ACP medicine, 3rd Edition

Infectious Disease

Syphilis and the Nonvenereal Treponematoses

Michael Augenbraun MD, FACP1

Associate Professor of Medicine

1State University of New York Downstate Medical Center

The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

September 2006

Syphilis

Syphilis is an infectious disease with complex acute and chronic manifestations that is transmitted primarily through sexual contact. The disease has been recognized for many centuries, although its origin remains unknown.

Epidemiology

Transmissible syphilis in the United States has become increasingly concentrated in a few geographic areas, particularly in the southeastern part of the country [see Figure 1]. It disproportionately affects minority populations and occurs more frequently in men than in women. Outbreaks have been reported in men who have sex with men. Sexual transmission rates from infected to uninfected persons may range from 30% to 60%.1,2,3

 

Figure 1. Rates of Primary and Secondary Syphilis in the U.S.

Rates of primary and secondary syphilis by (a) state and (b) county.

The incidence of syphilis declined from the 1940s through the 1980s, rose sharply in the late 1980s, then rapidly declined in the latter half of the 1990s, reaching 2.1 cases per 100,000 population in 2000, the lowest reported rate since the collection of reliable statistics began [see Figure 2].4 The rate then increased again from 2001 to 2004, primarily because of higher numbers of cases in men who have sex with men. The Centers for Disease Control and Prevention (CDC) estimates that the percentage of primary and secondary syphilis cases that occur in men who have sex with men rose from 5% in 1999 to 64% in 2004.5 Syphilis rates in 2004 remained the same in women, increased in the southern United States, and increased substantially in African American men.6

 

Figure 2. Reported Rates of Syphilis in the U.S. 1970-2004

Reported rates of syphilis in the United States from 1970 to 2004. The highest rate occurred in the late 1980s and early 1990s, after which the number of syphilis cases declined steeply, reaching a low of 2.1 per 100,000 population in the year 2000, then rising slowly to 2.7 per 100,000 population by 2004. The Healthy People 2010 target for primary and secondary syphilis cases is 0.2 per 100,000 population.7

In view of the low incidence rates of primary and secondary syphilis, its geographic confinement to a limited number of areas, the continued efficacy of penicillin therapy, and the reliability of serologic diagnostic tests, in 1999 the CDC initiated a program intended to eliminate syphilis in the United States, through the use of enhanced surveillance, greater cooperation with community groups in the remaining areas of high morbidity, and rapid outbreak response.7 The stated goal was to reduce primary and secondary cases to 1,000 or fewer in a given year and to increase the percentage of syphilis-free counties to 90% by the year 2005. Progress toward that goal is reflected in the fact that from 2000 to 2004, disparities between syphilis rates in African Americans and whites decreased, more than 75% of counties were consistently free of syphilis, and syphilis rates in the southern United States showed sustained reductions8; nevertheless, the CDC acknowledges the need for enhanced surveillance in women and better prevention measures in African Americans and men who have sex with men.6

Etiology

Syphilis is transmitted primarily through sexual contact. Transmission from mother to fetus through the placenta may result in congenital disease. Although the disease can also be transmitted through nonsexual contact with infectious lesions, laboratory accidents, and the administration of contaminated blood products, these methods of transmission are relatively rare. Humans are the only known host ofTreponema pallidum.

Pathogenesis and Disease Course

  1. pallidumis a bacterium belonging to the order Spirochaetales. This order also includes similar familiar bacteria genera, such asLeptospiraand Borrelia. All of these organisms are slender, helically coiled, gram-negative bacteria. Treponemal species other than T. pallidum may live as commensals in the oral cavity or the genital tract (e.g., T. denticola and T. oralis).
  2. pallidumprobably gains entry to the subcutaneous tissues through small abrasions in overlying skin and mucous membranes. The organism does not possess well-recognized virulence factors, such as lipopolysaccharide.9Once penetration of the epithelium occurs, organisms replicate locally at the site of inoculation and spread to regional lymph nodes. Depending on factors such as inoculation load and history of previous syphilis infection, the incubation period from exposure to clinical disease can range from 3 weeks to 3 months.

The characteristic first lesion of primary syphilis [see Table 1] is the chancre [see Figure 3]. It is typically an indurated and nontender ulcerative lesion, often accompanied by a nontender, nonsuppurative regional lymphadenopathy. In some patients, the chancre is inconspicuous, whereas in others it can be more than 1 to 2 cm in diameter. Although not common, multiple chancres may occur, particularly in HIV-infected persons. In the absence of effective therapy, the chancre resolves within 2 to 8 weeks. Healing may take longer in immunocompromised persons.

Table 1 Clinical Manifestations of Syphilis in Adults

Stage

Manifestations

Primary

Chancre and inguinal lymphadenopathy

Secondary

Rash, diffuse lymphadenopathy, fever, alopecia, condyloma latum, and mucous patches

Early latent

None (secondary syphilis may recur)

Late latent or latent syphilis of unknown duration

None

Tertiary

 

  Neurosyphilis

 

    Asymptomatic

None

    Meningitis

Headache, cranial nerve palsies, delirium, seizures, and findings of raised intracranial pressure

    Meningovascular

Hemiparesis, hemiplegia, aphasia, and seizures

    Parenchymatous

 

      General paresis

Memory loss, personality changes, cognitive dysfunction, confusion, and seizures

      Tabes dorsalis

Lightning pains, ataxia, pupillary abnormalities, and impaired proprioception

    Cardiovascular

Aortic aneurysm, aortic regurgitation, chest wall mass, and hoarseness

    Gummatous

Chronic inflammation with focal destructive lesions in nearly any tissue or organ of the body

 

Figure 3. Ulcerative Chancres

Indurated, nontender ulcerative chancres are the first lesions of early syphilis.

Spirochetemia develops soon after the appearance of the primary chancre, but clinical evidence of dissemination is rarely seen at the same time. Signs and symptoms of dissemination and secondary syphilis include fever, malaise, diffuse lymphadenopathy, patchy alopecia, headache, and classic hyperpigmented maculopapular rash on the palms and soles [see Figure 4]. Condylomata lata and mucous patches may appear in a variety of locations, such as the genitals and the gluteal and nasolabial folds [see Figure 5]. Other anatomic sites, such as the eyes, gastrointestinal mucosa, liver, and bones, may also be involved.

 

Figure 4. Hypermigmented Maculopapular Rash of Spirochetemia

A hyperpigmented maculopapular rash on the palms and soles is a classic sign of spirochetemia.

 

Figure 5. Condylomata

Highly infectious condylomata lata appear on genitalia and gluteal folds.

The clinical manifestations of secondary syphilis [see Table 1] resolve after weeks to months even without therapy, and the disease then enters the latent stage. During the early latency period, the signs and symptoms of secondary syphilis may recrudesce. This period generally lasts 1 year after infection but can extend to 4 or 5 years.10

Latent syphilis is, by definition, recognized only by reactivity on serologic testing. During the latency period, the organisms evade any meaningful host immunologic responses. Although infected persons mount both significant cell-mediated and humoral responses to infection, neither response is adequate for control. Many reasons have been postulated for this phenomenon, including the lack of immunogenic proteins and polysaccharides in the outer membrane of T. pallidum, as well as the organism's ability to cloak itself with host proteins.11

Once syphilis enters the latent phase, the course of disease is variable. Although the majority of infected persons will never suffer undue consequences, data from the Oslo Study suggest that years later, tertiary disease [see Table 1] will develop in approximately one third of these individuals, manifesting as neurosyphilis, cardiovascular syphilis, or gummatous (benign) syphilis.10 The pathology associated with tertiary syphilis is quite varied, and there is substantial overlap between clinical entities. Chronologically, meningeal and meningovascular symptoms (i.e., stroke) may be the earliest manifestations of symptomatic neurosyphilis. In later stages, parenchymatous disease with associated cognitive and long-tract signs becomes prominent. As in cardiovascular and gummatous syphilis, syphilis of the central nervous system is characterized by endarteritis.

Diagnosis

Depending on the stage of disease, the diagnosis of syphilis may be made by visualizing the organisms, by serologic studies, by pathology, or by clinical presentation. None of these methods is entirely sensitive or specific.

Clinical Manifestations

Primary syphilis

In primary syphilis, the chancre [see Pathogenesis, above] typically occurs at the site of inoculation and thus may appear anywhere in the genital region (i.e., penis, scrotum, inner thigh, buttocks, vaginal labia, cervix, or anus). Lesions may be single or multiple. Often, they occur where tissue proximates infected sites—so-called kissing lesions.

Typically, the chancre is indurated with a raised but clean margin. It is nontender. It may have a gray-white exudative covering, particularly if the lesion is secondarily infected. More commonly, it is clean without bleeding. There is associated nontender and nonsuppurative regional lymphadenopathy. Cervical or rectal chancres may result in deep pelvic noninguinal adenopathy.

Secondary syphilis

The widely varied clinical manifestations of secondary syphilis reflect the capacity of T. pallidum to disseminate virtually anywhere in the body within weeks of the appearance (and resolution) of the primary chancre. With spirochetemia, which develops after the first chancre [see Pathogenesis, above], comes a host of systemic symptoms that are relatively nonspecific, including headache, malaise, fatigue, arthralgias, myalgias, and diffuse painless lymphadenopathy. The finding of enlarged epitrochlear lymph nodes in the absence of any upper extremity pathology is considered to be highly suspicious for secondary syphilis.

The rash of secondary syphilis is one of the most common signs of the disease. The classic finding is maculopapular hyperpigmented lesions 3 to 10 mm in diameter, often with fine peripheral scaling on the palms and soles. There are so few clinical entities that cause these lesions that the presence of the lesions is nearly pathognomonic. Rash will be seen in 75% to 100% of patients at some point in the course of infection. However, the rash of secondary syphilis does not always fit this classic pattern. It may present in any of a variety of ways—macular, maculopapular, papular, pustular, or plaques of varying size—virtually anywhere on the body. Raised, moist, nontender plaques known as condylomata lata may form in intertriginous areas, such as in the gluteal fold, under the breasts, and in the inguinal area. Similar mucous patches may form on mucosal surfaces, such as the nares, mouth, vagina, and anus. These lesions can be confused with chancres but are not, strictly speaking, ulcers. They teem with spirochetes and are highly infectious. Secondary syphilis can also involve hair follicles, leading to patchy alopecia of scalp hair, as well as thinning of the eyebrows, eyelashes, and beard.

Skeletal manifestations of secondary syphilis can include osteitis, arthritis, and bursitis.12 Syphilitic hepatitis with hepatomegaly and an elevated alkaline phosphatase level may occur.13 Various forms of nephropathy, including glomerulonephritis and nephrotic syndrome, have also been noted in secondary syphilis.14 Gastritis with attendant abdominal pain, nausea, and vomiting can result from infiltration of the gastric mucosa by spirochetes.15 Both anterior and posterior uveitis can occur and may be either asymptomatic or associated with altered vision.16,17 Some of these cases come to light when the patient experiences failure to respond or worsening of symptoms after treatment with steroids.

Involvement of the CNS occurs early in syphilis.18 At least 40% of lumbar puncture samples from patients with secondary disease (more in some series) have been found to have CSF abnormalities. T. pallidum may actually be recovered from up to 30% of these samples. Whereas symptomatic parenchymatous neurosyphilis is often associated with late-stage syphilis, meningeal involvement may be seen during or shortly after the nonneurologic symptoms of secondary syphilis. This condition is characterized by findings typical of bacterial meningitis, including headache, stiff neck, photophobia, nausea, and vomiting. Cranial neuropathies associated with ocular and otic deficits, as well as facial nerve palsies, can occur. In some instances, papilledema associated with hydrocephalus has been reported, as have delirium, seizures, aphasia, and hemiplegia. Most patients no longer demonstrate the rash of secondary syphilis at the time these symptoms develop.

Latent syphilis

By definition, latent syphilis is not associated with any clinical finding. Early latency delineates that period after the resolution of secondary disease during which the signs and symptoms of secondary disease may recur. Although this latency period may last as long as 5 years, most cases of latent syphilis occur within the first to second year. After the latency period, tertiary syphilis develops.

Neurosyphilis

In most patients with primary or secondary syphilis who experience invasion of the CNS by spirochetes, CNS infection presumably resolves, with or without the administration of systemic antibiotics. In a small number of patients with CNS infection, CNS involvement continues and is characterized by asymptomatic CSF changes; patients are at high risk for progressive symptomatic neurologic disease for a period of years. It is difficult to ascertain which individuals may be at risk for continuing CNS involvement; anyone with presumably latent syphilis may harbor CSF changes suggesting continuing neurosyphilis.

Late symptomatic neurosyphilis may present as one of the following clinical syndromes (the syndromes often overlap):

  1. Meningovascular neurosyphilis. T. pallidumtends to cause endarteritis, which can compromise vascular supply to portions of the CNS and cause infarctions that clinically resemble any other cerebrovascular accident. These events can occur anywhere along the neuroaxis, including the cerebrum, the cerebellum, the brain stem, and the spinal cord. Signs and symptoms therefore correspond to the portion of the CNS involved. The time elapsed from primary syphilis to meningovascular syphilis is usually 5 to 12 years but may be as long as several decades.
  2. Parenchymatous neurosyphilis. Direct involvement of the CNS parenchyma results in a wide range of clinical syndromes characterized pathologically by fibrosis and atrophy. General paresis is a meningoencephalitic syndrome that may be similar in presentation to many psychiatric and neurologic disorders. Patients exhibit emotional lability, delusions, paranoia, and memory loss and may progress to dementia, delirium, and seizures. They may have difficulty with speech, and their pupils may become constricted and unresponsive to light and painful stimuli (Argyll Robertson pupil). They may lose the capacity for facial expressions and are noted to have trembling of the lips and tongue. In tabes dorsalis, there is a pronounced involvement of the dorsal roots and the posterior columns of the spinal cord. Patients complain of shooting pains in the back and lower extremities, where they also notice paresthesias. These paroxysms of pain can be referred to other locations, including the abdomen and the throat. Patients lose proprioception and vibratory sense and develop a wide-based gait. Optic atrophy may occur. Knee and ankle reflexes are diminished or lost entirely, plantar responses are flexor, and ataxia is usually present. Symptomatic parenchymatous disease develops 15 to 25 years after primary infection. The long-term outlook in general paresis without treatment is grim. Death may occur within months or, more likely, 4 to 5 years after the onset of symptoms. Untreated tabes dorsalis leads to eventual incapacitation, although it has been known to remit spontaneously.

Cardiovascular syphilis

After the introduction of antibiotics, cardiovascular syphilis became extremely rare. T. pallidum can cause endarteritis of the aortic vasa vasorum, leading to progressive medial necrosis and loss of elastic tissue, dilatation, and, eventually, aneurysm. The proximal thoracic aorta and the aortic arch are most commonly involved, whereas involvement of the abdominal aorta is extremely rare. Symptoms usually develop when the aneurysm begins to encroach upon or erode adjacent structures, such as the chest wall, the superior vena cava, the recurrent laryngeal nerve, the trachea, and the mainstem bronchi. These aneurysms rarely dissect. In 30% of cases, aortic root dilatation leads to aortic regurgitation in which there is no evidence of aortic stenosis. Uncommonly, the coronary artery ostia may be involved, causing ischemic heart disease. Cardiovascular syphilis is usually preceded by a latent period of 15 to 30 years.

Gummatous (benign) syphilis

As with neurosyphilis and cardiovascular syphilis, the incidence of late gummatous syphilis has declined dramatically since the introduction of effective antimicrobial agents. The hallmark of this disease are gummas, which are indolent, destructive granulomatous lesions of soft tissue and bone [see Figure 6]. They can lead to dramatic scarring and disfigurement. They are primarily immunologically mediated responses. Although almost any part of the body may be involved, gummas most frequently occur in soft tissue and skeletal structures. Gummas do not develop until decades after infection. They appear slowly, often as a nodule with minimal attendant inflammation. Central coagulative necrosis develops, with softening and involution of the lesion. Eventually, fibrosis occurs, with deep scarring. Involvement of the nasal septum can lead to collapse of the nasal structures. Perforation of the hard palate may occur. Skeletal lesions can lead to fractures.

 

Figure 6. Granulomatous Lesions

Granulomatous lesions called gummas are particularly destructive to soft tissue and bone.

Laboratory Tests

Primary syphilis

Clinical appearance of a genital ulcer is not adequate to establish its etiology. Dark-field microscopy of lesion exudate is a reliable diagnostic method. Incident light through a microscope fitted with polarizing lenses allows the viewer to identify the corkscrew morphology of treponemes as white against a black background [see Figure 7]. Exudate for dark-field microscopy can be collected from the base of a chancre that has been cleaned with saline and to which gentle pressure has been applied. Examination must be performed promptly because any drying of the specimen reduces the sensitivity of the test. Therapy, intentional or not, with antibiotics active against T. pallidum will rapidly reduce the yield of a dark-field specimen. Nonpathogenic treponemes in the oral cavity reduce the specificity of dark-field microscopy on lesions from this area. A direct fluorescent antibody to T. pallidum test (DFA-TP) can also be performed on lesion exudate when the immediate collection of a specimen is not possible. Nucleic acid amplification tests have been developed for T. pallidum, but these tests should be considered research tools.

 

Figure 7. Treponemes: Dark-field Microscopy

In dark-field microscopy, treponemes appear white against a black background.

Besides dark-field microscopy, the most commonly used tests for primary syphilis are serologic tests. Syphilis serology testing requires the use of two tests performed in sequence—one for screening and the other for confirmation. Screening tests are characterized by high sensitivity but variable specificity. They make use of standardized amounts of cardiolipin, cholesterol, and lecithin, to which T. pallidum-directed immunoglobulins (IgG or IgM) have an affinity. These tests include the Venereal Disease Research Laboratory (VDRL) test, rapid plasma reagin (RPR) test, unheated serum reagin (USR) test, and toluidine red unheated serum test (TRUST). All are flocculation tests in which visible (macroscopic, microscopic, or both) clumping occurs when test reagents are added to serum from a patient with syphilis. Results may be reported qualitatively or quantitatively. For quantitative results, testing is performed on sequentially diluted serum. The final dilution in which a reaction occurs is reported. Quantitative results are preferable. On repeat testing with the same type of nontreponemal serologic test (NTST), demonstration of a clinically significant difference requires a fourfold change in titer (e.g., from 1:16 to 1:4). Although the VDRL and RPR have equal validity, the RPR often yields slightly higher titers. Therefore, sequential tests in a given patient should use the same testing method, preferably performed by the same laboratory.19

In primary syphilis, the sensitivity of any of these NTSTs ranges only from 78% to 86%. IgM is detectable toward the end of the second week of infection; IgG is detectable usually in the fourth or fifth week. NTST results may be erroneously reactive in association with a number of other clinical factors, including older age, pregnancy, a history of intravenous drug use, and collagen vascular diseases.20Because of the possibility of false-positive results, diagnosis requires the use of more than one type of serologic test. Although NTSTs eventually become nonreactive in patients who have received appropriate treatment, some patients have a so-called serofast reaction, with long-term—or even life-long—persistence of low-titer nontreponemal antibodies.19

Treponemal-specific tests such as the fluorescent treponemal antibody absorption (FTA-ABS) and the T. pallidum particle agglutination (TP-PA) tests use fluorescent antibody and hemagglutinating antibody, respectively, to detect patients' antibodies to T. pallidum. In these cases, a suspension of T. pallidum serves as the antigenic target. These tests are not routinely quantified. Depending on the strength of the reaction, they may be reported as reactive, nonreactive, or inconclusive. In primary syphilis, these tests can become reactive before the NTSTs. False positive results occur in a small percentage of those tested, so these tests should not by themselves be used for screening. They are best used to confirm a reactive NTST.

Secondary syphilis

Dark-field microscopy may be useful for examining exudate from condylomata lata and mucous patches, but ordinarily, this test has limited utility in the diagnosis of secondary syphilis. Serologic tests remain the standard for diagnosing secondary syphilis. NTST titers are generally highest during secondary syphilis, because these tests quantitatively reflect the degree of immune response associated with infection. The likelihood of a false negative test in secondary syphilis is remote. An exception to this occurs in the event of the so-called prozone phenomenon, in which extremely high concentrations of reaginic antibodies block the flocculation process. This effect may be expected in no more than 2% of cases and can be overcome by performing repeated tests on diluted samples.

CSF findings in meningitis associated with secondary syphilis are nonspecific, except with use of the CSF-VDRL. A positive finding is invariably indicative of neurosyphilis unless there has been significant contamination of the CSF with blood. Sensitivity of the CSF-VDRL ranges only from 30% to 70%, so a negative test does not rule out neurosyphilis.21 Other abnormalities of the CSF that may occur with or without a reactive CSF-VDRL include a mononuclear pleocytosis with counts of 10 to 500 cells/mm3 and an elevated protein level of 46 to 200 mg/dl.

Latent syphilis

As disease activity wanes and immunologic mechanisms exert some control, the height of titer in the NTST declines. Titers of between 1:1 and 1:16 are not uncommon. Higher titers suggest but do not confirm the presence of disease activity. The treponemal serologic tests are also reactive.

Neurosyphilis

The laboratory diagnosis of neurosyphilis depends on the analysis of serologic tests and the CSF examination. The treponemal serologic test is almost always positive in patients with neurosyphilis, but it is not a specific marker for disease, because it is generally reactive for the life of the infected individual, whether treated or not. The NTSTs, generally regarded as sensitive but nonspecific in the evaluation of primary syphilis, are nonreactive in 25% to 30% of cases of neurosyphilis.22

CSF evaluation remains the gold standard by which neurosyphilis is diagnosed. Because lumbar puncture is associated with some morbidity, efforts have been made to define subgroups of patients with latent syphilis (i.e., patients who are asymptomatic with serologic evidence of disease) who may be at risk for asymptomatic neurosyphilis and therefore at a higher risk for progression to symptomatic late neurosyphilis. Some experts recommend CSF evaluation in latent syphilis if the serologic titer is 1:32 or higher. Current CDC guidelines recommend CSF examination in HIV-infected patients with late latent syphilis or syphilis of unknown duration.19

CSF analysis is warranted in any patient with serologic evidence of syphilis and neurologic, ophthalmologic, otic, or psychiatric disease. Tests conducted on the CSF should include a quantitative CSF-VDRL, a cell count with differential, and a protein assay. The VDRL is the only nontreponemal test that is standardized for CSF. In 25% to 30% of neurosyphilis cases, this test may be nonreactive. It is otherwise extremely specific and by itself may be diagnostic of neurosyphilis. The CSF cell count can range from 5 to 200/mm3, with a lymphocytic predominance. The CSF protein concentration is also usually increased, although levels should not exceed 200 g/dl. Lymphocytic pleocytosis and increased CSF protein concentrations are nonspecific for neurosyphilis and may be seen in a wide range of pathologic processes. The diagnosis of neurosyphilis in which the results of only these tests are abnormal rests on these findings and clinical suspicion. In some instances when tabes dorsalis has run its course, the CSF is completely normal.

Cardiovascular syphilis

As with other forms of tertiary syphilis, the nontreponemal serologic test for late cardiovascular syphilis may be nonreactive, whereas the treponemal-specific test is almost always reactive. Although a chest x-ray may be normal, it can also show a mediastinal mass consistent with the thoracic aortic aneurysm. Calcification of the aneurysm is often seen on radiograph but is not specific for syphilis.

Gummatous syphilis

Clinical suspicion is the most important tool in the diagnosis of late gummatous syphilis. Nontreponemal serologic tests are nonreactive in a sizable number of cases. The treponemal serologic tests should always be reactive. Interestingly, spirochetes are not often demonstrated in tissue biopsy specimens. Dark-field microscopy is of little use. More sensitive tests based on nucleic acid amplification may detect treponemal DNA in these lesions.23

Differential Diagnosis

Primary Syphilis

Any clinical condition likely to cause a genital ulcer should be considered in the differential diagnosis when primary syphilis is suspected. The most common cause of genital ulcer disease in the United States is herpes simplex virus type 2 (HSV-2) [see 7:XXVI Herpesvirus Infections]. The ulcers of HSV-2 are usually preceded by prodromal symptoms of burning and tingling; they pass through a series of predictable stages, including papules, vesicles, pustules, and ulcers, before healing. The ulcers are tender and shallow and have an erythematous base. Lesions are often multiple and can coalesce to form large, irregularly shaped ulcers. The course of illness varies, depending on whether it is a primary infection or a recurrence of established infection. The former may last as long as 3 weeks, whereas the latter usually resolves after 10 days. Diagnosis may be made on clinical grounds or with viral culture. Regional lymphadenopathy is common. Worldwide, the other common infectious cause of genital ulcer is chancroid, caused by Haemophilus ducreyi [see 7:XXII Vaginitis and Sexually Transmitted Diseases]. Chancroid is seen sporadically in the United States, usually in conjunction with focal urban outbreaks, but is a common cause of genital ulcer disease in developing countries. Chancroid lesions are painful and indurated, with ragged margins. Gram stain of exudate may reveal gram-variable rods that characteristically line up together in patterns referred to as a school of fish or railroad tracks. Special nutrient media with antibiotic supplements should be used for isolation of H. ducreyi.

Secondary Syphilis

It would be nearly impossible to list all the conditions to which secondary syphilis bears some resemblance. A rash of any description whose etiology may be construed as allergic, infectious, or immune mediated may potentially be syphilitic. Thus, syphilis testing for any patient with a rash of unknown etiology is warranted. The finding of a palmar rash or a rash on the soles of the feet—classic for syphilis—may be seen in a limited number of conditions, including Rocky Mountain spotted fever, atypical measles, and meningococcemia. A rash accompanying any of these alternative diagnoses would ordinarily be associated with more severe systemic illness than is seen with secondary syphilis. Syphilis needs to be considered in the differential diagnosis for aseptic meningitis. More typical causes for this condition may include enteroviruses, HSV-1, and medication-associated aseptic meningitis.

Latent Syphilis

In 1% to 2% of the general population, NTSTs such as the RPR, VDRL, and USR may be falsely reactive. In these circumstances, the treponemal serologic tests, such as the FTA-ABS and TP-PA, are nonreactive. False positive NTSTs are commonly associated with older age, pregnancy, collagen vascular disease, and intravenous drug use.

Neurosyphilis

Although the pattern of classic meningovascular or parenchymatous neurosyphilis may be recognizable, the clinically varied manifestations of CNS syphilis require the clinician to consider it with nearly any presentation. A wide array of stroke syndromes caused by thrombotic or hemorrhagic mechanisms should be included in the differential diagnosis. Neurosyphilis should be considered in a relatively young person with a history of sexually transmitted diseases who suffers a stroke and who otherwise has no risk factors for a cerebrovascular accident (e.g., atherosclerosis or hypertension). Diabetic neuropathy has been said to mimic tabes dorsalis. Neurosyphilis should be considered in the differential diagnosis of any patient presenting with a dementia.

Cardiovascular Syphilis

Cardiovascular pathology leading to ischemia is more likely to result from atherosclerotic disease than from syphilis. Likewise, aortic aneurysm formation secondary to long-standing hypertension would be more common than syphilitic aneurysms. Aortic regurgitation often follows aortic stenosis. Besides syphilitic aortitis, pure valvular regurgitation without stenosis may be seen in patients with congenital valvular disease (e.g., Marfan syndrome), healed infective endocarditis, or other cardiac trauma.

Gummatous Syphilis

The lesions of late benign syphilis may be easily confused with other granulomatous processes, such as tuberculosis, sarcoid, fungal infection, and, occasionally, neoplastic disease.

Treatment

Penicillin remains the antimicrobial agent of choice in all stages of syphilis [see Table 2]. The studies that established this therapeutic standard were conducted decades ago. They used varying formulations of penicillin not currently available and would not meet present standards for randomization, blinding, sample size, and other aspects of good study design. These studies provide a weak basis for conclusions about optimal management today.

Table 2 Treatment of Syphilis

Stage

Drug

Dose

Relative Efficacy

Cost of Regimen ($)*

Comment

Primary, secondary, and early latent syphilis

Benzathine penicillin G

2.4 million U I.M. once

Drug of choice

91

Doxycycline

100 mg p.o. twice a day for 14 days

14

Therapy for non-pregnant patients who are allergic to penicillin

Tetracycline

500 mg p.o. four times a day for 14 days

14

Ceftriaxone

1 g I.M. or I.V. daily for 8–10 days

340–430

Optimal dose has not been defined

Azithromycin

2 g p.o. once

64

Resistance in some areas

Late latent or latent syphilis of unknown duration

Benzathine penicillin G

2.4 million U I.M. once a wk for 3 wk (total 7.2 million U)

Drug of choice

273

May be associated with gastrointestinal upset

Doxycycline

100 mg p.o. twice a day for 28 days

28

Therapy for non-pregnant patients who are allergic to penicillin

Tetracycline

500 mg p.o. four times a day for 28 days

28

Tertiary syphilis (gummatous and cardiovascular)

Benzathine penicillin G

2.4 million U I.M. once a wk for 3 wk

Drug of choice

273

Doxycycline

100 mg p.o. twice a day for 28 days

28

Therapy for non-pregnant patients who are allergic to penicillin

Tetracycline

500 mg p.o. four times a day for 28 days

28

Neurosyphilis

Aqueous crystalline penicillin G

18–24 million U/day, given as 3–4 million U I.V. every 4 hr for 10–14 days

460–640

Procaine penicillin G and probenecid

Penicillin, 2–4 million U/day I.M. for 10–14 days; plus probenecid, 500 mg p.o. four times a day for 10–14 days

Penicillin, 360–1,000; probenecid, 23–33

Can be used if compliance is good

Ceftriaxone

2 g I.M. or I.V. daily for 10–14 days

860–1,200

Limited supporting data

Congenital syphilis

Aqueous crystalline penicillin G

100,000–150,000 U/kg/day, given as 50,000 U/kg/dose I.V. every 12 hr during the first 7 days of life and every 8 hr thereafter for a total of 10 days

75

Procaine penicillin G

50,000 U/kg/day I.M. once a day for 10 days

60

Nonvenereal treponematoses (yaws, endemic syphilis, and pinta)

Benzathine penicillin G

Adults, 1.2 million U I.M. once; children, 600,000 U I.M. once

25–50

Doxycycline

100 mg p.o. twice a day for 14 days

14

Tetracycline

500 mg p.o. four times a day for 14 days

14

*Prices listed should be considered guidelines for relative cost, rather than an accurate reflection of the current market price.

Primary and Secondary Syphilis

Therapy for primary syphilis should serve two overlapping goals: (1) to reduce and eliminate the capacity of the infected person to transmit disease and (2) to achieve the microbiologic eradication of T. pallidum from the host to resolve clinical manifestations and avoid long-term sequelae.

Sexual transmission of syphilis occurs almost exclusively during the early stages of disease, when contact with infectious lesions is most common. Penicillin eliminates infectivity relatively easily. Early studies of penicillin demonstrated the ability of the drug to rapidly convert dark-field-positive lesions to dark-field-negative lesions and hasten their resolution.

All the clinical manifestations of primary and secondary syphilis will resolve without therapy. However, the resolution of clinical manifestations does not ensure the eradication of T. pallidum. In such circumstances, it is assumed that patients remain infected and have entered the latent stage of disease. Studies of therapeutic efficacy rely on changes in serologic markers that may or may not reflect microbiologic activity of disease. There is general agreement today that a fourfold (i.e., two-dilution) decrease in the NTST titer should occur as early as 3 months and as late as 12 or even 24 months after successful therapy. This notion is based on clinical experience and data from a study and subsequent reanalysis of the data.24,25 The criteria for failure and the need for retreatment in both of these studies were poorly defined. Although it has thus been easy to create general categories for the patterns of response expected after therapy, few studies since the introduction of penicillin have followed patients long enough to establish the risk of disease progression.

Penicillin therapy

For more than 3 decades, a single dose of benzathine penicillin G (2.4 million units I.M., typically divided into two injections given at different sites) has been the standard regimen for the treatment of primary syphilis and is currently recommended by both the CDC and the World Health Organization (WHO).19,26 Studies have demonstrated the efficacy of benzathine penicillin but have also suggested a 3% to 10% failure rate by the serologic criteria mentioned above.24 Where comparative data exist, this single-dose regimen appears to be nearly as effective, if not as effective, as a variety of more complicated regimens.27 The ease and cost-effectiveness of a single dose clearly favors its use over multiple-dose therapies or therapies requiring hospitalization for intravenous treatment.

Nonpenicillin therapy

It is advantageous to have alternative therapies to penicillin not only because of the possibility of resistant T. pallidum but also to treat patients who are allergic to penicillin [see Complications, below]. There have been few comparative trials that have examined the role of nonpenicillin therapies. Tetracyclines have been used for decades as an alternative to penicillin, and the CDC currently recommends doxycycline (100 mg orally twice a day for 14 days) as second-line therapy for nonpregnant patients with primary syphilis.19 A comparison study found this regimen as effective as single-dose benzathine penicillin for the treatment of early syphilis.28

Erythromycin congeners, primarily the potentially hepatotoxic estolate form, have also been studied and appear to be as effective as tetracyclines in the treatment of early-stage syphilis.24 However, oral absorption of erythromycin is erratic, and the difficulty of achieving adequate serum levels with the widely used base form makes this an unreliable choice for primary syphilis treatment. Questions regarding erythromycin resistance have also been raised. A high-dose amoxicillin-probenecid combination is another possible alternative, although compliance with such a complex oral regimen makes it difficult to recommend.

The third-generation cephalosporin ceftriaxone is a suitable alternative agent for syphilis treatment. In vitro and animal-model data, along with limited clinical studies, suggest that ceftriaxone should be effective.29 Despite its perceived efficacy, ceftriaxone probably should not be given as a single dose for the treatment of primary syphilis, because it would not remain at treponemicidal levels for an acceptable period. The proper dosage and duration of therapy are matters of conjecture, but some specialists recommend giving 1 g daily (I.M. or I.V.) for 8 to 10 days.

The macrolide antibiotic azithromycin has many properties that suggest its usefulness as therapy for primary syphilis. It is active against T. pallidum in vitro and has been effective in experimental models of syphilis.30,31 Although plasma concentration of azithromycin may be nearly impossible to measure, high levels are achievable in tissue.32 Its extremely long half-life makes it ideal therapy for T. pallidum, an organism with a prolonged doubling time. In a number of small studies, azithromycin in varying doses appeared effective in treating incubating, primary, and secondary syphilis.33,34 In a Tanzanian study in 328 patients, single-dose oral azithromycin (2 g) was as effective as intramuscular penicillin G benzathine for the treatment of early syphilis.35 Azithromycin resistance has been reported in the United States, however: for example, a San Francisco study found widespread resistance to azithromycin in T. pallidum. Those researchers recommended against using azithromycin to treat syphilis in communities where macrolide-resistant T. pallidum is present, and they recommended active surveillance for resistance in sites where azithromycin is used.36

Latent Syphilis

The successful treatment of latent syphilis is made problematic by a lack of clear and readily measurable clinical end points. By definition, there is no chancre or rash, the resolution of which would suggest response. The objective of therapy is the prevention of long-term sequelae. Other than waiting perhaps decades to see if late-stage disease develops, changes in serologic titers are the only indication of efficacy. Unfortunately, by its very nature, late latent syphilis elicits little in the way of an inflammatory response. Thus, nontreponemal serologic test results are often very low, and their decline after therapy may be proportionately slow. Seroreversal may never be achieved.

Because early latent syphilis occurs shortly after secondary syphilis appears to resolve, it should respond appropriately to similar single-dose and multiple-dose regimens. In most clinical settings, patients with latent-stage disease are unable to reliably give any history suggestive of recent primary disease and are usually treated as having late latent-stage disease.

Studies have suggested that penicillin, which is effective in primary disease, would be effective for latent disease as well. A variety of penicillin regimens were compared and patients followed over a wide range of periods37; benzathine penicillin G provided equivalent duration of in vivo drug levels with fewer injections, as compared with other forms of penicillin. The CDC recommends two regimens of benzathine pencillin G: a single dose of 2.4 million units I.M. for early latent syphilis, and three doses of 2.4 million units I.M. at 1-week intervals (7.2 million units total) for late latent syphilis or latent syphilis of unknown duration.19 Although direct supportive data are lacking, the latter regimen has been used effectively for decades; progression of disease is rare in patients so treated.

There are virtually no useful data on the treatment of latent syphilis with nonpenicillin therapies. Anecdotal evidence has been offered in support of 28-day regimens of tetracycline, chloramphenicol, or erythromycin.

Late Symptomatic Syphilis (Excluding Neurosyphilis)

Incidences of gummatous syphilis and cardiovascular syphilis have declined so dramatically in the penicillin era that it has been difficult to collect enough cases to conduct a study of newer therapeutic modalities. A few studies conducted on small groups of patients soon after the introduction of penicillin demonstrated that penicillin therapy probably halts the progression of gummatous disease, although existing damage to skin, mucous membranes, soft tissue, and skeletal structures is likely irreparable. The therapeutic efficacy of penicillin for cardiovascular syphilis has never been clearly established, because of the difficulty of establishing a diagnosis and determining the efficacy of therapy in patients with already advanced disease (i.e., cardiac structural damage).38 Despite suggestions that penicillin appeared to have some efficacy in preventing the progression of otherwise uncomplicated aortitis, carefully controlled studies comparing various therapies have never been conducted. In over 4 decades, there have been no studies examining the newer, long-acting preparations of penicillin, nor have there been studies of alternatives to penicillin.

Given the relative safety and ease of use of penicillin therapy for the treatment of cardiovascular syphilis, the WHO and the CDC recommendations appear reasonable, provided that patients are adequately evaluated for other complications of syphilis, such as neurosyphilis, and that adequate clinical and serologic follow-up can be performed.

Neurosyphilis

Frank symptomatic neurosyphilis, like cardiovascular syphilis and gummatous syphilis, has to a certain extent disappeared from clinicians' experience because of the success of therapies for primary and latent-stage disease. Although there is a significant body of work describing and essentially confirming the efficacy of penicillin in the treatment of neurosyphilis, this literature, like much of the literature on the treatment of syphilis, is compromised by poor posttreatment follow-up and poorly defined outcomes. Nonetheless, penicillin appears to be effective against neurosyphilis, in many instances improving or halting the inexorable progression of neurologic symptoms.

In the past, benzathine pencillin was used for the treatment of neurosyphilis; however, because of studies showing inadequate CSF penetration and reports of treatment failures, this agent is no longer recommended for this purpose. Instead, the CDC currently recommends aqueous crystalline penicillin G (18 to 24 million units a day, administered as 34 million units I.V. every 4 hours or as a continuous infusion) for 10 to 14 days.19 An alternative regimen for patients whose compliance can be assured is procaine penicillin (2.4 million units I.M. once daily) plus probenecid (500 mg orally four times a day) for 10 to 14 days.

There are no data from randomized, controlled trials that demonstrate that the efficacy of the current CDC recommendations is superior to that of previous recommendations. Some experts still contend, also in the absence of supporting data, that lower-dose regimens may be appropriate for patients with asymptomatic neurosyphilis.

The efficacy of high-dose intravenous therapy for neurosyphilis in certain circumstances is also questionable. It is probable that advanced parenchymal disease (e.g., paresis or tabes dorsalis) will not improve after even the most aggressive therapy and may in fact progress. In patients with neurosyphilis and concomitant HIV infection, disease progression may be seen after therapy.39 Controversy also exists regarding the efficacy of procaine penicillin G.39

Ceftriaxone is an attractive alternative to penicillin in the treatment of neurosyphilis.18,40 This agent has a long half-life, penetrates the CNS well, and has been shown in vivo and in vitro to have activity against T. pallidum. Although few well-designed trials support the clinical efficacy of ceftriaxone for the treatment of neurosyphilis, infectious disease specialists in the United States commonly use it as an alternative to penicillin.41

High-dose amoxicillin (2 g orally three times a day) combined with probenecid has been proposed as an alternative outpatient regimen for neurosyphilis because it has been documented to achieve treponemicidal levels of β-lactam antibiotic in the CSF.42,43,44 No randomized, controlled studies have been done to evaluate this regimen for this purpose.

Both chloramphenicol and doxycycline have been examined in individual cases and in small groups of patients with neurosyphilis.45,46Limited data suggest that these drugs may have efficacy in the treatment of neurosyphilis, but there is not enough evidence to make final recommendations.

Oral steroids are a frequent adjunct in the therapy of sensorineural deafness from neurosyphilis,47,48 but no controlled trials have been properly conducted to evaluate this practice.

Serologic Follow-up

In the treatment of syphilis, the lack of a microbe that can be cultured, the problem of latency, and the uncertainty of therapeutic efficacy combine to foster clinical reliance on quantitative changes in serologic markers to determine response to and adequacy of therapy. Few, if any, infectious diseases require similar follow-up after treatment.

Current standards of care require patients with primary syphilis to return for clinical and serologic evaluation 6 and 12 months after therapy.19 Patients with latent syphilis should have quantitative NTSTs repeated at 6, 12, and 24 months.19

HIV-coinfected patients are followed more regularly. Recurrence of disease or lack of resolution of signs or symptoms of disease after treatment may be considered evidence of treatment failure. As a measure of disease activity, a two-tube, or fourfold, dilution increase in the NTST during follow-up is also widely accepted as a marker of treatment failure. In all of these instances, distinguishing treatment failure from reinfection may be difficult. At the opposite end of the therapeutic spectrum, cure may reasonably be assumed to have occurred if the NTST becomes nonreactive after therapy. Unfortunately, this development may occur slowly if at all.

A fourfold dilution decrease in the NTST after treatment has become accepted as the measure of success. This finding will occur more rapidly after treatment of primary syphilis. Cumulative data and clinical experience over several decades indicate that in immunocompetent patients treated with standard regimens of benzathine penicillin G or tetracycline, the NTST should decline by two or three dilutions within 6 and 12 months of treatment, respectively. The proportion of patients expected to be seronegative within 12 to 24 months is less certain, but the weight of evidence suggests that at least 90% of patients with primary or secondary syphilis should serorevert within 1 or 2 years, respectively.

The treponemal-specific serologic tests revert to negative within 3 years in up to 25% of successfully treated patients with first-episode primary syphilis; therefore, a negative treponemal antibody test result does not always exclude a past history of syphilis.19,49 However, seroreversal of the treponemal antibody test results occurs rarely, if ever, after treatment of syphilis at the secondary stage or beyond or after treatment of a second episode of primary syphilis. Some data suggest a higher prevalence of nonreactive treponemal antibody tests in HIV-infected patients after treatment of syphilis.50 It is possible that HIV-infected persons serorevert more often than non-HIV-infected persons, but the issue is unresolved.

Serologic response after treatment in latent disease may be even more problematic than in primary disease. Long-term studies are not available. Another confounding issue is variation in the definition of late syphilis, which determines the dose or duration of therapy of latent infection. Most early writers defined late infection as syphilis of 4 years' duration, on the basis of observations that relapses of secondary syphilis in untreated individuals ceased after this interval. The usual cutoff in the United States, by contrast, is 1 year, after which sexual transmission is rare and classic tertiary syphilis begins to appear.51 The WHO defines late latent syphilis as infection of 2 years' duration.26All these definitions are arbitrary, and there are insufficient data for choosing among them on the basis of documented differences in the clinical or serologic response to various treatment regimens. Moreover, the duration of infection cannot be determined accurately in most asymptomatic seropositive patients, further confounding interpretation of the serologic response to treatment in most published studies.

Older data and the accumulated experience of recent years indicate that NTST results decline more slowly after treatment of late syphilis than after treatment of early syphilis and that these tests often remain reactive indefinitely, usually at low titer. Serologic titers in late latent syphilis and in tertiary syphilis decline slowly after treatment, and nonreactive tests will develop in only a minority of patients after upwards of 5 years.27 The serologic response to the treatment of symptomatic late-stage syphilis may also result in only gradual declines in the NTST. Whether this reflects failure to achieve biologic cure or is merely a serologic phenomenon (so-called immunologic memory) is unresolved. For clinical application, a reasonable guideline is that failure of the NTST to decline by two or more dilutions within 12 months of treatment of late syphilis and any subsequent rise in titer are indications for comprehensive reevaluation and retreatment.

CSF abnormalities in neurosyphilis are also slow to respond after therapy. When reactive, the CSF-VDRL may remain so for years. Increased CSF protein levels also resolve slowly. To ensure an appropriate response to therapy, patients who had initial pleocytosis should undergo repeat CSF examinations at 6-month intervals until the cell count returns to normal. Although the CDC suggests considering retreatment if the cell count has not decreased after 6 months or if CSF abnormalities persist after 2 years, there is no evidence that this condition is clearly indicative of treatment failure or that retreatment will result in an improved response. It is unclear whether serologic response can be expected to differ in all clinical settings, and it would be prudent to consider more frequent serologic follow-up for the HIV-infected patient treated for any stage of syphilis.

Despite considerable effort to develop guidelines for expected serologic response after treatment, it must be remembered that microbiologic response and serologic response are not synonymous. T. pallidum has been isolated by rabbit inoculation of lymph nodes of both patients and rabbits and has been identified histologically or immunochemically in aqueous humor after penicillin therapy that resulted in clinical and serologic resolution. Relapse (especially of neurosyphilis) has been reported after apparently adequate penicillin treatment of HIV-infected patients with primary syphilis.

Management of Sexual Partners and Incubating Syphilis

Syphilis treatment is not complete until treatment of sexual partners of the index case has been considered. The CDC recommends that sexual contacts exposed within the 90 days before diagnosis to an index case of primary, secondary, or early latent syphilis receive presumptive therapy, regardless of the serologic test results. For persons exposed more than 90 days before, therapy should be based on the serologic test results. The need for therapy for contacts of patients with latent or late-stage syphilis should be based on clinical evaluation.

High-risk sexual activity (as indicated by the recent acquisition of such sexually transmitted organisms as Chlamydia trachomatis andNeisseria gonorrhoeae) carries with it the risk of simultaneous acquisition of syphilis. Because the incubation period of syphilis may be much longer than that of diseases caused by these other organisms, neither clinical nor serologic evidence of syphilis may be present at the time of presentation for clinical care. It would therefore be advantageous for therapies directed toward C. trachomatis or N. gonorrhoeae to also adequately treat syphilis. Treatment with standard doses of ceftriaxone for gonorrhea will probably abort incubating syphilis. The same cannot be said for single-dose therapy with quinolone antibiotics that do not have activity against T. pallidum. Activity of single-dose cefixime against T. pallidum is uncertain. Spectinomycin is not active in this instance.52 Although data are lacking to support a 7-day course of doxycycline, this therapy may in fact be effective. Single-dose azithromycin may also be useful for this purpose in communities where resistant strains are not present.

Complications

Jarisch-Herxheimer Reaction

The Jarisch-Herxheimer reaction is an acute systemic syndrome characterized by fever, chills, headaches, myalgias, tachycardia, tachypnea, and nausea that occurs within the first few hours after the treatment of syphilis—usually secondary syphilis. It may result from the release of pyrogenic endotoxins from treponemes adversely affected by therapy. Treatment with anti-inflammatory agents during the first 24 to 48 hours is warranted. Some clinicians advocate the use of preemptive steroid therapy to mitigate any reaction in which additional end-organ damage (e.g., ocular or cardiovascular) may be problematic, but this practice is not supported by available data. In pregnancy, a Jarisch-Herxheimer reaction may precipitate premature labor or fetal distress.53 Pregnant women should be advised to seek obstetric evaluation if they note contractions or decreased fetal movements after syphilis treatment.

Penicillin Allergy and Desensitization

In the United States, 5% to 10% of the population may have a history of penicillin allergy, and life-threatening complications may result in 2% to 13% of related allergic events.54 Despite the relatively high risk of adverse events, there are certain clinical situations in which nonpenicillin therapies for syphilis are not acceptable and penicillin must be used (i.e., congenital syphilis, syphilis in pregnancy, and neurosyphilis).

Even where a history of penicillin allergy exists, the drug may not necessarily be contraindicated. A history of allergy may be inaccurate. Additionally, with the passage of time after an allergic event, many patients may stop expressing penicillin-specific IgE. Penicillin skin testing is a well-established means of securing the patient's true allergy status. The penicilloyl hapten moiety that is the largest product of penicillin metabolism is referred to as the major determinant and, conjugated to polylysine, is commercially available for skin testing. The remaining metabolites are referred to as the minor determinants and are available only at certain academic centers. Even in this setting, the quality criteria for their production have not been standardized. Major determinant skin testing, along with that for benzathine penicillin G (considered a minor determinant), should identify 90% to 97% of patients with penicillin allergy. Nearly all allergic patients will be identified if the other minor determinants are also used.55 Patients who have a positive response to any of the major or minor determinants should undergo either oral or intravenous desensitization.56

Desensitization is usually performed only in a hospital setting. Syphilis treatment regimens may be initiated immediately after the successful completion of desensitization. Unless penicillin therapy is continued indefinitely after desensitization, patients should be considered potentially allergic.

Special Situations

Syphilis in Pregnancy

All women should be screened for syphilis at the first prenatal visit, and those women who are at risk for syphilis should be screened again at 32 to 36 weeks of gestation.57 In most of the United States, some degree of prenatal testing is mandated by state law.58

Routine screening and confirmatory serologic tests should reveal syphilis in pregnant women. In pregnancy, quantitative nontreponemal tests reflective of previously treated syphilis may not be specifically indicative of syphilis. An increase in titer in this setting should be considered nonspecific.

The treatment of syphilis in pregnancy must not only cure disease in the adult and prevent sexual transmission but also prevent fetal infection via transplacental passage of T. pallidum [see Congenital Syphilis, below]. These goals can be achieved with therapeutic regimens recommended for the nonpregnant patient. Treatment late in pregnancy carries a greater risk of congenital disease than treatment earlier in pregnancy59; no other factors appear to conclusively increase the risk of congenital syphilis after appropriate therapy of the mother, provided that currently recommended doses are used and there is no serologic or clinical evidence of relapse or reinfection. Follow-up is no more difficult than after the treatment of the nonpregnant patient with syphilis.

Treatment of syphilis during pregnancy is with penicillin only. If the woman has a history of penicillin allergy, she should undergo desensitization and then be treated with penicillin. Tetracyclines are contraindicated in pregnancy. Erythromycin has proved unreliable for treatment of syphilis during pregnancy, and data are lacking on azithromycin or ceftriaxone.

Congenital Syphilis

Diagnosis

The CDC recommends that a quantitative NTST be performed in all infants born to mothers who have reactive nontreponemal and treponemal test results.19 The test should be performed on infant serum rather than umbilical cord blood, to eliminate the possibility of a false positive result from contamination of cord blood with maternal blood. Reactive standard serologic tests in the infant may reflect passive transfer of antibody. Although there is interest in the use of tests for IgM antibodies in the infant, such tests may be insensitive, and nonreactive tests should be interpreted with caution. Demonstration of the presence of T. pallidum by direct microscopic examination in the umbilical cord, placenta, nasal discharge, or skin lesions is considered definitive for diagnosis.

In most cases of congenital syphilis, the newborn is asymptomatic. Symptomatic disease may occur early or later after birth. In the perinatal period, involvement of the mucocutaneous tissues may be seen; it is characterized by rhinitis and a desquamative, vesicular, or bullous rash of the skin, particularly on the palms and on the soles of the feet. Hepatic disease can also occur and may result in significant morbidity and mortality. Hepatomegaly, splenomegaly, and hematologic abnormalities occur in this setting. Osteochondritis and perichondritis lead to the classic findings of the so-called saddle-nose deformity and saber shins. After 6 to 12 months, the child enters a latent phase of disease not unlike that seen in adults. Late-stage disease in children may manifest as interstitial keratitis, eighth-nerve deafness, arthropathy, and dental malformations.

Treatment

Except where adequate treatment and follow-up of the mother with syphilis can be documented more than 1 month before delivery, some therapeutic intervention will be necessary for the infant. No well-controlled study has determined the appropriate dose of penicillin for the infant suspected of having congenital syphilis. For those with symptomatic disease at birth, the CDC recommends 10 days of treatment with 50,000 U/kg of I.V. aqueous crystalline penicillin G every 12 hours for the first 7 days of life, then every 8 hours thereafter for the next 3 days.19 Alternatively, procaine penicillin G, 50,000 units/kg I.M. in a single daily dose, can be given for 10 days. These regimens can also be used in asymptomatic newborns whose serum quantitative nontreponemal serologic titer is the same as or less than fourfold the maternal titer and whose mothers received inappropriate, unsuccessful, or no treatment; alternatively, these infants can be treated with a single dose of benzathine penicillin G (50,000 units/kg I.M.).

In infants with no clinical signs of syphilis and whose serum quantitative nontreponemal serologic titer is the same as or less than fourfold the maternal titer and whose mother was appropriately and successfully treated for syphilis during pregnancy, the CDC recommends treatment with a single dose of intramuscular benzathine penicillin, 50,000 U/kg. Some specialists also provide this treatment for normal newborns whose mother was successfully treated for syphilis before pregnancy, especially in cases in which it is uncertain whether the patient will present for follow-up; however, it is doubtful that most infants receiving this therapy have syphilis at all.

There are no clinical trials examining the role of other antibiotics for the treatment of congenital syphilis. Nonpenicillin therapies recommended for syphilis in adults cannot automatically be recommended for syphilis in infants.

As in adults, serologic follow-up after treatment in infants is essential to ensure the adequacy of response. The ideal frequency of follow-up visits is poorly defined, and recommendations range from every month to every 3 months during the first 6 months, with continued follow-up through months 12 to 24, depending on response.

Syphilis in Children

Penicillin therapy

Children with primary, secondary, or early latent syphilis should be treated with benzathine penicillin G (50,000 U/kg I.M., to 2.4 million units in a single dose). Children with late latent syphilis or syphilis of unknown duration should also receive benzathine penicillin G (50,000 U/kg I.M., to 2.4 million units administered as three doses at 1-week intervals). In both cases, a CSF examination should be performed to rule out neurosyphilis.

Alternative therapy

The American Academy of Pediatrics recommends that tetracyclines be considered as an alternative to penicillin for both primary and latent disease in pediatric patients older than 9 years.57 Erythromycin may be considered for early acquired syphilis in children younger than 9 years (500 mg orally four times a day for 14 days). Follow-up must be ensured. Newer therapies, such as ceftriaxone and azithromycin, may also be effective. There are no studies to support any of these recommendations.

Syphilis and HIV

Risk behaviors that contribute to the transmission of syphilis are often the same as those that contribute to the transmission of HIV, and therefore, coinfection is common. Each infection has been demonstrated to have some effect on the other. Substantial evidence suggests that early-stage syphilis enhances the transmission of HIV.60,61 Presumably, the inflammatory milieu of syphilitic lesions can serve either as a portal of entry of HIV or as the route through which HIV may be transmitted to an uninfected partner.

In coinfected persons, the deleterious effect of HIV on the immune system can alter the natural history, diagnosis, and management of syphilis. Since the earliest years of the HIV epidemic, case studies have reported on patients who failed to respond to conventional doses of penicillin therapy and who often progressed rapidly from primary syphilis to neurosyphilis.62,63 Other important findings have included seronegative secondary syphilis,64 a likelihood of higher-titer NTSTs by stage,65 and an increased incidence of biologic false positive NTSTs.19,66

A study prospectively followed both HIV-seronegative and HIV-seropositive patients with primary syphilis who received either conventional penicillin therapy or an enhanced regimen of high-dose amoxicillin and probenecid. No neurologic complications and no differences in response to therapy were noted between the groups.42,67 Except for a tendency for HIV-infected persons to present with multiple chancres, as opposed to a single chancre in non-HIV-infected individuals, no significant differences were noted in presentation or rapidity to resolution of primary syphilis findings. In another study, the CSF white blood cell count, protein level, and VDRL results were slower to return to normal after therapy in HIV-infected patients than in non-HIV-infected patients.68 Clinical failures were not noted. A Danish study found that HIV-infected patients with syphilis tend to have lower CD4+ T cell counts and higher HIV RNA levels, and that both of these measures improved after treatment of syphilis.69

The propensity for T. pallidum to invade the CNS early during infection and the likely importance of immune mechanisms for its control suggest possible mechanisms for the risk of neurosyphilis in coinfected persons. This issue is further complicated by the likelihood for HIV-infected persons to have CSF abnormalities even in the absence of discernible CNS pathology.70 Many experts recommend that HIV-infected persons with latent syphilis or primary syphilis undergo a CSF evaluation and that those with CSF abnormalities be treated accordingly.

Nonvenereal Treponematoses

The nonvenereal treponematoses—yaws, endemic syphilis, and pinta—are a group of infections distributed throughout tropical and semitropical areas of the world. They are primarily noted to cause a variety of skin and skeletal lesions. There is little biologic difference between the treponemes that cause these conditions.71,72 Their distinguishing nomenclature is based primarily on the clinical disease that characterizes each. Each is linked to poor hygiene and person-to-person transmission and disproportionately affects children. As a result of mass treatment programs conducted in the 1950s and the 1960s, initiated primarily by the WHO in conjunction with local authorities, the incidences of all of the nonvenereal treponematoses are today quite low.

Yaws

Epidemiology

Yaws is a disease primarily affecting individuals who live in rural areas of the tropics. It is seen in parts of South America, Africa, Southeast Asia, and Oceania. In the Western Hemisphere, yaws occurs sporadically in small regions of Colombia, Haiti, Suriname, and Guyana. Propagation depends on a hot, humid climate. Persons younger than 15 years appear to be most at risk for acquisition of this infection. It is known by a number of names in different parts of the world, including frambesia, pian, bouba, and parangi.

Pathogenesis

  1. pallidumsubspecies pertenueis associated with yaws. Transmission occurs through skin-to-skin contact, where abrasions or other defects allow spirochetes to enter and cause infection. The incubation period of yaws is like that of syphilis. Within 9 days to 3 months, a granulomatous papule forms in the area of inoculation. This papule gradually enlarges and becomes either hyperkeratotic or frankly ulcerative, often with the development of an overlying amber crust of bacterial superinfection. As with syphilis, even in the absence of specific treatment, these primary lesions resolve.

Diagnosis

The diagnosis of yaws should be suspected in anyone with skin or bone lesions who has spent time in a tropical region.

Clinical manifestations

Systemic symptoms of fever, arthralgias, and regional lymphadenopathy occur in conjunction with the development of a diffuse rash similar in appearance to the primary lesion. Osteitis and periosteitis involving the fingers (polydactylitis), tibia (saber shin), and the paranasal maxillae can occur. Secondary lesions may resolve and then relapse over the course of many years. Gummatous lesions with significant dermal scarring and destruction of underlying bone occur years after infection. Whether CNS involvement occurs is debatable.

Laboratory tests

Dark-field microscopy of both primary and secondary lesions may yield spirochetes. Nonspecific treponemal serologic tests (e.g., VDRL or RPR) and treponemal-specific serologic tests (e.g., FTA-ABS or TP-PA) should be reactive in cases of yaws, but these tests cannot distinguish between yaws and other treponematoses.

Differential Diagnosis

The differential diagnosis includes syphilis, eczema, psoriasis, scabies, pyoderma, tuberculosis, leprosy, and ecthyma, as well as other processes.

Treatment

Penicillin remains the treatment of choice. For primary disease, doses of benzathine penicillin, 1.2 million units I.M. once in adults and 600,000 units I.M. once in children, should be adequate. Tetracyclines and chloramphenicol are acceptable alternatives. Close contacts of the patient should also be treated.

Endemic Syphilis

Epidemiology

Unlike yaws, endemic syphilis, or bejel, is epidemiologically restricted to the arid regions of the Middle East and North Africa. Like the other treponematoses, endemic syphilis is transmitted by close personal contact and affects primarily children living in rural areas.

Pathogenesis

Endemic syphilis is caused by the spirochete T. pallidum subspecies endemicum. The primary lesion of endemic syphilis usually occurs at a site of inoculation on the oral mucosa and is often unappreciated. This has led to the suspicion that contaminated utensils and drinking vessels may be involved in the spread of the disease.

As in the case of yaws, gummatous late-stage lesions result in destruction and deformation of the mucosa and bony structures, particularly of the mouth and nasal structures. Long bones are sometimes involved. Hyperkeratosis of the soles of the feet occurs. CNS disease is uncommon.

Diagnosis

The diagnosis of endemic syphilis should be considered in any person from an endemic area who has skin or bone disease.

Clinical manifestations

Secondary lesions, which may be the first manifestation of infection to be noticed, occur on and around the oral mucosa, as well as on other moist, nonkeratinized epithelium and in the intertriginous areas. In rare cases, lesions are disseminated across the surface of the body. Diffuse lymphadenopathy and osteitis are also seen in this circumstance.

Laboratory tests

Dark-field microscopy of primary and secondary lesions will be positive for spirochetes, and serologic testing will also be reactive.

Differential Diagnosis

The differential diagnosis of endemic syphilis includes many of the conditions considered in the differential diagnosis of yaws.

Treatment

As in the case of yaws, a single I.M. injection of 1.2 million units of benzathine penicillin is effective to eradicate disease.

Pinta

Epidemiology

Pinta (Spanish for blemish) occurs only in the Western Hemisphere and only in rural areas of southern Mexico and parts of Colombia. All age groups are susceptible to infection.

Pathogenesis

The organism that causes pinta, T. carateum, is transmitted through contact of broken skin with infectious lesions.

Within a few weeks of inoculation, a small papule develops at the infection site. The initial papule is followed rapidly by the appearance of other small, pruritic, erythematous papules around the site of the lesion.

Diagnosis

Pinta should be suspected in anyone with characteristic dermal lesions who has been in an endemic area.

Clinical manifestations

Papules may coalesce to form squamous plaques. They may then persist for some time before resolving and leaving areas of hypopigmentation. Within 3 to 12 months, a disseminated form of skin lesion known as a pintid appears, which is similar to the initial lesion. These also may coalesce. Diffuse lymphadenopathy is common. Eventually, longstanding lesions leave atrophic and hypopigmented patches, particularly in the area of the wrists, elbows, and ankles.

Laboratory tests

Except in the late stages of disease, dark-field microscopy of lesions is usually positive for spirochetes. Standard serologic tests for syphilis are usually reactive except during the earliest phases of disease.

Differential Diagnosis

Conditions with which pinta may be confused include tinea versicolor, vitiligo, and chloasma.

Treatment

The same penicillin doses used for yaws and endemic syphilis should be effective for pinta. Tetracyclines and chloramphenicol are acceptable alternatives. Lesions may be slow to heal. The hypopigmented, or achromic, lesions of late-stage pinta may never improve despite therapy.

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Editors: Dale, David C.; Federman, Daniel D.