Lyme Disease

AUTHOR: Glenn G. Fort, MD, MPH

Definition

Lyme disease is a multisystem inflammatory disorder caused by the transmission of a spirochete, Borrelia burgdorferi, via the bite of infected Ixodes ticks, taking 36 to 48 h for a tick to take a blood meal and transmit the infecting organism to the host. Table E1 summarizes the Centers for Disease Control and Prevention (CDC) Lyme disease surveillance case definition.

TABLE E1 2011 CDC Lyme Disease Surveillance Case Definition

Definition of Erythema Migrans (EM)
A skin lesion that typically begins as a red macule or papule and expands over a period of days to weeks to form a large round lesion, often with partial central clearing. A single primary lesion must reach ≥5 cm in diameter. Secondary lesions also may occur. Annular erythematous lesions occurring within several hours of a tick bite represent hypersensitivity reactions and do not qualify as EM. The diagnosis of EM must be made by a physician.
Confirmed
A case of EM with a known exposure ∗ A case of EM with laboratory evidence of infection ^† and without a known exposure A case with at least one late manifestation ^‡ that has laboratory evidence of infection
Probable
Any other case of physician-diagnosed Lyme disease that has laboratory evidence of infection
Suspected
A case of EM where there is no known exposure ∗ and no laboratory evidence of infection A case with laboratory evidence of infection but no clinical information available (e.g., a laboratory report)

CDC, Centers for Disease Control and Prevention; CSF, cerebrospinal fluid; Ig, immunoglobulin.

^∗Exposure is defined as having been (≤30 days before onset of EM) in wooded, brushy, or grassy areas (i.e., potential tick habitats) in a county in which Lyme disease is endemic (in which at least two confirmed cases have been acquired or in which established populations of a known tick vector are infected with B. burgdorferi). A history of tick bite is not required.

^†Positive culture for B. burgdorferi-or-two-tiered testing (positive or equivocal sensitive enzyme immunoassay [or immunofluorescent assay] followed by a Western immunoblot [both IgG and IgM tested if in the first 4 wk from symptom onset])-or-single-tier IgG immunoblot seropositivity.

^‡Recurrent, brief attacks of joint swelling in one or a few joints; lymphocytic meningitis, cranial neuritis (particularly facial palsy [may be bilateral]), radiculoneuropathy or, rarely, encephalomyelitis (requires CSF antibody production); acute onset of high-grade (second- or third-degree) atrioventricular conduction defects that resolve in days to weeks and are sometimes associated with myocarditis.

From 2011 CDC Lyme disease surveillance case definition. CDC, Centers for Disease Control and Prevention. Available at https://ndc.services.cdc.gov/case-definitions/lyme-disease-2011/.

Synonyms

Bannwarth syndrome (Europe)

Acrodermatitis chronica atrophicans

ICD-10CM CODES
A69.20		Lyme disease, unspecified
A69.21		Meningitis due to Lyme disease
A69.22		Other neurologic disorders in Lyme disease
A69.23		Arthritis due to Lyme disease
A69.29		Other conditions associated with Lyme disease

Epidemiology & Demographics

Incidence (in U.S.)

In the U.S., 4.4 cases/100,000 persons; it is the most common vector-borne infection in the U.S., with more than 30,000 new cases reported each yr. 90% of cases are found in Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Pennsylvania, Minnesota, Wisconsin, and California. The area of transmission in the U.S. is expanding farther into the South and upper Northeast (Fig. E1). The disease also occurs in Europe and Asia with a different Ixodes tick vector. Table E2 summarizes principal vector ticks and spirochetes associated with Lyme borreliosis.

Figure E1 Reported cases of Lyme disease-United States, 2015.

Each dot represents one case of Lyme disease and is placed randomly in the patient’s county of residence. The presence of a dot in a state does not necessarily mean that Lyme disease was acquired in that state. The place of residence is sometimes different from the location where the patient became infected.

From Centers for Disease Control and Prevention: National Center for Emerging and Zoonotic Infectious Diseases, Division of Vector-Borne Diseases. In Cherry JD et al: Feigin and Cherry’s textbook of pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

TABLE E2 Principal Vector Ticks and Spirochetes Associated With Lyme Borreliosis

Tick Species	Distribution	Genotype of Borrelia burgdorferi
Ixodes scapularis	Eastern North America	B. burgdorferi sensu stricto
Ixodes pacificus	Western North America	B. burgdorferi sensu stricto
Ixodes ricinus	Western and Central Europe	B. garinii, B. afzelii, B. burgdorferi sensu stricto
Ixodes persulcatus	Central Europe and Asia	B. garinii, B. afzelii

From Piesman J, Humair PF: The spirochetes and vector ticks of Lyme borreliosis in nature. In Sood SK (ed): Lyme borreliosis in Europe and North America, Hoboken, NJ, 2011, John Wiley & Sons.

Predominant Sex

Male = female

Predominant Age

Median age of 28 yr

Peak Incidence

May to November

Physical Findings & Clinical Presentation

Lyme disease may present in the following stages (Table E3):

Early localized stage (incubation period 3 to 30 days): Early Lyme disease, erythema migrans (EM); skin rash, often at site of tick bite (the CDC has defined EM rash as an expanding red macule or papule that must reach at least 5 cm in size, with or without central clearing); target lesions from ECM can be found in 60% to 80% of localized infections; possible fever, myalgias 3 to 32 days after tick bite
Early disseminated stage (incubation period 3 to 6 wk): Days to weeks later; multiorgan system involvement, including central nervous system (CNS) with aseptic meningitis-type picture or Bells palsy, joints (arthritis or arthralgias), cardiac including varying degrees of heart block; related to dissemination of spirochete
Late stage (incubation period month to year): Month to year after tick exposure; affects central and peripheral nervous system, cardiac, joints

Common presenting signs and symptoms include:

EM (Fig. E2). Most patients with EM (about 80%) have a single lesion, but the bacteria can disseminate hematogenously to other sites in the skin and result in often smaller erythema migrans lesions (Figs. E3 and E4).
Lymphadenopathy, neck pains, pharyngeal erythema, myalgias, hepatosplenomegaly.
Patients will complain of malaise, fatigue, lethargy, headache, fever/chills, neck pain, myalgias, back pain.

Figure E2 Erythema migrans.

(A) The site of the tick bite is visible near the center of the lesion. (B) Typical bull’s-eye lesion.

From Huppert HI, Dressler F: Lyme disease. In Cassidy J et al [eds]: Textbook of pediatric rheumatology, ed 6, Philadelphia, 2011, Saunders. In Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

Figure E3 Lyme disease (erythema chronicum migrans).

From Micheletti RG, et al: Andrews’ diseases of the skin, clinical atlas, ed 2, Philadelphia, 2023, Elsevier.

Figure E4 Disseminated Lyme disease (multiple erythema migrans lesions).

From Micheletti RG, et al: Andrews’ diseases of the skin, clinical atlas, ed 2, Philadelphia, 2023, Elsevier.

TABLE E3 Clinical Manifestations of Lyme Disease

Early Localized Infection
Occurs 3-30 days after tick bite EM in 80% of patients; single lesion, occasionally associated with fever, malaise, neck pain or stiffness, arthralgias and myalgias Systemic symptoms noted above in the absence of EM during summer months Borrelial lymphocytoma (rare, seen primarily in Europe)
Early Disseminated Infection
Occurs weeks to months after tick bite Profound malaise and fatigue common Multiple EM lesions with systemic symptoms similar to early localized infection Musculoskeletal Migratory polyarthralgias and myalgias Cardiac Carditis (<3% of untreated patients) Varying degrees of atrioventricular nodal block Mild myopericarditis Neurologic (<10% of untreated patients) Cranial neuropathies (especially facial nerve palsy) Radiculoneuropathies Lymphocytic meningitis Encephalomyelitis (primarily seen in Europe)
Late Disease
Occurs months to years after tick bite Arthritis (30% of patients) Acute monoarticular or migratory pauciarticular inflammatory arthritis, usually involving the knee Postantibiotic Lyme arthritis (<10% of patients with arthritis) Neurologic (rare) Peripheral neuropathies Mild encephalopathy Encephalomyelitis (primarily seen in Europe) Skin Acrodermatitis chronica atrophicans (primarily seen in Europe)

EM, Erythema migrans.

From Firestein GS, et al: Firestein & Kelley’s textbook of rheumatology, ed 11, Philadelphia, 2021, Elsevier.

Etiology

B. burgdorferi transmitted from bite of an Ixodes tick (mostly in the nymph stage but can also be from adult ticks). Human infection occurs through inoculation of spirochetes in infected saliva and usually requires tick attachment for more than 36 hr.

Clinical presentation, exposure to ticks in endemic area, and diagnostic testing for antibody response to B. burgdorferi. Serologic testing at early stages is usually negative; therefore, in early stage, documentation of erythema migrans lesion with a compatible epidemiologic history is sufficient for diagnosis, and laboratory testing is not indicated.

Differential Diagnosis

Chronic fatigue/fibromyalgia
Acute viral illnesses
Babesiosis
Human granulocytic anaplasmosis

Workup

Serologic testing is the principal means of laboratory diagnosis of Lyme disease. Current recommendations include using a sensitive enzyme immunoassay (EIA) or immunofluorescence assay, followed by a Western immunoblot assay for specimens yielding positive or equivocal results.

Laboratory Tests

ELISA testing and if positive or equivocal then followed by a Western blot immunoglobulin M (IgM) and IgG (Table E4). A Western blot IgM assay is positive if two of three bands present. The Western blot IgG is positive if five of ten bands present.
An alternative serologic test is the VlsE C6 ELISA (enzyme-linked immunosorbent assay) (C6 peptide), which detects an IgG response earlier and may be more sensitive than the ELISA, but its specificity is lower than the two-tier testing method.
In 2019, the FDA cleared several Lyme assays allowing for an EIA serology test rather than the Western Blot assay as the second test in the Lyme disease testing algorithm.
Early disease often is difficult to diagnose serologically, secondary to slow immune response.
Culturing of skin lesions (EM) and polymerase chain reaction (PCR) of synovial fluid or cerebrospinal fluid can also give the diagnosis of active infection.
Fig. 5 is an algorithm for the diagnosis and treatment of arthritis associated with Lyme disease.

Figure 5 Algorithm for the Diagnosis and Treatment of Arthritis Associated with Lyme Disease

Dmard, Disease-Modifying Antirheumatic Drug; DNA, Deoxyribonucleic Acid; Elisa, Enzyme-Linked Immunosorbent Assay; Ig, Immunoglobulin; IV, Intravenous; Nsaid, Nonsteroidal Antiinflammatory Drug; PCR, Polymerase Chain Reaction.

From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

TABLE E4 Criteria for Western Blot Interpretation in the Serologic Confirmation of Lyme Disease

Duration of Disease	Isotype Tested	Criteria for Positive Test
First month of infection	IgM	Two of the following three bands are present: 23 kD (OspC), 39 kD (BmpA), and 41 kD (Fla)
After first month of infection	IgG	Five of 10 bands are present: 18 kD, 21 kD, 28 kD, 30 kD, 39 kD, 41 kD, 45 kD, 58 kD (not GroEL), 66 kD, and 93 kD

Ig, Immunoglobulin.

Modified from Centers for Disease Control and Prevention: Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease, MMWR Morb Mortal Wkly Rep 44:590-591, 1995.

Imaging Studies

ECG
Echocardiogram if conduction abnormalities are present with cardiac involvement
Computed tomography scan, MRI of brain in patients with CNS involvement

Early localized Lyme disease:

Doxycycline 100 mg bid in adults (children: 2 mg/kg twice daily if ≥8 yr) [doxycycline offers the advantage of treating possible coinfection with the bacterial agents of ehrlichiosis] for 10 to 14 days or amoxicillin 500 mg tid for adults (children: 50 mg/kg per day in three divided doses) for 14 to 21 days.
Alternative treatments for pregnancy and children ≦8 yr: Cefuroxime axetil 500 mg bid for 14 to 21 days (children: 30 mg/kg per day in two divided doses), azithromycin 500 mg PO for 7 to 10 days but should not be used as a first-line agent, as it is less effective than doxycycline and amoxicillin. NOTE: The American Academy of Pediatrics (AAP Red Book) now considers doxycycline safe regardless of age for up to 21 days.
A single dose of 200 mg doxycycline given within 72 h of removing an engorged Ixodes tick can significantly reduce the risk of development of Lyme disease in endemic areas and is reasonable prophylaxis in nonpregnant adults and children ≥8 yr old.

Early disseminated and late persistent infection:

28 days of treatment is often prescribed, although recent evidence supports treating patients with a 14-day course of oral doxycycline for early neurologic Lyme disease in ambulatory patients. Doxycycline and ceftriaxone appear equally effective for acute disseminated Lyme disease.
Arthritis: 28 days of doxycycline or amoxicillin plus probenecid.
Neurologic involvement requires parenteral antibiotics. Those who fail to respond should be treated with IV ceftriaxone or cefotaxime.
Ceftriaxone 2 g/day IV for 21 to 28 days; alternative: Cefotaxime 2 g q8h IV; alternative: Penicillin G 5 million U qid.
Cardiac involvement: IV ceftriaxone or cefotaxime plus cardiac monitoring.
Prolonged treatment with IV or PO antibiotic therapy for up to 90 days did not improve symptoms more than placebo.

Post-Lyme disease syndrome:

Presence of disabling symptoms such as fatigue, malaise, diffuse pains, and poor concentration, which may be due to an exuberant host inflammatory response even in patients who have received proper antibiotic treatment
Antibiotics are not indicated. Antibiotic treatment of patients with persistent unexplained symptoms despite previous antibiotic treatment of Lyme disease provides little, if any, benefit and carries significant risk
Supportive care

Disposition

The patient often needs careful follow-up and supportive care for the arthralgia-neuritis symptoms.
10% to 20% of treated patients may have lingering symptoms of fatigue, disrupted sleep, and musculoskeletal complaints. Repeat episodes of EM in appropriately treated patients are due to reinfection and not to relapse.

Referral

To a neurologist if significant neurologic complications (meningitis, myelitis, ophthalmoplegia, Bell palsy)
To a cardiologist if the patient develops evidence of cardiac conduction disturbances or pericarditis

A physician diagnosis of classic EM in an endemic region of Lyme disease is sufficient to make a definitive diagnosis.
In some patients with Lyme disease, nonspecific complaints such as headache, fatigue, and arthralgia may persist for months after appropriate (and ultimately successful) antibiotic treatment. Long-term antibiotic treatment does not provide additional beneficial effects.
There is no evidence of current or previous Borrelia burgdorferi infection in most patients evaluated at university-based Lyme disease referral centers. Psychiatric comorbidity and other psychologic factors are prominent in the presentation and outcome of some patients who inaccurately ascribe longstanding symptoms to “chronic Lyme disease.”
It is important to realize that one tick bite can transmit Lyme disease and the bacterial agents of either ehrlichiosis or babesiosis (protozoan parasite), or even both, and these latter agents require separate serologic testing and possibly therapy. Ehrlichiosis is treated with doxycycline, but Babesia would require a different therapy. Powassan virus can also be transmitted by the Ixodes tick bite and causes an encephalitis seen in eastern Canada and northcentral, northeastern, and upper midwestern United States. Cases have been increasing.
Tick bite protection: EPA-registered insect repellents containing DEET, picaridin, IR3535, oil of lemon eucalyptus (OLE), para-menthane-3,8-diol (PMD), or 2-undecanone can prevent ticks from attaching when applied and can last for several hours. OLE and PMD products cannot be used on children under 3 yr of age.

Related Content

Lyme Disease (Patient Information)

Berende A. : Randomized trial of longer-term therapy for symptoms attributed to Lyme diseaseN Engl J Med. ;374:1209-1220, 2016.
Halperin J.J. : Chronic Lyme disease: misconceptions and challenges for patient managementInfect Drug Resist. ;15:119-128, 2015.
Hu L.T. : In the clinic. Lyme diseaseAnn Intern Med. ;164(9):ITC65-ITC80, 2016.
Nadelman R.B. : Differentiation of reinfection from relapse in recurrent Lyme diseaseN Engl J Med. ;367:1883-1890, 2012.
Sanchez E. : Diagnosis, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: a reviewJ Am Med Assoc. ;315:1767-1777, 2016.
Shapiro E.D. : Lyme diseaseN Engl J Med. ;370:1724-1731, 2014.
Yeung C., Baranchuk A. : Diagnosis and treatment of Lyme carditis: JACC review topic of the weekJ Am Coll Cardiol. ;73:717-726, 2019.

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