GONOCOCCAL INFECTIONS ARE THE second most common reportable infectious diseases in the United States,1–3 accounting for annual direct medical costs that exceed $1.1 billion.4,5 Untreated gonorrhea is an important cause of pelvic inflammatory disease (PID), tubal infertility, ectopic pregnancy, and chronic pelvic pain, and may facilitate HIV transmission.6–10 Despite dramatic declines in rates throughout the 1980s and much of the 1990s, since 1998, the numbers of reported cases of gonorrhea have changed little, and recent evidence of persistently high gonorrhea rates among adolescents and minorities in some inner-city settings suggests the need for improved infection control efforts.4,11–21 Many uninsured or medically underserved women attend inner-city emergency departments (EDs) as a usual source of health care,5,22–30 rendering EDs potentially high-yield screening opportunities for detecting and treating gonococcal infections and other sexually transmitted diseases (STDs).23,26,28–31
However, gonorrhea screening in EDs has been hampered by logistical difficulties in specimen collection (i.e., the complaints bringing patients to the ED did not warrant pelvic examination) and inability to provide follow-up care. A potential solution to this problem lies in the adoption of 2 new diagnostic tools: urine-based nucleic acid amplification tests (NAAT) and an antigen detection test currently in development called the rapid immunochromotographic strip test (RIS). Neither test requires invasive specimen collection procedures, thus bypassing the need for a pelvic examination, although they differ in some important aspects. Urine-based NAAT such as ligase chain reaction (LCR) and polymerase chain reaction (PCR) are extremely sensitive,2,32–37 but results can take several days, during which time untreated infected patients may be lost to follow-up.38 In contrast, point-of-care tests such as the RIS, which can be performed using clinician- or patient-collected vaginal swabs, are somewhat less sensitive but allow for same-visit treatment.39
The clear advantages of urine-based NAAT technology—high sensitivity and ease of collection—and the promise of a new rapid point-of-care test that does not require cervical samples; could each potentially simplify specimen collection for gonorrhea testing in women and pave the way for practical ED-based screening programs. We therefore sought to quantify the tradeoffs between screening strategies that rely on less sensitive and relatively inexpensive tests and more sensitive and costly options that provide immediate results and thereby improve gonorrhea treatment rates.
We developed a state-transition Markov model to simulate screening, diagnosis, and treatment of gonorrhea in a hypothetical cohort of U.S. women receiving care at EDs. The model was used to calculate the clinical benefits (averted cases of PID, gains in life expectancy, and quality-adjusted life expectancy) and lifetime costs (in 2002 U.S. dollars) associated with alternate screening strategies in which we varied the sample type (urine, endocervical, or vaginal swabs), the test technology (Gram stain, NAAT, RIS), and the sample collection method (by the physician or the patient). The comparative performance of alternative screening strategies was measured by the incremental cost effectiveness ratio (defined as the additional cost of a specific strategy, divided by its additional clinical benefit, compared with the next least expensive strategy). We adopted a societal perspective and followed the reference-case recommendations of the Panel on Cost effectiveness in Health and Medicine.40 Sensitivity analyses were performed to determine how changes in estimated values affect the results. Costs and quality-adjusted life years were discounted to present value at an inflation-adjusted rate of 3% per annum.
The 5 strategies evaluated included: 1) Gram stain of cervical secretions obtained by a physician during a speculum-guided pelvic examination; 2) NAAT of a cervical specimen obtained by a physician during a pelvic examination; 3) NAAT on a patient-obtained urine specimen; 4) RIS on a patient-obtained vaginal specimen; and 5) RIS on a clinician-obtained vaginal specimen. We compared performance of strategies that restricted screening to age groups at which prevalence is highest (15–19, 15–24) to more inclusive strategies that involved screening all women between the ages of 15 and 29. We assumed that there would be opportunity to screen eligible women, on average, once per year.23,28,29,31
The model was developed to follow a cohort of 10,000 nonpregnant, sexually active 15-year-old women at high risk for gonococcal infection throughout their lifetime. The course of disease in the absence of screening is represented as a sequence of transitions between mutually exclusive health states, each of which describes a woman’s clinical condition and resource utilization. Health states are defined to reflect uncomplicated gonorrhea, progression to acute upper genital tract infection (i.e., PID), and 3 categories of sequelae secondary to PID (ectopic pregnancy, infertility, and chronic pelvic pain). Health states are further stratified to distinguish between initial, recurrent, and persistent infections. In the context of our model, a persistent infection refers to a lower genital tract infection, treated or untreated, which persists in the lower genital tract as a subclinical infection for at least 12 months.
The model uses transition probabilities established from the literature to move women through different health states over time. The time horizon of the analysis extends over a woman’s lifetime and is divided into equal increments of time, during which women “transition” from one health state to another. In each 6-month cycle, uninfected women have an age-dependent risk of acquiring acute infection.2,3,19,41 Women with a current infection may spontaneously resolve, have persistent infection, or may progress to develop acute PID. Women who develop acute PID face a future risk of developing any 1 of 3 major complications: ectopic pregnancy, chronic pelvic pain, or tubal infertility. A proportion of women with acute PID develop symptoms, and we assumed that these patients would seek care and be treated. These women still face a probability of long-term complications (e.g., tubal infertility), albeit at a lower risk than untreated patients.42 We conservatively assumed that in any 1 cycle, a woman may only experience 1 of the long-term complications of PID. Women who resolve their acute PID retain their history of prior infection and are eligible for a new acute infection. Women may die from complications related to acute PID or other causes.43–46
The target population for the screening program was composed of women presenting to the ED with nongenitourinary symptoms. Women detected as having acute infection through screening, and who are effectively treated, return to a healthy state but retain a history of disease and can acquire new infections. Women with undetected infection (e.g., as a result of a false-negative test) or in whom treatment fails may spontaneously resolve, remain persistently infected, or progress to upper genital tract infection. Women with asymptomatic PID who are falsely identified as having an acute lower tract infection accrue the costs of screening and treatment for gonorrhea, but their subsequent risk of long-term complications related to acute PID is higher than women who are appropriately treated for PID.
We made the following additional assumptions: 1) Fifteen percent of women without an initial complaint of genitourinary symptoms are identified as having symptoms at triage and were treated at the same visit.23,29 2) In simulating an urban-area ED, we assumed furthermore that as a result of alternative diagnoses or extenuating circumstances, only half of symptomatic women would receive a pelvic examination. 3) Women with gonorrhea identified in triage as having genitourinary symptoms, or detected through screening, are treated for gonorrhea according to national STD guidelines.47
Table 1 summarizes values and plausible ranges for clinical and quality-of-life variables used for the base case analysis.2,5,18,23,25,29,30,33,34,36,37,39,41,43,44,48–68
Gonorrhea rates are highest among women aged 15 to 19 and decline thereafter with age.49 We estimated an annual incidence of acute gonococcal infection of 6% for females aged 15 based on data from Mehta et al., which reported gonorrhea test positivity by urine ligase chain reaction during a 6-month period for patients aged 18 to 31 presenting to an ED in Baltimore, Maryland.23 We capitalized on data from the U.S. Centers for Disease Control and Prevention (CDC) on age-specific annual incidence rates of infection for females aged 10 to 65 to estimate the relative reduction in incidence with increasing age.69 We then applied these relative incidence rate reductions to our initial estimate of 6% for women aged 15 to 19. Using these methods, our model predicted that 34% and 32% of incident gonococcal infections occurred among 15 to 19 and 20 to 24 year olds, respectively, compared with 38% and 36% in these same age groups reported by the CDC.
Probabilities for PID-related ectopic pregnancy, infertility, and chronic pelvic pain were derived from cohort studies of women with laparoscopically verified PID.41,43,53,55,60,70 Test characteristics for the Gram stain, NAAT, and RIS strategies were derived from the literature.2,5,23,33,34,36,37,39,66–68
Reported rates of return for treatment of a positive urine-based NAAT range from 60% to 80%.24,29,71,65 We assumed that 70% of women with positive NAAT would return to the ED for treatment, but sensitivity analysis was performed over a wide range of return rates. There are no reported data on the willingness of clinic or ED patients to wait for rapid gonorrhea tests because rapid tests in men have only recently been approved. The manufacturer’s product label for the Binax Now rapid test available for chlamydia indicates that RIS results take 20 minutes for results. Based on the experience reported with on-site rapid HIV tests showing between 93% and 100% of patients remained at the testing site long enough to receive results on their initial visit,72,73 we assumed that all patients testing positive by Gram stain or RIS received results and were treated during the initial ED visit in the base case, but we varied this parameter widely in sensitivity analysis.
Lacking empiric data, we used quality weights from an Institute of Medicine study on vaccine development for gonorrhea and applied them to health states reflecting chronic pelvic pain (0.60) and infertility (0.82), where 0 represents death and 1 represents perfect health. These utilities were derived from the Health Utilities Index (HUI) Mark II.57,74,75 In the base case, we assume a 10-year decrement in health-related quality of life for both chronic pelvic pain and infertility, but we vary both the quality weights and the duration of the quality-of-life decrement associated with these complications extensively in sensitivity analysis. As a result of the short duration of both acute PID (1–10 days) and ectopic pregnancy (1–2 weeks), we did not assume a quality-of-life decrement over the course of these acute complications. For all other health states, we used population sex- and age-adjusted weights derived from time tradeoff estimates reported in the literature.40,76
The direct medical and nonmedical cost estimates and plausible ranges used in the base case analysis3,5,25,53,57,59,63,64,77–83 are shown in Table 2. The cost of a pelvic examination ($25.35), including the cost of materials and time costs of an emergency physician (15 minutes) and a registered nurse (17 minutes), were derived from published estimates and from an expert panel.63,64,83 The median net income of emergency medicine physicians ($184,000) from the Occupational Outlook Handbook of the Bureau of Labor Statistics was used to derive an hourly wage of $59 based on a 60-hour work week.78 Based on median annual earnings of registered nurses ($45,780) and a 40-hour workweek, we derived an hourly nursing wage of $22.
The cost of collecting a cervical specimen for women screened by NAAT included the cost of a pelvic examination, the NAAT cost per specimen (inclusive of technician time and overhead), and the cost of a thermocycler. The Gram stain cost also included that of a pelvic examination. We used the methods and implied lab technician time per NAAT urine and endocervical specimen reported by Howell et al. to calculate the technician time costs (and laboratory overhead) associated with the processing of diagnostic specimens for each of the 5 detection strategies.63
We estimated an hourly wage of $19.63 based on median annual earnings for clinical lab technologists from the Bureau of Labor Statistics, assuming a 40-hour workweek.78 Technician time costs for the Gram stain and RIS detection methods were calculated similarly. The Gram stain strategy included the costs of a glass slide, crystal violet stain, Gram’s iodine, and acetone; the urine-based NAAT strategy costs included a urine collection cup; and the RIS strategies included the cost of an intravaginal swab. Time spent by clinical personnel and patients for collection of a urine specimen and a patient-obtained RIS intravaginal swab is negligible and was therefore not modeled in the base case; we included the cost of physician time for a physician-collected RIS intravaginal swab (2 minutes). Because the RIS test kit is not yet marketed, we estimated its cost ($20) from the price of currently available rapid tests for chlamydial infections79 and from an expert panel, and we varied it extensively in sensitivity analysis. The cost of the NAAT kit ($14) was obtained from published estimates, as was the cost of Gram stain materials.63,64,79 Following Howell et al.,63 the total cost of each test specimen was the technician time and laboratory overhead plus assay costs, including the cost of a thermocycler for the NAAT and a pelvic examination for the NAAT cervical test and the Gram stain. The costs of follow-up contact activities for all women tested with NAAT and for the additional ED treatment visit for women testing positive by NAAT were derived from the medical literature.5,63,81,83,84
There is a wide range of estimates in the published literature of direct costs associated with PID and its sequelae.25,44,53,55,57,59,77,85–89 We assumed an average-per-person lifetime cost of PID of $2220 for the base case and average lifetime costs of PID-related sequelae (e.g., infertility, ectopic pregnancy, chronic pelvic pain) ranging from $1310 to $7060, depending on the specific complication. These estimates were varied widely in sensitivity analysis. All costs were translated into 2002 U.S. dollars using the Consumer Price Index before the 3% discount rate was applied.90
Before evaluating the potential impact of screening strategies, we assessed the ability of our model to predict reasonable estimates of the intermediate disease-specific outcomes secondary to gonorrhea infection. First, we used input data for gonorrhea incidence reflective of the national female average instead of that of a high-risk ED population.1 We then used the model to project the cumulative age-related incidence of symptomatic acute PID attributable to gonorrhea (Fig. 1). Results of this analysis suggest that the age-related pattern of symptomatic acute PID is consistent with estimates of self-reported PID in the United States.91 In addition, the model predicts cumulative proportions of symptomatic PID of 4%, 5.9%, and 6.6% in age groups 20 to 24, 25 to 34, and 35 to 39, respectively, or alternatively, that approximately 30% of all self-reported PID is caused by gonorrhea.
This is consistent with expert opinion and CDC data indicating that 20% to 50% of PID is attributable to gonorrhea.1
Base Case Analysis
Screening women in all 3 age groups (i.e., all women between 15 and 29 years) with urine-based NAAT prevented 1247 cases of PID over the lifetime of the cohort, increased quality-adjusted life expectancy by over 1 month, and saved $177 per patient compared to no screening (Table 3). Compared with urine-based NAAT over the 15- to 29-year range, screening with RIS using clinician-obtained vaginal swabs prevented an additional 220 cases of PID and had an incremental cost effectiveness ratio of $6490 per quality-adjusted life year (QALY). The cost per PID case averted and cost per QALY were somewhat less when screening was focused on women in younger age ranges. Screening with RIS on a patient-obtained specimen, with Gram stain, and with NAAT on a cervical specimen were less effective and cost more per person compared with the previous strategies (i.e., dominated).
To evaluate the impact of selected variables on overall cost effectiveness, univariate sensitivity analyses were conducted for women aged 15 to 29 (Table 4). Cost effectiveness estimates were most influenced by the incidence of infection, the proportion of women who did not receive timely treatment after a positive NAAT, the probability of immediate on-site treatment after a positive RIS test, test characteristics, and the costs of the screening tests. Results were less sensitive to NAAT characteristics, duration of the quality-of-life decrement for chronic pelvic pain and infertility, the cost of an ED treatment visit, the risk of symptomatic PID, and the risk of reinfection with second and third infections.
To explore the impact of assumptions about acquiring acute infection, we varied the incidence of infection (first, second, and third episodes) between 5% and 200% of the base case value (i.e., 6% per year). When the incidence of infection was greater than 50% of the base case (greater than 3% per year), urine-based NAAT was more effective and less expensive than no screening, and screening with the RIS test on a clinician-obtained specimen became increasingly cost effective. When the incidence of infection was less than 50% of the base case, no screening was the least costly and most effective strategy; at even lower incidence levels, screening with both urine-based NAAT and with the RIS test on a clinician-obtained sample was decreasingly cost effective because the additional QALYs gained were increasingly more costly compared with the next least costly alternative. However, provided the probability of acute infection was greater than 15% of the base case, screening with urine-based NAAT remained less than $10,000 per QALY compared with no screening.
The comparative value of urine-based NAAT screening versus RIS was most sensitive to the likelihood of loss to follow-up when a second visit was required. For example, if fewer than 50% of women with gonorrhea detected using urine-based NAATs returned for treatment, the RIS test on a clinician-obtained specimen dominated all other strategies. However, if 80% or more women with positive urine-based NAAT results returned for treatment, the incremental cost effectiveness ratio associated with RIS exceeded $50,000 per QALY (Fig. 2).
The choice between screening tests was also sensitive to their comparative performance and costs. For example, if the sensitivity of the Gram stain was increased above 75%, the Gram stain strategy cost under $3500 per QALY compared with urine-based NAAT. If the RIS test cost was halved, the RIS test on a clinician-obtained specimen dominated all other strategies as the least costly and most effective alternative. At twice the cost, that strategy cost under $25,000 per QALY compared with screening with urine-based NAAT.
Our results indicate that screening women aged 15 to 29 with urine-based NAAT provided cost savings to society compared with no screening over a wide range of assumptions. Provided that most infected women are notified and treated as test results become available, given the high sensitivity and ease of specimen collection for NAATs, these tests offer a robustly cost effective solution for targeted screening programs in previously hard-to-reach asymptomatic populations.
Alternatively, as point-of-care tests such as RIS become available, screening with these tests will also be cost effective over a wide range of plausible costs and test characteristics through improving the proportion of infected women who are treated. Specifically, compared with a base case that reflects current data, and in large part as a result of improvements related to immediate treatment, we found that screening eligible women aged 15 to 29 by the rapid test on a clinician-obtained vaginal specimen was always most effective, preventing the greatest number of PID cases. We based the RIS cost on the best available data and assumed that the RIS would have a higher list price than that of NAATs. However, charges to patients may ultimately be higher for NAATs. Our results suggest that as the RIS cost decreases relative to NAAT, the strategy becomes more cost effective relative to all other alternatives. Provided the annual incidence of gonorrhea was at least half the base case (i.e., 3%) RIS on a clinician-obtained vaginal specimen was also cost effective compared with many other preventive health interventions.
Although the estimates of cost effectiveness were not very sensitive to variation in selected model variables, the choice of optimal strategy was. The choice between different screening tests (NAAT vs. RIS vs. Gram stain) was most influenced by assumptions about the proportion of patients lost to follow-up after a positive NAAT, the probability of immediate on-site care after a positive RIS test, and the relative testing costs. Presumptive diagnosis of gonorrhea by microscopic examination of Gram-stained smears collected during a pelvic examination is cheap, quick, and easy to perform, and when examined by experienced personnel, has a high specificity. As a result of its low sensitivity in women, however (26–88%), it is generally reserved for settings with a relatively high prevalence of infection such as sexually transmitted disease clinics. Our results lend weight to this argument, suggesting that despite its clear advantages in terms of time and cost, in settings where the prevalence of infection is 6% or less, the Gram stain strategy is only optimal compared with NAAT and RIS if it has a test sensitivity of greater than 88%.
Screening programs in populations with a documented high prevalence of gonococcal infection such as military recruits, prison inmates and detainees, and high school students have been shown to be clinically beneficial and cost effective.92–99 The study by Mehta and colleagues is the only published study to date examining the cost effectiveness of providing gonorrhea and chlamydia screening services in a high-risk ED setting. Although our analysis differs in some respects, like Mehta et al., we found that urine-based NAAT screening of women in a similar age group, with similar disease prevalence, was a highly cost effective and often cost-saving strategy depending on the comparator.
Although the estimates of incidence in our base case analysis may not be representative of all inner-city EDs, our policy conclusions may be applicable to other venues where the provision of follow-up care is a significant barrier and sexually transmitted disease rates are high. For example, women entering community jails are at high risk for gonorrhea, but efforts to integrate screening with admission have not been feasible, in part because women are often released before test results are available. Strategies that permit point of care treatment in such settings would likely be attractive investments.
Our analysis has several limitations. There is still considerable uncertainty about the natural history of acute gonococcal infection. Persistent infection, a term used to specify continued infection despite antibiotic therapy,100 is often difficult to distinguish from reinfection. Therefore, whether serially positive tests represent persistent or repeat infections, how reinfection and persistence influence estimates of the mean duration of a gonococcal infection, and the observed prevalence of gonococcal PID are areas of much clinical debate and key sources of uncertainty. The epidemiology of PID is further complicated by the fact that it is often asymptomatic and caused by pathogens other than Neisseria gonorrhoeae. Our choice of a state transition model (generally used to represent complicated chronic diseases in which the risk of clinical events changes over time) rather than a transmission model was a purposeful tradeoff made to more fully capture the costs and consequences associated with the long-term sequelae of gonococcal infection. Our analysis therefore does not consider transmission to sexual partners and newborns, the impact of partner notification, averted male sequelae, and the potential of enhanced transmission of HIV. Inclusion of these parameters, however, would likely increase the numbers of infected individuals and thus the costs and clinical consequences of untreated gonorrhea, thereby improving the case for screening.
Several other assumptions used in this article should also be acknowledged. For this model, we choose to use the performance characteristics of Gram stain of endocervical secretions as one standard for comparison. We acknowledge that Gram stain is not likely to be used for gonorrhea screening in most urgent care settings. Nonetheless, unlike RIS, or, to a lesser degree, NAAT, gram stain is a familiar, inexpensive, widely available rapid test for gonorrhea diagnosis that serves as a useful comparator that may be appropriate in other high-risk settings. Because many studies have explored the technique in which clinicians obtain vaginal swabs but do not use speculums, we also modeled clinician-obtained vaginal swabs to reflect the available data. However, given data from a number of recent studies comparing clinician-obtained vaginal swabs with patient-collected swabs, which suggest similar results, we presume that implementation of opportunistic sexually transmitted disease screening in an inner-city ED would use patient-collected swabs rather than specimens collected by clinicians. Finally, motivated by recent evidence of pools of undetected gonorrhea among some inner-city populations, our analysis conservatively focused on screening only for gonorrhea in high-risk ED settings. We recognize that coinfection with Chlamydia trachomatis will occur in some patients and would represent an additional potential benefit of a screening program. Therefore, our analysis likely underestimates the effectiveness and cost effectiveness of opportunistic screening. Although consideration of cotherapy or diagnostic tests that would provide test results for both N. gonorrhoeae and C. trachomatis would add complexity to the model and complicate interpretation of these results, this will be an important priority for future work.
U.S. gonorrhea rates have leveled off in the past few years, suggesting that testing in new settings should augment the current focus of gonorrhea control in sexually transmitted disease clinics, high schools, and prisons. Gonorrhea control efforts are made more urgent by the growing problem of antibiotic resistance to N. gonorrhoeae and recent prospective studies showing that treatment of sexually transmitted diseases can reduce incident cases of HIV.6–10,101 The introduction of powerful new gonorrhea test technologies coupled with a growing concern about scarce public health resources have led to a reevaluation of sexually transmitted disease screening practices in an effort to identify those most at risk of infection.102 The promise of a noninvasive rapid test that permits immediate treatment for gonorrhea, coupled with recent studies identifying adolescents and young adults attending EDs as high-prevalence populations5,22–30,103–105 and the results of this analysis all lend support to the emerging consensus that further declines in gonorrhea rates may require public health investments in new, high-prevalence settings such as EDs as the next critical frontier for sexually transmitted disease screening.26
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