Posttreatment Chronic Lyme Disease—What It Is Not

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 oli-goarthritis among children and adults in eastern Connecticut, subsequent epidemi-ologic 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 spiro-chete from a small number of patients [3, 4]. Increasingly sophisticated methods for detecting and genotyping LD spi-rochetes 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 pathogen-esis 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]. Li-poprotein-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, er-ythema 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 …