SEXUALLY TRANSMITTED INFECTIONS (STI)

General Goal: To know the major cause(s) of these infections, how they are transmitted, and the major manifestations of the infections.

Specific Educational Objectives: The student should be able to:

1. Identify the common cause of each of the STI's discussed in this handout and the next two STI handouts. Know the common or pathognomonic signs of the infections.

2. Describe the major manifestations of each infection and differentiate it from other infections in the course.

2. Use serology in diagnosing syphilis. You should be familiar with the pathogenesis of syphilis. You do not have to know all the information in the handout about neurosyphilis.

3. Describe how you diagnose, treat and prevent these infections.

Reading: MEDICAL MICROBIOLOGY by P.R. Murray, K.S. Rosenthal, G.S. Kobayashi and M.A. Pfaller, 3rd Edition. depends on the organism.

F.S. Southwick, Infectious Diseases in 30 Days, 1^st edition, McGraw Hill. p. 289-318.

Lecture: Dr. Neal R. Chamberlain

References: 

1. Burstein GR, Zenilman JM. Nongonococcal urethritis--a new paradigm. Clin Infect Dis 1999 Jan;28 Suppl 1:S66-73
2. Hoeprich, PD., MC. Jordan, and AR. Ronald. Infectious Diseases: A Treatise of Infectious Processes. 5th edition. 1994. J.B. Lippincott Company, Philadelphia, PA.
3. CDC. The national plan to eliminate syphilis from the United States. Atlanta, Georgia: US Department of Health and Human Services, CDC, National Center for HIV, STD, and TB Prevention, 1999:1--84.
4. Primary and Secondary Syphilis --- United States, 1999. MMWR. 50(01);113-117.
5. Sexually Transmitted Disease Guidelines 2002. Recommendations and Reports
   May 10, 2002/Vol. 51/No.RR-6 (http://www.cdc.gov/std/treatment/TOC2002TG.htm)

OVERVIEW

It is important to understand at least five key points about all STI's in this country today:

1. STI's affect men and women of all backgrounds and economic levels. They are most prevalent among teenagers and young adults. Nearly two-thirds of all STI's occur in people younger than 25 years of age.

2. The incidence of STI's is rising, in part because in the last few decades, young people have become sexually active earlier yet are marrying later. In addition, divorce is more common. The net result is that sexually active people are more likely to have multiple sex partners and are more likely to acquire STI's.

3. Usually STI's cause no symptoms. This is especially true in women. If symptoms develop, they may be confused with those of other diseases not transmitted through sexual contact. Even when an STI causes no symptoms a person who is infected may be able to pass the disease on to a sex partner (ex. genital herpes, HIV).

4. Health problems caused by STI's tend to be more severe and more frequent for women than for men. This is because of the increased frequency of asymptomatic infections. As a result many women do not seek care until serious problems develop.

• Some STI's can spread into the uterus and fallopian tubes to cause pelvic inflammatory disease (PID), which in turn is the major cause of  both involuntary infertility and ectopic (tubal) pregnancy.
• STI's in women also may be associated with cervical cancer (e.g. Papillomavirus infections).
• STI's can be passed from a mother to her baby before, during, or immediately after birth. Some of these infections of the newborn can be cured easily (ex. opthalmia neonatorium), but others may cause a baby to be permanently disabled (ex. congenital syphilis or CMV) or even die (e.g. Herpes Simplex virus, HIV).

STI Prevention

The prevention and control of STIs is based on the following five major concepts: 

1. education and counseling of persons at risk on ways to adopt safer sexual behavior; 

2. identification of asymptomatically infected persons and of symptomatic persons unlikely to seek diagnostic and treatment services;

3. effective diagnosis and treatment of infected persons; 

4. evaluation, treatment, and counseling of sex partners of persons who are infected with an STI; and 

5. preexposure vaccination of persons at risk for vaccine-preventable STIs (Hep A and B)

Prevention of STIs begins with changing the sexual behaviors that place persons at risk for infection. Since STI control activities reduce the likelihood of transmission to sex partners, treatment of infected persons constitutes primary prevention of spread within the community.

Sexual Transmission

The most reliable way to avoid transmission of STIs is to abstain from sexual intercourse (i.e., oral, vaginal, or anal sex) or to be in a long-term, mutually monogamous relationship with an uninfected partner. Counseling that encourages abstinence from sexual intercourse is essential for patients who are being treated for an STI or whose partners are undergoing treatment and for persons who wish to avoid the possible consequences of sexual intercourse (e.g., STI/HIV and unintended pregnancy).

If two people wish to become sexually active the following can lower the chances a person will acquire a STI.

• Test both partners for STIs, including HIV, before initiating sexual intercourse.
• If a person chooses to have sexual intercourse with a partner whose infection status is unknown or who is infected with HIV or another STI, a new condom should be used for each act of insertive intercourse.

Preexposure Vaccination

Preexposure vaccination is one of the most effective methods for preventing transmission of Hepatitis A and B infections. Hepatitis B virus infection frequently is sexually transmitted, hepatitis B vaccination is recommended for all unvaccinated persons being evaluated for an STI. In addition, hepatitis A vaccine is currently licensed and is recommended for men who have sex with men (MSM) and illegal drug users (both injection and non-injection).

Prevention Methods

Male Condom

When condoms are used consistently and correctly, they are effective in preventing the sexual transmission of HIV infection and can reduce the risk for other STIs (i.e., gonorrhea, chlamydia, and trichomoniasis). Since, condoms do not cover all exposed areas, they are more effective in preventing infections transmitted by fluids from mucosal surfaces (e.g., gonorrhea, chlamydia, trichomoniasis, and HIV) than in preventing those transmitted by skin-to-skin contact (e.g., herpes simplex virus [HSV], HPV, syphilis, and chancroid).

Female Condoms

Laboratory studies indicate that the female condom is an effective mechanical barrier to viruses, including HIV. If used consistently and correctly, the female condom may substantially reduce the risk for STIs. When a male condom cannot be used properly, sex partners should consider using a female condom.

Vaginal Spermicides, Sponges, and Diaphragms

Recent evidence has indicated that vaginal spermicides containing nonoxynol-9 (N-9) are not effective in preventing cervical gonorrhea, chlamydia, or HIV infection. Frequent use of spermicides containing N-9 has resulted in genital lesions, which may be associated with an increased risk of HIV transmission. Spermicides alone are not recommended for STI/HIV prevention.

The vaginal contraceptive sponge appears to protect against cervical gonorrhea and chlamydia, but its use increases the risk for candidiasis. Diaphragm use has been demonstrated to protect against cervical gonorrhea, chlamydia, and trichomoniasis. Neither vaginal sponges nor diaphragms should be relied on to protect women against HIV infection. Diaphragm and spermicides have been associated with an increased risk of bacterial urinary tract infection in women.

Condoms and N-9 Vaginal Spermicides

Condoms lubricated with spermicides are no more effective than other lubricated condoms in protecting against the transmission of HIV and other STIs.

Rectal Use of N-9 Spermicides

Recent studies have demonstrated that N-9 may increase the risk of HIV transmission during vaginal intercourse. Although similar studies have not been conducted among men who use N-9 spermicide during anal intercourse with other men, N-9 can damage the cells lining the rectum, thus providing a portal of entry for HIV and other sexually transmissible agents. Therefore, N-9 should not be used as a microbicide or lubricant during anal intercourse.

Nonbarrier Contraception, Surgical Sterilization, and Hysterectomy

Women who are not at risk for pregnancy might incorrectly perceive themselves to be at no risk for STIs, including HIV infection. Contraceptive methods that are not mechanical or chemical barriers offer no protection against HIV or other STIs.

The STI's will be divided into 5 different groups based on their clinical presentations:

1. Diseases Characterized by Genital Ulcers

2. Diseases Characterized by Urethritis and Cervicitis

3. Other STI's

   • Pelvic inflammatory Disease

   • Genital Warts (Human Papillomavirus Infections)

   • Epididymitis

   • Proctitis, Proctocolitis, and Enteritis

4. Diseases Characterized by Vaginal Discharge

5. Ectoparasitic Infections

A. Diseases Characterized by Genital Ulcers

Most young, sexually active patients who have genital ulcers have genital herpes, syphilis, or chancroid. The frequency of each disease differs by geographic area and patient population; however, genital herpes is the most prevalent of these diseases. In urban areas with large amounts of prostitution chancroid is more common but not as common as genital herpes. In the Southeastern U.S. syphilis is more common that in other parts of the country.

The diseases covered in this section include:

1. Genital Herpes

2. Syphilis

3. Chancroid

4. Granuloma Inguinale 

5. Lymphgranuloma Venereum

More than one of these diseases can be present in a patient who has genital ulcers. Each disease has been associated with an increased risk for HIV infection. Not all genital ulcers are caused by sexually transmitted infections.

A diagnosis based only on the patient's medical history and physical examination often is inaccurate. Evaluation of all patients who have genital ulcers should include:

•  a serologic test for syphilis; 
• a diagnostic evaluation for genital herpes; 
• and in settings where chancroid is prevalent, a test for Haemophilus ducreyi. 

Specific tests for evaluation of genital ulcers include:

• serology, and either darkfield examination or direct immunofluorescence test for T. pallidum;
• culture or antigen test for herpes simplex virus (HSV); and
• culture for H. ducreyi.

There are several characteristics of these infections that may aid in the diagnosis. Primary syphilis lesions are usually indurated (hard) and painless. Genital herpes and chancroid ulcers are oftentimes painful and are not indurated. There is usually only one syphilitic primary ulcer whereas, there are usually more than one ulcer present in chancroid and genital herpes. Genital herpes ulcers are preceded by vesicular lesions that then break open and result in irregularly shaped ulcers. Chancroid and syphilitic ulcers, also called chancres, are usually more uniform in shape.

1. Genital Herpes (= herpes genitalis)  

Genital herpes is a recurrent life-long inflammatory viral disease of the male and female genital tract. 

• Herpes simplex virus (HSV) exists as two closely related forms which are antigenically and biologically distinct. Five percent to 30% of first-episode cases of genital herpes are caused by HSV-1, but clinical recurrences are much less frequent for HSV-1 than HSV-2 genital infection. Therefore, identification of the type of the infecting strain has prognostic importance and may be useful for counseling purposes.
  • HSV-1 is primarily transmitted by nonvenereal routes, particularly following contact with infected saliva and is responsible for facial and oropharyngeal infections like herpetic gingivostomatitis and the common cold sore or fever blister.
  • HSV-2 is usually transmitted venereally or maternally to newborn infants and is responsible for genital herpes and neonatal infections. -- also it has been linked epidemiologically with carcinoma of the cervix

• approximately 20% of genital herpes cases are due to HSV-1
• HSV-2 may induce oropharyngeal infections

B. Epidemiology

• HSV is an extremely successful and ubiquitous parasite of man; it is estimated that 10% of adult U.S. population experiences symptomatic genital herpes and the incidence is increasing.
• At least 50 million people in the U.S. are infected with HSV.
• Most persons infected with HSV-2 have not been diagnosed. Many such persons have mild or unrecognized infections but shed virus intermittently in the genital tract.
• Acquisition of HSV-2 is by either sexual contact with a symptomatic person or transfer to a fetus/newborn from an infected mother.
• Risk of infection is approximately 75% following contact with a symptomatic case.

B. Epidemiology

• HSV is an extremely successful and ubiquitous parasite of man; it is estimated that 10% of adult U.S. population experiences symptomatic genital herpes and the incidence is increasing.
• At least 50 million people in the U.S. are infected with HSV.
• Most persons infected with HSV-2 have not been diagnosed. Many such persons have mild or unrecognized infections but shed virus intermittently in the genital tract.
• Acquisition of HSV-2 is by either sexual contact with a symptomatic person or transfer to a fetus/newborn from an infected mother.
• Risk of infection is approximately 75% following contact with a symptomatic case.

Genital Herpes in Pregnancy

Severe disease due to HSV can result in the neonate or the fetus following infection with HSV. These infections include; disseminated infection, pneumonitis, hepatitis, or complications of the central nervous system (e.g., meningitis or encephalitis).

Most mothers of infants who acquire neonatal herpes lack histories of clinically evident genital herpes. The risk for transmission to the neonate from an infected mother is high (30%--50%) among women who acquire genital herpes near the time of delivery and is low (<1%) among women with histories of recurrent herpes at term or who acquire genital HSV during the first half of pregnancy. However, because recurrent genital herpes is much more common than initial HSV infection during pregnancy, the proportion of neonatal HSV infections acquired from mothers with recurrent herpes remains high. Prevention of neonatal herpes depends both on preventing acquisition of genital HSV infection during late pregnancy and avoiding exposure of the infant to herpetic lesions during delivery.

Women without known genital herpes should be counseled to avoid intercourse during the third trimester with partners known or suspected of having genital herpes. In addition, pregnant women without known orolabial herpes should be advised to avoid cunnilingus during the third trimester with partners known or suspected to have orolabial herpes.

C. Manifestations

1. Primary genital herpes acquired following sexual contact with symptomatic partner
• Incubation period of 2-7 days (2-21 days)
• Initial manifestations include local pain, tenderness, itching sensation, dysuria, and in females, a profuse, watery vaginal discharge.
• Initial lesions are papules on a red erythematous base but they rapidly develop into vesicles and later ulcers covered with a grayish exudate.
• In females the vesicles develop on labia majora and minora, vaginal mucosa, cervix, and perineal region.
• In males the lesions typically appear on the glans penis, the prepuce, and the shaft of the penis.
• Of course the vesicles are full of infectious virus, so contact via scratching can spread the infection anywhere, including extra genital regions.
• These lesions are self-limiting and heal in about 3 weeks.
• 75% of patients present with a painful, nonsuppurative inguinal, pelvic and/or femoral lymphadenopathy.
• Constitutional symptoms:
• headache
• malaise
• myalgias
• approximately 15% of cases also have herpetic pharyngitis
2. The manifestations of recurrent genital herpes are similar but less severe, and resolve faster.
• Recurrence is generally at about 4 months after the first episode and then at approximately 6-8 week intervals and may be hormonally triggered during menses.

3. Newborns who pick up the virus during passage through the birth canal of a symptomatic female usually develop disseminated infection with a 60- 70% fatality rate.

• It is estimated that 1 in 20,000 deliveries is potentially involved.
• There is a 50% chance of infection.
• The virus can also cross the placenta and result in stillbirth or extreme teratogenic effects.

• The virus is introduced into the genital mucosa by sexual contact with an HSV infected partner. Symptomatic AND asymptomatic HSV infected sexual partners can spread the infection to an uninfected partner.
• Viral replication induces an erythematous papule that swells into a fluid-filled vesicle. -- This fluid has much infectious virus and degenerating cells containing eosinophilic intranuclear inclusion bodies and multinucleated giant cells. -- Eventually these vesicles rupture to leave small ulcers covered with a grayish exudate. -- The lesions heal in about 3 weeks.
• During primary infections you have extensive viremia and regional lymphadenopathy.
• Eventually local interferon as well as specific antibody and CMI will curtail virus replication.
• The virus invades local nerve endings, ascends the axons, and establishes latency in the sacral ganglia, however.
• This is the usual source of recurrence because the virus reactivates, travels down the axon, and causes new lesions in the epidermis.

• A clinical diagnosis based upon presence of vesicular lesions in genital area and sexual history is important and highly suggestive.
• other disease may cause similar lesions so laboratory backup is important.
• Laboratory approaches for the diagnosis of genital herpes include:
• Virus isolation, demonstration of characteristic CPE in target cells, and inhibition of CPE with type specific antisera. The sensitivity of culture declines rapidly as lesions begin to heal, usually within a few days of onset.
• Cytologic examination -- Scrape off cells from the base of the ulcer and look for eosinophilic intra nuclear inclusion bodies and multi-nucleated giant cells.
• Direct immune fluorescent staining of cells scraped off the base of the ulcer.
• Because false-negative HSV cultures are common, especially in patients with recurrent infection or with healing lesions, type-specific serologic tests are useful in confirming a clinical diagnosis of genital herpes. Both type-specific and nonspecific antibodies to HSV develop during the first several weeks following infection and persist indefinitely. Because almost all HSV-2 infections are sexually acquired, type-specific HSV-2 antibody indicates anogenital infection, but the presence of HSV-1 antibody does not distinguish anogenital from orolabial infection. Accurate type-specific assays for HSV antibodies must be based on the HSV-specific glycoprotein G2 for the diagnosis of infection with HSV-2 and glycoprotein G1 for diagnosis of infection with HSV-1.

Patients having a first episode of genital herpes should be advised that

• episodic antiviral therapy during recurrent episodes might shorten the duration of lesions and suppressive antiviral therapy can ameliorate or prevent recurrent outbreaks.
• Treatment does not cure.

First clinical episode:

• Acyclovir 400 mg orally three times a day for 10 days, OR
• Acyclovir 200 mg orally five times a day for 10 days, OR
• Famciclovir 250 mg orally three times a day for 5-10 days, OR
• Valacyclovir 1 g orally twice a day for 10 days.

Recommended Regimens for Episodic Recurrent Infection:

• Acyclovir 400 mg orally three times a day for 5 days, OR
• Acyclovir 200 mg orally five times a day for 5 days, OR
• Acyclovir 800 mg orally twice a day for 5 days, OR
• Famciclovir 125 mg orally twice a day for 5 days, OR
• Valacyclovir 500 mg orally twice a day for 5 days.

Recommended Regimens for Daily Suppressive Therapy

• Acyclovir 400 mg orally twice a day, OR
• Famciclovir 250 mg orally twice a day, OR
• Valacyclovir 250 mg orally twice a day, OR
• Valacyclovir 500 mg orally once a day, OR
• Valacyclovir 1,000 mg orally once a day.

Recurrent Episodes of HSV Disease:

1. When treatment is started during the prodrome or within 1 day after onset of lesions, many patients who have recurrent disease benefit from episodic therapy.
2. Daily suppressive therapy reduces the frequency of genital herpes recurrences by greater than or equal to 75% among patients who have frequent recurrences (i.e., six or more recurrences per year). Suppressive treatment with acyclovir reduces but does not eliminate asymptomatic viral shedding.

These antiviral compounds have NO effect on establishment of latency and subsequent recurrences can and do occur. However, the recurrences maybe less numerous and less severe.

Severe Disease
IV therapy should be provided for patients who have severe disease or complications necessitating hospitalization, such as disseminated infection, pneumonitis, hepatitis, or complications of the central nervous system (e.g., meningitis or encephalitis). Acyclovir 5-10 mg/kg body weight IV every 8 hours for 5-7 days or until clinical resolution is attained.

G. Prognosis

• The primary lesions heal spontaneously and it is usually a self-limiting disease.
• The patient must be educated as to the clinical course of the disease, the likelihood of reccurrence, and the potential for infecting others.

H. Prevention

Patients who have genital herpes should be told about the natural history of the disease, with emphasis on the potential for recurrent episodes, asymptomatic viral shedding, and sexual transmission.

Patients should be advised to abstain from sexual activity when lesions or prodromal symptoms are present and encouraged to inform their sex partners that they have genital herpes. The use of condoms during all sexual exposures with new or uninfected sex partners should be encouraged.

Sexual transmission of HSV can occur during asymptomatic periods. Asymptomatic viral shedding occurs more frequently in patients who have genital HSV-2 infection than HSV-1 infection and in patients who have had genital herpes for less than 12 months. Such patients should be counseled to prevent spread of the infection.

The risk for neonatal infection should be explained to all patients, including men. Childbearing-aged women who have genital herpes should be advised to inform health-care providers who care for them during pregnancy about the HSV infection.

At the onset of labor, all women should be questioned carefully about symptoms of genital herpes, including prodrome, and all women should be examined carefully for herpetic lesions. Women without symptoms or signs of genital herpes or its prodrome can deliver vaginally. Most specialists recommend that women with recurrent genital herpetic lesions at the onset of labor deliver by cesarean section to prevent neonatal herpes.

2. Syphilis

Syphilis is a sexually transmitted infectious disease caused by the bacterium Treponema pallidum.

A. T. pallidum has a number of characteristics which are important for diagnosis. 

1. The spiral shaped morphology and characteristic motility pattern (they spin around their longitudinal axis in a corkscrew type manner) are important for diagnosis via darkfield microscopy. Here is a picture of the cross section of the organism.
2. T. pallidum cannot be grown in vitro.

1. Man is the only known host and transmission is virtually always by direct contact with infectious lesions, generally through sexual contact.
2. The incidence is highest in sexually active people (20-29 year old group).
3. The number and rate of 1^o and 2^o (P&S) syphilis cases reported in 1999 were the lowest ever reported in the United States.
4. There are approximately 6,000-7,000 new cases of 1° and 2° or P&S syphilis diagnosed per year
5. Approximately 30% of exposed people contract the disease.
6. In 1999, 6657 cases of P&S syphilis were reported in the United States (2.5 per 100,000 population), a 5.4% decrease from the 7035 cases (rate: 2.6) reported in 1998 and a 22% decrease from the 8556 cases (rate: 3.2) reported in 1997.
7. The South continues to have the highest rate in the country (rate: 4.5)
8. From 1998 to 1999, rates declined 10% in the South (from 5.0 to 4.5) and 12.5% in the Northeast (0.8 to 0.7). The rate for the West remained unchanged (1.0), and the rate for the Midwest increased from 1.9 in 1998 to 2.2 in 1999.
9. P&S syphilis rates have declined in 28 states since 1998, and 39 states have rates below the national health objective for 2000 of 4.0.
10. Nine of the 11 states that have rates above the 2000 objective are in the South.
11. In 1999, of 3115 U.S. counties, 2473 (79.4%) reported no cases of P&S syphilis.
12. In 1999, 22 counties and Baltimore, Maryland; Danville, Virginia; and St. Louis, Missouri, accounted for 50% of all reported P&S syphilis cases in the United States.
13. Syphilis continues to disproportionately affect minority populations despite progress in reducing this racial disparity. P&S syphilis rates for African Americans have remained substantially higher than those for Caucasians. However, the magnitude of this difference has decreased 30% since 1997.
14. The persistence of racial disparities in syphilis incidence is, in part, attributable to differences between African Americans and Caucasians regarding poverty and in access to and use of health-care services, especially in the rural South.
15. Historically, rates of syphilis have been higher for men than women. The male-to-female rate ratio peaked at 3.5:1 in 1980 during the height of syphilis transmission among men who have sex with men (MSM) and decreased to 1:1 in 1994; since then, it has increased gradually.

C. The manifestations of syphilis depend on the stage of disease the patient is in.

1. Manifestations of primary syphilis: a) hard chancre (lesion on female); and b) regional lymphadenitis.

• Following an incubation period of approximately 3 weeks (10-90 days, referred to as the incubation phase of syphilis), the principal lesion, a hard chancre, develops.
1. Syphilitic chancres are indurated (= hard chancre)
2. They are highly infectious
3. They may occur anywhere on the body
4. They are painless
5. Chancres will heal in 3-6 weeks.
• Regional lymphadenopathy adjacent to the chancre may develop during primary syphilis.
1. The nodes are firm, nonsuppurative
2. It may persist for months, despite healing of the chancre.

• Lesions generally begin 6-8 weeks after the appearance of the initial chancre and may overlap the time when the chancre is still present.
• The principal manifestations of 2° syphilis are skin and mucous membrane lesions, as well as manifestations of systemic disease.
1. Skin and mucous membrane lesions include
• Skin lesions vary from macular, papular, or occasional pustular and nodular type rashes. Can occur on the palms and the soles.
• Patchy alopecia
• Condyloma lata - moist, flat, confluent plaques
•  Mucous patches
2. Manifestations of systemic disease during 2° syphilis include
• Malaise
• Anorexia
• Headache
• Sore throat
• Arthralgia
• Low grade fever
• Generalized lymphadenopathy
• 2° syphilis lasts 2-6 weeks before the patient enters the latent phase.
• There is a high bacteremia during secondary syphilis.

• Its duration is highly variable.
• Approximately 25% of patients experience a relapse of 2° syphilis.
• Only about 1/3 of latent cases progress to 3° syphilis.

4. Tertiary or late syphilis is a noncontagious but highly destructive phase of syphilis which may take many years to develop; it may manifest itself in several forms:

• Late benign or gummatous syphilis is the most common form of 3° syphilis.
• It develops in 15% of untreated cases within 1-10 years after infection.
• Gummas are nodular lesions characterized by a granulomatous inflammation.
• Gummas may be in any organ.
• Cardiovascular syphilis
• 10% of untreated syphilis cases develop this 10-40 years after initial infection.
• The basic lesion is an aortitis consisting of necrosis resulting from thickening and hardening of the vasa vasorum. -- The elastic tissue is replaced by fibrous tissue -- This is manifested by:
• Aortic regurgitation because of altered aortic valve function
• Aneurysm because of weakened vessel walls
• Obstruction of the coronary ostia
• Neurosyphilis
• Symptoms of neurosyphilis are expressed only in approximately 8% of untreated cases and then only 5-35 years after infection. Invasion of the CNS occurs early when generalized dissemination occurs (2° syphilis).

• """Neurosyphilis is categorized into 4 forms:
• Asymptomatic neurosyphilis in which there are no symptoms of CNS involvement but the CSF is abnormal:
• Elevated lymphocytes
• Elevated protein
• Positive CSF VDRL tests
• Approximately 20% of these patients progress to symptomatic neurosyphilis
• Forms of symptomatic neurosyphilis
• Acute meningitis
1. Seen within 2 years of infection
2. A lot like other meningitis
3. Headache
4. Vertigo nausea, vomiting
5. Generalized convulsions
6. Cervical rigidity
7. Positive Kernig's and Brudzinski's signs
8. The third cranial nerve is most often affected
• Chronic meningovascular
1. Seen 2-5 years, but no later than 10 years of infection
2. A proliferative endarteritis and perivascular infiltration with lymphocytes (perivascular cuffing)
3. Leads to blocking of blood vessels and necrosis of nerve tissue
4. Gradual intellectual and emotional deterioration
5. Most commonly the middle and posterior arteries are involved. Usually see a weakening in one side.
6. Headache, nausea, vomiting
7. 3rd, 4th, 6th cranial nerves are affected most often.
• General paresis
• About 5% of patients experience general paresis
• Seen 20 or more years after untreated infection
• Symptoms:
• Personality changes: neurosis, euphoria, depression, over activity, paranoia
• Affect: Reaction to a problem is inappropriate to the problem. Often act in an "all-out" type of reaction much like a child.
• Reflexes: Hyperactive
• Eyes: Argyll Robertson pupils
• Sensorium: Delusions, illusions, hallucinations, and paranoid ideas
• Intellect: Reduction in mental capacity, orientation, retention and recall, calculations, judgment, and insight
• Speech: Slurred speech, S & L pronounced slowly, tremors of lips and tongue, repeats last few words, face often smooth and mask like
• Several forms of general paresis
• Early stage
• Simple dementia
• Euphoric or expansive paretic
• Agitated paretic
• Depressed paretic
• Tabes dorsalis
1. 5-20 years after the 1° or 2° stages.
2. 3 stages
• preataxic - lightning like pain radiating from the gluteal region to the heel or foot paresthesia of the soles of the feet; feels like walking on carpet or wood, also patient develops a loss of sense of position and passive motion. Poor control of the extremities.
• Atoxic - loss of deep sensory abilities, difficulty in maintaining balance, sways side to side when eyes are closed, holds body stiffly.
• Paralytic - requires one or 2 canes to walk, cannot feel feet touching surfaces.
3. Treatment will not help.""""

5. Congenital syphilis results when maternal syphilis spreads in utero to the fetus after the 4th month of gestation.

• If the mother is highly infective, the baby will be stillborn or present with a fulminating case of syphilis manifested initially (during first 2 years of life) by:
1. Rhinitis, snuffles followed by skin and mucocutaneous lesions similar to those of adult 2° syphilis
2. Osteochondritis (inflamed bone and cartilage and osteitis (inflammation of bone)
3. Hepatosplenomegaly and lymphadenopathy
4. Immune complex-induced glomerulonephritis
5. Death in first 2 years is due to pulmonary hemorrhage, 2° bacterial infection or hepatitis
• Late congenital syphilis (after 2 years of age) manifestations
1. In 60% of 2-year survivors the infection is subclinical.
2. The remainder develop manifestations similar to those of adults with 3° syphilis, as well as the following:
• Clutton's joints = painless symmetrical hydrarthrosis of the knee joint
• Deafness
• Hutchinson's teeth = notched and narrow edged permanent incisors
• Mulberry molars
• Bone abnormalities:
• Saddle nose
• Saber shins
• Rhagades = fissures, cracks or fine linear scars in the skin especially around the mouth and other regions subjected to frequent movement.

1. The organisms enter the body via minute abrasions of epithelial cell linings, by penetrating mucous membranes or via hair follicles, and then there is a rapid systemic spread via the blood and lymphatics.
2. The most prominent histologic features are vascular changes caused by endarteritis and periarteritis (perivascular cuffing).

E. Diagnosis of syphilis is accomplished via: 

1. Evaluation of presenting signs and symptoms as well as contact history
2. Darkfield examination of exudative material in syphilitic lesions

• Direct fluorescent Ab test for T. pallidum(DFAT-Tp)
1. Serological approaches using treponemal or nontreponemal tests
• Nontreponemal tests measure anti-treponemal antibody using a cross reactive cardiolipin lecithin as an antigen rather than the actual bacterial antigens.
• VDRL slide test (Venereal Disease Research Laboratories)
• USR - (Unheated Serum Reagin)
• RPR 18 mm circle card (Rapid Plasma Reagin)
• TRUST (Toluidine Red Unheated Serum Test)
• RST (Reagin Screen Test)
• Treponemal antigen tests rely upon antigens derived directly from T. pallidum.
• Examples include:
• FTA-ABS or fluorescent treponemal antibody-absorption test where you mix spirochetes with the patient's serum, add FITC-tagged anti-human globulin and look for fluorescence in a fluorescent microscope.
• FTA-ABS double staining - same as FTA-ABS except also add anti-human antibody with a red fluorescent dye.
• MHATP T. pallidum hemagglutination test where you mix formalinized, tanned sheep erythrocytes coated with T. pallidum antigens with the patient's serum and look for agglutination.

False + serological reactions in non-treponemal antigen tests are quite common and may occur in patients with:

1. hepatitis
2. infectious mononucleosis
3. viral infections
4. malaria
5. pregnancy
6. connective tissue disease like SLE
7. disease with Ig abnormalities
8. in some healthy people

False positives in direct treponemal tests are more rare because they are more specific; they are associated with:

1. diseases with Ig abnormalities
2. multiple myeloma
3. SLE

1. In untreated cases:
• 25% of people experience one or more relapses with the development of mucocutaneous lesions during the first four years.
• Approximately 33% will develop manifestations of late syphilis.
• The remaining 66% do not develop manifestations of late syphilis but signs are present at autopsy.
2. Treatment during 1° and 2° syphilis aborts the process but the changes associated with 3° syphilis are irreversible for the most part (except for gummas).

1. Patients who have primary or secondary syphilis should be treated with the following regimen: Benzathine penicillin G 2.4 million units IM in a single dose.
2. Early Latent Syphilis: Benzathine penicillin G 2.4 million units IM in a single dose.
3. Late Latent Syphilis or Latent Syphilis of Unknown Duration: Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM each at 1-week ntervals.
4. Tertiary Syphilis: Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at 1-week intervals.
5. Recommended Regimen for Children: Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose.
6. Congenital Syphilis: Aqueous crystalline penicillin G 100,000-150,000 units/kg/day, administered as 50,000 units/kg/dose IV every 12 hours during the first 7 days of life, and every 8 hours thereafter for a total of 10 days; OR Procaine penicillin G 50,000 units/kg/dose IM a day in a single dose for 10 days.
7. Identify source contact, examine and treat.
8. Treatment of congenital syphilis.
• Treatment of mother before 16th week of pregnancy prevents congenital syphilis.
• Treatment after the 16th week also helps fetus but may not alleviate all of the future manifestations. Treat child if maternal treatment is inadequate, unknown, with drugs other than penicillin, or if follow-up is not ensured, treat child with penicillin.
POST TREATMENT FOLLOW-UP IS IMPORTANT. Jarisch-Herxheimer Reaction: Intensification of existing syphilitic lesions and/or exacerbation of old ones following administration of penicillin; the reaction subsides in 24 hours and you should simply warn the patient to expect it. 

In October 1999, CDC, in collaboration with other federal partners, launched the National Plan to Eliminate Syphilis in the United States. In 1998, Congress initiated funding for the syphilis elimination effort. Syphilis elimination is defined as the absence of sustained transmission (i.e., no transmission after 90 days of the report of an imported index case). The national goal for syphilis elimination is to reduce primary and secondary (P&S) syphilis to <1000 cases (rate: 0.4 per 100,000 population) and to increase the number of syphilis-free counties to 90% by 2005.

To sustain progress toward syphilis elimination, communities must understand local patterns of syphilis transmission and develop intervention strategies, including education, risk reduction, and screening of persons at risk for this disease.

3. Chancroid or soft chancre disease  

Chancroid is an acute sexually transmitted disease characterized by genital ulceration and suppuration caused by the organism Haemophilus ducreyi.

A. Haemophilus ducreyi (= Ducrey's bacillus) is a Gram(-) rod which grows in chains.

B. Epidemiology

1. Transmission of H. ducreyi is almost exclusively by sexual contact.
2. Hygiene and cleanliness are important determinants of contagiousness.
3. The incidence in the U.S. has declined; <1,500 cases/year.
4. Prostitution is a major cause of spread (seen a lot during Korean and Vietnam wars).
5. About 10% of persons who acquire chancroid in the United States are coinfected with T. pallidum or HSV

C. Clinical manifestations

• There is an incubation period of 1-14 days after exposure before you get the development of the characteristic lesion, the soft chancre.
• Chancre development begins as a small inflammatory papule.
• The lesion is a true ulcer.
• In contrast to the syphilis chancre, the chancroid is extremely painful.
• The chancroid lacks induration and is referred to as a soft chancre.
• Initially the lesion is typically solitary but by autoinoculation multiple lesions develop.
• Accompanying chancroid development is an acute, painful inflammatory inguinal lymphadenopathy in > 50% of cases.

D. Pathology and pathogenesis

• The organism enters the body through skin abrasions.
• It induces a papule or vesicle which ulcerates.
• There is a dense inflammatory exudate with PMNs but not mononuclear cells.

E. Diagnosis

• Evaluation of lesion as well as sexual history.
• Specific diagnosis depends upon culture of H. ducreyi.
• A probable diagnosis, for both clinical and surveillance purposes, can be made if all the following criteria are met: a) the patient has one or more painful genital ulcers; b) the patient has no evidence of T. pallidum infection by darkfield examination of ulcer exudate or by a serologic test for syphilis performed at least 7 days after onset of ulcers; c) the clinical presentation, appearance of genital ulcers and, if present, regional lymphadenopathy are typical for chancroid; and d) a test for HSV performed on the ulcer exudate is negative. 
• The combination of a painful ulcer and tender inguinal adenopathy, symptoms occurring in one third of patients, suggests a diagnosis of chancroid; when accompanied by suppurative inguinal adenopathy, these signs are almost pathognomonic.
• Differential diagnosis involves distinguishing
• Primary genital herpes type 2 infection
• Primary syphilis
• Lymphogranuloma venereum
• Granuloma inguinale
• Trauma
G. Prognosis
• Soft chancres may heal quickly and spontaneously (enhanced with improved hygiene).
• They may persist and induce deep scars.

H. Therapy

1. Azithromycin 1 g orally in a single dose,
        OR
   Ceftriaxone 250 mg intramuscularly (IM) in a single dose,
        OR
   Ciprofloxacin 500 mg orally twice a day for 3 days,
        OR
   Erythromycin base 500 mg orally three times a day for 7 days.
2. Patients should be reexamined 3-7 days after initiation of therapy.
3. Patients who are uncircumcised and patients with HIV infection do not respond as well to treatment.
4. If treatment is successful, ulcers usually improve symptomatically within 3 days and objectively within 7 days after therapy.
5. Clinical resolution of fluctuant lymphadenopathy is slower than that of ulcers and may require needle aspiration or incision and drainage, despite otherwise successful therapy. Aspiration of fluctuant lymph nodes to remove the pus.

4. Granuloma inguinale (also called lupoid ulceration granuloma of the pudenda and granuloma contagiosa) 

This disease is a chronic, indolent, ulcerative, granulomatous disease of the skin and lymphatics.

A. Etiology

• Calymmatobacterium granulomatis is the etiological agent; it is a Gram -rod with characteristic bipolar staining so they have a safety pin-like appearance in stained tissue preparation. -- We call them Donovan bodies.

• It is endemic in the tropics and very rare in the U.S.; probably < 100 cases/year.
• A venereal disease that is sexually transmitted but is not very contagious.

• Genital lesions are present in 90% of infected patients and in 80% of these there is no other area of involvement.
• Initially the lesions are papules that tend to ulcerate slowly.
• The ulcerated lesions are irregular in shape with a rolled border on a beefy red, cobblestone base (image 1 and 2).
• Patients develop subcutaneous granulomas in the inguinal regions; they do not involve the lymph nodes usually, so we call them pseudo-buboes.

• The organism gains entry by direct inoculation through skin abrasions or mucous membranes.
• One or more indurated papules form which progress to characteristic ulceration.
• The most important sign is the presence of mononuclear cells with intra cytoplasmic vacuoles packed with the bacteria or Donovan bodies as they are called.

• Evaluate the nature of the lesion (nodules which erode to form painless, beefy, granulomatous ulcers) and sexual history.
• Demonstrate the pathopneumonic enlarged mononuclear cells containing vacuoles filled with Donovan bodies.

• In order of preference:
• Trimethoprim-sulfamethoxazole one double-strength tablet orally twice a day for a minimum of 3 weeks, OR
• Doxycycline 100 mg orally twice a day for a minimum of 3 weeks.
Alternative therapy
• Ciprofloxacin 750 mg orally twice a day for a minimum of 3 weeks, OR
• Erythromycin base 500 mg orally four times a day for a minimum of 3 weeks.
• Follow-up weekly
• Check sex partners

5. Lymphogranuloma Venereum or LGV

LGV is a sexually transmitted disease caused by Chlamydia trachomatis and is characterized by acute inguinal lymphadenitis + genital ulceration. - it is also called:

• Durand-Nicolas-Faver disease
• Tropical or climate bubo
• Poradenitis
• Lymphopathia venereum
• Lymphogranuloma inguinale

• There are 2 main serologically distinct groups of Chlamydia, C. trachomatis and C. psittacosis; the LGV chlamydias belong to the C. trachomatis group.
• Within this group, 3 separate immunotypes, designated L₁ - L₃ based on surface antigens, can cause LGV.

• The disease is transmitted primarily through sexual contact.
• The disease predominates in tropical and subtropical nations of Africa and Asia.

• Following an incubation period of 3 to 30 days, a primary genital lesion develops, usually a herpetiform lesion; it is usually very transitory.
• After the initial lesion heals the patient develops lymphadenitis which is the 2nd chief manifestation; followed by genito anorectal syndrome.
• Primary inguinal syndrome:
• Begins 2-6 weeks after exposure as a painful inguinal lymphadenopathy. -- During the acute stage there may be systemic manifestations
• fever
• chills
• headache
• anorexia
• myalgias
• arthralgias
• hypergammaglobulinemia
• splenomegaly
• Genito-anorectal syndrome which occurs either following rectal intercourse or via spread from genital infection sites. (usually seen in women).
• Rectal strictures
• Genital elephantiasis, a chronic induration of the penis or vulva due to lymphatics obstruction.
• Late complications:
• Development of abscesses.
• Development of draining fistulas.
• Women: destruction of the urethra.

• Chlamydia enter the body through small breaks or abrasions in the skin and induce a local genital lesion as well as regional lymph node involvement and systemic effects because macrophages phagocytize them and carry them around as intracellular parasites.
• The histologic picture of the initial genital lesion is essentially that of a nonspecific granuloma.
• Inguinal lymphadenopathy is extensive and may split the inguinal mass into 1/2s separated by Poupart's ligament, producing an almost pathopneumonic groove sign for LGV.

• Clinical manifestations
• LGV complement fixation test (LGV-CFT) not very sensitive or specific. Look for a four-fold rise in titer between acute and convalescence serum.
• Ultimate isolation of the organism using tissue culture (LGV grows well in McCoy cells). -- Culturing the organism is not routinely attempted

• the initial lesion is very transient and the lymphadenitis resolves in several months; serious disease is rare and rectal stricture is the most common complication.

• Doxycycline 100 mg orally twice a day for 21 days or Erythromycin base 500 mg orally four times a day for 21 days.
• Surgical drainage of pus and correction of rectal strictures as well as other fistulas.
• Check patient at weekly intervals for resolution of lesions.
• Check sex partners.

Differential Characteristics of Genital Ulcer Diseases

Send comments and email to Dr. Neal R. Chamberlain, nchamberlain@atsu.edu
Revised 9/1/04
©2004 Neal R. Chamberlain, Ph.D., All rights reserved.