What's the fuss about fungus?
Dermatologist nail experts discuss the diagnosis and management of onychomycosis as well as increasing resistance to anti-fungal therapies.
By Allison Evans, Assistant Managing Editor, January 1, 2024
Onychomycosis (tinea unguium) represents the highest proportion of nail disorders seen in clinical practice. With long and often unappealing therapeutic options, fully treating this condition can be a struggle for both physicians and patients. Left untreated, onychomycosis may result in secondary infection and pain and negatively impact patients’ quality of life.
Onychomycosis is a fungal infection of the nails that causes discoloration, thickening, and separation of the nail from the nail bed. It is caused by a variety of organisms, but most cases are caused by dermatophytes, most commonly Trichophyton rubrum.
There are some well-known risk factors for onychomycosis, said Shari Lipner, MD, PhD, FAAD, associate professor of Clinical Dermatology, associate attending physician, and director of the Nail Division at the New York-Presbyterian Hospital/Weill Cornell Medical Center. “Having tinea pedis is a significant risk factor for having onychomycosis, and so is hyperhidrosis and having contacts in the household who have onychomycosis or tinea pedis.” Other common underlying conditions include trauma to the nail, diabetes, older age, immunosuppression, and psoriasis.
“The primary precipitating factor for getting onychomycosis is having athlete’s foot,” agreed Boni Elewski, MD, FAAD, James Elder professor and chair of Dermatology at the University of Alabama. “You may not even know you have athlete’s foot because it can be asymptomatic. Often, you just have dry feet. Sometimes the only clinical finding is dryness or very subtle dryness.”
Children rarely get onychomycosis. “If I see a child with onychomycosis, you can probably bet money that one of the parents has it because it’s pretty uncommon in kids,” Dr. Lipner remarked. “It is important that if dermatologists see onychomycosis in a child, to bring in parents and siblings to make sure they are being treated as well.” The risk of transmission to other family members when one member is affected is about 44% to 47%.
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Key takeaways from this article:
Onychomycosis is caused by a variety of organisms, but most cases are caused by dermatophytes, most commonly Trichophyton rubrum.
Despite the numerous risk factors, about half of patients who present with an abnormal nail will not have onychomycosis.
There are a lot of mimickers of onychomycosis, so never treat empirically. Always perform diagnostic testing, including KOH and microscopy, PAS stain, and/or fungal culture, and the underutilized but effective PCR test.
Not all testing methods are equal. Performing a histopathology exam with PCR provides the most optimal diagnostic efficacy as the former indicates the presence of a fungal invasion in the nail plate and the latter identifies the pathogen thereby enabling targeted therapies.
Terbinafine resistance could become a major health care burden. Physicians should consider testing for T. indotineae and/or resistance mutations when a patient presents with extensive and/or recalcitrant dermatomycosis including onychomycosis.
Despite the numerous risk factors, according to Dr. Elewski, many patients who present with an abnormal nail will not have onychomycosis. “Half of abnormal nails are caused by fungus, but the other half aren’t,” she warned. “The most important part of approaching a patient with onychomycosis is making the correct diagnosis. If you assume that all abnormal nails are caused by a fungus, then you’re going to be wrong half of the time.”
The clinical signs of onychomycosis include thickening of the nail plate, separation of the nail plate from the nail bed, and discoloration of the nail plate, said Aditya K. Gupta, MD, PhD, MBA/HCM, MA, FECMM, FAAD, FRCPC, professor in the department of Medicine at the University of Toronto. “In severe cases, complete destruction of the nail plate can occur with further spread to surrounding digits. These characteristics can often be confused with those of non-fungal nail disorders such as nail psoriasis, lichen planus, nail trauma, and subungual melanoma.”
“The most important part of approaching a patient with onychomycosis is making the correct diagnosis. If you assume that all abnormal nails are caused by a fungus, then you’re going to be wrong half of the time.”
There are a lot of mimickers of onychomycosis, Dr. Lipner said. “Podiatric issues and chronic trauma to the toenails can cause dystrophic nails. Retronychia, which is a disorder of nail growth and malalignment, is also in the differential diagnosis of onychomycosis. Several patients per week with retronychia are referred to my nail specialty clinic. Often, they have been treated for years with both topical and oral antifungals, but they never had fungus to begin with.” Many nail conditions look similar to onychomycosis; however, these mimickers are treated very differently.
If a patient presents solely with fingernail onychomycosis, this is another reason to be suspicious of an onychomycosis diagnosis. Fingernail onychomycosis is not common. “Patients generally do not have fingernail onychomycosis unless they also have toenail onychomycosis,” Dr. Lipner said.
“Psoriasis can look like onychomycosis,” Dr. Elewski said. “And if you have abnormal fingernails, I think you have to first ask yourself whether it could be psoriasis because 5% of people with psoriasis have it only in their nails and may have no other cutaneous manifestation.”
Who’s diagnosing onychomycosis?
According to a research letter published in JAAD, most patients were initially diagnosed by podiatrists (51.2%), followed by general practitioners (23.3%) and dermatologists (13.1%). Across specialties, confirmatory laboratory testing was infrequent (15.3%); 12.0% of patients received a histopathology test, 2.8% a fungal culture, 2.1% direct microscopy, and 2.1% fungal polymerase chain reaction; 0.5% received antifungal susceptibility testing.
Patients seen by dermatologists more frequently received confirmatory testing (31.0%) than those seen by podiatrists (16.9%) or general practitioners (5.2%). Overall, of the 18,128 patients prescribed an oral antifungal drug (most frequently terbinafine [88.2%]), 9.7% received confirmatory diagnostic testing.
There are no official guidelines on confirmatory testing, noted Dr. Gupta. “The choice of test will often depend on the turnaround time, indication of fungal viability, ability to identify genus/species as well as accessibility and cost.”
“Clinical examination may look consistent with onychomycosis,” said Dr. Lipner, “but I never treat empirically because even I, someone who sees nails all day long, can be wrong once in a while.” The most common presentation of onychomycosis is yellowing, onycholysis, and subungual hyperkeratosis. Usually, these patients have had the condition for a long time before they see a dermatologist, so waiting days or weeks for a diagnosis is not going to change their prognosis at all. “It is definitely worth the wait to use confirmatory testing to make the correct diagnosis,” she added.
For Dr. Lipner, diagnosis is critical. “Treating empirically is really a disservice to the patient. Treating for any nail disease is a long process because the nail grows so slowly, so if you are on the wrong track, the patient is definitely not going to get better — and may even get worse.”
In one study, it was found that one quarter of general practitioners misdiagnosed onychomycosis evidenced by negative KOH, PCR, and fungal culture (doi: 10.3399/BJGPO.2022.0186), Dr. Gupta noted. “In everyday practice, accurately diagnosing onychomycosis often requires laboratory diagnosis in addition to a clinical suspicion for onychomycosis,” he added.
Confirming the diagnosis of onychomycosis with laboratory testing is important for ensuring appropriate therapy and avoiding unnecessary antifungal exposure. “If empirical treatment is provided for clinically suspected onychomycosis in dystrophic nails, correct treatment is delivered only half the time,” Dr. Lipner said. “In the era of antifungal-resistant dermatophytosis, a renewed, cross-specialty emphasis on guideline-based onychomycosis treatment is needed, emphasizing antifungal stewardship to preserve available treatment options.”
Currently available diagnostic techniques include a mix of visual identification methods that increase the visibility of nail dystrophy and/or fungal structures (e.g., hyphae/yeast) and organism identification methods that provide the genus/specifies of infecting fungi. Diagnostic methods include KOH with microscopy, PAS staining, fungal culture, and molecular techniques including PCR and MALDI-TOF mass spectrometry, Dr. Gupta said.
KOH microscopy and histopathology
“As dermatologists, we have a good number of options to diagnose onychomycosis. The quickest and cheapest way is to do a scraping of the debris under the nail, put it on a glass slide, stain with KOH, and do microscopy,” Dr. Lipner said. “The issue with this technique is that to do the test legally, a lab that is CLIA certified is required, which not everyone has. Additionally, the reliability of the test is dependent on how much training a dermatologist has had and how often it is done.”
Another easy way to test is to take a clipping, Dr. Lipner said. “That is actually easier than taking a scraping from under the nail. But you want to make sure that you are not clipping an area of the nail plate that is too distal. You want to clip as proximal as you can so that it is painless for the patient. Then you send the clipping for histopathology and the dermatopathologist will stain with either PAS or GMS, which is a very sensitive test for diagnosing onychomycosis.”
Histopathology is reportedly the most sensitive of the conventional onychomycosis diagnostic methods; however, as with KOH, it does not provide the identity or viability of the organism. Submission of a nail plate alone may not detect nail bed infection. “With both KOH with microscopy and with histopathology, you cannot identify the species, so you do not know for sure if it’s T. rubrum. For the average onychomycosis patient, it does not really matter. Most of these cases are T. rubrum and management is not going to really change,” Dr. Lipner remarked.
“For many years, the gold standard was considered fungal culture for which you gather subungual debris. But it has to be pretty abundant to grow a fungal culture, and it is time consuming to scrape under the nail carefully and not hurt the patient,” Dr. Lipner said. “Laboratories also vary vastly in their ability to culture out these organisms. For some of them, it may be negative every or almost every single time, and other labs have a higher positivity rate. But even the good laboratories do not have a culture rate of 100%.”
“Even though KOH and culture have lower costs, KOH testing cannot confirm that the fungal agent is viable or identify the genus/species for targeted treatment (e.g., terbinafine for dermatophytes vs. azoles for non-dermatophyte molds or yeasts),” Dr. Gupta said. Additionally, culture is associated with a low sensitivity with two to four weeks of turnaround time that can delay treatment.
There is another technique that dermatologists have not really incorporated into their practice, although Dr. Lipner recommends that they should — PCR. “You need much less material to get the diagnosis and the turnaround time is 24 to 48 hours. It is very, very sensitive for detecting the presence of fungus and the species. I recommend that dermatologists consider utilizing this test because the sensitivity is much higher than it is for a fungal culture. PCR is three to four times less likely to yield a false-negative result compared with a fungal culture.”
“For the optimal diagnostic efficacy, it is recommended to conduct a combined histopathology examination with PCR,” Dr. Gupta added.
However, its drawback lies in its false-positive rate attributed to environmental contaminants, lack of standardization in design (e.g., primer selection), and cost of the test, Dr. Gupta noted. “Hence, a histopathology examination (PAS/GMS staining), which provides direct evidence of a fungal invasion in the nail plate, is recommended to rule out false-positive results especially if non-dermatophyte molds or yeasts are suspected.”
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Dermatophytoses of the fingernails and toenails are particularly difficult to eradicate with drug treatment because of factors intrinsic to the nail — the hard, protective nail plate, sequestration of pathogens between the nail bed and plate, and slow growth of the nail — as well as the relatively poor efficacy of the early pharmacologic agents, said Dr. Elewski. However, onychomycosis is not self-healing and may become the source of more widespread disease.
“When I was a dermatology resident,” Dr. Elewski said, “there was nothing really to treat patients with. There was griseofulvin, which didn’t work that well. In the nineties, new drugs came out for onychomycosis: terbinafine and itraconazole were both approved for onychomycosis. Fluconazole was approved in other countries and was studied in the U.S. but never got the indication here, although it’s used off-label, especially in resistant cases.”
In general, oral medications for onychomycosis are given for three months for toenails. Topical treatments require a year of daily application, so the time of treatment is very different, Dr. Lipner noted. “But there’s no getting around the growth rate of the nail itself. Even though you could use an oral antifungal and treat for three months, it is still going to take a toenail a year or even longer to grow out completely. Whether you prescribe a topical or oral medication, even though the time of treatment is different, the time it will take for the nail to appear normal will be exactly the same.”
“Orals tend to be more effective treatments and there may be compliance issues with topicals since patients have to apply it for a year, which is a big commitment even for a type A personality patient,” Dr. Lipner said.
“It is important to consult patients regarding the long treatment duration that’s often required for onychomycosis, and especially toenail onychomycosis due to slower nail growth,” Dr. Gupta said. “Maintenance therapies (e.g., topical efinaconazole) may be needed for two to three years, or longer, especially for at-risk patients such as those with diabetes, peripheral vascular disease, or nail trauma.”
“Physicians tend to prefer terbinafine over itraconazole because itraconazole has drug-drug interactions, and you can’t give it with certain drugs, like statins,” Dr. Elewski said. “Also, it was discovered that it can have a negative inotropic effect on the heart and can cause some people to go into heart failure.”
Cost also comes into play, Dr. Elewski noted. “With insurance, itraconazole may cost a considerable amount per month.” It generally requires prior authorizations.
While having these approved drugs did change the treatment landscape, the cure rates are not that exciting, said Dr. Elewski. As per the rigorous criteria set by the FDA for cure rates, terbinafine has a cure rate of 38% while itraconazole is only 14%, although clinical improvement rates are significantly higher.
“I liken the FDA standards to if a dermatologist prescribed isotretinoin and said that your acne is only cured if you say your skin is perfectly smooth when the treatment’s done. But you’re going to have scars,” Dr. Elewski said. “If the nail doesn’t look normal, which takes quite some time after infection, the FDA doesn’t consider it cured.”
Prior to 2014, there was only one FDA-approved topical medicine, which was ciclopirox lacquer. In 2014, two more topicals were approved — tavaborole and efinaconazole — although topicals are typically only effective for milder disease or used in combination treatment, Dr. Elewski said.
Recurrence can arise one year or more after the infection has been eradicated and is commonplace, possibly affecting more than half of the patients who have been treated successfully. A relapse or reinfection rate of 20-25% has been quoted in the literature following initial successful therapy, with recurrence rates varying from 6.5% to 53% (doi: 10.1159/000448056).
To manage disease recurrence, considerations can be given to combination therapies (oral and topical) such as oral terbinafine or itraconazole with topical efinaconazole, Dr. Gupta said. “If the patient is unresponsive to oral terbinafine, a second prolonged course (>12 weeks) or a dosage increase (250 to 500 mg/day) can be considered; however, antifungal susceptibility testing and resistance testing by PCR may be required. If terbinafine resistance is suspected, then treatment switching to azoles is advisable.”
Resistance to antifungal therapy
“Over the past 10 years or so, we have been encountering T. rubrum terbinafine-resistant strains,” Dr. Lipner said. “This is definitely something to be worried about because if we lose terbinafine, we do not have many remaining treatment choices.”
“Terbinafine works by interfering with an enzyme in the fungus called squalene epoxidase, and fungi have evolved or mutated to have defects in this enzyme, so the fungus gets around it. You can give terbinafine, and nothing happens,” said Dr. Elewski, “and I think it’s more common than we probably think.”
She sees cases like this every week. Dr. Elewski sends cultures out for fungal susceptibility testing that show in vitro that T. rubrum is resistant to terbinafine. This is a problem, not only in the U.S., but worldwide. “The good news is that itraconazole and fluconazole probably work, but we don’t know for how long. And, of course, there are the potential drug interactions and cardiotoxicity with itraconazole,” she said.
Dr. Elewski typically uses itraconazole for terbinafine-resistant cases. “You can do 200 mg/day for three months minimum, but for resistant cases you’re probably going to need six months. Or you can pulse it, which is 400 mg/day every day for one week, one week a month for five or six consecutive months.”
“It’s no longer treat for three months. I treat aggressively until the patient is cured and the nail is as normal as it can be. While labels indicate treatment for three months, some of the nails improve while others do not. The ones that don’t probably were already resistant or became resistant, which increasingly has spread across the globe,” Dr. Elewski said.
The other option is to go to topical treatment, like efinaconazole and tavaborole, Dr. Elewski added. “But their cure rates are not very good; they’re better for milder disease.”
Dr. Elewski urges dermatologists to practice antifungal stewardship. For years, many physicians have looked at an abnormal nail and decided it’s fungus. “We give people a drug when they don’t need it because it’s not a fungus. Remember that 50% of abnormal toenails don’t have fungus.”
“We need to be sure that we don’t rely on our eye and we should test before we prescribe. We’re all concerned about resistance, and it’s, in part, because of the overuse of these medications,” Dr. Elewski emphasized.
During the past decade, an epidemic of severe, antifungal-resistant tinea has emerged in South Asia because of the rapid spread of Trichophyton indotineae, a novel dermatophyte species, explained Dr. Gupta. “The U.S. CDC has reported two initial cases between 2021 to 2023 in New York, both cases were unresponsive to oral terbinafine, and one case was suspected to be the result of local transmissions (doi: 10.15585/mmwr.mm7219a4).” T. indotineae infections are highly transmissible and characterized by widespread, inflamed, pruritic plaques on the body (tinea corporis), the crural fold, pubic region, and adjacent thigh (tinea cruris), or the face (tinea faciei).
A recent randomized trial of 60 dermatophytosis patients from India showed that 250 mg/d oral terbinafine treatment for four weeks led to a suboptimal mycological cure rate of 25.9%, Dr. Gupta said. “No significant improvements were observed when the dose was increased to 500 mg/d” (doi: 10.25259/IJDVL_74_2022). The outbreak strain — later identified as T. indotineae — requires molecular identification (e.g., PCR, DNA sequencing) as it is almost morphologically indistinguishable from the T. mentagrophyte/interdigitale complex.”
“Treatment switch to itraconazole appears to be an effective option, with regimens reported thus far including 200 mg/day for 12-16 weeks or longer, or pulse itraconazole therapy for three pulses or longer. Combining two agents with different modes of action such as oral itraconazole with topical efinaconazole or topical ciclopirox may improve the likelihood of treatment response,” Dr. Gupta said.
Treatments under investigation
There are some azoles either under development or in trials for toenail onychomycosis showing very good efficacy, Dr. Lipner said. There’s posaconazole, albaconazole, and fosravuconazole, which is a prodrug of ravuconazole.
“Newer triazoles (e.g., posaconazole, voriconazole) have been used off-label for treating recalcitrant onychomycosis patients,” Dr. Gupta added. “However, laboratory monitoring should be performed per clinical indication. In case reports, oral voriconazole 200 mg/day and topical voriconazole 1% cream has been tried successfully in patients unresponsive to terbinafine and itraconazole,” he continued.
While some studies have looked at laser therapy as a potential option, the FDA has completely different criteria for device approval versus a drug. “For drugs, the FDA requires mycologic and complete cure, and for lasers, they only ask for temporary cosmetic improvement in the nail,” said Dr. Lipner. “Device companies do not need to show that it actually eradicated the fungus. There are studies that show that the nail looks better afterwards, but they are very small studies that were not well controlled. The other issue is that the laser is very painful.”
Topical terbinafine is also being studied for the treatment of onychomycosis. While there was a study showing good efficacy, the problem with the topical solution is that it turned the nail opaque, Dr. Lipner said. “Even though the mycological cure rates were sky high, because the nail did not look normal, the complete cure rates were low. There are ongoing trials dosing the terbinafine solution differently to attempt to improve the complete cure rate.”
What do you need to know about emerging, antifungal medication-resistant dermatophyte infections?
Physician Editor Kathryn Schwarzenberger, MD, FAAD, talks with Avrom S. Caplan, MD, FAAD, about his JAMA Dermatology paper, ‘Trichophyton mentagrophytes Internal Transcribed Spacer Genotype VIII.’ Read more.