Warren S Joseph, DPM gives an in-depth look at onychomycosis. Dr Joseph discusses the epidemiology of onychomycosis as well as the pathophysiology behind it. He reviews how onychomycosis develops, how it is diagnosed and most importantly how it can have a significant impact on diabetic patients.
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Warren Joseph, DPM
Roxborough Memorial Hospital
Editor - Journal of the APMA
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Warren Joseph Warren S Joseph, DPM, FIDSA has disclosed that he receives Honorarium/Expenses, is a Consultant to and serves on the Speaker's Bureau for Pfizer and Merck.
Warren Joseph: Hello. My name is Warren Joseph. I’m a podiatrist and infectious disease specialist at Roxborough Memorial Hospital in Philadelphia. And I’m editor of the Journal of the American Podiatric Medical Association. In this lecture, we’re going to talk about onychomycosis. Basically, what is it and how’s it diagnosed. Now, I will tell you that onychomycosis is big. It is become so popular and there’s been such excitement about and yes I know it’s hard to believe that you get towards excitement in onychomycosis put together in the same sense, that I can’t even give an onychomycosis lecture in one talk anymore. Pusan [Phonetic] asked me to break it down into a couple of different talks. What I’m going to do is I’m going to cover the background on onychomycosis, what is it, how do we diagnose it. And then in a second lecture, we’ll talk about some of the treatments of onychomycosis including what’s driving the excitement on onychomycosis, the release of two new FDA approved topical treatments, efinaconazole and tavaborole. But that’s a different lecture. Let’s talk about the background on what is onychomycosis. Now, I know that talking about onychomycosis to a group of podiatrist is really bringing coals to Newcastle. You all see it 20, 30 times a day but I think it’s important that we’d look if there’s a science behind it. I mean this is not just something you look at and you debride and you send out. There’s actually an incredible amount of science that’s being done and it’s been done in the area of onycho. This was a rare condition, just about a hundred years ago. I remember looking at a copy of Sabouraud’s book on topical dermatology. Now, you’re all familiar with Sabouraud and Sabouraud’s agar, and it’s basically the medium which fungus is frequently grown. Well, in his book, published in the late 1890’s in France, he said that the dermatomycosis of the foot is a rare condition. So 100, 110 years ago, this was rare. Over the years, we’ve had more and more onychomycosis and tinea pedis. Now, by the way, when I say onychomycosis and tinea pedis, I mean the two almost interchangeably as I’m going to show you these two are interchangeably diseases. They’re not interchangeable diseases, they’re heavily, heavily related diseases. Why is onycho, why is tinea becoming more common? Well, because of lifestyle changes, urbanization, more people crowded into tighter spots. Communal bathing facilities, I’m not so sure about that. That comes up all the time. And I always ask the audience, how many of you communally bathe? Not that there’s anything wrong with that but I usually don’t get a lot of hands being raised about that but okay, maybe communal bathing facilities. Certainly swimming pools, swimming pool decks have been found to have a lot of fungus. Occlusive footwear, we tend not to change our shoes the way we should. Patients who are wearing inexpensive shoes that are made out of rubber or plastic might not give their feet a chance to dry out. Increasing diabetes and HIV, both of those conditions are related to more onychomycosis and then there are certain occupations that are in increased risk such as miners, soldiers and runners. You’re going to see more onycho, more tinea in these populations. People who are traumatizing their feet, people are wearing the same shoes over and over again that you might see the general population. What are some soft numbers I can give you? I call these the fungus facts, sorry about that. But these aren’t real firm numbers. No one knows for certain but it’s estimated that between 35 and 36 million people in the United States have onychomycosis. Only about 6.3 million have actually been diagnosed by a physician and only about 2.5 million receive treatment each year. That leaves someone in the neighborhood of 33 million untreated patients with onychomycosis. I was going to kick out of this number because I remember when terbinafine, Lamisil oral first came out. I would lecture on it and people come up when they say, “Warren, this drug looks too effective. Why would I use it? I’m going to cure way my practice? Cure way your practice, you got 33 million untreated patients out there and then maybe if you actually cure a few them, you might actually get more patients coming up. At least some of these 33 million that didn’t think there was anything that could be done.” More on this on the lecture on treatment. But to me, I look at this and I come to onychomycosis as an infectious disease. Certainly, if you read a lot of literature on onychomycosis, if you go to lectures on onychomycosis, frequently it’s being given by dermatologist. Dermatologists look at onychomycosis as a disease of the skin and the nail. I don’t.
I look at onychomycosis as an infection. And because of that, it needs to be treated with anti-infectives. We don’t think twice about treating bacterial infections with an antibiotic. Why do we always have all these issues about treating a fungal infection like onychomycosis with an antifungal? There’s a genetic predisposition to onychomycosis. Nardo Zaias out of Miami showed that there’s an autosomal dominant trait that’s passed within families that confers a cell-mediated immune deficit that keeps patients from being able to clear the onychomycosis from their skin. It’s a progressive disease. It can start in one part of one toenail, can spread to the rest of that toenail to other toenails, from one nail to other parts of the body and from one nail to other parts of the foot. It can cause an immunologic response. It can affect the quality of life and we’re going to talk about all of that. And as with any infection, even though you get rid of it, it can come back, the organisms are ubiquitous. Well, we need to talk about epidemiology and I know, I know, I mentioned the word epidemiology, all your eyes glaze over. But basically, it’s straight forward. All that it says is when you look at the epidemiology of an infection, you have to concern yourself with three aspects. There is a host, a pathogen and an environment. And you have to take care of all three of those in order to treat the infection. Now there’s not a lot we can do with the host. Certainly, with increasing ages, more onychomycosis. Some numbers I’ve seen patients over 70, about 50% of them have onycho. There’s the genetic predisposition I mentioned before. Peripheral arterial disease, diabetes, HIV, all lead to more onychomycosis. That’s the host. Certainly, the pathogen, we’re going to talk about that in the treatment section, we can get rid of the pathogen but we can also manage the environment. And by the environment, we mean hygiene of the patient. We know the patients who don’t practice good hygiene tend to have more fungal infections. The shoe gear, I mention before, patients wearing occlusive shoes, not changing their shoes frequently enough, not allowing their shoes to air out, are going to lead to more fungus. Hyperhydrosis, communal habitat, we know there’s more onychomycosis in sniffs and in nursing homes, in military areas. People who are living together and then contagion, we talk about the pool decks being an issue. Certainly, we can try to manage the environment. We could get rid of the pathogen, we can’t do a lot about the host. We mentioned before, I mentioned before about the age and there does seem to be an age demographic that is more prone to onychomycosis. In this particular slide, you see 65 to 75, 21.2, 21.9, so almost 22% of patients, 24% of patients. About half of the patients with onychomycosis are 65 older. That’s the population most frequent we seen by podiatrist, much more so than in the dermatology world. We see more onychomycosis in a patient population that’s more prone to onychomycosis than through the dermatologist. Then we look at the pathogen. And if we look into mycology of onychomycosis, you have to realize that almost all onychomycosis and tinea pedis for that matter are caused by the dermatophytes. In particular, T. rubrum, Trichophyton rubrum. To a lesser extent, there’s T. mentagrophytes, now known a T. interdigitale. That seems to be more commonly associated with white superficial onychomycosis. The T. rubrum and distal subungual onychomycosis, moccasin tinea pedis, this is the organism. What about the nondermatophytic molds? This came up a lot during what I called the Lamisil-Sporanox wars because Lamisil didn’t really have good activity against molds, Sporanox did. And before speaking programs, whereas highly regulated as they are nowadays, you go to a Lamisil program and they talk about how dermatophytes cause it. And then you go to a Sporanox program. I talk about how you have to be aware of all the molds and Lamisil doesn’t work against the molds. Well, the fact is, the derms will tell you, up to 10% of onychomycosis is caused by nondermatophytic molds. Organisms such as Scopulariopsis brevicaulis, Scytalidium dimidiatum, Aspergillus, Fusarium, Acremonium. I’m not sure that I’ll buy it. Why? Because by definition, a dermatophyte works by digesting human keratin, they can live in the skin and the nail. The subungual, the nail bed, stratum corneum, that’s where the infection is. The molds aren’t capable of that. I look in molds as being kind of like what we get with the diabetic foot ulcer.
If you take a swab of the diabetic foot ulcer, what are you going to grow? Staph, strep, E. coli, Proteus, pseudomonas, everything known to man. It doesn’t necessarily mean that any of these are actually causing infection. It could just be that they’re colonizers, same with these molds that we find in onychomycosis. I’m not sure how much onychomycosis is actually caused by these molds. Let’s look at the pathophysiology and the clinical presentation of onycho from a little more scientific standpoint. Back in 1972, Nardo Zaia, again, out of Miami, the same gentleman who did the work on the genetics of onychomycosis, came up with the classification system of onycho that’s still use to this day in the scientific literature on onychomycosis basically he said, there is distal subungual, white superficial, proximal subungual and then one associated – onychomycosis associated with mucocutaneous candidiasis. Forget about it, we don’t see it in the toes so it’s only those first three. But what’s amazing to me is how little we know about this in podiatry. I remember a lecture, and you have to present residency summit in New Jersey, I had about 200 residents in the room. And I ask a question, “How many people in this room can recite for me Lauge-Hansen classification of ankle fractures?” Every single resident in that room raise their hand. I said, “Okay, how many of you can recite for me the Zaias classification on onychomycosis.” Not a single resident raise their hand. What I said is, “Let me get this straight, everyone in this room knows the classification system for condition that one quarter of you will treat twice a year. None of you know the classification system used in every scientific article about a condition you’re going to see 20 to 30 times a day.” That’s just wrong. I think it’s an indictment on our educational system, both at the school level and at the residency level that you’re not learning the science of the most common condition you treat. Well, science? Come on, how much science is there in onychomycosis? Well, I’m a big believer in signing after something called My NCBI. I’ve referred to it in some of my other lectures. But basically, you go to pubmed.gov where you do your Medline searches and there’s a little tab, you hit for My NCBI. And you can sign up for e-mails, either daily, weekly, monthly, whatever you want on any topic of interest. I get three a day, not three a day. Every Monday morning, three. Every Monday morning, I get one on onychomycosis, one on, excuse me, one on diabetic foot infection and one on osteomyelitis. And I will tell you, week in and week out, there are more papers published in the area of onychomycosis than there are in the areas of diabetic foot infection and osteomyelitis. Yet people in our profession, even though we are the number one treaters of this condition, we don’t do anything about it, we don’t bother to learn the science behind it. I think we need to. Alright, let me get off the soapbox a little bit here. Back couple of years ago, they added a fifth type of onychomycosis, they call that endstage onychomycosis or total dystrophic onychomycosis. That’s actually just onychomycosis going wild. This is what we see in podiatry on a regular basis. And then there are different subtypes. There’s secondary onychomycosis, endonyx onychomycosis, the world lateral was added to distal subungual onychomycosis and now called distal lateral onychomycosis. But I really think you’re good if you’re familiar with the first three, distal or now distal lateral subungual, white superficial and proximal subungual. Well, how does onychomycosis develop? Here’s a cross-section of a nail unit and what you can find is that there’s a break in the hyponychial seal between the nail bed and the nail plate. That allows fungus usually from either the environment or the skin, so the tinea pedis to invade up under the toenail and set up shop causing distal subungual onychomycosis. Starts distally, spreads proximally. Well, you can also have invasion from the eponychium. This is where you have proximal subungual onychomycosis and this used to be extremely common and it was associated most with HIV and AIDS. Nowadays, you’re seeing it a little bit more with conditions such as the patient going to their mani-pedi and having their cuticle pushed back, that might be where you see more proximal subungual onychomycosis because of the advent of the highly effective antiretroviral therapies or HAART therapies as we call them, it is decreasing the amount of AIDS we have, even in HIV positive patients.
You get distal onycholysis with distal subungual onychomycosis and you can see the nail is infected from distal and it spreads proximally. A little digger the dermatophyte there and jumping up under the toenail, just lifting up that toenail, squeezing out just right everyone on TV, or everybody who was watching their TV when those commercials were running. Again, distal subungual onychomycosis and you’re all familiar with how that looks. So just looking at it from a slightly different way, you got these three little wings here, the green is where you get the invasion for distal subungual onychomycosis, the blue is where you get the invasion for proximal subungual onychomycosis. And if you look superficially on the orange, that’s where you get the white superficial onychomycosis, again, usually caused by T. interdigitale. So there’s proximal subungual, you can see as opposed to the invasion starting distally, it starts proximally. Here is the white superficial. It almost looked like somebody took some white toenail polish or little white chalk and rubbed it on the top of the nail. Again, caused by T. interdigitale more than by T. rubrum and the T. rubrum caused distal subungual onychomycosis that we’re so familiar with. But I think you have to remember with that less little animation. Onychomycosis is not primarily an infection of the nail plate. Onychomycosis is primarily an infection of the nail bed stratum corneum and that is what’s led to difficulties with treating this disease because the drug you’re using has to be able to do whatever mechanism get to the nail bed and that’s where the infection is. So let’s talk about diagnosis. If you look at laboratory diagnosis of onychomycosis, it’s pretty clear, the evidence is out there that the PAS stain, the Periodic acid-Schiff stain is probably the best way to go. It’s relatively rapid, it is very sensitive, it’s just not particularly specific. It won’t tell you what organism you find, it just tells you that yes, there’s fungus or no, there’s fungus. Certainly, from a more specific standpoint, you can look at fungal culture because fungal culture is going to tell you. Yes or no, there’s fungus and the fungus is an X, Y or Z. The problem with fungal culture is they’ve got about a 50% false negative rate. About half of the cultures you take, even in patients, rough fungus may not grow. Furthermore, they have to grow in optimal conditions. It can take weeks for the fungus to grow out. And unlike with bacteria where you can just stick in a machine and it tells you what the organism is to this day for a fungal infection, you have to have a skilled mycologist to what’s called a wet mount on a slide, look at the Chlamydia, look at the hyphae and determine that wedges by them looking in a microscope which organism you have. It’s very specific but it’s not a particularly sensitive test and it takes a long time to get. Alright, certainly, there are newer techniques that are being used such as PCR, polymerase chain reaction which is rapid, sensitive and specific. But here’s a little bit of a twist. It may actually be a little too sensitive. You get organism that we don’t even know if they’re pathogenic or not. I think PCR is fascinating, I think going to be the wave of the future in both bacteriologic and fungal diagnosis. I think just a little more work needs to be done on it. But if you are using it, I think it’s a really cool way to go. Well, why do you want to do a laboratory test? Well, certainly, the dermatologist will tell you that 50% or 5-0% of all distal foot nails are not fungal. Oh, they’re not fungal? What are they then? Well, they’re dystrophic secondary to lichen planus or psoriasis or trauma or congenital abnormalities. You have to do a test before you start treatment. Well, I’m not necessarily sold on that because I think in podiatry, a good majority of what we see in the way of dystrophic nails are in fact onychomycosis. Well, other reasons to do a laboratory test. It may be more cost-effective to treat based on a laboratory test than on clinical findings alone. Why is that? Well, you don’t want to start a therapy especially a potentially expensive therapy if you’re haven’t confirmed the fact that fungus is causing the infection. It may just be one of those nonfungal dystrophies. So there is a cost effectiveness issue there. You can reduce the risk of drug-related side effects in patients with mycologically confirmed onychomycosis.
Because again, if you’re treating a patient, especially with an oral and they don’t onycho and they had an adverse event because of that oral, you’re going to be really kind of up the creek without a paddle and I’m going to show you that in a second. An identification of the type of dermatophyte versus nondermatophyte on our species may assist with the treatment choice. As I mentioned before, some anti-fungals are better against nondermatophytic molds. Some anti-fungals are better against the dermatophytes. So if you had an organism, maybe that will help you as long as it’s a good culture. But to me, here’s the real kicker, the main reason to do one of these is because third party payers usually require. Before they end up approving a drug, they usually say, “You got to prove it’s there.” Well, do they want yes, no, it’s fungus or do they want more than that? Most payers are okay with just yes, it’s fungus, no, it’s not fungus, KOH, PAS, anything. But I’ve heard of some payers that want a genus and species of the fungus before they pay. That really is going to be the limiting factor. Because frankly, clinical diagnosis, I hate to tell you, works as well as laboratory diagnosis and I’m not just saying that. Everything I say I back up with evidence. And I’m going to show you those studies. There’s also a medical-legal risk, especially starting an oral medication without confirming the diagnosis. I reviewed a couple of cases of death by terbinafine and this is where they hand the doc. They don’t hand the doc on failure to do laboratory testing for blood work, things like that. They get the doc on failing taken from the diagnosis. And in fact, if you look at the Lamisil package insert, its right there. This is right for terbinafine package insert, right under indications and usage to the second line, it says prior to initiating treatment, appropriate nail specimens for laboratory testing, and I even tell you what testing that is, KOH, fungal culture and nail biopsy should be obtained to confirm the diagnosis of onychomycosis. If you start using an oral and you haven’t confirmed the diagnosis and the patient has an adverse event, you’re in some trouble with that just because of what it says in the package insert. But again, I really do believe that clinical diagnoses are accurate. Excuse me. Here’s a study out of the British Journal of Dermatology that shows physicians, now, this was out of the UK so they do not use podiatrist. But it says physicians were able to accurately diagnosed fungal nail disease based on clinical observation only and the positive predictive value is 0.91. The positive predictive value of clinical diagnosis was twice that of a laboratory test. So it really is an accurate diagnosis. These are two other pairs, one other paper added to the first paper both from the British Journal. We think that in patients in which a dermatologist considers onychomycosis the most probable diagnosis and plantar desquamation is present. Plantar desquamation equals tinea pedis, you got it. Clinical diagnosis is enough to start therapy, this is my favorite line, as the positive predictive values are higher than those of laboratory test. I do believe that clinical diagnosis is a good way to go, as long as using topicals and the payers aren’t requiring it, I think the evidence backs it up. What about quality of life? Back in 1998, Lynn Drake, President of the American Academy of Dermatology published a paper on onychomycosis and quality of life. And she found that 48% of patients with onychomycosis have pain. That’s a huge number. And then when we try to get onychomycosis therapy covered, what is the payer say? “Oh, we’re not covering that, it’s a cosmetic.” What cosmetic condition causes pain in 48% of patients? Embarrassment, 3/4 of patient are embarrassed. Okay, there’s embarrassment but then there’s embarrassment. I had a patient come to see me years ago. He had 10 toenails and 10 fingernails involved. He was a priest. He couldn’t do his job. Why? He was concerned not about his toenails at about his fingernails because he was concerned about how giving communion his parishioners were staring at his fingers. I had to assure him that the oral antifungal I was going to give him were the only work in his toes because in the commonwealths of Pennsylvania, I’m not licensed to treat the fingers but lo and behold, there was a miracle. He must have known somebody, he goes all 10 toenails and all 10 fingernails cleared. That’s embarrassment, right. 3.8 physician visits per year, because of onychomycosis, and they might just be coming to see us. But that’s a burden on the healthcare system. This is not just a cosmetic condition. We talked about Zaias and his looking at the genetics of onychomycosis before showing the autosomal dominant trait that’s passed among families.
And Pettygroves [Phonetic] do suggest autosomal dominant inheritance. Every affected child had at least one infected parent. Keep that in mind when you’re seeing both parents and children to look at the other. Now, certainly, not husband and wife, they’re not genetically related. What Zaias also said, is because his patients are genetically predisposed, not only do they have tinea pedis but they also have, excuse me, not only do they have onychomycosis, but they also have tinea pedis, tinea cruris and tinea corporis. They have fungal infections throughout their body. Again, they’re genetically predisposed to develop an infection in an organism that is ubiquitous in the environment. You need to check for that. We’re going to end up just talking about onychomycosis in some special populations, in particular, patients with diabetes. Back in 1998, Aditya Gupta of Canada. The patients with diabetes had 2.8 times more onychomycosis than patients without diabetes. And that’s just recently been confirmed by some work in the Italian literature by Papini. Patients with diabetes were two to fourfold more likely to have both onychomycosis in tinea pedis than patients who didn’t have diabetes. Well, what happens in a patient with diabetes? You have a patient who has a neuropathic foot. Now on top of that neuropathic foot put a big foot toenail. And put that toenail in a shoe, it’s a couple of sizes too small, because we know patients with diabetes who are neuropathic tend to wear shoes that are little too small. You can imagine the set up for the pressure or what I call the click, click squish syndrome as you debriding away. And what you see is because of the neuropathy, because of the thickening and the elongation, I know this is more onychogryphosis really than onychomycosis but you can see onychomycosis leading to secondary diabetic ulcerations. This is your patient everyday of the week, you see this multiple times a day. And this is what I call the click, click squish syndrome because as you go debriding those nails, your debriding five, four, three, two and you get to that hallux nail and you go squish. And that bead of pus comes out from under the toenail and as you debride away, you notice not only is there onychomycosis, there’s now also subungual ulceration. And remember back to your days in lower extremity anatomy how much tissue is there between the nail, the nail bed and the distal phalanx. Now you have onychomycosis leading to osteomyelitis. And this is just another example of the click, click, squish syndrome where you have the subungual ulceration. And in this case, I just wiped away the pus that it started draining out. But you could see the ulceration underneath and just another case of an ulceration and a nail bed. This has never really been not closely looked at, the date is not great. This is relatively old, this is 15-year-old day which is an abstract presented at the American Diabetes Association that showed that patients who had diabetes with onychomycosis, you know, the purple bars versus without onychomycosis or blue bars had more gangrene and foot ulceration. People with onycho had more complications than people without. Now, this is not causation data. This doesn’t say that the onychomycosis cause the gangrene or the ulceration. It just was association data because all they were able to look at was billing codes and this is what they came up with. We know there’s at least some association there. In conclusion, onychomycosis is an infection. As an infection, it should not be ignored, you should treat it with anti-infectives. It’s almost always caused by T. rubrum, it’s a progressive condition and has significant clinical consequences including decreased quality of life and in patients with diabetes, you can end up with secondary bacterial infections. And that’s what I have. With that, I want to thank you very much. If you’re still interested in onychomycosis and some of the treatment regimens, in particular, the new topical treatment regimens, I would direct you to my present lecture on treatment of onychomycosis. Thank you.