Syphilis Screening: Missing the Forest for the Trees

Kenneth Katz

A public relations debacle for a new class of syphilis tests is unwarranted, and really just a case of bad spin.

Editor’s note: The author does not work for a testing manufacturer, and has no conflict of interest.

Advice for a new class of syphilis tests: get new spin doctors.

The public relations debacle for those tests, called enzyme or chemiluminescence (EIA/CIAs) tests, started on February 11. That’s when CDC’s weekly MMWR journal published a report on “reverse sequence” syphilis screening, in which laboratories use EIA/CIA tests to help diagnose syphilis.

According to the report, which evaluated “reverse sequence” screening at five U.S. laboratories from 2006 to 2010, nearly 18% of all positive EIA/CIA test results were not confirmed by other syphilis tests. That suggests that the EIA/CIA results were “false positives.”

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The press pounced.

“Test Gets Almost One in Five Syphilis Cases Wrong,” headlined a widely published Associated Press article that CDC itself featured verbatim (headline included!) on its websites. “Reverse sequence” screening has “problems with false positives,” another article asserted, and can lead to “unnecessary anxiety and treatment.” Yet another ran under the headline “After syphilis scare, health experts advise retests.”

Sounds scandalous.

Not so. The problem was, really, one of bad spin. By highlighting the unimpressive performance of false-positive EIA/CIA tests, and not the high accuracy of “reverse sequence” algorithms overall, the MMWR report – and, in turn, the press – missed the forest for the trees.

Understanding why starts with the crucial fact that confirming a laboratory diagnosis of syphilis always requires more than a single test.[1]

The traditional screening algorithm involves two tests. If the first is negative, the laboratory can stop. The patient doesn’t have syphilis. If it’s positive, the laboratory does a second, confirmatory test.[2]

“Reverse sequence” algorithms start with EIA/CIA tests. EIA/CIA tests are closely related to the second type of test done in the traditional algorithm, which is why algorithms that start with EIA/CIA tests are called “reverse sequence.” algorithms.  If the EIA/CIA test is positive, the laboratory does a second test, which, if positive, confirms a syphilis diagnosis.[3]

But If the second test is negative, the laboratory must break the tie with a third test.  A positive tiebreaker confirms syphilis.[4]

If the tiebreaker is negative, then syphilis is unlikely. In those cases, according to recommendations provided in a prior MMWR report and reinforced in the more recent report, syphilis should not necessarily be diagnosed or treated. Rather, the patient typically should be retested for syphilis in several weeks. (Ultimately, as in any other disease, clinical management decisions when syphilis is suspected should rest not on laboratory results alone but on an examination of all relevant clinical and epidemiologic data.)

Unfortunately, both the MMWR report’s title (which begins, ominously, with the words “discordant results”) and text mostly focused on EIA/CIA tests, rather than “reverse sequence” algorithms overall. It’s no surprise that the press followed suit. (The press further assumed, incorrectly, that patients were unnecessarily diagnosed with and treated for syphilis solely on the basis of positive EIA/CIA results.)

The accuracy of EIA/CIA tests is important, in and of itself, to laboratories, because it dictates how often they’ll have to run tiebreaker tests. But to clinicians and patients, the performance of any single test in a laboratory screening algorithm for syphilis – EIA/CIA tests included – doesn’t much matter. What really counts is the performance of the algorithm overall.

Looked at that way, it’s a different story entirely. Of 140,176 specimens analyzed in the MMWR report, in fact, only 866, or 0.6%, had results suggesting that the EIA/CIA result was a false positive. Sure, the EIA/CIA test itself got almost one in five results wrong – but the overall “reverse sequence” algorithm got it right more than 99 times out of 100.

Not too shabby.

Nevertheless, why not stick with the gold standard for the laboratory diagnosis of syphilis –the traditional algorithm – which, after all, CDC continues to recommend?

The answer comes down to economics. EIA/CIA tests can be automated. That means they can be done relatively cheaply. Other types of syphilis tests, meanwhile, must be done manually, and, hence, more expensively. Because about 95% of specimens (based on data in a prior MMWR report and the more recent report) require only the relatively cheap EIA/CIA test, it’s more efficient for high-volume laboratories to start (and in most cases stop) after a single, cheap, automated test.

Furthermore, CDC does not recommend against using “reverse sequence” screening, and, in fact, has made recommendations regarding interpretation results of “reverse sequence” algorithms. And the FDA has approved a number of EIA/CIA tests for use in the laboratory diagnosis of syphilis.

There are potential downsides to “reverse sequence” algorithms. They might help the bottom line of laboratories. But accounting for all costs associated with false-positives suggests that “reverse sequence” screening can in fact be more expensive, compared with traditional algorithms, for the health-care system as a whole. Additionally, the anxiety likely experienced by the small percentage of patients told they need to retest for syphilis cannot be discounted.

Whether “reverse sequence” syphilis screening truly contributes to public health efforts to prevent and control syphilis, then, is still an open question. With syphilis rates rising in the United States, it’s an important one. But answering it requires a more meaningful framing of the pros and cons of different approaches to diagnosing syphilis in the laboratory than occurred in this case.

Next time, in other words, the spin doctors should set their sights on the forest of syphilis testing, not its trees.


[1] For the syphiliterati, two caveats. First, the exception to this rule is persons who have had syphilis in the past, for whom only one test should be performed. But that test is not an EIA/CIA or related treponemal test, so the accuracy of EIA/CIA tests is not relevant to those cases. Second, this article only refers to the laboratory diagnosis of syphilis on the basis of serologic tests, not other laboratory tests used in some cases (e.g., darkfield microscopy, histopathologic examination, or polymerase chain reaction-based testing).

[2] Determining whether it’s a new case or a previously treated cases of syphilis requires additional laboratory and clinical data.

[3] The same caveat noted in footnote 2 also applies here.

[4] Again, the same caveat noted in footnote 2 applies here.

Roundups Sexual Health

This Week in Sex: The Sexually Transmitted Infections Edition

Martha Kempner

A new Zika case suggests the virus can be transmitted from an infected woman to a male partner. And, in other news, HPV-related cancers are on the rise, and an experimental chlamydia vaccine shows signs of promise.

This Week in Sex is a weekly summary of news and research related to sexual behavior, sexuality education, contraception, STIs, and more.

Zika May Have Been Sexually Transmitted From a Woman to Her Male Partner

A new case suggests that males may be infected with the Zika virus through unprotected sex with female partners. Researchers have known for a while that men can infect their partners through penetrative sexual intercourse, but this is the first suspected case of sexual transmission from a woman.

The case involves a New York City woman who is in her early 20s and traveled to a country with high rates of the mosquito-borne virus (her name and the specific country where she traveled have not been released). The woman, who experienced stomach cramps and a headache while waiting for her flight back to New York, reported one act of sexual intercourse without a condom the day she returned from her trip. The following day, her symptoms became worse and included fever, fatigue, a rash, and tingling in her hands and feet. Two days later, she visited her primary-care provider and tests confirmed she had the Zika virus.

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A few days after that (seven days after intercourse), her male partner, also in his 20s, began feeling similar symptoms. He had a rash, a fever, and also conjunctivitis (pink eye). He, too, was diagnosed with Zika. After meeting with him, public health officials in the New York City confirmed that he had not traveled out of the country nor had he been recently bit by a mosquito. This leaves sexual transmission from his partner as the most likely cause of his infection, though further tests are being done.

The Centers for Disease Control and Prevention (CDC)’s recommendations for preventing Zika have been based on the assumption that virus was spread from a male to a receptive partner. Therefore the recommendations had been that pregnant women whose male partners had traveled or lived in a place where Zika virus is spreading use condoms or abstain from sex during the pregnancy. For those couples for whom pregnancy is not an issue, the CDC recommended that men who had traveled to countries with Zika outbreaks and had symptoms of the virus, use condoms or abstain from sex for six months after their trip. It also suggested that men who traveled but don’t have symptoms use condoms for at least eight weeks.

Based on this case—the first to suggest female-to-male transmission—the CDC may extend these recommendations to couples in which a female traveled to a country with an outbreak.

More Signs of Gonorrhea’s Growing Antibiotic Resistance

Last week, the CDC released new data on gonorrhea and warned once again that the bacteria that causes this common sexually transmitted infection (STI) is becoming resistant to the antibiotics used to treat it.

There are about 350,000 cases of gonorrhea reported each year, but it is estimated that 800,000 cases really occur with many going undiagnosed and untreated. Once easily treatable with antibiotics, the bacteria Neisseria gonorrhoeae has steadily gained resistance to whole classes of antibiotics over the decades. By the 1980s, penicillin no longer worked to treat it, and in 2007 the CDC stopped recommending the use of fluoroquinolones. Now, cephalosporins are the only class of drugs that work. The recommended treatment involves a combination of ceftriaxone (an injectable cephalosporin) and azithromycin (an oral antibiotic).

Unfortunately, the data released last week—which comes from analysis of more than 5,000 samples of gonorrhea (called isolates) collected from STI clinics across the country—shows that the bacteria is developing resistance to these drugs as well. In fact, the percentage of gonorrhea isolates with decreased susceptibility to azithromycin increased more than 300 percent between 2013 and 2014 (from 0.6 percent to 2.5 percent).

Though no cases of treatment failure has been reported in the United States, this is a troubling sign of what may be coming. Dr. Gail Bolan, director of CDC’s Division of STD Prevention, said in a press release: “It is unclear how long the combination therapy of azithromycin and ceftriaxone will be effective if the increases in resistance persists. We need to push forward on multiple fronts to ensure we can continue offering successful treatment to those who need it.”

HPV-Related Cancers Up Despite Vaccine 

The CDC also released new data this month showing an increase in HPV-associated cancers between 2008 and 2012 compared with the previous five-year period. HPV or human papillomavirus is an extremely common sexually transmitted infection. In fact, HPV is so common that the CDC believes most sexually active adults will get it at some point in their lives. Many cases of HPV clear spontaneously with no medical intervention, but certain types of the virus cause cancer of the cervix, vulva, penis, anus, mouth, and neck.

The CDC’s new data suggests that an average of 38,793 HPV-associated cancers were diagnosed each year between 2008 and 2012. This is a 17 percent increase from about 33,000 each year between 2004 and 2008. This is a particularly unfortunate trend given that the newest available vaccine—Gardasil 9—can prevent the types of HPV most often linked to cancer. In fact, researchers estimated that the majority of cancers found in the recent data (about 28,000 each year) were caused by types of the virus that could be prevented by the vaccine.

Unfortunately, as Rewire has reported, the vaccine is often mired in controversy and far fewer young people have received it than get most other recommended vaccines. In 2014, only 40 percent of girls and 22 percent of boys ages 13 to 17 had received all three recommended doses of the vaccine. In comparison, nearly 80 percent of young people in this age group had received the vaccine that protects against meningitis.

In response to the newest data, Dr. Electra Paskett, co-director of the Cancer Control Research Program at the Ohio State University Comprehensive Cancer Center, told HealthDay:

In order to increase HPV vaccination rates, we must change the perception of the HPV vaccine from something that prevents a sexually transmitted disease to a vaccine that prevents cancer. Every parent should ask the question: If there was a vaccine I could give my child that would prevent them from developing six different cancers, would I give it to them? The answer would be a resounding yes—and we would have a dramatic decrease in HPV-related cancers across the globe.

Making Inroads Toward a Chlamydia Vaccine

An article published in the journal Vaccine shows that researchers have made progress with a new vaccine to prevent chlamydia. According to lead researcher David Bulir of the M. G. DeGroote Institute for Infectious Disease Research at Canada’s McMaster University, efforts to create a vaccine have been underway for decades, but this is the first formulation to show success.

In 2014, there were 1.4 million reported cases of chlamydia in the United States. While this bacterial infection can be easily treated with antibiotics, it often goes undiagnosed because many people show no symptoms. Untreated chlamydia can lead to pelvic inflammatory disease, which can leave scar tissue in the fallopian tubes or uterus and ultimately result in infertility.

The experimental vaccine was created by Canadian researchers who used pieces of the bacteria that causes chlamydia to form an antigen they called BD584. The hope was that the antigen could prompt the body’s immune system to fight the chlamydia bacteria if exposed to it.

Researchers gave BD584 to mice using a nasal spray, and then exposed them to chlamydia. The results were very promising. The mice who received the spray cleared the infection faster than the mice who did not. Moreover, the mice given the nasal spray were less likely to show symptoms of infection, such as bacterial shedding from the vagina or fluid blockages of the fallopian tubes.

There are many steps to go before this vaccine could become available. The researchers need to test it on other strains of the bacteria and in other animals before testing it in humans. And, of course, experience with the HPV vaccine shows that there’s work to be done to make sure people get vaccines that prevent STIs even after they’re invented. Nonetheless, a vaccine to prevent chlamydia would be a great victory in our ongoing fight against STIs and their health consequences, and we here at This Week in Sex are happy to end on a bit of a positive note.

Roundups Sexual Health

This Week in Sex: A Reason to Celebrate on Tax Day?

Martha Kempner

Same-sex married couples get a long-awaited policy change (but maybe not a tax break), there’s encouraging news about the development of a male contraceptive method, and the month of April brings some much-needed attention to sexually transmitted diseases.

This Week in Sex is a summary of news and research related to sexual behavior, sexuality education, contraception, STIs, and more.

Tax Day 2016: A Reason to Celebrate for Same-Sex Couples

Many in the United States dread this time of year because it means dealing with the Internal Revenue Service (IRS). But there is something to celebrate this time around: 2016 is the first year that every married same-sex couple can file both federal and state taxes together.

After the U.S. Supreme Court ruling striking down part of the Defense of Marriage Act in 2013, the IRS changed its rules to allow legally married same-sex couples to be treated as married for federal tax purposes. While this was a step forward for equality, it actually made tax filing far more complicated for some couples, as NPR explains. Those who lived in a state where same-sex marriage was not recognized would have to file federal taxes as a married couple, but state taxes as individuals. To make matters trickier, state taxes are often based on your federal tax return; some couples had to create mock individual federal returns just to figure out what they owed their state.

This all changed in June 2015, when the Supreme Court ruled in Obergefell v. Hodges that no state can prevent same-sex couples from marrying and all must recognize their unions, effectively legalizing marriage equality nationwide. So this makes Tax Day 2016 the first day that all married couples—regardless of gender—will be treated equally.

While many are celebrating the symbolic victory, some couples may be shocked to find out that they actually owe more taxes as a married couple.

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Another Step Toward Male Contraception

Over the last few decades, researchers have developed numerous ways to prevent pregnancy, from hormonal pills that block ovulation to IUDs that slow the movement of sperm through the reproductive tract. Up until now, male contraception has been limited to one barrier method, condoms, and one permanent one, vasectomies. Now, a new study lends some proof of concept for possible reversible male contraception methods.

As Rewire has reported, one method in development, known as Vasalgel, is intended to be injected into the vas deferens and create a physical barrier preventing sperm from leaving the testicles. Scientists behind Vasalgel say they intend for it to be reversible with another injection. This could be on the market as soon as 2018. But scientists are still looking for other ways to temporarily render males infertile—possibly ones that do not involve an injection into the testicles.

A new study suggests new chances for one such method. University of Virginia researchers are focused on an enzyme known as TSSK2, which helps make sperm motile. They think this enzyme could be the key to a contraceptive method because it is only found in the testicles and only involved in the very last state of sperm production. In theory, this means that blocking this enzyme could produce nonswimming sperm without causing side effects in the rest of the body. They have found a way to mass produce this enzyme in a laboratory, and their next step is to test existing drugs to see if any can bond only to TSSK2 in the testicles without affecting the rest of the body.

Clearly, they are years away from an actual male birth control pill based on this concept. But this is not the only idea for a male birth control pill under development. As Rewire reported last year, other scientists are working with existing drugs to block a protein called calcineurin and have successfully rendered mice infertile by doing so.

While men wait—though it’s still unclear if many are really interested in their own pill—we should all remember that between condoms, pills, patches, rings, and IUDs, there are many methods couple can rely on for preventing pregnancy.

April is STD Awareness Month

With so many months and even weeks dedicated to disease, causes, or remembrances, it can be easy to let them pass unrecognized. But we here at Rewire thought it was important to remind our readers that April is STD Awareness Month, because the epidemic in this country is growing out of control. For the first time in a decade, cases of chlamydia, gonorrhea, and syphilis are all on the rise.

Syphilis—a disease that not long ago, we thought could be eradicated—has increased by 40 percent between 2010 and 2014. While much of this increase is seen in men who have sex with men, rates among women are increasing as well. There has also been an increase in cases of ocular syphilis, which infects the eyes and can cause permanent blindness.

Along with this, we have seen a rise in the rate of congenital syphilis, which occurs when an infected woman passes the bacteria to her infant. As Rewire reported, the rate of congenital syphilis increased 38 percent between 2012 and 2014. Congenital syphilis can cause miscarriage, stillbirth, severe illness in the infant, and even early infant death. There were 438 nationwide cases of congenital syphilis in 2014, which led to 25 stillbirths and eight deaths within 30 days of birth.

Rewire has also been reporting on the possibility of antibiotic-resistant strains of gonorrhea that could turn a once easy-to-treat bacterial infection into a very dangerous disease.

We really do need to be aware of STDs and take steps to prevent them in ourselves and our communities. The CDC has given us all three easy tasks for this month—Talk, Test, Treat. So, for April, let’s talk openly about STDs with our friends, relatives, and partners; get tested if we’ve been exposed to any risk; and of course, seek treatment if necessary.