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 Table of Contents  
REVIEW ARTICLE
Year : 2014  |  Volume : 2  |  Issue : 1  |  Page : 48-53

Fungal nail disease (Onychomycosis); Challenges and solutions


1 Department of Microbiology, Kasturba Medical College, Manipal University, Manipal, Mangalore, Karnataka, India
2 Department of Dermatology, Yenepoya Medical College, Yenepoya University, Mangalore, Karnataka, India

Date of Web Publication4-Jun-2014

Correspondence Address:
M. Manjunath Shenoy
Department of Dermatology, Yenepoya Medical College, Yenepoya University, Mangalore - 575 018, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2321-4848.133811

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  Abstract 

Onychomycosis (fungal nail infection) is caused by three groups of fungal pathogens namely dermatophyte molds (DM), non-DM (NDM) and yeasts. It is primarily a cosmetic problem but may induce impact on quality of life. Clinically it is characterized by five morphologically distinctive types; distal lateral subungual onychomycosis (DLSO), superficial white onychomycosis (SWO), proximal subungual onychomycosis (PSO), and endothrix onychomycosis. It is difficult to detect the fungal agent responsible for a particular type of onychomycosis by clinical features alone. Mycological methods like direct demonstration of fungal agents by potassium hydroxide mount or nail plate histopathology with Periodic acid Schiff (PAS) staining are sensitive methods for the detection of pathogens. Fungal culture alone is commonly used as a standard for the detection of etiological agent. Molecular biological techniques are currently used only in research laboratories or epidemiological purposes. Therapy is generally not satisfactory. Both topical and systemic agents are used in the therapy. Topical Ciclopirix and Amorolfine are found to be effective but only in early and limited disease. Terbinafine and Itraconazole seems to be the best drugs for the systemic therapy. Clinical cure rates are generally lower than the mycological cure rates.

Keywords: Onychomycosis, dermatophyte, fungal culture, terbinafine


How to cite this article:
Shenoy MS, Shenoy MM. Fungal nail disease (Onychomycosis); Challenges and solutions. Arch Med Health Sci 2014;2:48-53

How to cite this URL:
Shenoy MS, Shenoy MM. Fungal nail disease (Onychomycosis); Challenges and solutions. Arch Med Health Sci [serial online] 2014 [cited 2017 Oct 22];2:48-53. Available from: http://www.amhsjournal.org/text.asp?2014/2/1/48/133811


  Introduction Top


Onychomycosis (fungal nail infection) is not a life-threatening disease and it is primarily a cosmetic problem by causing disfigurement. It may as a reservoir of cutaneous and systemic infection. It is caused by three groups of fungal agents namely dermatophyte molds (DM), non-DM (NDM) and yeasts. Role of dermatophytes in onychomycosis is well-established. Fungi other than dermatophytes are often isolated from abnormal nails, which were often considered as colonizers or contaminants. However, currently it is generally accepted that they are capable of causing nail disease. Nondermatophytes are often accountable for a significant number of onychomycosis and may outnumber that caused by dermatophytes in certain geographic areas. [1] Some of these NDM are also capable of producing invasive fungal diseases in neutropenic and immune-suppressed patients, and hence their eradication may be essential. [2] Candida albicans is the most common yeast associated with onychomycosis, and is seen generally in the presence of finger nail paronychia. It can directly invade the nails in chronic mucocutaneous candidiasis, a condition associated with immunodeficiency. [3] It is difficult to clinically diagnose onychomycosis since many other nail diseases can resemble. It is even more difficult to obtain etiological diagnosis since isolation of the causative agent by microbiological techniques is a challenge. It is difficult to treat onychomycosis because eradication of the fungus (mycological cure) from the nail is difficult. In spite of the mycological cure, structural abnormality of the nail may not get corrected.


  Etiology and Prevalence Top


There seems to be a great geographic variation in the incidence of onychomycosis. Several factors such as age, climate, occupation, travel and hygiene seems to play a role in the prevalence of the disease. There is great variation in the agents causing onychomycosis in various geographic areas. Undoubtedly, dermatophytes are the most common causative organisms. Trichophyton rubrum is the most common causative agent among the dermatophytes followed by Trichophyton mentagrophytes. [4] Prevalence as high as 51.6% for NDM has been reported, but in general it is much less. [1] Dermatophytes affect both finger and toe nails but NDM generally affect toe nails. NDM are saprophytic and plant pathogens. Aspergillus species were more frequently isolated than other agents among the NDM. [5],[6],[7]] Scopulariopsis brevicaulis has also been reported as a frequent cause of onychomycosis. [8] [Table 1] shows the causes of dermatophytic and NDM onychomycosis. C. albicans is the most common cause of onychomycosis caused by yeasts but other Candida species are also rarely reported. Studies show various prevalence, but approximately 90% in toenail and 50% in fingernail infections may be caused by dermatophytes. [9],[10]
Table 1: List of dermatophytic and nondermatophytic moulds reported to be a cause of onychomycosis


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  Clinical Features Top


There are no specific clinical patterns for onychomycosis caused by DM and NDM, and all patterns as seen with dermatophytic infections are seen with NDM too. [9] It is difficult to distinguish dermatophytic infections from NDM infections by clinical features alone. Prior history of trauma, absence of tinea pedes and lack of response to systemic antifungals may suggest a possibility of onychomycosis due to nondermatophytes. Mechanical and chemical factors have a role in nail infection with surface adhesion followed by the invasion in to the layers of nail apparatus seems to be the determinants in the pathogenesis and the eventual type of onychomycosis. [10],[11]

Clinical forms of onychomycosis are distal lateral subungual onychomycosis (DLSO) [Figure 1], superficial white onychomycosis (SWO), proximal subungual onychomycosis (PSO), endothrix onychomycosis and total dystrophic onychomycosis (TDO) [Figure 2]. [9],[10],[11] Relative lack of effective cell-mediated immunity in the nail apparatus seems to make the nail more vulnerable to fungal infections. [11] There is also increased incidence of onychomycosis with advancing age. [12] Candidal onychomycosis is more frequent in women. [13]

Distal lateral subungual onychomycosis is the most common form of onychomycosis. The nail plate gets first affected from the under and lateral edges, and then spreads proximally along the nail bed resulting in to deposition of debris under the nail (subungual hyperkeratosis) and lifting up of the nail plate (onycholysis). PSO is a rarer form and is often reported in the presence of HIV disease. Fungus enters through the proximal part of the nail plate from under the surface of the proximal nail fold. Nail on the proximal part becomes yellow-white discolored and that gets spread distally across the nail bed. SWO is also a rare variety where there is a direct invasion of the nail plate with white discoloration and flakiness without nail bed being affected. Endonyx onychomycosis begins as DLSO, but nail plate gets discolored with minimal or no subungual hyperkeratosis or onycholysis. All these varieties eventually may lead to TDO over a long period of time.
Figure 1: Distal and lateral subungual onychomycosis of great toe with tinea pedes

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Figure 2: Total dystrophic onychomycosis of great toe nail

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Dermatophytes like T. rubrum, T. mentagrophytes, Trichophyton tonsurans, Epidermophyton floccosum are known to be causative agents of DLSO. Nondermatophytes that may be associated with DLSO are S. brevicaulis, Aspergillus species, Acremonium species and Fusarium oxysporum. [10] White superficial onychomycosis onychomycosis may be caused by T. mentagrophytes, Acremonium species, Aspergillus species and Fusarium. [10],[14]

It is difficult to distinguish onychomycosis caused by the various types of fungi. Associated infection of the foot (tinea pedes) is a feature favoring dermatophyte infections, but there are exceptions. [15] Nondermatophyte onychomycosis is often associated with inflammation of nail folds (paronychia), white discolotration of nail plates (leukonychia), or dark discoloration (melanonychia). [16],[17]

Yeast like C. albicans is a part of the normal flora of the skin, mucosa and gut. Nail infection by them may result due to four underlying mechanism namely chronic paronychia, secondary candidiasis, distal nail infection, or as a manifestation of chronic mucocutaneous candidiasis. [18] The most common form of Candida onychomycosis manifests secondary to paronychia, which is seen usually in patients with wet occupations. Damage to the cuticle is an important factor in pathogenesis, due to which yeasts and bacteria enter the subcuticular space at the proximal part of the nail. [18] Secondary candidal onychomycosis occurs in other diseases of the nail apparatus, most notably psoriasis. Chronic mucocutaneous is a rare variety seen in association with an immunocompromised state. There is direct invasion of the nail plate and swelling of the proximal and lateral nail folds leading to a pseudo-clubbing ("chicken drumstick"). [10]


  Laboratory Diagnosis Top


Collecting the nail specimen and transport

Heavily soiled nails especially toe nails have to be cleaned with soap and water; rub with alcohol to remove bacteria before collecting the nail sample. [19] The collection techniques recommended for different sites of infection of the nail apparatus for optimal recovery of the fungus are summarized in [Table 2]. [10],[20] The sample is collected on a sterile black filter paper or cardboard folder and transported to the mycology laboratory.
Table 2: Nail sampling for the laboratory diagnosis of onychomycosis


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  Specimen Analysis Top


Direct microscopy and laboratory culture for fungus is done to confirm and identify the etiological agent. Culture is mandatory even if the preliminary microscopic examination is negative as even a small amount of fungus is sufficient to isolate it in culture.


  Direct Microscopy Top


Different methods of microscopic techniques with or without stains are used as screening tests for confirming the presence or absence of fungi in the nail specimens even if the false negativity of this method amounts to 5-15%. [10] Most commonly potassium hydroxide mount is used as the microscopic method in the diagnostic laboratories. Adding a drop of parker blue-black ink or lactophenol cotton blue helps to visualize the fungal elements clearly. Use of chlorazol black E helps to differentiate between the fungi and elastic fibers or cotton fibers. Calcoflour white stain helps to confirm the presence of the fungi without any doubt. The only disadvantage of this stain is the requirement of fluorescent microscope.

Histopathological examination of nail clippings using periodic acid-Schiff stain helps to differentiate onychomycosis from other nail disorders such as psoriasis, or lichen planus. The test has very high sensitivity, and may also help to observe the depth of tissue invasion, type of mold (whether dermatophyte or nondermatophyte) to some extent. [20],[21]


  Culture Top


With the growing problem of antifungal resistance to common drugs culture of the specimens of onychomycosis helps to identify the causative organism and also has the advantage of subjecting the isolate to antifungal susceptibility testing. The nails are cultured on different media which suppress the contaminating bacteria and fungi. Onychomycosis can be due to dermatophyte or NDM therefore two media are used one selective for dermatophyte with cycloheximide and another without which allows NDM to grow. If there is growth on both it is dermatophyte otherwise it is NDM. To prevent the growth of the bacteria the Sabouraud dextrose agar with or without antibiotics like gentamicin or chloramphenicol and Littman's oxgall medium is used. NDM grows in 5-6 days while Candida grows within 24-48 h of culture. Candida species can be identified and antifungal susceptibility can be done using conventional and automated methods.

Isolation of dermatophyte always confirms the pathogen but the problem arises for the laboratory personnel when a NDM grows. It should be distinguished from contaminant and true pathogen. It is recommended to follow Gupta et al. inoculum counting (Walshe and English criteria) method in diagnosis of onychomycosis caused by nondermatophytic filamentous fungi. [9] If NDM is isolated, it should be considered as laboratory contaminants unless KOH or microscopy demonstrates atypical frond-like hyphae or if the same organism is repeatedly isolated. [10]

Molecular typing methods like polymerase chain reaction-restriction fragment length polymorphism can be used for epidemiological, research and confirmation purposes. They are time consuming and expensive methods usually done only by research laboratories. These methods cannot distinguish between true pathogens and contaminants on the sample. Immuno-histochemistry and dual flow cytometry can be used to identify mixed infections and for quantification of the fungal load.


  Treatment Top


There have been controversies regarding the therapy of onychomycosis. The available therapeutic options have not been proven to be universally efficacious, duration of therapy is long, and the drugs used are not very safe. Onychomycosis primarily a cosmetic problem, but it may have a negative psychological impact on afflicted persons. Persistence of the fungus in nail can serve as a reservoir for systemic infections and communicate the fungal infections to family members. Uniform guidelines for the therapy are also lacking. All these issues shall be discussed with the patients before the onset of the therapy. Convenient, cost effective antifungals with high and long-lasting cure rates are necessary, and many new therapies for onychomycosis are under investigation. [22]

It is preferable to establish the infection with laboratory methods before the therapy has begun. This will not ease the treating physician to choose the regime, but also to predict the prognosis. In spite of eradication of the fungus (mycological cure), anatomical abnormality of the nails may not be corrected (clinical cure). This may be especially true for nondermatophyte infections, because the nail may be abnormal prior to the fungal invasion. [23] Both topical and systemic therapies are used in onychomycosis. Combination of drugs with oral and topical therapy is also advocated and seems to be superior to the systemic therapy alone.

Currently available antifungal drugs for oral use include itraconazole, terbinafine, fluconazole, griseofulvin and ketoconazole. [24] All these drugs were found effective for the treatment of dermatophyte onychomycosis. Itraconazole or terbinafine may be useful in NDM infection too. Itraconazole and terbinafine have demonstrated efficacy and safety against some cases of S. brevicaulis toe onychomycosis. [24] Griseofulvin and ketoconazole is not recommended by many for onychomycosis given its very long duration of therapy and potentially serious adverse effects respectively. Fluconazole is less effective than terbinafine and itraconazole in the treatment of onychomycosis, but it is a choice when patients do not tolerate other oral antifungal agents. [25] Minimal dosing of fluconazole should be 150 mg/week for at least 6 months. Itraconazole and terbinafine appear to be the best systemic drugs for the therapy of onychomycosis due to their reservoir effects in the nails; however therapy is of long duration ranging from 6 weeks to 3 months or longer. Candidial onychomycosis responds to treatment with itraconazole and fluconazole. Addition of amorolfine to oral itraconazole pulse therapy is beneficial in the treatment of Candida fingernail onychomycosis. [26]

Topical treatment with terbinafine (with nail avulsion) or ciclopirox can be successful in the treatment of onychomycosis caused by dermatophytosis and certain nondermatophytes. [23] Ciclopirox may have a broad antimicrobial profile including dermatophytes, yeasts and nondermatophytes, and activity of ciclopirox and terbinafine suggests many instances of synergy. [27] Amorolfine is a structurally unique, topical antifungal agent, which possesses both fungistatic and fungicidal activity against dermatophyte, dimorphic, some dematiaceous and filamentous fungi, and some yeast. Application of amorolfine 5% nail lacquer once or twice weekly for up to 6 months produced mycological and clinical cure in approximately 40-55% of patients with mild onychomycosis. [28]

Recently the drugs such as itraconazole and terbinafine are used in pulsed manner. [29],[30] It is popularly given for 1 week in a month and such two to three pulses seem to be as effective as continuous treatment. This has enabled compliance, reduced cost and possibly lesser adverse effects. Newer drugs like posaconazole is being evaluated in the therapy. [31] Very recent addition to the therapeutic armamentarium is the 1064 nm neodymium-doped yttrium aluminum garnet laser, whose results are encouraging but the therapeutic regime needs optimization. [32]


  Conclusion Top


Onychomycosis is a cosmetic problem with negative psychological impact especially for the people in certain professions like front desk office, food industries, actors etc. Clinical and etiological diagnosis is challenging. Therapeutic outcome is not very satisfactory. [33] Newer regimes, drugs and even laser and light based therapies are being explored. For the future, it is an important area of research for the dermatologists and mycologists.

 
  References Top

1.Ungpakorn R, Lohaprathan S, Reangchainam S. Prevalence of foot diseases in outpatients attending the Institute of Dermatology, Bangkok, Thailand. Clin Exp Dermatol 2004;29:87-90.  Back to cited text no. 1
    
2.Cuenca-Estrella M, Gomez-Lopez A, Mellado E, Buitrago MJ, Monzón A, Rodriguez-Tudela JL. Scopulariopsis brevicaulis, a fungal pathogen resistant to broad-spectrum antifungal agents. Antimicrob Agents Chemother 2003;47:2339-41.  Back to cited text no. 2
    
3.Kirkpatrick CH. Chronic mucocutaneous candidiasis. Pediatr Infect Dis J 2001;20:197-206.  Back to cited text no. 3
    
4.Kaur R, Kashyap B, Bhalla P. Onychomycosis - epidemiology, diagnosis and management. Indian J Med Microbiol 2008;26:108-16.  Back to cited text no. 4
[PUBMED]  Medknow Journal  
5.Bassiri-Jahromi S, Khaksar AA. Nondermatophytic moulds as a causative agent of onychomycosis in Tehran. Indian J Dermatol 2010;55:140-3.  Back to cited text no. 5
[PUBMED]  Medknow Journal  
6.Hilmioglu-Polat S, Metin DY, Inci R, Dereli T, Kilinç I, Tümbay E. Non-dermatophytic molds as agents of onychomycosis in Izmir, Turkey - A prospective study. Mycopathologia 2005;160:125-8.  Back to cited text no. 6
    
7.Ramani R, Srinivas CR, Ramani A, Kumari TG, Shivananda PG. Molds in onychomycosis. Int J Dermatol 1993;32:877-8.  Back to cited text no. 7
    
8.Bonifaz A, Cruz-Aguilar P, Ponce RM. Onychomycosis by molds. Report of 78 cases. Eur J Dermatol 2007;17:70-2.  Back to cited text no. 8
    
9.Singal A, Khanna D. Onychomycosis: Diagnosis and management. Indian J Dermatol Venereol Leprol 2011;77:659-72.  Back to cited text no. 9
[PUBMED]  Medknow Journal  
10.Elewski BE. Onychomycosis: Pathogenesis, diagnosis, and management. Clin Microbiol Rev 1998;11:415-29.  Back to cited text no. 10
    
11.Grover C, Khurana A. Onychomycosis: Newer insights in pathogenesis and diagnosis. Indian J Dermatol Venereol Leprol 2012;78:263-70.  Back to cited text no. 11
[PUBMED]  Medknow Journal  
12.Westerberg DP, Voyack MJ. Onychomycosis: Current trends in diagnosis and treatment. Am Fam Physician 2013;88:762-70.  Back to cited text no. 12
    
13.Arenas R. Onychomycosis. Clinico-epidemiological mycological and therapeutic aspects. Gac Med Mex 1990;126:84-9.  Back to cited text no. 13
    
14.Gupta AK, Elewski BE. Nondermatophyte causes of onychomycosis and superficial mycoses. Curr Top Med Mycol 1996;7:87-97.  Back to cited text no. 14
    
15.Romano C, Valenti L, Difonzo EM. Two cases of tinea pedis caused by Scytalidium hyalinum. J Eur Acad Dermatol Venereol 1999;12:38-42.  Back to cited text no. 15
    
16.Gianni C, Romano C. Clinical and histological aspects of toenail onychomycosis caused by Aspergillus spp.: 34 cases treated with weekly intermittent terbinafine. Dermatology 2004;209:104-10.  Back to cited text no. 16
    
17.Godoy P, Nunes E, Silva V, Tomimori-Yamashita J, Zaror L, Fischman O. Onychomycosis caused by Fusarium solani and Fusarium oxysporum in São Paulo, Brazil. Mycopathologia 2004;157:287-90.  Back to cited text no. 17
    
18.Roberts DT, Taylor WD, Boyle J, British Association of Dermatologists. Guidelines for treatment of onychomycosis. Br J Dermatol 2003;148:402-10.  Back to cited text no. 18
    
19.Ghannoum MA, Isham NC. Dermatophytes and dermatophytoses. In: Anaissie EJ, Micheal RM, Micheal AP, editors. Clinical Mycology. 2 nd ed., Ch. 16. Philadelphia: Churchill Livingstone, Elsevier; 2009. p. 375-84.  Back to cited text no. 19
    
20.Shenoy MM, Teerthanath S, Karnaker VK, Girisha BS, Krishna Prasad MS, Pinto J. Comparison of potassium hydroxide mount and mycological culture with histopathologic examination using periodic acid-Schiff staining of the nail clippings in the diagnosis of onychomycosis. Indian J Dermatol Venereol Leprol 2008;74:226-9.  Back to cited text no. 20
[PUBMED]  Medknow Journal  
21.Gupta AK, Cooper EA, MacDonald P, Summerbell RC. Utility of inoculum counting (Walshe and English criteria) in clinical diagnosis of onychomycosis caused by nondermatophytic filamentous fungi. J Clin Microbiol 2001;39:2115-21.  Back to cited text no. 21
    
22.Kumar S, Kimball AB. New antifungal therapies for the treatment of onychomycosis. Expert Opin Investig Drugs 2009;18:727-34.  Back to cited text no. 22
    
23.Tosti A, Piraccini BM, Lorenzi S. Onychomycosis caused by nondermatophytic molds: Clinical features and response to treatment of 59 cases. J Am Acad Dermatol 2000;42:217-24.  Back to cited text no. 23
    
24.Gupta AK, Gregurek-Novak T. Efficacy of itraconazole, terbinafine, fluconazole, griseofulvin and ketoconazole in the treatment of Scopulariopsis brevicaulis causing onychomycosis of the toes. Dermatology 2001;202:235-8.  Back to cited text no. 24
    
25.Brown SJ. Efficacy of fluconazole for the treatment of onychomycosis. Ann Pharmacother 2009;43:1684-91.  Back to cited text no. 25
    
26.Rigopoulos D, Katoulis AC, Ioannides D, Georgala S, Kalogeromitros D, Bolbasis I, et al. A randomized trial of amorolfine 5% solution nail lacquer in association with itraconazole pulse therapy compared with itraconazole alone in the treatment of Candida fingernail onychomycosis. Br J Dermatol 2003;149:151-6.  Back to cited text no. 26
    
27.Gupta AK, Kohli Y. In vitro susceptibility testing of ciclopirox, terbinafine, ketoconazole and itraconazole against dermatophytes and nondermatophytes, and in vitro evaluation of combination antifungal activity. Br J Dermatol 2003;149:296-305.  Back to cited text no. 27
    
28.Haria M, Bryson HM. Amorolfine. A review of its pharmacological properties and therapeutic potential in the treatment of onychomycosis and other superficial fungal infections. Drugs 1995;49:103-20.  Back to cited text no. 28
    
29.Song Y, Zhong SX, Yao L, Cai Q, Zhou JF, Liu YY, et al. Efficacy and safety of itraconazole pulses vs. continuous regimen in cutaneous sporotrichosis. J Eur Acad Dermatol Venereol 2011;25:302-5.  Back to cited text no. 29
    
30.Gupta AK, Lynch LE, Kogan N, Cooper EA. The use of an intermittent terbinafine regimen for the treatment of dermatophyte toenail onychomycosis. J Eur Acad Dermatol Venereol 2009;23:256-62.  Back to cited text no. 30
    
31.Elewski B, Pollak R, Ashton S, Rich P, Schlessinger J, Tavakkol A. A randomized, placebo-and active-controlled, parallel-group, multicentre, investigator-blinded study of four treatment regimens of posaconazole in adults with toenail onychomycosis. Br J Dermatol 2012;166:389-98.  Back to cited text no. 31
    
32.Hees H, Jäger MW, Raulin C. Treatment of onychomycosis using the 1 064 nm Nd:YAG laser: A clinical pilot study. J Dtsch Dermatol Ges 2014;12:322-9.  Back to cited text no. 32
    
33.Shenoy MM, Shenoy SM. Nondermatophytic onychomycosis. In: Sacchidanand S, Savitha AS, editors. Nail & its Disorders. 1 st ed. New Delhi: Jaypee; 2013. p. 149-57.  Back to cited text no. 33
    


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Introduction
Etiology and Pre...
Clinical Features
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