Natural history of untreated syphilis

Syphilis is caused by the spirochete bacterium, Treponema pallidum, which enters the body through miniscule breaks in the skin of the external genitalia that occur during sexual intercourse. Once the spirochete has entered, the untreated disease progresses through four consecutive stages: primary, secondary, latent and tertiary syphilis. Antibiotic treatment at any stage short of tertiary can prevent the late, life-threatening sequelae of the disease. Syphilis may also be transmitted from a woman to her fetus at any point during pregnancy, with serious consequences.

The primary lesion of syphilis, the chancre, develops in venereal locations close to where T. pallidum typically enters the body: the penis, labia, perineum, anus or rectum. Chancres are painless, small papules that persist for 1–2 months and heal spontaneously.

The secondary stage of syphilis is a disseminated form. Blood-borne spirochetes populate the dermis throughout the body causing a widespread papular rash over the trunk and extremities. Because the disease is systemic, fever, myalgias, lymphadenopathy, sore throat and headache are common. Secondary syphilis can also be associated with immune complex deposition in the joints, kidneys and eyes, leading to arthritis, glomerulonephritis, nephrotic syndrome and uveitis. Untreated secondary syphilis resolves over 4–12 weeks, leaving the patient symptom free. The subsequent months to years until the onset of symptoms of tertiary syphilis is known as the latent period.

Tertiary syphilis usually appears many years after the disseminated stage. Tertiary syphilis can involve multiple organs, including the cardiovascular and nervous systems. Overall, about one-quarter of untreated patients develop recognizable late (tertiary) complications of syphilis, one-quarter have asymptomatic lesions demonstrable at autopsy and half have no anatomic lesions attributable to syphilis present at autopsy. About half of the patients with symptomatic tertiary syphilis will die as a direct result of the disease, typically of cardiovascular complications.

Infection of the placenta and fetus will occur in virtually 100% of pregnant women who suffer the spirochetemia accompanying primary or secondary syphilis. Complications of syphilis in pregnancy include miscarriage, stillbirth, premature delivery and congenital syphilis. The manifestations of congenital syphilis are protean. Its neonatal mortality rate is 50%.

Syphilis is treated with penicillin in all but highly allergic patients.

Epidemiology of syphilis

Syphilis was very common in many parts of the world until antibiotic therapy became available in the 1940s. The prevalence of the disease fell dramatically after World War II but began to increase again in the 1960s. Up to 75% of cases go unreported. Women and men at high risk for contracting syphilis are young, from lower socioeconomic groups, and have multiple sexual partners. Some 10–50 syphilitic organisms are sufficient to cause infection and about one-third of the sexual contacts of an infected person will become infected. The incidence of congenital syphilis parallels that in women and is increasing. Mandatory prenatal screening has reduced the incidence of late congenital syphilis; late or absent prenatal care is the biggest risk factor for congenital syphilis.

Biology of T. pallidum

Treponema pallidum is a member of the bacterial order Spirochaetaceae, and closely related to two other treponemas responsible for human disease: Treponema pertenue, which causes yaws, and T. carateum, which causes pinta. Neither electron microscopic examination nor DNA analyses can distinguish between these three organisms. It is believed that the different diseases that develop reflect adaptations of the organism and the host to different points of entry into the body.

Treponema pallidum is a relatively fragile organism that cannot survive for more than a few hours outside moist areas of the body. Its microbiology is very poorly understood because the organism cannot be maintained in cell culture.

Most of the manifestations of syphilis are secondary to the inflammatory reaction caused by the organism. Polymorphonuclear cells arriving at the site of the inoculum ingest the spirochetes but do not kill them. Lymphocytes and macrophages are recruited to the site. They also surround, but do not kill the treponemes. Antitreponemal antibodies are produced, sometimes in quantities that cause immune complex glomerulonephritis. It remains both amazing and unknown how T. pallidum is able to evade host defenses and establish an infection. The site of primary infection is surrounded by a mucoid material composed of hyaluronic acid and chondroitin sulfate that may alter the host defenses. The best clue available to explain the persistence of disease is the finding that delayed type sensitivity to treponemal antigens is absent in secondary syphilis. New spirochetes inoculated into the system are not infectious while the original infection persists. This is a common mechanism in chronic parasitic diseases, called “premunition”; the host resists reinfection but cannot clear the initial infection.

Once the systemic phase of the infection is established, spirochetes are present virtually everywhere in the infected tissues. However, inflammation occurs preferentially around small vessels and causes intimal hyperplasia and obliterative endarteritis. The subsequent focal ischemic necrosis and fibrosis are responsible for the many late manifestations of the disease.

The inflammatory changes caused by the spirochetes are most striking in congenital syphilis. The placenta is diffusely fibrotic with inflammation and necrosis of the fetal blood vessels in the placental villi. The resulting vascular insufficiency leads to poor fetal growth (intrauterine growth restriction) and stillbirth. Fibrosis of the liver and spleen cause fetal anemia. Compensatory extramedullary hematopoeisis promotes hepatosplenomegaly and the development of pleural effusions and ascites (fetal hydrops). Some infants will have a skin rash that closely resembles that of secondary syphilis. A runny nasal discharge loaded with spirochetes (snuffles) may be the only hint of congenital syphilis at birth.

The late manifestations of syphilis, both congenital and tertiary, involve vasculitis and parenchymal damage in the central nervous system.