Sexually Transmitted Bacterial Infections

Developed Countries

In developed countries, most patients who have genital ulcers have herpes simplex virus (HSV), syphilis, or chancroid. The differential diagnosis of genital ulcers is presented in Table 10.2 . The frequency of each disease differs by geographic area and patient population. Herpes is the most prevalent. A patient may have more than one of these diseases. Not all genital ulcers are caused by sexually transmitted infections STIs. Each disease is associated with an increased risk for human immunodeficiency virus (HIV) infection. A diagnosis-based history and physical examination is often inaccurate. All patients who have genital ulcers should have a serologic test for syphilis and diagnostic tests for herpes. Tests to consider include the following:

• Rapid plasma reagin (RPR) or Venereal Disease Research Laboratories (VDRL)

• Syphilis immunoglobulin G (IgG), and if positive order RPR

• Dark-field examination for Treponema pallidum

• Culture, polymerase chain reaction (PCR), and/or antigen test for HSV

• Culture for Haemophilus ducreyi (special media)

• Biopsy if treatment fails

• HIV testing if ulcers are caused by T. pallidum or H. ducreyi

• Consider HIV testing for patients with HSV

HIV testing should be performed in patients who have genital ulcers caused by T. pallidum or H. ducreyi and considered for those who have ulcers caused by HSV.

Treatment of genital ulcers is often desirable before test results are available. Treat for the most likely diagnosis. If the diagnosis is unclear, treat for syphilis or for both syphilis and chancroid if the patient lives in an area where H. ducreyi is a significant cause of genital ulcers. Even after complete diagnostic evaluation, at least 25% of patients who have genital ulcers have no laboratory-confirmed diagnosis ( Tables 10.2 and 10.3 ).

Incidence

In the United States, the CDC reports that there were 88,042 newly diagnosed (all stages) cases of syphilis in 2016, compared with 39,513 diagnoses of HIV in 2015 ( Fig. 10.6 ). Of the syphilis cases 27,814 were primary and secondary syphilis and the majority occurred among gay, bisexual, and men who have sex with men. This is an increase of 17.6% from 2015. The rates of syphilis have been increasing in heterosexual men and women as well. In 2016, 628 cases of congenital syphilis were reported—the highest since 1998. Congenital syphilis is more likely to occur in infants born to black and Hispanic mothers. In developing countries, several hundred thousand stillbirths and neonatal deaths occur yearly and after malaria, syphilis is the second leading cause of preventable neonatal deaths. Syphilis is becoming a global public health problem (5.6 million new cases per year) with the highest prevalence in Africa and more than 60% of new cases occurring in low-income and middle-income countries. Urban settings in high- and middle-income countries are seeing a resurgence of syphilis in men who have sex with men, as well as an increase in neurosyphilis and ocular syphilis.

Stages

Untreated syphilis may pass through three stages. Syphilis begins with the infectious cutaneous primary and secondary stages that may terminate without further sequelae or may evolve into a latent stage that lasts for months or years before the now-rare tertiary stage, marked by the appearance of cardiovascular, neurologic, and deep cutaneous complications ( Fig. 10.7 ).

The CDC defines the stages of syphilis as follows:

• 1

  Infectious syphilis includes the stages of primary, secondary, and early latent syphilis of less than 1 year's duration.

• 2

  Latent infections (i.e., those lacking clinical manifestations) are detected by serologic testing. Latent syphilis is divided into early latent disease of less than 1 year's duration and early latent disease of greater than 1 year's duration.

• 3

  Late latent disease has a duration of 4 years or longer ( Table 10.12 ).

  TABLE 10.12

  Staging in Persons With a Diagnosis of Syphilis (i.e., Confirmed Reactive Serology)

  From New York City Department of Health and Mental Hygiene and the New York City STD Prevention Training Center. The Diagnosis and Management of Syphilis: An Update and Review. March 2019. Reprinted by permission. The table is based on Nandwani R, Evans D. Are you sure it's syphilis? a review of false positive serology. Int J STD AIDS 1995;6(4):241–8 and Hook III EW, Marra CM. Acquired syphilis in adults. N Engl J Med 1992;326(16):1060–69.

  Stage	Diagnostic Criteria	Probable Exposure Date
  Primary	Consistent Exam Findings Usually a single, painless, rubbery ulcer (genital or nongenital) that is found to be positive by dark-field/DFA/PCR or that is highly suspicious for a syphilitic chancre on clinical grounds	Within the past 3 months
  Secondary	Consistent Exam Findings (± dark-field positive lesion) Cutaneous eruption (generalized or localized) without explanation Palmar or plantar rash Mucous patches (membranous lesions of tongue, buccal mucosa, lips) Condylomata lata (moist, flat, whitish-gray plaques) Patchy alopecia	Within the past 6 months
  Early latent	Negative exam (i.e., no findings consistent with primary or secondary syphilis) plus Any of the following within the past 12 months: 1 History of unequivocal symptoms of primary or secondary syphilis or 2 Serologic conversion or 3 A 2 dilution (4-fold) rise in nontreponemal titer in a person who has previously received adequate treatment for a syphilis infection or 4 Exposure to an infectious case of syphilis * or 5 Only possible exposure has been within the past 12 months	Within the past year
  Late latent	Negative exam (i.e., no findings consistent with primary or secondary syphilis) plus Any of the following more than 12 months ago: 1 History of unequivocal symptoms of primary or secondary syphilis or 2 Serologic conversion or 3 A 2 dilution (4-fold) rise in nontreponemal titer in a person who has previously received adequate treatment for a syphilis infection or 4 Exposure to an infectious case of syphilis * or 5 No possible exposure within the past 12 months	Longer than 1 year ago
  Latent syphilis of unknown duration	No signs or symptoms of primary or secondary syphilis and insufficient information to determine the duration of infection or the most likely time of exposure	Uncertain If the nontreponemal titer is ≥1:32, there is a greater likelihood of recent infection (i.e., within the previous 12 months)

  DFA, direct fluorescent antibody; PCR, polymerase chain reaction.

  * An infectious case includes primary, secondary, or early latent syphilis.

Risk of Transmission

The greatest risk of transmission occurs during the primary, secondary, and early latent stages of disease. The patient is most infectious during the first 1 to 2 years of infection. Patients with secondary syphilis are the most contagious because of the large number of lesions. The risk of acquiring syphilis from an infected partner is 10% to 60%. One third of persons with a single exposure to early syphilis will become infected. The organism is highly infectious; the disease can be transmitted with as few as 10 organisms present.

Treponema pallidum

T. pallidum, the organism responsible for syphilis, is a very small, spiral bacterium (spirochete) whose form and corkscrew rotation motility can be observed only by dark-field microscopy ( Fig. 10.8 ). The reproductive time is estimated to be 30 to 33 hours, in contrast to most bacteria, which replicate every 30 minutes. Serum levels of antibiotics must therefore persist for at least 7 to 10 days to kill all replicating organisms. The Gram stain cannot be used, and growing the bacteria is difficult.

Primary Syphilis

Primary syphilis, characterized by a cutaneous ulcer ( Figs. 10.9 to 10.13 ), is acquired by direct contact with an infectious lesion of the skin or the moist surface of the mouth, anus, or vagina. From 10 to 90 days (average, 21 days) after exposure, a primary lesion, the chancre, develops at the site of initial contact. Chancres are usually solitary, but multiple lesions are not uncommon. Extragenital chancres account for 6% of all chancres, and most occur on the lips and in the oral cavity and are transmitted by kissing or orogenital sex. The lesion begins as a papule that undergoes ischemic necrosis and erodes, forming a 0.3- to 2.0-cm, painless to tender, hard, indurated ulcer; the base is clean, with a scant, yellow, serous discharge. Because the chancre began as a papule, the borders of the ulcer are raised, smooth, and sharply defined ( Fig. 10.9 ). The chancre of chancroid is soft and painful. Painless, hard, discrete regional lymphadenopathy occurs in 1 to 2 weeks; the lesions never coalesce or suppurate unless there is a mixed infection. Without treatment, the chancre heals with scarring in 3 to 6 weeks. Painless vaginal ( Fig. 10.10 ) and anal lesions may never be detected. The differential diagnosis includes ulcerative genital lesions such as chancroid, herpes progenitalis, aphthae (Behçet syndrome), and traumatic ulcers such as those that occur with biting. If untreated, approximately 25% of the infections progress directly to the second stage; the other 75% enter latency.

Secondary Syphilis

Secondary syphilis is characterized by mucocutaneous lesions, a flu-like syndrome, and generalized adenopathy. Asymptomatic dissemination of T. pallidum to all organs occurs as the chancre heals, and the disease then resolves in approximately 75% of cases (see Fig. 10.7 ). In the remaining 25%, the clinical signs of the secondary stage begin approximately 6 weeks (range, 2 weeks to 6 months) after the chancre appears and last for 2 to 10 weeks. Cutaneous lesions are preceded by a flu-like syndrome (sore throat, headache, muscle aches, meningismus, and loss of appetite) and generalized, painless lymphadenopathy. Hepatosplenomegaly may be present. In some cases lesions of secondary syphilis appear before the chancre heals. The distribution and morphologic characteristics of the skin and mucosal lesions are varied and may be confused with numerous other skin diseases. As with most other systemic cutaneous diseases, the rash is usually bilaterally symmetric ( Figs. 10.14 to 10.19 ).

Lesions

The lesions of secondary syphilis have certain characteristics that differentiate them from other cutaneous diseases. There is little or no fever at the onset. Lesions are noninflammatory, develop slowly, and may persist for weeks or months. Pain or itching is minimal or absent. There is a marked tendency to polymorphism, with various types of lesions presenting simultaneously, unlike other eruptive skin diseases in which the morphologic appearance of the lesions is uniform. The color is characteristic, resembling a “clean-cut ham” or having a coppery tint. Lesions may assume a variety of shapes, including round, elliptic, or annular. Eruptions may be limited and discrete, profuse, generalized, or more or less confluent and may vary in intensity.

The types of lesions in approximate order of frequency are maculopapular, papular, macular, annular, papulopustular, psoriasiform, and follicular. The lesions in black individuals are marked by the absence of dull-red color. Lesions occur on the palms or soles in most patients with secondary syphilis (see Figs. 10.15 and 10.20 ). Unlike the pigmented melanotic macules frequently seen on the palms and soles of older black patients, lesions of secondary syphilis of the palms and soles are isolated, oval, slightly raised, erythematous, and scaly. Temporary irregular (“moth eaten”) alopecia of the beard, scalp, or eyelashes may occur (see Fig. 10.14 ). Moist, anal, wart-like papules (condylomata lata) are highly infectious (see Fig. 10.19 ). Lesions may appear on any mucous membrane. All cutaneous lesions of secondary syphilis are infectious; therefore, do not touch any lesions that are unidentifiable. The differential diagnosis is vast. The commonly observed diseases that may be confused with secondary syphilis are pityriasis rosea (especially if the herald patch is absent), guttate psoriasis (psoriasis that appears suddenly with numerous small papules and plaques), lichen planus, tinea versicolor, and exanthematous drug and viral eruptions.

The diagnosis is based primarily on clinical and serologic grounds. Histologic studies, in the majority of cases, may confirm the disease.

Cellular immune processes are responsible for the cutaneous manifestations of secondary syphilis. Coinfection with HIV-1 has little effect on the cutaneous response to T. pallidum .

Approximately 25% of untreated patients with secondary syphilis may experience relapse, most of them (approximately 90%) during the first year, a small percentage in the second year, and none after the fourth year.

Latent Syphilis

Latent syphilis is defined as syphilis characterized by seroreactivity without other evidence of disease. Patients who have latent syphilis and who acquired syphilis within the preceding year are classified as having early latent syphilis. In latent syphilis, the clinician depends on the accuracy of the patient's history that there were characteristic signs and symptoms or that the blood test, the result of which has been discovered to be positive, was nonreactive at a specific time ( Table 10.12 ).

Early latent syphilis can be diagnosed if, within the year preceding the evaluation, the patient reports the following:

• 1

  There was a documented seroconversion (i.e., RPR, VDRL not a false-positive test result) without evidence of active disease or 4-fold or greater increase in titer of a nontreponemal test. Often the physician is unable to confirm the specific time interval of conversion.

• 2

  Unequivocal symptoms of primary or secondary syphilis were present.

• 3

  A sex partner was documented to have primary, secondary, or early latent syphilis.

By convention, early latent syphilis is of 1-year or less duration and late latent syphilis is of more than 4 years’ duration. The periods of 1 and 4 years were established to help predict a patient's chance of experiencing relapse with signs of secondary infectious syphilis. Approximately 25% of untreated patients in the secondary stage may experience a relapse, most of them (approximately 90%) during the first year, a small percentage in the second year, and none after the fourth year. The patient who experiences a relapse with secondary syphilis is infectious.

Patients who have latent syphilis of unknown duration should be treated as if they have late latent syphilis. Nontreponemal serologic titers (i.e., RPR, VDRL) usually are higher during early latent syphilis than late latent syphilis. However, early latent syphilis cannot be reliably distinguished from late latent syphilis solely on the basis of nontreponemal titers. All patients with latent syphilis should undergo careful examination of all accessible mucosal surfaces (i.e., the oral cavity, the perineum in women, and underneath the foreskin in uncircumcised men) to evaluate for internal mucosal lesions. All patients who have syphilis should be tested for HIV infection.

Tertiary Syphilis

In a small number of untreated or inadequately treated patients, systemic disease develops, including cardiovascular disease, central nervous system (CNS) lesions, and systemic granulomas (gummas) ( Fig. 10.21 ).

Syphilis and Human Immunodeficiency Virus

Syphilis (a genital ulcer disease) facilitates and is a cofactor for HIV transmission. Syphilis is associated with an increased risk of acquiring and transmitting HIV. The natural history of syphilis is altered by the HIV. Reports describe an accelerated progression through the syphilitic stages in HIV patients.

Treatment of patients coinfected with syphilis and HIV is controversial; progression and relapse of neurosyphilis have been reported. Syphilis can increase the likelihood of HIV transmission and acquisition. HIV seroprevalence is high among patients with syphilis in the United States. The standard recommended doses of penicillin may not be effective for HIV-infected patients with syphilis. For most patients with coinfections of HIV and syphilis, laboratory tests for diagnosis and posttreatment follow-up can be interpreted as they would in an immunocompetent person.

Congenital Syphilis

Congenital syphilis is a problem in parts of the world where women do not receive prenatal care. T. pallidum can be transmitted by an infected mother to the fetus in utero . In untreated cases stillbirth occurs in 19% to 35% of reported cases, 25% of infants die shortly after birth, 12% are without symptoms at birth, and 40% will have late symptomatic congenital syphilis. The Treponema can cross the placenta at any time during pregnancy and can pass into the placenta as early as 9 to 10 weeks of gestation. Adequate therapy of the infected mother before the sixteenth week of gestation usually prevents infection of the fetus. Treatment after 18 weeks may cure the disease but not prevent irreversible neural deafness, interstitial keratitis, and bone and joint changes in the newborn. The fetus is at greatest risk when maternal syphilis is of less than 2 years’ duration. The ability of the mother to infect the fetus diminishes but never disappears in late latent stages. Condylomata lata and furuncles of Barlow can be seen toward the end of the first year of life. The clinical manifestations occur in an early and late form.

Early Congenital Syphilis

Early congenital syphilis is defined as syphilis acquired in utero that becomes symptomatic during the first 2 years of life. It usually appears in the first week of life. The findings can be viewed as an exaggeration of those of acquired secondary syphilis. The fetal stigmata seen before the age of 2 years include eruptions characteristic of secondary syphilis. There are influenza-like respiratory symptoms in 20% to 50%, hepatosplenomegaly or lymphadenopathy in 50% to 75%, and mucocutaneous changes in 40% to 50% of affected persons. Maculopapular rash and desquamating erythema of the palms and soles are common. Deep fissures at the angle of the mouth (“split papules”) may be seen ( Fig. 10.22 ). A highly infectious hemorrhagic nasal discharge, “snuffles,” is a characteristic early sign. Bone and joint symptoms are common.

A vesiculobullous variant, “pemphigus syphiliticus,” may occur with vesicles, bullae, and erosions. Osteochondritis with the “sawtooth” metaphysis seen on radiographs and periostitis appear with tender limbs and joints. Nontender generalized adenopathy, alopecia, iritis, and failure to thrive occur less frequently.

Late Congenital Syphilis

Symptoms and signs of late congenital syphilis become evident after age 5 years. The average age at first diagnosis is 30 years. It may be difficult to distinguish from acquired syphilis. The most important signs are frontal bosses (bony prominences of the forehead) (87%), saddle nose (74%), short maxilla (83%), high-arched palate (76%) ( Fig. 10.23 ), mulberry molars (more than four small cusps on a narrow first lower molar of the second dentition), Hutchinson teeth (peg-shaped upper central incisors of the permanent dentition that appear after age 6 years) (63%) ( Fig. 10.24 ), Higouménaki's sign (unilateral enlargement of the sternoclavicular portion of the clavicle as an end result of periostitis) (39%), and rhagades (linear scars radiating from the angle of the eyes, nose, mouth, and anus) (8%). Hutchinson triad (Hutchinson teeth, interstitial keratitis [ Fig. 10.25 ], and cranial nerve VIII deafness) is considered pathognomonic of late congenital syphilis.

Syphilis Serology

Culture of T. pallidum is not available. The diagnosis of syphilis is based on serologic findings ( Table 10.13 ) and/or dark-field microscopic examination of the organism or direct immunofluorescent microscopy ( Table 10.14 ). The latter two procedures require special equipment and an experienced technician.

The interpretation of reactive serologic tests for syphilis is shown in Fig. 10.26 and Table 10.15 . Two classes of immunoglobulin M (IgM) and IgG antibodies are produced in response to infection with T. pallidum; these are nonspecific antibodies measured by the VDRL and RPR tests and specific antibodies measured by the fluorescent treponemal antibody absorption (FTA-ABS) test (see Table 10.15 ), microhemagglutination assay (MHA-TP), or syphilis IgG assay (MFI). The IgM antibodies are present in the second week of infection, and they disappear 3 months after treatment for early syphilis and 12 months afterward for late syphilis. They do not pass through the placenta or blood–brain barrier. IgG antibodies reach high levels in 4 to 5 weeks and may persist for life (see Fig. 10.26 ).

Conventional Testing

Historically, the serologic testing algorithm for syphilis included an initial nontreponemal screening test, such as the RPR or the VDRL tests. These tests measure the host's antibody response to nontreponemal antigens, but they lack specificity. Therefore, a positive result by RPR or VDRL requires confirmation by a treponemal-specific test, such as the FTA-ABS test or MHA-TP.

Initial Screening by Syphilis IgG Assay

Recently, enzyme immunoassays (EIAs) and multiplex flow immunoassays (MFIs) were introduced to assess serologic response to T. pallidum . The syphilis IgG assay detects IgG-class antibodies to T. pallidum . The syphilis IgG assay is highly sensitive and specific and is now commonly performed. Specimens testing positive by the treponemal-specific assay are then tested by RPR to provide supplementary serologic data, as well as to provide an indication of the patient's disease state and history of treatment.

Syphilis Antibody Response

During early primary syphilis, serology tests may be negative. As the disease progresses, IgG-class antibodies to T. pallidum reach peak titers, and may persist indefinitely regardless of the disease state or prior therapy. T. pallidum IgG antibodies persist indefinitely, regardless of the treatment status of the patient. To determine if a patient has been treated for syphilis, the RPR test is performed. If the RPR is positive, the results may suggest active, untreated syphilis. A positive syphilis screening test and a negative RPR test most likely suggest past, successfully treated syphilis.

Reverse Algorithm Screening

Syphilis screening using the reverse algorithm first tests sera for T. pallidum –specific IgG antibodies ( Fig. 10.27 ). A positive IgG treponemal test suggests infection with T. pallidum at some point in the past, but does not distinguish between treated and untreated infections. This is because treponemal tests (e.g., EIA, MFI, or FTA-ABS) may remain reactive for life, even following adequate therapy. Therefore, the results of a nontreponemal assay, such as RPR, are needed to provide information on a patient's disease state and history of therapy.

In some patients, the results of the treponemal screening test (syphilis IgG) and RPR may be discordant (e.g., syphilis IgG positive and RPR negative). To discriminate between a falsely reactive screening result and past syphilis, the CDC recommends performing a second treponemal-specific antibody test using a method that is different from the initial screen test (e.g., Treponema pallidum particle agglutination [TP-PA]).

In the setting of a positive syphilis IgG screening result and a negative RPR, a positive TP-PA result is consistent with (1) past, successfully treated syphilis, (2) early syphilis with undetectable RPR titers, or (3) late/latent syphilis in patients who do not have a history of treatment for syphilis. Further historical evaluation is necessary to distinguish between these scenarios ( Table 10.16 ).

In the setting of a positive syphilis IgG screening result and a negative RPR, a negative TP-PA result is most consistent with a falsely reactive syphilis IgG screen (see Table 10.16 ). If syphilis remains clinically suspected, a second specimen should be submitted for testing by the syphilis serology algorithm.

Treatment of Syphilis

Patients to be treated for syphilis should have a baseline serum RPR determination. The best indication of successful therapy is a decreasing RPR titer.

The drug of choice in the treatment of syphilis is benzathine penicillin G (see Table 10.1 and Table 10.4 ). Box 10.1 shows the current WHO recommendations for treatment of syphilis.