Lyme Disease (Borrelia burgdorferi)

Etiology

Lyme disease is caused by the spirochete Borrelia burgdorferi sensu lato (broad sense). In North America, B. burgdorferi sensu stricto (strict sense) causes almost all cases; a recently discovered species in the upper Midwestern United States, Borrelia mayonii (belonging to the group B. burgdorferi sensu lato), also causes Lyme disease, but the illness is slightly different, with more diffuse rashes and gastrointestinal symptoms. In Europe, the species Borrelia afzelii and Borrelia 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 kDa, respectively), and the 41 kDa 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 United States. These differences include the greater incidence of radiculoneuritis in Europe.

Epidemiology

Lyme disease has been reported from more than 50 countries, predominately distributed in forested areas of Asia; northwestern, central, and eastern Europe; and in the northeastern and midwestern United States. In Europe, most cases occur in the Scandinavian countries and in central Europe, especially Germany, Austria, and Switzerland, while in the United States, 95% of cases occurred in 16 states in 2017: Connecticut, Delaware, Maine, Maryland, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, North Carolina, Pennsylvania, Rhode Island, Vermont, Virginia, West Virginia, and Wisconsin ( Fig. 249.1 ).

In the United States, in excess of 20,000 confirmed cases have been reported annually to the Centers for Disease Control and Prevention (CDC) over the last decade, and reported cases have trended upward since 1995, with an approximate 9% increase of reported cases in 2017 compared to 2016. In 2017, the most recent year national data are available, more than 29,000 confirmed cases and more than 13,000 probable cases were reported. The 3-yr averaged national incidence is estimated at 8.5 cases per 100,000 population, and for the last decade the national incidence has ranged from a low of 7.0 cases per 100,000 (2012) to a high of 9.8 cases per 100,000 (2009). In endemic areas, the reported annual incidence ranges from 20 to 100 cases per 100,000 population, although this figure may be as high as 600 cases per 100,000 population in hyperendemic areas. The reported incidence of disease is bimodal. There is an initial peak among children 5-14 yr of age followed by a second peak among adults 55-69 yr of age. In the United States, Lyme disease is diagnosed in boys slightly more often than in girls, and 94% of patients are of European descent. Early Lyme disease 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.

Lyme disease is designated a nationally notifiable disease by the CDC and Council for State and Territorial Epidemiologists. Healthcare providers, hospitals, laboratories, and other parties are required by law to notify local health departments when a confirmed or probable case of Lyme disease occurs. The local health departments in turn report cases to the state and territorial health departments; it is voluntary in turn for these authorities to report data to the CDC, and therefore the actual number of Lyme disease cases as well as incidence is likely underreported and underestimated. Lyme disease was the 6th most common notifiable disease reported to the CDC in 2017.

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 United States, 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 United States. 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 2nd 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 United States, 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 show 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. Most patients with Lyme disease do not remember the tick bite that transmitted the infection.

The tick species that carry B. burgdorferi may be geographically expanding in the U.S. I. scapularis also transmits other microorganisms, namely Anaplasma phagocytophilum and Babesia microti, as well as a recently described species, Borrelia miyamotoi. Simultaneous transmission can result in coinfections 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 a result of 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 by antibiotics.

Clinical Manifestations

The clinical manifestations of Lyme disease are divided into early and late stages ( Table 249.1 ). 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.