Chapter 75
Lyme Disease
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Lyme disease is the most common vector-associated disease in the United States. It was described as a separate entity in 1977, when Steere and coworkers evaluated a cluster of children in Lyme, Connecticut, who were thought to have juvenile rheumatoid arthritis.1 Shortly thereafter it became apparent that Lyme disease was a multisystem disease that affected the skin, nervous system, heart, and joints.2 The identification of erythema migrans as the typical dermatologic manifestation of the illness and the rural setting of the disease clusters suggested that the disorder was transmitted by an arthropod.3 This lesion, which begins as an erythematous papule that expands to form a red ring, was first described by Afzelius in 1921. Certain Ixodes ticks were implicated as vectors of the disease by epidemiologic studies of patients with erythema migrans.4–6 In 1982, Burgdorfer and Barbour isolated the spirochete, now called Borrelia burgdorferi,7 from Ixodes scapularis ticks.8 The patients' immune responses were linked with this organism when the spirochete was isolated from patients with Lyme disease in the United States9,10 and from those with erythema migrans, Bannwarth's syndrome (radicular pain, preceded in a few cases by erythema, followed by chronic lymphocytic meningitis and sometimes cranial or peripheral neuritis), or acrodermatitis in Europe.11–13

This chapter reviews the epidemiology, established animal models, and genetic risk factors of borreliosis and summarizes the clinical features, laboratory diagnosis, treatment, and prevention of the disease.

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Spirochetes are gram-negative bacteria, slender and motile, with 3 to 30 uneven coils. They are coiled in a helical shape with one or more complete turns.14,15 The Borrelia species are microaerophilic, fastidious bacteria. They, along with leptospira and treponema, belong to the eubacterial phylum of spirochetes.16 The Borrelia species, like all other spirochetes, have a protoplasmic cylinder encased by a cell membrane, a flagellum, and finally an outer membrane that is loosely associated with the underlying structures.16 The entire outer membrane can move to one end of the cylinder, a phenomenon that may be important in cellular adherence called capping or patching.17 B. burgdorferi is the longest (20 to 30 μm) and narrowest (0.2 to 0.3 μm) of the Borrelia species and has the fewest flagella (7 to 11).18 It has a ratio of guanine to cytosine of approximately 1:3, and it is 31% to 59% DNA homologous with other borrelia.19 Only a few of the 30 different proteins that make up B. burgdorferi have properties that are currently understood.20,21 Two major basic proteins, called outer surface protein A (30 to 32 kd)17,22 and outer surface protein B (34 to 36 kd),23 and a 66-kd polypeptide24 are thought to be located on the outer membrane. The 41-kd antigen located on the flagellum is similar to flagellar antigens of other spirochetes,25 and the 58- or 60-kd antigen appears to be a heat-shock protein that is cross-reactive with an equivalent antigen (58 to 65 kd) in a wide range of bacteria.26 The cell wall of B. burgdorferi was found to contain a lipopolysaccharide with endotoxin-like properties, similar to gram-negative polysaccharide, in one study27 but not in another.28

The outer membrane of B. burgdorferi is unique in that the genes encoding it are located on plasmids. This may be advantageous to the organism in making antigenic changes in these proteins.16 All the isolates of B. burgdorferi examined have had four to nine pieces of extrachromosomal plasmid DNA,29,30 including the superficial coiled variety and an unusual type of linear plasmid that has not been found in other prokaryotic organisms.30 The function of only one plasmid, a 49-kb linear plasmid, has been clearly delineated. It has been cloned and shown to produce the two chief outer surface proteins of the spirochete, A and B.31,32 The two proteins may vary in their molecular weights and reactivity with monoclonal antibodies in different isolates or from different passages of the same isolate.22,33 This in vitro observation, along with the observation that outer surface protein B may not be produced in culture,22,34 suggests that the outer membrane of the organism undergoes antigenic variation. The extent of variation is minor compared with that in relapsing-fever borrelia. The loss of infectivity of isolates after passage has been correlated with the loss of particular plasmids in culture,22,35 suggesting that the plasmids may code for proteins that are important in pathogenicity.

Borrelia species grow best at 33°C in a complex liquid medium called Barbour-Stoenner-Kelly medium,36 although B. burgdorferi can grow in colonies when this medium is solidified with 1.3% agarose.37 Borrelia grow slowly compared with most bacteria. Each spirochete grows in length for 12 to 24 hours before dividing into two cells.36 Although a primary isolate of this spirochete is easily obtained from ticks, it is difficult to obtain from patients.9,10 After 10 to 15 passages, B. burgdorferi loses its pathogenicity in culture and the organisms are no longer infectious.33

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Borrelia burgdorferi is transmitted by certain Ixodes ticks6,38–41 and possibly by biting flies.42–44 Ixodes ticks that are part of the Ixodes ricinus complex include Ixodes scapularis in the northeastern and midwestern United States,6,38 Ixodes pacificus in the western United States,39 Ixodes ricinus in Europe,40 and Ixodes persulcatus in Asia.41 A number of ixodid ticks are found in Australia; however, the vector of infection has not yet been identified.

Ticks of the I. ricinus complex go through three stages during their 2-year life cycle: the larval, nymph, and adult stage. They feed once during each of the three stages; larval ticks take one blood meal in late summer, nymphs feed during the following spring and early summer, and adults feed during that autumn.45 The preferred host for both the larval and nymph stages of I. scapularis in the United States is the white-footed mouse, Peromyscus leucopus.38 It is critical that the tick, in both of its immature stages, feed on the same host because the life cycle of the spirochete depends on horizontal transmission. B. burgdorferi is transmitted from infected nymphs to mice in early summer and from infected mice to larvae in late summer. The larvae then molt to become infected nymphs that begin the cycle in the following year.46 The white-footed mice are tolerant to infection with B. burgdorferi and are capable of remaining spirochetemic throughout the summer without an inflammatory response.38 The life cycle of the larval and nymph stages is as follows: the tick feeds on the infected mouse, the spirochetes remain in the midgut of the tick until the following year, and then they develop into nymphs. The tick attaches itself to another host, and the nymphs migrate to the tick's salivary glands and are injected with its saliva as it feeds.47,48 The tick must remain attached for 24 hours or more before transmission occurs.49

The preferred host for I. scapularis's adult stage is the white-tailed deer.50 The deer are not involved in the life cycle of the spirochete but are probably critical to the survival of the ticks.51 If the deer are withdrawn from the life cycle, the ticks may adapt and survive on other animal hosts.51 Clinical Lyme disease is not known to occur in wild animals, although it does occur in domestic animals, including dogs,52 horses,53–55 and cattle.55,56 Lyme disease may occur even in urban areas where there are parks with trees. In Bridgeport, Connecticut, 28% of deer were found to be infected with adult female ticks.57

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The Syrian hamster58,59 has been shown to be susceptible to infection by human and tick isolates of B. burgdorferi. At least 91% of Syrian hamsters had one or more culture-positive organs when infected with 108 spirochetes by intraperitoneal injection.58 In this study, a spirochetemia was present for the first 6 days of infection. At 14 days postinfection, when spirochetemia could not be detected, spirochetes were isolated from the spleen, kidney, liver, testes, brain, and 45% of homogenized eyes. Spirochetes were isolated from the eyes and kidney of one animal 52 days postinfection, suggesting that these organisms may cause a persistent multiorgan infection. In another study, seven hamsters were inoculated intraperitoneally with B. burgdorferi and examined by both cultural and histologic techniques at 1 to 9 months postinfection.59 The eyes of four of the seven hamsters were culture-positive for spirochetes 14 days after inoculation. Spirochetes were noted in the vitreous of two of the seven hamsters by histology. More spirochetes were found in the eye than in the liver, spleen, or kidneys. No pathologic tissue changes were noted in the globes, except for occasional mononuclear phagocytic cells in the vitreous. The only pathologic tissue changes noted in this study were a rare lymphocytic focus in the liver of one hamster and a chronic portal triaditis in another.

The lack of morphologic organ damage and severe inflammation in these experimentally infected hamsters contrasts with histopathologic alterations seen in infected human tissue.60 The spirochete has been demonstrated in the vitreous of a patient with a panophthalmitis.61 It is possible that the lack of a cellular response and an intermittent spirochetemia in small animals may be factors in the continuing presence and maintenance of the spirochete in its natural habitat.59

Many other animal models of Lyme disease have been developed, including gerbil, guinea pig, dog, and rat. The animal models that have been studied the most, however, are the mouse, hamster, and monkey models.62 Rhesus monkeys inoculated with B. burgdorferi have an illness similar to human Lyme disease. Pachner and colleagues have found elevated blood and spinal fluid levels of interleukin-6 in infected monkeys.63,64

Animal models have been used particularly to study the pathogenesis of Lyme neuroborreliosis.64 The adult Rhesus monkey has developed erythema migrans within a few weeks after intradermal injection with the N40Br strain of B. burgdorferi.64 Anti-B. burgdorferi antibodies may develop within the first few weeks and in the third and fourth week after the injection. Spirochete DNA can be detected in the blood using polymerase chain reaction (PCR). Soon after, the animals develop spirochetal invasion of the central nervous system with 50 to 300 white cells and antibodies against B. burgdorferi in the spinal fluid. These studies support the concept that spirochetemia and invasion of the spinal fluid occur at an early stage in Lyme disease, even though they may be clinically asymptomatic. It also adds support to the theory that B. burgdorferi can cause latent infection in both central and peripheral nervous tissue.65

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HLA specificities encoded by certain class II, d-locus alleles of the major histocompatibility complex are associated with susceptibility to a number of diseases with autoimmune features. The class II molecules are expressed primarily on B cells and macrophages that bind and present antigen to T-helper cells, which then initiate an immune response against these antigens. The development of autoimmune responses can influence genetic variations in the structure of class II molecules by affecting the composition of the T-cell sequencing in the development of self-tolerance during thymic maturation or by determining the type and manner of antigen binding.

Several studies have found an association between HLA-DR2 and DR4 and certain manifestations of Lyme disease.66–68 In a study of 32 patients with meningopolyneuritis,66 56% were HLA-DR2-positive and 46% were HLA-DR4-positive. In a study of 22 patients with acrodermatitis,67 52% had HLA-DR2.69,70 A recently described late neurologic manifestation of Lyme disease, borrelial encephalomyelitis,71 may resemble multiple sclerosis. Multiple sclerosis is also associated with an increased frequency of HLA-DR2.72 It is still uncertain whether encephalomyelitis has an immunogenetic basis.

Steere and coworkers demonstrated an association of chronic Lyme arthritis with HLA-DR4 and HLA-DR2 alleles.68 Of 80 patients with Lyme arthritis, 57% of those with chronic arthritis were associated with this histocompatibility antigen complex. Only 23% of those with arthritis of moderate duration (6 to 11 months) and only 9% of those with arthritis of short duration (1 to 5 months) had this specificity. After the HLA-DR4-positive patients were excluded from each group, a secondary association was noted with HLA-DR2 in 75% of the remaining patients with chronic arthritis, 50% of those with arthritis of moderate duration, and only 20% of those with arthritis of short duration.

The presence of HLA-DR4 in patients with arthritis was associated with a lack of response to antibiotic therapy. The frequency of treatment failure was not significantly increased in patients with HLA-DR2 specificity even after the exclusion of HLA-DR4-positive patients from the analysis. Thus, it is possible that the molecular basis of susceptibility may not be the same for both specificities.

On the basis of their results, Steere and colleagues postulated alternative mechanisms for the development of chronic Lyme arthritis in genetically susceptible persons.68 The class II molecules of the HLA-DR4 or DR2 haplotype may combine with a distinct arthritogenic epitope of B. burgdorferi that has molecular mimicry with a component of the host. An autoimmune response may result from the interaction of T-helper cells with the major histocompatibility complex that continues for some time after the organism has been killed. An alternative mechanism is a result of thymic selection, whereby the class II molecules may choose potentially autoreactive T-cell clones that can be triggered by a spirochetal peptide that functions as a superantigen.72 Conversely, these patients may have deleted T-cell clones necessary for the elimination of the spirochete during thymic maturation with subsequent persistent spirochetal (12 to 48 months in duration) infection, accompanied by an ineffective immune response that causes injury to the host.

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Lyme disease is classified in three stages:
  1. Early localized disease, where early skin lesions develop and are associated with nonspecific systemic signs and symptoms
  2. Early disseminated disease, in which other skin lesions, cardiac dysfunction, and neurologic disturbances, or a combination of these, can develop, usually occurring about 10 months after the tick bite
  3. Chronic disseminated disease, in which arthritis and late neurologic findings may predominate.74 Late infection may begin months to years after the tick bite and may occur in the absence of any prior features of Lyme disease.75


Early localized disease is characterized by a rash known as erythema migrans, which occurs in 50% to 75% of patients. Only about 14% to 30% recall the tick bite.76 Erythema migrans starts usually as an erythematous macule or papule at the site of the bite, with the lesion typically developing 3 days to 1 month after the bite and expanding in a circular fashion, often increasing up to 20 to 30 cm in diameter. Erythema migrans rash may occur anywhere on the body except the palms, soles, and mucous membranes. Most lesions clear within 1 to 2 months, often leaving some minimal hyperpigmentation. Some patients may develop multiple lesions. Erythema migrans is the best clinical marker of the disease.77

In association with erythema migrans, patients often develop fatigue, malaise, lethargy, fever, chills, arthralgias, myalgias, and regional adenopathy.74 Neurologic manifestations include headache, neck stiffness, mild confusion, and lethargy.76,78 Signs and symptoms of early localized disease clear within 3 to 4 weeks. Ocular manifestations of early localized Lyme disease are limited. Conjunctivitis has been reported in about 10% of patients.74 Subconjunctival hemorrhage and a mild self-limiting episcleritis have also been reported in early Lyme disease.79


Early disseminated disease begins 1 to 6 months after early localized infection with cutaneous, cardiac, and neurologic manifestations. Carditis occurs in 8% to 10% of untreated patients, with conduction defects and myocardial myopathy. About 10% to 12% of patients have meningitis, encephalitis, cranial neuropathy, most often facial (unilateral or bilateral), peripheral neuropathy, radiculopathy, or myelitis. The triad of cranial neuritis, particularly facial palsy, radiculoneuritis, and meningitis is classic for Lyme disease. The radiculopathies are often asymmetric and are characterized by mixed motor and sensory loss throughout the body. The shoulder girdle is the region most commonly affected, producing brachialplexopathy.80 Vallat and associates81 performed electrophysiologic studies of affected extremities that suggested some demyelination of both the proximal and distal nerve segments. Perivascular infiltration of lymphocytes and plasmacytes around epineural blood vessels is present in histologic sections of these lesions. B. burgdorferi has not been seen in these lesions, although IgM antibodies to B. burgdorferi have been shown to bind to normal human axons.82 The cranial and peripheral neuropathies are usually associated with meningitis. The cerebrospinal fluid characteristically has a lymphocytic pleocytosis, with elevated protein and normal glucose levels.83,84

Approximately 60% of patients in the United States have short-lived attacks of asymmetric, oligoarticular arthritis affecting large joints 2 weeks to 2 years after the onset of disease.85 The knee is most commonly involved, with the polymorphonuclear leukocyte being the predominant white cell in the synovial fluid. Migratory pain in tendons, bursae, muscle, and bone86 is not uncommon. A few cases of myositis, osteomyelitis, and panniculitis have been reported.

Intraocular inflammation, such as iridocyclitis or vitritis, can be seen in early disseminated Lyme disease. Pars planitis, vitritis, panophthalmitis,32,39,40 and granulomatous iritis have been seen. Occasionally uveitis is a presenting eye sign of Lyme disease.87 Spirochetes have been isolated from the iris.88 Nummular infiltrates or an interstitial keratitis-like picture can be seen both in early disseminated and chronic disseminated infection.89 Other ocular manifestations include macular edema, choroiditis, optic disc edema, optic neuritis, and optic atrophy.79,90 Their pathogenesis may be either immune-mediated or secondary to active infection or vasculitis. A complete listing of eye findings is shown in Table 1.


TABLE 75-1. Ophthalmic Manifestations of Lyme Disease

Early LocalizedFollicular conjunctivitis
 Subconjunctival hemorrhages
Early Disseminated 
 Anterior SegmentFollicular conjunctivitis
 Nummular keratitis
 Orbital myositis
 Neuro-OphthalmicSeventh nerve palsy
 Sixth nerve palsy
 Optic neuritis
 Optic neuropathy
 Optic atrophy
 Horner's syndrome
 Argyll-Robertson pupil
Late Disease 
 Anterior SegmentInterstitial keratitis
 Nummular keratitis
 Neuro-OphthalmicCortical blindness


Unilateral panendophthalmitis was described by Kaufman and colleagues30,61 in a patient who received an inadequate course of antibiotic therapy. Review of the vitrectomy specimen showed spirochetes in the vitreous by staining. Schubert and associates87 also demonstrated spirochetes in the vitreous of another patient with vitritis secondary to Lyme disease.


The chronic disseminated stage of Lyme disease begins months to years after the tick bite in untreated patients and is characterized by involvement of joints, skin, subcutaneous tissue, and the nervous system.

Chronic arthritis usually affects one or a few large joints, with classically the knees involved most frequently. T lymphocytes appear to play a significant role in the pathogenesis of Lyme arthritis.91 Continual joint inflammation rarely lasts for more than several years, with recurrences decreasing by 10% to 20% each year.92 In severe cases, chronic arthritis may lead to erosion of cartilage and bone.92 B. burgdorferi, which can stimulate the production of interleukin-1,93 has been cultured from synovial fluid.94,95 The synovial fluid also has elevated levels of prostaglandin E2,96 which may cause synovial proliferation and activate collagenase.

Acrodermatitis chronica atrophicans, which has been observed primarily in Europe,75 is the late skin manifestation of Lyme borreliosis. It begins with bluish-red discoloration and swollen skin on an extremity. Inflammation is gradually replaced by atrophy of the skin and underlying subcutaneous tissue. Eventually the skin has a parchmentlike appearance with an underlying visible vascular pattern. Histopathologically, the rete ridges of the epidermis are often lost, with telangiectasias and a mononuclear cell infiltrate seen in the dermis.13 B. burgdorferi has been cultured from these lesions up to 10 years after their onset.13

Chronic neurologic involvement affecting the central and peripheral nervous systems is characterized by a chronic progressive encephalomyelitis, focal encephalitis, organic brain syndrome, psychiatric syndromes, a multiple sclerosis-like picture, peripheral neuropathy, and even stroke.97 Ackermann and coworkers98 described progressive borrelial encephalomyelitis characterized by spastic paraparesis or tetraparesis, ataxia, cognitive impairment, bladder dysfunction, and cranial neuropathy, particularly deficits of the seventh or eighth cranial nerve. Halperin and associates described chronic neurologic syndromes involving the peripheral99 and central100 nervous systems. The syndrome affecting the peripheral nervous system was characterized by paresthesias and electrophysiologic evidence of axonal neuropathy.101 The syndrome involving the central nervous system was manifested by encephalopathy and memory impairment.100 The patients with central involvement usually had intrathecal production of antibodies to B. burgdorferi; those with peripheral nervous system involvement did not. Logigian and colleagues101 defined the chronic neurologic abnormalities in 27 patients with previous signs of Lyme disease and current evidence of immunity to B. burgdorferi. Twenty-four patients (89%) had a mild encephalopathy characterized by memory loss, mood changes, or sleep disturbance, and 19 patients (70%) had polyneuropathy with radicular pain or distal paresthesias. Associated symptoms included fatigue (74%), headache (48%), arthritis (37%), and hearing loss (15%).

The cerebrospinal fluid is almost always abnormal in patients with progressive encephalomyelitis of chronic disseminated Lyme disease, with significant pleocytosis and a moderate increase in protein. Increased concentrations of IgG and occasionally both IgM and IgA are noted. Oligoclonal bands are commonly present.102 Neuroimaging studies may show periventricular and subcortical white matter changes consistent with demyelination.103

The pathogenesis of ophthalmic findings of late disseminated Lyme disease may be secondary to any of the following:

  • Immune complex-mediated inflammatory reaction
  • Vasculitis
  • Autoimmunity secondary to molecular mimicry
  • Inflammatory response to live B. burgdorferi, leading to production of cytokines.104

Ophthalmic manifestations of chronic disseminated disease overlap with those seen in early disseminated disease. They include stromal keratitis,88,105–107 episcleritis,107,108 orbital myositis,109 and cortical blindness.110 Interstitial keratitis can be seen.88,106 The stromal keratitis is characterized by multiple nebular opacities with indistinct borders at varying levels of the stroma. Stromal edema and neovascularization can be present.88,106 Stromal keratitis may occur earlier in the disease than has been reported because patients with stromal keratitis may be asymptomatic. Although B. burgdorferi has not been demonstrated by corneal culture or histologic examination, direct infection cannot be ruled out. Lyme keratitis has been attributed to an immune response because of a demonstrated response to steroids without concomitant antibiotic.106 Unfortunately, there is no good information available in reference to the mechanism and the pathogenesis of late disseminated disease.

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The most commonly used test for detection of Lyme disease is the enzyme-linked immunosorbent assay (ELISA). This test measures the binding of circulating serum antibody to antigen; however, techniques differ. Enzyme marker converts a colorless substrate solution to a colored one and is quantified with a spectral photometer. ELISA is considered more sensitive than the immunofluorescent antibody (IFA), which was initially used. ELISA has been shown to be more sensitive and specific and is more easily automated and standardized.111 IgM usually peaks within about 3 to 6 weeks after the onset of erythema migrans and declines slowly, although it may remain elevated for months to years.111 IgG is often not detectable for the first 4 to 6 months, but levels may then remain elevated for years after clinical remission. Significant interlaboratory variability occurs with both IFA and ELISA.111 A positive test may indicate only exposure to B. burgdorferi, not necessarily an active infection. In hyperendemic areas, up to 8% of persons who live in the region and 15% of outdoor workers may have measurable antibody without infection.112–114

Western blot analysis now is mandatory to confirm all cases in which the ELISA is positive. Laboratory testing is not considered positive for Lyme disease unless a Western blot is positive. The Centers for Disease Control and Prevention recommends a two-step approach. IgM immunoblot is considered positive if two of the following three bands are present: 24 kDa, 39 kDa, and 41 kDa. For IgG to be considered positive, 5 of the following 10 bands need to be present: 18 kDa, 21 kDa, 28 kDa, 30 kDa, 39 kDa, 41 kDa, 45 kDa, 58 kDa, 66 kDa, and 93 kDa.115–117

Because Borrelia and Treponema spirochetes share antigens, false-positive reactions can occur in serologic tests when whole cells or sonicates of B. burgdorferi are used.118 Cross-reactivity with syphilis should not be a problem because both diseases can usually be distinguished by performing Venereal Disease Research Laboratory (VDRL) analysis. False-positive serologic results can also occur in Rocky Mountain spotted fever, autoimmune diseases, and amyotrophic lateral sclerosis.119 Sensitivity and specificity of the ELISA have been improved by using a preparation of the 41-kd flagellar antigen alone,120 a flagellin-enriched preparation,24 or preparations of outer surface proteins.24,121 Western blot analysis can be used to clarify a falsepositive result.122 Patients with a positive ELISA who do not have Lyme disease are likely to have a negative result with Western blot analysis. A positive ELISA and a positive Western blot without current clinical symptoms do not always indicate active Lyme disease. Occasionally a patient may have a positive ELISA and a positive Western blot that may represent previous infection, not a sign of current active infection.

False-negative results frequently occur during the first few weeks of infection. This may be because of the transient immunosuppression occurring soon after the onset of Lyme disease,123 or the low levels of specific anti-B. burgdorferi antibody overlapping the background values of antispirochetal or cross-reacting antibodies found in normal subjects.124 Mertz and c-workers modified the ELISA by including a Treponema reiteri adsorption step that preferentially decreases background activity in normal control serum specimens and enhances the sensitivity of the test from 79% to 88%.125

Methods to diagnose Lyme disease during the first 3 weeks of infection are being investigated. A vigorous T-cell response to B. burgdorferi occurs during the early stage of infection and usually precedes the humoral response. Although this information has been applied clinically by limiting dilution analysis with good result,126 additional experience with this assay is needed to establish its usefulness. B. burgdorferi has been detected in the urine of mice and humans.127 PCR may be a more sensitive way to make the diagnosis; however, it is still considered investigational. PCR is a sensitive means of diagnosis of Lyme disease but unfortunately is not readily available. Problems with PCR include the following:

  • It is labor-intensive.
  • It can be falsely positive secondary to contamination.
  • The test is not standardized.
  • It is expensive.
  • It does not differentiate between DNA from live and dead organisms.65

The role of PCR continues to be evaluated. The diagnosis of Lyme disease should, therefore, be based on clinical history, including symptoms and exposure to tick vector and physical findings, as well as laboratory data.

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Doxycycline or tetracycline is effective treatment for early Lyme disease. Studies have shown that treatment courses for 2 to 3 weeks are as effective as those for 3 to 4 weeks.128,129 Parenteral therapy is usually given to patients with either early disseminated or chronic disseminated stages of the disease, except those with isolated arthritis, who may still respond to oral therapy alone.130 In a prospective randomized multicenter study comparing parenteral ceftriaxone (2 g once daily for 14 days) with oral doxycycline (100 mg twice a day for 21 days) in patients with acute disseminated B. burgdorferi infection without meningitis, it was shown that both treatments were equally effective in preventing late manifestations of disease.131 Extracutaneous manifestations such as cardiac or neurologic ones (other than cranial nerve VII) or arthritis resistant to oral antibiotics are best treated with intravenous ceftriaxone. Oral doxycycline, amoxicillin, tetracycline, cefuroxime, axetil, and erythromycin are the antibiotic choices for treatment of early localized infection. Penicillin may be used but is not superior to amoxicillin. Azithromycin can be used but is less effective than amoxicillin. Tetracycline should not be used in pregnant woman or in children younger than 9 years. Intravenous ceftriaxone, cefotaxime, or penicillin is recommended for late manifestations. Ceftriaxone is the drug of choice with intravenous therapy.132 For most patients with early Lyme disease or Lyme arthritis, intravenous therapy is no more effective than oral therapy, is more likely to lead to serious complications, and is more costly.133

Possible complications from treatment include the Jarisch-Herxheimer reaction,134 which occurs 1 to 2 hours after initial treatment of spirochetal infection.128,129,134 It is characterized by abrupt onset of fever, chills, myalgia, headache, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension. This transient immunologic reaction occurs in about 15% of patients with early disseminated infection.

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The best prevention includes avoiding exposure to ticks and checking for ticks at the end of the day after spending time outdoors. People should wear trousers tucked into socks and long-sleeved shirts. The most commonly used repellents include DEET135–137 (diethyltoluamide), but it is unfortunately short-lasting, can be absorbed through the skin, and has been associated with side effects, including seizures and neurologic symptoms. If a tick is found, it should be removed as quickly as possible because the risk of infection is minimal if tick attachment is less than 24 hours. The tick should be removed by gentle upward traction with tweezers, without twisting.
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Vaccines in combination of OspA of B. burgdorferi have been shown to protect mice from infection, whether delivered by passive transfer of monoclonal antibody or by active immunization using a recombinant vaccine.138 OspA obtained from one strain of B. burgdorferi has been shown to protect against infection by a variety of other strains. Vaccine trials are currently in progress in humans.139
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1. Steere AC, Malawista SE, Snydman DR et al: Lyme arthritis: An epidemic of oligoarticular arthritis in children and adults in three Connecticut communities. Arthritis Rheum 20:7, 1977

2. Steere AC, Malawista SE, Hardin JA et al: Erythema chronicum migrans and Lyme arthritis: The enlarging clinical spectrum. Ann Intern Med 86:685, 1977

3. Steere AC: Lyme disease. N Engl J Med 321:586, 1989

4. Steere AC, Broderick TF, Malawista SE: Erythema chronicum migrans and Lyme arthritis: Epidemiologic evidence for a tick vector. Am J Epidemiol 108:312, 1978

5. Wallis RC, Brown SE, Kloter KO, Main AJ Jr: Erythema chronicum migrans and Lyme arthritis: Field study of ticks. Am J Epidemiol 108:322, 1978

6. Steere AC, Malawista SE: Cases of Lyme disease in the United States: Locations correlated with distribution of Ixodes dammini. Ann Intern Med 91:730, 1979

7. Johnson RC, Schmid GP, Hyde FW et al: Borrelia burgdorferi sp. nov.: Etiologic agent of Lyme disease. Int J Sys Bacteriol 34:496, 1984

8. Burgdorfer W, Barbour AG, Hayes SF et al: Lyme disease: A tick-borne spirochetosis? Science 216:1317, 1982

9. Steere AC, Grodzicki RL, Kornblatt RL et al: The spirochetal etiology of Lyme disease. N Engl J Med 308:733, 1983

10. Benach JL, Bosler EM, Hanrahan JP et al: Spirochetes isolated from the blood of two patients with Lyme disease. N Engl J Med 308:740, 1983

11. Ackerman R, Kabatzki J, Boisten HP et al: Spirochaten Atiologie der Erythema chronicum migrans Krankheit. Dtsch Med Wochenschr 109:92, 1984

12. Preac-Mursic V, Wilske B, Schierz G et al: Repeated isolation of spirochetes from the cerebrospinal fluid of a patient with meningoradiculitis Bannwarth. Eur J Clin Microbiol 3:564, 1984

13. Asbrink E, Hovmark A: Successful cultivation of spirochetes from skin lesions of patients with erythema chronica migrans afzelius and acrodermatitis chronica atrophicans. Acta Pathol Microbiol Immunol Scand 93:161, 1985

14. Reik L Jr: Lyme disease. In Scheld WM, Whitley RJ, Durack DT (eds): Infections of the Central Nervous System, p 657. New York, Raven Press, 1991

15. Reik L Jr: Lyme Disease and the Nervous System. New York, Thieme Medical Publishers, 1991

16. Barbour AG, Hayes SF: Biology of Borrelia species. Microbiol Rev 50:381, 1986

17. Barbour AG, Tessier SL, Todd WJ: Lyme disease spirochetes and Ixodes tick spirochetes share a common surface antigenic determinant defined by a monoclonal antibody. Infect Immun 41:795, 1983

18. Hovind-Hougen K, Asbrink E, Stiernstedt G et al: Ultrastructural differences among spirochetes isolated from patients with Lyme disease and related disorders, and from Ixodes ricinus. Zentralbl Bakteriol Mikrobiol Hyg 263: 103, 1986

19. Hyde FW, Johnson RC: Genetic relationship of Lyme disease spirochetes to Borrelia, Treponema, and Leptospira spp. J Clin Microbiol 20:151, 1984

20. Barbour AG, Burgdorfer W, Grunwaldt E et al: Antibodies of patients with Lyme disease to components of the Ixodes dammini spirochete. J Clin Invest 72:504, 1983

21. Craft JE, Fischer DK, Shimamoto GT et al: Antigens of Borrelia burgdorferi recognized during Lyme disease: Appearance of a new immunoglobulin M response and expansion of the immunoglobulin G response late in the illness. J Clin Invest 78:934, 1986

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