GONORRHEA INFECTIONS CAUSE SUBSTANTIAL morbidity and healthcare costs1 and facilitate HIV transmission.2–4 Although gonorrhea rates have declined dramatically since 1975 in the United States, hyperendemic foci persist, especially in urban areas.5–10 As a result of underreporting11 and the large number of asymptomatic and undetected infections,12 the true burden of gonorrhea infection in the United States is likely underestimated. Traditional public health interventions, including partner referral services, have not impacted gonorrhea rates.13–16 The Healthy People 2010 objectives include the reduction of national gonorrhea rates to below 19 per 100,000.17 To meet these goals, innovative disease control and prevention activities are necessary.
High-risk individuals, or “core transmitters,” disproportionately contribute to the endemicity/hyperendemicity of gonorrhea.18–21 Although safe and effective single-dose treatment is available, gonorrhea reinfections can account for as much as 48% of reported morbidity.6,22–27 Gonorrhea reinfections after treatment have consistently found to be associated with male gender,23,25 black race,23,25–29 younger age,23,25,26 low socioeconomic status,25–28 and increased number of sexual partners.25,26,29
In Baltimore, we have shown that those with reinfections were more likely to live closer to other repeaters.6 However, most studies of reinfection are limited to retrospective cohorts defined through clinic or health department data, where most infections detected are through testing those with clinical symptoms. Therefore, estimated reinfection rates are likely underestimated as a result of ascertainment biases inherent in passive surveillance.
Active health department-initiated partner referral and treatment services are generally not offered for gonorrhea in the United States as a result of limited resources and large disease burden.16 In 2001, an expert panel convened by the Centers for Disease Control and Prevention (CDC) recommended the rescreening of those with gonorrhea 3 to 6 months after initial infection. The panel also recommended developing interventions that target those most likely to transmit infection.30 In areas with large gonorrhea disease burdens, detecting those at highest risk for reinfection and facilitating partner services may prove to be an effective means to control gonorrhea transmission in a community and decrease population-level morbidity.
On the basis of the CDC recommendations, the Baltimore City Health Department (BCHD) implemented procedures in 2003–2004 for active follow-up of all persons diagnosed with urogenital gonorrhea in the sexually transmitted disease (STD) clinics to evaluate this activity as a possible disease control strategy. Here we describe our experience, and the estimated impact in case finding, as well as incidence and risk factors of gonorrhea reinfection.
Materials and Methods
In 2003, BCHD instituted procedures in its 2 STD clinics for active follow-up of persons diagnosed with gonorrhea to screen for repeat infection. Between September 2003 and May 2004, clinician staff counseled all clients diagnosed with urogenital gonorrhea at the 2 Baltimore STD clinics that they would be offered follow-up at 3 months to assess for repeat infection. Clinical specimen collection and gonorrhea testing procedures by culture in our setting have been previously described.31 All patients diagnosed with gonorrhea were given standard antibiotic treatment regimens32 along with an appointment card for follow-up.
A project coordinator identified and assigned disease investigation specialists (DISs) gonorrhea cases to follow up. Weekly, the project coordinator identified patients with gonorrhea who had been treated 3 months before and determined if they had been diagnosed with a gonorrhea infection within 2 weeks before follow-up. If patients were diagnosed and treated within the prior 2 weeks, follow-up was not initiated; all other patients were assigned to DISs for active follow-up. Three months after the date of treatment for the original (baseline) gonorrhea episode, DISs attempted to locate the client if they did not return as scheduled to obtain a urine specimen for nucleic acid amplification testing (NAAT) for both gonorrhea and chlamydia. Clients were contacted up to 3 times by DISs either in person or by telephone and DISs offered to meet the client in their homes, schools, or workplace as desired. Clients were eligible for one follow-up visit during the study period; therefore, if the client were to become reinfected and attend the STD clinic for evaluation a second time, they were not evaluated 3 months later.
At the follow-up visit, clients were offered an additional research component of the Baltimore Repeaters Project (BRP), which involved a 30-minute behavioral interview. Written informed consent was obtained. As compensation for participation in the research interview, clients received a $20 gift card to either a local grocer or retail store. Interviews were conducted in person and DIS-recorded results on standardized forms.
Urine specimens were tested for gonorrhea and chlamydia using Amplicor polymerase chain reaction (Roche Diagnostic Systems, Branchburg, NJ). Urine specimens and BRP forms (including the research interview) were linked using a barcode system. DISs attempted to notify and facilitate treatment on all with infection identified through follow-up testing. Clients were assured that all data were confidential and that urine specimens would not be tested for drugs. The protocols were approved by both the BCHD and Johns Hopkins University School of Medicine Institutional Review Boards.
Data Collection and Aggregation
Our analysis includes clients diagnosed with urogenital gonorrhea at the baseline clinic visit as well as demographic, behavioral, and clinical characteristics collected at that time. For those who were located and consented to survey participation, we included any follow-up data collected, including the research interview. At the end of the project period, we queried all BCHD morbidity records to determine if clients were diagnosed with subsequent gonorrhea, chlamydia, early syphilis, and/or HIV infections either before or during the analysis period. This included cases diagnosed at the STD clinics and other BCHD clinics as well as cases reported by private providers.
Data from the baseline clinical visit, the Health Department morbidity record, follow-up visit data, research interview (when conducted), and the post hoc morbidity abstraction were aggregated into a master dataset for evaluation. Clients’ residential addresses were geocoded using the ArcGIS software (Environmental Systems Research Institute [ESRI], Redlands, CA).
The outcome of interest was first gonorrhea reinfection event, which was either identified through morbidity reporting in the follow-up period or as a positive test through active follow-up measures. Gonorrhea episodes that occurred 14 or more days after the initial baseline infection were considered reinfections.6,24 We compared those who completed follow-up procedures at 3 months with those who did not using chi-squared statistics for categorical variables and Wilcoxon rank sum test for continuous data.33 Additionally, we compared characteristics across reasons for not attending the follow-up visit (i.e., refusal, inability to locate, residence outside of Baltimore). We coded residential addresses and created a map of the proportion of reported gonorrhea that was the result of repeat infections.6 We then classified those with repeat infections according to the level of repeat gonorrhea burden in their census tract of residence.
We estimated the incidence of reinfection using person-time analysis. For each individual, person-time accrued from the time of treatment for the initial infection until the time of the first reinfection (either identified through follow-up or abstraction) or until July 31, 2004, in which those without a reinfection were administratively censured. Therefore, clients who did not complete urine testing at the 3-month follow-up visit and had no reported gonorrhea episodes during the project period reported to the BCHD contributed person-time from the date of treatment of the baseline infection to the administrative censoring date. Incidence rates were calculated by dividing the total number of gonorrhea reinfection by the total accrued person-time. All person-time is presented per 100 person-years. Ninety-five percent confidence intervals were calculated assuming a Poisson distribution for the log rate parameter.34
A total of 667 individuals were diagnosed with urogenital gonorrhea infection at the initial clinic visit and were scheduled for recommended follow-up procedures. Of these, 178 (27%) completed the field-based follow-up testing procedures. Efforts to reevaluate clients for gonorrhea reinfection were unsuccessful in 489 (73%): 263 (54%) could not be located, 170 (35%) refused, and 56 (11%) resided outside of Baltimore City or could not be evaluated for other reasons. All 178 who had a urine specimen obtained at follow-up also completed the research interview. Table 1 shows demographic, behavioral, and clinical characteristics of those with gonorrhea diagnosed at the baseline visit. Most were male (82%), black (95.8%), and 17% resided in a census tract in the highest quintile of reported repeat gonorrhea infection for 2001–2002.
Table 2 shows comparisons between those who completed follow-up procedures and those who did not. Although females were more likely to have been seen at follow-up, few other differences existed. Those who did not get the 3-month evaluation were more likely to report condom use at last sex. A total of 489 persons with gonorrhea at baseline did not have follow-up testing, most (54%) because they could not be located.
Overall, 54 individuals had a gonorrhea reinfection during 390.8 person-years of follow-up for an incidence of 13.8 per 100 person-years (95% confidence interval [CI], 10.6–18.0 per 100 person-years). The incidence of gonorrhea reinfection among those who did not return for the follow-up visit but were identified through morbidity review only was 12.7 per 100 person-years (95% CI, 8.9–17.6 per 100 person-years). Overall, the median time to reinfection was 103 days (range, 20–279 days). Among the 178 who completed follow-up, 5 had a positive urine test for gonorrhea (cumulative incidence of 2.8%) and 6 had a positive chlamydia urine test (cumulative incidence of 3.4%). Table 3 displays the incidence rates, univariate relative rates (RR), and their 95% confidence intervals. Although females (RR = 1.55) and whites (RR = 3.9) had a trend toward higher reinfection risk, these findings did not reach statistical significance. Other demographic characteristics did not differentiate gonorrhea repeaters from those with only one infection.
Among covariates collected at the baseline clinic visit, sexual behaviors were not associated with gonorrhea reinfection. Although there was a trend toward increasing risk of gonorrhea reinfection with larger numbers of sex partners (not shown), this finding was not statistically significant. An analysis limited to those with a definitively determined reinfection status (those who completed follow-up and those who had a gonorrhea diagnosis identified through the morbidity search) yielded similar results (not shown).
We implemented and evaluated a programmatic gonorrhea control recommendation from the CDC to rescreen and treat for reinfection. We found the rate of reinfection to be high at 13.8 per 100 person-years through a combination of active and passive surveillance. However, active, prospective attempts to evaluate gonorrhea clients for reinfection were successful in only approximately one fourth of eligible clients. A large number of clients did not have follow-up testing because they could not be located, refused to participate, or were not within city borders. We were not able to identify risk factors predictive of reinfection that could be meaningfully applied to selective repeat testing strategies. We saw few differences between those who were tested in follow-up and those who were not.
Even after targeted and intensive field activities, nearly 75% of eligible clients did not return for gonorrhea reevaluation. This poor follow-up in the “real world” of urban STD clinics is not unique; Malotte et al evaluated different methods for improving return for gonorrhea retesting.35 In this study, the best intervention (counseling and a reminder) yielded less than a 30% return rate for repeat testing. Economic incentives did not improve return rates.35 Similarly, in a randomized trial of methods to encourage rescreening for gonorrhea and chlamydia, only 32% of STD clinic clients returned for a retest.36 In another study, systems to allow for chlamydia retesting through mail-in specimens yielded only a 23% response rate.37
Many factors make the follow-up of patients with gonorrhea uniquely challenging. Individuals with gonorrhea are more likely to reside in neighborhoods characterized by social disorganization.38,39 Social disorder can impose logistic barriers to retesting and impact on an individual’s health priorities and limit cooperation with testing procedures. Adolescent females having an unemployed parent or residing in a one-parent household were more likely to report having had a gonorrhea diagnosis.40 Instability in the household not only increases the risk of being infected with an STD, but can make the follow-up of infection more difficult. Patients with gonorrhea specifically have been shown to be less motivated to access follow-up medical care.41 Furthermore, gonorrhea clients may have been unable to return for follow-up as a result of incarceration. In our cohort, 12 individuals were incarcerated at the time of follow-up for a cumulative incidence of arrest of 1.8%. A recent ecologic analysis showed a moderate correlation between incarceration and gonorrhea rates.42 Finally, gonorrhea clients may have predisposing conditions making the return for follow-up more difficult. For example, in a sample of STD clinic patients, persons with psychopathology were nearly 4 times more likely to have an STD diagnosis than those without.43 These individual and social characteristics associated with gonorrhea that limit tracking and follow-up are unlikely to be unique to Baltimore and may limit the success of similar strategies in urban settings with high gonorrhea morbidity.
Our work has additional limitations. Conclusions based on our analysis were limited by the fact that reinfection status could not be determined in large proportion of the cohort, similar to what has been described by others.29 Here, females were more likely to return for the 3-month follow-up visit, whereas males were primarily identified through morbidity abstraction. This may bias our estimates of incidence. Although those lost to follow-up did not differ from those who completed repeat testing, the poor return rate has implications for nearly any intervention in this population. For practical reasons, we focused only on individuals identified with gonorrhea at the STD clinics (one third of all gonorrhea infections diagnosed in Baltimore) and not through the private sector. During the project period, STD clinicians who treated patients for their gonorrhea episode at gonorrhea recommended the follow-up testing at 3 months, a counseling measure we thought was important to further patient understanding of health department procedures. Counseling at baseline would have been impractical to initiate throughout the private sector. However, we recognize that STD clinic patients have unique behavioral characteristics, and findings from them might not generalize to all individuals with a similar STD diagnosis.44
We limited our follow-up to those with a urogenital gonorrhea infection at baseline. Because urine-based testing was used at follow-up, any reinfections of anal or pharyngeal sites would not have been identified at follow-up. In our clinic setting, anal or oropharyngeal gonorrhea accounts for a small proportion of total gonorrhea infections.45 Additionally, our method for urine-based testing (Amplicor; Roche Diagnostic Systems) is not licensed for use in females as a result of limited data and concerns for compromised sensitivity. However, internal validation studies conducted at the BCHD laboratory showed sensitivities above 97% when female urine specimens were tested and compared with endocervical gonorrhea culture. Therefore, we do not believe that reduced analytic sensitivity in women significantly lowered our estimate of reinfection risks. Although we had incomplete data on some behavorial characteristics from the baseline gonorrhea episode, missing data were not differentially distributed by clinic, gender, or other measured characteristics. Finally, given our limited success with follow-up testing, we have little statistical power to identify potentially meaningful and important risk factors for reinfection.
Active outreach and testing for repeat gonorrhea infection, linked to treatment if tests are positive, should decrease the community reservoir of infection and shorten the average duration of infectiousness for those contributing most to gonorrhea transmission in the community. This disease control strategy would be likely to be most fruitful in a city with hyperendemic gonorrhea rates and a large burden of repeat gonorrhea infections6,22–24,26,28 such as Baltimore, MD.12 In our cohort, the incidence of gonorrhea reinfection (13.8% per year) was higher than predicted by STD clinic-based surveillance,24 but most cases of reinfection were still detected in the follow-up period through passive systems. The uncertainty of predicting the best interval for the follow-up test along with the significant challenges of tracking and obtaining repeat specimens in patients with gonorrhea led to a poor yield in active case finding. Our data suggest that any guidelines to rescreen patients with gonorrhea 3 to 6 months after treatment is unlikely to be a cost-effective use of health resources. Although repeat infection very likely characterizes the core transmitters, our efforts do not indicate that active screening for repeat infection will lead to improved gonorrhea control and prevention.
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