LYME DISEASE

LYME DISEASE

Current Diagnosis

• Lyme disease is a spirochete tick-borne illness of public health importance in temperate regions of North America, Europe, and Asia.

• Evidence suggests that an infected tick must remain attached for at least 36 to 48 hours in order to produce Lyme disease.

• The most common objective manifestation of early localized disease is the characteristic erythema migrans rash.

• Erythema migrans is classically reported as a single uniform erythematous oval to circular lesion that expands for days to weeks and that may or may not produce central clearing of erythema on expansion (known as the “bull’s-eye” rash).

• The most common laboratory method endorsed by national guidelines recommends a two-tier serology testing protocol using an enzyme-linked immunosorbent assay (ELISA) as an initial screen, followed by the more specific Western immunoblot to confirm the diagnosis when the ELISA result is equivocal or positive.

• Intrathecal antibody synthesis and polymerase chain reaction (PCR) assays are important diagnostic methods for neuroborreliosis.

• PCR assays are an important diagnostic method for late Lyme arthritis.

• Antibodies produced in response to Borrelia species may persist for years following standard antimicrobial therapy; these persistently elevated levels should not be interpreted as an indication of ineffective treatment or chronic infection.

Current Therapy

• Highly effective oral antibiotics such as doxycycline (Vibramycin),1 amoxicillin (Amoxil),1 and cefuroxime axetil (Ceftin) are considered first-line agents.

• Experts recommend doxycycline (Vibramycin) as the preferred agent for oral treatment due to its activity against other tick-borne illnesses such as human granulocytic anaplasmosis (Anaplasma phagocytophilum), which may occur in as many as 10% of patients with Lyme disease.

• Doxycycline (Vibramycin) is contraindicated in pregnant and breastfeeding women and in children younger than 8 years.

• Intravenous regimens, such as cefotaxime (Claforan)1 or ceftriaxone (Rocephin),1 are reserved for patients with neurologic symptoms (e.g., meningitis with or without facial palsy), symptoms of cardiac disease and/or significant conduction abnormality (e.g., first-degree atrioventricular block and PR interval greater than 30 milliseconds, as well as second- or third-degree atrioventricular block), or, in a few cases, refractory Lyme arthritis.

• Patients with early Lyme disease characterized as a solitary erythema migrans lesion can be treated effectively with a 10-day course of doxycycline (Vibramycin).1

• Patients with early disseminated or late disease can be successfully treated with 10 to 28 days of therapy.

• Vaccination for Lyme disease is currently unavailable as a preventive measure for humans.

• The best preventive measures are represented by avoidance of areas with high tick burden (e.g., wooded or grassy areas with a large deer population) and personal protective measures (e.g., bathing following outdoor activities, frequent body checks for ticks, and wearing light-colored protective clothing and tick repellants [diethyltoluamide, DEET]).

• Randomized clinical trials found no evidence that prolonged antibiotic therapy provided benefit in patients with chronic Lyme disease.

1 Not FDA approved for this indication.

Epidemiology

Lyme disease, also known as Lyme borreliosis, is a spirochete tick- borne illness of public health importance in temperate regions of North America, Europe, and Asia. Among the spirochete genus Borrelia, the most common species associated with this illness is Borrelia burgdorferi sensu lato. This species is further classified into many different genospecies of which at least three are pathogenic to humans: B. afzelii, B. garinii, and B. burgdorferi sensu lato. All pathogenic spirochetes are transmitted to humans by the hard-bodied ticks of the Ixodes ricinus complex. B. afzelii, transmitted most commonly by Ixodes ricinus, and B. garinii, transmitted most commonly by Ixodes persulcatus, account for the majority of cases in Europe and Asia, respectively. In the United States, B. burgdorferi sensu lato, transmitted by the black-legged deer tick Ixodes scapularis (Ixodes pacificus on the West Coast), is the sole species to cause infection.

Hard-bodied Ixodid ticks typically have a 2- to 6-year life cycle with four stages of development: egg, larval stage, nymphal stage, and adult stage. Nymph ticks are most active during the period from late spring (May) to early autumn (September) and predominantly obtain blood meals from mice or voles, such as the white-footed mouse (Peromyscus leucopus), which serve as a natural reservoir for B. burgdorferi sensu lato. Although deer are not considered competent reservoirs for Borrelia spirochetes, they are important for the life cycle because they represent a sufficient source of blood meal for adult ticks to maintain the tick population. Although ticks may become infected at any active stage of the life cycle, nymphs and adult females are more likely to harbor the spirochete for further transmission to humans.

The occurrence of a tick bite and the duration of tick attachment are critical factors affecting the risk of spirochete transmission and onset of illness. Evidence suggests that an infected tick must remain attached for at least 36 to 48 hours during a blood meal in order for B. burgdorferi sensu lato to migrate from the tick midgut through the salivary glands and into the host to produce Lyme disease. Although nymphs and adult Ixodid tick species can transmit the bacterium, it is more likely to occur with nymphs.

As reported by the Centers for Disease Control and Prevention (CDC) for the surveillance of Lyme disease from 1992 through 2006, 93% of cases in the United States occurred within the following states: Connecticut, Delaware, Maine, Maryland, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, and Wisconsin. Lyme disease is associated with a distinct seasonality with the highest number of cases occurring between June and August each year, coinciding with increased nymph activity and outdoor human recreational events. Additionally, the disease is also associated with a slight male predominance and with greater incidence among persons age 5 to 9 years and 55 to 59 years.

Risk Factors

In the United States, the risk of Lyme disease is highest among persons, particularly males, who reside within those 12 states considered as having high endemic rates. Outdoor occupational activities, such as forestry, agricultural farming, and landscaping, with increased exposure to tick-infested areas are considered strong risk factors. Leisure outdoor activities, such as camping, hunting, fishing, and gardening, also place persons at risk for infection.

Clinical Manifestations

In general, the clinical manifestations of Lyme disease are similar among the three pathogenic species and follow three well-recognized clinical stages: early localized disease, early disseminated disease, and late disease.

Early Localized Disease

Lyme disease typically begins within 7 to 14 days (range of 3 to 30 days) following a tick bite that is associated with prolonged tick attachment (at least 36 hours in the United States). The most common objective manifestation of early localized disease, the characteristic erythema migrans rash, may develop in as many as 80% of patients.

This characteristic finding is classically reported to begin as a single uniform erythematous oval to circular lesion that expands for days to weeks with a median diameter of 16 cm (range of 5 to 70 cm).

Approximately 19% of erythema migrans rashes produce central clearing of erythema on expansion (known as the “bull’s-eye” rash). The skin lesion caused by B. afzelii often expands, or migrates, more slowly and persists for a longer period of time; therefore, it was initially known as erythema chronicum migrans. The CDC has defined erythema migrans as an expanding red macule or papule, with or without central clearing, which must reach at least 5 cm in size. Lesions most often occur at anatomic sites such as the abdomen, axilla, back, groin or inguinal region, and popliteal fossa and may be associated with nonspecific symptoms that often include chills, fatigue, fever, headache, or myalgia.

Early Disseminated Disease

Multiple erythema migrans lesions, which usually present from 3 to 5 weeks following an initial tick bite, may occur in up to 10% to 20% of patients and is the most common manifestation of early disseminated disease. Borrelia lymphocytoma, characterized as a painless red to blue nodule commonly located on the ear, breast, or scrotum, is an additional cutaneous manifestation of early disseminated disease that is more frequent in children and seen almost exclusively in Europe.

Each of the three pathogenic Borrelia species disseminates systemically via the lymphatic system or blood to primarily cause infection of the central nervous system, cardiovascular system, and musculoskeletal system; however, certain species may have a higher frequency to localize to certain areas. For example, whereas B. burgdorferi sensu lato often disseminates widely and tends to be more arthritogenic, B. garinii often disseminates less widely and is more neurotropic.

Musculoskeletal symptoms, such as transient oligoarticular arthralgia or myalgia that may also include joint swelling, are the most common extracutaneous manifestations of early disseminated disease.

Approximately 15% of patients may experience neurologic manifestations that may include altered mental status, headache, and neck pain and stiffness (indicating possible Lyme-associated lymphocytic meningitis), as well as motor or sensory radiculoneuropathy, mononeuritis multiplex, cerebellar ataxia, and myelitis. Lyme disease must be included in the differential diagnosis of a seventh cranial nerve palsy (known as Bell’s palsy), which is commonly unilateral but may rarely be bilateral. B. garinii is associated with a particular meningoradiculoneuritis called Bannwarth’s syndrome, which is characterized as painful motor and sensory peripheral radiculopathies, mostly of the cervical and lumbar region, in association with a cerebrospinal fluid lymphocytic pleocytosis. Finally, approximately 4% to 10% of patients may experience Lyme carditis, usually occurring within 1 to 2 months after a tick bite, which may present with dyspnea on exertion, fatigue, nonspecific chest pain, palpitations, or syncope. Evidence suggests that 49% of patients with Lyme carditis may have third-degree atrioventricular block, 28% may have some form of second- or first- degree atrioventricular block, and 23% may have no conduction abnormalities.

Late Lyme Disease

In the United States, the most common manifestation of late Lyme disease, which occurs in as many as 60% of patients, is arthritis.

Patients typically present approximately 6 months after an initial tick bite with joint pain and swelling and synovial fluid findings that suggest an inflammatory process. Late Lyme disease arthritis primarily involves the knees. Chronic antibiotic-refractory arthritis may develop in patients who are infected with B. burgdorferi sensu lato and also carry the HLA-DR4 alloantigen. Alternatively, a common late manifestation in Europe, associated with B. afzelii infection, is acrodermatitis chronica atrophicans (ACA), which is characterized initially as a progressive painless red to blue fibrous nodule, usually located on the extensor surfaces of the extremities, that eventually becomes atrophic. Rarely, late disease may present with an encephalomyelitis, an axonal polyneuropathy, or a subtle, subacute encephalopathy that typically manifests with cognitive impairment.

Diagnosis

According to the Infectious Diseases Society of America (IDSA) guidelines, the erythema migrans skin lesion is the only clinical manifestation sufficiently distinctive to make the diagnosis of Lyme disease in the absence of laboratory confirmation. Without an erythema migrans skin lesion, serology is the most common laboratory method endorsed by both the CDC and IDSA to confirm the diagnosis (Table 1). Currently, the CDC recommends a two-tier serology testing protocol using an ELISA as an initial screen, followed by the more specific Western immunoblot to confirm the diagnosis when the ELISA result is equivocal or positive. A positive IgM Western immunoblot requires at least two of three significant bands (23, 39, 41 kDa) to be present within 4 weeks’ duration of illness because these antibodies typically appear 2 to 4 weeks after the onset of an erythema migrans rash (IgM antibody production peaks at 6 to 8 weeks). A positive IgG Western immunoblot requires at least 5 of 10 significant bands (18, 23, 28, 30, 39, 41, 45, 58, 66, 93 kDa) because these antibodies typically appear after 4 to 6 weeks from the onset of an erythema migrans skin lesion (IgG antibody production peaks at 4 to 6 months and may remain positive for many years). Antibodies produced in response to Borrelia species may persist for years following standard antimicrobial therapy; these persistently elevated levels should not be interpreted as an indication of ineffective treatment or chronic infection. Evidence suggests that a new ELISA called the C6 peptide assay has comparable sensitivity and specificity to the standard two-tier protocol, but further evaluation is needed to determine the optimal use of this assay. Finally, PCR testing may be an option for selected patients with late Lyme arthritis or neurologic disease, and it has the highest sensitivity for Lyme disease using synovial fluid or tissue samples from patients with untreated late Lyme arthritis.

Table 1

Estimated Accuracy of Two-tier Serology by Stage and Manifestations of Lyme Disease

 

Abbreviations: PPV = positive predictive value; NPV = negative predictive  value.

* Data calculated from Branda JA et al: Clin Infect Dis 2010;50:20–6; however, the negative predictive value at this stage may more accurately be between 98% and  100%.

Treatment

Lyme disease treatment recommendations have been published by the IDSA and are guided mainly by the clinical manifestations and stage of the disease (Table 2). Although erythema migrans resolves without antimicrobial therapy, the goals of early treatment are to prevent dissemination and development of further clinical manifestations.

Evidence has demonstrated that most Borrelia species remain susceptible to many macrolides, most penicillins, many second- and third-generation cephalosporins, and tetracyclines. In general, highly effective oral antibiotics such as doxycycline (Vibramycin),1 amoxicillin (Amoxil),1 and cefuroxime axetil (Ceftin) are considered first-line agents. Many experts recommend doxycycline (Vibramycin) as the preferred agent for oral treatment due to its activity against other tick-borne illnesses such as human granulocytic anaplasmosis (Anaplasma phagocytophilum), which may occur in as many as 10% of patients with Lyme disease. Doxycycline (Vibramycin) is contraindicated in pregnant and breastfeeding women and in children younger than 8 years. Intravenous regimens, such as cefotaxime (Claforan)1 or ceftriaxone (Rocephin),1 are reserved for patients with neurologic symptoms (e.g., meningitis with or without facial palsy), symptoms of cardiac disease and/or significant conduction abnormality (e.g., first-degree atrioventricular block and PR interval greater than 30 milliseconds, as well as second- or third-degree atrioventricular block), or, in a few cases, refractory Lyme arthritis. In general, patients with early Lyme disease characterized as a solitary erythema migrans lesion can be treated effectively with a 10-day course of doxycycline (Vibramycin).1 Although the duration of treatment for early Lyme disease can range from 10 to 21 days, patients with early disseminated or late disease can be successfully treated with 10 to 28 days of therapy (duration depends on the choice of agent).

Table 2

Recommended Antibiotics* for the Treatment of Lyme Disease

Abbreviation: EM = erythema migrans.

1  Not FDA approved for this indication.

* All listed antibiotics other than doxycycline (Vibramycin) are classified as pregnancy class B (low pregnancy risk).

† Patients with Bell’s palsy and a normal cerebrospinal fluid examination can be treated with a 14-day course of the same antibiotics used to treat early localized disease. Additionally, patients with Lyme meningitis and an allergy or listed intolerance to beta-lactam antibiotics  may be treated with doxycycline (Vibramycin) 200–400 mg in two divided doses daily for 10– 28 days.

‡ Patients with persistent joint pain and swelling following initial therapy may undergo another course of oral antibiotics or a 2- to 4-week course of intravenous  antibiotics.

Lyme Disease Relapse versus Reinfection

Patients with untreated early Lyme infection who have not developed further cardiac or neurologic complications may occasionally experience recurrent erythema migrans lesions in association with episodes of arthritis that most often are due to relapse of the original infection. In contrast, patients who have been successfully treated for early Lyme disease with recommended antibiotic therapy may experience reinfection as the result of a new tick-transmitted spirochete characterized as recurrent erythema migrans lesions, with new anatomic locations, during subsequent Lyme transmission seasons (e.g., late spring and early summer). Recent evidence provides further support that recurrent erythema migrans in patients who have successfully completed recommended antibiotic therapy were associated with reinfection due to a new B. burgdorferi genotype (based on the evaluation of outer-surface protein C [OspC] genotypes).

Persistent Lyme Arthritis and Post– Lyme Disease Syndrome

In the United States, approximately 10% of patients who have objective evidence of Lyme and have completed treatment for B. burgdorferi sensu lato experience an antibiotic-refractory Lyme arthritis that is defined as persistent synovitis for greater than 1 month (following a 60-day course of oral doxycycline) or 2 months (following a standard course of intravenous ceftriaxone) duration despite negative PCR testing on synovial fluid. Persistent Lyme arthritis is a distinct entity from the post–Lyme disease syndrome (also referred as chronic Lyme disease) in which patients may experience nonspecific symptoms (e.g., arthralgia, concentration difficulties, fatigue, headache, memory deficits, or myalgia) with or without clinical or laboratory evidence of Lyme disease. Whereas advocates of the term chronic Lyme disease suggest a latent intracellular infection that may require months to years of antimicrobial therapy for eradication, critics suggest that continued symptoms are explained by an autoimmune response that is triggered by an association between Lyme disease and certain human leukocyte antigen (HLA) haplotypes (e.g., HLA-DR4). Recent evidence from a mouse model of Lyme disease proposes that the persistence of inflammatory spirochete antigens, but not infectious live bacteria, in close association with cartilage may also provide an explanation of the nonspecific musculoskeletal symptoms associated with antibiotic-refractory Lyme arthritis. Although controversy exists regarding the pathogenesis and treatment of post–Lyme disease syndrome, or chronic Lyme disease, four randomized clinical trials found no evidence that prolonged antibiotic therapy provided benefit in long-term symptom remission. Currently, the American Academy of Pediatrics, American Academy of Neurology, American College of Rheumatology, and IDSA do not recommend prolonged antibiotic therapy for chronic Lyme disease.

Prevention

Vaccination for Lyme disease is currently unavailable as a preventive measure for humans. LYMErix (SmithKline Beecham Biologicals, Philadelphia, PA), a recombinant lipoprotein outer-surface protein A vaccine, was removed from the market in 2002 due to limited demand; therefore, vaccination for Lyme disease is unavailable as a preventive measure for humans. Currently, the best preventive measures are represented by avoidance of areas with high tick burden (e.g., wooded or grassy areas with a large deer population) and personal protective measures (e.g., bathing following outdoor activities, frequent body checks for ticks, and wearing light-colored protective clothing and tick repellants [diethyltoluamide, DEET]).

Removal of ticks within 24 hours of attachment using fine-tipped forceps (with care taken to grasp the tick as close to the skin as possible without compressing the body) can also prevent the acquisition of Lyme disease. Antibiotic prophylaxis, using a single 200-mg dose of doxycycline (Vibramycin)1 within 72 hours of tick removal, in adults and children 8 years or older has been recommended in the United States for engorged ticks that have been attached for 36 hours or longer. Amoxicillin (Amoxil)1 prophylaxis is not recommended in persons in whom doxycycline is contraindicated (e.g., pregnant and breastfeeding women, and children younger than 8 years) due to insufficient data on dose, duration, and efficacy.

References

1.     Bacon R.M., Kugeler K.J., Mead P.S.Centers for Disease Control and Prevention (CDC). Surveillance for Lyme disease—United States, 1992–2006. MMWR Surveill Summ. 2008;57:1–9.

2.    Bockenstedt L.K., Gonzalez D.G., Haberman A.M., et al. Spirochete antigens persist near cartilage after murine Lyme borreliosis therapy. J Clin Invest. 2012;122:2652–2660.

3.     Branda J.A., Aguero-Rosenfeld M.E., Ferraro M.J., et al. 2-Tiered antibody testing for early and late Lyme disease using only an immunoglobulin G blot with the addition of the VlsE band as the second tier test. Clin Infect Dis. 2010;50:20–26.

4.    Coulter P., Lema C., Flayhart D., et al. Two-year evaluation of Borrelia burgdorferi culture and supplemental tests for definitive diagnosis of Lyme disease. J Clin Microbiol. 2005;43:5080–5084 (Erratum: J Clin Microbiol 2007;45:277).

5.     Fallon B.A., Keilp J.G., Corbera K.M., et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology. 2008;70:992–1003.

6.      Klempner M.S., Hu L.T., Evans J., et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med. 2001;345:85–92.

7.    Krupp L.B., Hyman L.G., Grimson R., et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology. 2003;60:1923–1930.

8.    Nadelman R.B., Hanincova K., Mukherjee P., et al. Differentiation of reinfection from relapse in recurrent Lyme disease. N Engl J Med. 2012;367:1883–1890.

9.       Nadelman R.B., Nowakowski J., Fish D., et alTick Bite Study Group. Prophylaxis with a single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med. 2001;345:79–84.

10.       Stupica D., Lusa L., Ruzic-Sabljic E., et al. Treatment of erythema migrans with doxycycline for 10 days versus 15 days. Clin Infect Dis. 2012;55:343–350.

11.    Wormser G.P., Dattwyler R.J., Shapiro E.D., et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43:1089–1134 (Erratum: Clin Infect Dis 2007;45:941).

12.       Wormser G.P., Ramanathan R., Nowakowski J., et al. Duration of antibiotic therapy for early Lyme disease: a randomized, double-blind, placebo-controlled trial. Ann Intern Med.  2003;138:697–704.

13. Wright W.F., Riedel D.J., Talwani R., et al. Diagnosis and management of Lyme disease. Am Fam Physician. 2012;85:1086–1093.

1  Not FDA approved for this  indication.

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