Primary stage

The primary lesion develops 10–90 days after infection (median of 3 weeks) as an indolent papule, followed by surface necrosis and the typical well-circumscribed ulceration that is firm to palpation (chancre). It is accompanied by enlarged regional lymph nodes. Histopathologically, the microorganism is observed among cells typical of a Th1-predominant cellular response; the latter leads to macrophage activation and destruction of a large number of treponemes. Several pathogenic mechanisms have been proposed, including an antigenically inert treponemal cell surface, resistance to phagocytosis, and premature down-regulation of the local host immune response.

Secondary stage

The secondary stage is characterized by dissemination and multiplication of the microorganism in different tissues, either simultaneously with or up to 6 months after healing of the primary local lesion. This stage follows primary syphilis in almost every patient who does not receive appropriate treatment. Circulating immune complexes (which contain treponemal outer membrane proteins), human anti-fibronectin antibodies, and complement are present during this stage of the disease and play a role in the pathogenesis of the different types of lesions .

Secondary syphilis is characterized by a broad spectrum of clinical manifestations involving the skin as well as systemic signs such as malaise, fever, and generalized lymphadenopathy. It lasts several weeks or months, with relapses in ~25% of patients. Pregnant women can infect a fetus via transplacental passage of the microorganism.

Latency

Latency is the period between healing of the clinical lesions and appearance of late manifestations, and it can last for many years. About 70% of untreated individuals will remain in this stage for the rest of their lives and are immune to new primary infection (see Fig. 82.1 ). Latent syphilis is divided into early (1 year or less) and late (more than 1 year) subsets, and it is characterized by positive serologic tests for specific antibodies (see below) without clinical signs or symptoms. Infectivity may occur intermittently due to the presence of treponemes in the bloodstream, and pregnant women with latent syphilis may infect the fetus in utero .

Tertiary stage

The tertiary stage is also called late syphilis and is characterized by the presence of a small number of organisms and a high cellular immune reactivity against the organism. Signs of late syphilis can be recognized in approximately one-third of untreated individuals several months to years after being infected with treponemes (see Fig. 82.1 ). The microorganisms may invade the central nervous and cardiovascular systems as well as the skin (and other organs), leading to damage related to host delayed-type hypersensitivity responses, which produce local inflammation and gummas in affected tissues.

Syphilis and HIV

Syphilis and other STIs that produce genital ulcers further increase the risk of acquiring HIV. Reasons for the increased risk of HIV transmission include:

• •
  

  lack of an epithelial barrier due to ulceration of the skin or mucous membranes

  
  
• •
  

  large numbers of macrophages and T cells with receptors for HIV

  
  
• •
  

  production of cytokines by macrophages stimulated by treponemal lipoproteins.

Primary syphilis

The chancre usually presents as a single, indolent, round or oval, indurated ulcer ( Fig. 82.5 ) that is associated with regional adenopathy. Some patients report a preceding painless papule that enlarged and ulcerated a few days later. The time of onset ranges from 10 to 90 days (average 3 weeks) after T. pallidum exposure. Untreated, chancres heal within a few weeks ( Fig. 82.6 ).

Chancres of primary syphilis.

The lesions are firm to palpation and are occasionally multiple. Sites of chancres can include the penis ( A , B ), perianal area ( C ) and lip ( D ). Occasionally, other sites are affected, e.g. fingers.

Clinical manifestations of syphilis.

L, lues; LI, primary syphilis; LII, secondary syphilis; LIII, tertiary syphilis.

Adapted from Fritsch P, Zangerle R, Stary A. Venerologie. In: Fritsch P (ed). Dermatologie und Venerologie. Berlin: Springer, 2004:865–86.

Asymptomatic infections are common due to unrecognized chancres, especially when located in the cervical region in women; in these cases, syphilis is more frequently diagnosed during the secondary stage. The same applies to chancres located in the anal, perianal, or rectal areas (see Fig. 82.5C ), seen more commonly in MSM. The mechanism of spontaneous healing without treatment is not well understood and seems to depend on local immunity.

Laboratory diagnosis of primary syphilis includes the following:

• •
  

  The presence of treponemes by darkfield microscopic examination of fluid from the surface of the chancre is the most sensitive and specific method for the diagnosis of primary syphilis (see Fig. 82.3 ).

  
  
• •
  

  Antibodies to cardiolipin are present in about 80% of individuals at the onset of clinical symptoms. Cardiolipin, a component of mammalian cells, seems to be modified by treponemes such that antibodies are produced by the infected person and can be measured by the rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) assay.

  
  
• •
  

  Antibodies to surface proteins of T. pallidum as detected by hemagglutination assays ( T. pallidum h em a gglutination test [TPHA], m icro h em a gglutination assay for antibodies to T. pallidum [MHA-TP]), or f luorescent t reponemal a ntibody abs orption (FTA-ABS) assay are present in 90% of patients with clinical symptoms of primary syphilis. Since antibodies usually remain positive for life, a differentiation between primary syphilis and a prior infection may not be possible and darkfield examination should be undertaken.

Secondary syphilis

The secondary stage of the disease results from the hematogenous and lymphatic dissemination of treponemes after a few weeks or months (3–10 weeks). It is characterized by recurrent disease activity, with mucocutaneous as well as systemic manifestations. Prodromal symptoms include low-grade fever, malaise, sore throat, adenopathy, weight loss, muscle aches, and sometimes a headache from meningeal irritation ( Table 82.4 ).

During the second stage of syphilis, the most commonly observed clinical presentation (80%) is a generalized, non-pruritic papulosquamous eruption ( Fig. 82.7 ). Lesions can range from 1–2 mm to 15–20 mm in diameter, and they vary in color from pink to violaceous to red–brown. Mucosal lesions range from small, superficial ulcers that resemble painless aphthae to large gray plaques ( Fig. 82.8A,B ). Condylomata lata are often observed in the moist regions of the anogenital area due to local spreading of the microorganisms ( Fig. 82.8C,D ). Lymph node enlargement is present in the majority of patients. Focal neurologic findings occasionally occur.

Secondary syphilis.

Widespread exanthem of pink papules ( A ), subtle minimally inflamed lesions localized to the arms in an HIV-positive man ( B ) and generalized papulosquamous lesions ( C ). Lesions on the palms ( D ) and soles ( E, F ) can have a collarette of scale.

B, Courtesy, Kalman Watsky, MD.

Orogenital lesions of secondary syphilis.

Oral lesions can vary from small superficial ulcers ( A ) to mucous patches ( B ). Condylomata lata in the vulvar ( C ) and anal ( D ) areas may be misdiagnosed as HPV infection (i.e. condylomata acuminata).

Additional clinical presentations of secondary syphilis include annular or figurate plaques with central hyperpigmentation on the face ( Fig. 82.9A ), non-scarring “moth-eaten” alopecia, split papules at the oral commissures ( Fig. 82.9B ), granulomatous nodules and plaques ( Fig. 82.9C ), and crusted necrotic lesions ( Fig. 82.9D ). Malignant syphilis (lues maligna) is extremely rare; the disseminated lesions resemble primary chancres ( Fig. 82.9E ).

Less common manifestations of secondary syphilis.

A Annular plaques with central hyperpigmentation on the forehead. B Split papule at the oral commissure. C Granulomatous nodules and plaques. D Necrotic lesion with scale-crust in a patient with AIDS. E “Malignant” syphilis with multiple necrotic, ulcerated and crusted lesions associated with severe constitutional symptoms.

D, Courtesy, Judit Stenn, MD.

Without treatment, the lesions resolve over several weeks to months. Relapse occurs in ~20% of patients within 1 year, often with mucosal or mucocutaneous manifestations in the anogenital area.

Laboratory diagnosis of secondary syphilis includes the following:

• •
  

  Presence of treponemes by darkfield examination of serous exudates from localized lesions of the skin and mucous membranes (the exception being the oral cavity; see below).

  
  
• •
  

  Serologic tests are more useful in secondary, as compared to primary, syphilis. Cardiolipin antibodies (e.g. RPR or VDRL tests) as well as specific antibodies are always positive in patients with secondary syphilis; a mistakenly or temporarily negative non-treponemal test rarely occurs due to the prozone phenomenon or HIV infection, respectively (see Table 82.8 ).

  
  
• •
  

  Spirochetes can be detected by immunohistochemistry in the majority of biopsy specimens.

• •
  

  All patients should be tested for HIV infection, and testing should be repeated in those who fail to respond to treatment.

  
  
• •
  

  Patients with ocular symptoms (e.g. photophobia, visual changes) should undergo ophthalmologic evaluation to assess for uveitis and neuroretinitis, including slit-lamp examination.

  
  
• •
  

  A lumbar puncture and cerebrospinal fluid (CSF) analysis should be performed in patients with ocular or neurologic (e.g. headache, hearing loss, cranial neuropathies) signs/symptoms and when treatment failure is suspected (e.g. persistent/recurrent signs/symptoms or failure of non-treponemal test titers to decline fourfold within 6–12 months). Patients with HIV are at increased risk for neurosyphilis, especially if they have a CD4 count <350 cells/ml and/or a RPR titer of ≥1 : 32; however, unless neurologic symptoms are present, CSF examination in HIV patients has not been associated with improved clinical outcomes.

Latent syphilis

After a period of 3–12 weeks, untreated secondary syphilis typically resolves spontaneously, leaving the patient in an asymptomatic state. Diagnosis is based on a positive syphilis serology test result in the setting of no clinical evidence of treponemal infection. The two stages are:

• •
  

  Early latent stage: within 1 year of the onset of latency (CDC definition), with the possibility of recurrence of the disease. About 90% of secondary relapses occur within the first year.

  
  
• •
  

  Late latent stage: after 1 year from the onset of the disease (CDC definition); relapses after 1 year are very infrequent. This disease state may last for many months or years.

Diagnosis of latent syphilis is established by reactivity in an RPR or VDRL assay, a positive MHA-TP or FTA-ABS test, and the absence of any clinical signs of the disease. The diagnosis is easy to establish if there is a history of a chancre or skin manifestations that fit the clinical picture of syphilis. In many cases, however, the medical history provides no useful information regarding the presence of clinical symptoms in the previous weeks to months or whether the patient was previously treated. In such instances, differentiation between early and late latency is not possible and patients are regarded as having late latent syphilis from a management standpoint (see below). Response of latent syphilis to treatment is indicated by a decline in the RPR or VDRL titer. Persistently high (e.g. lack of a fourfold decline within 12–24 months) or rising titers are a sign of treatment failure, and examination of the CSF should be performed.

Tertiary (late) syphilis

Classic tertiary syphilis, as a consequence of untreated syphilis, is nowadays rare. It has a variable range of manifestations that appear months to years after initial infection ( Fig. 82.10 ). In particular, these include involvement of the skin, bones, CNS, heart, and great vessels. Approximately one-half of patients with tertiary syphilis have “benign” late syphilis with the development of gummas, about one-quarter develop cardiovascular manifestations, and one-quarter develop neurologic symptoms (see Fig. 82.1 ).

Clinical manifestations of late syphilis.

Adapted from Fritsch P, Zangerle R, Stary A. Venerologie. In: Fritsch P (ed.). Dermatologie und Venerologie. Berlin: Springer, 2004:865–86.

In tertiary syphilis, non-treponemal serologic tests are usually positive with high titers. Patients with tertiary syphilis (or any symptoms related to late syphilis) should undergo lumbar puncture and CSF examination to determine if neurosyphilis is present before therapy is initiated.

“Benign” late syphilis

The most common feature of late syphilis is gummas, which are locally destructive lesions in the skin, bones, liver, and other organs. The gummas in the skin are nodular or noduloulcerative lesions, often with an arciform pattern ( Fig. 82.11 ). They remain for weeks to months and then involute with scarring, but eventually new nodules reappear. With treatment, resolution of the lesions is prompt and complete. A solitary gumma that is located subcutaneously may become necrotic, similar to a “cold” abscess, resulting in ulceration of the skin or mucous membranes as well as destruction of underlying bones.

Cutaneous gummas of tertiary syphilis.

Arciform, erythematous eroded plaques with central scarring.

Bones are affected as frequently as the skin. Within the bone, a gumma is destructive and is typically accompanied by periostitis and osteitis. Clinical manifestations include pain, swelling, and limited range of motion. Other sites that can be affected by gummas include the tongue and oral cavity, upper respiratory tract, myocardium, and digestive as well as nervous systems.

Neurosyphilis

Although classically a manifestation of tertiary syphilis, neurosyphilis can occur at any stage of the disease. Neurosyphilis is the reflection of a chronic (or sometimes acute) form of meningitis, with vascular and parenchymatous sequelae in the cerebrum and spinal cord ( Table 82.5 ) . Asymptomatic neurosyphilis is defined by the presence of abnormalities in the CSF (see below), but in the absence of any neurologic symptoms or clinical findings. While in some individuals the CSF abnormalities may resolve spontaneously or persist into advanced age, asymptomatic neurosyphilis can progress to late symptomatic neurosyphilis.

The basic pathomechanism for cerebrovascular syphilis is an infarction secondary to syphilitic endarteritis; this can result in hemiparesis or hemiplegia. Parenchymatous neurosyphilis, including general paresis, dementia paralytica, and paretic neurosyphilis, is due to direct invasion of the cerebrum by treponemes. It is a rare and late form of neurosyphilis, with dementia and neurologic symptoms such as paralysis progressing, if untreated, until death occurs.

Tabes dorsalis, which affects up to a third of patients with neurosyphilis after a long latent period, has a number of typical clinical signs and symptoms, including diplopia, lightning pains (painful paresthesias, especially of the extremities), loss of vibratory and position sense, reduced reflexes in the legs, ataxia, sphincter dysfunction, visceral crisis (abdominal, rectal, and laryngeal pain), and Argyll Robertson pupils (abnormal pupillary light reflexes: loss of direct and consensual; retention of accommodation). Tabes dorsalis may burn out even without treatment.

Congenital syphilis

Congenital syphilis was initially described in 1497 and is therefore the oldest recognized congenital infection. In 1906, it was demonstrated via the Wassermann test that transmission of syphilis to the fetus required an infection in the pregnant woman.

There was an upsurge in congenital syphilis in Eastern Europe in the late 1990s, which paralleled the increased incidence of syphilis in adults and adolescents in this region. In the early 1990s, an increased frequency of congenital syphilis was also observed in some inner-city minority populations in the US . In the US, there are currently ~12 cases of congenital syphilis per 100 000 live births. The risk of mother-to-child transmission of untreated syphilis and its potential consequences are outlined in Table 82.6 .

Early congenital syphilis

Infants generally present with symptoms during the neonatal period or within the first 3 months of life ( Fig. 82.12 ). At the latest, they develop symptoms within the first 2 years of life. Typical manifestations are marasmic syphilis (i.e. cachexia) and skin lesions similar to those of acquired secondary syphilis ( Fig. 82.13 ), except that they may be bullous (pemphigus syphiliticus) and tend to be more erosive. Additional clinical findings are “snuffles” (bloody or purulent mucinous nasal discharge), perioral and perianal fissures, lymphadenopathy, and hepatosplenomegaly. Skeletal involvement (i.e. osteochondritis) may result in pseudoparalysis of Parrot because of reduced movement of the extremities due to pain; other manifestations include anemia, thrombocytopenia, syphilitic pneumonitis (pneumonia alba), hepatitis, nephropathy, and congenital neurosyphilis.

Time course for clinical manifestations of congenital syphilis.

Adapted from Fritsch P, Zangerle R, Stary A. Venerologie. In: Fritsch P (ed). Dermatologie und Venerologie. Berlin: Springer, 2004:865–86.

Congenital syphilis.

Red–brown plaques on the plantar surface.

Late congenital syphilis and stigmata

Late congenital syphilis in a child or adolescent corresponds to tertiary syphilis in an adult and is not infectious. The stigmata represent the delayed consequences of localized inflammation at the sites of treponemal infection ( Table 82.7 ). In about one-third of children, an interstitial keratitis is seen; this finding together with typical dental abnormalities (Hutchinson teeth) and neural deafness forms the Hutchinson triad.

Table 82.7

Stigmata of congenital syphilis.

STIGMATA OF CONGENITAL SYPHILIS

Cutaneous

• Rhagades – radial periorificial (mouth, nose, eyes, anus) scars at sites of previous fissures

Dental

• Hutchinson teeth – peg-shaped, notched permanent incisors * • Mulberry molars – multiple rounded rudimentary cusps on the permanent first molars • Caries due to defective enamel

Skeletal

• Saddle nose – depression of the nasal root due to destruction of cartilage/bone • Frontal bossing of Parrot (“Olympian brow”) • Hypoplastic maxilla, relatively prominent mandible • High palatal arch ± perforation • Higouménakis’ sign – thickening of the medial clavicle • Scaphoid scapulae • Saber shins – anterior tibial bowing • Clutton’s joints – painless synovitis and effusions of the knees

Other

• Eighth nerve deafness * • Interstitial keratitis leading to corneal ulcers and opacities *

 

* Components of Hutchinson triad.

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