Biomedical Issues in Syphilis Control

EVEN BEFORE THE OCCURRENCE of the syphilis epidemic that occurred in the mid-1980s and early 1990s, United States syphilis rates were 50- to 100-fold higher than in most other developed countries.1,2 These figures are particularly troublesome because, on a theoretical basis, endemic syphilis is an eradicable disease. The biologic characteristics of Treponema pallidum, the available diagnostic tests, and recommended therapy combine to permit reliable diagnosis, cure of disease, and prevention of spread to others. This article will provide a brief overview of the biologic characteristics of T. pallidum and the biomedical tools and opportunities that might be used to eradicate syphilis in the United States. In 1937, in Shadow on the Land,3 Dr. Thomas Parran outlined his formula for syphilis control in the United States. These recommendations were subsequently adopted in large part by the U.S. Public Health Service and have guided syphilis control efforts for the nearly 60 years since the book's publication. His formula for syphilis control3 included: Case finding with serologic screening programs to identify infected individuals; Prompt therapy for those who are infected in order to reduce their infectivity to others as well as to reduce the chance that their disease would progress; Identification, testing, and therapy for recent, asymptomatic sexual partners of patients with infectious syphilis to prevent development of infections that were still in the incubating stage; Routine serologic evaluation (screening) as part of premarital testing and in the course of early pregnancy (premarital syphilis screening has more recently been demonstrated to contribute little to modern syphilis control however targeted serologic screening continues to be advocated); Public education regarding the symptoms, complications and treatment for syphilis. Parran believed that without community participation, syphilis could not be controlled. The tendency for any sexually transmitted diseases (STD) pathogen to persist within a population can be expressed by the simple equation, R = βCd, in which R is the reproductive rate of the infection.4 “R” is determined by the multiplicative interplay of three variables: the infectivity of the causative agent (β); partner selection characteristics of infected individuals (c); and the duration that the infection can be transmitted to others (D). Each of these component variables summarize a number of potential contributors to changing infection rates. When R exceeds 1 each infected individual generates, on average, more than one new infection within the population and the numbers of cases increase. Conversely, if R is less than 1 the infection is being removed at a greater pace than new cases are being generated. The more R is below 1, the more rapidly the infection will be removed from the population. Thus, the goal of syphilis eradication can be accomplished by reducing R to below 1.0 and keeping it there. “β” represents the probability of transmission of the infectious agent for exposed individuals, reflecting both intrinsic biologic characteristics of the pathogen and host susceptibility which may be modifiable. With the rare exception of parenteral transmission, syphilis in adults is primarily spread through direct lesion contact between infected and uninfected individuals.1,5,6 Thus, syphilis is most infectious during its primary and secondary stages when cutaneous and mucosal lesions are present; studies of untreated partners of early syphilis patients revealed transmission to occur in 30–50% of exposed individuals.1,7,8 For syphilis, the efficiency of transmission (β) could be reduced by decreasing the susceptibility of infected persons to acquisition through increased use of barrier contraceptives or theoretically either by use of microbicidal (and spermicidal) agents, such as Nonoxynol-9 or by vaccines to reduce susceptibility to infection. Because no effective vaccine for syphilis is available, the major components of syphilis eradication efforts that might reduce β are interventions and efforts to promote increased use of condoms, barrier contraceptives, and spermicidal preparations. The C component of the reproductive rate equation represents partner selection variables (e.g., how many partners individuals have within the population per unit time, who those partners are, how often partners are changed, or how often individuals have multiple simultaneous partners) and the likelihood that infected individuals will pair with uninfected partners thereby providing further opportunities for spread of infection within the population. The C parameter is incorporated in discussions regarding so called “core groups,” and core group behaviors.1,4,9 At the present time, better definition of the true “core groups” (those individuals whose partner selection characteristics result in a disproportionate contribution to population syphilis rates) and methods for interrupting spread of infection by those individuals is of paramount for syphilis control. It is possible that decades of disproportionate emphasis on biomedical interventions to control syphilis, without equal emphasis on better definition of the behaviors that increase risk for syphilis transmission, methods for reducing transmission by individuals practicing high-risk behaviors, and interventions to reduce those risks may be part of the reason U.S. syphilis rates remain 50- to 100-fold higher than for other developed nations. In the United States, the primary focus of recent biomedical efforts to eradicate (or for the less ambitious-control) syphilis has emphasized case finding and treatment of infected individuals. With increasingly efficient case finding (diagnosis) and effective treatment, the duration of infectivity (D) can be foreshortened, thereby reducing the likelihood that infected individuals would spread infection to others. The biologic characteristics of T. pallidum as they help and hinder effective diagnosis and therapy are major determinants of D (Table 1). With control efforts focusing on diagnosis and therapy, the variables that comprise D are more effected by the biology of T. pallidum than by other determinants of the reproductive rate. Although the net effect of these various biomedical parameters that impact efforts to control syphilis is such that the disease should theoretically be eradicable, certain characteristics of the organism also work to hinder effective diagnosis and therapy.TABLE 1: Selected Characteristics of Treponema pallidum and Their Impact on Syphilis Control EffortsThe accuracy of clinical diagnosis of syphilis based on clinical signs and symptoms in the absence of laboratory tests, even when performed by experienced STD clinicians, is notoriously inaccurate.10 Laboratory diagnostic tests that could provide results while patients are still present are not readily available in most clinical settings. Treponema pallidum is a long, thin bacteria that cannot be readily visualized by usual light microscopy.5 As a result, morphologic diagnosis of T. pallidum in clinical specimens relies on darkfield microscopy, a diagnostic tool that is primarily available in only a minority of publicly funded STD clinics. T. pallidum also can be seen using light microscopy if special stains are used.5,11–13 These silver, immunofluorescent, or immunochemical stains, however, are also not available on a routine basis in most clinical settings. Polyclonal and monoclonal fluorescent antibody tests for demonstration of T. pallidum in clinical specimens have been well described for more than 20 years.11–13 However, like darkfield microscopy, these tests are not widely available. Thus, for most clinicians there is no test analogous to the Gram's stain for diagnosis of gonorrhea to aid clinicians in syphilis diagnosis. Consequently, other than in specialized STD clinics, most clinicians lack the tools to demonstrate T. pallidum in clinical specimens from patients with suspected syphilis. The absence of a rapidly performed, widely available test for syphilis diagnosis, combined with the protean clinical manifestations of this disease compromise clinical syphilis diagnosis. In addition, Treponema pallidum cannot be readily cultivated in vitro for sustained periods.5 The organism can be propagated in laboratory animals including rabbits and guinea pigs; however, the organism's long division time (33 hours–5 days), the high cost of laboratory animals, and the technical expertise required to perform these assays make the possibility of performing “syphilis cultures” impractical. Most clinicans rely on serologic testing for syphilis diagnosis.1,14 In patients with reactive non-treponemal serological tests such as the Venereal Disease Research Laboratory or Rapid Plasma Reagin tests, confirmed by a reactive treponemal test such as a fluorescent treponemal antibody absorbed or microhemagglutination-T. pallidum tests, a serological diagnosis of syphilis can be made with a high degree (more than 99%) of specificity.14 The sensitivity of serologic tests for syphilis vary with the stage of disease. In patients with primary syphilis, serologic testing has a sensitivity of 75–80%, failing to diagnose those patients who have not yet developed a sufficient antibody response for purposes of diagnosis.1,6,14 In patients with more longstanding primary lesions or secondary syphilis however, the sensitivity of serological diagnosis approaches 99%. The “window” when serologic tests are non-diagnostic, however, clearly contributes to missed syphilis diagnoses and in aggregate, contribute to increased D. Two other facets of Treponema pallidum biology however substantially augment efforts to control syphilis. The first is that the long division time of T. pallidum contributes to the relatively long time between exposure/acquisition of infection and the development of active infection (lesion formation), at which time the infected individual becomes infectious for sexual partners. The mean time from exposure to development of clinically apparent, infectious lesions is 21 (range 7–60) days.6 This period in which the infection is “incubating” provides a window of opportunity for case finding and administration of preventative therapy. Thus, unlike bacterial STDs with far shorter incubation periods (e.g., gonorrhea, chancroid), the relatively long incubation period of syphilis provides public health officials with a realistic period in which to identify, notify, and provide preventative therapy for exposed individuals. In settings where contact notification is performed accurately and efficiently, D can be foreshortened dramatically through preventive therapy. A second attribute of the organism that facilitates control efforts is the continuing sensitivity of T. pallidum to the antimicrobial agents used for therapy.1,5,6 Again, unlike in Neisseria gonorrhoeae or Haemophilus ducreyi that have developed substantial and troublesome antimicrobial resistance in recent years, T. pallidum remains sensitive to the bactericidal effect of penicillin in low concentrations. As a result, benzathine penicillin continues to provide effective therapy for patients with all stages of syphilis other than neurosyphilis.1,6,15 This continued sensitivity and the availability of long acting penicillin formulations (e.g., benzathine penicillin G) work in favor of public health efforts to control this infection. However, at least 3–5% of human immunodeficiency virus-seronegative early syphilis patients treated with benzathine penicillin will fail therapy.15 There are no proven alternatives to benzathine penicillin for single dose therapy of the up to 10% of Americans who report penicillin allergy.16 Rather, these individuals must be treated with doxycycline, 100 mg orally twice daily for 14–30 days (depending on the stage of infection). Thus, despite, the utility of penicillin as a tool for syphilis control, better alternative therapies are needed and might contribute to further reductions of the average duration of infectivity for syphilis patients. In summary then, the formula R = βCd describes a number of potential areas in which syphilis control efforts might be improved. There continues to be a need for improved diagnostic tests and for reliable, easily administered alternatives to benzathine penicillin to supplement currently available biomedical tools for syphilis control. Nonetheless, the available biomedical tools for syphilis control have been successfully used with far more success in other developed nations than in the United States. Parran's framework for syphilis control still appears to be reasonable and potentially efficacious. In the United States, the first four facets of his plan (case finding, prompt and effective therapy, treatment for sexual partners, and routine screening of selected populations) have each been implemented and, although each could be improved, are being carried out. In contrast, his fifth objective, community education about and participation in control efforts, has not been accomplished and may be the key to the success or failure of current and future efforts to eradicate endemic syphilis from the United States.