31 - HIV Infection

Editors: McPhee, Stephen J.; Papadakis, Maxine A.; Tierney, Lawrence M.

Title: Current Medical Diagnosis & Treatment, 46th Edition

Copyright 2007 McGraw-Hill

> Table of Contents > 34 - Infectious Diseases: Spirochetal

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Infectious Diseases: Spirochetal

Richard A. Jacobs MD, PhD


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), through minor skin or mucosal lesions; sites of inoculation are usually genital but may be extragenital. The risk of developing syphilis after unprotected sex with an individual with early syphilis is approximately 30 50%. The organism is extremely sensitive to heat and drying but can survive for days in fluids; therefore, it can be transmitted in blood from infected persons. Syphilis can be transferred via the placenta from mother to fetus after the tenth week of pregnancy (congenital syphilis).

The immunologic response to infection is complex, but it provides the basis for most clinical diagnoses. The infection induces the synthesis of a number of antibodies, some of which react specifically with pathogenic treponemes and some with components of normal tissues (see below). If the disease is untreated, in most cases these immune reactions fail to eradicate existing infection and may contribute to tissue destruction in the late stages. Patients treated early in the disease are fully susceptible to reinfection.

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) the infectious stage is liable to 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.

As a result of intensive public health efforts and the introduction of penicillin during and after World War II, there was a reduction in the incidence of infectious syphilis. There was a resurgence of disease in the 1960s and 1970s, but the incidence never reached that of the pre-penicillin era. In the early 1980s, the incidence of infectious syphilis increased, with a particularly high rate among homosexual men. In the mid-1980s, there was a slight decrease, primarily a result of changes in sexual practices in response to the AIDS epidemic. Between 1985 and 1990, there was again a dramatic increase in infectious syphilis, with more than 50,000 cases of primary and secondary syphilis reported in 1990. This increase was broad based, affecting both men and women in inner city, urban, and rural areas, particularly in the southern regions of the United States. Although adolescent and young adult blacks were primarily affected, increases were seen in other ethnic groups also, as well as adults over 60 years of age. Limited access to health care, decreases in health department clinical services, increased use of illicit drugs (especially crack cocaine ), the exchange of sex for drugs or money to buy drugs, and the difficulty of contact tracing when multiple sexual partners are involved all contributed to the dramatic increase. Concomitantly with the increase in acquired syphilis, there has also been an increase in congenital syphilis, particularly in urban areas. In response to this increase in infectious syphilis in 1998, the United States Congress allocated funds for a syphilis elimination program. This included intensive syphilis control programs targeting high-risk populations (women of childbearing age, sexually active teens, drug users, inmates of penal institutions, persons with multiple sexual partners or those who have sex with prostitutes) emphasizing screening, early treatment, contact tracing, and condom use. The effort was initially successful, as evidenced by a decrease in the number of primary and secondary cases reported in 2000 (5979 cases) compared with 1998 (7035 cases). However, in 2003, the number of cases was 7,177, the highest since 1997. These increases occurred mainly among men (suggesting that the increase is


likely in the group of men having sex with men and is due to disinhibition with availability of highly active antiretroviral therapy and the nonuse of condoms in partners who are HIV positive), whereas the number of cases actually declined among women and non-Hispanic blacks. Most cases are still reported from the South, but urban outbreaks (New York City, San Francisco) are being reported with increasing frequency, primarily among men having sex with men. Despite the increase in primary and secondary syphilis in men who have sex with men, there has not been a concomitant increase in the number of HIV cases.

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

Primary syphilis
  Genital ulcer: painless ulcer with clean base and firm indurated borders
  Regional lymphadenopathy
Secondary syphilis
  Skin and mucous membranes
  Rash: diffuse (including palms and soles), macular, papular, pustular, and combinations
    Condylomata lata
    Mucous patches: painless, silvery ulcerations of mucous membrane with surrounding erythema
  Generalized lymphadenopathy
  Constitutional symptoms
    Fever, usually low-grade
    Arthralgias and myalgias
  Central nervous system
    Cranial neuropathies (II-VIII)
    Renal: glomerulonephritis, nephrotic syndrome
    Liver: hepatitis
    Bone and joint: arthritis, periostitis
Late syphilis
  Late benign (gummatous): granulomatous lesion usually involving skin, mucous membranes and bones, but any organ can be involved
    Aortic insufficiency
    Coronary ostial stenosis
    Aortic aneurysm
      Hemiparesis or hemiplegia
    Tabes dorsalis
      Impaired proprioception and vibratory sensation
      Argyll Robertson pupil
      Shooting pains
      Romberg's sign
      Urinary and fecal incontinence
      Charcot joint
      Cranial nerve involvement (II-VIII)
    General paresis
      Personality changes
      Hyperactive reflexes
      Argyll Robertson pupil
      Decreased memory
      Slurred speech
      Optic atrophy

Laboratory Diagnosis

Because the infectious agent of syphilis cannot be cultured in vitro, diagnostic measures must rely mainly on serologic testing, microscopic detection of T pallidum in lesions, and other examinations (biopsies, lumbar puncture, radiographs) for evidence of tissue damage.

A. Serologic Tests for Syphilis

(Table 34-2.) There are two general categories of serologic tests for syphilis: (1) Nontreponemal tests detect antibodies to lipoidal antigens present in either the host or in T pallidum. The original antigens used to measure these nonspecific antibodies (reagin) were crude extracts of beef heart or liver and resulted in significant numbers of false-positive reactions. The cardiolipin-cholesterol-lecithin preparation presently used is much purer and gives fewer false-positive reactions. (2) Treponemal tests use live or killed T pallidum as antigen to detect antibodies specific for pathogenic treponemes.

1. Nontreponemal antigen tests

The most commonly used nontreponemal antigen tests are the Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR), 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 are therefore used primarily 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.

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

Test Stage
Primary Secondary Tertiary
VDRL 75 85% 99% 95%
FTA-ABS 85 95% 100% 98%
1Based on untreated cases.
VDRL = Venereal Disease Research Laboratory test; FTA-ABS = fluorescent treponemal antibody absorption test.


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 1:32. 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 importantly, false-positive serologic reactions are frequently encountered in a wide variety of nontreponemal states, 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 tests also occur more commonly in HIV-seropositive patients (4%) than in HIV-seronegative patients (0.8%). False-positive reactions are usually of low titer and transient and may be distinguished from true positives by specific treponemal antibody tests. 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 titers of RPR 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 should be performed at the same laboratory.

Nontreponemal antibody titers are used to assess adequacy of therapy. The time required for the VDRL or RPR to become negative depends on the stage of the disease, the height of the initial titer, and whether the infection is an initial or repeat episode. In general, individuals with repeat infections, higher initial titers, and more advanced stages of disease at the time of treatment have a slower seroconversion rate and are more likely to remain serofast (ie, titers do not become negative). Older data derived from more intensive treatment regimens than are presently used indicate that in primary and secondary syphilis, the VDRL usually decreases fourfold by 3 months and eightfold by 6 months. Furthermore, seronegativity was seen in 97% of those with primary syphilis and 76% of those with secondary syphilis at 2 years. More recent data based on currently recommended treatment regimens (see below) suggest that decreases in titer may be slower ie, in primary and secondary syphilis it may take 6 months to see a fourfold decrease in titer and 12 months to see an eightfold drop. In patients with early latent syphilis, response is even slower, with a fourfold drop in titer taking 12 24 months. Seronegativity was seen in 72% of patients with primary syphilis and only 56% of those with secondary syphilis after 3 years. Additional studies support a slower decline in titers with currently recommended treatment regimens.

2. Treponemal antibody tests

The fluorescent treponemal antibody absorption (FTA-ABS) test measures antibodies capable of reacting with killed T pallidum after absorption of the patient's serum with extracts of nonpathogenic treponemes. The FTA-ABS test is of value principally in determining whether a positive nontreponemal antigen test is false-positive or is indicative of syphilis. Because of its great sensitivity, particularly in the late stages of the disease, the FTA-ABS test is also of value when there is clinical evidence of syphilis but the nontreponemal serologic test for syphilis is negative. The test is positive in most patients with primary syphilis and in almost all patients with secondary syphilis. Like nontreponemal antigen tests, the specific treponemal antibody test may revert to negative with adequate therapy. This is seen almost exclusively in initial infections in individuals with primary syphilis. In one study, 11% of individuals with a first episode of primary syphilis were seronegative by the FTA-ABS test at 1 year posttreatment, and 24% were negative by 3 years. Immunologic status may also affect antibody titers. Seven percent of asymptomatic HIV-infected patients became seronegative after treatment, as opposed to 38% of symptomatic HIV-infected individuals. The long-held belief that a positive FTA-ABS persists indefinitely is clearly not valid, and this test therefore cannot be used as a reliable marker of previous infection. False-positive FTA-ABS tests occur rarely in systemic lupus erythematosus and in other disorders associated with increased levels of -globulins, malaria, leprosy, and other spirochetal infections. It is noteworthy that Lyme disease may cause a false-positive FTA-ABS test but rarely causes a false-positive reaginic test. The T pallidum hemagglutination (TPHA) test and the T pallidum particle agglutination (TPPA) test are comparable in specificity and sensitivity to the 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.

Final decisions about the significance of the results of serologic tests for syphilis must be based on a total clinical appraisal.

B. Microscopic Examination

In infectious syphilis, T pallidum may be shown by darkfield microscopic examination of fresh exudate from lesions or material aspirated from regional lymph nodes. The darkfield examination requires considerable experience and care in the proper collection of specimens and in the identification of pathogenic spirochetes by observing characteristic features of morphology and motility. Repeated examinations may be necessary. 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. Slides are fixed and treated with fluorescein-labeled antitreponemal antibody that has been preabsorbed with nonpathogenic treponemes. The slides are then examined for fluorescing spirochetes in an ultraviolet microscope. Because of its simplicity and convenience to clinicians (slides can be mailed), this technique has replaced darkfield microscopy in most health departments and medical center laboratories.


C. Spinal Fluid Examination

Cerebrospinal fluid findings in neurosyphilis are variable. In classic cases, there is an elevation of total protein, lymphocytic pleocytosis, and a positive cerebrospinal fluid reagin test (VDRL). However, cerebrospinal fluid may be completely normal in neurosyphilis, and the VDRL may be negative. In one study, 25% of patients with primary or secondary syphilis in whom T pallidum was isolated from cerebrospinal fluid had a normal cerebrospinal fluid examination. In later stages of syphilis, normal cerebrospinal fluid analysis in the presence of infection can occur, but it is unusual. Because false-positive reagin tests rarely occur in the cerebrospinal fluid, a positive test confirms the presence of neurosyphilis. Because the cerebrospinal fluid VDRL may be negative in 30 70% of cases of neurosyphilis, a negative test does not exclude neurosyphilis. The use of cerebrospinal fluid FTA-ABS in the diagnosis of neurosyphilis is controversial. It is a highly sensitive test but lacks specificity, and a high serum titer of FTA-ABS may result in a positive cerebrospinal fluid titer in the absence of neurosyphilis. However, because the test is so sensitive, a negative cerebrospinal fluid FTA-ABS is strong evidence against the diagnosis of neurosyphilis.

Cerebrospinal fluid examination is recommended depending on the clinical manifestations and the stage of disease, as discussed below. Asymptomatic neurosyphilis (ie, positive cerebrospinal fluid findings without symptoms) requires prolonged penicillin treatment as given for symptomatic neurosyphilis. Adequate treatment is indicated by gradual decrease in cerebrospinal fluid cell count, protein concentration, and VDRL titer. Rarely, serologic tests of cerebrospinal fluid may remain positive for years after adequate treatment of neurosyphilis even though all other parameters have returned to normal.


A. Specific Measures

1. Penicillin

Penicillin, as benzathine penicillin G or aqueous procaine penicillin G, is the drug of choice for all forms of syphilis and other spirochetal infections. Effective tissue levels must be maintained for several days or weeks because of the spirochete's long generation time (about 30 hours). Penicillin is highly effective in early infections and variably effective in the late stages. The principal contraindication is hypersensitivity to the penicillins. The recommended treatment schedules are included below in the discussion of the various forms of syphilis.

2. Other antibiotic therapy

Oral tetracyclines are effective in the treatment of syphilis for patients who are allergic to penicillin. Tetracycline, 500 mg orally four times daily for 14 days, or doxycycline, 100 mg orally twice daily for 14 days, is given for primary, secondary, and early latent syphilis. In syphilis of more than 1 year's duration or of unknown duration, treatment is continued for 28 days in the same doses.

Preliminary data suggest that both ceftriaxone and azithromycin are effective for the therapy of early syphilis and are now accepted alternative regimens to penicillin after doxycycline and tetracycline. The recommended dose of ceftriaxone is 1 g daily either intramuscularly or intravenously for 8 10 days. Azithromycin can be administered as a single oral dose of 2 g. However, azithromycin resistance has been documented from several geographic areas (reported to be 56% in San Francisco in 2004 compared with 0% in 2000). Azithromycin should be used only if no alternatives are available, and the patient can be monitored closely. Ceftriaxone at a higher dose of 2 g daily intramuscularly or intravenously for 10 14 days can also be used as alternative therapy for neurosyphilis in patients with non-immunoglobulin E (IgE)-mediated hypersensitivity to penicillin.

B. 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.

C. Public Health Measures

Patients with infectious syphilis must abstain from sexual activity until rendered noninfectious by antibiotic therapy. All cases of syphilis must be reported to the appropriate public health agency for assistance in identifying and treating 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 was negative.

D. Empiric Postexposure Treatment

Patients who have been exposed to infectious syphilis within the preceding 3 months may be infected but seronegative and thus should be treated as for early syphilis. Persons exposed more than 90 days previously should be treated based on serologic results. If their partners are unavailable for testing or unreliable for follow-up, empiric therapy is indicated. Others at high risk either for infection (ie, those with other sexually transmitted diseases and those infected with HIV) or its consequences (ie, pregnant women) should undergo serologic tests for syphilis. The present recommended therapy for gonorrhea (single-dose ceftriaxone or cefpodoxime) may not be effective in treating incubating syphilis. Therefore, patients with gonorrhea and a known exposure to syphilis should be treated with separate regimens effective against both diseases.

Complications of Specific Therapy

The Jarisch-Herxheimer reaction is ascribed to the sudden massive destruction of spirochetes by drugs and release of toxic products and is manifested by fever and aggravation of the existing clinical picture. It is most likely to occur in early syphilis. It usually begins


within the first 24 hours and subsides spontaneously within the next 24 hours of penicillin treatment. Treatment should not be discontinued unless the symptoms become severe or threaten to be fatal or unless syphilitic laryngitis, auditory neuritis, or labyrinthitis is present, where the reaction may cause irreversible damage.

The reaction may be prevented or modified by simultaneous administration of antipyretics or corticosteroids, though no proved method of prevention exists.

Follow-Up Care

Because treatment failures can occur and reinfection is always a possibility, patients treated for syphilis should be monitored clinically and serologically. Response to therapy is difficult to assess, and no definite criteria exist for cure in patients with primary or secondary syphilis. In primary and secondary syphilis, failure of nontreponemal antibody titers to decrease fourfold by 6 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. If titers fail to decrease fourfold by 6 months, 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 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, therapy has either failed or the patient has been reinfected. 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. In patients with latent 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 and lumbar puncture should be performed and re-treatment given according to the stage of the disease.


Avoidance of sexual contact is the only completely reliable method of prophylaxis but is an impractical public health measure for obvious reasons. Annual screening for syphilis among men who have sex with men has been recommended based on preliminary data suggesting that this may decrease the rate of transmission. High-risk individuals (those who have multiple encounters with anonymous partners or who have sex in conjunction with the use of drugs) should be screened every 3 6 months.

A. Mechanical

The standard latex condom is effective but protects covered parts only. The exposed parts should be washed with soap and water as soon after contact as possible. This applies to both sexes.

B. Antibiotic

If there is known exposure to infectious syphilis, abortive penicillin therapy may be used. Give 2.4 million units of procaine penicillin G intramuscularly. Azithromycin administered as a single 1 g dose is also effective as preventive therapy in individuals exposed to infected partners, and in some areas Public Health Departments are giving azithromycin packets to persons with syphilis to give to sexual contacts whom they meet in high-risk venues. Treatment of gonococcal (and chlamydial) infection with tetracyclines and ceftriaxone is probably effective against incubating syphilis in most cases. However, other antimicrobial agents (eg, spectinomycin, quinolones) may be ineffective in aborting preclinical syphilis. Because of concerns about treating incubating syphilis with nonpenicillin regimens, patients treated for gonorrhea should have a serologic test for syphilis 3 6 months after treatment.

Course & Prognosis

The lesions associated with primary and secondary syphilis are self-limiting and resolve with few or no residua. Late syphilis may be highly destructive and permanently disabling and may lead to death. In broad terms, if no treatment is given, about one-third of people infected with syphilis will undergo spontaneous cure, about one-third will remain in the latent phase throughout life, and about one-third will develop serious late lesions. (See Table 34-3.)

Table 34-3. Natural course of untreated syphilis in immunocompetent individuals.

Stage of Disease Likelihood of Developing Clinical Manifestations Comment
Latent 24% 90% of relapses occur in first year after infection.
  Benign (gummatous) 15% Seen 1 46 years postinfection. Many patients have more than one late manifestation.
  Cardiovascular 10% Seen only in persons in whom syphilis develops after 15 years of age. Onset 20 30 years postinfection.
  Neurosyphilis 6.5% Asymptomatic neurosyphilis has been reported in 8 40%.
    Early symptomatic 5% Occurs weeks to years after infection; can coexist with primary and secondary disease; manifests as meningitis, cranial neuritis, ocular involvement, meningovascular disease (stroke).
    Late (tertiary) 5 10% 2 50 years after primary infection; tabes or general paresis.

Clinical Stages of Syphilis

1. Primary Syphilis

Essentials of Diagnosis

  • History of sexual contact (often unreliable).

  • Painless ulcer on genitalia, perianal area, rectum, pharynx, tongue, lip, or elsewhere 2 6 weeks after exposure.

  • Nontender enlargement of regional lymph nodes.

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

  • Serologic test for syphilis often positive.

General Considerations

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, labia, cervix, or anorectal region. Anorectal lesions are especially common among men who have sex with men. The primary lesion occurs occasionally in the oropharynx (lip, tongue, or tonsil) and rarely on the breast or finger. The chancre starts as a small erosion 10 90 days (average, 3 4 weeks) after inoculation that rapidly develops into a painless superficial ulcer with a clean base and firm, indurated margins, 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. Although the classic ulcer of syphilis has been described as nontender, nonpurulent, and indurated, only 31% of patients have this triad.

Laboratory Findings

The serologic test for syphilis is usually positive 1 2 weeks after the primary lesion is noted; rising titers are especially significant when there is a history of previous infection. Immunofluorescence or darkfield microscopy shows treponemes in at least 95% of chancres. Cerebrospinal fluid pleocytosis has been reported in 10 20% of patients with primary syphilis.

Differential Diagnosis

The syphilitic chancre may be confused with chancroid (usually painful), lymphogranuloma venereum (uncommon in the United States), genital herpes, or neoplasm. Any lesion on the genitalia should be considered a possible primary syphilitic lesion.


Benzathine penicillin G, 2.4 million units intramuscularly in the gluteal area, is given once. For the nonpregnant penicillin-allergic patient, doxycycline, 100 mg orally twice daily for 2 weeks, or tetracycline, 500 mg orally four times a day for 2 weeks, can be used. There is more clinical experience with tetracycline, but compliance is probably better with doxycycline. As noted above, ceftriaxone and azithromycin can be used in the penicillin-allergic patient, although increasing resistance to azithromycin has limited its usefulness (see preceding section on Other antibiotic therapy ).

2. Secondary Syphilis

Essentials of Diagnosis

  • Generalized maculopapular skin rash.

  • Mucous membrane lesions, including patches and ulcers.

  • Weeping papules (condylomas) in moist skin areas.

  • Generalized nontender lymphadenopathy.

  • Fever.

  • Meningitis, hepatitis, osteitis, arthritis, iritis.

  • Many treponemes in scrapings of mucous membrane or skin lesions by immunofluorescence or darkfield microscopy.

  • Serologic tests for syphilis always positive.

General Considerations & Treatment

The secondary stage of syphilis usually appears a few weeks (or up to 6 months) after development of the chancre, when sufficient dissemination of T pallidum has occurred to produce 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 not vesicular), though the maculopapular rash is the most common. The skin lesions usually are generalized; involvement of the palms and soles is especially suspicious. Annular lesions simulating ringworm are observed in dark-skinned individuals. Mucous membrane lesions range from ulcers and papules of the lips, mouth, throat, genitalia, and anus ( mucous patches ) to a diffuse redness of the pharynx. Both skin and mucous membrane lesions are highly infectious at this stage. Specific lesions condylomata lata are fused, weeping papules on the moist areas of the skin and mucous membranes.

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 most cases. The cutaneous and mucous membrane lesions often show T pallidum on darkfield microscopic examination. A transient cerebrospinal fluid pleocytosis is seen in 30 70% of patients with secondary syphilis, though only 5% have positive serologic cerebrospinal fluid reactions. There may be evidence of hepatitis or nephritis (immune complex type). Circulating immune complexes exist in the blood and are deposited in blood vessel walls.

Skin lesions may be confused with the infectious exanthems, pityriasis rosea, and drug eruptions. Visceral lesions may suggest nephritis or hepatitis due to other causes. The diffusely red throat may mimic other forms of pharyngitis.

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 is as for neurosyphilis (see below). Isolation of the patient is important.

3. Relapsing Syphilis (Early Latent Syphilis)

The essentials of diagnosis are the same as in secondary syphilis.

The lesions of secondary syphilis heal spontaneously, but secondary syphilis may relapse if undiagnosed or inadequately treated. These relapses may include any of the findings noted under secondary syphilis: skin and mucous membrane, neurologic, ocular, bone, or visceral. Unlike the usual asymptomatic neurologic involvement of secondary syphilis, neurologic relapses may be fulminating, leading to death. 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.

Treatment is as for primary syphilis unless central nervous system disease is present.

4. Late Latent ( Hidden ) Syphilis

Essentials of Diagnosis

  • No physical signs.

  • History of syphilis with inadequate treatment.

  • Positive serologic tests for syphilis.


General Considerations & Treatment

Latent syphilis is the clinically quiescent phase during the interval after the disappearance of secondary lesions and before the appearance of tertiary symptoms. Early latency is defined as the first year after infection, during which time most infectious lesions recur ( relapsing syphilis ); after the first year, the patient is said to be in the late latent phase. Transmission to the fetus, however, can probably occur in any phase. There are (by definition) no clinical manifestations during the latent phase, and the only significant laboratory findings are positive serologic tests. A diagnosis of latent syphilis is justified only when the cerebrospinal fluid is entirely negative, radiographic studies and physical examination show no evidence of cardiovascular involvement, and false-positive tests for syphilis have been ruled out. The latent phase may last from months to a lifetime.

It is important to differentiate latent syphilis from a false-positive serologic test for syphilis, which can be due to the many causes listed above.

Treatment of late latent syphilis or latent syphilis of unknown duration is with benzathine penicillin G, 2.4 million units intramuscularly three times at 7-day intervals (total dose: 7.2 million units). The only alternative to penicillin for therapy of late latent syphilis is doxycycline, 100 mg orally twice daily, or tetracycline, 500 mg orally four times a day, both for 28 days. If there is evidence of central nervous system involvement, a lumbar puncture should be performed and, if positive, the patient should receive treatment as for neurosyphilis. Only a small percentage of serologic tests will be appreciably altered by treatment with penicillin. The treatment of this stage of the disease is intended to prevent the late sequelae.

5. 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 seen in about one-third of untreated patients (Table 34-3). Late lesions probably represent, at least in part, 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 ( benign late syphilis ) 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.


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.

Mucous Membranes

Late lesions of the mucous membranes are nodular gummas or leukoplakia, highly destructive to the involved tissue.

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.


Late ocular lesions are gummatous iritis, chorioretinitis, optic atrophy, and cranial nerve palsies, in addition to the lesions of central nervous system syphilis.

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.

Gastrointestinal System

Gummas involving the liver produce the usually benign, asymptomatic hepar lobatum. A picture resembling Laennec's 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.

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 congestive heart failure; and (3) weakness of the wall of the aorta, with saccular aneurysm formation 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.

Treatment of tertiary syphilis (excluding neurosyphilis; see following section) is as for late latent syphilis. Reversal of positive serologic tests does not usually occur. A second course of penicillin therapy may be given if necessary. There is no known method for reliable eradication of the treponeme from humans in the late stages of syphilis. Viable spirochetes are occasionally found in the eyes, in cerebrospinal fluid, and elsewhere in patients with adequately treated syphilis, but claims for their capacity to cause progressive disease are speculative.

Nervous System (Neurosyphilis)

Neurosyphilis (15 20% of late syphilitic lesions; often present with cardiovascular syphilis) is also a progressive, disabling, and life-threatening complication. It develops more commonly in men than in women and in whites than in blacks. Asymptomatic 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).

A. Classification

There are four clinical types.


1. Asymptomatic neurosyphilis

This form is characterized by spinal fluid abnormalities (positive spinal fluid serology, increased cell count, occasionally increased protein) without symptoms or signs of neurologic involvement.

2. Meningovascular syphilis

This form is characterized by meningeal involvement or changes in the vascular structures of the brain (or both), producing symptoms of 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 cerebrospinal fluid shows increased cells (100 1000/mcL), elevated protein, and usually a positive serologic test for syphilis. The symptoms of acute meningitis are rare in late syphilis.

3. 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 well to accommodation), and muscular hypotonia and hyporeflexia. Impairment of 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). The cerebrospinal fluid may have a normal or increased cell count (3 200/mcL), elevated protein, and variable results of serologic tests.

4. 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 becomes slovenly, irresponsible, confused, and psychotic. The cerebrospinal fluid findings resemble those of tabes dorsalis. Combinations of the various forms of neurosyphilis (especially tabes and paresis) are not uncommon.

B. Special Considerations in Treatment of Neurosyphilis

It is most important to prevent neurosyphilis by prompt diagnosis, adequate treatment, and follow-up of early syphilis. Indications for lumbar puncture vary depending on the stage of the disease and the host's immune status. In early syphilis (primary and secondary syphilis and early latent syphilis of less than 1 year's duration), invasion of the central nervous system by T pallidum with cerebrospinal fluid abnormalities occurs commonly, but neurosyphilis rarely develops in patients who have received the standard therapy outlined above. Thus, unless clinical symptoms and signs of neurosyphilis or ophthalmologic involvement (uveitis, neuroretinitis, optic neuritis, iritis) are present, a lumbar puncture in early syphilis is not recommended as part of the routine evaluation. In latent syphilis, the decision to perform a lumbar puncture should be individualized. Routine lumbar puncture for all patients is not indicated since the yield is low and findings rarely influence therapeutic decisions. Cerebrospinal fluid evaluation is recommended, however, in the later stages of syphilis if neurologic or ophthalmologic symptoms and signs are present, if therapy other than with penicillin is to be given, if the patient is HIV positive (see next section), 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). Some experts also routinely recommend lumbar puncture for all individuals with latent syphilis if the serum nontreponemal antibody titer is 1:32. In the presence of definite cerebrospinal fluid or neurologic abnormalities, one should treat for neurosyphilis. The pretreatment clinical and laboratory evaluation should include neurologic, ocular, cardiovascular, psychiatric, and cerebrospinal fluid examinations.

The regimen of 2.4 million units of benzathine penicillin intramuscularly weekly for 3 consecutive weeks results in low to undetectable cerebrospinal fluid levels of penicillin, and treatment failures have been described when this regimen has been used to treat neurosyphilis. For these reasons, current recommendations for the therapy of neurosyphilis include higher doses of short-acting penicillin to achieve better penetration and higher levels of drug in the cerebrospinal fluid. Recommended regimens include 18 24 million units per day of aqueous crystalline penicillin G given as 3 4 million units intravenously every 4 hours or as a continuous infusion for 10 14 days. Alternatively, 2.4 million units of procaine penicillin can be given intramuscularly once daily along with 500 mg of probenecid orally four times daily, both for 10 14 days. Because of concerns about slowly dividing organisms that may persist after only 10 14 days of therapy, many experts recommend subsequent administration of 2.4 million units of benzathine penicillin intramuscularly once weekly for 3 weeks as additional therapy. Ceftriaxone, 2 g intramuscularly or intravenously once daily for 10 14 days, can be used as an alternative to penicillin. Because other regimens for neurosyphilis have not been adequately studied, patients with a history of an IgE-mediated reaction to penicillin should be skin tested for allergy to penicillin and, if positive, desensitized.

All patients should have spinal fluid examinations at 6-month intervals until the cell count is normal. Response may be gauged by clinical improvement and reversal of cerebrospinal fluid changes. In general, cerebrospinal fluid white blood cell count and cerebrospinal


fluid VDRL normalize more quickly (usually in 12 months) than cerebrospinal fluid protein concentration, which can remain abnormal for extended periods, making it less useful as an indicator of success or failure of therapy. A second course of penicillin therapy may be given if the cell count has not decreased at 6 months or is not normal at 2 years. Not infrequently, there is progression of neurologic symptoms and signs despite high and prolonged doses of penicillin. These treatment failures may be related to the unexplained persistence of viable T pallidum in central nervous system or ocular lesions in at least some cases.

6. Syphilis in HIV-Infected Patients

Interpretation of serologic tests should be the same for HIV-positive and HIV-negative individuals. Because syphilis has variable clinical manifestations and an unpredictable course, evaluation of case reports of unusual clinical or laboratory manifestations of syphilis in HIV-infected patients is difficult. Although unusual serologic responses have been reported in HIV-positive patients, including high titers of nontreponemal tests, delayed appearance of positive titers, and false-negative tests, most HIV-positive patients respond serologically in somewhat the same way as noninfected patients. Some recommend that all HIV-positive men be screened twice a year by RPR or VDRL to identify latent disease and to appropriately identify the stage of the syphilis. By establishing a serologic history, unnecessary lumbar punctures required for latent syphilis of unknown duration can be avoided. Because of concerns about false-negative serologic tests or a delayed immunologic response, 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.

The diagnosis of neurosyphilis in HIV-infected patients is complicated by the fact that cerebrospinal fluid abnormalities are frequently seen and may be due to neurosyphilis or HIV infection itself. The significance of these abnormalities is unknown, and similar abnormalities are frequently seen in non-HIV-infected patients with primary or secondary syphilis. Despite occasional reports of neurosyphilis developing in HIV-infected patients despite appropriate therapy for early disease, most HIV-infected patients with primary or secondary syphilis respond appropriately to currently recommended regimens. Thus, although some recommend a cerebrospinal fluid examination for all HIV-positive patients with syphilis, such testing is probably not needed in those with early disease. In contrast, a lumbar puncture should be performed in HIV-positive patients if they have late latent syphilis or syphilis of unknown duration, if neurologic signs are present, or if therapy has failed. A recent study found that HIV-positive patients with a nontreponemal antibody titer 1:32 had a sixfold increased risk of having neurosyphilis, and if the CD4 count was 350/mcL, there was a threefold increased risk of neurosyphilis, suggesting that these subgroups should also undergo lumbar puncture. Following treatment, cerebrospinal fluid white blood cell counts normalize within 12 months regardless of HIV status, while the cerebrospinal fluid 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.

Treatment of HIV-positive patients with primary and secondary syphilis is the same as for HIV-negative patients. Because of concerns about the adequacy of this therapy, some experts recommend additional therapy with 2.4 million units of benzathine penicillin intramuscularly weekly for 3 weeks instead of single-dose therapy. Because of ongoing concerns about adequacy of therapy, careful clinical and serologic follow-up should be done at 3, 6, 9, 12, and 24 months.

HIV-infected patients with late latent syphilis, syphilis of unknown duration, and neurosyphilis should be treated like HIV-negative individuals, with follow-up at 6, 12, 18, and 24 months.

Because clinical experience in treating HIV-infected patients with syphilis is based on penicillin regimens, few options exist for treating the penicillin-allergic patient. For primary, secondary, and early latent syphilis, doxycycline or tetracycline regimens can be used. For late latent syphilis, latent syphilis of unknown duration, and neurosyphilis, penicillin regimens should be used even if this requires skin testing and desensitization.

7. Syphilis in Pregnancy

All pregnant women should have a nontreponemal serologic test for syphilis at the time of the first prenatal visit. In women suspected of being 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 preferred treatment is with penicillin in dosage schedules appropriate for the stage of syphilis (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.


8. 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, and if the disease is left untreated it produces the characteristic stigmas of syphilis interstitial keratitis, Hutchinson's 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 with delayed onset of symptoms despite negative serologic tests at birth, especially in infants born to high-risk mothers (HIV-positive, illicit drug users). 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.

Gilleece Y et al: Management of sexually transmitted infections in HIV positive individuals. Curr Opin Infect Dis 2005;18:43.

Goh BT: Syphilis in adults. Sex Transm Infect 2005;81:448.

Golden MR et al: Update on syphilis: resurgence of an old problem. JAMA 2003;290:1510.

Hall CS et al: Managing syphilis in the HIV-infected patient. Curr Infect Dis Rep 2004;6:72.

Marra CM. Neurosyphilis. Curr Neurol Neurosci Rep 2004;4:435.

Marra CM et al: Normalization of cerebrospinal fluid abnormalities after neurosyphilis treatment: does HIV status matter? Clin Infect Dis 2004;38:1001.

O'donnell JA et al: Neurosyphilis:A current review. Clin Infect Dis Rep 2005;7:277.

Sexually transmitted diseases treatment guidelines 2002. MMWR Recomm Rep 2002;51(RR-6):1.

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, including the newer tests such as CAPTIA Syph G; 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.

Yaws (Frambesia)

Yaws is a contagious disease largely limited to tropical regions that is caused by T pallidum subsp 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 frequent and are called crab yaws. 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.


Pinta is a non-sexually transmitted spirochetal infection caused by Treponema 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 an organism indistinguishable from T pallidum subsp 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.

Antal GM et al: The endemic treponematoses. Microbes Infect 2002;4:83.

Nnoruka EN: Skin diseases in south-east Nigeria: a current perspective. Int J Dermatol 2005;44:29.

Miscellaneous Spirochetal Diseases

Relapsing Fever

Relapsing fever is endemic in many parts of the world. The main reservoir is rodents, which serve as the source of infection for ticks (eg, ornithodoros). The distribution and seasonal incidence of the disease are determined by the ecology of the ticks in different areas. In the United States, infected ticks are found throughout the West, especially in mountainous areas, but clinical cases are uncommon in humans.

The infectious organism is a spirochete, Borrelia recurrentis, though other poorly characterized Borrelia-like organisms can cause similar disease. It may be transmitted transovarially from one generation of ticks to the next. The spirochetes occur in all tissues of the tick, and 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. Different species (or strain) names have been given to Borrelia in different parts of the world where the organisms are transmitted by different ticks.

When an infected person harbors lice, the lice become infected with Borrelia by sucking blood. A few days later, the lice serve as a source of infection for other persons. Large epidemics may occur in louse-infested populations, and transmission is favored by crowding, malnutrition, and cold climate.

Clinical Findings

A. 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 (macular, popular, petechial) of rashes 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.

B. Laboratory Findings

During episodes of fever, large spirochetes are seen in blood smears stained with Wright's 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 with B recurrentis can cause false-positive indirect fluorescent antibody and Western blot tests for Borrelia burgdorferi, and some cases may be misdiagnosed as Lyme disease. Cerebrospinal fluid 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 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.

An effective means of chemoprophylaxis has not been developed.


A single dose of tetracycline or erythromycin, 0.5 g orally, or a single dose of procaine penicillin G, 400,000 600,000 units intramuscularly, probably


constitutes adequate treatment for louse-borne relapsing fevers. Because of higher relapse rates, tick-borne disease is treated with 0.5 g of tetracycline or erythromycin given orally four times daily for 5 10 days. Jarisch-Herxheimer reactions occur commonly following treatment and may be life-threatening. Treatment with aspirin but not hydrocortisone may ameliorate this reaction. The Jarisch-Herxheimer reaction is mediated in part by tumor necrosis factor, and administration of antibody to this cytokine prior to antibiotic therapy is effective in preventing the reaction.


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.

Dworkin MS et al: Tick-borne relapsing fever in North America. Med Clin North Am 2002;86:417.

Roscoe C et al: Tick-borne relapsing fever. Am Fam Physician 2005;72:2039.

Rat-Bite Fever (Spirillary Rat-Bite Fever, Sodoku)

Rat-bite fever is an uncommon acute infectious disease caused by Spirillum minus. It is transmitted to humans by the bite of a rat. Inhabitants of rat-infested slum dwellings and laboratory workers are at greatest risk.

Clinical Findings

A. Symptoms and Signs

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 again in a few more days. 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.

B. 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 Streptobacillus moniliformis or isolation of the causative organism in culture. Rat-bite fever must also be distinguished from tularemia, rickettsial disease, Pasteurella multocida infections, and relapsing fever by identification of the causative organism.


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.


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

Freels LK et al: Rat bite fever: three case reports and a literature review. Clin Pediatr 2004;43:291.

Ojukwu IC et al: Rat-bite fever in children: case report and review. Scand J Infect Dis 2002;34:474.


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's syndrome) is characterized by impaired renal and hepatic function, abnormal mental status, and hemorrhagic pneumonia and has a 5 40% mortality rate.

General Considerations

Leptospirosis is an acute and often severe infection that frequently affects the liver or other organs and is caused by Leptospira interrogans, which is a diverse organism consisting of 24 serogroups and over 200 serovars. The three most common serovars of infection are Leptospira icterohaemorrhagiae of rats, Leptospira canicola


of dogs, and Leptospira pomona of cattle and swine, but no specific serovars have been linked to severity of illness. The disease is worldwide in distribution, and the incidence is higher than usually supposed. The leptospires are often transmitted to humans by the ingestion of food and drink contaminated by the urine of the reservoir animal. The organism may also enter through minor skin lesions and probably via the conjunctiva. Recreational cases have followed 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. The incubation period is 2 20 days.

Clinical Findings

A. Symptoms and Signs

Anicteric leptospirosis, the more common and milder form of the disease, is often biphasic. 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, cerebrospinal fluid, and tissues. Following a 1- to 3-day period of improvement in symptoms and absence of fever, the second or immune phase begins. Leptospires are absent from blood and cerebrospinal fluid 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's syndrome) is the most severe form of the disease, characterized by impaired renal and hepatic function, abnormal mental status, hemorrhagic pneumonia, hypotension, and a 5 40% mortality rate. Symptoms and signs often are continuous and not biphasic.

Pretibial fever, a mild form of leptospirosis caused by Leptospira autumnalis, occurred during World War II at Fort Bragg. In pretibial fever, there is patchy erythema on the skin of the lower legs or generalized rash occurring with fever.

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

B. Laboratory Findings

The leukocyte count may be normal or as high as 50,000/mcL, 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) is seen in 50% of cases. In cases with meningeal involvement, organisms may be found in the cerebrospinal fluid 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's 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, of which several are available. Agglutination tests (microscopic, using live organisms, and macroscopic, using killed antigen) become positive after 7 10 days of illness, peak at 3 4 weeks, and may persist at high levels for many years. Thus, to make a diagnosis, a fourfold or greater rise in titer must be documented. The agglutination tests are cumbersome to perform and require trained personnel. Indirect hemagglutination, enzyme immunosorbent assay (EIA), and enzyme-linked immunosorbent assay (ELISA) tests are also available. The IgM EIA is particularly useful in making an early diagnosis, since it is positive as early as 2 days into illness, a time when the clinical manifestations may be nonspecific, and it is extremely sensitive and specific (93%). Polymerase chain reaction (PCR) methods (presently investigational) appear to be sensitive, specific, positive early in disease, and able to detect leptospiral DNA in blood, urine, cerebrospinal fluid, and aqueous humor. Serum creatine kinase (CK) is usually elevated in persons with leptospirosis and normal in persons with hepatitis.


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


Various antimicrobial drugs, including penicillin, ceftriaxone, and tetracyclines, show antileptospiral activity. Penicillin (eg, 1.5 million units every 6 hours intravenously) or ceftriaxone (1 g daily intravenously) is the drug of choice in severe leptospirosis and is especially effective if started within the first 4 days of illness. Jarisch-Herxheimer reactions may occur. Doxycycline, 100 mg orally twice daily for 7 days, is also effective as therapy if started early, but this agent is most often used in mild to moderate disease. Although therapy for mild disease is controversial, most clinicians treat with oral penicillin, 500 mg four times daily, or doxycycline, 100 mg orally twice daily, for 7 days. Effective prophylaxis consists of doxycycline, 200 mg orally once weekly during the risk of exposure.


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


Ahmad SN et al: Laboratory diagnosis of leptospirosis. J Postgrad Med 2005;51:195.

Bharti AR et al: Leptospirosis: a zoonotic disease of global importance. Lancet Infect Dis 2003;3:757.

Edwards CN et al: Prevention and treatment of leptospirosis. Expert Rev Anti Infect Ther 2004;2:293.

Faucher JF et al: The management of leptospirosis. Expert Opin Pharmacother 2004;5:819.

Kobayashi Y: Human leptospirosis: Management and prognosis. J Postgrad Med 2005;51:201.

Ricaldi JN et al: Leptospirosis in the tropics and in travelers. Curr Infect Dis Rep 2006;8:51.

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 United States 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 caused by the spirochete B burgdorferi and is transmitted to humans by ixodid ticks that are part of the Ixodes ricinus complex. Four genomic groups of the B burgdorferi sensu lato group have been identified: B burgdorferi sensu stricto, which causes disease in North America and less commonly in Europe and Asia; Borrelia garinii and Borrelia afzelii, which are the predominant etiologic agents of Lyme disease in Europe and Asia; and Borrelia bissettii sp nov found in California. Lyme disease is the most common vector-borne disease in the United States and is being reported with increasing frequency, but the true incidence is not known as overreporting remains a problem. In 2003, there were 21,273 cases reported from 45 states and the District of Columbia, an increase of 10% over 2002. Most cases (90%) were reported from the mid-Atlantic, northeastern, and north central regions of the country. As in years past, cases were reported from states without known enzootic cycles of B burgdorferi, raising questions about the accuracy of diagnosis. Because clinical manifestations are nonspecific and because laboratory diagnosis is insensitive early in the illness (see below), many patients are diagnosed with Lyme disease who do not have it. In a Lyme disease clinic at a major teaching hospital in an endemic area, only 23% of patients referred for active disease were found to have it. The consequences of overdiagnosis and overtreatment of Lyme disease are substantial. Individuals previously treated for Lyme disease, whether they actually had the disease or not, were avid users of the health care system, with multiple office visits to several different physicians resulting in numerous prescriptions for unnecessary antibiotics and frequent days of missed work.

The overreporting and overdiagnosis of Lyme disease are in part explained by the discovery of a nonculturable spirochete in the Lone Star tick (Amblyomma americanum). This organism produces a Lyme disease-like illness referred to as STARI (Southern tick-associated rash illness) with a skin lesion indistinguishable from erythema migrans. As the Lone Star tick is found in the midwest and southern areas where enzootic cycles for B burgdorferi have not been reported, cases of Lyme disease reported from these areas are probably due to this newly discovered organism.

The vector of Lyme disease varies geographically and is Ixodes scapularis (also known as Ixodes dammini) in the northeastern, north central, and mid-Atlantic regions of the United States; Ixodes pacificus on the West Coast; I 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.

Ticks feed once during each of their three stages of life. Larval ticks feed in late summer, nymphs in the following spring and early summer, and adults during the fall. In the northeastern United States and the mid-Atlantic states, the preferred host for the nymphs and larvae is the white-footed mouse (the black-striped mouse in Europe). This animal is tolerant of infection a fact that is critical in maintaining infection, since the mouse can remain spirochetemic and transmit the agent to the larvae the following spring after being infected by the nymphal form in early summer. Adult ticks prefer the white-tailed deer as host. Although only 20 25% of nymphs harbor spirochetes compared with 50 65% of adults, most infections occur in the spring and summer (when nymphs are active), and fewer cases occur in the cooler months (October to April), when adults feed. This is probably due to the greater abundance of nymphs; greater human outdoor activity in spring and summer, when nymphs feed; and the fact that adult ticks are larger, easier to detect by the human host, and thus can be removed before disease is transmitted. Less than 1% of larvae are infected with spirochetes, and transmission of the disease through contact with larvae is unlikely. In the western United States, the I pacificus nymph prefers to feed on lizards, which are not susceptible to infection. It is only the few nymph and larval ticks that feed on wood rats, which can be infected, that are capable of transmitting disease.

The increased incidence of Lyme disease is due in part to the resurgence of the once-decimated deer population, the spread of tick vectors to new areas (infected Ixodes ticks have been isolated from migratory birds), and the encroachment of suburbs on once rural areas, bringing humans and ticks into closer proximity.


Factors contributing to increased reporting include enhanced provider awareness and better laboratory surveillance.

Under experimental conditions, ticks must feed for 24 36 hours or longer to transmit infections. 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 less than 72 hours, though rare cases have been documented with attachment of less than 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. Exposure to I pacificus is unlikely to result in disease, since so few ticks are infected, but this is not true of exposure to I scapularis. 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, since the vast majority of cases occur when ticks feed for at least 24 hours.

Ixodes ticks are smaller than the more common dog ticks (Dermacentor variabilis). Larvae are less than 1 mm in size, and the adult female is 2 3 mm in size, with a red body and black legs. After a blood meal, ticks can reach two to three times their unengorged size. Because the 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.

Congenital infection has been documented, but the exact frequency and manifestations have not been clearly defined. Similarly, because the organism can be latent, it is not known if women infected prior to becoming pregnant can activate the disease and transmit infection to the fetus. In one retrospective study, 5 of 19 pregnancies complicated by Lyme disease resulted in an adverse outcome, but all of the outcomes were different and could not be conclusively linked to infection. Several serosurveys involving over 2000 pregnant women in endemic areas have not found any association between seropositivity in prospective mothers and the prevalence of congenital malformations, fetal death, and prematurity. Thus, if B burgdorferi causes a congenital syndrome like some other spirochetal illnesses, it must be extremely uncommon.

Clinical Findings

The typical clinical description of Lyme disease divides the illness into three stages: stage 1, flu-like symptoms and a typical skin rash (erythema migrans); stage 2, weeks to months later, Bell's 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.

A. Symptoms and Signs

1. 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. A flu-like illness with fever, chills, and myalgia occurs in about 50% of patients. 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. Vesicular, urticarial, and evanescent erythema migrans have all been reported. Similarly, chemical reactions to tick and spider bites, drug eruptions, urticaria, and staphylococcal and streptococcal cellulitis have been mistaken for erythema migrans.

Completely asymptomatic disease, without erythema migrans or flu-like symptoms, can occur, but is very uncommon in the United States. Serosurveys done as part of vaccination trials found asymptomatic seroconversion in 7% or less of the population.

2. Stage 2, Early Disseminated Infection

Up to 44% of patients with erythema migrans are bacteremic (especially if multiple lesions are present) leading to dissemination of the spirochete resulting in a wide variety of symptoms and signs. This usually occurs within days to weeks after inoculation of the organism. The most common manifestations involve the skin, central nervous system, and musculoskeletal system. In about 50% of patients, secondary lesions develop that are not associated with a tick bite. These lesions are similar in appearance to the primary lesion but are usually smaller. A rare skin lesion (1% of patients) seen primarily in Europe is Borrelia lymphocytoma. This presents as a small reddish nodule or plaque on the ear in children and on the nipple in adults. Headache and stiff neck can occur, as well as migratory pains in joints, muscles, and tendons. Fatigue and malaise are common. Generally, the neurologic and musculoskeletal symptoms are intermittent and last only hours to a few days, whereas fatigue is persistent. After hematogenous spread, the organism sequesters


itself in certain areas and produces focal symptoms. Some patients experience cardiac (4 10% of patients) or neurologic (10 20% of patients) manifestations. Involvement of the heart includes myopericarditis, with atrial or ventricular arrhythmias and heart block. Neurologic disease is most commonly manifested as aseptic meningitis with mild headache and neck stiffness, Bell's palsy, or encephalitis with irritability, personality change, and forgetfulness that can wax and wane. Even in the absence of symptoms, seeding of the central nervous system can occur. Peripheral neuropathy (sensory or motor), transverse myelitis, and mononeuritis multiplex have also been described. Conjunctivitis, keratitis, and, rarely, panophthalmitis can occur.

3. 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. Musculoskeletal complaints develop in up to 60% of patients. Clinical manifestations are quite variable and include (1) joint and periarticular pain without objective findings (perhaps a manifestation of fibromyalgia that may be triggered by Lyme disease); (2) frank arthritis, mainly of large joints, that is chronic or recurrent over years (recurrences become less severe, less frequent, and shorter with time); and (3) chronic synovitis, which may result in permanent disability. The pathogenesis of chronic Lyme arthritis may be an immunologic phenomenon rather than persistence of infection. The observations that individuals with chronic arthritis have an increased frequency of HLA-DR4 gene expression, antibodies to OspA and OspB protein in joint fluid (major outer surface proteins of B burgdorferi), lack B burgdorferi DNA in synovial fluid as detected by PCR, and often fail to respond to antibiotics all support the inference of an immunologic mechanism.

Both the central and the peripheral nervous systems may be involved. Subacute encephalopathy, characterized by memory loss, mood changes, and sleep disturbance, is the most common chronic neurologic manifestation. An axonal polyneuropathy, manifested as distal sensory paresthesias or radicular pain, can occur either alone or, more commonly, in association with encephalopathy. Most of these patients have objective signs of disease when tested by electromyography. A rare form of chronic neurologic dysfunction leukoencephalitis presents with cognitive dysfunction, spastic paraparesis, ataxia, and bladder dysfunction. This form of the disease is seen more commonly in Europe than in the United States.

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 and is due to infection with B afzelii, a species 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. At least two cases of diffuse fasciitis with eosinophilia, a rare entity that resembles scleroderma, have been associated with infection with B burgdorferi.

B. 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.

Laboratory confirmation requires detection of specific antibodies to B burgdorferi in serum, either by indirect immunofluorescence assay (IFA) or ELISA; the latter is now preferred, because it is more sensitive and specific. A Western blot assay that can detect both IgM and IgG antibodies is used as a confirmatory test. 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. A two-test approach is now recommended for the diagnosis of active Lyme disease. All specimens positive or equivocal by ELISA or IFA should be tested by Western immunoblot. When Western immunoblot is done during the first 4 weeks of illness, both IgM and IgG should be tested. 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.

VlsE is an outer surface lipoprotein of B burgdorferi. A new ELISA measuring antibodies against a peptide that is in the invariant region of this lipoprotein has been studied in a number of different clinical scenarios. The test is done in a single step (as opposed to the current two-step test recommended by the Centers for Disease Control and Prevention), is easy to standardize, and is less expensive than two-step testing. The ELISA appears to be as sensitive and specific as the current two-step test in the diagnosis of late stage disease and it is more sensitive for early disease.


Caution should be exercised in interpreting serologic tests. Serologic tests are not subject to national standards, and interlaboratory variation of results 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). In addition, 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 American College of Physicians 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 does not require laboratory confirmation. (Tests are often negative at this stage.)

2. Late disease requires objective evidence of clinical manifestations (recurrent brief attacks of monoarticular or oligoarticular arthritis of the large joints; lymphocytic meningitis, cranial neuritis [Bell's palsy], peripheral neuropathy or, rarely, encephalomyelitis but not headache, fatigue, paresthesias, or stiff neck alone; atrioventricular conduction defects with or without myocarditis) and laboratory evidence of disease (two-stage testing with ELISA and Western blot, as described above).

3. Patients with nonspecific symptoms without objective signs of Lyme disease should not have 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 neuroborreliosis is unclear, as sensitivity and specificity of cerebrospinal fluid serologic tests have not been determined. However, it is rare for a patient with neuroborreliosis to have positive serologic tests on cerebrospinal fluid without positive tests on serum (see below).

5. Other tests such as the T cell proliferative assay, PCR testing, and urinary antigen detection have not yet been studied well enough to be routinely used (see discussion below).

Positive cultures for B burgdorferi can be obtained early in the course of disease. Aspiration of erythema migrans lesions has yielded positive cultures in up to 30% of cases, whereas culture of a 2-mm punch biopsy is positive in 50 70%. PCR of a skin biopsy is even more sensitive, with positivity rates of 80%. In early disease, blood cultures are positive in up to 50% if large volumes (9 mL) are used, but cerebrospinal fluid is rarely culture positive. The ability to culture organisms from skin lesions is greatly influenced by antibiotic therapy. Even a brief course of several days will result in negative cultures. Special silver staining of chronically inflamed synovial tissue demonstrates spirochetes in one-third of patients.

PCR is very specific for detecting the presence of Borrelia DNA, but sensitivity is variable and depends on which body fluid is tested and the stage of the disease. 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 cerebrospinal fluid samples in acute neuroborreliosis are PCR positive, and only 25% are positive in chronic neuroborreliosis. The significance of a positive reaction is unclear. 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. In chronic Lyme arthritis, some have suggested that a positive PCR indicates active infection that requires further therapy, while others have found a positive reaction despite months of therapy, suggesting that the presence of DNA is indicative of an autoimmune arthritis.

The diagnosis of neuroborreliosis is often difficult since clinical manifestations, such as subtle memory impairment, may be difficult to document. Most patients with neuroborreliosis have a history of previous erythema migrans or monoarticular or polyarticular arthritis, and the vast majority have antibody present in serum. When cerebrospinal fluid is sampled, there may not be evidence of an inflammation (pleocytosis, elevated protein), but localized antibody production, ie, a ratio of cerebrospinal fluid to serum antibody of > 1.0, can often be demonstrated. The role of other tests such as PCR in detection of DNA or ELISA in detecting the presence of outer surface protein A (OspA) antigen is unclear, but in difficult cases these tests can be performed and, if positive, help establish the diagnosis. In addition, many patients with neuroborreliosis will have a peripheral neuropathy that may be detected by electromyography. In the absence of any of the above findings, it is difficult to make the diagnosis of central nervous system Borrelia infection.

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 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), and microscopic hematuria have been reported in 10% or less of patients.


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.

Routine use of prophylactic antibiotics following tick bites is not recommended. Analysis of the cost-effectiveness of prophylactic therapy suggests that antibiotics


administered for 2 weeks would be beneficial in preventing illness in endemic areas, where the risk of acquiring disease following a tick bite is 3.6% or greater. However, prospective studies designed to examine the effect of prophylaxis have shown conflicting results. Two studies have shown no benefit of prophylaxis, but one study resulted in a decrease in erythema migrans from 3.2% in patients given placebo to 0.4% in those given a single 200-mg dose of doxycycline following a documented tick bite from I scapularis. Because most patients in whom Lyme disease develops are symptomatic and since treatment of early disease prevents late sequelae, it is reasonable to reserve treatment for patients in whom symptoms develop rather than to routinely administer prophylactic antibiotics unless the risk is extremely high (endemic area, documented Ixodes tick bite, feeding at least 40 hours). Exceptions might include situations in which the follow-up is uncertain, the patient is extremely anxious, the patient is a pregnant woman, or the tick was engorged when removed.

A highly effective (75% efficacy) recombinant vaccine (LYMErix, SmithKline Beecham) using a conserved region of B burgdorferi known as OspA has been removed from the market. Low sales were cited as the reason for withdrawal. However, initial controversy surrounding the vaccine concerned the theoretical possibility of inducing an autoimmune arthritis in recipients. Despite the fact that no cases of vaccine-induced arthritis had been documented, concerns about potential legal actions probably contributed to the decision to withdraw the product.


Antibiotic sensitivity of B burgdorferi has been established in vitro. Tetracycline is effective against the spirochete, but penicillin is only moderately so. Erythromycin is effective in vitro but has been disappointing in clinical trials. Ampicillin, ceftriaxone, azithromycin, cefuroxime, and imipenem are also effective in vitro, but aminoglycosides, ciprofloxacin, and rifampin are not.

Present recommendations for therapy are outlined in Table 34-4. In general, infection confined to skin is treated for 2 3 weeks, although courses of doxycycline as short as 10 days have been shown to be effective. For central nervous system disease (with the exception of Bell's palsy), intravenous therapy is used. Other organ system involvement usually responds to oral medication. 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. Isolated Bell's palsy (without meningitis or peripheral neuropathy) can be treated with doxycycline or amoxicillin 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.

Table 34-4. Treatment of Lyme disease.

Manifestation Drug and Dosage
Tick bite No treatment in most circumstances (see text); observe
Erythema migrans Doxycycline, 100 mg orally twice daily, or amoxicillin, 500 mg orally three times daily, or cefuroxime axetil, 500 mg twice daily all for 2 3 weeks
Neurologic disease  
  Bell's palsy Doxycycline, or amoxicillin as above for 2 3 weeks
  Other central nervous system disease Ceftriaxone, 2 g intravenously once daily, or penicillin G, 18 24 million units daily intravenously in 6 divided doses, or cefotaxime, 2 g intravenously every 8 hours all for 2 4 weeks
Cardiac disease  
  First-degree block (P-R < 0.3 seconds) Doxycycline or amoxicillin as above for 2 3 weeks
  High-degree atrioventricular block Ceftriaxone or penicillin G as above for 30 60 days (see text)
  Oral dosage Doxycycline or amoxicillin as above for 30 60 days (see text)
  Parenteral dosage Ceftriaxone or penicillin G as above for 2 4 weeks
Acrodermatitis chronicum atrophicans Doxycycline or amoxicillin as above for 4 weeks
Chronic Lyme disease or post-Lyme disease syndrome Symptomatic therapy

The need for a lumbar puncture in patients with seventh nerve palsy is controversial. Some perform lumbar puncture on all patients with Bell's 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 for 14 days is frequently used and is comparable in efficacy to ceftriaxone. First- and second-degree heart block can be treated with oral agents, but third-degree block should be treated with ceftriaxone or penicillin, and the patient should be admitted to the hospital for monitoring.


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 or amoxicillin) are as effective as intravenous regimens (ceftriaxone or penicillin). A reasonable approach to the patient with Lyme arthritis is to start with oral therapy for 30 days, and if this fails (persistent or recurrent joint swelling), to re-treat with an oral regimen for 60 days or switch to an intravenous regimen for 2 4 weeks. Re-treatment should be delayed for several months because of the slow resolution of joint symptoms. 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 are often confronted with 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 the diagnosis of Lyme disease is primarily a clinical one, and 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 (approximately $5000) and has been associated with significant adverse effects (cholelithiasis). 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.


Lyme disease, babesiosis (see Chapter 35), and 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 ehrlichiosis. 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 ehrlichiosis are more likely to have leukopenia. Patients with Lyme disease and babesiosis may have longer-lasting and more severe symptoms. Thus, persistent symptoms after what appears to be appropriate therapy for Lyme disease should raise the possibility of coexisting babesiosis.

Even in patients with documented Lyme disease, immunity is not complete. Individuals who live in endemic areas are subject to reinfection.


Most patients respond to appropriate therapy with prompt resolution of symptoms within 4 weeks. With adequate therapy, only a small percentage of patients will not respond or will develop a late relapse. 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. The terms chronic Lyme disease or post-Lyme disease syndrome have been applied to patients with documented Lyme disease who have been adequately treated but have persistent nonspecific symptoms such as fatigue, arthralgias, myalgias, and neurocognitive complaints. These entities are poorly defined, and the patients comprise a heterogeneous group. Although there is a tendency to treat these patients with multiple or prolonged courses of oral or intravenous antibiotics, there are no data suggesting that this is efficacious, and the prolonged use of antibiotics in this setting is emphatically discouraged.

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 neuroborelliosis is favorable, with complete recovery in 75% of patients. Of the remaining individuals, only 12% had sequelae that affected their daily activities.

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Bunikis J et al: Laboratory testing for suspected Lyme disease. Med Clin North Am 2002;86:311.

Coyle PK et al: Neurologic aspects of Lyme disease. Med Clin North Am 2002;86:261.

Depietropaolo DL et al: Diagnosis of Lyme disease. Am Fam Physician 2005;72:297.

Halperin JJ: Central nervous system Lyme disease. Curr Infect Dis Rep 2004;6:298.

Hayes EB et al: How can we prevent Lyme disease? N Engl J Med 2003;348:2424.

Hengge UR et al: Lyme borreliosis. Lancet Infect Dis 2003;3:489.

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Current Medical Diagnosis & Treatment 2007
Current Medical Diagnosis and Treatment 2007 (Current Medical Diagnosis & Treatment)
ISBN: 0071472479
EAN: 2147483647
Year: 2004
Pages: 49
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