any exclusionary medical conditions including lack of inflammatory disorders.

约10%至20%的早期莱姆病患者在接受规范治疗后，会出现病因不明的持续性症状，这类病症被称为治疗后莱姆病综合征（posttreatment Lyme disease syndrome, PTLDS）。本研究旨在探讨治疗后莱姆病综合征与急性期及治疗后多个时间点的免疫介质水平之间的关联。
本研究共纳入76名经医师确诊存在移行性红斑（erythema migrans）的受试者，以及26名无莱姆病病史的健康对照者。研究团队在为期1年的随访中共完成6次采样，每次均对64种细胞因子、趋化因子及炎症标志物进行检测。本研究在治疗结束后6个月及1年时，采用纳入症状与功能影响的PTLDS操作化定义进行评估，并将受试者分为转归健康组、仅症状组及PTLDS组三类临床转归组别。
微阵列显著性分析显示，64种免疫介质中有7种在不同临床转归组别间存在差异表达。控制潜在混杂因素的广义对数几率回归分析显示，治疗后T细胞趋化因子CCL19的水平与临床转归组别存在独立关联。受试者工作特征分析显示，治疗结束后1个月时，CCL19水平>111.67 pg/ml的临界值对后续发生PTLDS的预测灵敏度为82%，特异度为83%。
我们推测，PTLDS患者体内持续升高的CCL19水平，可能反映了次级淋巴组织远端部位持续存在的免疫介导反应。本研究结果表明，CCL19在急性感染阶段及治疗后阶段均具有重要意义，可作为PTLDS的免疫风险因子。发现潜在的PTLDS生物标志物预测因子，有助于进一步阐明其病理生理机制，并可在获取恰当且特异性临床信息的前提下，开发早期干预手段。
本研究对早期莱姆病患者及年龄、性别匹配的对照者的血清样本中的65种免疫与炎症介质进行了表征分析。上述样本来自一项前瞻性队列研究，该研究的受试者均为从美国中大西洋莱姆病流行地区招募的确诊急性莱姆病患者，队列定义明确。仅纳入符合美国疾病控制与预防中心（Centers for Disease Control and Prevention, CDC）病例判定标准的、未经治疗的确诊早期莱姆病患者，且入组时存在活动性移行性红斑皮损。既往有莱姆病病史，或存在与长期疲劳、疼痛或神经认知症状相关的混杂基础疾病的患者均被排除。对照者为非住院人群，年龄与性别与病例组匹配，且无莱姆病病史，也不存在任何排除标准中提及的疾病（包括无炎症性疾病）。