How to diagnose Lyme Disease?

1.

Wormser, Gary P. (2024). In Goldman-Cecil Medicine (pp. 2022). DOI: 10.1016/B978-0-323-93038-3.00296-3

The diagnosis of Lyme disease requires clinical suspicion and often requires targeted laboratory testing (Table 296-2). In the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) era, diagnosis can be delayed, either because symptoms are misattributed or patients delay seeking medical care., Erythema migrans skin lesions may go unnoticed by the patient because of the absence of prominent local symptoms and occurrence on parts of the body that are difficult for the patient to visualize. Therefore, a complete skin examination should be performed for any patient thought to have early localized or disseminated Lyme disease. Erythema migrans, which is the only clinical manifestation sufficiently distinctive to allow a clinical diagnosis in the absence of a supporting laboratory test, is diagnosed on the basis of recognition of the characteristic appearance of the skin lesion in persons who live in or have recently traveled to areas endemic for Lyme disease. For non–erythema migrans presentations of Lyme disease, the mainstay of laboratory diagnosis is two-tier serologic testing in which the first-tier test is usually a sensitive enzyme-linked immunosorbent assay (EIA).,If the EIA result is positive or equivocal, separate IgM and IgG immunoblots are performed on the original serum sample. If symptoms have persisted for at least 4 weeks, then specifically the IgG immunoblot should be positive for the results to be interpreted as evidence of seropositivity. An alternative two-tier testing strategy is to use a different EIA as the second-tier test. Untreated patients who remain seronegative for 6 to 8 weeks are unlikely to have Lyme disease, and other possible diagnoses should be pursued. Omitting the first-tier EIA or interpreting the immunoblot with alternative criteria that are not evidence based will potentially decrease the specificity of testing and is not recommended. False-positive results on the IgM immunoblot may be due to cross-reactive antibodies that arise from polyclonal B-cell stimulation. Probably the most common cause of false-positive results, however, is the overreading of nonspecific weak bands.

Diagnosis Diagnosis is based on history of exposure to ticks in an endemic area, clinical presentation, and if needed, serology results History of a tick bite is not necessary for diagnosis; many patients with documented Lyme disease do not report a known tick bite On physical examination, health care provider diagnosis of the classic erythema migrans rash acquired in a high incidence area is sufficient for a definitive diagnosis of Lyme disease In North American cases with a clinical presentation otherwise consistent with Lyme disease, laboratory diagnosis is based on 2-tiered serologic testing; if ELISA result is positive or equivocal, then conduct confirmatory Western blot assay or enzyme immunoassay (another ELISA test) In July 2019, FDA approved a revised approach called modified two-tier testing, allowing for 2 enzyme immunoassays to be performed, obviating the need for the technically demanding immunoblot that often causes delay in test results For patients not living in areas where Lyme disease is endemic and with no history of travel to endemic areas, testing for Lyme disease is not recommended owing to low pretest probability of infection and high rate of false-positive results Testing patients with only nonspecific subjective symptoms (eg, fatigue) is not recommended owing to low positive predictive value Testing for the VlsE or C6 peptide by ELISA detects other Borrelia species in addition to Borrelia burgdorferi and can be used to diagnose infection acquired outside North America In patients with suspected meningeal involvement, perform lumbar puncture to evaluate cell count, chemistry, and CSF (cerebrospinal fluid) Borrelia burgdorferi –specific antibodies, both to confirm the diagnosis and to exclude other causes (eg, bacterial meningitis) Antibody testing for Borrelia burgdorferi should be ordered as a CSF index that requires simultaneous CSF and serum specimens

Diagnosis Serology 2-tiered approach is recommended, beginning with an ELISA or enzyme immunoassay and followed by a confirmatory Western blot analysis (standard two-tier testing [STTT]) or another ELISA or enzyme immunoassay (modified two-tier testing [MTTT]) First step: ELISA or enzyme immunoassay If result is positive or equivocal, then proceed to second tier (a confirmatory Western blot testing or enzyme immunoassay) to improve specificity Sensitivity is lower within the first few weeks of infection; if Lyme disease is suspected and test result is negative within the first few weeks after potential infection, repeat the test Second step: either Western blot (STTT) or another ELISA/enzyme immunoassay (MTTT) Western blot If this result is also positive, the diagnosis is confirmed Positive test result involves the following: First 30 days after onset of symptoms, IgM: 2 out of 3 bands (23 kDa, 39 kDa, 41 kDa) After first month of infection, only use the IgG result: at least 5 out of 10 bands (18 kDa, 21 kDa, 28 kDa, 30 kDa, 39 kDa, 41 kDa, 45 kDa, 58 kDa, 66 kDa, 93 kDa) Most patients have detectable IgG and IgM no later than 4 to 8 weeks after infection; at that point, if IgM alone is detected without IgG, this likely represents a false-positive result CDC does not recommend using IgM enzyme immunoassay/immunofluorescent assay or the immunoblot component if patient has had symptoms or signs for longer than 30 days, owing to high likelihood of false-positive results in this setting Second ELISA or enzyme immunoassay test (MTTT) If this result is also positive, the diagnosis is confirmed

2.

Swami, Sanjeev K. (2025). Lyme Disease (Borrelia burgdorferi). In Nelson Textbook of Pediatrics (pp. 1881). DOI: 10.1016/B978-0-323-88305-4.00268-6

In the appropriate epidemiologic setting (endemic area, season), typical erythema migrans is pathognomonic. Occasionally, the diagnosis of erythema migrans may be difficult because the rash initially can be confused with nummular eczema, tinea corporis, granuloma annulare, an insect bite reaction, southern tick–associated rash illness, or cellulitis. The relatively rapid expansion of erythema migrans helps distinguish it from these other skin lesions. The other clinical manifestations of Lyme disease are less specific and may be confused with other conditions; the monoarticular or oligoarticular arthritis sometimes is confused with a septic joint or other causes of arthritis in children, such as juvenile idiopathic arthritis or rheumatic fever; the facial nerve palsy caused by Lyme disease is clinically indistinguishable from Bell palsy, although bilateral involvement is much more common with Lyme disease; Lyme meningitis generally occurs in the warmer months, the same period that enteroviral meningitis is prevalent. Therefore for all disease manifestations other than erythema migrans, it is recommended to have laboratory confirmation of infection withB. burgdorferi. AlthoughB. burgdorferihas been isolated from the blood, skin, CSF, myocardium, and synovium of patients with Lyme disease, the organism is difficult to isolate in culture (cultivation is largely relegated to research laboratories). Infection is usually identified by the detection of antibody in serum. Although some laboratories offer polymerase chain reaction as a diagnostic test for Lyme disease, its sensitivity is poor because of the low concentrations of bacteria in many sites, especially CSF. Other antigen-based tests, including a test forB. burgdorferiantigens in urine, are unreliable. Clinicians should be aware that some laboratories use alternative diagnostic tests and/or alternative interpretive criteria that are not evidence based, leading to a false diagnosis of Lyme disease. The CDC and the Food and Drug Administration recommend against using these tests.

3.

Kobayashi T, Auwaerter PG. Infectious Disease Clinics of North America. 2022;36(3):605-620. doi:10.1016/j.idc.2022.04.001.

Publish date: September 4, 2022.

Standard 2-tier testing (STTT), incorporating a screening enzyme immunoassay (EIA) or an immunofluorescence assay (IFA) that reflexes to IgM and IgG immunoblots, has been the primary diagnostic test for Lyme disease since 1995. In 2019, the Food and Drug Administration approved a modified 2-tier test strategy using 2 EIAs: offering a faster, less expensive, and more sensitive assay compared with STTT. New technologies examine early immune responses to Borrelia burgdorferi have the potential to diagnose Lyme disease in the first weeks of infection when existing serologic testing is not recommended due to low sensitivity.

4.

National Library of Medicine (MedlinePlus)

Publish date: August 3, 2022.

Result Interpretation What do the results mean? Lyme disease is difficult to diagnose. The symptoms are common to many conditions, and test results alone can't diagnose the disease. To make a diagnosis, your provider will consider your test results along with your medical history, exposure, and symptoms. You may also need other tests. A negative blood test result means that antibodies to fight the Lyme disease bacteria were not found in your blood. If you had symptoms for longer than 30 days before your test, you probably don't have Lyme disease. But if you had symptoms for less than 30 days before you gave your blood sample, you may need to have another Lyme disease test. That's because it may take a few weeks for your body to make enough antibodies to show up on a test. If your test was done too soon, you could be infected even though your test was negative. This is called a "false negative." A positive blood test result means that antibodies to fight the Lyme disease bacteria were found in your blood. In this case, the Centers for Disease Control and Prevention (CDC) recommends a second blood test on the same blood sample. If the second test is positive and you have symptoms of infection, you probably have Lyme disease. But positive test results don't always mean that Lyme disease is causing your symptoms. You could have antibodies from a past case of Lyme disease that your body successfully fought off months or even years ago. It's also possible to have a "false positive." That means you don't have antibodies that fight Lyme disease bacteria, even though the test says you do. The test may have mistakenly found antibodies that fight other bacteria or diseases, such as certain autoimmune diseases . And it's possible that these diseases are causing your symptoms, not Lyme disease. The results from a cerebrospinal fluid (CSF) test can help show whether Lyme disease has spread to your nervous system. A negative CSF test result means that no Lyme disease antibodies were found in your cerebrospinal fluid. But it doesn't rule out Lyme disease in your nervous system. You may need more tests. A positive CSF test result means that Lyme disease antibodies were found in your cerebrospinal fluid.