Chapter 19. Syphilis

• • Sexually transmitted disease causing a wide range of systemic manifestations.
• • Clinical disease occurs in well-characterized stages: primary (chancre), secondary (rash, swollen glands, systemic symptoms) and tertiary (dementia, neuromotor, gummatous, cardiovascular symptoms).
• • Latent periods of variable duration occur between clinical manifestations of disease.
• • Clinical disease is confirmed and latent disease diagnosed by two-stage serologic tests.

Syphilis is a complex disease caused by the spirochete Treponema pallidum. It occupies an interesting place in the history of disease, appearing explosively as a virulent epidemic in Europe during the age of exploration, a time of intense scientific inquiry. Although syphilis incidence has waxed and waned over the centuries since, it has never really abated. Penicillin has been and remains the therapy of choice.

Unique among the sexually transmitted diseases, syphilis is characterized by a potential to cause a wide range of systemic manifestations. It can involve nearly every organ system in a variety of ways acutely or more commonly in an insidious and chronic fashion. Latent periods between clinical manifestations may be of variable duration. It has the potential to cause serious congenital disease and appears to enhance the transmission of human immunodeficiency virus (HIV).

Syphilis is typically acquired sexually or congenitally. Rare cases of acquisition through contaminated blood products have been reported. Syphilis can also be spread by skin or mucosal contact with an infectious lesion (eg, through nonsexual direct contact such as skin to skin or kissing). The risk of syphilis following sexual exposure to an individual with infectious syphilis is probably about 30% and is dependent on a variety of factors, including the extent and location of disease in the source patient. Long-standing immunity following infection after treatment does not occur, and repeated infections are possible.

Most syphilis infections are sexually transmitted; therefore, measures that prevent sexual exposure, such as condom use or reduction in the number of sex partners, are effective in reducing the risk of acquiring syphilis. Syphilis is unique among the sexually transmitted diseases because of a well-characterized prolonged incubation period during which infection can be aborted by prophylactic treatment. After sexual exposure infection may be prevented with penicillin G benzathine therapy.

Preventive treatment is highly effective and a mainstay of syphilis control programs. Persons who may have been exposed to syphilis are contacted and offered preventive therapy. Those who receive timely preventive therapy will not undergo seroconversion (see later discussion of serologic testing). Waiting for serologic test results before treatment is not recommended in patients who report syphilis exposure, because the opportunity to prevent infection may be missed. All persons who report exposure should receive preventive treatment, regardless of serologic test results.

Symptoms and Signs

Typical of syphilis is its clinical progression through several well-characterized stages, outlined below.

Primary Syphilis

Incubation after exposure typically lasts from 1 week to 3 months. The initial manifestation is the chancre (Figure 19–1), an indurated, nontender lesion at the site of exposure. Several lesions may occur at once, but they are more often solitary. Disease is transmissible through contact with a chancre. In conjunction with the appearance of the chancre, patients usually develop nonsuppurative, nontender inguinal lymphadenopathy. Primary lesions can appear at any site of inoculation, including the perineum, vagina, cervix, anus, or rectum. Lesions can also appear on the lips or in the oropharynx.

Secondary Syphilis

Without therapy the lesions of primary syphilis typically resolve over a period of about 3 weeks. By this time spirochetemia, first to regional lymph nodes and then systemically, has already occurred. Either coincident with the resolution of the primary lesion or more commonly several weeks later, the clinical manifestations of secondary syphilis develop. These have long been considered to be among the most diverse of all clinicopathologic phenomena. Most often they present as a diffuse maculopapular rash (Figure 19–2). Papulosquamous lesions with fine circumferential scaling may involve the palms and soles (Figure 19–3). Moist heaped-up lesions, termed condylomata lata, are seen in the intertriginous areas such as the buttocks and the upper thighs (Figure 19–4). Similar lesions, termed mucous patches, appear in the nasolabial folds and in the mouth. The moist lesions characteristic of condylomata lata and the mucous patch may transmit disease in a particularly efficient manner. Rashes covered in keratinized epithelium are less likely to transmit infection.

Patchy alopecia, diffuse lymphadenopathy, pharyngitis, or fever may also be present. Focal involvement of various organ systems, such as gastritis, uveitis, hepatitis, periostitis, meningitis, and cerebrovascular accidents, can occur as manifestations of secondary syphilis. The period of spirochetemia that is linked to the development of secondary syphilis is the most likely opportunity for transplacental transmission in the pregnant woman.

Latent Syphilis

As in primary syphilis, the clinical manifestations of secondary stage disease abate with time (ie, weeks) even in the absence of specific therapy. At this point the disease is considered to have entered a latent period. Studies have demonstrated that about 25% of untreated persons with latent syphilis may have recrudescent secondary symptoms within a 4- to 5-year period after their initial resolution. The majority of these events occur within 1 year. For the sake of convention this period within 1 year of exposure is regarded as the “early latent” period. Beyond this time frame a period of long-term or “late” latency develops in which there are no clinical manifestations of infection. For most of these patients, one of three outcomes can be anticipated: spontaneous resolution of infection, persistent latent infection with some level of immunologic control, or development of tertiary syphilis after a period of years or decades. As many as one third of untreated patients with latent syphilis may go on to develop tertiary syphilis. Sexual transmission of syphilis in the latent stage is not likely.

Tertiary Syphilis

This stage is characterized by an element of end-organ damage. There are three types of tertiary disease: neurosyphilis, cardiovascular syphilis, and gummatous (or late benign) syphilis.

Neurosyphilis

T pallidum appears to have a particular predilection for the nervous system. Even in early-stage disease, invasion of the central nervous system is well documented. Although usually asymptomatic, in some instances there may be ocular manifestations such as uveitis or even cerebrovascular accidents. Central nervous system disease that manifests after long periods of latency is characterized by either vascular compromise of some portion of the neuroaxis or chronic debilitating loss of function that correlates with parenchymal destruction.

General paresis is characterized by a combination of psychiatric and neurologic findings. The letters in the word PARESIS correspond to the prominent findings associated with this aspect of disease: Personality (emotional lability), Affect (flat), Reflexes (hyperreflexivity), Eye (Argyll-Robertson pupil), Sensorium (illusions, delusions, hallucinations), Intellect (memory, judgment impairment), and Speech (slurring). The classic Argyll-Robertson pupil of late neurosyphilis is characterized by a pupil that constricts upon accommodation but not to light.

Another classic late-stage neurosyphilis syndrome is tabes dorsalis. As a result of demyelination of the posterior columns of the spinal cord, patients develop abnormalities in gait, as well as various sensory abnormalities, including characteristic “lightening” pains, bladder and bowel dysfunction, and a positive Romberg sign. The clinical presentation is usually some portion or combination of these symptoms.

A host of inflammatory ocular and otic manifestations is also attributable to neurosyphilis, as are other cranial nerve abnormalities. It is more than reasonable to consider syphilis in the differential diagnosis of nearly any psychiatric or neurologic presentation. Neurosyphilis is discussed in more detail in Chapter 20.

Cardiovascular Syphilis

Unlike neurosyphilis, and probably as a result of the widespread use of systemic antibiotics with activity against T pallidum for different clinical conditions, cardiovascular syphilis is not as common today as it once was. T pallidum damages the muscular intima of the aorta and with time the resultant weakening leads to the development of an aortic aneurysm, usually of the ascending arch. Dissection, however, is uncommon. Dilation resulting from syphilitic aortitis in turn leads to aortic regurgitation. Involvement of the coronary ostia may compromise myocardial blood flow.

Gummatous (or Late Benign) Syphilis

Gummatous disease is also extremely uncommon and is characterized by indolent destructive lesions of skin, soft tissue, and bony structures. Significant scarring may result in disfigurement. Visceral organs and the central nervous system may also be involved. Gummas may vary widely in size from small defects to large tumor-like masses. Interestingly, treponemes cannot routinely be found in tissue specimens from these lesions. The process is suspected to be largely immune mediated.

Laboratory Findings

Under ordinary circumstances T pallidum cannot be cultivated in agar-based medium. Beyond clinical suspicion, diagnosis is made or confirmed through the use of darkfield microscopy, two-stage serologic tests, nucleic acid amplification tests (NAATs), direct antigen tests, or special tissue stains. The first two tests are the most commonly available. Clinicians should inform patients that reactive laboratory tests for syphilis are reportable to public health authorities.

Darkfield Microscopy

T pallidum is too slender to be adequately observed by ordinary light microscopy and fails to take up usual stains. Instead it can be observed using darkfield techniques, which require a microscope equipped with a special condenser that angles light to allow only those rays reflected by the object of interest to enter the objective. The organism appears white against an otherwise black background, hence the term darkfield. Under such observation, the treponeme can be visualized as a corkscrew-shaped organism rotating along its long axis.

Darkfield microscopy is only useful when examining the moist lesions of primary syphilis or condylomata lata. For darkfield specimen collection, lesions must first be cleaned with saline-soaked gauze. Serous exudate is then pressed against a glass slide, which must be immediately examined before the specimen desiccates. Darkfield examination may also be used for aspirates from involved lymph nodes. The yield from resolving lesions is low.

Serologic Tests

Traditionally, a diagnosis of syphilis of any stage should be confirmed through the use of two-stage serologic tests.

Nontreponemal Tests

Initial testing is performed with a nontreponemal serologic test. These tests use a laboratory-prepared lecithin-cholesterol antigen to detect treponemal-directed antibody in the target serum specimen. The sensitivity of these tests (which include rapid plasma reagin [RPR], Venereal Disease Research Laboratory [VDRL], and toluidine red unheated serum test [TRUST]), is very good. Specificity is slightly less reliable. A variety of factors can produce false-positive reactions, including older age, autoimmune disease, intravenous drug use, and recent vaccination.

Nontreponemal tests can be performed both quantitatively and qualitatively. Repeated tests on serially diluted specimens allow for a determination of the strength of the reaction, which roughly correlate with the extent of infection. Conversely, treatment success can be measured by demonstration of declining nontreponemal test titers over time. Because up to 20% of nontreponemal tests may be nonreactive in primary syphilis, if that is a concern either repeat testing 1 week later or testing with a treponemal specific test is indicated.

Treponemal-Specific Tests

To rule out false-positive tests, when used for diagnosis, reactive nontreponemal serologic tests must be confirmed. This is done using treponemal-specific tests, which include the fluorescent treponemal antibody absorbed (FTA-ABS), T pallidum particle agglutination (TP-PA), and T pallidum hemagglutination assay (TPHA). The antigens for these tests vary, but all have in common the use of true treponemal antigen as a key reagent. The microhemagglutination–T pallidum (MHA-TP) test is no longer commercially available in the United States.

Treponemal tests tend to be labor intensive and expensive when compared with the nontreponemal tests. They are usually interpreted qualitatively and may remain reactive for the remainder of the life of the individual irrespective of the success of therapy. They are considered both sensitive and specific. The treponemal-specific tests may become reactive before the nontreponemal tests in the earliest stages of primary infection. That observation leads some experts to recommend the use of treponemal specific tests in the evaluation of a patient with suspected primary syphilis. Commonly, if the nontreponemal serologic test is nonreactive, the testing algorithm ceases.

Laboratories, particularly those processing large numbers of specimens, recently have been turning to enzyme-linked immunoassay technologies that make use of the treponemal-specific test as a screening test. Reactive tests by this method may be confirmed and quantitated by a traditional nontreponemal-specific test. Discordant tests may be further examined using a traditional treponemal test. The significance of an isolated reactive treponemal-specific test is unclear. It may reflect a false-positive test or a previously treated (knowingly or unknowingly) case of syphilis.

Nucleic Acid Amplification Tests

The advantages of tests that rely on nucleic acid amplification techniques to diagnose infectious diseases are obvious. They are exquisitely sensitive as well as very specific. They do not rely on viable organisms yet directly assay those organisms. These techniques are available primarily as a research tool; however, in certain public health facilities or clinics connected to academic research centers, T pallidum nucleic acid amplification tests such as polymerase chain reaction are available to clinicians to help with syphilis diagnosis.

Biopsy and Special Stains

Treponemes can on rare occasions be visualized in tissue using special stains, including silver stain.

Determination of Syphilis Stage

The staging of syphilis is an important aspect of the clinical diagnosis. Identification of the disease stage determines the treatment, further management, and partner notification practices.

Incubating Syphilis

Between the period of exposure until just before development of signs, serologic tests are not reactive. Diagnosis is purely presumptive and is based on a history of sexual exposure to someone with syphilis. Treatment at this stage will prevent seroconversion and development of clinical disease.

Primary Syphilis

The chancre of primary syphilis is similar to yet unlike the ulcers of the other common causes of genital ulcer disease. Clinicians are highly likely to misdiagnose a genital ulcer purely on clinical grounds. Therefore, diagnostic tests for other etiologic agents of genital ulcer disease should be performed in addition to those performed for syphilis (eg, herpes simplex virus culture or PCR).

If darkfield microscopy is available, exudate from the lesion may be examined for spirochetes. The sensitivity of darkfield microscopy is somewhat operator dependent as well as dependent on the quality of the specimen. If characteristic corkscrew-shaped organisms are observed in a specimen from a patient who is likely to have syphilis, then the diagnosis is almost certain. Care must be taken, however, because nonpathogenic spirochetes are sometimes observed in the oral or rectal secretions of persons without syphilis. If a darkfield microscope is unavailable, then direct fluorescent antibody testing of the specimen may be appropriate.

Serologic testing supports the suspicion of syphilis. In the earliest phases of primary syphilis, the nontreponemal serologic test may be nonreactive while the treponemal-specific test is almost always reactive. However, within a short time (eg, days) both tests should be reactive.

Secondary Syphilis

A rash of any type in a sexually active individual should be considered as potential syphilis until proven otherwise. The appearance of syphilis-associated rashes is so varied that reliance on some “characteristic” quality would be a mistake. Ordinarily, rashes of secondary syphilis do not present as ulcerative lesions and therefore do not yield moist surfaces for proper darkfield examination. The only exceptions are the perineal lesions of condylomata lata and mucous patches of the oropharyngeal area.

Reflecting the systemic nature of this stage of infection, nontreponemal test titers are high. Although truly nonreactive (or low-titer) nontreponemal test results in secondary syphilis have been reported, they are very uncommon. One situation that calls for caution in interpreting serologic tests is the so-called prozone phenomenon, which occurs when the concentration of antitreponemal antibodies is so high that the characteristic flocculation reaction that produces a reactive specimen cannot occur. This phenomenon is overcome by diluting the specimen and rerunning the test.

Latent Syphilis

By definition latent syphilis is clinically inapparent. The only evidence of infection is a reactive serologic test. The nontreponemal serologic test titer is usually fairly low (ie, ≤1:8).

Tertiary Syphilis

Diagnostic criteria for neurosyphilis are discussed in detail in Chapter 20. Reactive serologic tests in the setting of an aortic aneurysm may be construed as evidence of cardiovascular syphilis. A definitive diagnosis requires a pathologic specimen (ie, tissue biopsy). The range of tissues involved and the varying extent of inflammation that may be manifest in syphilitic gummas mean that almost any chronic destructive lesions of the body may be caused by syphilis. Serologic tests are usually reactive. Titers may range from reactive at only low dilution to reactive at very high dilutions. The prozone phenomenon was described earlier. Rare treponemes may be visualized on pathologic specimens.

Sir William Osler is often quoted on the topic of syphilis, which was a common diagnosis in his day. Nothing is more accurate than his reflection that, “Syphilis, which begins its pathological existence as a modest, inactive Hunterian chancre, soon enters upon a career that is unsurpassed for the inclusiveness and variety of its manifestation . . it is almost impossible to describe its clinical symptoms without mentioning almost every symptom of every disease known.”

In light of this it seems almost futile to devise a list of other diseases whose manifestations may suggest or be suggested by the symptoms of syphilis. Obviously the chancre of syphilis calls to mind the other common etiologies of genital ulcer disease, such as herpes simplex and chancroid. Lesions of herpes may be distinguished from syphilis by their superficial, nonindurated and painful nature. Viral culture of herpetic lesions is usually positive when lesions are open and moist. Chancroid is currently uncommonly seen in the United States. These lesions are painful like herpes but indurated like syphilis. Special culture media can be used for identification but is not readily available. Gram stain may demonstrate the characteristic gram-negative organisms. Polymerase chain reaction testing may also distinguish one etiology of genital ulcer disease from another but is also not commonly available. It should also be recognized that a genital ulcer may harbor more than one pathogen. The concomitant lymphadenopathy may be confused with herpes, lymphogranuloma venereum, HIV, or lymphoma. Although classically characterized by hyperpigmented lesions on the palms and soles as well as fine scaling, the rash of secondary syphilis can be confused with almost any etiology of rash. Therefore, syphilis needs to be considered when evaluating a rash in any sexually active individual.

Neurosyphilis can appear early or as a late manifestation of syphilis. It can manifest with either motor or sensory deficits. Cranial nerves can be involved. There may be cognitive abnormalities or behavioral disturbances. Almost any disturbance of the central nervous system could be attributed to neurosyphilis. Cardiovascular disease should be considered in the development of aortic aneurysms, aortic valve regurgitation, and even the acute coronary syndrome. Gummatous disease may resemble a wide range of destructive or tumor-like lesions. Ulcers, inflammatory lesions, tumors, and fungal or mycobacterial processes may all bear some similarity to the gumma of syphilis.

Risk-taking behavior that predisposes individuals to acquire syphilis also predisposes them to other sexually transmitted diseases. All patients with syphilis need to be evaluated for other sexually transmitted diseases. For patients with early-stage syphilis, this should include screening for Neisseria gonorrhoeae and Chlamydia trachomatis infections. Evaluation for herpes simplex virus infection, human papillomavirus infection, and hepatitis B virus infection might also be warranted. In all instances of syphilis, whether early or late, patients should be tested for HIV infection.

Complications of syphilis develop in about one third of patients with untreated infection. As previously discussed, these can include progressive infection of the central nervous, cardiovascular, or musculoskeletal system, but any organ system can be involved.

Pharmacotherapy

Penicillin G

Sixty years after it was demonstrated effective in the treatment of syphilis, penicillin G remains the treatment of choice for this infection. No other antibiotic has the proven track record of penicillin. The goal of therapy for syphilis is twofold: (1) render the individual noninfectious, and (2) halt disease progression and eliminate latency.

The use of benzathine G penicillin, or long-acting penicillin, is recommended in the treatment of early or latent syphilis. T pallidum has a slow metabolism, dividing more slowly than other bacteria but more quickly than mycobacteria, and the benzathine G penicillin formulation provides a long duration of antitreponemal therapy.

It is fairly obvious when penicillin or other antibiotics rapidly eliminate the risk of transmission of disease in the individual with communicable forms of syphilis such as the chancre of primary infection or condylomata lata and mucous patches of secondary disease. Within 24–48 hours of treatment, lesions begin to resolve and viable treponemes may no longer be recovered.

It is well documented that very early in the course of disease treponemes disseminate from even the most localized lesion, first to regional lymph nodes, and then elsewhere throughout the body, including distant lymph nodes and the central nervous system. Manifestations of infection in these areas may be subclinical. In this circumstance the only way to monitor the effectiveness of therapy is to serially repeat quantitative nontreponemal serologic tests with the goal of achieving at least a twofold dilutional decline or, in the best case, negative serologic tests. Unfortunately, the decline in test titers happens over a long period, up to 12–24 months. In some cases, serologic negativity may never occur; in these cases, patient titers are considered “serofast.” Typical serofast titers are ≤1:8. Whether the persistence of a positive titer reflects continued treponemal infection after therapy remains to be demonstrated.

Other Antibiotic Agents

Although penicillin G remains the most commonly used agent in the treatment of syphilis, other antibiotics have demonstrated efficacy. Because of limited data and limited clinical experience, these agents remain alternatives to penicillin and when used are limited to early-stage disease. They include the tetracyclines, in particular doxycycline (because of its less-frequent dosing compared with tetracycline and its favorable side-effect profile). Another option is the third-generation cephalosporin ceftriaxone, which is easy to administer and provides excellent central nervous system penetration. Although there was interest in the use of erythromycin to treat syphilis, reports of failure, particularly in pregnancy, have led to its elimination as a treatment option.

Data from several randomized controlled trials suggest that the azalide antibiotic azithromycin is useful in the treatment of early-stage syphilis. Unfortunately there have been several concomitant reports of failure in patients who received this therapy along with in vitro data that demonstrates the presence of treponemal genetic elements encoding for azithromycin resistance. Azithromycin therapy for syphilis is not recommended by the Centers for Disease Control and Prevention (CDC), and, if used, should be administered cautiously with close follow-up. Caution should also be exercised when using any of these alternative agents for the treatment of syphilis in immunocompromised individuals.

Stage-Specific Therapy

Treatment of syphilis depends on the stage of disease at diagnosis. Because of the long doubling time of the treponeme, antibiotics are usually administered either as a depot injection or orally over a prolonged period of time. Recommendations from the CDC are summarized in Table 19–1. There is no indication for adjunctive therapy.

Early-Stage Syphilis

Primary, secondary, and early latent syphilis can be treated with a single injection of 2.4 million units of intramuscular penicillin G. As an alternative in penicillin-allergic patients, doxycycline, 100 mg orally twice daily, may be used for 14 days. Ceftriaxone can also be used as an alternative to penicillin. It is active against T pallidum and is well tolerated. One to 2 g intramuscularly daily for 8–10 days has been recommended. Treatment of early latent syphilis follows the approach for primary and secondary syphilis because it is believed that the replicative capacity of treponemes at this stage is similar.

Latent and Late Latent Syphilis

Treatment of late latent syphilis (including latent syphilis of unknown duration) requires a prolonged course of therapy. A dose of intramuscular benzathine penicillin, 2.4 million units, is given once and then repeated at weekly intervals two more times, for a total of three weekly injections. This assures up to 4 weeks of treponemicidal blood levels of penicillin. If a dose is missed, it has been suggested that the series of injection may be continued as long as no more than 14 days has passed between injections. If more time has elapsed, the series should be restarted. As an alternative, doxycycline (100 mg orally twice daily for 28 days) may be substituted, with the caveats as noted above.

Tertiary Syphilis and Neurosyphilis

Tertiary forms of syphilis are treated similarly to late latent disease except that evaluation of cerebrospinal fluid (CSF) should be performed before therapy is initiated. Neurosyphilis requires its own therapeutic approach. To achieve adequate penicillin levels in the central nervous system, it is recommended that patients receive intravenous penicillin G, 3–4 million units every 4 hours for 10–14 days. Many experts recommend that at the conclusion of this therapy patients receive two or three weekly doses of benzathine penicillin G, as previously noted, to eliminate the risk that latent forms of syphilis will persist. Procaine penicillin G, 2.4 million units intramuscularly once daily for 10–14 days, along with probenecid, 500 mg orally four times daily, is an acceptable substitute. As an alternative, ceftriaxone can also be used, but data as to efficacy are limited.

Penicillin Allergy Testing and Desensitization

Although alternatives to penicillin are available, there are situations for which no good alternative exists. These situations include pregnancy, neurosyphilis, and to some extent HIV infection. Although patient reports of allergy to penicillin often turn out not to suggest risk of anaphylactic reaction, they remain a cause for concern. For such individuals, skin testing can be performed using the commercially available major determinants (Pre-Pen; Taylor Pharmacal Company, Decatur, IL) and penicillin G itself, which contains most but not all the minor determinants. Minor determinants are unfortunately not all commercially available (but can sometimes be obtained through the Allergy/Immunology section at some major medical centers). A small but real proportion of truly allergic patients (3%) may be misidentified when the panel containing Pre-Pen and penicillin G is used. There is cross-reaction with cephalosporins in individuals with penicillin allergy, but the frequency of that cross-reactivity appears to be low (<5%).

In cases of documented allergy where penicillin must be used, desensitization can be performed following any of several protocols (see Table 19–2). Desensitization lasts only as long as the penicillin is administered. Its effect does not persist beyond clearance of penicillin when therapy is complete. Both skin testing and desensitization should be performed in a controlled and monitored setting.

Response to Therapy

The efficacy of any syphilis therapy can be assessed by the resolution of clinical manifestations and the decline in serologic titers. Resolution of clinical manifestations by itself may be misleading, because even in the absence of therapy the clinical manifestations of syphilis (eg, chancre of primary disease or rash of secondary disease) will resolve. If clinical manifestations of early-stage disease respond to therapy, they do so quickly. Within 24–48 hours the chancre and rash should show clear evidence of resolution. Treponemes should no longer be observed in lesion exudates under darkfield microscopy.

Frequently following the treatment of secondary syphilis, and occasionally after treatment for primary syphilis, patients experience the rapid development of fever, headache, and myalgias. Signs may include hypotension and, if measured, an elevated white cell count. These findings are presumably secondary to an immunologically mediated process known as the Jarisch-Herxheimer reaction. This reaction is ordinarily self-limited and can be treated with antipyretics and analgesics. Because confusion with a reaction to penicillin therapy may occur, all patients treated for early syphilis should be made aware of the possibility of this immunologic reaction.

Current guidelines supported by decades of clinical experience recommend that successful therapy be followed by a fourfold decline (eg, 1:32 to 1:8) in the nontreponemal serologic test titer. The time course over which this can be expected to occur remains an area open to some conjecture. Clearly this cannot be reliably expected by 1 month after therapy. In early-stage syphilis, this decline should be seen within 6 months after therapy and certainly by 12 months. In latent forms of disease, such a decline can be seen by 12 months but may take even longer. The lower the titer when the patient begins therapy, the longer it may take to see a decline—if one is ever achieved. In either early or latent syphilis, the reactive nontreponemal test may never completely resolve, (ie, the “serofast” reaction). The clinical significance of this is unclear.

Sometimes titers may fail to decline or in fact even rise. Distinguishing failure of therapy from reinfection has long been one of the most vexing challenges in syphilis management. Obviously, the individual likely to have been reinfected simply needs retreatment. In the absence of evidence that this may have occurred, titers that do not decline sufficiently or those that rise after therapy should be considered evidence of treatment failure. In this situation, a lumbar puncture should ordinarily be performed to rule out neurosyphilis, and retreatment should be initiated, usually with the longer duration of treatment (three weekly injections).

The damage that occurs in tertiary disease is not likely to be reversed by any therapy. Halting progression of disease is a more realistic expectation. Declining serologic titers, as previously described, should occur. In patients with neurosyphilis, repeated examinations of CSF are necessary to assess proper response to therapy. By 6 months, improvement in lymphocytic pleocytosis should be seen as the earliest indicator of successful therapy. A decline in the CSF VDRL may take longer.

Special Populations

HIV-Infected Patients

It has been of concern for more than 20 years that patients who contract syphilis and have underlying HIV infection may manifest disease in unusual ways and may respond less well to therapy than those who do not have HIV infection. Despite several case reports describing rapid progression to tertiary disease, false-negative serologic tests for secondary syphilis, and failure of therapy, no well-collected data support the contention that these observations are anything other than random events. Although there seems to be no reason to require anything other than standard therapies for HIV patients found to have syphilis, it would be prudent to monitor serologic results in such patients more frequently than in non–HIV-infected individuals. Current recommendations suggest that this can be done every 3 months after treatment for early syphilis and every 6 months after treatment for latent forms of syphilis.

There continues to be some debate about the risk of progression to neurosyphilis in HIV-infected individuals, and hence the indication for lumbar puncture. Many experts continue to recommend CSF analysis in any HIV-infected patient with latent syphilis. Others extend this recommendation to those with early-stage syphilis despite the recognized fact that CSF abnormalities are common in early-stage syphilis for all patients. Yet others limit the recommendation for these invasive procedures to only those HIV-infected individuals with significant immunosuppression (ie, CD4 count <350/mL). Although most experts agree there is need for concern, there appears to be no consensus on what course to pursue.

Pregnant Women

Syphilis can be readily transmitted to the unborn child of a pregnant woman at any stage of infection. The consequences of such infection for the infant can be severe and range from asymptomatic infection to neurologic disease, hepatitis, periostitis, and stillbirth. Screening for syphilis in all pregnant women is a routine part of obstetric care. Testing should be performed at the outset of prenatal care and in high-risk patients or high-incidence areas repeated at 28 weeks’ gestation and again at delivery. Stillborn delivery after 20 weeks’ gestation warrants syphilis testing in the mother.

Biologic false-positive tests (ie, reactive nontreponemal tests and a nonreactive treponemal-specific test) can occur in pregnancy. Care must be taken to confirm any reactive serologic test in this patient population. In the event of infection, treatment for the pregnant woman is exactly as it would be for the nonpregnant patient. As previously mentioned, penicillin G is the only recommended treatment for syphilis in pregnancy; there are no acceptable alternatives. Pregnant women with a history of penicillin allergy should undergo skin testing to confirm the allergy and then desensitization, if necessary, according to protocol. In pregnant women, the Jarisch-Herxheimer reaction (discussed earlier) may precipitate a miscarriage. To reduce that risk, pregnant patients are best treated in a monitored and controlled setting for 24–48 hours. Serologic testing after therapy in a pregnant woman should be performed frequently to determine both response to therapy and the possibility of reinfection.

Sex Partners

A few simple rules should be followed for the management of sex partners of those with syphilis. Transmission of syphilis is most likely during the mucocutaneous manifestations of early disease (primary and secondary stages). All sex partners within 90 days of the diagnosis of early-stage syphilis (ie, primary, secondary, or early latent) in the index case should be treated presumptively with a single intramuscular dose of benzathine penicillin G. In this circumstance treatment of the partner is administered irrespective of the serologic test result in that individual. For partners with exposure occurring more than 90 days before diagnosis of syphilis in an index case, presumptive treatment is considered if follow-up cannot be assured. Otherwise, treatment can be guided by either clinical findings or serologic testing. For partners of patients with latent disease of unknown duration, late latent disease, or tertiary disease, treatment may be withheld pending serologic test results. Some experts recommend treating this last group presumptively if the serologic titers in the index case are 1:32 or higher.

The management of both early and latent stages of syphilis should be within the purview of most clinicians. When serologic results fail to follow the expected course after therapy, patients are best referred to an infectious disease specialist. Referral is likewise probably best for the management of HIV-infected patients with syphilis and for the workup and treatment of other manifestations of syphilis, such as neurosyphilis, cardiovascular syphilis, and gummatous syphilis. Management of sex partners can often be handled most properly and expeditiously with the help of local public health authorities.

Early-stage, communicable syphilis is a reportable disease in all 50 states of the United States. It is the responsibility of all clinicians who diagnose syphilis to report such cases promptly to the public health authorities. Laboratories are routinely required to report cases to local public health authorities, and clinicians may be contacted by local public health authorities after the receipt of a laboratory-reported case.

When treated according to the guidelines outlined earlier and followed carefully with serial serologic tests, almost all patients should be assured of disease elimination with no serious long-term sequelae. Patients who have suffered end-organ damage as a result of tertiary syphilis may, after therapy, see a halt in the progression of signs and symptoms. Unfortunately, resolution of pathologic damage done to that point may not occur.

• • Treponemal-specific tests may become reactive before nontreponemal tests in the earliest stages of primary syphilis infection. That observation leads some experts to recommend the use of treponemal specific tests in the evaluation of a patient with suspected primary syphilis.
• • When interpreting serologic tests, clinicians should be aware of the prozone phenomenon, which occurs when the concentration of antitreponemal antibodies is so high that the characteristic flocculation reaction that produces a reactive specimen cannot occur. This phenomenon is overcome by diluting the specimen and rerunning the test.
• • The lower the serologic titer when the patient begins therapy, the longer it may take to see a decline—if one is ever achieved.