STDs/STI.Froberg.3-4-10.Heather Grothe
Purpose
 Learn for the most common/important STIs:
 The classification and characteristics of each etiologic agent, epidemiology, prevalence (incr/decr), spectrum of clinical disease, diagnosis, pathology, treatment (pharmacology lectures) and prevention.
Organisms
1. Viruses
 Herpes simplex viruses: HSV-1 & HSV-2
 Human papilloma viruses: HPV
 Human Immunodeficiency Virus: HIV (covered elsewhere)
 Hepatitis B Virus: HBV (covered elsewhere)
2. Protozoa
 Trichomonas vaginalis
3. Bacteria
 Chlamydia trachomatis
 Neisseria gonorrhoeae
 Treponema pallidum
 Haemophilus ducreyi
Important Concepts
 Many STIs asymptomatic/subclinical
 Are 5 of the 10 most common infections reported by CDC
 Rates of STIs probably underestimated
 Concurrent infections common
 Nearly all STIs

risk of HIV infection
 > 15 million STIs per year in US
 Rates in US double those of England, Canada, Germany, Sweden
 While syphilis & gonorrhea have declined recently, chlamydia, HPV & HSV have all

 Physicians may not include an adequate sexual Hx and genital exam as part of routine H & P
 www.cdc.gov/std/
Frequency/Impact
 HPV: ~ 20 million infected in US, 5.5 million new infections per year
 HSV-2: ~ 45 million infected in US
 Chlamydia*: > 3 million new infections per year in US
 Trichomoniasis: ~ 5.5 million infected
 Gonorrhea*: ~ 360,000 cases reported in 2001
 Syphilis*: ~ 6,000 cases reported in 2001, 440 congenital

Reportable in Minnesota
HSV 1 & 2
 Enveloped DNA viruses causing cold sores & genital herpes
 Genital herpes mostly HSV-2, but HSV-1 increasing (up to 40% in some populations)
 Facial herpes mostly HSV-1 (5% HSV-2)
 Antibodies to one somewhat inhibitory to the other
 Genomes show 50-70% homology between HSV-1 & HSV-2
 Man only natural host
Clinical Disease
 Localized vs disseminated (

in immunosuppressed)
 Herpes Labialis : cold sores
 Ocular Herpes: keratoconjunctivitis
 Herpes Genitalis
 Cutaneous lesions: herpetic whitlow
 Meningitis- esp in newborns or immunocomprimised
 Encephalitis: temporal lobe
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 Neonatal herpes
Herpesvirus Particle
 HSV-2 virus particle. Note that all herpesviruses have identical morphology and cannot be distinguished from each other by electron microscopy.
Herpes
 HSV is spread by contact, virus is shed in saliva, tears, genital and other secretions.
 Most common form of infection results from a kiss given to a child or adult from a person shedding the virus.
 HSV-1 1

infection is usually trivial or subclinical in most individuals.
 There are 2 peaks of incidence, the first at 0 - 5 years and the second in the late teens, when sexual activity commences.
 About 10% of the population acquires HSV infection through the genital route and the risk is concentrated in young adulthood.
Herpes Pathology
 Latency in craniospinal ganglia
 Reactivation: 45% for facial, 60% for genital
 More likely (to become reactivated) if immunosuppressed
 Triggers: stress, menstruation, infection, fever
 Genital recurrence: 1.6 episodes/yr,

with time
 Asymptomatic shedding highest in 1st six months following 1

infection – doesn’t have to have clinical disease to shed the virus
Genital Herpes
 Causes latent & recurrent infections
 Transmission: direct contact (genital/genital or oral/genital)
 Most transmission when there are no active lesions
 1
 infection often more severe than recurrences
 60% of pts have recurrent disease
Genital Herpes Pathology
 Infection by direct contact with mucocutaneous tissue breaks
 Prodrome of tingling, burning, pain
Polykaryons with intranuclear inclusions at base of vesicle
 Papule

vesicle

ulcer
 Intra-nuclear inclusions (Cowdry A & B), multinucleated giant cells at base of vesicle-(polykaryon)
 Ulcer

2

infection (Staph, Strep, Candida)
Neonatal Herpes
 HSV spread to neonate during vaginal delivery (doesn’t cross placenta)-contact problem
 Mostly from asymptomatic mothers
 Incidence: 1/4000 LBs in US
 Transmission more common with 1

vs recurrent infection (33 vs 3% in one series)
 Earlier gestational delivery

risk
 Caesarian section

risk
 80% due to HSV-2
 50% mortality
 CS x within first 10 days of life
 Pathology: foci of necrosis in multiple organs (liver, adrenal, lung, brain)
 Long-term CNS deficits/blindness in 25-30%
Cowdry A inclusion s of
HSV
Herpes/Histo
 Polykaryons with intranuclear inclusions (nucleus looks clear, chromatin to periphery of cell
Laboratory Diagnosis
 Virus Isolation o HSV-1 and HSV-2 are among the easiest viruses to cultivate. It usually takes only 1 - 5 days for a result to be available. Is gold standard.
 Direct Detection o Tzanck smear of vesicle base
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o Immunofluorescence of skin scrapings - can distinguish between HSV and VZV o PCR - now used routinely for the diagnosis of herpes simplex encephalitis
 Serology o Not that clinically useful.
 Cell Culture o Cytopathic Effect of HSV in cell culture: Note the ballooning of cells.
Herpes Treatment
 Antiviral chemotherapy indicated where the primary infection is especially severe, dissemination, sight is threatened, and herpes simplex encephalitis.
 Acyclovir – this is the drug of choice for most situations.

I.V. (HSV infection in normal and immunocompromised patients)

Oral (treatment and long term suppression of mucocutaneous herpes and prophylaxis of HSV in immunocompromised patients)

Cream (HSV infection of the skin and mucous membranes)

Ophthalmic ointment
 Famciclovir and valacyclovir – oral only, more expensive than acyclovir.
Acyclovir
 Converted to acyclovir monophosphate by viral thymidine kinase
 Then to acyclovir triphosphate by cellular kinases

inhibits viral DNA polymerase

early termination of viral
DNA
 ~1% of HSV lack thymidine kinase

resistant to acyclovir (amy be higher in some sub-populations)
Human Papilloma Virus
 Naked dsDNA virus of papovavirus family
 Produce latent & chronic infections
 HPV replicates in epithelial cells of skin, vagina, cervix, larynx, etc.
 Transmitted by direct contact
 Tumorogenic: causes warts, anogenital condylomas and dysplasia
 60-100 different types described, 30-40 infect human genitalia
 Classified by genotyping (not serotyping like most other viruses)
 Small virus (55 nm), circular DNA with 10 ORFs (E1-8, L1 & L2)
 New type defined as having < 50% homology with known HPV types
Clinical Disease
 Common warts: verruca vulgaris
 Most common types: 1, 2, 4
 Predilection for keratinized epithelium/do not cause genital lesions (except HPV 2)
 Laryngeal warts: HPV 11 (~congenital transmission, can be big problem and obstruct breathing)
Tumorogenic Types
 Anogenital warts (condyloma accuminatum): HPV 6, 10, 11, 40-45 (episomal viral DNA)
 Types 6 & 11 ~ 70%
 Cervical cancer: HPV 16, 18, 33, 45, 46
 70% HPV 16 or 18 (integrated viral DNA)
 HPV 16 most common type (50%) overall
 HPV genomes found in >95% of all cervical cancer specimens
(squamous cell & adenocarcinomas)
 270,000 deaths from cervical cancer worldwide
Pathology
 Infected epithelial cells

koilocytes
 Koilocytes: cells with

nuclear size,

N/C, irregular nuclear contours (raisinoid), nuclear hyperchromasia, perinuclear halo
 Can transform cells in culture
 E6 binds p53 (early degradation blocks apoptosis)
 E7 binds Rb gene (unrestrained cell proliferation)
E7 from HPV replaces E2F at binding site with pRb. This allows transcriptional activation and cell proliferation.
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Epidemiology
 Incidence and prevalence unknown
 65% of sexual contacts of partners with condylomas displayed genital warts within 6 weeks
 Multiple HPV types in ~ 25% of infections
 Most infections spontaneously regress within 2 yrs
 Most common in young adults, decline with age
 Only a small minority of women with HPV DNA by molecular techniques have gross or microscopic abnormalities
 HPV infection

4x if HIV +
HPV
 Pathology & Rx: refer to lecture on cervix
 HPV 16 vaccine clinical trials:
 Females age 16-23 got HPV-16 virus- like-particle vaccine (x3) or placebo, followed and tested for HPV-16 infection for ~17 months
 768 got vaccine with 0 HPV-16 infections
 765 got placebo with 41 HPV-16 (3.8%/100 women-years) infections (NEJM 2002;347:1645-51)
Vaccine
 Gardasil

recombinant virus-like particles (VLPs) from L1 protein (major capsid protein) o Lack viral DNA- thus no way they can get the infection o Prevents infection from types 6, 11, 16 & 18 (cause condylomas and dysplasia) o 6 & 11 cause ~90% of genital warts o FDA approved June 2006
Trichomonas vaginalis
 Ubiquitous flagellated protozoan, most common non-viral STD per WHO
 Lives in lumen of vagina, urethra, prostatic ducts, under foreskin of uncircumcised males
 Does not invade tissues
 170 million cases worldwide
 Causes trichomoniasis
 Humans only natural host
 Fastidious, anaerobe
 Iron from menses may facilitate overgrowth
 Not reportable in US (~3-6 million new cases/yr)
 Prevalence in STD clinics may approach 40%
 Much less frequent in men (~5% of urethritis)
 Peak incidence 16-35 yrs of age
 
risk if African-American, multiple sexual partners
Trichomoniasis
 Transmission via sexual intercourse
 Rate of infectivity estimated at 70-80%
 Rates higher from men to women than women to men
 Incubation period 4-28 days
 Not spread by fomites
Clinical Disease
 Acute or chronic vaginitis
 Yellow-green, frothy or bubbly, purulent discharge, pruritis and dysuria
 Discharge in < 50% of women
 Exacerbated by menses (pH 5-5.5)
 Urethritis more common in men
 White, milky urethral discharge
Pathology
 Gross: discharge, multiple, punctate hemorrhages and/or areas of capillary dilitation on cervix (“strawberry cervix”)
 Organism may adhere to squamous epithelium
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 Acute inflammation
Diagnosis & Treatment
 Wet mount of scrapings of vaginal fornices
 Can see motile organisms under phase contrast microscope
 Others: Giemsa stain of scrapings , PAP smear, ELISA on vaginal secretions
 Rx: metronidazole

82-100% cure rates
 Should Rx sexual partners of women that have this
Chlamydia trachomatis
 Small Gram negative bacterium , Obligate intracellular pathogens
 Biphasic developmental cycle
 Infectious form is elementary body (EB) : 0.3-0.4
 m
 EB is metabolically inert, more spore like
 EB taken up by epithelial cells

reticulate body (RB) :RB metabolically active, Utilizes host cell ATP for energy
 Multiples by binary fission within endosome (inclusion body with 100-500 progeny)
 Result

host cell ruptures or expels inclusion body -> then spread to ther tissue
 Infect columnar epithelium
 Chlamydia inhibit fusion of endosome with lysosomes (resist intracellular killing)
 Multiple biovars
 D-K cause nongonococcal urethritis in men; urethritis, cervicitis, salpingitis and pelvic inflammatory disease
(PID) in women
 Can cause inclusion conjunctivitis in neonates
 L1-3 cause lymphogranuloma venereum (LGV rare in US- <600/yr)
Epidemiology
 Most common bacterial STD in developed world
 Rate in STD clinics 15-19%
 Leading cause of ectopic pregnancy (PID)
 Risk factors: < 25 yrs, African-American race, multiple sexual partners. Concurrent infection with GC
 Majority of infections subclinical
 Incubation period ~ 3 weeks
Diagnosis
 Cell culture (takes 3-7 days) of vigorous swab of mucous membranes: use dacron or rayon swabs-submit in viral/chlamydial transport medium at 4

C
 Endocervix preferred site (urethra from men)
 DFA, gene probes, EIA
Clinical Disease
 Ophthalmia neonatorum ( inclusion conjunctivitis) acquired during passage through birth canal
 May develop pneumonitis
 Adults may get from autoinoculation from genital tract (trachoma)- inflammation of the keratoconjuctival tissue
 Males: 75% symptomatic
 urethritis, dysuria & pyuria, proctitis
 Females: 80% asymptomatic, some cervicitis, urethritis, salpingitis
 40% of untreated females

pelvic inflammatory disease (PID)
 Leads to tubal pregnancy, infertility
 Tubal pregnancy = leading cause of 1st trimester pregnancy-related deaths
 Females with chlamydia 3-5 fold

risk of HIV
More Clinical Disease
 Reiter’s Syndrome: conjunctivitis, polyarthritis & genital infection

most HLA-B27 +
 Lymphogranuloma venereum (L biovars): painful “buboes” = enlarged draining lymph nodes, may develop elephantiasis, ulcers or fistulas
Treatment
 Tetracycline or erythromycin
 No vaccines
 Penicillin ineffective
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 Important since gonococcus co-infections may occur
Gonorrhea
 Neisseria gonorrhoeae
 Gram negative diplococci, gonococcus (GC)
 Frequently found intracellularly in PMNs
 Is oxidase positive: cytochrome C oxidase phenylenediamine black color
 Have pili

attach to mucosal surfaces
 Pili show antigenic variation
 Protein II (opacity)

clumping (self-aggregation)
 IgA proteases

may degrade host IgA (produces in reproductive tract)
 LPS
 May bind to sperm, rbcs, non-ciliated fallopian tube epithelium
 May invade

dissemination
Epidemiology
 Incidence declining
 May be under diagnosed in females (more apparent in males)
 Still 500-700,000 cases per year in US
 Highly contagious: 50% transmission rate
 Chlamydia coexists in 45-50% of pts with gonorrhea
PAP smear with chlamydial inclusion body
Clinical Disease
 Incubation 2-7 days
 Males: urethritis, dysuria, pyuria (copius urethral discharge), epididymitis, proctitis, orchitis
 Conjunctivitis in newborns exposed to infected secretions in birth canal
 50% of women asymptomatic
 Cervicitis, adenitis, proctitis, salpingitis, ovaritis, PID in 15% (less likely to cuase PID- CHalmydia main culprit)
 Disseminated : more common during pregnancy (endocytosis of GC) seen in 0.3 - 3% of pts
 Dermatitis

papules & pustules with hemorrhagic component
 Arthritis

knees, elbows, tenosynovitis
 Rarely

endocarditis, meningitis, Waterhouse-Friderichsen syndrome (hemorrhagic infarction of adrenals)
Diagnosis
 Culture on Thayer-Martin media in high CO
2
(oxidase + colonies)
 Gram negative cocci in pairs
 GC don’t ferment maltose, meningococci do –( can distinguish from neisseri mennigits)
 Gene Probe
Treatment
 Penicillin resistance 15-19%
 Tetracycline resistance 17-23%
 Emerging fluoroquinolone resistance
 No resistance to 3rd generation cephalosporins
 Disseminated: 7-14 days
Syphilis
 Treponema pallidum
 Spirochete with axial filament (motile)
Gonorrhea
 Gram negative but too thin to see by light microscopy (0.2 by 6-15
 m)
 Man only natural host (grows in rabbit skin/testes)
 Never cultured in vitro
 Transmission by direct sexual contact- with the open sores from syphyllis
 Periods of latency and clinical disease
 Infection may last decades
 Since arrival of penicillin in 1940’s, rate has

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 Produces no known toxins
 Pathology likely from humoral and cellular immune responses
 Syphilis

risk of HIV (HIV

risk of neurosyphilis) – b/c it causes open ulcer on genitalia
Clinical Disease
 “Great Imposter”
 Three stages: each involve lesser numbers with more severe CS x
 1

syphilis

chancre (hard, clean, painless, shallow ulcer) occurs ~ 3weeks after exposure o Chancre: male

70% on penis or scrotum, female

50% on vulva or cervix, rest

lips, oral cavity, finger, base is teeming with treponema o Chancre resolves in 3-8 weeks

Rx o May have fever, lymphadenopathy
 2

stage

2-10 weeks after

1 o 2
 
dissemination of spirochetes: diffuse macular rash including soles & palms, lymphadenopathy, erosions on mucous membranes, condyloma lata – these are anogenital warts (look a lot like HPV)
 3

stage

latency may last decades
 Three categories of tertiary syphilis: o Cardiovascular

aortitis, aortic aneurysm, aortic insufficiency (80% of mortality)- invasde vasovasorum of atora, develop aortic aneurism o Neurosyphilis

general paresis, meningovasculitis, tabes dorsalis (loss of posterior columns), psychiatric disease o Benign tertiary syphilis

gummas = necrotizing granulomas

skin, bones, subQ
Congenital Syphilis
 Treponemes cross placenta after 5th month of gestation (more common if early syphilis)
 Causes stillbirth, spontaneous abortion (50% mortality), early or late congenital syphilis
 Early congenital: desquamating skin lesions,vesicles on mucous membranes, osteochondritis, pulmonary fibrosis, hepatosplenomegaly
 Late congenital: interstitial keratitis, gummas, saddle nose, saber shin (> 2 yrs), Charcot joints
 Classic triad: interstitial keratitis, notched incisors, eighth-nerve deafness
Pathology
 Treponemes adhere to endothelium

obliterative endarteritis
 Two major types of lesions: o perivascular plasma cells ( also lymphocytes, macrophages) o Gummas

necrotizing granulomas 2

to delayed type hypersensitivity
Diagnosis
 Screening serology via non-treponemal tests:
1.
VDRL (Venereal Disease Research Laboratory)
2.
RPR (Rapid Plasma Reagin)
 These test for anti-cardiolipin antibodies (are
 in syphilis & many other diseases)
 Are sensitive but non-specific
 If chancre present

dark field microscopy of material from base of lesion
 May be seen in silver stains or DFA staining of condylomas and skin lesions (less reliable)
 Confirmatory Tests for 2

& 3

syphilis : more specific and expensive o FTA-ABS most widely used, remains + after Rx (TOC) o Microhemagglutination-TP also used
Hutchinson (notched) incisors
Treatment
 Penicillin - no known resistance
 Single dose for active, multiple doses for latent
 May see Jarisch-Herxheimer reaction following Rx of 2

or 3

syphilis (hypersensitivity)
 Like other STIs

condoms may not entirely prevent
Chancroid
 Haemophilus ducreyi
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 Gram negative rod
 Now uncommon in US, common in Africa & SE Asia
 Causes soft chancre: painful genital ulcer
 Can be confused with syphilis, herpes, LGV
 Male:female ratio 9:1
 Predisposes to HIV
 Characterized by single or multiple ulcers and inguinal adenopathy
 Grows on chocolate agar

gram negative coccobacilli
 Presumably make cytotoxin and endotoxin
Rx and Prevention
 Some resistance to ampicillin and penicillin
 Condoms may prevent
Vaginitis
 Yeast vaginitis

80-90% Candida albicans
 Are NL flora

overgrowth (birth control pills, antibiotics, diabetes)
 May be sexually transmitted (usually not)
 Dx: KOH wet mount for yeast, pseudohyphae & hyphae
 Dysuria, creamy discharge
 Rx: nystatin, imidazoles
Bacterial Vaginitis
 Gardnerella vaginalis
 Gram negative anaerobe
 NL flora
 Mild signs/increased odor (fishy)
 Dx: clue cells-epithelial cells covered with bacteria
 Rx: alter microenvironment
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