Ahrens, Katherine MPH*; Bradbury, K Jayne MPH*; Bauer, Heidi M. MD, MPH*; Samuel, Michael C. DRPH*; Gould, Gail*; Donatoni, Giannina PhD†; Higgins, Chandra MPH†; Kerndt, Peter MD, MPH†; Bolan, Gail MD, MPH*
Diagnostic testing is an essential component of successful sexually transmitted disease (STD) control programs as it ensures definitive diagnosis in symptomatic patients and facilitates screening in asymptomatic individuals. Clinical laboratories are the cornerstone of public health efforts to effectively identify STDs and conduct disease surveillance. Although California regulations require both health care providers and laboratories to report persons testing positive for selected STDs, the majority of disease reports are initially received from laboratories.1,2 In addition, laboratory technicians have expertise in test technologies, interpretation of results, and use and limitations of specific test types, therefore playing an important role in educating clinicians about diagnostic quality assurance and performance issues.
Monitoring levels of testing, laboratory practices, and trends in the use of technology enhances STD control efforts by improving the interpretation of STD trends, creating valuable partnerships with laboratories, facilitating the evaluation of screening programs, and investigating outbreaks.3–5 The increase in use of more sensitive tests for chlamydia screening and diagnosis provided a partial explanation for local and national increases in chlamydia incidence.6 Further, partnerships with laboratories and electronic data transmission have enabled broad-based prevalence monitoring at family planning clinics.7 Documenting trends in STD test volume and the use of superior diagnostic tests enables the evaluation of compliance with current STD test recommendations.8,9 In addition, these data aid in the examination of aberrations in disease detection that may result from an increase in false positives caused by a loss of test specificity or cross-contamination. Knowing laboratory capacity to perform culture and susceptibility testing is essential for investigating treatment failures and suspected outbreaks of drug-resistant gonorrhea.
In 1985, the Centers for Disease Control and Prevention (CDC) first recommended routine collection of laboratory testing information as part of STD surveillance activities.10 In 2002, the CDC updated this recommendation, and provided the California survey instrument as a template.11 Key findings from the California Annual Clinical Laboratory Survey from 1996 to 2003 are described here.
Respondents and Recruitment
The California Annual Clinical Laboratory Survey is a cross-sectional, self-administered survey of laboratory services and practices among licensed clinical laboratories in California that reported performing STD tests. The California Department of Health Services STD Control Branch (CA STD) and Los Angeles County (LAC) Department of Health Services STD Program (LA STD) have jointly administered the survey since 1996. That year, surveys were mailed to the laboratory directors of all laboratories licensed with the California Department of Health Services Laboratory Field Services. In subsequent years through 2002, except 1998 when the CA STD did not implement the annual survey, CA STD surveyed all California laboratories (excluding LAC laboratories) that reported STD testing in the previous year. In addition, all laboratories for which no STD testing information was known from previous years as well as newly licensed laboratories were surveyed each year. In 2003, CA STD resurveyed all licensed laboratories in California (excluding LAC laboratories) to include laboratories that may have started conducting STD testing. For all survey years, 1996 through 2003, LA STD surveyed laboratories in LAC that performed STD testing, as determined by contacting all licensed laboratories in LAC or through collaboration with a knowledgeable local laboratory consultant. Survey participation was voluntary and no incentives were offered. Because the survey was considered a component of routine public health assessment activities, formal human subjects research review was not sought. Only data collected by both CA STD and LA STD in the years 1996 through 2003 were included in the analysis.
Procedures for follow-up varied by year and by survey administrator. In general, for laboratories outside of LAC, nonrespondents received up to three telephone calls and a site visit. In 2002, staff shortages necessitated only minimal follow-up efforts, with nonrespondents receiving between zero and two phone calls. In 2003, nonrespondents received up to eight telephone calls but no site visits. For all survey years, nonrespondents in LAC received telephone calls and site visit follow-up.
Data Collection and Test Technologies
CA STD and LA STD jointly designed the survey instruments based on an original template developed by LA STD. The instrument included questions on the volume and types of tests for chlamydia, gonorrhea, syphilis, chancroid, human immunodeficiency virus (HIV), hepatitis B, herpes simplex virus (HSV), and human papillomavirus (HPV); other laboratory practices including gray zone analyses and verification testing for chlamydia and antibiotic resistance testing for gonorrhea were assessed. The survey did not distinguish between tests that were conducted on specimens from within the state of California and those that were conducted on out-of-state specimens. Test types were added or deleted throughout the survey years in response to changes in the availability and introduction of new FDA-cleared test technologies. Open-ended questions were included for all diseases to allow respondents to indicate their use of technologies not specifically listed on the survey.
Data were collected on the following chlamydia test types: culture, direct fluorescent antibody (DFA), enzyme immunoassay (EIA), DNA probe assays (Gen-Probe PACE® 2, Digene Hybrid Capture® II), nucleic acid amplification tests (NAATs) (Abbott Laboratories LCx®, Roche Amplicor®, Gen-Probe AmpCT/APTIMA®, and Becton-Dickinson BDProbeTec® ET). Data on verification practices for positive EIA and DNA probe tests were collected since 1997; confirmation and repeat testing of chlamydia results in the gray zone was also assessed since 2000. Data collected on gonorrhea test types included Gram stain, culture, DNA probe (as above), and NAATs (as above). Data on β-lactamase testing at laboratories performing gonorrhea cultures were collected since 2001.
Data collected on syphilis test types included nontreponemal serology tests (rapid plasma reagin (RPR) and Venereal Disease Research Laboratory (VDRL)), treponemal serology tests (fluorescent treponemal antibody absorption (FTA-Abs), Treponema pallidum particle agglutination (TP-PA), microhemagglutination assay Treponema pallidum (MHA-TP), and Captia Syphilis-G® EIA), darkfield, and direct fluorescent antibody Treponema pallidum (DFA-TP). The survey distinguished between qualitative nontreponemal serology tests, generally used for screening, and quantitative nontreponemal serology tests generally used to assess titer level and response to treatment. Starting in 1997, data on laboratory practices of ruling out prozone reaction or diluting “rough” RPR positive tests were collected. Chancroid tests included culture.
Data were collected on the following HIV test types: serum EIA, oral EIA, urine EIA, qualitative polymerase chain reaction (PCR), Western Blot, and immunofluorescent assays (IFA). Related tests included viral load testing and CD4 counts. Hepatitis B tests included surface antigen serology tests only. Data collected on HSV test types included culture, IFA, DFA, HSV-2 type-specific IgG and IgM serology tests (Focus Technologies HerpSelect®), HSV nontype-specific serology tests, and unspecified serology tests. Data collected on HPV tests included hybrid capture DNA assays (Digene Hybrid Capture System® and Digene Hybrid Capture II®).
Data were also collected on laboratory facility type. Categories included free-standing private, health maintenance organization, blood bank, public health, nonprofit hospital, private hospital, and other laboratories.
Response rates were calculated for each year by dividing the number of laboratories that responded and reported STD testing by the number of laboratories that were considered eligible or potentially eligible. Eligible laboratories included those known to perform STD testing; potentially eligible laboratories included those with unknown STD testing status. Laboratories that responded to the survey but did not perform STD tests were considered ineligible. Discrepancies and anomalous test volumes were investigated via telephone follow-up and appropriate corrections were made to the data. For the years in which LA STD and CA STD surveys were not identical, tests listed as other were recoded to reflect consensus categories.
The volume of tests performed for each STD was summed by test technology and then compared between years. Similar test technologies were grouped together for analysis: NAATs for chlamydia and gonorrhea, syphilis nontreponemal serology tests, HSV-2 type-specific serology tests, and HIV EIA tests. CD4 counts and HIV viral load tests were analyzed separately because they are primarily used for clinical management and not for diagnostic purposes. Quantitative nontreponemal serology tests were also excluded from this analysis because it was impossible to distinguish those that were being used for diagnostic testing and those being used to assess titer level and response to treatment. Test volume and practices were summarized and compared by facility type over time. For select analyses, trends were assessed specifically among public health laboratories. Data were analyzed using SAS statistical software (SAS Institute, version 9.1, Cary, NC).
The response rate by year ranged from 77% to 99% (Table 1). Response rates for LAC laboratories were higher than the rest of California (average 97.3% vs. 88.9%). From 1996 to 2003, the total number laboratories in California that conducted STD testing decreased 31% from 734 to 508, whereas the total number of reported chlamydia, gonorrhea, and syphilis tests increased from 8.1 million to 9.3 million (Table 1). From 2002 to 2003, there was only a 4% increase in test volume even though the response rate increased from 77% to 92% and the number of laboratories reporting testing increased from 384 to 508 between these years. Chlamydia, gonorrhea, syphilis, HIV, and hepatitis B each accounted for approximately 20% of all STD tests each year since 1999; HSV and HPV accounted for 0.1% to 3.0% of STD tests.
The majority of STD testing was conducted in a relatively small number of private laboratories. In 2003, nonpublic health laboratories conducted 92.9% of all STD tests combined. Between 1996 and 2003, free-standing private laboratories (a subset of private laboratories) accounted for increasing proportions of total STD testing (40.9% in 1996 to 47.8% in 2003). In contrast, public health laboratories conducted only 7.1% to 10.4% of all STD testing over the survey years. From 1996 to 2003, the high-volume laboratories conducted an increasing majority of tests. The proportion of all STD tests reported by the 50 largest laboratories increased from 70.1% to 79.8% from 1996 to 2003. Further, the proportion of STD tests reported by the 10 largest laboratories increased from 42% to 48% over the same time period.
The number of chlamydia tests increased steadily over the years surveyed from 2.2 million in 1996 to nearly 3.0 million in 2003 (Fig. 1). Since the introduction of NAATs in the mid-1990s, the use of this technology increased from 4.9% of all chlamydia tests in 1996 to 66.3% in 2003. Among public health laboratories, NAATs use increased from 29.4% to 98.5% over this same time period. DNA probe testing decreased from a high of 61.0% of tests in 1999 to 30.4% in 2003. The use of EIA, DFA, and other less sensitive technologies decreased steadily from 33.8% in 1996 to 1.6% in 2003. Culture accounted for less than 5% of chlamydia tests each survey year. Among the laboratories performing EIA tests for chlamydia, the percentage that reported EIA verification ranged widely from 3.3% to 45.2%, with no apparent trend over time. Among laboratories performing DNA probe testing, the percentage reporting DNA probe verification decreased from 44.0% in 1997 to 13.9% in 2003. Additionally, of the laboratories that reported DNA probe testing, most reported confirming or repeating test results that were in the gray zone, ranging from 90.2% in 1999 to 76.6% in 2002; however, of these laboratories, only a minority reported using a different test to confirm findings in the gray zone, ranging from 18.4% in 2002 to 26.1% in 2000. There was no apparent trend over time.
The number of gonorrhea tests increased from 2.1 million in 1996 to 3.0 million in 2003 (Fig. 2) mirroring the trend for chlamydia testing. Gonorrhea test technologies shifted during this period; the use of culture decreased from 42.3% of all gonorrhea tests in 1996 to 10.3% in 2003 while NAATs increased from 0.6% to 59.0%. Among public health laboratories, NAATs use increased from 1.7% to 85.0% over this same time period. DNA probe testing decreased from a peak in 1999 of 59.7% to 28.8% in 2003. From 1996 to 2003, the proportion of laboratories reporting culture testing decreased from 69.8% to 58.5% overall and from 81.8% to 60.5% in public health laboratories. Over half (59.3%) of laboratories that performed gonorrhea culture reported β-lactamase testing in 2003.
The number of syphilis tests decreased from nearly 3.8 million in 1996 to approximately 3.3 million tests each year since 1999 (Table 1). Nontreponemal tests comprised the majority of syphilis tests, accounting for 81.7% to 92.3% of total syphilis tests each year, with no apparent trend. The proportion of laboratories that performed nontreponemal tests in 1997–2003 that reported diluting out inconclusive, or rough, negative tests to rule out prozone reactions varied by year: 48.2% in 1997 to a peak of 64.7% in 2001 to only 45.3% in 2003.
With the exception of 1997, fewer than 300 chancroid tests were reported each year (Table 1). All chancroid tests performed were cultures.
The number of HIV tests increased from 2.4 million in 1996 to 3.1 million in 2003; however, the test volume was relatively constant after 1999 (Table 1). The majority of these tests were serum EIA tests. Hepatitis B surface antigen test volume was relatively constant at approximately 2.6 to 2.8 million tests each year.
The number of HSV tests generally increased over the survey years (Table 1). Direct antigen and culture testing both decreased between 1997 and 2003 (61.5% to 32.3% and 12.4% to 4.1%, respectively). Concurrently, serological testing increased from 35.3% of tests in 1996 to 63.5% of tests in 2003. From 1999 to 2002 the majority (62.0–92.7%) of serological tests were HSV-2 type specific; however, in 2003 less than half (46.3%) of serologic tests were type-specific. Removing an anomalous laboratory in 2003, raised the type-specific test proportion to 82%. The number of HPV tests also increased over the survey years. Over 99.8% of HPV tests in 2003 were Hybrid Capture II DNA assays.
Analysis of the California Annual Clinical Laboratory Survey data demonstrated that STD testing, particularly chlamydia, gonorrhea, and HIV, increased in California between 1997 and 2003; testing was increasingly concentrated in high volume laboratories; private laboratories conducted the majority of STD testing; and laboratories shifted away from culture and nonamplified tests in favor of NAATs for chlamydia and gonorrhea testing. Test volume trends demonstrated decreased syphilis testing, level hepatitis B testing, and infrequent but increasing HSV and HPV testing. Verification testing for chlamydia EIA and DNA probe assays was not widespread while unnecessary β-lactamase testing of gonococcal isolates was common. Gray zone testing declined slightly between 2000 and 2003, however repeat gray zone testing remained high.
Close collaborations with laboratories are essential as we advance electronic reporting of case data and prevalence monitoring projects. Between 1996 and 2003, the number of laboratories that conducted STD testing dropped by nearly a third, while the overall reported volume of STD testing increased. This consolidation of laboratories may pave the way for more efficient communication between health departments and laboratories since 80% of STD testing is conducted in the 50 highest volume laboratories. Further, the majority of testing was conducted by private laboratories. The shift towards commercial laboratories emphasized the importance of establishing linkages between health departments and nonpublic health laboratories to optimize laboratory technologies and practices. This finding also underscores the limitations of the recent national public health laboratory survey, at least in its applicability to STD testing in California.5 While we found public health laboratories to report adopting new testing technologies at a greater frequency than private laboratories, further comparison of public versus private laboratories is needed.
The increase in chlamydia and gonorrhea testing in California likely reflected increases in screening, particularly in response to managed care efforts to improve the Health Plan Employer Data and Information Set (HEDIS) measure established in 1999 for chlamydia screening of sexually active women 15–25 years of age.12 The parallel increases in gonorrhea testing likely resulted from the availability of combined chlamydia and gonorrhea tests. Because of their superior sensitivity, NAATs are recommended for chlamydia screening8 and our data demonstrated that NAATs have been widely implemented. NAATs are approved for noninvasive specimens such as urine and vaginal swabs as well as endocervical and urethral swabs, which facilitates screening in asymptomatic men and screening in nonclinical settings.13 This expanded screening combined with the enhanced diagnostic sensitivity may partly explain the increase in chlamydia incidence in California. Multiple factors led to the increase in NAAT use, including promotion by the California Chlamydia Action Coalition.14 Despite recommendations by the National Chlamydia Laboratory Committee,15 our data showed no increase in EIA verification over time, a decrease in DNA probe verification of positive results, and a consistently small percentage of laboratories that reported confirming test results in the gray zone with a different test type. Lack of verification testing further compromises the performance of these nonamplified chlamydia tests.
The decline in the use of culture-based diagnostic testing for gonorrhea may significantly hinder the ability of laboratories in California to monitor antimicrobial susceptibilities to recommended treatments. This observation has been documented in other local and national laboratories surveys.4,5 Resistance monitoring in California is particularly important due to widespread fluoroquinolone resistant strains that limit gonorrhea treatment options.16–18 Recent developments in nucleic acid based technology that allow for nonculture based antimicrobial resistance testing may provide alternatives to culture.19 Despite surveillance data showing that penicillin-resistant gonorrhea is endemic in the United States and California,20 over half of laboratories performing gonorrhea cultures reported β-lactamase testing of isolates.
Our finding that syphilis, HIV, and hepatitis B testing accounted for nearly two thirds of STD testing each year was likely related to routine screening (e.g., blood banking, prenatal care, and military in-take). Reasons for the decrease in syphilis test volume between 1996 and 1999 are unclear; however, they may be partly related to declines in survey response rate. Although there was an increase in syphilis among men who have sex with men (MSM) in California starting in 2000,21,22 an increase in screening was not discernible from the survey data. Interpretation of syphilis testing trends is limited by the exclusion of quantitative nontreponemal serology tests from this analysis. Despite CDC recommendations to dilute rough nontreponemal syphilis tests to detect a positive result when blocking antibody obscures accurate reading,11 over half of laboratories neglected this practice.
After the observed increase in 1999, HIV test volume remained relatively constant over the years surveyed. The reasons for the rise in HIV testing seen in 1999 are unclear and may be a survey artifact. With recent CDC recommendations to incorporate universal HIV testing into routine medical practice, future increases in HIV testing are expected.23
The introduction of HSV-2 type-specific serology in 1999 improved diagnosis of genital herpes and facilitated screening of at-risk asymptomatic individuals. Although the majority of serological tests in California from 1996 through 2002 were HSV-2 type specific, less than half of serologic tests in 2003 were type-specific tests. This finding should be interpreted with caution because HSV test survey questions changed substantially from 2001 to 2003. Further, because of the relatively small volume of HSV testing and recent release of HSV-2 serology testing recommendations,24,25 definitive conclusions regarding trends in HSV serology testing in California are difficult to make. Regardless, HSV serology tests that do not distinguish between HSV-1 and HSV-2 have limited clinical value.26
The increase in HPV testing was largely attributable to the introduction of HPV DNA tests in 2000. Because cytopathology laboratories were not specifically recruited and may not have considered themselves to be conducting STD testing, the reported HPV test volumes may underestimate actual rates. HPV testing is likely to continue to increase with expanding use of liquid-based cytology and reflex testing for atypical squamous cells of undetermined significance (ASC-US) and adjunct screening in women age 30 and older.27,28
This survey had several important limitations. Laboratories outside of LAC that reported no STD testing in 1996 or in any subsequent year were not surveyed again until 2003, which may have resulted in an underestimate of testing. Our resurvey of all licensed clinical laboratories in 2003, which resulted in an increase in the number of laboratories by 31% but a concurrent increase in STD volume of only 4%, alleviated concerns related to potential missed test volume for 1997–2002. The voluntary nature of the survey along with fluctuations in response rate and changes in participation over time may have resulted in inconsistencies in the summary data. Because data were self-reported and generally not validated using a second source, recording errors and estimates may have resulted in inaccuracies in the summary data. Exclusion of quantitative nontreponemal serology tests from the analysis may have limited the interpretability of syphilis testing trends, as it is possible that some of these tests may have been used for diagnostic purposes. Finally, the survey instrument was not designed to distinguish between tests performed on instate versus out-of-state specimens, limiting the applicability of these results to interpret California STD surveillance data.
The assessment of STD diagnostic testing facilitates the development and evaluation of laboratory-based interventions as well as programs to promote STD screening. Further, documenting trends in diagnostic technologies enhances our understanding of the epidemiology of STDs and monitoring laboratory capacity and practices facilitates implementation of STD control activities.
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12. National Committee for Quality Assurance. The State of Health Care Quality 2005: Industry Trends And Analysis. 2005. Available at http://www.ncqa.org/Docs/SOHCQ_2005.pdf
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. Accessed July 15, 2005.
16. Centers for Disease Control and Prevention. Increases in fluoroquinolone-resistant Neisseria gonorrhoeae
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among men who have sex with men–United States, 2003, and revised recommendations for gonorrhea treatment, 2004. MMWR Morb Mortal Wkly Rep 2004;53:335–338.
18. Bauer HM, Mark KE, Samuel M, et al. Prevalence of and associated risk factors for fluoroquinolone-resistant Neisseria gonorrhoeae
in California, 2000–2003. Clin Infect Dis 2005;41:795–803.
19. Giles JA, Falconio J, Yuenger JD, et al. Quinolone resistance-determining region mutations and por type of Neisseria gonorrhoeae
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20. Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2003 Supplement: Gonococcal Isolate Surveillance Project (GISP) Annual Report–2003. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2004.
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23. Centers for Disease Control and Prevention. Advancing HIV prevention: New strategies for a changing epidemic–United States, 2003. MMWR Morb Mortal Wkly Rep 2003;52:329–332.
24. Guerry SL, Bauer HM, Klausner JD, et al. Recommendations for the selective use of herpes simplex virus type 2 serological tests. Clin Infect Dis 2005;40:38–45.
26. Morrow RA, Brown ZA. Common use of inaccurate antibody assays to identify infection status with herpes simplex virus type 2. Am J Obstet Gynecol 2005;193:361–362.
27. Wright TC Jr, Schiffman M, Solomon D, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol 2004;103:304–309.
28. Wright TC Jr, Cox JT, Massad LS, et al. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;287:2120–2129.