Fungal nail infections, i.e., onychomycosis, can originate from yeasts, dermatophytes, and nondermatophyte molds (NDMs), in contrast to tinea unguium, which refers to fungal nail infections exclusively caused by dermatophytes¹. NDMs account for 3~25% of all onychomycosis cases^2-4. Conversely, Aspergillus spp. account for 7.7~100% of all NDM-caused onychomycosis cases and 0.5~3% of all onychomycosis cases. In the last two decades, the incidence of onychomycosis due to Aspergillus infection has been increasing, especially in Asia^3,4. Aspergillus spp. are saprophytic fungi found in soil, decaying plants, household and hospital dust, and fruit, vegetable, and grain surfaces^4-6. Fungi, including Aspergillus, are zoonotic infectious agents naturally transmitted between animals and humans and can cause various infections in humans and animals, such as dogs and cats^6,7.

The clinical manifestations of onychomycosis due to Aspergillus spp. are nonspecific and can mimic onychomycosis caused by dermatophytes; however, distolateral subungual onychomycosis is the most common form of Aspergillus spp. infection of nails^3,4. Pulse therapy with oral itraconazole and terbinafine exhibits good efficacy against onychomycosis caused by NDMs^3,8.

A 25-year-old woman was referred to our clinic with a 2-month history of white spots on fingernails and toenails. She indicated that white patches and brittle nails in the absence of pain and itching appeared on right little finger, with the same symptoms developing in left ring finger and right middle toe one week later. The patient denied trauma preceding the symptoms. For this complaint, the patient clipped her nails and did not take any medication. However, she did not observe improvement and the regrown nails were brittle with white patches.

The patient was a veterinarian who frequently interacted with dogs and cats. The patient suffered finger swelling three years ago and developed brown blotchy spots on her face accompanied by swelling of the nose, ears, and face. The patient was treated for rheumatoid arthritis (RA) with long-term systemic corticosteroids without improvement. She was referred to the leprosy division of an outpatient dermato-venereology clinic, where she was diagnosed with lepromatous leprosy with type 2 reaction. She was administered leprosy drugs and prednisone, which led to improvement. However, one month later, the patient was referred to the mycology division with white spots on nails.

The dermatologic examination revealed subungual white spots on the distal edge of the nail plate as well as nail dystrophy in the fifth finger of right hand and the fourth finger of left hand. Additionally, a white spot on the surface nail plate was observed on the third nail of right foot (Fig. 1). Potassium hydroxide (KOH) examination of the fingernails and toenails revealed hyphae. The first nail culture showed growth of two types of fungal colonies representing the A. niger and A. flavus complexes. The repeated second nail culture showed the growth of only A. flavus (Fig. 2).

Figure 1. Dermatologic status of the patient at the initial visit; Clinical appearance of the fingernails (A) and the toenails (B)

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Figure 2. Nail culture results (A) Results of the first (left) and second (right) nail cultures (B) Microscopically, the black colony exhibits the characteristic appear- ance of A. niger (potassium hydroxide preparation, ×400). (C) Microscopically, the yellow-green colonies exhibit the characteristics of A. flavus (potassium hydroxide preparation, ×400).

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The patient was diagnosed with distolateral subungual and superficial white onychomycosis and treated with four cycles of itraconazole at 400 mg/day for one week, with 3-week breaks between cycles. KOH examination of the toenails performed after the fourth itraconazole cycle still showed hyphae, and the A. flavus colonies were growing in the nail culture, whereas the KOH examination and the culture of fingernail were negative. Clinically, the third nail of right foot and the fourth nail of left hand appeared to be returning to normal (Fig. 3A, C). The fifth nail of right hand exhibited clinical improvement but did not completely revert to normal. Itraconazole therapy was discontinued. Reevaluation two months later revealed negative findings with KOH examination and toenail culture, whereas the nail on the fifth finger of the right hand was not clinically reverting to normal (Fig. 3B).

Figure 3. Clinical progression of the patient before and after the fourth cycle of itraconazole pulse therapy (A) Fourth fingernail of left hand, (B) Fifth fingernail of right hand, (C) Third toenail of right foot

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Aspergillus spp. are typically considered as contaminants in onychomycosis, although they can also be causative organ- isms^3,4. Aspergillus spp. as a cause is considered if the case fulfills three of the following criteria: (i) KOH examination showing fungal elements, (ii) nail biopsy showing fungal elements; (iii) culture showing NDM growth, (iv) repeated cultures showing the same NDM growth without dermato- phytes; (v) culture growth of the same fungus found in 5 or more than 20 inoculums, and (vi) molecular examination showing NDMs^2-4.

In the present case, KOH examination revealed hyphae on both fingernails and toenails and two types of fungal colonies grew in the first nail culture. One of the colonies had a silky greenish-yellow surface, yellow dots, white margins, and a yellowish back. Long conidiophores with rough surfaces and biseriate phialides were observed under the microscope, indicating the presence of the A. flavus complex. The second colony had a black surface and cream back; microscopic examination revealed long, smooth conidiophores, indicating the A. niger complex^8,10. Unfortunately, the second nail culture only showed colony growth matching the A. flavus com- plex, without dermatophyte growth. Therefore, the present case met three of the six criteria for NDMs as the causative organism (A. flavus), whereas the A. niger complex could be considered a contaminant.

Many factors are associated with the development of onychomycosis due to NDMs, including hot and humid climates, older age, use of closed shoes, hyperhidrosis, nail trauma, chronic skin disease, immunosuppression, occupa- tional exposure, poor hygiene, barefoot walking, diabetes mellitus, use of communal locker rooms, and paronychia1,3,4. Onychomycosis is observed in 20~30% of patients with leprosy. Nails in patients with leprosy are prone to change and develop onychomycosis compared with the general population, mainly due to unrecognized nail trauma, which often occurs due to peripheral nerve disorder that increases the risk of NDM infection¹¹. Leprosy reaction is defined as an acute or chronic inflammatory episode that is immunologically mediated in patients with leprosy, and corticosteroids are the main therapeutic option for leprosy reactions^12,13. Leprosy-related acute arthritis often results from a leprosy reaction and clinically presents as inflammatory polyarthritis affecting the small joints of hands and feet, similar to that observed in RA. Patients with leprosy and arthritis do not require additional glucocorticoids; significant improvement is usually achieved after the start of leprosy therapy, even if the patients do not completely recover¹⁴.

The present patient was at risk due to immunosuppression secondary to corticosteroid therapy for leprosy reactions. The patient was in an immunosuppressed state before the treatment for leprosy reaction. She was initially diagnosed with RA and received long-term corticosteroid treatment, which failed, and the diagnosis was revised to arthritis due to leprosy, with improvement of finger swelling following appropriate treatment. Although the patient denied nail trauma before the initial complaints, peripheral nerve disorders caused by leprosy infection can cause unrealized nail trauma, which can lead to onychomycosis.

Fungal skin infections are the most common infections associated with pets. In a study by Sudipa et al., ⁸ of the 15 dogs free-roaming dogs in Bali included in the study had Aspergillus spp. on skin (53.55%), with A. fumigatus and A. niger as the two main species⁶. In a study of 20 cats, Mokhtar reported that A. flavus, A. nidulans, and A. niger were isolated from 20 (100%), 15 (75%), and 5 (25%) cats, respectively⁷. The present patient was a veterinarian and had frequent, direct interaction with dogs and cats, which could be a source of Aspergillus transmission. Additionally, the nail culture revealed the growth of A. flavus and A. niger colonies, although A. niger did not grow in the second nail culture. These findings are consistent with those of Mokhtar and Sudipa et al., where A. flavus and A. niger were the most commonly found Aspergillus spp. in dogs and cats.

In patients with onychomycosis, oral antifungals are pre- ferred because of their superior efficacy compared to topical therapy; the limited diffusion of topical drugs to the nail leads to reduced therapeutic efficacy^9,15. The British Association of Dermatologists recommends terbinafine and itraconazole as first-line therapeutics for onychomycosis. In vitro studies show that Aspergillus spp. exhibit the best sensitivity to itraconazole, followed by miconazole, ketoconazole, and terbinafine¹⁶. In many countries, itraconazole pulse therapy with 3~4 cycles is approved for the treatment of toenail onychomycosis¹⁷. Certain patient characteristics may require a longer course of treatment or higher dosages. These con- ditions include comorbidities such as immunosuppression, diabetes, a greater number of affected fingers, more severe disease manifestation, resistance, and cooccurrence of der- matophyte infection and resistance3.

The present patient was treated with four cycles of itraconazole at 400 mg/day. The 2-month evaluation after the end of treatment revealed complete cure of the fourth fingernail in left hand and the third toenail in right foot, with mycologic cure in the fifth fingernail of right hand.

NDMs should be considered not only as contaminants but also as causative agents in patients with onychomycosis. Mycologic examination is essential to confirm the diagnosis of onychomycosis caused by NDMs. Dogs and cats, which are the most common pets, can be a source of the transmission of fungal infections, including Aspergillus spp. Itraconazole pulse therapy is an effective approach in onychomycosis due to A. flavus.