CHAPTER 82: LYME BORRELIOSIS

Lyme borreliosis is caused by a spirochete, Borrelia burgdorferi sensu lato, that is transmitted by ticks of the Ixodes ricinus complex. The infection usually begins with a characteristic expanding skin lesion, erythema migrans (EM; stage 1, localized infection). After several days or weeks, the spirochete may spread to many different sites (stage 2, disseminated infection). Possible manifestations of disseminated infection include secondary annular skin lesions, meningitis, cranial neuritis, radiculoneuritis, peripheral neuritis, carditis, atrioventricular nodal block, or migratory musculoskeletal pain. Months or years later (usually after periods of latent infection), intermittent or persistent arthritis, chronic encephalopathy or polyneuropathy, or acrodermatitis may develop (stage 3, persistent infection). Most patients experience early symptoms of the illness during the summer, but the infection may not become symptomatic until it progresses to stage 2 or 3.

Lyme disease was recognized as a separate entity in 1976 because of a geographic cluster of children in Lyme, Connecticut, who were thought to have juvenile rheumatoid arthritis. It became apparent that Lyme disease was a multisystemic illness that affected primarily the skin, nervous system, heart, and joints. Epidemiologic studies of patients with EM implicated certain Ixodes ticks as vectors of the disease. Early in the twentieth century, EM had been described in Europe and attributed to I. ricinus tick bites. In 1982, a previously unrecognized spirochete, now called Borrelia burgdorferi, was recovered from Ixodes scapularis ticks and then from patients with Lyme disease. The entity is now called Lyme disease or Lyme borreliosis.

B. burgdorferi, the causative agent of Lyme disease, is a fastidious microaerophilic bacterium. The spirochete’s genome is quite small (~1.5 Mb) and consists of a highly unusual linear chromosome of 950 kb as well as 17–21 linear and circular plasmids. The most remarkable aspect of the B. burgdorferi genome is that there are sequences for more than 100 known or predicted lipoproteins—a larger number than in any other organism. The spirochete has few proteins with biosynthetic activity and depends on its host for most of its nutritional requirements. It has no sequences for recognizable toxins.

Currently, 13 closely related borrelial species are collectively referred to as Borrelia burgdorferi sensu lato (i.e., “B. burgdorferi in the general sense”). The human infection Lyme borreliosis is caused primarily by three pathogenic genospecies: B. burgdorferi sensu stricto (“B. burgdorferi in the strict sense,” hereafter referred to simply as B. burgdorferi), Borrelia garinii, and Borrelia afzelii. B. burgdorferi is the sole cause of the infection in the United States; all three genospecies are found in Europe, and the latter two species occur in Asia.

Strains of B. burgdorferi have been subdivided according to several typing schemes: one based on sequence variation of outer-surface protein C (OspC), a second based on differences in the 16S–23S rRNA intergenic spacer region (RST or IGS), and a third called multilocus sequence typing. From these typing systems, it is apparent that strains of B. burgdorferi differ in pathogenicity. OspC type A (RST1) strains seem to be particularly virulent and may have played a role in the emergence of Lyme disease in epidemic form in the northeastern United States in the late twentieth century.

The 13 known genospecies of B. burgdorferi sensu lato live in nature in enzootic cycles involving 14 species of ticks that are part of the I. ricinus complex. I. scapularis (Fig. 137-1) is the principal vector in the eastern United States from Maine to Georgia and in the midwestern states of Wisconsin, Minnesota, and Michigan. I. pacificus is the vector in the western states of California and Oregon. The disease is acquired throughout Europe (from Great Britain to Scandinavia to European Russia), where I. ricinus is the vector, and in Asian Russia, China, and Japan, where I. persulcatus is the vector. These ticks may transmit other agents as well. In the United States, I. scapularis also transmits Babesia microti; Anaplasma phagocytophilum; Ehrlichia species Wisconsin; Borrelia miyamotoi; and, in rare instances, Powassan encephalitis virus (the deer tick virus) (see “Differential Diagnosis,” below). In Europe and Asia, I. ricinus and I. persulcatus also transmit tick-borne encephalitis virus.

Ticks of the I. ricinus complex have larval, nymphal, and adult stages. They require a blood meal at each stage. The risk of infection in a given area depends largely on the density of these ticks as well as their feeding habits and animal hosts, which have evolved differently in different locations. For I. scapularis in the northeastern United States, the white-footed mouse and certain other rodents are the preferred hosts of the immature larvae and nymphs. It is critical that both of the tick’s immature stages feed on the same host because the life cycle of the spirochete depends on horizontal transmission: in early summer from infected nymphs to mice and in late summer from infected mice to larvae, which then molt to become the infected nymphs that will begin the cycle again the following year. It is the tiny nymphal tick that is primarily responsible for transmission of the disease to humans during the early summer months. White-tailed deer, which are not involved in the life cycle of the spirochete, are the preferred host for the adult stage of I. scapularis and seem to be critical to the tick’s survival.

Lyme disease is now the most common vector-borne infection in the United States and Europe. Since surveillance was begun by the Centers for Disease Control and Prevention (CDC) in 1982, the number of cases in the United States has increased dramatically. More than 30,000 new cases are now reported each summer, but the actual number of new cases is probably closer to 300,000 annually. In Europe, reported frequencies of the disease are highest in the middle of the continent and in Scandinavia.

To maintain its complex enzootic cycle, B. burgdorferi must adapt to two markedly different environments: the tick and the mammalian host. The spirochete expresses outer-surface protein A (OspA) in the midgut of the tick, whereas OspC is upregulated as the organism travels to the tick’s salivary gland. There, OspC binds a tick salivary-gland protein (Salp15), which is required for infection of the mammalian host. The tick usually must be attached for at least 24 h for transmission of B. burgdorferi.

After injection into the human skin, the spirochete downregulates OspC and upregulates the VlsE lipoprotein. This protein undergoes extensive antigenic variation, which is necessary for spirochetal survival. After several days to weeks, B. burgdorferi may migrate outward in the skin, producing EM, and may spread hematogenously or in the lymph to other organs. The only known virulence factors of B. burgdorferi are surface proteins that allow the spirochete to attach to mammalian proteins, integrins, glycosaminoglycans, or glycoproteins. For example, spread through the skin and other tissue matrices may be facilitated by the binding of human plasminogen and its activators to the surface of the spirochete. Some Borrelia strains bind complement regulator–acquiring surface proteins (FHL-1/reconectin, or factor H), which help to protect spirochetes from complement-mediated lysis. Dissemination of the organism in the blood is facilitated by binding to the fibrinogen receptor on activated platelets (α_IIbβ₃) and the vitronectin receptor (α_vβ₃) on endothelial cells. As the name indicates, spirochetal decorin-binding proteins A and B bind decorin, a glycosaminoglycan on collagen fibrils; this binding may explain why the organism is commonly aligned with collagen fibrils in the extracellular matrix in the heart, nervous system, or joints.

To control and eradicate B. burgdorferi, the host mounts both innate and adaptive immune responses, resulting in macrophage- and antibody-mediated killing of the spirochete. As part of the innate immune response, complement may lyse the spirochete in the skin. Cells at affected sites release potent proinflammatory cytokines, including interleukin 6, tumor necrosis factor α, interleukin 1β, and interferon γ. Patients who are homozygous for a Toll-like receptor 1 polymorphism (1805GG), particularly when infected with highly inflammatory B. burgdorferi RST1 strains, have exceptionally high levels of proinflammatory cytokines. The purpose of the adaptive immune response appears to be the production of specific antibodies, which opsonize the organism—a step necessary for optimal spirochetal killing. Studies with protein arrays expressing ~1200 B. burgdorferi proteins detected antibody responses to a total of 120 spirochetal proteins (particularly outer-surface lipoproteins) in a population of patients with Lyme arthritis. Histologic examination of all affected tissues reveals an infiltration of lymphocytes, macrophages, and plasma cells with some degree of vascular damage, including mild vasculitis or hypervascular occlusion. These findings suggest that the spirochete may have been present in or around blood vessels.

In enzootic infection, B. burgdorferi spirochetes must survive this immune assault only during the summer months before returning to larval ticks to begin the cycle again the following year. In contrast, infection of humans is a dead-end event for the spirochete. Within several weeks or months, innate and adaptive immune mechanisms—even without antibiotic treatment—control widely disseminated infection, and generalized systemic symptoms wane. However, without antibiotic therapy, spirochetes may survive in localized niches for several more years. For example, B. burgdorferi infection in the United States may cause persistent arthritis or, in rare cases, subtle encephalopathy or polyneuropathy. Thus, immune mechanisms seem to succeed eventually in the near or total eradication of B. burgdorferi from selected niches, including the joints or nervous system, and symptoms resolve in most patients.

Early infection: stage 1 (localized infection)

Because of the small size of nymphal ixodid ticks, most patients do not remember the preceding tick bite. After an incubation period of 3–32 days, EM usually begins as a red macule or papule at the site of the tick bite that expands slowly to form a large annular lesion (Fig. 82-1). As the lesion increases in size, it often develops a bright red outer border and partial central clearing. The center of the lesion sometimes becomes intensely erythematous and indurated, vesicular, or necrotic. In other instances, the expanding lesion remains an even, intense red; several red rings are found within an outside ring; or the central area turns blue before the lesion clears. Although EM can be located anywhere, the thigh, groin, and axilla are particularly common sites. The lesion is warm but not often painful. Approximately 20% of patients do not exhibit this characteristic skin manifestation.

Early infection: stage 2 (disseminated infection)

In cases in the United States, B. burgdorferi often spreads hematogenously to many sites within days or weeks after the onset of EM. In these cases, patients may develop secondary annular skin lesions similar in appearance to the initial lesion. Skin involvement is commonly accompanied by severe headache, mild stiffness of the neck, fever, chills, migratory musculoskeletal pain, arthralgias, and profound malaise and fatigue. Less common manifestations include generalized lymphadenopathy or splenomegaly, hepatitis, sore throat, nonproductive cough, conjunctivitis, iritis, or testicular swelling. Except for fatigue and lethargy, which are often constant, the early signs and symptoms of Lyme disease are typically intermittent and changing. Even in untreated patients, the early symptoms usually become less severe or disappear within several weeks. In ~15% of patients, the infection presents with these nonspecific systemic symptoms.

Symptoms suggestive of meningeal irritation may develop early in Lyme disease when EM is present but usually are not associated with cerebrospinal fluid (CSF) pleocytosis or an objective neurologic deficit. After several weeks or months, ~15% of untreated patients develop frank neurologic abnormalities, including meningitis, subtle encephalitic signs, cranial neuritis (including bilateral facial palsy), motor or sensory radiculoneuropathy, peripheral neuropathy, mononeuritis multiplex, cerebellar ataxia, or myelitis—alone or in various combinations. In children, the optic nerve may be affected because of inflammation or increased intracranial pressure, and these effects may lead to blindness. In the United States, the usual pattern consists of fluctuating symptoms of meningitis accompanied by facial palsy and peripheral radiculoneuropathy. Lymphocytic pleocytosis (~100 cells/μL) is found in CSF, often along with elevated protein levels and normal or slightly low glucose concentrations. In Europe and Asia, the first neurologic sign is characteristically radicular pain, which is followed by the development of CSF pleocytosis (meningopolyneuritis or Bannwarth’s syndrome); meningeal or encephalitic signs are frequently absent. These early neurologic abnormalities usually resolve completely within months, but in rare cases chronic neurologic disease may occur later.

Within several weeks after the onset of illness, ~8% of patients develop cardiac involvement. The most common abnormality is a fluctuating degree of atrioventricular block (first-degree, Wenckebach, or complete heart block). Some patients have more diffuse cardiac involvement, including electrocardiographic changes indicative of acute myopericarditis, left ventricular dysfunction evident on radionuclide scans, or (in rare cases) cardiomegaly or fatal pancarditis. Cardiac involvement lasts for only a few weeks in most patients but may recur in untreated patients. Chronic cardiomyopathy caused by B. burgdorferi has been reported in Europe.

During this stage, musculoskeletal pain is common. The typical pattern consists of migratory pain in joints, tendons, bursae, muscles, or bones (usually without joint swelling) lasting for hours or days and affecting one or two locations at a time.

Late infection: stage 3 (persistent infection)

Months after the onset of infection, ~60% of patients in the United States who have received no antibiotic treatment develop frank arthritis. The typical pattern comprises intermittent attacks of oligoarticular arthritis in large joints (especially the knees), lasting for weeks or months in a given joint. A few small joints or periarticular sites also may be affected, primarily during early attacks. The number of patients who continue to have recurrent attacks decreases each year. However, in a small percentage of cases, involvement of large joints—usually one or both knees—is persistent and may lead to erosion of cartilage and bone.

White cell counts in joint fluid range from 500 to 110,000/μL (average, 25,000/μL); most of these cells are polymorphonuclear leukocytes. Tests for rheumatoid factor or antinuclear antibodies usually give negative results. Examination of synovial biopsy samples reveals fibrin deposits, villous hypertrophy, vascular proliferation, microangiopathic lesions, and a heavy infiltration of lymphocytes and plasma cells.

Although most patients with Lyme arthritis respond well to antibiotic therapy, a small percentage in the northeastern United States have persistent (antibiotic-refractory) arthritis for months or even for several years after receiving oral and IV antibiotic therapy for 2 or 3 months. Although more often these patients are initially infected with RST1 strains of B. burgdorferi, this complication is not thought to result from persistent infection. Results of culture and polymerase chain reaction (PCR) for B. burgdorferi in synovial tissue obtained in the postantibiotic period have been uniformly negative. Rather, infection-induced autoimmunity, retained spirochetal antigens, or both may play a role in this outcome. Antibiotic-refractory arthritis is associated with a higher frequency of certain class II major histocompatibility complex molecules (particularly HLA-DRBI*0401 or -*0101 molecules); the Toll-like receptor 1 polymorphism 1805GG, which leads to exceptionally high levels of cytokines and chemokines in affected joints; and low frequencies of FoxP3+ T regulatory cells in synovial fluid, which correlate with longer posttreatment durations of arthritis. The recent identification of a novel human autoantigen, endothelial cell growth factor, as a target of T and B cell responses in patients with Lyme disease provided the first direct evidence of autoimmune T and B cell responses in this illness. However, multiple spirochetal or additional yet-to-be identified autoantigens may have a role in antibiotic-refractory arthritis.

Although rare, chronic neurologic involvement also may become apparent from months to several years after the onset of infection, sometimes after long periods of latent infection. The most common form of chronic central nervous system involvement is subtle encephalopathy affecting memory, mood, or sleep, and the most common form of peripheral neuropathy is an axonal polyneuropathy manifested as either distal paresthesia or spinal radicular pain. Patients with encephalopathy frequently have evidence of memory impairment in neuropsychological tests and abnormal results in CSF analyses. In cases of polyneuropathy, electromyography generally shows extensive abnormalities of proximal and distal nerve segments. Encephalomyelitis or leukoencephalitis, a rare manifestation of Lyme borreliosis associated primarily with B. garinii infection in Europe, is a severe neurologic disorder that may include spastic paraparesis, upper motor-neuron bladder dysfunction, and, rarely, lesions in the periventricular white matter.

Acrodermatitis chronica atrophicans, the late skin manifestation of Lyme borreliosis, has been associated primarily with B. afzelii infection in Europe and Asia. It has been observed especially often in elderly women. The skin lesions, which are usually found on the acral surface of an arm or leg, begin insidiously with reddish-violaceous discoloration; they become sclerotic or atrophic over a period of years.

The basic patterns of Lyme borreliosis are similar worldwide, but there are regional variations, primarily between the illness found in North America, which is caused exclusively by B. burgdorferi, and that found in Europe, which is caused primarily by B. afzelii and B. garinii. With each of the Borrelia species, the infection usually begins with EM. However, B. burgdorferi strains in the eastern United States often disseminate widely; they are particularly arthritogenic, and they may cause antibiotic-refractory arthritis. B. garinii typically disseminates less widely, but it is especially neurotropic and may cause borrelial encephalomyelitis. B. afzelii often infects only the skin but may persist in that site, where it may cause several different dermatoborrelioses, including acrodermatitis chronica atrophicans.

Post–Lyme syndrome (chronic Lyme disease)

Despite resolution of the objective manifestations of the infection with antibiotic therapy, ~10% of patients (although the reported percentages vary widely) continue to have subjective pain, neurocognitive manifestations, or fatigue symptoms. These symptoms usually improve and resolve within months but may last for years. At the far end of the spectrum, the symptoms may be similar to or indistinguishable from chronic fatigue syndrome (Chap. 38) and fibromyalgia. Compared with symptoms of active Lyme disease, post-Lyme symptoms tend to be more generalized or disabling. They include marked fatigue, severe headache, diffuse musculoskeletal pain, multiple symmetric tender points in characteristic locations, pain and stiffness in many joints, diffuse paresthesias, difficulty with concentration, and sleep disturbances. Patients with this condition lack evidence of joint inflammation, have normal neurologic test results, and may exhibit anxiety and depression. In contrast, late manifestations of Lyme disease, including arthritis, encephalopathy, and neuropathy, are usually associated with minimal systemic symptoms. Currently, no evidence indicates that persistent subjective symptoms after recommended courses of antibiotic therapy are caused by active infection.

The culture of B. burgdorferi in Barbour-Stoenner-Kelly (BSK) medium permits definitive diagnosis, but this method has been used primarily in research studies. Moreover, with a few exceptions, positive cultures have been obtained only early in the illness—particularly from biopsy samples of EM skin lesions, less often from plasma samples, and occasionally from CSF samples. Later in the infection, PCR is greatly superior to culture for the detection of B. burgdorferi DNA in joint fluid; this is the major use for PCR testing in Lyme disease. However, because B. burgdorferi DNA may persist for at least weeks after spirochetal killing with antibiotics, detection of spirochetal DNA in joint fluid is not an accurate test of active joint infection in Lyme disease and cannot be used reliably to determine the adequacy of antibiotic therapy. The sensitivity of PCR determinations in CSF from patients with neuroborreliosis has been much lower than that in joint fluid. There seems to be little if any role for PCR in the detection of B. burgdorferi DNA in blood or urine samples. Moreover, this procedure must be carefully controlled to prevent contamination.

Because of the problems associated with direct detection of B. burgdorferi, Lyme disease is usually diagnosed by the recognition of a characteristic clinical picture accompanied by serologic confirmation. Although serologic testing may yield negative results during the first several weeks of infection, almost all patients have a positive antibody response to B. burgdorferi after that time. The limitation of serologic tests is that they do not clearly distinguish between active and inactive infection. Patients with previous Lyme disease—particularly in cases progressing to late stages—often remain seropositive for years, even after adequate antibiotic treatment. In addition, ~10% of patients are seropositive because of asymptomatic infection. If these individuals subsequently develop another illness, the positive serologic test for Lyme disease may cause diagnostic confusion. According to an algorithm published by the American College of Physicians (Table 82-1), serologic testing for Lyme disease is recommended only for patients with at least an intermediate pretest probability of Lyme disease, such as those with oligoarticular arthritis. It should not be used as a screening procedure in patients with pain or fatigue syndromes. In such patients, the probability of a false-positive serologic result is higher than that of a true-positive result.

For serologic analysis of Lyme disease in the United States, the CDC recommends a two-step approach in which samples are first tested by enzyme-linked immunosorbent assay (ELISA) and equivocal or positive results are then tested by western blotting. During the first weeks of infection, both IgM and IgG responses to the spirochete should be determined, preferably in both acute- and convalescent-phase serum samples. Approximately 20–30% of patients have a positive response detectable in acute-phase samples, whereas ~70–80% have a positive response during convalescence (2–4 weeks later). After 4–8 weeks of infection (by which time most patients with active Lyme disease have disseminated infection), the sensitivity and specificity of the IgG response to the spirochete are both very high—in the range of 99%—as determined by the two-test approach of ELISA and western blot. At this point and thereafter, a single test (that for IgG) is usually sufficient. In persons with illness of >2 months’ duration, a positive IgM test result alone is likely to be false-positive and therefore should not be used to support the diagnosis.

According to current criteria adopted by the CDC, an IgM western blot is considered positive if two of the following three bands are present: 23, 39, and 41 kDa. However, the combination of two such bands may still represent a false-positive result. Misuse or misinterpretation of IgM blots has been a factor in the incorrect diagnosis of Lyme disease in patients with other illnesses. An IgG blot is considered positive if 5 of the following 10 bands are present: 18, 23, 28, 30, 39, 41, 45, 58, 66, and 93 kDa. In European cases, no single set of criteria for the interpretation of immunoblots results in high levels of sensitivity and specificity in all countries.

The most promising second-generation serologic test is the VlsE C6 peptide IgG ELISA, which employs a 26-mer of the sixth invariant region of the VlsE lipoprotein of B. burgdorferi. The results achieved with this test are similar to those obtained with the standard two-test approach (sonicate IgM and IgG ELISA and western blot). The principal advantage of the C6 peptide ELISA is the early detection of an IgG response, which renders an IgM test unnecessary. However, not all patients with late Lyme disease have a response to the C6 peptide, and this test is not quite as specific as sonicate western blot. Thus, at present, a two-test approach that includes western blot is still recommended. Blotting can also be helpful in assessing the duration of current or past disease.

After successful antibiotic treatment, antibody titers decline slowly but responses (including that to the VlsE C6 peptide) may persist for years. Moreover, not only the IgG but also the IgM response may persist for years after therapy. Therefore, even a positive IgM response cannot be interpreted as confirmation of recent infection or reinfection unless the clinical picture is appropriate.

Classic EM is a slowly expanding erythema, often with partial central clearing. If the lesion expands little, it may represent the red papule of an uninfected tick bite. If the lesion expands rapidly, it may represent cellulitis (e.g., streptococcal cellulitis) or an allergic reaction, perhaps to tick saliva. Patients with secondary annular lesions may be thought to have erythema multiforme, but neither the development of blistering mucosal lesions nor the involvement of the palms or soles is a feature of B. burgdorferi infection. In the eastern United States, an EM-like skin lesion, sometimes with mild systemic symptoms, may be associated with Amblyomma americanum tick bites. However, the cause of this Southern tick-associated rash illness (STARI) has not yet been identified. This tick may also transmit Ehrlichia chaffeensis, a rickettsial agent (Chap. 83).

As stated above, I. scapularis ticks in the United States may transmit not only B. burgdorferi but also B. microti, the red blood cell parasite causing babesiosis (Chap. 124); A. phagocytophilum, the agent of human granulocytotropic anaplasmosis (Chap. 83); Ehrlichia species Wisconsin; B. miyamotoi, a relapsing fever spirochete (Chap. 81); or (rarely) Powassan encephalitis virus (the deer tick virus, which is closely related to European tick-borne encephalitis virus) (Chap. 106). Although babesiosis and anaplasmosis are most often asymptomatic, infection with any of these agents may cause nonspecific systemic symptoms, particularly in the young or elderly, and co-infected patients may have more severe or persistent symptoms than patients infected with a single agent. Standard blood counts may yield clues regarding the presence of co-infection with Anaplasma or Babesia. Anaplasmosis may cause leukopenia or thrombocytopenia, and babesiosis may cause thrombocytopenia or (in severe cases) hemolytic anemia. IgM serologic responses may confuse the diagnosis. For example, A. phagocytophilum may elicit a positive IgM response to B. burgdorferi. The frequency of co-infection in different studies has been variable. In one prospective study, 4% of patients with EM had evidence of co-infection.

Facial palsy caused by B. burgdorferi, which occurs in the early disseminated phase of the infection (often in July, August, or September), is usually recognized by its association with EM. However, in rare cases, facial palsy without EM may be the presenting manifestation of Lyme disease. In such cases, both the IgM and the IgG responses to the spirochete are usually positive. The most common infectious agents that cause facial palsy are herpes simplex virus type 1 (Bell’s palsy; Chap. 88) and varicella-zoster virus (Ramsay Hunt syndrome; Chap. 89).

Later in the infection, oligoarticular Lyme arthritis most resembles reactive arthritis in an adult or the pauciarticular form of juvenile idiopathic arthritis in a child. Patients with Lyme arthritis usually have the strongest IgG antibody responses seen in Lyme borreliosis, with reactivity to many spirochetal proteins.

The most common problem in diagnosis is to mistake Lyme disease for chronic fatigue syndrome (Chap. 38) or fibromyalgia. This difficulty is compounded by the fact that a small percentage of patients do in fact develop these chronic pain or fatigue syndromes in association with or soon after Lyme disease. Moreover, a counterculture has emerged that ascribes pain and fatigue syndromes to chronic Lyme disease when there is little or no evidence of B. burgdorferi infection. In such cases, the term chronic Lyme disease, which is equated with chronic B. burgdorferi infection, is a misnomer, and the use of prolonged, dangerous, and expensive antibiotic treatment is not warranted.

The response to treatment is best early in the disease. Later treatment of Lyme borreliosis is still effective, but the period of convalescence may be longer. Eventually, most patients recover with minimal or no residual deficits.

Reinfection may occur after EM when patients are treated with antimicrobial agents. In such cases, the immune response is not adequate to provide protection from subsequent infection. However, patients who develop an expanded immune response to the spirochete over a period of months (e.g., those with Lyme arthritis) have protective immunity for a period of years and rarely, if ever, acquire the infection again.

Protective measures for the prevention of Lyme disease may include the avoidance of tick-infested areas, the use of repellents and acaricides, tick checks, and modification of landscapes in or near residential areas. Although a vaccine for Lyme disease used to be available, the manufacturer has discontinued its production. Therefore, no vaccine is now commercially available for the prevention of this infection.