The best documented vector is the deer tick, I. scapularis, whose geographic distribution correlates with the endemic foci in the eastern United States. The major areas where this organism is found are the eastern seaboard (e.g., Massachusetts, Rhode Island, Connecticut, New York, New Jersey, Maryland), the upper Midwest (e.g., Wisconsin, Minnesota), and the West (e.g., California, Nevada, Utah, Oregon). In the West, the tick associated with this disease is I. pacificus. In Europe, cases of EM, with or without neurologic findings, have occurred primarily in the geographic range of the I. ricinus tick. The taiga tick, I. persulcatus, is responsible for disease in Asia. The disease is more widespread than previously thought, implicating other potential vectors. A rash similar to EM has been described in humans residing in the southeastern and south-central United States. It is associated with the lone star tick Amblyomma americanum. This Lyme-like rash has been named Southern tick-associated rash illness (STARI).

The occurrence of Lyme disease peaks during summer and early fall. Cases cluster in sparsely settled and wooded areas. However, the conversion of farmland to woodland and finally to wooded suburbs has contributed to the spread of the increasing populations of deer and white-footed mice to more densely populated human areas and to the increasing prevalence of Lyme disease. As many as 67% of the patients in many studies do not report a history of tick bite, probably because of the small size (i.e., no larger than a pinhead) of the unengorged nymphal tick.

B. burgdorferi adapts to markedly different environments, the tick and its mammalian hosts, to complete its life cycle. The spirochete survives in the dormant state in the midgut of the nymphal tick during the fall, winter, and early spring. In the midgut, the organism primarily expresses OspA. With feeding in late spring or early summer, OspA is down-regulated, and OspC, required for infection of the mammalian host, is
up-regulated. The spirochete also binds mammalian plasminogen and its activators, present in the blood meal, thus facilitating spread of the organism.

Immune cells first encounter the organism at the site of the bite. Complement-mediated lysis of the organism may be the first line of defense. As part of the innate immune response, macrophages opsonize and kill the organism. Inflammatory cells within the skin lesions produce primarily Th1 proinflammatory cytokines. Within days, most patients mount an IgM antibody response to OspC or the 41-kDa flagellar protein. Both innate and adaptive cellular elements are mobilized to control the infection.

Within days to weeks after onset, B. burgdorferi often disseminates by binding to certain host proteins and adhering to integrins, proteoglycans, or glycoproteins on host cells or tissue matrices. As in the tick, this may be facilitated by the binding of plasminogen and its activators. Despite an active immune response, B. burgdorferi may survive during this phase by changing or minimizing antigenic expression of surface proteins and by inhibiting certain critical host immune responses. Certain lipoproteins may also contribute. Ultimately, both innate and adaptive immune responses are required to control the dissemination of infection. Even without antibiotics, these immune mechanisms may control infection and symptoms resolve. However, the organism may still survive in localized niches such as joints for years. Months after onset, about 50% of untreated patients experience intermittent attacks of arthritis associated with neutrophil extravasation into joints to set up joint inflammation. These patients often have high antibody responses to many spirochetal proteins, suggestive of hyperimmunization. Eventually, even in untreated patients, most experience resolution of attacks of arthritis, as immune mechanisms seem to successfully eradicate the organism from the joints.

The manifestations of Lyme disease can by divided into three stages (Box 156.1). These findings can be seen in isolation or concurrently. The incubation period usually is 3 to 32 days. The most common clinical finding is the skin rash (EM) (Fig. 156.1), which usually begins 4 to 20 days after the tick bite. An erythematous macule or papule forms at the site of the bite and gradually enlarges to form a large, plaque-like erythematous annular lesion with a median diameter of 16 cm. Early EM commonly has homogenous or central redness. The middle of the lesion often becomes clear, but it can be indurated or uniformly erythematous. It may have a vesicular or necrotic center. These lesions can occur anywhere on the body, but the usual sites are the thigh, buttocks, and axillae. Multiple secondary annular lesions are seen on approximately one-half of the patients (early dissemination—stage 2). The average duration of the untreated skin lesion is approximately 3 weeks. Often, EM is associated with systemic symptoms, most commonly malaise, fatigue, headache, stiff neck, and arthralgia. Fever usually is low grade, but it may be as high as 40°C. Lymphadenopathy, which is usually regional and associated with EM, and anicteric hepatitis, conjunctivitis, or pharyngitis also may occur. Infrequently, the flu-like symptoms may be seen without the characteristic rash. Respiratory and gastrointestinal symptoms are notably absent. These symptoms usually resolve over the course of several days, but they may occur intermittently for several weeks.