Some patients need more than just routine screening for sexually transmitted infections (STIs). For those with genital lesions or discharge, accurate diagnosis and timely treatment can improve quality of life while preventing re-infection, according to Elisa Choi, MD, FACP, a Boston-based internist and infectious disease subspecialist.
Dr. Choi spoke on “Common Ambulatory Genitourinary and Sexually Transmitted Infections” at Internal Medicine Meeting 2016, focusing mainly on nonpregnant women and non-HIV-infected patients.
Types of syphilis
Syphilis, which is caused by Treponema pallidum, has several stages of infection, Dr. Choi noted. Primary infection is characterized by chancre or an ulcer and is typically painless, whereas secondary syphilis develops after a patient goes untreated for weeks or months. “And that is typically characterized by a bit more systemic symptoms, rash, generalized lymphadenopathy, and more prominent and disseminated mucocutaneous lesions,” she said.
Without treatment, a patient may develop tertiary syphilis, which has some end-organ involvement, Dr. Choi said. Tertiary syphilis may affect the cardiovascular system with aortitis and other valvar involvement, as well as the nervous system, and there may be some evidence of cutaneous involvement in the form of gummatous lesions, she said.
Manifestations of neurosyphilis, which affects the central nervous system, include cranial nerve deficits, stroke, meningitis, acute mental status changes, and ophthalmological and auditory abnormalities. “This can be confusing for a lot of people because often, it's thought of as occurring late in syphilitic infection. ... It actually can occur at any stage of syphilis infection, particularly with syphilitic meningitis—that can happen early on,” Dr. Choi said.
Similarly, ocular syphilis can occur at any stage of infection and can even be the presenting manifestation of early syphilis, she noted. “Its manifestations are quite varied and heterogeneous, and virtually any chamber of the eye can be affected by ocular syphilis,” Dr. Choi said.
Latent syphilis, or asymptomatic infection, falls into 2 categories: early latent syphilis and late latent syphilis, depending on when the infection was likely acquired, she said. “Often, that's unknown, particularly if a patient is found to be incidentally positive on serologic testing for syphilis and there's no prior baseline to compare, in which case that would be late latent syphilis of undetermined duration.”
The darkfield microscopy exam that was previously used to confirm syphilis is rarely used today because of technical limitations, Dr. Choi explained. Serologic tests are much more common and include the treponemal tests, T. pallidum particle agglutination assay (TP-PA) and fluorescent treponemal antibody absorption (FTA-ABS), which are more specific for T. pallidum, and the nontreponemal tests, rapid plasma reagin (RPR) and the venereal disease research laboratory test (VDRL). “These are very good screening tests because they're quite sensitive, but they can also lead to false positives in numerous conditions, including autoimmunity, HIV, pregnancy, and post-immunizations,” Dr. Choi said.
Syphilis is serologically confirmed when both a nontreponemal and a treponemal test are positive, she said. The standard testing algorithm is to use a nontreponemal screening test and, if the result is positive, perform a treponemal test. If that result is also positive, the diagnosis is confirmed, Dr. Choi said. With an alternative testing algorithm, which is becoming more widely used, the order is reversed, with the treponemal test followed by a nontreponemal test. Again, active infection is diagnosed if both tests are positive, she said.
However, if both tests are not positive, “There are 3 subsequent clinical scenarios [when the first-step treponemal test is positive] that become a fair bit more confusing using this different nontraditional testing and screening algorithm,” Dr. Choi said. If the treponemal test is positive and the second-step nontreponemal test is negative, another treponemal test with a different modality should be performed. If that additional treponemal test is negative and if there is no epidemiological risk of syphilis, then the first-step treponemal test could be considered a false positive, she said.
Another scenario is if the first-step treponemal test is positive, the second-step nontreponemal test is negative, and the additional treponemal test is positive. “If ... there was syphilis previously and it was treated, then this is considered past infection if the additional treponemal test is positive, and no additional treatment is needed,” Dr. Choi said, noting that if there is any concern about acute infection, the patient should be retested in about 2 to 4 weeks to exclude new infection or re-infection.
One final scenario involves a positive result on the first-step treponemal test, a negative result on the second-step nontreponemal test, and a positive result on an additional treponemal test with a different modality. “If [the second treponemal test is] positive and there's no prior history of syphilis treatment, presuming the patient is asymptomatic, this should then trigger treatment for late latent syphilis,” she said.
To diagnose neurosyphilis, there must be positive reactive serologic testing in addition to relevant neurological symptoms, Dr. Choi said. A lumbar puncture should be performed, including 2 types of tests of the cerebrospinal fluid (CSF), she explained. Dr. Choi suggested first performing the VDRL, which is specific but not sensitive—if positive, this test is diagnostic.
If the VDRL is negative, consider getting an FTA on the CSF, as this test is sensitive but not specific, she said. “If that's positive, then that will potentially be consistent with neurosyphilis,” Dr. Choi said. “I should point out that since it's insensitive in CSF, a negative VDRL doesn't rule out neurosyphilis.”
Ocular syphilis should be confirmed with positive serum serology and a detailed ophthalmologic exam to pin down the exact nature of the ophthalmological involvement, she said. “Keep in mind: Ocular syphilis can present without other signs and symptoms of syphilis,” said Dr. Choi. “CSF evaluation should be undertaken in ocular syphilis, even without any neurologic symptoms, because of the risk of developing neurosyphilis.”
Treatment and management “can really be summed up in 1 word: penicillin,” Dr. Choi said. Early latent, primary, or secondary syphilis can be treated with a single intramuscular (IM) shot, whereas late latent syphilis or latent syphilis of unknown duration is treated with 3 weekly doses of IM penicillin. “Even late-stage tertiary syphilis, in the absence of any abnormal CSF findings, can also be treated [with] IM penicillin with 3 weekly doses,” Dr. Choi said.
Neurosyphilis and ocular syphilis must be treated much more aggressively because the disease course is much more involved, she said. Treatment typically requires up to 2 weeks of high-dose IV penicillin therapy, Dr. Choi said. People who can't tolerate or don't want parenteral treatment can instead receive a 10-to 14-day regimen of IM procaine penicillin once daily with probenecid, 500 mg 4 times daily, to enhance drug levels, she said.
Before using antibiotics to treat patients with syphilis, be sure to counsel them about Jarisch–Herxheimer reaction, an acute systemic febrile response that typically occurs within the first 1 to 2 days of treatment, Dr. Choi said. “Otherwise, the patient may get quite alarmed, and this typically happens due to that sort of ‘burst’ of all the Treponema when they are starting to be killed by bactericidal killing from the penicillin.”
Follow-up is very important after a syphilis diagnosis, Dr. Choi emphasized. In addition to testing for HIV in patients with syphilis or any STI, clinicians should conduct follow-up nontreponemal testing after a syphilis diagnosis to determine disease course and treatment response, she said. She noted that treponemal tests should never be used as tests of cure because they remain indefinitely positive, even after successful treatment.
Additionally, some patients have what's called a serofast reaction, where there is a low-titer, persistent positive RPR. “That doesn't necessarily mean they failed treatment, but you may need to look at the case individually on a 1-on-1 basis to determine if they need further evaluation for more advanced syphilis disease,” she said.
In early latent syphilis, check a repeat serology at 6 and 12 months, at which point there should be a 4-fold quantitative decrease in the titer, Dr. Choi said. “If that doesn't happen, you may want to consider looking at the CSF to see if there might be some occult neurosyphilis, and you certainly would want to consider re-treatment and also repeat HIV testing,” she said. Clinicians should follow serologies for latent syphilis for up to 24 months and should perform CSF evaluation if the titer has not decreased 4-fold by this point, Dr. Choi said. “Given this is latent syphilis, if the person should develop syphilis symptoms, then [clinicians] really do need a lumbar puncture to evaluate for neurosyphilis.”
Neurosyphilis and ocular syphilis may require follow-up CSF testing at 6-month intervals until any abnormalities originally seen in the CSF profile resolve, Dr. Choi said. If there is no normalization at 2 years post-treatment, clinicians should consider re-treating the patient, she noted.
Herpes simplex virus
Although genital herpes is typically caused by type 2 herpes, type 1 genital herpes has become more common, particularly in younger women and men who have sex with men, Dr. Choi said. “Many cases of herpes transmission occur when a person is either asymptomatic or they have very very mild disease,” she said. “And that becomes problematic because it's often hard to counsel patients about how they can protect themselves and their partners.”
Serologic tests for genital herpes are “not typically helpful in trying to make the acute diagnosis of genital herpes because they may not turn a serology positive early in infection, and there are some accuracy issues with the IgM serologies—in particular, they may persist in recurrent infection,” she said. Also, a microbiologic diagnosis can be tricky because the tests are fairly insensitive, and negative results don't exclude infection, she said.
Serologic testing for herpes simplex virus (HSV) can be warranted in patients with a history of recurrent genital herpes but no prior lab confirmation, sexual partners of known HSV-infected individuals, and patients with recurrent genital symptoms with negative HSV cultures or polymerase chain reaction tests, Dr. Choi said. The current recommendation is not to screen the general population with herpes serology, “but you certainly would want to consider that if you're looking at a patient in terms of STI risks,” she said.
All initial presentations of genital herpes must be treated with antivirals because of the substantially higher risk of neurologic involvement and complications, as well as the potential for more severe and prolonged symptoms, Dr. Choi said. “You do want to point out to the patient and also be aware yourself that antivirals against HSV do not eradicate latent infection and thus recurrent HSV can be problematic, and you should also HIV test them,” she said.
For initial and recurrent HSV and for suppressive therapy, the 3 typical agents are acyclovir, valacyclovir, and famciclovir at multiple daily doses for 7 to 10 days, Dr. Choi said. “We don't actually have data to support that any one particular treatment is more superior to others, so it often depends on cost and also ease of the frequency of dosing.”
Treatment is typically longer for a first episode of genital herpes, whereas recurrent episodes require shorter treatment durations, Dr. Choi said. “If somebody is starting to have more than 6 episodes a year, then you really want to consider the idea of suppressive therapy, and [higher doses of] the same 3 agents ... will be used, but this is often a judgment call on the part of the physician and the patient.”
Urethritis and cervicitis
The last 2 categories of STIs Dr. Choi discussed include urethritis and cervicitis, which affect men and women, respectively. Urethritis can be subdivided into 2 categories: gonococcal urethritis (GU) and nongonococcal urethritis (NGU), both of which warrant testing for gonorrhea and chlamydia because of frequent co-infection, Dr. Choi said.
Patients with urethritis will often present with symptoms that can mimic a urinary tract infection (UTI), such as dysuria, objective evidence of urethral inflammation (pruritus or erythema), and urethral discharge, she noted. Clinicians should typically try to confirm a GU diagnosis with a nucleic acid amplification test (NAAT), she said.
She noted a shift from prior guidelines in terms of treating GU with dual therapy. “You want to treat, regardless of whether you're concerned about chlamydia co-infection, with both ceftriaxone and azithromycin. And that's primarily because of concern for emerging resistance,” Dr. Choi said, noting that a course of doxycycline may be used instead of azithromycin as an alternative second agent.
With NGU, there are a number of different organisms at play that are fairly difficult to culture, “so in particular with NGU, you rely on the NAATs for diagnostic confirmation,” she said. Symptoms are often indistinguishable from GU, with potentially a little less purulent urethral discharge, Dr. Choi said. A single dose of azithromycin or a 7-day course of doxycycline is usually used to treat NGU, but if neither of those is viable, fluoroquinolones or older macrolides may be used, she said. “Often, you're treating this presumptively, even before you're confirming the diagnosis.”
Although NAAT results typically come back quickly, clinicians often need to make a point-of-care decision before confirmation, Dr. Choi said. Also, she noted that Mycoplasma is a common cause of NGU and a cause of persistent or recurrent urethritis in one-third of cases, but no currently available test can capture it. “So you definitely want to suspect that if a man presents to you with recurrent symptoms and seems to have ‘failed’ therapy,” she said.
With both categories of urethritis, be sure to counsel patients to abstain from sexual intercourse until they and their partners have completed their treatment and for at least 7 days afterward, she said. “And as is the recurring theme of all of these infections, you must be testing for HIV and other STIs, as well,” she stressed. Additionally, make sure patients return 3 months after treatment for retesting, “and that's irrespective of the partner's status with respect to treatment because there's a high risk of re-infection,” she said.
If the initial treatment fails because of nonadherence or because the patient's partner was not treated, clinicians may re-treat with the same drug, Dr. Choi said. But in other persistent or recurrent cases, re-treat with azithromycin, particularly if that was not part of the original regimen, since Mycoplasma responds better to azithromycin than doxycycline, she said. If azithromycin fails, she recommended re-treating with moxifloxacin.
Trichomonas vaginalis is another cause of persistent urethritis, but for men, there is no FDA-approved NAAT for this etiology, Dr. Choi noted. So if a man presents with recurrent urethritis, consider treating presumptively with metronidazole or tinidazole for the possibility of trichomonas, particularly if everything else has failed (including treatment for Mycoplasma), she said. “And again, partner testing and evaluation as well as further testing of other STIs is key.”
Cervicitis is characterized by a mucopurulent endocervical discharge and some persistent endocervical bleeding, particularly after a swab of the endocervix, Dr. Choi said. “However, infectious cervicitis can actually be asymptomatic, and there can be other symptoms that are a little bit confusing to make the diagnosis,” she said, noting that women may report intermenstrual vaginal bleeding or “vaginal” discharge versus cervical discharge.
There is no determined cause in most cases of infectious cervicitis, but since chlamydia and gonorrhea are often implicated, clinicians may want to preferentially use the NAAT for these organisms on any obtained samples, Dr. Choi said. Clinicians should also evaluate for bacterial vaginosis (BV) and trichomonas.
Again, presumptive treatment is often started at the point of care when a patient presents with these symptoms, Dr. Choi said, particularly women under age 25, those with risk factors for STIs, and those who may not return for follow-up or be reachable after the NAAT results return.
“If you're looking for and find BV and trichomonas, treat them as well, but you may be able to defer treatment until confirmation if you find that your assessment is that the patient is relatively at low risk of having other STIs,” she said.