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Sexually Transmitted Infections and the Adolescent

Topic I: Common Syndromes of Lower Genital

Tract Sexually Transmitted Infections

Topic IA: Cervicitis

I. Causes

A. Major recognized sexually transmitted pathogens

1. Endocervicitis

a. C. trachomatis

b. N. gonorrhoeae

c. Herpes simplex virus

2. Ectocervicitis

a. Trichomonas vaginalis

b. Herpes simplex virus

B. Multiple other bacteria, including non-sexually transmitted organisms

1. Mycoplasmas do not cause cervicitis, but are isolated as

commensal organisms from lower genital tracts (cervix, vagina) of

healthy women

C. Fungal -- C. albicans - ectocervicitis

D. Non-microbial causes

1. Autoimmune

2. Malignancy

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3. Physical, chemical, and irradiation trauma

II. Diagnostic Approach

A. Careful history and physical examination (includes full pelvic

examination)

B. Examination of vaginal pool

1. pH -- non-specific to cause, but sensitive to many abnormalities of

vaginal flora and cervix (> 4.5 is abnormal)

2. Microscopy of normal saline and potassium hydroxide mounts --

presence of PMNs, clue cells, trichomonads, blastospores and

pseudohyphae

C. Gram stain of cervical secretions -- PMNs

D. Microbiology laboratory tests

1. Tests for C. trachomatis and N. gonorrhoeae

2. Test for herpes simplex virus if lesions noted

III. Presumptive Treatment

A. In general, for gonorrhea and chlamydia

B. For other specific pathogens if a high index of suspicion

Topic IB: Urethritis

I. Major Sexually Transmitted Pathogens Are Common Causes

A. In males and in females

B. Organisms associated with urethritis

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1. N. gonorrhoeae -- about 30 - 50% of all urethritis

2. C. trachomatis -- about 50% of all nongonococcal urethritis

3. Herpes simplex virus

4. Mycoplasmas -- although multiple species, most famous are

a. Ureaplasma urealyticum -- about 30% of all

nongonococcal urethritis

b. Mycoplasma hominis

c. Mycoplasmas genitallure -- about 20 - 25% of all

nongonococcal urethritis

II. Differential Diagnosis

A. STD (as above)

B. UTI

C. Vulvitis in females -- associated with external dysuria

1. Herpes simplex virus

2. Candida

3. Human papillomavirus

4. Maceration from discharge of cervicitis or vaginitis

III. Diagnostic Approach to Symptoms of Urethritis

A. Urinalysis

B. Urine culture -- selected patients

C. Full pelvic examination (female patients)

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D. Examination of vaginal pool (pH, microscopy)

E Gram stain of urethral discharge (male patients)

F. Tests for N. gonorrhoeae and C. trachomatis

G Tests for other pathogens based on findings

1. Mycoplasma organisms not usually identified as part of

routine clinical care

a. Not visible by Gram stain

b. Require special culture media -- different species have

different, fastidious metabolic requirements

c. PCR methods applied in research laboratories -- able to

identify species

IV. Approach to Treatment

A. Male patients -- treat presumptively for gonorrhea and chlamydia

B. Female patients -- treat presumptively based on findings

1. For gonorrhea and chlamydia if evidence of cervicitis

2. For UTI if evidence for this diagnosis

C. Treat for other infections based on findings

1. Mycoplasma organisms generally sensitive to doxycycline

2. U. urealyticum quite and M. hominis somewhat sensitive to

azithromycin

Topic II: Common Bacterial Causes of Cervicitis and Urethritis

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Topic IA: Neisseria gonorrhoeae

I. Biology of Neisseria gonorrhoeae

A. Requires immediate physical contact between mucosal surfaces

for transmission

B. Prefers columnar and transitional epithelium for growth. Infects a variety

of tissues -- urethra, genital glands, cervical canal, fallopian tubes,

epididymis, anus and distal rectum, conjunctivae, and the pharynx

C. Development of microbial resistance

1. Chromosome mediated based on transformation of

exogenous DNA from strains that have developed antibiotic-

resistant genes

a. Usually a cumulative effect of multiple chromosomal

mutations (except resistance to spectinomycin has been a

single step mutation)

b. Produces a range of different antibiotic sensitivities that are

usually not drug specific -- has affected sensitivities to

penicillins, tetracyclines, erythromycin, spectinomycin,

quinolones

c. Pili necessary for taking up transforming DNA intothe cell

2. Plasmid mediated

a. Takes a single step to acquire an appropriate plasmid

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b. Accounts for resistance to all B-lactam antibiotics -multiple

plasmids encode for B-lactamase production

c. High-level tetracycline resistance is plasmid mediated

II. Epidemiology of Gonococcal Infections

A. 1995 rates per 100,000 for

1. 10- 14 year olds-- 42

2. 15 - 19 year olds-- 665

3. 20 - 24 year olds -- 646

4. 10 - 65 plus year olds-- 150

B. Rates for adolescent females (15 - 19 years) highest of all age groups

among women (and all age groups overall), and rates for adolescent

males second highest of all age groups among males

1. Despite some variation, rates of gonorrhea have been

generally decreasing since 1986 among adolescent females,

and since 1991 for adolescent males. Between 1992-95, rates

declined by 35% for male adolescents and by 14% for female

adolescents

C. Burden for gonorrhea largely among Black adolescents -- rates 27 times

higher than rates for White adolescents

III. Diagnostic Formulation of Gonococcal Infections

A. Clinical presentations

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1. Uncomplicated urogenital infections

a. Incubation period -- 1 - 14 days

b. Symptoms are non-specific

c. Males -- urethritis. Are infective prior to onset of symptoms,

and without treatment, can become asymptomatic yet remain

infective

d. Females -- cervicitis and urethritis, inflammation of Bartholin's

duct

2. Rectal infections

a. From practice of receptive anal intercourse -- symptoms are

variable; include anal pruritus, painless mucopurulent rectal

discharge, mucus-coated stools, minimal rectal bleeding and

in the case of overt proctitis, rectal pain, tenesmus and

secondary constipation

b. From local contamination by infected cervico-vaginal exudate

-- usually asymptomatic

3. Pharyngitis

a. Fellatio is a more efficient mechanism of transmission

than is receptive oral sex -- more common in females and gay

males

b. Severity of symptoms and infections variable, but often

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asymptomatic

c. Spontaneous resolution within 12 weeks if untreated

4. Disseminated gonococcal infection (DGI)

a. Untreated mucosal gonococcal infections can disseminate

through a bacteremia in 0.5 - 3% of patients

b. Clinical syndrome of DGI

1) Arthritis (30-40%), tenosynovitis (80%), and/or dermatitis

(50-75%)

2) Primary mucosal infection asymptomatic inabout 50% of

cases

3) Cultures from blood, joint fluid or skin lesions are

positive in less than half of cases (proven DGI if such a

culture is positive)

4) Culture from primary mucosal site of infection is positive

in 80% of cases (probable DGI)

5) Complement deficient individuals may be at greater risk

for developing DGI

B. Laboratory testing for gonococcal infections

1. Gram stained smears of urethral discharge (Gram negative

diplococci within or adjacent to PMNs) -- recommended for males

only

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a. High sensitivity in symptomatic males -- 90 - 95%. In

asymptomatic males (and from female cervix) -- 50 - 70% b.

High specificity in males -- 95 - 100%

2. Culture

a. Necessary to determine antimicrobial sensitivity and

resistance

b. Sensitivities are significantly lower (about 70 - 90%)

compared to nucleic acid amplification techniques

c. Selective media to support growth requirements of N.

gonorrhoeae, with antibiotics added to suppress the growth of

organisms with less fastidious requirements

d. Incubate at 35-36E degrees C in a high humidity and high

CO2 (4-6%) atmosphere

3. Nonculture tests -- advantages and disadvantages

a. Advantages

1) Do not depend on viable organisms, so useful when

transport to laboratory is difficult

2) Rapid processing time

3) For some methods, may be able to eliminate invasive

collection procedures

4) May be able to process testing for more than one

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organism simultaneously

b. Disadvantages -- cost and inability to determine antibiotic

susceptibilities

4. Non-culture tests

a. EIA test characteristics (polyclonal antigonococcal

antibodies for detection of gonococcal antigen) --

1) Urethra -- sensitivity 83 - 100%. Specificity 94 100%

2) Cervix -- sensitivity 73- 100%. Specificity 76 100%

b. ELISA test characteristics (two monoclonal anti-

gonococcal antibodies and a urease-based detection

system) -- sensitivity 98%. Specificity 100%

c. Nucleic acid hybridization for detection of rRNA -- sensitivities

and specificities approach 100% for both

urethral and endocervical specimens. Available

commercially in combination with a probe for detection of C.

trachomatis

d. Ligase chain reaction -- sensitivities/specificities vary by

specimen type

1) Male urethral swab -- 100% / 100%

2) Male urine -- 90% / 100%

3) Female cervical swab -- 90 - 95% / 100%

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4) Female urine -- 50 - 95% / 100%

III. Management of Gonococcal Infections

A. Single dose treatment of uncomplicated mucosal gonococcal

infections -- each has demonstrated efficacy of at least 95% for

genital and anal infections

1. Ceftriaxone 125 mg IM or

2. Cefixime 400 mg orally or

3. Ciprofloxacin 500 mg orally (only for individuals at least 18 years

who have completed their growth. Gonococcal strains in certain

geographic regions of the United States have decreasing

susceptibility to fluoroquinolones) or

4. Ofloxacin 400 mg orally (see note for ciprofloxacin)

B. Patients require simultaneous evaluation and treatment for C.

trachomatis

C. Patients who are at risk for syphilis should be tested

D. Sex partners need evaluation and treatment for gonorrhea and chlamydia

Topic lB: Chlamydia trachomatis

I. Biology of C. trachomatis

A. Non-motile, obligate intracellular bacteria that live exclusively in

human columnar and transitional epithelia

B. Of 15 serovars, nine are associated with urethritis and cervicitis

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C. Life cycle composed of two stages

1. Elementary body survives outside of cells. Has cell wall. Is

metabolically inactive

2. Reticulate body is intracellular form without a cell wall.

Replicates by binary fission. Metabolically active using host

cell's ATP and nutrients

II. Epidemiology of Chlamydial Infections

A. Most prevalent bacterial STD

1. Formal national reporting across all states started in 1996

2. United States rates per 100,000 population in 1995 -- 182

a. 1995 rates reported by gender (not age based)

1) Males-- 52

2) Females --290

a) Reflects increased detection of asymptomatic

infection through formal screening

b) Reflects treatment in males for non-gonococcal

urethritis but without specific testing for chlamydia

3. Comparison of rates in adolescent females to other age groups --

in family planning clinic sites, girls less than age 18 consistently

have the highest percent positivity, followed closely by 18 - 19 year

olds

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B. Declining prevalence of chlamydial infections -- documented following

implementation of large-scale screening and treatment programs.

Decreases range from 36 - 62%

C. Transmission rates -- 68% from either gender to the other

2. Nonculture methods

a. Leukocyte esterase (LE) test -- rapid dipstick test for use with

urine specimens

1) Can detect urethritis, but cannot identify its cause; a

positive LE test requires further diagnostic testing to

determine organismal etiology

2) Recommended only for use in screening asymptomatic

adolescent males -- unsatisfactory performance in

women and in older men

3) Sensitivity/specificity variable in adolescent males 31-

100% / 83-100%

b. Antigen detection methods (DFA, EIA, rapid point-of-care)

1) Direct fluorescent antibody (DFA) test -- one of the most

useful tests available

a) Only available test that permits simultaneous

assessment of specimen adequacy by visualization

of columnar epithelial cells

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b) Disadvantage -- processing of specimens is

laborious and requires highly trained and

experienced technologists

c) Using monoclonal antibody reagents specific for the

MOMP (major membrane outer protein), which is

species specific

i. Relative to culture -- sensitivity/specificity 80 -

90% / 98 - 99%

ii. Poorer test characteristics if kit based on LPS

(lipopolysaccharide) antigens, which are not

evenly distributed on the elementary body

surface and are similar across species

d) Frequently used today as a confirmation test for

positive results of other nonculture tests and in

discrepancy analyses of DNA amplification tests

2) Enzyme immunoassay (EIA) tests

a) Based on antibodies to the LPS antigen, which is

not specific to C. trachomatis

b) Advantages

i) Short processing time -- 3 - 4 hours

ii) Technically less complex than DFA

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c) Limitation -- Antibodies to the LPS antigen may

cross-react with the LPS of other gram-negative

bacteria, which reduces specificity (produces false

positive results)

i) Blocking antibody assays help to improve the

specificity and should always be used if screening

in a low prevalence population

d) Test characteristics vary by commercial kit

i) Chlamydiazyme (endocervix, male urethra, male

urine)

-- overall sensitivity 73%; overall specificity 97 -

98% ii) Microtrak EIA -- overall sensitivity for

male urine and endocervix 82-83%; overall

sensitivity for male urethra 97%; specificity 96-

100%

3) Rapid, point-of-care tests

a) EIA technology in formats based on membrane

capture or latex immunodiffusion -- results

qualitative

b) Advantages -- can be performed in office, rapid (30

minutes), and no sophisticated equipment needed

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c) Disadvantages -- decreased specificity due to

cross-reactivity with LPS from other bacteria

d) Sensitivities compared to culture -- endocervix 52-

85%; urethra 65-85%

e) Specificity -- greater than 95%

c. Nucleic acid detection methods

1) DNA hybridization probe -- most commonly used test for

C. trachomatis in public health laboratories (PACE 2)

a) Comparative test characteristics

i) Sensitivity 85%; specificity 98-99% using

expanded culture standard

ii) Sensitivity 77-93% compared to DNA

amplification -can be enhanced by using a probe

competition assay

b) Advantage -- Can be used in conjunction with a

probe to detect N. gonorrhoeae for these two

organisms' simultaneous detection

2) Nucleic acid amplification tests

a) Important advance in field of chlamydial diagnosis

i) Techniques are highly sensitive and specific

ii) Can use noninvasive specimen collection

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techniques on asymptomatic individuals

b) Polymerase chain reaction (PCR) -- commercial

Amplicor kit is approved for cervical, male urethral

and male urine specimens

i) Based on cryptic plasmid DNA present in C.

trachomatis strains

ii) Sensitivity 92-96%; specificity 98-99%

iii) False-negative results can occur from inhibitors

-expensive and difficult to correct

iv) Should not be used as test-of-cure -- can

continue to detect chlamydial DNA residues for

up to 3 weeks following successful antibiotic

treatment of infection

c) Ligase chain reaction (LCR) -- approved for

diagnostic use in late 1995 (Lcx)

i) Overall sensitivity 94%. Overall specificity 99-

100%

ii) Highly sensitive using female urine and female

vulvar/vaginal swabs (PCR is also, but is not

approved for these sites of collection)

3. Summary comparison of diagnostic methods' relative limits of

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detection of numbers of chlamydial elementary bodies

a. Amplified DNA-- 1 - 10

b. Culture -- 5 - 102

c. DFA-- 10- 500

d. DNA probe -- 500 - 104

e. EIA-- 5000- 105

4. Selecting screening and diagnostic tests

a. Screening for C. trachomatis infection is cost effective

because of the high costs of untreated infections and their

sequelae

b. For screening asymptomatic individuals

1) If the population has a low prevalence of infection, must

choose a test with high specificity -- positive results using

DFA, EIA, or a DNA probe among a low prevalence

population should be confirmed

2) If cannot use invasive sampling techniques, or if require

the highest sensitivity, use nucleic amplification test

3) In adolescent males, cost effective to combine LE

screening with either EIA, or, even better, with DNA

amplification for formal diagnosis

c. Selecting a test for diagnosing a symptomatic patient -not

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necessary to confirm positive results among nonculture tests

d. Selecting a test when legal implications exist for a positive

result

1) Must use culture -- remains standard for legal purposes

2) Nonculture tests not sufficiently evaluated for cases of

sexual assault and abuse

e. Selecting a test for other sites and preadolescent ages -culture

recommended from urethra of asymptomatic boys, anorectum

of all ages and both genders, vagina of prepubertal girls,

nasopharynx of infants because nonculture tests not

adequately evaluated

f. Selecting a test for test-of-cure

1) Not routinely recommended during immediate

posttreatment period, given efficacy of antimicrobial

agents

2) If performed, need to use culture -- window period during

which chlamydial antigen and nucleic acids remain

detectable, even though organisms have been killed

IV. Management of Genital Chlamydial Infections

A. Antibiotic treatment recommended by CDC, 1993

1. Recommended regimens

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a. Doxycycline, 100 mg orally 2 times a day for 7 days or

b. Azithromycin, 1 gm orally in a single dose

2. Alternative regimens

a. Ofloxacin, 300 mg orally 2 times a day for 7 day or

b. Erythromycin base, 500 mg orally 4 times a day for 7 days or

Erythromycin ethylsuccinate, 800 mg orally 4 times a day for

7 days

B. All sexual partners should be referred for evaluation and treatment of C.

trachomatis and N. gonorrhoeae

Topic III: Complications of Urethritis and Cervicitis

Topic IIIA: Complications of Bacterial Urethritis

I. Persistent or recurrent urethritis

A. Differential diagnosis

1. Reinfection

2. Noncompliance with antibiotic treatment

3. Infection by another organism

a. Ureaplasma urealyticum -- some strains are resistant to

tetracyclines

b. Trichomonas vaginalis

c. Herpes simplex virus

d. Human papillomavirus

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e. Staphylococcus saprophyticus

4. Infected prostate

II. Epididymitis

A. Frequency -- less than 1% of sexually transmitted urethritis

B. Diagnostic considerations

1. Differential diagnosis

a. Testicular torsion

b. Trauma

c. Tumor

2. Laboratory and imaging studies

a. Gram stained smear of urethral secretions

b. Tests for N. gonorrhoeae and C. trachomatis

c. Midstream urine for Gram stain and culture -- urinary

pathogens in insertive partner who practices anal intercourse

d. Doppler ultrasonography or radionuclide scan to

differentiate epididymitis from torsion

D. Treatment -- ceftriaxone 250 mg IM and oral doxycycline course

E. Diagnostic considerations if swelling and tenderness persist

1. Testicular cancer

2. Tuberculosis

3. Fungal epididymitis

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III. Sexually Acquired Reactive Arthritis (SARA or Reiter's Syndrome)

A. Epidemiology

1. Risk of developing following a bacterial sexually transmitted

urethritis -- 1 - 3%

2. Majority of studies have been based on males -- rates in females

uncertain, but thought to be 5 - 9 times more prevalent in males

B. Biology

1. Complex interactions among microbes, genetics and immune

responses that are not fully understood, but that result in

chronic inflammation

2. HLA-B27 haplotype associated with increased risk for disease and

a more severe disease course

3. Strong association with C. trachomatis infection

a. 50% with SARA have evidence of active urogenital mucosal

infection (serotypes D - K)

b. Chlamydial antigens, DNA, bacterial fragments and membrane

components, and whole bacteria can be demonstrated in the

synovial fluid and in synovial membranes

c. Direct pathogenic role versus interaction with immune

system to produce an arthritogenic factor

4. Association with other organisms

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a. Campylobacter

b. Salmonella

c. Shigella

d. Yersinia

e. Ureaplasma

C. Clinical manifestations of SARA (Reiter's syndrome)

1. Clinical elements

a. Acute arthritis, usually polyarticular (80%)

b. Lower genital tract inflammation

c. Conjunctivitis and other ocular manifestations -- anterior

uveitis may develop over time -- 12%

d. Mucocutaneous lesions -- 50%. Are frequently painless and

subtle

e. Constitutional symptoms -- malaise, fever, anorexia and

weight loss

f. Electrocardiographic and AV conduction abnormalities

g. Assorted serious and rare complications

2. Clinical course variable

a. Clinical resolution of an initial episode over 3 - 5 months --

66%

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b. Persistence of symptoms for more than a year -- 15 -- 30%

c. Recurrence of symptoms over several year period -- >50%

d. Development of destructive joint disease, spondylitis,

crippling foot deformities -- 5 - 16%

Topic IllB: Pelvic Inflammatory Disease

I. Biology

A. Definition -- A clinical diagnosis that represents an infection ascending

from the lower female genital tract (vagina and cervix) through the

endometrium to the level of the fallopian tubes, and that may involve the

ovaries and pelvic peritoneum

B. Polymicrobial process

1. Canalicular ascent of organisms from vagina and cervix -thought

that a sexually transmitted cervicitis alters the microenvironment of

vagina to permit overgrowth of its normal flora, which ascend

opportunistically to the upper genital tract

2. Organisms

a. Classic bacterial agents are N. gonorrhoeae and C.

trachomatis-- 60 - 75%

b. Aerobic and anaerobic bacteria isolated from fallopian tubes,

frequently in mixed cultures -- 25 - 50%

1) Most common anaerobes -- Bacteroides, Peptococcus,

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Peptostreptococcus sp.

2) Most common facultative aerobes -- G. vaginalis,

Streptococcus species, E coli, H. influenzae, and

coagulase negative staphylococci

c. Mycoplasmas

1) M. hominis (10 - 30%) and U. urealyticum (4%)

2) Despite isolation rates, roles in causing PID unclear -- M.

hominis isolated in pure culture, U. urealyticum only in

mixed culture

d. Viruses -- roles not clear

1) Herpes simplex virus -- 11%

2) Other viruses -- coxsackie B5 and echo 6 viruses

II. Epidemiology of Pelvic Inflammatory Disease

A. Adolescents compose 17% of cases

1. Almost 3% of female teenagers have self-reported a history of PID

2. Estimated risk of developing among sexually active adolescents --

one in eight

III. Diagnostic Formulation of Pelvic Inflammatory Disease

A. Differential diagnosis

1. Acute pain

a. Appendicitis

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b. Pyelonephritis

c. Ectopic pregnancy

d. Adnexal torsion

e. Ruptured ovarian cyst

2. Long-standing or chronic pain

a. Endometriosis

b. Pelvic adhesions

c. Ovarian cyst

d. Chronic intestinal disease

B. Formulating a diagnosis by CDC's 1993 consensus criteria

1. Minimal triad of physical examination findings

a. Lower abdominal tenderness

b. Adnexal tenderness

c. Cervical motion tenderness

2. Additional routine diagnostic criteria (each enhances specificity of

diagnosis)

a. Oral temperature > 38.3E C

b. Abnormal cervical or vaginal discharge (inflammatory

response)

c. Elevated erythrocyte sedimentation rate

d. Elevated c-reactive protein

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e. Documented cervical infection with N. gonorrhoeae or C.

Trachomatis

3. Elaborate diagnostic criteria (when medically necessary to

aggressively pursue an accurate diagnosis)

a. Histopathologic evidence of endometritis on endometrial biopsy

b. Tubo-ovarian abscess on ultrasonography

c. Laparoscopic visual confirmation of inflammatory

IV. Antibiotic Management of Pelvic Inflammatory Disease

A. Antibiotic management recommended by CDC consensus

1. Two antibiotics are always needed to be able to cover N.

gonorrhoeae, C. trachomatis and anaerobes

2. Inpatient

a. Either cefoxitin or cefotetan IV PLUS doxycycline IV or orally

or

b. Clindamycin IV PLUS gentamicin IV or IM

c. Parenteral antibiotics should be continued for at least 48

hours after substantial clinical improvement occurs

3. Outpatient

a. Either ceftriaxone IM or cefoxitin IM PLUS probenecid PLUS

doxycycline or

b. Ofloxacin orally PLUS either clindamycin or metronidazole

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orally

4. Antibiotic courses should be continued for 14 days

V. Complications of Pelvic Inflammatory Disease

A. Short-term complications

1. Perihepatitis (Fitz-Hugh-Curtis Syndrome)

a. Infection of perihepatic capsule -- 5 - 20%

b. Treated using in-patient antibiotic regimen

2. Tubo-ovarian abscess formation

a. Develops in 7 - 16%

b. Polymicrobial flora that include aerobic, facultative and

anaerobic (isolated in 63 - 100% of cases) organisms c. May

be clinically difficult to distinguish from uncomplicated PID

1) Wide range of severity

2) Clinician may not be able to palpate an adnexal mass

3) Pelvic ultrasonography most ~important diagnostic

imaging technique

d. Treatment

1) 75% of patients can be treated successfully with broad

spectrum IV antibiotic course

2) Larger TOAs (more than 6 cm diameter) are more likely

to require drainage or more aggressive surgical

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intervention

B. Long-term complications

1. Ectopic pregnancy

a. Risk increased 6 - 10 times following a single episodeof PID

b. 8% of pregnancies following one episode of PID are ectopic

c. Risk increased significantly if two or more chlamydial

infections

2. Chronic pelvic pain

a. 12% of women after a single episode, and 67% following three

episodes

b. Associated with the extensiveness of peritubal adhesions

and the degree of dysmorphology of the tubes'fimbriated ends

3. Infertility

a. Caused by scarring and occlusion of fallopian tubes' lumens

b. Rates following episodes of PID

1) One episode-- 11%

2) Two episodes-- 25%

3) Three or more episodes -- 43%

c. Chlamydial infection -- organism most associated with tubal

factor infertility

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Topic IV: Approach to Vesiculo-ulcerative Diseases

I. Differential Diagnosis in the United States

A. By prevalence (all cases, not just adolescent age group)

1. Herpes simplex -- at least 250,000 new cases a year

2. Syphilis -- 16,500 new cases in 1995

a. Most recent peak in 1990 -- 50,223 new cases

3. Chancroid -- 606 new cases in 1995

a. Most recent peak in 1988 -- 5001 new cases

4. Lymphogranuloma venereum -- 235 new cases in 1994; not

nationally notifiable since 1995

a. Most recent peak in 1991 -- 471 new cases

b. Consistently fewer than 500 new cases a year since 1973

5. Granuloma inguinale -- 3 new cases in 1994; not nationally

notifiable since 1995

a. Most recent peak in 1990 -- 97 new cases

b. Consistently fewer than 100 new cases a year since 1972

B. By geographic region

1. Syphilis-- Southeast

2. Chancroid -- States with more than 100 new cases in 1995 --

New York and Louisiana (rates more than 1/100,000; together

account for 77% of all new cases in the United States)

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II. Comparative Clinical Clues

A. Comparison of incubation periods

1. Herpes simplex -- 2 - 7 days

2. Syphilis -- 10 - 90 days (mean 21 days)

3. Chancroid -- 2 - 35 days (usually 4 - 10 days)

4. LGV -- 5 - 40 days (usually 7 - 21 days)

B. Description of lesions (in immunocompetent patient)

1. Herpes simplex

a. Primary lesion -- vesicle

b. Number -- multiple, may be in clusters, may coalesce

c. Size of ulcers -- 1-2 mm diameter

d. Depth of ulcer -- superficial

e. Base of ulcer -- erythematous, non-purulent

f. Painful

2. Primary syphilis (Treponema pallidum)

a. Primary lesion -papule

b. Number of ulcers -- usually single, but up to several

c. Size of ulcer -- 2-20 mm diameter

d. Depth of ulcer -- superficial or deep

e. Base of ulcer -- sharp margin, indurated rounded borders,

nonpurulent (unless secondarily infected)

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f. Pain -- not usual, unless secondarily infected

3. Chancroid (Haemophilus ducreyi)

a. Primary lesion -- painless papule, which becomes a pustule

b. Number of ulcers -- multiple, may coalesce (mean 4.5)

c. Size of ulcers -- 2-20 mm diameter (usually 1-2 cm)

d. Depth of ulcer-- deep

e. Base of ulcer -- ragged border, purulent, friable

f. Painful

4. Lymphogranuloma venereum (Chlamydia trachomatis serotypes

L1, L2 or L3)

a. Primary lesion -- papule or pustule

b. Number of ulcers -- one (frequently presents without

ulceration) to several

c. Size of ulcer-- 2-10 mm diameter

d. Depth of ulcer -- superficial or deep

e. Base of ulcer -- varies

f. Painful (about 50% of initial lesions are asymptomatic and

heal without scarring)

C. Description of lymphadenopathy

1. Herpes simplex -- tender, bilateral

2. Primary and secondary syphilis -- nontender, bilateral

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3. Chancroid -- buboes

a. Tender, unilateral (67%) -- develops acutely 1 - 2 weeks after

primary lesion in 50% of men and 35% of women

b. Unilocular fluctuance (central necrosis and liquification)

c. May suppurate -- spontaneous rupture if not treated and if size

exceeds 5 cm

4. LGV

a. Tender, unilateral or bilateral

b. Multilocular fluctuance

c. May suppurate

1) May rupture with chronic sinus formation

2) With rectal involvement, likely to develop rectal stricture

and perineal fistulas

D. Different vesiculoulcerative STDs can coexist in the same patient and in

the same lesion

III. Approach to Laboratory Diagnosis

A. Test lesions for herpes simplex virus

B. Darkfield microscopy or direct fluorescent antibody test of lesional

material for Treponema pallidum

C. Syphilis serology

D. Test lesions for H. ducreyi (selected cases)

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1. Gram stain smears have low sensitivity and specificity

2. Culture

a. Fastidious growth requirements -- difficult to isolate

b. Limited success outside of experienced laboratories

3. DNA probes -- not sensitive enough to detect H. ducreyi for clinical

use, but high specificity can confirm identification of isolates

4. PCR

a. Variable sensitivity and specificity in research reports

b. Commercial multiplex PCR assay under development

1) For simultaneous detection of H. ducreyi, T. pallidum,

and herpes simplex virus from genital ulcers

2) Resolved sensitivities for each organism -- 98%, 91%,

and 100%

3) Specificities for each organism -- 100%, 99%, 100%

E. Test selected cases for LGV

1. Culture

2. PCR

F. Tests for other STDs, including gonorrhea and chlamydia

G. Test for HIV infection

IV. Treatment for H. ducreyi and LGV (more common infections covered in their

own sections)

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A. H. ducreyi

1. CDC recommended regimens

a. Azithromycin 1 gm orally (single dose) or

b. Ceftriaxone 250 mg IM (single dose) or

c. Erythromycin 500 mg orally q.i.d, for 7 days

2. Resistance (by plasmid acquisition) reported internationally, but not

domestically to erythromycin, amoxicillin-clavulanic acid (alternative

regimen) and ciprofloxacin (alternative regimen)

3. Widespread resistance to

a. Ampicillin

b. Trimethoprim with sulfonamide

c. Tetracyclines

d. Aminoglycosides

B. LGV -- doxycycline 100 mg orally twice daily for 21 days

Topic V: Major Causes of Vesiculo-ulcerative Disease

Topic VA: Syphilis

I. Biology

A. Treponema pallidum

I. Microaerophilic spirochete

2. Humans represent its only natural host

3. Transmitted by sexual contact through organisms living in open

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lesions of genital, anal, and oral mucosa

a. Efficiency of transmission -- 33%

b. Penetrates intact mucosa, but requires an abrasion to invade

keratinized skin

4. Genetically conservative

B. Dissemination within the host

1. Invades vascular system and is hematogenously disseminated

2. Causes local and system inflammatory and immunologic responses

3. Invades CNS in 24% of patients during primary phase, even

before seroconversion, but only 5 - 10% of untreated persons

eventually develop clinical neurological disease

II. Epidemiology of Syphilis

A. Incidence and prevalence have varied since World War II

1. Rates dropped sharply with availability of penicillin -- nadir in 1956

2. Rates rose during 1960's, with 10-year cycles of recurrent peaks

and troughs

3. Most recent epidemic in 1980's, with peak rate in 1990 -largely

among heterosexual, minority populations

a. Crack cocaine use and associated sexual behaviors

b. Increasing poverty and social disorganization

c. Increasing urbanization

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d. Disintegration of marriage

4. Rates have dropped since 1990

5. Current rates per 100,000 population (1995)

a. 10- 14 year olds-- 0.6

b. 15 - 19 year olds --10.0 (males - 6.6. females - 13.6) c. 20 - 24

year olds--17.2 d. 10 - 65 plus year olds -- 6.3

6. Geographic distribution -- highest rates in Southeastern states and

in urban areas in other regions of the country

7. Race and ethnicity

a. Large disparities, with Black population having largest

burden of suffering -- rates among Black adolescents 55

times higher than among White adolescents

8. Concept of core sex partner pool

a. Smaller group within a community with high rates ofinfection

and partner exchange

b. Responsible for maintenance of high community rates

c. Spreads to other community members sporadically, but

disease is better controlled among this more diffuse group

because of decreased numbers of sexual contacts and higher

likelihood of receiving treatment

III. Diagnostic Formulation of Syphilis

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A. Clinical presentation

1. Primary syphilis

a. Starts with first clinical manifestation of infection, a papule that

progresses to an ulcer over one to several weeks

b. Ulcer heals gradually within several weeks

c. Patient may be unaware of lesion because it is asymptomatic

and is frequently hidden from view

d. Some patients may experience a period of latency following

healing of chancre and before onset of symptoms of secondary

syphilis

1) Are seroreactive, however

2) Represents a period of active bacterial replication

2. Secondary syphilis

a. Develops between 6 and 24 weeks following inoculation

b. Represents disseminated infection with involvement of multiple

organ systems -- skin, lymphatics, GI tract, bones, kidneys,

eyes, CNS

c. Constitutional symptoms in about 70% -- fever, malaise,

anorexia, weight loss, pharyngitis, laryngitis, arthralgia, and

generalized, usually painless, lymphadenopathy

d. Highly variable skin rashes (syphilids) in about 75%, but may

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not be noticed by patient

1) Are closed skin lesions that are relatively non-infectious

2) Not vesicular, and rarely pustular. Other forms common.

May be pruritic

3) Distribution

a) Usually begin on trunk as symmetric discrete

macules

b) Lesions on palms and soles in about 67%

4) May persist for weeks or months

5) May evolve in form or have multiple variations present

simultaneously (e.g., macular progress to papular)

6) May have temporary patchy alopecia or loss of eyebrows

e. Mucocutaneous lesions -- are highly infectious; contain large

numbers of spirochetes

1) Condyloma lata -- occur in warm, moist intertriginous

areas -vulva, scrotum, anal verge, inner thighs, axillary

and gluteal folds

2) Mucous patches -- mucosa of mouth, pharynx, vulva,

vagina, cervix, glans penis, anal canal

f. Central nervous system involvement

1) From hematogenous seeding

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2) Asymptomatic involvement in 8 - 40%

3) Acute aseptic meningitis in 1 - 2%

4) More serious CNS problems rare -- stroke and cranial

nerve dysfunction (III, VI, VII, VIII)

5) Anterior uveitis many occur

g. Unusual clinical manifestations -- glomerulonephritis, nephrotic

syndrome, hepatitis, arthritis, periostitis

h. Time course -- signs and symptoms last for several weeks

without treatment

i. Latent phase

1) Develops after resolution of signs and symptoms of

secondary syphilis -- quiescent phase

2) Infectious relapse will occur in about 25% of untreated,

usually within first year of infection, but ma,' recur up to

five years

3. Patients who have HIV and syphilis

a. More likely to present in secondary stage

b. More likely to have persistence of chancres

4. Late or tertiary syphilis -- will not be presented, because it takes

years to decades to develop, and does not present until adulthood

B. Laboratory evaluation

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1. Diagnosis must be presumed by microscopic identification,

serologic tests, or molecular biology-based tests

2. Direct diagnosis

a. Dark-field microscopy

1) When lesions are present, the easiest and most direct

means of establishing a diagnosis

2) Requires fresh material from chancres, mucocutaneous

lesions or aspirated lymph nodes

3) Demonstrates characteristic morphology and motility --

may be difficult to distinguish morphology from

commensal treponemes of GI tract

4) Sensitivity about 80%

b. Direct fluorescent antibody test (DFA-TP) -- can be used for

examination of material from oral and anal lesions, and from

paraffin-embedded tissue sections, but requires fluorescence

microscopy equipment

c. Polymerase chain reaction (PCR)

1) Technology helped by the extreme genetic stability of T.

pallidum

2) Sensitivity a problem because of non-specific inhibitors

of PCR reaction

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3) T. pallidum primers have been incorporated into a

commercial PCR kit for evaluation of genital ulcer

disease

4) Greatest clinical value anticipated to be in the diagnosis

of neurosyphilis and congenital syphilis, given the

inadequacy of serologic tests in these areas

3. Indirect non-treponemal (reagin) serologic tests

a. Widely used as initial clinical screens and to monitor disease

activity following treatment

b. Measure IgG and IgM flocculating antibodies to lipoidal

material released from damaged host cells as well as

lipoprotein-like material released from treponemes. Antigenic

material is a standardized mixture of cardiolipin, cholesterol

and lecithin

c. To quantify host antibody in reactive sera, serial dilutions are

performed to a nonreactive endpoint

d. Reactivity based on stage of syphilis

1) Primary -- Reactivity does not develop until 1 - 4 weeks

following appearance of chancre. If disease suspected

and serology is negative, periodic retesting should be

performed for 3 months

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2) Secondary -- Tests are virtually always reactive (titer at

least 16)

3) Tertiary -- Tests may be non-reactive in 25 - 33% of

patients

e. Prozone phenomenon -- false negative result occurring in 1 -

2% of sera with such a high antibody titer that there is antibody

excess compared to the antigen

f. Specific tests

1) VDRL Slide Test -- flocculation of antigen-antibody

complexes. Serum needs to be heat-inactivated, and

results need to be viewed with a microscope. Only test

recognized as standard for use on CSF

2) Unheated Serum Reagin (USR) Test -- Microscopic test

otherwise similar to VDRL, but using a standardized

antigen and not requiring heating of serum

3) Rapid Plasma Reagin (RPR) Test -- Most widely used

test. Charcoal is added to the USR antigen to permit

macroscopic visualization of the antigen-antibody

complexes

4) Toluidine Red Unheated Serum Test (TRUST) -- red

paint is added to the USR antigen to permit macroscopic

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visualization of the antigen-antibody complexes

5) VDRL-EIA and VDRL-ELISA -- Both use VDRL antigen

g. False positive reactivity common -- usually low titer

1) Acute processes --Mycoplasma and pneumococcal

pneumonia, scarlet fever, viral hepatitis, varicella,

infectious mononucleosis, tuberculosis, malaria,

immunizations

2) Chronic processes -- systemic lupus erythematosus,

injection drug use, multiple blood transfusions, pregnancy

4. Indirect treponemal serologic tests

a. Used to confirm the diagnosis of syphilis -- to differentiate

between true positive and false positive results of a reactive

non-treponemal antibody test

1) More sensitive than non-treponemal tests (80 - 85%) in

detecting primary syphilis

2) Virtually always reactive in secondary and tertiary

syphilis

3) Have a 1% false positivity rate themselves -- can be

positive with Lyme disease, infectious mononucleosis,

and systemic lupus erythematosus

b. Are qualitative, expensive and have technical demands

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c. Because usually remain active for life, their clinical utility is

limited to confirming the diagnosis of syphilis

-- some treated patients may serorevert within 36 months

d. Specific treponemal serologic tests

1) Fluorescent treponemal antibody absorption (FTA-ABS)

test -- uses indirect immunofluorescence to detect serum

antibody-T, pallidum antigen complexes

2) Microhemagglutination assay for antibodies to T.

pallidum (MHA-TP) -- based on ability of reactive sera to

agglutinate red blood cells coated with T. pallidum

sonicates

3) Treponemal EIA -- Commercial kits already in use.

Similar sensitivities and specificities to FTA-ABS and

MHA-TP

IV. Management of Syphilis

A. Antibiotic treatment

1. Parenteral penicillin G is the antibiotic of choice for treating

primary and secondary syphilis

a. In cases uncomplicated by HIV or pregnancy, use benzathine

penicillin G, 2.4 million units IM in a single dose

b. If duration of disease is unknown use a larger total dose of

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benzathine penicillin G, 7.2 million units total, administered in

three weekly doses of 2.4 million units each

c. Neurosyphilis -- requires high dose aqueous crystalline

penicillin G delivered IV daily for 10 - 14 days

d. Single dose ceftriaxone is not a recommended treatment,

although ceftriaxone does have anti- treponemal activity and

may eradicate incubating syphilis

B. Other clinical considerations

1. Test all patients with syphilis for HIV infection

2. Evaluate for neurosyphilis if any of following conditions exist --

neurologic or ophthalmic signs or symptoms, treatment failure, HIV

infection, high non-treponemal titer (especially if not clear that

duration of infection is less than a year), and non-penicillin therapy

planned

3. Evaluate all female patients for pregnancy

C. Follow-up

1. Re-evaluate clinically and serologically at 3 and at 6 months

following treatment

a. Should demonstrate resolution of signs and symptoms

b. Should have a fourfold (two dilution) decrease in titer

D. Management of sex partners

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1. Reporting to health department to ensure sexual contact tracing

2. Should be treated presumptively, even if seronegative

Topic VB: Sexually Acquired Herpes Simples Virus (HSV) Infections

I. Biology of Herpes Simplex Virus

A. Characteristics of organism

1. Linear, double-stranded DNA genome

2. Two serovars of HSV -- 90% of genital infections caused by HSV-2

B. Pathogenesis of infection

1. Intimate physical contact required for transmission to mucosal and

skin cells

2. Latent infections

a. Latently infected host cell maintains viral genome, but does

not die

b. Thought to be largely harbored in the neurons of the

peripheral nervous system -- in sensory or autonomic nerve

root ganglia

II. Epidemiology of HSV Genital Infections

A. Transmission of virus

1. 70% of cases transmitted during periods of asymptomatic virus

shedding

2. Overall annual transmission rate in heterosexual couples to

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vulnerable partner

a. To women-- 10%

b. To men--4%

B. Relationship of HSV-2 with cervical cancer -- evidence from

epidemiological and molecular studies

III. Diagnostic formulation of HSV Genital Infections

A. Clinical presentation of primary infection

1. Asymptomatic and mild infections prevalent -- only 20% of those

with antibodies to HSV-2 recall symptomatic disease

2. Clinical course

a. Initial phase

1) Incubation period - about one week (2 - 12 days)

2) Painful vesicles, which become pustular, spread

bilaterally over external genital area, for first several

days. Coalesce into large areas of ulceration

3) Constitutional symptoms peak within first four days and

resolve by tenth day -- fever, headache, malaise, and

myalgia

b. Second phase

1) Ulceration persists from day 4 -15

2) New vesicular lesions may continue to form between

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days 4 - 10

c. Third phase

1) Healing starts by day 12

2) Lesions crust and become asymptomatic by 14 days

3) Healing of lesions fairly complete by day 22

4) Development of tender, but non-suppurative, bilateral

lymphadenopathy during second and third weeks

d. Viral shedding during primary infection

1) Median 12 days

2) HSV can be isolated from urethra in 28% of males and

76% of women, and from cervix in 88% of women

e. Associated clinical processes

1) Ecto-cervicitis -- squamous epithelium becomes red and

friable, and may have ulcerative lesions

2) Pharyngitis -- associated with oral-genital exposure

3) Symptomatic proctitis from ano-genital contact

f. Complications in immunocompetent patients

1) CNS involvement -- meningeal symptoms frequent, but

usually don't require hospitalization; sacral radiculopathy

of autonomic nervous system; transverse myelitis

2) Nongenital lesions, probably by autoinoculation

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3) Disseminated cutaneous and visceral infection rare --

pregnancy and atopic dermatitis may be predisposing

4) Pelvic inflammatory disease by direct extension into

upper genital tract

5) Involvement of other organ systems -- hepatitis,

pneumonia thrombocytopenia, monoarticular arthritis

6) Vulvovaginal candidiasis in 14% of women during second

week

B. Clinical presentation of recurrent genital herpes

1. Rates of recurrence

a. Within first year, 90% of those with HSV-2 and 60% of those

with HSV-1

b. Median rate is 5 episodes a year -- variable

2. Prodromal symptoms experienced by half

3. Symptom and signs are less severe and of shorter duration

C. Asymptomatic infection

1. Thought that about 60% of primary HSV infections are

asymptomatic or have extremely mild symptoms

2. Asymptomatic viral shedding in women with history of HSV-2

a. Accounts for more than 30% of total days of viral shedding

b. Present on 2 - 4% of all days

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c. Up to 55% of infected women demonstrate it when cultures

obtained daily

d. Most likely to occur during the first 3 - 12 months following

resolution of primary infection

D. Laboratory testing for HSV genital infection

1. Confirmatory laboratory studies recommended, especially for initial

episode or for an atypical recurrence

a. Culture or antigen tests for HSV

b. Evaluation for syphilis

1) Non-treponemal serological test

2) Lesion material examined for T. pallidum

c. Consideration of co-existence of more than one process in

same lesion (syphilis, chancroid, LGV)

2. Direct examination of clinical specimens

a. Demonstrate cytopathic changes of multinucleated giant cells

-- Tzanck preparations and Papanicolaou smears of scraped

lesional material less sensitive (range 30 - 80%)

b. Immunofluorescence

1) Direct and indirect fluorescent antibody tests (DFA and

IFA) -- most commercial kits are for DFA

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2) Sensitivities/specificities for DFA -- 78 - 85% / 85 98%

c. Immunoenzyme methods -- are replacing DFA procedures for

examination of clinical lesional material; use bright-field

microscopy

d. Enzyme immunoassays

1) Detect viral antigen in solution rather than directly from

lesional cells

2) Sensitivity > 90%. Specificities 85 - 100% for detection of

symptomatic disease. Less sensitive for detection of

asymptomatic viral shedding

e. Nucleic acid probes -- hybridization of DNA sequences are

available in commercial kits

f. Polymerase chain reaction -- greatest clinical value will be for

rapid detection of HIV in CSF for diagnosis ofherpes encephalitis

3. Virus isolation by culture

a. Most sensitive method other than PCR

b. Chance of growth dependent on clinical phase

1) Vesicular -- 94%

2) Pustular-- 87%

3) Ulcerated -- 70%

4) Crusted-- 27%

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c. Typing as HSV-1 or HSV-2 by IFA or EIA

IV. Patient Management

A. Therapeutic and management goals -- unable to eradicate latent virus

1. Hastening rate of healing and resolution of symptoms and lesions

2. Limiting frequency and severity of complications

3. Preventing and limiting subsequent clinical recurrences

4. Decreasing transmission of H IV infection

B. Acyclovir currently only drug that is label approved for HSV infection in

immunocompetent patients -- oral or IV use based on disease severity

Topic VI: Human Papillomavirus (HPV) Anogenital Infections

I. Biology of HPV Anogenital Infections

A. Small DNA viruses that belong to papovavirus family

B. More than 70 characterized to date, and 34 types associated with

anogenital mucosal lesions

C. Mechanisms of disease

1. Viral entry through site of epithelial disruption to the basal germinal

layer of anogenital mucosa and skin

2. Koilocytosis is the specific cytopathic effect in infected mature

squamous epithelial cells -- large clear perinuclear zone with

irregular dense marginal cytoplasm and enlarged hyperchromatic

nuclei with abnormal mitotic figures

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3. Specificity in types of lesions produced by HPV types

a. 6, 11 -- anogenital condylomata

b. 16, 18, 31, 42 -- Bowenoid papulosis, vulvarintraepithelial

neoplasia, Bowen's disease

c. 6, 11,16, 18, 31, 33, 35 -- cervical intraepithelialneoplasia,

dysplasias of genital mucosa

d. 16, 18, 31, 33, 35 -- invasive cancer

4. Time courses

a. Majority of HPV genital infections are transient

b. HPV positive individuals demonstrate infection with

different types over time

c. Persistence of infection more likely among types known to be

cancer associated

D. Associated with the development of squamous epithelial cancers of

anogenital area -- cervix, vulva, vagina, penis, anus

II. Epidemiology of HPV Anogenital Infections

A. Most prevalent viral STD

1. Estimates of prevalence range from 10 - 50% of sexually active

individuals

2. 0.5 - 3% of routinely screened Pap smears show evidence of HPV

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infection

3. Accounts for 5% of all STD clinic visits

4. Overall visit rate appears to be declining since 1987 peak ofabout

355,000 visits

B. Transmission rate -- 40 - 50% of men whose female partners have I-IPV

infection also show evidence

III. Diagnostic Formulation of HPV Anogenital Infections

A. Clinical presentations

1. Four categories of disease

a. Latent -- presence of HPV DNA in absence of demonstrable

disease

b. Acuminate -- Anogenital exophytic condylomas or warts

growing on moist anogenital skin or mucosa. In dry areas (e.g.,

penile shaft), may present as keratotic plaques

1) Symptoms variable -- asymptomatic, local burning and

pruritus, discharge, post-coital bleeding, hematuria

2) Time course -- mean duration from exposure to lesion

appearance 2 - 3 months, but could be as long as 8

months

c. Subclinical disease -- lesions that are invisible to routine

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inspection, but that become apparent following application of

acetic acid and magnification (aceto-conditioning)

d. Neoplastic transformation

1) Demonstration of HPV DNA in invasive carcinoma cell

lines

2) Similarity of epidemiologic profiles between HPV genital

infection and cervical carcinoma

3) Other cofactors may be important facilitators of a

neoplastic transformation

2. Differential diagnosis

a. Condylomata lata, a mucocutaneous lesion of syphilis

b. Molluscum contagiosum

c. Non-genital HPV types arising coincidentally -- verruca

vulgaris

d. Normal anatomic variants -- skin tags, pearly penilepapules

B. Laboratory studies

1. Inspection with magnifying lens -- will not detect subclinical disease

2. Cytology -- Pap smear responsible for decreases in mortality from

cervical carcinoma. Cellular atypia and koilocytosis. However, not

very sensitive for detecting intraepithelial lesions, due in part to

sampling error and errors in interpretation of routine screens

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3. Histology of biopsy specimens -- more sensitive than Pap smears

in detecting HPV infection (koilocytes) and dysplasia, but invasive.

Enhanced by immunohistochemical staining

4. Colposcopy, urethroscopy, anoscopy -- magnification. Biopsy of

lesions may be performed

5. Tissue culture -- cannot be routinely grown

6. Demonstration of virus -- definitive diagnosis of HPV

infection and disease requires cytologic or histologic

changes and virus identification

a. Several hybridization techniques -- HCM, the most sensitive,

is a recent improved version of the Hybrid Capture System.

50-fold more sensitive; detects 1000 I-IPV genomes per assay.

Can detect 13 carcinogenic HPV types, which is considered

virtually exhaustive

b. Polymerase chain reaction -- Sensitive; can detect DNA

from 10 - 100 HPV DNA molecules from a specimen

containing 50,000 cells. Can use DNA from fresh or fixed

tissue or cells

1) Novel HPV sequences are being identified with advanced

technology, restriction fragment length polymorphism

(RLFP) analysis

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IV. Management of HPV Infections

A. Treatment is not uniformly successful, and there is a substantial chance

of recurrence

B. Majority of therapies are mechanically cytodestructive or cytotoxic

C. Indications

1. High grade lesions of dysplasia (usually cervical) -- require

ablative therapy. LEEP (loop electrosurgical excision procedure),

CO2 laser vaporization, cervical conization, cryotherapy

2. Exophytic lesions -- can be treated by a variety of agents. None

eradicates HPV infection, and recurrences are common. Goal is to

remove the lesions and to ameliorate patients' symptoms without

significant trauma to surrounding tissue

3. Subclinical disease -- Treatment not currently recommended

D. Response and recurrence rates of common treatments for HPV infection

Treatment Response rate Recurrence rate

Cryotherapy 63-88% (70%) 21-39% (30%)

Trichloroacetic acid 61-81% (70%) 36%

Podophyllin 32-79% 27-65%

Podophyllotoxin 45-88% (73%) 33-60%

CO2 laser vaporization 31-91% (76%) 3-95% (25%)

Excisional biopsy 70% 30%

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Topical 5-fluorouracil 10-73% (ext genitalia) 10-25%

5-95% (urethral)

50-90% (vaginal)

Interferon alpha-n3 65% (includes 26% partial) 0-33%

Interferon alpha-2b 19-53% (dose dependent) 0-33%

Topic VII: Diagnostic Approach to Vaginitis in Adolescents

I. Comparative Macroscopic Characteristics

A. Appearance

1. Normal -- flocculent and cream-colored

2. Candidiasis -- curdy and cream-colored

3. Trichomoniasis -- bubbly and yellow-green (up to 50%)

4. Bacterial vaginosis -- homogeneous, watery and gray (69%)

B. Vaginal pH

1. Normal-- <4.6

2. Candidiasis -- < 4.6

3. Trichomoniasis -- > 4.5 (66 - 91%)

4. Bacterial vaginosis -- > 4.5 (97%)

C. Odor

1. Normal -- none

2. Candidiasis -- none

3. Trichomoniasis -- none to malodorous

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4. Bacterial vaginosis -- none to fishy

D. Potassium hydroxide (KOH) odor test

1. Normal --negative

2. Candidiasis -- negative

3. Trichomoniasis -- confounded by malodor (75%)

4. Bacterial vaginosis -- accentuated fishy odor (43%

II. Comparative Microscopic Characteristics (normal saline mounts)

A. Squamous epithelial cells -- normal in each except bacterial

vaginosis, for which at least 10 - 20% should represent clue cells (78%)

-- bacteria adsorbed to surface cause a heavily stippled appearance of

at least part of cytoplasm and a shaggy appearance to at least part of the

cell membrane

B. Polymorphonucleocytes (PMNs)

1. Normal -- few

2. Candidiasis -- few to a moderate number

3. Trichomoniasis -- many. May be TNTC (75%)

4. Bacterial vaginosis -- few

C. Other cellular elements

1. Normal -- lactobacilli prominent

2. Candidiasis -- pseudohyphae and blastospores (visualized more

easily using KOH mount) (50 - 90%)

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3. Trichomoniasis -- motile trichomonads (40 - 80%)

4. Bacterial vaginosis -- few lactobacilli, but prominence of small

pleomorphic morphotypes (89%)

D. Laboratory tests in clinical practice

1. Candidiasis

a. Culture -- performed under certain circumstances

b. Slide latex agglutination test -- polyclonal antibodies reactive

to multiple Candida species. Less sensitive than culture, but

highly specific

2. Trichomoniasis

a. Culture not usual in clinical practice

b. Direct immunofluorescence assay (DFA) -- sensitivity/

specificity 86% / 99%. Able to detect 77% of cases with

negative normal saline mounts

c. DNA probe commercially available -- also detects

bacterial vaginosis. Sensitivity/specificity 80% / 98%

d. Stained preparations and Papanicolaou smears not

sufficiently sensitive (50 - 70%)

3. Bacterial vaginosis

a. Gram stain -- 3 variations developed, which require the

counting obacterial morphotypes across oil immersion

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fields and comparing the proportions o lactobacilli with less

desirable morphotypes (short gram variable rods, crescent

rods, cocci). May include the presence of clue cells.

Sensitivity/specificity 89% / 83%

b. Oligonucleotide probe commercially available -- also detects

trichomoniasis. Sensitivity/specificity > 90% / 78-97%

c. Culture for associated organisms not helpful -- G. vaginalis

and M. hominis commonly present in women without BV, and

Mobiluncus difficult to isolate by culture

Topic VIII: Common Causes of Vaginitis in Adolescents

Topic VIllA: Vulvovaginal Candidiasis

I. Biology

A. Represents symptomatic invasion of vaginal epithelial cells by acommon

commensal organism originating from the perianal area B. Common

species

1. Candida albicans strains represent 85 - 90% of yeast isolated from

vagina

2. Torulopsis glabrata

a. Collection of blastospores; cannot assume pseudohyphal or

chlamydospore forms

b. Resistance to common treatment agents (azoles)

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3. C. tropicalis

a. Clusters of blastospores growing from a central stem

b. May be resistant to topical agents

C. Classification of infection

1. Sporadic primary -- idiopathic

2. Sporadic secondary -- eg, pregnancy, following an antibiotic course

3. Recurrent primary (RVVC) -- 3 mycologically proven symptomatic

episodes in the previous year

a. Complex causation that is not well understood

1) Impaired cell-mediated immunity at local vaginal mucosal

level (systemic CMI intact)

2) IgE antibodies may contribute to RVVC -associated with

histamine release (directly responsible for symptoms),

which enhances the production of PGE2, which promotes

germ tube (pseudohyphae) formation

3) More likely to be associated with a non-albicans species,

especially Torulopsis glabrata

b. Sources of organisms in RVVC -- usually from relapse. May be

reinfection from GI tract or sexual partner

4. Recurrent secondary -- e.g., diabetes mellitus, hormone

replacement therapy, AIDS, immunosuppressive therapy

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II. Epidemiology of Vulvovaginal Candidiasis

A. Colonization of asymptomatic healthy women -- 20 - 25% by point

prevalence studies

B. Very common -- about 75% of women experience a lifetime episode

C. About 5% of women with primary sporadic infection will develop recurrent

vulvovaginal candidiasis

III. Management of Vulvovaginal Candidiasis

A. Pharmacologic -- azoles inhibit cytochrome P450-dependent 14-a-

demethylation of lanosterol

1. Imidazoles -- original agents. Some now available without

prescription (clotrimazole, miconazole, tioconazole, butoconazole)

2. Triazoles -- May have enhanced efficacy because of their high

selectivity for yeast cytochrome rather than for human microsomal

cytochrome

a. Terconazole -- topical

b. Fluconazole -- oral

1) Development of resistant C. albicans isolate in

immunocompromised patients

2) Requires higher mean inhibitory concentrations, so is

less fungistatic than terconazole

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3) Single dose effectiveness based on its long half-life (36

hours) and high concentration in vaginal secretions

B. Principles of antimicrobial treatment in candidiasis

1. Treat only patients with evidence of tissue invasion, not

asymptomatic patients that demonstrate onlycolonization

2. Recognize that no agent is fungicidal; each is fungistatic

3. Considerations in choosing agent

a. Acute versus recurrent episode

b. Severity of symptoms

c. Fungal species

d. Immune competence of patient

C. Agent choices

1. For patient with an initial or infrequent episodes of C. point

prevalence studies

B. Very common -- about 75% of women experience a lifetime episode

C. About 5% of women with primary sporadic infection will develop recurrent

vulvovaginal candidiasis

III. Management of Vulvovaginal Candidiasis

A. Pharmacologic -- azoles inhibit cytochrome P450-dependent 14-a-

demethylation of lanosterol

1. Imidazoles -- original agents. Some now available without

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prescription (clotrimazole, miconazole, tioconazole, butoconazole)

2. Triazoles -- May have enhanced efficacy because of their high

selectivity for yeast cytochrome rather than for human microsomal

cytochrome

a. Terconazole -- topical

b. Fluconazole -- oral

1) Development of resistant C. albicans isolate in

immunocompromised patients

2) Requires higher mean inhibitory concentrations, so is

less fungistatic than terconazole

3) Single dose effectiveness based on its long half-life (36

hours) and high concentration in vaginal secretions

B. Principles of antimicrobial treatment in candidiasis

1. Treat only patients with evidence of tissue invasion, not

asymptomatic patients that demonstrate only colonization

2. Recognize that no agent is fungicidal; each is fungistatic

3. Considerations in choosing agent

a. Acute versus recurrent episode

b. Severity of symptoms

c. Fungal species

d. Immune competence of patient

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C. Agent choices

1. For patient with an initial or infrequent episodes of C. albicans

vaginitis -- any formulation effective, including imidazole topical

derivatives and oral triazole agent, fluconazole

2. For patient with recurrent episodes or non-C, albicans species

a. Use topical triazole, terconazole -- no demonstrated resistance

b. RWC can be managed by

1) Weekly use of topical agent -- clotrimazole orterconazole

2) Several month course of fluconazole

3) Boric acid topically in a gelatin capsule

3. No conclusive empirical benefit from ingestion of or local

application of Lactobacillus (e.g., yogurt or cultures)

Topic VIIIB: Trichomoniasis

I. Biology -- sexually transmitted, unicellular flagellated anaerobic protozoan

functioning as an extracellular parasite in human lower genital tract

II. Epidemiology of Trichomoniasis

A. Most prevalent non-viral STD on a world-wide basis -prevalences within

STD clinic samples (using non-molecular techniques of diagnosis):

females -- 15 - 30%; males -- 5 - 20%

B. High transmission rates at 48 hours post coitus with an infected partner:

70 - 85%

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C. Incubation period for development of clinical symptoms

variable -- 3 - 28 days, but occasionally up to 6 months

D. Frequently co-associated with other STDs -- gonorrhea, chlamydia,

human papillomavirus, herpes simplex virus

III. Management of Trichomoniasis

A. General principles

1. All patients should be treated, even if they are asymptomatic 2. All

patients should be evaluated for other STDs

B. Systemic oral metronidazole is the drug of choice (in order to eradicate

organisms in the vagina, urethra, periurethral glands, and Bartholin's

glands)

II. Management of Bacterial Vaginosis

A. Rationale for treatment

1. Alleviation of symptoms

2. Prevention of significant gynecologic and obstetric morbidity.

Associations demonstrated between untreated BV and

a. Pelvic inflammatory disease

b. Plasma cell endometritis

c. Infection following trans-cervical invasive procedures

d. Amniotic fluid infection

e. Postcesarean endometritis

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f. Possible association with intrauterine growth retardation

g. Premature labor and delivery

B. Recommended treatment of bacterial vaginosis

1. Metronidazole 500 mg orally, 2 times a day for 7 days -- short term

cure rates of at least 90%, but a single 2 gm dose has only a 84%

effectiveness at one week and 73% at 4 weeks

2. Other alternative regimens

a. Systemic clindamycin -- one week course

b. Intravaginal topical clindamycin cream -- one week course

1) Recommended during first trimester of pregnancy.

Thereafter, any regimen can be used

c. Intravaginal topical metronidazole gel -- five day course

3. Treatment of sexual partners -- not currently recommended, given

inconsistent ability to demonstrate enhanced effectiveness or

decreased rate of relapse. May be offered in cases of recurrence

Topic Ix: Vulvovaginitis in Prepubertal Females

I. Differential Diagnosis of Prepubertal Vulvovaginitis

A. Bacterial infections

1. Nonspecific mixed infections from contamination by urine and

feces - 70%

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2. Specific non-sexually transmitted infections (respiratory, skin,

enteropathic pathogens)

3. Bacterial vaginosis

4. Sexually and vertically transmitted infections

B. Fungal infections

C. Protozoan infections -- trichomoniasis

D. Parasitic infections -- Enterobius vermicularis

E. Viral infections

1. Sexually and vertically transmitted

2. Involvement as part of a systemic infection -- varicella, rubella,

infectious mononucleosis

F. Contact irritation or allergic reactions -- soaps, shampoos, detergents

G. Vulvar or perineal skin diseases

1. Local --lichen sclerosis, seborrheic or atopic dermatitis

2. Involvement as part of systemic disorder (Steven-Johnson

syndrome, Kawasaki disease, psoriasis)

H. Physical factors

1. Physical trauma -- sand play, abuse, non-intentional

2. Tight garments -- maceration

3. Foreign body

4. Anatomic abnormalities

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a. Neoplasms and polyps

b. Prolapsed urethra

c. Ectopic ureter

d. Draining pelvic abscess or rectal fistula

e. Labial agglutination

I. Somatoform complaints

II. Clinical Tests and Procedures for Prepubertal Vulvovaginitis

A. Microscopy -- normal saline and potassium hydroxide preparations

1. Squamous epithelial cells and clue cells, WBCs, RBCs,

trichomonads, parasitic ova, pseudohyphae/buds, sperm

B. Cultures for bacteria

1. Pyogens, gram negative organisms, anaerobes

2. Request quantification of all predominant isolates

C. Cultures for sexually transmitted pathogens -- N. gonorrhoeae and C.

trachomatis

D. Scotch tape test for pinworms

E. Consider cultures for Candida and fungi

F. Vaginoscopy if discharge persists following treatment, recurs, or if foreign

body is suspected

III. Specific Circumstances in Prepubertal Vulvovaginitis

A. Bloody vaginal discharge

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1. Shigella or S. pyogenes infections

2. Foreign body

3. Neoplasm

4. Trauma

B. Normal vaginal discharge

1. From estrogenic stimulation of vaginal epithelium

a. Newborns (maternal)

b. Pubescent, premenarchal girls

2. Normal saline microscopy -- normal squamous epithelial cells, no

WBCs, and usually, lactobacilli

C. Sexual abuse

1. Considerations

a. Must use culture systems for N. gonorrhoeae and for C.

trachomatis

b. Consider vertical transmission of C. trachomatis and human

papillomavirus infections in infants and young children

1) C. trachomatis -- up to 3 years

2) HPV -- up to 20 months. 10 - 37% of cases have no

discernible etiology

c. Herpes simplex virus genital lesions (HSV-1 or HSV -2) could

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represent autoinoculation in children

d. Significance of genital mycoplasmas in children's urogenital

tracts is unclear -- U. urealyticum present in 25% of

asymptomatic children's vaginas

2. Consensus regarding likelihood of sexual abuse for specific

organisms

Association with Recommended

Infection sexual abuse medical action

Gonorrhea1 Certain Report2

Syphilis1 Certain Report

Chlamydia1 Certain to probable Report

Condylomata acuminata1 Probable Report

Trichomoniasis1 Probable Report

Herpes 1 (genital lesions) Possible Report

Herpes 2 Probable Report

Bacterial vaginosis Uncertain Medical follow-up

Candidiasis Unlikely Medical follow-up

1. If not acquired perinatally.

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2. To public agency in community mandated by state law to receive

reports of suspected sexual abuse.

3. Unless there is a clear history of autoinoculation.

IV. Management of Prepubertal Vulvovaginitis

A. Treat specific pathogens with appropriate antimicrobial agent

B. Nonspecific vaginitis

1. Initial steps

a. Excellent toilet hygiene

b. Bathing and skin protection from irritation

2. For persistent or recurrent problem

a. Broad spectrum oral antibiotic course

b. Topical estrogen cream

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