The perils of overlooking lesser-known STIs

Ann Griswold, PhD

January 2014—When it comes to sexually transmitted infections, most clinicians and laboratories are well versed in diagnosing those caused by chlamydia, gonorrhea, HIV, and syphilis. But a host of lesser-known STIs often go undiagnosed, despite their surprising prevalence.

Many of these STIs receive little publicity because they’re not considered reportable by the Centers for Disease Control and Prevention and the Council of State and Territorial Epidemiologists—a requirement that depends on a variety of factors, including whether an intervention is available and a public health response is indicated, and whether the disease or condition represents a threat to public health.

But recent findings are challenging long-held notions about these pathogens, making a case for greater awareness.

“Trichomonas vaginalis is the most common sexually transmitted infection that is curable, at 7.2 million cases per year. But it’s not reportable,” says Kimberle Chapin, MD, D(ABMM), director of microbiology and molecular diagnostics at Lifespan Academic Medical Center, Providence, RI, and a professor of pathology and medicine at Brown Alpert Medical School. “So the question is, should it be reportable? Why is it that most people don’t know about T. vaginalis, including physicians? Now that we have very good diagnostic test methods, many investigators are looking to get physicians, public health officials, and STD guidelines to reflect the epidemiology and potential health ramifications of TV as an STI.”

And while the newly recognized sexually transmitted pathogen Mycoplasma genitalium is more prevalent than gonorrhea in many settings, it has not yet entered the public eye, perhaps because it’s exceedingly difficult to culture and no commercial tests are available to detect infection. Other pathogens, like herpes simplex virus, are well publicized but can prove tricky to diagnose definitively, particularly given new developments.

Here’s a rundown of the current challenges facing the diagnosis of three STIs—T. vaginalis, M. genitalium, and genital herpes—and how laboratories can help.

Historically, there has been little interest in developing diagnostics for T. vaginalis, largely due to misconceptions about the pathogen’s prevalence and severity.

“Trichomonas vaginalis was originally thought to be relatively uncommon because the test methods we had 10 to 20 years ago just weren’t sufficient in detecting it,” says Erik Munson, PhD, technical director at Wheaton Franciscan Laboratories in Milwaukee, Wis. Wet mount, the most common test used to detect T. vaginalis until recently, is only about 50 percent as sensitive as the newer nucleic acid amplification assays.

Moreover, because the STI is not reportable, there are few strong measurements of its prevalence. Dr. Chapin says, “The CDC stopped collecting data on patients over age 50, which is unfortunate because that’s really where we see a lot of cases of this infection in both men and women.”

Perhaps the biggest reason for placing T. vaginalis on the back burner was its longstanding reputation as a “nuisance” pathogen—one unlikely to cause serious harm. In men, the STI typically causes nongonococcal urethritis, and it can lead to prostatitis in some men. In women, the most prominent symptoms are vulvar irritation, itchiness, and burning.

Recent studies, however, have painted a darker picture of the pathogen’s risks. If not treated early, T. vaginalis can contribute to preterm labor and low birth weight, and it can exacerbate other STIs. “Some of the studies, especially in Africa, have shown that Trichomonas vaginalis allows for easier transmission of HIV from sexual partner to sexual partner,” Dr. Munson says. “The inflammatory response elicited by Trichomonas vaginalis could recruit HIV-positive T lymphocytes to the site of the next sexual exposure and allow for a conduit of transmission of HIV to that sexual partner.”

Similar effects have been reported in women co-infected with T. vaginalis and human papillomavirus. “Women who have T. vaginalis infections clear HPV at a slower rate than women who do not have T. vaginalis infections,” Dr. Munson says. Slower clearance may contribute to the persistence of high-risk HPV.

In recent years, research by Drs. Chapin and Munson and others has done much to address the misconceptions about this pathogen. After publishing a few studies that revealed the surprising prevalence of T. vaginalis, particularly among women older than 40, Dr. Chapin began drumming up interest in improved diagnostics.

To find a better alternative to wet mount, Drs. Chapin and Munson examined several test methods in various populations, including symptomatic and asymptomatic patients, and groups as diverse as child abuse victims and prisoners. Dr. Chapin’s study of a simple lateral flow assay, the OSOM Trichomonas Rapid Test, was found to work well in diagnosing symptomatic patients.

But highly sought-after molecular options remained limited. “Over the years, it became clear—just as it became clear 10 to 15 years ago with chlamydia and gonorrhea—that the amplified test methods are much more sensitive for both screening as well as diagnosing symptomatic patients,” Dr. Chapin says.

So she helped convince Hologic to enter into a clinical trial with its Trich ASR assay to pursue FDA 510k clearance for the Aptima Trichomonas vaginalis assay, a nucleic acid amplification test. In 2011, the FDA approved the assay for use on Hologic’s high-volume TIGRIS batch analyzer, using ribosomal RNA isolated from female urine, cervical or vaginal swabs, or ThinPrep samples from symptomatic or asymptomatic women. In 2013 the assay was approved for use on Hologic’s random-access Panther instrument using the same samples, with the exception of urine.

A 2011 study by Dr. Chapin’s group revealed that the Aptima assay is statistically more sensitive than the Affirm assay by Becton Dickinson. The Affirm assay relies on vaginal swabs from symptomatic women, but it offers the convenience of distinguishing T. vaginalis from two other causes of vaginitis, Candida species and Gardnerella vaginalis. New to the market is the BD Viper XTR Trichomonas, an FDA-cleared and automated assay for detecting T. vaginalis in asymptomatic and symptomatic women that uses SDA amplified technology.

Awareness of the FDA-cleared molecular assays for T. vaginalis is growing, but Drs. Munson and Chapin remain concerned that large numbers of asymptomatic patients are undiagnosed.

Guidance from the CDC is currently limited to screening symptomatic women and those at high risk for infection, according to a statement from the CDC’s Division of STD Prevention. “Testing for trichomoniasis should be performed in women seeking care for vaginal discharge,” the statement says. “Screening for trichomoniasis in women can be considered in those at high risk for infection (i.e. women who have new or multiple partners, have a history of STDs, exchange sex for payment, and use injection drugs).”

However, recent studies have estimated that about 40 to 60 percent of infected patients, both men and women, tend to be asymptomatic. That could increase the spread of infection to sexual partners unless proactive screening is included in annual exams to identify asymptomatic patients.
“If these patients are not diagnosed with a highly sensitive diagnostic test, there’s a possibility that they are going to be coming back and seeking health care again within six months, with a more stark symptomatic picture,” Dr. Munson says.

Though trichomoniasis affects both sexes, the so-called revolving door phenomenon is particularly burdensome for women. “A lot of women have never been tested, and they may have been going back and forth to their doctor with miscellaneous symptoms that are similar to bacterial vaginosis,” Dr. Chapin says. “But because bacterial vaginosis is not treated as a sexually transmitted infection, their partners aren’t getting treated. So you see a lot of women coming back to their physicians and essentially never getting the right diagnosis.”

Part of the problem is that many clinicians aren’t aware of the importance of differentiating between bacterial vaginosis and trichomoniasis. “I have some doctors who will actually say to me, ‘Well, what difference does it make if I diagnose it? I can do a pH strip, and if I get a pH of greater than 4.5, they’re both treated the same.’” Dr. Chapin recalls her shock at discovering this common sentiment among providers, noting that bacterial vaginosis is essentially caused by an alteration of normal vaginal flora, while trichomoniasis is a true STI.

“In fact, there are different guidelines for how you should treat T. vaginalis versus bacterial vaginosis,” Dr. Chapin says. “But even worse—what if I said to a patient, ‘You have an STD and I’m going to treat you, but I’m not going to treat your partner. And I’m not going to tell you about the associated risks to you, your partner, potentially your pregnancy, or anything else.’ I mean, we would never do that for chlamydia.”

Her message to pathologists and laboratory managers is clear: “It’s pertinent that we educate people about the possibility that docs may be using a poor test method, and to think a little differently about how we approach this disease.”

In late February, Dr. Chapin will join the American Sexual Health Association as it convenes experts and opinion leaders from federal agencies, academia, industry, and nonprofit organizations to discuss the most effective ways to raise awareness of trichomoniasis and to identify research and policy gaps.

Though much progress has been made in recent years, at least one problem remains: The FDA-cleared assays are indicated only for women, despite the high prevalence of trichomoniasis in men.