STIs and STI treatment

Question 1

HPV structure, transmission, genome maintenance in host cell?

Answer 1

• • circular dsDN, icosahedral capsid composed of L1 and L2 “late” proteins that self assemble (Vaccine basis!)
• • Non enveloped = more stable, can survive on skin/fomites

– transmitted via skin-skin contact /fomites

• • Benign tumor cells (warts) –> extrachromosomal genome
• • Malignant tumor (cervical carcinomas) –> integrated into host genome (E6 and 7, with E2 disruption - loss of regulation)

Question 2

how do papilloma viruses grow in permissive vs non - permissive cells? how does this effect tx?

Answer 2

• initially infect germinal cells (non permissive = no viruses produced) and transform them
• germinal cells mature/migrate to skin surface –> become permissive /produce virus progeny
• • tx: difficult to completely eradicate infection while virus remains in germinal cell layer
• • proliferating cells also shed virus ie spread via direct contact and tend to cluster

Question 3

HPV Subtypes for:

• • common warts (verruca vulgaris or plana),
• • Anogenital (condyloma acuminata vs condyloma plana),
• • sub clinical papilloma infection (SPI) / cervical / penile / oral / neck cancers, laryngeal papilloma

Answer 3

– common warts - don’t know

– anogential:
acuminata = 6 and 11
plana = 16, 18

– SPI and carcinomas = 16, 11, 31, 33

Question 4

Koilocyte

Answer 4

– squamous epithelial cells that are indicative of HPV infection

Histo: vacuolated cytoplasm

Question 5

SPI

Answer 5

Sub Clinical Papilloma Infection: not readily detected, more of a concern than condyloma plana or acuminata bc of link to cervical cancer

Question 6

Laryngeal Papilloma

Answer 6

• • chronic, benign warts in respiratory tract that generally appear < 5 yo (Genotypes 6 and 11)
• • due to maternal HPV infection intrapartum

**Associated with respiratory distress –> 3% = deaths

Question 7

Epidermodysplasia

Answer 7

– inherited immune deficiency = can’t fight off HPV = numerous lesions throughout lifetime

Question 8

co-factors for risk of cervical cancer development?

Answer 8

Smoking and concomitant HSV or HIV infection

Question 9

HPV Dx? tx?

Answer 9

Dx: Routine Pap smears –> colposcopy for abnormal results to look for dyspolasia
**cannot be grown in culture! – use PCR to dx genotype?

Tx:

• • wart removal: Bi or trichloroacetic acid brushed on denatures proteins, cryotherapy, LEEP (loop electrosx excision), Podofilox (anti mitotic), Imiquimod (TLR 7 = inc T cell response),
• • Vaccine: gardasil (L1 capsid protein = 16, 18, 6, 11) and cervarix (16, 18 only)

Question 10

Common urethritis/cervicitis (PID) agents?

Answer 10

Chlamydia trachomatis, Neisseria gonorrhoeae, ureaplasma urelyticum (mycoplasma)

Question 11

Primary symptoms of Ct and GC? laboratory dx?

Answer 11

Presentation: dysuria, penile/vaginal exudation

DX: NAAT (nuc acid amp) on urine or exudate – bc they typically occur together!

• -> GC = Oxidase+, G- stain + PMNs or Thayer Martin / chocolate agar medium (+ vanc/nystatin/colistin to xNormal flora)
• -> Ct = no cocci on G stain, no polys

Question 12

Can you use flouroquinolones for GC?

Answer 12

NO – no longer recommended due to resistance

Question 13

How do you treat sexual contacts of GC/Ct infected pts?

Answer 13

??

Question 14

Lymphogranuloma venereum (LGV) and Trachoma and C. Pneumoniae

Answer 14

LGV = more invasive strain of Ct –> invades inguinal LNs and causes ulceration at site of entry
— may have CHANCROID (painful, no hard rim)

Trachoma = Ct Strain that is potentially BLINDING chronic dz, prevelant in Asia, Middle East, Africa (do not cause urethritis)

Chlamydia Pneumoniae = Resp infections / PNA

Question 15

High risk populations for GC, Ct (and ureaplasma)? are infections always clinically apparent?

Answer 15

Risk: sexually active, multiple partners, a partner w/ multiple partners, inner city, African American, 15-24 yo age groups

UNAPPARENT INFECTIONS ARE COMMON!!!

Question 16

GC and Ct treatment

Answer 16

Tx: Ceftriaxone + Azithromycin or Doxy
GC (beta lactam resistant) = Ceftriaxone (IM) +/-
Ct (intracellular) = Axithromycin / Doxycyclin

Question 17

GC, Ct, ureaplasma virulence factors

Answer 17

GC: No capsule, LOS shedding (not classic LPS!) = inflammatory response, IgA1ase,
+ ANTIGENIC VARIATION (pilS –> pilE – silent inserts into expression locus) = no vaccine / reinfection common!
+ can DISSEMINATE = septicemia or rash

Ct: Obligate INTRACELLULAR parasite (G- Ish, deficient peptidoglycan), heat shock protein/low tox LPS –> inflammatory response!
+ distinct development cycle: Elementary Bodies (EB) = inert/ non infectious –> Reticulate bodies (RB) = grow in membrane vacuole

**Damage to human host = mainly result of inflammatory response

Ureaplasma: lack cell wall (not b-lactam susceptible),

Question 18

Lower GU, upper GU, and other infections caused by GC and Ct?

Answer 18

• • Lower UG: cervicitis / urethritis
• • Upper UG: PID / salpingitis / epididymitis / prostatitis

– Other:
> Rectal infection (MSM),
> pharyngitis (Oral sex - GC only),
> Conjunctivitis in newborn “ophthalmia neonatorum” (Ct usually), Infant PNA (Ct only),
> Disseminated dz (GC only) = sepsis / rash / aseptic arthritis (Reiter’s syndrome) /endocarditis / meningitis

Question 19

Urethritis discharge in GC vs Ct?

Answer 19

GC – “the clap” - thick, purulent

Ct – less purulent, milky

Question 20

symptoms of infant Ct pneumonia?

Answer 20

• • Repetitive staccato cough w/ tychypnea (wheezing is rare!)
• • Afebrile, hyperinflation/bilateral infiltrates on CXR, preceding/concurrent conjunctivitis hx possible

– vertical transmission!
– raised IgM levels
Diff dx: RSV, ureaplasma, CMV, adenovirus, influenza, pertussis

Question 21

Def, Symptoms, and consequences of PID?

Answer 21

PID: inflammatory process involving a variable combo of endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis

• dull to severe lower abdominal pain (often starting w/ onset of menstrual cycle)
• fever
• Cervical motion tenderness + adnexal tenderness

Consequences: sterility, ectopic pregnancy, chronic pelvic pain, hospitalization, tubo-ovarian abscess,

**overt symptoms less common w/ Ct, but damage worse with Ct!

Question 22

HSV structure? Hallmark? replication cycle?

Answer 22

Structure:

• large dsDNA virus w/ icosohedral capsid + lipid envelope
• COMPLEX = 90+ Proteins = several anti herpetic Rx’s

Hallmark:
– LATENCY = quiescent virus genome in dorsal root ganglia = recurrent infections

Rep cycle:

• fuses w/ plasma membrane in pH Independent manner
• nucleocapsid released –> migrates to nucleus
• immediate early expression (transcriptional regulator proteins / modify host RNA polymerase)
• Replicate viral genome
• “late” class proteins produced (structural)
• viral assembly in nucleus
• virus buds from plasma membrane

Question 23

Important “early” proteins in HSV replication? Why?

Answer 23

1) DNA polymerase = ultimate target of acyclovir and famciclovir
2) Thymidine kinase = required for phosphorylation / activation of acyclovir (increases cell specificity of ACV)

** Thymidine kinase mutations = resistance to ACV – particularly important w/ AIDS patients

Question 24

How does HSV form multinucleated giant cells? how is this diagnostically important?

Answer 24

– viral glycoproteins respsonsible for fusion (entry) = same as those present in plasma membrane of infected cell late in replication –> adjacent infected / uninfected cells can fuse and form giant cells

** Virus can spread cell to cell w/out progeny release!

** TZANCK SMEAR = diagnostic test taking cells from ulcerous lesion, looking for giant cells w/ nuclear inclusion bodies

Question 25

LAT

Answer 25

Latency Associated Transcript: HSV gene whose product is an RNA species that silences subset of cellular gene to prevent apoptosis in infected neuron -- NO VIRUS PARTICLES PRODUCED during maintenence period **Decline in cell mediated immunity (stress, etc) --> virus reactivation --> recurrent infection in epithelial cells innervated by latent infected neuron

Question 26

Diseases caused by HSV1 vs. HSV2

Answer 26

HSV1: herpes labialis/fever blister, gingivostomatitis, keratitis, ENCEPHALITIS (+ conjunctivitis, blepharitis, urogential lesions) HSV2: Cervicitis, vulvular and penile vesicles, MENINGITIS, (SEM dz possible, urethritis - rare, perianal and vaginal vesicles, encephalitis) * *Generally self-limiting! * *Disseminated disease -- immunocompromised and neonates! = can be severe/fatal!

Question 27

Primary vs. Recurrent HSV infection

Answer 27

**1o = generally worse symptoms/longer duration Oral: - 1o = gingivostomatitis, - recur = fever blister(s), both +/- fever/HA Ocular: - 1o = blepharitis/conjunctivitis, usually children - recur keratitis = corneal scarring if not treated Genital: - 1o males = penile vesicles, 1o females = ext/int vesicles - recur = generally fewer lesions / heal more quickly, frequency diminishes w/ time * *both = +/- prodromal/flu-like symptoms = tip off to recurrence CNS: - 1o HSV2 = Aseptic Meningitis / Encephalitis in neonates - recur HSV1 = Encephalitis in Adults (trigeminal N) * *70% mortality w/out treatment

Question 28

Neonatal HSV infections: symptoms/progression, chance of maternal transmission / delivery options

Answer 28

Symptoms: - -> develop 1-2 week postpartum, - -> can be limited to skin / eyes / mouth (SEM) w/ "zoster like" rash - -> or be more severe w/ CNS involvement (encephalitis: seizures, irritability, coma) - -> or disseminate to multiple organs **75% severe infections = death, significant sequelae * *1o maternal infection = 30% chance transmission vs. recurrance = 2-3% chance -- maternal Abs may be protective * * DO A C-SECTION if mother presents with herpetic lesions!!

Question 29

HSV dx -- genital, meningitis, encephalitis, neonatal

Answer 29

Genital: - - Gold standard = PCR screening of vesicle swab (can distinguish serotypes!) * historically = virus was cultured or TZANCK SMEAR done Meningitis: -- RULE OUT BACTERIAL SOURCE! = CSF used for PCR / culture Encephalitis: -- CSF rarely positive, can do EEG followed by PCR amplification and southern blot confirmation Neonatal/congenital: -- PCR / culture --> CHECK LFTs/Liver enzymes for disseminated disease!

Question 30

What Ag is used to serotype HSV?

Answer 30

Abs to Glycoprotein G -- virus envelope component **Only indicates PAST INFECTION unless you monitor for IgM vs. IgG

Question 31

HSV treatment

Answer 31

**NO CURE -- infected? = infected for life due to latency AntiHSV --- lessens disease episode: 1) Acyclovir (dGuanine analog = xViral DNA polymerase) 2) Vidarabine and triflouridne (base analog, used in keratitis) 3) Foscarnet (pyrophosphate analog blocks pyrophosphate exchange) 4) Docosonal (Over the counter cold sore med, host membrane modifier =xFusion) * Neonatal/congenital herpes = IV, high dose ACV for 14 - 21 days * Herpes encephalitis = high dose IV ACV for 10 days - 3 wks * immunocompromised = aggressive ACV tx

Question 32

Most common agents causing BV/vaginitis? transmission/cause?

Answer 32

Candida albicans and C. glabrata -- aka candidiasis Gardnerella vaginalis, Mobiluncus spp. and other ANAEROBES Trichomonas Vaginalis -- single cell protozoan! = frank pathogen/sexually transmitted * *Candididasis and anaerobes = Opportunistic! -- overgrowth of normal flora, not sexually transmitted due to disruption of other normal flora, especially G+ lactobacilli which maintain low pH by H2O2 production ex) sex, douching, IUDs, menstrual cycle, preg, antibiotics

Question 33

Is BV generally a single agent disease?

Answer 33

NO, usually a combination of various anearobes

Question 34

Vulvovaginal Discharge character in: normal vs. candidiasis, trichomonal, bacterial vaginitis

Answer 34

Normal: variable, clear/white, non-homogenous/patchy Candidiasis: scant, white, clumped "cottage cheese", pH < 4.5 Bacterial: moderate, white/grey, adherent/coats vagina, homogenous, MALODOROUS (anaerobes), pH > 4.5 Trichomonas: PROFUSE, yellow/green, frothy, homogenous, pH > 4.5

Question 35

Microscopy of vaginal epithelial cell culture in: normal vs. candidiasis, trichomonal, bacterial vaginitis

Answer 35

normal: normal epithelial cells + G+ lactobacilli predominate Candidiasis: leukocytes, epithelial cells, mycelia or pseudomycelia + yeast/branching hyphea on KOH wet mount BV: CLUE CELLS (vaginal epithelial cells w/ adherent bacteria), a few leukocytes, lactobacilli outnumbered by mixed flora Trich: leukocytes/PMNs, trichomonads (size of PMNs w/ TWITCHING MOTILITY!)

Question 36

Symptoms of cystitis, pylonephritis, cervicitis

Answer 36

cystitis: dysuria, suprapubic pain, leukocytes/polys in urine, ^bacteria in urine Pylonephritis: cystitis signs/symp + Significant fever, flank pain, WBC and RBC casts in urine Cervicitis: dysruia, mucopurulent discharge (from cervix), +/- fever/abdominal pain/pruritis

Question 37

TX: candidiasis, BV, trich

Answer 37

Candidiasis: intravaginal Imidazole, oral fluconazole -- partner = nothing if asymptomatic / tx for contact dermatitis BV: Metronidazole or Clindamycine (intravagnially) -- partner: none Trich: Metronidazole -- partner = metronidazole

Question 38

DM /immunodeficient and Vaginitis?

Answer 38

Can suffer from CHRONIC CANDIDIASIS (genital and oral)

Question 39

Syphilis/Treponema pallidum: structure? Hallmark? dev/proliferation?

Answer 39

Structure: spirochete (spiral bacterium) = inner periplasm w/ peptidoglycan + outer sheath (no LPS), axial filaments = motile **too thin to see on G stain/direct light transmission microscopy Hallmarks: 1o = non painful chancre/ulcer @ site of entry, 2o = systemic infection w/ snail track lesions +/- palmar and sole rash/condylomata lata Proliferation: distinct sequential phases, including latent phase that can last for years (continue for life/3o dz)

Question 40

Syphilis Immune Response

Answer 40

- Rigorous humoral / cellular response that DOES NOT eliminate infection * *host cellular immune response controls infection but ALSO PATHOLOGY (esp tertiary syphilis)

Question 41

1o, 2o, 3o syphilis

Answer 41

1o = 2-3 wk incubation, painless chancre/non tender inguinal lymphadenopathy, resolves in 3-6 wks 2o = 1-2 months following infections, disseminated infection (blood and lymph): - hyperpigmented/maculopapular rash +/- palms and soles - SNAIL TRACK LESIONS on mucous membranes - Condylomata lata (wart like lesions @ moist skin folds) 3o = almost any organ can be affected (heart, CNS, skin, bone)

Question 42

Congenital syphilis: symptoms at birth? transmission? early/late symptoms? tx?

Answer 42

- may or may not have symptoms at birth - disseminated infection transmitted transplacentally after 1st trimester via blood - early = snuffles, bullous rash, snail track lesions, condylomata lata, enlarged liver/spleen - late (~2 years) = stigmata may develop, bone abnormalities (saber shins / frontal bossing), vision defects, Hutchinson's triad Tx: 10 day course crystalline Pen G or Procaine Pen G

Question 43

Hutchinson's triad?

Answer 43

CONGENITAL SYPHILIS - late symptom possibility 1. notched incisors/screwdriver teeth 2. Keratitis 3. deafness

Question 44

Syphilis dx

Answer 44

1st: NON TREPONEMAL SEROLOGIC TEST -- RPR (rapid plasma reagin) or VDRL (venereal disease research lab test) * sensitive, but not specific Next: Treponemal test -- FTA-ABS (flourescent treponemal Ag absorbed...have to remove cross reacting Abs against normal spirochetal flora) * specific **non treponemal = Ag is NOT T. PALLIDUM -- beef heart cardiolipin instead = cheaper, relatively sensitive, good to monitor antibiotic efficacy!

Question 45

How long will T pallidum titers remain high?

Answer 45

Can remain high for months after patient is cured of syphilis!

Question 46

Darkfield Microscopy

Answer 46

Historical method of diagnosing T. pallidum/syphilis (or useful early on -- titers are not high enough) -- light projected at oblique angle --> light refracted through objective lens if spirochete is present

Question 47

Treatment for syphilis/T pallidum?

Answer 47

Large, single dose of Pen G Macrolides, azithromycin as alternatives

Question 48

Which STIs are reportable to health department?

Answer 48

- - Syphilis - - GC - - Ct

Question 49

E6, E7, E2

Answer 49

``` E6 = binds/inactivates p53 E7 = binds/inactivates RB ``` E2 = regulates E6 and E7 expression -- get's disrupted when viral DNA is inserted into host DNA

Question 50

Do acyclovir/valacyclovir and famciclovir cause DNA chain termination? how are they metabolized/prodruging? toxicity?

Answer 50

NO - competitively inhibit viral DNA polymerase by competing w/ dGTP for incorporation into viral DNA Valacyclovir --> acyclovir (better bioavailability) Famciclovir -- deacetylated--> Penciclovir Toxicity: acyclovir /valACV = neurotoxicity/seizures Famaciclovir = n/a

Question 51

Benzathine Pen G: uses, special?, limitations

Answer 51

Uses: syphilis, latent syphilis Special bc: IM administration = drug depot that liberates drug for 2 weeks -- good for non compliant pts Limitations: poor penetration of CSF, not good for neurosyphilis

Question 52

Jarisch Herxheimer Reaction

Answer 52

-- chills, fever, HA, myalgias, arthralgias +/- cutaneous lesions may become more prominent - common w/ secondary syphilis after Pen G administration -DO NOT STOP DRUG!