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. Sexually Transmitted Diseases Surveillance 2008. ( http://www.cdc.gov/std/stats08/main.htm)

5. 2006 Treatment Guidelines ( http://www.cdc.gov/std/treatment/ )

Overview

Sexually transmitted infections (STI's) are among the most common infectious diseases in the U.S. More than 21 STI's have now been identified, and they affect more than 20 million men and women in the U.S. each year.

It is important to understand at least six key points about STI's:

1. STI's affect men and women of all backgrounds and economic levels. They are most prevalent among teenagers and young adults. Nearly 50% of all STI's occur in people between the ages of 15 and 24.

2. The incidence of STI's is rising because 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 result in no symptoms. This is especially true in women. If symptoms develop, they may be confused with other diseases. An infected asymptomatic person can give their infection to their sexual partners (e.g., chlamydial infection, genital herpes, human papillomavirus infections, HIV).

4. Health problems caused by STI's tend to be more severe and more frequent for women than for men. 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 involuntary infertility and ectopic (tubal) pregnancy.

• STI's in women also may be associated with cervical cancer (i.e., 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 treated with antimicrobial agents and eliminated (e.g., opthalmia neonatorium), but others may cause a child to be permanently disabled (e.g., congenital syphilis or CMV) or die (e.g., Herpes Simplex virus, HIV).

• When diagnosed and treated early, many STIs can be treated effectively. Some infections have become resistant to the drugs used to treat them and now require different types of antibiotics. Some cannot be cured and can be terminal (e.g., HIV, HPV, HBV).

• Having STI's, especially ulcerative STI’s, other than HIV/AIDS increases one's risk for acquiring HIV when experiencing unprotected sexual interactions with a HIV-infected partner.

The STI's will be divided into 4 different groups based on their clinical presentations:

• Diseases Characterized by Genital Ulcers

• Diseases Characterized by Urethritis and Cervicitis

• Other STI's

• Pelvic inflammatory Disease

• Genital Warts (Human Papillomavirus Infections)

• Diseases Characterized by Vaginal Discharge

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. Not all genital ulcers are caused by sexually transmitted infections. In around 25% of patients with genital ulcers there is no laboratory confirmed diagnosis.

In urban areas with large amounts of prostitution chancroid is more common but not as common as genital herpes. In the southern parts and urban areas of the U.S. syphilis is more common that in other parts of the country.

The diseases covered in this section include:

• Genital Herpes

• Syphilis

• Chancroid

• Granuloma Inguinale 

• Lymphogranuloma 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 STI’s. 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:

1. A serologic test for syphilis; 

2. A diagnostic evaluation for genital herpes; 

3. In settings where chancroid is prevalent, a test for Haemophilus ducreyi. 

• Specific tests for evaluation of genital ulcers include:

1. Serology (RPR- rapid plasma reagin test), and either darkfield examination or direct immunofluorescence test for Treponema pallidum;

2. Culture or serologic test for herpes simplex virus (HSV); and

3. Culture for Haemophilus ducreyi.

There are several characteristics of these infections that may aid in the diagnosis.

• Primary syphilitic 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 is 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.

GENITAL HERPES

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

Etiology

Herpes simplex virus (HSV) exists as two closely related forms, which are antigenically and biologically distinct. Approximately, 80% of the cases of genital herpes are caused by HSV-2. Five to 50% of first-episode cases of genital herpes are caused by HSV-1. Clinical recurrences are less frequent for HSV-1 than HSV-2 genital infection. Therefore, identification of the type of the infecting strain has prognostic significance and may be useful for counseling purposes.

• HSV-1 is usually transmitted by non-venereal 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. It has also been linked epidemiologically with carcinoma of the cervix

The rule of HSV-1 above the waist and HSV-2 below the waist is no longer strictly true. Approximately 20% of symptomatic genital herpes cases are due to HSV-1. HSV-2 infection of the oropharynx can also result in oropharyngeal disease (i.e., stomatitis, cold sores).

Manifestations

Primary genital herpes acquired following sexual contact with an infected partner has an incubation period of 2-7 days (2-21 days). Initial manifestations include local pain, tenderness, itching sensation, and dysuria. The pain associated with dysuria in females is described as more of an “external pain”. The pain is felt in the vulva and around the opening of the urethra in females. This external dysuria can help differentiate it from the dysuria felt during cystitis and pyelonephritis (more internal pain). A profuse watery vaginal discharge may also occur.

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. The vesicles are full of infectious virus, so contact via scratching can spread the infection anywhere. These lesions are self-limiting and heal in about 3 weeks.

Seventy-five percent of patients present with a painful, nonsuppurative inguinal, pelvic and/or femoral lymphadenopathy. Constitutional symptoms include headache, malaise and myalgias. Approximately 15% of cases also have herpetic pharyngitis.

The manifestations of recurrent genital herpes are similar but less severe, and resolve faster. Recurrence usually occurs about 4 months after the first episode and then at approximately 6-8 week intervals and may be hormonally triggered during menses.

Newborns that 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. These infections include; disseminated infection, pneumonitis, hepatitis, or complications of the central nervous system (e.g., meningitis or encephalitis). The virus can also cross the placenta and result in stillbirth or extreme teratogenic effects.

Epidemiology

• It is estimated that 10% of the adult population in the US experiences symptomatic genital herpes and the incidence is increasing.

• 15-20% of the U.S. population has antibodies to HSV-2.

• Most persons infected with HSV-2 have not been diagnosed. Many persons have mild or unrecognized infections but shed virus intermittently in the genital tract

• With once a day sampling shedding of HSV-2 in the genital tract by immunocompetent patients occurs in 2-40% of days if tested by culture and in 20-30% of days if tested by PCR. If patients are samples four times a day, the rates of shedding are two- to four-fold higher with many shedding episodes lasting less than 12 hours.

• Immunosuppressed patients shed HSV-2 at even higher rates (20-80% of days).

• Most people are infected by HSV following contact with an asymptomatic HSV-infected person.

• Acquisition of HSV-2 is by either sexual contact with an infected person or transfer to a fetus/newborn from an infected mother.

• Risk of infection is approximately 75% following contact with a symptomatic person.

• More than 90% of adults have antibodies to HSV-1 by their fifth decade of life.

Genital Herpes in Pregnancy

• 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, since recurrent genital herpes is much more common than primary HSV infection during pregnancy, the proportion of neonatal HSV infections acquired from mothers with recurrent herpes remains high.

Pathogenesis

The virus gains access to 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. The vesicular fluid has many infectious virus particles 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.     When multinucleated giant cells are seen on a Giemsa stained smear of the vesicular fluid or from the base of an ulcer the smear would be considered Tzanck test positive.

During primary infections the patient has a viremia and regional lymphadenopathy. Eventually local interferon as well as specific antibody and cell mediated immunity will curtail virus replication. However, during the primary infection the virus invades local nerve endings, ascends the axons, and establishes latency in the sacral ganglia. These infections last a lifetime. Following reactivation of the virus it travels down the axon and produces new lesions in the epidermis or is shed as viral particles in the mucosa.

Diagnosis

A clinical diagnosis based upon presence of vesicular lesions in genital area and sexual history is helpful but is relatively insensitive and nonspecific. Other diseases may cause similar lesions so laboratory testing is important. The prognosis of the patient is associated with the type of HSV the patient has acquired (HSV-1 less severe, fewer recurrences vs. HSV-2 more severe, more recurrences). Therefore, a clinical diagnosis of genital herpes should be confirmed by the laboratory. Laboratory approaches for the diagnosis of genital herpes include:

• Confirmation of a clinical diagnosis involves detection of virus (by culture), viral antigen, or viral DNA in scrapings from lesions.

• DNA: Detection of viral DNA by PCR is the most sensitive.

• Virus; demonstration of characteristic cytopathic effects (CPE) in target cells, and inhibition of CPE with type specific antisera. Takes 48-96 h to identify HSV using culture. The sensitivity of culture declines rapidly as lesions begin to heal, usually within a few days of onset.

• Viral antigen: spin amplified culture with subsequent staining for HSV antigen shortens the time to identify HSV to less than 24 h.

• Cytologic examination: Cells scraped off the base of the ulcer placed on a slide and stained (Giemsa stain) for microscopic evaluation may contain eosinophilic intra-nuclear inclusion bodies and multi-nucleated giant cells (Tzanck test). Sensitivity is low; 30% and few physicians know how to get a good sample.

Asymptomatic carriers: Type-specific serological tests can be used to identify asymptomatic carriers of HSV-1 and HSV-2. Type-specific antibodies to HSV develop during the first several weeks following infection and persist indefinitely. Since 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. No reliable IgM test is currently available for detecting acute infections.

Type-specific assays for HSV antibodies are 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.

Therapy and Prevention

Patients experiencing their 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. However, treatment does NOT cure. Treatment of the first clinical episodes, for episodic recurrent lesions and for daily suppressive therapy includes acyclovir, famciclovir or valacyclovir.

Recurrent Episodes of HSV Disease:

• 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.

• 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 (can also use famciclovir or valacyclovir) reduces but does NOT completely eliminate asymptomatic infectious 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

Intravenous acyclovir therapy should be given to patients who have severe disease or complications necessitating hospitalization, such as disseminated infection, pneumonitis, hepatitis, or complications of the central nervous system (i.e., meningitis or encephalitis).

Prevention

To prevent further spread of the infection counseling of these patients should include the following. 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 of HSV-2 sexual transmission can be decreased by the daily use of valacyclovir by the infected person.

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.

Early in labor, all women that are seropositive for HSV-1 and/or HSV-2, have a history of recurrent HSV, or a primary infection of HSV during pregnancy should be questioned carefully about symptoms of genital herpes, including prodrome. They should be examined carefully for herpetic lesions. A cervicovaginal swab sample should be obtained and sent to the lab for viral culture or HSV DNA PCR testing. Women without symptoms or signs of genital herpes or its prodrome can deliver vaginally.

However, if the cervicovaginal swab results indicate the presence of HSV then begin IV acyclovir treatment of the neonate OR swab the neonates throat, nasopharynx, eyes and rectum immediately and at 5 to 10 day intervals. Send the swabs for HSV culture and/or HSV DNA PCR testing. If any of the swab cultures/PCRs are positive begin IV acyclovir treatment. The child should be examined immediately after birth and periodically for lethargy, skin lesions or fever.

The child should be delivered by cesarean section if the mother has prodromal signs of HSV recurrence, primary genital herpetic lesions or recurrent genital herpetic lesions at the onset of labor.

Prevention of neonatal herpes depends both on preventing acquisition of genital HSV infection during late pregnancy (third trimester) 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.

SYPHILIS

Etiology

Syphilis is a sexually transmitted infectious disease caused by the bacterium Treponema pallidum. Treponema pallidum has a number of characteristics, which are important for diagnosis.  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. This organism could not be grown in vitro until 2018.

Manifestations

The manifestations seen depend on the stage of disease the patient is in. There are four stages of syphilis in adults; primary, secondary, latent and tertiary syphilis.  

Manifestations of primary syphilis include a hard painless chancre and regional lymphadenitis. Following an incubation period of approximately 3 weeks (10-90 days), the principal lesion, a hard chancre, develops. Syphilitic chancres are indurated (i.e., hard chancre) and are highly infectious. They may occur anywhere on the body and are painless. The chancre will heal in 3-6 weeks. Regional lymphadenopathy adjacent to the chancre may develop during primary syphilis. The swollen lymph nodes are firm, nonsuppurative. Lymphadenopathy may persist for months, despite healing of the chancre.

The manifestations of secondary syphilis usually begin 6-8 weeks after the appearance of the initial chancre and may overlap the time when the primary chancre is present. The principal manifestations of secondary syphilis are skin and mucous membrane lesions, as well as manifestations of systemic disease. The skin and mucous membrane lesions are lesions that vary from macular, papular, or occasional pustular and nodular type rashes. They can occur on the palms and the soles. The patient may also have patchy alopecia, condyloma lata (moist, flat, confluent plaques), and mucous patches. Systemic manifestations include malaise, anorexia, headache, sore throat, arthralgia, low grade fever, and generalized lymphadenopathy. Secondary syphilis lasts 2-6 weeks before the patient enters the latent phase. There is a high bacteremia during secondary syphilis.

Lesions in primary and secondary syphilis contain large numbers of Treponema pallidum and can cause infection in those who touch the lesions without protective gloves.

Latent syphilis is by definition the stage in which there is a positive serological test for syphilis in the absence of any clinical disease symptoms. Its duration is highly variable. Approximately 25% of patients experience a relapse of secondary syphilis during this latent period. Only around 1/3 of patients that progress to latent syphilis have signs and symptoms of tertiary syphilis.

Tertiary or late syphilis is a noncontagious but highly destructive phase of syphilis, which may take many years to develop; it can manifest itself in several forms. Late benign or gummatous syphilis is the most common form of tertiary 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 tertiary syphilis occurs in 10% of untreated syphilis cases about 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 of the aorta can occur because of weakening in the vessel walls and obstruction of the coronary ostia can occur.

Neurosyphilis symptoms are observed in about 8% of untreated cases and about 5-35 years after infection. Invasion of the CNS occurs early during generalized dissemination in secondary syphilis. Asymptomatic neurosyphilis can result in no symptoms of CNS involvement but the CSF is abnormal (i.e., elevated lymphocytes, elevated protein, positive CSF-VDRL tests). Approximately 20% of these patients progress to symptomatic neurosyphilis.

Symptomatic forms of symptomatic neurosyphilis include acute meningitis, chronic meningovascular, general paresis and Tabes dorsalis. Symptoms in acute meningitis are seen within 2 years of infection and are a lot like other meningitis symptoms (i.e., headache, vertigo nausea, vomiting, generalized convulsions, cervical rigidity, positive Kernig's and Brudzinski's signs). Symptoms of chronic meningovascular can be seen 2-5 years after infection, but no later than 10 years of infection. A proliferative endarteritis and perivascular infiltration with lymphocytes (i.e., perivascular cuffing) can be observed in pathological specimens. This leads to blocking of blood vessels and necrosis of nerve tissue and gradual intellectual and emotional deterioration. Most commonly the middle and posterior arteries are involved. Usually see a weakening on one side. The patient may also have a headache, nausea, and vomiting.

Symptoms of general paresis are seen in 5% of untreated patients and may be observed 20 or more years after untreated infection. Symptoms include:

• 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 exist

• Early stage
• Simple dementia
• Euphoric or expansive paretic
• Agitated paretic
• Depressed paretic

Symptoms of Tabes dorsalis can be observed 5-20 years after the primary or secondary stages. It occurs in 3 stages preataxic, atoxic and paralytic stages. Preataxic patient experience lightning like pain radiating from the gluteal region to the heel or foot paresthesia of the soles of the feet and they mention walking feels like walking on carpet or wood. They also develop a loss of sense of position and passive motion and have poor control of their extremities. Atoxic patient lose deep sensory abilities have difficulty in maintaining balance, sway side to side when eyes are closed and hold their body stiffly. Paralytic patients require one or two canes to walk and cannot feel their feet touch surfaces.

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 early (i.e., during first 2 years of life; early onset syphilis) by:

1. Rhinitis (snuffles) followed by skin and mucocutaneous lesions similar to those of adult secondary syphilis

2. Osteochondritis (inflamed bone and cartilage)

3. Hepatosplenomegaly and lymphadenopathy

4. Immune complex-induced glomerulonephritis

5. Death in first 2 years is due to pulmonary hemorrhage, secondary bacterial infections or hepatitis.

Late congenital syphilis (i.e., after 2 years of age; late onset syphilis) manifestations occur in 40% of 2-year survivors. This infection is subclinical in the rest. Those that have symptoms will have manifestations similar to those of adults with tertiary 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.).

Epidemiology

• Humans are the only known host and transmission is virtually always by direct contact with infectious lesions, generally through sexual contact.

• The incidence is highest in sexually active people (20-29-year-old group).

• The national rate of reported P&S syphilis cases reached an historic low in 2000 and 2001, but has increased almost every year since then.

• The increases in P&S syphilis were largely due to an increase among men, and in particular among MSM.

• However, during 2013–2014, rates increased among both men and women in every region of the country.

• Rates of reported congenital syphilis cases also increased in every region of the country during 2013–2014.

• MSM continued to account for the majority of P&S syphilis cases in 2014.

• Nationally, the highest rates of P&S syphilis in 2014 were observed among men aged 20–29 years, among men in the West and in the South, and among black men.

Pathogenesis

The organisms enter the body via minute abrasions of epithelial cell linings, by penetrating mucous membranes or via hair follicles. The organisms slowly multiply at the site of the infection and some will in time gain access to the bloodstream and the lymphatics and seed the skin, endothelial cells, cartilage, joints, bones, neurons and mucous membranes. The organisms multiplying at the initial site of infection will in 10 to 90 days cause the hard chancre seen in primary syphilis.

The bacteria that are taken by the lymphatics to the lymph nodes will initially cause the regional lymphadenopathy seen in primary syphilis and the generalized lymphadenopathy seen in later stages of the disease. The organisms taken to the skin and mucous membranes by the bloodstream cause the lesions seen in secondary (mucous patches, macules) and tertiary (gummas) syphilis. Those organisms taken to the neurons and brain can if not treated cause the neurological symptoms seen in tertiary syphilis. Bacteria taken to the endothelial cells cause the aneurysms seen in cardiovascular syphilis. The most prominent histologic features are vascular changes caused by endarteritis and periarteritis (perivascular cuffing).

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 of disease are present at autopsy. Treatment during primary and secondary syphilis aborts the process but the changes associated with tertiary syphilis, except for gumma formation, are irreversible.

Congenital syphilis occurs following infection of the placenta and the bacteria spread via the fetuses’ bloodstream to all the areas mentioned above. Since their infection is from the onset systemic rather than localized, symptoms in the neonate with early onset disease are similar to those of secondary syphilis in adults. Late onset symptoms in the infant are similar to those of tertiary syphilis in adults except that since the infant’s bones are still developing more damage is seen in the infant to the teeth, long bones and joints.

Diagnosis

Diagnosis involves evaluation of presenting signs and symptoms as well as contact history. An examination of exudative material in syphilitic lesions using a dark field microscope or a fluorescence microscope after application of fluorescent antibiotics directed against Treponema pallidum to the patient sample. This is usually performed in early primary syphilis before serological tests become positive.

Serological tests are frequently used and are positive within a week following appearance of the chancre in primary syphilis, during all of secondary and latent syphilis as well as during most of tertiary syphilis. Two different types of serological tests are used; treponemal and nontreponemal tests. Nontreponemal tests also called reagin tests are used for screening and to determine treatment efficacy. Treponemal tests are used to confirm a positive nontreponemal test.

1. Reagin tests use a cross reactive cardiolipin lecithin as an antigen rather than the treponemal antigens.

• VDRL slide test (Venereal Disease Research Laboratories)

• RPR (Rapid Plasma Reagin)

• Nontreponemal antibody titers usually correlate with disease activity, and results should be reported quantitatively. These tests usually become nonreactive with time after treatment and can be used to determine the patients’ response to treatment.

• In some patients, nontreponemal antibodies can persist at a low titer for a long period of time, sometimes for the life of the patient. This response is referred to as the serofast reaction.

• False positive serological reactions in non-treponemal antigen tests are quite common and may occur in patients with: Hepatitis, infectious mononucleosis, viral infections, malaria, pregnancy, connective tissue disease like SLE, diseases with Ig abnormalities and in some healthy people.

1. Treponemal antigen tests rely upon antigens derived directly from T pallidum.

• In the FTA-ABS or fluorescent treponemal antibody-absorption test spirochetes are mixed with the patient's serum. A FITC-tagged anti-human globulin is then added and then examined for fluorescence spirochetes in a fluorescent microscope.

• The MHATP T pallidum hemagglutination test involves mixing formalinized, tanned sheep erythrocytes coated with T pallidum antigens with the patient's serum and looking for hemagglutination.

• TP-PA T pallidum particle agglutination.

• The majority of patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of treatment or disease activity. However, 15%–25% of patients treated during the primary stage become serologically nonreactive after 2–3 years. These treponemal tests do not correlate with disease activity and should not be used to assess treatment response.

• False positives in treponemal tests are not as common because they are more specific. False positives are associated with: Ig abnormalities, multiple myeloma, and SLE

Therapy and Prevention

Benzathine penicillin G administered intramuscularly in one dose is the treatment of choice for primary and secondary syphilis. To contain further spread of the disease the patient should help in identifying their sexual contacts and encourage them to be examined and treated if infected. Treatment of a pregnant woman before the 16th week of pregnancy prevents congenital syphilis. Treatment after the 16th week also helps the fetus but may not alleviate all of the future manifestations. Treat the neonate if maternal treatment is inadequate, unknown, with drugs other than penicillin, or if follow-up is not ensured. Treat the neonate with aqueous crystalline penicillin G intravenously.

Post treatment follow-up is important because some patients may experience the Jarisch-Herxheimer Reaction. This reaction to therapy is an intensification of existing syphilitic lesions and exacerbation of old ones following administration of penicillin. The reaction subsides in 24 hours and you should warn the patient to expect it. If symptoms are severe they should seek medical care quickly.

T pallidum only infects humans and is treatable with antibiotics. If all infected individuals could be identified and treated syphilis could be eliminated. 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. Treat those with syphilis, identify their sexual partners, test the sexual partners to see if they are infected, and treat infected sexual partners. No vaccine is currently available to prevent this infection.

CHANCROID

Etiology

Chancroid or soft chancre disease is an acute sexually transmitted infection characterized by genital ulceration and suppuration caused by the organism Haemophilus ducreyi. Haemophilus ducreyi (i.e., Ducrey's bacillus) is a Gram-negative coccobacillus that grows in chains.

Manifestations

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

Epidemiology

• Transmission of H. ducreyi is almost exclusively by sexual contact.

• Around 6-10 cases of chancroid are reported each year in the U.S.

• Prostitution is a major cause of spread.

• About 10% of persons who acquire chancroid in the U.S. are coinfected with T pallidum or HSV.

Pathogenesis

The organism enters the body through skin abrasions. It induces a papule or vesicle that ulcerates. There is a dense inflammatory exudate with PMN’s but not mononuclear cells. Soft chancres may heal quickly and spontaneously. Healing is enhanced with improved hygiene. The chancres may persist and induce deep scars.

Diagnosis

Diagnosis includes evaluation of lesions for pain upon touch and induration (if indurated and painless it is more likely to be syphilis) and a sexual history should be obtained. 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:

1. The patient has one or more painful genital ulcers.

2. 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.

3. The clinical presentation, appearance of genital ulcers and, if present, regional lymphadenopathy are typical for chancroid; and

4.  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.

Therapy and Prevention

Chancroid can be treated with azithromycin, ceftriaxone, ciprofloxacin, or erythromycin. Patients should be reexamined 3-7 days after initiation of therapy. Patients who are uncircumcised and patients with HIV infection do not respond as well to treatment. If treatment is successful, ulcers usually improve symptomatically within 3 days and objectively within 7 days after therapy. Clinical resolution of fluctuant lymphadenopathy is slower than that of ulcers and may require needle aspiration or incision and drainage, despite otherwise successful therapy. Finding and treating the patient’s infected sexual partners prevents further spread of the disease.

GRANULOMA INGUINALE

Overview

This disease is a chronic, indolent, ulcerative, granulomatous disease of the skin and lymphatics that has also been called Donovanosis, lupoid ulceration granuloma of the pudenda and granuloma contagiosa. 

Etiology

Klebsiella granulomatis is the etiological agent; it is an intracellular Gram-negative rod with characteristic bipolar staining that frequently results in a safety pin-like appearance in stained tissue preparations. These safety pin appearing bacteria seen in the vacuoles of phagocytic cells are called Donovan bodies.

Manifestations

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 highly vascularized and bleed easily on contact. The lesions are painless irregular in shape with a rolled border on a beefy red, cobblestone base. Patients develop subcutaneous granulomas in the inguinal regions; they do not usually involve the lymph nodes, so they are called pseudo-buboes.

Epidemiology

This disease is endemic in the tropics and is rare in the U.S. with fewer than 20 cases/year. Most cases of this disease are seen in foreign travelers. This disease is not very contagious.

Pathogenesis

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

Diagnosis

Evaluate the nature of the lesion (nodules which erode to form painless, beefy, granulomatous ulcers) and sexual history. Smear material from the lesion on a slide to look for the pathognomonic enlarged mononuclear cells containing vacuoles filled with Donovan bodies (safety-pin shaped bacteria).

Treatment and Prevention

Treat patients with azithromycin, doxycycline, ciprofloxacin, erythromycin OR trimethoprim-sulfamethoxazole for at least 3 weeks and until all lesions have completely healed. Addition of an aminoglycoside (gentamicin) may be needed if improvement is not evident in the first few days of treatment. Check the patients weekly until lesions resolve. Check sex partners for lesions and treat if infected.

LYMPHOGRANULOMA VENEREUM (LGV)

Overview

LGV is a sexually transmitted disease caused by Chlamydia trachomatis and is characterized by acute inguinal lymphadenitis and genital ulceration. It is also called Durand-Nicolas-Favre disease, tropical or climate bubo, Poradenitis, Lymphopathia venereum, or Lymphogranuloma inguinale.

Etiology

Chlamydia trachomatis consists of three distinct biovars. Only two the trachoma and lymphogranuloma venereum (LGV) biovars cause human disease. The biovars are further subdivided into serotypes or serological variants (serovars) based on differences in their major outer membrane proteins (MOMP). The disease LGV is associated with five serovars L1, L2, L2a, L2b, and L3.

Chlamydia trachomatis serovars D-K cause urethritis, epididymitis, proctitis, conjunctivitis (ophthalmia neonatorum), cervicitis, endometritis, salpingitis, perihepatitis and Reiter’s syndrome. Discussed later in this handout.

Chlamydia trachomatis serovars A, B, Ba and C cause an infection of the eyes called trachoma (Dr. Stuart).

Manifestations

Following an incubation period of 3 to 30 days, a primary genital lesion develops, usually a herpetiform lesion. After the initial lesion heals the patient develops lymphadenitis, which is the 2nd chief manifestation; followed by genito-anorectal syndrome. The initial herpetiform lesion is transient and the lymphadenitis resolves in several months; serious disease is rare and rectal stricture is the most common complication.

Primary inguinal syndrome- Begins 2-6 weeks after exposure as a painful inguinal or femoral lymphadenopathy that is usually unilateral. During the acute stage there may be systemic manifestations include; fever, chills, headache, anorexia, myalgias, arthralgias, hypergammaglobulinemia and splenomegaly. A self-limited genital ulcer or papule is sometimes seen at the site of inoculation.

Genito-anorectal syndrome- occurs either following rectal intercourse or via spread from genital infection sites and is more common in women and homosexual men. Signs and symptoms include: Rectal strictures, genital elephantiasis (a chronic induration of the penis or vulva due to lymphatics obstruction). Late complications include: development of abscesses, development of draining fistulas, and in women: destruction of the urethra.

Epidemiology

• This disease is transmitted primarily through sexual contact.

• LGV is more common in tropical and subtropical areas of Africa and Asia.

Pathogenesis

Chlamydia enters the body through small breaks or abrasions in the skin and induces a local genital lesion as well as regional lymph node involvement and systemic effects because macrophages phagocytize them and carry them throughout the body 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 halves separated by Poupart's ligament, producing an almost pathognomonic groove sign for LGV.

Diagnosis

Genital and lymph node specimens (i.e., lesion swab or bubo aspirate) may be tested for C. trachomatis by culture, direct immunofluorescence, or nucleic acid detection. Definitive identification can be made by isolation of the organism using tissue culture (LGV grows well in McCoy cells). Culturing the organism is rarely attempted. Chlamydia serology (complement fixation titers >1:64) can support the diagnosis in the appropriate clinical context. 

Treatment and Prevention

Patients can be treated with doxycycline for 21 days. Surgical drainage of pus and correction of rectal strictures as well as other fistulas may be required. Check patient at weekly intervals for resolution of lesions. Check sex partners for lesions and treat if infected.