To make a diagnosis of Aspergillus onychomycosis, the following are required:
- Positive detection by direct microscopy
- Either a repeated culture, or molecular detection of Aspergillus spp. (provided no dermatophyte is isolated)
Aspergillus spp. are emerging causative agents of non-dermatophyte mould onychomycosis (NDMO). Proper clinical diagnosis, laboratory workup, and adequate antifungal therapy are the standard of care for all forms of aspergillosis.
A. niger complex, A. flavus complex and A. terreus complex are the most common etiologic Aspergillus species; other rare and emerging species described include A. tubingensis, A. sydowii, A. alliaceus, A. candidus, A. versicolor, A. unguis, A. persii, A. sclerotiorum, A. uvarum, A. melleus, A. tamari, and A. nomius (English and Atkinson, 1974; Nouripour-Sisakht et al., 2015; Zotti et al., 2015).
A recent review on the epidemiology of onychomycosis due to Aspergillus species has shown that Aspergillus spp. constitutes up to 7.7–100% of the proportion of NDMO and between <1% and 35% of all cases of onychomycosis in the general population and higher among diabetic populations accounting for up to 71% in the elderly (Bonifaz et al., 2007; Gianni and Romano, 2004; Gupta et al., 2007; Hilmioğlu-Polat et al., 2005; Romano et al., 2005). About 10 million cases of onychomycosis are attributable to Aspergillus species.
The affected nail may have been previously subjected to trauma and is most often a toenail; peripheral vascular disease is occasionally implicated. Damage can also be induced by hormonal disturbances (diabetes mellitus, Cushing's syndrome, and hypothyroidism) or by HIV/AIDS immunosuppression or on-going biological (immunosuppressive) therapies (Ogawa et al., 2012). The risk of having Aspergillus onychomycosis among diabetics increases with age and duration of diabetes (Wijesuriya et al., 2015).
Aspergillus onychomycosis is seen more among individuals with occupational exposures such as vegetable vendors (Banu et al., 2013) and among babassu coconut breakers (Nascimento et al., 2014), diabetics, and the elderly (Gupta et al., 2007). Some individuals diagnosed with onychomycosis due to Aspergillus spp. do not have identifiable predisposing conditions/occupational risk factors. In fact, Soltani and colleagues in their study reported that up to 70% of patients with Aspergillus onychomycosis had no predisposing conditions (Soltani et al., 2015). Onychomycosis due to Aspergillus spp. is very uncommon in children (Lange et al., 2006; Romano et al., 2005).
Aspergillus spp. are ubiquitous environmental moulds found in soil, decaying vegetation and water and are not transmitted from person to person (Kwon-Chung and Sugui, 2013). Infection starts under the nail near the hyponychium where spores may have lodged or at the lateral nail folds, or on a diseased nail plate colonised by Aspergillus spp (Moore and Weiss, 1948). Once the fungus starts to grow, the infection spreads back toward the cuticle. It looks much the same as any fungal nail infection, discolouring the nail, causing it to become thick, distorted, and flaky (Zaias et al., 2014) An early experimental study with A. versicolor using healthy nail samples showed that A. versicolor could only grow on the surface of the nail without penetrating the nail plate, an evidence of the non-keratinolytic potentials of the Aspergillus spp. (Richardson, 1997). Aspergillus spp. growing in nature often produce colourful pigments; therefore, an Aspergillus nail infection may well appear greenish, black, brown, or various other shades (Banu et al., 2013). The fungus will not, however, spread to the surrounding skin like some other fungal causes of nail infection (Banu et al., 2013).
Particular features suggestive of Aspergillus infection are a chalky, deep white nail with early involvement of the lamina and painful perionyxis without pus (Gianni and Romano, 2004). The toenails are involved 25 times more frequently than fingernails (Banu, 2013). There are 2 common patterns of disease: destructive and superficial white onychomycosis (SWO)(Onsberg et al., 1978; McAleer, 1981; Piraccini and Tosti, 2004), but lateral and distal onychomycosis may also be seen (Bonifaz et al., 2007). In a systematic review of NDMO, Gupta et al (Gupta et al., 2012) reported that Aspergillus spp. manifests as proximal subungual onychomycosis (PSO) in 37.5% of the cases, distal-lateral subungual onychomycosis (DLSO) in 26.1%, and SWO in 25.5%.
Variations of clinical presentations have been observed among the different Aspergillus spp. For example, a study in India showed A. flavus causing 19.2% of DLSO, 18.8% of total dystrophic onychomycosis (TDO), and 9.1% SWO. In contrast, A. niger was associated with 11.5% of DLSO, 10.1% of TDO, 9.1% of SWO, and 6.3% of mixed pattern onychomycosis (MPO), whereas A. fumigatus was associated with DLSO in 2% of the patients, 5.8% TDO and 6.3% MPO (Raghavendra et al., 2015).
Fig 1 caption. Distal-lateral subungual onychomycosis due to Aspergillus ochraceopetaliformis (left); mixed-pattern onychomycosis (total dystrophic onychomycosis and superficial white onychomycosis) due to Aspergillus candidus (middle); yellowish pigmentation of the nail plate with mild hyperkeratosis due to Aspergillus versicolor (right).
A positive direct microscopy, repeated culture or molecular detection of Aspergillus spp., provided no dermatophyte was isolated, is sufficient to diagnose Aspergillus onychomycosis.
The isolation of Aspergillus spp. from nail specimens may mean several things: causative agent, colonizer or contaminant. The diagnosis of onychomycosis due to Aspergillus spp. is both clinical and mycological. Since there are no specific signs associated with onychomycosis due to Aspergillus spp., it is not possible to diagnose it based solely on physical appearance.
Microscopy of nail clippings yields positive results in 84% of cases (Gianni and Romano, 2004). Mycological culture on Sabouraud’s dextrose agar with or without cycloheximide yields fungal isolates in less than 50% of the cases. However, combining KOH preparation and culture, sensitivity is increased to 85.8% (Grover, 2003). Isolation rate is higher for nail samples obtained by drilling (83%) compared to scraping (67%) (Kashyap et al., 2008).
The differential diagnosis for onychomycosis due to Aspergillus spp. is very broad and includes yeast nail infections, tinea unguium, non-Aspergillus spp. NDMO, and other non-fungal nail infections and disorders.
Aspergillus versicolor grown on malt extract agar (left) and Sabouraud agar (middle). H&E staining of a sample of nail infected with Aspergillus ochraceopetaliformis.
Aspergillus spp. isolated from nail specimens are not usually susceptible to most of the topical and systemic antifungals used to treat dermatophytes. Inadequate treatment may lead to resistance and recurrence of infection. It should be noted that comparative clinical trials on the treatment of Aspergillus onychomycosis have not been done to date, and that recommendations have been based on case studies.
Several reports have described the efficacy of itraconazole (200mg daily) for Aspergillus onychomycosis (Scher and Barnett, 1990) and pulsed terbinafine (Gianni and Romano, 2004). The duration of therapy depends on which nails are affected and the extent of infection. Affected fingernails typically require 3 months of therapy and toenails at least 6 months. Itraconazole performs better than terbinafine in vitro (Ameen et al., 2014).
Topical amorolfine hydrochloride 0.25% is not always active against Aspergillus spp. (Li et al., 2004) and is not recommended, although one patient is described with A. candidus onychomycosis whose affected big toenail did respond to 6 months of therapy (Piraccini et al., 2002). If only one nail is affected alternative options include avulsion (removal) of the nail or dissolution of the nail with urea paste (BSMM, 1995).
Citing this page
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Dr. Felix Bongomin, MB ChB, M.Sc.
Clinical Research Associate
National Aspergillosis Centre
Education and Research Centre
Manchester University NHS Foundation Trust
Manchester M23 9LT UK
David W. Denning FRCP FRCPath FIDSA FMedSci
Professor of Infectious Diseases in Global Health
Director, National Aspergillosis Centre
Education and Research Centre
Manchester University NHS Foundation Trust
Manchester M23 9LT UK