Chlamydia trachomatis

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Chapter 218 Chlamydia trachomatis

Margaret R. Hammerschlag

Chlamydia trachomatis is subdivided into 2 biovars: lymphogranuloma venereum (LGV) and trachoma, which is the agent of human oculogenital diseases other than LGV. Although the strains of both biovars have almost complete DNA homology, they differ in growth characteristics and virulence in tissue culture and animals. In developed countries, C. trachomatis is the most prevalent sexually transmitted disease, causing urethritis in men, cervicitis and salpingitis in women, and conjunctivitis and pneumonia in infants.

218.1 Trachoma

Margaret R. Hammerschlag

Trachoma is the most important preventable cause of blindness in the world. It is caused primarily by the A, B, Ba, and C serotypes of C. trachomatis. It is endemic in the Middle East and Southeast Asia and among Navajo Indians in the southwestern USA. In areas that are endemic for trachoma, such as Egypt, genital chlamydial infection is caused by the serotypes responsible for oculogenital disease: D, E, F, G, H, I, J, and K. The disease is spread from eye to eye. Flies are a common vector.

Trachoma begins as a follicular conjunctivitis, usually in early childhood. The follicles heal, leading to conjunctival scarring that can result in an entropion, with the eyelid turning inward so that the lashes abrade the cornea. It is the corneal ulceration secondary to the constant trauma that leads to scarring and blindness. Bacterial superinfection can also contribute to scarring. Blindness occurs years after the active disease.

Trachoma can be diagnosed clinically. The World Health Organization (WHO) suggests that at least 2 of 4 criteria must be present for a diagnosis of trachoma: lymphoid follicles on the upper tarsal conjunctivae, typical conjunctival scarring, vascular pannus, and limbal follicles. The diagnosis is confirmed by culture or staining tests for C. trachomatis performed during the active stage of disease. Serologic tests are not helpful clinically because of the long duration of the disease and the high seroprevalence in endemic populations.

Poverty and lack of sanitation are important factors in the spread of trachoma. As socioeconomic conditions improve, the incidence of the disease decreases substantially. Endemic trachoma has been controlled in most instances by administering topical tetracyclines (or, rarely, erythromycin ointment) daily for periods of 6-10 wk or intermittently over a 6-mo period. Oral doxycycline is effective but is contraindicated in children <8 yr of age. Oral erythromycin requires frequent dosing, which is impractical in the control of endemic trachoma. Several studies have reported that 1-6 doses of oral azithromycin are equivalent to 30 days of treatment with topical oxytetracycline/polymyxin ointment. The WHO recommends single-dose azithromycin (20 mg/kg, maximum 1g) for the treatment of trachoma in children. A study from Tanzania demonstrated that mass treatment with a single dose of azithromycin to all the residents of a village dramatically reduced the prevalence and intensity of infection. This effect continued for 2 years after treatment, probably by interrupting the transmission of ocular C. trachomatis infection.

Bibliography

Chidambaram JD, Alemayehu W, Melese M, et al. Effect of a single mass antibiotic distribution on the prevalence of infectious trachoma. JAMA. 2006;295:1142-1146.

Grassley NC, Ward ME, Ferris S, et al. The natural history of trachoma infection and disease in a Gambian cohort with frequent follow-up. PloS Negl Trop Dis. 2008;2:e341.

House JI, Ayele B, Porco TC, et al. Assessment of herd protection against trachoma due to repeated mass antibiotic distributions: a cluster randomized trial. Lancet. 2009;373:1111-1118.

Nieuwenhuis RF, Ossewaarde JM, Götz HM, et al. Resurgence of lymphogranuloma venereum in Western Europe: an outbreak of Chlamydia trachomatis serovar L2 proctitis in the Netherlands among men who have had sex with men. Clin Infect Dis. 2004;39:996-1003.

Solomon AW, Peeling RW, Foster A, et al. Diagnosis and assessment of trachoma. Clin Microbiol Rev. 2004;17:982-1011.

Taylor HR. Elimination of blinding trachoma revolves around children. Lancet. 2009;373:1061-1063.

218.2 Genital Tract Infections

Margaret R. Hammerschlag

Epidemiology

There are an estimated 3 million new cases of chlamydial sexually transmitted infections each year in the USA. C. trachomatis is a major cause of epididymitis and is the cause of 23-55% of all cases of nongonococcal urethritis, although the proportion of chlamydial nongonococcal urethritis has been gradually declining. As many as 50% of men with gonorrhea may be co-infected with C. trachomatis. The prevalence of chlamydial cervicitis among sexually active women is 2-35%. Rates of infection among girls 15-19 yr of age exceed 20% in many urban populations but can be as high as 15% in suburban populations as well.

Children who have been sexually abused can acquire anogenital C. trachomatis infection, which is usually asymptomatic. Culture is the only method that should be used for diagnosis of C. trachomatis from these sites when a prepubertal child is being tested for suspected sexual abuse. However, because perinatally acquired rectal and vaginal C. trachomatis infections can persist for ≥3 years, the detection of C. trachomatis in the vagina or rectum of a young child is not absolute evidence of sexual abuse.

Clinical Manifestations

The trachoma biovar of C. trachomatis causes a spectrum of disease in sexually active adolescents and adults. Up to 75% of women with C. trachomatis have no symptoms of infection. C. trachomatis can cause urethritis (acute urethral syndrome), epididymitis, cervicitis, salpingitis, proctitis, and pelvic inflammatory disease. The symptoms of chlamydial genital tract infections are less acute than those of gonorrhea, consisting of a discharge that is usually mucoid rather than purulent. Asymptomatic urethral infection is common in sexually active men. Autoinoculation from the genital tract to the eyes can lead to concomitant inclusion conjunctivitis.

Diagnosis

Definitive diagnosis of genital chlamydial infection is accomplished by isolation of the organism in tissue culture and confirmed by microscopic identification of the characteristic inclusions using fluorescent antibody staining in culture specimens obtained from the urethra in men and the endocervix in women. Care should be taken to obtain epithelial cells, not only discharge. C. trachomatis can be cultured in cycloheximide-treated HeLa, McCoy, and HEp-2 cells. Chlamydia culture has been further defined by the Centers for Disease Control and Prevention (CDC) as isolation of the organism in tissue culture and as confirmation of the characteristic intracytoplasmic inclusions by fluorescent antibody staining.

Alternatively, a nonculture method, specifically a nucleic acid amplification test (NAAT) can be used. These tests have high sensitivity, perhaps even detecting 10-20% greater than culture, while retaining high specificity. Three Food and Drug Administration (FDA)-approved NAATs are comercially available for detecting C. trachomatis: polymerase chain reaction (PCR; Amplicor Chlamydia test, Roche Molecular Diagnostics, Nutley, NJ), strand displacement amplification (SDA; ProbeTec, BD Diagnostic Systems, Sparks, MD), and transcription-mediated amplification (TMA; Amp CT, Gen-Probe, San Diego, CA). PCR and SDA are DNA amplification tests that use primers that target gene sequences on the cryptogenic C. trachomatis plasmid that are present at approximately 10 copies in each infected cell. TMA is a ribosomal RNA amplification assay. All 3 assays are also available as co-amplification tests for simultaneously detecting C. trachomatis and Neisseria gonorrhoeae.

The currently available commercial NAATs are FDA approved for cervical swabs from adolescent girls and women, urethral swabs from adolescent boys and men, and urine from adolescents and adults. The latest version of TMA was recently approved for use with vaginal swabs in adolescents and adults. Use of urine avoids the necessity for a clinical pelvic examination and can greatly facilitate screening in certain populations, especially adolescents, although several studies have now demonstrated that endocervical specimens and vaginal swabs are superior to urine for NAAT. Self-collected vaginal specimens appear to be as reliable as specimens obtained by a health care professional.

Data on use of NAATs for vaginal specimens or urine from children are very limited and insufficient to allow making a recommendation for their use. The CDC recommends that NAATs may be used as an alternative to culture only if confirmation is available. Confirmation tests should consist of a 2nd FDA-approved NAAT that targets a different gene sequence from the initial test.

The etiology of most cases of nonchlamydial nongonococcal urethritis is unknown, although Ureaplasma urealyticum and possibly Mycoplasma genitalium are implicated in up to one third of cases (Chapter 216). Proctocolitis may develop in individuals who have a rectal infection with an LGV strain (see Chapter 218.4, later).

Treatment

The 1st-line treatment regimens recommended by the CDC for uncomplicated C. trachomatis genital infection in men and nonpregnant women include azithromycin (1 g PO as a single dose) and doxycycline (100 mg PO twice a day for 7 days). Alternative regimens are erythromycin base (500 mg PO 4 times a day for 7 days), erythromycin ethylsuccinate (800 mg PO 4 times a day for 7 days), ofloxacin (300 mg PO twice a day for 7 days), and levofloxacin (500 mg PO once daily for 7 days). The high erythromycin dosages might not be well tolerated. Doxycycline and quinolones are contraindicated in pregnant women, and quinolones are contraindicated in persons younger than 18 yr. For pregnant women, the recommended treatment regimen is erythromycin base (500 mg PO twice a day for 7 days) or amoxicillin (500 mg PO 3 times a day for 7 days). Alternative regimens for pregnant women are erythromycin base (250 mg PO 4 times a day for 14 days), erythromycin ethylsuccinate (800 mg PO 4 times a day for 7 days or 400 mg PO 4 times a day for 14 days), and azithromycin (1 g PO in a single dose). Amoxicillin at a dosage of 500 mg PO 3 times a day for 7 days is as effective as any of the erythromycin regimens and is much better tolerated. However, experience with all these regimens is still limited.

Empirical treatment without microbiologic diagnosis is recommended only for patients at high risk for infection who are unlikely to return for follow-up evaluation, including adolescents with multiple sex partners. These patients should be treated empirically for both C. trachomatis and gonorrhea.

Sex partners of patients with nongonococcal urethritis should be treated if they have had sexual contact with the patient during the 60 days preceding the onset of symptoms. The most recent sexual partner should be treated even if the last sexual contact was more than 60 days from onset of symptoms.

Complications

Complications of genital chlamydial infections in women include perihepatitis (Fitz-Hugh-Curtis syndrome) and salpingitis. Of women with untreated chlamydial infection who develop pelvic inflammatory disease, up to 40% will have significant sequelae; approximately 17% will suffer from chronic pelvic pain, approximately 17% will become infertile, and approximately 9% will have an ectopic (tubal) pregnancy. Adolescent girls may be at higher risk for developing complications, especially salpingitis, than older women. Salpingitis in adolescent girls is also more likely to lead to tubal scarring, subsequent obstruction with secondary infertility, and increased risk for ectopic pregnancy. Approximately 50% of neonates born to pregnant women with untreated chlamydial infection will acquire C. trachomatis infection (see Chapter 218.3, next). Women with C. trachomatis infection have a 3-5-fold increased risk for acquiring HIV infection.

Prevention

Timely treatment of sex partners is essential for decreasing risk for reinfection. Sex partners should be evaluated and treated if they had sexual contact during the 60 days preceding onset of symptoms in the patient. The most recent sex partner should be treated even if the last sexual contact was >60 days. Patients and their sex partners should abstain from sexual intercourse until 7 days after a single-dose regimen or after completion of a 7-day regimen.

Annual routine screening for C. trachomatis is recommended for all sexually active female adolescents, for all women 20-25 years of age, and for older women with risk factors such as new or multiple partners or inconsistent use of barrier contraceptives. Sexual risk assessment might indicate more frequent screening of some women.

Bibliography

Bébéar C, de Barbeyrac B. Genital Chlamydia trachomatis infections. Clin Microbiol Infect. 2009;15:4-10.

Black CM, Driebe EM, Howard LA, et al. Multicenter study of nucleic acid amplification tests for detection of Chlamydia trachomatis and Neisseria gonorrhoeae in children being evaluated for sexual abuse. Pediatr Infect Dis J. 2009;28:608-613.

Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2010, MMWR (in press).

Gaydos CA, Theodore M, Dalesio N, et al. Comparison of three nucleic acid amplification tests for detection of Chlamydia trachomatis in urine specimens. J Clin Microbiol. 2004;42:3041-3045.

Girardet RG, Lahoti S, Howard LA, et al. The epidemiology of sexually transmitted infections in suspected child victims of sexual assault. Pediatrics. 2009;124:79-86.

Hammerschlag MR, Guillén CD. Medical and legal implications of testing for sexually transmitted infections in children. Clin Microbiol Rev. 2010;23:493-506.

Hwang L, Shafer MA. Chlamydia trachomatis infection in adolescents. Adv Pediatr. 2004;51:379-407.

Schachter J, McCormack WM, Chernesky MA, et al. Vaginal swabs are appropriate specimens for diagnosis of genital tract infection with Chlamydia trachomatis. J Clin Microbiol. 2003;41:3784-3789.

218.3 Conjunctivitis and Pneumonia in Newborns

Margaret R. Hammerschlag

Epidemiology

Chlamydial genital infection is reported in 5-30% of pregnant women, with a risk for vertical transmission at parturition to newborn infants of about 50%. The infant may become infected at 1 or more sites, including the conjunctivae, nasopharynx, rectum, and vagina. Transmission is rare following cesarean section with intact membranes. The introduction of systematic prenatal screening for C. trachomatis infection and treatment of pregnant women has resulted in a dramatic decrease in the incidence of neonatal chlamydial infection in the USA. However, in countries where prenatal screening is not done, such as the Netherlands, C. trachomatis remains an important cause of neonatal infection, accounting for >60% of neonatal conjunctivitis.

Inclusion Conjunctivitis

Approximately 30-50% of infants born to mothers with active, untreated chlamydial infection develop clinical conjunctivitis. Symptoms usually develop 5-14 days after delivery, or earlier in infants born after prolonged rupture of membranes. The presentation is extremely variable and ranges from mild conjunctival injection with scant mucoid discharge to severe conjunctivitis with copious purulent discharge, chemosis, and pseudomembrane formation. The conjunctiva may be very friable and miight bleed when stroked with a swab. Chlamydial conjunctivitis must be differentiated from gonococcal ophthalmia, which is sight threatening. At least 50% of infants with chlamydial conjunctivitis also have nasopharyngeal infection.

Pneumonia

Pneumonia due to C. trachomatis can develop in 10-20% of infants born to women with active, untreated chlamydial infection. Only about 25% of infants with nasopharyngeal chlamydial infection develop pneumonia. C. trachomatis pneumonia of infancy has a very characteristic presentation. Onset usually occurs between 1 and 3 mo of age and is often insidious, with persistent cough, tachypnea, and absence of fever. Auscultation reveals rales; wheezing is uncommon. The absence of fever and wheezing helps to distinguish C. trachomatis pneumonia from respiratory syncytial virus pneumonia. A distinctive laboratory finding is the presence of peripheral eosinophilia (>400 cells/mm3). The most consistent finding on chest radiograph is hyperinflation accompanied by minimal interstitial or alveolar infiltrates.

Infections at Other Sites

Infants born to mothers with C. trachomatis can develop infection in the rectum or vagina. Although infection in these sites appears to be totally asymptomatic, it can cause confusion if it is identified at a later date. Perinatally acquired rectal, vaginal, and nasopharyngeal infections can persist for ≥3 years. C. pneumoniae can also be confused with C. trachomatis infection in nasopharyngeal cultures if a genus-specific monoclonal antibody is used to confirm the culture.

Diagnosis

Definitive diagnosis is achieved by isolation of C. trachomatis in cultures of specimens obtained from the conjunctiva or nasopharynx. Nonculture methods including direct fluorescent antibody (DFA) and NAATs are available, but only the DFA is currently approved for diagnosis of chlamydial conjunctivitis with sensitivities of ≥90% and specificities of ≥95% for conjunctival specimens compared with culture. Accuracy for nasopharyngeal specimens is not as good. Data on use of NAATs for diagnosis of C. trachomatis in children are limited. Limited data suggest that PCR may be equivalent to culture for detecting C. trachomatis in the conjunctiva of infants with conjunctivitis.

Treatment

The recommended treatment regimen for C. trachomatis conjunctivitis or pneumonia in infants is erythromycin (base or ethylsuccinate, 50 mg/kg/day divided 4 times a day PO for 14 days). The rationale for using oral therapy for conjunctivitis is that 50% or more of these infants have concomitant nasopharyngeal infection or disease at other sites, and studies have demonstrated that topical therapy with sulfonamide drops and erythromycin ointment is not effective. The failure rate with oral erythromycin remains 10-20%, and some infants require a 2nd course of treatment. The results of 1 small study suggest that a short course of azithromycin (20 mg/kg/day once daily PO for 3 days) is as effective as 14 days of erythromycin. Mothers (and their sexual contacts) of infants with C. trachomatis infections should be empirically treated for genital infection. An association between treatment with oral erythromycin and infantile hypertrophic pyloric stenosis has been reported in infants <6 wk of age who were given the drug for prophylaxis after nursery exposure to pertussis.

Prevention

Neonatal gonococcal prophylaxis with topical erythromycin or tetracycline ointment, or silver nitrate, does not appear to prevent chlamydial ophthalmia or nasopharyngeal colonization with C. trachomatis or chlamydial pneumonia. The most effective method of controlling perinatal chlamydial infection is screening and treatment of pregnant women. For treatment of C. trachomatis infection in pregnant women, the CDC currently recommends either azithromycin (1 g PO as a single dose) or amoxicillin (500 mg PO 3 times a day for 7 days) as 1st-line regimens. Erythromycin base (250 mg PO 4 times a day for 14 days) and erythromycin ethylsuccinate (800 mg 4 times a day for 7 days, or 400 mg PO 4 times a day for 14 days) are listed as alternative regimens. Reasons for failure of maternal treatment to prevent infantile chlamydial infection include poor compliance and re-infection from an untreated sexual partner.

Bibliography

Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2010, MMWR (in press.

Hammerschlag MR, Gelling M, Roblin PM, et al. Treatment of neonatal chlamydial conjunctivitis with azithromycin. Pediatr Infect Dis J. 1998;17:1049-1050.

Rours GIJG, Hammerschlag MR, De Faber JTHN, et al. Chlamydia trachomatis as a cause of neonatal conjunctivitis in Dutch infants. Pediatrics. 2008;121:e321-e326.

218.4 Lymphogranuloma Venereum

Margaret R. Hammerschlag

LGV is a systemic sexually transmitted disease caused by the L1, L2, and L3 serotypes of the LGV biovar of C. trachomatis. Unlike strains of the trachoma biovar, LGV strains have a predilection for lymphoid tissue. About 20 cases of LGV have been reported in children, and <1,000 cases are reported in adults in the USA annually. There has been a resurgence of LGV infections among men who have sex with men in Europe and the USA. Many of the men were HIV infected and used illicit drugs, specifically methamphetamines.

Clinical Manifestations

The 1st stage of LGV is characterized by the appearance of the primary lesion, a painless, usually transient papule on the genitals. The 2nd stage is characterized by usually unilateral femoral or inguinal lymphadenitis with enlarging, painful buboes. The nodes may break down and drain, especially in men. In women, the vulvar lymph drains to the retroperitoneal nodes. Fever, myalgia, and headache are common. The 3rd stage is a genitoanorectal syndrome with rectovaginal fistulas, rectal strictures, and urethral destruction. Among men who have sex with men, rectal infection with LGV can produce a severe, acute proctocolitis, which can be confused with inflammatory bowel disease or malignancy.

Diagnosis

LGV can be diagnosed by serologic testing or by culture of C. trachomatis or molecular testing for C. trachomatis from a specimen aspirated from a bubo. Most patients with LGV have complement-fixing antibody titers of >1 : 16. Chancroid and herpes simplex virus can be distinguished clinically from LGV by the concurrent presence of painful genital ulcers. Syphilis can be differentiated by serologic tests. However, co-infections can occur.

Treatment

Doxycycline (100 mg PO bid for 21 days) is the recommended treatment. The alternative regimen is erythromycin base (500 mg PO 4 times/day for 21 days). Azithromycin (1 g PO once weekly for 3 wk) may also be effective but clinical data are lacking. Sex partners of patients with LGV should be treated if they have had sexual contact with the patient during the 30 days preceding the onset of symptoms.

Bibliography

Blank S, Schillinger JA, Harbatkin D. Lymphogranuloma venereum in the industrialized world. Lancet. 2005;365:1607-1608.

Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2010, MMWR (in press.

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