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High prevalence of Chlamydia trachomatis infections in adolescent females not having pelvic examinations: Utility of PCR-based urine screening in urban adolescent clinic setting
JOURNAL OF ADOLESCENT HEALTH 1997;21:80-86
ORIGINAL ARTICLE
High Prevalence of Chlamydia trachomatis Infections in Adolescent Females Not Having Pelvic Examinations: Utility of PCR-Based Urine Screening in Urban Adolescent Clinic Setting M. K I M O H , M . D . , C H A R I T Y M. R I C H E Y , B.S., M I T C H E L L S. P A T E , M.T., P E R N E L L R. B R O W N , R.N., A N D E D W A R D
W . H O O K III, M . D .
Purpose: To determine utility of polymerase chain reaction (PCR)-based urine screening for Chlamydia trachomatis in the care of adolescent females in an urban clinic. Methods: Females >_15 years of age attending an adolescent clinic were approached consecutively. Each enrollee was interviewed to determine the primary reason(s) for the clinic visit and was queried about genitourinary symptoms. Nonsterile voided urine specimens were tested for C. trachomatis using PCR-based analysis. Endocervical C. trachomatis cultures were obtained from the subjects who had a pelvic examination. Main outcome measures were chlamydia infection rates in clinic attendees whether a pelvic examination was performed or not. Results: A total of 315 (99.4%) of 317 patients approached agreed to participate. Overall, 47 (14.9%) patients had positive urine PCR tests. The chlamydia infection rate detected by urine PCR was 22.1% (19 of 86) among those who had pelvic examinations performed and 12.2% (28 of 229) among those who did not (p = .03; odds ratio 2.04; 95% confidence interval 1.02, 4.06). Sixty From the Departments of Pediatrics (M.K.O., P.R.B.) and Medicine (C.M.R., M.S.P., E.W.H.), University of Alabama at Birmingham, Birmingham, Alabama, USA. This study was presented in part at the annual meeting of the Society for Adolescent Medicine, Arlington, Virginia, March 20-24, 1996, and at the annual meeting of the Southern Society for Pediatric Research, New Orleans, Louisiana, January 31-February 2, 1996. Address correspondenceto: M. K. Oh, M.D., Department of Pediatrics, University of Alabama at Birmingham, TCHA-CHOB, University Station, Birmingham, AL 35294. Manuscript acceptedNovember 11, 1996.
1054-139X/97/$17.00 PII $1054-139X(96)00311-4
percent (28 of 47) of chlamydia infections identified during the study period were identified by the urine screening test. Conclusion: Urine screening was accepted by vast majority of female adolescents attending the clinic irrespective of reason for the clinic visit, and was highly effective in identifying unsuspected C. trachomatis infections, particularly among girls attending the clinic for reasons unrelated to reproductive health care and as an interim screening tool for adolescent family-planning clients. © Society for Adolescent Medicine, 1997 KEY WORDS:
Chlamydia trachomatis Asymptomatic chlamydial infection Polymerase chain reaction Adolescents Urine screening Females Endocervical culture Pelvic examination Nucleic acid amplification
Chlamydia trachomatis infections are the m o s t comm o n bacterial sexually t r a n s m i t t e d diseases (STD) in the United States (1). A l t h o u g h readily eradicable following a p p r o p r i a t e treatment, c h l a m y d i a l infections r e m a i n a major contributor to bacterial STD m o r b i d i t y in w o m e n , causing pelvic i n f l a m m a t o r y disease (PID), infertility, a n d ectopic p r e g n a n c y , a n d leading to vertical t r a n s m i s s i o n (2,3). While C. tracho-
© Societyfor AdolescentMedicine, 1997 Published by ElsevierScienceInc., 655 Avenue of the Americas,New York,NY 10010
August 1997
matis is a common cause of cervicitis and urethritis syndromes, the majority of C. trachomatis infections are asymptomatic (3,4). As a result, screening is a critical component of efforts to control this widespread infection. Until recently, screening required collection of urogenital swab specimens for diagnostic testing. In efforts to avoid the logistical difficulties and patient discomfort associated with collection of swab specimens, a number of investigations have evaluated urine as a potential analyte for nonculture chlamydia testing. Unfortunately, most evaluations of commercially available antigen detection tests have suggested that while urine may provide accurate results, urine test sensitivity is less than for the same tests performed on swab specimens (5). Recent studies of nucleic acid amplification tests such as polymerase chain reaction (PCR) (6-9) and ligase chain reaction (LCR) (10-13) suggest that with these tests, urine test results are comparable to swab specimens for chlamydia detection. Thus, the high sensitivity of nucleic acid amplification tests performed on urine could provide new opportunities for chlamydia screening. This study was performed to explore the utility of urine PCR screening for C. trachomatis in females attending an urban general adolescent medicine clinic, irrespective of whether they had pelvic examinations performed. We sought to determine the utility of urine PCR screening in terms of the adolescent patients' willingness to accept urine STD screening, the prevalence of chlamydia in clinic attendees who did not have a pelvic examination, and performance of the urine PCR screening compared with the endocervical culture for chlamydia diagnosis.
Materials and Methods
Study Subjects and Study Setting Between March and November 1995, as part of a surveillance project to determine the prevalence of C. trachomatis in residents of Jefferson County, Alabama, urine screening for C. trachomatis was offered in the Children's Hospital of Alabama Adolescent Clinic. During the initial triage phase, each female clinic patient 15 years of age or older who had not taken antibiotics in the preceding 14 days was approached for a verbal consent to participate in the study. The study was explained as a urine screening for chlamydia infection, one of the most common STDs among young females that is often asymptomatic and for which treatment will be offered if the infection is found. All consenting females had urine
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specimens collected for chlamydia screening regardless of their reason for clinic attendance. In the triage area, each participant was asked by a clinic nursing staff about the primary reason for the visit (e.g., medical checkup, family planning, STD contact, genitourinary complaints, miscellaneous complaints). Irrespective of reason for visit, each patient was also queried about the presence of genitourinary symptoms (dysuria, vaginal discharge, pelvic/abdominal pains, etc.) by the research assistant using a standardized data collection form. Participants were not asked if they were sexually active; however, a history of prior chlamydia, gonorrhea, or PID was obtained. The service providers were unaware of the urine screening status. The usual clinical evaluation, including inquiring about sexual activity, and management for patients by their health care providers were not altered owing to this study. Pelvic examinations were performed only if clinically indicated, based upon the judgment of the clinician following consideration of the primary reason for the visit, symptoms, past medical history, and physical findings. Pelvic examinations are routinely performed on female patients on their first family planning visit and annually thereafter. For sexually active females, interim clinic visits for family planning are scheduled at 3-month intervals regardless of choice of birth control method. Pelvic examinations are performed during interim visits only if clinically indicated. Endocervical swabs for C. trachomatis and Neisseria gonorrhoeae culture are obtained from all patients undergoing pelvic examination for any reason. The study was approved by the Institutional Review Board for H u m a n Subject Use of the University of Alabama at Birmingham (UAB).
Specimen Collection Patients were asked to provide the first 30-50 cc of a non-clean-catch urine specimen in sterile plastic containers. Specimens were then refrigerated at 4°C until they were transported to the UAB STD Research Laboratories the same day.
Laboratory Methods Polymerase chain reaction analysis of urine specimens was performed at the UAB STD Research Laboratories using the Roche Amplicor PCR assay (Roche Molecular Systems, Branchburg, NJ) according to the manufacturer's instructions. Positive and negative controls were included in each PCR run.
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Table 1. Detection of Chlamydia trachomatis in Adolescent Clinic Patients by Reasons for Visit, Symptoms and Pelvic Examination Status Pelvic Exam on Index Visit Urine PCR
Performed (n = 86)
Not Performed (n = 229)
Total (n = 315)
N + / N tested (% pos) 19/86 (22.1%)
N + / N tested (% pos) 28/229 (12.2%)
N + / N tested (% pos) 47/135 (14.9%)
Primary reason for visit* Family planning (n = 128) Checkup (n = 101) STD contact (n = 5) GU complaints (n = 25) Extra-GU complaints (n = 38) No reason given (n = 37) Any GU symptoms (n = 76) GU symptomst Vaginal discharge (n = 39) Abd/pelvic pains (n = 24) Dysuria (n = 9) Vaginal bleeding (n = 5) Other GU symptoms (n = 6) No GU symptoms (n = 239)
11/44 (25.0%) 5/22 (22.7%) 0/1 1/11 (9.1%) 1/6 (16.7%) 2/9 (22.2%) 8/36(22.2%)
13/84 6/79 0/4 2/14 5/32 4/28 6/40
(15.0%) (7.6%) (12.5%) (15.6%) (14.3%) (15.0%)
24/128 (18.8%) 11/101 (10.9%) 0/5 3/25 (12.0%) 6/38 (15.8%) 6/37 (16.2%) 14/76 (18.4%)
7/27 (25.9) 2/7 (28%) O/4 0/1 0/1 11/50 (22.0%)
1/12 (8.3%) 5/17 (29.0%) 0/5 0/4 0/5 22/189 (11.6%)
8/39 (20.5%) 7/24 (29.2%) 0/9 0/5 0/6 33/239 (13.8%)
GU = Genitourinary. * Eighteen patients had more than one reason. t Six had more than one GU symptom.
Management of PCR-Positive Patients P o l y m e r a s e chain r e a c t i o n - p o s i t i v e patients w h o w e r e not p r e s u m p t i v e l y treated on the index visit w e r e contacted a n d instructed to return to the clinic at the earliest possible clinic session. O n the treatm e n t visit, endocervical s w a b s for C. trachomatis a n d N. gonorrhoeae culture, f r o m those w h o h a d not h a d a pelvic e x a m i n a t i o n d u r i n g the screening visit, w e r e obtained w h e n e v e r possible.
Statistical Methods In a n a l y z i n g the data set, S t u d e n t ' s t-test, Fisher's exact test, a n d chi-square analysis w e r e u s e d as a p p r o p r i a t e , to c o m p a r e the factors associated w i t h h a v i n g a pelvic e x a m i n a t i o n at the clinic visit, determ i n e variables that are associated w i t h positive urine PCR test, a n d d e t e r m i n e sensitivity a n d specificity of the urine PCR analysis c o m p a r e d w i t h the endocervical s w a b culture m e t h o d .
Results Characteristics of the Study Subjects A total of 315 (99.4%) of 317 patients a p p r o a c h e d a g r e e d to participate. Seventy-five percent (235) of participants w e r e A f r i c a n - A m e r i c a n a n d 25% w e r e white. M e a n age + s t a n d a r d deviation w a s 16.6 + 1.1 years (range 15-18). The self-reported p r i m a r y reasons for clinic a t t e n d a n c e at triage w e r e family-
p l a n n i n g service in 128 (40.6%), a medical c h e c k u p in 101 (32.1%), g e n i t o u r i n a r y c o m p l a i n t s in 25 (7.9%), as STD contacts in 5 (1.6%), a n d miscellaneous, including n o n g e n i t o u r i n a r y c o m p l a i n t s in 75 (23.8%) (Table 1). In 18 cases, m u l t i p l e reasons for the visit w e r e recorded. W h e n q u e s t i o n e d b y the research assistant, g e n i t o u r i n a r y s y m p t o m s w e r e a c k n o w l e d g e d b y 76 patients (24.1%) (Table 1). A history of C. trachomatis infection w a s r e p o r t e d b y 51 (16.2%), N. gonorrhoeae b y 33 (10.5%), a n d PID b y 22 (7.0%) subjects.
Pelvic Examination on the Index Visit (Table 1) D u r i n g the index visit, 86 subjects (27.3%) h a d pelvic e x a m i n a t i o n s a n d endocervical s w a b s for culture obtained. Patients requesting for f a m i l y - p l a n n i n g services w e r e m o r e likely to h a v e a pelvic examination t h a n those a t t e n d i n g for other reasons [44 (34%) of 128 vs. 42 (22.5%) of 187; p = 0.02; o d d s ratio (OR) 1.8, 95% confidence interval (CI) 1.1, 3.1]. N o other self-reported p r i m a r y reasons for the visit w e r e significantly associated w i t h p e r f o r m a n c e of pelvic examinations. G e n i t o u r i n a r y s y m p t o m s w e r e r e p o r t e d b y 76 patients, of w h o m 47.4% h a d pelvic examinations, as c o m p a r e d w i t h 20.9% (50 of 239) of those w h o denied g e n i t o u r i n a r y s y m p t o m s (p < .0001; OR = 3.4; 95% CI = 1.9, 6.1). Patients w h o r e p o r t e d vaginal discharge w e r e significantly m o r e likely to h a v e a pelvic e x a m i n a t i o n t h a n those w h o did not [27 (70%) of 39 vs. 59 (21%) of 275; p < .0001; O R 8.3; 95% CI 3.8,
A u g u s t 1997
18.5]. No other categories of genitourinary symptoms correlated with likelihood of having a pelvic examination. Of 24 patients with symptoms of abdominal pains, 7 had a pelvic examination on index visit. The remaining 17 who did not have pelvic examinations included those who had a pelvic examination in another clinic and referred for follow-up (6 patients), 4 who had a PID recently (completed treatment more than 2 weeks prior to the index visit), 3 who denied sexual activity, 2 who refused a pelvic examination, a n d / o r those who had other attributable diagnosis (gastritis, dysmenorrhea, urinary tract infection, myalgia).
Results of Urine PCR Screening for C. trachomatis (Table 1) Overall, 47 patients (14.9%) had positive urine PCR tests. Of those, only 19 (40.4%) had a pelvic examination performed during the index visit. The 28 (59.6%) remaining chlamydia infections were detected among patients who did not have a pelvic examination during the index visit. Thus, the chlamydia infection rate detected by PCR was 22.1% among those who had pelvic examinations performed and 12.2% among those who did not (p = .03; OR = 2.04; 95% CI = 1.02, 4.06). The urine PCR positive rate was 18.8% among the family planning clients and 12.3% in nonfamily-planning clients (p = .1). Although patients who came to the clinic for family-planning services were more likely to have a pelvic examination, the positive rate was not significantly different (p = .19) among family planning clients who did (11 of 44) or did not undergo pelvic examination (13 of 84). Patients with lower abdominal pains were significantly more likely to be infected than those without [7 (29.2%) of 24 patients with lower abdominal pains vs. 40 (13.8%) of 291 those without pains; p = .04; OR = 2.6; 95% CI = 0.9, 7.2]. Those 7 PCR positive patients who had abdominal pains included 5 who did not have pelvic examinations during the index visit: 2 denied sexual activities, 2 had a pelvic examination in the emergency department (2 and 5 days prior to the index visit, respectively), and 1 family-planning client had a pelvic examination 10 weeks before and refused a repeat examination. No other historical variables including past history of chlamydia were predictive of positive urine PCR test. Among the 28 patients who had positive urine PCR tests but did not have pelvic examinations, the primary reasons for visit included family-planning
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Table 2. Comparison of Urine PCR With Endocervical Tissue Culture/DFA Confirmatory Test for Chlamydia trachomatis in Adolescent Clinic Patients Who Had a Pelvic Examination Endocervical Culture/DFA + Urine PCR
+ -
Total
22 0
22
3 67 70
25 67 92
Note. Specificity = 96%; sensitivity = 100%; positive predictive value = 88%; negative predictive value = 100%. PCR = polymerase chain reaction. Endocervical cultures were obtained on the return treatment visit in six cases.
interim visits (13), check-up (6), and a variety of other complaints.
Comparison of Urine PCR With Endocervical Culture/Direct Fluorescent Antibody (DFA) Test Endocervical cultures for chlamydia were performed on 92 patients (Table 2): 86 during the screening visit and 6 at the time of the return visit for treatment. All patients with positive C. trachomatis cultures also had positive urine PCR tests. In addition, in seven (7.6%) cases, PCR tests were positive and cultures were negative. Culture transport media from the seven patients were examined with DFA test for C. trachomatis. Four of seven had positive DFA assays for chlamydial elementary bodies; thus, the resolved positive predictive value of the urine PCR test was 88% and negative predictive value 100%, using endocervical culture/DFA confirmation tests as the reference standard.
Management Outcome of PCR-Positive Patients Of 47 patients with a positive urine PCR test for chlamydia, 10 (21.3%) were treated during the index visit because of symptoms, physical findings, a n d / o r a history of STD contact. Five of these 10 presumptively treated patients had a pelvic examination on the index visit: 5 who did not have pelvic examinations included 4 STD contacts and 1 case referred for a treatment of gonorrhea diagnosed elsewhere. Thirty-five additional patients (74.5%) were contacted and returned, and 2 patients (4.3%) were lost to follow-up. Of the 35 who returned, 33 were treated. The remaining 2 were not treated: In 1, discrepancy
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between endocervical culture (negative) and urine screening (positive) was noted when the patient returned; DFA confirmation test on the endocervical swab specimen was negative. In the other, both the patient and her mother indicated disbelief and requested a repeat test. Repeat testing yielded positive endocervical culture and a second urine PCR assay positive for C. trachomatis. At the time of her second return visit, the patient received therapy for chlamydial infection and family-planning services.
Discussion
Until recently, accurate laboratory detection of STD has required collection of specimens in the course of genitourinary examination. The inconvenience and discomfort associated with examination and specimen collection in males is often discussed as an impediment to STD control efforts (14). Our data suggest that similar problems may be operative for adolescent females and that urine-based screening offers the potential to detect larger numbers of infected individuals through routine screening, irrespective of the reason for seeking medical care in adolescent clinics. Our study confirms that while cost-effective in identifying C. trachomatis infections among young women, universal screening of at-risk populations such as young family-planning clinic clients (15-17) fails to include sexually active adolescents who are not using family-planning services. The emotional and physical discomfort of pelvic examinations for adolescent girls is well described in previous publications (18-21). The most common sources of anxiety about the pelvic examination for adolescents are fear of discovery of disease, fear of pain, and embarrassment about both undressing and personal cleanliness. Thus, anxiety about a pelvic examination may act as a deterrent to receipt of needed health care (18). In addition, the procedure may be anxiety-provoking for providers (20), contributing to reluctance among some health care providers to perform pelvic examination (21). Finally, STD symptoms may be absent or unreported, which, in combination with denial of sexual activity may preclude performance of a pelvic examination. In our study, we chose not to ask specifically about sexual activity, but the verbal consent format clearly stated that the screening was for an STD. Nonetheless, we experienced little difficulty in obtaining verbal consent for the urine STD screening from patients ---15 years of age. Our study clearly demonstrated that
JOURNALOF ADOLESCENTHEALTHVol. 21, No. 2
urine screening for chlamydia in adolescent clinics such as ours is a highly effective means for identification of unsuspected C. trachomatis infections, particularly among girls attending the clinic for reasons unrelated to reproductive health care, and as an interim screening tool for adolescent family-planning clients. Sixty percent of infected cases identified during the study period would have been missed if the urine screening program were not in place. Another interpretation of our data is that health care providers at our clinic should be performing more pelvic examinations on adolescents who attend clinics for medical care. While such a policy might increase chlamydia detection somewhat, it is not always possible in general adolescent clinic settings such as ours. We detected infections in patients seen for school physicals and those seen for acute nongenitourinary problems, as well as in clients who did not acknowledge sexual activity. Our study highlights the fact that the presence of nonspecific abdominal complaints in adolescent females must alert the provider to consider an STD, regardless of the primary reason for clinic attendance. In such patients who refused pelvic examinations a n d / o r denied sexual contact, urine screening facilitated the diagnosis. The optimal interval for repeat chlamydia screening in adolescent females at risk has yet to be determined (22-24). Studies have shown that recurrent infection rates are the highest among adolescents and young w o m e n (25). Thus, an annual pelvic examination often may not be sufficient for the detection of reinfection among sexually active adolescent females (22,23,26). In many family-planning clinics, although yearly examinations and screening for STD are performed, the common practice for clients receiving injectable contraceptives is to provide them following a brief interview without examination at the frame of 3-monthly interval visits. Similarly, visits for family planning may only be scheduled for oral contraceptive patients at 12month intervals. Our data favor incorporation of interval evaluation for STD risk and diagnostic specimen collection into clinical protocols of family planning for adolescents. The availability of sensitive, accurate tests which can be performed on urine specimens for detection of chlamydia (or gonorrhea) seems to be a useful intermediate solution with potential to improve health care and STD control in adolescents without acting as a disincentive for patients or compromising efficiency and clinic flow. The benefits of improving identification of C. trachomatis infection in adolescents are clear. In ad-
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dition to the possibility of earlier detection and treatment, and decreasing risk of transmission, the benefits include opportunities to provide further risk assessment and risk reduction counseling for other sexually transmissible conditions, such as unplanned pregnancy. Many patients attending adolescent clinics are seen for reasons unrelated to their reproductive health, and as a result no clear indication for pelvic examination, and yet may still be at risk for chlamydial infections. While routine urine screening of adolescent females using PCR detects a substantial number of infections, these benefits must be weighed against several potential disadvantages, including the cost of the test and the ability to insure treatment for the patient and her sexual contact(s). Especially in cases of young adolescents, the provider must also be prepared to address confidentiality issues. The applicability of our data to younger adolescents is limited by the exclusion from our study of subjects under 15 years of age. Another possible limitation of our study is absence of endocervical samples from all patients, preventing comparison of the results of urine PCR to cell culture of endocervical swabs for clearly defining the performance of urine screening. Requiring swab specimens would have reduced the participation rate significantly, as shown by Brannstrom et al. (27). While the sensitivity of urine screening may be less than the same test or culture performed on swab specimens (6), the accuracy of the test is supported by our comparison data from the subset of the subjects w h o had both urine PCR and endocervical cultures performed (Table 2). In addition, other published studies confirmed the high sensitivity and specificity of PCR based chlamydia tests of urine for women and men (6-9). We do not advocate urine screening instead of endocervical screening. Urine screening may increase the opportunity for screening high-risk populations for chlamydia infection at times when pelvic examinations cannot be done or are not indicated for the specific visit, creating opportunities for more comprehensive evaluation including a pelvic examination, screening for other STDs, and preventive health care counseling. Noninvasive C. trachomatis screening using urine specimens may help improve reproductive health of adolescent and young w o m e n and may improve compliance with the scheduled follow-up for many women at risk for STD. The authors acknowledge Rosie Florence, the research assistant, for data information collection; Jane R. Schwebke, M.D., and Carolyn Seymore Ashworth, M.D., for review of the manuscript and assistance in editing. This study was supported by Grant
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R30/CCR411489 from the Centers for Disease Control and Prevention, Atlanta, Georgia.
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17. Handsfield H, Jasman L, Roberts P, et al. Criteria for selective screening for Chlarnydia trachomatis infection in women attending family planning clinics. JAMA 1986;255:1730-4. 18. Millstein SG, Adler NE, Irwin CE. Sources of anxiety about pelvic examinations among adolescent females. J Adolesc Health Care 1984;5:105-11. 19. Seymore C, DuRant RH, Jay MS, et al. Influence of position during examination, and sex of examiner on patient anxiety during pelvic examination. J Pediatr 1986;108:312-7. 20. Frye CA, Weisberg RB. Increasing the incidence of routine pelvic examinations: Behavioral medicine's contribution. Women Health 1994;21:33-55. 21. Domar AD. Psychological aspects of the pelvic exam: individual needs and physician involvement. Women Health 1985;10: 75-90. 22. Fortenberry JD, Evans DL. Routine screening for genital Chlamydia trachomatis in adolescent females. Sex Transm Dis 1989;16:268-72.
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23. Oh MK, Cloud GA, Fleenor M, et al. Risk for gonococcal and chlamydial cervicitis in adolescent females: incidence and recurrence in a prospective cohort study. J Adolesc Health 1996;18:270-75. 24. Blythe MJ, Katz BP, Batteiger BE, et al. Recurrent genitourinary chlamydial infections in sexually active female adolescents. J Pediatr 1992;121:487-93. 25. Hillis SD, Nakashima AK, Marchbanks PA, et al. Risk factors for recurrent Chlamydia trachomatis infections in women. Am J Obstet Gynecol 1994;170:801-6. 26. Oh MK, Cloud GA, Baker SL, et al. Chlamydial infection and sexually behavior in young pregnant teenagers. Sex Transm Dis 1993;20:45-50. 27. Brannstrom M, Josefsson GB, Cederberg A, Liljestrand J. Prevalence of genital Chlamydia trachomatis infection among women in a Swedish primary health care area. Scand J Infect Dis 1992;24:41-6.
ORIGINAL ARTICLE
High Prevalence of Chlamydia trachomatis Infections in Adolescent Females Not Having Pelvic Examinations: Utility of PCR-Based Urine Screening in Urban Adolescent Clinic Setting M. K I M O H , M . D . , C H A R I T Y M. R I C H E Y , B.S., M I T C H E L L S. P A T E , M.T., P E R N E L L R. B R O W N , R.N., A N D E D W A R D
W . H O O K III, M . D .
Purpose: To determine utility of polymerase chain reaction (PCR)-based urine screening for Chlamydia trachomatis in the care of adolescent females in an urban clinic. Methods: Females >_15 years of age attending an adolescent clinic were approached consecutively. Each enrollee was interviewed to determine the primary reason(s) for the clinic visit and was queried about genitourinary symptoms. Nonsterile voided urine specimens were tested for C. trachomatis using PCR-based analysis. Endocervical C. trachomatis cultures were obtained from the subjects who had a pelvic examination. Main outcome measures were chlamydia infection rates in clinic attendees whether a pelvic examination was performed or not. Results: A total of 315 (99.4%) of 317 patients approached agreed to participate. Overall, 47 (14.9%) patients had positive urine PCR tests. The chlamydia infection rate detected by urine PCR was 22.1% (19 of 86) among those who had pelvic examinations performed and 12.2% (28 of 229) among those who did not (p = .03; odds ratio 2.04; 95% confidence interval 1.02, 4.06). Sixty From the Departments of Pediatrics (M.K.O., P.R.B.) and Medicine (C.M.R., M.S.P., E.W.H.), University of Alabama at Birmingham, Birmingham, Alabama, USA. This study was presented in part at the annual meeting of the Society for Adolescent Medicine, Arlington, Virginia, March 20-24, 1996, and at the annual meeting of the Southern Society for Pediatric Research, New Orleans, Louisiana, January 31-February 2, 1996. Address correspondenceto: M. K. Oh, M.D., Department of Pediatrics, University of Alabama at Birmingham, TCHA-CHOB, University Station, Birmingham, AL 35294. Manuscript acceptedNovember 11, 1996.
1054-139X/97/$17.00 PII $1054-139X(96)00311-4
percent (28 of 47) of chlamydia infections identified during the study period were identified by the urine screening test. Conclusion: Urine screening was accepted by vast majority of female adolescents attending the clinic irrespective of reason for the clinic visit, and was highly effective in identifying unsuspected C. trachomatis infections, particularly among girls attending the clinic for reasons unrelated to reproductive health care and as an interim screening tool for adolescent family-planning clients. © Society for Adolescent Medicine, 1997 KEY WORDS:
Chlamydia trachomatis Asymptomatic chlamydial infection Polymerase chain reaction Adolescents Urine screening Females Endocervical culture Pelvic examination Nucleic acid amplification
Chlamydia trachomatis infections are the m o s t comm o n bacterial sexually t r a n s m i t t e d diseases (STD) in the United States (1). A l t h o u g h readily eradicable following a p p r o p r i a t e treatment, c h l a m y d i a l infections r e m a i n a major contributor to bacterial STD m o r b i d i t y in w o m e n , causing pelvic i n f l a m m a t o r y disease (PID), infertility, a n d ectopic p r e g n a n c y , a n d leading to vertical t r a n s m i s s i o n (2,3). While C. tracho-
© Societyfor AdolescentMedicine, 1997 Published by ElsevierScienceInc., 655 Avenue of the Americas,New York,NY 10010
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matis is a common cause of cervicitis and urethritis syndromes, the majority of C. trachomatis infections are asymptomatic (3,4). As a result, screening is a critical component of efforts to control this widespread infection. Until recently, screening required collection of urogenital swab specimens for diagnostic testing. In efforts to avoid the logistical difficulties and patient discomfort associated with collection of swab specimens, a number of investigations have evaluated urine as a potential analyte for nonculture chlamydia testing. Unfortunately, most evaluations of commercially available antigen detection tests have suggested that while urine may provide accurate results, urine test sensitivity is less than for the same tests performed on swab specimens (5). Recent studies of nucleic acid amplification tests such as polymerase chain reaction (PCR) (6-9) and ligase chain reaction (LCR) (10-13) suggest that with these tests, urine test results are comparable to swab specimens for chlamydia detection. Thus, the high sensitivity of nucleic acid amplification tests performed on urine could provide new opportunities for chlamydia screening. This study was performed to explore the utility of urine PCR screening for C. trachomatis in females attending an urban general adolescent medicine clinic, irrespective of whether they had pelvic examinations performed. We sought to determine the utility of urine PCR screening in terms of the adolescent patients' willingness to accept urine STD screening, the prevalence of chlamydia in clinic attendees who did not have a pelvic examination, and performance of the urine PCR screening compared with the endocervical culture for chlamydia diagnosis.
Materials and Methods
Study Subjects and Study Setting Between March and November 1995, as part of a surveillance project to determine the prevalence of C. trachomatis in residents of Jefferson County, Alabama, urine screening for C. trachomatis was offered in the Children's Hospital of Alabama Adolescent Clinic. During the initial triage phase, each female clinic patient 15 years of age or older who had not taken antibiotics in the preceding 14 days was approached for a verbal consent to participate in the study. The study was explained as a urine screening for chlamydia infection, one of the most common STDs among young females that is often asymptomatic and for which treatment will be offered if the infection is found. All consenting females had urine
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specimens collected for chlamydia screening regardless of their reason for clinic attendance. In the triage area, each participant was asked by a clinic nursing staff about the primary reason for the visit (e.g., medical checkup, family planning, STD contact, genitourinary complaints, miscellaneous complaints). Irrespective of reason for visit, each patient was also queried about the presence of genitourinary symptoms (dysuria, vaginal discharge, pelvic/abdominal pains, etc.) by the research assistant using a standardized data collection form. Participants were not asked if they were sexually active; however, a history of prior chlamydia, gonorrhea, or PID was obtained. The service providers were unaware of the urine screening status. The usual clinical evaluation, including inquiring about sexual activity, and management for patients by their health care providers were not altered owing to this study. Pelvic examinations were performed only if clinically indicated, based upon the judgment of the clinician following consideration of the primary reason for the visit, symptoms, past medical history, and physical findings. Pelvic examinations are routinely performed on female patients on their first family planning visit and annually thereafter. For sexually active females, interim clinic visits for family planning are scheduled at 3-month intervals regardless of choice of birth control method. Pelvic examinations are performed during interim visits only if clinically indicated. Endocervical swabs for C. trachomatis and Neisseria gonorrhoeae culture are obtained from all patients undergoing pelvic examination for any reason. The study was approved by the Institutional Review Board for H u m a n Subject Use of the University of Alabama at Birmingham (UAB).
Specimen Collection Patients were asked to provide the first 30-50 cc of a non-clean-catch urine specimen in sterile plastic containers. Specimens were then refrigerated at 4°C until they were transported to the UAB STD Research Laboratories the same day.
Laboratory Methods Polymerase chain reaction analysis of urine specimens was performed at the UAB STD Research Laboratories using the Roche Amplicor PCR assay (Roche Molecular Systems, Branchburg, NJ) according to the manufacturer's instructions. Positive and negative controls were included in each PCR run.
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Table 1. Detection of Chlamydia trachomatis in Adolescent Clinic Patients by Reasons for Visit, Symptoms and Pelvic Examination Status Pelvic Exam on Index Visit Urine PCR
Performed (n = 86)
Not Performed (n = 229)
Total (n = 315)
N + / N tested (% pos) 19/86 (22.1%)
N + / N tested (% pos) 28/229 (12.2%)
N + / N tested (% pos) 47/135 (14.9%)
Primary reason for visit* Family planning (n = 128) Checkup (n = 101) STD contact (n = 5) GU complaints (n = 25) Extra-GU complaints (n = 38) No reason given (n = 37) Any GU symptoms (n = 76) GU symptomst Vaginal discharge (n = 39) Abd/pelvic pains (n = 24) Dysuria (n = 9) Vaginal bleeding (n = 5) Other GU symptoms (n = 6) No GU symptoms (n = 239)
11/44 (25.0%) 5/22 (22.7%) 0/1 1/11 (9.1%) 1/6 (16.7%) 2/9 (22.2%) 8/36(22.2%)
13/84 6/79 0/4 2/14 5/32 4/28 6/40
(15.0%) (7.6%) (12.5%) (15.6%) (14.3%) (15.0%)
24/128 (18.8%) 11/101 (10.9%) 0/5 3/25 (12.0%) 6/38 (15.8%) 6/37 (16.2%) 14/76 (18.4%)
7/27 (25.9) 2/7 (28%) O/4 0/1 0/1 11/50 (22.0%)
1/12 (8.3%) 5/17 (29.0%) 0/5 0/4 0/5 22/189 (11.6%)
8/39 (20.5%) 7/24 (29.2%) 0/9 0/5 0/6 33/239 (13.8%)
GU = Genitourinary. * Eighteen patients had more than one reason. t Six had more than one GU symptom.
Management of PCR-Positive Patients P o l y m e r a s e chain r e a c t i o n - p o s i t i v e patients w h o w e r e not p r e s u m p t i v e l y treated on the index visit w e r e contacted a n d instructed to return to the clinic at the earliest possible clinic session. O n the treatm e n t visit, endocervical s w a b s for C. trachomatis a n d N. gonorrhoeae culture, f r o m those w h o h a d not h a d a pelvic e x a m i n a t i o n d u r i n g the screening visit, w e r e obtained w h e n e v e r possible.
Statistical Methods In a n a l y z i n g the data set, S t u d e n t ' s t-test, Fisher's exact test, a n d chi-square analysis w e r e u s e d as a p p r o p r i a t e , to c o m p a r e the factors associated w i t h h a v i n g a pelvic e x a m i n a t i o n at the clinic visit, determ i n e variables that are associated w i t h positive urine PCR test, a n d d e t e r m i n e sensitivity a n d specificity of the urine PCR analysis c o m p a r e d w i t h the endocervical s w a b culture m e t h o d .
Results Characteristics of the Study Subjects A total of 315 (99.4%) of 317 patients a p p r o a c h e d a g r e e d to participate. Seventy-five percent (235) of participants w e r e A f r i c a n - A m e r i c a n a n d 25% w e r e white. M e a n age + s t a n d a r d deviation w a s 16.6 + 1.1 years (range 15-18). The self-reported p r i m a r y reasons for clinic a t t e n d a n c e at triage w e r e family-
p l a n n i n g service in 128 (40.6%), a medical c h e c k u p in 101 (32.1%), g e n i t o u r i n a r y c o m p l a i n t s in 25 (7.9%), as STD contacts in 5 (1.6%), a n d miscellaneous, including n o n g e n i t o u r i n a r y c o m p l a i n t s in 75 (23.8%) (Table 1). In 18 cases, m u l t i p l e reasons for the visit w e r e recorded. W h e n q u e s t i o n e d b y the research assistant, g e n i t o u r i n a r y s y m p t o m s w e r e a c k n o w l e d g e d b y 76 patients (24.1%) (Table 1). A history of C. trachomatis infection w a s r e p o r t e d b y 51 (16.2%), N. gonorrhoeae b y 33 (10.5%), a n d PID b y 22 (7.0%) subjects.
Pelvic Examination on the Index Visit (Table 1) D u r i n g the index visit, 86 subjects (27.3%) h a d pelvic e x a m i n a t i o n s a n d endocervical s w a b s for culture obtained. Patients requesting for f a m i l y - p l a n n i n g services w e r e m o r e likely to h a v e a pelvic examination t h a n those a t t e n d i n g for other reasons [44 (34%) of 128 vs. 42 (22.5%) of 187; p = 0.02; o d d s ratio (OR) 1.8, 95% confidence interval (CI) 1.1, 3.1]. N o other self-reported p r i m a r y reasons for the visit w e r e significantly associated w i t h p e r f o r m a n c e of pelvic examinations. G e n i t o u r i n a r y s y m p t o m s w e r e r e p o r t e d b y 76 patients, of w h o m 47.4% h a d pelvic examinations, as c o m p a r e d w i t h 20.9% (50 of 239) of those w h o denied g e n i t o u r i n a r y s y m p t o m s (p < .0001; OR = 3.4; 95% CI = 1.9, 6.1). Patients w h o r e p o r t e d vaginal discharge w e r e significantly m o r e likely to h a v e a pelvic e x a m i n a t i o n t h a n those w h o did not [27 (70%) of 39 vs. 59 (21%) of 275; p < .0001; O R 8.3; 95% CI 3.8,
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18.5]. No other categories of genitourinary symptoms correlated with likelihood of having a pelvic examination. Of 24 patients with symptoms of abdominal pains, 7 had a pelvic examination on index visit. The remaining 17 who did not have pelvic examinations included those who had a pelvic examination in another clinic and referred for follow-up (6 patients), 4 who had a PID recently (completed treatment more than 2 weeks prior to the index visit), 3 who denied sexual activity, 2 who refused a pelvic examination, a n d / o r those who had other attributable diagnosis (gastritis, dysmenorrhea, urinary tract infection, myalgia).
Results of Urine PCR Screening for C. trachomatis (Table 1) Overall, 47 patients (14.9%) had positive urine PCR tests. Of those, only 19 (40.4%) had a pelvic examination performed during the index visit. The 28 (59.6%) remaining chlamydia infections were detected among patients who did not have a pelvic examination during the index visit. Thus, the chlamydia infection rate detected by PCR was 22.1% among those who had pelvic examinations performed and 12.2% among those who did not (p = .03; OR = 2.04; 95% CI = 1.02, 4.06). The urine PCR positive rate was 18.8% among the family planning clients and 12.3% in nonfamily-planning clients (p = .1). Although patients who came to the clinic for family-planning services were more likely to have a pelvic examination, the positive rate was not significantly different (p = .19) among family planning clients who did (11 of 44) or did not undergo pelvic examination (13 of 84). Patients with lower abdominal pains were significantly more likely to be infected than those without [7 (29.2%) of 24 patients with lower abdominal pains vs. 40 (13.8%) of 291 those without pains; p = .04; OR = 2.6; 95% CI = 0.9, 7.2]. Those 7 PCR positive patients who had abdominal pains included 5 who did not have pelvic examinations during the index visit: 2 denied sexual activities, 2 had a pelvic examination in the emergency department (2 and 5 days prior to the index visit, respectively), and 1 family-planning client had a pelvic examination 10 weeks before and refused a repeat examination. No other historical variables including past history of chlamydia were predictive of positive urine PCR test. Among the 28 patients who had positive urine PCR tests but did not have pelvic examinations, the primary reasons for visit included family-planning
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Table 2. Comparison of Urine PCR With Endocervical Tissue Culture/DFA Confirmatory Test for Chlamydia trachomatis in Adolescent Clinic Patients Who Had a Pelvic Examination Endocervical Culture/DFA + Urine PCR
+ -
Total
22 0
22
3 67 70
25 67 92
Note. Specificity = 96%; sensitivity = 100%; positive predictive value = 88%; negative predictive value = 100%. PCR = polymerase chain reaction. Endocervical cultures were obtained on the return treatment visit in six cases.
interim visits (13), check-up (6), and a variety of other complaints.
Comparison of Urine PCR With Endocervical Culture/Direct Fluorescent Antibody (DFA) Test Endocervical cultures for chlamydia were performed on 92 patients (Table 2): 86 during the screening visit and 6 at the time of the return visit for treatment. All patients with positive C. trachomatis cultures also had positive urine PCR tests. In addition, in seven (7.6%) cases, PCR tests were positive and cultures were negative. Culture transport media from the seven patients were examined with DFA test for C. trachomatis. Four of seven had positive DFA assays for chlamydial elementary bodies; thus, the resolved positive predictive value of the urine PCR test was 88% and negative predictive value 100%, using endocervical culture/DFA confirmation tests as the reference standard.
Management Outcome of PCR-Positive Patients Of 47 patients with a positive urine PCR test for chlamydia, 10 (21.3%) were treated during the index visit because of symptoms, physical findings, a n d / o r a history of STD contact. Five of these 10 presumptively treated patients had a pelvic examination on the index visit: 5 who did not have pelvic examinations included 4 STD contacts and 1 case referred for a treatment of gonorrhea diagnosed elsewhere. Thirty-five additional patients (74.5%) were contacted and returned, and 2 patients (4.3%) were lost to follow-up. Of the 35 who returned, 33 were treated. The remaining 2 were not treated: In 1, discrepancy
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between endocervical culture (negative) and urine screening (positive) was noted when the patient returned; DFA confirmation test on the endocervical swab specimen was negative. In the other, both the patient and her mother indicated disbelief and requested a repeat test. Repeat testing yielded positive endocervical culture and a second urine PCR assay positive for C. trachomatis. At the time of her second return visit, the patient received therapy for chlamydial infection and family-planning services.
Discussion
Until recently, accurate laboratory detection of STD has required collection of specimens in the course of genitourinary examination. The inconvenience and discomfort associated with examination and specimen collection in males is often discussed as an impediment to STD control efforts (14). Our data suggest that similar problems may be operative for adolescent females and that urine-based screening offers the potential to detect larger numbers of infected individuals through routine screening, irrespective of the reason for seeking medical care in adolescent clinics. Our study confirms that while cost-effective in identifying C. trachomatis infections among young women, universal screening of at-risk populations such as young family-planning clinic clients (15-17) fails to include sexually active adolescents who are not using family-planning services. The emotional and physical discomfort of pelvic examinations for adolescent girls is well described in previous publications (18-21). The most common sources of anxiety about the pelvic examination for adolescents are fear of discovery of disease, fear of pain, and embarrassment about both undressing and personal cleanliness. Thus, anxiety about a pelvic examination may act as a deterrent to receipt of needed health care (18). In addition, the procedure may be anxiety-provoking for providers (20), contributing to reluctance among some health care providers to perform pelvic examination (21). Finally, STD symptoms may be absent or unreported, which, in combination with denial of sexual activity may preclude performance of a pelvic examination. In our study, we chose not to ask specifically about sexual activity, but the verbal consent format clearly stated that the screening was for an STD. Nonetheless, we experienced little difficulty in obtaining verbal consent for the urine STD screening from patients ---15 years of age. Our study clearly demonstrated that
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urine screening for chlamydia in adolescent clinics such as ours is a highly effective means for identification of unsuspected C. trachomatis infections, particularly among girls attending the clinic for reasons unrelated to reproductive health care, and as an interim screening tool for adolescent family-planning clients. Sixty percent of infected cases identified during the study period would have been missed if the urine screening program were not in place. Another interpretation of our data is that health care providers at our clinic should be performing more pelvic examinations on adolescents who attend clinics for medical care. While such a policy might increase chlamydia detection somewhat, it is not always possible in general adolescent clinic settings such as ours. We detected infections in patients seen for school physicals and those seen for acute nongenitourinary problems, as well as in clients who did not acknowledge sexual activity. Our study highlights the fact that the presence of nonspecific abdominal complaints in adolescent females must alert the provider to consider an STD, regardless of the primary reason for clinic attendance. In such patients who refused pelvic examinations a n d / o r denied sexual contact, urine screening facilitated the diagnosis. The optimal interval for repeat chlamydia screening in adolescent females at risk has yet to be determined (22-24). Studies have shown that recurrent infection rates are the highest among adolescents and young w o m e n (25). Thus, an annual pelvic examination often may not be sufficient for the detection of reinfection among sexually active adolescent females (22,23,26). In many family-planning clinics, although yearly examinations and screening for STD are performed, the common practice for clients receiving injectable contraceptives is to provide them following a brief interview without examination at the frame of 3-monthly interval visits. Similarly, visits for family planning may only be scheduled for oral contraceptive patients at 12month intervals. Our data favor incorporation of interval evaluation for STD risk and diagnostic specimen collection into clinical protocols of family planning for adolescents. The availability of sensitive, accurate tests which can be performed on urine specimens for detection of chlamydia (or gonorrhea) seems to be a useful intermediate solution with potential to improve health care and STD control in adolescents without acting as a disincentive for patients or compromising efficiency and clinic flow. The benefits of improving identification of C. trachomatis infection in adolescents are clear. In ad-
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dition to the possibility of earlier detection and treatment, and decreasing risk of transmission, the benefits include opportunities to provide further risk assessment and risk reduction counseling for other sexually transmissible conditions, such as unplanned pregnancy. Many patients attending adolescent clinics are seen for reasons unrelated to their reproductive health, and as a result no clear indication for pelvic examination, and yet may still be at risk for chlamydial infections. While routine urine screening of adolescent females using PCR detects a substantial number of infections, these benefits must be weighed against several potential disadvantages, including the cost of the test and the ability to insure treatment for the patient and her sexual contact(s). Especially in cases of young adolescents, the provider must also be prepared to address confidentiality issues. The applicability of our data to younger adolescents is limited by the exclusion from our study of subjects under 15 years of age. Another possible limitation of our study is absence of endocervical samples from all patients, preventing comparison of the results of urine PCR to cell culture of endocervical swabs for clearly defining the performance of urine screening. Requiring swab specimens would have reduced the participation rate significantly, as shown by Brannstrom et al. (27). While the sensitivity of urine screening may be less than the same test or culture performed on swab specimens (6), the accuracy of the test is supported by our comparison data from the subset of the subjects w h o had both urine PCR and endocervical cultures performed (Table 2). In addition, other published studies confirmed the high sensitivity and specificity of PCR based chlamydia tests of urine for women and men (6-9). We do not advocate urine screening instead of endocervical screening. Urine screening may increase the opportunity for screening high-risk populations for chlamydia infection at times when pelvic examinations cannot be done or are not indicated for the specific visit, creating opportunities for more comprehensive evaluation including a pelvic examination, screening for other STDs, and preventive health care counseling. Noninvasive C. trachomatis screening using urine specimens may help improve reproductive health of adolescent and young w o m e n and may improve compliance with the scheduled follow-up for many women at risk for STD. The authors acknowledge Rosie Florence, the research assistant, for data information collection; Jane R. Schwebke, M.D., and Carolyn Seymore Ashworth, M.D., for review of the manuscript and assistance in editing. This study was supported by Grant
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R30/CCR411489 from the Centers for Disease Control and Prevention, Atlanta, Georgia.
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23. Oh MK, Cloud GA, Fleenor M, et al. Risk for gonococcal and chlamydial cervicitis in adolescent females: incidence and recurrence in a prospective cohort study. J Adolesc Health 1996;18:270-75. 24. Blythe MJ, Katz BP, Batteiger BE, et al. Recurrent genitourinary chlamydial infections in sexually active female adolescents. J Pediatr 1992;121:487-93. 25. Hillis SD, Nakashima AK, Marchbanks PA, et al. Risk factors for recurrent Chlamydia trachomatis infections in women. Am J Obstet Gynecol 1994;170:801-6. 26. Oh MK, Cloud GA, Baker SL, et al. Chlamydial infection and sexually behavior in young pregnant teenagers. Sex Transm Dis 1993;20:45-50. 27. Brannstrom M, Josefsson GB, Cederberg A, Liljestrand J. Prevalence of genital Chlamydia trachomatis infection among women in a Swedish primary health care area. Scand J Infect Dis 1992;24:41-6.