Polish up: What’s new in diagnosing and treating onychomycosis

Hello Shari. Welcome to our podcast. Thanks for joining us today.

Dr Shari Lipner: It’s great to be here, Gina.

Gina: It’s a real pleasure to have you with us as well. So this topic is something I’m super excited to learn more about. I know it’s a really common condition that’s really overlooked. In fact, it’s actually one of the most common skin conditions in the world, I think. So let’s begin with what is onychomycosis and how prevalent is it?

Dr Shari Lipner: So onychomycosis is also known as a nail fungal infection, and it is one of the most common things that we see in clinical practice. And in fact, it makes up fifty percent of the nail disorders that we see. So if a patient comes in with a nail problem and you flip a coin, you know, half the time, it’s going to be nail fungus. So globally, it affects about five to six percent of the population, although estimates vary. But, in terms of what people are concerned about, it’s very, very common.

Gina: And what are the typical causes? What are the typical fungi that cause the condition?

Dr Shari Lipner: So it is broken up into basically three groups of organisms. One is the dermatophytes. Those are by far the most common causes of onychomycosis, mostly trichophyton rubrum, and some cases of trichophyton mentagrophytes. Then the next category is non-dermatophytes. So this includes organisms like fusarium and aspergillus. You have to be careful with those though because, you know, sometimes you can do a PCR or a culture and those will grow out, but we think that they are not always pathogens. Sometimes they can be contaminants. So if you do find one of those organisms, the textbook answer is you should probably repeat that culture or PCR either two or even three times to make sure it is real, and not just chase it.

Then finally, the last category is yeasts like candida albicans. But that is also a little bit controversial because sometimes they are also contaminants that can live on the skin and do not necessarily cause the infection. So I think there really is the importance of clinical pathological correlation, you know, looking at the patient’s nails and then looking at what your test results are, and you cannot just treat the test results, you have to treat the patient with the test results. So I think the vast majority of cases are really dermatophytes, and particularly trichophyton rubrum.

Gina: Are we seeing a shift then in the types we see? Is one more common than the other?

Dr Shari Lipner: You know, I think it is hard to tell because if we look at some of these larger studies, sometimes contaminants are coming out in the lab. So there are some studies showing a shift to non-dermatophytes, or a shift in, let us say, in older individuals to non-dermatophytes. But in my practice, I think most infections are trichophyton rubrum. So, you know, it is hard to know because organisms can vary in different parts of the country or different parts of the world. But I think the take home message for patients, because they ask about organisms, is that most of the cases are trichophyton rubrum, and I would not worry about it too much because we treat a lot of them very similarly.

Gina: And so what are the classic signs you are looking for when a patient comes to you with a nail to kind of define that it is onychomycosis?

Dr Shari Lipner: So first of all, generally, we are looking at toenails when we are talking about onychomycosis. While you can get onychomycosis in the fingernails, it is more common if the patient also has it in the toenails, plus there has been some trauma to the fingernails such as slamming it in a door, or nail biting or nail picking. But generally, onychomycosis is more common in the toenails.

It generally affects the great toenail, although more than one toenail can be affected, especially in severe cases. And generally, you will see xanthonychia, meaning yellow nail, an area of onycholysis, which is detachment of the nail plate from the nail bed, as well as subungual hyperkeratosis.

Now one important sign is looking at the plantar feet and the interweb spaces, because that can be a clue that there is tinea pedis there. And if a patient has nail changes plus scale on their feet, of course it could be psoriasis, but it makes you think more about onychomycosis.

Gina: How about the impact on the people living with this? I know it is often overlooked, but I am sure for some patients it really does impact their quality of life in some way.

Dr Shari Lipner: Absolutely.Patients really, really care about their nails. And yes, it can be an aesthetic problem such as for people who swim or go to the beach or want to wear open toed shoes, or even go to get a pedicure. They may be embarrassed to go because they may feel that people are scared of their feet or may not want to touch their feet. And particularly if it involves the hands, that can certainly be stigmatising.

But it goes beyond aesthetics, and nails can be painful—both fingernails and toenails. It can be hard to fit shoes.It can cause changes in the gait. And in people with diabetes, especially those who are not well controlled, there can be secondary infection, sometimes leading to amputations.

Gina: Definitely more than cosmetic then. So when it comes to looking at diagnosing it, why is it so important to confirm that it actually is onychomycosis before you even start treatment?

Dr Shari Lipner: So there are a lot of reasons to confirm the diagnosis. Yes, in practice, physicians and dermatologists are busy. Yes, it takes longer to confirm the diagnosis, but there are a lot of reasons why it is important.

Number one, there are a lot of mimics of onychomycosis. And although it is the most common nail disease, certainly things like psoriasis, retronychia, mechanical nail disorders, onychomatricomas, those are just a few, can resemble onychomycosis.

So you could be making the wrong diagnosis, and nails do not respond the way skin does. Right? If someone has a plaque of psoriasis and you give them clobetasol for a few weeks, they are likely going to get better. But with nails, because they grow so slowly, you may not know if the nail is getting better for six months. That is a long time to treat the nail and have the wrong diagnosis. And, you know, while we try to give medications that are safe and counsel patients about risks and benefits, we can sometimes have rare and dangerous side effects. For instance, one of the drugs we use is terbinafine, and terbinafine can cause smell and taste disturbances. Not often, but sometimes these can be permanent. It can cause rashes, gastrointestinal upset, and rarely, it can cause cases of hepatotoxicity, some of which are irreversible.

So those are a few reasons.

There is even another reason now to confirm the diagnosis, and that is because we are seeing cases of terbinafine resistance.

If we are giving terbinafine or other antifungals without checking and treating non fungal infections, that is how we are making antifungal resistance worse. So just as a community, it is important to check before prescribing antifungals.

Gina: Indeed vitally important. So when it comes to traditional diagnostics then, what do we currently use? What are the mainstay diagnostics?

Dr Shari Lipner: Yes, so in terms of diagnosis, we have a lot of great choices.

If you are in a setting where you have a CLIA-certified microscope, and you have practised doing KOH with microscopy, it is the most low cost type of diagnosis, and it is the quickest. You can get results within minutes, and it is very rewarding to try to treat the patient basically right at the visit.

However, not everyone has the expertise to do that. Some practices do not have microscopes, and so there are other options.

Fungal culture was considered the gold standard for a very long time, and the reason for that is because it is the only test that will tell you both the viability and identity of the organism. So if you are thinking about non dermatophytes, for example, that is the time where you would want to know the identity of the organism. The problem with fungal cultures is that there is a very high false negative rate. A lot of the time there will be fungus, but the test will not show it. That can be very frustrating. That can be very misleading. And also it can take a very long time for the fungus to grow—let us say, four weeks, sometimes even more.

And labs vary in their culture abilities. I have used different labs. Some, all the cultures are negative all the time, and some have, like, a fifty percent success rate. So that is also a challenge.

One of the newer techniques is using molecular biology to diagnose nail fungus, so using PCR. It is pretty amazing because you can get results within days, and you can also know the identity of the organism. Some negatives to it are that it can amplify any piece of DNA. So it can amplify contaminants, which could be confusing for the physician who is treating the patient. Also, cost can vary, and insurance coverage can vary. And if you are using a lot of probes, the cost can be prohibitive. But let us say you are using just a couple of probes, it may be more reasonable.

And then finally, I think what is really exciting in the last few years is using machine learning to diagnose onychomycosis. So, you know, our eye is only as good as our eye, but sometimes the AI can see patterns and help diagnose onychomycosis. There have been a few studies looking at it. I do not think it is quite ready for prime time. I think, you know, probably our other tests are better at diagnosing onychomycosis and are more accurate, but it is something to look forward to.

Now one more test I do want to mention is a clipping with histopathology, because that is the test that I use most often. The reason is, it is very quick and easy to do in a busy practice. What you want to do is clip back to the most proximal onycholytic area, because that is where the fungus likes to live, and also try to get some scrapings from the nail. There is a very good sensitivity in terms of detecting fungus with histopathology.

The only negative is you do not know the identity or viability of the organism, but that is really my go to test.

Gina: I know at the recent American Dermatology meeting, there was a lot said about AI and how it could change how we work. They also did a lot on onychoscopy. How is it being used?

Dr Shari Lipner: Yes. Onychoscopy is dermoscopy of the nail unit. And it is, again, something that you can get very good at if you practise it and look at patterns. I actually find dermoscopy very helpful in diagnosing onychomycosis. I would not use just my clinical examination and dermoscopy to make the diagnosis. I think it is an aid to some of the other diagnostic tests we spoke about, such as histopathology. But some patterns that we can see with the dermatoscope are jagged edges and a ruin-like pattern, and that can be very convincing of onychomycosis.

Gina: So once we have confirmed the case, the next big question, I suppose, is how do we treat it and treat it effectively? What are the current mainstay treatments that we actually use in practice?

Dr Shari Lipner: Treatment has to be individualised. I do not think an AI-like algorithm can treat a patient with onychomycosis, because there are so many things to consider.

Number one, what is the number of nails affected, and what is the severity of the disease? Do they have one nail affected? Do they have ten nails affected? Do they have twenty nails affected? How thick is the nail? So, you know, how is that penetration going to be? What is the surface area of the nail involved? What is the quality of life of the patient? And then what are their comorbidities? What is their compliance going to be like? You know, are they able to swallow pills? Do they have the flexibility to apply the medication? And then, of course, we always have to deal with cost and insurance coverage.

So, in general, in the United States, we have a few oral options and we have a few topical options. Certainly not as many options as, let us say, we have in diseases like psoriasis. There is a limited number of options, and the options are sort of slow at coming out.

Some of the standard treatments we use include terbinafine. It is one of the most common medications I use. The dose is two hundred and fifty milligrams for three months for toenails, but then you have to wait for the toenails to grow out. We also have itraconazole, which is an excellent antifungal, but it does have a lot of drug–drug interactions, and there are risks of cardiotoxicity, and there can be neurological problems.

Then finally, there is also fluconazole, which does not have the same cardiotoxicity risk, but it does have those drug–drug interactions. It is used off-label in the United States for the treatment of onychomycosis.

And then we have three topical options. The first is ciclopirox. That was the first topical ever approved. The success rate, the efficacy, is so-so in the clinical trials.

The other issue with ciclopirox is it gets caked on, and so it is important for the physician to counsel the patient on how to apply the medicine and also to remove it once per week. It also requires either debridement or clipping weekly, so you have to work with the medicine.

The two newer medicines are tavaborole and efinaconazole, and those are easier to use because you do not need to clip and you do not need to remove the lacquer or the solution once per week. Generally, those have better efficacy than their predecessor, ciclopirox.

Gina: So when we talk about treatment, I suppose the ultimate end goal is a cure. But when we talk about cure, are we aiming for a nail that looks completely healthy again, or should we be focusing more on confirming that the fungus has been fully eradicated through lab tests?

Dr Shari Lipner: Yes. So I think those are important concepts to understand because, you know, the FDA requires, and other agencies require, criteria that we do not really use in clinical practice.

Some of the criteria that are used in clinical trials are mycological cure, and that is defined as a negative KOH and a negative culture. And keep in mind, some people do not do any of these things in practice.

Then a complete cure is a mycological cure and a completely normal-looking nail.

And so, as we get older and walk around and participate in sports activities and have traumas to our nails, sometimes our nails do not look like they did when we were five years old. And so even if we eliminate the fungus, there still can be mechanical issues, and the nail may not look perfect.

And so I think when physicians are looking at data, it is better to look at mycological cures, because that gives a more realistic view of real life. Right? Because I think with complete cures, that is hard because there are so many other factors going on.

But in real life practice, generally what I do is I examine the patient, I make the diagnosis mycologically, I give them treatment. If I am giving oral treatment, I do meet with them in the interim and just monitor for side effects, sometimes check labs, meet with them at the end of therapy to talk about prevention of recurrences. And then, especially with telemedicine—which is not hard for patients to do—I follow them after that because the nail still has to grow out. Then you can see whether they need a booster dose or if any other therapy is needed.

Gina: Now we have touched on this a bit before, but when you are picking between oral and topical, what are the decisions you are making to decide which is best for your patient?

Dr Shari Lipner: Yes. So I think it is really a partnership.

For me, I really like treating orally because I think the cure rates are best. I think compliance is best. Yes, terbinafine is a cheap medication and generally, you know, relatively safe.

But, you know, it is a partnership. And also for people with more mild to moderate disease, I give them the choice. So if they have a single nail, let us say less than fifty percent of the surface area affected, not so thick, I think it is fine for them to use oral medication or topical medication.

But I generally do not offer people topical medication if they have a lot of nails affected and high severity of disease because I just do not think it is going to work.

Gina: We have talked about success rates just a moment ago. So why do some patients still fail treatment despite, you know, you said there are six options available at least to you?

Dr Shari Lipner: Yes. So there can be a lot of reasons that patients fail therapy.

Sometimes it is because the therapy really is not working. So let us say you gave them terbinafine and there is terbinafine resistance.

I think that is probably a rare reason for someone to fail therapy.

Another reason for failure could be that they are not really taking the medicine regularly. And I think that is particularly true for topicals, especially because for women at least, and some men, they want to use nail polish. And so it is not really compatible together.

And, you know, probably the most common reason, not in my practice, but for people who come to me after failing three courses of terbinafine, is that the diagnosis was wrong. They really have retronychia or psoriasis.

So if a patient came to me and had failed a treatment, I would say, let us recheck the diagnosis first.

Gina: And when it comes to efficacy then, is there anything new in the world of topicals coming out—any new research or studies underway?

Dr Shari Lipner: Yes. So there has been a lot of effort put into studies on topical terbinafine.

That study was actually very efficacious if we look at mycological cure—so excellent efficacy in terms of mycological cure. But when we look at complete cure in those studies, it was very, very low, like, abysmally low. And that is because of the formulation of the medicine. It turned the nail opaque, and then that precluded calling something a complete cure. So I think that was the issue with that.

I think there is some work into different dosing of the drug to achieve that complete cure, but in terms of mycological cure, it was very good.

And then there are some drugs that have been studied in vitro or have gone through preliminary clinical trials. A couple of examples are ME 1111, which inhibits succinate dehydrogenase, that underwent in vitro studies. There is amphotericin B, which is actually an old drug, but it is being used now to treat onychomycosis. It affects ergosterol and cell membrane permeability. And finally, there is NP 213, which blocks fungal peptidases and proteases.

I also read a study using vitamin E along with essential oils topically, and there was a very good mycological cure rate in that study.

Gina: When it comes to systemic therapy, is much happening there?

Dr Shari Lipner: Yes. I mean, we do have some available antifungals that have been studied for other fungal infections that potentially could be available to us, although they are not commonly used in clinical practice. So there is voriconazole, there is oteseconazole, there is posaconazole, there is fosravuconazole.

You know, I think they are really used more in the infectious disease world. But potentially, if there were a patient with terbinafine-resistant infection or another azole-resistant infection, we could consider using those.

You know, approvals could be hard for them, and some of them do have potential cardiotoxicity, and you have to monitor patients with EKGs.

So I like to use the medicines that are generally the safest. I think doing EKGs in a dermatology office would probably scare off a lot of patients.

Gina: I would reckon so, yes. So it looks like there are some developments going on, maybe some in the far distant future, maybe some a bit nearer, but medications are probably here to stay and are going to remain the cornerstone of treatment. But there seems to be a growing interest in things like lasers, devices, and combinations of all these therapies, especially for stubborn or recurring cases. So when it comes to lasers and devices, where do we currently stand with that?

Dr Shari Lipner: Yes. So there has been a lot of interest in lasers. There have been a lot of small studies using lasers. The laser studies generally are not as robust as the clinical trials that have been done with drugs like efinaconazole or terbinafine. They are much smaller studies. They do not require the same stringent endpoints.

And lasers are approved in the United States by the FDA for temporary cosmetic improvement in the nail. So, you know, I think that is something you have to explain to patients because they want to come in, they do not want to do a daily treatment, they want a quick fix.

And so I think when you explain to them in those terms, that they are getting a temporary cosmetic improvement, I think they understand it better. The other thing about lasers, and I have tried it on a few patients, is that it is extremely painful. And I think, you know, patients do not expect that.  They think they are getting, like, a beauty treatment or something, and they do not expect it to be painful. So, pain, and number two, I do not think the data is really there to show that we have great mycological cure rates.

There are some other devices though that may be reasonable combined with other treatments. So, my group and others have used a micro drill. So, drilling tiny little holes in the nail to help with penetration of topical medications. That is something that we have been interested to look at, and it is an exciting idea.

Another device that is being studied right now is a microwave device, and that is undergoing trials. So I think the jury is still out on the microwave device.

Gina: But I suppose these could be good options for those who cannot take systemic therapy. Or could they be used in combination? Could you tell us a bit about combination or adjuvant approaches that are also being explored at the moment?

Dr Shari Lipner: Yes. So, you know, let me define what I mean by combination.

I am not really a fan of giving patients multiple treatments at once, like terbinafine plus efinaconazole, or efinaconazole plus tavaborole, or terbinafine plus itraconazole, because, you know, I am kind of a one drug per patient person. I like to see if the drug is working before I switch treatments. And if you give two at the same time and nothing is working, then you do not know. And if you give two and the patient gets better and then gets the infection again, you do not know what really worked. Is it both together? Is it one? Is it the other? So, I like sort of a cleaner treatment pattern. But I think there are some combinations that are reasonable.

So for instance, let us say someone has ten toenails with onychomycosis and they are very thick, and let us say they have contraindications to systemic therapy, drug–drug interactions, or they had a prior issue with terbinafine. That would be a case where I want the nail to be thinner so that I can use the topical. One thing you can do is use a cream like urea, which can chemically debride the nail, and then apply the antifungal. Or I often partner with a podiatrist who can do debridement in the office with a mechanical device, and then I can use a topical antifungal. I think that is a really good example of combination treatment.

The only other time I would use combination treatment is for patients with dermatophytomas and onychomycosis that is distal lateral subungual. So what I mean by that is, dermatophytomas have been around for a while, but I think there is more interest in them lately. They are these fungal balls. Multiple studies have shown that oral treatment is really ineffective in penetrating that ball, and it used to be thought that the only way to get rid of it was to surgically remove that patch of dermatophytoma and then give terbinafine.

But we are finding that the topical medicines really penetrate that fungal ball. So both tavaborole and efinaconazole are really effective in treating dermatophytomas.

So if I had a patient with pretty extensive onychomycosis who also had a dermatophytoma, I would consider treating both with terbinafine to treat the overall onychomycosis (distal lateral subungual), and then specifically efinaconazole for the patch of dermatophytoma.

Gina: Perfect. So, of course, even the best treatment plans can full short if we do not think ahead. So I thought we could talk about what can be done in preventing recurrence and supporting long term success. What is the current thinking on how we could help patients prevent recurrence?

Dr Shari Lipner: Yes. So I think that is the most important conversation to have with the patient. When I finish treatment, I say to the patient (and most of them listen) that when you are done with treatment, have one more visit with me, and that can be on telemedicine so it is easy for them, because we are going to talk about prevention of recurrences.

Because if you do not meet with me, there is a good chance that the fungus is going to come back, and we are going to be back here in a year doing the same treatment again. And we are seeing cases of terbinafine resistance, so who knows if the terbinafine will work the second time? That usually gets them to follow up with me.

And when I first started doing nails, my mentor, Dr Scher, told me that every year I would get patients back to give terbinafine again because the recurrence rate is through the roof.

So what I do, and this is based on a study by Prof. Avner Shemer, that is quite old now, more than a decade old, is they looked at patients who completed terbinafine or itraconazole, and then used an antifungal cream to their feet once a week. The recurrence rate was much lower in the group that used the antifungal topical versus the group that did not.

So when they finish their treatments with me, I say, now you are going to use an antifungal to your feet every night.

To me, I think they probably will not use it every night, but if they use it a few nights a week, I think I am golden. And I hardly ever see recurrences when they do that.

So it is a rare patient that comes back to me a couple of years later and says, oh, I have these nails again, is it back? And I ask, have you been using the antifungal to your feet? And they say no. And so it is really only those patients who I think get recurrences.

Gina: And in terms of adherence, we mentioned it quite a few times. Some of these treatments are very long term, especially topical treatments. Is there any new advice on how to help patients keep to their regime and keep going?

Dr Shari Lipner: I think in general, the on-label indication is a year. Definitely for older patients and more severe cases, it could be a year and a half.

Yes, it is a lot to go through. I think compliance is an issue. I think telling them, here is your bottle and here are twelve refills, here you go, that is not the way to do it.

So for people with toenail onychomycosis, I will generally meet them on a televisit every three to four months. I think that really helps keep them honest. It helps them compare pictures to the previous ones and say, oh, there is actually some improvement here—and that will urge them to go on with it.

Also, being reasonable with the patient. So if someone has an event, a wedding or something, and they want to use nail polish and they are using topicals, I do not think you should be a barbarian about it. I say, OK, you have an event, it is fine. Leave the nail polish on for three to four days, take it off, and then you can restart.

There is also a small study looking at using gel nail polish along with treatment, and there was good efficacy in terms of mycological cure with gel nail polish. It is a small study, so I am a little hesitant to completely recommend that, but it may be something that people can do along with gel nail polish.

Gina: Are there apps out there to remind patients to actually do it? I’d find that really helpful.

Dr Shari Lipner: Oh, yes. Certainly for off-label fluconazole, for that drug, I usually prescribe one hundred and fifty milligrams weekly until the nail grows out, and we recommend they set a phone reminder so that they remember to take it. Because it is actually easier to remember to apply your topical every day or take your terbinafine every day. But when you have to do something once a week, it is very, very hard.

Gina: I bet. So looking ahead then, how do you feel clinical practice is changing in terms of strategies? Well, you mentioned it is kind of shifting to a more personalised approach.

Dr Shari Lipner: I think we have learned more about onychomycosis. I think it has to be a personalised approach. I think confirmation is super important.

I am excited to see what AI can do for us, not just in terms of making the diagnosis, because I do not think we are quite there yet, but I think AI would have a good place in calculating the severity of disease for us. So if it could calculate something like an onychomycosis severity index, I think that would really help people in terms of deciding the right treatments.

Gina: Indeed.

I thought we would end by giving some key takeaways. For clinicians listening, what are your key takeaways about the management of this condition?

Dr Shari Lipner: Yes. So, first of all, I think physicians should realise that nails are very important to patients. It is not just the sidebar. I see patients sometimes just for their onychomycosis for the visit, not skin check, hair, and nails,just nails. I focus on the nail. So I think it is important to them, and we need to realise that, and it could really affect quality of life.

I think I am a stickler for confirming a diagnosis. You have a lot of different tests at your disposal to do that. And then you need to take an individualised approach to treating onychomycosis. If there is a high severity of disease and a lot of nails are affected, I think these patients really need to have oral treatment if there are no contraindications.

For more mild to moderate disease, I think topicals or orals are possible, and then a frank conversation about prevention of recurrences can really go a long way.

Gina: And for the patients, what would you want them to know about what is new in nail fungus treatment, and why it matters to seek help and care?

Dr Shari Lipner: I think what is important for patients to know is that they really need to see someone who is an expert in seeing nails, and that the diagnosis should be confirmed.

From all my years of practice and seeing so many nail patients, I think patients are the most frustrated when they have seen multiple doctors and they have got the wrong treatments.

So I would say to patients, make sure someone is confirming that diagnosis before giving you an antifungal.

Gina: Perfect. Well, that is it for today. A big thank you to you, Shari, for joining us. It has been really insightful to hear all you have to tell us about this very neglected condition. And, as always, a pleasure to meet you again.