Case 1

A seventy-year-old woman from Yucatan, a housewife with a history of diabetes mellitus treated with metformin and glargine insulin, also treated with ezetimibe-simvastatin for dyslipidemia, developed onychomycosis on her left foot, affecting the first, second, and third nail plates with associated distal onycholysis and xanthonychia. The rest of the skin and appendages showed no abnormalities. She reported six months of progression with the development of xanthonychia on the affected nails. A mycological study revealed conidial heads and filaments with potassium hydroxide (KOH) preparation (Fig. 1). Aspergillus flavus grew in the culture media.

Figure 1: Conidial heads and filaments with a KOH preparation (20x).

Case 2

A forty-year-old woman from Yucatan with no significant medical history presented localized onychomycosis on her left foot, affecting the first nail plate, with distal onycholysis and mild xanthonychia. The rest of the skin and appendages showed no alterations. She reported four months of progression with color changes in the nails and mentioned previous trauma. In the KOH preparation, conidial heads and filaments were observed (Fig. 2a). The culture was positive for Aspergillus flavus in two isolates (Fig. 2b).

Figure 2: (a) Conidial heads and filaments (Chlorazol black; 20x). (b) Positive culture for Aspergillus flavus in two isolates.

Case 3

A 22-year-old woman from Yucatan, residing in a rural area, with no significant medical history but with exposure to soil and water, presented localized onychomycosis on her left foot, affecting the first nail plate, with xanthonychia and onycholysis on the outer lateral edge. The rest of the skin and appendages showed no alterations. She reported several months of progression but could not recall the exact duration. The KOH preparation revealed conidial heads (Fig. 3). The culture was positive for Aspergillus spp. in two isolates.

Figure 3: Conidial heads in a KOH preparation (20x).

DISCUSSION

In general, non-dermatophyte molds are secondary invaders of previously damaged nails [3]. Aspergillus species are the leading cause of onychomycosis caused by NDM [2], representing 0.5–3% of all onychomycosis cases. However, some recent series report their isolation in up to 50% of samples, suggesting they are more prevalent than previously considered [5]. This may be higher in special populations, particularly in diabetic patients, in whom it has been isolated in up to 71% of cases. A predominance in females has been reported [7,8], while it is very rare in pediatric patients [5].

The most commonly reported species are A. terrei, A. flavus complex, and A. niger complex [1,5]. These are ubiquitous environmental molds found in soil, decomposing vegetation, and water, and are not transmitted from person to person [5]. The toenails are affected twenty-five times more often than fingernails due to exposure to soil, water, and vegetation [5]. It is common for patients to have a history of previous trauma or paronychia [8].

Clinically, onychomycosis caused by Aspergillus spp. resembles cases caused by dermatophytes, with changes in color, subungual hyperkeratosis (thickening), onycholysis, and nail dystrophy. Dermatophytoma formation under the nail has been observed in some cases [5]. Some clinical presentations have been associated with specific pathogens, such as Aspergillus niger, which is linked to black or greenish discoloration in the lunula, and infections by Aspergillus clavatus, A. terrei, A. flavus, and A. niger are associated with total dystrophic onychomycosis of the hands and feet [6].

All cases mentioned here occurred in women, one of whom had diabetes as a probable predisposing comorbidity, and the other two had a history of repeated local trauma and exposure to soil elements.

The absence of specific clinical signs requires conducting a mycological examination to confirm the suspicion of fungal infection and establish a clinical-etiological correlation [5,6]. In some cases, conidial heads may be observed in the KOH preparation, particularly in long-standing cases or those presenting with onycholysis [5].

Mycological cultures on Sabouraud agar, with or without cycloheximide, have an isolation rate for NDM in 50% of the cases. However, when combined with KOH preparation, the sensitivity is 85.8%. The isolation rate is higher in nail samples obtained by drilling when compared to scraping [5].

In our cases, diagnosis was made through a mycological study, with conidial heads identified in the KOH preparation in two cases (cases 1 and 2). Cases 2 and 3 were confirmed with two positive serial cultures for NDM, without dermatophyte growth, confirming these pathogens as the cause of the observed nail changes.

Since positive NDM cultures from nail specimens do not always equate to causality, Gupta et al. [2] proposed a series of criteria, of which three or more must be met to confirm the etiological diagnosis: (1) positive KOH preparation, (2) positive culture for NDM, (3) repeated culture (2–3 times) with NDM isolation, without dermatophyte isolation, (4) histopathology with positive periodic acid–Schiff (PAS) for fungal elements, (5) isolation of NDM from 5 of 20 nail fragments, and (6) molecular identification. However, KOH preparation and serial cultures, or molecular identification, in the absence of dermatophyte isolation, are sufficient to diagnose onychomycosis caused by Aspergillus [5].

Therapeutic options for NDM onychomycosis remain limited, yet infections caused by Aspergillus spp. generally respond well to systemic antifungals. There are no standardized treatment guidelines, so therapeutic decisions are currently based on expert opinion [2,5,8].

Tosti et al. recommend terbinafine at a dose of 250 mg per day or itraconazole pulses at 400 mg per day for one week per month for 2–4 months, either option being suitable [5]. In an in vivo study conducted in the Philippines, pulse terbinafine therapy (500 mg per day for one week per month) showed complete resolution in 30 of 34 patients. In another study, itraconazole proved superior to terbinafine in vitro [5].

There are case reports of onychomycosis caused by Aspergillus spp. in India and Eastern Europe, where the efficacy of pulse itraconazole treatment combined with 50% urea/5% amorolfine, avulsion combined with topical terbinafine, and monotherapy with an optimized solution of amphotericin B (unavailable in Mexico) was demonstrated [8,9].

Topical luliconazole and efinaconazole, either as monotherapy or in combination with terbinafine or oral itraconazole, have shown high success rates in a case series of Aspergillus spp. onychomycosis in Japan [5].

In 2012, Gupta et al. proposed a treatment algorithm for confirmed NDM onychomycosis, suggesting the initiation of topical treatment with efinaconazole or tavaborole, or systemic treatment with itraconazole or terbinafine as the first line of therapy, tailoring the decision based on the patient’s comorbidity profile and clinical scenario, and evaluating antifungal susceptibility, as well as excluding a mixed infection if treatment fails [6,8].

Hand nail infections typically require three months of treatment, and foot nails require at least six months of treatment [5].

The treatments used for the patients we are reporting were systemic itraconazole and fluconazole, based on the available therapeutic consensus, following an oral dosage until complete clinical and mycological resolution.

CONCLUSIONS

Onychomycoses are the most common nail disorders, with those caused by NDM being an increasingly prevalent entity in recent decades, with Aspergillus spp. identified as the most frequent causative agent in this category [2]. This clinical variant often requires a predisposing condition, as these molds lack the necessary keratinases to invade and parasitize the nail apparatus, such as prior trauma, anatomical abnormalities, or immunosuppressive states [2,6], with women being the most affected group, likely due to occupational associations with household tasks. The clinical presentation is often indistinguishable from other onychomycoses, making a mycological study essential, and always considering the need to exclude contaminant fungi through serial cultures, as well as complementing with molecular identification techniques when available [5,6,8,9]. Although a good response to systemic antifungal therapy has been observed, the treatment regimen has not yet been standardized [2,5,8], largely due to the relatively low frequency with which it occurs and the limited number of reports in the medical literature, highlighting the importance of reporting such cases.