Clinical Education Initiative URETHRITIS. Elizabeth Asiago-Reddy, MD

Transcription

1 Clinical Education Initiative URETHRITIS Elizabeth Asiago-Reddy, MD 3/13/2017

2 Urethritis [video transcript] 00:00:07 - [Elizabeth] Thanks so much for having me and I'm sorry for the technical difficulties. Certainly everyone tried to make sure that we were all prepared and despite the best of our attempts, we're a bit behind. So bear with me. 00:00:21 So I'll try to go through a bit quickly. I have received some funds from Amgen and Janssen to my institution for studies on which I'm the principal investigator, and I was formerly a Gilead Speaker, Bureau speaker last year. 00:00:38 So I wanted to go through differential diagnosis, diagnosis of urethritis, standard treatments for urethritis, and a little bit about partner treatment and urethritis. 00:00:44 So this is a common syndrome with about three million episodes in the U.S annually. Most of the cases are in men less than 35 years of age and are even more common in men less than 24 years of age. I apologize for the background noise. Reported symptoms include burning, urgency, and urethral discharge. I've also heard tingling quite a bit from my patients. Discharge may be mucoid or mucopurulent. Watery discharge is quite variable from person to person, and maybe physiologic depending on the patient, or maybe pathologic. And important to point out that urethritis alone is not typically associated with fever, abdominal pain, testicular pain, or back pain. So any of those should point to a different diagnosis. 00:01:34 We're gonna go through some cases. So this is a 23-year-old male graduate student who presents to the sexually transmitted infection center with three days of burning with urination and a whitish urethral discharge. He's had two partners in the last month and five partners in the last three months, all female. He gives and receives oral sex. He's had no chronic medical problems, and no systemic symptoms, and he has no genital ulcers, and he's worried about a swab because it's too painful. He also just urinated 20 minutes ago. 00:02:03 So which of the following is true about the diagnosis of urethritis in this case? Sensitivity of a urine to detect Chlamydia will be too low because he has just voided. Dacron swabs, spatulas, plastic loops are all reasonable means of obtaining a urethral specimen, should he allow them. Milked discharge should not be sent to the lab for analysis. Spun urine and leukocyte esterase would have about the same ability to detect urethritis in this case. So in this case, B is the correct answer. So all of these are reasonable 1

3 tools to use in order to, actually tools is probably not the right word. Sorry about that. Instruments to use in order to obtain a specimen. 00:02:45 So really at the point of care, it's ideal if there are diagnostics available that can help distinguish immediately from gonococcal versus non gonococcal urethritis. So gram stain or methylene blue stain of urethral fluid are both adequate and have a high sensitivity in order to detect gonorrhea initially as the separation point for how to treat patients. So often times as many of you are aware, we will suspect gonorrhea up front due to purulent discharge in patient symptoms. So for that, majority of cases of gonorrhea are symptomatic and it appears that maybe among men who have sex with men they're a little bit less likely to have symptoms in a urethral infection but generally speaking, upwards of 95% of patients will have symptoms. Use of plastic loops actually have been studied as a means to potentially decrease pain over other options for urethral swab with Dacron swab coming next in line, and after you kind of looked at whether or not the patient has intercellular diplococci, you want to get a sense for whether there are white blood cells and how many white blood cells per high power field in order to make the diagnosis of urethritis. 00:04:02 So a couple other points before we go to the number of white blood cells that you'll be looking for. Leukocyte esterase from First Void Urine has been shown to have inadequate sensitivity for diagnosis. So that would be a standard urine strip or microscopic urinalysis. However, it's better than nothing. So if you have no other option to try to make a diagnosis, its sensitivity is about 75%. Spun urine does improve the sensitivity over a standard leukocyte esterase test. And ideally once you've gotten that fluid, either urine or the urethral fluid, you would want to send that off for NAAT testing because obviously at the point of care, you're only making that distinction between gonococcal versus non gonococcal urethritis. So ideally you want to be sending that test off for NAAT testing for chlamydia, gonorrhea, and hopefully Mycoplasma genitalium and trichomonas vaginalis, which we'll discuss more throughout the presentation. One of the questions that I've had come up a lot as well: what about this patient who just voided 20 minutes ago, is his urine PCR not gonna be viable? And actually at least for chlamydia, the system studied several times and there's no evidence that you need a first void urine in order to get a good sample for chlamydia. 00:05:23 So what about this diagnosis of urethritis with two versus five white blood cells for high power fields? So this is a new recommendation in the CDC guidelines in 2015 to go from using the cut off of five white blood cells per high power field to two, and that really came from the Denver study. Which looked at more than 36,000 men, and you can really see from this graph that at zero or one leukocytes per high power field, there are very few cases of chlamydia. Where as it shot up all the way to 15% once you got up to two white blood cells per high power field. Not all studies have confirmed this, and there's some controversy surrounding this, but there are several other small studies that look very similar to this major study in which you get up to pretty high prevalences of chlamydia at relatively low white blood cell counts. On the other hand, Europe has not yet adopted these guidelines and is still using the cut off 2

4 of five, and a recent study from Sweden showed that only 1.5% of patients with less than five PMN or leukocytes per high power field had chlamydia. So some controversy still with that, but along with this big Denver study plus several other smaller U.S studies, it looks like there is evidence for the cut off of two white blood cells to diagnose urethritis. 00:06:51 So what are the pathogens we're dealing with here? So the big three, bacterial pathogens are really chlamydia. Which accounts for about 15 to 40% of cases, gonorrhea- between 2 to 8% of cases. Mycoplasma genitalium is a rising component of the urethritis picture, and we'll talk again more about that organism. Making up about 15 to 25% of cases. Other bacteria that may be involved- so ureaplasma urealyticum, ureaplasma parvum, which is kind of a possible one and less evidence for that in studies. Various enterobacteriaceae like E. Coli, Klebsiella. Haemophilus influenzae appears to be a relatively unusual but definitely a known pathogen. Neisseria meningitidis can also cause this, and gardnerella and other vaginal anaerobes might also be implicated, and again, the data for gardnerella and other vaginal anaerobes are somewhat controversial with different studies, implicating these as pathogens in men and other studies not. Just to go back a little bit to ureaplasma. It looks like a ureaplasma urealyticum appears to be an immunologically mediated process with some people experiencing clearly symptomatic infection and others remaining totally asymptomatic, and there's some evidence that the level of sexual experience, so more sexually experienced patients with more history of partners are less likely to be symptomatic with ureaplasma. Viral pathogens include herpes simplex virus, adenovirus, and possibly Epstein-Barr Virus, and of course parasitic we have trichomonas vaginalis. 00:08:34 So this is, I thought, one of the nicer studies. Although it's actually 10 years old at this point, but looking at causes of urethritis. These were among Australian men presenting to STI clinic in Sydney, and this was both symptomatic and asymptomatic, and the goal was to compare pathogens present in men who were symptomatic with the urethritis compared to those who were asymptomatic without urethritis. So looking at the pathogens that were identified, if there's a star, it means that this was significantly associated with urethritis compared to asymptomatic patients and patients without urethritis, and so interestingly, not surprisingly, chlamydia making up the bulk of infection. Mycoplasma genitalium making up a substantial portion of symptomatic. HSV-1 and adenovirus also forming a significant portion, and the authors point out in this study that a substantial proportion of their patients where men who have sex with men, who receive oral sex, which they thought contributed to the prevalence of HSV-1 and adenovirus in this study. Gardnerella vaginalis on the other hand in this study was negatively associated with symptomatic urethritis. So that's what the two stars stand for, and then the other pathogens, there was really no association. So you'll see here there was quite a bit of ureaplasma identified, but actually no association with symptomatic versus asymptomatic or urethritis versus non urethritis. 00:10:11 This study was interesting. It looked more at patients who were definitively symptomatic presenting to a large number of very diverse settings in the U.S including primary care offices, OBGYN offices, STD 3

5 centers. And they only looked at symptomatic patients, and they only looked at patients who received a microbiological diagnosis. But I think what's very interesting here is the very prominent role of Mycoplasma in both women and men. So since this talk is focused mostly on men, looking here at the prevalence of Mycoplasma among symptomatic men with a diagnosis, it was 1/3 of patients across this broad swath of different locations in the U.S. And interestingly trichomonas, which they diagnosed using PCR was also pretty impressively prevalent. But Mycoplasma made its place as well as part of coinfections. So was pretty common to have co-infections in men and very common to have co-infections in women. The amount of trich in women in this study was also very impressive. Again these are all people who are in some way symptomatic and had a diagnosis. So that's a big part of why this number looks so big for the women. 00:11:30 So we're at a real challenging point here I think, because we still do not have, and I think I've emphasized from the last couple of slides the role that Mycoplasma genitalium is playing in urethritis, and yet we have no FDA approved assay for genitalium available in the U.S. However, the CDC has now recommended the M. genitalium ASR assay from Hologic, which is a PCR assay, and I think that is helpful in moving us in the right direction in terms of starting to implement this more broadly. From the perspective of trich, we know that you can culture this organism or you can try to look at it in a wet mount from urethral secretions. However, the sensitivity, particularly of trying to look for this in urethral secretions is very low. So the use of NAAT testing is especially helpful for men with either urethritis symptoms or potentially with a partner who has trich. So in those cases, just partner treatment is recommended. So the use of NAAT testing for trich is really gonna expand our ability to detect this pathogen and properly treat in symptomatic men. If there's any kind of question as well as to what the diagnosis is, there may be a need to do bacterial culture, so bacterial culture with immediate plating on top of agar can isolate of course Neisseria gonorrhoeae as well as neisseria meningitidis and H. Flu. Viral culture is rarely used. So ideally NAAT or direct fluorescence antibody can identify HSV. And generally speaking we don't have very good commercial assays available to identify adenovirus. 00:13:34 All right so case two: this is a 42-year-old machinist who's recently divorced from his wife and says he just started having encounters with other men. He reports only receptive oral intercourse. So partners have given him oral sex without any anal sex. Five days after his last encounter, he noted redness on his penis associated with dysuria and whitish-yellowish discharge. On exam, he is noted to have bilateral conjunctivitis and obvious meatitis without ulcers. Gram stain notes a mononuclear predominance. 00:13:56 So this is a picture showing what meatitis looks. You can see really the amount of erythema around the urethral opening. Which is somewhat unique to this pathogen and a couple other pathogens. 00:14:09 Which pathogen is most classic for this presentation? Chlamydia trachomatis with Reiter's syndrome, herpes simplex virus, adenovirus, or hemophilus influenzae? So actually this is most classic for 4

6 adenovirus, and this patient with bilateral conjunctivitis and the meatitis is really presenting very classically for adenovirus. So that's the classical presentation. Receiving oral sex is the sort of classical history that you would get for adenoviral urethritis, and you can, as well, get meatitis with herpes simplex virus. You can get conjunctivitis with chlamydia, but putting all of those pieces together, this is most consistent with adenovirus. Also of note is the prevalence of, as I said on a previous slide, gram stain noting a mononuclear predominance. So rather than PMN, you'll actually see monos on the gram stain if you have someone who's astute to look for those. 00:15:16 Okay so another interesting case. This is a 27-year-old information technologist who presents with heavy mucopurulent urethral discharge. He reports three female partners in the last three months and has had oral, vaginal, and anal sex. Gram stain reveals abundant gram negative intracellular diplococci. He is treated empirically for gonorrhea and symptoms resolve. However, NAAT testing later returns negative for neisseria gonorrhea. 00:15:41 So again, abundant gram negative diplococci. So this is a slide of what his urethral gram might have looked like. You can see here all these different diplococci, and the cells are right here. So these are inside the cells. 00:16:00 So what happened here? Which of the following is true about this pathogen? It is always reportable to the local health department. It is preventable by vaccine. Partners should receive standard therapy for gonorrhea, or oral sex is a risk factor. 00:16:16 So this is most consistent with Neisseria meningitidis. So I talked about, I'll go through the two cases now. The first one we talked about with the man with bilateral conjunctivitis, meatitis, and urethritis, and that was most consistent with viral urethritis. So again, like I said, more common in people who have received receptive oral intercourse. HSV urethritis may or may not be accompanied by ulcers, and prolonged or relapsing symptoms may be a clue to HSV. HSV, especially for its initial, the first time the individual is infected, can present with constitutional symptoms as well. So fever, malaise, and adenovirus presents with conjunctivitis in about 30% of cases. The next case was actually a case of neisseria meningitidis urethritis. And this may reveal itself in cases where the gram stain and the NAAT testing are discordant. So you have a gram stain where you're seeing gram negative diplococci, but the NAAT test says no gonorrhea. So we're actually experiencing a number of cases of this recently, a small number, but it's kind of raised a red flag for us because it's a new thing at our STI center at Onondaga County, and we are kind of seeing this in the typical pattern of people who have received oral sex. These tend to be young men and more common among African Americans and more common among men who have sex with women. So this is typically caused by non-typeable strains of neisseria meningitidis. So that's an important point because the vaccine which only covers, the current vaccine that we have, only covers four strains of neisseria meningitidis and these are not the ones that are typically found in 5

7 this setting. And really the implications for partners are unclear. So this does appear to respond as this patient in the case responds to standard treatment. However, whether or not partners really need to be treated is not clear. So it looks like the likelihood of that partner clearing the organism from their throat is not that great if they are treated. So I think certainly if there was a situation where somebody was having more current urethritis on the basis of this, a partner treatment should be attempted. But as a general rule in terms of partner speaking, it appears that the counsel that we've gotten in the process of working up these cases that we've seen at Onondaga County is that standard partner referral and treatment for neisseria meningitidis at this point is not necessarily recommended. 00:18:57 All right so we're gonna go back to case one. So this was our guy who came in, our grad student who initially said you're not swabbing my urethra. Then he said okay, all right you can go ahead. So we went ahead and did the swab and he was found to have NGU, so non gonococcal urethritis with 10 white blood cells per high power field. So he said, "I wanna get rid of this thing "once and for all." and he asked that azithromycin he receives in clinic will definitely cure him. So he's gonna get a gram of azithromycin in clinic for non-gonococcal urethritis. Which is gonna be presumed to be chlamydia until proven otherwise. And he wants to know whether this will definitively cure him. 00:19:42 So the real, chlamydia has been the pathogen that we're really treating for when we're treating non gonococcal urethritis because of this known potential effects in pelvic inflammatory disease and infertility in women. So we're really trying to treat the man both to resolve the symptoms that are going on and also to prevent transmission to women. So there have been ongoing controversies over whether doxycycline or azithromycin is a better therapy for chlamydia. In addition, in the era of now Mycoplasma genitalium playing a large role in diagnoses of urethritis, we also are asking ourselves, okay, what is the best empiric therapy that may also include Mycoplasma genitalium? So this was a nice randomized clinical randomized controlled study, which looked both at efficacy of doxycycline versus azithromycin for patients with symptomatic urethritis. And then also had an arm on each side plus or minus tinidazole for up front treatment of trichomonas vaginalis. So basically what this study is showing in the end, it showed that the microbiological cure rate for patients randomized to the doxycycline therapy arm was significantly better than patients randomized to the azithromycin arm. So here you can see these are patients who had chlamydia and they're now returning for test of microbiological cure, and there were, in the doxycycline arm, no patients had chlamydia on repeat testing. All 34 that had been positive were negative and four were missing data, and the azithromycin arm, five patients continued to test positive for chlamydia with 22 negative and nine missing, and that was a significant result. I'm gonna jump down first to Mycoplasma before going over the trichomonas information. So Mycoplasma on the other hand, we had the opposite effect. So in the doxycycline arm, those who had Mycoplasma, 16 remained positive while five turned negative, versus the azithromycin arm- 6 remained positive while 17 were subsequently negative, and this was strongly significant favoring azithromycin as a treatment for Mycoplasma genitalium over doxycycline. However, even this here is not that great of a cure rate. So we still had six positives after therapy with azithromycin. Trich, bottom line, there was really no difference in cure rates between the two groups, but some of that was due to small numbers. But there was not, in 6

8 this study, evidence that patients should be treated up front with tinidazole for urethritis in this particular population, and some of that seems to have to do also with the fact that trichomonas may be more of a transient infection in men and may self resolve even without treatment. 00:22:55 So again, recapping. That study randomized clinical trial showed that doxycycline was better for chlamydia, but azithromycin was better for Mycoplasma. And upfront when we see somebody and we're doing point of care, we don't know which one they have. So that obviously is a challenge. Nonetheless, different, a couple other studies including these two other randomized controlled trials by Manhart and Geisler have both documented parity with azithromycin versus doxycycline for cure of urethritis. So not all studies are consistently showing the same thing there. What we do know is that poor adherence to doxycycline has been demonstrated to result in low chlamydia cure rates. And therefore, we generally speaking, do use azithromycin as our standard for care for non-gonococcal urethritis in the U.S, and the CDC recommends either azithromycin one gram or doxycycline. So CDC's saying either one is fine. I would say most places and most STI centers use the azithromycin because you can just get it over with in a single dose. CDC also has levofloxacin and erythromycin as alternatives. 00:24:08 Now what do we do about Mycoplasma genitalium? So, many places don't have a good diagnosis available for this. We're treating empirically, and then we saw that even when using azithromycin, which appears to be better than doxycycline, we still have a number of treatment failures. So this is a meta analysis looking at the resolution of Mycoplasma using azithromycin in studies over time, and this is the year that the study was conducted in, this is the year that it was published, and what you can see is a clear trend away from microbiological cure using azithromycin. So we have more and more drug resistance to azithromycin amongst Mycoplasma specimens. So again, here you can see many of the patients were cured. Though again confidence intervals were large, but many of the patients erred on the side of being cured, where as here we see less microbiological cure going on with time. 00:25:08 A couple other points to make. Five day courses of azithromycin have been looked at and do not appear to offer any benefit from Mycoplasma over a single dose. So what does CDC recommend? If you know or strongly suspect that the patient has Mycoplasma is to treat with moxifloxacin 400 milligrams daily for seven days. So unfortunately other fluoroquinolones do not appear to have enhanced efficacy over doxycycline. So looking at levaquin, ofloxacin, they do not appear to perform better. It's really the moxifloxacin. Which is unfortunate because moxifloxacin is very expensive and I've run into difficulties with patients' insurances picking it up. 00:25:48 All right so going back to our 23-year-old. He got his one gram of azithromycin in clinic, and he returns two weeks later with persistent symptoms. He denies sexual activity since he was treated. Review of laboratory studies demonstrates negative NAAT for gonorrhea and chlamydia as well as negative HIV combo screen and syphilis serology. His gram shows two polymorphonuclear cells per high power field. 7

9 00:26:12 Should he receive any therapy in addition to moxifloxacin. So we basically just said, you've got persistent urethritis, he's failed azithromycin. He's not reinfected. So that was key right? We've gone over with him, he said absolutely I have not had sex. So reinfection is often times, as you're aware, the biggest reason why people have persistent symptoms, and even if people take their azithromycin together with their partner on the same day but then start having sex, because of different clearance rates, they could potentially still reinfect each other. So first thing is to make sure the person has not been reinfected and doesn't simply need another dose of azithromycin, or a switch to doxycycline particularly if they have documented chlamydia. This patient doesn't have chlamydia, he hasn't had sex, so we don't think he's been reinfected with anything, and he hasn't responded. So we wanna give him moxifloxacin because we think he probably has Mycoplasma genitalium, but might he also have trich? So thinking about whether or not to give him metronidazole, should we wait to see a prescription of additional medications depends on pathogen frequency at the center he's attending. He should receive tinidazole two grams times one dose. He should receive metronidazole 500 milligrams BID, and that should say times seven days, or he should receive valacyclovir 500 milligrams TID times seven to ten day. So the answer here really is that prescription of additional medications depends on pathogen frequency at the center he is attending, and sorry it looks like this did not project well. Basically the recommendations are, if trich is prevalent, he should be empirically treated for trich as well. What prevalent means seems to vary from study to study, but at least around even two to five percent of sample testing women testing positive for trich, men should be empirically treated for trich if they have urethritis that has not responded to azithromycin and is not chlamydia. 00:28:09 All right so make sure I don't get get this again. So this is the last few slides here. So what if any testing or treatment should this patient's partner receive? So going back to partners in general. Those with confirmed gonorrhea, all partners for the last 60 days should be empirically treated. So sought out and treated. Again with the exception, like we said, certainly Neisseria meningitidis is a different story. Chlamydia again, partners in the last 60 days should be empirically sought out and treated empirically. Trichomonas, the time period is undefined. However, it is recommended that partners are treated. And all of those, obviously we want them to test, but regardless of their testing, they should be empirically treated with the standard recommendations for whatever pathogen their partner had. It's important to remember that the CDC does recommend expedited partner therapy for both chlamydia and trichomonas. Although New York State law currently only covers chlamydia. So New York State law does not have a plan for trichomonas at this point. So chlamydia is what you can treat with expedited partner therapy. Meaning you simply give a script to the partner without having to evaluate them. Partners of patients with known Mycoplasma genitalium should be evaluated and treated if symptomatic. If asymptomatic it is not routinely recommended but up to the judgment of the clinician. So this is very tricky in how do we know if we are presuming that somebody has Mycoplasma genitalium? It really ideally we want to have their partners come in for evaluation. However, that's not always easy to do and especially when you're not telling the person really what they're diagnosed with. So I think throughout the slides today I've really tried to emphasize that I think increased awareness of and ability to test for Mycoplasma is really gonna be important, because if we're presuming our case one patient has 8

10 Mycoplasma genitalium, what if he now does start having intercourse with his partner again, he gets reinfected, he gets symptomatic again. We're gonna get into a vicious cycle. So with him, I would consider treating his partner on that basis. 00:30:26 And I also want to just bring it back to women. So for a very long time, there has been question as to whether Mycoplasma genitalium is a significant pathogen in women with some studies suggesting that it is, and some studies suggesting that it isn't. And it's then partially for that reason that the level of testing for it and trying to make a firm diagnosis has not been, I think it's higher priority. But the data are starting to point more clearly toward Mycoplasma genitalium being a significant pathogen in women, and this is just one of several slides from this meta-analysis looking at association between Mycoplasma genitalium and pelvic inflammatory disease. Which join together show an odds ratio of approximately two for risk of pelvic inflammatory disease with the presence of Mycoplasma genitalium in women. 00:31:25 So persistent urethritis- what if somebody now comes back again a third time and they're just not getting better? So at that point you really need to differentiate inflammation from pelvic pain syndrome without inflammation. So some individuals, especially after having had a sexually transmitted infection, can develop a chronic pelvic pain syndrome, and that chronic pelvic pain syndrome can manifest itself as pain with ejaculation, burning, pain with urination, and also sometimes even blood in the ejaculate. However, when you actually test these individuals, they do not actually demonstrate that they have urethritis according to the guidelines for two cells per high power field. So in those cases, really this becomes more of a management of a chronic pain syndrome than a management of urethritis. There have been a couple case reports of sacral neuropathies which can present with urethritis like symptoms. So if you have somebody who really seems that they're very insistent; they're having symptoms and you can't identify urethritis, one thing that may help is to use a first morning void, which may improve detection of low grade urethritis. So ideally obviously you wanna send NAAT testing for all of the pathogens that we've discussed. Including ureaplasma, which we didn't spend a lot of time discussing today. You obviously wanna plate specimens as possible just to make sure you're not missing a bacterial pathogen- though clearance of these pathogens actually tends to be high. And really there's no recommendation for empiric treatment if all of these tests are negative. 00:33:18 So this is just, I'm not gonna spend a lot of time on this slide 'cause I think you guys really, most of you probably know this, but it's just to make the point that it's important to distinguish between urinary tract infection and urethritis. With urinary tract infection having more frequency, urgency, flank pain, et cetera. And for men, less than age 45, you may be able to just treat a single UTI without sending them in to a urologist for workup. Certainly if they have more than one, then definitely further workup is recommended. 9

11 00:33:53 So this is really treatment for UTI. Seven to ten days of Bactrim or ciprofloxacin, and the Bactrim use would depend on the spectrum of pathogens and their resistance to Bactrim with a cut off of 20% in your community. In addition, in such a case, rectal exam should be performed to exclude presence of prostatitis in patients with fever or back pain. So that's really just kind of pointing out that again, urethritis should strictly present with those local urethral symptoms, and due to time, I didn't go into epididymitis and that's however pain in the testicles is not classic for most cases of urethritis and certainly unilateral pain associated with swelling is more a phenomenon consistent with epididymitis than urethritis. 00:34:40 So in summary, this is a common problem. Chlamydia and gonorrhea still make up a majority of cases in many settings. Mycoplasma genitalium is increasing in prevalence and it is azithromycin drug resistant. Trichomonas may be underdiagnosed in many populations, and new recommendations are more conservative in terms of the cut off when we're looking at the CDC 2015 guidelines in terms of diagnosis, treatment, and follow up for patients with urethritis. Urethritis can be distinguished from other more serious infections via symptoms being confined only to the urethra. Sorry I need to put my CEI slide up. 00:35:18 So thank you very much to the CEI for sponsoring this and I guess we can open the lines for questions. 00:35:42 - [Woman] If there are any questions, please let us know. If not, thank you very much for doctor Reddy for presenting this. 00:35:55 - [Margie] Can I ask a question? 00:35:57 - [Woman] Yup, go ahead. 00:35:59 - [Margie] Hi Elizabeth, this is Margie. Thank you very much, that was great. I wonder, I'm seeing a patient right now who has perhaps this chronic pain syndrome. It's someone who never had a diagnosed STI but reported symptoms that were thought to be urethritis shortly after a sexual encounter and now has gone several months with this pain without inflammation, and I was wondering if you've seen patients like that and if you've had any success in sort of managing them just as pain? 00:36:39 - [Elizabeth So I have seen patients like that, and I can say I haven't had the greatest success and I think some of that is related more to fragmentation of care because if we are seeing them in STD center then 10

12 it would not be considered a location where we follow them so much for pain. I think actually there are a couple, so one of the urologists here at Upstate did refer, I know one of the patients who we had seen both that our private ID clinic as well as an STD center and urology. We referred the patient ultimately to acupuncture and apparently he did very well. I was told this by someone at our ID associates clinic. That's the one case I know of someone who was successfully treated in that setting, but I think it actually can be very difficult because it seems that a number of the patients that we've seen in that situation are absolutely 100% convinced that they have an infection. (audio cut) Kind of move past that, seems to be very difficult. 00:37:44 - [Margie] Yeah yeah, okay thanks. 11