Laboratory Considerations for Male Chlamydia Screening

Men provide a reservoir for continued transmission of C. trachomatis to women, thus representing a population for potential targeted screening. There are no formal recommendations by professional organizations for screening men for chlamydia, however, guidance has been provided by the Centers for Disease Control and Prevention (CDC) for clinical sites wishing to screen men, who are primarily asymptomatic. This article describes and reviews the methods for laboratory diagnosis of Chlamydia trachomatis in men. The current recommendations for screening heterosexual men for chlamydia is using urine and testing by nucleic acid amplification tests (NAATs).

Chlamydia trachomatis is the most common reportable bacterial sexually transmitted disease in the United States, with estimates being 3-4 million new cases per year1. While most chlamydia-associated morbidity is in women, men provide a reservoir for continued transmission for new and recurrent infection among women, and thus represent a population for targeted screening, especially if they are asymptomatic2. The CDC has not made any formal recommendations for screening males for chlamydia, but has recently offered guidance for sites currently screening or planning to institute male screening3. The guidelines include jailed males over 30 years of age, males attending STD clinics, men attending Job Corps training, males in the military, and males in HIV clinics, as well as males entering juvenile facilities with >2% prevalence and males in emergency departments, high schools, and adolescent clinics with high chlamydia prevalences in the community3.

Clinicians have traditionally collected urethral swabs as the diagnostic specimen for detection of chlamydia and these may have posed a barrier for screening men. Now that urine-based nucleic acid amplification tests (NAATs) are available, these have been shown to perform better than urethral culture, enzyme immunoassay (EIA), direct fluorescent assay (DFA) or nucleic acid probe for detection of chlamydia4-10. The availability of non-invasive chlamydia testing should potentially lead to more widespread screening of asymptomatic males in the community2,11.

For men who have sex with men (MSM), rectal samples (and/or pharyngeal specimens for gonorrhea) may be the specimen of choice, as urethral swabs or urine samples may miss many infections; however these samples are not yet FDA cleared for NAAT assays, although some laboratories have performed verification studies and are using them. Pharyngeal swabs are not recommended for screening for chlamydia in men (or MSM) because of very low prevalences, but because many pharyngeal samples get tested for gonorrhea, positive pharyngeal chlamydia results may be returned to the clinician. Treatment should be given for such infections until we have further research to recommend otherwise.

Nucleic Acid Amplification Testing (NAAT)

Although older tests for the detection of chlamydia in men include culture in tissue culture cells, direct fluorescent antibody (DFA) tests, enzyme immunoassay (EIA), nucleic acid probe hybridization, only NAAT assays are now recommended for detecting chlamydia in men. NAAT assays include several available commercial tests; polymerase chain reaction (PCR), real time PCR, strand displacement hybridization (SDA), and transcription mediated hybridization (TMA). While all of these tests can be performed with urethral swabs, they are also FDA-cleared for use with first catch urine (FCU) samples. The NAATs are considered the most sensitive tests available. Urine is the specimen of choice when using NAAT assays because the sensitivity and specificity are not usually significantly different between urine and urethral swabs; urines may even be higher sensitivity. Urine specimens are recommended additionally because they are non-invasive and may result in more men being screened10.

Rapid, antigen point-of-care (POC) tests are not yet of sufficient sensitivity for use with urine specimens. Thus, the recommendation for screening symptomatic and especially asymptomatic men is to use a NAAT assay on a “first void” part (15-20 ml) of a urine (FVU) sample3.

Medico-legal Issues

The moderate to poor sensitivity of C. trachomatis culture limits its diagnostic utility and the need to obtain a urethral swab followed by extensive laboratory processing restricts it from use in screening. In contrast, C. trachomatis culture is recommended for medico-legal cases for detection of chlamydia in cases of investigations of sexual abuse due to its near perfect specificity12. The use of NAATs for medico-legal investigations has received some attention13,14 and the demonstrated accuracy may allow acceptance of these tests in the future by the legal system.

Patient Symptom Status

When men are symptomatic and are attending a clinic, they should receive a complete urogenital examination, with either urethral or urine samples obtained for diagnostic testing using the most sensitive and specific test available, i.e. a NAAT test, which has been recommended by the CDC as the test of choice15. When populations of asymptomatic men, who are non-health-care-seeking, are being screened, the use of non-invasive samples, such as urine, is recommended 3. Such samples eliminate the requirement for a clinician for sample collection and their use can be cost-effective, especially when surveying large numbers of persons16-24. When these non-invasive samples are used to screen asymptomatic persons for chlamydia, only a NAAT test can be used as none of the other older tests have high enough sensitivity.

Use of NAAT assays has the ability to influence the epidemiology of chlamydia in male population groups

The number of infections detected by NAAT may be up to 80% higher than those found with the use of older tests25,26. NAATs are quite accurate in screening asymptomatic men, even though the burden of bacterial load may be low16,17. A national household survey sample demonstrated a prevalence of chlamydia infection of 2.8%23. A large screening program in four cities in the U.S. demonstrated a chlamydia prevalence of 7% in mostly asymptomatic males2. High prevalence (4-5%) of chlamydia infections in male military recruits has been demonstrated17,24. Recent surveys of young adults and adolescents in the Adolescent Health Study originally enrolled in schools using NAAT technology also indicated substantial prevalence of chlamydia in men age 18-26 yr (overall, 3.67%; White men, 1.38%; Black men, 11.12%)16. A large city-wide school survey has indicated prevalence for males of 2.5%26. Screening in nontraditional settings such as the National Job Training Program for males has indicated that the overall chlamydia prevalence was 8.2%27. Detention centers, jails, urban shelters, community cohorts of injection drug users, and emergency departments have also been screened for chlamydia in men with prevalences as high as 14.3%-15% and encouraging results for a high proportion of infected men receiving treatment28-32.

Urine-based screening for chlamydia is also acceptable to males in screening settings17,33-34. Without NAAT testing of urine from males these studies would not have been performed. Increasing public health interest in screening males is an important prevention message to reduce reservoirs of infection available for transmission to females.

Other Laboratory Considerations

NAATS measure DNA or RNA rather than live organisms; therefore, care should be used in using amplification tests for test-of-cure assays. Residual nucleic acid from cells rendered non-infectious by antibiotic therapy may give a “positive” amplified test for up to 3 weeks after therapy, when the patient is actually cured of viable organisms35-36. Ordinarily, the CDC does not recommend a test-of-cure test for either men or women37. Additionally it is not necessary to confirm positive NAATs in screening populations of low prevalence38.

Cost Issues

NAATs assays are more expensive than older non-culture, non-amplified tests and are often too expensive for many public health programs. Studies in males have indicated they are cost-effective for preventing sequelae in women39-40. The high cost of NAATS relative to other FDA cleared technologies and competing responsibilities created difficulty the public health sector in implementing NAAT screening.

Summary

NAAT assays are the test of choice for testing males for chlamydia and urine is the specimen of choice. For those programs interested in testing males in various high-prevalence venues, guidance is available from the CDC3. Future research is needed to definitively make official recommendations for screening males.

Special thanks to Charlotte Gaydos, DrPh, International Union against Sexually Transmitted Infections (IUSTI), and The Johns Hopkins University for writing this brief. Information presented is adapted from the article “Laboratory Aspects of Screening Men for Chlamydia trachomatis in the New Millennium” by Gaydos CA, Ferrero DV, Papp J., published in Sex Transm Dis 35(11 suppl): S44-50, 2008.

References

  1. Centers for Disease Control and Prevention. Sexually transmitted disease surveillance, 2005. Atlanta, GA: U.S. Department of Health and Human Services, 2006. CDC. 2006.
  2. Schillinger JA, Chapman JB, Rietmeijer CA et al. Prevalence of Chlamydia trachomatis infection among men screened in four US cities. Sex Transm Dis. 2005;32:74-77.
  3. Centers for Disease Control and Prevention. Male Chlamydia Screening Consultation, March 28-29, 2006, Meeting Report. http://www cdc gov/std/chlamydia/ChlamydiaScreening-males pdf. 2007;accessed July 6, 2007:1-11.
  4. Jaschek G, Gaydos C, Welsh L, Quinn TC. Direct detection of Chlamydia trachomatis in urine specimens from syptomatic and asymptomatic men by using a rapid polymerase chain reaction assay. J Clin Microbiol. 1993;31:1209-1212.
  5. Shafer M, Schachter J, Moncada J et al. Evaluation of urine-based screening strategies to detect Chlamydia trachomatis among sexually active asymptomatic young males. JAMA. 1993;270:2065-20795.
  6. Chernesky MA, Chong S, Jang D, Luinstra K, Sellors J, Mahony JB. Ability of commercial ligase chain reaction and pcr assays to diagnose Chlamydia trachomatis infections in men by testing first void urine. J Clin Microbiol. 1997;35:982-984.
  7. Van Der Pol B, Quinn T.C., Gaydos CA et al. Evaluation of the AMPLICOR and Automated COBAS AMPLICOR CT/NG Tests for the Detection of Chlamydia trachomatis. J Clin Microbiol. 2000;38 :1105-1112.
  8. Van Der Pol B, Ferrero D, Buck-Barrington L et al. Multicenter evaluation of the BDProbeTec ET system for the detection of Chalmydia trachomatis and Neisseria gonorrhoeae in urine specimens, female endocervical swabs, and male urethral swabs. J Clin Microbiol. 2001;39:1008-1016.
  9. Marrazzo JM, Whittington WH, Celum CL et al. Urine-based screening for Chlamydia trachomatis in men attending sexually transmitted disease clinics. Sex Transm Dis. 2001;28:219-225.
  10. Chernesky MA, Martin DH, Hook EW 3rd et al. Ability of new APTIMA CT and APTIMA GC assays to detect Chlamydia trachomatis and Neisseria gonorrhoeae in male urine and urethral swabs. J Clijn Microbiol. 2005;43:127-131.
  11. Marrazzo JM, White CL, Krekeler B et al. Community-based urine screening for Chlamydia trachomatis with a ligase chain reaction assay . Ann Intern Med. 1997;127:796-803.
  12. Hammerschlag MR. Use of nucleic acid amplification tests in investigating child sexual abuse. Sex Transm Inf. 2001;77:153-154.
  13. Jespersen DJ, Flatten M, Jones MF, Smith TF. Prospective comparison of cell culture and nucleic acid amplification tests for laboratory diagnosis of Chlamydia trachomatis infections. J Clin Microbiol. 2005;43:5324-5326.
  14. Black CM, Driebe EM, Beck-Sague CM et al. Multi-center study of urogenital chlamydial infections in children evaluated for sexual abuse. Proceeding of the 11th International Symposium on Human Chlamydial Infections. 2006;Ontario, Canada:89-92.
  15. Centers for Disease Control and Prevention. Screening Tests To Detect Chlamydia trachomatis and Neisseria gonorrhoeae Infections–2002. MMWR. 2002;51 (No. RR-15):1-38.
  16. Miller WC, Ford CA, Morris M et al. Prevalence of chlamydial and gonococcal infections among young adults in the United States. JAMA. 2004;291:2229-2236.
  17. Arcari CM, Gaydos JC, Howell MR, McKee JKT, Gaydos CA. Feasibility and short-term impact of linked education and urine screening interventions for chlamydia and gonorrhea in male army recruits. Sex Transm Dis. 2004;31:443-447.
  18. Blake DR, Gaydos CA, Quinn TC. Cost-effectiveness analysis of screening adolescent males for Chlamydia trachomatis on admission to detention. Sex Transm Dis. 2004;31:85-95.
  19. Blake DR, Quinn T.C., Gaydos C.A. Should asymptomatic males be included in chlamydia screening programs? Cost-effectiveness of Chlamydia Screening Among Male and Female Entrants to a National Job Training Program. Sex Tansmit Dis. 2008;35:91-101.
  20. Wang LY, Burstein GR, Cohen DA. An economic evaluation of a school-based sexually transmitted disease screening program. Sex Tansmit Dis. 2002;29:737-745.
  21. Gift TL, Lincoln T, Tuthill R et al. A cost-effectiveness evaluation of a jail-based chlamydia screening program for men and its impact on their partners in the community. Sex Tansmit Dis. 2006;33 suppl:S103-S110.
  22. Chen H, Macaluso M, Vermund SH, Hook IEW. Relative accuracy of nucleic acid amplification tests and culture in detecting chlamydia in asymptomatic men. J Clin Micro. 2001;39:3927-3937.
  23. Mertz KJ, McQuillin GM, Levine WC et al. A pilot study of the prevalence of chlamydial infection in a national household survey. Sex Trans Dis. 1998;25:225-228.
  24. Cecil JA, Howell MR, Tawes JJ et al. Features of Chlamydia trachomatis and Neisseria gonorrhoeae infection in male army recruits. J Infect Dis. 2001;184:1216-1219.
  25. Schachter J. Chlamydia trachomatis: the more you look, the more you find – how much is there? Sex Transmit Dis. 1998;25:229-231.
  26. Black CM, Marrazzo JM, Johnson RE et al. Head -to-head multicenter comparison of DNA probe and nucleic acid amplification tests for Chlamydia trachomatis in women performed with an improved reference standard. J Clin Microbiol. 2002;40:3757-3763.
  27. Asbel LE, Newbern AC, Salmon M, Spain CV, Goldberg M. School-based screening for Chlamydia trachomatis and Neisseria gonorrhoeae among Philadelphia public high school students. Sex Tansmit Dis. 2006;33:614-620.
  28. Joesoef MR, Mosure DJ. Prevalence of Chlamydia in young men in the United Stated from newly implemented universal screening in a National Job Training Program. Sex Tansmit Dis. 2006;33:636-639.
  29. Mehta SD, Rothman RE, Kelen GD, Quinn T.C., Zenilman J.M. Clinical aspects of diagnosis of gonorrhea and Chlamydia infection in an acute care setting. Clin Infect Dis. 2001;32:655-659.
  30. Gaydos CA, Hardick J, Willard N et al. Screening asymptomatic males for Chlamydia trachomais and Neisseria gonorrhoeae in a detention center setting. Internat J STD & AIDS. 2001;12 (suppl 2):83-85.
  31. Mertz KJ, Schwebke JR, Gaydos CA, Beidinger HA, Tulloch SD, Levine WC. Screening women in jails for chlamydial and gonococcal infection using urine tests: Feasibility, acceptability, prevalence, and treatment rates. Sex Trans Dis. 2002;29:271-276.
  32. Plitt SS, Garfein RS, Gaydos CA, Strathdee SA, Sherman SG, Taha TE. Prevalence and correlates of Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis infections and bacterial vaginosis among a cohort of young injection drugusers in Baltimore, Maryland. Sex Trans Dis. 2005;32:446-453.
  33. Grimley DM, Annang L, Lewis I et al. Sexually transmitted infections among urban shelter clients. Sex Tansmit Dis. 2006;33:666-669.
  34. Marrazzo JM, Ellen JM, Kent C.K. et al. Acceptability of urine-based screening for Chlamydia trachomatis to asymptomatic young men and their providers. Sex Tansmit Dis. 2006;34:147-153.
  35. Monroe KW, Weiss HL, Jones M, Hook III EW. Acceptability of urine screening for Neisseria gonorrhoeae and Chlamydia trachomatis in adolescents at an urban emergency department. Sex Transmit Dis. 2003;33:850-853.
  36. Gaydos CA, Crotchfelt KA, Howell MR, Kralian S, Hauptman P, Quinn TC. Molecular amplification assays to detect chlamydial infections in urine specimens from high school female students and to monitor the persistence of chlamydial DNA after therapy. J Infect Dis. 1998;177:417-424.
  37. Workowski KA, Lampe MF, Wong KG, Watts MB, Stamm WE. Long-term eradication of Chlamydia trachomatis genital infection after antimicrobial therapy. JAMA. 1993;270:2071-2075.
  38. 38. Centers for Disease Control and Prevention. Sexually transmitted disease treatment guidelines 2006. MMWR August 4, 2006; 55 (No. RR-11):1-100. available at www.cdc.gov/std/treatment/2006/rr5511.pdf. (erratum published in the MMWR Weekly issue dated September 15, 2006, Vol. 55, No. 36. (accessed 02-28-07). CDC. 2007.
  39. Schachter J, Chow JM, Howard H, Bolan G., Moncada J. Detection of Chlamydia trachomatis by Nucleic Acid Amplification Testing: Our Evaluation Suggests that CDC-Recommended Approaches for Confirmatory Testing Are Ill-Advised. J Clin Microbiol. 2006;44:2512-2517.
  40. Blake DR, Gaydos CA, Quinn TC. Cost-effectiveness analysis of screening adolescent males for Chlamydia trachomatis on admission to detention. Sex Transm Dis. 2004;31:85-95.
  41. Blake DR, Quinn T.C., Gaydos C.A. Should asymptomatic males be included in chlamydia screening programs? Cost-effectiveness of Chlamydia Screening Among Male and Female Entrants to a National Job Training Program. Sex Transmit Dis. 2008;35:91-101.