Sexually Transmitted Diseases: Syphilis PDF

26 Sexually Transmitted PA RT Diseases Chapter 1...

26 Sexually Transmitted PA RT Diseases Chapter 170 :: Syphilis :: Susan A. Tuddenham & Jonathan M. Zenilman interest and importance to dermatologists, especially AT-A-GLANCE as morbidity from syphilis rises in the developed world and continues in the developing world. A disease caused by the spirochete Treponema pallidum subspecies pallidum that is almost exclusively sexually transmitted. In the United States, syphilis disproportionately HISTORICAL PERSPECTIVE affects men who have sex with men and African Whether syphilis arose in the New World, the Old American heterosexual communities. World, or both remains a controversial subject. 1-3 The most common and recognizable manifestations Pandemics of syphilis began in the Old World in are usually cutaneous. Naples, Italy, 1 year after Columbus returned from Syphilis passes through 4 distinct clinical phases: the New World. 2,4,5 Syphilis earned the monicker “great pox,”5 to distinguish it from another viru- Primary stage, characterized by a chancre. lent disease with cutaneous manifestations, small- Secondary stage, characterized typically by skin pox. The disease takes its name from a poem, called eruption(s) with or without lymphadenopathy Syphilis, Sive Morbus Gallicus (Syphilis, or the French and organ disease. Disease), written in 1530 by Giralomo Fracastoro, A latent period of varied duration, characterized by a physician and poet of Verona. Part of the poem the absence of signs or symptoms of disease, with recounts the story of a shepherd, named Syphi- only reactive serologic tests as evidence of infection. lus, who, as punishment for angering Apollo, was Tertiary stage, with cutaneous, neurologic, or afflicted with the disease known as syphilis.4 Other cardiovascular manifestations. names besides Morbus Gallicus and the Great Pox Neurosyphilis and ophthalmic syphilis can occur by which the disease has been known include lues, at any stage. the Great Mimic, the Great Masquerader, the Great Imitator, and the Neapolitan disease.4 The cause The recommended treatment for most types of of syphilis, the bacterium T. pallidum, was discov- syphilis is benzathine penicillin G, with dose and ered by Schaudinn and Hoffman in 1905.6 Darkfield administration schedule determined by disease stage. microscopy was pioneered in 1906 by Landsteiner, Any patient diagnosed with syphilis should be and serologic testing for syphilis was pioneered in tested for other sexually transmitted infections, 1910 by Wasserman.5 including HIV. Because of the skin manifestations, syphilis his- torically has been of major interest to dermatologists, who were leaders in syphilis research and treat- DEFINITIONS ment in Europe and the United States, especially in the prepenicillin era.7-12 One of the leading American Syphilis is a sexually transmitted infection caused dermatology journals, currently called Archives by Treponema pallidum subspecies pallidum. Many of Dermatology, was before 1955 called Archives of of its manifestations are cutaneous, making it of Dermatology and Syphilology. An editorial explaining Kang_CH170_p3145-3172.indd 3145 04/12/18 3:05 pm 26 the jettisoning of “Syphilology” from the journal’s title stated: prevention and control, emphasizing screening, treat- ment, community involvement, and education.22,24 The diagnosis and treatment of patients with syphilis is Penicillin was first used to treat syphilis in 1943, and no longer an important part of dermatologic practice. became widely available in the postwar era.5 As a The papers on syphilis that are now submitted to the result of effective treatment, syphilis incidence then Archives are few and far between. Few dermatologists declined sharply in the 1950s, followed by a modest now have patients with syphilis; in fact, there are decid- rebound through the mid-1980s. In the late 1980s and edly fewer patients with syphilis, and so continuance of early 1990s syphilis reemerged in the United States the old label, “Syphilology,” on this publication seems in the South and in large cities, disproportionately no longer warranted. affecting black Americans, and associated with crack Elsewhere in the world, however, the link between cocaine and commercial sex workers.2,25 The waning of dermatology and syphilology (and other sexually the crack epidemic and development of the National transmitted diseases) remains stronger.13,14 Plan to Eliminate Syphilis from the United States, Treatments for syphilis in the prepenicillin era released in 1999 by the Centers for Disease Control Part 26 included burning sores with hot irons, rubbing and Prevention (CDC), resulted in declining rates in mercury-containing ointments (calomel) on lesions, heterosexuals.26 However, since the late 1990s, there administering mercury orally, and treating with arseni- has been a dramatic increase in incidence in men who cals, including salvarsan (also called “606” or arsphen- have sex with men in the United States and other :: amine), which was the first systemic treatment and developed countries. Sexually Transmitted Diseases was discovered by Ehrlich and Hata in 1909.5 Arsenical and other heavy metal-based therapies required multi- ple injections for at least a year, and were highly toxic. Recognition that T. pallidum was heat sensitive led the EPIDEMIOLOGY Viennese psychiatrist Julius Wagner von Jauregg to In 2000 and 2001, the rate of reported primary and develop syphilis malariotherapy in 1917,15 an accom- secondary syphilis in the United States was the plishment for which he received the Nobel Prize in lowest it had been since reporting began in 1941, at Medicine in 1927.16 That therapy involved inoculating 2.1 cases per 100,000 population. Unfortunately, syphi- syphilis patients with malaria, allowing them to expe- lis incidence in the United States has been increasing rience, optimally, between 10 and 12 febrile episodes, steadily since 2001; the rate of primary and second- and then treating them with quinine.10,16-18 The treat- ary syphilis (which is indicative of incident infec- ment reportedly led to complete or partial remission of tion) was 6.3 cases per 100,000 population in 2014, the neurosyphilis (general paresis) in a substantial propor- highest rate reported since 1994.27 The current syphi- tion of patients, although it killed an estimated 10% of lis epidemic in the United States has been primarily those receiving the therapy.17 driven by increasing cases among gay, bisexual, and Two studies have provided the most insight into the other men who have sex with men (MSM). Of 19,999 natural history of syphilis. The first was a retrospec- reported cases of primary and secondary syphilis tive study of approximately 2000 persons with syphilis in 2014, 12,226 (61.1%) were among MSM and 3,407 in Oslo, where mercury treatments standard in other (17.0%) were among men without information about places were not used.18 The second was the infamous the gender of the sex partner. Among male cases with Tuskegee syphilis study, in which 399 black men from information on gender of sex partner, 82.9% occurred Alabama who had late syphilis were prospectively in MSM.27 Incidence of syphilis and other sexually followed from 1932 to 1972.19 The men were denied transmitted infections among MSM had declined treatment for syphilis, even after the discovery of the during the AIDS epidemic, and the subsequent effectiveness of penicillin for the disease. There were increased incidence among MSM has been attributed multiple other serious ethical lapses in the study. The to a number of factors, including a decrease in safe aftermath of the study led to major changes in ethical sex practices resulting from successful HIV treat- requirements for conducting clinical research in the ments, use of the internet to meet sex partners, sero- United States.20 sorting (ie, attempting to choose sex partners who Of historical interest, persons said to have suffered share the same HIV status), and an increase in use from syphilis include Ivan the Terrible, Henry VIII, of recreational drugs, including methamphetamine Henri de Toulouse-Lautrec, and Al Capone,5 among and erectile dysfunction medicines.2,28,29 Studies that many others.21 Osler, aware of the high prevalence and led to the approval, in 2012, for the use of oral anti- protean manifestations of syphilis, has been quoted as retroviral medications for pre-exposure prophylaxis saying, “He who knows syphilis knows medicine.”5 By to prevent HIV acquisition in high-risk individuals the early 1930s, it was estimated that approximately generally did not report increased sexual risk behav- 10% of Americans had syphilis, with 500,000 new infec- ior or acquisition of sexually transmitted infections.30 tions and 60,000 cases of congenital syphilis per year.22 However, how widespread rollout of preexposure In 1937, Surgeon General Thomas Parran, keenly inter- prophylaxis may affect syphilis rates, particularly in ested in syphilis, published a book, titled Shadow on the MSM, remains to be seen.31 The epidemics of HIV and Land,23 that focused on the substantial public health syphilis in the United States MSM population have 3146 harms of the then-prevalent disease.22 Parran devel- been intimately linked. Not only are a high propor- oped and implemented a national program for syphilis tion of patients coinfected (in 2014, 51.2% of cases Kang_CH170_p3145-3172.indd 3146 04/12/18 3:05 pm  of reported primary and secondary syphilis among MSM were also HIV-positive),27 but incident syphi- TABLE 170-1 26 lis infection also is associated with a significantly Stages of Syphilis increased risk of HIV acquisition.32-34 All patients diagnosed with syphilis should be tested for the other Contact (one-third become infected) sexually transmitted infections, including HIV. Con- ↓ (10-90 days) versely, all patients diagnosed with HIV should also Primary (chancre) be tested for the other sexually transmitted infections, ↓ (3-12 weeks) including syphilis.35 Neurosyphilis Secondary Although rising syphilis incidence in the United can occur (mucocutaneous lesions, organ involvement) States is primarily attributable to cases in MSM, the (including general male and female populations are affected as ↓ (4-12 weeks) ocular syphilis) well. During 2013-2014, the primary and secondary Early latent → Relapsing (1/4) syphilis rate increased 14.4% in men and 22.7% in (1 year from contact) Chapter 170 :: Syphilis women.27 The increase in women has been particu- ↓ larly concerning because of a concomitant rise in Late latent (more than 1 year) reported cases of congenital syphilis. In 2015, the Continue late latent Tertiary (one-third) CDC released a report warning of a 38% increase (two-thirds) Late benign (16%) in reported cases of congenital syphilis between Cardiovascular (10%) 2012 and 2014. Although rates in all ethnic groups Neurosyphilis (5% to increased, the rate of congenital syphilis in blacks 10%) remained approximately 10 times the rate among whites in 2014.36 Rates of primary and secondary syphilis nationwide are highest in persons 20 to 29 years old. There is a different clinical (including cutaneous) manifestations. major health disparity; blacks are disproportionately Table 170-1 outlines the natural history of syphilis. affected by primary and secondary syphilis, with rates in 2014 more than 5 times higher than rates among non–Hispanic whites overall.27 Recently, there has been an increase in reported EXPOSURE AND cases of ocular syphilis. Between December 2014 and INCUBATING SYPHILIS March 2015, 12 cases of ocular syphilis were reported from San Francisco, California, and Seattle, Washing- Syphilis in adults is almost exclusively sexually acquired, ton. Several of these patients suffered severe sequelae, when a person comes in contact with infectious lesions including permanent vision loss. Subsequent case of syphilis on another person. Of note, these lesions are finding indicated more than 200 cases reported over only present during primary or secondary syphilis, so the past 2 years from 20 states. As a result, in October the infection is considered sexually transmissible solely 2015, the CDC released a clinical advisory calling for in these stages. Importantly, patients with early latent vigilance and careful screening for visual complaints syphilis (within the first year of infection) can relapse in any patient at risk for syphilis.37,38 into secondary syphilis and become infectious again.16 Internationally, morbidity from syphilis remains Infectious lesions of syphilis in adults, which include substantial. Each year an estimated 12 million new chancres, condyloma lata, and mucous patches, can be cases of syphilis occur, and 1 million pregnancies are present anywhere on the body but are typically located complicated by syphilis.2 in or around the genital, anal, or oral area. Direct con- tact with infectious lesions during oral, vaginal, or anal sex, or during other sexual activities, can result in inoc- CLINICAL FEATURES ulation and infection. Lesions on keratinized skin (eg, secondary syphilis palmoplantar lesions and maculo- When considering syphilis in the differential diagno- papular rash on the trunk) typically do not contain suf- sis in a patient, clinicians should take into account the ficient treponemes to be infectious, and prophylaxis for epidemiology and routes of transmission of the dis- persons exposed to noninfectious lesions such as those ease. This requires taking a complete sexual history. is neither necessary nor indicated. Infectious lesions Patients should be asked about partners (including of congenital syphilis include discharge from rhinitis gender and number of recent sexual partners), sexual (“snuffles”) and bullous lesions on the skin. practices (including anatomic exposure site and use Nonsexually acquired syphilis rarely occurs39 and of condoms), and past history of sexually transmit- when it does, it is usually via blood transfusion (of ted infections. Effective interviewing skills charac- unscreened blood),40 accidental inoculation in an occu- terized by respect and a nonjudgmental attitude are pational setting (eg, laboratory or health care worker)41 critical to obtaining an accurate assessment of behav- or nonoccupational setting (eg, tattooing),42 or through ioral risk.35 exposure in utero.43 Transmission to the fetus may Untreated syphilis is characterized by multiple dis- occur at any stage of maternal infection, although it is 3147 tinct stages of disease, each of which is associated with far more likely in the early stages of disease.16,44 Kang_CH170_p3145-3172.indd 3147 04/12/18 3:05 pm 26 Estimates of the risk of acquisition (“transmission efficiency”) of syphilis following sexual exposure to a person with infectious syphilis are varied and have been derived in 2 types of sources.45 The first source are data from 3 prospective placebo-controlled trials of prophylactic treatment, in which 9%,46 28%,47 or 63%48 of sexual contacts to syphilis acquired syphilis. The second source is from studies of persons identified as sex contacts in contact-tracing interviews of persons diagnosed with syphilis, in which 18% to 88% of con- tacts acquired syphilis.45 Nevertheless, the relatively high estimates of syphilis acquisition following expo- sure underscores the importance of prompt treatment and testing of sexual contacts, as discussed ‘Disease Figure 170-2 Early chancre on the penile shaft, demon- Part 26 Reporting and Management of Persons Exposed to Syphilis’ section. Persons recently exposed to and strating a clean base. infected with syphilis who have yet to manifest signs or symptoms of the disease are said to have incubating multiple chancres have been reported in 32% to 47% of :: syphilis. cases.51 The absence of any of the typical features of a Sexually Transmitted Diseases chancre does not rule out syphilis, however. Variations in clinical presentation can result from the number of PRIMARY SYPHILIS spirochetes inoculated, the patient’s immune status, concurrent antibiotic therapy, and impetiginization.52-54 Because they are typically painless, patients might not Primary syphilis is the first stage of syphilis, and is be aware of chancres, especially if painless and located characterized by the appearance of 1 or more chan- in areas that are not visible, such as the ventral uncir- cres. Treponemes in the cerebrospinal fluid (CSF) can cumcised penis, anus, vagina, cervix, or oral cavity.55,56 be demonstrated in up to 30% of primary and second- Common genital locations for a chancre in men ary syphilis cases.49 There may be overlap of second- include the glans, the coronal sulcus, and the ary syphilis or even neurosyphilis manifestations with foreskin.57,58 Retraction of the foreskin when a chancre primary syphilis. is present on the underside causes the foreskin to flip suddenly, a sign known as the dory flop, after the move- CUTANEOUS FINDINGS ment of a dory, a small wooden fishing boat, which flips suddenly when overturned.57 The dory flop sign At the inoculation site, a chancre develops after an can help distinguish chancres from other nonindu- incubation period that ranges from 10 to 90 days rated causes of genital ulcer disease, such as herpes (average: 3 weeks). The chancre starts as a dusky red simplex virus infection and chancroid, that present macule that evolves into a papule and then a round- without the induration that leads to the sudden flip to-oval ulcer (Figs. 170-1 to 170-4). The typical chancre, of the foreskin. Uncommon presentations include also called a Hunterian chancre or ulcus durum (hard giant necrotic chancre, phagedenic chancre (a deep, ulcer), ranges in diameter from a few millimeters to bright-red, necrotic ulcer with a soft base and exudate, 2 cm and is sharply demarcated with regular, raised resulting from secondary bacterial infection associated borders that are indurated, giving the lesion a carti- with immunosuppression), phimosis resulting from laginous feel. The base is usually clean, and the chan- cre is classically painless. Pain can be reported,50 and 3148 Figure 170-1 Early chancre presenting as a large oval ulcer Figure 170-3 Chancre on the penile shaft, demonstrating with elevated borders on the shaft of the penis. a clean base and elevated borders Kang_CH170_p3145-3172.indd 3148 04/12/18 3:05 pm  26 Figure 170-4 Chancres on the labia in a female. Chapter 170 :: Syphilis Figure 170-6 Chancre in the perianal area. Fecal material adherence of a chancre on the foreskin to the glans, is also present in the area. endourethral ulcers leading to swelling or serosangui- nous discharge, and balanitis.56,58 called monorecidive syphilis or chancre redux, arise in the Common genital locations in women include the setting of untreated or inadequately treated syphilis cervix, labia majora, labia minora, fourchette, urethra and are rare.71 and perineum (see Fig. 170-4).58,59 Chancres in women, Table 170-2 outlines the differential diagnosis of especially labial ones, can be more edematous than chancres. indurated.58 Edema indurativum is a unilateral labial swelling with rubbery consistency and intact surface, indicative of a deep-seated chancre. NONCUTANEOUS FINDINGS Extragenital chancres occur where there may be In 60% to 70% of cases of primary syphilis, painless exposure, and are most frequent in the oropharyngeal regional lymphadenopathy arises 7 to 10 days after the cavity.60,61 Syphilis can be transmitted via either recep- chancre appears, especially when the chancre’s loca- tive or active oral sexual exposure, and is seen in both tion is genital. Unilateral lymphadenopathy is more heterosexual and MSM.62,63 Oral lesions are often larger common earlier in the course of disease, with bilateral and may lack the indurated borders that are more typi- involvement later in the course.71 cal in keratinized tissues (Fig. 170-5). Anal sex can lead to development of chancres in the perianal (Fig. 170-6) or anal areas that can be difficult to detect on routine physical examination.50,64 Digital or other65,66 contact with the oral, genital, or anal areas, or receiving a bite SECONDARY SYPHILIS (eg, on the nipple during sex)67 can also lead to infec- Secondary syphilis is essentially an infectious vasculi- tion and chancre on the exposed area. tis, characterized by localized or diffuse mucocutane- The chancre heals in 3 to 6 weeks without treatment ous lesions, often with generalized lymphadenopathy, and 1 to 2 weeks with treatment. Scarring typically does in the presence of laboratory evidence from tissues or not occur, although thin atrophic scars may occur.55 sera consistent with syphilis.72 Cutaneous and mucosal Coinfection with herpes simplex virus or Haemophilus locations are most common.73 ducreyi, the causative organism of chancroid, can be present in rare cases.68-70 Relapses of primary syphilis, TABLE 170-2 Differential Diagnosis of Primary Syphilis Infectious Aphthous ulcer Chancroid Erosive candidal vulvitis or balanitis Granuloma inguinale Herpes simplex Lymphogranuloma venereum Vaccinia Noninfectious Basal cell carcinoma Behçet disease Fixed-drug eruption Squamous cell carcinoma Traumatic erosion or ulcer 3149 Figure 170-5 Chancre on the tongue. Kang_CH170_p3145-3172.indd 3149 04/12/18 3:05 pm 26 Part 26 Figure 170-9 Secondary syphilis lesions: multiple, hyper- pigmented scaly papules on the palms. :: Sexually Transmitted Diseases not pathognomonic for, syphilis. The face is typically spared in these generalized syphilids, although seb- orrheic dermatitis–like lesions around the hairline, termed the Crown of Venus or corona veneris, can form a Figure 170-7 Rash of secondary syphilis with nonscaling, crown-like pattern.55 Lesions are not usually pruritic,58 oval pink, ill-defined macules and patches on the trunk. although pruritus was reported in up to 40% of patients in one study.58 The presentation of the rash overall can CUTANEOUS FINDINGS be subtle or florid, or can develop from subtle mac- ules to more florid papules over time.75 Erythematous Lesions of secondary syphilis, classically called syphi- to copper-colored round papules or macules, well lids or, when affecting the skin, syphiloderms,58 typically demarcated and sometimes with an annular scale, are erupt 3 to 12 weeks after the chancre appears (up to present on the palms and soles in nearly 75% of cases 6 months after exposure). In some cases lesions of the (Figs. 170-9 to 170-12) and classically cross the palmar secondary syphilis develop while the chancre is still creases.51 Plantar lesions can be variously mistaken present,51,53 with overlap more common among HIV- for calluses (clavi syphilitici). Plantar lesions can also infected persons.53 Rash is present in nearly all cases of extend to the lateral and posterior aspects of the foot secondary syphilis, although the specific type of rash (Fig. 170-13). varies.51,52,74 Erythematous macules (roseola syphilitica) Other dermatologic manifestations include a or maculopapules are commonly present symmetri- patchy nonscarring alopecia, described as moth-eaten cally on the trunk and extremities in 40% to 70% of (see Fig. 170-11) or, less commonly, a diffuse alope- cases (Fig. 170-7), with papular, papulosquamous, or cia of the scalp. Loss of lateral third of the eyebrows lichenoid presentations less common.51,74 A white scaly can occur. Annular papules and plaques can be ring on the surface of papulosquamous lesions, called present around the mouth and nose, in a presenta- the Biett collarette (Fig. 170-8), is characteristic of, but tion colloquially referred to as “nickels and dimes” Figure 170-8 Papulosquamous syphilitic eruption with Figure 170-10 Secondary syphilis lesions: multiple, 3150 erythematous, well-demarcated, flattened plaques cov- hyperpigmented papules with more pronounced scale on ered with scales (Biett collarette). the palms. Kang_CH170_p3145-3172.indd 3150 04/12/18 3:05 pm  26 Figure 170-11 Secondary syphilis lesions on palm and Chapter 170 :: Syphilis moth-eaten alopecia of secondary syphilis. Figure 170-15 Papules of secondary syphilis on the penis. (Fig. 170-14).58 Papules and plaques, sometimes annular and occasionally papulosquamous, also can be present on the penis and scrotum (Fig. 170-15). Mucous patches are white-to-yellow erosions on the Figure 170-12 Secondary syphilis lesions on sole of foot. tongue that efface lingual papillae (Fig. 170-16).58 Confluence of mucous patches on the tongue has been termed plaques fauchée en prairie. Mucous patches can be present elsewhere in the oral cavity (Fig. 170-17), on other mucous membranes (such as on the genita- lia), or at the corners of the mouth, where they appear as “split papules,” with an erosion traversing the cen- ter (Fig. 170-18). Mucous patches are teeming with Figure 170-13 Plantar lesions of secondary syphilis extending to the lateral aspect of the foot. Figure 170-14 Annular plaques of secondary syphilis on Figure 170-16 Mucous patches of the tongue in secondary 3151 the face, colloquially referred to as “nickels and dimes.” syphilis. Note lack of typical lingual papillae in affected areas. Kang_CH170_p3145-3172.indd 3151 04/12/18 3:05 pm 26 Part 26 Figure 170-19 Condyloma lata, presenting as moist pap- ules in the perineum. :: Sexually Transmitted Diseases Figure 170-17 Mucous patches on hard palate. spirochetes and, hence, highly infectious. Also highly infectious are condyloma lata, which present as moist, flat, well-demarcated papules or plaques with macerated or eroded surfaces in intertriginous areas, Figure 170-20 Condyloma lata, presenting as moist, flat- commonly in the labial folds in females or in the peri- topped plaques on the buttocks. anal region in all patients (Figs. 170-19 to 170-21).58 However, any moist intertriginous area of the body can harbor condyloma lata, including the axillae, web spaces between toes, and the folds under breasts, umbilicus (Fig. 170-22) or an abdominal pannicu- lus. Mucous patches and condyloma lata have been reported in 8% and 17% of patients with secondary Figure 170-18 Split papule, a type of mucous patch of 3152 secondary syphilis that can be present at the angle of the mouth, with a characteristic slit traversing its center. Figure 170-21 Condyloma lata in a female. Kang_CH170_p3145-3172.indd 3152 04/12/18 3:06 pm  26 Figure 170-22 Moist papule in the umbilicus in secondary Figure 170-24 Multiple hyperpigmented papules of Chapter 170 :: Syphilis syphilis. secondary syphilis on the arm. Without treatment, the secondary stage typically syphilis, respectively.51 Malignant lues is a rare mani- recedes 4 to 12 weeks after it appears. Scarring typi- festation that presents as crusted or scaly papules and cally does not occur, although pigmentary changes plaques that can ulcerate or become necrotic, with an (leukoderma colli syphiliticum or, if on the neck, oyster shell-like surface (Fig. 170-23). These lesions, “necklace of Venus”) can result55 from inhibition of described as rupioid, are often seen in association melanogenesis. Dermal atrophy, possibly related to with high nontreponemal titers and systemic symp- elastin degradation, may occur. Absence of syphilids toms.76 Nail changes including fissuring, onycholysis, in cinnabar-containing red tattoos has been reported as Beau lines, and onychomadesis have been reported.55 well, possibly resulting from the antitreponemal effect Less-common presentations of secondary syphilis of mercury in cinnabar.81 include hyperkeratotic, lichenoid, nodular, follicu- lar, pustular, frambesiform, and corymbose erup- tions and palmoplantar keratodermas (Figs. 170-24 NONCUTANEOUS FINDINGS to 170-26).56,77-80 With the exception of mucous patches and condyloma lata, cutaneous manifestations of In addition to neurosyphilis (including ocular secondary syphilis do not contain a substantial num- syphilis),82 discussed in section “Neurosyphilis” ber of treponemes and, therefore, are not typically patients with secondary syphilis may experience sys- infectious. temic symptoms that include sore throat, malaise, The maculopapular rash of secondary syphilis can headache, weight loss, fever, musculoskeletal aches, resemble almost any generalized or localized macu- pruritus, and hoarseness.74 Pharyngitis and tonsillitis,83 lopapular eruption (Table 170-3); mucous membrane laryngitis,84 gastritis,85 hepatitis,85 renal disease (mem- lesions resemble mucosal manifestations of other der- branous glomerulopathy),86 and periostitis87 have all matoses, and syphilitic hair loss has to be separated been reported in secondary syphilis, as have hemato- from other etiologies of alopecias. logic abnormalities including lymphopenia, anemia, and elevated erythrocyte sedimentation rate.88 Lymph- adenopathy is common, and is often bilateral and sym- metric in distribution.58 Figure 170-23 Sharply marginated, necrotic ulcers of sec- ondary syphilis described as “rupioid,” covered by thick, Figure 170-25 Hyperkeratotic lesions of secondary syphi- 3153 dirty crusts (like oyster shells). lis on the soles. Kang_CH170_p3145-3172.indd 3153 04/12/18 3:06 pm 26 of primary and secondary (collectively termed early syphilis), whereas late syphilis requires an extended therapeutic course.35 Persons who acquired syphilis during the preced- ing year can be diagnosed with early latent syphilis. A patient can be classified as having early latent syphilis if, within the year preceding discovery of the reactive serologic test, the patient had 1 of the following: 1. Documented seroconversion or a sustained (longer than 2 weeks) fourfold or greater increase in nontreponemal test titers; 2. Unequivocal symptoms of primary or secondary syphilis; 3. A sex partner documented to have primary, sec- Part 26 Figure 170-26 Psoriaform lesions of secondary syphilis on ondary, or early latent syphilis; or the arm. 4. Reactive nontreponemal and treponemal tests if the patient’s only possible exposure occurred within the previous 12 months.35 :: LATENT SYPHILIS Sexually Transmitted Diseases To make a diagnosis of early latent syphilis based on the first or third criterion above, clinicians often need, The secondary stage is followed by an asymptomatic and should seek, the assistance of the local health stage with no clinical findings, with seroreactivity by department. Because syphilis diagnoses and results definition the only evidence of infection. So-called of reactive serologic tests for syphilis are reportable latent syphilis is a diagnosis of exclusion, after pri- in every state and territory of the United States, local mary, secondary, and tertiary syphilis (including or state health departments compile (or attempt to neurosyphilis) have been ruled out. Asymptomatic compile) records of all syphilis diagnoses and reactive patients who have acquired syphilis within the last serologic titers for persons residing in the jurisdiction. year are classified as having “early latent” infection.35 Clinicians can contact the “reactor desk” of their local The distinction between early latent and asymptomatic or state health jurisdiction, where syphilis diagnostic syphilis acquired more than 1 year ago (often termed and titer histories are maintained, to inquire about a late latent syphilis), is important for 2 reasons. First, patient’s titer history and prior diagnoses and treat- up to 25% of patients with early latent syphilis may ments, so that a patient can be staged as having early relapse into secondary syphilis, leading to possible latent syphilis according to the first criterion above. sexual transmission.16 Second, clinical management of Public health workers can also search diagnostic and patients with early latent syphilis differs from man- titer histories in their databases for the names of sex agement of patients with late latent syphilis.16,35 The partners identified by seroreactive patients, to enable treatment of early latent syphilis is the same as that staging patients with early latent syphilis under the third criteria above. Patients in whom the duration of infection cannot be established based on the criteria reference above TABLE 170-3 should be assumed to have late latent syphilis and Differential Diagnosis of the Maculopapular must be managed accordingly. Latent syphilis may Rash of Secondary Syphilis remain indefinitely or progress to the tertiary stage. Most Likely Drug eruption Pityriasis rosea TERTIARY SYPHILIS Psoriasis Viral eruption Late manifestations of syphilis are rarely seen. How- Differential for condyloma lata: Condyloma acuminata ever, historically, on the basis of information from the Consider Oslo and Tuskegee studies, approximately one-third of Balanitis patients with untreated latent syphilis progress to ter- Cutaneous T-cell lymphoma tiary syphilis, typically after 15 to 40 years, while the Dermatophytosis Eczema other two-thirds remain in latency.16 Tertiary syphilis Erythema multiforme manifestations may include gummas (granulomatous, Granuloma annulare erosive, nodular lesions which most commonly affect Lichen planus the skin and bones), and cardiovascular syphilis.35 Lupus erythematosus Although neurosyphilis can occur at any stage of dis- Sarcoid ease (see “Neurosyphilis” later), late manifestations of Vasculitis neurosyphilis are also considered to be a manifestation 3154 Vulvitis of tertiary syphilis. Kang_CH170_p3145-3172.indd 3154 04/12/18 3:06 pm  CUTANEOUS FINDINGS 26 The signs and symptoms of syphilis that occur after secondary syphilis that do not involve the cardio- vascular or nervous systems have historically been referred to as late benign syphilis. Lesions of late benign syphilis are caused by delayed-type hypersensitivity responses to the small number of treponemes pres- ent in the involved tissue or organ.54 The hallmark of late benign syphilis is the gumma, a granulomatous nodular lesion with variable central necrosis, which most commonly affect the skin or mucous membranes (80% of gummas).54 Gummas are nontender pink to dusky-red nodules or plaques that vary in size from Chapter 170 :: Syphilis millimeters to many centimeters in diameter. They favor sites of previous trauma and may arise anywhere on the body, but are more common on the scalp, fore- head (Fig. 170-27), buttocks, and presternal, supracla- vicular, or pretibial areas. The nodule is initially firm but develops a gummy consistency from accumulation of necrotic tissue. Gummas may grow both horizon- tally and vertically, and many assume geometric con- figurations. Small ulcers and abscesses may be present within the lesions. As the central gumma heals, new Figure 170-28 Aggressive gumma of the forehead caus- lesions may develop on the periphery, forming scal- ing destruction of the calvarium, mimicking advanced, destructive basal cell carcinoma. loped borders. In contrast to noduloulcerative lesions, gummas are deeper and more destructive (Fig. 170-28). Tissue necrosis eventuates in cylindrical, punched-out ulcers with clean granulomatous bases covered with leave thickened, pitted, ridged scars. Pseudochancre adherent yellow-white slough (Fig. 170-29). The ulcer redux refers to a solitary gumma of the penis. may enlarge, remain unchanged, or heal spontane- Gummas involving the mucous membranes typi- ously, even as the gumma enlarges. Superficial gum- cally affect the palate, nasal mucosa, tongue, tonsils, mas heal with atrophic scars, whereas deeper lesions and pharynx. The lesions ulcerate and can be disfigur- ing, as when they cause a saddle-nose deformity from destruction of nasal cartilage and bone, or perforation Figure 170-27 Disfiguring gummatous infiltration of Figure 170-29 Two deep, punched-out ulcers in the pop- the glabella and forehead with scattered ulcerations in a liteal fossa covered with an adherent yellow slough at the 3155 60-year-old woman with late benign syphilis. base. This is the classical appearance of nodular gummas. Kang_CH170_p3145-3172.indd 3155 04/12/18 3:06 pm 26 Part 26 :: Sexually Transmitted Diseases A B Figure 170-30 Destruction of the nasal cartilage and bone by a gumma leads to a saddle nose (A) and to the perforation of the nasal cartilage and skin and thus to considerable mutilation (B). of the nose or palate (Fig. 170-30).54 Gummas do not NONCUTANEOUS FINDINGS heal without appropriate antibiotic therapy, but in the setting of appropriate therapy respond briskly, leaving Besides the skin and mucous membranes, gummas scars.16 Chronic interstitial glossitis can develop even can affect practically any organ, but especially the after penicillin treatment and may undergo malignant bones, as well as the liver, heart, brain, stomach, and degeneration (Fig. 170-31). upper respiratory tract.16 When they involve critical Other manifestations of late benign syphilis affect- organs such as the brain, gummas can have serious ing the skin include granulomatous nodular and complications.91 noduloulcerative lesions and psoriasiform plaques.55 Historically, cardiovascular manifestations of ter- Nodular and noduloulcerative lesions are superfi- tiary syphilis affected 10% to 40% of those infected and cial, firm, painless, dull-red, shiny, flat nodules that were thought to be responsible for most deaths caused range in size from several millimeters to 2 cm. They by syphilis.16 Syphilis typically causes syphilitic aorti- appear in a grouped configuration, can coalesce into tis, leading to aortic regurgitation in 10% of individuals large plaques or ulcerate, and can resemble granuloma with untreated disease,92 and can also cause coronary annulare.89,90 Psoriasiform plaques are most commonly ostial stenosis and saccular aneurysm.93 T. pallidum seen on the arms, back, and face. DNA has been detected in an aortic aneurysm, dem- Table 170-4 outlines the differential diagnosis of der- onstrating that infection of the aorta leads to direct matologic manifestations of tertiary syphilis. damage to the tissue.94 TABLE 170-4 Differential Diagnosis of Tertiary Syphilis Consider Deep fungal infections Granulomatosis with polyangiitis (Wegener polyangiitis) Leishmaniasis Lupus vulgaris Lymphomas Metastatic carcinoma Psoriasis Sarcoid Sarcomas 3156 Figure 170-31 Premalignant, chronic, interstitial glossitis Vasculitis secondary to gummatous infiltration of the tongue. Kang_CH170_p3145-3172.indd 3156 04/12/18 3:06 pm  NEUROSYPHILIS OCULAR SYPHILIS 26 Although the syndromes may not always overlap, Infection of the CNS by T. pallidum can occur during ocular syphilis has generally been considered to be a any stage of infection. “Neuroinvasion,” in which subset of neurosyphilis, and as per CDC recommenda- T. pallidum disseminates to CSF and meninges, occurs tions should be clinically managed as such.35 Given the very early in syphilis.95 Neuroinvasion can be tran- recent increase in reported cases, clinicians should be sient, with the body clearing the infection, or more careful to ask about eye symptoms in evaluating any sustained, in which case it is called asymptomatic patient suspected to have syphilis. Ocular syphilis may neurosyphilis, defined by CSF abnormalities. Asymp- occur during any stage of infection, and may involve tomatic neurosyphilis, if discovered, is usually treated almost any portion of the eye. Chancres or gummas to prevent progression to symptomatic neurosyphilis, of the conjunctiva, conjunctivitis, and scleroconjuncti- although benefits of treatment for asymptomatic neu- vitis; syphilitic interstitial keratitis; anterior, posterior, rosyphilis are not well documented. and pan uveitis; multiple retinal complications includ- Chapter 170 :: Syphilis Early symptomatic neurosyphilis typically mani- ing retinal detachment, cataracts, and glaucoma, as fests as meningitis, resulting in meningismus, fever, well as optic nerve involvement (including papillitis, or cranial nerve abnormalities (especially cranial retrobulbar neuritis, optic atrophy, optic nerve gumma, nerves II, III, IV, VI, VII, and VIII), or meningovasculi- and various stroke syndromes) are among the clinical tis, resulting in meningitis with stroke, usually affect- syndromes that have been described. Furthermore, ing the portion of the brain supplied by the middle multiple manifestations of syphilis can be observed cerebral artery.95 Uveitis is the most common ophthal- in the eye, such as pupillary abnormalities (includ- mic manifestation of early neurosyphilis (see “Ocular ing the Argyll Robertson pupil), palsies of the third, Syphilis” below), presenting as eye pain, redness, fourth and sixth nerve, usually from syphilitic basilar and photophobia, and sensorineural hearing loss is meningitis, and focal gummas along the nerves, brain- the most common manifestation of otologic syphilis. stem infarction, or syphilitic aneurysmal compression Ophthalmic and otologic manifestations of early neu- or hemorrhage that may involve the optic and oculo- rosyphilis are managed in the same way as neurologic motor nerves. Syphilitic basilar meningitis or gum- manifestations.35,95 mas may cause a chiasmal syndrome with bitemporal Early symptomatic neurosyphilis is not uncom- hemianopia. Finally, eyelid chancres or condyloma lata mon. A review of syphilis cases among HIV-infected of the eyelids have been described, although these do men in 4 large U.S. cities during 2002 to 2004 showed not directly involve the eye.37,97-99 that almost 2%, including persons at each stage of infection, had symptomatic early neurosyphilis. Ocular abnormalities were most common among those affected, followed by other cranial nerve CONGENITAL SYPHILIS involvement, acute meningitis, other syndromes (headache, altered mental status, or both), and cere- Congenital syphilis results from infection in utero brovascular accidents. Of those with symptomatic with T. pallidum. Transplacental fetal infection can early neurosyphilis, nearly one-third had persistent occur at any time during pregnancy and at any stage neurologic deficits 6 months after receiving appro- of maternal infection.100 Probability of transmis- priate treatment.96 sion of infection depends on the stage of infection in The 2 syndromes commonly associated with late an untreated mother, ranging from 70% to 100% in neurosyphilis are general paresis of the insane, also primary syphilis, 40% for early latent syphilis, and known as dementia paralytica, and tabes dorsalis.95 10% for late latent syphilis.101 Because infection is General paresis presents as a rapidly progressive spread hematogenously, a chancre is not present on dementia, accompanied by personality changes. Tabes the fetus or infant.100 In 30% to 40% of cases, congenital dorsalis presents with sensory ataxia and bowel and syphilis results in stillbirth.43 Of infants who survive, bladder dysfunction, resulting from damage to the two-thirds are asymptomatic at delivery and only later posterior columns of the spinal cord. Tabes dorsalis develop symptoms.100 can be accompanied by an Argyll Robertson pupil Clinical findings in symptomatic infants are similar (which accommodates, but does not react to, light) and to congenital infections caused by cytomegalovirus, optic atrophy. These syndromes are now very rare in toxoplasmosis, herpes simplex virus, rubella, and the developed world. other infections.43 The most prominent manifesta- Clinicians diagnosing a person with syphilis tions of early congenital syphilis, defined as syphilis should perform a neurologic review of systems and in a child younger than 2 years of age, include fever, perform a neurologic examination. According to rash, hepatosplenomegaly, and persistent rhinitis CDC recommendations, indications for CSF exami- (“snuffles”).100 Hydrops fetalis (edema), lymphade- nation in persons with syphilis include neurologic, nopathy, neurosyphilis, leukocytosis, thrombocyto- ophthalmic, or otologic signs or symptoms; evidence penia, periostitis, and osteochondritis also may be of active tertiary syphilis; or treatment failure. HIV present, with the pain associated with osteochon- infection in-and-of-itself is not an indication for CSF drotic lesions causing the infant to refuse to move 3157 examination.35 the affected anatomic area (“pseudoparalysis of Kang_CH170_p3145-3172.indd 3157 04/12/18 3:06 pm 26 Figure 170-32 Bullous eruptions on the soles of a new- born with early prenatal syphilis. Bullae have ruptured and Part 26 now present as erosions (“syphilitic pemphigus”). Parrot”).43,100 If present at delivery, the rash is usu- :: ally bullous (“syphilitic pemphigus”; Fig. 170-32) and very infectious.100 Rash that presents at 2 weeks Sexually Transmitted Diseases or more after birth, however, is typically maculo- papular, with small copper-red lesions similar to lesions of secondary syphilis most commonly affect- ing the hands and feet.43 Desquamation and crusting Figure 170-34 Early prenatal syphilis in a newborn. The can then occur.102 Other cutaneous lesions present skin is dry and wrinkled, with a yellowish-brownish hue. can include condyloma lata (Fig. 170-33), mucous There is hemorrhagic rhinitis. This is what Diday described as “a little wrinkled potbellied (not seen here) old man with patches, fissures around the lips, nares, or anus, and a cold in his head.” Note also the aged appearance of the petechiae from thrombocytopenia.43 The skin of the fingers in this newborn. syphilitic neonate is often dry and wrinkled and, in newborns with fair skin, may have a café-au-lait hue (Fig. 170-34). peg-shaped notched central incisors (Hutchinson Late congenital syphilis is defined as disease occur- teeth; Fig. 170-36) and mulberry molars, resulting ring in a child who is at least 2 years old that typi- from syphilis vasculitis in developing tooth buds. cally manifests over the first 2 decades of life.43 Many Other manifestations include eighth nerve deafness manifestations of late congenital syphilis result from and eye abnormalities, including interstitial keratitis, damage caused during early infection and are not glaucoma, or corneal scarring. The Hutchinson triad reversible with treatment. Those manifestations refers to Hutchinson teeth, interstitial keratitis, and include scars (rhagades; Fig. 170-35) resulting from eighth nerve deafness.43 cutaneous fissures; a saddle-nose deformity, result- Of note, as with any sexually transmitted disease, ing from destruction of nasal cartilage; frontal bossing the diagnosis of syphilis in a child beyond the neonatal (Olympian brow), thickening of the sternoclavicular period should raise the question of child abuse.35 portion of the clavicle (Higoumenakia sign), anterior bowing of the midtibia (saber shins), and scaphoid scapula, all resulting from chronic periostitis; and Figure 170-35 Perioral rhagades are linear scars that result 3158 Figure 170-33 Hyperpigmented papules of syphilis in a from ulcerations that appear during early congenital syph- neonate. ilis and persist to adulthood. Kang_CH170_p3145-3172.indd 3158 04/12/18 3:06 pm  test results in the presence of HIV infection,117 especially with lower CD4 cell counts. Additionally, HIV-infected 26 persons with syphilis can experience “neurorelapse,” meaning the development of neurosyphilis following appropriate treatment for primary, secondary, or early latent syphilis, and declines in nontreponemal titers consistent with cure.95 HIV infection can sometimes complicate serologic diagnosis of syphilis and subsequent followup, as unusual serologic responses have been observed in HIV-infected persons with syphilis.35 False-negative Figure 170-36 The presence of small, notched, peg- serologic test results in the setting of the prozone shaped upper incisors (Hutchinson teeth) is also part of phenomenon118 and seronegative syphilis119 have the late congenital syphilis triad. been reported. Also, serofast reactions (ie, persistently Chapter 170 :: Syphilis reactive nontreponemal test results, even following appropriate treatment) can occur.120 When syphilis is suspected clinically and serology is nonreactive, skin SYPHILIS AND HIV biopsy can be useful diagnostically, as can darkfield microscopy35,121 or polymerase chain reaction (PCR)- INFECTION based assays for T. pallidum,68 if available. CDC treatment recommendations for syphilis do not Chap. 168 discusses cutaneous manifestations of the depend on HIV infection status, and are supported by HIV. limited data indicating that outcomes are not improved The interaction of syphilis and HIV infection is with more intense or prolonged treatment.29,35,122 Titers complex.29 The clinical presentation of syphilis varies in might decline more slowly in appropriately treated minor ways between HIV-infected and HIV-uninfected HIV-infected persons,29,35,123 particularly in those who persons.29 HIV-infected persons are more likely to have lower titers on initial diagnosis.124 Compared present with more than 1 chancre and with larger and with HIV-uninfected persons, HIV-infected persons deeper chancres in primary syphilis,53,103 and are more with primary or secondary syphilis should have more likely to manifest signs of secondary syphilis while at frequent followup (Table 170-5).35 least 1 chancre is present.53,104 Atypical and aggressive presentations of syphilis in HIV-infected persons might also be more common, although those presentations are not thought to be unique to HIV coinfection.29,103 ETIOLOGY AND Some studies have shown syphilis to transiently increase HIV viral load and decrease CD4+ T-cell PATHOGENESIS count during infection, with resolution following T. pallidum subspecies pallidum is a motile, spiral- treatment.105-111 Those changes might facilitate HIV shaped bacterium for which humans are the only natu- transmission by HIV-infected patients coinfected ral host.16 T. pallidum ranges in size from 5 to 16 µm in with syphilis.29,109 An effect of syphilis on progression length and is 0.2 to 0.3 µm in diameter.121 The bacterium to AIDS or mortality has not been found.112 Syphilis is surrounded by a cytoplasmic membrane, which also is associated with HIV acquisition,113 and all per- is itself enclosed by a loosely associated outer mem- sons presenting with syphilis who are not known to brane. Between those membranes lies a thin layer of be infected with HIV should be tested for HIV.35 The peptidoglycan, which provides structural stability and disruption of epidermal or mucosal barriers caused houses endoflagella, organelles that are responsible for by syphilis ulcers, and the migration to these lesions T. pallidum’s characteristic corkscrew motility. Micro- of inflammatory cells that are targets for HIV are scopically the bacterium is indistinguishable from 2 biologic mechanisms that might account for the syn- other pathogenic treponemes that cause nonvenereal ergy between the 2 infections. Common behavioral diseases, including T. pallidum subspecies endemicum factors (eg, lack of condom use) also likely contribute (bejel), T. pallidum subspecies pertenue (yaws), and to risk of coinfection. All HIV-infected persons enter- T. pallidum subspecies carateum (pinta). The T. pallidum ing HIV care should have a serologic test for syphi- genome, sequenced in 1998,125 is 1.14 Mb in length, lis, which should be repeated yearly thereafter in all relatively small for a bacterium.16 those who are sexually active, or more frequently The bacterium has very limited metabolic capabili- (every 3 to 6 months) if indicated (depending on risk ties, making it reliant on host pathways for many of behaviors).114 HIV infection also is associated with its metabolic needs.16,73 T. pallidum does not survive repeat syphilis infection.115 more than a few hours to days outside its host and can- Because of its effect on the immune system, HIV infec- not be cultured easily in vitro for sustained periods, tion is thought to increase risk of neurosyphilis.29,95 This complicating efforts to understand the organism.16,73 is based on studies correlating abnormal CSF findings Instead, it must be propagated in mammals, with with advanced HIV disease116 and failure to normalize rabbits the preferred species because, following testis 3159 CSF–VDRL (Venereal Disease Research Laboratory) inoculation, rabbits, unlike mice, experience disease Kang_CH170_p3145-3172.indd 3159 04/12/18 3:06 pm 26 TABLE 170-5 Centers for Disease Control and Prevention Recommendations for Treatment and Followup of Adults with Primary, Secondary, Early Latent, or Late Latent Syphilis.35 ALTERNATIVE TREATMENT TIME FRAME FOR PENICILLIN-ALLERGIC SCHEDULE FOR TO EXPECT STAGE OF DISEASE HIV STATUS OF RECOMMENDED PERSONS (NONPREGNANT FOLLOWUP AFTER FOURFOLD PERSON TREATMENTa WOMEN ONLYb) TREATMENTc DECLINE IN TITERd Primary or HIV-uninfected Benzathine penicillin G, Doxycycline 100 mg orally 6 and 12 months 6 to 12 months secondary 2.4 million units, adminis- twice daily for 14 days tered IM in a single dose HIV-infected Benzathine penicillin G, Doxycycline 100 mg orally 3, 6, 9, 12, and 6 to 12 months 2.4 million units, adminis- twice daily for 14 days 24 months tered IM in a single dose Part 26 Early latent HIV-uninfected Benzathine penicillin G, Doxycycline 100 mg orally 6, 12, and 24 months 12 to 24 months 2.4 million units, adminis- twice daily for 14 days after treatment tered IM in a single dose :: HIV-infected Benzathine penicillin G, Doxycycline 100 mg orally 6, 12, 18, and 12 to 24 months 2.4 million units, adminis- twice daily for 14 days 24 months Sexually Transmitted Diseases tered IM in a single dose Late latent (>1 year), HIV-uninfected Benzathine penicillin G: Doxycycline 100 mg orally 6, 12, and 24 months 12 to 24 months or latent of 3 doses of 2.4 million twice daily for 28 days after treatment unknown duration units IM given at 1 week intervals HIV-infected Benzathine penicillin G: Doxycycline 100 mg orally 6, 12, 18, and 12 to 24 months 3 doses of 2.4 million twice daily for 28 days 24 months units IM given at 1 week intervals a Initial treatment is the same for HIV-uninfected and HIV-infected persons. b Pregnant women must not be treated with doxycycline. If allergic to penicillin, pregnant women must be desensitized and then treated with benzathine penicillin G. c Some persons (eg, men who have sex with men or women who become pregnant) should be screened appropriately in addition to being followed at the recommended intervals to assess clinical and serologic response to treatment. d If titers have not declined fourfold after the stated time frame, consider reinfection or treatment failure (including treatment failure because of neurosyphi- lis). If at any time after treatment signs or symptoms of syphilis appear, also consider those same possibilities. manifestations.16,73 T. pallidum divides slowly, taking and CD8+ T cells predominate in lesions of second- from 30 to 50 hours in vitro. That slow reproduction ary syphilis.73 Infection leads also to elaboration of rate has important implications for treatment, which T-helper (Th)-1 cytokines, including interleukin-2 must be present in the body for a long period to assure and interferon-γ, although downregulation of the Th1 effectiveness against the bacterium.16 response during secondary syphilis, coincident with Following inoculation, T. pallidum attaches to host the peaking of antibody titers,73 might contribute cells, including epithelial, fibroblast-like, and endo- to the organism’s ability to evade the host immune thelial cells, likely by binding to fibronectin, laminin, response.54,127 Subtyping studies of T. pallidum have or other components of host serum, cell membranes, linked certain strains of the organism to neurosyphilis.128 and the extracellular matrix.16 It can invade rapidly The humoral immune response begins with produc- into the bloodstream—within minutes of inoculation, tion of immunoglobulin (Ig) M antibodies approxi- based on rabbit models—and can cross many barriers mately 2 weeks after exposure, followed 2 weeks in the body, such as the blood–brain barrier and the thereafter by IgG antibodies.126 IgM, in addition to IgG, placental barrier, to infect many tissues and organs. continues to be produced during infection and can lead That dissemination leads ultimately to manifestations to immune-complex formation.126 Antibody titers peak of syphilis distant from the site of the initial chancre(s) during bacterial dissemination in secondary syphilis.73 in an infected person and in a developing fetus.16 Some antibodies cross-react with other treponemal T. pallidum lacks virulence factors common to species, and some are specific for T. pallidum subspe- many other bacteria, including lipopolysaccharide cies pallidum. The immune response is somewhat active endotoxin.16 It does, however, produce a brisk immune against the organism, helping block attachment of the response, mediated by membrane lipoproteins,126 that organism to host cells, confe