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THE REAL WORLD OF STD PREVENTION

Should Female Partners of Men With Non-Gonococcal Urethritis, Negative for Chlamydia trachomatis and Mycoplasma genitalium, Be Informed and Treated? Clinical Outcomes From a Partner Study of Heterosexual Men With NGU

Jason J. Ong, PhD, MMed, MBBS,* Angela Sarumpaet, MBBS,* Eric P.F. Chow, PhD,*Catriona Bradshaw, PhD,*Marcus Chen, PhD,*Tim Read, PhD,*and Christopher K. Fairley, PhD*

Background: To determine if female partners of men with pathogen- negative non-gonococcal urethritis (NGU) are at risk of genital infection. Methods: Secondary data analysis using health records from a large sexually transmitted disease clinic in Melbourne of 1710 men and their female partners attending on the same day from January 2006 to April 2015. Proportions of female partners with symptoms suggesting genital infection or pelvic inflamma- tory disease (PID) were determined for: (1) men with NGU and no Chlamydia trachomatis or Mycoplasma genitalium (referred to as pathogen-negative NGU) (n = 91); 2) men with urethral C. trachomatis (n = 176); 3) men with urethral M. genitalium (n = 26); and 4) asymptomatic men (n = 652). Results: Female partners of men with pathogen-negative NGU experienced deep pelvic pain (adjusted odds ratio [AOR], 2.2; 95% confidence interval [CI], 1.14.4), post coital bleeding (AOR, 2.4; 95% CI, 1.24.9), and dysuria (AOR, 3.7; 95% CI, 1.68.6) more commonly and were diagnosed with PID more commonly (AOR, 4.8; 95% CI, 2.111.3) than the female partners of asymptomatic men. Pelvic inflammatory disease was not more likely to be diagnosed in the female partners of men with genital warts (AOR, 1.4; 95% CI, 0.54.4) or candidiasis (AOR, 1.2; 95% CI, 0.43.5) than the female partners of asymptomatic men. The female partners of men with chlamydia experienced post coital bleeding more (AOR, 1.9; 95% CI, 1.03.6) and were more likely to be diagnosed with PID (AOR, 3.6; 95% CI, 1.68.0). Conclusions: The female partners of men with pathogen-negative NGU may be at increased risk of genital infection, even if a recognised pathogen is not identified in the man.

U rethritis is one of the most common clinical presentations in

sexual health and is caused by a number of sexually transmit-

ted pathogens. It is categorized as either gonococcal (Neisseria

From the *Melbourne Sexual Health Centre, Alfred Health, Carlton; and Central Clinical School, Monash University, Clayton, Victoria, Australia J.O. and A.S. contributed equally to this article. This work was supported by the Australian National Health and Medical Research Council (NHMRC) programme grant (No. 568971). The NHMRC also supports the 3 authors with Early Career Fellowships (JJO No. 1104781, EPCF No. 1091226, TRHR No. 1091536). Conflict of interest: None declared. Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journals Web site (http://www.stdjournal.com). Correspondence: Jason J. Ong, PhD, MMed, MBBS, FRACGP, Melbourne Sexual Health Centre, 580 Swanston Street, Carlton, Victoria 3053, Australia, Central Clinical School, Monash University, Clayton Victoria, Australia. Email: jong@mshc.org.au. Received for publication June 3, 2016, and accepted September 12, 2016. DOI: 10.1097/OLQ.0000000000000546 Copyright © 2016 American Sexually Transmitted Diseases Association All rights reserved.

gonorrhea) or non-gonococcal urethritis (NGU). Various studies have identified causative agents for NGU with the most common causes being Chlamydia trachomatis (accounting for 2050% of cases) followed by Mycoplasma genitalium (1025% of cases), but other pathogens such as adenovirus, Trichomonas vaginalis, and herpes simplex virus (HSV) have also less commonly been as- sociated with NGU. 16 These same studies report no detectable pathogens (ie, pathogen-negative NGU) in 2861% of cases. There is evidence to support the treatment of sexual part- ners of men with NGU due to a known pathogens, such as C. trachomatis and M. genitalium, as published data show these women are at risk for acquiring the same pathogen and are at higher risk for complications, such as pelvic inflammatory disease (PID) and its sequelae of chronic pelvic pain, ectopic pregnancy, and infertility. 79 Consequently, international treatment guidelines recommend treatment for female sexual partners of men with NGU in whom these pathogens are detected. 1012 However, clinicians vary in the extent to which they advise men with NGU to send their female partners for assessment and treatment. 13 There is no consensus regarding the treatment of fe- male partners of men with pathogen-negative NGU in national guidelines. There were no recommendations in Australia until mid-2016 when guidelines changed to recommend partners of NGU should be traced back for a minimum of 4 weeks, but there is no suggestion of how to manage these partners. 11 The United Kingdom's recommendation is based on expert opinion that treat- ment of female partners is prudent to potentially reduce female morbidity and risk of recurrent/persistent NGU in the index male.10 In the United States, they recommend treatment of female partners of men with NGU based on research, suggesting that women may still test positive for chlamydia even if their male sex- ual partners do not. 12,14 These inconsistencies in guidelines are likely to be due to a paucity of clinical studies that determine whether female sexual partners of men with pathogen-negative NGU are also at risk of any harm and therefore should be informed and treated. 15 Despite calls 10 years ago in an editorial by Handsfield 15 to address the question of whether there is any asso- ciated morbidity in female partners of men with pathogen-negative NGU, there remains no substantial empirical data to inform treatment decisions. We aimed to compare genital symptoms suggestive of geni- tal infection or PID among the female sexual partners of men with pathogen-negative NGU and compared these to female partners of: men with urethral C. trachomatis, men with urethral M. genitalium, or asymptomatic pathogen-negative men. We hypothe- sized that if the proportion of female partners of men with pathogen-negative NGU who experienced symptoms of genital in- fection or PID were similar to the partners with men with NGU

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Pathogen-Negative NGU

caused by C. trachomatis or M. genitalium, this would build the case for the need to recommend contact tracing and routine assess- ment of female partners. Conversely, if the clinical features of fe- male sexual partners of men with pathogen-negative NGU were more like partners of asymptomatic men, then further management of female partners may not be warranted.

METHODS

Study Population

Melbourne Sexual Health Centre (MSHC) is the only public sexual health clinic in Melbourne, Australia. Between January 2006 and April 2015, 35,241 individual heterosexual male patients and 30,899 individual heterosexual female patients attended MSHC. We firstly identified 3104 heterosexual men who indicated they were attending with their female partners on the same day. We then matched each sexual partnership by identifying the female partner's full name and/or patient identification number entered by the clini- cians into the medical record, and the date of consultation. We ex- cluded 1394 partnerships because we could not identify the female sexual partner. Therefore, 1710 heterosexual partnerships with consultations for both the male and their female partners linked on the same day were included in our analysis (Fig. 1).

Data Collection

Patients provided their demographics, main reason for presenting, and sexual history using computer-assisted self- interviewing. They were also asked if they were attending with their current sexual partner and if so, that person's name. Data from computer-assisted self-interviewing included in this study were: age, number of sexual partners in the last 3 months, and the consistency of condom use (always or not always with penile-vaginal sex) in the preceding 3 months. The clinician re- corded the clinical findings in the patient's health record and se- lected a diagnosis from a pre-determined list. It is general clinic policy that patients who attend with their sexual partner are seen by different clinicians. A full electronic health record re- placed a paper based record in March 2011. 16

Definitions

Pathogen-negative NGU was defined as men presenting with urethritis who had a negative test for N. gonorrhea, C. trachomatis, and M. genitalium. Urethritis was defined as any of the following urethral symptoms: urethral discharge, dysuria or urethral irritation, alone or in combination, lasting less than a month in sexually active men. We did not require microscopic ev- idence of urethral inflammation as we have previously found this to be unreliable in predicting the presence of pathogens. 2 To ex- clude gonorrhea, a urethral swab was performed where clinically indicated for smear and Gram stain and N. gonorrhoeae culture using modified Thayer Martin medium, and a first pass urine for strand displacement amplification (ProbeTec-ETCT amplified DNA assay; Becton, Dickinson). All men with NGU were tested for C. trachomatis by strand displacement amplification (ProbeTec-ETCT amplified DNA assay; Becton, Dickinson) and M. genitalium PCR. 17 Patients attending MSHC were initially assessed by the tri- age nurse to be symptomatic or asymptomatic. Pelvic inflamma- tory disease was a clinical diagnosis where clinicians used the following standardized criteria: sexually active woman at risk for STIs who experienced pelvic or lower abdominal pain and had at least one of the following signs on pelvic examination (cervical motion tenderness or uterine tenderness or adnexal tenderness). Predominance of leukocytes in vaginal secretions and signs of cer- vicitis were used to increase specificity of the diagnosis. Men were defined as asymptomaticfor the purposes of the control group if they were classified as asymptomatic by the triage nurse and had a diagnosis of asymptomaticby the doctor and tested negative for

  • C. trachomatis. Asymptomatic men were not tested for urethral

gonorrhea or M. genitalium. We reviewed all electronic records from March 9, 2011, to April 20, 2015, of women to determine the proportion who had specific individual symptoms suggestive of genital infection (deep

pelvic pain, postcoital bleeding, and dysuria). We did not review 379 paper records (before March 9, 2011) because these were kept off site and were expensive to retrieve. We therefore reviewed symptoms in 1331 women who had an electronic record.

Pathogen-Negative NGU caused by C. trachomatis or M. genitalium , this would build the case for

Statistical Analysis

Data were analyzed using SPSS (version 20). Univariate lo- gistic regression was used to calculate the odds ratios (OR), and 95% confidence intervals (CI) for the associations between each fe- male diagnosis (ie, symptoms suggestive of genital infection or PID) and the clinical diagnosis of the male (urethral C. trachomatis,

  • M. genitalium, pathogen-negative NGU and asymptomatic men as

the control group). To account for differences in sexual risk behav- iors, the multivariate logistic regression adjusted for consistency of condom use and the number of male partners reported by the female within the last 3 months. As previous studies have identified C. trachomatis and M. genitalium in female sexual partners of men with pathogen-negative NGU, 14 we also excluded women with these diagnoses from our final analysis. In a sample size calculation, 85 men with pathogen-negative NGU and 650 asymptomatic men provided 80% power to detect an OR of at least 2 for the presence of symptoms in women. This research was approved by the Alfred Health Human Ethics Committee (Project 74/15).

RESULTS

Table 1 summarizes key characteristics of the 1710 hetero- sexual partnerships by gender of the patient. Among the 1710 men in these partnerships, 91 (5%) had pathogen-negative NGU, 176 Figure 1. Flowchart of selection of the study population. (10%) were diagnosed with C. trachomatis and 26 (2%) with M.

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Ong et al.

TABLE 1. Demographics of the Sexual Partnerships

Characteristics

Males (n = 1710)

Females (n = 1710)

Demographic and behavioral characteristics Age No. opposite sex partners in last 3 mo

n

Median (IQR) 28 (2434) 1 (12) % (95% CI)

n

Median (IQR) 26 (1767) 1 (12) % (95% CI)

Condom use in the last 3 mo Always

186

11 (1012)

177

10 (911)

Not always

1392

81 (7983)

1218

71 (6973)

Missing Diagnoses

132

8 (79)

315

19 (1721)

Asymptomatic*

652

38 (3640)

732

43 (4145)

Urethral C. trachomatis

176

10 (911)

155

9 (810)

Urethral M. genitalium

26

2 (13)

9

1 (12)

Pathogen-negative NGU

91

5 (46)

-

-

Pelvic inflammatory disease

-

-

85

5 (46)

*Negative for C. trachomatis. IQR, interquartile range.

genitalium. Among the females in these partnerships, 155 (9%) were diagnosed with C. trachomatis and 9 (1%) were diagnosed with M. genitalium. For female sexual partners of men with pathogen-negative NGU, 6 (7%) of 91 of females had C. trachomatis and were excluded from subsequent analyses, and none had M. genitalium. The analysis for symptoms in 1331 women concurrently at- tending with their male partners showed that female sexual part- ners of men with pathogen-negative NGU had an increased odds (adjusted OR [AOR], 3.2; 95% CI, 1.85.5) of reporting any symptoms during triage compared with the asymptomatic control group (Table 2). This was of a similar magnitude to female sexual partners of men with urethral chlamydia (AOR, 1.8; 95% CI, 1.22.7). The female partners of men with pathogen-negative NGU also had significantly increased odds of reporting deep pel- vic pain (AOR, 2.2; 95% CI, 1.14.4), postcoital bleeding (AOR, 2.4; 95% CI, 1.24.9), and dysuria (AOR, 3.7; 95% CI, 1.68.6) compared with the control group of female partners of asymptom- atic men after adjusting for the number of male partners and the consistency of condom use in the last 3 months (Table 3) but not vaginal discharge (OR, 0.8; 95% CI, 0.41.6) or vulvovaginal itch (OR, 1.2; 95% CI, 0.53.0). Further, the female sexual partners of men diagnosed with pathogen-negative NGU had an increased odds (AOR, 4.8; 95% CI, 2.111.3) of being diagnosed with PID (Table 4). Again, this was of similar magnitude to female sexual partners of men diag- nosed with urethral chlamydia (AOR, 3.6; 95% CI, 1.68.0). A subanalysis of female partners who had a cervical swab sent for gram stain (n = 120) showed greater but nonsignificant odds of el- evated polymorphonuclear leukocytes on their cervical gram stain

of female partners of men with NGU (OR, 2.3; 95% CI, 0.96.0) compared with female partners of asymptomatic men (Supple- mentary Table 1 and 2, http://links.lww.com/OLQ/A143).

DISCUSSION

This study addresses the methodologically challenging is- sue of whether there are adverse health consequences for the fe- male partners of men with pathogen-negative NGU. We found that these women were just as likely to have PID and symptoms suggestive of a genital infection, as the female partners of men with urethral C. trachomatis. The female partners of men without symptoms or diagnosed with conditions not associated with PID, such as genital warts or candidiasis were not more likely to have PID. These findings suggest that the female sexual partners of men with pathogen-negative NGU may be at increased risk of gen- ital infection. Although there are potential biases associated with this study, it provides strong evidence to support contacting female partners. Our findings support guideline recommendations that female partners of men with pathogen-negative NGU be rou- tinely contacted and clinically assessed and raise the clinical issue of whether they may benefit from antibiotic treatment. There were a number of strengths to our study. The inclu- sion of the large number of sexual partnerships, the use of a control group (female sexual partners of men who were asymptomatic), and comparator groups (female sexual partners of men with C. trachomatis or M. genitalium) allowed a precise estimation of risk between a group thought to be at low risk of harm (control) and those known to be at substantial risk of harm (C. trachomatis and M. genitalium). We excluded female partners of men with

TABLE 2. Logistic Regression Analysis of Females Reporting any Symptoms During Triage According to the Male Sexual Partner's Diagnosis

Male Diagnosis

Female With Symptoms Crude: OR (95% CI)

P

Adjusted OR* (95% CI)

P

Asymptomatic, N = 625

276 (44%)

1.0 (reference)

1.0 (reference)

Urethral C. trachomatis, N = 162

93 (57%)

1.7 (1.22.4)

0.002

1.8 (1.22.7)

0.005

Urethral M. genitalium, N = 26

16 (62%)

2.0 (0.94.5)

0.086

2.1 (0.85.5)

0.114

Pathogen-negative NGU, N = 85

60 (70%)

3.0 (1.95.0)

<0.001

3.2 (1.85.5)

<0.001

*Adjusted for condom use and number of male sexual partners in the last 3 months. Excluded 27 females with missing data on symptoms.

Excluded 6 sexual partnerships where the female sexual partners of the 91 men with pathogen-negative NGU were diagnosed with chlamydia despite their male partners testing negative.

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Pathogen-Negative NGU

TABLE 3. Logistic Regression Analysis for Specific Symptoms Among Female Partners of Men Who Were Asymptomatic, Compared With Men Diagnosed With Pathogen-Negative NGU C. trachomatis or M. genitalium

Male Diagnosis

Symptoms by Clinician Number

Crude OR (95% CI)

P

Adjusted OR (95% CI)

P

Asymptomatic

Deep pelvic pain 58 (10%)

1.0 (reference)

1.0 (reference)

Urethral C. trachomatis

18 (14%)

1.5 (0.82.6)

0.193

1.7 (0.93.2)

0.099

Urethral M. genitalium

2 (10%)

0.9 (0.24.1)

0.923

1.2 (0.35.3)

0.855

Pathogen-negative NGU

12 (20%)

2.2 (1.14.4)

0.024

2.4 (1.24.9)

0.017

Asymptomatic

Postcoital bleeding 53 (9%)

1.0 (reference)

1.0 (reference)

Urethral C. trachomatis

21 (17%)

1.9 (1.13.3)

0.018

1.9 (1.03.6)

0.045

Urethral M. genitalium

4 (19%)

2.3 (0.87.1)

0.148

1.9 (0.56.9)

0.333

Pathogen-negative NGU

12 (20%)

2.4 (1.24.9)

0.012

2.5 (1.25.1)

0.013

Asymptomatic

Dysuria 23 (4%)

1.0 (reference)

1.0 (reference)

Urethral C. trachomatis

8 (6%)

1.6 (0.73.7)

0.267

1.0 (0.32.9)

0.928

Urethral M. genitalium

2 (10%)

2.6 (0.612.1)

0.210

1.4 (0.211.1)

0.764

Pathogen-negative NGU

8 (13%)

3.7 (1.68.6)

0.003

2.6 (1.06.7)

0.056

Asymptomatic

Vaginal discharge 115 (21%)

1.0 (reference)

Urethral C. trachomatis

27 (23%)

1.1 (0.71.8)

0.591

Urethral M. genitalium

11 (42%)

2.7 (1.26.2)

0.013

Pathogen-negative NGU

10 (17%)

0.8 (0.41.6)

0.462

Asymptomatic

Vulvovaginal itch 52 (10%)

1.0 (reference)

Urethral C. trachomatis

10 (9%)

0.9 (0.41.8)

0.766

Urethral M. genitalium

1 (4%)

0.4 (0.02.7)

0.992

Pathogen-negative NGU

6 (10%)

1.2 (0.53.0)

0.635

pathogen-negative NGU who were diagnosed with C. trachomatis or M. genitalium from the analysis. This strengthens our findings that increased symptoms suggestive of genital infection were not caused by C. trachomatis or M. genitalium in female partners. There were limitations to our analysis. First, men with NGU were not systematically tested for other causes for NGU such as T. vaginalis, HSV, or adenovirus as these were not routine clinical tests. However, these organisms are uncommon or rare causes of NGU (0.34%) in Melbourne, 2 and HSVand adenovirus are not known to be associated with PID, suggesting this limitation is unlikely to explain our findings. We also did not test for ureaplasma species because of their uncertain role in NGU, and in routine clinical practice, these tests are not undertaken. 2 Second, PID may be underdiagnosed without the criterion standard of lap- aroscopic or histological confirmation, as neither were undertaken routinely in outpatient clinical practice. Third, there is a risk for as- certainment bias where the doctor seeing the female may be more likely to overinterpret the clinical findings, such as the bimanual examination, if they know there is a male partner with NGU. There is a further important bias in our study. It would be reasonable to assume that symptomatic female partners of men with NGU would be more likely to attend with their male partners

than asymptomatic women, and therefore, the women would be more likely to be symptomatic than women who attended as part- ners of asymptomatic men. If this bias was operating, it could re- sult in our findings that symptoms and PID were associated with men with pathogen-negative NGU. To address this concern, we looked at the risk of symptoms and PID in the women whose male partners had symptomatic conditions not associated with PID, such as genital warts and candidiasis. However, we found that the female partners of men with genital warts, or candidiasis were no more likely to have PID than the female partners of men with- out symptoms. Yet a known cause of PID, chlamydia in men, was not surprisingly associated with a higher risk of PID. Our observa- tion that pathogen-negative NGU in men was associated with PID in their female partners suggests that this bias did not explain the association but there may be other unidentified biases (eg, concur- rency) operating that we did not measure. Three other studies of female partners of men with chlamydia- negative NGU have been published over the last 35 years. All were small case series with 99, 75, and 41 partners, none included a control group, and none tested men for M. genitalium. 14,18,19 Furthermore, these studies focused on the diagnosis of concomitant STIs in female partners, whereas our study examined the clinically significant

TABLE 4. Logistic Regression Analysis of Females Diagnosed With PID According to the Male Sexual Partner's Diagnosis

 

Male Diagnosis

Female With PID

Crude: OR (95% CI)

P

Adjusted OR* (95% CI)

P

Asymptomatic N = 652

17 (3%)

1.0 (reference)

1.0 (reference)

Urethral C. trachomatis N = 176

18 (10%)

4.3 (2.18.4)

<0.001

3.6 (1.68.0)

0.002

Urethral M. genitalium N = 26

2 (8%)

3.1 (0.714.2)

0.123

3.5 (0.716.8)

0.112

Genital warts N = 114

4 (4%)

1.4 (0.44.1)

0.586

1.4 (0.54.4)

0.533

Candidiasis N = 158

5 (3%)

1.2 (0.43.4)

0.699

1.2 (0.43.5)

0.687

Pathogen-negative NGU N = 85

10 (12%)

5.0 (2.211.4)

<0.001

4.8 (2.111.3)

<0.001

*Adjusted for condom use and number of male sexual partners in the last 3 months.

Excluded 6 sexual partnerships where the female sexual partners of the 91 men with pathogen-negative NGU were diagnosed with chlamydia despite their male partners testing negative.

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Ong et al.

endpoints of PID and symptoms suggestive of genital infection such as deep pelvic pain, postcoital bleeding, and dysuria. Our study ad- dresses previous studies' limitations by testing for both C. trachomatis and M. genitalium and provided a large number of linked sexual part- ners of men who were asymptomatic (n = 652) as the control group, increasing the statistical power of the study. On the basis of our findings, until we can determine the pathogens causing NGU, we suggest that current guidelines con- sider recommending female sexual partners of men with pathogen-negative NGU be contacted and advised to have prompt clinical assessment and testing. There are currently no guidelines or published evidence to guide the antibiotic choice for treatment of an asymptomatic female partner of the man with pathogen- negative NGU. Until we determine the likely causative pathogen and its precise treatment, one reasonable option may be to offer the same management as men with C. trachomatis/M. genitaliumnegative NGU (ie, azithromycin 1 g once off or doxycycline 100 mg twice daily 7 days). We hypothesize that if the organisms are the same, this management should also work for the female partner. An increased risk of genital infection and PID might be expected in female partners of men with pathogen-negative NGU, simply due to failure to detect pathogens in some of those men. This might be due to imperfect sampling or test sensitivity or because of natural clearance of infection. It is harder to explain why this risk remained elevated in women, even after exclusion of women with C. trachomatis and M. genitalium. Further studies are needed to identify whether this might be due to other potential pathogen(s) causing NGU. Bradshaw's case-control study of men with NGU found that men with pathogen-negative NGU reported similar symptoms to pathogen-positive cases, suggesting that in- fection with potential pathogens that are not currently identifiable may be a likely cause. 2 Pathogens being investigated as causal agents of pathogen-negative NGU include biovars of Ureaplasma urealyticum, 20 22 or specific BV-associated bacteria. 23 Other pathogens under consideration include other herpes viruses, such as cytomegalovirus or Epstein-Barr virus, as a cause of gen- ital ulceration. 24,25 Identifying the pathogen(s) that is transmitted between the sexual partners would strengthen the importance of identifying and treating female sexual partners of men with pathogen-negative NGU. The key message of this study is that the odds of symptoms among the female partners of men with pathogen-negative NGU were similar in magnitude to those in female partners of men with chlamydia, a known cause of PID. This provides indirect evidence of an underlying infectious etiology in a significant proportion of these women and would suggest that female sexual partners of men with NGU undergo clinical assessment and the consideration of antibiotics.

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Sexually Transmitted Diseases Volume 44, Number 2, February 2017

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