Spirochetes are distinguished by the helical shape of the bacteria. Pathogenic spirochetes include Treponema, Leptospira, and Borrelia. Both Treponema and Leptospira are too thin to be seen using brightfield microscopy but are clearly seen using darkfield or phase microscopy. Borrelia are thicker and can also be stained and seen using brightfield microscopy.
Epidemiology of Lyme Disease
Lyme disease was recognized in 1976 because of close clustering of cases in Lyme, Connecticut, and is now the most commonly reported tick-borne illness in the US. It has been reported in 49 states, but > 90% of cases occur from Maine to Virginia and in Wisconsin, Minnesota, and Michigan. On the West Coast, most cases occur in northern California and Oregon. Lyme disease also occurs in Europe, across the former Soviet Union, and in China and Japan.
In the US, Lyme disease is caused primarily by Borrelia burgdorferi and to a lesser extent by B. mayonii, which has recently been found in the upper midwestern states. In Europe and Asia, Lyme disease is caused primarily by B. afzelii, B. garinii, and B. burgdorferi. Onset is usually in the summer and early fall. Most patients are children and young adults living in heavily wooded areas.
Lyme disease is transmitted primarily by 4 Ixodes species worldwide:
I. scapularis (the deer tick) in the northeastern and north central US
I. pacificus in the western US
I. ricinus in Europe
I. persulcatus in Asia
In the US, the white-footed mouse is the primary animal reservoir for B. burgdorferi and the preferred host for nymphal and larval forms of the deer tick. Deer are hosts for adult ticks but do not carry Borrelia. Other mammals (eg, dogs) can be incidental hosts and can develop Lyme disease. In Europe, larger mammals such as sheep are hosts for the adult tick.
Deer ticks
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Pathophysiology of Lyme Disease
B. burgdorferi enters the skin at the site of the tick bite. After 3 to 32 days, the organisms migrate locally in the skin around the bite, spread via the lymphatics to cause regional adenopathy or disseminate in blood to organs or other skin sites. Initially, an inflammatory reaction (erythema migrans) occurs before significant antibody response to infection (serologic conversion).
Symptoms and Signs of Lyme Disease
Lyme disease has 3 stages:
Early localized
Early disseminated
Late
The early and late stages are usually separated by an asymptomatic interval.
Erythema migrans is the characteristic physical finding of early Lyme disease. It begins as a red macule at the site of the Ixodes tick bite. Classically, the macule expands with central clearing, as in this image, but, in many patients, no central clearing occurs. Some patients have central erythema surrounded by a pale ring, and a few develop vesicular or ulcerated centers.
Image courtesy of Thomas Habif, MD.
Erythema migrans may manifest as a rash with central erythema surrounded by a pale ring.
LARRY MULVEHILL/SCIENCE PHOTO LIBRARY
Erythema migrans can resemble a bull's eye, with central erythema surrounded by a pale ring and outer erythematous halo.
CDC/SCIENCE PHOTO LIBRARY
Early-localized stage
Erythema migrans, the hallmark and best clinical indicator of Lyme disease, is the first sign of the disease. It occurs in at least 75% of patients, beginning as a red macule or papule at the site of the tick bite, usually on the proximal portion of an extremity or the trunk (especially the thigh, buttock, or axilla), between 3 days and 32 days after a tick bite. Because tick nymphs are so small, most patients do not realize that they have been bitten.
The area expands, often with clearing between the center and periphery resembling a bull’s eye, to a diameter ≤ 50 cm. Darkening erythema may develop in the center, which may be hot to the touch and indurated. Without therapy, erythema migrans typically fades within 3 to 4 weeks.
Many patients with erythema migrans have a single lesion. Some patients develop multiple erythema migrans lesions, which are signs of early hematogenous dissemination (1 Early-localized stage reference Lyme disease is a tick-transmitted infection caused by the spirochete Borrelia species. Early symptoms include an erythema migrans rash, which may be followed weeks to months later by... read more 
). Mucosal lesions do not occur. Apparent recurrences of erythema migrans lesions after treatment are caused by reinfection, rather than relapse, because the genotype identified in the new lesion differs from that of the original infecting organism.
Early-localized stage reference
1. Nadelman RB, Hanincová K, Mukherjee P, et al: Differentiation of reinfection from relapse in recurrent Lyme disease. N Engl J Med 367(20):1883–1890, 2012. doi: 10.1056/NEJMoa1114362
Early-disseminated stage
Symptoms of early-disseminated disease begin days or weeks after the appearance of the primary lesion, when the bacteria spread through the body. Soon after onset, nearly half of untreated patients develop multiple, usually smaller annular secondary skin lesions without indurated centers. Cultures of biopsy samples of these secondary lesions have been positive, indicating dissemination of infection.
Patients also develop a musculoskeletal, flu-like syndrome, consisting of malaise, fatigue, chills, fever, headache, stiff neck, myalgias, and arthralgias that may last for weeks. Because symptoms are often nonspecific, the diagnosis is frequently missed if erythema migrans is absent; a high index of suspicion is required. Frank arthritis is rare at this stage. Less common are backache, nausea and vomiting, sore throat, lymphadenopathy, and splenomegaly.
Symptoms are characteristically intermittent and changing, but malaise and fatigue may linger for weeks. Resolved skin lesions may reappear faintly, sometimes before recurrent attacks of arthritis, in late-stage disease.
Neurologic abnormalities develop in about 15% of patients within weeks to months of erythema migrans (generally before arthritis occurs), commonly last for months, and usually resolve completely. Most common are lymphocytic meningitis (cerebrospinal fluid [CSF] pleocytosis of about 100 cells/mcL) or meningoencephalitis, cranial neuritis (especially Bell palsy Facial Nerve Palsy Facial nerve (7th cranial nerve) palsy is often idiopathic (formerly called Bell palsy). Idiopathic facial nerve palsy is sudden, unilateral peripheral facial nerve palsy. Symptoms of facial... read more 
, which may be bilateral), and sensory or motor radiculoneuropathies, alone or in combination.
Myocardial abnormalities occur in about 8% of patients within weeks of erythema migrans. They include fluctuating degrees of atrioventricular block (1st-degree, Wenckebach, or 3rd-degree) and, rarely, myopericarditis with chest pain, reduced ejection fractions, and cardiomegaly.
Late-stage disease
In untreated Lyme disease, the late stage begins months to years after initial infection. Arthritis develops in about 60% of patients within several months, occasionally up to 2 years, of disease onset (as defined by erythema migrans). Intermittent swelling and pain in a few large joints, especially the knees, typically recur for several years. Affected knees commonly are much more swollen than painful; they are often hot but rarely red. Baker cysts may form and rupture. Malaise, fatigue, and low-grade fever may precede or accompany arthritis attacks. In about 10% of patients, knee involvement is chronic (unremittent for ≥ 6 months).
Other late findings (occurring years after onset) include an antibiotic-sensitive skin lesion (acrodermatitis chronica atrophicans) and chronic central nervous system abnormalities, either polyneuropathy or a subtle encephalopathy with mood, memory, and sleep disorders.
Some patients have symptoms such as fatigue, headache, joint and muscle aches, and cognitive problems after successful antibiotic treatment. These symptoms are collectively referred to as post-treatment Lyme disease syndrome (PTLDS). Although some patients with such subjective symptoms are assigned the diagnosis of chronic Lyme disease, there is no clear evidence that these patients have viable Borrelia remaining in their body. The cause of these continuing symptoms is currently unclear, and treatment with more antibiotics does not help.
Diagnosis of Lyme Disease
Clinical evaluation, supported by acute and convalescent serologic testing
Erythema migrans is usually diagnosed clinically because it develops before serologic tests become positive (1 Diagnosis references Lyme disease is a tick-transmitted infection caused by the spirochete Borrelia species. Early symptoms include an erythema migrans rash, which may be followed weeks to months later by... read more , 2 Diagnosis references Lyme disease is a tick-transmitted infection caused by the spirochete Borrelia species. Early symptoms include an erythema migrans rash, which may be followed weeks to months later by... read more ).
Cultures of blood and relevant body fluids (eg, CSF, joint fluid) may be obtained, primarily to diagnose other pathogens.
Acute (IgM) and convalescent (IgG) antibody titers 2 weeks apart may be helpful (3 Diagnosis references Lyme disease is a tick-transmitted infection caused by the spirochete Borrelia species. Early symptoms include an erythema migrans rash, which may be followed weeks to months later by... read more ); positive enzyme-linked immunosorbent assay (C6 ELISA) titers should be confirmed by a second enzyme immunoassay (EIA) or Western blot test. However, seroconversion may be late (eg, > 4 weeks) or occasionally absent (eg, if patients received prior antibiotic therapy), and positive IgG titers alone represent previous exposure. If only IgM bands are detected on Western blot, especially long after exposure, the results are often false positive. Polymerase chain reaction (PCR) testing of CSF or synovial fluid is often positive when those sites are involved.
Consequently, diagnosis of Lyme disease depends on both test results and the presence of typical findings. A classic erythema migrans rash strongly suggests Lyme disease, particularly when supported by other elements (eg, recent tick bite, exposure to endemic area, typical systemic symptoms).
In areas where Lyme disease is endemic, many patients report arthralgias, fatigue, difficulty concentrating, or other nonspecific symptoms. Few patients who have these symptoms but have had no history of erythema migrans or other symptoms of early-localized or early-disseminated Lyme disease actually have Lyme disease. In such patients, elevated IgG titers (with normal IgM titers) indicate past exposure, not current or persistent infection, and may, if misinterpreted, lead to long and unnecessary courses of antibiotic therapy. There is no evidence linking B. burgdorferi infection to this fibromyalgia-like or chronic fatigue–like syndrome.
Differential diagnosis
In the absence of rash, diagnosis is more difficult.
Early-disseminated disease may mimic juvenile idiopathic arthritis Juvenile Idiopathic Arthritis (JIA) Juvenile idiopathic arthritis is a group of rheumatic diseases that begins by age 16. Arthritis, fever, rash, adenopathy, splenomegaly, and iridocyclitis are typical of some forms. Diagnosis... read more 
in children and reactive arthritis Reactive Arthritis Reactive arthritis is an acute spondyloarthropathy that often seems precipitated by an infection, usually genitourinary or gastrointestinal. Common manifestations include asymmetric arthritis... read more 
and atypical rheumatoid arthritis Rheumatoid Arthritis (RA) Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more 
in adults. Findings that are often present in rheumatoid arthritis but not Lyme disease include morning stiffness, subcutaneous nodules, iridocyclitis, mucosal lesions, rheumatoid factor, and antinuclear antibodies. Late-stage Lyme disease lacks axial involvement, which distinguishes it from spondyloarthropathies Overview of Seronegative Spondyloarthropathies Seronegative spondyloarthropathies (seronegative spondyloarthritides) share certain clinical characteristics (eg, inflammatory back pain, uveitis, gastrointestinal symptoms, rashes). Some are... read more with peripheral joint involvement.
In the US, human granulocytic anaplasmosis Ehrlichiosis and Anaplasmosis Ehrlichiosis and anaplasmosis are caused by rickettsial-like bacteria. Ehrlichiosis is caused mainly by Ehrlichia chaffeensis; anaplasmosis is caused by Anaplasma phagocytophilum... read more (a rickettsial infection) and babesiosis Babesiosis Babesiosis is infection with Babesia species of protozoa. Infections can be asymptomatic or cause a malaria-like illness with fever and hemolytic anemia. Disease is most severe in asplenic... read more as well as Borrelia miyamotoi relapsing fever and Powassan virus Powassan virus Arbovirus (arthropod-borne virus) applies to any virus that is transmitted to humans and/or other vertebrates by certain species of blood-feeding arthropods, chiefly insects (flies and mosquitoes)... read more encephalitis are also transmitted by I. scapularis and have a common geographic distribution in the northeastern and upper Midwest. Patients ill with any one of the diseases transmitted by I. scapularis may be concurrently infected with the other diseases it transmits. A clinician should suspect that patients with Lyme disease also have
Babesiosis (if they have hemolytic anemia and thrombocytopenia)
Human granulocytic anaplasmosis (if they have elevated aminotransferase levels, leukopenia, inclusion bodies in neutrophils, and/or thrombocytopenia)
Acute rheumatic fever Rheumatic Fever Rheumatic fever is a nonsuppurative, acute inflammatory complication of group A streptococcal pharyngeal infection, causing combinations of arthritis, carditis, subcutaneous nodules, erythema... read more 
is considered in the occasional patient with migratory polyarthralgias and either an increased PR interval or chorea (as a manifestation of meningoencephalitis). However, patients with Lyme disease rarely have heart murmurs or evidence of a preceding streptococcal infection.
Human monocytotropic ehrlichiosis Ehrlichiosis and Anaplasmosis Ehrlichiosis and anaplasmosis are caused by rickettsial-like bacteria. Ehrlichiosis is caused mainly by Ehrlichia chaffeensis; anaplasmosis is caused by Anaplasma phagocytophilum... read more , which is caused by Ehrlichia chaffeensis and transmitted by Amblyomma americanum (the Lone Star tick), occurs mainly in the southeastern and south central US and is unlikely to be confused with Lyme disease.
In southern and mid-Atlantic states, bites from the A. americanum tick may result in an erythema migrans–like rash accompanied by nonspecific self-limited systemic symptoms and signs. No specific infectious agent has yet been identified as the cause of this disorder (called southern tick-associated rash illness [STARI]).
Lyme disease may cause Bell palsy and, in summer, can manifest with a musculoskeletal aseptic meningitis syndrome that mimics other causes of lymphocytic meningitis or that mimics peripheral neuropathies.
Diagnosis references
1. Sanchez E, Vannier E, Wormser GP, et al: Diagnosis, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: A review. JAMA 315 (16):1767–1777, 2016. doi: 10:1001/jama.2016.2284
2. Bush LM, Vazquez-Pertejo MT: Tick borne illness—Lyme disease. Dis Mon 64(5):195–212, 2018. doi: 10.1016/j.disamonth.2018.01.007
3. Branda JA, Steere AC: Laboratory diagnosis of Lyme borreliosis. Clin Microbiol Rev 34(2):34:e00018-19. doi: 101128/CMR.00018-19
Treatment of Lyme Disease
Multiple alternatives that vary with stage of disease but typically include amoxicillin, doxycycline, and ceftriaxone
Most features of Lyme disease respond to antibiotics, but treatment of early disease is most successful. In late-stage disease, antibiotics eradicate the bacteria, relieving the arthritis in most people. However, a few genetically predisposed people have persistent arthritis even after the infection has been eliminated because of continued inflammation. Table see Table: Guidelines for Antibiotic Treatment of Lyme Disease in Adults* Guidelines for Antibiotic Treatment of Lyme Disease in Adults* 
shows adult treatment regimens for various manifestations of Lyme disease. Treatment in children is similar except that doxycycline is avoided in children < 8 years of age and doses are adjusted based on weight.
For symptomatic relief, nonsteroidal anti-inflammatory drugs (NSAIDs) may be used.
Complete heart block may require a temporary pacemaker.
Tense knee joints due to effusions require aspiration. Some genetically predisposed patients with arthritis of the knee that persists despite antibiotic therapy may respond to arthroscopic synovectomy.
Prevention of Lyme Disease
Precautions against tick bites ( see Tick Bite Prevention Tick Bite Prevention ) should be taken by people in endemic areas. Deer tick nymphs, which attack humans, are small and difficult to see. Once attached to the skin, they gorge on blood for days. Transmission of B. burgdorferi does not usually occur until the infected tick has been in place for > 36 hours. Thus, searching for ticks after potential exposure and removing them promptly can help prevent infection.
Although a single dose of oral doxycycline 200 mg has been shown to reduce the likelihood of Lyme disease after a deer tick bite, routine antibiotic prophylaxis to prevent Lyme disease after a recognized tick bite is not recommended. Patients with a known tick bite can easily be instructed to monitor the bite site and seek care if rash or other symptoms occur; the diagnostic dilemma of Lyme is most prominent when there is no history of tick bite. According to the 2020 Infectious Diseases Society of America (IDSA) guidelines, antibiotic prophylaxis should be offered only when all the following circumstances exist (1 Prevention reference Lyme disease is a tick-transmitted infection caused by the spirochete Borrelia species. Early symptoms include an erythema migrans rash, which may be followed weeks to months later by... read more ):
The attached tick can be reliably identified as an adult or nymphal I. scapularis tick.
The tick is estimated to have been attached ≥ 36 hours (based on degree of engorgement of the tick with blood or time of exposure).
Prophylaxis can be started within 72 hours of tick removal. (See How to Remove a Tick How To Remove a Tick Ticks should be removed from the skin to prevent tick-borne disease (eg, Rocky Mountain spotted fever, Lyme disease, tularemia, tick paralysis, babesiosis, anaplasmosis, ehrlichiosis, tick-borne... read more .)
Patients live in or have visited an area where ≥ 20% of these ticks are infected with B. burgdorferi (generally only in parts of New England, parts of the mid-Atlantic states, and parts of Minnesota and Wisconsin).
Doxycycline is not contraindicated; it is contraindicated only in pregnant or lactating women, children < 8 years of age, and people who have had an allergic reaction to a tetracycline antibiotic.
Prevention reference
1. Lantos PM, Rumbaugh J, Bockenstedt LK, et al: Clinical practice guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the prevention, diagnosis and treatment of Lyme disease. Clin Infect Dis 72(1):e1–e48, 2021. doi: 10.1093/cid/ciaa1215
Key Points
In the US, > 90% of Lyme disease cases occur from Maine to Virginia and in Wisconsin, Minnesota, and Michigan; Ixodes scapularis (the deer tick) is the primary vector in these areas.
In the US, the white-footed mouse is the primary animal reservoir for Borrelia burgdorferi and the preferred host for nymphal and larval forms of the deer tick; deer are hosts for adult ticks but do not carry Borrelia.
Lyme disease has 3 stages: early localized, early disseminated, and late.
Erythema migrans is the first and best clinical indicator; it occurs in ≥ 75% of patients.
In endemic areas, few patients who have arthralgias, fatigue, difficulty concentrating, or other nonspecific symptoms but who have had no history of erythema migrans or other symptoms of early-localized or early-disseminated Lyme disease actually have Lyme disease.
Diagnose clinically if typical rash is present; otherwise, do acute and convalescent serologic testing (C6 ELISA confirmed by enzyme immunoassay or Western blot).
Treat with oral or parenteral antibiotics depending on disease manifestations.
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
amoxicillin |
Amoxil, Dispermox, Moxatag, Moxilin , Sumox, Trimox |
doxycycline |
Acticlate, Adoxa, Adoxa Pak, Avidoxy, Doryx, Doxal, Doxy 100, LYMEPAK, Mondoxyne NL, Monodox, Morgidox 1x, Morgidox 2x , Okebo, Oracea, Oraxyl, Periostat, TARGADOX, Vibramycin, Vibra-Tabs |
ceftriaxone |
Ceftrisol Plus, Rocephin |
tetracycline |
Emtet-500, Panmycin, Sumycin |
