Harrisons Manual of Medicine, 18th Ed.

Chapter 104. Lyme Disease and Other Nonsyphilitic Spirochetal Infections


Microbiology and Epidemiology

Borrelia burgdorferi, the causative agent of Lyme disease, is a fastidious microaerophilic spirochete. The human infection Lyme borreliosis is caused primarily by three pathogenic genospecies: B. burgdorferi sensu stricto (hereafter referred to as B. burgdorferi), Borrelia garinii, and Borrelia afzelii.

• B. burgdorferi is the sole cause of Lyme borreliosis in the United States; all three genospecies are found in Europe, and the latter two species occur in Asia.

• Lyme disease is the most common vector-borne illness in the United States, with >25,000 cases each year.

– Ixodes ticks transmit the disease.

– I. scapularis, which also transmits babesiosis and anaplasmosis, is found in northeastern and midwestern states; I. pacificus is found in western states.

• The white-footed mouse is the preferred host for larval and nymphal ticks. Adult ticks prefer the white-tailed deer as host.

• Nymphal ticks transmit the disease to humans during the early summer months after feeding for ≥24 h.

Clinical Manifestations

Lyme disease usually begins with erythema migrans (EM; stage 1, localized infection) before disseminating (stage 2) or causing persistent infection (stage 3).

• Stage 1 (localized infection): After an incubation period of 3–32 days, EM develops at the site of the tick bite (commonly the thigh, groin, or axilla) in 80% of pts.

– The classic presentation is a red macule that expands slowly to form an annular lesion with a bright red outer border and central clearing. Central erythema, induration, necrosis, vesicular changes, or many red rings within an outer ring are also possible.

– Most pts do not remember the preceding tick bite.

• Stage 2 (disseminated infection): Given that some pts do not notice EM, many pts present within days or weeks after infection with secondary annular skin lesions, nonspecific systemic symptoms, neurologic deficits, or cardiac manifestations due to hematogenous spread.

– Nonspecific symptoms include severe headache, mild neck stiffness, fever, chills, migratory musculoskeletal pain, arthralgias, malaise, and fatigue. These symptoms subside within a few weeks, even in untreated pts.

– Neurologic deficits occur in ~15% of pts and may include meningitis; encephalitis; cranial neuritis, including bilateral facial palsy; motor or sensory radiculoneuropathy; mononeuritis multiplex; ataxia; or myelitis. Lymphocytic pleocytosis (~100 cells/μL) is found in CSF, often along with elevated protein levels and normal or slightly low glucose concentrations.

– Cardiac involvement occurs in ~8% of pts. Atrioventricular (AV) block of fluctuating degree is most common, but acute myopericarditis is possible. Cardiac involvement usually lasts for only a few weeks but may recur.

• Stage 3 (persistent infection): ~60% of untreated pts in the United States develop frank arthritis, usually consisting of intermittent attacks of oligoarticular arthritis in large joints (especially the knees) that last for weeks or months.

– Joint-fluid cell counts range from 500 to 110,000/μL (average, 25,000/μL); the majority of the cells are neutrophils.

– Arthritis can persist despite eradication of spirochetes.

– Chronic neurologic involvement (e.g., subtle encephalopathy affecting memory, mood, or sleep; peripheral neuropathy) is less common. In Europe, severe encephalomyelitis is seen with B. garinii infection.

– Acrodermatitis chronica atrophicans, a late skin manifestation, is seen in Europe and Asia and is associated with B. afzelii infection.

• Chronic Lyme disease: For months or years afterward, a small percentage of pts have pain, neurocognitive manifestations, or fatigue symptoms—a syndrome indistinguishable from chronic fatigue syndrome. There is no evidence that these symptoms are caused by active infection.


Serologic evidence combined with a compatible clinical picture is the usual basis for diagnosis.

• Only 20–30% of pts have positive serologic results in acute-phase samples, whereas 70–80% have positive results in convalescent-phase samples obtained 2–4 weeks later. Of note, serologic tests do not discriminate between active and past disease.

– Serologic analysis consisting of a two-step approach (ELISA screening with western blot confirmation for cases with positive or equivocal results) is recommended only for pts with at least an intermediate pretest likelihood of having Lyme disease.

– IgM and IgG testing should be done in the first 2 months of illness, after which IgG testing alone is adequate.

– CDC-adopted criteria dictate that the IgM western blot must show at least 2 of 3 defined bands and that the IgG western blot must show at least 5 of 10 defined bands to be considered positive.

• PCR is most useful for joint fluid, is less sensitive for CSF, and has little or no utility for plasma or urine.

• Although culture of the organism is possible, it is reserved primarily for research settings.

TREATMENT Lyme Borreliosis

• Doxycycline (100 mg bid) is the agent of choice for men and non-pregnant women with localized or disseminated infection and is also effective against anaplasmosis (Chap. 105).

– Amoxicillin (500 mg tid), cefuroxime (500 mg bid), erythromycin (250 mg qid), and newer macrolides—preferred in that order—are alternative agents.

– Except in cases of neurologic disease and third-degree AV block, the drug can usually be taken by mouth.

– More than 90% of pts have good outcomes with a 14-day course of treatment for localized infection or a 21-day course for disseminated infection.

• For pts with objective neurologic abnormalities (with the possible exception of isolated facial palsy), IV treatment with ceftriaxone for 14–28 days should be given. Cefotaxime or penicillin is an alternative.

• Pts with high-degree AV block (PR interval, >0.3 s) should receive IV therapy for at least part of the course; cardiac monitoring is recommended.

• Pts with Lyme arthritis should be treated with 30 days of oral doxycycline or amoxicillin.

– For pts who do not respond to oral agents, re-treatment with IV ceftriaxone for 28 days is appropriate.

– If joint inflammation persists after therapy but PCR testing for B. burgdorferi DNA in joint fluid gives negative results, anti-inflammatory agents or synovectomy may be successful.

• For pts diagnosed with chronic Lyme disease, no data demonstrate that additional antibiotic therapy is helpful.


The risk of infection with B. burgdorferi after a recognized tick bite is so low that antibiotic prophylaxis is not routinely indicated. However, if an attached, engorged I. scapularis nymph is found or if follow-up will be difficult, a single 200-mg dose of doxycycline, given within 72 h of the tick bite, effectively prevents the disease.


Early treatment results in an excellent prognosis. Most pts recover with minimal or no residual deficits.


Microbiology and Epidemiology

The endemic treponematoses—yaws (Treponema pallidum subspecies pertenue), endemic syphilis (T. pallidum subspecies endemicum), and pinta (T. carateum)—are nonvenereal chronic diseases acquired during childhood and caused by organisms closely related to the agent of syphilis, T. pallidum subspecies pallidum.

• Disease is transmitted by direct contact.

• The most recent WHO estimate (1997) suggested that there are 460,000 new cases per year and a prevalence of 2.5 million infected persons.

• Disease is limited to people in rural areas of developing nations and recent émigrés from these regions.

Clinical Manifestations

The major clinical distinctions made between venereal syphilis and the nonvenereal treponematoses are the apparent lack of congenital transmission and of CNS involvement in the nonvenereal infections. However, these distinctions may not be entirely accurate.

• Yaws is characterized by the development of one or more primary lesions (“mother yaw”) followed by multiple disseminated skin lesions.

– 3–4 weeks after acquisition of the organism, the pt develops a papule that ultimately enlarges, is associated with regional lymph-adenopathy, and heals spontaneously within 6 months.

– Late gummatous lesions of the skin and long bones affect 10% of untreated persons and are similar to the destructive lesions of leprosy and leishmaniasis.

• Endemic syphilis is initially localized to mucocutaneous and mucosal surfaces. Pts develop an intraoral papule, which is followed by mucous patches on the oral mucosa and mucocutaneous lesions resembling the condylomata lata of secondary syphilis. Destructive gummas, osteitis, and gangosa (destruction of the nose, maxilla, palate, and pharynx) are more common in endemic syphilis than in late yaws.

• Pinta is the most benign of the treponemal infections in that it does not cause destructive lesions or involve tissues other than the skin. The disease has three stages that are characterized by marked changes in skin color.


Diagnosis is based on clinical presentation, dark-field microscopy of scrapings from lesions, and serologic testing (as for venereal syphilis).

TREATMENT Endemic Treponematoses

Benzathine penicillin (1.2 million units for adults, 600,000 units for children <10 years of age) is the treatment of choice. Doxycycline is probably an effective alternative.


Microbiology and Epidemiology

Leptospires are spirochetal organisms that cause an important zoonosis with a broad spectrum of clinical manifestations.

• The organisms are small enough to pass through filters used to sterilize culture medium.

• The most important sources of transmission to humans are rats, dogs, cattle, and pigs. Transmission can occur during contact with urine and other excreta (e.g., placenta, products of parturition) from infected animals or during exposure to contaminated environments.

• Only ~50–100 cases in the U.S. are passively reported annually to the CDC, but these numbers are likely to represent significant underestimates given that leptospirosis is not a notifiable disease.

Clinical Manifestations

After an average incubation period of 5–14 days, infection by Leptospira results in a subclinical infection, an undifferentiated febrile illness, or Weil’s disease (the most severe form).

• Leptospirosis is a biphasic illness. The initial leptospiremic phase lasts 3–10 days and is characterized by fever. After another 3–10 days (the immune phase), some pts experience a return of fever, headache, and other systemic symptoms in association with the clearance of leptospires from the blood.

– Only the initial phase is responsive to antibiotic therapy.

– Nonspecific physical findings may include conjunctival suffusion, nonexudative pharyngeal erythema, muscle tenderness, rales on lung auscultation, jaundice, meningismus, and hypo- or areflexia (particularly in the legs).

• Weil’s disease is characterized by variable combinations of jaundice, acute renal injury, hypotension, and hemorrhage—most commonly involving the lungs. Cardiac involvement (e.g., myocarditis), severe myalgias (occasionally mimicking acute abdomen), rash, and neurologic findings (e.g., aseptic meningitis) are common.


A high index of suspicion prompting elicitation of a detailed exposure history is critical and guides confirmatory testing.

• Serologic assays are the diagnostic mainstay in leptospirosis. The microscopic agglutination test is the gold standard and typically is performed only in reference laboratories, such as the CDC. Most other serologic tests use a saprophytic leptospire as the antigen and provide nonspecific results.

• Definitive diagnosis rests on demonstration of the organism by culture isolation (which takes weeks), detection of nucleic acids or antigen in body fluids (a method typically limited to research settings), or immunohistochemical visualization in tissue.

– Leptospires can be cultured from blood and CSF during the first 7–10 days of illness.

– Urine cultures are positive in the second week of illness and can remain positive for months or years despite antibiotic therapy.

TREATMENT Leptospirosis

• Prompt initiation of antibiotics probably shortens the course of severe leptospirosis and prevents the progression of mild disease.

• For mild disease, oral doxycycline is the drug of choice. Azithromycin may also be effective.

• For severe disease, parenteral treatment with penicillin, ceftriaxone, or cefotaxime should be given. From a pragmatic viewpoint, severe leptospiral disease frequently requires empirical initiation of broad-spectrum parenteral therapy before the diagnosis is confirmed.



Borrelia recurrentis causes louse-borne relapsing fever (LBRF) and is transmitted from person to person by the body louse. In this disease, spirochetes are introduced when the louse is crushed (e.g., by scratching) and the insect’s infected hemolymph contaminates the skin. Tick-borne relapsing fever (TBRF), a zoonosis usually transmitted via the bite of various Ornithodoros ticks, is caused by multiple Borrelia species.


TBRF is endemic in the western United States, southern British Columbia, the plateau regions of Mexico, Central and South America, the Mediterranean, Central Asia, and much of Africa. Only 13 counties have accounted for ~50% of all U.S. cases. Little is known about the epidemiology of LBRF, but it is well described in East Africa.

Clinical Manifestations

Symptoms are similar, although not identical, in the two types of relapsing fever.

• In addition to fever, pts commonly develop headaches, myalgias, chills, nausea/vomiting, and arthralgias.

– Jaundice; CNS involvement; petechiae on the trunk, extremities, and mucous membranes; epistaxis; and blood-tinged sputum are more likely in LBRF.

– Neurologic findings (e.g., meningitis, focal deficits, paralysis, altered sensorium) may occur in 10–30% of cases and are more common in LBRF.

• For TBRF and LBRF, the mean incubation periods are 7 and 8 days, respectively; the average durations of the first episode are 3 and 5.5 days, respectively; and the average times between the first episode and the first relapse are 7 and 9 days, respectively. Relapsing febrile episodes are typically of shorter duration than the first episode.


Laboratory confirmation is made by the detection or isolation of spirochetes from blood during a febrile episode. Microscopic examination of Wright- or Giemsa-stained thick or thin blood smears or buffy coat analysis is most common.

• PCR techniques offer greater sensitivity but are limited to research settings.

• Serologic confirmation of TBRF is possible but is hampered by lack of standardization. An ELISA or an indirect fluorescent antibody assay can be performed; if positive, the results of these tests are confirmed with an immunoblot.

TREATMENT Relapsing Fever

• One dose of doxycycline (100 mg) or erythromycin (500 mg) is effective for LBRF; a 7- to 10-day course of either antibiotic is recommended for TBRF. Monitoring the pt for a Jarisch-Herxheimer reaction (an acute exacerbation of symptoms including hypotension, tachycardia, and marked elevation of body temperature) for the first 12 h after the first dose of antibiotic is recommended.

• If CSF pleocytosis is detected in the setting of meningitis or encephalitis, the pt should be treated with parenteral antibiotics.


LBRF has a fatality rate of 5% for treated pts; the rate is much lower for pts with TBRF.


For a more detailed discussion, see Lukehart SA: Endemic Treponematoses, Chap. 170, p. 1389; Vinetz JM: Leptospirosis, Chap. 171, p. 1392; Dworkin MS: Relapsing Fever, Chap. 172, p. 1397; and Steere AC: Lyme Borreliosis, Chap. 173, p. 1401, in HPIM-18. For a discussion of syphilis, see Chap. 92 in this manual.