JEADV REVIEW ARTICLE. Abstract. Conflicts of interest. Funding sources

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1 DOI: /jdv JEADV REVIEW ARTICLE Opportunistic toenail onychomycosis. The fungal colonization of an available nail unit space by non-dermatophytes is produced by the trauma of the closed shoe by an asymmetric gait or other trauma. A plausible theory N. Zaias,* S.X. Escovar, G. Rebell Dermatology division, Greater Miami Skin and Laser, Mount Sinai Medical Center, Miami Beach, FL, USA *Correspondence: N. Zaias. nardozaias@aol.com Abstract Opportunistic 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 abnormalities. 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 primarily 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 interest None declared. Funding sources None declared. Introduction Arecentreport 1 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 toenail 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 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 relationship between the nail unit and a member of the order Mycota. Onychomycosis can exist when a fungus either initiates the invasion of the nail unit, as we see in the chronic dermatophytosis 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 dermatophytes 2 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-

Opportunistic toenail onychomycosis 1003 Figure 1 Asymmetric Gait Nail Unit Signs (AGNUS) dermatophyte free, showing the shoe pressure bending the nail plate matrix medially (lateral arrows) and

Figure 2 Asymmetric Gait Nail Unit Signs subungual hyperkeratosis, from shoe pressure on nail plate and subsequently on nail bed, dermatophyte free. greater than the clinician suspects.

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.

Whenever there is toenail onycholysis, NB keratosis and NP surface abnormalities, there will be a possible colonization by environmental fungi.

2 Opportunistic toenail onychomycosis 1003 Figure 1 Asymmetric Gait Nail Unit Signs (AGNUS) dermatophyte free, showing the shoe pressure bending the nail plate matrix medially (lateral arrows) and producing the half omega curvature of AGNUS. At same time it also produces onycholysis (arrows down) and the hyperkeratosis of the distal toe skin (arrows up). Figure 2 Asymmetric Gait Nail Unit Signs subungual hyperkeratosis, from shoe pressure on nail plate and subsequently on nail bed, dermatophyte free. greater than the clinician suspects. Of the available studies combined, 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. Methods The dermatologic literature relating to Opportunistic onychomycosis from 1960 to 2012 was reviewed. The clinical pictures of the affected toenail units included in the reports were analysed 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. Results AGNUS is the most common toenail unit damage. It is dermatophyte free but can coexist with any other affliction of toenails for independent reasons. Typical AGNUS images, Figs 1 3, demonstrate the toenail unit niches available from AGNUS. The figures presented in all reviewed articles on opportunistic fungi show characteristic AGNUS features, see Figs Fungi reports and their confirmation are summarized in Table All the clinical images of the halluces are identical to what is described as AGNUS. Discussion We 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 3 Asymmetric Gait Nail Unit Signs White superficial onychomycosis like clinical but dermatophyte free (arrows down), curved nail plate (lateral arrows) and onycholysis (arrows up). duce in a keratinous environment can colonize the available nail unit niche. Thus, it is a reasonable hypothesis to propose that opportunistic 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 Figure 4 Acremonium species (Cephalosporium) colonizing the onycholysis of AGNUS. Arrow up points at onycholysis (Courtesy Elsevier).

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

Elsevier). Figure 9 Aspergillus terreus colonizing AGNUS onycholysis and Nail bed keratosis.

Figure 7 Left: Aspergillus niger colonizing AGNUS onycholysis (Nail Plate cut, arrow up).

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

AGNUS clinical signs have not been recognized before 2012 when the AGNUS publication

3 1004 Zaias et al. Figure 5 Colonization of nail plate surface due to AGNUS (Courtesy Elsevier). Figure 8 Aspergillus niger colonizing AGNUS onycholysis and NB keratosis (Courtesy Elsevier). Figure 6 Aspergillus flavus colonizing dystrophic nail plate and Nail bed of AGNUS (Courtesy Elsevier). Figure 9 Aspergillus terreus colonizing AGNUS onycholysis and Nail bed keratosis. Nail plate cut, arrow up. (courtesy Elsevier). Figure 7 Left: Aspergillus niger colonizing AGNUS onycholysis (Nail Plate cut, arrow up). Right: Note AGNUS characteristic omega-shaped NP (Courtesy Brit J Derm). Figure 10 Fusarium colonizing AGNUS and Nail bed keratosis (Courtesy Elsevier). 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 WSO 25 could have been the colonization of a trachonychia damage on the surface of the NP

Opportunistic toenail onychomycosis 1005 Figure 11 Scopulariopsis brevicaulis, colonizing AGNUS onycholysis and Nail bed keratosis (arrow down) (Courtesy Elsevier).

(a) (b) Figure 14 AGNUS changes in a patient who also has Paraneoplastic acral vascular syndrome (courtesy Elsevier). (c) Figure 12 So-called dermatophytoma. (a) AGNUS onycholysis (arrow).

commonly seen in AGNUS and that Trichophyton interdigitale (mentagrophytes) also found in the interdigital spaces, set up household there to clinically appear as WSO.

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.

4 Opportunistic toenail onychomycosis 1005 Figure 11 Scopulariopsis brevicaulis, colonizing AGNUS onycholysis and Nail bed keratosis (arrow down) (Courtesy Elsevier). Figure 13 Pseudomonas colonizing AGNUS onycholysis and NB keratosis (Courtesy Elsevier). (a) (b) Figure 14 AGNUS changes in a patient who also has Paraneoplastic acral vascular syndrome (courtesy Elsevier). (c) Figure 12 So-called dermatophytoma. (a) AGNUS onycholysis (arrow). (b) Onycholysis and NB keratosis (arrow). (c) Nail plate cut to show onycholysis and fungal colony (up right lines and asterisk). (d) Fungal mass in onycholytic space (Courtesy Elsevier). commonly seen in AGNUS and that Trichophyton interdigitale (mentagrophytes) also found in the interdigital spaces, set up household there to clinically appear as WSO. (d) In another experiment by a group of Spanish dermatologists 26 attempted to prove Koch s postulates, inoculated cultures of dermatophyte 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 scarification 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.

5 1006 Zaias et al. Table 1 Reported and confirmed non-dermatophytic fungi producing opportunistic onychomycosis Organism Acremonium (Cephalosporium) species. Figure 4 Confirmed reports 5 9,10 Arthroderma trabeculatum Not confirmed 11 Aspergillus candidus. Figure ,13 Aspergillus flavus. Figure Aspergillus glaucus 3 12 Aspergillus nidulans Not confirmed 13 Aspergillus niger. Figures ,16 Aspergillus terreus. Figure Aspergillus ustus Aspergillus versicolor Fusarium oxysporum and F. solani. Figure ,18 Lasiodiplodia sydowii Not Confirmed 19 Onychocola canadiensis 5 20,21 Phyllostictina sydowii Not Confirmed 22 Pyrenocheta unguis hominis Not Confirmed 23 Scopulariopsis brevicaulis. Figure 11 Many reports 8,24 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 abnormalities, as shown in Fig. 14, who clinically had AGNUS and developed paraneoplastic vascular disease in that toe. The treatment of opportunistic onychomycosis Treatment 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 colleagues 8 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 antifungals 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. References 1 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: Zaias N, Rebell G. Introducing the syndromes of human dermatophytosis. Cutis 2001; 6(Suppl. 5): 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: Zaıas N, Oertel I, Elliott DF. Fungi in nail. J Invest Dermatol 1969; 53: Gupta AK, Konnikov N, MacDonald PM et al. Prevalence and epidemiology of toe nail onychomycosis in diabetic subjects: a multicenter survey. Br J Dermatol 1998; 139: Haneke E, Roseeeuw D. The scope of onychomycosis: epidemiology and clinical features. Int J Dermatol 1999; 38: Scherer WP, McCreary JP, Hayes WW. The diagnosis of onychomycosis in a geriatric population. J Am Podiatr Med Assoc 2001; 91: Vander Straten MR, Balkis MM, Ghannoum MA. The role of non dermatophyte molds in onychomycosis: diagnosis and treatment. Dermatol Ther 2002;15: Negroni P. Una nueva Musedinacea (Cephalosporium) parasitica del hombre. Rev Soc Argent Biol 1930; 6: Gupta AK, Drummond-Maine C, Cooper EA et al. Systematic review of non-dermatophyte mold onychomycosis: diagnosis, clinical types, epidemiology and treatment. J Am Acad Dermatol 2011; 66: Blomqvist K. Athroderma tuberculatum isolated from finger nail and beard. Dermatologica 1969; 138: Tosti A, Piraccini BM, Lorenzi S, Iorizzo M. Treatment of non-dermatophyte mold and Candida onychomycosis. Dermatol Clin 2003; 21: Kaben U. Aspergilus candidum link als erreger einer Konikomycose. Hauthr Geshlechtskr 1962; 32: Bereston ES, Keil H. Onychomycosis due to Aspergilus flavus. Arch Derm Syphilol 1941; 44: Bereston ES, Waring WS. Aspergillus infection of the nails. Arch Derm Syphilol 1946; 54: Tosti A, Piraccini BM. Proximal subungual onychomycosis due to Aspergillus niger: report 2 cases. Br J Dermatol 1998; 139: Moore Weiss R. Onychomycosis caused by Aspergillus terreus. J Invest Dermatol 1948; 11: Rush-Munro FM, Black Dingley JM. Onychomycoses caused by Fusarium oxysporum. Aust J Dermatol 1971; 12: Restrepo A, Arango M, Herta H, Uribe L. The isolation of (Lasiodiplodia) Brotriodiplodia theobromae from a nail lesion. Sabouraudia 1976; 14: Sigler L, Congly H. Toe nail infection caused by Onychocola canadiensis. J Med Vet Mycol 1990; 28: Gupta AK, Horgan-Bell CB, Summerbell RC. Onychomycosis associated with Onychocola canadiensis: ten case report and a review of the literature. J Am Acad Dermatol 1998; 39: Gip L, Paldrok H. Onychomycosis caused by Phyllostictina Sydow. Acta Derm Venereol 1967; 47: Punithalingam E, English MP. Pyrenochaeta unguis-hominis on human toenails. Trans Br Mycol Soc 1975; 64: Brumpt E. Precis de Parasitologie. Masson, Paris, Zaias N. Superficial white onychomycosis. Sabouraudia 1966; 5: Vilanova X, Cassanovas M, Francino F. Onychomycosis an experimental study. J Invest Dermatol 1956; 27: Roberts DT, Evans EG. Dermatophytoma. Br J Dermatol 1998; 138: 188.

Fungal Resistance, Biofilm, and Its Impact In the Management of Nail Infection

Fungal Resistance, Biofilm, and Its Impact In the Management of Nail Infection Faculty Raza Aly, PhD, MPH Professor Emeritus University of California Medical Center (MSSF) Professor, Dermatology Faculty