Epidemiology

Lyme disease surveillance began in 1982 at the CDC, and Lyme disease became a nationally reportable disease in 1991. In 2000, Lyme disease accounted for more than 90% of all reported cases of vector-borne illness in the United States.¹⁷¹

In the United States in 2001, 17,029 cases were reported in 43 states; in 2009, there were 38,468 cases from 50 states and the District of Columbia.⁶⁸ Preliminary 2010 CDC data show 27,895 cases.⁶⁹ The national incidence of Lyme disease is 8.2 cases per 100,000 population, although 12 states reported 95% of the cases. Columbia County, New York, reported the highest incidence of Lyme disease in both 2001 and 2002.⁶⁷ Reasons for recent increases in the number of reported cases are multifactorial and most likely include public and physician awareness, increases of reservoir host populations, increased range of the vectors, efflux of people from urban cores to suburban areas (which results in more human–host–vector interfaces). Lyme disease is grossly underreported in many areas.^55,75,254

Patients of any age may become infected, but the incidence has two peaks: among children aged 5 to 14 years and among adults aged 50 to 59 years. Fifty-nine percent had an onset of illness in June and July, and 78% of the cases occurred in the months of May through August. Fewer than 7% of the cases began in winter months.

Lyme disease is a worldwide problem, diagnosed or found on all continents. Sporadic cases in Australia have yet to be proved as having originated in Australia and may have been imported in patients who spent time in areas endemic for Lyme disease.^180,314 Polymerase chain reaction (PCR) analysis of approximately 12,000 field-captured ticks in Australia failed to find any evidence of Borrelia-like infection.³¹⁵

The primary vectors for Lyme disease worldwide are ticks of the I. ricinus complex. In the eastern half of the United States, the primary vector is I. scapularis, known more commonly as the black-legged tick or deer tick. The primary vector in the western United States is Ixodes pacificus, the western black-legged tick.²⁷⁴ In Europe, Asia, and Northern Africa, I. ricinus, the castor bean tick, is the main vector. In Japan, China, and eastern Russia, it is Ixodes persulcatus, the taiga tick. Transmission of the spirochetes to humans is almost exclusively by infected nymphs or adults. Larvae are usually not infected until they feed on an infected host, pick up the spirochetes from this host, and then become infective as a seeking nymph. Unlike in many other tick-borne diseases, there is minimal transmission of the causative spirochetes from an infected female to her eggs.^271,285

Transmission of the disease in the United States outside of the areas in which I. ricinus complex ticks are found, although rare, does occur, thus implicating other vectors. Several other tick species (Amblyomma, Dermacentor, Haemaphysalis, Rhipicephalus, and other Ixodes species) have been found infected with the spirochetes, but they are not successful in transmitting the spirochetes to a host.^234,263 Various nontick arthropods, including some biting flies, mosquitoes, and the cat flea, have been shown to harbor spirochetes, but they do not transmit spirochetes to a host or do so very rarely.^{230,234,300,368} In many of the nontick arthropod cases, disease transmission is presumed to take place by a “dirty syringe” type of mechanism, in which the vector feeds partially on a spirochete-laden host, only to momentarily later inject the spirochetes into the next host.^230,235

Reservoir host species are numerous, and they vary worldwide depending on the location and climate. At least 125 species of mammals, birds, and reptiles are important hosts to Ixodes ticks throughout the world.¹⁹⁹ In the northeastern United States, the preferred host for I. scapularis larvae and nymphs is the white-footed mouse, Peromyscus leucopus. In Europe and Asia, various rodents are the primary hosts for the larvae and nymphs. Larger mammals, most often deer, usually serve as hosts for the adults. In more temperate areas of the world, there is a much wider variety of hosts, including reptiles, birds, and mammals.

In the southeastern United States, the cotton mouse (Peromyscus gossypinus), the cotton rat (Sigmodon hispidus), and other mammals, reptiles, and birds serve as primary hosts for larvae and nymphs.^106,199,273 Bird species readily harbor spirochetes, whereas lizard species do not. The reptilian hosts, almost exclusively lizards, account for a large amount of the immature (larval and nymphal) tick population.²⁷³ Lizard sera and mule deer sera appear to deactivate spirochetes via a borreliacidal protein.^213,376 The high numbers of ticks parasitizing lizards instead of mice and the lizards’ apparent inability to harbor the spirochetes may partially account for the differences in Lyme disease incidences between certain geographic areas.⁷⁶

The migration of larger mammalian and avian hosts is one means by which ticks spread into new areas, often spreading various diseases with them.^9,82,202 Host populations increase when appropriate predators are absent; these fluctuations can amplify tick populations tremendously. One deer can host several thousand ticks of various stages; deer population studies have shown that decreasing or eradicating deer populations leads to marked decreases in tick populations in subsequent years.^143,292

The interaction between spirochete and host begins when the spirochete enters the salivary gland of the tick during the feeding process. Transmission to another vertebrate also occurs during the feeding process, which explains why disease transmission usually occurs only after a tick has been on a host for 48 to 72 hours. B. burgdorferi spirochetes show no transmission to mice in less than 24 hours, with maximal transmission occurring between 48 and 72 hours.⁹⁴ Another study showed that tick attachment for greater than 72 hours was more likely to transmit disease.³³⁷

Clinical Manifestations

Lyme disease has a myriad of constitutional, dermatologic, neurologic, cardiac, and musculoskeletal symptoms. The most common are vague myalgias, headache, fatigue, neck stiffness, and arthralgias. Rarely, gastrointestinal complaints or ocular complaints such as conjunctivitis, iritis, and keratitis may be reported. Collectively, these symptoms are difficult to distinguish from a benign viral syndrome, which is one of the reasons Lyme disease is easily misdiagnosed by both patients and physicians.¹⁶

Lyme disease is multisystemic and multiphasic. The disease is classically divided into three stages based on the chronologic relationship of symptoms to the original tick bite, with different clinical manifestations at each stage (Figure 51-9). There is no clear delineation distinguishing one stage from another, however, and signs and symptoms of different stages often overlap.

FIGURE 51-9 Time course and frequency of symptoms in Lyme disease. Approximately 50% of victims report recent tick bite. The initial stage I symptoms occur in approximately 70% to 80% of infected individuals. Weeks after the initial tick bite, the skin, nervous system, and joints are most often affected as the spirochete spreads hematogenously. Stage II symptoms typically begin 4 to 10 weeks after the initial infection and occur in approximately 50% of untreated patients. Stage III typically starts much later, often 1.5 to 2 years and rarely more than 5 years after initial infection.

(Modified from Schmid GP: Epidemiology and clinical similarities of human spirochetal diseases, Rev Infect Dis 11[Suppl 6]:S1460, 1989.)

The disorder usually begins as a localized infection with constitutional findings and associated symptoms (stage I) (Box 51-1).^139,268 Within days to weeks, spirochetes may disseminate through blood or lymph, and neurologic, cardiac, or joint abnormalities may develop (stage II). Finally, chronic, persistent infection of the joints, nervous system, skin, or eyes may occur months or years later (stage III).

Although the exact roles of the infecting spirochete, spirochetal antigens, and host immune responses are unclear, tissue invasion and persistence of infection probably cause many of the later manifestations of Lyme disease. This concept is supported by isolation of B. burgdorferi from blood, skin lesions (erythema migrans), and CSF.^28,354 The organism has also been identified in the eye,³⁵¹ myocardium,²³⁹ and synovium.³³⁴ Patients at all stages of disease respond to appropriate antimicrobial therapy, and early treatment generally leads to an excellent long-term prognosis.

Early Localized Disease (Stage I)

The ability of patients to remember a tick bite varies, frequently by species of tick, as some bites are more painful than others. Early localized disease typically begins as a localized erythema migrans rash or lesion, which occurs 7 to 10 days (range, 3 to 32 days) after a tick bite. Approximately 75% of patients with Lyme disease develop an erythema migrans lesion.^148,211,264 In one prospective study in New England, erythema migrans was reported in almost 90% of patients with Lyme disease. A large number of these patients were children, however, who often have a greater febrile and dermatologic response.^{60,139,140,346} There are small regional variations in the development of erythema migrans, which may be due to infections with agents other than B. burgdorferi, such as B. lonestari or a similar agent.^{125,246,247,345} Erythema migrans may appear anywhere on the body but usually occurs at or near the site of the tick bite. In cases with a single erythema migrans lesion, the most common sites include the head and neck region (26%), extremities (25%), back (24%), abdomen (9%), axillae (8%), groin (5%), and chest (3%).¹³⁹ In Europe, up to 18% of patients present with disseminated or multilocular erythema migrans.²¹¹

The erythema migrans rash is variable in size, ranging from 2 cm (0.8 inches) to more than 60 cm (24 inches) in diameter, and is usually in a circular pattern. To meet the CDC case definition of Lyme disease, the lesion must be at least 5 cm (2 inches). It usually begins as a red macule or papule, with an area of central clearing that becomes more apparent as the lesion expands in size (Figure 51-10). The central region may become indurated and, rarely, necrotic. The borders, which are usually bright red, may expand as much as 1 cm/day (0.4 inch day). These borders are usually flat, although rarely they may be raised or indurated. Occasionally, there are multiple, alternating concentric rings of erythema and clearing, a rash pattern referred to as “bull’s-eye.” The rash is usually warm to the touch.

FIGURE 51-10 Author’s leg with classic Lyme disease erythema migrans rash.

(Courtesy Gregory A. Cummins.)

The lesions are sometimes difficult to differentiate from local immune reactions to the tick salivary proteins, and are sometimes confused with secondary bacterial cellulitic reactions. Local immune reactions usually occur within hours of the tick bite and are very pruritic. Secondary cellulitic reactions typically occur within a few days of the tick bite and lack central clearing and rapid expansion.

Patients often describe the lesion as burning but may also report itching or pain. Children may develop temperatures to 40° C (104° F), but low-grade fevers are more common in adults. Constitutional symptoms, such as malaise and myalgias, may also be present. Generalized lymphadenopathy is rare, but local lymphadenopathy may occur.

Erythema migrans fades after an average of 3 to 4 weeks (range, 1 to 14 weeks) without treatment; with antibiotics, the lesion resolves after several days and seldom recurs.³⁵³ Although the erythema migrans lesions resolve without treatment, untreated patients are at risk for developing early (stage II) or late (stage III) disseminated disease.

Early Disseminated Disease (Stage II)

Untreated Lyme disease may enter the second stage, early disseminated disease, within days to weeks after the initial infection. The spirochetes spread from the skin to other organs via blood or the lymphatics. Although organisms can be visualized in peripheral blood smears, they are very difficult to culture from blood. B. burgdorferi has a preference for certain tissues, but it can be found in nearly any organ.³⁴⁸

Dermatologic

Disseminated erythema migrans is the most common manifestation of stage II disease. These secondary lesions are usually smaller, there are usually many of them, and they may lack the central clearing. They may appear anywhere on the body, with the exceptions of the palms and soles. Ten percent to 15% of patients have more than 20 such lesions; rarely, there are more than 100. Blistering and mucosal involvement do not occur—an important feature in differentiating these lesions from erythema multiforme. Other skin manifestations include a malar rash (10% to 15%) and (rarely) urticaria.³⁵³

Borrelial lymphocytoma, an unusual dermatoborreliosis, appears in Europe and western Asia in approximately 1% of patients. Patients typically present with a firm nodule that is red, purple, or blue and one to several centimeters in diameter. It is usually solitary, but multiple lesions may occur in approximately 25% of cases. It often occurs in areas of cooler body temperature, with approximately 80% on the nipple or areola, 10% on the earlobe, and 10% on other areas (including the scrotum).²³⁸ It is caused by Borrelia afzelii in approximately 90% of cases, although it has been seen with B. bissettii and B. garinii.²³⁸ Histologically, it consists of cutaneous lymphoid hyperplasia, usually in deep portions of the dermis. It may be confused with well-differentiated nodular lymphoma.²⁶⁴ There is associated pruritus, but otherwise it is benign and resolves with appropriate antibiotic therapy.

Neurologic

Neurologic manifestations occur in 10% to 40% of untreated or improperly treated patients.²⁷⁶ Meningitis, encephalitis, and meningoencephalitis are the major neurologic findings of early disseminated disease; lethargy, forgetfulness, disorientation, somnolence, dizziness, photophobia, and incoordination are the most common signs and symptoms. Mood disturbances may also be seen, especially in pediatric patients.²⁷ Nuchal rigidity is sometimes present, along with a severe headache. Lumbar puncture reveals CSF with pleocytosis (usually less than 1000 cells/mm³), typically with lymphocyte predominance and high protein level.

Paralysis of the facial nerve (cranial nerve VII) may occur and persist for months, and usually resolves spontaneously.^72,279 Bilateral facial nerve paresis or paralysis may occur in 25% of cases with cranial nerve VII involvement, usually evolving asymmetrically. Bilateral facial palsy is an unusual physical finding and should suggest Lyme disease, although this finding may also be caused by sarcoidosis, herpes zoster, or the human immunodeficiency virus (HIV).

Radiculoneuronitis may be present in various nerves, causing burning, stabbing, or shooting pain. Large nerve bundles such as the brachial plexus are more commonly involved. Mononeuritis multiplex may be present, with peripheral motor weakness and sensory pain. Other neurologic findings are rare but include pseudotumor cerebri, chorea, and dementia.^138,185,302

Gastrointestinal

Ten percent of patients may develop hepatitis, hepatomegaly, and generalized abdominal pain. Hepatic involvement does not progress to hepatic failure; symptoms usually resolve in less than 1 week but may persist for several weeks. Splenomegaly may also occur.²⁶⁸

Cardiac

Untreated or improperly treated Lyme disease leads to cardiac manifestations in up to 10% of cases.³⁴⁹ Although cardiac involvement is usually self-limited and rarely life-threatening, temporary intervention is required in some cases.^162,197 The most common cardiac manifestation of Lyme disease is conduction delay, which may be of any degree and is found in 80% of cases with cardiac involvement.²⁷⁵ Electrophysiologic studies indicate that the block is at the level of the atrioventricular node. The block does not respond to atropine, suggesting a direct effect on the node.^275,310 In cases of complete heart blocks, the presence of spirochetes can be confirmed in cardiac tissue by cardiac biopsy. Noninvasive imaging modalities such as cardiac MRI can be used to document improvement in response to antibiotics.^89,197

Conduction delays usually, but not always, resolve with appropriate antibiotic therapy. Patients with first-degree atrioventricular block and a PR interval exceeding 300 msec, as well as all patients with second- and third-degree heart blocks should be admitted for observation and antibiotic treatment. Patients with third-degree heart block require temporary transvenous pacing and may require permanent pacemaker implantation.

More diffuse cardiac involvement, such as myopericarditis, is found in about one-half of patients with cardiac involvement. The electrocardiograph (ECG) in such patients usually demonstrates diffuse, nonspecific changes (Figure 51-11). Radionuclide angiography may demonstrate left ventricular dysfunction, but this is seldom clinically significant. Cardiomegaly due to Lyme disease rarely occurs in U.S. patients, although dilated cardiomyopathy is often reported in Europe.^336,344 Valvular involvement is uncommon.

FIGURE 51-11 An electrocardiograph of a patient with acute myopericarditis.

(Courtesy Gregory A. Cummins.)

At least one death has been linked to cardiac involvement,²³⁹ but abnormalities usually resolve completely, often within 1 to 2 weeks.³⁴⁹ Severe cardiac complications have been described in pediatric patients but are relatively rare.¹³⁹

Rheumatologic

Monoarticular arthritis develops in 60% of patients with erythema migrans who are not treated, usually occurring between 4 weeks and 2 years after the onset of illness.³⁵⁸ Although common in North America, arthritis is rarely a finding in other areas of the world.^71,348

In adult patients, arthritis may occur in a migratory pattern, involving many joints, usually one joint at a time. Joint involvement typically occurs for about a week (median, 8 days), but it may persist for months. Many patients have repeated episodes of arthritis, and each subsequent recurrence is less severe. Soreness often persists between episodes, never fully resolving, and persistent morning stiffness is common. The knee is most commonly affected, followed by the shoulder, elbow, temporomandibular joint, ankle, wrist, hip, metatarsals, and metacarpals.³⁹⁹ Joint swelling is not common except in the knee, and the joints are typically described as more sore than painful. Chronic effusions often occur.

In pediatric patients, arthritis appears an average of 4.3 months after initial infection, with a broad range of a few days to 20 months.^139,140 Approximately 50% of pediatric patients have multiple recurrences, although complete remission between episodes is typical and chronic arthritis is uncommon. Ninety percent of children in a large study had arthritis in at least one knee.¹⁴⁰

Synovial fluid of involved joints has a median WBC count of 25,000/mm³, with polymorphonuclear leukocyte predominance. Synovial membrane biopsy shows cellular hypertrophy, vascular proliferation, and mononuclear cell infiltrate.^352,356 PCR testing of synovial fluid is positive in 85% of cases of Lyme arthritis.

The organism may also persist in synovial tissue. Four patients who completed antibiotic therapy for Lyme arthritis and who subsequently had negative PCR testing of synovial fluid had positive PCR testing of the synovial membrane.²⁸⁹ This persistence may account for the reactivation of Lyme arthritis that has been described after autologous chondrocyte transplantation for degenerative joint disease or cartilage injury.²⁴⁴

“Chronic Lyme Disease”

There is considerable debate over whether a chronic form of Lyme disease exists. Some patients develop chronic persistent Lyme disease symptoms despite repeated antibiotics. Whether this is a sequela of pathogen resistance or chronic auto-inflammation, auto-immunity or a form of fibromyalgia is highly debated.¹⁴⁵ A collection of symptoms, lumped into a category sometimes referred to as postborreliosis syndrome or post–Lyme disease syndrome (PLDS), consists of signs and symptoms such as persistent fatigue, sleep disorders, depression, cognitive defects, mood swings, and other neuropsychiatric manifestations.²²⁸ This symptom complex fails to respond to traditional antibiotics.

This collection of symptoms might be an entirely separate disease, or partially treated Lyme disease, or the disease complicated by the cystic form, which is difficult to treat. As early as the early 1900s, spirochetes were noticed to have developed into cysts, also called blebs or vesicles. Today, these cysts are called spherocytes, or the L-form of the spirochete.⁴⁶ These spherocytes are induced under adverse conditions, such as the presence of antibodies targeted against the spirochetes, adverse pH, or adverse temperatures. Thus, the spherocytes may be responsible for the spirochetes’ surviving conditions that would kill or deactivate the typical spirochete form.²⁶⁶ When environmental conditions again become favorable for the spirochetes, the cysts or spherocytes convert back to the traditional spirochete form.⁴⁰

Further research is likely to yield more information about the existence of and appropriate treatment of the cystic form of the disease, such as the addition of antiprotozoal medications to the treatment regimen.^41,42 Patients afflicted with these persistent symptoms are very active in pursuing formal recognition and treatment of these disorders through political, legislative, and research means. However, at the present time, there is no evidence-based medicine to support prolonged antibiotic therapy for patients with any manifestation of Lyme disease.⁴⁰⁷

Lyme Disease in Pregnancy

Fetal demise may result in mothers who develop Lyme disease in pregnancy.^{232,243,320,390} Transplacental transmission of Lyme disease is rare but appears to be associated with an increased risk of cardiac malformations.³⁹⁸

Lyme disease in pregnancy should be aggressively treated. A 1996 prospective study of 58 pregnant women with erythema migrans given oral or intravenous (IV) penicillin or ceftriaxone reported only seven adverse outcomes, none clearly associated with Lyme disease.²³⁷ The American College of Obstetrics and Gynecology recommends oral penicillin or amoxicillin for 3 weeks in pregnant women with cutaneous involvement or recent tick bites in endemic areas. For patients with severe acute disease, or disseminated or late disease, 3 weeks of parenteral penicillin is recommended. If the patient is allergic to penicillin, parenteral erythromycin is recommended.^11,111 Tetracyclines should not be used in pregnancy.

Diagnosis

The CDC has established a surveillance case definition for Lyme disease. This case definition requires exposure to ticks in an endemic county and an erythema migrans lesion, diagnosed by a physician, that is larger than 5 cm (2 inches). In this definition, exposure requires outdoor activities within 30 days of the onset of the lesion. An endemic county is one in which at least two confirmed cases of Lyme disease have been acquired, or known tick vectors are established. It is important to note that Lyme disease case definitions are designed for national reporting, not individual patient diagnosis. The clinical diagnosis of Lyme disease is based on history, clinical suspicion, and a working knowledge of the disease process and epidemiology; laboratory tests may be performed but generally serve only to confirm the presence of the disease.

Routine laboratory examinations may reveal nonspecific findings, such as elevated liver enzymes (alanine transaminase [ALT], aspartate transaminase [AST], and/or gamma-glutamyltransferase [GGTP]) decreased leukocyte count, and elevated erythrocyte sedimentation rate. Immunoglobulins A and G (IgA and IgG) are usually normal, whereas IgM is usually elevated, especially in severe disseminated disease. Culture is the gold standard for diagnosis but is often difficult to obtain. Biopsy of an erythema migrans skin lesion is positive in 60% of punch biopsies from the leading edge of the lesion, and this figure may be as high as 80% in specialty centers.³² The production of anti–B. burgdorferi antibody develops slowly, and serologic assays in the first 3 to 6 weeks of illness are often negative unless severe disease is present.^257,328 In some patients, treatment with antibiotics may blunt or entirely suppress the antibody response; in others, IgG and IgM antibodies may persist for years after resolution of clinical symptoms.¹²¹ Patients with complicated Lyme disease (with neurologic, cardiac, or joint involvement) or those in remission are more likely to have elevated specific antibody titers.^257,328 Serologic testing has the highest predictive value in patients with a pretest probability of having Lyme disease between 20% and 80%.³⁷⁴ Patients from endemic areas with an 80% or higher pretest probability of having the disease benefit from empiric treatment, not testing. Patients with a pretest probability of less than 20% have a high likelihood of a false-positive testing.

Indirect immunofluorescent assay (IFA), enzyme-linked immunosorbent assay (ELISA), and Western blot test are the most commonly used tools to detect antibodies to B. burgdorferi. For diagnostic purposes, ELISA appears to be the most accurate, with 89% sensitivity and 72% specificity. Low levels of agreement are common between various laboratories and individual assays.³²⁵ Western blot has proved to be a poor screening tool. New tests using recombinant proteins or synthetic peptides as ELISA antigens yield detection rates for serum antibodies of 20% to 50% for early disease, 70% to 90% for early disseminated disease, and nearly 100% in late disease.⁴⁰⁰ Although Western blot is a poor screening tool, it is useful to confirm a positive ELISA result.

Only positive serologic assays confirmed by Western blot meet the criteria for laboratory diagnosis, according to the CDC national consensus panel. Many disease states, including other treponemal diseases, autoimmune diseases, and some viral diseases may give false-positive ELISA results.²⁵⁷ Antibodies directed toward oral flora may also cause false-positive results.^10,257

A current research tool, reverse transcriptase DNA PCR, is both highly sensitive and specific for Lyme disease. With decreasing costs and increasing availability, PCR is rapidly finding its way into the diagnostic armamentarium.^116,221

Patients with vague nonspecific symptoms such as chronic fatigue, musculoskeletal pains, and other neuropsychiatric signs and symptoms, in the absence of true Lyme disease signs and symptoms, should, in general, not undergo serologic testing for Lyme disease. Positive results in such patients are probably falsely positive and may create an inordinate amount of confusion and conflict.

The importance of appreciating the limitations of serologic testing cannot be overstated. In one study, only 23% of patients referred to the Lyme Disease Clinic at New England Medical Center had active Lyme disease, and a majority of those without Lyme disease had been treated inappropriately with antibiotics.³⁵⁶ In this study, the most common reason for lack of response to antibiotics was misdiagnosis. The limitations of laboratory testing in Lyme disease include lack of sensitivity and specificity of serologic tests and considerable interlaboratory and intralaboratory variability in test results.³²⁵ Persistence of antibodies in patients with past or asymptomatic infection with B. burgdorferi also complicates serologic testing. PCR testing in these situations would likely clarify the disease diagnosis.²²¹ If another illness develops, as occurred in 20% of patients referred to the New England Medical Center clinic, it may be incorrectly attributed to Lyme disease. This is particularly problematic in patients with nonspecific symptoms of chronic fatigue or fibromyalgia, in whom the predictive value of a positive ELISA is low.

Overdiagnosis of Lyme disease has significant health system and patient care implications. In another study of 209 individuals referred to a university-based Lyme disease clinic with a diagnosis of the disease, only 21% met the criteria for active Lyme disease, 60% had no evidence of current or previous infection, and 19% had evidence of previous but not active disease. The 79% of patients without active Lyme disease displayed significant anxiety and stress related to their diagnosis of Lyme disease, used considerable health care resources, and had frequent adverse antibiotic reactions.³⁰¹

Treatment

Although most manifestations of Lyme disease resolve spontaneously without treatment,³¹⁷ treatment of Lyme disease with appropriate antibiotics hastens recovery in all stages of the disease. Both in vitro and in vivo studies have confirmed that B. burgdorferi is highly sensitive to tetracyclines, aminopenicillins, ceftriaxone, and imipenem.^170,188,189 The macrolides, oral second- and third-generation cephalosporins, and chloramphenicol all seem to have equal efficacies.^5,188 Although fluoroquinolones have traditionally not been effective against Borrelia species, the fourth-generation fluoroquinolone antibiotics seem to have good efficacy in vitro.²⁰⁶ However, some B. burgdorferi strains are showing in vitro resistance to the newest fluoroquinolones.¹³⁷ Table 51-3 lists general antimicrobial therapy options and recommendations for Lyme disease.

TABLE 51-3 Antimicrobial Recommendations for Lyme Disease

* Total daily dose shown to be divided (if necessary) as indicated.

† For multiple lesions of erythema migrans, use treatment for early localized disease for at least 21 days. For isolated facial palsy, use treatment for early localized disease for at least 21-28 days.

‡ Neurologic involvement limited to an isolated facial palsy should be treated as early disease.

§ For mild cardiac involvement (i.e., first-degree atrioventricular block with PR interval less than 0.30 second).

¶ For second- or third-degree heart block, although no evidence indicates that intravenous is better than oral regimens.

In early localized Lyme disease (stage I), amoxicillin and doxycycline are the drugs of choice. Tetracyclines should not be used in pregnancy, in lactating women, or in children under age 9 years. The recommended treatment duration is 10 to 20 days. In one study, 10 days of treatment with doxycycline showed the same efficacy as 20 days, with fewer side effects. This may rarely be extended to 4 weeks if symptoms persist or recur, although no hard evidence exists for doing so.⁴⁰⁷ Medications that will penetrate the CSF are ideal and may lead to less disease recurrence.²²⁹ Sequestering of spirochetes in the brain may account for some apparent antibiotic failures, as not all antibiotics cross the blood–brain barrier.

Within the first 24 hours of treatment with antibiotics, up to 15% of patients develop a Jarisch-Herxheimer reaction (JHR), which manifests as a rise in temperature, vasodilation, and hypotension.²⁶⁹ Normal saline infusion around the time of initial dosing of antibiotics may help reduce the degree of hypotension. In rare cases, JHR may be severe and fatal. Symptoms rarely persist beyond 24 hours.

Disseminated disease (stages II and III) should be treated according to severity. In mild disseminated disease (such as secondary erythema migrans or cranial nerve VII palsy), 3 weeks of oral doxycycline is as effective as 2 weeks of parenteral ceftriaxone.⁸⁴ In patients initially treated with oral antibiotics who are therapeutic failures or in whom disease recurs, parenteral antibiotics are indicated. Patients with severe disseminated disease (neuroborreliosis, high-degree heart block) require parenteral antibiotics for up to 4 weeks.^83,227 Ease of once-daily administration of ceftriaxone makes it a better choice for both inpatient and outpatient administration than other typically used agents requiring administration three or four times daily.^83,84

Neurologic symptoms begin to improve with therapy within 1 week, although full resolution may take 7 to 8 weeks.³⁵⁷ Prolonged oral antibiotics are often necessary to treat stage III arthritis, sometimes for as long as 4 to 8 weeks.³⁵⁷ Delayed clinical response in arthritis is not uncommon. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also reduce symptoms, and reduce disease recurrence by simultaneously treating the inflammation.¹⁴⁵

No vaccines are presently available for the prevention of Lyme disease in humans. A vaccine based on recombinant outer surface protein A (OspA) was approved in 1998 but was removed from the market by the manufacturer in 2002. The vaccine had limited efficacy, required frequent boosters, was expensive, could not be used in children, and resulted in an apparent immunogenic reaction in some vaccinated individuals.¹⁶³ Future vaccines, although still in their infancy, will most likely use polyvalent outer surface protein C (OspC).

Treatment of asymptomatic tick bites in patients who are in areas endemic for Lyme disease is controversial, although this does not stop patients from requesting care. In one survey, physicians in Maryland reported seeing 11 times as many patients seeking help after “tick bites” as they did actual cases of Lyme disease.⁷⁵ Three randomized, placebo-controlled studies have addressed antibiotic prophylaxis for tick bites.^6,74,327 Of patients in the placebo groups, 1% to 3.4% developed Lyme disease or had evidence of seroconversion, even though 15% to 30% of ticks were infected; no patients in the treatment groups developed Lyme disease. A meta-analysis of the three studies concluded that there was no significant difference between the groups, and that routine prophylaxis of tick bites is not warranted except in pregnancy, even in endemic areas.³⁸⁹

Many physicians do not adhere to this recommendation, however. Maryland physicians ordered serologic testing in two-thirds of patients with asymptomatic tick bites and treated more than one-half with prophylactic antibiotics.¹³¹ The concern often cited for such practices is that patients with tick bites who become infected may not develop erythema migrans (when the disease is easily treated) but go on to develop the late and more serious manifestations of Lyme disease. Some of these decisions are likely driven by patient pressure, as well as defensive medicine.

The risk of serious late sequelae in untreated patients with a tick bite, however, is extremely low, for three reasons. First, less than 5% of those bitten by the I. scapularis tick in endemic areas become infected. Second, most patients with an identified tick bite remove the tick before it has been attached for the 24 to 48 hours required to transmit an infectious inoculum of B. burgdorferi. Finally, 80% to 90% of the few patients who become infected develop erythema migrans, which makes diagnosis and treatment easy. Physicians must therefore weigh a number of factors related to the likelihood of disease acquisition in deciding whether to treat asymptomatic tick bites with antibiotics. These factors include species and stage of the offending tick, duration of attachment, geography, and patient factors such as pregnancy. If a decision is made to treat, reasonable initial antibiotic choices include a 10-day course of either amoxicillin or doxycycline.

Overtreatment of presumed Lyme disease with antibiotics has significant health care ramifications. If the patient does not have Lyme disease, treatment failure is virtually ensured. Patients being treated for Lyme disease have a significant amount of anxiety regarding the diagnosis.³⁰¹ Adverse drug reactions may occur. Overuse of antibiotics has led to resistance to multiple antibiotics by many organisms, although resistance to tetracycline is not documented for Borrelia.¹²

Epidemiology

Ornithodoros ticks generally inhabit rodent burrows and nests, and cracks and crevices in human and animal habitats, caves, and similar locations. Habits and patterns of infection vary between tick species. In parts of Africa, ticks live in the dust and cracks of earthen-floored huts, and sporadic cases are seen throughout the year. In the Middle East, Mexico, and southwestern United States, ticks live in the guano on cave floors, and human infection is often associated with visiting or camping in caves.

The majority of cases of TBRF in the United States are attributed to B. hermsii. Its vector, O. hermsi, inhabits the coniferous forest biome, where it lives in remains of dead trees and burrows inhabited by mice, rats, and chipmunks. Ticks are carried by rodents into poorly maintained cabins and huts. Lodging in such shelters by hikers and hunters is a major factor in acquiring relapsing fever,^126,179 and rodent-proofing such shelters dramatically reduces the risk of acquiring TBRF.²⁷⁷ Occasional cases are also caused by O. turicata (transmitting B. turicatae) in Texas (associated with travel into caves) and adjacent areas of the Southwest; O. parkeri (transmitting B. parkeri) rarely bites humans.¹⁷⁷

TBRF is found throughout most of the world, and endemic areas include 14 western states, from Colorado to California up to the Pacific Northwest,^109,126,179 and southern British Columbia in North America. TBRF is also found throughout the plateau regions of Central and South America, central Asia, Mediterranean countries, and most of Africa. TBRF is not a mandatory reportable disease, and is thus, like many tick-borne diseases, grossly underreported. In California, where reporting of relapsing fever is encouraged, two to 12 cases are reported per year, with only 25 cases per year nationwide.^109,67 Large outbreaks have been reported from Spokane County in Washington,³⁶⁹ Colorado,³⁷² and the north rim area of the Grand Canyon.⁶¹ Between 1985 and 1996, the 285 cases of TBRF reported in the United States occurred in California, Colorado, Idaho, Texas, Washington, Arizona, New Mexico, Nevada, Oregon, Utah, and Wyoming.³⁷² Although the vast majority of cases occur in states where TBRF is endemic, a review of 450 cases of TBRF acquired in the United States from 1977 to 2000 noted that 7% of cases were diagnosed in states where it is not endemic.¹⁰⁷ TBRF is more common in men, presumably because of increased exposure to tick vectors, and occurs primarily during summer months. TBRF is rarely fatal in adults, but in infants younger than age 1 year, case fatality rates may be 20% or higher.^220,338