Sexual Transmited Disease

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
b. Consistently fewer than 500 new cases a year since 1973
5. Granuloma inguinale -- 3 new cases in 1994; not nationally
notifiable since 1995
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)
33
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)
34
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
35
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
36
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
37
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
38
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
39
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
40
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
41
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
42
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
43
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
44
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
45
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
46
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
47
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
48
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
49
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
50
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
51
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%
52
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
53
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
54
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
55
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
56
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
57
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%
58
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
59
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%)
60
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
61
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)
62
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
63
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
64
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
65
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
66
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%
67
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
68
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%
69
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
70
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
71
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
72
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.
73
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
74

Sexual Transmited Disease

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Sexual Transmited Disease

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Sexually Transmitted Infections and the Adolescent

Topic I: Common Syndromes of Lower Genital

Tract Sexually Transmitted Infections

Topic IA: Cervicitis

A. Major recognized sexually transmitted pathogens

c. Herpes simplex virus

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

C. Fungal -- C. albicans - ectocervicitis

D:\FILES\Review Courses\Peds ID\Peds ID 1\Sexually Transmitted Infections.wpd

II. Diagnostic Approach

A. Careful history and physical examination (includes full pelvic

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

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

D:\FILES\Review Courses\Peds ID\Peds ID 1\Sexually Transmitted Infections.wpd

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

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

II. Differential Diagnosis

A. STD (as above)

C. Vulvitis in females -- associated with external dysuria

1. Herpes simplex virus

4. Maceration from discharge of cervicitis or vaginitis

III. Diagnostic Approach to Symptoms of Urethritis

B. Urine culture -- selected patients

C. Full pelvic examination (female patients)

D:\FILES\Review Courses\Peds ID\Peds ID 1\Sexually Transmitted Infections.wpd

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

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

Topic II: Common Bacterial Causes of Cervicitis and Urethritis