Posttreatment chronic Lyme disease--what it is not.

Received 24 April 2005; accepted 4 May 2005; electronically published 4 August 2005. Potential conflicts of interest: none reported. Reprints or correspondence: Dr. Justin Radolf, University of Connecticut Health Center, Center for Microbial Pathogenesis, 263 Farmington Ave., Farmington, CT 06030-3710 (jradolf@up .uchc.edu). The Journal of Infectious Diseases 2005;192:948–9 2005 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2005/19206-0002$15.00 We have come a long way in our understanding of Lyme disease (LD). Although it was originally mistaken for juvenile rheumatoid arthritis when it first appeared in the mid-1970s as an epidemic of oligoarthritis among children and adults in eastern Connecticut, subsequent epidemiologic investigations established a probable microbial etiology for the disease [1]. This prediction was fulfilled by the discovery in 1981 of a new spirochetal bacterium, Borrelia burgdorferi, residing within the midgut of a new species of hard tick, Ixodes scapularis [2], and, shortly thereafter, by the isolation of the spirochete from a small number of patients [3, 4]. Increasingly sophisticated methods for detecting and genotyping LD spirochetes in ticks, small mammal reservoirs, and humans—an incidental host— have enabled investigators to define the disease’s enzootic cycle, major clinical manifestations, and prevalence in the United States and globally [5]. Although B. burgdorferi is far from an easy bacterium to study, considerable progress has been made in unraveling the mechanisms that enable this zoonotic parasite to cycle back and forth between 2 strikingly different milieus. Studies of LD pathogenesis have been greatly facilitated by the availability of the bacterium’s genomic sequence [6, 7] and by the development of techniques for genetically manipulating virulent spirochetes [8]. The development of a murine model that faithfully reproduces most clinical features of the disease represents another milestone in LD research [9]. Work in the murine model, in conjunction with in vitro and translational studies in humans, has firmly established that disease manifestations result from the inflammatory response evoked by the spirochete and its constituents [10, 11]. The borrelial genome encodes an astonishing number (1150) of lipid-modified polypeptides [6, 7], including numerous outer surface proteins (Osps) that are expressed at different times during the enzootic cycle [12]. Lipoprotein-mediated activation of innate immune cells is believed to be a principal trigger of acute inflammation at sites of infection [10]. Most patients with LD present with a slowly expanding annular skin lesion, erythema migrans (EM), which develops at the site of tick feeding [5]. Although ostensibly localized at the time of presentation, patients with solitary EM often have impressive flulike symptoms (malaise, headache, arthralgias, myalgias) that are believed to be indicative of spirochetal dissemination [5]. Indeed, culture and/or polymerase chain reaction (PCR)–based studies indicate that as many as one-half of patients with EM are spirochetemic at presentation, although spirochete concentrations in the blood are usually quite low [13]. Thus, B. burgdorferi appears to be a potent inducer of inflammation in vivo, and this supposition is mirrored by in vitro systems in which extremely low spirochete:cell ratios elicit the production of proinflammatory cytokines [14]. In addition to being disproportionate to the visible lesion, constitutional symptoms may take weeks to months to resolve after therapy. Physicians need to anticipate this enigmatic delayed response and not rush to re-treat. The major clinical controversies in LD center on the small percentage of patients who do not return to a state of well-being after therapy. Two posttreatment syndromes have been distinguished [15]. The rarer one is a persistent large-joint synovitis that, on the basis of negative PCR results and culture analyses of synovial fluids, is clearly not due to persistent infection. The association between this syndrome and the HLA-DR4 histocompatibility allele [16] was the first major evidence that “treatment-resistant Lyme arthritis” is an autoimmune process. Subsequent studies demonstrating possible molecular mimicry between an immunodominant epitope of OspA and a peptide derived from lymphocyte function–