Etiology

Lyme disease is caused by the spirochete Borrelia burgdorferi sensu lato (broad sense). In North America, B. burgdorferi sensu stricto (strict sense) causes virtually all cases, and in Europe, the species B. afzelii and B. garinii also cause disease. The 3 major outer-surface proteins called OspA, OspB, and OspC (which are highly charged basic proteins of molecular weights of about 31, 34, and 23 kd, respectively) and the 41 kd flagellar protein are important targets for the immune response. Differences in the molecular structure of the different species are associated with differences in the clinical manifestations of Lyme borreliosis in Europe and the USA. These differences include the greater incidence of radiculoneuritis in Europe.

Epidemiology

Lyme disease has been reported from >50 countries. In the USA approximately 20,000 cases were reported in 2006; however, because of incomplete reporting of cases, it is estimated that the actual number of cases is much higher. From 1992 through 2006, 93% of cases occurred in 10 states: Connecticut, Delaware, Maryland, Massachusetts, Minnesota, New Jersey, New York, Pennsylvania, Rhode Island, and Wisconsin (Fig. 214-1). In endemic areas, the reported annual incidence ranges from 20 to 100 cases/100,000 population, although this figure may be as high as 600 cases/100,000 population in hyperendemic areas. In Europe, most cases occur in the Scandinavian countries and in central Europe, especially Germany, Austria, and Switzerland. The reported incidence is highest among children 5-9 yr of age, with a second peak of disease activity in middle-aged adults. In the USA, Lyme disease is diagnosed in boys slightly more often than in girls, and 94% of patients are of European descent. Early Lyme disease (described later) usually occurs from spring to early fall, corresponding to deer tick activity. Late disease (chiefly arthritis) occurs year round. Among adults, outdoor occupation and leisure activities are risk factors; for children, location of residence in an endemic area is the most important risk for infection.

Figure 214-1 The approximate distribution of predicted risk for Lyme disease in the USA. The risk varies by the distribution of Ixodes scapularis and Ixodes pacificus, the proportion of ticks that are infected at each stage of the tick’s life cycle, and the presence of grassy or wooded locations favored by white-tailed deer.

(From the Centers for Disease Control and Prevention: Reported cases of Lyme disease—United States, 2009 [website]. http://www.cdc.gov/ncidod/dvbid/lyme/ld_Incidence.htm. Accessed November 11, 2010.)

Transmission

Lyme disease is a zoonosis caused by the transmission of B. burgdorferi to humans through the bite of an infected tick of the Ixodes genus. In the eastern and midwestern USA, the vector is Ixodes scapularis, the black-legged tick that is commonly known as the deer tick, which is responsible for most cases of Lyme disease in the USA. The vector on the Pacific Coast is Ixodes pacificus, the western black-legged tick. Ixodes ticks have a 2-yr, 3-stage life cycle. The larvae hatch in the early summer and are usually uninfected with B. burgdorferi. The tick can become infected at any stage of its life cycle by feeding on a host, usually a small mammal such as the white-footed mouse (Peromyscus leucopus), which is a natural reservoir for B. burgdorferi. The larvae overwinter and emerge the following spring in the nymphal stage, which is the stage of the tick most likely to transmit the infection. The nymphs molt to adults in the fall and then adults spend the second winter attached to white tailed deer (Odocoileus virginianus). The females lay their eggs the following spring before they die, and the 2-yr life cycle begins again.

Several factors are associated with increased risk for transmission of B. burgdorferi from ticks to humans. The proportion of infected ticks varies by geographic area and by stage of the tick’s life cycle. In endemic areas in the northeastern and midwestern USA, 15-25% of nymphal ticks and 35-50% of adult ticks are infected with B. burgdorferi. By contrast, I. pacificus often feeds on lizards, which are not a competent reservoir for B. burgdorferi, reducing the chance that these ticks will be infected. The risk for transmission of B. burgdorferi from infected Ixodes ticks is related to the duration of feeding. Experiments in animals have shown that infected nymphal ticks must feed for 36-48 hr, and infected adults must feed for 48-72 hr, before the risk for transmission of B. burgdorferi becomes substantial. If the tick is recognized and removed promptly, transmission of B. burgdorferi will not occur.

Ixodes scapularis also transmits other microorganisms, namely Anaplasma phagocytophilum and Babesia microti. Simultaneous transmission can result in co-infections with these organisms and B. burgdorferi.

Pathology and Pathogenesis

Similar to other spirochetal infections, untreated Lyme disease is characterized by asymptomatic infection, clinical disease that can occur in stages, and a propensity for cutaneous and neurologic manifestations.

The skin is the initial site of infection by B. burgdorferi. Inflammation induced by B. burgdorferi leads to the development of the characteristic rash, erythema migrans. Early disseminated Lyme disease results from the spread of spirochetes through the bloodstream to tissues throughout the body. The spirochete adheres to the surfaces of a wide variety of different types of cells, but the principal target organs are skin, central and peripheral nervous system, joints, heart, and eyes. Because the organism can persist in tissues for prolonged periods, symptoms can appear very late after initial infection.

The symptoms of early disseminated and late Lyme disease are due to inflammation mediated by interleukin 1 and other lymphokines in response to the presence of the organism. It is likely that relatively few organisms actually invade the host, but cytokines serve to amplify the inflammatory response and lead to much of the tissue damage. Lyme disease is characterized by inflammatory lesions that contain both T and B lymphocytes, macrophages, plasma cells, and mast cells. The refractory symptoms of late Lyme disease can have an immunogenetic basis. Persons with certain HLA-DR allotypes may be genetically predisposed to develop chronic Lyme arthritis. An autoinflammatory response in the synovium can result in clinical symptoms long after the bacteria have been killed.

Clinical Manifestations

The clinical manifestations of Lyme disease are divided into early and late stages (Table 214-1). Early Lyme disease is further classified as early localized or early disseminated disease. Untreated patients can progressively develop clinical symptoms of each stage of the disease, or they can present with early disseminated or with late disease without apparently having had any symptoms of the earlier stages of Lyme disease.

Table 214-1 CLINICAL STAGES OF LYME DISEASE

EM, erythema migrans.

Early Localized Disease

The first clinical manifestation of Lyme disease in most patients is erythema migrans (Fig. 214-2). Although it usually occurs 7-14 days after the bite, the onset of the rash has been reported from 3 to 30 days later. The initial lesion occurs at the site of the bite. The rash is generally either uniformly erythematous or a target lesion with central clearing; rarely, there are vesicular or necrotic areas in the center of the rash. Occasionally the rash is itchy or painful, though usually it is asymptomatic. The lesion can occur anywhere on the body, although the most common locations are the axilla, periumbilical area, thigh, and groin. It is not unusual for the rash to occur on the neck or face, especially in young children. Without treatment, the rash gradually expands (hence the name migrans) to an average diameter of 15 cm and typically remains present for 1-2 wk. Erythema migrans may be associated with systemic features, including fever, myalgia, headache, or malaise. Co-infection with Babesia microti or Anaplasma phagocytophilum during early infection with B. burgdorferi is associated with more severe systemic symptoms.

Figure 214-2 Skin manifestations of Lyme borreliosis. A, Erythema migrans on the upper leg, showing central clearing. B, Erythema migrans expanding around the umbilicus; note central clearing.

(From Stanek G, Strle F: Lyme borreliosis, Lancet 362:1639–1647, 2003.)