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A test that won't die: the serologic test for syphilis

2009; Wiley; Volume: 49; Issue: 4 Linguagem: Inglês

10.1111/j.1537-2995.2009.02119.x

1537-2995

Louis M. Katz,

Syphilis Diagnosis and Treatment

"Even diseases have lost their prestige, there aren't so many of them left. . . . Think it over . . . no more syphilis, no more clap, no more typhoid . . . antibiotics have taken half the tragedy out of medicine."1 Not withstanding this assertion, we still test our donors for syphilis in the 21st century. Why, and shall we continue? Inquiring minds (including at the FDA) want to know! "(W)e again request comments and data concerning whether establishments could discontinue syphilis testing without adversely affecting the safety of the blood supply. If we receive adequate data, we will eliminate or modify this testing requirement in the final rule." 2 The bacterium Treponema pallidum is the etiologic agent of venereal syphilis (in developing countries closely related strains cause nonvenereal bejel and yaws). In the developed world, the organism is primarily transmitted from an infected partner during sex. Primary infection classically manifests as a painless sore at the inoculation site, followed in approximately one-third of untreated infections by bacteremic dissemination of the organism. Dissemination gives rise to, among other findings, the classic palms-and-soles rash of secondary syphilis. A fraction of untreated secondary cases progress to latency and some subsequently to tertiary syphilis with its protean destructive effects on bone, soft tissue, the heart, the central nervous system, and other tissues. Transfusion transmission was historically recognized as a severe, acute secondary infection with fever, malaise, and the generalized rash. Testing donor blood is spectacularly successful for preventing transfusion-transmitted infections when tests with appropriate performance are available. Donor screening assays have been implemented and improved successively for more than 50 years, and some have achieved remarkable sensitivity and specificity. A serologic test for syphilis (STS) was the first applied in the 1930s as the Wasserman test. In the 1950s, it was the first test mandated for US donors and stood alone before the discovery of the Australia antigen almost two decades later. Syphilis among healthy donors is identified by detection and confirmation of antibodies to T. pallidum. STS is quite insensitive for transfusion transmission since the spirochetemia associated with the event often clears before antibodies are detectable.3 This fact was recognized years ago by mentors of mine in Iowa City, Drs. Robert Hardin and Elmer DeGowin, who advocated examination of male donors' genitals for signs of primary syphilis.4 The suggestion was not adopted enthusiastically. By the time a newly infected blood donor's STS is positive, spirochetes are likely no longer present in donated blood.5 The study by Orton and colleagues5 found that 0 of 169 confirmed seropositive donors had circulating T. pallidum nucleic acid. The study could not stratify the donors by stage of syphilis and so does not address the key issue, the infectivity of donors identified using extant testing procedures, with sufficient power. More than 100 transfusion syphilis cases were published before World War II, and many more certainly occurred. The last alleged case of transfusion-transmitted syphilis in the United States, however, was in 1966.6 All 30 "implicated" donations were STS negative, as were all 27 donors who were subsequently retested. Since then, hundreds of millions of components have been transfused in this country without another recognized case. A single subsequent case from the developed world (The Netherlands) was reported in 1983.7 Both implicated donors were negative when the donation specimen was tested, again demonstrating the poor sensitivity of STS for infectious donations. Explanations for the disappearance of transfusion transmission of T. pallidum, despite poor test performance, and aside from the putative effect of donor testing, include: 1) the dramatic decline in the incidence of early syphilis in the United States over the decades, more than an order of magnitude, reducing the reservoir of donors able to transmit;8 2) the end of direct donor-to-recipient transfusion combined with the fastidiousness of T. pallidum in stored blood—the latter attributed to poor survival in refrigerated red blood cells and to the high oxygen tension in platelets stored at higher temperatures;9, 10 3) the ubiquitous administration of antibiotics for trivial to serious viral, bacterial, and noninfectious clinical syndromes, especially to those sick enough to be transfused; 4) donor deferral for behavioral correlates of syphilis risk (e.g., male sex with males [MSM], occurrence of recent sexually transmitted infection [STI] in donors, exchange of drugs or money for sex, injection drug use); 5) passive surveillance for transfusion-transmitted syphilis compounded by the failure of recognition by physicians (who may have never seen syphilis, venereal or otherwise); and 6) donor illness during spirochetemia severe enough to prevent their presentation to donate blood or causing deferral. The validity and relative contribution of each of these factors is unquantified. The report from the 1995 NIH Consensus Development Conference on infectious diseases testing of donors11 reviews an FDA advisory committee's 1985 recommendation to eliminate the STS because of the disappearance of transfusion-transmitted syphilis. Action was never taken because of the test's putative utility as a surrogate test for human immunodeficiency virus (HIV) infection. The consensus panel opined that evidence of surrogate value from STS for HIV (and hepatitis B virus [HBV], hepatitis C virus [HCV], and human T-lymphotropic virus [HTLV]) was lacking and did not justify its continued use, but that "Because the contribution of serologic tests for syphilis in preventing transfusion-transmitted syphilis is not understood, the panel concludes that testing of donors for syphilis should continue."11 Another argument for retention of STS is the accrual of public health and individual donor/patient benefits after identification with syphilis and referral for evaluation, treatment, and tracing contacts. This rationale for syphilis screening is straightforward, if quantitatively unimpressive. For 6 years (1995-2000), 22 primary and 81 secondary syphilis cases identified through donor screening were reported to the CDC, of whom they estimated 58% (approx. 10 per year) to be volunteer donors.12 These cases represent 0.4% of US primary and secondary cases reported during the interval. Does this public health role justify continuing the STS in collection facilities? That debate is beyond the scope of this editorial, but clearly, as long as we continue testing, donors and their partners must be properly notified and evaluated. With regard to the potential utility of STS testing as a surrogate for other transfusion-transmitted infections, this effect could be mediated in one or more ways. It might be positive in those infected with a second pathogen sharing epidemiology with syphilis before the second organism is recognized as a blood safety threat or a test for the second pathogen is developed. Anti-HBcore and alanine aminotransferase testing for non-A, non-B hepatitis before HCV serology in 1990 are examples.13 MSM as a behavioral surrogate for donor HIV risk was used to substantial benefit early in the AIDS epidemic.14 More than 60% of primary and secondary syphilis in the US is among MSM,9 so MSM may function similarly for syphilis (reducing the utility of STS). Similarly, a surrogate test might be positive before infection with a recognized organism by virtue of shared epidemiology, so STS might exclude from the donor pool a current donor destined to acquire a transfusion-transmissible infection in the future. A surrogate test might be positive earlier after infection (have a shorter window) than a specific test for infection. Here one might think about an inflammation marker being positive before antibody seroconversion after infection with an organism. Likewise, were two infections acquired simultaneously and one had a shorter test-negative window, a test for the one with the shorter window might function as a surrogate for the other. I know of no valid examples in transfusion medicine for these effects. Finally, a surrogate may be positive when a specific marker is falsely negative or where there is a testing or data handling error; contemporary estimates of these risks suggest they are inconsequential.15 The final nail in the coffin of STS as a surrogate for other transfusion-transmissible infections, if we need one, is the study by Zou and coworkers16 in this issue of TRANSFUSION. They queried the enormous American Red Cross (ARC) database and demonstrate that seroconversion to a confirmed positive syphilis serology would have detected zero new HBV, HCV, or HTLV infections among more than 3,000,000 fully tested repeat donors during 2006 through 2007. There was a single simultaneous identification of a donor infected with both HIV and T. pallidum. There are no lookback data, nor data on testing subsequent donations among a group of STS converting donors for other infections after reentry, but the ARC investigators, using estimated window periods and current US donation rates, suggest that syphilis testing may remove an undetected HIV infected donor every 10 years. Certainly, if surrogacy were the only argument for continued use of STS, we would not be doing the test, but surrogacy no longer drives the requirement for STS. It is the inability of the blood community to prove the negative proposition that transfusion-transmitted syphilis will not happen absent this insensitive test, that is, that elimination of the test will not "adversely affect the safety of the blood supply."2 We are in a circular trap: since the intervention is already in place, we cannot study STS-positive donors for their ability to transmit. If we want a study using an infectivity surrogate like T. pallidum nucleic acids, powering it requires that we document the minimal infectious dose and corresponding required sensitivity of a nucleic acid test assay to exclude infectivity and also that we articulate what is an acceptable risk, a number that has not been forthcoming. The fact that not one case has been reported in more than 40 years is considered an anecdote, not systematic surveillance data, and hence is discounted for recognition bias. We are left with a sense that a single additional case of syphilis from blood transfusion after elimination of STS (and failure to identify 10 donors annually with early syphilis for evaluation and treatment) is not an acceptable tradeoff, despite the substantial advantages of doing away with STS. Even more perplexing is the belief that no one would ask us to do the test if we were not already committed, especially in the face of current epidemiologic conditions and contemporary rigorous US volunteer donor management (deferral for MSM, commercial sex, parenteral drug use, recent treatment for STI). The direct cost of donor STS screening is trivial. However, the cost of test nonspecificity is substantial, which compounds the dilemma addressed above regarding the inherent insensitivity of syphilis antibody screening. The vast majority of contemporary reactive STS results in donors are biological false positives, unrelated to syphilis, especially where nontreponemal assays are used (<1% confirmed during 2008, data on file Mississippi Valley Regional Blood Center). Many true positives are the "serologic scar" of remote (often treated) infection and pose no risk to blood recipients. These false positives cause unnecessary destruction of thousands of perfectly suitable components annually, and this serologic detritus from old syphilis results in donor notification and deferral, donor rancor, public health reporting, and consumption of the public health resources used to evaluate them. We have other conundrums being handled similarly: approaches that defer tens of thousands of donors for recreational travel to the tourist meccas of Mexico for minuscule malaria risk, when residents and immigrants from sub-Saharan Africa missed by our historic approaches are the source of the rare residual transfusion transmissions;17 year-round testing for West Nile virus RNA; and, most recently, the self-inflicted wound of (near) universal testing for infection with Trypanosoma cruzi. The absence of recognized transmission in the face of an intervention perpetuates the intervention and the endorsement of inefficient blood safety policies. We (the blood community and the regulators) are unable to articulate an answer to the question "how safe is safe enough?" for the set of blood safety measures we have already implemented. We must address this fundamental policy issue to establish priorities for our menu of potential future threats and interventions and to move solutions through development and deploy them with the urgency their importance demands. The experience of four decades with no recognized transfusion-transmitted syphilis, during which we have implemented a many-layered approach to blood safety addressing a substantial proportion of the risk of T. pallidum infection in the donor base, suggests that the time is ripe to reconsider the use of STS. The author claims no conflict of interest.