Chlamydia trachomatis Infections: Progress and Problems
- Reprints or correspondence: Dr. Walter E. Stamm, Division of Allergy and Infectious Diseases (Box 356523), University of Washington School of Medicine, 1959 NE Pacific St., Seattle, WA 98195.
Abstract
Chlamydia trachomatis infections are the most common bacterial sexually transmitted disease in the United States. A substantial proportion of initial infections in both men and women are asymptomatic. Use of nucleic acid amplification-based diagnostic tests on first-void urine makes it possible to initiate community-based screening programs aimed at identifying asymptomatically infected men and women. Directly observed single-dose therapy with azithromycin is now available. Screening programs have been demonstrated to reduce the overall prevalence of chlamydial infection in the tested population and to reduce the incidence of subsequent pelvic inflammatory disease in previously screened women. The sequelae of chlamydial infections are likely due to immunopathologically mediated events in which both the chlamydial 60 kDa heat-shock protein and genetic predisposition of specific patients play a role. An improved understanding of immunologic events leading to upper genital tract scarring is needed to target specific interventions and facilitate development of a vaccine.
In 1995, the World Health Organization estimated that 89 million cases of Chlamydia trachomatis infection occurred worldwide [1]. In the United States, C. trachomatis infections are the most commonly reported bacterial disease, with an estimated 4–5 million cases occurring annually. Further, according to the Institute of Medicine's recent report on sexually transmitted diseases (STDs) [2], the sequelae of C. trachomatis infections in women, namely pelvic inflammatory disease (PID), infertility, and ectopic pregnancy, are the most costly outcome of any STD except human immunodeficiency virus (HIV)/AIDS, resulting in an estimated 4 billion dollars in health care costs per annum. Finally, recent studies suggest that chlamydial infection of the lower genital tract may be an important risk factor facilitating sexual transmission of HIV infection. For all of these reasons, improved means for prevention and control of C. trachomatis infection are urgently needed. Recent advances have been made in several important areas, including a clearer understanding of the epidemiology of C. trachomatis infection, development of new diagnostic tests, and the advent of single-dose therapy for uncomplicated chlamydial genital infections. In the long term, an improved understanding of the pathogenesis of chlamydial infections, especially the immunopathologic events that result in upper genital tract infection and scarring, will lead to either novel immune interventions or development of an effective vaccine.
Epidemiology of C. trachomatis Infection
The two most common sexually transmitted infections caused by C. trachomatis are urethritis in the male and cervicitis in the female. These sites represent the portal of entry of infection in men and women, respectively. While C. trachomatis has traditionally been considered as the etiologic agent in ∼40%–60% of males presenting with nongonococcal urethritis, recent data suggest the epidemiology of this infection is changing. In some parts of the United States, where Chlamydia control programs have been enacted, C. trachomatis now accounts for only 10%–20% of cases of nongonococcal urethritis [3]. However, recent epidemiologic studies emphasize that there is a very substantial prevalence of asymptomatic or minimally symptomatic chlamydial urethral infections, especially in younger men [4]. These infections are of considerable importance epidemiologically, as they are usually not detected nor treated and thus may represent an important reservoir for chlamydial infection in women. Similarly, it is now thought that 70%–90% of endocervical infections in women caused by C. trachomatis are asymptomatic and that these infections may persist for months to years [4]. Early detection and treatment of these asymptomatic infections is necessary to prevent subsequent upper genital tract infection and its sequelae. Approaches to such screening are discussed below.
Immunopathologic Events in C. trachomatis Infection
The immunologic response to C trachomatis infection appears to play a major role in inducing immunopathology as well as in providing immune protection [5]. One important determinant of immunity appears to be the 40-kDa major outer membrane protein (MOMP), which induces both neutralizing antibody and T cell-mediated immune responses. Antibody to MOMP neutralizes chlamydial infectivity, both in cell cultures and in animal models [5]. However, allelic polymorphism in the MOMP gene appears to occur relatively frequently, either through point mutations or, in some cases, through recombinational events [6]. Polymorphism of this type may represent a type of immune evasion, since even single amino acid changes in MOMP may result in escape from neutralizing antibodies [7]. The extent to which such polymorphism actually serves as a means of immune escape in vivo is an important unanswered question with obvious implications for vaccine development.
Considerable attention has focused recently on the C. trachomatis 60-kDa heat-shock protein (Chsp60) [4, 5, 8]. This protein, a member of the Gro-E1 family, exhibits ∼50% homology with human heat-shock proteins. Thus, an immune response initiated by chlamydial infection may result in cross-reactivity with human cells and tissues. This may be one mechanism through which Chlamydia-induced immune responses may ultimately be detrimental. Recent studies by ourselves and others [9, 10] have demonstrated that a higher proportion of women with PID than of control populations demonstrate antibody to Chsp60. Further, women with sequelae of PID, including tubal infertility and ectopic pregnancy, also demonstrate a high prevalence of antibody to Chsp60 [4, 5]. Among those with PID, women having laparoscopically verified perihepatitis or evidence of severe tubal adhesions or obstruction demonstrate the highest proportion of seropositivity and highest antibody titers to this protein [9, 11]. Whether these antibody titers indicate that Chsp60 is actually directly involved in inducing immunopathology or whether it simply is a byproduct of persistent chlamydial infection remains unclear.
Also of recent interest is the apparent genetic restriction of immune responses to C. trachomatis infection. Both in trachoma and in women with PID, an increased risk of infection appears in selected persons with HLA class I [12, 13]. Similarly, in the macaque model of PID, evidence of rapid adhesion formation appears correlated with specific HLA class I allo-types [14]. Finally, the specific chlamydial strain that infects a patient may be of importance in inducing upper genital tract pathology. Dean et al. [15] reported that specific serovar F chlamydial strains characterized by unusual nucleotide substitutions (so-called F variants) were seen more frequently among isolates from the upper genital tract.
As with cervicitis, increasing evidence suggests that many cases of chlamydial upper genital tract infection are clinically silent, leading to the concept of “silent salpingitis” [4]. It has been estimated that asymptomatic upper genital tract infection resulting from Chlamydia probably occurs three times as often as does symptomatic PID. Silent salpingitis thus occurs considerably more frequently than does symptomatic PID as a prelude to upper genital tract scarring and subsequent infertility. In-creasing evidence suggests that sequelae of chlamydial cervical infection in women may be associated with either persistent or recurrent infection of the upper genital tract. Studies using in situ hybridization, immunocytochemistry, culture, polymerase chain reaction, and electron microscopy demonstrate persistence of C. trachomatis in the fallopian tubes of women with tubal infertility [16, 17]. Similar persistence seems apparent in the macaque model of PID [18]. Repeated infection of the lower and upper genital tract with Chlamydia also appears to be a important risk factor for tubal infertility.
Diagnosis of C. trachomatis Infections by Nucleic Acid Amplification
Until recently, a major hindrance in controlling chlamydial infections has been the absence of a widely available sensitive, specific, and inexpensive diagnostic test. For this reason, much research has been devoted to the development of such a test in the last decade. Currently, several diagnostic alternatives to cell culture are available [19, 20]. The first generation of these tests used antigen detection (either direct fluorescent antibody or EIA) done on swab specimens collected from the urethra or cervix. While simpler than culture and more widely available than cell culture techniques, these tests remained inferior to culture in terms of sensitivity and specificity [ 19, 20]. The most important recent advance in Chlamydia diagnostics has been the development of automated methods for the detection of amplified C. trachomatis DNA or RNA. The two most widely available methods, ligase chain reaction and polymerase chain reaction, are now available for identifying chlamydial infection in men or women. A more recently developed alternative method, transcription-mediated amplification, amplifies a target sequence on the Chlamydia ribosomal RNA. These amplified tests represent a major improvement over previous methods, because they are the first methodologies that are actually more sensitive than culture while retaining a high specificity [19, 20]. Additionally, these tests are capable of detecting the small amounts of chlamydial DNA that are present in either voided urine or in self-collected vaginal swabs. Thus, this new technology makes possible the use of novel specimen types, namely first-void urine in men or women or self-collected vaginal swabs in women, that may facilitate Chlamydia screening programs. More detailed discussion of these tests can be found in recent reviews [19, 20].
Treatment
C. trachomatis infections have long been effectively treated with tetracycline, doxycycline, or erythromycin. Fortunately, clinically evident antimicrobial resistance has not developed in C. trachomatis as yet, perhaps because the extracellular elementary body is relatively inert and has little genetic interaction with other organisms from which resistance genes might be acquired, whereas the metabolically active and dividing forms of the organism are sequestered within inclusions in epithelial cells. While all of the aforementioned antimicrobials are active against Chlamydia in vitro and are effective in vivo, they are thought to require at least 7 days of administration for clinical and microbiologic effectiveness. This has been assumed to be because C. trachomatis resides within the protective environment of epithelial cells and has a 48- to 72-h life cycle, thus requiring prolonged administration of an antimicrobial.
An important new alternative for treatment of chlamydial infections is the development of single-dose azithromycin therapy [3, 21–23]. A single 1-g dose of azithromycin appears to demonstrate efficacy in the treatment of chlamydial cervical infection and in the treatment of nongonococcal urethritis equal to that of 7 days of traditional doxycycline [22, 23]. Unfortunately, azithromycin is considerably more expensive than doxycycline, which may limit its application in Chlamydia control programs. Despite the considerably higher procurement costs, however, cost-effectiveness analyses indicate that the markedly improved compliance with single-dose azithromycin therapy compared with the poor compliance seen with 7-day regimens of doxycycline results in an overall reduction in subsequent morbidity and cost among those treated with azithromycin [24]. Ideally, single-dose azithromycin should be used as directly observed therapy for patients with chlamydial infection [25].
Prevention of C. trachomatis Infections
Current approaches to prevention of chlamydial infection are predicated on the following considerations: The majority of chlamydial infections in women are asymptomatic, asymptomatic infection can and often does result in silent salpingitis and tubal scarring and infertility, delayed treatment increases these risks, and urethritis in young males also may be frequently asymptomatic. Taken together, these considerations suggest that periodic screening of high-risk persons for chlamydial infection should be an effective control measure.
Several approaches to screening have been undertaken and studied [4, 26, 27]. In high-risk populations, such as those who attend STD clinics, family planning clinics, juvenile detention clinics, and the like, routine screening of all attendees (both men and women)—an approach known as universal screening—has frequently been implemented and has often been highly successful. The cost of universal screening may be prohibitive in clinical settings with a lower prevalence of infection, however, and approaches to selective screening in such populations have been developed. Among young women, selective screening criteria that effectively define a high-prevalence group have included young age (generally adolescence); multiple, new, or symptomatic male sex partners; the presence of mucopurulent cervicitis; and inconsistent use of barrier contraception [4].
The effectiveness of selective screening for C. trachomatis infection in women has been demonstrated in a number of recent studies, two of which have been done in the Pacific Northwest. In Region X of the United States (the Pacific North-west), extensive screening for C. trachomatis infection began among young women attending all family planning clinics in the region in 1988. Subsequently, similar screening was extended to all STD clinics in the region beginning in 1993. In family planning clinics, the prevalence of C. trachomatis infection declined from 10%–12% in the late 1980s to only 3%–5% in 1995 [28]. These highly significant decreases in prevalence were observed in all participating states. The selective screening program implemented in these clinics thus dramatically reduced the prevalence of C. trachomatis infection. Similar results have been seen in other screening programs elsewhere in the United States and in Sweden [4, 29].
A second important study done at Group Health Cooperative, a large health maintenance organization (HMO) in Seattle, evaluated the effectiveness of a Chlamydia screening program in preventing PID [30]. Thus, women in the HMO who satisfied selective screening criteria for chlamydial infection were randomized to either a group whose members received a cervical screening test for Chlamydia or a control group, whose members received standard care but no testing. Screened subjects who were infected with Chlamydia were treated with doxycycline. Subjects were then followed for 1 year and assessed for incidence of symptomatic PID. The results demonstrated that women in the intervention (screening) group had a marked reduction in subsequent symptomatic PID (odds ratio, 0.44; 95% confidence interval, 0.2–0.9).
Both of these studies strongly support the concept that Chlamydia screening, done either universally or in a selective manner, can have a dramatic impact on the overall prevalence and complications of C trachomatis infection. While as yet there have not been studies to assess the impact of Chlamydia screening in young males on the overall prevalence of infection in men and/or women, it would seem likely that screening programs in high-risk young males would also have a beneficial effect in controlling this disease. Use of noninvasively collected urine specimens tested by DNA amplification techniques now provides the opportunity to test these approaches, and such studies are ongoing. Use of urine specimens or self-collected vaginal swabs also affords the opportunity to develop programs for community-based screening. Thus, rather than confining screening to clinics attended by patients, it is now possible to carry out screening programs in schools or other public facilities. An initial such study done in Seattle demonstrated a high prevalence of asymptomatically infected young men and women identified through school-based clinic screening [31].
Conclusion
In both industrialized and developing countries, C. trachomatis infections remain one of the most important STDs in terms of incidence, prevalence of serious complications, and associated health care costs. Recent advances in our understanding of the epidemiology of these infections indicates the need for selective screening programs targeted at high-risk persons who satisfy selective screening criteria. The development of new, more sensitive diagnostic tests that allow the use of novel specimens, such as urine or self-collected vaginal swabs, makes such programs feasible and extends their potential into the community beyond traditional health care settings. Directly observed single-dose therapy with azithromycin is now available for chlamydial infection and has the potential to greatly increase user compliance and potentially increase use effectiveness. Recent research suggests that the sequelae of chlamydial infections may be due to immunopathologically mediated events; the chlamydial 60-kDa heat-shock protein may play an important role in this process, as may genetic predisposition of specific patients. In the longer term, a clearer understanding of the immunopathologic events leading to upper genital tract scarring is needed to target specific interventions and to facilitate development of a vaccine.
- © 1999 by the Infectious Diseases Society of America
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