**7. Syphilis**

*Treponema pallidum*, a thin (0.1-0.18 µm by 6-15 µm) flagellated spirochete, is the etiologic agent of syphilis. *Treponema* spirochetes invade mucous membranes or penetrate through breaks in the skin. Although syphilis is typically acquired via sexual contact the disease can also be transmitted transplacentally and by exposure to blood or lesion exudates from infected persons in the primary and secondary stages of disease.

#### **7.1 Epidemiology**

Prior to the antibiotic era, syphilis was a very prevalent disease, particularly in large urban areas. Since then, the incidence has been steadily declining but there are still 12 million new cases each year around the world. Unlike many other STIs, the incidence of syphilis is higher in older individuals and is highest in men aged 30-45. Globally, congenital syphilis is a significant problem and it is estimated that neonatal mortality from syphilis exceeds that of neonatal tetanus, neonatal HIV infection, and mortality from malaria in pregnancy. There is no lasting immunity to syphilis and patients can be re-infected.

### **7.2 Clinical manifestations**

Syphilis presents a wide spectrum of clinical manifestations as it progresses through the different stages of the disease: primary, secondary, latency, and tertiary. Syphilis, particularly the secondary stage, mimics many other infections and has been given the moniker, the "great imitator". The primary stage of syphilis is usually characterized by the appearance of a single sore (chancre) at the site of syphilis entry, although multiple lesions can be present. The chancre appears 10-90 days after infection, approximately 2-3 weeks on average. The chancre is typically a firm, round, and painless ulcer, 1-2 cm in size, which is highly infectious and will spontaneously resolve in 1-6 weeks. Chancres can also be present at non-genital sites, the anus, mouth, or perineum. Regional lymphadenopathy that is rubbery, painless, and bilateral is usually present.

Without treatment the systemic skin rash and mucocutaneous lesions of secondary syphilis appear 4-6 weeks after the primary lesion in approximately 25% of patients following dissemination of the disease throughout the body. Occasionally the symptoms of secondary syphilis will occur prior to resolution of the initial chancre. The red macropapular rash is symmetrical, non-pruritic, and present throughout the body including the palms of hands and soles of feet and may lead to hair loss. White, patchy, raised lesions on mucocutaneous surfaces, known as condylomata latum may also be present. The rash and lesions are accompanied by fever, malaise, and generalized lymphadenopathy. Rare

Therapeutic use of sulfonamides, penicillin, erythromycin, and fluoroquinolones has been largely discontinued due to the development of widespread resistance to these agents. Azithromycin, 2 g orally, is effective but concerns over the prior ease of development of macrolide resistance in *N. gonorrhoeae* should limit its use to special circumstances. Gonococcal infections of the pharynx are more difficult to eliminate and are treated with ceftriaxone, 250 mg IM in a single dose, plus azithromycin, 1 g orally in a single dose, or doxycycline, 100 mg orally twice a day. Neonates born to infected mothers are given erythromycin ointment to the eyes to prevent blindness. Patients infected with *N. gonorrhoeae* are frequently co-infected with *Chlamydia*, and additional treatment for this

*Treponema pallidum*, a thin (0.1-0.18 µm by 6-15 µm) flagellated spirochete, is the etiologic agent of syphilis. *Treponema* spirochetes invade mucous membranes or penetrate through breaks in the skin. Although syphilis is typically acquired via sexual contact the disease can also be transmitted transplacentally and by exposure to blood or lesion exudates from

Prior to the antibiotic era, syphilis was a very prevalent disease, particularly in large urban areas. Since then, the incidence has been steadily declining but there are still 12 million new cases each year around the world. Unlike many other STIs, the incidence of syphilis is higher in older individuals and is highest in men aged 30-45. Globally, congenital syphilis is a significant problem and it is estimated that neonatal mortality from syphilis exceeds that of neonatal tetanus, neonatal HIV infection, and mortality from malaria in pregnancy. There

Syphilis presents a wide spectrum of clinical manifestations as it progresses through the different stages of the disease: primary, secondary, latency, and tertiary. Syphilis, particularly the secondary stage, mimics many other infections and has been given the moniker, the "great imitator". The primary stage of syphilis is usually characterized by the appearance of a single sore (chancre) at the site of syphilis entry, although multiple lesions can be present. The chancre appears 10-90 days after infection, approximately 2-3 weeks on average. The chancre is typically a firm, round, and painless ulcer, 1-2 cm in size, which is highly infectious and will spontaneously resolve in 1-6 weeks. Chancres can also be present at non-genital sites, the anus, mouth, or perineum. Regional lymphadenopathy that is

Without treatment the systemic skin rash and mucocutaneous lesions of secondary syphilis appear 4-6 weeks after the primary lesion in approximately 25% of patients following dissemination of the disease throughout the body. Occasionally the symptoms of secondary syphilis will occur prior to resolution of the initial chancre. The red macropapular rash is symmetrical, non-pruritic, and present throughout the body including the palms of hands and soles of feet and may lead to hair loss. White, patchy, raised lesions on mucocutaneous surfaces, known as condylomata latum may also be present. The rash and lesions are accompanied by fever, malaise, and generalized lymphadenopathy. Rare

infection may be appropriate, dependent on local prevalence of these STIs.

infected persons in the primary and secondary stages of disease.

is no lasting immunity to syphilis and patients can be re-infected.

rubbery, painless, and bilateral is usually present.

**7. Syphilis** 

**7.1 Epidemiology** 

**7.2 Clinical manifestations** 

manifestations of secondary syphilis include hepatitis, glomerulonephritis, and keratitis. Neurosyphilis can occur at any stage of syphilis but is classically associated with tertiary syphilis. Clinical manifestations of early neurosyphilis include acute syphilitic meningitis that typically involves cranial nerves III, VI, VII and VIII; or meningovascular syphilis, a stroke-like syndrome with seizures. Secondary syphilis is usually the fist clinical presentation in persons practicing receptive vaginal or anal intercourse as the primary lesions are often not noticed.

Whereas some secondary syphilis can spontaneously resolve, if untreated, approximately two thirds of secondary syphilis cases enter into a prolonged period of latency where symptoms of infection are absent. Relapses of secondary symptoms may occur in up to 25% of untreated patients, usually within the first year of infection. The latent stage can last for up to 25-30 years but if untreated, about one third of latent infections will progress to tertiary syphilis. Tertiary syphilis is rare in developed countries due to early diagnosis and treatment of syphilis. Tertiary syphilis is characterized by destructive lesions known as gummas, neurologic involvement, and cardiovascular lesions. Gummas, are highly destructive granulomas, usually in the skin, bone and mucosal areas but are sometimes found in other tissues such as genitals, lung, stomach, liver, spleen, spinal cord, breast, brain, and heart. Onset is 10-15 years after infection. Cardiovascular syphilis generally appears about 20-30 years after infection when lesions in the cardiac vasculature produce ascending aortic aneurysm, aortic insufficiency, or coronary ostial stenosis. In tertiary neurosyphilis focal endoarteritis in the blood vessels of the brain and spinal cord provokes signs and symptoms, usually decades after infection, which may resemble other neurologic diseases. Clinical manifestations typically include general paresis and tabes dorsalis. The presence of oral syphilitic lesions is common, particularly in primary and secondary syphilis, and in regions with a high prevalence of syphilis other health care workers, such as dentists, need to be aware of this risk.

#### **7.3 Congenital syphilis**

Worldwide each year over 2 million pregnant women, 1.5% of all pregnancies, test positive for syphilis. *Treponema* spirochetes can cross the placenta to infect the fetus resulting in severe adverse pregnancy outcomes. Untreated maternal syphilis will result in stillbirth, premature birth, neonatal death, or congenital infection in up to 80% of pregnancies in developing countries. An estimated 25% of all stillbirths and 11% of neonatal deaths in developing countries are due to fetal syphilis exposure. Symptoms of early congenital syphilis in children less than 2 year old include cutaneous and mucocutaneous lesions, macropapular rash, hepatosplenomegaly, lymphadenopathy, bone alterations from osteitis and osteochondritis, meningitis, pneumonia, and testicular masses. Hematologic abnormalities such as thrombocytopenia and anemia may occur. Early congenital syphilis is more common than late congenital syphilis. Late congenital syphilis in children >2 year old is characterized by Hutchinson's triad, Saddle nose, and bone deformations such as Saber shins. Hutchinson's triad includes tooth deformations where the crown of the incisors is wider in the cervical portion than at the incisor edge and a crescent-shaped notch is present at the incisor edge, interstitial keratitis which can lead to blindness, and eighth nerve deafness. Saddle nose refers to collapse of the bridge and resulting dorsal depression due to erosion of septal support, giving a saddled appearance. Saber shin is a malformation of the tibia with sharp anterior bowing. Interstitial keratitis is the most common manifestation of

Sexually Transmitted Infections in the Tropics 471

allergic non-pregnant patients with neurosyphilis are treated with doxycycline, 200 mg orally twice daily for 4 weeks or tetracycline, 500 mg orally four times daily for 4 weeks. Non-penicillin allergic pregnant women diagnosed with syphilis are treated with penicillin according to the stage of infection. Early congenital syphilis should be treated with intravenous aqueous crystalline penicillin G at 50,000 units/kg/dose every 12 hours for the first 7 days and every 8 hours for the next 3 days. Alternatively early congenital syphilis is treated with IM injections of procaine penicillin at 50,000 units/kg daily for 10 days. Late congenital syphilis is treated with intravenous or intramuscular aqueous crystalline penicillin G at 50,000 units/kg/dose every 4-6 hours for 10-14 days. For penicillin allergic children, after the first month of life, administer erythromycin, 7.5-12.5 mg/kg orally, 4

*Haemophilus ducreyi*, a fastidious Gram-negative facultative anaerobic coccobacillus, is the causative agent of chancroid. Chancroid is transmitted by vaginal, anal, or oral sex with an infected individual. The organism enters thru breaks in the epithelium and resides primarily in the extracellular spaces. *Haemophilus ducreyi* can resist phagocytosis and untreated lesions

Globally, chancroid is the most common cause of genital ulcer disease in regions where the disease is endemic. WHO estimates the annual global incidence to be about 6 million cases. Chancroid occurs in parts of Africa, south-east Asia and the Caribbean where it accounts for 23-56% of genital ulcer disease. Chancroid is more common in men than women and more common in areas where HIV prevalence is high (>8%). The incidence of chancroid is much lower in developed countries and sporadic outbreaks there are associated with travel, prostitution, and drug use. Chancroid, as are all genital ulcer producing STIs, is a risk factor

After an incubation period of several days to two weeks, a tender erythematous papule develops at the site of inoculation which progresses to a pustular stage. The pustle ruptures within 2-3 days to form a painful genital ulcer with soft edges. Chancroid ulcerative lesions vary from 3-50 mm across but are typically 10-20 mm. Chancroid ulcers can be irregular, round, or oval in shape, are sharply circumscribed with an undermined edge, and contain a grey or yellow purulent exudate. Lesions will have a surrounding cutaneous erythema. One half of men have only a single ulcer and lesions typically appear on the penis: penile shaft, coronal sulcus, prepuce, urethral meatus, and glans. In women infection is often subclinical. Women have multiple ulcers more frequently than men that may merge to form large ulcers. Ulcers in women occur on the fourchette, labia majora, labia minora, cervix, perianal region, and inner thighs. "Kissing ulcers" may develop on the skin surfaces apposing the initial ulcer. Women may also experience dysuria and dyspareunia. Rectal sores in men or women may bleed or cause pain during defecation. Buboes, swelling of the inguinal lymph nodes, occur in one third to one half of infected individuals 1-2 weeks after the ulcers form and these may rupture, producing draining abscesses. The development of buboes is a more

times daily for 4 weeks.

may take months to heal.

**8.1 Epidemiology** 

for HIV transmission.

**8.2 Clinical manifestations** 

**8. Chancroid** 

late congenital syphilis. These adverse pregnancy outcomes can be prevented by syphilis screening to identify and treat maternal infections prior to 24 weeks gestation.

#### **7.4 Diagnosis**

Initial diagnosis of syphilis is typically based on clinical presentation. *Treponema* spirochetes are Gram negative but they cannot be visualized using conventional light microscopy. Darkfield microscopy and direct fluorescent antibody test of spirochetes from lesion exudates and tissue provide definitive diagnosis of early syphilis. These tests however are not utilized in most settings. Presumptive diagnosis of syphilis relies on two types of testing for antibody in blood serum or cerebrospinal fluid. The Venereal Disease Research Laboratory (VDRL) and Rapid Plasma Reagin (RPR), Toluidine Red Unheated Serum (TRUST), and Unheated Serum Reagin (USR) tests utilize a non-treponemal antigen. The VDRL and RPR tests are the most widely used of these. VDRL and PRP testing is most sensitive in the middle stages of the disease, early syphilis and late stage disease may be missed. Detectable antibody titers are not attained until 1-4 weeks after appearance of the chancre and titers often decline to undetectable levels in latency. Non-treponemal tests are nonspecific and can give false-positive results and occasionally false negative results under conditions of antibody excess which can occur during secondary syphilis. Positive results are confirmed with a test utilizing treponemal antigens, such as the fluorescent treponemal antibody absorbed (FTA-ABS) test, treponemal enzyme immunoassay (EIA), microhemagglutination assay for *T. pallidum* antibodies (TPHA), and direct fluorescent antibody-*T. pallidum* test (DFA-TP). These tests are more sensitive than non-treponemal tests in detecting primary and tertiary syphilis. Non-treponemal test antibody titers usually correlate with disease activity and become non-reactive with time after treatment. Treponemal test antibody titers do not correlate disease activity and most (75-85%) will remain reactive for the rest of their lives. Commercially available point-of care tests for syphilis have been introduced recently although these are too expensive for most situations in the developing world.

#### **7.5 Treatment**

Benzathine penicillin G, 2.4 million units by intramuscular injection (IM) in a single dose for adults or 50,000 units/kg IM for children, is the preferred treatment for primary, secondary, and early latent stage syphilis. Alternatively, procaine penicillin at 1.2 million units IM daily for 10 days is used. Penicillin allergic non-pregnant patients may be treated with doxycycline, 100 mg orally twice daily for 2 weeks or tetracycline, 500 mg orally four times daily for 2 weeks. Penicillin allergic pregnant patients may receive erythromycin, 500 mg orally, 4 times daily for 14 days. Late latent stage syphilis and tertiary syphilis is treated with three doses benzathine penicillin G at 1 week intervals, 2.4 million units IM each dose for adults and 50,000 units/kg for children. Alternatively, procaine penicillin at 1.2 million units IM daily for 20 days is used. Penicillin allergic non-pregnant patients with late latent stage or tertiary syphilis may be treated with doxycycline, 100 mg orally twice daily for 4 weeks or tetracycline, 500 mg orally four times daily for 4 weeks. Penicillin allergic pregnant patients may receive erythromycin, 500 mg orally 4 times daily for 4 weeks. Neurosyphilis is treated with intravenous aqueous crystalline penicillin G, 3-4 million units every 4 hours (18-24 million units per day) for 10-14 days, or with daily IM injections of procaine penicillin, plus 500 mg probenecid orally 4 times daily, both for 10-14 days. Penicillin allergic non-pregnant patients with neurosyphilis are treated with doxycycline, 200 mg orally twice daily for 4 weeks or tetracycline, 500 mg orally four times daily for 4 weeks. Non-penicillin allergic pregnant women diagnosed with syphilis are treated with penicillin according to the stage of infection. Early congenital syphilis should be treated with intravenous aqueous crystalline penicillin G at 50,000 units/kg/dose every 12 hours for the first 7 days and every 8 hours for the next 3 days. Alternatively early congenital syphilis is treated with IM injections of procaine penicillin at 50,000 units/kg daily for 10 days. Late congenital syphilis is treated with intravenous or intramuscular aqueous crystalline penicillin G at 50,000 units/kg/dose every 4-6 hours for 10-14 days. For penicillin allergic children, after the first month of life, administer erythromycin, 7.5-12.5 mg/kg orally, 4 times daily for 4 weeks.
