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UPDATE ON LYMPHOGRANULOMA VENEREUM (LGV) Speaker: Marguerite Urban, MD

11/30/2016

Update on Lymphogranuloma Venereum (LGV) [video transcript]

- Okay, so this is an update on LGV, lymphogranuloma venereum, and the objectives are to just go over the clinical manifestations and review the current diagnostic methods. I have no financial disclosures, but I will mention some non FDA approved diagnostic methods or treatments that are described in the literature. So just as background, LGV, as you know, is caused by chlamydia trachomatis, its very specific serovars, the L1 through L3 serovars, and classically, it's been most common in tropical and subtropical climates like Africa, Southeast Asia, Latin America, the Caribbean, and kind of rare in North America, but since 2003, there have been increasing reports in Europe and North America and these have largely been confined to outbreaks in men who have sex with men, communities where men have sex with men where there have also been very high rates of HIV co-infection. They have presented more as a proctitis or proctocolitis, and within these outbreaks, there have been actually fairly few heterosexual cases seen. The pathophysiology are traditional chlamydia infection is part of the serovars D through K, and these infect columnar epithelium, so the chlamydias that cause usually urethritis or cervicitis, and generally, as you know, these are often asymptomatic. When symptoms are present, they are the symptoms of mucosal inflammation like you're urethritis, cervicitis, proctitis, et cetera. In contrast, the chlamydia serovars that cause LGV infect monocytes and macrophages and they have a different clinical manifestation that is typically divided into three stages. These are sometimes called primary, secondary, and tertiary, like similar nomenclature to syphilis. I've called them here just local infection, regional lymphadenopathy dissemination, and then potential complications. The primary infection has an incubation, which depending on who you read, is somewhere between three and 30 days. Sometimes it was listed as three to 10 days, in some authorities, it's three to 30 days, and this is a local inflammation that starts as a papule and then evolves into a pustule or small ulcer. It's generally, classically, very self- limited, and usually fairly asymptomatic and not noticed, generally only two to three days. But in these recent reports of proctitis, there have been some cases with ulcers that persisted more than a month. When it's short-lived, it's often not noticed. I can't say that I've ever seen an ulcer due to LGV. This is a CDC slide that shows the typical very small ulcer. The secondary stage is the regional dissemination, and that occurs two to six weeks after that primary lesion and generally manifests with lymph node involvement. In classic LGV, you would have a short-lived ulcer and then inguinal or femoral very large nodes, and in this rectal involvement, those nodes are not visible because they're retroperitoneal or intraabdominal. In this phase, you may also be systemically ill with fevers, malaise, arthralgias, and sort of like other systemic infections. Those lymph nodes, particularly the inguinal and femoral ones can progress to form buboes, and even have draining sinus tracts. And here is another CDC slide that you've probably seen in some other LGV presentation, because again, there's not a whole lot of experience with this in North America. And this is showing very, very prominent lymph nodes in both the inguinal and femoral region and you can get what's known as a groove sign where you have sort of a mountain, valley, mountain with the two sets of nodes and the inguinal ligament in between. The third stage is really the stage of complications which is a result of the chronic inflammation, and this is fibrosis or strictures that occur wherever the inflammation was, so it could be urethral strictures, or rectal strictures, or some sort of regional lymphangitis, even genital elephantiasis, and in the classic reports, this has been more common in women. And again, a CDC slide showing that sort of lymphedema of the genital region in a woman. So these more recent outbreaks, which have been described since 2003,

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have been almost exclusively in communities of men who have sex with men, and when you go to do a talk like this and pull up a literature review, you can pretty much find a report from most countries in Western Europe describing an outbreak in MSM and fewer reports in North America. These have been largely due to the L2 serovar. There have been some sub-serovars, I don't know what the correct term is, but L2, L2b, and even a recombinant strain reported, L2c. The most common manifestation is this anorectal syndrome that looks for all the world like proctitis with rectal pain, tenesmus, mucoid or bloody discharge, and sometimes abdominal or back pain and fevers. There have been very high rates of co-infection. In most reports, somewhere between 50 and 87%. Importantly, there have also been asymptomatic cases recorded where these serovars were recovered. In the Netherlands, this has been as high as 40%. In the UK, some reports are as low as 1%, and there's different reports in between there in the mid 20s. I'm gonna just review a couple of these reports. The first one comes from Amsterdam which looked at LGV in their MSM population between 2005 and 2012. They routinely screen for gonorrhea, chlamydia, hepatitis B, HIV, and syphilis. They recorded symptoms, did a routine physical exam, and if the patient reported receptive anal intercourse, they did an anoscopy. Everyone had urethral testing for chlamydia, as well as rectal testing, and any ulcers were also tested for chlamydia, as were aspirates of any buboes that were noted. If that chlamydia test was positive, they did an in house PCR to specifically look for LGV serovars, and if the patient reported anorectal symptoms where they had visible inflammation on that anoscopy, they did a gram stain from an anal source and they recorded the number of white cells and if they observed GC. If they had an ulcer, they also tested for syphilis and herpes. And this shows their results, so this was not a small study, so these were 48,000 plus men who have sex with men, and then the second line is the reason for the chlamydia test, so they either had receptive anal sex in the prior six months, they had a visible ulcer, or they had insertive anal sex, and then on the third line, you can see the positivity rate. So for those who had receptive anal sex, they had 10% positivity rate for chlamydia, and going down below that, 1.2% of those total tested were positive for an LGV serotype. I don't know if you can see on the bottom there is 11.3% of those chlamydia positives were actually an LGV serotype, so a little more than 10% of rectal chlamydia positives were an LGV serotype in their population. Surprising to me, I wasn't familiar with this, the genital ulcers that they swabbed, they had about a 4% positivity for chlamydia, and of those, it was 15% that were an LGV serotype, and in those who had insertive anal sex in the prior six months, they had a background positivity of 4.7% for chlamydia, and by their protocol, those patients did not have the LGV test done. This is a look at the positivity rate for actually the LGV serovars over time. These are quarters, and the raw numbers are, sort of in the middle there, is about 25, so they were ranging between 25 about about 40 per quarter, and that increased over time with their highest rates just before they ended the study. They had overall 411 LGV cases in 365 men from the rectal sites and 10 cases in 10 men from the ulcers. Of those, they looked at symptoms and they excluded 84 who also had gonorrhea, because they weren't sure if the symptoms would be coming from the gonorrhea. So of that remainder, they looked at symptoms and they found 27% lacked all symptoms. So they really had no signs or symptoms. About 60% reported a symptom, and about 50% had some anorectal inflammatory sign, that could have been mucus, or an ulceration, or some combination of those. When they looked at that anal swab looking for a gram stain, 85% of the LGV serovars, those who had LGV positive, had more than 10 polys per high power field on that anal swab. And that has been shown in other studies as well. When they looked at HIV co-infection, it was quite high: 81.9%. It was 83% of the rectal specimens and 50% of the inguinals. They had 17 that they didn't know. They had a background high positivity of prior or current syphilis,

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they don't break it down for you, but almost 70% were TPPA positive, so it could've been current, it could've been prior. About a quarter were also GC positive. They didn't notice any trends in these co- infections over time. So overall, they saw an increase in LGV over time. This has been a similar large reports out of the UK, and interestingly, about 40% of their cases were asymptomatic, whereas in the UK, it's ranged between 1% and 25%. This is a slide looking at LGV serovars in another large study of tests sent in the UK. This was across the UK. And these were sent on men who had rectal positive chlamydia tests, or after a certain point in time, they also included HIV positive men who also had rectal symptoms, but not necessarily a positive test. And again, these are quarters and they're going up over time, so they end up with about 1,000 cases per year in 2015. A little closer to home, we have a report just out last month in the MMWR, that is a cluster of LGV cases in Michigan. There had been no LGV reported in Michigan in 2005, and then in August, they had a patient who came in with penile ulcer and inguinal adenopathy who had known, well-controlled HIV. They were able to diagnose chlamydia by swabbing the ulcer for chlamydia. They don't actually tell you what test they did, I assume that they did some sort of NAAT test, but it's not confirmed, and then they identified that chlamydia as LGV by enlisting the help of the CDC later. They put out a couple of health alerts initially through the population of HIV providers and then statewide, and they end up with three more cases compatible with LGV in a relatively short period of time, and so they initiated an official outbreak investigation with CDC's help. They came up with a case definition, so there were three types of cases. You could be a suspected case, where basically you have a clinically compatible illness, so proctitis or some sort of genital ulcer adenopathy syndrome, or you were a partner of somebody with a probable or a confirmed case. A probable case is sort of the same as a suspected, but now you've ruled out syphilis, gonorrhea, and herpes, and you have a positive chlamydia test, but you don't yet have a serovar or, again, a partner of that, or a confirmed case where you actually identify the LGV serovar. So what they identify are 38 cases, all who were in men who have sex with men who also have HIV infection, although this may be again because they sent out this targeted messaging to HIV providers. 11 of those 38 cases were probable and six of the 38 were suspected by the health department, and then ultimately when the testing was done at CDC, they were able to confirm 21 of the 38 cases, so 55%. Of those confirmed cases, 19 were rectal. The median age was 29. They ranged from 19 to 60. As I said, these were all people who had co-infection with HIV with a median CD4 count of 483, with a big range between 270 and 1200 plus. They had HIV RNA levels, and 12 of the 21 were undetectable. Of the remaining nine, they had a relatively low copy number, less than 10,000 copies. Interestingly, six of the 38 were actually diagnosed as HIV in the course of this evaluation. Four of 28 were also HCV positive, which I didn't mention earlier, but has been reported particularly in the Netherlands. Six of the 38 also had syphilis. Three of the 38 also had GC in the throat and six in the rectum, and of the whole 38, 19 had symptoms of proctitis. That's really the end of what they tell you. They're really just alerting you that this has happened in Michigan and to be mindful that these serovars are present in the United States as well. I'm gonna switch now to just talk about how to make the diagnosis overall of LGV. It's historically diagnosed, what I learned in medical school, was that you used serology, and now in most guidelines that are published, this is a little bit dismissed, and that's because there are really no standards for the serologies and there's concern about cross reactivity with other chlamydial species even, not even just other serovars, but other species. However, if you do use serology, the titers that would be suggestive of a true positive would be a micro immunofluorescence titer that's quite high, greater than 1:256, or a complement fixation titer that's 64 or greater. If you have serologies over time and can show rising

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titers, that's also very suggestive. You can also look for the organism and you can do that because we now have these NAATs available. It's all or very close to all of the commercially available tests include the LGV serovars in their testing, but you only get a positive or a negative readout when you do the chlamydia test. So when you have a positive, you don't know if it's the usual D through K serovar or the L serovars. Then there's the added complication that, as we all probably know all to well, the NAATs are not FDA approved for testing on rectal sites unless your laboratory's gone through some validation process. Once you have a positive chlamydia on a NAAT, then you have the second problem of identifying the specific serovars, and there really is no test approved to do that that distinguishes LGV from non-LGV. This is done much more commonly in Europe, and in the US, there have been a number of sort of in house molecular test developed, PCR, genotyping, that detect the serovars. Some detect only these L2s that have been reported more recently. Some detect all LGV serovars, but they don't specify which one. The CDC recommends doing some additional molecular procedure known as PCR genotyping to try and differentiate this. They do have a test in house that they used in this Michigan outbreak and they also suggest that a positive serology might support the diagnosis in the appropriate clinical context. Within New York state, Wadsworth Laboratories, the state lab, does offer a L2 PCR, which is performed on rectal or urethral specimens that are known to be positive for chlamydia already, and we can, if you're interested in how to do that, we can send out that information with follow up emails after this session. The treatment of LGV for 50 plus years that the recommendation has been doxycycline 100 bid for three weeks, for 21 days. There's been some talk of using azithromycin weekly times three because of its success in genital chlamydial infection, but just in terms of case reports, the cure rates might be inferior, so that I think is a little bit on the outs right now. There have been rare cases in these recent outbreaks in MSM of treatment failure despite the doxycycline, and those cases have subsequently been treated with moxifloxacin, some 21 days, some only 10 days with success, but that's sort of at the level of very few case reports. I just wanted to run through what a typical case might look like. This is an example of a proctitis. This is out in the last couple of months. It comes from Baylor. It's a 60-year-old, HIV-positive man with a normal CD4 count, undetectable HIV viral load who developed hematochezia and had rectal bleeding actually for a month. He had two to three stools per day, some pain, bloating. No history of inflammatory bowel disease. On sigmoidoscopy, he had a rectal mass with numerous fragments and what was described as necroinflammatory ulcer base and two polyps. They did biopsies, and the biopsies were acute cryptitis, crypt abscess formation, and diffuse acute and chronic inflammatory infiltrates. Ultimately, microbiologic testing was done and he was identified to have a chlamydial positive from a rectal swab. He was treated with doxycycline for three weeks and his symptoms and findings on repeat colonoscopy had resolved. The partner also had similar proctitis symptoms and had a colonoscopy with similar findings and similar biopsies, also treated with doxycycline. This has led to a little bit of a flurry of case reports in the GI literature of people being evaluated for inflammatory bowel disease ultimately found to have LGV rectally. And here's another recent case that's inguinal, also fairly close to home. This came out of Ottawa and also was in the last month or so. It's a 34 year old man who came in with a two-week history of painful, red swollen inguinal bump, no other symptoms. He went to an urgent care where he was treated with cloxacillin with no improvement. He did have a history of unprotected insertive and receptive oral and anal sex with male partners. When he was seen at this STD clinic, he had a very large, tender, inguinal node actually described as a bubo, and they did some testing, which was all negative, chlamydia, gonorrhea, syphilis negative, but he was also newly positive for HIV. They did send antibody and his micro

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immunofluorescence titer was quite high at 512, so that would be one dilution higher than what is generally considered positive for this. So they diagnosed him as a probable LGV. He was treated with doxycycline for three weeks and his bubo did resolve, and he was advised to have his partners treated. In the case definition in Canada, because the diagnosis was by serology, he didn't count as a case, and that was sort of their impetus to publish that report. There are various case reports of misdiagnoses as lymphoma because of the adenopathy, several of inflammatory bowel disease, and some even of rectal cancers. As I alluded to earlier, there have been a couple of case reports of treatment failure after doxy where they've responded to moxifloxacin, and there are now two or three reports of a reactive of arthritis that occurs several weeks after an episode of LGV. So in conclusion, there's a shift in epidemiology and in sort of, at least in Western Europe and the US, I think we're more likely to now see rectal presentations of LGV than inguinal. The cases are highest in men who have sex with men and there are lots of reports of co-infection with other conditions. The diagnosis is particularly different because of the lack of available testing. And really, I think at this point, we're probably considering empiric treatment for LGV consistent syndromes when you don't have access to diagnostic tests, particularly in men who have sex with men with proctitis, so if you don't have a test for chlamydia or LGV, I would probably go ahead and just treat as LGV, recognizing that there would be some overtreatment. If the chlamydia's positive but no LGV test is done, same thing, I'd probably treat as LGV recognizing that sometimes we're overtreating. If you have access or can send to Wadsworth, you can treat based on the result. It's a little trickier I think in an asymptomatic man who has sex with other men who might have a rectal chlamydia positive, and if you don't have access to that serovar testing, not really sure what the right thing to do there is. It does seem that there are some reports of asymptomatic infection. Whether they go on and have complications is hard to know. I think the verdict is out and maybe you might want to consider treatment based on your local prevalence. We have a bibliography that will come out with your email after our session today. So that's the end of our didactic presentation.

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