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Onychomycosis: Diagnosis and definition of cure

´ Richard K. Scher, MD, FACP,a Amir Tavakkol, PhD, Dip Bact,b Bardur Sigurgeirsson, MD, PhD,c Roderick J. Hay, DM,d Warren S. Joseph, DPM,e Antonella Tosti, MD,f Philip Fleckman, MD,g Mahmoud Ghannoum, MSc, PhD,h David G. Armstrong, DPM,i Bryan C. Markinson, DPM,j and Boni E. Elewski, MDk New York, New York; East Hanover, New Jersey; Reykjavik, Iceland; Belfast, Ireland; Coatesville, Pennsylvania; Bologna, Italy; Seattle, Washington; Cleveland, Ohio; North Chicago, Illinois; and Birmingham, Alabama

Until now, there has been no agreement on criteria defining resolution of onychomycosis. Most published reports use clinical and mycological cure, which comprises a completely normal-appearing nail plate, and negative nail culture and microscopy results, as the end point for defining success of therapeutic intervention. Reported here is the definition of onychomycosis, which delineates both primary and secondary criteria for diagnosis of onychomycosis and identifies clinical and laboratory parameters to define a resolved fungal nail infection. Onychomycosis cure is defined by the absence of clinical signs or the presence of negative nail culture and/or microscopy results with one or more of the following minor clinical signs: (1) minimal distal subungual hyperkeratosis; and (2) nail-plate thickening. Clinical signs indicative of persistent onychomycosis at the end of the observation period include (1) white/yellow or orange/brown streaks or patches in or beneath the nail plate; and (2) lateral onycholysis with subungual debris. Although nail appearance will usually continue to improve after cessation of therapy, the nails may have a persistent abnormal appearance even in cases where treatment has been effective. ( J Am Acad Dermatol 2007;56:939-44.)

O

nychomycosis is estimated to affect approximately 2% to 13% of the population of North America and Europe.1-7 Both physician and patient expectations of treatment

outcome are influenced by the widely varying perceptions of what constitutes cure of onychomycosis. Yet, physicians often do not discuss with their patients the likely end result of therapy.

honoraria, and salary from this company. He is also an advisory board member, investigator, and consultant for Stiefel and has received grants and honoraria from this company. Dr Hay is an advisory board member receiving honoraria from Barrier. Dr Tosti is an advisory board member receiving honoraria from both Stiefel and Galderma. Dr Ghannoum is an investigator and speaker receiving grants and honoraria from Pfizer; and investigator and speaker receiving grants and honoraria from Enzon; an investigator and consultant receiving grants and honoraria from Schering-Plough; and investigator and speaker receiving grants and honoraria from Merck; an investigator receiving grants and honoraria from Vicuron; and a consultant receiving honoraria from NexMed. Dr Armstrong is an advisory board member and investigator for Lilly. He is also an advisory board member of, investigator for, and receives honoraria from Pfizer. Dr Markinson is a speaker, consultant, and advisory board member receiving honoraria and stock options for Bradley Pharmaceuticals and is an advisory board member receiving honoraria from Stiefel. Dr Elewski is an advisory board member receiving honoraria from Anacor and Stiefel and an investigator for Barrier and Novartis. Accepted for publication December 21, 2006. Reprint requests: Boni E. Elewski, MD, Department of Dermatology, University of Alabama, 700 18 St S, Suite 414, Birmingham, AL 35233. E-mail: [email protected] Published online February 20, 2007. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2006.12.019

From the Department of Dermatology, Columbia University, New Yorka; Dermatology Clinical Research, Novartis Pharmaceuticals Corporation, East Hanoverb; Department of Dermatology, University of Iceland, Reykjavikc; Queens University Belfastd; Veterans Administration Medical Center, Coatesvillee; Department of Dermatology, University of Bolognaf; Department of Medicine (Dermatology), University of Washington School of Medicine, Seattleg; Department of Dermatology, Case Western Reserve University, Clevelandh; Dr William M. Scholl College of Podiatric Medicine at Rosalind Franklin University of Medicine and Science, Green Oaks, North Chicagoi; Department of Orthopedic Surgery, Mount Sinai Medical Center, New Yorkj; and Department of Dermatology, University of Alabama, Birmingham.k Supported by Novartis Pharmaceuticals Corporation. Disclosure: This report is based on a consensus conference sponsored by Novartis Pharmaceuticals Corporation. Technical assistance from CPE Communications is appreciated. All contributors have received honoraria from Novartis Pharmaceuticals Corporation for their participation in the consensus conference meeting that formed the basis for this article. Dr Tavakkol is Director of Dermatology Clinical Research at Novartis Pharmaceuticals Corporation. All authors received honoraria from Novartis and are consultants/advisors, speakers, and investigators for Novartis. Dr Scher is a consultant, and investigator, and received honoraria and grants from Barrier. He is also an advisory board member, consultant, and received honoraria from Stiefel. Dr Sigurgeirsson is an investigator, consultant, and speaker for Galderma and has received grants,

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Table I. Diagnosis of onychomycosis caused by dermatophytes

Clinical Primary criteria White/yellow or orange/brown patches or streaks Secondary criteria* Onycholysis Subungual hyperkeratosis/debris Nail-plate thickening Laboratory Positive microscopic evidence Positive culture of dermatophyte

*Tinea pedis often occurs concomitantly with pedal onychomycosis, and tinea manuum with infected fingernails.

Table II. Poor prognostic factors

Areas of nail involvement [ 50% Significant lateral disease Subungual hyperkeratosis [ 2 mm White/yellow or orange/brown streaks in the nail (includes dermatophytoma14) 5. Total dystrophic onychomycosis (with matrix involvement) 6. Nonresponsive organisms (eg, Scytalidium mold) 7. Patients with immunosuppression 8. Diminished peripheral circulation 1. 2. 3. 4.

other nails, in some cases one or more of the other toenails will continue to show signs of infection.13

Further, clinicians base their therapeutic decisions on results of clinical trials. However, the current clinical trial data are often difficult to interpret and compare because there have been numerous definitions of ``cure'' and different measures used to assess treatment efficacy. Most published studies use different combinations and definitions of mycological cure (often defined as negative potassium hydroxide [KOH] microscopy and culture results), clinical cure (often defined as a percentage [eg, 80%-100%] of nail plate that is visibly clear of infection), and complete cure (mycological plus clinical cure) to define efficacy and cure. Large-scale and adequately powered clinical trials using the most stringent efficacy criteria often show low rates of therapeutic response and complete cure than seen in clinical practice or published studies. The lack of consistency in defining and measuring cure is one reason for the disparity between the results of therapy, as recorded in drug trials, and experience from clinical practice. For example, in an analysis of 26 published clinical studies for oral treatment of toenail onychomycosis, a complete cure was achieved in only 25% to 50% of patients receiving standard courses of therapy,8 and complete cure rates in the range of 14% to 38% have been reported in the prescribing information of Food and Drug Administrationeapproved oral agents.9,10 In clinical trials, efficacy assessments are often based on final evaluations at 48 to 52 weeks, but a toenail may not grow fully for up to 78 weeks.11,12 Although one would not expect all studies to be the same, variations in study designs might also account for some disparities in cure rate. In addition, many clinical studies base treatment success on the progress of a single target toenail, whereas in clinical practice, patients and physicians evaluate the potentially different responses of all toenails. Although mycological cure in a target toenail usually corresponds with similar trends in the

DIAGNOSIS OF ONYCHOMYCOSIS

The criteria for the diagnosis of dermatophyte onychomycosis, including both laboratory and clinical features, are summarized in Table I. Dependence on culture of an organism alone is not sufficient for the diagnosis of infectionea fungus isolated from a normal nail does not demonstrate infection. The reverse is also trueean abnormal nail without mycological confirmation is insufficient to make an accurate diagnosis of onychomycosis. The accurate diagnosis can be made only when both positive laboratory and clinical criteria are present. Tinea pedis and tinea manuum offer clinical clues of infection because they often occur concomitantly with pedal onychomycosis. Certain nail changes may be nonspecific. Onycholysis, for example, may result from trauma but could also be seen in psoriasis, as is subungual hyperkeratosis. Nail-plate thickening is also relatively nonspecific because it may be associated with trauma, onychogryphosis, lichen planus, and psoriasis. Other nail anomalies that are generally unrelated to onychomycosis include longitudinal or transverse ridging, pits, onychoschizia, and dryness of the nail plate. Surface leukonychia may be seen in some forms of onychomycosis, including white superficial onychomycosis and proximal white subungual onychomycosis, but is otherwise nonspecific. These factors make diagnosis of onychomycosis on clinical grounds alone difficult and correlation with mycological evidence critical. It should be noted that a variety of clinical signs present at the initial clinical evaluation indicate a poor overall prognosis for ultimate cure. These factors are listed in Table II.14,15 Definitive laboratory criteria include positive microscopic evidence of septate hyphae and/or arthroconidia (KOH preparation, Calcofluor white, Sigma-Aldrich, St Louis, Mo), periodic acideSchiff, and/or biopsy, and positive fungal culture findings for dermatophytes (Trichophyton, Epidermophyton,

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Table III. Proposed definitions of cure when assessing patients with onychomycosis in clinical trials

Criteria for cure: A) 100% Absence of clinical signs of onychomycosis (mycology not required) OR B) Negative mycological laboratory results with one or more of following clinical signs i) Distal subungual hyperkeratosis or onycholysis leaving less than 10% of nail plate affected ii) Nail-plate thickening that does not improve with treatment because of comorbid condition Criteria for noncure: A) Presence of positive mycological results OR B) Any one of the 4 clinical signs, even in the presence of negative mycological results i) Residual major changes ([10%) of the nail plate compatible with dermatophyte infection ii) White/yellow or orange brown/patches or streaks in or beneath the nail iii) Lateral onycholysis with debris in an otherwise clear nail plate iv) Hyperkeratoses on the lateral nail plate/nailfold edge (Fig 1, D)

or Microsporum species) or certain nondermatophyte nail pathogens (eg, Scytalidium dimidiatum and S hyalinum). Candida albicans can occasionally be a pathogen in fingernail disease, but clinical correlation is critical. Other nondermatophyte nail pathogens (certain species of Acremonium, Alternaria, Aspergillus, Fusarium, Onychocola, and Scopulariopsis) must be isolated from sequential specimens to prove origin, and correlation with direct microscopy and clinical changes is required. Mycology test results should be used to confirm the clinical diagnosis and it should be noted that absence of a proof is not a proof of absence. Successful eradication of the fungus may leave the nail abnormal and the residual changes may be totally unrelated to infection (eg, onychoschizia) or a result of damage to the nail unit from long-standing disease (eg, onycholysis). If onychomycosis is suggested based on clinical observation, diagnostic laboratory tests should be performed. If these produce negative findings, they should be repeated. Clinical manifestations of other nail disordersesuch as psoriasis, neosplasms, and lichen planusemay mimic those of onychomycosis but can be diagnosed by nail-unit biopsy.16-18

need to have realistic expectations of successful treatment outcome. Mycological cure signifies that the fungal infection has been successfully treated and has resolved, but it will not necessarily result in a 100% normal nail.19 Both intrinsic and extrinsic factors may influence the appearance of the nail. Trauma to the nail unit, particularly the bed and plate, may precede the development of onychomycosis and even a return to mycological negativity will not necessarily produce a normal-appearing nail. In severe cases of onychomycosis, up to 10% of the nail surface is likely to remain abnormal in appearance even when mycology indicates a cure of fungal infection.20

CLINICAL SIGNS ACCEPTABLE IN CURED CASES AT THE END OF THE OBSERVATION PERIOD

Several minor clinical signs that, when combined with negative mycology laboratory results, may be present in a patient who has been successfully cured are summarized in Table III. Although repeated mycological testing is not necessary, if clinical suggestion of infection is strong, a second sample should be taken to confirm the negative mycological results. The presence of minor clinical signs (Table III) and positive mycological laboratory results indicates that the nail is not cured, and further treatment and/or appropriate follow-up may be indicated. In contrast, in the absence of clinical signs of onychomycosis, mycology laboratory assessments (eg, either KOH or cultures) are not required to validate cure, although some physicians consider mycological confirmation optimal practice. Certain clinical signs may require diagnostic mycology laboratory tests to confirm cure. Distal onycholysis that has improved from baseline but affects more than 10% of the nail might be a clinical concern.

PRACTICAL CONSIDERATIONS FOR ASSESSING CURE

Although the goal of patients seeking treatment is almost always a normal-appearing nail, it has been suggested that cure of all 10 toenails is a desired clinical outcome, but the latter may be unattainable. It is important that patients understand the distinction between cure of their nail infection and gross appearance of the affected (now treated) nail, because some residual change is likely after chronic infection. Assessment of cure should not rely entirely on visual appearance, and patients and physicians

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Fig 1. Examples of pretreatment and posttreatment of onychomycosis. A, Patient (36-year-old man) who recently experienced subtle change of big toenail. There is mild distal onycholysis with bilateral edge involvement. In this case, it was impossible to make diagnosis of onychomycosis without laboratory confirmation. Microscopy produced positive results and Trichophyton rubrum was cultured from lateral edge. B, Patient (34-year-old man) with onychomycosis of distal subungual type with approximately 30% distal involvement. There is onycholysis with mild distal hyperkeratosis and nail-plate fragility. Microscopy revealed positive findings and T rubrum was cultured. C, Patient (29-year-old man) with distal lateral subungual onychomycosis (DLSO). Nail is 90% involved. Nail plate is thickened and subungal hyperkeratosis is apparent. This nail has several negative prognostic factors and is likely to be difficult to treat. On first sample, microscopy revealed positive findings, but culture produced negative results. However, T rubrum was grown on culture when second, more proximal sample was obtained. D, Patient (46-year-old woman) treated with standard course of oral antifungal. At baseline, nail had 50% area involvement and matrix was affected. Photograph was taken 18 months after treatment was initiated. Patient was satisfied and, on examination, only slight distal onycholysis and scaling/hyperkeratosis of lateral nailfolds was noted. When edge was trimmed, very little subungual debris could be found. Material was sent for culture; the microscopy revealed positive findings and T rubrum was cultured. E, Patient (64-year-old man) with severe onychomycosis before treatment was initiated. Nail displays several negative prognostic signs. Whole nail plate is involved; nail is thick; dermatophytoma is seen at left lateral edge; and there is severe hyperkeratosis at lateral edge. F, Patient was treated with standard course of oral antifungal. T rubrum could be cultured from nail up to 3 months after treatment was initiated and microscopy revealed positive findings for up to 1 year. Both culture and microscopy results remained negative at 18 and 24 months. Clinically, there is slight discoloration at distal edge of nail and minimal onycholysis is noted. These signs are minor and are compatible with cure because both microscopy and culture results were negative. G, Before treatment was initiated, 100% of nail plate was involved. Patient (37-year-old woman) was treated with standard course of oral therapy. T rubrum was cultured and microscopy revealed positive findings up to 6 months after treatment was initiated. Both parameters remained negative thereafter at 9, 12, 18, and 24 months. Clinical status improved continuously during and after treatment. Photograph shows nail at 12 months. Distal onycholysis can be seen, and considerable hyperkeratosis was noted when distal nail plate was removed. These signs are compatible with cure only in light of negative microscopy and culture results. Hyperkeratosis was not apparent at 18 and 24 months, but mild distal onycholysis could still be seen.

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Lateral nail plate/nailfold edge hyperkeratosis may also warrant additional tests.

RECURRENCE OF ONYCHOMYCOSIS

Recurrence (relapse or reinfection) of onychomycosis is not uncommon, with reported rates ranging from 10% to 53%.21-23 Recurrence often implies that, although the clinical signs have resolved, either mycological cure was not achieved with the initial treatment or a new infection has developed during or immediately after the treatment period. Thus, ensuring that mycological cure is achieved is important in questionable cases, so that relapse may be avoided. Positive mycological laboratory findings (KOH, periodic acideSchiff, or culture) are not consistent with cure. Examples of treated onychomycosis resulting in cure with and without residual clinical signs, and uncured onychomycosis, are depicted in Fig 1.

TIMING OF OBSERVATIONS

When evaluating newly formed nails for clearance of infection, it is important to remember that the time required for visible clearance of the infection is dependent on the rate of nail growth. Generally, it takes 12 to 18 months for a newly formed toenail plate, and 4 to 6 months for a fingernail to replace a diseased nail.24,25 Several factors may influence the rate of nail growth, including the age of the patient (the rate of linear nail growth decreases by 50% during a normal life span26), concomitant conditions,24 and certain medications that may cause either an increase or decrease in nail growth.24,27 Immediately after completion of therapy with one of the newer, long-lasting, systemic antimycotics, the nail usually does not appear to be clear of infection. A proximal area of normal-appearing nail, representing newly formed nail plate that is devoid of infection, may be present. Visible clearance of the infection will occur after the process of nail-plate turnover is complete.25 Thus, the concept of cure should allow for progress and growth from baseline. The same cure criteria should be applied during follow-up evaluations.

CONCLUSIONS

A nail plate with a normal appearance is not always attainable after a successful therapeutic onychomycosis regimen. Permanent nail anomalies may persist after elimination of the fungal pathogen in spite of the resolution of infection. Clinical and mycological criteria are important to ascertain both the diagnosis and resolution of onychomycosis.

REFERENCES 1. Elewski BE, Charif MA. Prevalence of onychomycosis in patients attending a dermatology clinic in northeastern Ohio for other conditions. Arch Dermatol 1997;133:1172-3.

2. Roberts DT. Prevalence of dermatophyte onychomycosis in the United Kingdom: results of an omnibus survey. Br J Dermatol 1992;126(Suppl):23-7. 3. Sais G, Jucgla A, Peyri J. Prevalence of dermatophyte onychomycosis in Spain: a cross-sectional study. Br J Dermatol 1995;132:758-61. 4. Heikkila H, Stubb S. The prevalence of onychomycosis in Finland. Br J Dermatol 1995;133:699-703. 5. Svejgaard EL, Nilsson J. Onychomycosis in Denmark: prevalence of fungal nail infection in general practice. Mycoses 2004;47:131-5. 6. Sigurgeirsson B, Steingrimsson O, Sveinsdottir S. Prevalence of onychomycosis in Iceland: a population-based study. Acta Derm Venereol 2002;82:467-9. 7. Gupta AK, Jain HC, Lynde CW, Watteel GN, Summerbell RC. Prevalence and epidemiology of unsuspected onychomycosis in patients visiting dermatologists'; offices in Ontario, Canadae a multicenter survey of 2001 patients. Int J Dermatol 1997;36: 783-7. 8. Epstein E. How often does oral treatment of toenail onychomycosis produce a disease-free nail? An analysis of published data. Arch Dermatol 1998;134:1551-4. 9. Sporanox (itraconazole) [prescribing information]. Titusville, NJ: Janssen; 2004. 10. Lamisil (terbinafine HCl) [prescribing information]. East Hanover, NJ: Novartis; 2004. 11. Werschler WP, Bondar G, Armstrong D. Assessing treatment outcomes in toenail onychomycosis clinical trials. Am J Clin Dermatol 2004;5:145-52. 12. De Cuyper C. Long-term outcomes in the treatment of toenail onychomycosis. Br J Dermatol 1999;141:15-20. 13. Gupta AK, Ryder J, Summerbell RC. Comparison of efficacy criteria across onychomycosis trials: need for standardization. Int J Dermatol 2003;42:312-5. 14. Roberts DT, Evans EG. Subungual dermatophytoma complicating dermatophyte onychomycosis. Br J Dermatol 1998;138: 189-90. 15. Scher RK, Baran R. Onychomycosis in clinical practice factors contributing to recurrence. Br J Dermatol 2003;149(Suppl):5-9. 16. Weinberg JM, Koestenblatt EK, Tutrone WD, Tishler HR, Najarian L. Comparison of diagnostic methods in the evaluation of onychomycosis. J Am Acad Dermatol 2003;49: 193-7. 17. Elewski BE, Hay RJ. Update on the management of onychomycosis: highlights of the third annual international summit on cutaneous antifungal therapy. Clin Infect Dis 1996;23: 305-13. 18. Trepanier EF, Amsden GW. Current issues in onychomycosis. Ann Pharmacother 1998;32:204-14. 19. Elewski BE. A full ``cure'' for onychomycosis is not always possible. Arch Dermatol 1999;135:852-3. 20. Hay RJ. The future of onychomycosis therapy may involve a combination of approaches. Br J Dermatol 2001;145(Suppl): 3-8. 21. Sigurgeirsson B, Olafsson JH, Steinsson JB, Paul C, Billstein S, Evans EG. Long-term effectiveness of treatment with terbinafine vs itraconazole in onychomycosis: a 5-year blinded prospective follow-up study. Arch Dermatol 2002;138: 353-7. 22. De Doncker PD, Gupta AK, Marynissen G, Stoffels P, Heremans A. Itraconazole pulse therapy for onychomycosis and dermatomycoses: an overview. J Am Acad Dermatol 1997;37: 969-74. 23. Villars VV, Jones TC. Special features of the clinical use of oral terbinafine in the treatment of fungal diseases. Br J Dermatol 1992;126(Suppl):61-9.

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24. Geyer AS, Onumah N, Uyttendaele H, Scher RK. Modulation of linear nail growth to treat diseases of the nail. J Am Acad Dermatol 2004;50:229-34. 25. Del Rosso JQ. Advances in the treatment of superficial fungal infections: focus on onychomycosis and dry tinea pedis. J Am Osteopath Assoc 1997;97:339-46.

26. Orentreich N, Markofsky J, Vogelman JH. The effect of aging on the rate of linear nail growth. J Invest Dermatol 1979; 73:126-30. 27. Jones HE, Zaias N. Double-blind, randomized comparison of itraconazole capsules and placebo in onychomycosis of toenail. Int J Dermatol 1996;35:589-90.

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