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Home , Bubo, Chancre, Klebsiella granulomatis

Clinical Education Initiative [email protected]

CHANCROID AND OTHER UNUSUAL STIS Tara Babu, MD Assistant Professor in Medicine Department of Infectious Diseases University of Rochester Medical Center

5/14/2018

Chancroid and Other Unusual STIs [video transcript]

[00:00:06] My name is Melinda Godfrey, I'm the coordinator for the New York State STD Center for Excellence. Thank you for participating in today's webinar, the topic today is chancroid and other unusual STIs. And I'd like to particularly thank the New York State Department of Health AIDS Institute, they allow us to bring you these free Lunch and Learn webinars. And to let you know our next webinar Lunch and Learn will be on July 9th, and the topic will be Sexually Transmitted and Pregnancy. And just a quick plug, there is still time to register for our fourth annual STD Conference in Lake Placid that will be on June 1st. There will be a full day conference on STDs, PrEP, U equals U. And there are some great hotel discounts for anybody that needs to stay overnight up there.

[00:01:21] So without further ado I will introduce our speaker today Dr. Tara Babu is an Assistant Professor in Medicine at the University of Rochester Medical Center and she specializes in the treatment of transplant infectious diseases and sexually transmitted diseases. She completed her residency in internal medicine at the University of Massachusetts Medical Center. Following residency, she pursued a clinical and research fellowship in infectious diseases at the University of Rochester Medical Center. During her final year of fellowship she obtained specialized training in transplant infectious diseases at Massachusetts General Hospital. I'd like to now turn over and introduce our speaker Dr. Tara Babu.

[00:02:29] Thank you, Melinda. So as she mentioned, today I'm going to be discussing chancroid and other unusual sexually transmitted infections. So I got the opportunity to pick what those would be. The focus of the presentation will really be on chancroid, but then I thought I would also mention donovanosis and then I will actually talk about LGV as well.

[00:03:00] So I have no financial disclosures, and these are the overall objectives for my presentation. I'm going to, like I said, discuss epidemiology, diagnosis, and treatment for chancroid. And we'll go over the epidemiology, diagnosis, and treatment of donovanosis. And finally I'll also talk about, briefly, the diagnosis and treatment for or LGV, which as some of you may know is actually more common in the United States than the above two diseases.

[00:03:43] So first I'm going to talk about chancroid. Chancroid is caused by ducreyi which is a small, fastidious, what that means is it's difficult to grow, gram negative rod that requires a very complicated growth pattern. It needs an enriched growth media with Hemin. It has to be incubated at 33 to 35 degrees in high humidity with CO2 enrichment. If you're actually lucky to grow it, it usually does grow around 48 to 72 hours and when you see it on gram stain, it looks like this picture here. You can see the organism clumping with those gram negative rods. And it's often called a school of fish or

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railroad track appearance. This morphology, as I said, can occasionally actually be seen on gram stain, so it's very difficult to culture. And then again it's very difficult to even see on gram stain. The gram staining for actually has a very low sensitivity, ranges in studies anywhere between 5 and 63 percent. And it's specificity ranges anywhere between 51 and 91 percent.

[00:05:13] Some of the risk factors for acquisition of chancroid are unprotected sex, a high number of sexual partners about greater than 15 per year, that's been reported in some studies. Contact with a sex worker, cocaine use, there's a poor association with poor hygiene, and also lack of circumcision has been associated with chancroid acquisition. It's been found that circumcision is protective against some infections including chancroid, and it's thought that this may be because the moist area under the foreskin is conducive for replication of the .

[00:06:07] In terms of pathogenesis, really skin breakdown is thought to be part of the way that Haemophilus ducreyi infects. In one study, 70 percent of women who had contact with an infected man developed the disease. This is a very infectious bacteria. In a study where they inoculated humans, one colony forming unit caused disease in 50 percent of cases. When they inoculated with 100 colony forming units of Haemophilus, 90 percent of the volunteers had . So it is a very infectious bacteria.

[00:07:00] The bacteria infects stratified squamous epithelia cells of mucosa. So the way that the infection happens is there is some sort of breach in the skin. The skin is really our first defense for infections. It is what we call the innate immune system, it protects us from infections in general. When there's a breach in the skin or in the mucosal layer, Haemophilus ducreyi is able to enter and infect the mucosal epithelium. Once it infects the epithelial cells, you can see this is the histology of skin here with the squamous epithelial cells, once it infects the epithelial cell basically there is an immune response. So polymorphonuclear leukocytes and macrophages, they go to the site where the breach is where the infection is occurring. This leads to cytokine response and inflammatory response that's been found to produce IL-2 specifically and IL-6, which are interleukins. They recruit mononuclear cells to the dermis and this does actually include CD4 cells. The reason I mention this is, I'll mention it later, but chancroid does increase acquisition of HIV. So part of the thought is, not only is there a breec in mucosa that can allow HIV to infect, but CD4 cells are actually being recruited where the infection occurs. And we do know that HIV does infect CD4 cells. So once the inflammatory reaction happens, then you get the clinical findings of a formation with an erythematous base which can ulcerate, which I will talk about again in a few minutes. The incubation time for Haemophilus ducreyi is actually fairly short, it is thought to be around three to seven days and that's where you'll see the first papule formation. Also a note which is interesting about Haemophilus ducreyi is that it does cause a non-genital infection as well. Particularly in endemic countries, it can cause cutaneous ulcerations in children. They can get ulcers on their limbs, on their arms and their legs.

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[00:09:19] So like I said Haemophilus ducreyi is a very infectious bacteria, it's very virulent. And so there has been several studies to look at why it's so virulent and there are some postulated ideas. One of them is that there are virulence factors that mediate that initial infection. So when the Haemophilus ducreyi infects the cells, it's thought that it has this pili, this kind of protrusion structure that helps it infect cells. And then also outer membrane proteins on the bacteria cause actual tissue damage. It's also been found that the Haemophilus ducreyi has hemolysins, it has heat shock proteins, and it has or LPS which is also associated with mechanisms for gram negative bacteria in general and septic shock. It's thought to be part of the reason why people get so so sick when they have septic shock, is the lipopolysaccharide that gram negative bacteria have on their membranes. But it's thought that the hemolysins, the heat shock proteins, and the lipopolysaccharide actually give the bacteria the ability to invade host defenses. So it's a difficult bacteria for the immune system to attack. And then also it's thought that the lipopolysaccharide itself gets resistance to specific alpha- and beta- defensins. So these are part of the host defense immune system.

[00:11:02] So the epidemiology of chancroid is actually, it's pretty interesting and it's also confusing. I think that right now it's very unclear what the epidemiology is worldwide. It is endemic to some African countries, we do know that, and particularly there have been outbreaks in like I said, risk factors. Sex workers and also between cocaine users. So the interesting thing about it is that the rates have changed. So this was a meta-analysis that was done where they looked at several studies, 35 studies before 2000 looking at GUD, which is genital disease. And then after 2000 they looked at 14 studies. And you can see the rates of GUD changed. So the rates before 2000 were anywhere between 0 and 69 percent which has a large range. And then after 2000 it was 0 to 15 percent, part of the reason for this is due to campaigns to decrease the rates of GUD in these countries. But then also what clouds the picture is that, like I mentioned, it's a very difficult infection to actually diagnose. It's difficult to grow. It's difficult to stain on gram stain, so it's potential that the reporting of this disease is also very difficult for us to completely understand. But there have been strong efforts to decrease the amount of disease in those countries. Also as I mentioned, Haemophilus ducreyi does cause non-genital ulcers in children and there were 6 studies that reported the rates of that anywhere between 9 and 60 percent.

[00:12:56] So I'm not going to talk too much about the non-genital ulcer disease that it causes because this is more of a sexually transmitted infection conference. But I thought I should include this paper because it is actually fairly newly published. And it's one of the first papers to maybe show why it's causing non-genital ulcer disease in children. So this study was a cross-sectional study that was done in Lihir Island which is in Papua New Guinea, and it's kind of interesting they did a cross-sectional study where they took people who were asymptomatic who had no signs of infection and they swabbed their skin. They swabbed bed sheets and they also actually collected flies and studied them as well. And they kind of stratified the people into two groups, so they were people who were asymptomatic but lived in households of people who had cases of leg ulcers and then people who had no contact with people who had leg ulcers. And they did PCR testing for Haemophilus ducreyi. So what they actually found was that there is a rate of just asymptomatic carraige on people's skin, was 21 percent out of 78 people that they

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swabbed. And interestingly they actually found Haemophilus ducreyi NAAT positive testing in flies. So 90 percent out of just 10 flies that were collected were positive for Haemophilus ducreyi. And then they also found it in about 33 percent of the bedsheets of the people that they had swabbed, two out of six, so not a big number. But it is interesting and it does suggest that it actually can be on fomites, if it's on bedsheets.

[00:15:04] So what about the epidemiology in the United States? Well chancoid, luckily, is actually fairly low in the United States. In 2016 there were about seven cases reported. And you can see overall there's been a very low downtrend and it's stayed very well over several years.

[00:15:32] So before I talk about the epidemiology and some of the studies from the United States, I just want to mention this idea again of genital ulcer disease and the differential, because it will come up. So several of the STDs that cause genital ulcer disease are chancroid, , and herpes. Herpes is the most common out of all of these. And then , which is donovanosis. And LGV. What's not mentioned here are that there are several other non-infectious causes for genital ulcer disease, including , malignancy, Behcet's, which is an autoimmune disease, can also be associated with genital ulcer disease. So it's important when you're thinking about the differential of genital ulcer disease to not only just think about infections, there are several other causes for general ulcer disease.

[00:16:38] So in terms of the epidemiology that has been found in the United States and again I will say this is rare in the United States. The epidemiology from one study that was done in New Orleans and you can see the year was 1995 from this study, was that it was primarily found in minorities African- Americans and Hispanics. Chancroid was found in heterosexuals, was associated with female sex workers and their clients, and was found to more commonly been reported in men which is true for chancroid in general, and also associated with crack cocaine and exchange of sex for drugs with the outbreak. So where these risk factors and epidemiology came from was, like I said, it was a study that was done in New Orleans in 1995 where they took 299 men who were negative for syphilis. So they had genital ulcer disease but were negative for syphilis, and actually 39 percent of them were positive for Haemophilus ducreyi by culture and 19 percent of them were positive for herpes.

[00:18:10] And this is another old study, it was in 1998 and it was a study done in 10 US cities looking at ulcer disease again. And it was basically looking at patients who had genital ulcers and specimens were done, this time by a multiplex PCR, and they looked to see what the epidemiology of the ulcer disease was. You can see in Chicago it was about 12 percent, and in Memphis 20 percent. So decently high rates. But the reason I just wanted to bring this up was again when we're talking about genital ulcer disease, herpes still is especially in the U.S. the number one cause of general ulcer disease. And you can see also that there are decent percentages of syphilis as well in these patients.

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[00:19:10] So now that we've talked about the epidemiology of chancroid, I think we should talk about the clinical presentation of it. So it commonly begins as a painful pustule that subsequently ulcerates. And as you know, painful pustules can be several things including herpes when you first see them. It's often multiple, not just one lesion. It can have a necrotic base. It can also have a purulent exudate which can be grey or yellow with necrosis, like I said. If you scrape the lesion it may bleed. It also has this punched biopsy appearance, which you can see in this picture here. And then you can see that the edges are excavated in.

[00:20:04] The ulcers can resolve and heal without any treatment, somewhere between four and six weeks of infection. However in up to 50 percent of the cases, the ulcer stage can then also be accompanied by tender inguinal that is pyogenic. So you've heard of the bubo before, it is basically a soft fluctuatant, purulent-filled lymph node. And it's very painful and it typically is ipsilateral, it's on the same side as the lesion. If present, it can be pathognomonic for chancroid. And if there is a bubo present, not only do you need to treat with antibiotics but aspiration is also important. I think of it as a , it is pus under pressure that needs to be evacuated in order to treat because antibiotics are not as good getting into these pockets of pus.

[00:21:11] And this is just another picture of the chancroid lesion. And you can see here it's got the raised edges, they're not indurated. But they do have a soft consistency and sometimes you may hear the term soft chancre.

[00:21:32] And this is a picture of chancroid with a bubo as well. Like I said that happens in about 50 percent of the cases.

[00:21:51] So we're looking at these pictures. You might be thinking that, well there are some subtleties to it but it really does look like everything else and you wouldn't be wrong thinking that. So this is a picture of the primary syphilis chancre. And you can see here it looks very similar to the ulceration of a chancroid. And so primary syphilis is different in chancroid, and like I'll say typically it's different in chancroid in that it usually begins as an that subsequently ulcerates. So instead of the papule to ulceration like chancroid, it's more of an erythema that ulcerates. Other differences are that primary syphilis, the chancre tends to be indurated. It has a clean base and has a clear exudate. While like I said in chancroid, the lesion has the excavated border and has more of like a white/grey exudate. One of the big differences I'd say between the two of them is primary syphilis in general is painless, while chancroid is painful. Both can cause lymphadenopathy and in syphilis it's often unilateral lymphadenopathy and again it's non-tender. While in chancroid, 50 percent of the lympadenopathy that causes the bubo is painful and fluctuant.

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[00:23:23] And this is just another picture of a syphilis chancre.

[00:23:31] It's also important to know that confection can occur just like other sexually transmitted infections. If you have one, you could have another. And in several studies there has been coinfection documented. Syphilis and chancroid can occur together. Herpes and chancroid can occur together. And in particular HIV and chancroid can occur together, and chancroid does increase the acquisition again for HIV. So HIV testing is imperative in general when you see somebody with genital ulcer disease.

[00:24:11] And here, this is a lesion of somebody who actually does have coinfections. So this is syphilis and chancroid together.

[00:24:27] There are some rare manifestations of chancroid. There is giant chancroid which is exactly what it sounds like, it's an ulcer that expands at the edges. It's very rare. The ulcer can be shallow but then can cover a very wide area, like a large portion of a penile for instance. Chancroid can also, in males, it can cause . It can cause a very purulent urethritis and I'll get to diagnostics, but if someone's got urethritis you're going to be swabbing them anyway but if you have a suspicion for chancroid that's when you would send the pus from the urethra as well. And then in women it can rarely also cause rectovaginal fistulas, but this is like I said a very rare thing.

[00:25:24] So in terms of the clinical evaluation for genital ulcers you want to document the appearance. So like we talked about size, number, chancroid tends to be multiple lesions. Whether there is absence or presence of induration. Whether there's exudate. What color is the exudate. You want to document the lymphadenopathy that the patient has, whether it's ipsilateral or contralateral, on the same side of the lesion or on the opposite side of the lesion. Whether it's both sides, bilateral. You want to document the size and the number. Degree of firmness, it's also important to notice whether it's tender lymphadenopathy. The other thing I would say is you don't want to just do an inguinal exam, but you also want to check the femoral lymph nodes as well. And you want to culture for Haemophilus ducreyi if it's available. And you want to also culture a PCR for herpes. If you can, you can do a dark field microscopy for Treponema palidum, syphilis, or PCR. You can do a syphilis ELISA, RPR, or FTA but know that in primary syphilis this might be falsely negative if it's early syphilis. And then all these patients should have HIV testing and they should have and at all sites exposed, including extragenital testing.

[00:26:59] So in men, the majority of ulcers tend to be at the prepuce or frenulum. Here is prepuce here. And then the coronal sulcus, which is down here. It less commonly occurs at the glans, the penile shaft, the meatus and less commonly patients have anal involvement.

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[00:27:25] Some of the complications in man include phimosis. They can get a secondary bacterial infection, they can actually get a pretty bad secondary bacterial infection. You can get like a , but you can also get a . And there have been reports of severe secondary bacterial infection after someone has been infected with chancroid. And then like I mentioned before, men can also urethral discharge but this is uncommon.

[00:28:02] So in women, the typical location is the fourchette, which is posterior. The labia, the vestibule, and the clitoris. And large periurethral ulcers can be present, they're not as common. But the exam when you see a patient, in general who has a sexually transmitted infection, you want to evaluate the vaginal walls and the cervix. Patients who have cervix involvement may be completely asymptomatic. Women are also less likely to have ulcerations and spontaneously resolve than men. Oh and one thing I will mention that's interesting about chancroid is in females when they're pregnant, they actually have for some reason more aggressive manifestation than when they're not pregnant.

[00:29:04] So in terms of laboratory diagnosis, it really requires high suspicion for chancroid. The clinical manifestations like I said can really be indistinguishable from herpes and syphilis. We went through some of the typical findings for chancroid, but nothing is ever typical I think in clinical medicine, and it can be difficult to differentiate these different infections. So you can look for or you can culture for Haemophilus ducreyi, but like I said it's a very fastidious very finicky bacteria, it's very difficult to grow. It's even difficult to gram stain. But it does require selective culture medium, which is referred to as NYC medium. It apparently isn't readily available in upstate New York laboratories. So if it's suspected, you should call the health department and get assistance from the laboratories so you can obtain the media.

[00:30:17] So just a word on diagnostic sampling. So like I said, it really is a difficult diagnosis to make. So diagnostic sampling is key. When you do the diagnostic sampling you can flush the base of the ulcer with sterile saline and then need to use Dacron or cotton or a calcium alginate swab. You want to do multiple samples to improve the yield. And then if a patient has any of that urethral or vaginal discharge, you can send that as well, which you'll also be sending for other sexually transmitted infections. The ulcer base does have a higher yield than actually the bubo, and it's important to get that swab to the lab because as you know it's difficult to grow and it has a short time span outside the body. So it's viable for two to four hours on a swab. In terms of the bubo, not only for therapeutic but also diagnostic, you can take a needle and syringe and just aspirate the purulent material. You want to go into normal tissue though because you want to reduce that contamination from breaking through the skin and causing you know a bacterial super infection. And if possible again you want to culture as soon as possible, because again it is a fastidious organism and it's very difficult to grow. And if available, you can also send the bubo and also be the ulcer aspirants for PCR.

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[00:32:11] Really clinical diagnosis based on observation and epidemiology is really how you make a diagnosis, not just on microbiology. And part of what you need to do is rule out some of the more typical on infections like herpes and syphilis. If there is a bubo it is highly likely to be chancroid. As we'll talk about, there are other diseases you can see a bubo in, but are also rare. If there is a case that you're concerned about for chancroid it is reported and should be reported to the Health Department particularly because when we see chancroid it tends to be an outbreak and so we need to look for contacts.

[00:33:06] So the CDC has criteria for clinical diagnosis for chancroid and so are the clinical diagnosis includes one or more painful ulcers, genital ulcers, and then if it has that clinicial presentation plus regional lymphadenopathy typical for chancroid like a bubo. Although I will say this happens in about 50 percent of cases. You want to also rule out the exceptions, so no evidence of syphilis by dark field microscopy or PCR. And also the HSV culture in PCR are negative from the exudate.

[00:33:54] So why do we treat chancroid? Part of the reason we treat it is to cure the infection. To reduce the symptoms of the patient, to prevent transmission because it is so highly infectious, to reduce HIV transmission. And there has been studies that have shown decreasing chancroid decreased HIV in certain areas in Africa. And because despite successful treatment of the underlying disease, it's important to know that the lesions may be still slow to resolve. So despite even getting the treatment, these patients can eventually have scarring so you know they they might still have sequelae from the infection even if you do treat them.

[00:34:39] In terms of treatment, the treatment is basically all of these things can be recommended. They used to, in the 1980s and 90s, give trimethoprim-sulfamethoxazole or Bactrim, amoxicillin or tetracycline, however there were emergence of resistant strains of Haemophilus ducreyi in low income countries. And so there were kind of this worldwide increase in therapeutic failures and it forced a change in the regimen. So the current recommendations are one of the four drugs here, ceftriaxone 250 milligrams intramuscularly, azithromycin 1 gram times one, ciprofloxacin 500 milligrams twice a day for three days, or erythromycin 500 milligrams three times a day for seven days. And again the case is reportable to the Health Department and the Health Department will provide prophylactic treatment for all sexual partners within the previous two weeks of exposure.

[00:35:48] And this was a recent Cochrane review that I thought I would include that the focus was on macrolide treatment to see if azithromycin was superior to the other treatments. They looked at several studies and found basically that there was no difference between the types of antibiotics in sexually active adults with genital ulcer diseases that were compatible with chancroid. So that previous slide with the four regiments is still the recommended treatment for chancroid.

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[00:36:22] And so what about HIV patients? Well there just isn't enough data on these patients right now. HIV patients they are at risk for treatment failure. They do have ulcers that sometimes are more slowly to heal than non-HIV patients, and it's unclear whether a single dose regimen versus a multi-dose regimen is as effective. There are some recommendations that the ciprofloxacin or erythromycin regimen might be preferred in HIV-positive patients. However, more research needs to be looked at for that.

[00:37:05] In terms of follow up, the recommendation from the CDC is to re-examine patients three to seven days after starting treatment. If successful the ulcer usually approves within three to seven days after therapy. There is a high risk for HIV so it's important to check patients again for HIV in one month and then I will add that chancroid has not been found to give immunity to patients. So once you've been infected, you can be infected with chancroid.

[00:37:42] And prevention, so things to talk about with your patients. Abstinence from drugs and alcohol. Consistent condom use. Limiting sexual partners. Avoiding high risk sex partners, sex workers. Advocating for 100 percent condom use should also be encouraged because these are at the highest risk for chancroid.

[00:38:05] And so in summary chancroid is rare in the United States and other developed countries, but I think the epidemiology is changing in the developing world. Patients typically present with a painful genital ulcer. And the diagnosis of chancroid is challenging, but clinical criteria should really be taken into account to make a diagnosis and you need to rule out, particularly in the United States, the more typical actions of herpes and syphilis.

[00:38:42] So next I'm going to talk about donovanosis. So donovanosis is caused by granulomatis and that's another gram negative just like Haemophilus ducreyi. And it also is a cause for genital ulcer disease. Klebsiella granulomatis used to be called Calymmatobacterium granulamatis, however it has been renamed and part of it is due to when they did molecular testing they found that it was very similar to the Klebsiella bacteria. It is named after donovanosis, because actually was the one who recognized it in Madras or Chennei in 1905. So it's been around for a while. It was first described in Calcutta in 1882 and then it was recognised by Charles Donovan in 1905. And it was first noticed as a serpiginous ulcer, and that's how it was identified in 1882. So the reason it's called donovanosis is based on Donovan but it's also because he named these Donovan bodies. And you can see a picture of them right here, and what they are is they are intracytoplasmic gram negative bacteria that affect the macrophages. They have this kind of safety pin appearance and eventually the cysts that the bacteria are in will rupture and it releases infection into the host. And so it can infect other cells.

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[00:40:35] In terms of epidemiology, it is a rare infection. It's mostly endemic in , Papua New Guinea, the Caribbean, Brazil, Africa, and . In the United States there are few cases that are now reported but there was a higher reporting back in the day. One article I found said that there were somewhere between 5000 and 10000 cases that were reported in 1947 in the United States.

[00:41:07] So when I was doing my literature for you, I came across this old journal. It was the Journal of American Medical Association, so JAMA. And it's reporting 15 cases of donovanosis in 1926. So this is not a new disease, but thankfully it is rare in the United States. Unfortunately it's still prevalent in other endemic countries.

[00:41:39] So some of the risk factors and associations thought to be with donovanosis are poor hygiene, it is a loose association. Lower socioeconomic status. Men are more affected than women. And again, just like chancroid, it does increase the risk for HIV acquisition.

[00:42:03] In terms of symptoms, so it is slower than chancroid, symptoms usually for somewhere between 1 and 12 weeks after infection. Now this is a painless infection. So unlike chancroid it is painless. It is a slowly progressive ulcerative lesion on the genitals and it can affect the perineum. The genitals are affected in about 90 percent of cases and the inguinal area in about 10 percent of cases. Extragenital cases do occur, they occur in about 6 percent. And it's been reported on lips, gums, cheeks, palettes, and . And some of the atypical cases that have been reported in children typically affect the facial region. And here's a picture here of donovanosis.

[00:43:03] So these are the four types of lesions that you can see with donovanosis. There is the classic ulcerogranulomatous lesion, granulomatous just means it's granuloma and so it's an ulcer with inflammation in the region. It can have this hypertrophic or verrucous ulcer, so like a or like a heaped up lesion which you can see with syphilis or even HPV. It can have a necrotic lesion, and then it can also be sclerotic. And like I said the genitals get infected in about 90 percent of cases, while the inguinal area in about 10 percent.

[00:43:45] So in men the commonly infected areas are their prepuce, the coronal sulcus, the frenulum, and the glans.

[00:43:55] In women the common areas that are affected are the labia minora and the fourchette. Cervical lesions of note can look like carcinoma. So on inspection you might think the patient actually has . So biopsy needs to be done.

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[00:44:19] So this was a study actually done in where it is endemic, and it was done over a three year period of time where they looked at 61 patients who are women who had donovanosis. And they found that the typical presentation for it was genital ulceration, higher percentage in pregnant patients than non-pregnant patients. About 20 percent of these patients presented which genital track bleeding. And about 54 percent of them had their area that was affected.

[00:44:56] The infection can lead to complications just like chancroid, men can have phimosis. There's also reports of urethral, vaginal, and anal stenosis with this infection. Again on appearance it can look like cervical or even ovarian cancer, so a biopsy needs to be done. I mentioned there are several reports actually of extragenital spread and then it can't have hematogenous spread which can go to bone, it can go to liver, it can also get rid of joints and cause like a septic arthritis picture.

[00:45:36] And these are some of the complications that I mentioned, in women neoplastic changes and pseudo-elephantiasis has been reported and this is actually a picture from a journal from Brazil and a woman has pseudo-elephantiasis of her genital area. And then like I had mentioned, stenosis as well.

[00:46:00] In terms of transmission, it's mostly transmitted through vaginal and anal intercourse, rarely through oral. There is some suggestion of ingestion of fecal matter of an infected person, and there was a study that found that the Klebsiella in stool and it was very similar in morphology to the Klebsiella that actually causes the genital infection. And there has been reports of vertical transmission to the baby through the infected birth canal.

[00:46:29] It is very low in terms of infectious capabilities, unlike chancroid. It typically needs repeated exposure in order to cause infection.

[00:46:45] In terms of diagnosis, the diagnosis is done by visualization or dark-staining those Donovan bodies. So the bacteria within those cysts, the intracytoplasmic cysts and the inflammatory cells. you can do a giemsa stain or wright stain that will show large mononuclear cells with the cysts and the gram negative Donovan bodies in the cysts. It is difficult to culture just like Haemophilus ducreyi and there is no FDA-cleared molecular testing for detecting Klebsiella granulomatis.

[00:47:27] In terms of sampling, to get a good quality smear you want to swab and roll over the ulcer. Sometimes you need to clean the debris before you do that. The smear should be taken first when you're looking for a donovanosis prior to swabs for other STDs. And then again, you can do a rapid giemsa or wright stain if you have that capability.

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[00:47:50] The treatment for donovanosis is longer than chancroid, the recommendation is azithromycin 1 gram per week or 500 milligrams daily for at least three weeks. And it's really monitoring for clinical improvement, you want to see all the lesions completely healed. Sometimes patients actually do end up having to go to surgery for resection for this.

[00:48:15] And these are some of the alternative regimens that have been recommended. Doxycycline, ciprofloxacin, and trimethoprim-sulfamethoxazole. But again, it's treatment and watching for improvement in the lesion. And erythromycin.

[00:48:41] And in pregnant and lactating women, they should be treated with a macrolide regimen and if it's not improving, you can add a gentamicin aminoglycoside to look for improvement in the disease.

[00:49:01] In terms of follow up, the patients need to be followed up clinically because you're watching for clinical improvement. In terms of management of sexual partners, persons who have had sexual contact within 60 days before onset of the patient's symptoms can be offered an exam and offer therapy because you know it is a slower incubator than for instance Haemophilus ducreyi.

[00:49:28] And in the last few minutes I'm going to talk about lymphogranuloma venereum, LGV. So I know this is an unusual STI discussion and this isn't as unusual actually as the other two diseases that I just talked about, but I'm just going to talk about it very quickly because it is one of the five sexually transmitted infections that I mentioned for genital ulcer disease. So it is caused by chlamydia which is trachomatis which is not uncommon as we know. It is the most common bacteria STI. It is caused by a different serovar than the typical , so it's caused by L1, L2, and L3. Historically LGV was most common in tropical areas and subtropical climates, Africa, Asia, Latin America, and the Caribbean. However we are seeing an increase in Europe and in North America. The outbreaks that have been reported have been mostly associated with men who have sex with men communities who also have high rates of HIV coinfection. It typically presents as a and a proctocolitis in these patients. And there have been occasional heterosexual cases that have been reported.

[00:50:51] So in terms of pathophysiology, so typical Chlamydia trachomatis infection that we see all the time is by the serovars D-K and they infect the columnar epithelium of the mucosa. It is often asymptomatic but can cause, if it does have symptoms, mucosal inflammation. And we see the typical urethritis, , proctitis, conjunctivitis, and then neonatal infection from the mother. C. trachomatis L1 through L3 or LGV infects different cells in the host, it infects monocytes and macrophages. And really manifests as three stages of infection. You can get the local infection, you can get the regional dissemination, and there are complications from the infection.

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[00:51:41] So in terms of primary infection, the incubation time is anywhere from three to 30 days. It presents a localized inflammation and it can be papule kind of starting out just like chancroid. But then it can evolve into a pustule, maybe like herpes or a small ulcer. It can be self-limited, so it can go away in two to three days and sometimes patients don't even notice the primary infection.

[00:52:05] This is just a picture of LGV from the CDC website.

[00:52:14] In terms of regional dissemination, that happens about two to six weeks after that primary lesion. Patients again might not even notice they had the primary lesion. And it manifests as a regional lymphadenopathy, it can either cause inguinal or femoral lymphadenopathy or depending on where it's infecting, you can actually see retroperitoneal or intraabdominal lymphadenopathy and that's when the primary lesion was in the rectum. So a different area draining two different lymph nodes. Patients can have systemic symptoms, so this sounds very similar to maybe secondary syphilis, and they can have fevers, malais,e kind of flu-like symptoms, arthralgias. The lymph node can progress, it can actually form a bubo and cause a draining sinus track.

[00:53:08] In terms of diagnosis for LGV. Historically it's been diagnosed with the antibody testing, so you'd have a clinical syndrome such as a bubo with a positive serology and you could do a blood test with either microimmunofluorescence to MIF, or you could do compliment fixation and if they had high serologies, this could be suggestive of LGV. Or a rising titer from a previous titer. However there are concerns for cross activity and it really hasn't been evaluated for rectal infection.

[00:53:51] There is no FDA approved test to get down to the actual serovar for the LGV. But the CDC for instance has a test that actually has widespread lab use in New York state, and does have a test that looks particularly at L2 serovars because that is actually what we've seen in the outbreaks particularly in the U.S, is the L2 serovars. So you can actually send out a test to look for L2 serovar if you're suspecting LGV. And Wadsworth State Lab does offer that PCR testing to be performed on urethral and rectal specimens that are known to be positive for Chlamydia.

[00:54:47] In terms of treatment, additional molecular procedures can be used to differentiate the LGV, and again Wadsworth does offer that L2 PCR performed on rectal and urethral specimens. If you have a known positive chlamydia and you are suspecting LGV.

[00:55:10] The important thing to know about LGV versus other chlamydia infections is that it's a longer treatment course. So these patients get treated for a longer duration. This is a three week treatment of LGV. So you're not going to give them that 1 dose of azithromycin or the 7 days of doxycycline. You're

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going to get them 21 days of doxycycline. The standard recommendation is actually for doxycycline 100 milligrams twice a day for three weeks or 21 days. Some people have used erythromycin, just one gram once a week for three weeks because it's easier for patients to take. Although there is some caution with that because there have been case reports of failures with that. So the cure rates do appear superior when using doxycycline, based on the evidence. But there have been rare cases also of reported treatment failure with doxycycline. Those patients were then successfully treated with moxifloxacin 400 milligrams a day for 21 days.

[00:56:16] So in conclusion LGV is kind of shifting in epidemiology, similar to chancroid, except it's increasing. It looks like we're seeing more cases in the United States and in Europe. The two syndromes that are being reported are the inguinal infection or the rectal proctitis/proctocolitis. It's important to know that this is happening highest in the men who have sex with men population. So in this MSM population, there is high risk for HIV, syphilis, hepatitis C ,and other sexually transmitted infections as well. It can be very difficult but we do have the ability to do the L2 serovar testing, particularly at Wadsworth lab.

[00:57:00] So in conclusion I just wanted to give a full summary of all the sexually transmitted infections that cause genital ulcer disease here. And here you can see the diseases. Herpes, primary syphilis, chancroid, LGV and granuloma inguinale or donovanosis. The pathogens that cause them. The clinical manifestations that can be different with each one, and the incubation times. And importantly whether they're painful or painless which can help differentiate them and the adenopathy characteristics that you see. Again I will say that nothing in medicine is typical, I think in clinical medicine we see a lot of overlap and also not to forget that these patients are at risk for coinfections. So they could have syphilis and chancroid, and not to forget that just because it's a typical presentation doesn't mean it's actually that disease.

[00:58:08] Finally I just want to mention the CEI Hotline. It's staffed by actually Mount Sinai for HIV and Hep C and by us at University of Rochester for the STD Hotline. Dr. Urban and I are for the STD Hotline, you can get one of us any day, week day during the week. Thank you.

[00:58:35] Thank you Dr. Babu very much for that information. I have about two minutes to ask you about five questions. So I'm going to try to get through what I can and then we can send out the answers that we don't get through. The first one is that near the beginning you talked about heat shock proteins. And the question is what are heat shock proteins?

[00:59:15] Yeah so they're basically, they are proteins that are produced by the cells in response to an exposure to stressful condition. So a lot of bacteria have them and it helps, let me go back to that slide.

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So a lot of cells have them, but then a lot of bacteria have them. And it helps the bacteria invade the cells. Basically the reason I presented that was because it's a very very virulent bacteria. Haemophilus ducreyi, one colony forming unit which is very very small, can cause 50 percent of infections in patients. There's been a lot of kind of basic science studies where they've looked at why that is. And they found that Haemophilus ducreyi has these things. It has hemolysins, which means it breaks down heme with blood cells. It has heat shock proteins which are proteins intrinsic to the bacteria. And then it has this outside layer of lippolysaccharide and it helps it keep it away from actually getting recognised by the immune system. So these are just evolutionary ways for it to infect people and survive.

[01:01:06] Thank you.

[01:01:11] It is actually 1:01 so why don't we, Gail can we send out the answers to the other questions?

[01:01:19] She says that we can send out the answers to the other questions.

[01:01:22] Okay why don't we do that so that everybody can get back to their work. Thank you for joining us on the Lunch and Learn today. And our next Lunch and Learn is on July 9th. And that'll be on pregnancy and HSV. And our June 1st conference in Lake Placid, you can still register for that. And I want to thank you, Dr. Babu, for your time today.

[End]

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