Treponema pallidum (Syphilis)

Four diseases are associated with pathogenic treponemes: (1) venereal syphilis, caused by Treponema pallidum subsp. pallidum ; (2) yaws, caused by T. pallidum subsp. pertenue ; (3) endemic syphilis, or bejel, caused by T. pallidum subsp. endemicum ; and (4) pinta, caused by T. carateum . These diseases are thought to have diverged from a single disease 10,000 to 100,000 years ago under the influence of population migration and environmental factors. The pathogenic treponemes cannot be distinguished by serologic tests (nontreponemal and treponemal) or morphologic features, but newer molecular techniques can distinguish T. pallidum from the other treponemes. The treponemal diseases evolve over many years in 3 symptomatic stages: a primary stage, marked by a single highly contagious cutaneous or mucous membrane lesion; a secondary stage, the consequence of disseminated organisms, which results in highly infectious cutaneous and mucous membrane lesions, with other organs also affected; an asymptomatic latent stage; and a tertiary symptomatic stage, marked by destructive lesions. These diseases also share an early immune response that modifies the course but does not prevent the disease from progressing. In all cases, a cure is achievable by relatively small doses of penicillin, and humans are the only host.

Treponemal diseases can be differentiated by epidemiology and mode of transmission. Syphilis is caused by T. pallidum subsp. pallidum , occurs globally, and is acquired by sexual contact or congenital infection (mother-to-child transmission).

Microbiology and Pathogenesis

Between 1905 and 1910, Schaudinn and Hoffmann identified T. pallidum as the cause of syphilis, Wasserman described a diagnostic serologic test, and Ehrlich discovered that salvarsan (an arsenic-based compound) could be used for treatment. T. pallidum cultivation in the laboratory still requires propagation in rabbit testes, but application of modern molecular techniques is providing an increased understanding of the interaction between treponemes and the host. The T. pallidum Nichols strain DNA sequence was published in 1998, and this led to other advances in understanding the structure and function of the organism. Molecular techniques led to subtyping of T. pallidum , and with increasing discrimination these techniques have improved knowledge of geographic subtype differences and have been used to investigate the epidemiology and spread of syphilis. Molecular techniques also have identified significant sequence changes in genes ( tpr ) that cluster in T. pallidum subspecies, thus supporting a genetic basis for species classification.

Treponemes are tapered, thin, spiral bacilli (5–15 μm in length, 0.15 μm in width) that exhibit corkscrew locomotion. Infection starts with penetration through minor abrasions in the skin or intact mucous membrane. Only spirochetes that adhere to cells replicate, and cell division occurs every 30–33 hours. At least 50 T. pallidum organisms are necessary to initiate infection; larger inocula shorten the incubation period. T. pallidum structure consists of outer and cytoplasmic membranes, a thin peptidoglycan layer, and 3 endoflagella that lie in the periplasmic space at each end and are responsible for motility. The outer membrane contains a small number of poorly immunogenic transmembrane proteins ( T. pallidum rare outer membrane proteins, or TROMP), but it does not contain lipopolysaccharide. Highly antigenic lipoproteins (47, 34, 17, and 15 kds) are localized to the subsurface cytoplasmic membrane and are not exposed on the cell surface. ^, Host reaction to infection includes cellular and humoral immune responses with more than 60 specific antibodies identified by sodium dodecyl sulfate–polyacrylamide gel electrophoresis. Antibodies directed to the prominent, 47-kd treponemal antigen are the earliest detected by Western blot. Macrophages activated in the presence of specific antibody ingest and destroy large numbers of organisms. However, it is unclear why this process and other immune reactivity hasten healing of the primary lesion but do not halt infection. Various hypotheses suggest that (1) a lack of antigenic reactivity in the outer membrane acts as an immunologic barrier, (2) a change in membrane-bound immunoproteins after dissemination allows organisms to evade antibody-mediated immunity, or (3) treponemes surround themselves with host material and thus delay the host cell response.

Spirochetes preferentially adhere to endothelial cells. Vasculitis with a predominance of mononuclear and plasma cells surrounding the involved vessels is typical of syphilitic lesions. In primary and secondary disease, infectious treponemes are demonstrated easily in lesions. These lesions heal completely, whereas tertiary lesions result in irreversible tissue destruction and fibrosis. Tertiary lesions consist of gummas and cardiovascular and central nervous system (CNS) disease. Gummas are large, granulatomous lesions with a central necrotic mass surrounded by plasma cells, lymphocytes, and monocytes; multinucleated giant cells are not present. Organisms usually are not found in these lesions, which are thought to represent a hypersensitivity phenomenon. Gummas occur in both acquired and congenital disease. Cardiovascular syphilis, another tertiary manifestation, is associated with pathologic changes in the proximal aorta that consist of inflammation-induced obliterative endarteritis of the vasa vasorum leading to medial necrosis. Although inflammatory changes begin in the early stages of infection, clinical manifestations appear 10–40 years later. Tertiary neurosyphilis is the result of chronic meningeal inflammation, which affects primarily the meninges but also can involve the brain and spinal cord. Meningeal, meningovascular, parenchymatous, and gummatous neurosyphilis also occurs after untreated congenital infection.

Epidemiology

Syphilis is acquired by sexual contact (including oral sex) and, extremely rarely, by other forms of close contact. Congenital syphilis is a consequence of undiagnosed, untreated, or inadequately treated maternal syphilis. Globally, the prevalence of active syphilis infections in pregnant women is estimated to have remained stable between 2012 and 2016 (the most recent year for which modelled estimates are available), but the incidence of adverse outcomes has fallen—probably reflecting the increased access to antenatal care, screening and treatment. Using Spectrum STI (sexually transmitted infection) models, it was estimated that a global average of 0.7% of pregnant women had active syphilis in 2016, meaning approximately 1 million women in total. Regional rates of active syphilis in pregnant women remained stable in most regions except the Americas and the Eastern Mediterranean, which both trended to nonsignificant increases. The authors of this modelling estimated that approximately 355,000 adverse pregnancy outcomes arose as a result of this level of syphilis prevalence.

An understanding of transmission, the development of serologic tests to detect asymptomatic infections, and effective penicillin treatment led to a steady decline in the numbers of cases in Western Europe and the US after a peak during World War II. Reported cases of syphilis in the US remained at low levels until 1986, when the number of cases increased sharply, with the epidemic peaking in 1990. This epidemic was associated mostly with heterosexual transmission, poverty, use of crack cocaine, human immunodeficiency virus (HIV) infection, and minority (predominantly Black) ethnic background. Primary and secondary syphilis rates declined from 1990 to 2000, but have since increased annually following the lowest ever rate in 2000. ^, Men accounted for most (85.7%) primary and secondary cases of syphilis in 2018, predominantly men who have sex with men (MSM). However, heterosexual outbreaks continue to occur. ^, Geographic variations are seen, with the western and the southern US tending to have higher rates than the rest of the country. Syphilis rates differ among racial and ethnic groups; in 2018, compared with the White population, the rate of primary and secondary syphilis was 4.7 fold higher in the Black population and 2.2 fold higher in the Hispanic population.

The prevalence of seroreactivity in pregnant women in the US generally is <1%. The syphilis epidemic of the early 1990s was associated with an increase in congenital syphilis in the US. In 1988, the US Centers for Disease Control and Prevention (CDC) modified the criteria for case surveillance, which also contributed to increases in reports. The number of cases of congenital syphilis declined after 1991 ; cases increased 23% from 2005 to 2008, primarily in the South, and fell again from 2009 to 2012. Since 2012 (the lowest recorded rate since 1988) rates of congenital syphilis have increased every year. Risk factors for maternal-to-child transmission continue to include lack of prenatal care, ^, late prenatal care, and lack of maternal screening and appropriate, timely treatment. Recent data show that the most common missed opportunities to prevent congenital syphilis are lack of adequate maternal treatment despite a timely diagnosis during pregnancy (30.7%) and lack of timely prenatal care (28.2%). Because the most important risk is birth to a mother who received no prenatal care, tests for syphilis always should be offered when pregnant women with no record of prenatal screening seek any type of healthcare.

Clinical Manifestations

Acquired Syphilis

Primary Syphilis

Untreated syphilis is a chronic disease evolving in 3 symptomatic stages. Primary syphilis follows approximately 30% of sexual exposures. The incubation period of 1–4 weeks is influenced by the number of organisms in the inoculum. The typical primary chancre is a single, painless papule that erodes to form an ulcer with a reddened base and rolled edges. A small inoculum may produce only a papule. Primary lesions can occur in both the genital and oral areas. Women may not notice primary disease because a chancre in the vagina or on the cervix is not visible. Both men and women may ignore a visible lesion because it is painless (unless secondarily infected) and heals completely in 3–6 weeks. Painless nonsuppurative enlargement of local lymph nodes accompanies the chancre and can persist for months. Primary lesions contain infectious treponemes, and hematogenous dissemination begins within hours after superficial invasion of organisms and continues throughout primary and secondary disease.

Secondary and Latent Syphilis

Secondary syphilis is a systemic, multiorgan disease that begins 6–12 weeks after infection. In 15% of patients, the primary chancre is still present when symptoms of secondary disease begin. Mucocutaneous lesions are common, usually beginning on the trunk and eventually involving most of the body, including palms and soles. Salmon-pink macules, 5–10 mm in size, evolve to copper-colored papules that occasionally develop a follicular or pustular appearance. Untreated, skin lesions regress to hypopigmented or hyperpigmented papules that persist for months. Painless generalized lymphadenopathy is found in 85% of patients. In 10% of patients, raised, enlarged, broad, flat papules (condylomata lata) develop in warm, moist areas (vulva, anus, scrotum, and axilla). White-to-grey patches on mucous membranes also are detected in 10% of patients. Fewer than 10% of patients develop transient patchy alopecia and loss of other body hair, including eyebrows and beard, as a result of spirochetal invasion of hair follicles. Arthritis, osteitis, gastritis, hepatitis, splenomegaly, and nephrotic syndrome occur in some patients. CNS involvement is common in secondary syphilis, and, although it is usually asymptomatic, 1%–2% of patients have acute meningitis. Lukehart and associates, using the rabbit infectivity test (RIT), demonstrated that 40% of patients with early syphilis had either treponemes in the cerebrospinal fluid (CSF) or a reactive CSF Venereal Disease Research Laboratory (VDRL) test result. Common constitutional symptoms of fever, malaise, aches, pains, and sore throat are nonspecific; the diagnosis relies on serologic testing.

Even without treatment, complete resolution of secondary syphilis occurs after 3–12 weeks, and disease enters the latent phase. Early latent syphilis is defined as the first year after infection, and late latent syphilis is defined as more than a year after infection. Relapses of secondary syphilis occur in approximately 25% of untreated patients during early latent syphilis, but patients with late latent syphilis are asymptomatic. Although patients are asymptomatic, CSF examination is included in evaluation of some patients with latent syphilis because CSF abnormalities correlate with subsequent symptomatic tertiary neurosyphilis. A study evaluating CSF findings in adults with syphilis (most with late latent syphilis and also HIV infection) showed that a serum rapid plasma regain (RPR) titer ≥1:32 was predictive of neurosyphilis in all patients, and a CD4 ⁺ T-lymphocyte count of ≤350 cells/μL was a second risk factor in adults with HIV infection. Patients’ immunity during late latency seems to protect against relapse, but it does not prevent progression of syphilis to the tertiary stage. Patients previously treated for syphilis can still acquire syphilis but are more likely to be asymptomatic.

Tertiary Syphilis

Tertiary disease occurs in approximately 30% of untreated patients. Manifestations are divided into 3 main subgroups: neurosyphilis, cardiovascular syphilis, and late benign syphilis (gummas). Tertiary neurosyphilis includes several clinical syndromes: meningeal, meningovascular, and parenchymatous syphilis (including general paresis and tabes dorsalis). Manifestations appear within a few months of primary infection (meningeal syphilis) or 20–30 years later. Meningeal syphilis manifests as cranial nerve palsies, sensorineural deafness, and hydrocephalus. Meningovascular syphilis causes a stroke syndrome resulting from infarction secondary to syphilitic endarteritis, with the middle cerebral artery the most common site. The findings of general paresis can be summarized by the mnemonic PARESIS: personality; affect; reflexes (hyperactive); eye (Argyll Robertson pupils, which react to accommodation but not to light); and abnormalities of sensorium (illusions, delusions, hallucinations), intellect (decreased recent memory, orientation, judgment, insight), and speech. Tabes dorsalis describes the symptoms and signs of demyelination of the posterior column and roots of the spinal cord. Patients can have more than one form of neurologic disease. Treatment can arrest the disease; however, the extent of underlying disease determines whether signs and symptoms resolve.

Cardiovascular syphilis , which occurs from 10 to 40 years after infection, is seen in 10% of patients with tertiary disease. An aneurysm in the ascending portion of the aorta, aortic insufficiency from aortic root dilation, and coronary artery disease are commonly recognized signs.

Benign tertiary syphilis refers to the presence of gummatous lesions in skin, bones, and, rarely, in other organs. Lesions vary in size from microscopic to clearly visible. Gummas are considered benign because they rarely involve vital body structures, but gummas can be destructive. Cutaneous gummas can ulcerate, and bone lesions are painful. Failure to treat or a delay in treatment is associated with disfiguring scars.

Syphilis Associated With HIV Infection

Syphilis and HIV infection exhibit “epidemiologic synergy,” and coinfection is common. The presence of HIV infection is thought to alter the clinical expression of syphilis, response to therapy, and the results of serologic tests. Antibody titers can be higher than expected, but occasionally false-negative results or delayed seroreactivity can occur. In addition, people with HIV infection and early syphilis can be at higher risk for both neurologic complications and treatment failure with currently recommended regimens. Adults with neurosyphilis and HIV infection are less likely to revert from a reactive CSF VDRL test result than are adults without HIV infection. Patients with syphilis should be tested for HIV infection and vice versa. Patients with coinfection require careful and more frequent follow-up.

Mother-to-Child Transmission

Transplacental transmission of syphilis can give rise to a range of adverse outcomes. A meta-analysis of 6 studies found that 52% of pregnancies in women with untreated syphilis led to adverse fetal-neonatal outcomes. This percentage included 21% of pregnancies ending in fetal loss or stillbirth, 9% in neonatal death, and 6% in prematurity or low birth weight. Signs or symptoms of infection (i.e., congenital syphilis) occurred in 15% of maternal infections. These data confirm the findings in historical studies. Preventing adverse outcomes of pregnancy (through screening and treatment with penicillin) is most effective when interventions are delivered in the first 2 trimesters. Penicillin is estimated to be effective at preventing adverse pregnancy outcomes in approximately 82% cases of stillbirths, 64% of preterm deliveries, 80% of neonatal deaths, and 97% of cases of clinical disease in infected infants. Women who first attend antenatal care in the third trimester are more than twice as likely to have an adverse outcome compared with women screened and treated in the first 2 trimesters, and in the case of congenital syphilis the risk is almost threefold higher.

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