Point-of-care diagnosis of STIs in women

Rapid diagnosis is the point of point-of-care (POC) testing, which eliminates the middleman (the centralized laboratory). By using it to detect sexually transmitted infections (STIs) on-the-spot, you can identify and treat patients sooner, preventing the spread of disease and reducing complications.^1,2 In fact, one in four tests are already being done at the site of patient care.³ These efficient tests are gaining wider acceptance because they have the potential to improve patient outcomes and significantly reduce errors and costs, with sensitivity and specificity that approach or exceed that of lab-based testing.

Delays in any of the steps traditionally involved in STI diagnosis and treatment can permit transmission to continue, increasing risk of complications, especially when patients don't return for care.⁴ And your own medicolegal risk may be increased if, for example, lab results are lost. POC testing also may have an impact on your office staff, because you'll need fewer employees to collect and collate test results and make follow-up phone calls to patients and pharmacies.

Point-of-care tests for common STIs

[Table 1 shows the sensitivity, specificity, time to results, and level of Clinical Laboratory Improvement Amendments (CLIA) complexity for currently available POC tests for genital herpes simplex virus type 2 (HSV-2), chlamydia, and gonorrhea.] Over-the-counter tests are available or being developed for some STIs, such as HIV, but home testing is not without its problems.⁵ Though HIV testing is beyond the scope of this article, rapid testing in labor and delivery has obvious potential advantages for women without prenatal care. Readers interested in learning more about POC testing for HIV should consult a study by Dewsnap and Mcowan.⁶ Whatever the suspected infection, consider POC testing after careful discussion with the patient and interpret test results within the overall framework of a detailed sexual history, physical examination, population prevalence of the disease, and diagnostic test performance characteristics.

Genital Herpes Simplex Virus Type 2. Most women with HSV have no symptoms, but it can cause painful ulcers that are recurrent but treatable. Type-specific antibodies to HSV develop during the first few weeks after infection and persist indefinitely. Accurate type-specific HSV serologic testing depends on detecting antibodies to two related but antigenically distinct viral envelope glycoproteins: gG-1 for HSV-1 and gG-2 for HSV-2.⁷ By distinguishing between HSV-2-which causes over 80% of recurrent genital herpes-and HSV-1, you can determine if a patient is at risk of acquisition or has evidence of prior infection with either subtype. However, recent evidence suggests that the epidemiology of genital herpes infection may be evolving. One research group studying college-aged men and women reported a reversal of the usual HSV-1/HSV-2 ratio over a 9-year period.⁸ The investigators observed a significant increase in the proportion of genital herpes infections linked with HSV-1 (from 31% in 1993 to 78% in 2001), and the trend was more pronounced in women and younger people.

Tests for type-specific antibodies have improved the accuracy of epidemiologic studies. The 2006 CDC treatment guidelines for STI recommend using type-specific testing based on IgG for diagnosis of genital herpes.⁹ They also recommend that "the serologic type-specific glycoprotein G (gG)-based assays should be specifically requested when serology is performed."⁹ Use of serology to establish a clinical diagnosis is reasonable, given the low sensitivity of culture (53%) and of antigen tests (51%) to detect HSV in recurrent lesions.^10,11 Moreover, nearly all patients with HSV-2 antibody have genital herpes, even if they have no symptoms when tested.

At this time, a rapid POC test for clinics is only available for HSV-2. In 1999 the FDA approved the POCkit HSV-2 POC test (Diagnology, Belfast, Northern Ireland), which can detect HSV-2 antibodies from capillary blood or serum in roughly 6 minutes during a clinic visit. The POCkit test has a median time to seroconversion of 2 weeks.¹² This "moderately complex" test can be performed in CLIA-certified settings. The POCkit HSV-2 test was briefly off the market and has been reintroduced under the names "biokitHSV-2 Rapid Test" (Biokit USA, Lexington, MA) and "Sure-Vue HSV-2 Kit" (Fisher Scientific International, Inc., Hampton, N.H.). A simpler version of the test designed for use in clinics or offices without CLIA accreditation, the POCkit HSV-2 holos, has been studied in trials, but its current status is unknown.

[A drawback of these tests is that the presence of HSV IgG antibodies doesn't differentiate latent from active infections.] Only culture can determine whether a suspicious lesion is due to HSV. A single sample won't allow you to discriminate between a true primary infection and a recurrence. Moreover, a misdiagnosis could occur if the test results are equivocal because of factors such as low titer antibodies during seroconversion, an inherently low titer antibody response, or technical artifacts.¹³ Finally, according to the biokitHSV-2 Rapid Test package insert, the test is intended for use in high-prevalence populations, such as STI clinics. False-positive results can occur, especially in low-prevalence settings.⁹ If you get a positive result with the test on a patient who has a low likelihood of HSV infection, consider the result presumptive and confirm it with an alternate method, such as Western blot. Because HSV-1 is the predominant serotype of genital herpes in certain regions of the country, relying on tests that only evaluate for HSV-2 can provide a false sense of security.¹⁴

[Despite its limitations, POC testing for HSV has several practical uses: (1) diagnosis of HSV infection in patients with atypical complaints; (2) identification of asymptomatic carriers; and (3) identification of individuals at risk for acquiring new HSV infections.] It can also identify pregnant women with HSV-2 who have no symptoms but are at risk for shedding at delivery, reducing potential vertical transmission. Strategies for using the test results in this setting, however, are still limited. Because false-negative HSV cultures are common, especially in patients with recurrent infection or healing lesions, type-specific serologic tests may be useful in confirming a clinical diagnosis of genital herpes with HSV-2.⁹ The CDC recommends that practices that provide care for patients who have STIs or are at risk of the infections make available both virologic and type-specific serologic tests for HSV.⁹ HSV testing may also be appropriate in prenatal and HIV clinics.¹⁵

Chlamydia. Perhaps the best evidence for chlamydia screening comes from a well-designed randomized, controlled trial that showed a 56% reduction in pelvic inflammatory disease (PID) in women who were screened and treated, compared to those in the usual-care group.¹⁶ The need for POC testing for chlamydial infections is supported by studies indicating that most women who test positive for Chlamydia trachomatis during screening are not treated within 2 weeks of their initial screening visit.^17,18 Rapid tests for C trachomatis can be performed on endocervical swabs within 30 minutes, don't require costly or sophisticated equipment, and are packaged as single units.¹⁹ The results are read qualitatively.

POC tests for chlamydial infection are usually more expensive and are thought to have lower sensitivity than their less-rapid laboratory-based counterparts. POC tests for C trachomatis include solid-phase enzyme immunoassays (EIA) and a solid-phase optical immunoassay. Like EIAs, these tests use antibodies against lipopolysaccharide (LPS) that detect all three Chlamydia species that infect humans, and have the same potential for false-positive results caused by cross-reactions with other microorganisms. The antibodies directed at the LPS may cross-react with the LPS of other Gram-negative organisms (e.g., Escherichia, Klebsiella, and Enterobacter species) and therefore produce false-positive results.²⁰ Though POC tests for C trachomatis are less sensitive than lab-based tests, they should be considered in situations where screening-test-positive persons might fail to return for treatment or return after substantial delays.

Gonorrhea. The reliability of POC tests for Neisseria gonorrhoeae in women is limited. In men, Gram's stain is most dependable for rapid identification of N gonorrhoeae in urethral exudates. In women, however, microscopic identification of Gram's-stained endocervical specimens has a sensitivity of only about 60%, and a skilled microscopist is necessary to achieve adequate specificity in women. Gram's stain for gonorrhea is not typically performed in the office and is not currently recommended for testing women for N gonorrhoeae infection.²¹ Accurate, reliable modes of POC testing for gonorrhea infection in women are still pending.

How does predictive value relate to disease prevalence?

To evaluate POC test results, it's critically important to understand how their accuracy is measured and applied. Results typically are reported in terms of sensitivity, specificity, and positive and negative predictive values. Most clinicians know the definitions for these characteristics, but the concepts aren't always correctly applied to patients.²² For a brief review of the relevant epidemiologic concepts, see the box-along with a bonus table-on the Contemporary OB/GYN Web site at http://www.contemporaryobgyn.net). The discussion explains why, in general, if treatment is inexpensive and side effects are rare, [it's more important for tests to have high sensitivity than high specificity.²³]

Test performance characteristics

Sensitivity of a test: the probability that the test will correctly identify an individual with disease as positive.

Specificity of a test: the probability that a nondiseased individual will be correctly identified as negative.

In effect, these measures are asking, if we screen a population, what proportion of people who have the disease will be correctly identified? In the clinical setting, a different question may also be important, namely, if a patient tests positive, what is the probability that she has the disease?

Positive predictive value: the probability that a positive test correctly indicates that the person tested is infected.

Negative predictive value: the probability that a negative test correctly indicates that the person tested is uninfected.

Notably, unlike the sensitivity and specificity of the screening test, which can be considered intrinsic characteristics of the test itself, the predictive value depends on the prevalence of the disease in the population tested and, for infrequently occurring diseases, the specificity of the test being used. As noted, generally speaking, if treatment is cheap and side effects are rare, it's more important for tests to have high sensitivity than a high specificity.²²

In certain settings with low disease prevalence, the disease probability from a given diagnostic test result may be grossly overestimated. Thus, in practice, it becomes even more critical to understand how the predictive values of a diagnostic test are affected by the true proportion of diseased individuals in the population being screened, the specificity of the test, and (to a lesser extent) the sensitivity of the test.

Table A illustrates how the positive predictive value of POC diagnostic tests for the STIs we've discussed may differ considerably based on the prevalence of disease in the population. For example, a POC test for HIV applied to a population of heterosexual STI clinic attendees with a 2.3% HIV prevalence yields a positive predictive value of 88.8%, compared to only 25% when applied to the general population with a 0.1% HIV prevalence. In effect, when applied to the general population, only one-fourth of positive HIV POC tests correctly indicate that the person tested is infected. Screening the general population for a relatively infrequent disease can waste resources and may yield few previously undetected cases for the amount of effort involved. However, if a high-risk subset can be identified and the test can be targeted to this population, the screening program is likely to be more productive and efficient. In addition, a high-risk population may be more motivated to participate in a screening program and be more likely to act upon recommendations if their screening results are positive.

POC testing regulations

As more diagnostic testing shifts to the bedside and gains popularity with clinicians, adequate safeguards must be put into place to prevent medical errors and reduce risk.²⁴ How frequently POC testing is associated with serious medical errors is unknown.²⁵ Given the technology's rapid growth, we must make an effort to detect and prevent errors, even if only a fraction of them actually cause significant harm.²³ POC testing regulations have stemmed from concerns over quality and the risk of medical consequences.²⁶ The 1988 CLIA regulations set quality standards for all lab testing, regardless of where the test is performed.²⁷

Categorizing commercially marketed in vitro diagnostic tests under CLIA is now the Food and Drug Administration's purview. The agency has assumed chief responsibility for CLIA complexity categorization functions, including assigning in vitro diagnostic test systems to one of three CLIA regulatory categories based on potential public health risk: (a) waived tests; (b) tests of moderate and (c) high complexity. ["Moderate complexity" tests are subject to specific personnel requirements and particular activities and are required to ensure quality.] In addition, labs certified to run moderate complexity tests must be inspected every other year. By contrast, tests waived from the CLIA requirements are considered so simple and accurate that there's little risk of an incorrect result. Five times as many labs can run CLIA-waived tests (vs. the "moderate complexity" certified labs). Bottom line: a CLIA waiver means a test will be more widely available. Personnel standards, quality control, quality assurance, and proficiency testing requirements apply when performing FDA-cleared STI tests that are rapid enough to qualify as POC tests.

POC testing in nontraditional settings

POC testing is used in several nontraditional settings, where urgent medical circumstances dictate fast turnaround or patients have a tendency not to return for test results. POC testing may be a fruitful way to reach out to individuals disproportionately impacted by the STI epidemic who are less likely to access STI treatment in traditional health-care settings. Such settings include prisons, juvenile detention centers, drug or alcohol programs, syringe exchange programs, homeless shelters, adolescent health clinics with high STI rates, drop-in centers for homosexual youth, and clinics dedicated to specific populations, such as migrant workers.²⁸

Future directions

When used appropriately, POC diagnostic testing can improve patient outcomes because of the immediate availability of critical test results and fast turnaround in treatment. POC tests offer several advantages in scenarios where it would be difficult to ensure a high return rate, and in groups that are very likely to continue to transmit STIs during the delay in treatment associated with lab-based STI tests. Even patients who do return for lab results may transmit STIs to others in the interval after being tested. Some POC tests are just as effective as more sensitive laboratory tests. But the technology does have limitations. POC diagnostic testing outside the clinical lab might contribute to serious medical errors due to poorly trained or uncertified operators, poor security of test results and quality control data, and limited access to electronic medical records.^1,2,24,29 In addition, you would think that removing from specialized clinics testing for infections that carry a stigma-like STIs-would be a good thing. But doing so may actually lead to a rise in depression, suicide, and a violent reaction from a patient's sex partner to the news of her STI-violence that might have been averted with an appropriate counselor present to filter and interpret the results. POC tests typically cost more than tests designed for lab use, and because of their relative insensitivity, the cost benefit of immediate results is lost if processing is done after the patient visit. Before implementing POC testing, compare the sensitivity, disease prevalence, cost, and treatment rate for these diagnostics to laboratory testing and ask yourself whether the benefits of treating patients who would otherwise not receive care outweighs the additional costs and less-favorable sensitivity of testing in the office. The cost-effectiveness of POC testing strategies also needs to be considered in the context of existing public health resources.

Newer technologies may permit POC testing with PCR at the bedside (fluorescent PCR with microfluidics), which could expand the capabilities of rapid microbiologic testing way beyond current levels. The FDA has recently approved a rapid GBS test that can be performed at the bedside in approximately 90 minutes. The Cepheid Xpert GBS assay can be used to rapidly diagnose women with unknown GBS status who present in labor and is moderately complex from a CLIA standpoint. Trials currently are under way using other rapid group B streptococcus testing in laboring women that may have substantially shorter turnaround time (30 to 45 minutes.) If these tests prove to be sufficiently sensitive and specific and provide very quick results, management algorithms may one day focus on testing laboring women for GBS and treating those with positive results, rather than testing at 35 to 37 weeks. In addition, using results of rapid testing in laboring women with unknown GBS may prevent the presumptive treatment of hundreds of thousands of pregnant women who are GBS negative.

POC testing has reached everyday practice, and with it the possibility of practicing more efficiently with fewer resources and faster results. The most important potential benefit of these diagnostics, however, is improved patient outcomes. Compared to traditional testing, POC testing can eliminate unnecessary treatment of noninfected individuals, reducing the likelihood of antibiotic resistance, and foster rapid identification and treatment of women early in the course of infection, which should prevent complications.

DR. PATEL is a Research Investigator, and DR. PEARLMAN is S. Jan Behrman Professor in Reproductive Medicine and Vice Chair and Service Chief, Obstetrics and Gynecology, as well as Associate Chief of Staff at University of Michigan Hospitals, Ann Arbor, Mich.

REFERENCES

1. Kost GJ. Guidelines for point-of-care testing. Improving patient outcomes. Am J Clin Pathol. 1995;104:S111-S127.

2. Kost GJ, Ehrmeyer SS, Chernow B, et al. The laboratory-clinical interface: point-of-care testing. Chest. 1999;115:1140-1154.

3. Stephans EJ. Developing open standards for point-of-care connectivity. IVDT Technology. 1999;5:22-25.

4. Ward H, Mertens TE, Thomas C. Health seeking behaviour and the control of sexually transmitted disease. Health Policy Plan. 1997;12:19-28.

5. Anonymous. FTC: home-use tests for HIV can be inaccurate. AIDS Policy Law. 2004;19:3.

6. Dewsnap CH, Mcowan A. A review of HIV point-of-care tests. Int J STD AIDS. 2006;17:357-359.

7. Morrow RA, Friedrich D. Inaccuracy of certain commercial enzyme immunoassays in diagnosing genital infections with herpes simplex virus types 1 or 2. Am J Clin Pathol. 2003;120:839-844.

8. Roberts CM, Pfister JR, Spear SJ. Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students. Sex Transm Dis. 2003;30:797-800.

9. Sexually transmitted diseases treatment guidelines 2006. Centers for Disease Control and Prevention. MMWR Recomm Rep. 2006 Aug 4;55(RR-11):1-94.

10. Lafferty WE, Krofft S, Remington M, et al. Diagnosis of herpes simplex virus by direct immunofluorescence and viral isolation from samples of external genital lesions in a high-prevalence population. J Clin Microbiol. 1987;25:323-326.

11. Wald A, Zeh J, Barnum G, et al. Suppression of subclinical shedding of herpes simplex virus type 2 with acyclovir. Ann Intern Med. 1996;124:8-15.

12. Ashley RL, Eagleton M, Pfeiffer N. Ability of a rapid serology test to detect seroconversion to herpes simplex virus type 2 glycoprotein G soon after infection. J Clin Microbiol. 1999;37:1632-1633.

13. Ashley RL. Performance and use of HSV type-specific serology test kits. Herpes. 2002;9:38-45.

14. U.S. Centers for Disease Control and Prevention. Tracking the hidden epidemics. Trends in STDs in the United States 2000.

15. Wald A, Ashley-Morrow R. Serological testing for herpes simplex virus (HSV)-1 and HSV-2 infection. Clin Infect Dis. 2002;35:S173-S182.

16. Scholes D, Stergachis A, Heidrich FE, et al. Prevention of pelvic inflammatory disease by screening for cervical chlamydial infection. N Engl J Med. 1996;334:1362-1366.

17. Hook EW 3rd, Spitters C, Reichart CA, et al. Use of cell culture and a rapid diagnostic assay for Chlamydia trachomatis screening. JAMA. 1994;272:867-870.

18. Schwebke JR, Sadler R, Sutton JM, et al. Positive screening tests for gonorrhea and chlamydial infection fail to lead consistently to treatment of patients attending a sexually transmitted disease clinic. Sex Transm Dis. 1997;24:181-184.

19. Rani R, Corbitt G, Killough R, et al. Is there any role for rapid tests for Chlamydia trachomatis? Int J STD AIDS. 2002;13:22-24.

20. False-positive results with the use of chlamydia tests in the evaluation of suspected sexual abuse-Ohio, 1990. MMWR Morb Mortal Wkly Rep. 1991;39:932-935.

21. Johnson RE, Newhall WJ, Papp JR, et al. Screening tests to detect Chlamydia trachomatis and Neisseria gonorrhoeae infections-2002. MMWR Recomm Rep. 2002;51:1-38; quiz CE1-4.

22. Steurer J, Fischer JE, Bachmann LM, et al. Communicating accuracy of tests to general practitioners: a controlled study. BMJ. 2002;324:824-826.

23. Mabey D, Peeling RW, Perkins MD. Rapid and simple point of care diagnostics for STIs. Sex Transm Infect. 2001;77:397-398.

24. Kost GJ. Preventing medical errors in point-of-care testing: security, validation, safeguards, and connectivity. Arch Pathol Lab Med. 2001;125:1307-1315.

25. Witte DL, VanNess SA. Frequency of unacceptable results in point-of-care testing. Arch Pathol Lab Med. 1999;123:761.

26. Nichols JH. Quality in point-of-care testing. Expert Rev Mol Diagn. 2003;3:563-572.

27. U.S. Food and Drug Administration. CLIA - Clinical Laboratory Improvement Amendments, 2005.

28. CDC Revised guidelines for HIV counseling, testing, and referral. MMWR Recomm Rep. 2001;50:1-57.

29. Kilgore ML, Steindel SJ, Smith JA. Continuous quality improvement for point-of-care testing using background monitoring of duplicate specimens. Arch Pathol Lab Med. 1999;123:824-828.