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Leishmaniasis

DD 1005 Leishmaniasis
Sidney Klaus, MD interviewed by Stuart Brown, MD

Recorded Time: 22:38

STUART BROWN:
Hello, this is Stuart Brown. And I’m having a conversation today with Sidney Klaus, who is professor of medicine at Dartmouth Medical School and chief of the section of dermatology at White River Junction-Vermont VA Medical Center. With his enormous background, he’s developed an interest in cutaneous leishmaniasis, which is becoming more common in newer areas around the world. Let’s start with this, Sid. What causes leishmaniasis?

SIDNEY KLAUS:
Leishmaniasis is caused by a parasite that is a member of the Trypanosomatidae family, which also includes trypanosomiasis. There are perhaps 30 or 40 different species of Leishmania but only about 10 that we know of that cause significant human diseases

STUART BROWN:
I mentioned that it’s now spreading. How is spread to start with, within patients as well as what’s causing it to spread around areas?

SIDNEY KLAUS:
In patients, it’s spread usually by a vector, which is the sandfly, which is sort of a mosquito-like insect. And the sandfly gets its disease from reservoirs. And the reservoirs in cutaneous leishmaniasis are largely animals. Now, the reason it’s spreading is that the urbanization of the world has caused increased breeding sites of sandflies. And, in addition, there are changes in the way in which these animals and vectors interact. There are other forms of leishmaniasis that are spread from individual to individual, the so-called anthroponotic type of leishmaniasis. And we know that in those forms, people migrating from one part of the world where there is no leishmaniasis into another where leishmaniasis is endemic can bring the disease into fruition, can enlarge the number of patients that are being involved.

STUART BROWN:           
Where do we find this most commonly?

DR. SIDNEY KLAUS:        
It’s found in tropical areas of the world. There are two major divisions of leishmaniasis. There is the new world form, which is found largely in South America, Brazil and Peru are two countries in which leishmaniasis is very prevalent.

STUART BROWN:           
It’s more equatorial then?

SIDNEY KLAUS:   
It’s more equatorial, more tropical, because the sandfly breeds more easily in warmer areas of the world. And in the old world, it’s found in two or three spots. Around the Mediterranean basin, there is one type of leishmaniasis. And in the Middle East, another form of leishmaniasis. And so those are the main areas. It’s also found in the horn of Africa, where Sudan and Ethiopia are, there is another form of leishmaniasis in that part of the world.

STUART BROWN:           
You’ve mentioned where we’re finding it. How frequent is it?

SIDNEY KLAUS:   
That’s an interesting question, because it’s one of the probably least well documented large diseases. It certainly is one of the World Health Organization’s most important tropical diseases. There probably are 12 million people currently involved but maybe more than that, because most countries don’t require reporting of leishmaniasis. In the cutaneous form, there probably are, oh, about a million and a half new cases yearly.

STUART BROWN:           
Speaking of new cases, we in Texas are starting to get more and more, and we’re not certain as to why several have been reported, and they’re very interesting. And it was felt possibly it’s coming from Mexico but there is no consistent answer as to how that is coming north. And it’s coming up into north Texas. Now, that doesn’t mean we’ve had a million cases, but we’ve had at least eight or ten.

SIDNEY KLAUS:   
Yes, there are reports that the areas in which leishmaniasis is found is spreading somewhat. That’s true in Texas and also it’s true in the form found in Italy, where now leishmaniasis has been found in northern Italy, close to the Swiss border.

STUART BROWN:           
The organism is in the sandfly, picked up from another mammal, bitten and deposited subepidermally in a human. And then this little parasite, who’s enjoyed several different homes, is now in our skin. What happens then?

SIDNEY KLAUS:   
The old story was that it would stay there for, oh, two or three days and then finally the macrophages would come along, ingest the parasite. The parasites actually would begin to change their form from this flagellated form found in the insect into a non-flagellated form called an amastigote within the macrophage. And then it would start to divide. Finally, if there were enough of them, they would burst out of the macrophage and other macrophages would come by to gobble them up. And that’s where the parasite would remain.

STUART BROWN:           
Well, in other words, the first line of histiocytes grab them and they support them, whereas the second line of histiocytes come along and say, “Okay, this is your funeral spot.”

SIDNEY KLAUS:   
Right, and that can happen for maybe a month or two months or three months down the line. It’s interesting now that why the parasites apparently can resist the initial wave of macrophages has just recently over the last year or two been studied. And what happens is that the first cells that come along and ingest the parasites are not the macrophages but are polys, are neutrophils. What happens is that the polys come along and ingest these organisms. The organisms usually then burst out of the polys and then the macrophages come along and again will take in the organisms. It has been found recently that the polys appear to be almost accessories to the infection. Because in animals, where they can eliminate the neutrophils entirely and just allow the parasites to be in the skin, they are easily killed by the macrophages early on. But once they’ve gone through the neutrophil, they then become resistant to the macrophages. So in a sense, our neutrophils appear to be on the side of the parasite for a short period of time.

STUART BROWN:           
That’s very interesting.

SIDNEY KLAUS:   
It is interesting.

STUART BROWN:           
What do we expect to see, as either signs or understand as symptoms?

SIDNEY KLAUS:
The disease is spread by the bite of the sandfly. And the sandfly then delivers the parasites through its proboscis into the skin. So the very first sign would be something like an insect bite. That would remain for an incubation period of a week or up to a month.

STUART BROWN:           
The bite remains?

SIDNEY KLAUS:   
No, what appears to be a bite. And then gradually, a papule develops at the site of the bite where these parasites are multiplying within the skin.

STUART BROWN:           
Do people feel the bite?

SIDNEY KLAUS:
It can cause a little bit of a sting but not much in the way of itching. It’s interesting that the vector, the sandfly, is a pool feeder. It doesn’t put its proboscis into a capillary to get the blood. It actually has to sever the capillaries, wait for the blood to collect, and then it pulls out the blood. So there’s usually a little hemorrhagic spot where the sandfly bites. But it does cause a little bit of discomfort but not very much. The sandfly is interesting, people don’t recognize very easily that it is around because it doesn’t buzz the way a mosquito buzzes.

STUART BROWN:           
How big is the insect?

SIDNEY KLAUS:
Half the size of a mosquito. That’s a problem in terms of protection because it can get through the mesh size of an ordinary mosquito netting. In any event, so what happens is that the papule develops. It can on the average of, oh, three or four weeks after the bite. And then slowly, it ulcerates. And so the characteristic early sign of leishmaniasis is an ulcer, painless generally, with a slightly elevated border.

STUART BROWN:           
About how big is the ulcer?

SIDNEY KLAUS:   
It can be about 1 cm, sometimes it’s larger, 1 to 2 cm. It can even get much larger than that.

STUART BROWN:           
And after the ulcer, the evolution is what?

SIDNEY KLAUS:
In most cases, the lesion will stay like that for up to three or four months. And then spontaneously clear. And I would say that probably 80 to 90 percent of leishmaniasis in the world is not treated. People don’t worry about it very much. It does leave a scar but it just goes away and that’s what happens. Now, with the study, it’s been found that most individuals harbor some living parasites for the remainder of their lives.

STUART BROWN:           
But localized?

SIDNEY KLAUS:   
Localized in macrophages. And unless they have some sort of immune problem, the parasites don’t go anywhere and they never know that they’re there.

STUART BROWN:           
So in some people who become immunosuppressed, it can recrudesce?

SIDNEY KLAUS:   
That’s exactly what’s happened in some cases in Europe, where patients had been bitten by flies. The disease in that part of the world is caused by Leishmania infantum. The lesions clear and then the patient may develop HIV infection many years later and the disease recrudesces.

STUART BROWN:           
This describes the cutaneous one. Do all lesions all around the world, with the different names of leishmaniasis, look like this?

SIDNEY KLAUS:
The early lesions do, but there are variations. For example, in South America, there is a mucocutaneous form. What happens is that the lesion developed, just as I described. But then later, there is actually metastasis of the parasites from the skin to usually the mucus membranes around the nose and mouth. And causes a tremendous amount of inflammation.

STUART BROWN:           
And then cicatrization?

SIDNEY KLAUS:
Yes, in some causes the mucus membrane, the mucocutaneous forms, don’t spontaneously clear. And the patients can go on and die from that disease.

STUART BROWN:           
Can it be contagious from one person to the other by contact with sputum?

SIDNEY KLAUS:
No. Almost no spontaneous contagion from one individual to another. In some parts of the world, where we know that cutaneous leishmaniasis causes a significant scar, it’s still done that mothers, for example, will find someone with leishmaniasis, with an active lesion, and inoculate the buttocks of their daughters with this disease, knowing that it’s going to eventually go away but leave a scar. This produces some degree of immunity. And so the child will not develop a lesion on their face, where they have these disfiguring scars, but will keep it on their buttocks. And this is a way of saving the face from scarring.

STUART BROWN:           
Was that all the mucocutaneous and the cutaneous form or do we have some others? Because I certainly remember some other named types.

SIDNEY KLAUS:
Yes, there are other types of leishmaniasis, especially presenting on the skin. Another one is diffuse cutaneous leishmaniasis, where only a few lesions develop, no ulcerations, but nodules or papules develop. And then can develop in very large areas, sometimes all over the body, and they remain for a very long period of time. They apparently don’t spontaneously remit.

STUART BROWN:           
That’s not from multiple bite?

SIDNEY KLAUS:
No. No, that’s from a single bite or a single inoculation. There are other forms where sometimes when the parasite will recrudesce again or develop again, there is another kind of leishmaniasis that’s called Leishmania recidivans. And in this case, it usually occurs around the site of the original bite but looks very granulomatous. And the differential diagnosis includes tuberculosis or cutaneous tuberculosis.

STUART BROWN:           
I should think syphilis would be in there, as well?

SIDNEY KLAUS:   
And syphilis, sure.

STUART BROWN:           
Are there any internal manifestations of this?

SIDNEY KLAUS:   
In the cutaneous form, not.

STUART BROWN:           
But that’s by definition.

SIDNEY KLAUS:
By definition. There is an internal form, usually caused by Leishmania donovani. This is prevalent in India and also in Ethiopia. This causes a rather severe and very commonly fatal generalized Leishmania. The organism gets into the liver, the kidney, the bone marrow, and may eventually cause the death of the individual.

STUART BROWN:           
In India, is this a major form?

SIDNEY KLAUS:   
Yes, that is the major form. That’s called the kala-azar and is also characterized by a darkening of the skin in India.

STUART BROWN:           
Is that where the term Delhi boil came from?

SIDNEY KLAUS:
Yes, there are lots of local names for the cutaneous form. For example, Aleppo boil or Baghdad boil. They are all related to cutaneous leishmaniasis. The systemic form, this kala-azar, usually does not cause any early cutaneous lesions. Though if the disease is treated by some of these anti-leishmanial drugs, later on there can be a PKDL form of the disease developing, which is post kala-azar dermal leishmaniasis. And in that case, also produces multiple papules or nodules on the skin that may, in fact, be a reservoir for further Leishmania spread by sandflies in that part of the world.

STUART BROWN:           
You’ve given a description. Know what to anticipate. But how do we prove the diagnosis?

SIDNEY KLAUS:   
Well, there are multiple ways of proving the diagnosis. I think in areas of the world where you don’t have access to PCR, which is the current way certainly in the United States, easiest way is to either do a skin smear, which means taking a scalpel blade and you make a slit from the center of the ulcer out to the periphery, just over that elevated border. And then scrape the slides of that slit, smear it on a slide, air dry it, put some alcohol on it, and then stain it with Giemsa. And what one finds there are the presence of the parasite organisms within macrophages that you’ve unroofed by the procedure. And that is a very easy way of making the diagnosis, gives you almost instantaneous form of diagnosis for skin leishmaniasis. You could also do a biopsy. A lot of people rely on that because they don’t know how to do the skin slits. And in that case, the organisms are pretty easily seen on an H&E specimen. The organisms are within the macrophages. They’re very close to the epidermis and so that’s where you look to see what happens. And there are other ways, as well. You can actually culture the organisms and see them in culture. And they change their form from the usual amastigotic or without flagella form that you see in the skin into a flagellated organism that moves around rather quickly within the material that you’ve cultured it in.

STUART BROWN:
Aside from the fact that there is a spontaneous cure in a number of these cases, does one need to treat any of them? Or do we just wait it out? Can you prevent the cicatrization if we treat it?

SIDNEY KLAUS:
That’s thought to be so. That the earlier the treatment, the less severe the scarring is going to be. Also, there’s always the possibility of systemic spread of the organism. So that I think that in most cases, if treatment is available, I would recommend treatment.

STUART BROWN:           
And what treatments do we have available?

SIDNEY KLAUS:
In the United States, there is only one form of treatment really available. And that is the use of pentavalent antimony. And this is given intravenously. Usually at a relatively low dose. However, given daily for three weeks. And it does have, in its own way, side effects. There can be EKG changes. People can have hepatic problems. They can have renal problems. Now, it is recommended that if one knows that you have the benign form of leishmaniasis, that is coming from, for example, the Middle Eastern area, and it’s found to be Leishmania major by PCR, one does not have to treat at all. Now, there are off-label uses of certain antibiotics that seem to be effective. And one of them is an agent called paromomycin. Which is a very effective cure of Leishmania. It’s been shown that probably it will reverse the onset of the Leishmania lesion in about 90 percent of the cases. This is applied twice daily for a week or longer and the Leishmania disappears.

STUART BROWN:           
How about some of the newer antibiotics that we are getting out there? I know paromomycin has been out for a long time, but not necessarily the treatment of choice. Although to me, I prefer that to having my liver involved.

SIDNEY KLAUS:
Paromomycin is probably one of the most widely studied of the topical agents. There are a number of others. But I think that, for example, some of the antifungal agents have been examined. They’re not quite as reliable I think as paromomycin. There is a topical preparation of amphotericin B that has been used.

STUART BROWN:           
Topical amphotericin B, I can handle. I don’t like the systemic because that takes my kidneys away.

SIDNEY KLAUS:   
That’s right. And so that’s another approach to the treatment. I think one has to examine or watch people who have leishmaniasis fairly carefully. If the topical therapy does not work, then one should really have to move to systemic therapy.

STUART BROWN:           
You talked about the PCR for aiding the diagnosis and/or culture. Does the CDC do either of those for you?

SIDNEY KLAUS:   
Yes, they will. And, in fact, if you have formalin fixed tissue from a biopsy, that still is available for PCR. And so you can, after contacting CDC, you can send that down and they’ll actually give you a speciation of the Leishmania. And I really would like to emphasize that that really is important. Because that says something about the possible seriousness of the problem.

STUART BROWN:           
You mentioned earlier the women in the Middle East transferring it to their buttocks to try to give some sort of immunity. If you’ve had a primary infection, does that really give you immunity?

SIDNEY KLAUS:
In most cases, it does.

STUART BROWN:           
So therefore, these moms are correct?

SIDNEY KLAUS:
They’re correct. And the immunity usually lasts the lifetime of the individual. And that’s one of the things, as I mentioned before, about migrants coming into an area where there is leishmaniasis that is spread from individual to individual, the anthroponotic form, those are the people who are most likely to have it because they haven’t been exposed to it previously.

STUART BROWN:           
Do we have any protection against this to avoid getting the bite?

SIDNEY KLAUS:
There are lots of ways that individuals can guard against leishmaniasis, if you’re in an area where you know that there is leishmaniasis present. In fact, the government has made great strides in informing the troops in the Middle East about these protection measures, which has reduced the frequency of Leishmania infections greatly to the soldiers who are in Iraq or Afghanistan. The things that you can do, first of all, sandflies, the vectors, are usually evening and night biters.

STUART BROWN:           
That’s why they’re related to mosquitos.

SIDNEY KLAUS:
Right, so you try to stay inside during those periods of time, if you can. Another thing is that the biting apparatus, the proboscis of the sandfly is unable – it is very short, unable to go through clothing. And so long sleeves are very useful.

STUART BROWN:           
What do you use on your face, since that’s one of the common sites of bites?

SIDNEY KLAUS:   
An insect repellant, very effective.

STUART BROWN:           
How often does it have to be applied? Will it last overnight?

SIDNEY KLAUS:
Yes, it would. The other thing, of course, is to sleep under a netting. But as I mentioned before, the openings to the ordinary mosquito netting would allow the smaller sandfly to get through. But now, the services are using permethrin, which is an anti-insect repellant. Permethrin-impregnated sleeping nets, which actually also are very effective in preventing the disease.

STUART BROWN:           
What about measures as one uses oil on water to block mosquitos? What about some comparable measure to cut down on the sandfly population?

SIDNEY KLAUS:   
That has been used in the past. For example, when DDT was being used, it was actually very effective in cutting down on sandflies, so that was important, as well. So DDT or agents that will reduce the sandfly population are important. The other thing, of course, is that you can prevent, in urban areas especially, try to prevent sandfly breeding by being careful about standing water or pools, because that’s where the sandflies breed. One can also take care of the reservoirs for these anthroponotic forms of leishmaniasis. That would include, for example, either eliminating or trying to eliminate the common reservoir for Leishmania major, which is called the Psammomys, or fat desert rat. And they live in little burrows. And what one then does is actually can fumigate the burrows to eliminate these animals. That will cut down on Leishmania.

STUART BROWN:           
Any other points you wish to make?

SIDNEY KLAUS:
Well, I think that if you’re out camping in an area where there is leishmaniasis and you can recognize where the reservoirs live, they have burrows that you can recognize, just stay away from those areas. Now, ordinarily the sandfly has a very short flying range, about 50 meters. And so you don’t have to go very far away from the areas where the reservoirs are. And so that is another way of sort of personal protection.

STUART BROWN:           
Well, Sid, I certainly want to thank you deeply for this information. Because although many of us a long time ago studied these third world diseases or tropical dermatology, we certainly have forgotten them from lack of, pardon the, pun exposure. And I think that with this rising, with troops being over there and possibly bringing back the disease, it should heighten our awareness of the possibility of it and recognizing it, diagnosing it, proving it, and treating it. Thank you very, very much.

SIDNEY KLAUS:
Thank you.

Reproduced with permission from the American Academy of Dermatology, Copyright 2011. All rights reserved.

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