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Obstetrics & Gynecology 2002;100:579-584
© 2002 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Predicting Chlamydial and Gonococcal Cervical Infection: Implications for Management of Cervicitis

Jeanne M. Marrazzo, MD, MPH, H. Hunter Handsfield, MD and William L. H. Whittington

From the Department of Medicine, University of Washington School of Medicine, Seattle, Washington; and Public Health, Seattle and King County STD Clinic, Harborview Medical Center, Seattle, Washington.

Address reprint requests to: Jeanne M. Marrazzo, MD, MPH, Harborview Medical Center, Box #359931, 325 Ninth Avenue, Seattle, WA 98104; E-mail: jmm2{at}u.washington.edu.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To define utility of age and cervical findings in predicting infection with Chlamydia trachomatis and Neisseria gonorrhoeae among women universally tested for both infections, and to assess the independent contribution of Gram stain (GS) smear of endocervical secretions.

METHODS: Visits by women to Seattle sexually transmitted diseases clinics from 1995 through 1999 were retrospectively reviewed. All women had endocervical GS and cultures for C trachomatis and N gonorrhoeae performed. Predictive values of age, cervical signs, and inflammation on GS (more than 30 polymorphonuclear leukocytes per 1000 x field) were calculated.

RESULTS: Among 6230 women, prevalence of C trachomatis and N gonorrhoeae was 6.9% and 2.1%, respectively; 520 women (8.3%) had either organism detected. Age, cervical signs (mucopus, induced bleeding), and inflammation on endocervical GS were independently associated with infection. However, the positive predictive value (PPV) of any cervical finding for infection was less than 19% in women 25 years and older. Inflammation on endocervical GS was the sole indicator of infection in 79 of 520 (15%) infections, but was insensitive in the absence of mucopurulent cervicitis (sensitivity, 26%; PPV, 21%).

CONCLUSION: Cervical signs suggesting chlamydial or gonococcal infection have higher positive predictive value (PPV) in younger women. The PPV of inflammation on endocervical GS is too low to recommend its use to direct empiric treatment in the absence of mucopurulent cervicitis, especially in women 25 years and older. Further, its low sensitivity in detecting infection in women without mucopurulent cervicitis does not justify routine use. Signs suggesting mucopurulent cervicitis should be interpreted in the context of age, and empiric treatment may not be indicated in women aged 25 years and older.

The association between mucopurulent cervicitis and cervical infection with Chlamydia trachomatis and Neisseria gonorrhoeae is well established.1–3 The Centers for Disease Control and Prevention (CDC) recommends testing for both of these organisms if mucopurulent cervicitis is present.4 These guidelines also recommend that empiric treatment of mucopurulent cervicitis directed at these infections should be provided if the local prevalence of chlamydial or gonorrhea infection is high, or if the likelihood of a woman’s return for treatment based on a positive test is judged to be low. However, diagnostic precision for mucopurulent cervicitis may vary, and the predictive value of individual cervical findings suggestive of mucopurulent cervicitis may vary with patients’ age.5

The independent value of inflammation as detected by Gram stain of a smear of endocervical secretions as a criterion for mucopurulent cervicitis, especially in predicting chlamydial infection, has been variable.3,6–11 Although the CDC’s guidelines stopped including inflammation on endocervical Gram stain as presumptive evidence of chlamydial infection in 1993,12 and the sensitivity of endocervical Gram stain for detection of N gonorrhoeae at the cervix is approximately 50%,13 this test continues to be used in many settings, particularly those that provide dedicated sexually transmitted disease (STD) services.10 In fact, a recent study performed in Canada concluded that the "use of endocervical Gram smear results together with clinical information can be used to identify high risk women for C trachomatis infection."11

We studied a large sample of women universally tested for cervical chlamydial and gonococcal infection in an STD clinic in order to define the roles of age and clinical signs of cervical infection as independent predictors of cervical chlamydial and gonococcal infection, and as indicators for empiric antimicrobial therapy. We also examined the independent predictive value of the Gram stain smear of endocervical secretions for the presence of these infections.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Electronic client records for new problem visits from 1995 through 1999 to the Public Health, Seattle and King County STD Clinic at Harborview Medical Center in Seattle were analyzed. The analysis of the data presented in this article was approved by the University of Washington Human Subjects Review Committee. Follow-up visits were excluded, as were those from women who did not undergo pelvic examination. Demographic data were collected at clinic registration; other information (patient complaints, physical examination findings, laboratory results, and final diagnosis) was recorded by clinicians on a standardized form. Clinicians performed Gram stain smear of endocervical secretions and quantified polymorphonuclear cells per 1000 x (oil immersion) field (PMN/HPF) using a standardized clinic protocol that averaged the PMN number in each of at least ten fields. C trachomatis and N gonorrhoeae were identified by endocervical cultures as previously described.14

For the analysis, mucopurulent cervicitis was defined if both 1) easily induced endocervical bleeding or mucopurulent endocervical exudate were present on examination, and 2) 30 or more PMN/HPF were present on Gram stain smear of endocervical secretions. Women with signs of pelvic inflammatory disease, including fundal, adnexal, or cervical motion tenderness, were excluded, as we reasoned that these women would be empirically treated for chlamydial and gonococcal infection regardless of cervical findings. Univariate associations between subjects’ characteristics and the presence of chlamydial infection were assessed using {chi}2 analysis. Positive predictive values and confidence intervals were calculated using EpiInfo 6.0 (CDC), and multivariable analysis was performed using logistic regression analysis with SPSS 10.05 (Chicago, IL). All tests for statistical significance were two-sided. Women for whom variables of interest were not recorded had those variables coded as missing, and were included in the multivariable analysis.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Records for 11,014 visits by women to the clinic during the study period were reviewed. Of these, 6230 new problem visits by women who underwent pelvic examination, did not have signs of pelvic inflammatory disease, and were tested for C trachomatis and N gonorrhoeae were included in the analysis. Subjects’ age distribution, race, sexual history, and cervical findings are displayed in Table 1Go. Of these 6230 women, 430 (6.9%) had C trachomatis and 133 (2.1%) had N gonorrhoeae detected by culture of the cervix. Report of presence or absence of induced endocervical bleeding was missing for 302 (4.8%) of all women, and of findings on Gram stain of endocervical secretions, 162 women (2.6%).


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  		Table 1. Association of Chlamydial or Gonococcal Cervical Infection With Demographic, Clinical, and Laboratory Findings
 
The most frequently noted sign of cervical infection was 30 or more PMN/HPF on Gram stain smear of endocervical secretions (15.4%), followed by easily induced endocervical bleeding (13.8%) and mucopurulent endocervical discharge (5%). Except for easily induced bleeding, the prevalence of cervical signs decreased with increasing age. Relative to women age 25 years and older, younger women were significantly more likely to have 30 or more PMN/HPF on Gram stain smear of endocervical secretions (17.7% versus 14.2%; P < .001), mucopurulent endocervical discharge (6.0% versus 4.2%; P = .001), and a diagnosis of mucopurulent cervicitis (8.3% versus 6.5%; P = .006). The frequency of cervical signs did not differ for women infected only with N gonorrhoeae compared with those infected only with C trachomatis (data not shown).

As depicted in Figure 1Go, the prevalence of infection with either organism declined with increasing age for women with and without mucopurulent cervicitis. The prevalence of gonococcal infection declined 70%, from 4.0% in women younger than 20 years to 1.2% in women 30 years and older. Similarly, prevalence of chlamydial infection declined 87%, from 15.9% in women younger than 20 years to 2.1% in women 30 years and older. The prevalence of cervical infection among women with mucopurulent cervicitis was significantly lower in women 25 years and older relative to younger women with mucopurulent cervicitis (39% versus 17%, respectively; P < .001). Similarly, among women without mucopurulent cervicitis, the prevalence of cervical infection was higher in the younger women (11.3% versus 3.2%; P < .001).



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  		Figure 1. Prevalence of cervical infection with C trachomatis or N gonorrhoeae by age and presence of mucopurulent cervicitis (MPC).

Marrazzo. Predictors of Cervical STD. Obstet Gynecol 2002.

 
Whereas all cervical findings and a diagnosis of mucopurulent cervicitis were independently associated with an increased likelihood of infection with either organism, the strong association between younger age and infection was independent of the presence of any cervical finding (Table 1Go). Nonwhite race was associated with a two-fold increase in detection of infection. Report of two or more sex partners in the last 2 months was associated with a small increase in risk of infection (P = .03); report of a new sex partner during the same time was not (P = .6). Controlling for year of visit did not significantly affect these findings. There were no statistically significant associations between a woman’s having a value missing in the medical record for any of the variables noted and her likelihood of cervical chlamydial or gonococcal infection.

The positive predictive values (PPV) of all cervical findings and of Gram stain smear of endocervical secretions for cervical infection were significantly higher in women younger than 25 years old than in women 25 years or older, and approximately 40% of all women 19 years or younger who had any cervical finding were infected with either organism (Table 2Go). Among women 25 years or older, only the presence of mucopus demonstrated a PPV above 18% for any age group (18.6% in women 25–29 years old).


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  		Table 2. Positive Predictive Values (PPV) of Features Associated with Cervical Chlamydial or Gonococcal Infection by Age Group
 
Figure 2Go outlines the effect of age, the presence of a clinical sign (defined as endocervical mucopurulent discharge or easily induced bleeding), and inflammation on Gram stain smear of endocervical secretions on the detection of chlamydial or gonococcal infection. Detection of inflammation on Gram stain smear improved the PPV of a clinical sign to predict infection for all age groups, and among women younger than 20 years old, was noted in the absence of any cervical sign in 28 infections (16% of all infections in this age group). However, inflammation on endocervical Gram stain was relatively insensitive in detecting infection in women without either cervical sign (sensitivity 26.5%, seen in 79 of 308 infections), and among all 520 infected women, provided the only indication of chlamydial or gonococcal infection in 79 (15.2%).



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  		Figure 2. Detection of cervical infection with C trachomatis or N gonorrhoeae utilizing age and cervical findings (number of women positive/number tested). Cervical sign is defined as the presence of either mucopurulent discharge or easily induced bleeding. GS = Gram stain.

Marrazzo. Predictors of Cervical STD. Obstet Gynecol 2002.

 

   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our analysis of a large number of women universally tested for endocervical infection with C trachomatis and N gonorrhoeae by culture yielded several clinically important findings. First, the data indicate that signs of cervicitis should be interpreted in the context of age. Cervical signs suggesting chlamydial or gonococcal infection had higher PPV in younger women. Approximately one in three women less than 25 years old with any cervical finding had infection with one or both of these pathogens; 40% of young women with mucopus alone were infected. These data support empiric treatment of young women with these findings.4 Because culture was used to detect C trachomatis, and is less sensitive than nucleic acid amplified tests such as ligase or polymerase chain reaction, it is likely that chlamydial infection was missed in some women with mucopus; thus, our estimate likely underestimates the true PPV of this finding.

In contrast, a relatively small proportion of women older than 25 years with any cervical finding had C trachomatis or N gonorrhoeae documented (9–17%, depending on the sign). Although all women with mucopurulent cervicitis should undergo diagnostic testing for these infections with the most sensitive test available, our data suggest that treatment for presumed chlamydial or gonococcal infection is not routinely indicated in women 25 years and older. Certain conditions may modify this approach for individual women seen in clinical practice, including sexual behavior risk factors that were not measured in this study, or if the likelihood of a woman’s return for treatment based on a positive test is judged to be low.

The third major finding of our analysis is that the sensitivity of Gram stain smear of endocervical secretions was low in the absence of mucopurulent cervicitis (sensitivity, 26%). Further, its PPV was too low (21% in all women) to justify its use to direct empiric treatment in the absence of mucopurulent cervicitis, especially in women older than age 25 (14%). Most studies that have directly examined the use of Gram stain of endocervical secretions have also concluded that the test has little independent utility in predicting cervical chlamydial infection.9,10,15,16 Among women with a C trachomatis prevalence of 14%, mucopurulent discharge and 30 or more PMN/HPF on Gram stain smear of endocervical secretions had similar sensitivities (24% and 25%, respectively), specificities (89% and 88%), and PPVs (29% and 24%) for chlamydial infection.9 The authors concluded that the presence of 30 or more PMN/HPF on endocervical Gram stain was a poor screening tool for chlamydial infection. Although the PPV of endocervical Gram stain may be improved by using a higher cutoff for PMN/HPF, one large study noted that 94% of all chlamydial infection would have been detected using criteria that did not include the Gram stain.16 Although such reports have discouraged routine use of endocervical Gram stain in many clinic settings, the test continues to be used in many venues that provide targeted STD evaluation and management.10 A recent study concluded that the test might be useful in populations with chlamydia or gonorrhea prevalence above 9%, although the presence of 30 or more PMN/HPF on endocervical Gram stain had a sensitivity of only 23% for detection of chlamydial infection detected by the ligase chain reaction assay.10 As in our study, others have noted that all cervical findings have a higher PPV for chlamydial infection in younger women.5,8

An additional argument against obtaining Gram stain smear of endocervical secretions concerns the variability in specimen adequacy. In a study of 214 STD clinic clients, inflammation on endocervical Gram stain independently predicted chlamydial infection; however, this relationship held true only when the analysis excluded the 24% of smears that were judged to be inadequate.6 Myziuk et al studied a low cutoff value (> 10 PMN/HPF) in predicting chlamydial cervical infections, and found that 55% of the Gram stains were inadequate; further, use of adequately performed Gram stains did not significantly increase the likelihood of predicting chlamydial infection.11

Our study has significant limitations. Our findings may not be generalizable to women in non-STD clinic settings with different C trachomatis prevalence. In particular, settings with significantly different prevalence of C trachomatis or N gonorrhoeae should carefully examine the predictive value of cervicitis in women age 25 years and older to help inform decisions about empiric antibiotic therapy. Second, we employed culture for the diagnosis of C trachomatis. Increased detection of C trachomatis by nucleic acid amplified tests (NAAT) relative to culture may be highest in infections not associated with findings of mucosal inflammation17,18; the PPV of cervical findings may change and should be studied when NAAT are used. However, culture for C trachomatis in our laboratory has demonstrated a sensitivity of 85–87% relative to expanded diagnostic standards incorporating NAAT.19 The differential sensitivity of NAAT and culture for N gonorrhoeae have been shown to be less than that for chlamydial infection.20

Appropriate treatment of cervicitis caused by C trachomatis and N gonorrhoeae is important to prevent infection of the upper genital tract and associated sequelae, and to interrupt transmission to sex partners. Moreover, treatment of cervicitis caused by C trachomatis or N gonorrhoeae results in decreased cervical shedding of human immunodeficiency virus, and may be an important means of decreasing the infectivity of human immunodeficiency virus–seropositive women.21 Our data support empiric treatment along with diagnostic testing for these infections in women younger than 25 years in whom induced bleeding or cervical mucopus are detected, and only diagnostic testing for women 25 years and older. The performance of Gram stain smear of endocervical secretions in predicting chlamydial or gonococcal cervical infection does not justify its routine use. Although C trachomatis and N gonorrhoeae are the predominant causes of mucopurulent cervicitis, the cervix appears normal in most of these infections (58% in this study). This is especially true for chlamydial infection, for which control in women relies not only on recognition and appropriate treatment of cervical inflammation, but also on routine screening of sexually active women as recommended by current guidelines.22


   Footnotes
 
Presented in part at the STIs at the Millenium Conference, May 2000, Baltimore, Maryland.

This study was supported in part by National Institutes of Health grant R29-AI41153-04 (JMM).

PII S0029-7844(02)02140-3

Received November 27, 2001. Received in revised form February 25, 2002. Accepted March 21, 2002.


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Paavonen J, Critchlow CW, DeRouen T, Stevens CE, Kiviat N, Brunham RC, et al. Etiology of cervical inflammation. Am J Obstet Gynecol 1986;154:556–64.[Medline]

2. Paavonen J. Chlamydia trachomatis: A major cause of mucopurulent cervicitis and pelvic inflammatory disease in women. Curr Probl Dermatol 1996;24:110–22.[Medline]

3. Brunham RC, Paavonen J, Stevens CE, Kiviat N, Kuo CC, Critchlow CW, et al. Mucopurulent cervicitis—the ignored counterpart in women of urethritis in men. N Engl J Med 1984;311(1):1–6.[Abstract]

4. Centers for Disease Control and Prevention. 1998 guidelines for treatment of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep 1998;47(RR-1):1–111.[Medline]

5. Critchlow CW, Wolner-Hanssen P, Eschenbach DA, Kiviat NB, Koutsky LA, Stevens CE, et al. Determinants of cervical ectopia and of cervicitis: Age, oral contraception, specific cervical infection, smoking, and douching. Am J Obstet Gynecol 1995;173:534–43.[Medline]

6. Katz BP, Caine VA, Jones RB. Diagnosis of mucopurulent cervicitis among women at risk for Chlamydia trachomatis infection. Sex Transm Dis 1989;16(2):103–6.[Medline]

7. Knud-Hansen CR, Dallabetta GA, Reichart C, Pabst KM, Hook EW 3rd, Wasserheit JN. Surrogate methods to diagnose gonococcal and chlamydial cervicitis: Comparison of leukocyte esterase dipstick, endocervical gram stain, and culture. Sex Transm Dis 1991;18:211–6.[Medline]

8. Moscicki B, Shafer MA, Millstein SG, Irwin CE Jr, Schachter J. The use and limitations of endocervical Gram stains and mucopurulent cervicitis as predictors for Chlamydia trachomatis in female adolescents. Am J Obstet Gynecol 1987;157(1):65–71.[Medline]

9. Nugent RP, Hillier SL. Mucopurulent cervicitis as a predictor of chlamydial infection and adverse pregnancy outcome. The Investigators of the Johns Hopkins Study of Cervicitis and Adverse Pregnancy Outcome. Sex Transm Dis 1992;19:198–202.[Medline]

10. Moore SG, Miller WC, Hoffman IF, Fox KK, Owen-O’Dowd J, McPherson JT, et al. Clinical utility of measuring white blood cells on vaginal wet mount and endocervical gram stain for the prediction of chlamydial and gonococcal infections. Sex Transm Dis 2000;27:530–8.[Medline]

11. Myziuk L, Romanowski B, Brown M. Endocervical Gram stain smears and their usefulness in the diagnosis of Chlamydia trachomatis. Sex Transm Infect 2001;77:103–6.[Abstract/Free Full Text]

12. Centers for Disease Control and Prevention. 1993 sexually transmitted diseases treatment guidelines. MMWR Morb Mortal Wkly Rep 1993;42(RR-14):1–102.[Medline]

13. Hook EW 3rd, Handsfield, HH. Gonococcal infections in the adult. In: Holmes KK, Sparling PF, Mardh P-A, Lemon SM, Stamm WE, Piot P, et al, eds. Sexually transmitted diseases, 3rd ed. New York: McGraw-Hill; 1999: 451–66.

14. Stamm WE, Tam M, Koester M, Cles L. Detection of Chlamydia trachomatis inclusions in Mccoy cell cultures with fluorescein-conjugated monoclonal antibodies. J Clin Microbiol 1983;17:666–8.[Abstract/Free Full Text]

15. Willmott FE. Mucopurulent cervicitis: A clinical entity? Genitourin Med 1988;64:169–71.[Medline]

16. Sellors J, Howard M, Pickard L, Jang D, Mahony J, Chernesky M. Chlamydial cervicitis: Testing the practice guidelines for presumptive diagnosis. CMAJ 1998;158(1): 41–6.[Abstract]

17. Marrazzo JM, Whittington WL, Celum CL, Handsfield HH, Clark A, Cles L, et al. Urine-based screening for Chlamydia trachomatis in men attending sexually transmitted disease clinics. Sex Transm Dis 2001;28:219–25.[Medline]

18. Geisler W, Suchland RJ, Whittington WLH, Stamm WE. Quantitative culture of Chlamydia trachomatis: Relationship of inclusion-forming units produced in culture to clinical manifestations and acute inflammation in urogenital disease. J Infect Dis 2001;184:1350–4.[Medline]

19. Lee HH, Chernesky MA, Schachter J, Burczak JD, Andrews WW, Muldoon S, et al. Diagnosis of Chlamydia trachomatis genitourinary infection in women by ligase chain reaction assay of urine. Lancet 1995;345:213–6.[Medline]

20. Koumans EH, Johnson RE, Knapp JS, St. Louis ME. Laboratory testing for Neisseria gonorrhoeae by recently introduced nonculture tests: A performance review with clinical and public health considerations. Clin Infect Dis 1998;27:1171–80.[Medline]

21. McClelland RS, Wang CC, Mandaliya K, Overbaugh J, Reiner MT, Panteleeff DD, et al. Treatment of cervicitis is associated with decreased cervical shedding of HIV-1. AIDS 2001;15(1):105–10.[Medline]

22. Centers for Disease Control and Prevention. Recommendations for the prevention and management of Chlamydia trachomatis infections, 1993. MMWR Recomm Rep 1993;42(RR-12):1–39.[Medline]




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