Sexually Transmitted Infections

Includes parts of CUAJ 2019 Penile Lesions Review

Epidemiology

Most common bacterial STI in the US (descending order):
1. Chlamydia
2. Gonorrhea
Risk factors:
- Number of lifetime sex partners
- Unprotected sex without use of a condom
- Risky sex partners
- Effect of alcohol or drugs on sexual decision making
Centers for Disease Control and Prevention Screening Recommendations
- Females
  - Annual chlamydia screening for all sexually active women age ≤ 25, as well as for women with risk factors such as new or multiple sex partners.
  - Annual gonorrhea screening for at-risk sexually active women, including women with new or multiple sex partners, or women who are living in areas with high rates of disease.
  - Syphilis, HIV, and chlamydia screening for all pregnant women, and gonorrhea screening for at-risk pregnant women starting early in pregnancy, with repeat testing as needed.
- Males
  - At least once-per-year screening for syphilis, chlamydia, gonorrhea, and HIV for all sexually active gay, bisexual, and other men who have sex with men (MSM).
  - Men who have multiple or anonymous partners should be screened more frequently for STIs, at 3- to 6-month intervals. More frequent screening is also recommended for MSM who use illicit drugs, particularly methamphetamine, or whose sex partners use them.
Reportable diseases in every US state (5):
1. Chlamydia
2. Gonorrhea
3. Syphilis
4. Chancroid
5. HIV/AIDS

Urethritis

Urethritis, or urethral inflammation, can be the result of STIs.
Classified as gonococcal vs. non-gonococcal
- Gonococcal Urethritis
  - Caused by Neisseria gonorrhoeae, a gram-negative diplococcus
    - An oxidase positive culture on Thayer-Martin medium is diagnostic of Neisseria gonorrhea
  - Incubation period: 3-14 days
- Non-gonococcal urethritis (NGU)
  - Caused by organisms other than Neisseria gonorrhoeae
    - Chlamydia trachomatis accounts for 15-40% of cases of NGU, with less common causes including Mycoplasma genitalium, Trichomonas vaginalis, adenoviruses, and herpes simplex virus type 1 (HSV-1)
  - Chlamydia
    - Gram-negative
    - Incubation period: 3-14 days (same as gonorrhea)
  - Mycoplasma genitalium
    - Mycoplasmas lack a cell wall and cannot be Gram stained.
    - Can become intracellular, which can establish a chronic infection and aid in avoidance of both immune response and antibiotics
    - Risk factors in men are young age, sexual intercourse in the past month, and a sex partner with a recent history of STI diagnosis or treatment
  - Ureaplasma
    - The evidence for Ureaplasma as a causative agent in NGU is conflicting
  - Trichomonas vaginalis
    - Flagellated parasite that exclusively infects the urinary tract
    - Common vaginal pathogen but also can cause urethritis in men
Natural History
- Gonorrhea
  - Complications in females: pelvic inflammatory disease (PID), tubal scarring, infertility, ectopic pregnancy, and chronic pelvic pain
  - Can increase the risk of contracting and transmitting HIV
  - Disseminated gonorrhea is rare today but can produce arthritis, dermatitis, meningitis, and endocarditis.
- Chlamydia
  - The major health risk of untreated chlamydial infections in men is transmission to their female partners resulting in PID
  - Complications in males include epididymitis and Reiter syndrome (conjunctivitis, urethritis, and reactive arthritis)
  - Ascending chlamydial infection in females can result in scarring of the fallopian tubes, PID, risk for ectopic pregnancy, pelvic pain, and infertility
Diagnosis and Evaluation
- History and Physical Exam
  - History
    - Symptoms of urethritis include urethral discharge, pruritus, and dysuria
    - Gonorrhea
      - Campbell’s: Men will usually have symptoms that cause them to seek treatment soon enough to prevent transmission to others. This could include urethritis, epididymitis, proctitis or prostatitis.
        CUAJ Penile Lesions Review 2019: In men, it is most often asymptomatic, but symptoms can include dysuria or mucopurulent discharge. [but multiple sources including Public Health Ontario and UptoDate say gonorrhea is symptomatic in most men)
      - Women are frequently asymptomatic.
    - Chlamydia
      - Symptoms in males include dysuria, urethral discharge, and epididymitis
        [UptoDate] up to 42% of men with NGU are asymptomatic
      - Up to 75% of women with chlamydial infection can be asymptomatic.
    - Mycoplasma genitalium
      - Most infected patients are symptomatic, but ≈25% may have asymptomatic urethral infection
  - Labs
    - Nucleic acid amplification tests (NAATs) performed on urine
      - Can be used to look for gonorrhoeae and chlamydia
        All patients should be tested for both gonorrhea and chlamydia, given the high association of co-infection.
      - Culture and hybridization tests that require urethral swab specimens are available. However, NAATs are preferred because of their higher sensitivity, and urethral swabs are no longer recommended for evaluation of urethritis
      - Culture for Mycoplasma genitalium is very difficult, and the diagnosis is made by NAATs or polymerase chain reaction (PCR)
      - NAAT has replaced wet mounts and culture for diagnosis of trichomonas vaginalis
Management
- Antibiotics
  - Current treatment of uncomplicated gonococcal infections involves ceftriaxone 250 mg IM single dose with
    - Azithromycin 1 gm PO x single dose or
    - Doxycycline 100 mg PO BID x 7 days
  - Dual therapy is required for both N. gonorrhoeae and chlamydia because of the high rate of coinfection
- All persons with gonorrhea should be tested for other STIs including syphilis and HIV

Ulcerative lesions of the male genitals

Classified as infectious vs. non-infectious

Infectious (5)	Non-infectious (6)
Herpes Syphilis Chancroid Lymphogranuloma venereum Donovanosis/granuloma inguinale	Trauma Malignancy Psoriasis Yeast Aphthae Fixed drug eruption

Infectious
- Epidemiology
  - In sexually active young US men, genital herpes is most common type of ulcer followed by syphilis
  - Chancroid occurs in some parts of the US
  - Lymphogranuloma venereum is increasing in incidence in MSM, including in the US.
  - Donovanosis/granuloma inguinale is endemic in some tropical and developing areas, including India; Papua, New Guinea; the Caribbean; central Australia; and southern Africa but usually does not occur in the US
- Diagnosis and Evaluation:
  - History and physical exam
  - Labs:
    - Herpes: Culture or NAAT/PCR testing for HSV, and diagnostic serology for determining the specific type of HSV
    - Syphilis: serologic testing and a darkfield examination if possible
    - Chancroid: testing for H. ducreyi should be performed in environments where chancroid is prevalent
    - Patients who are not known to be HIV positive should be tested for HIV
    - Even after complete diagnostic evaluation, 25% of patients with genital ulcers will have no laboratory-confirmed diagnosis.
  - Biopsy of ulcers is indicated if they are unusual or do not respond to initial therapy
  - Herpes
    - Most common cause of genital ulcers
    - Caused by the herpes simplex virus, a double-stranded DNA virus
      - HSV-1 causes mainly oral infections but now accounts also for 5-30% of first episodes of genital HSV infections
      - HSV-2 causes the majority of genital herpes and is transmitted by sexual contact
    - Females are more susceptible to HSV-2 infection and are more likely to have symptomatic infections. Most HSV-2 transmission thus occurs from individuals who do not know they are infected
    - HSV-2 infection seems to protect against HSV-1 infection, but HSV-1 gives only a small amount of protection from infection with HSV-2
    - Pathophysiology
      - HSV initiates replication in epithelial cells at the site of entry, damages the cells, and enters the ends of peripheral sensory nerves. Once in the nerve cell body, HSV enters a latent state
      - Recurrence and reactivation of virus occur with transportation in the peripheral nerves back to the mucosal or skin surface.
        Events that trigger reactivation of HSV include local trauma such as surgery or ultraviolet light, immunosuppression, or fever
      - Incubation period: 4-7 days after sexual intercourse
    - Diagnosis and Evaluation
      - History and Physical Exam
        History
        Patients have pain, burning, or itching, and 80% of women report dysuria.
        
        Other associated symptoms include flu-like symptoms, fever, headache, malaise, and myalgias.
        
        Possible complications include aseptic meningitis and autonomic dysfunction that can lead to urinary retention
        
        Physical Exam
        The classic first presentation of primary herpes is clusters of erythematous papules and vesicles on the external genitalia that do NOT follow a neural distribution
        
        Tender inguinal and femoral lymph nodes may be present.
        
        Over the next 2- 3 weeks, 75% of patients have new lesions, which can progress to vesicles and pustules and can coalesce into ulcers before crusting and healing
        
        Primary genital HSV-1 infection cannot be distinguished from HSV-2 infection on clinical examination alone, but requires laboratory testing.
        
        Insert figure
        
        Labs
        Options: NAAT or cell culture of a lesion
        NAAT is preferred due to increased sensitivity, and viral cultures are limited by the rate of viral shedding that can be intermittent and, therefore, cause false-negative results
        
        While the Tzanck preparation has historically been used, it should not be solely relied upon as it is non-specific and insensitive.
        
        In patients with no active lesions, serology must be used; specific immunoglobulin G (IgG) testing can distinguish the two types of HSV
      - Recurrent episodes
        Genital HSV-1 recurs much less frequently than genital HSV-2 infections
        
        HSV recurrences decrease after the first year
      - Management
        Treatment for a first clinical episode should be started on clinical grounds before laboratory confirmation of diagnosis.
        
        Currently available medications do not eradicate the virus, but aim to reduce the signs and symptoms of infection and prevent new lesions.
        Treatment of recurrent episodes reduces their severity and duration.
        Oral therapy within 24 hours of the first signs or symptoms of recurrence increases the chance of resolving a recurrence without lesions
        
        Options (3): -clovir
        Acyclovir (intravenous only)
        May be needed for those with neurologic complications, those unable to take oral medications, or those with widespread disease (e.g., immunocompromised patients)
        
        Valacyclovir
        
        Famciclovir
        
        Treatment is usually 7 to 10 days but should be extended if lesions are not adequately healed
        
        Lesions heal in 5-10 days in the absence of antiviral treatment

Syphilis
- Caused by Treponema pallidum
- Primary syphilis
  - Incubation period: typically 2-3 weeks, can range from 9-90 days for the appearance of lesions after infection
  - Lesion
    - Called “chancre”
    - Occurs at the initial site of infection
      - In male, lesions are typically on the glans, corona or perineal area
      - In females, lesions are typically on the labia or perianal area
    - Usually single and painless but can be multiple, and up to 25% of chancres can be painful
      - See Figure
  - Local non-tender lymphadenopathy is common
  - Untreated lesions heal spontaneously in 3-8 weeks
- Secondary syphilis
  - T. pallidum eventually becomes a systemic infection with bacteremia.
  - Appears 3-5 months after the initial infection
  - Characterized by a maculopapular rash, which is often widespread and involves the scalp, palms, and soles of the feet.
    - The rash can ulcerate and lead to condyloma lata, which are wart-like lesions.
  - Additional symptoms include fever, malaise, weight loss, patchy alopecia, and ocular inflammation
  - A broad vasculitis occurs in ≈10% of patients and may lead to hepatitis, iritis, nephritis, and neurologic problems including headache and cranial nerve involvement, especially VIII (auditory).
  - Relapses usually occur in the first year after infection and rarely after the second year. The infection then becomes latent and asymptomatic.
    - Latent syphilis is defined as seroreactivity with no clinical evidence of disease
- Tertiary or late syphilis
  - ≈35% of individuals with late latent syphilis will develop the late manifestations of syphilis, which include neurosyphilis, cardiovascular syphilis, and gummatous syphilis.
- Diagnosis and Evaluation
  - Labs
    - Darkfield examination
      - Cultures of T. pallidum are not possible
      - Direct tests include identification of T. pallidum under a dark-ground microscope
    - Serology
      - Categories of tests (2):
        Non-treponemal (directed against phospholipids)
        
        Treponemal (directed against T. pallidum polypeptides)
      - Non-treponemal
        Includes:
        Rapid plasma reagin (RPR) test
        
        Venereal Disease Research Laboratory (VDRL) test
        
        Toluidine red unheated serum test (TRUST)
        
        Need confirmation with a treponemal test because they can be positive in other conditions such as:
        Viral infections
        
        Pregnancy
        
        Malignancies
        
        Autoimmune disease
        
        Advanced age
        
        Used to monitor disease activity
      - Treponemal tests
        Includes
        FTA-ABS: fluorescent treponemal antibody absorption test
        
        MHA-TP: microhemagglutination assay for T. pallidum
        
        TP-HA: T. pallidum hemagglutination assay
        
        TP-PA: T. pallidum particle agglutination test
    - All patients with syphilis should be tested for HIV
- Management
  - Antibiotics
    - Standard treatment for all stages of syphilis is benzathine penicillin G
      - Stage and clinical manifestations of syphilis determine the preparation, dosage, and length of treatment
    - Jarisch-Herxheimer reaction
      - Not an allergic reaction to penicillin but occurs with treatment of the treponemes, and more commonly with treatment with penicillin and in early syphilis.
      - Consists of fever, malaise, nausea, and vomiting; may also be associated with chills and exacerbation of secondary rash.
      - Management
        Bed rest and nonsteroidal anti-inflammatory medications.