[STDs] Atlas of Syphilis

Atlas of Syphilis, Syphilis, Color Atlas & Synopsis of Sexually Transmitted Diseases, Bacterial Sexually Transmitted Diseases

Syphilis

Syphilis has been recognized as a distinct disorder since the late fifteenth century. It is one of the five originally recognized venereal diseases, along with gonorrhea, lymphogranuloma venereum, chancroid, and donovanosis (granuloma inguinale). Syphilis is characterized by a complex natural history that is largely determined by the unique character of the causative spirochete, Treponema pallidum, and the immunologic response to it. The pathogenesis is similar to that of tuberculosis. Both infections are caused by intracellular, slowly replicating pathogens whose containment depends on cell-mediated immunity; both are characterized by an outwardly benign primary infection that is accompanied by silent bacteremia with dissemination of organisms to various organs and by destructive granulomatous inflammation results if infection reactivates, often many years later, due to failure of immune surveillance or overt immunodeficiency.

Syphilis has overlapping primary, secondary, and tertiary stages over several years or decades, interspersed by periods of inactive (latent) infection. Globally, the most serious impact of the disease is from congenital infection, but the most common serious manifestation in adults is neurosyphilis. Although often considered a manifestation of tertiary infection years or decades after acquisition, both subclinical and overt neurological involvement are most common in syphilis under a year in duration. HIV-infected persons with syphilis may have aberrant results of serological tests for syphilis, blunted responses to antibiotic therapy, and perhaps an increased risk of neurosyphilis, but these effects appear to be uncommon. In this respect, the course of syphilis in persons with AIDS is substantially different than that of tuberculosis, despite the parallels in pathogenesis.

The incidence of infectious syphilis (primary, secondary, and early latent infection under a year in duration) fluctuated widely in the United States and Europe throughout the twentieth century, owing to increased case recognition, reporting, and perhaps truly rising incidence in the first half of the century, followed in the second half by rising and falling rates as various risk groups emerged and exhibited great variability in frequency of risk behaviors. Most dramatically in the past 25 years, rates of syphilis in industrialized countries have been driven largely by shifts in sexual behavior among men who have sex with men (MSM) in response to the spread of HIV and by improved treatment and survival in persons with AIDS. By the mid 1990s, the incidence of syphilis in the United States and many industrialized countries had declined to the lowest level at any time since national statistics were complied, and in 1999 the Centers for Disease Control and Prevention (CDC) announced plans to eliminate syphilis in the United States. Inmany geographic areas, however, a remarkable resurgence began around 2000 and has continued through the present time, with more than a doubling of reported cases through 2009, especially among MSM, many of whom were also infected with HIV.

In addition to MSM, syphilis rates worldwide are highest in the most disadvantaged populations. Population-level herd immunity has been proposed as a partial explanation for varying syphilis rates,

but most experts believe the variations are due exclusively to behavioral explanations and societal influences on behavior and access to health care. More than any other STD, except perhaps HIV/AIDS, syphilis thrives in settings of anonymous or furtive sexuality and where economic and social conditions, including poor access to health care, are most problematic. In the United States, heterosexually transmitted syphilis continues at high rates in disadvantaged minority populations, especially in the southeast and along the United States-Mexico border, where congenital syphilis continues to occur at unacceptable rates. Owing to these trends, syphilis elimination in the United States remains a forlorn hope for the foreseeable future. International efforts to control syphilis are largely driven by continued high rates of congenital infection in many developing countries.

EPIDEMIOLOGY

Incidence

• In the United States, 13,997 cases of primary and secondary (P&S) syphilis were reported in 2009; including early latent cases (<1 year duration), incidence in the United States approximates 31,000 cases annually

• Reported incidence of P&S syphilis rose 119% from 2000 (2.1 cases per 100,000) to 2009 (4.6 per 100,000)

• Geographic variability is great; 70% of U.S. counties reported no cases in 2009

• European Union had 17,603 reported cases (all stages) in 2007 (4.4 per 100,000); most countries had rates ranging from 1 to 8 per 100,000; in many countries, recently rising rates in MSM parallel U.S. trend

• Highest rates are in southern Africa and parts of Asia

Transmission

• Sexually transmissible only during primary, secondary, and early latent stages

• Requires exposure to moist mucocutaneous lesions (chancre, mucous patches, condylomata lata) that teem with spirochetes

• Congenital syphilis results from transplacental infection

• Rare cases of nonsexual transmission, typically from direct contact with infected persons’ nongenital lesions (e.g., nursing, premastication of infant food in some cultures)

Age

• All ages are susceptible

• Peak rates occur at older ages than most STDs; in the United States, 57% of reported P&S cases in 2009 were ≥30 years old (vs. 12% of chlamydia and 20% of gonorrhea cases)

• Late syphilis often diagnosed in persons ≥50 years of age.

Sex and Sexual Orientation

• Both sexes equally susceptible

• Population level sex distribution largely reflects proportion of cases in MSM; male:female ratio of reported P&S syphilis rose from 1.2 to 1 in 1996 to 5-6 to 1 from 2007 to 2009; trends are similar in many industrialized countries, especially in western Europe

• In King County, Washington 2009 annual rate of early syphilis estimated 342 per 100,000 MSM and 1,169 cases per 100,000 HIV-infected MSM (vs. 0.4 per 100,000 heterosexual men)

• High rates in HIV-infected MSM may be attributed in part to selection of partners of like HIV status (serosorting)

• Rare in exclusively homosexual women

Race/Ethnicity

• Race and ethnicity are markers of socioeconomic status, access to health care, education, and sexua network pattern.

• Reported rates of P&S syphilis, the United States, 2009

° Whites 4,256 cases (2.1 per 100,000)

° African Americans 7,335 cases (19.2 per 100,000)

° Hispanics 2,112 cases (4.5 per 100,000)

° Asian/Pacific Island ancestry 225 cases (1.6 per 100,000)

° Native Americans 61 cases (2.4 per 100,000)

Other Risk Factors

• Anonymous sexual partnerships

• Illicit drug use

• Commercial or coerced sex

• Low socioeconomic and educational attainment

• Population migration

• War and other settings of social disruption

• Undocumented immigrants in the United States

CLINICAL MANIFESTATIONS

Epidemiologic and Exposure History

• Almost all persons with infectious syphilis acknowledge new sex partner or a partner who has other

sexual relationships

• Unprotected sex, especially with anonymous or commercial partners

• Among males, sex with other men

• Heterosexual men and women affected by societal conditions addressed above

Symptoms and Examination

Primary Syphilis

• Incubation period 2–6 weeks, occasionally up to 3 months, from exposure to clinically evident primary syphilis

• Chancre often presents as a single painless or minimally painful round or oval ulcer, typically indurated, with a “clean” base with little or no purulent exudate

• Presence of classic chancre is insensitive but highly specific for diagnosis of syphilis; i.e. many chancres lack classic appearance, but most typical chancres are syphilitic

• Location: primarily sites most exposed during sexual activity

° External genitals (penile head and shaft, labia minor, vaginal introitus)

° Intravaginal or anal lesions also are common

° Oral chancres occur occasionally, depending on sexual practices

• Regional lymphadenopathy is common, generally bilateral, with firm, nonfluctuant, nontender or mildly tender nodes, without overlying erythema

• No systemic symptoms

• Asymptomatic infection is common, primarily due to chancres hidden from view (e.g., vaginal, anal, oral, or rectal)

• All clinical manifestations and course may be highly variable; atypical presentations are common

Secondary Syphilis

• May overlap with primary, e.g. persistent chancre in patients with secondary manifestations

• Most common presentation is generalized papulosquamous, nonpruritic skin rash, often involving palms and soles

• Atypical rashes, including pruritic ones, may occur

• Protean manifestations (syphilis has been called “the great imitator”): mucous patches (painless mucous membrane lesions), condylomata lata (genital or perianal warty excrescences), patchy (“moth-eaten”) alopecia, generalized lymphadenopathy, hepatosplenomegaly, abdominal pain due to gastric ulceration, fever, malaise, headache, immune complex polyarthritis, others

Neurosyphilis

• Early neurosyphilis occurs during secondary and early latent infection

• Main clinical manifestations of early neurosyphilis reflect meningovascular involvement: cranial nerve palsies, headache, hearing loss, vestibular dysfunction (e.g., vertigo), arterial occlusion (typically involving mid-size arteries) resulting in stroke

• Iritis and uveitis are common; syphilitic ocular disease always implies neurosyphilis and requires similar management

Tertiary (Late) Syphilis

• Classic tertiary syphilis now rare in most of the world; almost unheard of in the United States and western Europe, perhaps because many persons with latent syphilis receive incidental antibiotic therapy

• Main features are locally destructive granulomatous lesions (gummas) of skin, liver, bones, or other organs

• Signs of late neurosyphilis include tabes dorsalis and dementia, often with paranoid features (“general paresis”)

• Cardiovascular manifestations, e.g. ascending aortic aneurysm and aortic valve insufficiency, are now rare

Latent Syphilis

• By definition, asymptomatic infection at any time following primary syphilis

• Only detectable serologically

• Early latent (≤1 year, infectious) and late latent (>1 year, usually not transmissible)

• The distinction between early and late latent syphilis often is moot because duration is difficult to determine

Congenital Syphilis

• Severity ranges from asymptomatic to fatal

• Common early manifestations are spontaneous abortion, stillbirth, encephalitis, generalized skin rash, rhinitis (“snuffles”), hepatic dysfunction, consumption coagulopathy, multiple organ failure

• Later manifestations, usually not apparent at birth, include osteitis of long bones, maxillofacial and dental malformations, keratitis, neurosensory hearing loss, and chronic neuropsychological deficits

LABORATORY DIAGNOSIS

Identification of T. pallidum

• T. pallidum cannot be grown in vitro; no culture test exists

• Detection depends on visual, antigenic, or genetic detection

• Visualization requires darkfield or phase microscopy, or special staining techniques (e.g., silver stain, immunofluorescence)

Darkfield Microscopy

• Suitable specimens include saline-mounted scrapings from chancre or mucocutaneous lesion of secondary syphilis, or lymph node aspirate

• Identification of motile spirochetes typical of T. pallidum: 10–13 μm in length, one spiral turn per μm, characteristic rotational motility and flexion

• Performance of darkfield microscopy is poor for oral and anorectal lesions owing to frequent commensal spiral organisms with appearance similar to T. pallidum

Immunologic and Genetic Detection

• Polyclonal fluorescent antibody test is a specific and moderately sensitive substitute for darkfield microscopy, but not widely avaialable

• Sensitive and specific fluorescent mononclonal antibody and polymerase chain reaction (PCR) assays have been developed, but to date not commercially available.

Histopathology

• Silver stain or immunofluorescence microscopy of infected tissues

• Insensitive but specific, sometimes diagnostic

Serology

• Serological antibody tests are the mainstay of laboratory diagnosis for all stages of syphilis other than primary

Nontreponemal Tests

• Venereal Disease Research Laboratory (VDRL) test and variants, including rapid plasma reagin (RPR) and toluidine red unheated serum reagin test (TRUST)

• Descendents of the earliest serological tests (e.g., Wassermann)

• Detect antibody to cardiolipin (diphosphatidylchonine), a component of normal mammalian cell membranes and incorporated into T. pallidum

• Sensitive for all stages except primary syphilis

• Nonspecific; positive results require confirmation with a treponemal test

• Titer varies with activity of infection; useful to assess therapeutic response

Treponemal Antibody Tests

• Antibody to T. pallidum-specific antigens

• Agglutination tests, e.g. T. pallidum particle agglutination (TPPA), T. pallidum hemagglutination

(TPHA), and microhemagglutination assay for T. pallidum (MHA-TP)

• Fluorescent treponemal antibody-absorbed (FTA-ABS) is historic gold standard; labor-intensive and now infrequently employed, but remains useful when other tests give uncertain results

• Enzyme immunoassay (EIA), easily automated and suitable for efficient testing of large numbers of specimens; now widely available and increasingly used for screening

• Rapid assays using fluid flow technologies (e.g., dipstick); not yet commercially available in the United States

Use and Interpretation of Serological Tests

For most of the twentieth century, initial diagnostic testing and serological screening were undertaken with a nontreponemal assay such as VDRL, RPR, or TRUST. Newly positive results with these tests

require confirmation with a T. pallidum-specific antibody test such as MHA-TP, TPPA, or FTA-ABS. However, in recent years the development and rapid adoption of low-cost, high-throughput T. pallidum-specific tests using EIA and other technologies, and rapid dipstick testing in some settings, have led to use of treponemal assays for screening and initial diagnostic testing. RPR, VDRL, and TRUST retain their historic advantage of easy quantitation by dilutional titer, required for clinical staging and to monitor the response to therapy. Thus, the historic testing sequence often is now reversed: a T. pallidum-specific test such as EIA is performed first, followed by quantitative VDRL, RPR, or TRUST to assess disease activity.

Regardless of testing sequence, persons with newly positive results on either type of test typically require repeat testing with the alternate method.

The nontreponemal tests become reactive during primary syphilis, and about 70% of persons with primary syphilis have positive results. The nontreponemal titer peaks in the secondary stage, usually at a titer of 1:16 to 1:256, and declines thereafter, typically falling to 1:4 or lower in untreated late-latent infection.

The titer usually rises again if there is progression to tertiary syphilis, although exceptions are frequent and some patients with tertiary disease have low titers. Nontreponemal reactivity declines in response to successful treatment. For successfully treated primary and secondary syphilis, the titer declines by at least 2 dilutions (e.g., from 1:16 to 1:4, or from 1:64 to 1:16 or lower) within 3 months, and in 90% of patients the VDRL/RPR becomes negative by 12 months. In late syphilis, by contrast, low titers (usually 1:1–1:4) may persist after successful treatment. VDRL and RPR titers often vary from one another by one or two dilutions, and it is important that the same test, preferably performed in the same laboratory, be used to follow the serological response to treatment.

Biological false-positive results (i.e., reactive VDRL, RPR, or TRUST with negative treponemal test results) occasionally occur, often associated with pregnancy or immunologic disorders; the titer usually is 1:8 or lower. Classical biological false-positive results probably will become less common as T. pallidum-specific EIAs or other tests are used for initial screening; with negative results, nontreponemal testing will not be performed.

The treponemal tests FTA-ABS, MHA-TP, and TPPA revert to negative in up to 25% of persons treated for primary syphilis, but they remain positive indefinitely when treatment is delayed to the secondary stage or later. Once a treponemal antibody test is positive, repeat testing rarely is indicated; only the quantitative nontreponemal tests are used to monitor disease activity. Beyond the primary stage, active syphilis is rare if the VDRL or RPR test is negative. However, the duration and durability of seropositivity by EIA and other newer treponemal antibody tests have not been rigorously studied. Therefore, the clinical status, prognosis, and need for treatment are unknown among persons screened for syphilis and found to have reactive EIA but negative VDRL, RPR, or TRUST, especially in those seemingly at lifelong low risk for syphilis. Many such patients also have negative results with MHA-TP, TPPA, and FTAABS, creating diagnostic and therapeutic dilemmas, especially in persons seemingly at low risk for syphilis. Research to resolve these uncertainties is a high priority.

Cerebrospinal Fluid Examination

Neurosyphilis is the most common complication of syphilis and occurs primarily during early syphilis <1 year in duration. Examination of cerebrospinal fluid (CSF), obtained by lumbar puncture, is the primary diagnostic tool. No “gold standard” for CSF diagnosis of neurosyphilis exists. Reactive CSF–VDRL is highly specific and considered proof of neurosyphilis, but is insensitive, missing a substantial proportion of cases. Elevated CSF mononuclear leukocytes or CSF protein are strong indicators of probable neurosyphilis in patients with positive blood tests for syphilis. T. pallidum-specific serological tests on CSF (e.g., TPPA or FTA-ABS) are believed to be nonspecific and do not confirm a diagnosis of neurosyphilis. Clinicians evaluating patients for neurosyphilis are encouraged to consult with an expert. The primary indications for CSF examination are neurological symptoms or signs in persons with syphilis of any stage or duration. CSF examination also is indicated for patients whose VDRL or RPR titer does not decline at least 2 dilutions after treatment of syphilis, because low-dose penicillin (i.e., benzathine penicillin) may not eradicate T. pallidum sequestered in the central nervous system. For patients with syphilis >1 year in duration, without neurological symptoms, indications for CSF examination are VDRL or RPR titer ≥1:32; HIV infection; other signs or symptoms of active syphilis; or planned treatment with an antibiotic other than penicillin. Whether CSF examination should be routine in some patients with syphilis <1 year in duration, absent neurological symptoms or signs—i.e., to detect subclinical neurosyphilis and provide enhanced therapy, especially in HIV-infected patients—is a matter of current debate.

TREATMENT

Principles

Antibiotic levels sufficient to inhibit T. pallidum should be maintained in blood and infected tissues for at least 10 days for early syphilis and 4 weeks for late syphilis. The organism remains exquisitely sensitive to penicillin, which is rapidly treponemacidal, and penicillin G remains the drug of choice for all stages of the disease. Other penicillins, such as ampicillin and amoxicillin, are active but require multiple dose daily treatment for prolonged periods, making compliance difficult, and few clinical studies have documented clinical efficacy. Doxycycline and other tetracyclines are somewhat less active against T. pallidum, but owing to favorable pharmacokinetics and dosing frequency, they usually are used when penicillin cannot be given. Ceftriaxone is highly active against T. pallidum and sometimes is used when penicillin cannot be given, but clinical experience is limited. Azithromycin is an attractive oral treatment alternative that has proved effective against early syphilis in single 2.0 g doses. Unfortunately, the frequency of T. pallidum strains resistant to the macrolide antibiotics, once rare, is rising in some geographic areas, including parts of North America and Europe. Azithromycin may be useful in selected settings where resistance has not yet emerged, but all macrolides should be used with great caution, if at all, in most clinical settings. Most other antibiotic classes, including the fluoroquinolones, sulfonamides, and aminoglycosides, have no antitreponemal activity.

Many patients with early syphilis and a few with late syphilis experience Jarisch-Herxheimer reactions soon after onset of treatment, with fever, chills, malaise, headache, and sometimes increased prominence of the chancre, skin rash, or lymphadenopathy. The reaction is believed to result from release of treponemal antigens following rapid killing of T. pallidum; it typically begins 6–12 hours after treatment and resolves within 24 hours. Nonsteroidal anti-inflammatory drugs such as ibuprofen may speed symptomatic relief

Recommended Regimens

Primary, Secondary, and Early Latent Infection

Treatment of Choice

• Benzathine penicillin G 2.4 million units IM, single dose

Alternative Regimens for Penicillin-allergic Patients

• Doxycycline 100 mg PO bid for 2 weeks

• Tetracycline HCl 500 mg PO qid for 2 weeks

• Alternative regimens should be avoided for HIV-infected patients; those allergic to penicillin should

be desensitized and treated with penicillin

Late Syphilis (>1 Year Duration), Except Neurosyphilis

Treatment of Choice

• Benzathine penicillin G 2.4 million units IM once weekly for 3 doses

Alternative Regimens

• Doxycycline 100 mg orally bid for 4 weeks

• Tetracycline HCl 500 mg orally qid for 4 weeks

Neurosyphilis

Treatment of Choice

• Aqueous penicillin G 3–4 million units IV every 4 hours for 10 to 14 days

Alternative Regimen

• Procaine penicillin G 2.4 million units IM once daily, plus probenecid 500 mg PO qid, for 10–14 days

• Only penicillin is known to be effective; penicillin-allergic patients should be desensitized and treated with penicillin

Syphilis in Pregnant Women

• Treat with penicillin, appropriate to clinical stage

• Allergic patients should be desensitized and treated with penicillin

• Tetracyclines are contraindicated in pregnancy and erythromycin does not treat fetal infection

Congenital Syphilis

• Treatment issues are complex

• Treat with penicillin in consultation with an expert

Follow-up

Primary, Secondary, and Early Latent Syphilis

• Reexamine and obtain quantitative VDRL, RPR, or TRUST 1, 3, 6, and 12 months after treatment or until negative

• If VDRL, RPR, or TRUST remains reactive at any titer, repeat at 6- to 12-month intervals for 1–2 years

Late Syphilis

• Reexamine and obtain quantitative VDRL, RPR, or TRUST after 3, 6, and 12 months

• If test remains reactive at 12 months, repeat at 12-month intervals for 2–3 years

HIV-infected Patients

• Reexamine and obtain quantitative VDRL, RPR, or TRUST 1, 2, 3, 6, 9, 12, and 24 months after

treatment, even if test becomes negative before 24 months

Neurosyphilis

• Follow as appropriate for stage and HIV status

• If CSF abnormal before treatment, repeat CSF examination at 6-month intervals until cell count is within normal limits and CSF–VDRL negative

Management of Sex Partners

• Examine and obtain serologic tests for syphilis for all sex partners exposed during infectious period,

usually from exposure to start of treatment

• Treat seronegative partners who have had sex with an infectious case within preceding 3 months, using benzathine penicillin or other regimen effective against early syphilis

• In the United States and western Europe, local or regional health authorities usually will assist in identifying and notifying partners

PREVENTION

Screening

• Routine serology for persons at risk, especially those with characteristics of core transmitters

• Most states and many countries’ public health authorities recommend or require testing of all pregnant women

Reporting

• Required by law in all states in the United States and regional health authorities in most industrialized countries

• Reporting and epidemiologic analysis are instrumental to allocate resources, target prevention programs, and facilitate counseling and partner management services.

5–1. Chancre of penis in primary syphilis

CASE

Patient Profile Age 25, MSM, computer programmer

History Painless sore on penis for 10 days; frequently has sex with anonymous partners; “usually” uses condoms for anal but not oral sex; negative test for HIV 3 months earlier

Examination Indurated, nontender ulcer of penis, without purulent exudate; bilateral inguinal

lymphadenopathy with 2- to 3-cm rubbery, slightly tender nodes

Differential Diagnosis Classic chancre is highly specific for syphilis, but consider herpes and chancroid; slim possibility of cancer, pyogenic infection, and other nonsexually transmitted conditions

Laboratory Darkfield microscopy positive for T. pallidum; stat RPR positive; VDRL positive (titer 1:8), TPPA reactive; lesion culture for herpes simplex virus (negative); rectal NAATs for N. gonorrhoeae and C. trachomatis, pharyngeal culture for N. gonorrhoeae (all negative); HIV serology (negative)

Diagnosis Primary syphilis

Treatment Benzathine penicillin G 2.4 million units IM

Management of Partners Patient interviewed by health department counselor; no identifiable partners

Comment Classic presentation of primary syphilis; treatment would have been warranted even if darkfield and serological tests for syphilis had been negative; patient counseled about HIV risks and

prevention; follow-up syphilis serology scheduled after 1, 3, 6, and 12 months.

5–2. Two penile chancres in primary syphilis

CASE 2:

Patient Profile Age 32, married assembly line worker with 4-year history of recurrent genital herpes

History Two penile sores 3 weeks; “I thought my herpes was back”; treated 5 years previously for secondary syphilis; occasional anonymous sex with other men in bars or parks

Examination Two indurated, slightly tender penile lesions, with firmly adherent white exudate; bilateral, shotty, nontender inguinal lymphadenopathy

Differential Diagnosis Primary syphilis, recurrent herpes, possible chancroid

Laboratory Darkfield examination positive for spirochetes; stat RPR positive; VDRL reactive, titer 1:64; HSV culture negative; HIV serology negative

Diagnosis Primary syphilis

Treatment Benzathine penicillin G 2.4 million units IM

Management of Partners Patient referred his wife, in whom VDRL was negative; treated with benzathine penicillin G

Other Presentation with two lesions, past history of genital herpes, and the purulent-appearing exudate suggested possibility of genital herpes, but herpes rarely persists for >2 weeks, and multiple chancres occasionally occur in syphilis. A confirmatory treponemal antibody test (e.g., TPPA) was not done, because positive results would be expected due to prior secondary syphilis. The patient was scheduled for repeat HIV serology after 3 months and, at his request, was referred for professional counseling to address his compulsive risky sexual behavior.

5–3. Primary syphilis: darkfield-positive chancre;

atypically tender, nonindurated lesion.

CASE 3

Patient Profile Age 22, unemployed, crack cocaine addict; denied commercial sex but in past years “sometimes” accepted money or drugs from partners

History Painful genital sore for 5 days; only recent sex partner was her boyfriend, who also used cocaine

Examination Superficial, tender ulcer of vestibule; no lymphadenopathy or skin rash

Differential Diagnosis Genital herpes, chancroid, syphilis, trauma; less likely considerations included Behçet disease, Stevens-Johnson syndrome, and others

Laboratory Darkfield microscopy positive for T. pallidum; stat RPR (negative); lesion culture for HSV (negative); cervical cultures for N. gonorrhoeae and C. trachomatis (both negative); HIV serology negative

Diagnosis Primary syphilis

Treatment Benzathine penicillin G 2.4 million units IM

Partner Management Partner was referred and found to have latent syphilis of unknown duration,

with VDRL tier 1:16 and reactive TPPA; treated with benzathine penicillin G

Comment The clinical presentation suggested herpes or chancroid, based on the painful, tender, nonindurated genital ulcer, illustrating the nonspecific nature of some chancres. Up to 40% of patients with primary syphilis present before developing reactive serological tests, especially if tested within 2 weeks of onset. The patient was advised to return for follow-up syphilis serology testing after 1, 3, 6, and 12 months.

5–4. Condylomata lata in secondary syphilis;

such lesions contain large numbers of T. pallidum

(often darkfield-positive) and are highly

infectious.

CASE 4

Patient Profile Age 19, single beautician

History Referred for consultation because of genital and perianal warts of 6 weeks’ duration, not responding to weekly applications of podophyllin; 3 sex partners in previous 6 months; unconfirmed history of “severe reaction” to penicillin in early childhood

Examination Several flat, firm, slightly erythematous papular excrescences of perineum and perinatally; some perianal lesions superficially ulcerated; bilateral nontender inguinal lymphadenopathy; oral examination and skin of scalp, trunk, and extremities normal

Differential Diagnosis Secondary syphilis, genital warts, herpes

Laboratory Darkfield microscopy negative; stat RPR positive; VDRL positive, titer 1:128; TPPA positive; HIV serology, PCR for HSV, NAATs for C. trachomatis and N. gonorrhoeae (all negative)

Diagnosis Secondary syphilis with condylomata lata

Treatment Doxycycline 100 mg PO bid for 2 weeks

Partner Management Two of the patient’s 3 recent sex partners located and treated; one had latent

syphilis of unknown duration and the other was uninfected; third was not located

Comment The diagnosis was delayed because syphilis serology was not done because the referring clinician believed the patient had genital warts due to HPV. Doxycycline was prescribed because of history of penicillin allergy. All lesions resolved within 1 week. Follow-up syphilis serology was scheduled at 1, 3, 6, and 12 months.

5–5. Secondary syphilis rash of penis and palms.

CASE 5

Patient Profile Age 36, unemployed, IV drug user

History Painless, nonpruritic rash of hands, trunk, and penis for 3 months; anorexia with 10-lb weight loss; recalled a penile sore “a few months ago” that went away; “several” female sex partners in past year

Examination Slim, ill-appearing; papulosquamous eruption of trunk, genitals, extremities, palms, and soles; generalized nontender lymphadenopathy (cervical, inguinal, supraclavicular)

Differential Diagnosis Secondary syphilis, pityriasis rosea, viral syndrome, allergic rash, HIV infection

Laboratory Stat RPR positive; VDRL reactive, titer 1:512; TPPA positive; HIV serology positive; HIV viral load 1.2 million, CD4 lymphocyte count 320 cells per mm3; underwent lumbar puncture for CSF examination: cells and protein normal, CSF–VDRL negative

Diagnosis Secondary syphilis; HIV infection

Treatment Benzathine penicillin G 2.4 million units IM, single dose

Partner Management Patient cooperated with health department counselor to identify, locate, and treat three sex and/or needle-sharing partners; one had latent syphilis, unknown duration (VDRL titer 1:4); all were HIV negative

Comment The rash cleared promptly after penicillin therapy, but lymphadenopathy persisted and was

judged as resulting from HIV rather than syphilis. CSF examination was undertaken in light of recommendations by some experts that asymptomatic neurosyphilis be excluded in HIV-infected patients with nontreponemal antibody titer ≥1:32 and CD4 count <350 cells per mm3. Follow-up syphilis serology at 1, 2, 3, 6, 9, 12, and 24 months.

5–6. Treponema pallidum. a. Viewed by darkfield microscopy. b. Stained with

luorescein-conjugated monoclonal antibody to T. pallidum, with

Evans Blue counterstain, viewed by fluorescence microscopy.

5–7. Rapid plasma reagin (RPR) card test. Reactive serum (left) shows agglutination of carbon particles; control specimen (right) shows no agglutination. The RPR card test requires 10 minutes to perform. (Enlarged view; circles on RPR card are 1.5 cm in diameter.)

5–8. Primary syphilis: multiple chancres of the penis, under the retracted foreskin. Multiple chancres
occasionally occur, perhaps with increased frequency in moist areas such as the preputial sac. Pearly
penile papules also are present on the corona

5–9. Primary syphilis: atypical hypertrophic chancre of cervix. The patient presented

with a complaint of postcoital bleeding and was initially thought to

have cervical carcinoma, but syphilis was confirmed by darkfield examination,

serology, and rapid resolution of the lesion following benzathine penicillin G.

5–10. Primary syphilis: darkfieldpositive perianal chancre, atypically
nonindurated.

5–11. Primary syphilis: chancre of lower lip.
Although less common than genital or perianal lesions, oral chancres are not rare.

Primary and secondary syphilis in a man with AIDS, showing two darkfield-positive chancres

5-12. Primary and secondary syphilis in a man with AIDS, showing

two darkfield-positive chancres (white arrows)

and papular lesions of secondary syphilis (black arrows).

The patient also had a generalized maculopapular rash

consistent with secondary syphilis and VDRL was reactive at a

titer of 1:64. Anecdotal reports suggest that progression from primary to

secondary syphilis sometimes may be accelerated in HIV-infected patients.

5–13. Secondary syphilis: papular eruption of penis and scrotum.

Depigmented lesions are common in dark-skinned persons.

5–13. Secondary syphilis: papular eruption of penis and scrotum.

Depigmented lesions are common

in dark-skinned persons.

5–15. Secondary syphilis: papular rash of the sole of the foot.

5–16. Secondary syphilis: extensive hyperkeratotic plantar rash in an HIV-infected man with secondary syphilis. Note similarity to keratoderma blennorrhagica of reactive arthritis