CCL19 as a Chemokine Risk Factor for Posttreatment Lyme Disease Syndrome: a Prospective Clinical Cohort Study

Abstract

d 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.

Induction of Interleukin 10 by Borrelia burgdorferi Is Regulated by the Action of CD14-Dependent p38 Mitogen-Activated Protein Kinase and cAMP-Mediated Chromatin Remodeling

“…However, despite more efficient bacterial clearance from infected tissues (45), IL-10 Ϫ/Ϫ mice develop more severe and persistent inflammation, and similarly, antibody-mediated neutralization of IL-11 increased IL-12 production and spirochetal clearance while also heightening joint inflammation in infected mice (47). These results are consistent with findings in humans, in whom both innate and adaptive immune responses appear to be important in control of the infection; however, excessive or prolonged inflammatory responses are associated with more symptomatic early infection (13), post-Lyme symptoms after EM (48,49), and ARLA (50).…”

Post-treatment Lyme Disease as a Model for Persistent Symptoms in Lyme Disease

“…A muted immune response during acute infection, in the form of lower levels of circulating plasmablasts, has been associated with persistent symptoms after treatment (46). However, elevated levels of specific immune mediators such as IL-23 and CCL19 at disease onset and/or in the immediate convalescent period have been associated with the presence of persistent symptoms up to 1 year following treatment (47,48). It is unclear whether the magnitude of the initial antibody response to B. burgdorferi prior to treatment is of importance, as a negative serology has been found to be both associated and not associated with subsequent clinical outcomes (15,37).…”

“…Investigation into the role of an ongoing immune response in the symptomatology of patients with persistent symptoms is in its earliest stages. A handful of studies have suggested that inflammatory markers such as C-reactive protein, as well as immune mediators such as CCL19 and IL-23, remain elevated for months after completion of antibiotic therapy among patients with persistent symptoms (47,48,106). Anti-neural antibody reactivity is higher in those with persistent symptoms, even among those who are seronegative, compared to those who returned to health after treatment for Lyme disease (149).…”

Unconventional diagnostic tests for Lyme borreliosis: a systematic review

“…QUADAS-2 quality assessment demonstrated unclear risk of bias and uncertainty regarding applicability in this study [49].…”

“…In their recent prospective controlled study, Aucott et al described the T-cell chemokine CCL-19 as a potential immunological risk factor of PTLDS [49]. Seventy-six patients with physiciandocumented EM were followed for 1 year post-antibiotics: 11/76 (14.5%) developed PTLDS-compatible symptoms [49]. Persistently high 1-year CCL-19 levels were only observed in patients with PTLDS.…”