Chlamydia trachomatis

The most common sexually transmitted disease (STD) in the United States is Chlamydia trachomatis infection, with more than 4 million cases reported each year.[1] Recent advances in epidemiology, laboratory testing and treatment of chlamydial infection are designed to help curb transmission and decrease the long-term sequelae of this devastating disease.

C. trachomatis is an intracellular parasitic pathogen that is similar in cell-wall membrane structure to gram-negative bacteria. Principal sites of adult infection include the genitourinary tract and rectum. Conjunctivitis, perihepatitis and reactive arthritis may result. Invasion occurs as the organism penetrates columnar epithelial cells at the site of initial exposure.

The prevalence rate of C. trachomatis infection ranges from 3 percent in women and men seen in an asymptomatic population to more than 20 percent in people screened in STD clinics.[2]

The frequently asymptomatic presentation of the chlamydial organism makes it difficult for the primary care physician to diagnose and treat an early infection. The role of asymptomatic women in the transmission of Chlamydia has been well recognized: as many as two-thirds of infected women are asymptomatic. As many as one-fourth of infected men are asymptomatic.[3]

Signs and Symptoms

One-third of women in whom Chlamydia is eventually detected have local signs of infection.[2] The most common symptom is vaginal discharge from mucopurulent cervicitis, although some women also have spotting with intercourse. Mucopurulent cervicitis causes the cervix to be friable, edematous and covered with a tenacious yellow-green discharge. Any woman with mucopurulent cervicitis on pelvic examination, whether vaginal discharge is present or not, should be screened for Chlamydia. A study of women with mucopurulent cervicitis confirmed that visualization of yellow mucopurulent cervicitis and the presence of 10 or more polymorphonuclear leukocytes per microscopic field (x1,000) in a Gramstained specimen strongly suggested cervical C. trachomatis infection and not gonorrhea or herpes.[4] Infection with C. trachomatis is confirmed on culture in one-third to one-half of women with mucopurulent cervicitis.[2]

Irregular menstrual bleeding, heavy menses or lower abdominal pain with uterine tenderness on examination are possible symptoms of endometritis, which is present in 40 percent of women with mucopurulent cervicitis from chlamydial infection.[3] Women with either unilateral or bilateral adnexal tenderness may also have chlamydial salpingitis, which may account for half of the cases of endoscopically confirmed salpingitis.[3]

From 3 to 5 percent of women with acute pelvic inflammatory disease have perihepatitis (Fitz-Hugh-Curtis syndrome) with symptoms of pleuritic right upper quadrant abdominal pain and tenderness, with or without pelvic pain. On examination, 40 percent of these women have a temperature above 38[degrees]C (100.4[degrees]F) and adnexal tenderness consistent with salpingitis.[5] Although it was first thought that these "violin-string" adhesions between the liver and the anterior abdominal wall were always caused by infection with Neisseria gonorrhoeae, 80 percent of patients with proven Fitz-Hugh-Curtis syndrome were found to be culturally or serologically positive for C. trachomatis, while only 10 percent were culturally positive for N. gonorrhoeae.[2]

Some women initially present with the long-term sequelae of chlamydial disease, such as ectopic pregnancy, infertility or chronic abdominal pain. Women with a history of pelvic inflammatory disease have a 7- to 10-fold increase in risk for ectopic pregnancy, compared with women who never had an infection.[5] In one group of women with tubal-factor infertility, association with Chlamydia IgA antibody was strong, even among women with no known history of pelvic inflammatory disease.[6]

Urinary tract infections caused by C. trachomatis are much more commonly symptomatic in men than in women. Both gonorrheal urethritis and C. trachomatis urethritis may cause "sterile" pyuria, and both infections may be asymptomatic. Up to 50 percent of men with nongonococcal urethritis are infected with Chlamydia. Nongonococcal urethritis presents with symptoms of dysuria and a white to clear urethral discharge. It has an incubation period of seven to 21 days. Screening studies in STD clinics show that half of the urethral and cervical cultures in infected women are positive for Chlamydia at both sites.[5]

In young heterosexual men presenting with symptomatic epididymitis, chlamydial infection is the leading cause. Therefore, men with testicular pain, with or without urethral discharge, should be tested for Chlamydia.

Reiter's syndrome, a clinical symptom complex consisting of reactive arthritis, conjunctivitis and nongonococcal urethritis, has also been associated with Chlamydia; therefore, patients with symptoms consistent with Reiter's syndrome should also be tested for chlamydial infection.7 Chlamydia can cause proctitis 1n men and women practicing receptive anal intercourse. Women and homosexual men with anorectal pain, tenesmus, bleeding and rectal discharge should be cultured for chlamydial infection.

Table 1 shows the prevalence rate of C. trachomatis infection in association with some of the most common clinical syndromes in patients with STDs.

Screening Asymptomatic Patients

Since so many men and women infected with Chlamydia are asymptomatic, the Centers for Disease Control and Prevention (CDC) recommends screening patients who are most likely to contract chlamydial infection.[1] With this goal in mind, selective screening of targeted populations in whom the prevalence rate has been shown to exceed 5 percent has been suggested. For women, these populations include those attending family planning clinics or STD clinics, and prison inmates.[1]

Table 2 presents office screening recommendations for asymptomatic groups of patients. Sexually active adolescents should be screened during routine pelvic examinations. In addition to these groups, women aged 20 to 24 who inconsistently use barrier contraceptives, who have a new sex partner or who have had more than one sex partner during the past three months could benefit from screening. In women older than age 24, Chlamydia screening may be helpful if they have had a new sex partner within the past three months and are not using barrier contraception. Since serious perinatal complications could result from chlamydial infections, women who are pregnant as well as those who are seeking an abortion should be screened.[1]

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Adolescent males who are sexually active and men who are in the military, attending college or restrained in detention centers--populations in which the prevalence rate for Chlamydia is 5 percent or greater--are also good candidates for screening.[1] Any man seeking care in an STD clinic, where Chlamydia prevalence rates for males are as high as 20 percent, should be screened. Although routine screening of asymptomatic males has been difficult in the past because of the discomfort associated with urethral culture, the leukocyte esterase test (LET) for urine screening may be a more acceptable screening tool.

Some controversy exists as to whether Chlamydia testing is necessary in patients with symptoms consistent with chlamydial disease and for partners of patients known to be positive for Chlamydia. However, if the index patient is presently symptomatic, testing should be strongly considered since notifying partners may become a problem if definitive testing has not been performed. If the partner is unable or unwilling to come into the physician's office for evaluation and treatment, consideration should be given to treating that partner empirically in order to prevent reinfection of the index patient.

Aggressive testing can be effective in reducing overall disease incidence over time. For example, Sweden mandated Chlamydia cultures for all patients with symptoms, and these efforts decreased the number of cases of chlamydial infection over a six-year period.[8] Although the number of patients screened in various settings increased gradually over the six-year period studied, the number of people with cultures positive for Chlamydia decreased. The largest decline in positive cases occurred in venereal disease clinics where, despite an increase in the number of examinations, the number of diagnosed cases of chlamydial infection declined by two-thirds. Private practitioners, whose patient population had a prevalence rate of less than 5 percent, had a 50 percent decrease in positive cases over six years.

Selective screening also decreased the rate of infection in a group of family planning clinics in the United States.[9] In that study, 136 clinics followed specific testing criteria that were consistent with the 1994 CDC guidelines. The overall rates for Chlamydia infection fell from 10.9 percent to 6.8 percent over a three-year period, with the highest rates of decrease occurring in women aged 30 or older.

Laboratory Testing

CULTURES

Culture is still considered the gold standard of chlamydial testing, with test specificity approaching 100 percent. Because Chlamydia cultures are highly specific, they should be used when a false-positive rapid test would be unacceptable, as in rape cases. Cultures are also suggested by the CDC for evaluation of symptomatic urethritis and proctitis in men or women.[1] The sensitivity of Chlamydia cultures was difficult to establish until nonculture tests were developed. A study using nonculture tests with a confirmatory assay showed that the sensitivity of Chlamydia cultures was 75 to 80 percent.[10] The variation in sensitivity may be the result of sampling techniques and the difficulty in transporting specimens at the appropriate temperature to a laboratory facility. Cultures are often more expensive (about $40) than nonculture tests, and results can take three to seven days to obtain.

NONCULTURE TESTS

Rapid nonculture diagnostic tests for Chlamydia are about as specific (96 to 99 percent) as cultures but are less sensitive (70 to 90 percent).[1] Nonculture methods used in the detection of Chlamydia include the direct fluorescence antibody (DFA) test, enzyme immunoassay (EIA) test and nucleic acid hybridization (DNA probe) test. The LET is a noninvasive initial screening test for urethritis.

DFA Test. In this test, the endocervical specimen is placed on a slide treated with a fluorescent monoclonal antibody that binds to the elementary body form of Chlamydia. The slide is viewed by fluorescent microscopy. This test requires experienced laboratory technicians and varies in sensitivity according to the experience of the technician.

EIA Test. This test detects Chlamydia antigen using an antibody labeled with an enzyme and color substrate. The results are measured by a spectrophotometer. Because the antibody reacts to any type of Chlamydia, a blocking agent is added to decrease the false-positive rate. EIA is less costly than culture, about $28.

DNA Probe Test. This test checks for chlamydial ribosomal RNA by linking luminescent DNA with rRNA. Among men with symptomatic urethritis, DFA and EIA tests have a specificity of 97 to 99 percent and a sensitivity rate of 70 percent with urethral swab.[1] DNA probe testing costs about $30.

Although the CDC still recommends that a positive LET or Gram stain result be confirmed by urethral culture. new research has found that using nonculture tests to confirm a positive LET or Gram stain result may be sensitive and cost-effective. In a recent study, asymptomatic males aged 12 to 35 who were recruited from a youth detention center, a teen clinic, a college health service and a military screening clinic underwent screening for Chlamydia.[11] Each site had a prevalence rate of 7 percent for asymptomatic chlamydial infection, as determined by culture. Gram stain of the first voided morning urine sediment demonstrated equivalent specificity and improved sensitivity over urethral cultures for detecting Chlamydia.

In another study using LET as a screening tool followed by EIA, LET was both adequately sensitive and demonstrated good cost-effectiveness as a screening tool in high-prevalence populations of asymptomatic males.[12]

Nettleman and associates[13] question the usefulness of obtaining confirmatory testing on symptomatic high-risk patients. In this study of 10,000 patients seen in an STD clinic, it was found that empiric treatment of all patients attending the clinic was more cost-effective than Chlamydia cultures. In a more recent study, Nettleman and Bell[14] used DFA as a screening test in pregnant women, and confirmed positive DFA results with cultures. Although the statistical results showed that screening all pregnant women for Chlamydia was not cost-effective, the excess cost of screening with DFA was considered modest compared with the cost of using cultures for screening.

In order to optimize the sensitivity of these chlamydial tests, the CDC recommends that the clinician remove all secretions from the cervix before obtaining the specimen. The clinician should then insert the plastic swab 1 to 2 cm into the endocervical canal and rotate it for 10 to 30 seconds. It is important not to touch the vaginal wall with the swab, because vaginal secretions may raise the false-positive rate of the nonculture test. Table 3 presents other specimen-handling issues that are important in optimizing the yield from these rapid detection technologies.

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Urinary tract Chlamydia screening tests include Gram staining urine for the presence of white blood cells, and LET. Both tests have been advocated by some as cost-effective initial screening tools for urethritis.[11,12] LET is a urine dipstick, which can be used in the office to detect white blood cells in a first-voided urine specimen. Both this test and urine Gram staining are sensitive for detecting infection, but are not specific for the presence of Chlamydia or for the site of infection. A urinary tract infection or gonococcal urethritis could also cause the test to be positive. Both tests are relatively rapid, and LET is inexpensive at about $8.

OTHER TESTS

Supplemental general laboratory tests, such as erythrocyte sedimentation rate (elevated) and serum white blood cell count (elevated) may be helpful. A serum pregnancy test and pelvic ultrasound examination may be useful to differentiate unilateral salpingitis from ectopic pregnancy. Chlamydia serology has not been proved useful in differentiating previous Chlamydia infections from current infections.

Treatment

Table 4 presents current treatment options for chlamydial infections. Doxycycline (Vibramycin) has historically been the drug of choice for chlamydial infections, with an oral dosage of 100 mg twice daily for seven days. It is very effective against Chlamydia and quite inexpensive. A standard course of therapy, with a generic drug, costs about $4.

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Azithromycin (Zithromax), in a single 1-g dose (four 250-mg capsules or one granular packet), offers the significant advantage of increased compliance but is more expensive than generic doxycycline. In a prospective, randomized controlled trial comparing doxycycline and azithromycin, both medications had similar cure rates (98 percent versus 96 percent) and similar side-effect profiles.,5 Side effects of both drugs include diarrhea, nausea, vomiting and abdominal pain. Ofloxacin (Floxin) or erythromycin are alternative medications. Ofloxacin, in a dosage of 300 mg every 12 hours for seven days, has a 93 percent cure rate.[16]

Neither doxycycline nor azithromycin are recommended for use in pregnant women. The drug of choice in pregnant women is erythromycin base (E-Mycin, Ery-Tab), in a dosage of 500 mg four times a day for seven days. If the patient is intolerant to erythromycin base at the 500-mg dosage, the physician may consider 250 mg four times daily for 14 days as an alternative dosage. Amoxicillin (Amoxil, Polymox, Wymox), at 500 mg three times daily for seven to 10 days, is an acceptable but less effective alternative for women who are unable to tolerate erythromycin base. Clindamycin (Cleocin) may also be an effective alternative.[17]

Hospitalization for intravenous therapy should be considered for women with a temperature above 38[degrees]C (100.4[degrees]F), who have peritonitis or pelvic abscesses, or who do not clinically respond to outpatient therapy. Intravenous cefoxitin (Mefoxin), 2 g every six hours, plus doxycycline, 100 mg every 12 hours (either intravenously or orally) is appropriate therapy in nonpregnant patients. Alternative regimens include clindamycin, 900 mg every eight hours, plus gentamicin (Garamycin), 1.5 mg per kg every eight hours until the patient is improved, followed by doxycycline, 100 mg orally twice daily, for a total of 14 days.[17] In hospitalized pregnant women, appropriate treatment is intravenous clindamycin or erythromycin and gentamicin until the patient is afebrile for 48 hours, followed by oral erythromycin, 500 mg every six hours, for a total of 14 days.

REFERENCES

[1.] Recommendations for the prevention an l management of Chlamydia trachomatis infections, 1993. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 1993;42(RR12):1-39. [2.] Holmes KK, Cates W Jr, Lemon SM, Stamm WE, eds. Sexually transmitted diseases. 2d ed. New York: McGraw-Hill, 1990. [3.] Kassler WJ, Cates W Jr. The epidemiology and prevention of sexually transmitted diseases. Urol Clin North Am 1992;19:1-12. [4.] Brunham RC, Paavonen J, Stevens CE, Kiviat N, Kuo CC, Critchlow CW, et al. Mucopurulent cervicitis--the ignored counterpart in women of urethritis in men. N Engl J Med 1984;311:1-6. [5.] Adimora AA. Sexually transmitted diseases. Companion handbook. New York: McGraw-Hill, 1994. [6.] Sellors JW, Mahony JB, Chernesky MA. Rath DJ. Tubal factor infertility: an association with prior chlamydial infection and asymptomatic salpingitis. Fertil Steril 1988;49:451-7. [7.] Stamm WE, Holmes K Chlamydial infections. In: Wilson JD, et al., eds. Harrison s Principles of internal medicine. 12th ed. New York: McGraw-Hill, 1991 :765-70. [8.] Herrmann BF, Johansson AB, Mardh PA. A retrospective study of efforts to diagnose infections by Chlamydia trachomatis in a Swedish county. Sex Transm Dis 1991;18:233-7. [9.] Britton TF, Delisle S, Fine D. STDs and family planning clinics: a regional program for chlamydia control that works. Am J Gynecol Health 1992;6(3):24-31. [10.] Biro FM, Reising SF, Doughman JA, Kollar LM, Rosenthal SL. A comparison of diagnostic methods in adolescent girls with and without symptoms of chlamydia urogenital infection. Pediatrics 1994; 93:476-80. [11.] Shafer MA, Schachter J, Moncada J, Keogh J, Pantell R, Gourlay L, et al. Evaluation of urine-based screening strategies to detect Chlamydia trachomatis among sexually active asymptomatic young males. JAMA 1993;270:2065-70. [12.] Genc M, Ruusuvaara L, Mardh PA. An economic evaluation of screening for Chlamydia trachomatis in adolescent males. JAMA 1993;270:2057-64. [13.] Nettleman MD, Jones RB, Roberts SD, Katz BP, Washington AE, Dittus RS, et al. Cost-effectiveness of culturing for Chlamydia trachomatis. A study in a clinic for sexually transmitted diseases. Ann Intern Med 1986;105:189-96. [14.] Nettleman MD, Bell TA. Cost-effectiveness of prenatal testing for Chlamydia trachomatis. Am J Obstet Gynecol 1991;164(5 Pt 1):1289-94. [15.] Martin DH, Mroczkowsh TF, Dalu ZA, McCarty J, Jones RB, Hopkins SJ, et al. A controlled trial of a single dose of azithromycin for the treatment of chlamydial urethritis and cervicitis. The Azithromycin for Chlamydial Infections Study Group. N Engl J Med 1992;327:921-5. [16.] Sanford JP, et al., eds. Guide to antimicrobial therapy, 1994. Dallas: Antimicrobial Therapy, Inc., 1994. [17.] Drugs for sexually transmitted diseases. Med Lett Drugs Ther 1994;36(913):1-6.

CATHRYN B. HEATH, M.D. is assistant professor of family medicine at State University of New York (SUNY) Health Science Center at Syracuse. She is a graduate of Hahneman University School of Medicine, Philadelphia, and completed a residency at St. Vincent Health Center family practice residency, Erie, Pa.

JOHN M. HEATH, M.D. is assistant professor of family medicine at SUNY Health Science Center at Syracuse. He is a graduate of Hahneman University School of Medicine, Philadelphia, and completed a residency at St. Vincent Health Center family practice residency, Erie. He also completed a fellowship in geriatrics at the University of Cincinnati College of Medicine.

Address correspondence to Cathryn Heath M.D. SUNY Health Science Center at Syracuse, 475 Irving Ave., Suite 200, Syracuse, NY 13210.

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