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Fungal Nail Infections: Optimizing Diagnosis and Treatment

The Need for Accurate Diagnosis and Treatment of Onychomycosis

Roughly 50% of nail conditions result from a fungal infection. “Onychomycosis is far more than merely a cosmetic problem,” noted Phoebe Rich, MD, Associate Professor of Dermatology, Oregon Health Sciences University in Portland. “Depending on the series, between 2% and 18% of the population have toenail infections and the incidence is increasing. It can seriously affect the patient’s quality of life.”

This is also a chronic disease. The mean duration is greater than 10 years and it seldom remits spontaneously. The average person has involvement in five different nails (Elewski B. Int J Dermatol. 1997;36:754).

Lynn Drake and others found that nail infections can interfere with lifestyles and occupational endeavors. In their study, 50% of patients indicated levels of physical pain from toenail fungus. It can also create psychological stressors and compromise other aspects of a person’s life (Drake LA, et al. J Am Acad Dermatol. 1998;38:702). (Table 1)

More than 90% of infections are caused by a dermatophyte, a fungus that can live on the skin, hair, and nails. Other possible strains include yeast and Aspergillus. In other cases, it can be a fungal infection of the skin, such as ringworm, that isn’t an infection of the toenail itself (Elewski B, Hay RJ. Clin Infect Dis. 1996;23:305; Elewski B. Int J Dermatol. 1997;36:754).

Aging seems to be a factor in susceptibility for this infection as the incidence increases to perhaps as many as half the population over 70 years old. The incidence in toenails is roughly four times that of fingernails (Drake LA , et al. J Am Acad Dermatol. 1998;38:702).

Another concern is that it can be a portal for bacterial infections, leading to more serious problems such as cellulitis and gangrene. In one study, patients with fungal infections in their nails were 2.4 times more likely to develop cellulitis. Those with interdigital tinea pedis have a 3.2 fold increase in risk for cellulitis, probably related to bacteria entering the skin through cracks and crevices (Roujeau JC. Poster at 20th World Congress of Dermatology. 2002 Paris, France).

There is an especially high risk in patients with diabetes, the elderly, or those with compromised immune response. A study by Medstat showed a 4.7% risk of gangrene in diabetics with onychomycosis compared to 1% risk in those without diabetes (data from Medstat, 1995).

So, why are doctors hesitant to treat people with toenail infections? Some point to the expense of the medications.

However, Dr. Rich noted that 7% of hospital admissions are due to infections around the nails and there is a high mortality rate following lower extremity amputation in diabetics as counterbalancing economic statistics. If that was not enough incentive to treat, there are 50,000 lower extremity amputations in the U.S. every year at a direct cost of $600 million (Centers for Disease Control and Prevention. (1994). Diabetes in the United States: A strategy for prevention. Atlanta: US DHHS).

“One reason to aggressively treat onychomycosis is because we can,” said Dr. Rich. “We have excellent medications and it is not something people ‘just have to live with’.”

There are four clinical patterns seen in onychomycosis. Distal subungual onychomycosis (DSO) starts distally and moves proximally. This is thought to be the most common, and about 90% of infections fall into this category. DSO needs an oral medication for best treatment.

White superficial onychomycosis (WSO) leaves the nail more papery with chalky residue on the nail. It can be confused with keratin granulations that are often seen in people who wear nail polish. One way to differentiate between the two is that with keratin granulations, the residue generally follows where the nail polish was applied.

“This is not a fungal infection, but it looks like it,” said Dr. Rich. “This is why anything suspect should be worked up using potassium hydroxide (KOH). The differences can be readily seen in minutes under the microscope.”

A less common pattern is proximal subungual onychomycosis (PSO). In this instance, the fungus appears to get underneath the cuticle and grows proximal to distal. It is a deep infection that requires an oral medication.

The fourth kind is Candida onychomycosis, which occurs in a condition known as chronic mucocutaneous onychomycosis. These patients have an immune defect that allows the Candida to grow into their nail. Candida can also infect the nail unit secondarily in onycholysis. This is a multifactoral problem caused by trauma and exacerbated by contact irritants and excessive water exposure.

Candida can also infect the nail folds as in chronic paronychia. Bacteria, such as Staphylococci or Pseudomonas, as well as viral agents can cause acute paronychia. Cultures will be needed to establish the infective agent and the proper medication treatment.

“If half of the nail problems we see are onychomycosis, that means that half are not fungal,” said Dr. Rich. “The latter is the part we have to worry about since we don’t want to treat non-fungal nail problems with a systemic antifungal drug.”

Psoriasis of the nail can appear to be clinically similar to onychomycosis with discoloration, pitting, onycholysis, and subungual hyperkeratosis. Lichen planus of the nails may also, at first glance, look like a fungal infection. However, the differential can be made based on the ridges in the nail called onychorrhexis. The ridges are a typical feature of lichen planus in the nail.

Another condition that should be considered, although it is not common, is Darier’s disease. One of the diagnostic clues is red and white bands on the nail.
Reiter’s disease can easily be mistaken for toenail fungus because of the periungual scaling and hyperkeratosis, as well as a keratoderma blennorrhagica on the bottom of the foot.

“There are a number of systemic conditions that can also cause nail problems,” noted Dr. Rich. “While they can not confirm a diagnosis, they certainly provide clues that should increase your index of suspicion of an internal medical condition.”

Nails where the proximal half is white and distal half is brown is a characteristic of renal disease. Leukonychia, or white nails, are seen in patients with cardiovascular concerns and many other diseases. Small, white punctate leukonychias are due to trauma. Clubbing is often related to respiratory concerns.

Certain medications such as isotretinoin can result in painful paronychia. Koilonychia, or spoon nail, is usually associated with iron deficiency.

Pigmentation in the nails has many causes but should be considered for biopsy if a pigmented neoplasm is suspected. Other causes of pigmented bands in the nails including vitamin B12 deficiency, chemotherapy, or trauma should be considered. Longitudinal pigmentation can be seen as a normal finding in darkly pigmented individuals.

Acute bacterial infections, especially Staph, are another cause of paronychia. The nail folds are usually red, hot, and very painful and may become abscessed under the nail. After culturing the paronychia to confirm the organism, an oral antibiotic is used to treat the infection.

When fungal infection is in the differential, Dr. Rich suggests KOH testing of nail subungual debris for the presence of hyphal elements for most nails. A KOH prep confirms the presence or absence of fungus. When the identity of the specific species of fungus is desired, a culture of the nail debris is performed. Another method for diagnosing onychomycosis is clip the nail plate, drop it into formalin, and request the laboratory complete a Periodic Acid Schiff (PAS) stain. The results are usually available within a few days instead of the few weeks needed to culture.

“We treat onychomycosis because it is an infection that is eminently treatable,” said Dr. Rich. “Since oral antifungals have excellent safety profiles, there is no reason not to treat.”

In-Depth Analysis of Treatment Options

There are a number of methods to treat fungal infections of the toenail. Surgery is an option, but return is a problem unless the nail is killed. Urea preparations only soften the nail, although this can make treatments with other agents easier. Topical agents do not work well with deep-seated infections.

Oral agents also are available. Fluconazole is not approved for use in onychomycosis and has not proved to be very effective. Itraconazole is very useful for dermatophyte infection and had been approved for this indication. Terbinafine is also labelled for onychomycosis. Terbinafine should be used 12-16 weeks straight through at a dosage of 250 mg a day. Itraconazole also should not be pulsed. (Table 1)

“As far as getting into the nail plate, it is about the same for itraconazole versus terbinafine,” said Joseph Monroe, PA-C, MPAS, Dermatology and Derm-atology Surgery Specialist, The Springer Clinic, Tulsa, OK. “ Terbinafine gets into the nail faster. Itraconazole has a minor advantage with in vivo activity against Candida and some molds.”

A major disadvantage to using itraconazole is that it can react adversely with over 70 different drugs, largely related to cytochrome P-450 interactions. Mr. Monroe always suggests that the patient make sure they go to their regular pharmacy so that the computer and pharmacist can double check all of the other medications the person is taking. In addition, itraconazole is about half as effective as terbinafine against dermatophytes.

“Terbinafine has seven sites in the CYP450 isoenzyme pathway versus two for itraconazole,” he said. “This makes it much safer and with fewer drug interaction concerns.”

Hall and others undertook a surveillance study of 25,884 patients using a wide variety of concomitant medications including oral hypogly-cemic agents, antihypertension medications, and cho- lesterol lowering drugs. No clinically relevant drug interactions were seen (Hall M, et al. Arch Dermatol.1997;133: 1213). (Table 2)

Recent studies have confirmed that isolates of dermatophyte in the fingernail is quite rare. One exception is two-foot-one-hand disease. Some patients have a marked susceptibility to dermatophytes that results in the nails of both feet and one hand becoming infected. According to Mr. Monroe, treatment is usually 250 mg a day of terbinafine for six weeks. Studies show a success rate of 59%, although none have looked at the relapse rates (Package insert terbinafine).

“Generally terbinafine is a safe drug,” said Mr. Monroe. “Most experts get baseline blood labs, but not many routinely request follow-on labs. Although hepatotoxicity is possible, acetaminophen is twice as likely to elevate liver enzymes.”

The over-the-counter topical antifungal medications are not indicated for onychomycosis. Ciclopirox 8% nail lacquer can be used in patients who refuse to take a pill, although the cure rate is only 36% at best (Package insert ciclopirox).

There are head-to-head studies between continuous terbinafine versus intermittent itraconazole. The Icelandic extension of the Lamisil versus Itraconazole in Onychomycosis (LION) study was conducted to examine long-term efficacy and relapse rates following continuous terbinafine versus intermittent itraconazole. The subjects of this study were Icelandic patients who had participated in the LION study. This patient population was selected for long-term observation in part because of the geographical remoteness of Iceland, which makes it easier to follow patients for long periods of time.

When talking about optimal outcome (defined as being unable to find the organism or evidence of infection), terbinafine showed a 42% success rate over 49 to 54 months, much higher than the 18% rate seen in the next best drug, itraconazole (p < 0.0024). The study also showed a higher relapse rate for recurrences with itraconazole.

Subsequent terbinafine treatment resulted in clinical cure in 76% (19/25) of patients who failed their original treatment with terbinafine and subsequent terbinafine treatment resulted in clinical cure in 77% (36/47) of patients who failed their original treatment with itraconazole. Patients who fail their initial antifungal therapy are a difficult-to-treat group. The higher cure rates after a second course of therapy suggest that an individualized approach may be highly effective in patients with resistant disease (Sigurgeirsson B, et al. Arch Dermatol. 2002;138:353). (Figure 1)

Relapse is a problem in this population for a number of reasons that should be taken into account. Patient compliance is always a big concern. Environmental considerations such as a person’s need to wear boots at work are contributors. There also may be variations in a patient’s susceptibility that impact on the return of the infection.

Re-exposure is a large contributor. Many times the organism can be recovered from their bed, shoes, socks, carpets, and other areas around their home and work. As Mr. Monroe noted, “Unless you put them in the Witness Protection Program or burn all their stuff, they will get re-exposed.”

“The key takeaway is that correct diagnosis is critical,” said Mr. Monroe. “Multiple treatment options exist, but you have to match the correct option with the correct disease.”




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