Punching Above Their Weight

GENITAL INFECTION WITH CHLAMYDIA TRACHOMATIS (Ct) is the most common notifiable infectious disease in North America.1,2 When Wilson and Jungner3 outlined their principles for health-related screening programs in the late 1960s, they might have had a Ct-like infection in mind (though of course, Ct was not widely regarded as an important human pathogen until almost a decade later4). In addition to being common, genital Ct infection is likely to be asymptomatic in the absence of testing,5 and is likely to cause significant disease if left untreated6 (though how likely is still a source of debate7). Noninvasive, extremely accurate tests exist for the presence of asymptomatic Ct infection.8 Safe and highly effective treatment can be applied to individuals identified through screening.9 All of these attributes of Ct infection are described by Wilson and Jungner as conditions where screening is desirable.3 So why are we still arguing about whether screening for Ct makes sense? This argument persists because notwithstanding the apparent attractiveness of screening as outlined above, some feel that screening for Ct does not work well enough to justify the public health resources required.10 In particular, as outlined by Low in a controversial but well-reasoned review, Ct screening programs in numerous geographic locales have been associated with transient decreases in Ct prevalence, which then rebound (although not necessarily to baseline levels) after several years.10 Such patterns have been documented in Sweden and British Columbia.10,11 Ct prevalence in screened females in the Philadelphia High School STD Screening Program (PHSSSP) (which also screens students for infection with Neisseria gonorrhoeae) followed a similar pattern in its first 4 years.12,13 Why does this happen? In this issue of Sexually Transmitted Diseases, Anschuetz and colleagues from the Philadelphia Department of Public Health provide new information that may help us better understand the failure of Ct screening programs to meet their expected potential. Their insights may allow us to modify existing programs to enhance the likelihood of success. Anschuetz and colleagues have demonstrated that when we base our expectations of Ct screening program success on assumptions that would apply to noncommunicable diseases (e.g., that the most attractive target for screening is the population with the highest prevalence), we forget the essence of communicable diseases as described by Johann Geisecke, who noted that in a communicable disease, a case is also someone else’s risk factor.14 As applied to Ct, this means that when we treat a “case,” we should reduce the likelihood that individual’s sex partner (if uninfected) becomes a case; if the individual’s sex partner is already a case and is treated concurrently, we should decrease the likelihood that the individual is reinfected. If the partner is never treated, treating the case may represent nothing more than a transient interruption of that individual’s status as a case. This concept is intuitive to many clinicians and researchers involved in Ct research and control. Given the often limited success of contact tracing and partner notification efforts,15 a natural corollary of the above is that it would make sense to prevent the complications of Ct infection in females by decreasing prevalence in males. This idea has been sufficiently controversial, however, to inspire an extensive review of Ct screening in males, led by personnel at the US CDC.16 The article by Anschuetz and colleagues provides some important new insights that should inform policy in this regard. Briefly, this article is based on data collected as part of the PHSSSP described above. The PHSSSP is (to our knowledge) currently unique in the United States, as it makes urine-based screening for Ct and gonorrhea available to students at all public high-schools in a major US metropolitan area (whereas other school-based screening efforts, such as those in San Francisco17 and New Orleans,18 have been restricted to a subset of city schools). The scope of the program and the high burden of infection in this demographic group in Philadelphia make estimates of PHSSSP program effectiveness of general interest. Reviewing the data presented by Anschuetz and colleagues, we see that prevalence of Ct or gonorrhea infection in female program participants is approximately 4-fold higher than in male participants; from this point forward, we will focus on Ct rather than gonorrhea, as approximately 90% of infections in this population are with Ct.12 The high female-to-male prevalence ratio is not unexpected; national surveillance data for Ct in the United States (and Canada) show a similar female-to-male predominance.1,2 Such a predominance may be interpreted in several ways (none of which are mutually exclusive): it could mean that high-school females choose some male partners from their school cohort but also partner with men outside the school (and screening program); it could mean that Ct-infected males are far more infectious to females than vice versa; or it could mean that a relatively small proportion of high-school males are sexually active, but these individuals have a relatively large number of female sex partners, whereas high-school females tend to partner with these few males. The data provided by Anschuetz and colleagues suggest that this latter scenario may well be at play in Philadelphia high-schools (and likely elsewhere). Although males are less likely to be infected than females, the relatively small numbers of males who are infected at some point have subsequent rates of infection almost identical to those seen for infected females (around 40 infections per 100 person-years of observation), a finding which would be consistent with high numbers of female partners per male, if the likelihood of transmission from an infected partner is high. Furthermore, in this study, the treatment of sex partners identified by male participants makes no significant difference in the likelihood of future reinfection. This would be consistent with underreporting of sex partners or with relatively rapid acquisition of new, Ct-positive sex partners over time in males with baseline infection. Rapid reinfection of initially infected males, with concentration of Ct risk in a small proportion of the high-school male population, would also explain the fact that, during the course of the PHSSSP, prevalence in males has remained stable (at just above 2%),12,13 despite large changes in prevalence in females. By contrast, Anschuetz and colleagues identify nontreatment of identified sex partners as increasing the risk of subsequent reinfection in females by 150%! Again, this is consistent with a model in which several females are linked sexually to one male, whose infection status is profoundly influential in determining future infection risk. Of course, gaps between male and female sex behavior are unlikely to be the sole drivers of Ct “rebound” in the face of screening efforts. Truncation of an effective host immune response by treatment,11 risk compensation,19 and dwindling participation in screening programs by those most at risk could also contribute to a rebound phenomenon. However, Anschuetz and colleagues document that infected males in the PHSSSP influence Ct transmission in this population in a manner that is disproportionate to their prevalence; in boxing lingo, we might describe these individuals as “punching above their weight,” epidemiologically. How does this knowledge help us? Solutions may not be immediately apparent, but the work of Anschuetz and colleagues reinforces the importance of partner therapy for the prevention of recurrent infection in females.15 Based on the findings of Anschuetz and colleagues, we can make a case for incorporation of “patient-delivered partner therapy” (PDPT), sometimes also called “expedited partner therapy” (EPT) into programs like the PHSSSP. Recall that in the landmark trial of PDPT by Golden et al.,20 PDPT did reduce the risk of recurrent or persistent infections, but the effect was significantly stronger for gonococcal infections than for Ct infections. Perhaps this too reflects more rapid reinfection of treated males, who acquire infection from future partners, or concurrent untreated partners (though Golden’s data do not actually make this case, as the limited effect of PDPT in preventing Ct reinfection seems similar in both male and female participants).20 Could we turn these challenges on their head? What if at-risk males are, on average, more “sexually connected” than at-risk females? Could strategies aimed at engaging these individuals, and encouraging them to facilitate treatment of their sexual networks through PDPT, allow them to exert a disproportionate influence on disease control efforts, just as they appear to exert on Ct transmission currently? The high degree of collinearity between Ct risk in males, risk-seeking behaviors,21 and difficult social circumstances22 suggests that such an approach would be extremely challenging. Nonetheless, the work of Anschuetz and colleagues, in this article, brings us a bit closer to understanding the complexity of Ct ecology in school-aged individuals. Perhaps we ought to acknowledge that Ct screening is a work in progress, and insights and experiences derived from programs that do not live up to our fondest hopes can be used iteratively to develop subsequent generations of increasingly effective approaches to Ct control.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.