Borrelia burgdorferi (Lyme Disease)

Pathogenesis and Immunity

Lyme disease is caused by the spirochete Borrelia burgdorferi, a cylindrical, fastidious, microaerophilic bacterium that replicates very slowly and requires special medium for in vitro growth. Its cell membrane is covered by flagella and a loosely associated outer membrane. The 3 major outer surface proteins, OspA, OspB, and OspC (which are highly charged basic proteins with molecular weights of ∼31, 34, and 23 kd, respectively), as well as the 41-kd flagellar protein, are important targets for the immune response of humans. Biologic differences in strains of B. burgdorferi sensu lato presumably are responsible for differences in the clinical manifestations of Lyme borreliosis in Europe and in the US. B. burgdorferi sensu stricto is the genomospecies that causes the great majority of cases of Lyme disease in the US (although B. mayonii causes some cases of Lyme disease in the upper Midwest —see Chapter 186 ). By contrast, there is considerable variation in the genomospecies that cause Lyme disease in Europe, which include B. garinii, B. afzelli, and several others in addition to B. burgdorferi sensu stricto. The greater frequency of neurologic manifestations in Europe and of arthritis in the US likely is related to these differences.

Lyme disease is a zoonosis with complex pathogenesis. B. burgdorferi is inoculated by the tick into the skin and begins to spread locally. Local inflammation results in erythema migrans in most patients with symptomatic infection (≥90%). Days to weeks later, the spirochete can disseminate, through the bloodstream, to many other sites, including eye, muscle, bone, synovial tissue, central nervous system, and heart. Despite the low density of organisms and the fastidious nature of growth in vitro, B. burgdorferi has been isolated from blood or from affected tissues at all stages of illness. Relatively few organisms invade. Host mediators amplify the inflammatory response and cause much of the tissue damage. Preferring cell surfaces, the spirochete can adhere to many different cell types, a feature that may explain clinical manifestations of involvement in a broad array of organ systems. Because the organism can persist in tissues for prolonged periods when untreated, symptoms can appear months after infection. The host’s immune response is an important element in the pathogenesis of Lyme disease. Symptoms of early localized disease, early disseminated disease, and late disease usually are caused by inflammation as a direct result of the spirochete’s presence (it does not produce toxins). Some people with Lyme disease who are treated early in the course of infection do not develop antibodies and remain susceptible to subsequent infections. However, evidence indicates that strain-specific (as opposed to species-specific) immunity can develop after a single episode of erythema migrans ; a second case of erythema migrans virtually always results from a strain different from the one that caused the initial case. People with late Lyme disease rarely develop erythema migrans again, even with repeated exposure to ixodid ticks in endemic areas, a finding suggesting that these people have developed immunity.

Epidemiology

Disease in Humans

Although Lyme disease occurs throughout the northern hemisphere, endemicity varies widely. In the US, from 1992–2018, >90% of reported cases came from 10 states. Most cases had occurred in southern New England and in the eastern Mid-Atlantic states; fewer cases occurred in Wisconsin and in neighboring states. Incidence has been increasing in adjacent areas such as northern New England, western Pennsylvania, Ohio, and Virginia. Rarely, cases occur along the northern Pacific coast ( Fig. 185.1 ). In Europe, many cases occur in the Scandinavian countries and in central Europe, although the disease occurs throughout the region, including in Great Britain.

Although frequency has increased and the geographic distribution of Lyme disease in the US has expanded, the incidence of Lyme disease varies substantially from region to region and within local areas. ^, The annual number of reported cases in the US increased from 9908 reported cases in 1992 to 33,666 confirmed and probable cases in 2018. This change likely reflects both the increased incidence and the improved recognition and reporting of disease. Estimates of the incidence of disease are complicated by reliance on passive reporting of cases as well as by the high frequency of misdiagnosis of disease. Furthermore, seroepidemiologic studies indicate that some patients who have evidence of recent infection with B. burgdorferi are asymptomatic. ^, The reported annual incidence in the most highly endemic areas, such as Rhode Island, is approximately 56 cases per 100,000 persons, although in certain localized areas in which the disease is hyperendemic (e.g., Lyme, CT), the annual incidence can be as high as 1000 or more per 100,000 persons. The reported incidence is highest among children 5–14 years old. Most cases occur during the summer months.

Clinical Manifestations

Lyme disease generally is divided into 3 clinical stages: early localized disease, early disseminated disease, and late disease. ^, Box 185.1 shows the major clinical features of these stages.