REVIEW ARTICLE

Opportunistic toenail onychomycosis. The fungalcolonization of an available nail unit space bynon-dermatophytes is produced by the trauma of theclosed shoe by an asymmetric gait or other trauma. Aplausible theoryN. Zaias,* S.X. Escovar, G. Rebell

Dermatology division, Greater Miami Skin and Laser, Mount Sinai Medical Center, Miami Beach, FL, USA

*Correspondence: N. Zaias. E-mail: nardozaias@aol.com

AbstractOpportunistic onychomycosis is defined, when a non-dermatophyte mould is cultured from an abnormal nail unit in the

absence of a dermatophyte. The presumption is that the mould has caused the abnormal clinical appearance of the nail

unit, yet there are no data available to substantiate this claim. Reports have only identified the mould being recovered

from the nail unit niche. A review of the published dermatologic literature describing toenail opportunistic onychomycosis

by non-dermatophyte fungi has shown toenails with onycholysis, nail bed (NB) keratosis and nail plate surface abnormal-

ities. The appearance of these clinical changes is indistinguishable from the diagnosis of the Asymmetric Gait Nail Unit

Signs (AGNUS). AGNUS is produced by the friction of the closed shoe in patients with an asymmetric gait, resulting pri-

marily from the ubiquitous uneven flat feet. Most commonly, species of Acremonium (Cephalosporium), Aspergillus,

Fusarium, Scopulariopsis and rarely species of many different fungi genera are capable of surviving and reproducing in a

keratinous environment and change the clinical appearance of the involved nail unit. AGNUS toenails predispose to the

colonization by the non-dermatophyte opportunistic fungi but not by dermatophyte fungi.

Received: 2 January 2014; Accepted: 12 February 2014

Conflicts of interestNone declared.

Funding sourcesNone declared.

IntroductionA recent report1 clinically identified very prevalent toenail unit

signs, dermatophyte free, resulting from the pressure to the toes

and foot by the closed shoe, in subjects who had an asymmetric

gait due to the ubiquitous uneven flat feet. Clinically one or

more signs can be seen depending on which location of the toe-

nail unit the pressure is focused by the closed shoe while walking.

Initially, signs are seen unilaterally and when they are bilateral,

one side is always more severe than the other. These signs are:

1 Nail Plate (NP) curved on one side due to pressure of shoe on

the NP matrix while walking, Fig. 1 (lateral arrows inward).

2 Onycholysis and hyperkeratosis of distal toe skin, Fig. 1

(arrow up and down).

3 NB keratosis, similar to distal subungual onychomycosis

(DSO), dermatophyte free, Fig. 2.

4 Changes of the surface of the NP, similar to white superficial

onychomycosis (WSO), dermatophyte free, Fig. 3.

Onychomycosis is a general term that defines a physical rela-

tionship between the nail unit and a member of the order My-

cota. Onychomycosis can exist when a fungus either initiates the

invasion of the nail unit, as we see in the chronic dermatophyto-

sis and scytalidium syndromes, where there is involvement of

not only the nail units but also the skin of the soles and glabrous

skin.

Opportunistic onychomycosis by non-dermatophyte fungi(moulds) with the exception of scytalidium‘The infected’ nail unit is usually a solitary event, not

accompanied by tinea pedis as seen in onychomycosis by

dermatophytes2 and it does not follow an inheritance pattern,

as do dermatophyte onychomycosis.3 The fungi recovered are

all environmental and easily accessible to the human toenail

niche from the shoe. These fungi include many families and

genera, but only those that are capable to survive and repro-

© 2014 European Academy of Dermatology and VenereologyJEADV 2014, 28, 1002–1006

DOI: 10.1111/jdv.12458 JEADV

duce in a keratinous environment can colonize the available

nail unit niche.

Thus, it is a reasonable hypothesis to propose that opportu-

nistic fungi colonize available spaces of the toenail unit. Why are

toenail unit niches available? Mainly because of Asymmetric

Gait Nail Unit Signs (AGNUS). The prevalence of AGNUS is

greater than the clinician suspects. Of the available studies com-

bined, over a thousand patients with a clinical impression of

onychomycosis that were cultured for dermatophyte fungi, only

27–30% had dermatophyte fungi isolated.4–7 That could mean

that AGNUS was responsible for the majority of the remaining

70–73% of abnormal toenails. In these nails a large variety of

moulds were recovered. It is possible that a mould that can

sustain itself in nail unit niche can alter the substrate and make

the involved nail unit look more abnormal. Whenever there is

toenail onycholysis, NB keratosis and NP surface abnormalities,

there will be a possible colonization by environmental fungi.

MethodsThe dermatologic literature relating to ‘Opportunistic onycho-

mycosis’ from 1960 to 2012 was reviewed. The clinical pictures

of the affected toenail units included in the reports were anal-

ysed looking for AGNUS clinical signs such as onycholysis,

NB keratosis, half of an omega-shaped NP, NP surface damage

and hyperkeratosis of the affected skin of the distal toes.

ResultsAGNUS is the most common toenail unit damage. It is dermato-

phyte free but can coexist with any other affliction of toenails for

independent reasons. Typical AGNUS images, Figs 1–3, demon-

strate the toenail unit niches available from AGNUS. The figures

presented in all reviewed articles on opportunistic fungi show

characteristic AGNUS features, see Figs 4–14.

Fungi reports and their confirmation are summarized in

Table 1.8–24 All the clinical images of the halluces are identical to

what is described as AGNUS.

DiscussionWe propose the theory that opportunistic environmental fungi

of many genera can colonize toenail niches that exist because of

an asymmetric gait and the closed shoe (AGNUS), as long as

Figure 1 Asymmetric Gait Nail Unit Signs (AGNUS) – dermato-phyte free, showing the shoe pressure bending the nail plate matrixmedially (lateral arrows) and producing the half omega curvature ofAGNUS. At same time it also produces onycholysis (arrows down)and the hyperkeratosis of the distal toe skin (arrows up).

Figure 4 Acremonium species (Cephalosporium) colonizing theonycholysis of AGNUS. Arrow up points at onycholysis (CourtesyElsevier).

Figure 2 Asymmetric Gait Nail Unit Signs subungual hyperkera-tosis, from shoe pressure on nail plate and subsequently on nailbed, dermatophyte free.

Figure 3 Asymmetric Gait Nail Unit Signs – White superficialonychomycosis like clinical but dermatophyte free (arrows down),curved nail plate (lateral arrows) and onycholysis (arrows up).

© 2014 European Academy of Dermatology and VenereologyJEADV 2014, 28, 1002–1006

Opportunistic toenail onychomycosis 1003

they can survive and utilize keratinous material. AGNUS clinical

signs have not been recognized before 2012 when the AGNUS

publication appeared. It is very plausible that earlier descriptions

of clinical classifications of dermatophyte onychomycosis were

in fact aided by AGNUS-derived nail unit lesions. It is possible

that the authors description of WSO25 could have been the

colonization of a trachonychia damage on the surface of the NP

Figure 5 Colonization of nail plate surface due to AGNUS(Courtesy Elsevier).

Figure 6 Aspergillus flavus colonizing dystrophic nail plate andNail bed of AGNUS (Courtesy Elsevier).

Figure 7 Left: Aspergillus niger colonizing AGNUS onycholysis(Nail Plate cut, arrow up). Right: Note AGNUS characteristicomega-shaped NP (Courtesy Brit J Derm).

Figure 8 Aspergillus niger colonizing AGNUS onycholysis andNB keratosis (Courtesy Elsevier).

Figure 9 Aspergillus terreus colonizing AGNUS onycholysis andNail bed keratosis. Nail plate cut, arrow up. (courtesy Elsevier).

Figure 10 Fusarium colonizing AGNUS and Nail bed keratosis(Courtesy Elsevier).

© 2014 European Academy of Dermatology and VenereologyJEADV 2014, 28, 1002–1006

1004 Zaias et al.

commonly seen in AGNUS and that Trichophyton interdigitale

(mentagrophytes) also found in the interdigital spaces, set up

household there to clinically appear as WSO.

In another experiment by a group of Spanish dermatologists26

attempted to prove Koch’s postulates, inoculated cultures of der-

matophyte on the surface of scarified normal toenail plates and

occluded them. Lesions of WSO were seen after 1 month but as

soon as the occlusion was removed all lesions disappeared. No

lesions of DSO were seen. Could it be that the artifactual scarifi-

cation of the surface of the NP needs to be continuous, as seen

in the shoe damage produced by AGNUS?

Other descriptions and new classifications merit discussion

here. Recently described dermatophytoma, Fig. 12,27 is a fungus

ball of Fusarium in an onycholytic area of the NB produced by

AGNUS in a patient who for independent reasons also had T.

rubrum DSO.

(a)

(c)

(b)

(d)

Figure 12 So-called dermatophytoma. (a) AGNUS onycholysis(arrow). (b) Onycholysis and NB keratosis (arrow). (c) Nail plate cutto show onycholysis and fungal colony (up right lines and asterisk).(d) Fungal mass in onycholytic space (Courtesy Elsevier).

Figure 14 AGNUS changes in a patient who also has Paraneo-plastic acral vascular syndrome (courtesy Elsevier).

Figure 11 Scopulariopsis brevicaulis, colonizing AGNUS ony-cholysis and Nail bed keratosis (arrow down) (Courtesy Elsevier).

Figure 13 Pseudomonas colonizing AGNUS onycholysis and NBkeratosis (Courtesy Elsevier).

© 2014 European Academy of Dermatology and VenereologyJEADV 2014, 28, 1002–1006

Opportunistic toenail onychomycosis 1005

Another example of a mixed diagnosis is shown in Fig. 13. A

patient who had dermatophyte DSO coexisting with AGNUS

and finally the onycholytic space inhabited by Pseudomonas,

which tinted the nail space green.

Other diseases have been described to cause toenail abnormal-

ities, as shown in Fig. 14, who clinically had AGNUS and devel-

oped paraneoplastic vascular disease in that toe.

The treatment of opportunistic onychomycosisTreatment of onychomycosis caused by non-dermatophyte

moulds (NDM) is still not well standardized and several authors

underline the fact that NDM onychomycosis frequently does not

respond to systemic antifungals. The use of topicals with the NP

avulsion is commonly described but without reproducible

results.

In an interesting in vitro study, Vander-Straten and col-

leagues8 found that most opportunistic fungi had a very high

minimal inhibitory concentration (MIC) to 5-flurocytosine and

fluconazole. The best results were produced with amphotericin

B and itraconazole was a little better than ketoconazole.

In the reported studies, the treatment time with systemic anti-

fungals appeared to be very short to accomplish complete cure

when compared with the growth rate of the hallux NP and the

length of the infected nail plate.

In summary, we theorize it is impossible for opportunistic

fungi to infect a normal toenail unit without a previous

alteration of the nail unit anatomy, as for example onycholysis,

NB keratosis and superficial NP damage, as seen classically in

the majority of AGNUS cases and trauma.

References1 Zaias N, Rebel G, Casals G, Appel J. The asymmetric gait toenail unit sign

(AGNUS), fungus negative, produced by an asymmetric walking gait that

could be correctable in early life. Skinmed 2012; 10: 213–217.2 Zaias N, Rebell G. Introducing the syndromes of human dermatophyto-

sis. Cutis 2001; 6(Suppl. 5): 9–47.3 Zaias N, Tosti A, Rebell G et al. Autosomal dominant pattern of distal

subungual onychomycosis caused by T. rubrum. J Am Acad Dermatol

1996;34:302–304.4 Za�ıas N, Oertel I, Elliott DF. Fungi in nail. J Invest Dermatol 1969; 53:

140–142.5 Gupta AK, Konnikov N, MacDonald PM et al. Prevalence and epidemi-

ology of toe nail onychomycosis in diabetic subjects: a multicenter sur-

vey. Br J Dermatol 1998; 139: 665–671.6 Haneke E, Roseeeuw D. The scope of onychomycosis: epidemiology and

clinical features. Int J Dermatol 1999; 38: 7–127.7 Scherer WP, McCreary JP, Hayes WW. The diagnosis of onychomycosis

in a geriatric population. J Am Podiatr Med Assoc 2001; 91: 456–464.8 Vander Straten MR, Balkis MM, Ghannoum MA. The role of non derma-

tophyte molds in onychomycosis: diagnosis and treatment. Dermatol

Ther 2002;15: 89–98.9 Negroni P. Una nueva Musedinacea (Cephalosporium) parasitica del

hombre. Rev Soc Argent Biol 1930; 6: 653.

10 Gupta AK, Drummond-Maine C, Cooper EA et al. Systematic review of

non-dermatophyte mold onychomycosis: diagnosis, clinical types, epide-

miology and treatment. J Am Acad Dermatol 2011; 66: 494–502.11 Blomqvist K. Athroderma tuberculatum isolated from finger nail and

beard. Dermatologica 1969; 138: 229.

12 Tosti A, Piraccini BM, Lorenzi S, Iorizzo M. Treatment of non-dermato-

phyte mold and Candida onychomycosis. Dermatol Clin 2003; 21: 491–497.

13 Kaben U. Aspergilus candidum link als erreger einer Konikomycose.

Hauthr Geshlechtskr 1962; 32: 50.

14 Bereston ES, Keil H. Onychomycosis due to Aspergilus flavus. Arch Derm

Syphilol 1941; 44: 420.

15 Bereston ES, Waring WS. Aspergillus infection of the nails. Arch Derm

Syphilol 1946; 54: 552.

16 Tosti A, Piraccini BM. Proximal subungual onychomycosis due to Asper-

gillus niger: report 2 cases. Br J Dermatol 1998; 139: 156–157.17 Moore Weiss R. Onychomycosis caused by Aspergillus terreus. J Invest

Dermatol 1948; 11: 215.

18 Rush-Munro FM, Black Dingley JM. Onychomycoses caused by Fusarium

oxysporum. Aust J Dermatol 1971; 12: 18.

19 Restrepo A, Arango M, Herta H, Uribe L. The isolation of (Lasiodiplodia)

Brotriodiplodia theobromae from a nail lesion. Sabouraudia 1976; 14: 1.

20 Sigler L, Congly H. Toe nail infection caused by Onychocola canadiensis.

J Med Vet Mycol 1990; 28: 405–417.21 Gupta AK, Horgan-Bell CB, Summerbell RC. Onychomycosis associated

with Onychocola canadiensis: ten case report and a review of the litera-

ture. J Am Acad Dermatol 1998; 39: 410–417.22 Gip L, Paldrok H. Onychomycosis caused by Phyllostictina Sydow. Acta

Derm Venereol 1967; 47: 186–189.23 Punithalingam E, English MP. Pyrenochaeta unguis-hominis on human

toenails. Trans Br Mycol Soc 1975; 64: 539.

24 Brumpt E. Precis de Parasitologie. Masson, Paris, 1949.

25 Zaias N. Superficial white onychomycosis. Sabouraudia 1966; 5: 99–103.26 Vilanova X, Cassanovas M, Francino F. Onychomycosis an experimental

study. J Invest Dermatol 1956; 27: 77–101.27 Roberts DT, Evans EG. Dermatophytoma. Br J Dermatol 1998; 138: 188.

Table 1 Reported and confirmed non-dermatophytic fungi produ-cing opportunistic onychomycosis

Organism Confirmedreports

Acremonium (Cephalosporium) species.Figure 4

59,10

Arthroderma trabeculatum Not confirmed11

Aspergillus candidus. Figure 5 412,13

Aspergillus flavus. Figure 6 210–14

Aspergillus glaucus 312

Aspergillus nidulans Not confirmed13

Aspergillus niger. Figures 7–8 515,16

Aspergillus terreus. Figure 9 510–17

Aspergillus ustus 310–15

Aspergillus versicolor 28–10

Fusarium oxysporum and F. solani. Figure 10 44,18

Lasiodiplodia sydowii Not Confirmed 19

Onychocola canadiensis 520,21

Phyllostictina sydowii Not Confirmed22

Pyrenocheta unguis hominis Not Confirmed23

Scopulariopsis brevicaulis. Figure 11 Many reports8,24

© 2014 European Academy of Dermatology and VenereologyJEADV 2014, 28, 1002–1006

1006 Zaias et al.