The three stages of Lyme disease are classified based on early or late manifestations of the disease and whether it is localized or disseminated.
1. Stage 1, early localized infection
Stage 1 infection is characterized by erythema migrans (Figure 6–26). About 1 week after the tick bite (range, 3–30 days; median 7–10 days), a flat or slightly raised red lesion appears at the site, which is commonly seen in areas of tight clothing such as the groin, thigh, or axilla. This lesion expands over several days. Although originally described as a lesion that progresses with central clearing (“bulls-eye” lesion), often there is a more homogeneous appearance or even central intensification. About 10–20% of patients either do not have typical skin lesions or the lesions go unnoticed. Most patients with erythema migrans will have a concomitant viral-like illness (the “summer flu”) characterized by myalgias, arthralgias, headache, and fatigue. Fever may or may not be present. Even without treatment, the symptoms and signs of erythema migrans resolve in 3–4 weeks. Although the classic lesion of erythema migrans is not difficult to recognize, atypical forms can occur that may lead to misdiagnosis. Vesicular, urticarial, and evanescent erythema migrans have all been reported. Chemical reactions to tick and spider bites (these usually recede in 24–48 hours, whereas erythema migrans increases in size in this time period), drug eruptions, urticaria, and staphylococcal and streptococcal cellulitis have been mistaken for erythema migrans. Southern tick–associated rash illness (STARI) has a similar appearance, but it occurs in geographically distinct areas of the United States.
Completely asymptomatic disease, without erythema migrans or flu-like symptoms, can occur but is very uncommon in the United States. Serosurveys done as part of vaccination trials found asymptomatic seroconversion in 7% or less of the population.
2. Stage 2, early disseminated infection
Up to 50–60% of patients with erythema migrans are bacteremic, (especially if multiple lesions are present) leading to dissemination of the spirochete resulting in a wide variety of symptoms and signs and within days to weeks of the original infection, secondary skin lesions develop in about 50% of patients. These lesions are similar in appearance to the primary lesion but are usually smaller. Malaise, fatigue, fever, headache (sometimes severe), neck pain, and generalized achiness are common with the skin lesions. Most symptoms are transient. After hematogenous spread, some patients experience cardiac (4–10% of patients) or neurologic (10–15% of patients) manifestations, including myopericarditis, with atrial or ventricular arrhythmias and heart block. Neurologic manifestations include both the central and peripheral nervous systems. The most common CNS manifestation is aseptic meningitis with mild headache and neck stiffness. The most common peripheral manifestation is a cranial nerve VII neuropathy, ie, facial palsy (usually unilateral but can be bilateral, see Figure 24–1). A sensory or motor radiculopathy and mononeuritis multiplex occur less frequently. Conjunctivitis, keratitis, and, rarely, panophthalmitis can also occur. Rarely, skin involvement can be manifested as a cutaneous hypopigmented lesion called a borrelial lymphocytoma.
3. Stage 3, late persistent infection
Stage 3 infection occurs months to years after the initial infection and again primarily manifests itself as musculoskeletal, neurologic, and skin disease. In early reports, musculoskeletal complaints developed in up to 60% of patients, but with early recognition and treatment of disease, this has decreased to less than 10%. The classic manifestation of late disease is a monoarticular or oligoarticular arthritis most commonly affecting the knee or other large weight bearing joints. While these joints may be quite swollen, these patients generally report less pain compared to patients with bacterial septic arthritis. Even if untreated, the arthritis is self-limited, resolving in a few weeks to months. Multiple recurrences are common but are usually less severe than the original disease. Joint fluid reflects an inflammatory arthritis with a mean white blood cell count of 25,000/mcL (0.025/L) with a predominance of neutrophils. Chronic arthritis develops in about 10% of patients. The pathogenesis of chronic Lyme arthritis may be an immunologic phenomenon rather than persistence of infection. The observations that persons with chronic arthritis have an increased frequency of HLA-DR4 gene expression, antibodies to OspA and OspB protein in joint fluid (major outer surface proteins of B burgdorferi), lack B burgdorferi DNA in synovial fluid as detected by PCR, and often do not respond to antibiotics—all support the inference of an immunologic mechanism.
Rarely, the nervous system (both central and peripheral) can be involved in late Lyme disease. In the United States, a subacute encephalopathy, characterized by memory loss, mood changes, and sleep disturbance, is seen. In Europe, a more severe encephalomyelitis caused by B garinii is seen and presents with cognitive dysfunction, spastic paraparesis, ataxia, and bladder dysfunction. Peripheral nervous system involvement includes intermittent paresthesias, often in a stocking glove distribution, or radicular pain.
The cutaneous manifestation of late infection, which can occur up to 10 years after infection, is acrodermatitis chronicum atrophicans. It has been described mainly in Europe after infection with B afzelii, a genospecies that commonly causes disease in Europe but not the United States. There is usually bluish-red discoloration of a distal extremity with associated swelling. These lesions become atrophic and sclerotic with time and eventually resemble localized scleroderma. Cases of diffuse fasciitis with eosinophilia, an entity that resembles scleroderma, have been rarely associated with infection with B burgdorferi.
The diagnosis of Lyme disease is based on both clinical manifestations and laboratory findings. The US Surveillance Case Definition specifies a person with exposure to a potential tick habitat (within the 30 days just prior to developing erythema migrans) with (1) erythema migrans diagnosed by a clinician or (2) at least one late manifestation of the disease and (3) laboratory confirmation as fulfilling the criteria for Lyme disease.
Nonspecific laboratory abnormalities can be seen, particularly in early disease. The most common are an elevated sedimentation rate of more than 20 mm/h seen in 50% of cases, and mildly abnormal liver biochemical tests are present in 30%. The abnormal liver biochemical tests are transient and return to normal within a few weeks of treatment. A mild anemia, leukocytosis (11,000–18,000/mcL) (0.011–0.018/L), and microscopic hematuria have been reported in 10% or less of patients.
Laboratory confirmation requires serologic tests to detect specific antibodies to B burgdorferi in serum, preferably by ELISA and not by indirect immunofluorescence assay (IFA), which is less sensitive and specific and can cause misdiagnosis. A two-test approach is recommended for the diagnosis of active Lyme disease, with all specimens positive or equivocal by ELISA then confirmed with a Western immunoblot assay that can detect both IgM and IgG antibodies. IgM antibody appears first 2–4 weeks after onset of erythema migrans, peaks at 6–8 weeks, and then declines to low levels after 4–6 months of illness. The presence of IgM antibody in patients with prolonged symptoms persisting for several months is likely to be a false-positive result. IgG occurs later (6–8 weeks after onset of disease), peaks at 4–6 months, and may remain elevated at low levels indefinitely despite appropriate therapy and resolution of symptoms. When a Western immunoblot is done during the first 4 weeks of illness, both IgM and IgG should be tested. If the initial ELISA is negative, the result is considered final; Western immunoblot should not be performed. A negative Western immunoblot following an initial positive ELISA indicates as false-positive ELISA; the patient does not have evidence of exposure to B burgdorferi. A positive immunoblot requires that antibodies are detected against two (for IgM) or five (for IgG) specific protein antigens from B burgdorferi. Patients who may have acquired infection outside of the United States may require additional tests that include peptide antigens (C6, PepC10), which are conserved across species and strains.
If a patient with suspected early Lyme disease has negative serologic studies, acute and convalescent titers should be obtained since up to 50% of patients with early disease can be antibody negative in the first several weeks of illness. A fourfold rise in antibody titer would be diagnostic of recent infection. In patients with later stages of disease, almost all are antibody positive. False-positive reactions in the ELISA and IFA have been reported in juvenile rheumatoid arthritis, rheumatoid arthritis, systemic lupus erythematosus, infectious mononucleosis, subacute infective endocarditis, syphilis, relapsing fever, leptospirosis, enteroviral and other viral illnesses, and patients with gingival disease (presumably because of cross-reactivity with oral treponemes). False-negative serologic reactions occur early in illness, and antibiotic therapy early in disease can abort subsequent seroconversion.
The diagnosis of late nervous system Lyme disease is often difficult since clinical manifestations, such as subtle memory impairment, may be difficult to document. Most patients have a history of previous erythema migrans or monoarticular or polyarticular arthritis, and the vast majority have antibody present in serum. When CSF is sampled from patients with encephalopathy, there may be evidence of inflammation (pleocytosis or elevated protein, or both), and localized antibody production, ie, a ratio of CSF to serum antibody of greater than 1.0. PCR has low sensitivity and is not recommended for routine diagnosis. Elevated CSF levels of the chemokine CXCL13 have been associated with CNS Lyme disease, but they can also occur in other infections such as neurosyphilis. Patients with late disease and peripheral neuropathy almost always have positive serum antibody tests, usually have abnormal electrophysiology tests, and may have abnormal nerve biopsies showing perivascular collections of lymphocytes; however, the CSF is usually normal and does not demonstrate local antibody production.
Caution should be exercised in interpreting serologic tests because they are not subject to national standards, and inter-laboratory variation is a major problem. In addition, some laboratories perform tests that are entirely unreliable and should never be used to support the diagnosis of Lyme disease (eg, the Lyme urinary antigen test, immunofluorescent staining for cell wall–deficient forms of B burgdorferi, lymphocyte transformation tests, using PCR on inappropriate specimens such as blood or urine). Finally, testing is often done in patients with nonspecific symptoms such as headache, arthralgia, myalgia, fatigue, and palpitations. Even in endemic areas, the pretest probability of having Lyme disease is low in these patients, and the probability of a false-positive test result is greater than that of a true-positive result. For these reasons, the CDC has established guidelines for laboratory evaluation of patients with suspected Lyme disease:
The diagnosis of early Lyme disease is clinical (ie, exposure in an endemic area, with clinician-documented erythema migrans), and does not require laboratory confirmation. (Tests are often negative at this stage.)
Late disease requires objective evidence of clinical manifestations (recurrent brief attacks of monoarticular or oligoarticular arthritis of the large joints; lymphocytic meningitis, cranial neuritis [facial palsy], peripheral neuropathy or, rarely, encephalomyelitis—but not headache, fatigue, paresthesias, or stiff neck alone; atrioventricular conduction defects with or without myocarditis) and laboratory evidence of disease (two-stage testing with ELISA or IFA followed by Western blot, as described above).
Patients with nonspecific symptoms without objective signs of Lyme disease should not have serologic testing done. It is in this setting that false-positive tests occur more commonly than true-positive tests.
The role of serologic testing in nervous system Lyme disease is unclear, as sensitivity and specificity of CSF serologic tests have not been determined. However, it is rare for a patient to have positive serologic tests on CSF without positive tests on serum (see below).
Other tests such as the T cell proliferative assay and urinary antigen detection have not yet been studied well enough to be routinely used.
Cultures for B burgdorferi can be performed but are not routine and are usually reserved for clinical studies. Aspiration of erythema migrans lesions has yielded positive cultures in up to 30% of cases, whereas culture of a 2-mm punch biopsy is positive in 50–70%. PCR of a skin biopsy is even more sensitive, with positivity rates of 80%. In early disease, blood cultures are positive in up to 50% if large volumes (9 mL) are used, but CSF is rarely culture positive. The ability to culture organisms from skin lesions is greatly influenced by antibiotic therapy. Even a brief course of several days will result in negative cultures. Special silver staining of chronically inflamed synovial tissue demonstrates spirochetes in one-third of patients.
PCR is very specific for detecting the presence of Borrelia DNA, but sensitivity is variable and depends on which body fluid is tested, the stage of the disease, and collection and testing technique. In general, PCR is more sensitive than culture, especially in chronic disease but is not available in many clinical laboratories. Testing should not be done on blood or urine but has been successfully performed on synovial fluid and CSF. Up to 85% of synovial fluid samples are positive in active arthritis. In contrast, 38% of CSF samples in acute CNS Lyme disease are PCR positive compared with only 25% in chronic CNS disease. However, whether a positive PCR indicates persistence of viable organisms that will respond to further treatment or is a marker for residual DNA (not active infection) has not been clarified. A negative PCR result does not rule out disease.