Disorders of the Cervix

• Urethritis and cervicitis are the focus
• Dr. Karla Guadalupe Zavala Bravo is the presenter

Learning Objectives:

• Explain the mechanisms by which bacteria, viruses, and parasites cause urethritis and cervicitis.
• Differentiate between the signs and symptoms of urethritis and cervicitis in men and women.
• Interpret laboratory results (urinalysis, urine culture, swabs) to diagnose urethritis and cervicitis.
• Develop a treatment plan for urethritis or cervicitis, considering the specific causative agent and relevant patient factors based on literature review.

Urethritis

• Urethritis is inflammation of the urethra
• It is caused by bacteria, viruses, physical injury, or sensitivity to chemicals found in spermicides, contraceptive foams, and jellies.
• It is classified as gonococcal or non-gonococcal based on the presence or absence of Neisseria gonorrhoeae.

Urethritis Etiology:

• Bacterial causes include Neisseria gonorrheae, Chlamydia trachomatis, Ureaplasma urealyticum, and Garnerella vaginalis.
• Parasitic causes include Trichomonas vaginalis
• Viral causes include HSV
• Fungal causes include Candida albicans

Causes of Urethritis

• Inadequate hygiene
• Risky sexual behaviors:
  • Multiple sexual partners
  • High-risk sexual behavior, like anal sex without a condom
  • History of sexually transmitted diseases

Symptoms of Urethritis

• Urethral inflammation
• Vaginal or urethral discharge
• Dysuria
• Pain during sex
• Urgent need to urinate
• Itching or pain when not urinating
• Difficulty starting urination

Mycoplasma Genitalium

• Smallest free-living bacteria
• Lacks a cell wall whose cell membrane contains sterols
• Absence of cell wall makes it resistant to penicillins, cephalosporins, vancomycin, and antibiotics interfering with cell wall synthesis.
• Divides by binary fission and grows on artificial cell-free media
• It contains both DNA and RNA
• Facultatively anaerobic and grows very slowly at 1 to 16 hours

Pathophysiology of M. genitalium:

• Adheres to epithelial surfaces with adhesins (MgPa) on the tips of polar cells.
• Localizes intracellularly
• It stimulates TNF-α, IL-1α, IL-1β, IL-6, IL-8, and IL-10 production
• Produces variable surface lipoproteins, evading host defenses.
• It produces H₂O2/Superoxides resulting in tissue damage and persistence of infection.
• It stimulates or suppresses immune cells such as macrophages, monocytes, and lymphocytes.

Symptoms and Detection of Urethritis in Men and Women

• Urethritis in men usually causes urethral discharge, dysuria, or both, usually without increased urinary frequency.
• In asymptomatic women, may be found throughout the lower urogenital tract.
• The vagina contains the largest number of organisms.
• The periurethral area and the cervix are the next most densely colonized.
• Microscopy has no diagnostic value because mycoplasmas stain poorly with Gram stain.
• Antigen tests also have poor sensitivity and specificity and are not recommended.
• The most sensitive diagnostic tests involve nucleic acid amplification tests of species-specific gene targets.

Treatment for M.genitalium

• Tetracycline, erythromycin, and newer macrolides such as clarithromycin and azithromycin are active against M. genitalium.
• Non-gonococcal urethritis (NGU) gets treated with doxycycline (100 mg orally twice a day for 7 days) or azithromycin (1.0 gm as a single oral dose).

Herpes Simplex Virus (HSV)

• It is large and enveloped and contains double-stranded DNA
• The DNA core is surrounded by an icosahedral capsid with 162 capsomeres.
• The capsid is enclosed by a glycoprotein-containing envelope, mediating viral attachment, fusion, and escaping immune control.
• Proteins and enzymes attached to the capsid initiate replication.
• As an enveloped virus, HSV is sensitive to acid, solvents, detergents, and drying in the gastrointestinal tract

HSV Infection steps:

• Initiates infections through mucosal membranes or breaks in the skin.
• It replicates in the basal cells of lesions
• Retrograde transport leads to the sacral ganglia to establish latent infection.
• Infects the innervating neuron
• CD8 T cells and IFN-γ are key in maintaining latency.
• During reactivation, the virus goes back to the initial site of infection
• The vesicle fluid is infectious.
• May be inapparent or may produce vesicular lesions

HSV Infection

• Can be transmitted via mucosal shedding, leading to sexual or perinatal transmission
• It is usually without urinary urgency or frequency
• Internal dysuria is a symptom
• Pyuria is a symptom
• HSV causes urethral syndrome in women
• There is an absence of E. coli and other uropathogens >10²/mL in urine.
• In male patients, lesions develop on the glans or shaft of the penis, and sometimes in the urethra.
• May be caused by vesicle fluid, saliva, and vaginal secretions.

STI Etiology of the Urethral Syndrome:

• Young age
• More than one current sexual partner
• A new partner within the past month
• A partner with urethritis
• Coexisting mucopurulent cervicitis

Diagnosis & Treatment of Herpes Simplex

• Direct microscopic examination of cells from the lesion's base (Tzanck smear) can show multinucleated giant cells and Cowdry type A inclusion bodies.
• Cell culture can identify the cytopathologic effect.
• Assays of tissue biopsy, smear, cerebrospinal fluid, or vesicular fluid can detect HSV antigen or genome through enzyme immunoassay, immunofluorescent stain, in situ DNA probe analysis, or PCR.
• HSV type distinction (HSV-1 versus HSV-2) is determined by type-specific antibody, DNA probe analysis, and PCR
• Serology is not useful except for epidemiology.
• Antiherpes medications are nucleoside analogs activated by viral thymidine kinase, inhibiting viral DNA polymerase, essential for viral replication
• Treatment prevents or shortens primary or recurrent episodes, but does not eliminate latent infection.
• FDA-approved treatments include Acyclovir, Penciclovir, Valacyclovir, Famciclovir, and Trifluridine.

Chlamydia Trachomatis

• Obligate intracellular parasite
• Possesses inner and outer membranes similar to gram-negative bacteria
• Contains both DNA and RNA

Chlamydia Trachomatis cycle

• Has a unique developmental cycle forming metabolically inactive infectious forms (Elementary bodies)
• Metabolically active noninfectious forms can also be formed (Reticulate bodies).
• Infectious EBs attach to microvilli of susceptible cells
• Actively penetrates the host cell
• Remains within cytoplasmic phagosomes
• The bacteria replicate
• Within 6–8 hr, EBs reorganize to form the larger, metabolically active RBs.
• Between 18 and 24 hours later, the RBs begin reorganization into smaller EBs.
• Between 48 and 72 hours after infection, cells rupture, releasing infectious bacteria.
• Receptors for EBs are mainly restricted to nonciliated columnar, cuboidal, and transitional epithelial cells.
• Reiter syndrome (urethritis, conjunctivitis, polyarthritis, and mucocutaneous lesions) is caused by genital infection with C. trachomatis.
• The clinical signs of chlamydia can result from the direct destruction of cells that happens during replication or a proinflammatory cytokine response they stimulate.

Signs of Chlamydia Trachomatis

• In men, urethritis can produce urethral discharge, dysuria, or both, without urinary frequency
• Asymptomatic chlamydial infection is an important reservoir for spread
• Many women are asymptomatic
• Dysuria (>7-10 days) and frequency with chlamydial urethritis, pyuria, and no bacteriuria. 
• Signs such as urethral discharge, meatal redness, and swelling are uncommon.
• Gram stains showing >10 PMNs per 1000× field in women with dysuria without coliform bacteriuria support the diagnosis

Treatment for Chlamydia Trachomatis

• Lack of purulent exudate does not rule out chlamydial urethral infections
• Cannot be differentiated from gonorrhoea, so diagnostic tests for both should be done
• NAATs are the preferred test since they are 90 - 98 %sensitive and very specific
• Cell culture is specific, but relatively insensitive
• Genital infections are treated with a single dose of azithromycin or doxycycline for 7 days in adults.
• It may be prevented with safe sex practices an prompt treatment in symptomatic patients and their partners.

Cervicitis

• Cervicitis is inflammation of the cervix, the lower, narrow end of the uterus that opens into the vagina.

Risk factors

• History of STIs
• Partners with a history of STIs
• Systemic inflammatory diseases
• Chemical irritation from spermicides, douches, or latex in condoms
• Reaction to diaphragms, cervical caps, or tampons
• Radiation therapy

Symptoms of cervicitis:

• Large amounts of unusual vaginal discharge
• Frequent, painful urination
• Pain during sex
• Bleeding between menstrual periods
• Vaginal bleeding after sex not associated with a menstrual period

Mycoplasma Genitalium & Cervicitis:

• Azithromycin 1 g orally once is more effective than doxycycline for cervicitis.
• In treatment failures because of antibiotic resistant strains, 400 mg moxifloxacin orally once daily for 7-14 days may be used.
• Moxifloxacin may be given for 14 days to women detected with PID who fail to respond after 7-10 days

Chlamydia Trachomatis & Cervicitis

• It is an obligate intracellular parasite and is dependent on host cells to survive
• Infects columnar epithelial cells, and infection of the endocervical glands leads to mucopurulent or endocervical secretions.
• Can infect the endocervical tissue making it edematous and hyperemic
• The majority of genital tract infections in women are asymptomatic (80%)
• Symptomatic patients show mucopurulent discharge
• It can cause urethritis with or without a concurrent cervical infection.
• Differential diagnoses of mucopurulent discharge from the endocervical canal in a young, sexually active woman include the following:
  • Gonococcal endocervicitis
  • Salpingitis
  • Endometritis
  • Intrauterine contraceptive device-induced inflammation
• Can be detected with a swab from edematous ares from the cervix
• There can be hypertrophic ectopy of the cervix, with congested an easily bleeding lesions on minor trauma
• Detection of mucopurulent discharge indicates infection
• Plasma cells can be detected after a papalicolau test and mononuclear inflammatory cells and a infiltrate of subepitelial stroma can be seen during a cervical biospy
• Gram-stained prepations of endocervical exudate should show more then >20 neutrophils per microscopic field

Diagnosis of Cervicitis:

• Diagnosis is based on PMNs on a cervical swab.
• Available diagnostic tests include NAAT, culture, and enzyme-linked immunosorbent assay (ELISA) for endocervical specimens.
• The presence of chlamydiae is confirmed by either culture or NAAT.
• Newer NAAT collection kits permit specific collection from the vagina, the endocervix, or urine.
• Vaginal-swab specimens are as sensitive and specific as cervical-swab specimens.
• Urine samples are preferred for women following hysterectomy.

Neisseria Gonorrhoeae

• Aerobic gram-negative bacteria, typically coccoid shaped in diplococci with adjacent flattened sides
• Oxidase positive and produce catalase
• Produce acid with carbohydrate oxidation used for Neisseria species differentiation historically.
• The strains require cystine and an energy source (glucose, pyruvate, lactate)
• Many strains need amino acids, purines, pyrimidines, and vitamins in their media
• The bacteria attach to mucosal cells by invading the columnar and transitional epithelial cells of the cervix, while sparing the vaginal squamous epithelium.
• Gonococcus does not infect the squamous epithelial cells lining the vagina of postpubescent women.
• They travel through the cells, into the subepithelial space, and infection is established.
• Pili, PorB, and Opa proteins aid this attatchment
• Gonococcal LOS stimulates the release of TNF-α leading to most symptoms
• It can infect the upper female reproductive tract

Symptoms and Testing

Usually develops within 10 days of infection

• Symptoms are discharges
• dysuria indicates a concominant upper GI infection (10-20%)
• ascending genital infections (10-20%) can lead to salpingitis, tubo-ovarian, abscesses, and PID
• Microscopic inspection secretions typical reveals ~20 WBCs per high-power field
• Now NAATs are available and replace culture for clinical indication
• Currently with combination dual therapy for gonorrhea and azithromycin due to increase tetracycline

Antibiotic resistance

• Resistance to tetracycline and ciprofloxacin is prevalent, neither being recommended for treatment.

Recommendations

• The CDC recommends dual therapy with ceftriaxone and azithromycin.