Syphilis, a chronic systemic infection caused by Treponema pallidum subspecies pallidum, is usually sexually transmitted and is characterized by episodes of active disease interrupted by periods of latency. After an incubation period averaging 2–6 weeks, a primary lesion appears, often associated with regional lymphadenopathy. The secondary stage, associated with generalized mucocutaneous lesions and generalized lymphadenopathy, is followed by a latent period of subclinical infection lasting years or decades. Central nervous system (CNS) involvement may occur early in infection and may be symptomatic or asymptomatic. In about one-third of untreated cases, the tertiary stage appears, characterized by progressive destructive mucocutaneous, musculoskeletal, or parenchymal lesions; aortitis; or late CNS manifestations.
The Spirochaetales include four genera that are pathogenic for humans and for a variety of other animals: Leptospira species, which cause leptospirosis (Chap. 171); Borrelia species, which cause relapsing fever and Lyme disease (Chaps. 172 and 173); Brachyspira species, which cause intestinal infections; and Treponema species, which cause the diseases known collectively as treponematoses (see also Chap. 170). The Treponema species include T. pallidum subspecies pallidum, which causes venereal syphilis; T. pallidum subspecies pertenue, which causes yaws; T. pallidum subspecies endemicum, which causes endemic syphilis or bejel; and T. carateum, which causes pinta. Until recently, the subspecies were distinguished primarily by the clinical syndromes they produce. Researchers have now identified molecular signatures that can differentiate the three subspecies of T. pallidum by culture-independent methods based on polymerase chain reaction (PCR). Other Treponema species found in the human mouth, genital mucosa, and gastrointestinal tract have been associated with disease (e.g., periodontitis), but their role as primary etiologic agents is unclear.
T. pallidum subspecies pallidum (referred to hereafter as T. pallidum), a thin spiral organism, has a cell body surrounded by a trilaminar cytoplasmic membrane, a delicate peptidoglycan layer providing some structural rigidity, and a lipid-rich outer membrane containing relatively few integral membrane proteins. Endoflagella wind around the cell body in the periplasmic space and are responsible for motility.
T. pallidum cannot be cultured in vitro, and little was known about its metabolism until the genome was sequenced in 1998. This spirochete possesses severely limited metabolic capabilities, lacking the genes required for de novo synthesis of most amino acids, nucleotides, and lipids. In addition, T. pallidum lacks genes encoding the enzymes of the Krebs cycle and oxidative phosphorylation. To compensate, the organism contains numerous genes predicted to encode transporters of amino acids, carbohydrates, and cations. In addition, genome analyses and other studies have revealed the existence of a 12-member gene family (tpr) that bears similarities to variable outer-membrane antigens of other spirochetes. One member, TprK, has discrete variable (V) regions that undergo antigenic variation during infection, probably as a mechanism for immune evasion.
The only known natural host for T. pallidum is the human. T. pallidum can infect many mammals, but only humans, higher apes, and a few laboratory animals regularly develop syphilitic lesions. Virulent strains of T. pallidum are grown in rabbits.
Nearly all cases of syphilis are acquired by sexual contact with infectious lesions [i.e., the chancre, mucous patch, skin rash, or condylomata lata (see Fig. e7-20)]. Less common modes of transmission include nonsexual personal contact, infection in utero, blood transfusion, and organ transplantation.
Syphilis in the United States
With the advent of penicillin therapy, the total number of cases of syphilis reported annually in the United States declined significantly to a low of 31,575 in 2000—a 95% decrease from 1943—with <6000 reported cases of primary and secondary syphilis. Since 2000, the number of cases of infectious primary and secondary syphilis (a better indicator of disease activity) has more than doubled, with 13,500 cases reported in 2008. These cases have particularly affected men who have sex with men (MSM), many of whom are co-infected with HIV. This outbreak among MSM is occurring throughout North America. Increases in the number of cases among women in the United States in recent years indicate that heterosexual transmission is becoming more common. Surveillance of the number of new cases of primary and secondary syphilis has revealed multiple cycles of 7–10 years, which have been attributed to herd immunity in at-risk populations. A recent re-analysis of the data, however, fails to support this conclusion and proposes alternative explanations for the periodic rise and fall of infectious syphilis cases, including changing sexual behaviors and control efforts.
The populations at highest risk for acquiring syphilis have changed over time, with outbreaks among MSM in the late 1970s and early 1980s as well as at present. The epidemic that peaked in 1990 predominantly involved African-American heterosexual men and women and occurred largely in urban areas, where infectious syphilis was correlated significantly with the exchange of sex for crack cocaine. Although the rate of primary and secandary syphilis among African Americans declined from 1996 through 2003, the rate has nearly doubled since then and remains higher than rates for other racial/ethnic groups.
The incidence of congenital syphilis roughly parallels that of infectious syphilis in females. In 2008, 431 cases in infants <1 year of age were reported. The case definition for congenital syphilis was broadened in 1989 and now includes all live or stillborn infants delivered to women with untreated or inadequately treated syphilis.
One-third to one-half of individuals named as sexual contacts of persons with infectious syphilis become infected. Many will have already developed manifestations of syphilis when they are first seen, and ∼30% of asymptomatic contacts examined within 30 days of exposure actually have incubating infection and will later develop infectious syphilis if not treated. Thus, identification and treatment of all recently exposed sexual contacts continue to be important aspects of syphilis control.
Syphilis remains a significant health problem globally; the number of new infections is estimated at nearly 12 million per year. The regions that are most affected include sub-Saharan Africa, South America, China, and Southeast Asia (Fig. 169-1). During the past decade, the number of reported cases in China has increased 10-fold, and higher rates have been reported among MSM in many European countries. Worldwide, congenital syphilis has been reported to account for up to 50% of stillbirths, and between 500,000 and 1.5 million cases of congenital syphilis are estimated to occur annually.