Lectures 16 & 17 - Sexually Transmitted Diseases I & II Flashcards
What are the 4 modes of transmission of STDs?
- Sexual intercourse
- Oral-genital
- Anal-genital
- Hand-genital
Are there always signs and symptoms of STDs?
NOPE
What is trichomoniasis caused by?
The protozoan trichomonas vaginalis
Symptoms of trichomoniasis?
- Foamy, yellowish, unpleasant-smelling discharge
- Burning sensation
- Itching
- Painful urination
- Painful intercourse
Note: most carriers (70%) experience no symptoms, females more likely to have vaginitis, males have urethritis less often
How is trichomoniasis transmitted?
- Sexual contact
2. Items with discharged fluids on them: toilet seats, wet towels
What does trichomoniasis increase the risk of?
- Increases the risk of other STIs
- Premature deliveries
- Low birth weights
How is trichomoniasis diagnosed?
Swab and wet mount slide or PCR
How is trichomoniasis treated?
Oral metronidazole
What is chlamydia caused by?
Chlamydia trachomatis bacterial infection
Symptoms of chlamydia?
Often none but can induct significant inflammatory exudate
Does chlamydia affect more men or women?
Women
Consequences of untreated chlamydia?
- Affected cervix or fallopian tubes (pelvic inflammatory disease = PID)
- Scarring
- Infertility
- Affected prostate gland, seminal vesicles, epididymis
- Arthritis
- Conjunctivitis
- Urethritis
- Can infect newborns leading to blindness (trachoma)
Who should be screened for chlamydia?
- All sexually active women <25 yo
2. Women will new/multiple sex partners
How to test for chlamydia?
Culture or PCR
How is chlamydia treated?
- Azithromycin: 1 dose
- Doxycycline: 1 week
- Tetracycline
- Erythromycin
What is gonorrhea caused by?
Neisseria gonorrhoeae bacterial infection
What does gonorrhea cause?
Infection of the linings of the urethra, genital tract, pharynx, and rectum
Patients at risk for gonorrhea?
Males 20-24 and females 15-19
How is gonorrhea treated? What to note?
Antibiotics:
- Cephalosporins
- Injectable ceftriaxone + oral azithromycin (same drug as for chlamydia)
Note: high resistance rate because can incorporate cellular DNA = transformable
What can untreated gonorrhea cause?
Infertility
How many types of herpes viruses are there?
8
What are the 2 types of herpes simplex?
- Type 1: oral lesions
2. Type 2: genital lesions
Is there a cure for herpes? What to note?
NOPE, but some drugs greatly reduce lesions by interfering with viral DNA replication
Is there a vaccine for herpes?
NOPE
How is herpes treated?
- Acyclovir
- Valacyclovir
- Famciclovir
Do the herpes virus affect fertility?
NOPE
What is HIV?
Human immunodeficiency virus, a lentivirus, that causes acquired immune deficiency syndrome (AIDS)
How is HIV transmitted? Describe the transmission.
HIV enters most efficiently via mucous membranes of the genitals and anus => once passing the mucus membrane, the virus binds and infects CD4 T helper cells, macrophages or dendritic cells => virus replication begins to destroy helper T-lymphocytes => cellular immune responses become compromised at late times
What are high risk behaviors for HIV transmission?
- Exchange of body fluids
- Injecting drugs
- Receiving a blood transfusion prior to 1985
- Mother-to-infant transmission
Symptoms of acute HIV infection?
- Fever
- Weight loss
- Pharyngitis
- Malaise
- Headache
- Neuropathy
- Lymphadenopathy
- Skin rash
- Nausea
- Vomiting
- Enlargement of liver and spleen
- Myalgia
- Esophageal sores
- Mouth sores and thrush
Symptoms of chronic HIV infection?
May experience a number of opportunistic infections with colds, sore throats, fever, tiredness, nausea, night sweats
HIV test?
- ELISA detects antibodies
2. Western blot is a more expensive confirmatory test
How is HIV treatment?
Potent new drugs have slowed or blocked the progression from HIV infection to AIDS:
- Protease inhibitors block the HIV protease enzyme from cleaving precursor proteins to form mature virus proteins
- Other antivirals inhibit the HIV reverse transcriptase
=> Therapy currently consists of a cocktail of antiviral compounds (usually 3-4 drugs that inhibit viral reverse transcriptase and viral protease or Stribild (quad)
Has HIV ever been cured?
Once in an infant
Describe hepatitis B infections.
Acute and self-limited
Symptoms of hep B infection?
- Nausea
- Vomiting
- Aches
- Pains
- Decreased appetite
- Eventual jaundice
Diagnosis of hep B infection?
- Acute infection is determined by detection of antibodies against HBsAG => sero-conversion
- Chronic infection is determined by ELISA against surface antigen and inability to clear it
Describe the progression of hep B infection. What to note?
Acute infection => chronic infection => fatty liver => liver fibrosis => cirrhosis => primary hepatocellular carcinoma (HCC) after decades
Note: progression from acute to chronic is rare but 15-25% with long term chronic infection develop cirrhosis and cancer
What is special about the hep B virus?
BIG genome: 3.3 kB
How does hepatocellular carcinoma develop from chronic hep B infection?
Mechanism of tumor induction is not well understood, but may involve the HBV X protein and could be due to the constant inflammatory insult and induced cell regeneration
Treatment for chronic hep B? What to note?
There are interferon and antiviral treatments available for chronic disease, not curative
Vaccine for hep B? Describe it.
Hepatitis B surface antigen, HBsAg: recombinant, non-infectious and 90% effective.
What is syphilis caused by?
Trepona pallidum bacterial infection
Stages of syphilis? Describe each.
- Primary: development of a chancre that disappears in three to six weeks
- Secondary: 1 to 12 months after chancre disappears, a rash or white patches on the skin appear which last a few weeks or months
- Latent: infectious lesions, infection can be passed on to fetus (congenital syphilis)
- Late: heart damage, CNS damage, blindness, paralysis, dementia
How is syphilis treated?
Antibiotics: single intermuscular penicillin injection
Can the treponema bacterium become resistant to penicillin?
NOPE
What is a chancroid? Symptoms?
Bacterial infection with hemophilus ducreyi, a gram negative rod that induces well defined ulceration with undermined borders + tender lymph nodes
In what populations are chancroids found?
Developing countries and prostitutes
How are chancroids treated?
Antibiotics:
- Azithromycin
- Erythromycin
What are chancroids often confused with? How to tell the difference?
Syphilis chancres
Need for biopsy/smear
What is the most common STI?
HPV
What is the shell of each HPV particle made of?
95% L1 capsid protein
5% L2 capsid protein
What is the genetic information of HPV?
8 kb circular DNA in each HPV particle
Which has a more complicated genome: HPV or herpes?
Herpes
What are the early genes of the HPV virus involved in?
Regulating the replication of the virus
What are the 2 oncogenes of the HPV virus? Describe their functions. What to note?
E6: p53 degradation (tumor-suppressor gene) and telomerase induction
E7: pRb degradation (tumor-suppressor gene) and transactivation of c-jun
Always present in human cancers
How many types of HPV viruses? Which ones do I need to know?
More than 150
SKIN: never cause malignant tumors, only benign
- HPV-1: feet
- HPV-2: hands
- HPV-4
- HPV-5,7,8: rare clinical cases of epidermodysplasia
GENITAL, ANAL, and ORAL MUCOSA: can cause malignant tumors
- Low risk: HPV-6, 11, 42, 43, 44
- High risk: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68
How can some HPV viruses cause malignant tumors?
They have functioning E6 an E7 genes that allow them to live forever and keep replicating
What are the 2 phases of the papillomavirus life cycle? Do both low and risk risk HPV viruses have these?
PHASE 1: PRODUCTIVE INFECTION, both low and high risk viruses
1. Affect basal epithelial cells so there has to have been abrasion or irritation (sexual intercourse) for the virus to access them
- The viral DNA then remains into the basal cells and replicates as episome until it starts to make capsid proteins and expresses early and late genes to assemble as virus particles in upper cells of the epithelium => pathognomic koilocytosis on PAP smear
- Virus infected cells desquamate from the epithelium and infect normal epithelial cells
PHASE 2: MALIGNANT PROGRESSION, only high risk viruses
Viral genome integrates into the genome due to E2 gene being knocked out, causing E6/E7 increased expression => eventual cancer phenotype to form well-differentiated tumors => dysplastic cervical lesions
Does the HIV have a membrane envelop? What does this mean?
YUP - sensitive to detergents
Does the HPV have a membrane envelop? What does this mean?
NOPE - insensitive to detergents
Why are some HPV viruses only found in certain locations?
Replication requirements only found in certain locations
What are 3 benign mucosal tumors caused by HPV? What are they caused by?
- Condyloma accuminata
- Flat genital warts
- Laryngeal papillomas
Caused by low risk HPVs: 6 and 11 mainly
In which patients do laryngeal papillomas occur? Treatment? Complication?
Occur in newborns that aspirate fluid during birth
Treatment: surgical excision
If not treated can cause asphyxiation
Does koilocytosis on a PAP smear indicate either a low or high risk HPV virus?
NOPE
What do koilocytes represent on a PAP smear?
Acutely infected upper epithelial cells and capsid protein synthesis by the HPV virus
What cancers are caused by HPV?
- Cervical
- Vaginal
- Penile
- Oral
- Tongue
- Throat
- Anal
- Skin (?)
- Vulval
- Oropharyngeal (mainly in males)
What is important to note about the phase 2, malignant progression, of the HPV virus?
- No episomal viral DNA replication
- No late gene expressed: no longer infectious so no longer transmittable
- No capsid proteins synthesized
- No viral assembly
How does a malignant HPV virus appear on a PAP smear?
Very large nuclear:cytoplasm ratio
How do we grade the severity of a cervical cancer? What do we call these?
Cervical intraepithelial neoplasia
Based on how much of the epithelium is dysplastic: mild (CNI), moderate (CNII), or severe dysplasia (CNIII)
Why do cervical cancers arise at the region of transition from the endocervical canal lined by simple columnar epithelium to the stratified squamous non-keratinized epithelium?
Because the non-keratinized stratified squamous epithelium is only one cell thick there and because they have the right sensitivity to be transformed (express different types of genes) => same proteins expressed in cervical cancer and junctional zone cells
Why do HPV caused cancers arise at the anal/rectal junction and oralpharynx?
Transition from stratified squamous epithelium that decreases to a single cell layer to become
How are head and neck cancers related to the HPV virus?
Associated traditionally with tobacco and alcohol consumption and exposure to chemicals in the workplace, but now recognized that about 60-80% are associated with HPV infection
Are head and neck cancers more common in males or females? Any races? What to note?
More than twice as more common in males + males more than twice as likely to die
Disproportionately affects Blacks with younger age of incidence, increased mortality and more advanced disease at presentation
Increasing incidence of H&N cancers in younger age cohort of non-smoker, non-drinkers + several studies indicate that oral HPV is sexually acquired
Where do most head and neck HPV cancers occur?
- Tonsils
- Hypopharynx
- Oral cavity
- Larynx
Do HPV + patients with head and neck cancers respond better to chemotherapy/radiation than HPV- patients? Explain.
YUP
HPV cells make neoantigens , which are released during treatment so the cells have no immune response
Are HPV + tumors a completely distinct epidemiological, biological and clinical subset of tumors? Implications?
Maybe
Implications for treatment (may be more amenable to anti-EGFR therapies) and prevention with HPV vaccination
Further positive implication for adding vaccination of boys to that of girls
The incidence of which HPV tumor is increasing?
Oralpharynx cancers in men
What are the 2 main types of cervical cancer HPV viruses? What to note?
16 (65%) and 18 (15%)
16 accounts for >90% of head and neck tumors
Describe the timeline of the progression of cervical cancer.
- HPV infection
- Viral persistance and progression from 5 to 10 years
- Precancerous lesions after 10 years
- Cancer after about 20 years
What are the different stages of cervical cancer? Which stages can be cured?
- Stage 0: Carcinoma in situ, cervical intraepithelial neoplasia Grade III, but no invasion of basement membrane
- Stage I: The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded)
- Stage II: Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or lower third of the vagina
- Stage III: The carcinoma has extended to the pelvic wall. On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. The tumor involves the lower third of the vagina. All cases with hydronephrosis or non-functioning kidney are included, unless they are known to be due to other causes
- Stage IV: The carcinoma has extended beyond the true pelvis, or has involved (biopsy-proven) the mucosa of the bladder or rectum
All of them can be cured, but the earlier the better outcomes
How to diagnose cervical cancer? 3 ways
- Pap smear and biopsy: koilocytosis and cell morphology, L1 expression by IHC, using antibodies which are not type-specific
- Colposcopy: gross appearance of papillomas, with or without acetic acid visualization, lesions, high neovascularization
- HPV diagnostic tests: Hybrid Capture II assay based on DNA:RNA hybridization - detects multiple types of HPVs + PCR test
Usefulness of pap smears in diagnosing cervical cancers?
Once a year will insure you are safe, BUT if you have cancer only 50-80% chance it will be detected on pap smear
2 types of pap screening? Which is better?
- Conventional Pap Smear: cervical cell sample manually “smeared” onto slide for screening
- Liquid-Based: cervical cell sample put into liquid medium for suspension before automated thin layer/monolayer slide preparation => much better, 80% sensitivity
Limitations of the conventional pap smear?
- Majority of cells not captured
- Non-representative transfer
of cells - Clumping and overlapping of cells
- Obscuring material
=> high rate of false-negative results due to sampling and preparation errors
Describe the quality of Hybrid Capture II assay to diagnosis cervical cancer and HPV.
Clinical sensitivity of 95-100% for CIN 2/3 and cancer
Results of Hybrid Capture II assay and new PCR test to diagnosis cervical cancer and HPV?
High risk or low risk HPV viruses
How can external genital HPV lesions be treated?
- Acids (salicylic or trichloroacetic, the latter as a 90% solution)
- Mitotic inhibitors (podophyllotoxin, available commercially as Condylox or Podofilox, 0.5% cream)
- 5-fluorouracil (5-FU, 5% cream, off-label use)
- Cryotherapy (liquid nitrogen)
- Excision
How can internal genital HPV lesions (cervical, vaginal) be treated?
- Ablative
- Excisional
- Pharmaceutical
What are the 2 ablative therapies to treat internal genital HPV lesions (cervical, vaginal)? Describe each. Limitations?
- Cryotherapy: use of a probe containing carbon dioxide or nitrous oxide to freeze the entire transformation zone and area of the lesion
- Laser Vaporization Therapy: use of a laser to vaporize the transformation zone containing the lesion and requires suction to remove smoke
For both: cannot tell whether or not all of it has been ablated
What is the excisional technique to treat internal genital HPV lesions (cervical, vaginal)? How to do it best? What to note?
A cone of tissue is excised for further examination and/or to remove a lesion - tissue is usually stained with iodine (Lugol’s or Schiller’s solution) to demarcate the area of resection
Done with:
- Cold Knife
- Laser conization
- *LEEP (Loop Electrosurgical Excision Procedure): thin electric wire loop, which may have cutting and cautery currents
Note: 2 and 3 may be complicated by burn artifacts, and 3 can interfere with fertility and cause preterm births
3 ways to prevent cervical HPV infection?
- Abstinence
- Condoms: incomplete protection because some of the virus is in the hair follicles
- HPV vaccine: immunogen is the L1 capsid protein with 3 injections to cause IgG response so that irritation/abrasion and vaginal secretions and saliva will release IgGs to protect against virus => cannot get infection of the basal cells
How was the HPV vaccine created?
- Clone L1 gene into yeast or baculovirus
- Express and purify L1
- L1 protein self-assembles into a virus-like particle without any DNA
What 2 HPV viruses by Gardasil first generation? What about Gardasil 9?
- 16 and 18
- most common first 7 types of high risks viruses: 16, 18, 45, 31, 33, 52, 58, 35 => protect against 90-95% of all cervical cancers + 6/11 benign types important for laryngeal papillomas
Are vaccines against cervical infections also effective on oral infections?
YUP
What are the acute effects of the HPV vaccine?
- Pain
- Swelling
- Erythema
- Pruritus
- Fever
How many doses of the HPV vaccine are needed?
3 are given, but only 2 are needed before age 15, and new data even says maybe 1!
Can HPV vaccination be used to treat HPV infection?
Maybe if the infection is producing L1
How else can cervical neoplasia be treated (in progress)?
Artemisinin (active principle of the Chinese herb Artemisia annua) currently used clinically for treating drug-resistant malaria
List all STDs covered in order of prevalence.
- Human Papillomavirus
- Trichomoniasis
- Chlamydia
- Gonorrhea
- Herpes simple virus-2
- HIV and AIDS
- Hepatitis B
- Syphilis
