Lyme Disease
Lyme disease is a vector-borne zoonosis caused by Borrelia burgdorferi, which is a thin, spiral, motile, extracellular bacterium belonging to the family Spirochaetaceae. The hallmark of infection is erythema migrans, an annular erythematous skin lesion that usually appears at the site of the tick bite.
History
In 1976, Steere and colleagues noted an association between erythema migrans and a cluster of patients with knee arthritis in Old Lyme, Connecticut; they called this syndrome Lyme arthri-tis.1 In the subsequent decade, these investigators defined the multisystem nature of the disease and modified its name to Lyme disease.
Isolation of the Lyme disease pathogen was not accomplished until 1981, when Burgdorfer and colleagues demonstrated a new spirochete in Ixodes ticks collected on Shelter Island, New York.2 In 1982, spirochetes were identified in the midgut of the adult form of the deer tick I. dammini, and were named B. burgdorferi. Conclusive evidence that B. burgdorferi causes Lyme disease came in 1984, when B. burgdorferi was cultured from the blood of patients with erythema migrans, from the rash itself, and from the cerebrospinal fluid of a patient with meningoencephalitis and a history of erythema migrans.
Epidemiology
In the United States, surveillance for Lyme disease was begun by the Centers for Disease Control and Prevention (CDC) in 1982. Since that time, the number of reported cases has increased dramatically; nevertheless, as many as 90% of Lyme disease cases may be going unreported. Lyme disease has been reported in 49 of the 50 states, but most cases occur in the Northeast, the Midwest, and northern California. Nine states account for more than 90% of the nationally reported cases, with Connecticut leading the group. The other states are Rhode Island, New York, Pennsylvania, Delaware, New Jersey, Maryland, Massachusetts, and Wisconsin.3,4 The rising incidence of Lyme disease in the United States may be explained by multiple factors, including an increase in the numbers of ixodid ticks, the expansion of residential areas into previously rural woodlands (habitats favored by ixodid ticks and their hosts), an exploding deer population, and increased recognition.
The Lyme disease pathogen, B. burgdorferi, is maintained in and transmitted by ticks of the I. ricinus complex, including I. scapularis in the northeast and north central United States [see Figure 1], I. pacificus on the West Coast of the United States, I. ricinus in Europe, and I. persulcatus in Asia.5 In Europe, three genospecies of the B. burgdorferi sensu lato complex are pathogenic, including B. burgdorferi sensu stricto, B. garinii, and B. afzelii. B. burgdorferi is the only pathogenic species in North America. The varying relative distribution of these genospecies from region to region throughout Europe and Asia may account for the relative variability of disease syndromes associated with Lyme disease. In the United States, most patients have symptomatic illness,6,7 whereas in Europe most patients are asymptomatic.
In field studies in Connecticut and New York, B. burgdorferi has been found in 10% to 50% of nymphal and adult I. scapularis ticks.8,9 Although B. burgdorferi has been demonstrated in mosquitoes and deer flies, only ticks of the I. ricinus complex seem to be important in the transmission of the spirochete to humans.10 An enzootic cycle of infection is maintained through passage of B. burgdorferi back and forth between ticks and their hosts. Infected nymphal ticks transmit B. burgdorferi to mice, which serve as a reservoir from which uninfected larvae may acquire infecting organisms. In this manner, a high rate of infection can be maintained in the tick population when the organism, ticks, mice, and deer are all present in the environment.
In temperate climatic zones, the seasonal variation of onset of Lyme disease is explained by the ecology of the predominant tick vectors. The ixodid tick has a three-stage life cycle (larva, nymph, and adult) that spans 2 years. Larvae hatch from fertilized eggs in late spring and feed once for 2 or more days in midsummer. Preferred hosts include a broad range of small mammals. The next spring they molt into nymphs and feed again for 3 or 4 days, with the same host range. After this second blood meal, the nymphs molt into adults. Adult I. scapularis organisms have a narrower host range, with a preference for deer. Mating occurs on deer, and the female deposits her eggs and the cycle begins anew.11 During their 2-year life cycle, ticks typically feed once during each of the three stages, usually the late summer for larval ticks, the following spring for nymphs, and autumn for the adults. I. scapularis nymphs appear to be the most important vector for transmission of B. burgdorferi. According to laboratory studies, a minimum of 36 to 48 hours of attachment of the tick is required for transmission. In the United States, most cases involving B. burgdorferi occur between May and August, which corresponds with increased outdoor human and nymphal tick activity.
Figure 1 Ixodes scapularis, also known as deer tick or black-legged tick, is the vector of Lyme disease. Adult ticks are approximately 2.5 mm in size—about the size of a sesame seed.
The risk of infection in a given area depends largely on the density of the tick population, as well as on their feeding habits and animal hosts, which have evolved differently in different locations. In the northeastern and north central United States, I. scapularis ticks are abundant, and a highly efficient cycle of B. burgdorferi transmission occurs between immature larval and nymphal I. scapularis ticks and white-footed mice. This results in high rates of infection in nymphal ticks and a high frequency of Lyme disease in humans during the late spring and summer months.12,13 The proliferation of deer, which are the preferred host of the adult tick, was a major factor in the emergence of epidemic Lyme disease in the northeastern United States during the late 20th century.
I. scapularis and other ticks in the I. ricinus complex may transmit multiple pathogens. I. scapularis is also a vector for Anaplasma phagocytophila, which causes human granulocytic ehrlichiosis [see 7:XVII Infections Due to Rickettsia, Ehrlichia, and Coxiella] and Babesia microti, which causes babesiosis [see 7:XXX1V Protozoan Infections]. The proportion of I. scapularis or I. ricinus ticks coin-fected with both B. burgdorferi and A. phagocytophila is generally low, ranging from less than 1% to 6% in six geographic areas. A higher prevalence of tick coinfection (26%) has been reported in Westchester County, New York. The proportion of 1xodes ticks coinfected with B. burgdorferi and Babesia microti has ranged from 2% in New Jersey to 19% on Nantucket Island, Massachusetts. In patients with a confirmed tick-borne infection, coinfection rates as high as 39% have been reported. The most commonly recognized coinfection in most of the eastern United States is Lyme disease and babesiosis, accounting for approximately 80% of coinfections.14
Clinical manifestations
Lyme disease is a progressive infectious disease with a wide array of clinical manifestations. In general, three stages of the illness can be distinguished: early localized disease, early disseminated disease, and persisting late disease.
Infection begins locally in the skin after a feeding tick inoculates B. burgdorferi. In most persons, the initial sign of infection is the development of erythema migrans.15 Even at this early phase of infection, the clinical expression of the disease is highly variable. Some persons are relatively asymptomatic, whereas others experience fever, arthralgias, myalgias, conjunctivitis, meningis-mus, or multifocal erythema migrans, and still others develop more dramatic signs of infection, including acute meningitis, myocarditis with or without conduction block, hepatitis, myosi-tis, or frank arthritis. Up to 50% of infected persons will progress to symptomatic late disease if not treated during the acute phase of the infection. In the chronic phase of the illness, localized inflammatory processes may occur in one or more organ systems, particularly the nervous system and the musculoskeletal system.
Erythema Migrans
The most common manifestation of early localized Lyme disease is erythema migrans, which occurs in up to 85% of patients and develops 3 to 30 days (typically within the first 7 to 10 days) after the bite. The lesion generally appears at the site of a tick bite and is frequently located around the knees, in the axilla, or in the groin.
Erythema migrans usually begins as a red macule or papule, which expands over the course of days to weeks, presumably as the spirochetes spread centrifugally through the skin [see Figure 2]. Secondary cutaneous lesions may develop from hematogenous dissemination of spirochetes. Local symptoms include pruritus, tenderness, or paresthesias but are generally rare or absent in secondary lesions. Erythema migrans may also appear as a target lesion with variable degrees of central clearing and occasionally with vesicular or necrotic areas in the center.
In an observational cohort study in 10 endemic states, 118 patients with microbiologically confirmed erythema migrans presented a median of 3 days after symptom onset. Early erythema migrans commonly had homogeneous or central redness rather than peripheral erythema with partial central clearing. The most common associated symptoms were low-grade fever, headache, neck stiffness, arthralgia, myalgia, or fatigue.17 Subsequent episodes of erythema migrans have been reported in patients who received appropriate antimicrobial therapy for an initial episode, whereas primary failure of antibiotics is rare, occurring in only about 0.14% of patients.18
Lymphocytoma
Borrelial lymphocytoma is an uncommon early manifestation of Lyme disease (occurring in approximately 5% of cases), occurring more often in children than in adults.19 It is a tumorlike nodule that typically appears on the ear lobe, nipple, or scrotum and is characterized by a dense lymphocytic infiltrate in the dermis or subcutaneous tissue.20 Borrelial lymphocytoma is usually caused by B. garinii and B. afzelii and is seen more frequently in Europe than in the United States. The lymphocytoma may occur with other manifestations of infection, such as meningitis, choroiditis, or arthritis. Histopathologically, lymphocytoma may be difficult to differentiate from lymphoma. IgG or IgM antibodies against B. burgdorferi are found in the serum of 80% of all patients with borrelial lymphocytoma. Direct detection of B. burg-dorferi or specific DNA in lesional skin by culture or polymerase chain reaction is helpful to the diagnosis. In a study from Slovenia, 36 cases of borrelial lymphocytoma were detected during the period 1986 to 1990; patients were treated with antibiotic therapy, and all had complete recovery within an average of 3 weeks.
Acrodermatitis Chronica Atrophicans
In European patients, especially elderly women with B. afzelii infection, a chronic, slowly progressive skin condition called acrodermatitis chronica atrophicans may develop on sun-ex-posed acral surfaces.
Figure 2 An erythema migrans lesion has enlarged over several days and now has a red border with clearing in the center.
The organism has been cultured from such lesions as long as 10 years after the onset of the disease.22 These lesions may be preceded by erythema migrans and may represent a late or chronic stage of infection. Early lesions have ery-thematous nodules or plaques with central clearing and involve the extensor areas of the extremities or joints. Later lesions become atrophic and poikilodermatous, resembling scleroderma or lichen sclerosus et atrophicus.
Carditis
Within several weeks after the onset of Lyme disease, about 4% to 10% of untreated patients develop acute cardiac involvement—most commonly, fluctuating degrees of atrioventricular block; occasionally, acute myopericarditis or mild left ventricular dysfunction; and rarely, cardiomegaly or fatal pancarditis.23 Diffuse T wave changes, ST segment depression, and arrhythmias also are frequently observed. Patients may complain of dizziness, palpitations, dyspnea, chest pain, or syncope.24,25 Although temporary pacing is frequently required for complete heart block, permanent pacing is rarely needed.26 Recovery from the acute cardiac manifestations of Lyme disease is usually complete.
In Europe, B. burgdorferi has been isolated from endomyocar-dial biopsy samples from several patients with chronic dilated cardiomyopathy.27,28 However, this complication has not been observed in the United States.29 A study from the Netherlands noted improvement in left ventricular ejection fraction in eight of nine B. burgdorferi-seropositive patients with idiopathic dilated cardiomyopathy who were treated with antibiotics.30 Further studies are warranted to clarify the role of B. burgdorferi in acute and chronic heart failure.
Musculoskeletal Features
In the United States, arthritis is the predominant manifestation of disseminated B. burgdorferi infection, with about 60% of untreated patients developing joint manifestations, usually weeks to years after the initial infection. Months after the onset of illness, patients begin to have intermittent episodes of joint swelling and pain—primarily in the large joints and, occasionally, in the temporomandibular joint.23 Musculoskeletal features include arthralgia; intermittent episodes of migratory arthritis, usually monoarthritis or asymmetrical oligoarthritis; and chronic arthritis, usually of the knees.31 Patients with Lyme arthritis usually have higher Borrelia-specific antibody titers than patients with any other manifestations of the illness, including late neurologic manifestations.32 In an observational cohort study of 15 patients with Lyme arthritis, fibromyalgia, or both, symptoms of Lyme arthritis resolved with antibiotic therapy, whereas symptoms of fibromyalgia persisted in 14 of 15 patients treated with antibiotic therapy.33
Although most patients respond favorably to antibiotic therapy, about 10% of adults and fewer than 5% of children with arthritis associated with Lyme disease develop inflammatory joint disease that persists for longer than 1 year, which may eventually lead to joint destruction. In about 10% of patients, particularly those with HLA-DRB1*0401 or related alleles, knee arthritis persists for months or even years.32 Autoimmunity may develop within the inflammatory milieu of affected joints in these patients because of molecular mimicry between an im-munodominant T cell epitope of the outer surface protein A (OspA) of B. burgdorferi and human lymphocyte function-associated antigen-1, an adhesion molecule that is highly expressed on T cells in synovium.
Neurologic Involvement
Lyme disease is associated with both acute and chronic neurologic abnormalities, affecting both the central and peripheral nervous systems. All the neurologic syndromes associated with B. burgdorferi infection can occur without previous erythema mi-grans.35 Clinical data support the hypothesis that B. burgdorferi invades the nervous system early in the course of the infection. There is a high frequency of nonspecific complaints that may be referable to central nervous system involvement in patients with erythema migrans. In one series of 314 patients with erythema migrans, 64% had headache and 48% complained of a stiff neck.36 Additional evidence of early invasion of the nervous system is that within the first 3 months after infection, approximately 12% to 15% of patients experience acute meningitis, cranial neuritis, or painful radiculitis, alone or in combination.37
The distinguishing features of meningitis in Lyme disease are evident on CSF analysis: a mild CSF pleocytosis largely consisting of polymorphonuclear leukocytes or mononuclear cells, a modest elevation of the CSF protein level, and a normal CSF glucose level. Meningoencephalitis may be a prominent feature, manifesting as difficulty with memory and concentration and emotional lability.38 MRI abnormalities have been observed in more severely affected patients. In the absence of local antibody production, the diagnosis of chronic B. burgdorferi CNS infection is questionable, although this infection has been demonstrated to occur in rare cases.
Cranial neuropathies may occur with or without meningitis. Any cranial nerve may be affected by Lyme disease, but the seventh nerve (unilaterally and bilaterally) is by far the most frequently affected, with involvement in up to 10% of patients.38 Lyme disease may be responsible for approximately 25% of new-onset Bell palsy in an endemic area, with the palsy sometimes developing before positive serology for Lyme disease.39 Bell palsy in Lyme disease is presumably a peripheral neuropathy, given that no antibody has been found in the CSF of some patients who have been tested.
Lyme disease can cause a painful radiculitis that is manifested by neuropathic symptoms such as numbness, tingling, and burning. This radiculoneuropathy may affect the limbs or the trunk. Fifty percent of patients with this radiculitis have associated cranial nerve palsies. The peripheral nerve damage in Lyme disease is usually an axonopathy rather than a demyelinating syndrome.
Acute or subacute myelitis can occur and is associated with spastic paraparesis and CSF pleocytosis.41 In rare cases, mono-neuritis and a Guillain-Barre-like syndrome have been reported. Acute painful radiculoneuritis is the most striking early-stage neurologic syndrome. In the United States, a subtle form of Lyme encephalopathy, which seems to represent CNS infection, has been reported; it manifests predominantly with cognitive abnormalities. Less common neurologic manifestations include sudden sensorineural hearing loss, cerebellitis, intracranial an-eurysm, and myelitis.
Diagnosis
In patients in the United States, the diagnosis of Lyme disease is usually made on the basis of the characteristic clinical findings; a history of tick exposure in an area where the disease is endemic, and, except in patients with erythema migrans, an antibody response to B. burgdorferi by enzyme-linked immunosorbent assay (ELISA) and Western blot (immunoblot) testing, interpreted according to the criteria of the CDC and the Association of State and Territorial Public Health Laboratory Directors. 42,43 In endemic areas, the presence of the characteristic rash is often appropriate to trigger initiation of antibiotic therapy without serologic confirmation. Also, antibiotic treatment of early localized disease may blunt the antibody response.
Microscopy
B. burgdorferi, a loosely coiled spirochete that is approximately 0.2 pm wide and 10 to 30 pm long, is readily visible in skin-biopsy specimens observed by phase-contrast or dark-field microscopy. The organism can also be detected with acridine orange, Giemsa, or silver (Warthin-Starry or a modified Dieterle) stains or by fluorescent antibody techniques. In addition to being identified in skin, spirochetes have been observed in other tissues, such as the myocardium, synovium, and the nervous system, but the yields have been very poor because of low numbers of spirochetes. The routine use of skin biopsies of erythema mi-grans lesions for diagnosis of B. burgdorferi infection is limited by the need for special media and by the protracted periods needed for culture growth. Demonstration of B. burgdorferi from skin biopsies of erythema migrans by culture or PCR is generally not indicated, except perhaps in cases of reinfection when serology may not be helpful.
Culture
In patients presenting with erythema migrans, culture of the involved skin in Barbour-Stoenner-Kelly medium is virtually 100% specific and reasonably sensitive (57% to 86%) for B. burgdorferi.44 The yield from plasma samples is lower, and only occasionally have CSF samples in patients with meningitis yielded culture growth.
In patients with late-stage infection who develop arthritis, PCR testing is greatly superior to culture in the detection of B. burgdorferi in joint fluid.45 B. burgdorferi has not been isolated from the CSF of patients with chronic neuroborreliosis, and B. burgdor-feri DNA has been detected in CSF samples in only a small number of such patients. The Lyme urine antigen test has provided grossly unreliable results and, therefore, should not be used to support the diagnosis of Lyme disease.
Serology
Within 3 to 4 weeks after the onset of borrelial infection, an increase in the IgM response to one or more spirochetal antigens can be detected in most patients; the IgM response usually peaks after 6 to 8 weeks and then gradually declines. Humoral responses of IgM to other antigens gradually develop as the disease progresses. Although there are differences in antigenic responses between patients from North America and patients from Europe, antibodies against one or more of the major protein antigens (i.e., OspC [23 kd], 31 kd, 34 kd, 60 kd, or 66 kd) develop as the infection continues. Specific IgG and IgA responses gradually increase during the second and third months of infection and, once established, may remain detectable for years.
Some epitopes of antigenic components of B. burgdorferi, such as proteins with molecular masses of 41 kd and 60 kd, are common to Treponema pallidum, oral treponemes, and even Es-cherichia coli.47 Such cross-reactivity may result in a significant titer on ELISA screening (see below). False positive reactions have also been reported when sera from patients with juvenile rheumatoid arthritis, rheumatoid arthritis, systemic lupus ery-thematosus, infectious mononucleosis, or subacute bacterial endocarditis were analyzed for antibodies to B. burgdorferi.
Figure 3 Diagnosis of Lyme disease. (ELISA—enzyme-linked immunosorbent assay; IFA—immunofluorescence assay)
Serodiagnostic tests are insensitive during the first several weeks of infection. In the United States, only about 20% to 30% of patients have positive responses, usually of the IgM isotype, during this period.48 By convalescence, 2 to 4 weeks later, about 70% to 80% of treated patients have seroreactivity. After 1 month, the majority of patients with active infection have IgG antibody responses. In persons who have been ill for longer than 1 month, a positive IgM test result by itself is likely to be false positive; therefore, such a response should not be used to support the diagnosis in this setting.49 In patients with acute neuroborrelio-sis, especially those with meningitis, the intrathecal production of IgM, IgG, or IgA antibody against B. burgdorferi may often be demonstrated by antibody-capture enzyme immunoas-say, but this test is less often positive in patients with chronic neuroborreliosis.50
Two-step serologic testing Immunofluorescence assays (IFAs) and ELISAs are the two most commonly used methods for the detection of antibodies to B. burgdorferi. ELISAs are more sensitive than IFAs and offer the advantage of easier screening of large numbers of samples. Although B. burgdorferi antibody tests are potentially useful and constantly improving, they have limited sensitivity (primarily in early disease) and specificity, and they have not yet been standardized.51 These limitations have led to erroneous diagnoses and may have contributed to fundamental misunderstandings of Lyme disease. Therefore, a straightforward two-step serologic approach has been proposed by the CDC [see Figure 3]: a positive or equivocal first test, usually an ELISA or indirect IFA, is followed by an immunoblot test on the same serum sample, which can detect IgM and IgG antibodies to individual B. burgdorferi antigens.42,52
The following two criteria are used for interpretation of the immunoblot test:
• The IgM blot is positive if two of the three following bands are present: 23 kd (OspC), 39 kd, and 41 kd.
• The IgG blot is positive if five of the 10 following bands are present: 18 kd, OspC, 28 kd, 30 kd, 39 kd, 41 kd, 45 kd, 58 kd, 66 kd, and 93 kd.
If the immunoblot test result is negative, the reactive ELISA or IFA result was very probably false positive. Neither ELISA nor immunoblot testing permits detection of fourfold rises in antibody titer (seroconversion).
Some patients lack diagnostic serum levels of specific antibodies but have neurologic involvement and, as a result, have diagnostic levels of antibody in their CSF, because B. burgdorferi organisms reaching this immunologically privileged site remain viable and induce a local immune response.53,54 Intrathecal production of antibody against B. burgdorferi may be demonstrated by using the following formula:
If the ratio is greater than 1, localized production of anti-Borrelia antibodies has occurred.
After antibiotic treatment, antibody titers fall slowly, but IgG and even IgM responses may persist for many years after treatment. Thus, even an IgM response cannot be interpreted as a demonstration of recent infection or reinfection unless the appropriate clinical characteristics are present.
New serologic tests An ELISA has been developed on the basis of a conserved immunodominant portion (C6) of the B. burgdorferi variable surface antigen (VlsE).55 This assay can be used in vaccinated and unvaccinated patients. The C6 Lyme ELISA is important because it detects both IgM and IgG antibodies in patients with Lyme disease but not in uninfected vaccine recipients.56 This assay, when used together with an assay for another immunodominant antigen from OspC, may have the same level of specificity and sensitivity as the two-step approach (see above).
