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Allen C. Steere
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 hematogenously to many different sites (stage 2, disseminated infection). Possible manifestations of disseminated infection include secondary annular skin lesions, meningitis, cranial or peripheral neuritis, carditis, atrioventricular nodal block, or migratory musculoskeletal pain. Months to years later (usually after periods of latent infection), intermittent or chronic 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. Despite regional variations, the basic stages of the illness are similar worldwide.
Lyme disease was recognized as a separate entity in 1976 because of geographic clustering of children in Lyme, Connecticut, who were thought to have juvenile rheumatoid arthritis. The rural setting of the case clusters and the identification of EM as a feature of the illness suggested that the disorder was transmitted by an arthropod. It became apparent that Lyme disease was a multisystem 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 9 linear and 12 circular plasmids. B. burgdorferi contains many immunogenic proteins, including a number of differentially expressed lipoproteins, most of which are encoded by plasmid DNA. To date, three groups of pathogenic B. burgdorferi organisms, together referred to as B. burgdorferi sensu lato, have been identified. All North American strains have belonged to the first group, B. burgdorferi sensu stricto. Although all three of the identified groups have been found in Europe, most isolates there have been strains of group 2 (B. garinii) or group 3 (B. afzelii), and only the latter two groups have been found in Asia. These differences may well account for the clinical variations in the disease in different geographic regions.
Lyme borreliosis in all locations is transmitted by ticks of the I. ricinuscomplex: I. scapularis (also called I. dammini), I. pacificus, I. ricinus, and I. persulcatus. I. scapularis is the principal vector in the northeastern United States from Maine to Maryland and in the midwestern states of Wisconsin and Minnesota. 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 diseases as well. In the United States, I. scapularis also transmits babesiosis and human anaplasmosis; in Europe and Asia, I. ricinus and I. persulcatus also transmit tick-borne encephalitis.
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 northeast, the white-footed mouse is the preferred host of the immature larval and nymphal ticks. 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. Since surveillance was begun by the Centers for Disease Control and Prevention (CDC) in 1982, the number of cases has increased dramatically. More than 15,000 new cases are now reported each summer. In Europe, Lyme borreliosis is widely established in forested areas; there, the highest reported frequencies of the disease are in the middle of the continent and in Scandinavia. Cases have occurred in persons who reside in endemic suburban, wooded, or rural areas and in persons who visit, hike, camp, or hunt in these areas.
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 proteins A and B (OspA and OspB) in the midgut of the tick, whereas OspC is upregulated as the organism travels to the tick's salivary gland and thence to the mammalian host. The tick must usually be attached for at least 24 h for transmission of B. burgdorferi.
After injection into the human skin, B. burgdorferi may migrate outward, producing EM, and may spread hematogenously to other organs. A number of mechanisms may aid in spirochetal dissemination. For example, the sequences of OspC vary considerably among strains, and only a few groups of sequences are associated with disseminated disease. 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. During its dissemination and homing to specific sites, the organism attaches to certain host integrins, matrix glycosaminoglycans, and extracellular matrix proteins. For example, Borrelia 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. The only known virulence factors of B. burgdorferi are surface proteins that allow the spirochete to attach to mammalian cells.
Inflammatory innate immune responses are critical in the control of early disseminated infection. Spirochetal lipoproteins, which bind to the CD14 molecule and toll-like receptor 2 on macrophages, are potent activators of the innate immune response, leading to the production of macrophage-derived inflammatory cytokines. After the first several weeks of infection, T cells, which are part of the adaptive immune response, generally exhibit heightened responsiveness to B. burgdorferi antigens, and evidence of B-cell hyperactivity is found, including elevated total serum IgM levels, cryoprecipitates, and circulating immune complexes. Titers of specific IgM antibody to B. burgdorferi peak between the third and sixth week after disease onset. The specific IgG response develops gradually over months, with response to an increasing array of at least 12 spirochetal polypeptides and maximal expansion during the period of 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), suggesting that the spirochete may have been present in or around blood vessels.
Despite the innate and adaptive immune responses, B. burgdorferi may sometimes survive in certain sites. The ability of the spirochete to downregulate the expression of surface-exposed protein antigens is one important mechanism of immune evasion. In addition, during disseminated infection, a surface-exposed lipoprotein called VlsE undergoes extensive antigenic variation. However, the organism does not have mechanisms that help to protect it from antibiotic therapy. For example, B. burgdorferi has only been seen extracellularly in affected tissues; it has not been shown to “hide out” in intracellular locations, thereby evading antibiotic exposure.
Early Infection: Stage 1 (Localized Infection)
After an incubation period of 3 to 32 days, EM, which occurs at the site of the tick bite, usually begins as a red macule or papule that expands slowly to form a large annular lesion. As the lesion increases in size, it often develops a bright red outer border and partial central clearing. Because of the small size of ixodid ticks, most patients do not remember the preceding tick bite. 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. In Europe, EM is often an indolent localized infection of the skin; in contrast, in the United States, this lesion is associated with more intense inflammation and signs that often suggest dissemination of the spirochete.
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, mononeuritis multiplex, cerebellar ataxia, or myelitis—alone or in various combinations. In the United States, the usual pattern consists of fluctuating symptoms of meningitis accompanied by facial palsy and peripheral radiculoneuropathy. Lymphocytic pleocytosis (~100 cells per 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 (called meningopolyneuritis or Bannwarth's syndrome), but meningeal or encephalitic signs are frequently absent. In children, the optic nerve may be affected because of inflammation or increased intracranial pressure, which may lead to blindness. 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 pancarditis. Cardiac involvement usually lasts for only a few weeks but may recur. 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 to months in a given joint. Small joints and 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—becomes chronic and may lead to erosion of cartilage and bone. These patients have a higher frequency of the class II major histocompatibility complex alleles associated with rheumatoid arthritis, particularly HLA-DRBI*0401 or *0101 alleles, than patients with brief Lyme arthritis. Moreover, they may have persistent arthritis for months or even several years after the apparent eradication of spirochetes from the joints with antibiotic therapy. In these genetically susceptible individuals, it has been postulated that autoimmunity may develop within the proinflammatory milieu of the joints because of molecular mimicry between a dominant T-cell epitope of OspA and a similar sequence in a human protein.
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 less common, chronic neurologic involvement may also become apparent months or years after the onset of infection, sometimes following long periods of latent infection. The most common form of chronic central nervous system involvement is subtle encephalopathy affecting memory, mood, or sleep and often accompanied by 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 with 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 lesions in the periventricular white matter. The prolonged course of chronic neuroborreliosis following periods of latent infection is reminiscent of tertiary neurosyphilis.Acrodermatitis chronica atrophicans, the late skin manifestation of the disorder, has been associated primarily with B. afzelii infection in Europe and Asia. It has been observed mostly 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 culture of B. burgdorferi in Barbour-Stoenner-Kelly (BSK) medium permits definitive diagnosis, but this complex method has been used only in research studies. Moreover, with a few exceptions, positive cultures have been obtained only early in the illness—primarily from biopsy samples of EM skin lesions, less often from plasma samples, and occasionally from CSF samples. Later in the infection, polymerase chain reaction (PCR) is greatly superior to culture for the detection of B. burgdorferi DNA in joint fluid, and this has been the major use for PCR testing in Lyme disease. In one study, B. burgdorferi DNA was detected by PCR in synovial fluid samples from 75 (85%) of 88 patients and in none of 64 control samples. However, the sensitivity of PCR determinations in CSF from patients with neuroborreliosis has been much lower. 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, which must be carefully controlled to prevent contamination, is not routinely available.
Because of the problems associated with direct detection of B. burgdorferi, Lyme disease is usually diagnosed by the recognition of a characteristic clinical picture with serologic confirmation. Although serologic testing may yield negative results during the first several weeks of infection, most 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, about 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. Conversely, in rare instances, patients who receive inadequate antibiotic therapy during the first several weeks of infection may subsequently develop subtle joint or neurologic symptoms but are seronegative. The important point is that seronegative Lyme disease is usually a mild, attenuated illness that responds well to standard courses of antibiotic therapy. According to an algorithm published by the American College of Physicians (Table 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.
TABLE 1 Algorithm for Testing for and Treating Lyme Disease
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 month of infection, both IgM and IgG responses to the spirochete should be determined, preferably in both acute- and convalescent-phase serum samples. Approximately 20 to 30% of patients have a positive response detectable in acute-phase samples, whereas about 70 to 80% have a positive response during convalescence (2 to 4 weeks later). After 1 month 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 95% to 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 >1 month's 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 the 23- and 41-kDa bands may still represent a false-positive result. 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, there is less expansion of the antibody response, and no single set of criteria for the interpretation of immunoblots results in high levels of sensitivity and specificity in all countries.
Several second-generation tests that use recombinant spirochetal proteins or synthetic peptides have shown promising results. For example, an IgG ELISA employing a 26-mer peptide from invariant region 6 (IR6) of the VlsE lipoprotein has a sensitivity and a specificity similar to those achieved with the IgM and IgG two-test approach using sonicated whole spirochetes. However, the IR6 ELISA has a limitation similar to that affecting standard serology, in that a positive test result does not distinguish clearly between active and past infection. The IR6 ELISA may be of value with regard to European as well as American strains of the spirochete.
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 southeastern United States, an EM-like skin lesion, sometimes with mild systemic symptoms, may be associated with Amblyomma americanum tick bites, but the cause of this illness has not yet been identified.
In the United States, I. scapularis ticks may transmit not only B. burgdorferi but also Babesia microti, a red blood cell parasite, or Anaplasma phagocytophila, the agent of human anaplasmosis (formerly called the agent of human granulocytotropic ehrlichiosis; . Although babesiosis and anaplasmosis are most often asymptomatic, infection with any of these three agents may cause nonspecific systemic symptoms, and coinfected 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 coinfection. Anaplasmosis may cause leukopenia or thrombocytopenia, and babesiosis may cause thrombocytopenia or (in severe cases) hemolytic anemia. However, IgM serologic responses may confuse the diagnosis. For example, A. phagocytophila may elicit a positive IgM response to B. burgdorferi. The frequency of coinfection in different studies has been variable. In one prospective study, 4% of patients with EM had evidence of coinfection.
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, facial palsy without EM may be the presenting manifestation of Lyme disease. In such cases, both the IgM and IgG responses to the spirochete are usually positive. The most common infectious agents that cause
facial palsy are herpes simplex virus type 1 and varicella-zoster virus (Ramsay-Hunt syndrome;.
Later in the infection, oligoarticular Lyme arthritis most resembles reactive arthritis in an adult or the pauciarticular form of juvenile rheumatoid arthritis in a child. Patients with Lyme arthritis usually have the highest IgG antibody responses seen in the infection, with reactivity to many spirochetal proteins.
The most common problem in diagnosis is to mistake Lyme disease for chronic fatigue syndrome 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. Compared with Lyme disease, chronic fatigue syndrome or fibromyalgia tends to produce more generalized and disabling symptoms, including marked fatigue, severe headache, diffuse musculoskeletal pain, multiple symmetric tender points in characteristic locations, pain and stiffness in many joints, diffuse dysesthesia, difficulty with concentration, and sleep disturbances. Patients with chronic fatigue syndrome or fibromyalgia lack evidence of joint inflammation; they have normal results in neurologic tests; and they usually have a greater degree of anxiety and depression than patients with chronic neuroborreliosis.
As outlined in the algorithm, the various manifestations of Lyme disease can usually be treated successfully with orally administered antibiotics; the exceptions are objective neurologic abnormalities and third-degree atrioventricular heart block, which seem to require intravenous therapy. For early Lyme disease, doxycycline is effective in men and in nonpregnant women. An advantage of this regimen is that it is also effective against A. phagocytophila, which is transmitted by the same tick that transmits the Lyme disease agent. Amoxicillin, cefuroxime axetil, and erythromycin or its congeners are second-, third-, and fourth-choice alternatives, respectively. In children, amoxicillin is effective (not more than 2 g/d); in cases of penicillin allergy, cefuroxime axetil or erythromycin may be used. In contrast to second- or third-generation cephalosporin antibiotics, first-generation cephalosporins, such as cephalexin, are not effective. For patients with infection localized to the skin, a 14-day course of therapy is generally sufficient; in contrast, for patients with disseminated infection, a 21-day course is recommended. Approximately 15% of patients experience a Jarisch-Herxheimer-like reaction during the first 24 h of therapy. In multicenter studies, more than 90% of patients whose early Lyme disease was treated with these regimens had satisfactory outcomes. Although some patients reported symptoms after treatment, objective evidence of persistent infection or relapse was rare, and re-treatment was usually unnecessary.
One of these oral antibiotic regimens, when given for 30 to 60 days, or intravenous ceftriaxone, given for 14 to 28 days, is effective for the treatment of Lyme arthritis. Oral therapy is easier to administer, is associated with fewer side effects, and is considerably less expensive. However, the response to oral therapy may be slower than that to intravenous therapy, and some patients given oral therapy have subsequently developed overt neuroborreliosis, which may require intravenous therapy for a successful outcome. In the small percentage of patients with arthritis in whom arthritic symptoms persist for months or even years after the apparent eradication of spirochetes from the joints with antimicrobial therapy, treatment with anti-inflammatory agents or synovectomy may be successful.
For objective neurologic abnormalities (with the possible exception of facial palsy alone), parenteral antibiotic therapy seems to be necessary. Intravenous ceftriaxone, given for 14 to 28 days, is most commonly used for this purpose, but intravenous cefotaxime or intravenous penicillin G for the same duration may also be effective. In patients with high-degree atrioventricular block or a PR interval of >0.3 s, intravenous therapy for at least part of the course and cardiac monitoring are recommended, but the insertion of a permanent pacemaker is not necessary.
It is unclear how and whether asymptomatic infection should be treated, but patients with such infection are often given a course of oral antibiotics. Because maternal-fetal transmission of B. burgdorferi seems to occur rarely, if at all, standard therapy for the manifestations of the illness is recommended for pregnant women. Long-term persistence of B. burgdorferi has not been documented in any large series of patients after treatment with currently recommended regimens. Therefore, there is no indication for multiple, repeated antibiotic courses in the treatment of Lyme disease.
After appropriately treated Lyme disease, a small percentage of patients continue to have subjective symptoms, primarily musculoskeletal pain, neurocognitive difficulties, or fatigue. This so-called chronic Lyme disease or post–Lyme disease syndrome is a disabling condition that is similar to chronic fatigue syndrome or fibromyalgia. In a large study, one group of patients with post–Lyme disease syndrome received intravenous ceftriaxone for 30 days followed by oral doxycycline for 60 days, while another group received intravenous and oral placebo preparations for the same durations. No significant differences were found between groups in the numbers of patients reporting that their symptoms had improved, become worse, or stayed the same. Such patients are best treated for the relief of symptoms rather than with prolonged courses of antibiotics.
The risk of infection with B. burgdorferi after a recognized tick bite is so low that antibiotic prophylaxis is not routinely indicated. However, if an attached, engorged I. scapularis nymph is found or if follow-up is anticipated to be difficult, a single 200-mg dose of doxycycline, which effectively prevents Lyme disease when given within 72 h after the tick bite, may be administered.
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 (such as those with Lyme arthritis) have protective immunity for a period of years and do not 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.