Microbiology

N. gonorrhoeae, the causative agent of gonorrhea, is a gram-negative, nonmotile, non-spore-forming organism that grows singly and in pairs (i.e., as diplococci).

Epidemiology

The ∼450,000 cases reported in the United States in 2016 probably represent only half the true number of cases because of underreporting, self-treatment, and nonspecific treatment without a laboratory diagnosis.

• More than 70% of reported cases in the United States occur in 15- to 24-year-old women and 20- to 29-year-old men.
• Gonorrhea is transmitted from males to females more efficiently than in the opposite direction, with 50-70% of women acquiring gonorrhea during a single unprotected sexual encounter with an infected man. Roughly two-thirds of all infected men are asymptomatic.
• Drug-resistant strains are widespread. Penicillin, ampicillin, and tetracycline are no longer reliable therapeutic agents, and oral cephalosporins and fluoroquinolones are no longer routinely recommended. In addition, strains highly resistant to ceftriaxone and azithromycin have been isolated in several countries, and combined resistance may contribute to the failure of the currently recommended dual therapy (see below).

Clinical Manifestations

Except in disseminated disease, the sites of infection typically reflect areas involved in sexual contact.

• Urethritis and cervicitis have an incubation period of 2-7 days and ∼10 days, respectively. See above for details.
• Anorectal gonorrhea can cause acute proctitis in women (due to the spread of cervical exudate to the rectum) and MSM.
• Pharyngeal gonorrhea is usually mild or asymptomatic and results from oral-genital sexual exposure (typically fellatio). Pharyngeal infection almost always coexists with genital infection, resolves spontaneously, and is rarely transmitted to sexual contacts.
• Ocular gonorrhea is typically caused by autoinoculation and presents as a markedly swollen eyelid, hyperemia, chemosis, and profuse purulent discharge.
• Gonorrhea in pregnancy can have serious consequences for both the mother and the infant.
  • Salpingitis and PID are associated with fetal loss.
  • Third-trimester disease can cause prolonged rupture of membranes, premature delivery, chorioamnionitis, funisitis, and neonatal sepsis.
  • - Ophthalmia neonatorum, the most common form of gonorrhea among neonates, is preventable by prophylactic ophthalmic ointments (e.g., containing erythromycin or tetracycline), but treatment requires systemic antibiotics.
• Gonococcal arthritis results from dissemination of organisms due to gonococcal bacteremia. Pts present during a bacteremic phase (relatively uncommon) or with suppurative arthritis involving one or two joints (most commonly the knees, wrists, ankles, and elbows), with tenosynovitis and skin lesions. Menstruation and complement deficiencies of the membrane attack complex (C5-C9) are risk factors for disseminated disease.

Diagnosis

NAATs, culture, and microscopic examination (for intracellular diplococci) of urogenital samples are used to diagnose gonorrhea; NAAT of urine samples is most sensitive. A single culture of endocervical discharge has a sensitivity of 80-90%.

Microbiology

C. trachomatis organisms are obligate intracellular bacteria that are divided into two biovars: trachoma and LGV. The trachoma biovar causes ocular trachoma and urogenital infections; the LGV biovar causes LGV.

Epidemiology

The World Health Organization (WHO) estimates that >106.4 million cases of C. trachomatis infection occur annually worldwide; it is the most prevalent of all bacterial STIs. The estimated 2-3 million cases per year that occur in the United States make C. trachomatis infection the most commonly reported infectious disease in this country.

Clinical Manifestations

Of pts with C. trachomatis genital infections, 80-90% of women and >50% of men lack symptoms; other pts have very mild symptoms.

• Urethritis, epididymitis, cervicitis, salpingitis, PID, and proctitis are all discussed above.
• Reactive arthritis (conjunctivitis, urethritis or cervicitis, arthritis, and mucocutaneous lesions) occurs in 1-2% of NGU cases, many of which are due to C. trachomatis. More than 80% of pts have the HLA-B27 phenotype.
• LGV is an invasive, systemic STI that-in heterosexual individuals-presents most commonly as painful inguinal lymphadenopathy beginning 2-6 weeks after presumed exposure. Progressive periadenitis results in fluctuant, suppurative nodes with development of multiple draining fistulas. Spontaneous resolution occurs after several months. See Table 86-1 Clinical Features of Genital Ulcers for additional clinical details.

Diagnosis

NAATs of urine or urogenital swabs are the diagnostic tests of choice. Serologic testing may be helpful in the diagnosis of LGV and neonatal pneumonia caused by C. trachomatis, but it is not useful in diagnosing uncomplicated urogenital infections.

Microbiology and Epidemiology

Mycoplasmas are the smallest free-living organisms known and lack a cell wall. Mycoplasma hominis, M. genitalium, Ureaplasma parvum, and U. urealyticum cause urogenital tract disease. These organisms are commonly present in the vagina of asymptomatic women.

Clinical Manifestations

Ureaplasmas are a common cause of Chlamydia-negative NGU. M. hominis and M. genitalium are associated with PID. M. hominis is implicated in 5-10% of cases of postpartum or postabortal fever.

Diagnosis

PCR is most commonly used for detection of urogenital mycoplasmas; culture is possible but can be done primarily at reference laboratories. Serologic testing is not helpful.

Microbiology and Epidemiology

Treponema pallidum subspecies pallidum-the cause of venereal syphilis-is a thin, spiral organism with a cell body surrounded by a trilaminar cytoplasmic membrane. Humans are the only natural host, and the organism cannot be cultured in vitro.

• Cases are acquired by sexual contact with infectious lesions (chancre, mucous patch, skin rash, condyloma latum); nonsexual acquisition through close personal contact, infection in utero, blood transfusion, and organ transplantation is less common.
• There are ∼11 million new infections per year worldwide.
  • In the United States, 31,575 cases were reported in 2000.
  • The reported cases of primary and secondary syphilis combined (which better indicate disease activity) increased from <6000 in 2000 to 23,872 in 2015, primarily affecting MSM, ∼50% of whom were co-infected with HIV.
• The transmission rate of syphilis to sexual contacts is high: many exposed individuals already have developed manifestations of syphilis when they are first seen, and ∼30% of contacts who are asymptomatic 30 days after exposure will later develop syphilis if not treated. These figures underscore the importance of treating all recently exposed sexual contacts.

Pathogenesis

T. pallidum penetrates intact mucous membranes or microscopic abrasions and, within hours, enters lymphatics and the bloodstream to produce systemic infection and metastatic foci. After a median incubation period of ∼21 days, the primary lesion (chancre) appears at the site of inoculation, persists for 4-6 weeks, and then heals spontaneously. Generalized parenchymal, constitutional, mucosal, and cutaneous manifestations of secondary syphilis appear 6-12 weeks later despite high antibody titers, subsiding in 2-6 weeks. After a latent period, one-third of untreated pts eventually develop tertiary disease (syphilitic gummas, cardiovascular disease, neurologic disease).

Clinical Manifestations

Syphilis progresses through three phases with distinct clinical presentations: primary syphilis, secondary syphilis (followed by a period of latent infection), and tertiary syphilis. Syphilis can also be transmitted from mother to fetus.

• Primary syphilis: A chancre at the site of inoculation (penis, rectum, or anal canal, mouth, cervix, labia) is characteristic but often goes unnoticed. See Table 86-1 Clinical Features of Genital Ulcers for clinical details. Regional adenopathy can persist long after the chancre heals.
• Secondary syphilis: The protean manifestations of the secondary stage usually include mucocutaneous or cutaneous lesions and generalized nontender lymphadenopathy.
  • Skin lesions can be subtle but are often pale red or pink, nonpruritic macules that are widely distributed over the trunk and extremities, including the palms and soles.
  • In moist intertriginous areas, papules can enlarge and erode to produce broad, highly infectious lesions called condylomata lata.
  • Superficial mucosal erosions (mucous patches) and constitutional symptoms (e.g., sore throat, fever, malaise) can occur.
  • Less common findings include hepatitis, nephropathy, arthritis, and ocular findings (e.g., optic neuritis, anterior uveitis, iritis).
• Latent syphilis: Pts without clinical manifestations but with positive syphilis serology have latent disease. Early latent syphilis is limited to the first year after infection, whereas late latent syphilis is defined as that of ≥1 year's (or unknown) duration.
• Tertiary syphilis: The classic forms of tertiary syphilis include neurosyphilis, cardiovascular syphilis, and gummas.
  • - Neurosyphilis represents a continuum, with asymptomatic disease occurring early after infection and potentially progressing to general paresis and tabes dorsalis. Symptomatic disease has three main presentations, all of which are now rare (except in pts with advanced HIV infection). Meningeal syphilis presents as headache, nausea, vomiting, neck stiffness, cranial nerve involvement, seizures, and changes in mental status within 1 year of infection. Meningovascular syphilis presents up to 10 years after infection as a subacute encephalitic prodrome followed by a gradually progressive vascular syndrome. Parenchymatous involvement presents at 20 years for general paresis and 25-30 years for tabes dorsalis. A general mnemonic for paresis is personality, affect, reflexes (hyperactive), eye (Argyll Robertson pupils, which react to accommodation but not to light), sensorium (illusions, delusions, hallucinations), intellect (decrease in recent memory and orientation, judgment, calculations, insight), and speech. Tabes dorsalis is a demyelination of posterior columns, dorsal roots, and dorsal root ganglia, including ataxia; foot drop; paresthesia; bladder disturbances; impotence; areflexia; and loss of position, deep pain, and temperature sensations.
  • - Cardiovascular syphilis develops in ∼10% of untreated pts 10-40 years after infection. Endarteritis obliterans of the vasa vasorum providing the blood supply to large vessels results in aortitis, aortic regurgitation, saccular aneurysm, and coronary ostial stenosis.
  • - Gummas are usually solitary lesions showing granulomatous inflammation with central necrosis. Common sites include the skin and skeletal system; however, any organ (including the brain) may be involved.
• Congenital syphilis: Syphilis can be transmitted throughout pregnancy, but fetal disease does not become manifest until after the fourth month of gestation. All pregnant women should be tested for syphilis early in pregnancy.

Diagnosis

Serologic tests-both lipoidal (so-called nontreponemal) and treponemal-are the mainstays of diagnosis; changes in antibody titers can also be used to monitor response to therapy.

• Lipoidal serologic tests that measure IgG and IgM antibodies to a cardiolipin-lecithin-cholesterol antigen complex (e.g., rapid plasma reagin [RPR], Venereal Disease Research Laboratory [VDRL]) are recommended for screening or for quantitation of serum antibody. After therapy for early syphilis, a persistent fall in titer by ≥4-fold is considered an adequate response.
• Treponemal tests, including the agglutination assay (e.g., the TPPA test), the fluorescent treponemal antibody-absorbed (FTA-ABS) test, and treponemal enzyme or chemiluminescence immunoassays (EIAs/CIAs), are used to confirm the results of lipoidal tests and should not be used as screening tests because of high false-positive rates. Results remain positive even after successful treatment.
• LP is recommended for pts with syphilis and neurologic signs or symptoms, an RPR or VDRL titer ≥1:32, active tertiary syphilis, or suspected treatment failure and for HIV-infected pts with a CD4⁺ T cell count <350/µL.
  • CSF exam demonstrates mononuclear pleocytosis (>5 WBCs/µL) and increased protein levels (>45 mg/dL). A positive CSF VDRL test is specific but not sensitive; an unabsorbed FTA test is sensitive but not specific. A negative unabsorbed FTA test excludes neurosyphilis.
• Pts with syphilis should be evaluated for HIV disease.

Microbiology and Epidemiology

HSV is a linear, double-strand DNA virus, with two subtypes (HSV-1 and HSV-2).

• Exposure to HSV at mucosal surfaces or abraded skin sites permits viral entry into cells of the epidermis and dermis, viral replication, entry into neuronal cells, and centrifugal spread throughout the body.
• More than 90% of adults have antibodies to HSV-1 by age 40; 15-20% of the U.S. population has antibodies to HSV-2, with a higher prevalence in low-income countries.
• Unrecognized carriage of HSV-2 and frequent asymptomatic reactivations of virus from the genital tract foster the continued spread of HSV disease.
• Genital lesions caused by HSV-1 have lower recurrence rates in the first year (∼55%) than those caused by HSV-2 (∼90%).

Clinical Manifestations

See Table 86-1 Clinical Features of Genital Ulcers for clinical details. First episodes of genital herpes due to HSV-1 and HSV-2 present similarly and can be associated with fever, headache, malaise, and myalgias. More than 80% of women with primary genital herpes have cervical or urethral involvement. Local symptoms include pain, dysuria, vaginal and urethral discharge, and tender inguinal lymphadenopathy.

Diagnosis

HSV DNA detection by PCR is the most sensitive laboratory technique and is recommended for laboratory confirmation of HSV infection. HSV culture is indicated when antiviral sensitivity testing is required. Staining of scrapings from the base of the lesion with Wright's, Giemsa's (Tzanck preparation), or Papanicolaou's stain to detect giant cells or intranuclear inclusions is well described, but most clinicians are not skilled in these techniques, which furthermore do not differentiate between HSV and VZV.

Microbiology and Epidemiology

Also known as granuloma inguinale, donovanosis is caused by K. granulomatis. The infection is endemic in Papua New Guinea, parts of southern Africa, India, the Caribbean, French Guyana, Brazil, and Aboriginal communities in Australia; few cases are reported in the United States.

Clinical Manifestations

See Table 86-1 Clinical Features of Genital Ulcers for clinical details. Four types of lesions have been described: (1) the classic ulcerogranulomatous lesion that bleeds readily when touched; (2) a hypertrophic or verrucous ulcer with a raised irregular edge; (3) a necrotic, offensive-smelling ulcer causing tissue destruction; and (4) a sclerotic or cicatricial lesion with fibrous and scar tissue. The genitals are affected in 90% of pts and the inguinal region in 10%.

Diagnosis

Diagnosis is often based on identification of typical Donovan bodies (gram-negative intracytoplasmic cysts filled with deeply staining bodies that may have a safety-pin appearance) within large mononuclear cells in smears from lesions or biopsy specimens. PCR is also available.

Microbiology

Papillomaviruses are nonenveloped, double-strand DNA viruses. More than 125 HPV types are recognized, and individual types are associated with specific clinical manifestations. For example, HPV types 16 and 18 have been most strongly associated with cervical and anal cancers, causing 70-85% and ∼90% of cases, respectively; HPV types 6 and 11 cause genital warts (condylomata acuminata).

Epidemiology and Clinical Manifestations

• HPV is transmitted by sexual intercourse, by oral sex, and possibly by touching of a partner's genitalia.
• The interval between initial infection and the diagnosis of HPV-associated cancer may be >20 years, with HIV infection accelerating this progression.
• The physical appearance of warts varies with their anatomic location, ranging from soft, whitish papules on the vulva to raised, keratotic, pigmented plaques on the penis.
• Although subclinical cervical HPV infections are common, pts with cervical cancer present early on with eroded carcinomas that bleed easily; more advanced carcinomas present as ulcerated lesions or as an exophytic lesion.
• Anal cancer typically presents as rectal bleeding and pain or a mass sensation, although 20% of pts are asymptomatic.

Diagnosis

Most visible warts are diagnosed correctly by history and physical examination alone. The primary method used for cervical cancer screening is cytology via Pap smear every 3 years beginning at age 21; for women ≥30 years of age, the testing interval can be lengthened to 5 years if co-testing for HPV DNA is negative. Anal screening is accepted for high-risk groups.