Lyme borreliosis is the most frequent tick-transmitted disease in the United States. The wide spectrum of clinical manifestations of Lyme disease in the 3 stages of infection include early disease, early disseminated disease, and late (or chronic) disease. Serologic testing should begin with ELISA. If this test is reactive, immunoblot assay is indicated. Identification of the etiologic agent by culture or polymerase chain reaction should be confined to specific indications, such as neurologic and arthritic symptoms, and to specialized laboratories. Several antibiotics are effective against Lyme disease. Empiric treatment of patients with erythema migrans is recommended, without serologic testing. The diagnosis remains a challenge in the absence of skin lesions. Lyme disease can have debilitating effects if left untreated; early treatment can prevent systemic infection.

Lyme disease can have severe health consequences if left untreated. Caused by the spirochete Borrelia burgdorferi, Lyme disease is the most common tick-borne illness in the United States.¹ Some 23,300 cases of Lyme disease were reported to the Centers for Disease Control and Prevention (CDC) in 2005, for a national average of 7.9 cases per 100,000 persons.² In the 10 states where the infection is most common, there were 31.6 cases per 100,000 persons.³ According to the CDC, Lyme disease is endemic in Connecticut, Delaware, Maine, Maryland, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Pennsylvania, Vermont, and Wisconsin.³ The disease is also endemic in Europe and Asia.

The 3 pathogens causing the disease are B burgdorferi, Borrelia afzelii, and Borrelia garinii,⁴ but only B burgdorferi strains have been found in the United States. Lyme borreliosis is transmitted by ticks of the Ixodes ricinus complex, including Ixodes scapularis (Figure 1).¹ These ticks have larval, nymphal, and adult stages, and require blood meals at each stage. The risk of becoming infected with Lyme disease depends on the density of the ticks in the specific geographical area, their feeding habits, and animal hosts.⁴ The frequency of Lyme disease in humans is high during the late spring and throughout the summer months. The virulence factor of B burgdorferi is the outer surface proteins that allow the spirochete to attach to the mammalian cells.⁴

Illustrative Case

A 22-year-old woman was seen in the clinic in early summer for a progressively enlarging rash on her right cheek that first appeared 4 to 5 days ago. She also reported generalized malaise. She said that a tick bit her a few days ago when she was camping outdoors. She reported no pain, itching, fever, chills, or joint pain. On physical examination, her vital signs were normal. A nontender, 6- x 5-cm erythematous area with central clearing was noted on the right cheek (Figure 2), suggestive of erythema migrans. No tick or bite mark was seen. Examination of the heart, lungs, abdomen, and joints was normal. Laboratory testing showed normal values for hemoglobin, white blood cell count, serum glucose, renal and liver function, electrolytes, urinalysis, and erythrocyte sedimentation rate. The history and clinical findings were suggestive of Lyme disease. The patient was immediately started on a 21-day course of oral doxycycline (eg, Adoxa, Doryx, Periostat), which resulted in complete resolution of her symptoms.

Figure 1—The Ixodes scapularis tick is found on a wide range of hosts, including mammals, birds, and reptiles.

Clinical Features

Clinical manifestations of Lyme disease typically appear within 7 to 14 days after a tick bite, with an overall reported range of 3 to 30 days.⁵ The tick must feed for at least 24 hours before transmission of the spirochete (which is in the midgut of the tick) occurs. There are 3 stages of Lyme disease. Early infection (stage 1) consists of localized erythema migrans. This is followed within days or weeks by disseminated infection (stage 2) that affects the nervous system, heart, and especially the joints. The third stage, occurring within weeks to months of the second, is late or persistent infection.

Figure 2—A nontender, 6- x 5-cm erythematous area with central clearing suggestive of erythema migrans.

In more than 80% of patients in the United States, Lyme disease begins with a slowly expanding erythema migrans manifested by a skin lesion at the site of the tick bite.⁶ This is the most common manifestation of early Lyme disease, typically presenting as a centrifugally expanding, erythematous annular patch, with central clearing.⁷ The lesion should be at least 5 cm in its largest diameter for a definitive diagnosis.¹

In the absence of erythema migrans in a patient with signs and symptoms typical of Lyme disease, the physician should inquire about a possible tick bite and carefully review the patient's travel and outside activity history, as well as recent residency. Look for signs and symptoms of late complications (ie, neurologic, cardiac) of Lyme disease.

Associated features include flulike symptoms, such as malaise, fatigue, headache, and fever; arthralgia; myalgia; and regional lymphadenopathy. Erythema migrans in the United States tends to be faster spreading, more intensely inflamed, and of briefer duration than in Europe or in Asia.⁴ It is also more likely to be associated with systemic signs and symptoms, such as fever, fatigue, and myalgia,⁸ suggesting hematogenous dissemination.⁴ In one US study, spirochetes were cultured in plasma samples obtained from 50% of patients with erythema migrans. In Europe and Asia, erythema migrans is often an indolent, localized infection of the skin. (In these regions, acrodermatitis chronica atrophicans, caused primarily by B afzelii and occurring during the chronic phase of disease, is more common than in the United States.⁴)

Neurologic manifestations, occurring weeks to months after the tick bite, include lymphocytic meningitis, cranial neuritis, particularly of the facial nerve (including Bell's palsy), and radiculoneuritis (numbness, tingling, and aching pain).

Common musculoskeletal manifestations consist of migratory musculoskeletal pain. Untreated patients may have intermittent or chronic monoarticular or oligoarticular arthritis, primarily affecting the large joints, especially the knees. Studies suggest that from 9% to 26% of patients are coinfected with other tick-borne illnesses,¹⁰ primarily human granulocytic anaplasmosis or babesiosis, which should be suspected in patients with more severe initial symptoms, such as high-grade fever lasting more than 48 hours despite appropriate antibiotic therapy, and in those who live in areas with a high incidence of the 2 causative pathogens.¹

Late cardiac manifestations in untreated patients, also occurring weeks to months after the tick bite, primarily consist of conduction system abnormalities, such as progression to complete heart block and mild myocarditis. Ocular complications are rare and include follicular conjunctivitis, keratitis, periorbital edema, photophobia, and subconjunctival hemorrhage.

Diagnosis

In the United States, the diagnosis of Lyme disease is usually based on the characteristic clinical findings and a history of exposure in an area where the disease is endemic.

Serologic testing should be used only when the diagnosis is uncertain and there is at least an intermediate (20% to 80%) pretest probability of Lyme disease,¹¹ for example, in patients with signs or symptoms of disseminated disease who do not have the pathognomonic erythema migrans rash,¹ or in patients with recurrent oligoarticular inflammatory arthritis.¹² Serologic testing should not be ordered for patients who are asymptomatic, who have physician-diagnosed erythema migrans, or who are receiving empiric antibiotic treatment. In addition, serology should not be used as a test of cure, because serologic results may remain positive after Lyme disease has been successfully treated or cured.¹³

Serologic testing is performed in 2 steps, using serum samples obtained both during the acute phase (the first 2 weeks of infection) and the convalescent phase (2 weeks after the acute phase).¹ These tests are insensitive during the first several weeks of infection; seroreactivity increases during the convalescent phase. Detection rates for serum antibodies are 20% to 50% in stage 1, 70% to 90% in stage 2, and nearly 100% in stage 3 Lyme disease.¹⁴

ELISA is the first-tier test; if it is reactive (ie, there is an antibody response to B burgdorferi) or the result is equivocal, the same specimen should be retested by separate immunoglobulin (Ig) M and IgG standard Western blot assays.^1,15 The initial serologic response is IgM antibody; this becomes an IgG antibody response after 1 month. The antibody titer falls slowly after antibiotic treatment, but IgM and IgG responses may persist for many years. They are not, however, indicative of active infection.¹⁶

Polymerase chain reaction (PCR) analysis identifies the DNA of B burgdorferi, and culture of skin or blood specimens identifies Borrelia species. Neither test, however, is recommended in routine clinical practice, since both tests are cumbersome and expensive.¹ Except in the rare patient with acrodermatitis, positive culture has been obtained only in the early stage of Lyme disease, primarily from biopsy samples of erythema migrans lesions, 17 in about half of the time from plasma samples,⁹ and only occasionally from cerebrospinal fluid samples in patients with Lyme meningitis. In patients with Lyme arthritis whose symptoms persist despite appropriate treatment, PCR testing for B burgdorferi in a synovial fluid sample may be indicated to guide further therapy.¹ The experimental Lyme urine antigen test has not been clinically validated and should not be used to support the diagnosis.¹

An electrocardiogram should be performed if the patient has cardiovascular symptoms. Arthrocentesis with synovial fluid analysis can be used to exclude other causes of rheumatoid arthritis.

Treatment

In 2006, the Infectious Diseases Society of America updated their Lyme disease management guidelines and provided drug therapy recommendations (Table).¹ Empiric antibiotic therapy is recommended for adults with erythema migrans (even without serologic testing). The treatment for early localized or early disseminated Lyme disease—in those with erythema migrans who do not have neurologic signs and symptoms or advanced atrioventricular heart block—consists of a 14-day course of doxycycline 100 mg twice daily, amoxicillin (Amoxil) 500 mg 3 times daily, or cefuroxime axetil (Ceftin) 500 mg twice daily.¹

Doxycycline may be effective when used for 10 days, but up to 21 days of treatment may be required. For doxycycline and amoxicillin, the therapeutic course ranges from 14 to 21 days. There is no evidence that a longer treatment course offers any benefits.¹ Doxycycline is relatively contraindicated in women who are pregnant or lactating and in children younger than 8 years. Thus, one of the other 2 agents should be used in these patient populations. When one of the 3 first-line agents is not tolerated or is contraindicated, an oral macrolide antibiotic can be used, such as erythromycin (Ery-Tab, PCE Dispertab; adult dosage—500 mg 4 times daily for 14-21 days). Agents that should not be used to treat Lyme disease include first-generation cephalosporins, such as cephalexin (Keflex), and sulfonamides.¹

Parenteral therapy is usually required for treatment of patients with acute neurologic disease (ie, meningitis or radiculopathy), for patients with Lyme carditis who have second- or third-degree atrioventricular block, and for all hospitalized patients.¹

Patients with Lyme disease who do not receive appropriate antibiotic therapy are at risk of developing arthritis, neurologic manifestations, and cardiac abnormalities. However, these occur much less frequently than was reported 20 years ago, possibly because of better recognition and treatment of erythema migrans.¹

The frequency of Lyme disease after a recognized tick bite is only about 1%, because the tick must be attached for 24 hours for infection transmission to occur.¹⁸ If the attached tick is removed quickly, no treatment is usually required. However, a single 200-mg dose of doxycycline can effectively prevent Lyme disease in this scenario and may be offered to individuals who meet all the following criteria¹:

• The attached tick is identified as I scapularis and was attached for at least 36 hours
• Prophylaxis is started within 72 hours of the removal of the tick
• The rate of B burgdorferi  infection of these ticks is at least 20% in the local area
• Doxycycline is not contraindicated.

Prevention

Preventive measures include avoiding tick-infested areas, wearing protective and light-colored clothing (the latter allows easier identification of a tick), using repellants that contain N,N-diethyl-3-methylbenzamide (DEET), frequent checking of the skin and clothing for ticks, and modifying the landscape (eg, removing brush and leaf litter) in or near residential areas in the late spring and summer (May through August), when nymphal ticks feed.¹ An embedded tick should be removed with fine-tipped tweezers. After grasping the tick close to the skin, it should be pulled away from the skin using a steady motion. Do not use petroleum jelly, nail polish, a hot match, or other products to remove ticks.

A Lyme disease vaccine (LYMErix) was approved in 1998, but it was withdrawn from the market in 2002. The manufacturer cited poor demand as the reason for discontinuing the product, but sales of the vaccine had suffered after well-publicized reports of arthritis-like symptoms, muscle pain, and other adverse events after vaccination.¹⁹ The specific antibodies generated against borrelial outer surface proteins have been shown to have bactericidal activity against B burgdorferi, and they will likely be the focus of any next-generation Lyme disease vaccine.²⁰

Conclusion

Lyme disease is a complex illness that can be debilitating if not properly treated. Healthy People 2010, a program of the US Department of Health and Human Services, has included Lyme disease among its prevention priorities.²¹ The government is committed to the prevention and control of Lyme disease, with the goal of reducing the overall incidence by more than 40% in endemic areas by 2010.²¹

SELF-ASSESSMENT TEST

1. Erythema migrans occurs during which stage(s) of Lyme disease?

1. Stage 1
2. Stage 2
3. Stage 3
4. All stages

2. Which of the following statements regarding erythema migrans is true?

1. You should wait for serologic confirmation before starting treatment in a patient with erythema migrans
2. Patients with erythema migrans, which has an indolent course in the United States, do not require treatment
3. Start a 14- to 21-day course of oral antibiotic therapy to prevent complications in a patient with erythema migrans
4. The Borrelia organism cannot be cultured from the biopsy specimen of an erythema migrans lesion

3. In which of these settings would serologic testing be appropriate?

1. A patient with erythema migrans
2. A patient receiving empiric antibiotic therapy
3. A patient with recurrent oligoarticular arthritis
4. As verification that the patient is infection-free

4. Which of these agents is not effective for the treatment of Lyme disease?

1. Amoxicillin
2. Cefuroxime
3. Doxycycline
4. Cephalexin

5. Before administering doxycycline for the prevention of Lyme disease, a patient must meet all these criteria, except:

1. The tick was attached for <24 hours
2. Prophylaxis is started within 72 hours of tick removal
3. At least 20% of ticks in the area are infected with B Burgdorferi
4. The patient is not pregnant

(Answers at end of references list)

References

1. Wormser GP, Dattwyler RJ, Shapiro ED, 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.
2. Centers for Disease Control and Prevention. Reported cases of lyme disease by year, United States, 1991-2005. Available at www.cdc.gov/ncidod/dvbid/lyme/ld_UpClimbLymeDis.htm.
3. Centers for Disease Control and Prevention. Reported Lyme disease cases by state, 1993-2005. Available at www.cdc.gov/ncidod/dvbid/lyme/ld_rptdLymeCasesbyState.htm.
4. Steere AC. Lyme disease. N Engl J Med. 2001;345:115-125.
5. Wormser GP. Clinical practice. Early Lyme disease. N Engl J Med. 2006;354:2794-2798.
6. Chow CC, Evans AS Jr, Noonan-Toly CM, et al. Lyme disease trends—Dutchess County, New York, 1992-2000. Mt Sinai J Med. 2003;70:207-213.
7. Smith RP, Schoen RT, Rahn DW, et al. Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Ann Intern Med. 2002;136:421-428.
8. Strle F, Nadelman RB, Cimperman J, et al. Comparison of culture-confirmed erythema migrans caused by Borrelia burgdorferi sensustricto in New York State and by Borrelia afzelii in Slovenia. Ann Intern Med. 1999;130:32-36.
9. Wormser GP, Bittker S, Cooper D, et al. Comparison of the yields of blood cultures using serum or plasma from patients with early Lyme disease. J Clin Microbiol. 2000;38:1648-1650.
10. Belongia EA. Epidemiology and impact of coinfections acquired from Ixodes ticks. Vector Borne Zoonotic Dis. 2002;2:265-273.
11. American College of Physicians. Guidelines for laboratory evaluation in the diagnosis of Lyme disease. Ann Intern Med. 1997;127:1106-1108.
12. Tugwell P, Dennis DT, Weinstein A, et al. Laboratory evaluation in the diagnosis of Lyme disease. Ann Intern Med. 1997;127:1109-1123.
13. Ramsey AH, Belongia EA, Chyou PH, et al. Appropriateness of Lyme disease serologic testing. Ann Fam Med. 2004;2:341-344.
14. Wilske B, Fingerle V, Schulte-Spechtel U. Microbiological and serological diagnosis of Lyme borreliosis. FEMS Immunol Med Microbiol. 2007;49:13-21.
15. 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. 1995;44:590-591.
16. Kalish RA, McHugh G, Granquist J, et al. Persistence of immunoglobulin M or immunoglobulin G antibody responses to Borrelia burgdorferi 10-20 years after active Lyme disease. Clin Infect Dis. 2001;33:780-785.
17. Berger BW, Johnson RC, Kodner C, et al. Cultivation of Borrelia burgdorferi from erythema migrans lesions and perilesional skin. J Clin Microbiol. 1992;30:359-361.
18. Piesman J. Dynamics of Borrelia burgdorferi transmission by nymphal Ixodes dammini ticks. J Infect Dis. 1993;167:1082-1085.
19. US Food and Drug Administration. Updates: manufacturer discontinues only Lyme disease vaccine. Available at www.fda.gov/fdac/departs/2002/302_upd.html#lyme.
20. Brooks CS, Vuppala SR, Jett AM, et al. Identification of Borrelia burgdorferi outer surface proteins. Infect Immun. 2006;74:296-304.
21. US Department of Health and Human Services. Healthy People 2010. Washington, DC: US Department of Health and Human Services;
22. 2000.

Answers: 1. A; 2. C; 3. C; 4. D; 5. A.