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The disease syphilis was reported in the medical literature as early as 1495. In 1905, it was discovered that syphilis was caused by a spirochete type of bacteria, Treponema pallidum (originally called Spirochaeta pallida). The first diagnostic blood test for syphilis was the Wassermann test, a complement fixation test developed in 1906. This classic procedure (see, “Archives of Classic Procedures”) has subsequently been replaced by a variety of methods. In the treatment of syphilis, heavy metals, such as arsenic, were replaced by penicillin in the 1940s. Penicillin continues to remain the drug of choice for the treatment of this disease.


T. pallidum is a member of the order Spirochaetales and the family Treponemataceae (Fig. 18-1). The genus Treponema includes a number of species that reside in human gastrointestinal and genital tracts. T. pallidum, Treponema pertenue, and Treponema carateum are human pathogens responsible for significant worldwide morbidity (Table 18-1). Yaws, pinta, and bejel are diseases caused by bacteria closely related to T. pallidum. Yaws is common in the Caribbean, Latin America, Central Africa, and the Far East. Pinta is found only in Latin America and infection is limited to the skin. Bejel is found in eastern Mediterranean countries, the Balkans, and the cooler areas of North Africa.

Table 18-1

Treponema-Associated Diseases

Bacteria Associated Disease
T. pallidum Syphilis
T. pallidum (variant) Bejel
T. pertenue Yaws
T. carateum Pinta

Direct examination of the treponemes is most often performed with darkfield microscopy. Pathogenic treponemes appear as fine, spiral (8 to 24 coils) organisms approximately 6 to 15 µm long. They have a trilaminar outer membrane similar to that of gram-negative bacteria.

Pathogenic treponemes are not cultivatable with any consistency in artificial laboratory media. Outside of the host, the pathogenic treponemes are extremely susceptible to a variety of physical and chemical agents. Treponemes may remain viable for up to 5 days in tissue specimens removed from diseased animals and from frozen cryoprotected specimens.


Sexually transmitted diseases (STDs) remain a major public health challenge in the United States. The surveillance report by the Centers for Disease Control and Prevention (CDC) includes data on the three STDs that physicians are required to report to the agency—chlamydia, gonorrhea, and syphilis. Syphilis is considered to be primarily a venereal disease. It is the most common STD in the United States.

The three treponematoses—yaws, pinta, and bejel—are rarely seen in the United States but are prevalent in other countries. These diseases are associated with poverty, overcrowding, and poor hygiene.

In 2009, for the first time in 5 years, the CDC reported that syphilis cases did not increase overall among women. In addition, cases of congenital syphilis (transmitted from mother to infant) did not increase for the first time in 4 years. In 2008, 63% of the reported primary and secondary (P&S) syphilis cases were among men who have sex with men (MSM). In the surveillance period of 2004 to 2008, rates of P&S syphilis increased the most among 15- to 24-year-old men and women. The incidence of syphilis per capita is higher among blacks and Hispanics than among whites.

Syphilis remains a global problem, with an estimated 12 million people infected each year, despite the existence of effective prevention measures. The last decade has seen a pronounced resurgence of syphilis in countries of the Far East (e.g., China and Africa). Some fundamental social problems (e.g., poverty, inadequate access to health care, lack of education) are associated with disproportionately high levels of syphilis in certain populations.

Pathogenic treponemes are transmitted almost uniformly by direct contact. Treponemal infections of the skin or oral lesions contain many spirochetes that may be transmitted by personal, but not necessarily venereal, contact. These infections are generally acquired during childhood. In each of these diseases, infection elicits antibodies reactive in nontreponemal and treponemal methods.

Syphilis develops in 30% to 50% of the sexual partners of persons with syphilitic lesions. The risk of acquiring syphilis from a single sexual exposure to an infected partner is unknown. A high percentage of partners do seek medical treatment within 90 days of contact.

Syphilis can be acquired by kissing a person with active oral lesions. Very few cases of transfusion-acquired syphilis have been reported in recent years in the United States. During the first half of the twentieth century, however, syphilis was a major bloodborne infectious disease easily transmitted through the prevailing method of direct donor to patient blood transfusion. The danger of syphilis transmission still exists in tropical countries in which the organization of blood banks is deficient and the use of direct blood transfusion prevails in emergency situations. Refrigerated blood storage decreases accidental transmission of the microorganism because T. pallidum has a short survival period in stored blood. Spirochetes do not appear to survive in units of citrated blood at 4° C (39° F) for longer than 72 hours.

Cases have been reported of children who acquired syphilis by sharing a bed with an infected parent. In addition, syphilis may be transmitted transplacentally to the fetus. Spirochetes can be transmitted to the fetus during the last trimester of pregnancy, before the mother manifests postpartum evidence of infection.

Signs and Symptoms

Untreated syphilis is a chronic disease with subacute symptomatic periods separated by asymptomatic intervals, during which the diagnosis can be made serologically. The progression of untreated syphilis is generally divided into stages—primary, secondary, latent (hidden), and tertiary (late) (Table 18-2).

Table 18-2

Stages of Syphilis

Phase or Stage Features and Comments Test
Incubating phase The incubation period usually lasts ≈3 wk but can range from 10-90 days. Laboratory examination
Primary stage

Darkfield examination Secondary stage Latent (hidden) stage   Relapses of secondary syphilis Tertiary (late) stage


FTA-ABS, Fluorescent treponemal antibody absorption; RPR, rapid plasma reagin; TP-PA, Treponema pallidum particle agglutination assay; VDRL, venereal disease research laboratory.

Initially, T. pallidum penetrates intact mucous membranes or enters the body through tiny defects in the epithelium. On entrance, the microorganism is carried by the circulatory system to every organ of the body. Spirochetemia occurs very early in infection, even before the first lesions have appeared or blood tests become reactive. Before clinical or serologic manifestations develop, patients are said to be incubating syphilis. The incubation period usually lasts about 3 weeks but can range from 10 to 90 days.

Primary Syphilis

At the end of the incubation period, a patient develops a characteristic, primary inflammatory lesion called a chancre at the point of initial inoculation and multiplication of the spirochetes. The chancre begins as a papule and erodes to form a gradually enlarging ulcer, with a clean base and indurated edge (Fig. 18-2). Generally, it is relatively painless. In most cases, only a single lesion is present, but multiple chancres are not rare.

Chancres are typically located around the genitalia, but in about 10% of cases, lesions may appear almost anywhere else on the body (e.g., throat, lip, hands). In males, spirochetes are present in the lesion on the penis or discharged from deeper sites with semen. In females, infected lesions are usually located in the perineal region or on the labia, vaginal wall, or cervix. If the lesion is located inside the urethra, the only symptom may be a scanty, serous urethral discharge.

Of patients with primary syphilis of the external genitalia, 50% to 70% will subsequently develop inguinal adenopathy. Inguinal adenopathy, however, is less common with chancres involving the cervix or proximal part of the vagina because these sites are drained by the iliac nodes. Regional adenopathy may accompany primary inoculation at other sites; for example, cervical adenopathy may accompany a syphilitic lesion of the oral cavity.

The primary chancre will persist for 1 to 5 weeks and will heal completely in about 4 to 6 weeks, even without treatment. Regional adenopathy will also resolve itself.

Secondary Syphilis

Within 2 to 8 weeks (but occasionally as long as 6 months) after the appearance of the primary chancre, a patient may develop the signs and symptoms of secondary syphilis. In some patients, primary and secondary syphilis overlap and the chancre is still obvious. Other patients never notice the primary chancre and initially have manifestations of secondary syphilis (Fig. 18-3).

The secondary stage is characterized by a generalized illness that usually begins with symptoms suggesting a viral infection—headache, sore throat, low-grade fever, and occasionally a nasal discharge. Blood tests reveal a moderate increase in leukocytes, with a relative increase in lymphocytes.

The disease progresses with the development of lymphadenopathy and lesions of the skin and mucous membranes. Approximately 75% of syphilitic patients develop generalized adenopathy. About 80% have skin lesions, which contain a large number of spirochetes and, when located on exposed surfaces, are highly contagious. Macular lesions are common and a rash invariably involves the genitalia; this rash often is prominent on the palms and soles. Patients may also develop condylomata lata, flat lesions resembling warts in moist areas of the body (e.g., around the anus or vagina). These lesions do not reflect areas of inoculation but appear to be caused by hematogenous dissemination of spirochetes.

The central nervous system (CNS) is asymptomatically involved in about one third of patients. About 2% of cases manifest as acute syphilitic meningitis. Early CNS involvement may progress to neurosyphilis if untreated. Hepatitis and immune complex glomerulonephritis occasionally accompany secondary syphilis.

Secondary syphilis usually resolves within 2 to 6 weeks, even without therapy.

Late (Tertiary) Syphilis

The first manifestations of late syphilis are usually seen from 3 to 10 years after primary infection. About 15% of untreated syphilitic individuals eventually develop late benign syphilis, characterized by the presence of destructive granulomas. These granulomas, or gummas, may produce lesions resembling segments of circles that often heal with superficial scarring. The skeletal system is frequently affected, but treponemes are rarely seen.

Of untreated patients, 10% develop cardiovascular manifestations. T. pallidum may directly affect the aortic endothelium. Weakening of the blood vessels can occur as a syphilitic aneurysm, usually of the aortic arch.

In about 8% of untreated patients, late syphilis involves the CNS. Initially, CNS disease is asymptomatic and can be detected only by examination of cerebrospinal fluid (CSF). CSF should be examined in all patients being treated for syphilis of unknown duration or who have had syphilis for longer than 1 year.

Meningovascular syphilis usually manifests as a seizure or cerebrovascular accident (stroke). Spirochetes may also involve the brain tissues and cause general paresis, personality changes, dementia, and delusional states. Tabes dorsalis results from involvement of the posterior columns and dorsal roots of the spinal cord and is characterized by a broad-based gait. Impotence and bladder dysfunction are common in this disorder (see later, “Neurosyphilis”).

Congenital Syphilis

Congenital syphilis is caused by maternal spirochetemia and transplacental transmission of the microorganism. Untreated syphilis during pregnancy, especially early syphilis, can lead to stillbirth, neonatal death, or infant disorders such as deafness, neurologic impairment, and bone deformities. Congenital syphilis (CS) can be prevented by early detection of maternal infection and treatment at least 30 days before delivery. Changes in the population incidence of P&S syphilis among women usually are followed by similar changes in the incidence of CS. CDC national surveillance data from the period 2003 to 2008 in the United States have indicated that after declining for 14 years, the CS rate among infants younger than 1 year increased by 23%.

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