Current Medical Diagnosis & Treatment 2015

34

Spirochetal Infections

Susan S. Philip, MD, MPH

SYPHILIS

NATURAL HISTORY & PRINCIPLES OF DIAGNOSIS & TREATMENT

Syphilis is a complex infectious disease caused by Treponema pallidum, a spirochete capable of infecting almost any organ or tissue in the body and causing protean clinical manifestations (Table 34–1). Transmission occurs most frequently during sexual contact (including oral sex); sites of inoculation are usually genital but may be extragenital. The risk of acquiring syphilis after unprotected sex with an individual with infectious syphilis is approximately 30–50%. Rarely, it can also be transmitted through nonsexual contact, blood transfusion, or via the placenta from mother to fetus (congenital syphilis).

Table 34–1. Stages of syphilis and common clinical manifestations.

The natural history of acquired syphilis is generally divided into two major clinical stages: early (infectious) syphilis and late syphilis. The two stages are separated by a symptom-free latent phase during the first part of which (early latency) infectious lesions can recur. Infectious syphilis includes the primary lesions (chancre and regional lymphadenopathy), the secondary lesions (commonly involving skin and mucous membranes, occasionally bone, central nervous system, or liver), relapsing lesions during early latency, and congenital lesions. The hallmark of these lesions is an abundance of spirochetes; tissue reaction is usually minimal. Late syphilis consists of so-called benign (gummatous) lesions involving skin, bones, and viscera; cardiovascular disease (principally aortitis); and a variety of central nervous system and ocular syndromes. These forms of syphilis are not contagious. The lesions contain few demonstrable spirochetes, but tissue reactivity (vasculitis, necrosis) is severe and suggestive of hypersensitivity phenomena.

Public health efforts to control syphilis focus on the diagnosis and treatment of early (infectious) cases and their partners.

Most cases of syphilis in the United States continue to occur in men who have sex with men (MSM). However, despite the increase in primary and secondary syphilis in MSM in certain urban areas, such as San Francisco, a concomitant increase in the incidence of HIV has not been observed.

COURSE & PROGNOSIS

The lesions associated with primary and secondary syphilis are self-limiting, even without treatment, and resolve with few or no residua. Late syphilis may be highly destructive and permanently disabling and may lead to death. Many experts now believe that while infection is almost never completely eradicated in the absence of treatment, most infections remain latent without sequelae, and only a small number of latent infections progress to further disease.

CLINICAL STAGES OF SYPHILIS

  1. Primary Syphilis

 ESSENTIALS OF DIAGNOSIS

 History of sexual contact (may be unreliable).

 Painless ulcer on genitalia, perianal area, rectum, pharynx, tongue, lip, or elsewhere.

 Nontender enlargement of regional lymph nodes.

 Fluid expressed from lesion contains T pallidum by immunofluorescence or darkfield microscopy.

 Serologic nontreponemal and treponemal tests.

 Clinical Findings

  1. Symptoms and Signs

This is the stage of invasion and may pass unrecognized. The typical lesion is the chancre at the site or sites of inoculation, most frequently located on the penis (Figure 34–1), labia, cervix, or anorectal region. Anorectal lesions are especially common among MSM. Chancres also occur occasionally in the oropharynx (lip, tongue, or tonsil) and rarely on the breast or finger or elsewhere. An initial small erosion appears 10–90 days (average, 3–4 weeks) after inoculation then rapidly develops into a painless superficial ulcer with a clean base and firm, indurated margins. This is associated with enlargement of regional lymph nodes, which are rubbery, discrete, and nontender. Bacterial infection of the chancre may occur and may lead to pain. Healing occurs without treatment, but a scar may form, especially with secondary bacterial infection. Multiple chancres may be present, particularly in HIV-positive patients. Although the “classic” ulcer of syphilis has been described as nontender, nonpurulent, and indurated, only 31% of patients have this triad.

 Figure 34–1. Primary syphilis with a large chancre on the glans of the penis. (From Joseph Engelman, MD; San Francisco City Clinic.)

  1. Laboratory Findings
  2. Microscopic examination—In early (infectious) syphilis, darkfield microscopic examination by a skilled observer of fresh exudate from lesions or material aspirated from regional lymph nodes is up to 90% sensitive for diagnosis. The darkfield examination requires expertise for proper specimen collection and identification of characteristic features of morphology and motility of pathogenic spirochetes, and repeated examinations may be necessary. Therefore, this testing is usually only available in select sexually transmitted disease clinics. Darkfield examination of oral lesions is not recommended because of the presence of nonpathogenic treponemes in the mouth. Spirochetes usually are not found in late syphilitic lesions by this technique.

An immunofluorescent staining technique for demonstrating T pallidum in dried smears of fluid taken from early syphilitic lesions is available through some laboratories but is not widely available.

  1. Serologic tests for syphilis—(Table 34–2.) Serologic tests (the mainstay of syphilis diagnosis) fall into two general categories: (1) Nontreponemal tests detect antibodies to lipoidal antigens present in the host after modification byT pallidum. (2) Treponemal tests use live or killedT pallidum as antigen to detect antibodies specific for pathogenic treponemes.

Table 34–2. Percentage of patients with positive serologic tests for syphilis.1

  1. NONTREPONEMAL ANTIGEN TESTS—The most commonly used nontreponemal antigen tests are the Venereal Disease Research Laboratory (VDRL) and rapid plasmareagin (RPR) tests, which measure the ability of heated serum to flocculate a suspension of cardiolipin–cholesterol– lecithin. The flocculation tests are inexpensive, rapid, and easy to perform and have therefore been commonly used for routine screening. Quantitative expression of the reactivity of the serum, based on titration of dilutions of serum, is valuable in establishing the diagnosis and in evaluating the efficacy of treatment, since titers usually correlate with disease activity. A different, enzyme immunoassay (EIA)-based screening algorithm is discussed below.

Nontreponemal tests generally become positive 4–6 weeks after infection or 1–3 weeks after the appearance of a primary lesion; they are almost invariably positive in the secondary stage, with titers ≥ 1:16. In the late stages, titers tend to be lower (< 1:4). These serologic tests are not highly specific and must be closely correlated with other clinical and laboratory findings. The tests are positive in patients with non–sexually transmitted treponematoses (see below). More important, false-positive serologic reactions are frequently encountered in a wide variety of other conditions, including connective tissue diseases, infectious mononucleosis, malaria, febrile diseases, leprosy, injection drug use, infective endocarditis, old age, hepatitis C viral infection, and pregnancy. False-positive reactions are usually of low titer and transient and may be distinguished from true positives by performing a treponemal specific-antibody test. False-negative results can be seen when very high antibody titers are present (the prozone phenomenon). If syphilis is strongly suspected and the nontreponemal test is negative, the laboratory should be instructed to dilute the specimen to detect a positive reaction. The RPR and VDRL tests are equally reliable, but RPR titers tend to be higher than the VDRL. Thus, when these tests are used to follow disease activity, the same testing method should be used and preferably performed at the same laboratory.

Nontreponemal antibody titers are used to assess adequacy of therapy. The rate of the VDRL or RPR decline depends on various factors. In general, persons with repeat infections, higher initial titers, more advanced stages of disease, or those who are HIV-infected at the time of treatment have a slower seroconversion rate and are more likely to remain serofast (ie, titers decline but do not become nonreactive). Data based on currently recommended treatment regimens (see below) suggest that in primary and secondary syphilis it may take 6–12 months to see a fourfold decrease in titer.

  1. TREPONEMAL ANTIBODY TESTS—These tests measure antibodies capable of reacting withT pallidumantigens. The T pallidum hemagglutination (TPHA) test and the T pallidum particle agglutination (TPPA) test are comparable in specificity and sensitivity to the fluorescent treponemal antibody absorption test (FTA-ABS). The TPPA test, because of ease of performance, has supplanted the FTA-ABS test as the means of confirming the diagnosis of syphilis following a positive nontreponemal test. Newer treponemal tests used in reverse screening algorithms include EIA and chemiluminescence assay (CIA).

In traditional screening, the treponemal tests are used to determine whether a positive nontreponemal antigen test is a false-positive result (see above) or is indicative of syphilis. Because of their great sensitivity, particularly in the late stages of the disease, these tests are also of value when there is clinical evidence of syphilis but the nontreponemal serologic test for syphilis is negative. Treponemal tests are reactive in most patients with primary syphilis and in almost all patients with secondary syphilis (Table 34–2). Although a reactive treponemal-specific serologic test remains reactive throughout a patient’s life in most cases, it may (like nontreponemal antibody tests) revert to negative with adequate therapy. Final decisions about the significance of the results of serologic tests for syphilis must be based on a total clinical appraisal and may require expert consultation.

  1. EIA- ORCIA-BASED SCREENING ALGORITHMS—Newer screening algorithms reverse the traditional test order and begin with an automated treponemal antibody test, (eg, EIA or CIA) and then follow up with a nontreponemal test (RPR or VDRL) if the treponemal test is positive. This algorithm is faster and decreases labor costs to laboratories when compared with traditional screening. Compared with traditional treponemal-specific tests, the EIAs have sensitivities of 95–100% and specificities of 99–100%.

The reverse algorithms can cause challenges in clinical management. A positive treponemal test with a negative RPR or VDRL may represent prior, treated syphilis; untreated latent syphilis; or a false-positive treponemal test. Such results should be evaluated with a second treponemal test, but interpretation of discordant results is not yet fully standardized and a clinician may benefit from an expert opinion.

  1. RAPID TREPONEMAL TESTS—A single rapid treponemal test is approved for use in the United States, with others in development. Such rapid treponemal tests are commonly used worldwide, particularly in limited-resource settings.
  2. Polymerase chain reaction—Polymerase chain reaction (PCR) has been increasingly evaluated and utilized worldwide for the diagnosis of genital ulcer disease, including syphilis, but these tests are not yet commercially available in the United States.
  3. Cerebrospinal fluid examination—See Neurosyphilis section.

 Differential Diagnosis

The syphilitic chancre may be confused with genital herpes, chancroid (usually painful and uncommon in the United States), lymphogranuloma venereum, or neoplasm. Any genital ulcer should be considered a possible primary syphilitic lesion. Simultaneous evaluation for herpes simplex virus types 1 and 2 using PCR or culture should also be done in these cases.

 Prevention & Screening

Avoidance of sexual contact is the only completely reliable method of prevention but is an impractical public health measure. Latex or polyurethane condoms are effective but protect covered areas only. Men who have sex with men should be screened every 6–12 months, and as often as every 3 months in high-risk individuals (those who have multiple encounters with anonymous partners or who have sex in conjunction with the use of drugs). Pregnant women should be screened at the first prenatal visit and again in the third trimester if there are risk indicators, including poverty, sex work, illicit drug use, history of other sexually transmitted diseases, and residing in a community with high syphilis morbidity. Patients treated for other sexually transmitted diseases should also be tested for syphilis, and persons who have known or suspected sexual contact with patients who have syphilis should be evaluated and presumptively treated to abort development of infectious syphilis (see Treating Syphilis Contacts below).

 Treatment

  1. Antibiotic Therapy

Penicillin remains the preferred treatment for syphilis, since there have been no documented cases of penicillin resistant T pallidum (Table 34–3). In pregnant women, penicillin is the only option because it reliably treats the fetus (see below).

Table 34–3. Recommended treatment for syphilis.1

There are some alternatives to penicillin for nonpregnant patients, including doxycycline. There are also limited data for ceftriaxone, although optimum dose and duration are not well defined. Azithromycin has been shown to be effective but should be used with caution; it should not be used at all in MSM due to demonstrated resistance. All patients treated with a non-penicillin regimen must have close clinical and serologic follow up, as noted below.

  1. Managing Jarisch–Herxheimer Reaction

The Jarisch–Herxheimer reaction, manifested by fever and aggravation of the existing clinical picture in the hours following treatment, is ascribed to the sudden massive destruction of spirochetes and is not an IgE-mediated allergic reaction. It is most common in early syphilis, particularly secondary syphilis where it can occur in 66% of cases.

The reaction may be blunted by simultaneous administration of antipyretics, although no proved method of prevention exists. In cases with increased risk of morbidity due to the Jarisch–Herxheimer reaction (including central nervous system or cardiac involvement and pregnancy), consultation with an infectious disease expert is recommended. Patients should be reminded that the reaction does not signify an allergy to penicillin.

  1. Local Measures (Mucocutaneous Lesions)

Local treatment is usually not necessary. No local antiseptics or other chemicals should be applied to a suspected syphilitic lesion until specimens for microscopy have been obtained.

  1. Public Health Measures

Patients with infectious syphilis must abstain from sexual activity for 7–10 days after treatment. All cases of syphilis must be reported to the appropriate local public health agency in order to identify and treat sexual contacts. In addition, all patients with syphilis should have an HIV test at the time of diagnosis. In areas of high HIV prevalence, a repeat HIV test should be performed in 3 months if the initial test result was negative.

  1. Treating Syphilis Contacts

Patients who have been sexually exposed to infectious syphilis within the preceding 3 months may be infected but seronegative and thus should be treated as for early syphilis even if serologic tests are negative. Persons exposed more than 3 months previously should be treated based on serologic results; however, if the patient is unreliable for follow-up, empiric therapy is indicated.

 Follow-Up Care

Because treatment failures and reinfection may occur, patients treated for syphilis should be monitored clinically and serologically every 6 months. In primary and secondary syphilis, failure of nontreponemal antibody titers to decrease fourfold by 6–12 months may identify a group at high risk for treatment failure. Optimal management of these patients is unclear, but at a minimum, close clinical and serologic follow-up is indicated. In HIV-uninfected patients, an HIV test should be repeated (all patients with syphilis should have an HIV test at the time of diagnosis); a lumbar puncture should be considered since unrecognized neurosyphilis can be a cause of treatment failure; and, if careful follow-up cannot be ensured (3-month intervals for HIV-positive individuals and 6-month intervals for HIV-negative patients), treatment should be repeated with 2.4 million units of benzathine penicillin G intramuscularly weekly for 3 weeks. If symptoms or signs persist or recur after initial therapy or there is a fourfold or greater increase in nontreponemal titers, the patient has been reinfected (more likely) or the therapy failed (if a non-penicillin regimen was used). In those individuals, an HIV test should be performed, a lumbar puncture done (unless reinfection is a certainty), and re-treatment given as indicated above.

  1. Secondary Syphilis

 ESSENTIALS OF DIAGNOSIS

 Generalized maculopapular skin rash.

 Mucous membrane lesions, including patches and ulcers.

 Weeping papules (condyloma lata) in moist skin areas.

 Generalized nontender lymphadenopathy.

 Fever may be present.

 Meningitis, hepatitis, osteitis, arthritis, iritis may be present.

 Many treponemes in moist lesions by immunofluorescence or darkfield microscopy.

 Serologic tests for syphilis positive.

 Clinical Findings

The secondary stage of syphilis usually appears a few weeks (or up to 6 months) after development of the chancre, when dissemination of T pallidum produces systemic signs (fever, lymphadenopathy) or infectious lesions at sites distant from the site of inoculation. The most common manifestations are skin and mucosal lesions. The skin lesions are nonpruritic, macular, papular, pustular, or follicular (or combinations of any of these types, but generally not vesicular) and generalized; involvement of the palms and soles (Figure 34–2) occurs in 80% of cases. Annular lesions simulating ringworm may be observed in dark-skinned individuals. Mucous membrane lesions may include mucous patches (Figure 34–3), which can be found on the lips, mouth, throat, genitalia, and anus. Specific lesions—condylomata lata (Figure 34–4)—are fused, weeping papules on the moist areas of the skin and mucous membranes and are sometimes mistaken for genital warts. The mucous membrane lesions are highly infectious.

 Figure 34–2. Secondary syphilis lesions on the soles of the feet. (From Dr. Gavin Hart, Public Health Image Library, CDC.)

 Figure 34–3. Secondary syphilis mucous patch of the tongue. (From Kenneth Katz MD, MSc, MSCE.)

 Figure 34–4. Secondary syphilis perianal condylomata lata. (From Joseph Engelman, MD; San Francisco City Clinic.)

Meningeal (aseptic meningitis or acute basilar meningitis), hepatic, renal, bone, and joint invasion may occur, with resulting cranial nerve palsies, jaundice, nephrotic syndrome, and periostitis. Alopecia (moth-eaten appearance) and uveitis may also occur.

The serologic tests for syphilis are positive in almost all cases (see Primary Syphilis). The moist cutaneous and mucous membrane lesions often show T pallidum on darkfield microscopic examination. A transient cerebrospinal fluid (CSF) pleocytosis is seen in 40% of patients with secondary syphilis. There may be evidence of hepatitis or nephritis (immune complex type) as circulating immune complexes are deposited in blood vessel walls.

Skin lesions may be confused with the infectious exanthems, pityriasis rosea, and drug eruptions (Figure 34–5). Visceral lesions may suggest nephritis or hepatitis due to other causes.

 Figure 34–5. Secondary syphilis rash of the buttocks and legs. (From J. Pledger, BSS/VD, Public Health Image Library, CDC.)

 Treatment

Treatment is as for primary syphilis unless central nervous system or ocular disease is present, in which case a lumbar puncture should be performed and, if positive, treatment for neurosyphilis given (Table 34–3). See Primary Syphilis for follow-up care and treatment of contacts.

  1. Latent Syphilis

 ESSENTIALS OF DIAGNOSIS

 Early latent syphilis: infection < 1 year in duration.

 Late latent syphilis: infection > 1 year in duration.

 No physical signs.

 History of syphilis with inadequate treatment.

 Positive serologic tests for syphilis.

 General Considerations

Latent syphilis is the clinically quiescent phase in the absence of primary or secondary lesions. Early latent syphilis is defined as the first year after primary infection and may relapse to secondary syphilis if undiagnosed or inadequately treated (see above). Relapse is almost always accompanied by a rising titer in quantitative serologic tests; indeed, a rising titer may be the first or only evidence of relapse. About 90% of relapses occur during the first year after infection.

Early latent infection can be diagnosed if there was documented seroconversion or a fourfold increase in nontreponemal titers in the past 12 months; the patient can recall symptoms of primary or secondary syphilis; or the patient had a sex partner with documented primary, secondary, or early latent syphilis.

After the first year of latent syphilis, the patient is said to be in the late latent stage and noninfectious to sex partners. Transmission to the fetus, however, can probably occur in any phase. There are (by definition) no clinical manifestations during the latent stage, and the only significant laboratory findings are positive serologic tests. A diagnosis of late latent syphilis is justified only when the history and physical examination show no evidence of tertiary disease or neurosyphilis. The latent stage may last from months to a lifetime.

 Treatment

Treatment of early latent syphilis and follow-up is as for primary syphilis unless central nervous system disease is present (Table 34–3). Treatment of late latent syphilis is shown in Table 34–3. The treatment of this stage of the disease is intended to prevent late sequelae. If there is evidence of central nervous system involvement, a lumbar puncture should be performed and, if positive, the patient should receive treatment for neurosyphilis. Titers may not decline as rapidly following treatment compared to early syphilis. Nontreponemal serologic tests should be repeated at 6, 12, and 24 months. If titers increase fourfold or if initially high titers (≥ 1:32) fail to decrease fourfold by 12–24 months or if symptoms or signs consistent with syphilis develop, an HIV test should be repeated in HIV-uninfected patients, lumbar puncture should be performed, and re-treatment given according to the stage of the disease.

  1. Late (Tertiary) Syphilis

 ESSENTIALS OF DIAGNOSIS

 Infiltrative tumors of skin, bones, liver (gummas).

 Aortitis, aneurysms, aortic regurgitation.

 Central nervous system disorders, including meningovascular and degenerative changes, paresthesias, shooting pains, abnormal reflexes, dementia, or psychosis.

 General Considerations

This stage may occur at any time after secondary syphilis, even after years of latency, and is rarely seen in developed countries in the modern antibiotic era. Late lesions are thought to represent a delayed hypersensitivity reaction of the tissue to the organism and are usually divided into two types: (1) a localized gummatous reaction, with a relatively rapid onset and generally prompt response to therapy and (2) diffuse inflammation of a more insidious onset that characteristically involves the central nervous system and large arteries, is often fatal if untreated, and is at best arrested by treatment. Gummas may involve any area or organ of the body but most often affect the skin or long bones. Cardiovascular disease is usually manifested by aortic aneurysm, aortic regurgitation, or aortitis. Various forms of diffuse or localized central nervous system involvement may occur.

Late syphilis must be differentiated from neoplasms of the skin, liver, lung, stomach, or brain; other forms of meningitis; and primary neurologic lesions.

Although almost any tissue and organ may be involved in late syphilis, the following are the most common types of involvement: skin, mucous membranes, skeletal system, eyes, respiratory system, gastrointestinal system, cardiovascular system, and nervous system.

 Clinical Findings

  1. Symptoms and Signs
  2. Skin—Cutaneous lesions of late syphilis are of two varieties: (1) multiple nodular lesions that eventually ulcerate (lues maligna) or resolve by forming atrophic, pigmented scars and (2) solitary gummas that start as painless subcutaneous nodules, then enlarge, attach to the overlying skin, and eventually ulcerate (Figure 34–6).

 Figure 34–6. Gumma of the nose due to long-standing tertiary syphilis. (From J. Pledger, Public Health Image Library, CDC.)

  1. Mucous membranes—Late lesions of the mucous membranes are nodular gummas or leukoplakia, highly destructive to the involved tissue.
  2. Skeletal system—Bone lesions are destructive, causing periostitis, osteitis, and arthritis with little or no associated redness or swelling but often marked myalgia and myositis of the neighboring muscles. The pain is especially severe at night.
  3. Eyes—Late ocular lesions are gummatous iritis, chorioretinitis, optic atrophy, and cranial nerve palsies, in addition to the lesions of central nervous system syphilis.
  4. Respiratory system—Respiratory involvement by late syphilis is caused by gummatous infiltrates into the larynx, trachea, and pulmonary parenchyma, producing discrete pulmonary densities. There may be hoarseness, respiratory distress, and wheezing secondary to the gummatous lesion itself or to subsequent stenosis occurring with healing.
  5. Gastrointestinal system—Gummas involving the liver produce the usually benign, asymptomatic hepar lobatum. A picture resembling Laennec cirrhosis is occasionally produced by liver involvement. Gastric involvement can consist of diffuse infiltration into the stomach wall or focal lesions that endoscopically and microscopically can be confused with lymphoma or carcinoma. Epigastric pain, early satiety, regurgitation, belching, and weight loss are common symptoms.
  6. Cardiovascular system—Cardiovascular lesions (10–15% of late syphilitic lesions) are often progressive, disabling, and life-threatening. Central nervous system lesions are often present concomitantly. Involvement usually starts as an arteritis in the supracardiac portion of the aorta and progresses to one or more of the following: (1) narrowing of the coronary ostia, with resulting decreased coronary circulation, angina, and acute myocardial infarction; (2) scarring of the aortic valves, producing aortic regurgitation, and eventually heart failure; and (3) weakness of the wall of the aorta, with saccular aneurysm formation (Figure 34–7) and associated pressure symptoms of dysphagia, hoarseness, brassy cough, back pain (vertebral erosion), and occasionally rupture of the aneurysm. Recurrent respiratory infections are common as a result of pressure on the trachea and bronchi.

 Figure 34–7. Ascending saccular aneurysm of the thoracic aorta in tertiary syphilis. (Public Health Image Library, CDC.)

  1. Nervous system (neurosyphilis)—See following section.

 Treatment

Treatment of tertiary syphilis (excluding neurosyphilis) is the same as late latent syphilis (Table 34–3). Positive serologic tests do not usually become negative. Viable spirochetes are occasionally found in the eyes, in CSF, and elsewhere in patients with “adequately” treated syphilis, but claims for their capacity to cause progressive disease are speculative.

The pretreatment clinical and laboratory evaluation should include neurologic, ocular, cardiovascular, psychiatric, and CSF examinations. In the presence of definite CSF or neurologic abnormalities, one should treat for neurosyphilis.

  1. Neurosyphilis

 ESSENTIALS OF DIAGNOSIS

 Can occur at any stage of disease.

 Consider both clinical presentation and laboratory data.

 Carefully evaluate the neurologic examination in all patients and consider CSF evaluation for atypical symptoms or lack of decrease in nontreponemal serology titers.

 General Considerations

Neurosyphilis can occur at any stage of disease and can be a progressive, disabling, and life-threatening complication. CSF pleocytosis has been reported in 40% of patients with early syphilis. Asymptomatic CSF abnormalities and meningovascular syphilis occur earlier (months to years after infection, sometimes coexisting with primary and secondary syphilis) than tabes dorsalis and general paresis (2–50 years after infection).

 Clinical Findings

  1. Classification
  2. Asymptomatic neuroinvasion—This form is characterized by spinal fluid abnormalities (positive spinal fluidserology, increased cell count, occasionally increased protein) without symptoms or signs of neurologic involvement. There are no clear data to support that these asymptomatic CSF abnormalities have clinical significance.
  3. Meningovascular syphilis—This form is characterized by meningeal involvement or changes in the vascular structures of the brain (or both), producing symptoms of acute or chronic meningitis (headache, irritability); cranial nerve palsies (basilar meningitis); unequal reflexes; irregular pupils with poor light and accommodation reflexes; and when large vessels are involved, cerebrovascular accidents. The CSF shows increased cells (100–1000/mcL), elevated protein, and may have a positive serologic test (CSF VDRL) for syphilis. The symptoms of acute meningitis are rare in late syphilis.
  4. Tabes dorsalis—This form is a chronic progressive degeneration of the parenchyma of the posterior columns of the spinal cord and of the posterior sensory ganglia and nerve roots. The symptoms and signs are impairment of proprioception and vibration sense, Argyll Robertson pupils (which react poorly to light but accommodate for near focus), and muscular hypotonia and hyporeflexia. Impaired proprioception results in a wide-based gait and inability to walk in the dark. Paresthesias, analgesia, or sharp recurrent pains in the muscles of the leg (“shooting” or “lightning” pains) may occur. Crises are also common in tabes: gastric crises, consisting of sharp abdominal pains with nausea and vomiting (simulating an acute abdomen); laryngeal crises, with paroxysmal cough and dyspnea; urethral crises, with painful bladder spasms; and rectal and anal crises. Crises may begin suddenly, last for hours to days, and cease abruptly. Neurogenic bladder with overflow incontinence is also seen. Painless trophic ulcers may develop over pressure points on the feet. Joint damage may occur as a result of lack of sensory innervation (Charcot joint,Figure 34–8). The CSF may have a normal or increased cell count, elevated protein, and variable results of serologic tests.

 Figure 34–8. Neuropathic arthropathy (Charcot joint) from tertiary syphilis. (From Susan Lindsley, Public Health Image Library, CDC.)

  1. General paresis—This is generalized involvement of the cerebral cortex with insidious onset of symptoms. There is usually a decrease in concentrating power, memory loss, dysarthria, tremor of the fingers and lips, irritability, and mild headaches. Most striking is the change of personality; the patient may become slovenly, irresponsible, confused, and psychotic. The CSF findings resemble those of tabes dorsalis. Combinations of the various forms of neurosyphilis (especially tabes and paresis) are not uncommon.
  2. Laboratory Findings

See Serologic Tests for Syphilis, above; these tests should also be performed in cases of suspected neurosyphilis.

  1. Indications for a lumbar puncture—In early syphilis (primary and secondary syphilis and early latent syphilis of < 1 year duration), invasion of the central nervous system byT pallidumwith CSF abnormalities occurs commonly, but clinical neurosyphilis rarely develops in patients who have received standard therapy. Thus, unless clinical symptoms or signs of neurosyphilis or ophthalmologic involvement (uveitis, neuroretinitis, optic neuritis, iritis) are present, a lumbar puncture in early syphilis is not routinely recommended. In latent syphilis, routine lumbar puncture is not indicated since the yield is low and findings rarely influence therapeutic decisions. CSF evaluation is recommended, however, if neurologic or ophthalmologic symptoms or signs are present, if there is evidence of treatment failure (see earlier discussion), or if there is evidence of active tertiary syphilis (eg, aortitis, iritis, optic atrophy, the presence of a gumma).
  2. Spinal fluid examination—CSF findings in neurosyphilis are variable. In “classic” cases, there is an elevation of total protein, lymphocytic pleocytosis, and a positive CSF reagin test (VDRL). The serum nontreponemal titers will be reactive in most cases. In later stages of syphilis, normal CSF analysis in the presence of infection can occur, but it is unusual. False-positive reagin tests rarely occur in the CSF; a positive test confirms the presence of neurosyphilis. Because the CSF VDRL may be negative in 30–70% of cases of neurosyphilis,a negative test does not exclude neurosyphilis. The CSF FTA-ABS is sometimes used; it is a highly sensitive test but lacks specificity, and a high serum titer of FTA-ABS may result in a positive CSF titer in the absence of neurosyphilis.

 Treatment

Neurosyphilis is treated with high doses of aqueous penicillin to achieve better penetration and higher levels of drug in the CSF than is possible with benzathine penicillin G (Table 34–3). There are limited data for using ceftriaxone to treat neurosyphilis as well, but because other regimens have not been adequately studied, patients with a history of an IgE-mediated reaction to penicillin may require skin testing for allergy to penicillin and, if positive, should be desensitized. Patients treated for neurosyphilis should receive at least one dose of long-acting (benzathine) penicillin at the completion of therapy. Because of concerns about slowly dividing organisms that may persist after completing 10–14 days of therapy with short-acting aqueous penicillin G sodium or potassium, many experts recommend subsequent administration of 2.4 million units of the longer-acting benzathine penicillin G intramuscularly once weekly for up to 3 weeks as additional therapy.

All patients treated for neurosyphilis should have nontreponemal serologic tests done every 3–6 months. Guidelines established by the Centers for Disease Control and Prevention (CDC) recommend spinal fluid examinations at 6-month intervals until the CSF cell count is normal; however, there are data to suggest that in certain patients normalization of serum titers are an acceptable surrogate for CSF response. In general, CSF white blood cell count and CSF VDRL normalize more quickly (usually in 12 months) than CSF protein concentration, which can remain abnormal for extended periods. If the serum nontreponemal titers do not normalize, the CSF analysis should be repeated. A second course of penicillin therapy may be given if the CSF cell count has not decreased at 6 months or is not normal at 2 years.

  1. Syphilis in HIV-Infected Patients

Syphilis is common among HIV-infected individuals. Some data suggest that syphilis coinfection is associated with an increase in HIV viral load and a decrease in CD4 count that normalizes with therapy. Researchers from a prospective cohort study of HIV-infected individuals reported that they found no association with HIV disease progression in persons with syphilis coinfection. However, for optimal patient care as well as prevention of transmission to partners, guidelines for the primary care of HIV-infected patients recommend routine syphilis screening.

Interpretation of serologic tests should be the same for HIV-positive and HIV-negative persons. All HIV-positive patients in care should be screened at least annually to identify latent disease because by establishing a serologic history, unnecessary lumbar punctures and prolonged treatment for latent syphilis of uncertain duration can be avoided. If the diagnosis of syphilis is suggested on clinical grounds but reagin tests are negative, alternative tests should be performed. These tests include darkfield examination of lesions and direct fluorescent antibody staining for T pallidum of lesion exudate or biopsy specimens.

HIV-positive patients with primary and secondary syphilis should have careful clinical and serologic follow-up at 3, 6, 9, 12, and 24 months. HIV-infected patients with late latent syphilis, syphilis of uncertain duration, and neurosyphilis should be treated like HIV-negative individuals, with follow-up at 6, 12, 18, and 24 months. The use of antiretroviral therapy has been associated with reduced serologic failure rates after syphilis treatment.

The diagnosis of neurosyphilis in HIV-infected patients is complicated by the fact that CSF abnormalities are frequently seen if lumbar puncture is performed. The significance of these abnormalities is unknown, and similar abnormalities are frequently seen in non–HIV-infected patients with primary or secondary syphilis. Thus, CSF testing is not recommended in those with early disease and a normal neurologic examination. In contrast, a lumbar puncture should be performed in all patients, regardless of HIV-infection status, if neurologic signs are present or if therapy has failed. Following treatment, CSF white blood cell counts normalize within 12 months regardless of HIV status, while the CSF VDRL is slower to normalize in HIV-infected individuals, especially those with CD4 counts < 200 cells/mcL. As discussed above, the same criteria for failure apply to HIV-positive and HIV-negative patients, and re-treatment regimens are the same.

Because clinical experience in treating HIV-infected patients with syphilis is based on penicillin regimens, few options exist for treating the penicillin-allergic patient. Doxycycline or tetracycline regimens can be used for primary, secondary, and early latent syphilis as well as for late latent syphilis and latent syphilis of unknown duration though with caution and close follow-up (Table 34–3). For neurosyphilis, penicillin regimens are optimal even if this requires skin testing and desensitization; limited data exist for ceftriaxone.

  1. Syphilis in Pregnancy

All pregnant women should have a nontreponemal serologic test for syphilis at the time of the first prenatal visit (see Chapter 19). In women who may be at increased risk for syphilis or for populations in which there is a high prevalence of syphilis, additional nontreponemal tests should be performed during the third trimester at 28 weeks and again at delivery. The serologic status of all women who have delivered should be known before discharge from the hospital. Seropositive women should be considered infected and should be treated unless prior treatment with fall in antibody titer is medically documented.

The only acceptable treatment for syphilis in pregnancy is penicillin in dosage schedules appropriate for the stage of disease (see above). Penicillin prevents congenital syphilis in 90% of cases, even when treatment is given late in pregnancy. Tetracycline and doxycycline are contraindicated in pregnancy. Erythromycin should not be used because of failure to eradicate infection in the fetus, and insufficient data are available to justify a recommendation for ceftriaxone or azithromycin. Thus, women with a history of penicillin allergy should be skin tested and desensitized if necessary.

The infant should be evaluated immediately, as noted below, and at 6–8 weeks of age.

  1. Congenital Syphilis

Congenital syphilis is a transplacentally transmitted infection that occurs in infants of untreated or inadequately treated mothers. The physical findings at birth are quite variable: The infant may have many or minimal signs or even no signs until 6–8 weeks of life (delayed form). The most common findings are on the mucous membranes and skin—maculopapular rash, condylomas, mucous membrane patches, and serous nasal discharge (snuffles). These lesions are infectious; T pallidum can easily be found microscopically, and the infant must be isolated. Other common findings are hepatosplenomegaly, anemia, or osteochondritis. These early active lesions subsequently heal, but if the disease is left untreated it produces the characteristic stigmas of congenital syphilis—interstitial keratitis, Hutchinson teeth, saddle nose, saber shins, deafness, and central nervous system involvement.

The presence of negative serologic tests at birth in both the mother and the infant usually means that the newborn is free of infection. However, recent infection near the time of delivery may result in negative tests because there has been insufficient time to develop a serologic response. Thus, it is necessary to maintain a high index of suspicion in infants born to high-risk mothers. All infants born to mothers with positive nontreponemal and treponemal antibody titers should have blood drawn for an RPR or VDRL test and, if positive, be referred to a pediatrician for further evaluation and therapy.

 When to Refer

  • Consultation with the local public health department may help obtain all prior positive syphilis serologic results and may be helpful in complicated or atypical cases.
  • Early (infectious) syphilis cases may be contacted for partner notification and treatment by local public health authorities.

 When to Admit

  • Pregnant women with syphilis and true penicillin allergy should be admitted for desensitization and treatment.
  • Women in late pregnancy treated for early syphilis should have close outpatient monitoring or be admitted because the Jarisch-Herxheimer reaction can induce premature labor.
  • Patients with neurosyphilis usually require admission for treatment with aqueous penicillin.

Gayet-Ageron A et al. Sensitivity, specificity and likelihood ratios of PCR in the diagnosis of syphilis: a systematic review and meta-analysis. Sex Transm Infect. 2013 May;89(3):251–6. [PMID: 23024223]

Ghanem KG et al. Management of adult syphilis. Clin Infect Dis. 2011 Dec;53(Suppl 3):S110–28. [PMID: 22080265]

Seña AC et al. Novel Treponema pallidum serologic tests: a paradigm shift in syphilis screening for the 21st century. Clin Infect Dis. 2010 Sep 15;51(6):700–8. [PMID: 20687840]

Workowski KA et al; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010 Dec 17;59(RR-12):1–110. Erratum in: MMWR Recomm Rep. 2011 Jan 14;60(1):18. [PMID: 21160459]

NON–SEXUALLY TRANSMITTED TREPONEMATOSES

A variety of treponemal diseases other than syphilis occur endemically in many tropical areas of the world. They are distinguished from disease caused by T pallidum by their nonsexual transmission, their relatively high incidence in certain geographic areas and among children, and their tendency to produce less severe visceral manifestations. As in syphilis, organisms can be demonstrated in infectious lesions with darkfield microscopy or immunofluorescence but cannot be cultured in artificial media; the serologic tests for syphilis are positive; molecular methods such as PCR and genome sequencing are available but not widely used in endemic areas; the diseases have primary, secondary, and sometimes tertiary stages; and penicillin is the drug of choice. There is evidence that infection with these agents may provide partial resistance to syphilis and vice versa. Treatment with penicillin in doses appropriate to primary syphilis (eg, 2.4 million units of benzathine penicillin G intramuscularly) is generally curative in any stage of the non–sexually transmitted treponematoses. In cases of penicillin hypersensitivity, tetracycline, 500 mg orally four times a day for 10–14 days, is usually the recommended alternative. In a randomized controlled trial, oral azithromycin (30 mg/kg once) was noninferior to benzathine penicillin G for the treatment of yaws in children.

YAWS (Frambesia)

Yaws is a contagious disease largely limited to tropical regions that is caused by T pallidum subspecies pertenue. It is characterized by granulomatous lesions of the skin, mucous membranes, and bone. Yaws is rarely fatal, though if untreated it may lead to chronic disability and disfigurement. Yaws is acquired by direct nonsexual contact, usually in childhood, although it may occur at any age. The “mother yaw,” a painless papule that later ulcerates, appears 3–4 weeks after exposure. There is usually associated regional lymphadenopathy. Six to 12 weeks later, secondary lesions that are raised papillomas and papules that weep highly infectious material appear and last for several months or years. Painful ulcerated lesions on the soles are called “crab yaws” because of the resulting gait. Late gummatous lesions may occur, with associated tissue destruction involving large areas of skin and subcutaneous tissues. The late effects of yaws, with bone change, shortening of digits, and contractions, may be confused with similar changes occurring in leprosy. Central nervous system, cardiac, or other visceral involvement is rare. See above for therapy. The World Health Organization has set a goal of eliminating yaws by the year 2020.

PINTA

Pinta is a non–sexually transmitted spirochetal infection caused by T pallidum subspecies carateum. It occurs endemically in rural areas of Latin America, especially in Mexico, Colombia, and Cuba, and in some areas of the Pacific. A nonulcerative, erythematous primary papule spreads slowly into a papulosquamous plaque showing a variety of color changes (slate, lilac, black). Secondary lesions resemble the primary one and appear within a year after it. These appear successively, new lesions together with older ones; are most common on the extremities; and later show atrophy and depigmentation. Some cases show pigmentary changes and atrophic patches on the soles and palms, with or without hyperkeratosis, that are indistinguishable from “crab yaws.” Very rarely, central nervous system or cardiovascular disease is observed late in the course of infection. See above for therapy.

ENDEMIC SYPHILIS

Endemic syphilis is an acute or chronic infection caused by T pallidum subspecies endemicum. It has been reported in a number of countries, particularly in the eastern Mediterranean area, often with local names: bejel in Syria, Saudi Arabia, and Iraq, and dichuchwa, njovera, and siti in Africa. It also occurs in Southeast Asia. The local forms have distinctive features. Moist ulcerated lesions of the skin or oral or nasopharyngeal mucosa are the most common manifestations. Generalized lymphadenopathy and secondary and tertiary bone and skin lesions are also common. Deep leg pain points to periostitis or osteomyelitis. In the late stages of disease, destructive gummatous lesions similar to those seen in yaws can develop, resulting in loss of cartilage and saber shin deformity. Cardiovascular and central nervous system involvement are rare. See above for therapy.

Mitjà; O et al. Advances in the diagnosis of endemic treponematoses: yaws, bejel, and pinta. PLoS Negl Trop Dis. 2013 Oct 24;7(10):e2283. [PMID: 24205410]

Mitjà; O et al. Yaws. Lancet. 2013 Mar 2;381(9868):763–73. [PMID: 23415015]

Mitjà; O et al. Single-dose azithromycin versus benzathine benzylpenicillin for treatment of yaws in children in Papua New Guinea: an open-label, non-inferiority, randomised trial. Lancet. 2012 Jan 28;379(9813):342–7. [PMID: 22240407]

SELECTED SPIROCHETAL DISEASES

RELAPSING FEVER

The infectious organisms in relapsing fever are spirochetes of the genus Borrelia. The infection has two forms: tick-borne and louse-borne. The main reservoir for tick-borne relapsing fever is rodents, which serve as the source of infection for ticks. Tick-borne relapsing fever may be transmitted transovarially from one generation of ticks to the next. Humans can be infected by tick bites or by rubbing crushed tick tissues or feces into the bite wound. Tick-borne relapsing fever is endemic but is not transmitted from person to person. In the United States, infected ticks are found throughout the West, especially in mountainous areas, but clinical cases are uncommon in humans.

The louse-borne form is primarily seen in the developing world, and humans are the only reservoir. Large epidemics may occur in louse-infested populations, and transmission is favored by crowding, malnutrition, and cold climate.

 Clinical Findings

  1. Symptoms and Signs

There is an abrupt onset of fever, chills, tachycardia, nausea and vomiting, arthralgia, and severe headache. Hepatomegaly and splenomegaly may develop, as well as various types of rashes (macular, popular, petechial) that usually occur at the end of a febrile episode. Delirium occurs with high fever, and there may be various neurologic and psychic abnormalities. The attack terminates, usually abruptly, after 3–10 days. After an interval of 1–2 weeks, relapse occurs, but often it is somewhat milder. Three to ten relapses may occur before recovery in tick-borne disease, whereas louse-borne disease is associated with only one or two relapses.

  1. Laboratory Findings

During episodes of fever, large spirochetes are seen in blood smears stained with Wright or Giemsa stain. The organisms can be cultured in special media but rapidly lose pathogenicity. The spirochetes can multiply in injected rats or mice and can be seen in their blood.

A variety of anti-borrelia antibodies develop during the illness; sometimes the Weil–Felix test for rickettsioses and nontreponemal serologic tests for syphilis may also be falsely positive. Infection can cause false-positive indirect fluorescent antibody and Western blot tests for Borrelia burgdorferi, causing some cases to be misdiagnosed as Lyme disease. PCR assays have been developed but are not widely available. CSF abnormalities occur in patients with meningeal involvement. Mild anemia and thrombocytopenia are common, but the white blood cell count tends to be normal.

 Differential Diagnosis

The manifestations of relapsing fever may be confused with malaria, leptospirosis, meningococcemia, yellow fever, typhus, or rat-bite fever.

 Prevention

Prevention of tick bites (as described for rickettsial diseases) and delousing procedures applicable to large groups can prevent illness. Arthropod vectors should be controlled if possible.

Postexposure prophylaxis with doxycycline 200 mg orally on day 1 and 100 mg daily for 4 days has been shown to prevent recurrent fever following tick bites in highly endemic areas.

 Treatment

A single dose of tetracycline or erythromycin, 0.5 g orally, or a single dose of procaine penicillin G, 600,000–800,000 units intramuscularly (adults) or 400,000 units intramuscularly (children), probably constitutes adequate treatment for louse-borne relapsing fevers; however, some experts advocate for longer courses of treatment to prevent persistent infection. Because of higher relapse rates, tick-borne disease is routinely treated with 0.5 g of tetracycline or erythromycin given orally four times daily for 10 days. If central nervous system invasion is suspected, penicillin G, 3 million units intravenously every 4 hours, or ceftriaxone, 1 g intravenously daily, should be given for 10–14 days. Jarisch–Herxheimer reactions occur commonly following treatment and may be life-threatening, so patients should be closely monitored (see Syphilis, above). One study in patients with louse-borne relapsing fever showed that administration of anti-TNF antibodies prior to antibiotic therapy can be effective in preventing the reaction.

 Prognosis

The overall mortality rate is usually about 5%. Fatalities are most common in old, debilitated, or very young patients. With treatment, the initial attack is shortened and relapses are largely prevented.

Balicer RD et al. Post exposure prophylaxis of tick-borne relapsing fever. Eur J Clin Microbiol Infect Dis. 2010 Mar;29(3):253–8. [PMID: 20012878]

Cutler SJ. Relapsing fever—a forgotten disease revealed. J Appl Microbiol. 2010 Apr;108(4):1115–22. [PMID: 19886891]

Elbir H et al. Relapsing fever borreliae in Africa. Am J Trop Med Hyg. 2013 Aug;89(2):288–92. [PMID: 23926141]

RAT-BITE FEVER

Rat-bite fever is an uncommon acute infectious disease caused by the treponeme Spirillum minus (Asia), covered in this section, or the bacteria Streptobacillus moniliformis (North America). It is transmitted to humans by the bite of a rat. Inhabitants of rat-infested dwellings, owners of pet rats, and laboratory workers are at greatest risk.

 Clinical Findings

  1. Symptoms and Signs

In Spirillum infections, the original rat bite, unless secondarily infected, heals promptly, but 1 to several weeks later the site becomes swollen, indurated, and painful; assumes a dusky purplish hue; and may ulcerate. Regional lymphangitis and lymphadenitis, fever, chills, malaise, myalgia, arthralgia, and headache are present. Splenomegaly may occur. A sparse, dusky-red maculopapular rash appears on the trunk and extremities in many cases, and there may be frank arthritis.

After a few days, both the local and systemic symptoms subside, only to reappear several days later. This relapsing pattern of fever for 3–4 days alternating with afebrile periods lasting 3–9 days may persist for weeks. The other features, however, usually recur only during the first few relapses. Endocarditis is a rare complication of infection.

  1. Laboratory Findings

Leukocytosis is often present, and the nontreponemal test for syphilis is often falsely positive. The organism may be identified in darkfield examination of the ulcer exudate or aspirated lymph node material; more commonly, it is observed after inoculation of a laboratory animal with the patient’s exudate or blood. It has not been cultured in artificial media.

 Differential Diagnosis

Rat-bite fever must be distinguished from the rat-bite–induced lymphadenitis and rash of streptobacillary fever. Clinically, the severe arthritis and myalgias seen in streptobacillary disease are rarely seen in disease caused by S minus. Reliable differentiation requires an increasing titer of agglutinins against S moniliformis or isolation of the causative organism. Other diseases in the differential include tularemia, rickettsial disease, Pasteurella multocida infections, and relapsing fever.

 Treatment

Penicillin is given for 10–14 days. During the acute phase of illness, the intravenous route is used (1–2 million units every 4–6 hours) and once improvement has occurred, therapy is completed with oral medication, penicillin V 500 mg four times daily to complete 10–14 days of therapy. For the penicillin-allergic patient, tetracycline 500 mg orally four times daily or doxycycline 100 mg twice a day can be used.

 Prognosis

The reported mortality rate of about 10% should be markedly reduced by prompt diagnosis and antimicrobial treatment.

Khatchadourian K et al. The rise of the rats: a growing paediatric issue. Paediatr Child Health. 2010 Mar;15(3):131–4. [PMID: 21358889]

LEPTOSPIROSIS

 ESSENTIALS OF DIAGNOSIS

 Clinical illness can vary from asymptomatic to fatal liver and kidney disease.

 Anicteric leptospirosis is the more common and milder form of the disease.

 Icteric leptospirosis (Weil syndrome) is characterized by impaired kidney and liver function, abnormal mental status, and hemorrhagic pneumonia and has a 5–40% mortality rate.

 General Considerations

Leptospirosis is an acute and sometimes severe treponemal infection that is caused by multiple serovars of the spirochete, Leptospira interrogans. The disease is distributed worldwide, and it is among the most common zoonotic infections. The leptospires are often transmitted to humans by the ingestion of food and drink contaminated by the urine of an infected animal. The organism may also enter through minor skin lesions and probably via the conjunctiva. Reports of recreational cases in international travelers have been increasing, following swimming or rafting in contaminated water, and occupational cases occur among sewer workers, rice planters, abattoir workers, and farmers. Sporadic urban cases have been seen in the homeless exposed to rat urine.

 Clinical Findings

  1. Symptoms and Signs

Anicteric leptospirosis, the more common and milder form of the disease, is often biphasic. After an incubation period of 2–20 days, the initial or “septicemic” phase begins with abrupt fever to 39–40°C, chills, abdominal pain, severe headache, and myalgias, especially of the calf muscles. There may be marked conjunctival suffusion. Leptospires can be isolated from blood, CSF, and tissues. Following a 1- to 3-day period of improvement in symptoms and absence of fever, the second or “immune” phase begins; however, in severe disease the phases may appear indistinct. Leptospires are absent from blood and CSF but are still present in the kidney, and specific antibodies appear. A recurrence of symptoms is seen as in the first phase of disease with the onset of meningitis. Uveitis (which can be unilateral or bilateral and usually involves the entire uveal tract), rash, and adenopathy may occur. A rare but severe manifestation is hemorrhagic pneumonia. The illness is usually self-limited, lasting 4–30 days, and complete recovery is the rule.

Icteric leptospirosis (Weil syndrome) is the most severe form of the disease, characterized by impaired kidney and liver function, abnormal mental status, hemorrhagic pneumonia, hypotension, and a 5–40% mortality rate. Symptoms and signs often are continuous and not biphasic.

Leptospirosis with jaundice must be distinguished from hepatitis, yellow fever, rickettisal disease, and relapsing fever.

  1. Laboratory Findings

The leukocyte count may be normal or as high as 50,000/mcL (0.05/L), with neutrophils predominating. The urine may contain bile, protein, casts, and red cells. Oliguria is common, and in severe cases uremia may occur. Elevated bilirubin and aminotransferases are seen in 75%, and elevated creatinine (> 1.5 mg/dL) (> 132.6 mcmol/L) is seen in 50% of cases. In cases with meningeal involvement, organisms may be found in the CSF during the first 10 days of illness. Early in the disease, the organism may be identified by darkfield examination of the patient’s blood (a test requiring expertise since false-positives are frequent in inexperienced hands) or by culture on a semisolid medium (eg, Fletcher EMJH). Cultures take 1–6 weeks to become positive. The organism may also be grown from the urine from the tenth day to the sixth week. Diagnosis is usually made by means of serologic tests, including the microscopic agglutination test (considered the gold standard, but not widely available), and enzyme-linked immunosorbent assay (ELISA). PCR methods (presently investigational) appear to be sensitive, specific, positive early in disease, and able to detect leptospiral DNA in blood, urine, CSF, and aqueous humor. Serum creatine kinase (CK) is usually elevated in persons with leptospirosis and normal in persons with hepatitis.

 Complications

Myocarditis, aseptic meningitis, acute kidney injury, and pulmonary infiltrates with hemorrhage are not common but are the usual causes of death. Iridocyclitis may occur.

 Prevention

The mainstay of prevention is avoidance of potentially contaminated food and water.

Prophylaxis with doxycycline has been effective in trials but is not routinely recommended. Human vaccine is used in some limited settings but is not available in the United States.

 Treatment

Various antimicrobial drugs, including penicillin, ceftriaxone, and tetracyclines, show antileptospiral activity; however, meta-analysis has not demonstrated a clear survival benefit for any antibiotic. Doxycycline (100 mg every 12 hours orally or intravenously), penicillin (eg, 1.5 million units every 6 hours intravenously), and ceftriaxone (1 g daily intravenously) are used in severe leptospirosis. Jarisch–Herxheimer reactions may occur (see Syphilis, above). Although therapy for mild disease is controversial, most clinicians treat with doxycycline, 100 mg orally twice daily, for 7 days, or amoxicillin 50 mg/kg, divided into three doses daily. Azithromycin is also active, but clinical experience is limited.

 Prognosis

Without jaundice, the disease is almost never fatal. With jaundice, the mortality rate is 5% for those under age 30 years and 40% for those over age 60 years.

 When to Admit

Patients with jaundice or other evidence of severe disease should be admitted for close monitoring and may require admission to an intensive care unit.

Brett-Major DM et al. Antibiotics for leptospirosis. Cochrane Database Syst Rev. 2012 Feb 15;2:CD008264. [PMID: 22336839]

Guerrier G et al. The Jarisch-Herxheimer reaction in leptospirosis: a systematic review. PLoS One. 2013;8(3):e59266. [PMID: 23555644]

Musso D et al. Laboratory diagnosis of leptospirosis: a challenge. J Microbiol Immunol Infect. 2013 Aug;46(4):245–52. [PMID: 23639380]

Schreier S et al. Leptospirosis: current situation and trends of specific laboratory tests. Expert Rev Clin Immunol. 2013 Mar;9(3):263–80. [PMID: 23445200]

LYME DISEASE (Lyme Borreliosis)

 ESSENTIALS OF DIAGNOSIS

 Erythema migrans, a flat or slightly raised red lesion that expands with central clearing.

 Headache or stiff neck.

 Arthralgias, arthritis, and myalgias; arthritis is often chronic and recurrent.

 Wide geographic distribution, with most US cases in the Northeast, mid-Atlantic, upper Midwest, and Pacific coastal regions.

 General Considerations

This illness, named after the town of Old Lyme, Connecticut, is the most common tick-borne disease in the United States and Europe and is caused by genospecies of the spirochete B burgdorferi. In the United States, the causative genospecies is B burgdorferi senu strictu, whereas in Europe and Asia B garinii and B afzelii predominate. Most US cases are reported from the mid-Atlantic, northeastern, and north central regions of the country. The true incidence of Lyme disease is not known for a number of reasons: (1) serologic tests are not standardized (see below); (2) clinical manifestations are nonspecific; and (3) even with reliable testing, serology is insensitive in early disease.

The tick vector of Lyme disease varies geographically and is Ixodes scapularis in the northeastern, north central, and mid-Atlantic regions of the United States; Ixodes pacificus on the West Coast; Ixodes ricinus in Europe; and Ixodes persulcatus in Asia. The disease also occurs in Australia. Mice and deer make up the major animal reservoir of B burgdorferi, but other rodents and birds may also be infected. Domestic animals such as dogs, cattle, and horses can also develop clinical illness, usually manifested as arthritis.

Under experimental conditions, ticks must feed for 24–36 hours or longer to transmit infections. Most cases are reported in the spring and summer months. Human epidemiologic studies have indicated that the incidence of disease is significantly higher when tick attachment is for longer than 72 hours than if it is < 72 hours, though rare cases have been documented with attachment of < 24 hours. In addition, the percentage of ticks infected varies on a regional basis. In the northeastern and midwestern regions, 15–65% of I scapularis ticks are infected with the spirochete; in the western United States, only 2% of I pacificus are infected. These are important epidemiologic features in assessing the likelihood that tick exposure will result in disease. Eliciting a history of brushing a tick off the skin (ie, the tick was not feeding) or removing a tick on the same day as exposure (ie, the tick did not feed long enough) decreases the likelihood that infection will develop.

Because the Ixodes tick is so small, the bite is usually painless and goes unnoticed. After feeding, the tick drops off in 2–4 days. If a tick is found, it should be removed immediately. The best way to accomplish this is to use a fine-tipped tweezers to pull firmly and repeatedly on the tick’s mouth part—not the tick’s body—until the tick releases its hold. Saving the tick in a bottle of alcohol for future identification may be useful, especially if symptoms develop.

 Clinical Findings

Prior clinical description of Lyme disease divided the illness into three stages: stage 1, flu-like symptoms and a typical skin rash (erythema migrans, see Figure 6–28); stage 2, weeks to months later, facial (cranial nerve VII) palsy or meningitis; and stage 3, months to years later, arthritis. The problem with this simplified scheme is that there is a great deal of overlap, and the skin, central nervous system, and musculoskeletal system can be involved early or late. A more accurate classification divides disease into early and late manifestations and specifies whether disease is localized or disseminated.

  1. Symptoms and Signs
  2. Stage 1, early localized infection—Stage 1 infection is characterized by erythema migrans. About 1 week after the tick bite (range, 3–30 days; median 7–10 days), a flat or slightly raised red lesion appears at the site, which is commonly seen in areas of tight clothing such as the groin, thigh, or axilla. This lesion expands over several days. Although originally described as a lesion that progresses with central clearing (“bulls-eye” lesion), often there is a more homogeneous appearance or even central intensification. About 10–20% of patients either do not have typical skin lesions or the lesions go unnoticed. Most patients with erythema migrans will have a concomitant viral-like illness (the “summer flu”) characterized by myalgias, arthralgias, headache, and fatigue. Fever may or may not be present. Even without treatment, the symptoms and signs of erythema migrans resolve in 3–4 weeks. Although the classic lesion of erythema migrans is not difficult to recognize, atypical forms can occur that may lead to misdiagnosis. Chemical reactions to tick and spider bites (these usually recede in 24–48 hours, whereas erythema migrans increases in size in this time period), drug eruptions, urticaria, and staphylococcal and streptococcal cellulitis have been mistaken for erythema migrans. Southern tick–associated rash illness (STARI) has a similar appearance, but it occurs in geographically distinct areas of the United States.

Completely asymptomatic disease, without erythema migrans or flu-like symptoms, can occur but is very uncommon in the United States.

  1. Stage 2, early disseminated infection—Up to 50–60% of patients with erythema migrans are bacteremic and within days to weeks of the original infection, secondary skin lesions develop in about 50% of patients. These lesions are similar in appearance to the primary lesion but are usually smaller. Malaise, fatigue, fever, headache (sometimes severe), neck pain, and generalized achiness are common with the skin lesions. Most symptoms are transient, although fatigue may persist for months. After hematogenous spread, the organism may sequester itself in certain areas and produce focal symptoms. Some patients experience cardiac (4–10% of patients) or neurologic (10–15% of patients) manifestations. Cardiac involvement includes myopericarditis, with atrial or ventricular arrhythmias and heart block. Neurologic manifestations include both the central and peripheral nervous systems. The most common central nervous system manifestation is an aseptic meningitis with mild headache and neck stiffness. The most common peripheral manifestation is a cranial neuropathy, ie, facial palsy (usually unilateral but can be bilateral, seeFigure 24–2). A sensory or motor radiculopathy and mononeuritis multiplex occur less frequently. Conjunctivitis, keratitis and, rarely, panophthalmitis can also occur. Rarely, skin involvement can be manifested as a cutaneous hypopigmented lesion called aborrelial lymphocytoma.
  2. Stage 3, late persistent infection—Stage 3 infection occurs months to years after the initial infection and again primarily manifests itself as musculoskeletal, neurologic, and skin disease. In early reports, musculoskeletal complaints developed in up to 60% of patients, but with early recognition and treatment of disease, this has decreased to < 10%. The classic manifestation of late disease is a monarticular or oligoarticular arthritis most commonly affecting the knee or other large weight bearing joints. While these joints may be quite swollen, these patients generally report less pain compared to patients with bacterial septic arthritis. Even if untreated, the arthritis is self-limited, resolving in a few weeks to months. Multiple recurrences are common but are usually less severe than the original disease. Joint fluid reflects an inflammatory arthritis with a mean white blood cell count of 25,000/mcL (0.025/L) with a predominance of neutrophils. Chronic arthritis develops in about 10% of patients. The pathogenesis of chronic Lyme arthritis may be an immunologic phenomenon rather than persistence of infection.

Rarely, the nervous system (both central and peripheral) can be involved in late Lyme disease. In the United States, a subacute encephalopathy, characterized by memory loss, mood changes, and sleep disturbance, is seen. In Europe, a more severe encephalomyelitis caused by B garinii is seen and presents with cognitive dysfunction, spastic paraparesis, ataxia, and bladder dysfunction. Peripheral nervous system involvement includes intermittent paresthesias, often in a stocking glove distribution, or radicular pain.

The cutaneous manifestation of late infection, which can occur up to 10 years after infection, is acrodermatitis chronicum atrophicans. It has been described mainly in Europe after infection with B afzelii, a genospecies that commonly causes disease in Europe but not the United States. There is usually bluish-red discoloration of a distal extremity with associated swelling. These lesions become atrophic and sclerotic with time and eventually resemble localized scleroderma. Cases of diffuse fasciitis with eosinophilia, an entity that resembles scleroderma, have been rarely associated with infection with B burgdorferi.

  1. Laboratory Findings

The diagnosis of Lyme disease is based on both clinical manifestations and laboratory findings. The National Surveillance Case Definition specifies a person with exposure to a potential tick habitat (within the 30 days just prior to developing erythema migrans) with (1) erythema migrans diagnosed by a physician or (2) at least one late manifestation of the disease and (3) laboratory confirmation as fulfilling the criteria for Lyme disease.

Nonspecific laboratory abnormalities can be seen, particularly in early disease. The most common are an elevated sedimentation rate of > 20 mm/h seen in 50% of cases, and mildly abnormal liver function tests are present in 30%. The abnormal liver function tests are transient and return to normal within a few weeks of treatment. A mild anemia, leukocytosis (11,000–18,000/mcL) (0.011–0.018/L), and microscopic hematuria have been reported in ≤10% of patients.

Laboratory confirmation requires serologic tests to detect specific antibodies to B burgdorferi in serum, preferably by ELISA and not by indirect immunofluorescence assay (IFA), which is less sensitive and specific and can cause misdiagnosis. A two-test approach is recommended for the diagnosis of active Lyme disease, with all specimens positive or equivocal by ELISA then confirmed with an Western immunoblot assay that can detect both IgM and IgG antibodies. IgM antibody appears first 2–4 weeks after onset of erythema migrans, peaks at 6–8 weeks, and then declines to low levels after 4–6 months of illness. The presence of IgM antibody in patients with prolonged symptoms persisting for several months is likely to be a false-positive result. IgG occurs later (6–8 weeks after onset of disease), peaks at 4–6 months, and may remain elevated at low levels indefinitely despite appropriate therapy and resolution of symptoms. When an Western immunoblot is done during the first 4 weeks of illness, both IgM and IgG should be tested. A positive immunoblot requires that antibodies are detected against two (for IgM) or five (for IgG) specific protein antigens from B burgdorferi.

If a patient with suspected early Lyme disease has negative serologic studies, acute and convalescent titers should be obtained since up to 50% of patients with early disease can be antibody negative in the first several weeks of illness. A fourfold rise in antibody titer would be diagnostic of recent infection. In patients with later stages of disease, almost all are antibody positive. False-positive reactions in the ELISA and IFA have been reported in juvenile rheumatoid arthritis, rheumatoid arthritis, systemic lupus erythematosus, infectious mononucleosis, subacute infective endocarditis, syphilis, relapsing fever, leptospirosis, enteroviral and other viral illnesses, and patients with gingival disease (presumably because of cross-reactivity with oral treponemes). False-negative serologic reactions occur early in illness, and antibiotic therapy early in disease can abort subsequent seroconversion.

The diagnosis of late nervous system Lyme disease is often difficult since clinical manifestations, such as subtle memory impairment, may be difficult to document. Most patients have a history of previous erythema migrans or monarticular or polyarticular arthritis, and the vast majority have antibody present in serum. When CSF is sampled from patients with encephalopathy, there may be evidence of inflammation (pleocytosis or elevated protein, or both), and localized antibody production, ie, a ratio of CSF to serum antibody of > 1.0. PCR has low sensitivity and is not recommended for routine diagnosis. Elevated CSF levels of the chemokine CXCL13 have been associated with CNS Lyme disease, but they can also occur in other infections such as neurosyphilis. Patients with late disease and peripheral neuropathy almost always have positive serum antibody tests, usually have abnormal electrophysiology tests, and may have abnormal nerve biopsies showing perivascular collections of lymphocytes; however, the CSF is usually normal and does not demonstrate local antibody production.

Caution should be exercised in interpreting serologic tests because they are not subject to national standards, and inter-laboratory variation is a major problem. In addition, some laboratories perform tests that are entirely unreliable and should never be used to support the diagnosis of Lyme disease (eg, the Lyme urinary antigen test, immunofluorescent staining for cell wall–deficient forms of B burgdorferi, lymphocyte transformation tests, using PCR on inappropriate specimens such as blood or urine). Finally, testing is often done in patients with nonspecific symptoms such as headache, arthralgia, myalgia, fatigue, and palpitations. Even in endemic areas, the pretest probability of having Lyme disease is low in these patients, and the probability of a false-positive test result is greater than that of a true-positive result. For these reasons, the US Centers for Disease Control and Prevention has established guidelines for laboratory evaluation of patients with suspected Lyme disease:

  1. The diagnosis of early Lyme disease is clinical (ie, exposure in an endemic area, with physician-documented erythema migrans), and doesnotrequire laboratory confirmation. (Tests are often negative at this stage.)
  2. Late disease requires objective evidence of clinical manifestations (recurrent brief attacks of monarticular or oligoarticular arthritis of the large joints; lymphocytic meningitis, cranial neuritis [facial palsy], peripheral neuropathy or, rarely, encephalomyelitis—butnotheadache, fatigue, paresthesias, or stiff neck alone; atrioventricular conduction defects with or without myocarditis) and laboratory evidence of disease (two-stage testing with ELISA or IFA followed by Western blot, as described above).
  3. Patients with nonspecific symptoms without objective signs of Lyme disease shouldnothave serologic testing done. It is in this setting that false-positive tests occur more commonly than true-positive tests.
  4. The role of serologic testing in nervous system Lyme disease is unclear, as sensitivity and specificity of CSF serologic tests have not been determined. However, it is rare for a patient to have positive serologic tests on CSF without positive tests on serum (see below).
  5. Other tests such as the T cell proliferative assay and urinary antigen detection have not yet been studied well enough to be routinely used.

Cultures for B burgdorferi can be performed but are not routine and are usually reserved for clinical studies.

PCR is very specific for detecting the presence of Borrelia DNA, but sensitivity is variable and depends on which body fluid is tested, the stage of the disease, and collection and testing technique. In general, PCR is more sensitive than culture, especially in chronic disease. Up to 85% of synovial fluid samples are positive in active arthritis. In contrast, 38% of CSF samples in acute CNS Lyme disease are PCR positive compared with only 25% in chronic CNS disease. However, whether a positive PCR indicates persistence of viable organisms that will respond to further treatment or is a marker for residual DNA (not active infection) has not been clarified. A negative PCR result does not rule out disease.

 Complications

Based on several observational studies, B burgdorferi infection in pregnant women has not been associated with congenital syndromes, unlike other spirochetal illnesses such as syphilis.

Some patients and advocacy groups have claimed either a post-Lyme syndrome (in the presence of positive laboratory tests and after appropriate treatment) or “chronic Lyme disease” in which tests may all be negative. Both entities include nonspecific symptoms such as fatigue, myalgias, and cognitive difficulties (see Prognosis below). Expert groups are in agreement that there are no data to support that ongoing infection is the cause of either syndrome.

 Prevention

There is no human vaccine currently available. Simple preventive measures such as avoiding tick-infested areas, covering exposed skin with long-sleeved shirts and wearing long trousers tucked into socks, wearing light-colored clothing, using repellents, and inspecting for ticks after exposure will greatly reduce the number of tick bites. Environmental controls directed at limiting ticks on residential property would be helpful, but trying to limit the deer, tick, or white-footed mouse populations over large areas is not feasible.

Prophylactic antibiotics following tick bites is recommended in certain high-risk situations if all of the following criteria are met: (1) a tick identified as an adult or nymphal I scapularis has been attached for at least 36 hours; (2) prophylaxis can be started within 72 hours of the time the tick was removed; (3) more than 20% of ticks in the area are known to be infected with B burgdorferi; and (4) there is no contraindication to the use of doxycycline (not pregnant, age > 8 years, not allergic). The drug of choice for prophylaxis is a single 200-mg dose of doxycycline. If doxycycline is contraindicated, no prophylaxis should be given and the patient should be closely monitored for early disease, since short course prophylactic therapy with other agents has not been studied, and if early disease does develop, appropriate therapy is very effective in preventing long-term sequelae. Individuals who have removed ticks (including those who have had prophylaxis) should be monitored carefully for 30 days for possible coinfections.

 Coinfections

Lyme disease, babesiosis (see Chapter 35), and human granulocytic anaplasmosis (formerly human granulocytic ehrlichiosis) (see Chapter 32) are endemic in similar areas of the country and are transmitted by the same tick, I scapularis. Coinfection with two or even all three of these organisms can occur, causing a clinical picture that is not “classic” for any of these diseases. The presence of erythema migrans is highly suggestive of Lyme disease, whereas flu-like symptoms without rash are more suggestive of babesiosis or anaplasmosis. The complete blood count is usually normal in Lyme disease, but in patients with Lyme disease and babesiosis, anemia and thrombocytopenia are more common. Patients with Lyme disease and anaplasmosis are more likely to have leukopenia. Coinfection should be considered and excluded in patients who have persistent high fevers 48 hours after starting appropriate therapy for Lyme disease; in patients with persistent symptoms despite resolution of rash; and in those with anemia, leukopenia, or thrombocytopenia.

Even in patients with documented Lyme disease, immunity is not complete. Reinfection, although uncommon, is predominantly seen in patients successfully treated for early disease (erythema migrans) who do not develop antibody titers. Clinical manifestations and serologic response is similar to an initial infection.

 Treatment

Present recommendations for therapy are outlined in Table 34–4. For erythema migrans, antibiotic therapy shortens the duration of rash and prevents late sequelae. Doxycycline is most commonly used and has the advantage of being active against Anaplasma phagocytophilum (formerly Ehrlichia). Amoxicillin is also effective and is recommended for pregnant or lactating women and for those who cannot tolerate doxycycline. Cefuroxime axetil, is as effective as doxycycline, but because of its cost it should be considered an alternative choice for those who cannot tolerate doxycycline or amoxicillin or for those in whom the drugs are contraindicated. Erythromycin and azithromycin are less effective, associated with higher rates of relapse, and are not recommended as first-line therapy.

Table 34–4. Treatment of Lyme disease.

Isolated facial palsy (without meningitis or peripheral neuropathy) can be treated with doxycycline, amoxicillin, or cefuroxime axetil for 2–3 weeks. Although therapy does not affect the rate of resolution of the cranial neuropathy, it does prevent development of late manifestations of disease.

The need for a lumbar puncture in patients with seventh nerve palsy is controversial. Some clinicians perform lumbar puncture on all patients with facial palsy and others only if there are symptoms or signs of meningitis. If meningitis is present, therapy with a parenteral antibiotic is indicated. Ceftriaxone is most commonly used, but penicillin is equally efficacious. In European countries, doxycycline 400 mg/d orally for 14 days is frequently used and is comparable in efficacy to ceftriaxone.

Patients with atrioventricular block or myopericarditis (or both) can be treated with either oral or parenteral agents for 2–3 weeks. Hospitalization and observation is indicated for symptomatic patients, those with second- or third-degree block, and those with first-degree block with a PR interval ≥ 300 milliseconds. Once stabilized, hospitalized patients can be transitioned to one of the oral regimens to complete therapy.

Therapy of arthritis is difficult because some patients do not respond to any therapy, and those who do respond may do so slowly. Oral agents (doxycycline, amoxicillin, or cefuroxime axetil) are as effective as intravenous regimens (ceftriaxone, cefotaxime, or penicillin). A reasonable approach to the patient with Lyme arthritis is to start with oral therapy for 28 days, and if this fails (persistent or recurrent joint swelling), to re-treat with an oral regimen for 28 days or switch to an intravenous regimen for 2–4 weeks. If arthritis persists after re-treatment, symptomatic therapy with nonsteroidal anti-inflammatory drugs is recommended. For severe refractory pain, synovectomy may be required.

Based on the limited published data, therapy of Lyme disease in pregnancy should be the same as therapy in other patients with the exception that doxycycline should not be used.

Clinicians may encounter patients with nonspecific symptoms (such as fatigue and myalgias) and positive serologic tests for Lyme disease who request (or demand) therapy for their illness. It is important in managing these patients to remember (1) that nonspecific symptoms alone are not diagnostic; (2) that serologic tests are fraught with difficulty (as noted above), and in areas where disease prevalence is low, false-positive serologic tests are much more common than true-positive tests; and (3) that parenteral therapy with ceftriaxone for 2–4 weeks is costly and has been associated with significant adverse effects, including cholelithiasis and Clostridium difficile colitis. Parenteral therapy should be reserved for those most likely to benefit, ie, those with cutaneous, neurologic, cardiac, or rheumatic manifestations that are characteristic of Lyme disease.

 Prognosis

Most patients respond to appropriate therapy with prompt resolution of symptoms within 4 weeks. True treatment failures are thus uncommon, and in most cases re-treatment or prolonged treatment of Lyme disease is instituted because of misdiagnosis or misinterpretation of serologic results (both IgG and IgM antibodies can persist for prolonged periods despite adequate therapy) rather than inadequate therapy or response. Prolonged courses of antibiotic therapy for nonspecific symptoms that persist after completion of appropriate assessment (and treatment, if necessary) for Lyme disease is not recommended.

The long-term outcome of adult patients with Lyme disease is generally favorable, but some patients have chronic complaints. Joint pain, memory impairment, and poor functional status secondary to pain are common subjective complaints in patients with Lyme disease, but physical examination and neurocognitive testing fail to document the presence of these symptoms as objective sequelae. Similarly, in highly endemic areas, patients with a diagnosis of Lyme disease commonly complain of pain, fatigue, and an inability to perform certain physical activities when followed for several years. However, these complaints occur just as commonly in age-matched controls without a history of Lyme disease. Attempts to document chronic cardiac disease in patients treated for Lyme disease also have been unsuccessful. The long-term outcome of treated nervous system Lyme disease is favorable, with complete recovery in 75% of patients. Of the remaining individuals, only 12% had sequelae that affected their daily activities.

 When to Refer

Consultation with an infectious diseases specialist with experience in diagnosing and treating Lyme disease can be helpful in atypical or prolonged cases.

 When to Admit

Admission for parenteral antibiotics is indicated for any patient with symptomatic central nervous system or cardiac disease as well as those with second- or third-degree atrioventricular block, or first-degree block with a PR interval ≥ 300 milliseconds.

Halperin JJ et al. Common misconceptions about Lyme disease. Am J Med. 2013 Mar;126(3):264.e1–7. [PMID: 23321431]

Stanek G et al. Lyme borreliosis. Lancet. 2012 Feb 4;379(9814):461–73. [PMID: 21903253]

Wright WF et al. Diagnosis and management of Lyme disease. Am Fam Physician. 2012 Jun 1;85(11):1086–93. [PMID: 22962880]