Onychomycosis E-Book
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The definitive guide to one of the world's most prevalent dermatologic conditions Onychomycosis is a fungal nail disease that accounts for 40% of all nail disorders, affecting 1 out of 10 people at some stage in their lives. Compiled by leading dermatologists with expert knowledge of the condition, Onychomycosis: Diagnosis and Effective Management provides a clear and clinically focused reference tool for those looking to treat patients expediently and successfully. This in-depth guide covers all aspects of disease management, from differential diagnosis and lab analysis to topical and systemic treatments. Designed to be a functional and accessible resource, the text also highlights key learning points, with real-life case studies and helpful take-home messages included in each chapter. Coverage of recent innovations and cutting-edge methods ensure the content is relevant to today's dermatologists, while thorough explanations of routine techniques, prognostic factors, and epidemiology make this is an excellent handbook for anyone studying the disease for the first time. The book features: * A complete guide to the diagnosis and treatment of this common disorder * Key learning points, case studies, and take-home messages to aid quick and easy consultation * Insights from world-renowned dermatological experts from North America and Europe * Over 70 illustrations Onychomycosis is a reliable, easy-to-use companion for trainees and experienced specialists alike, and an invaluable asset to any clinic treating nail conditions.
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Table of Contents
Cover
1 The History of Onychomycosis
1.1 Introduction
1.2 The History and Discovery of Onychomycosis
1.3 The Early Epidemiology of Onychomycosis
1.4 History of Treatment of Onychomycosis
References
2 Epidemiology of Onychomycosis
2.1 Introduction and Background
2.2 History of Onychomycosis
2.3 Incidence of Onychomycosis
2.4 Etiology of Onychomycosis
2.5 Risk Factors of Onychomycosis
References
3 Tinea Pedis and Onychomycosis
3.1 Patterns of Tinea Pedis
3.2 Patterns of Presentation of Tinea Pedis with Onychomycosis
3.3 Associations with Tinea Pedis and Onychomycosis
References
4 Clinical Features
4.1 Introduction
4.2 Site of Nail Invasion
4.3 Color Change
4.4 Other Structural Changes
4.5 Key Clinical Diagnostic Features
4.6 Classification of Onychomycosis
4.7 Paronychia
4.8 Clues to the Diagnosis
4.9 Diagnostic Clues
4.10 Secondary Nail Plate Infection
References
5 Grading Onychomycosis
5.1 Introduction
5.2 Methods for Grading
5.3 Using the OSI Scale
References
6a Routine and Emerging Techniques in Onychomycosis Diagnosis
6a.1 Introduction
6a.2 Clinical Diagnosis
6a.3 Routine Laboratory Diagnosis
6a.4 Sample Collection
6a.5 Direct Microscopy
6a.6 Culture
6a.7 Histopathology
6a.8 Emerging Techniques for the Diagnosis of Onychomycosis
6a.9 Dermoscopy
6a.10 Confocal Microscopy
6a.11 Polymerase Chain Reaction Testing
6a.12 Flow Cytometry
6a.13 Infrared Technology
6a.14 Scanning Electron Microscopy
6a.15 Conclusions
References
6b Histopathology of Onychomycosis
6b.1 Introduction
6b.2 Histopathology: The PAS Technique
6b.3 Advantages
6b.4 Drawbacks
6b.5 Conclusion
References
6c Dermoscopy in the Diagnosis of Onychomycosis
6c.1 Introduction
6c.2 Technique of Nail Dermoscopy
6c.3 Dermoscopy in Distal Subungual Onychomycosis
6c.4 Dermoscopy in White Superficial Onychomycosis
6c.5 Dermoscopy in Proximal Subungual Onychomycosis
6c.6 Dermoscopy in Total Dystrophic Onychomycosis
6c.7 Conclusions
References
Case Study
7 Differential Diagnosis of Onychomycosis
7.1 Introduction
7.2 Differential Diagnosis of Distal Lateral Subungual Onychomycosis
7.3 Differential Diagnosis of Superficial White Onychomycosis (SWO)
7.4 Differential Diagnosis of Proximal Subungual Onychomycosis (PSO)
7.5 Differential Diagnosis of Total Dystrophic Onychomycosis (TDO)
7.6 Differential Diagnosis of Peculiar Forms of Onychomycosis
References
8 Predicting the Outcome of Treatment
8.1 Introduction
8.2 Predicting the Outcome: Prognostic Factors
8.3 Local Prognostic Factors
8.4 Patient Factors
8.5 Mycology
8.6 Treatment‐Related Factors
8.7 Concomitant Risk Factors
8.8 Recurrence
8.9 Summary
References
9a Topical Therapies for Onychomycosis
9a.1 Introduction
9a.2 Candidates for Topical Therapy
9a.3 Formulations of Topical Agents
9a.4 Older Antifungal Agents
9a.5 New Topical Antifungals
9a.6 Drugs in Development
9a.7 Challenges to Drug Efficacy
9a.8 Nail Polish Compatibility
9a.9 Topical Onychomycosis Therapy in Combination with Systemic Agents
9a.10 Conclusions
References
9b Systemic Treatment of Onychomycosis
9b.1 Introduction
9b.2 Terbinafine
9b.3 Itraconazole
9b.4 Fluconazole
9b.5 Posaconazole
9b.6 Summary
References
9c(i) Laser Devices in the Treatment of Onychomycosis
9c(i).1 Introduction
9c(i).2 Mechanism of Action against Fungi
9c(i).3 Device Parameters
9c(i).4 Types of Lasers
9c(i).5
In Vitro
Studies
9c(i).6
In Vivo
Studies
9c(i).7 Adverse Events
9c(i).8 Discussion
9c(i).9 Conclusion
References
9c(ii) Photodynamic Therapy (PDT) in the Treatment of Onychomycosis
9c(ii).1 Introduction
9c(ii).2 Conclusions
References
9c(iii) Onychomycosis and Iontophoresis
References
9c(iv) Nail Drilling
9c(iv).1 Introduction
9c(iv).2 Nail Drilling Techniques
9c(iv).3 Other Purposes
9c(iv).4 Conclusions
References
9d Physical Treatment of Onychomycosis
9d.1 Introduction
9d.2 Indications
9d.3 Mechanical Debridement
9d.4 Chemical Avulsion
9d.5 Surgical Avulsion
9d.6 Management
9d.7 Summary
References
9e Onychomycosis: Algorithm
Scheme A: Dermatophytes Onychomycosis
Scheme B: Molds Onychomycosis
* Systemic Treatment
9f Prevention of Relapse and Re‐Infection: Prophylaxis
9f.1 Introduction
9f.2 Is It Necessary to Prevent and Cure Onychomycosis?
9f.3 How to Improve Long‐Term Cure and Reduce the Relapse Rate
9f.4 Non‐Dermatophyte Mold Onychomycosis
9f.5 Treatment of Predisposing Factors to Reduce the Recurrence Rate
9f.6 Measures to Prevent Re‐Infection
9f.7 Prophylaxis of Onychomycosis
References
10 Future Treatments for Onychomycosis
10.1 Introduction
10.2 Oral Drugs
10.3 Topical Drugs
10.4 Devices
10.5 Photodynamic Therapy
10.6 Future Drug Development
10.7 Conclusion
References
11 Onychomycosis in Special Populations
11.1 Introduction
11.2 Diabetes
11.3 Athletes
11.4 Vascular Impairment
11.5 HIV Infection and AIDS
11.6 Elderly
11.7 Nail Psoriasis
11.8 Other Populations with High Prevalence of Onychomycosis
11.9 Children
References
12 Onychomycosis
12.1 Introduction
12.2 The Podiatric Approach
12.3 Prevention of Onychomycosis Recurrence
12.4 Considerations in Beginning Nail Treatment
12.5 How to Debride
12.6 Nail Grinding
12.7 Conclusion
References
13 Home Remedies for Onychomycosis
13.1 Introduction
13.2 Essential Oils
13.3 Other
13.4 Oral Treatments
13.5 Conclusion
References
Index
End User License Agreement
List of Tables
Chapter 01
Table 1.1 Early development of medical mycology and onychomycosis.
Table 1.2 Change prevalence of onychomycosis over time. Myc = Mycological series. Shows the ratio of onychomycosis patients to other patients with superficial mycoses. Pat = Patient series. Pat nail = Series of patients with nail disease. Shows the ratio of patients with onychomycosis to patients visiting a clinic or hospital. Pop = Population series. Shows the ratio of patients with onychomycosis to the general or otherwise defined population.
Table 1.3 The history of onychomycosis treatment.
Chapter 03
Table 3.1 Differential diagnosis of scaling hands and feet.
Table 3.2 Features associated with variants of tinea pedis.
Table 3.3 Patterns and characteristics of tinea pedis.
Table 3.4 Lifestyle and disease associations with tinea pedis.
Chapter 04
Table 4.1 Classification of onychomycosis.
Chapter 06a
Table 6a.1 Physical examination recommendations and common signs and symptoms present in onychomycosis.
Table 6a.2 Common signs of onychomycosis by subtype.
Table 6a.3 Routine diagnosis of onychomycosis.
Table 6a.4 Summary of emerging techniques for the diagnosis of onychomycosis.
Chapter 08
Table 8.1 A list of local, host related, and mycological prognostic factors.
Table 8.2 Factors that influence the linear nail growth rate of nails.
Chapter 09a
Table 9a.1 Currently available topical therapy for onychomycosis.
Table 9a.2 Comparative efficacies of topical antifungals for onychomycosis.
Chapter 09cii
Table 9c(ii).1 Cases and clinical trials published.
Table 9c(ii).2 Proposed treatment protocol of PDT in onychomycosis.
Chapter 12
Table 12.1 BMAD from 2014 demonstrating the ranks for the five states with the largest number of podiatrists: California, Florida, New Jersey, New York, Pennsylvania. All have the same pattern as the national level.
List of Illustrations
Chapter 01
Figure 1.1 The first page from Meissner’s paper where he describes his discovery of the fungal nature of onychomycosis.
Figure 1.2 Meissner’s original clinical drawings of infected nails.
Figure 1.3 Meissner’s original drawings of the microscopic appearance of onychomycosis.
Figure 1.4 Clinical photographs of patients with onychomycosis.
Figure 1.5 The percentage of patients with onychomycosis out of all other mycoses (dashed line, % on left y‐axis). The percentage of
T. rubrum
out of all other fungi (solid line, % on right y‐axis).
Figure 1.6 The percentage of patients with onychomycosis out of all other mycoses from Mexico [30] (dashed line). The percentage of
T. rubrum
out of all other fungi (solid line).
Chapter 03
Figure 3.1 Tinea pedis of the 4th–5th web space.
Figure 3.2 Moccasin tinea pedis.
Figure 3.3 Tinea incognito with central clearance and papules with scale at the margins.
Chapter 04
Figure 4.1 Streaking pattern in onychomycosis due to
Trichophyton mentagrophytes
.
Figure 4.2 Onychomycosis due to
Fusarium
species showing mixed patterns of infection and cellulitis associated with dissemination in a neutropenic patient.
Figure 4.3 Onycholysis with
Paecilomyces
.
Figure 4.4 Clinical classification of onychomycosis.
Figure 4.5 Distal and lateral onychomycosis due to
S. brevicaulis
.
Figure 4.6 Superficial onychomycosis due to
Acremonium
.
Figure 4.7 Totally dystrophic onychomycosis due to
C. albicans
in a patient with chronic mucocutaneous candidiasis.
Figure 4.8 Early DLSO caused by
N. dimidiatum
.
Chapter 05
Figure 5.1 Notched onychomycosis‐affected nail. Many studies notch the nail to monitor growth.
Figure 5.2 Grading proximity to the matrix. This nail would be graded as a 4 because the most proximal involvement falls in the fourth quadrant.
Figure 5.3 Distal lateral subungual onychomycosis (DLSO) with dermatophytoma. Note the yellow, dense blotches identifying the several dermatophytomas.
Figure 5.4 Distal subungual onychomycosis with subungual hyperkeratosis. The hyperkeratosis would be measured from nail bed to bottom of nail plate, considered significant if > 2 mm.
Chapter 06a
Figure 6a.1 Clinical appearance of onychomycosis. (a) Great toenail with hyperkeratosis, subungual debris, yellowing and onycholysis. (b) Long‐standing onychomycosis with hyperkeratosis, subungual debris, onycholysis, and nail plate splitting.
Figure 6a.2 Ideal subungual sample.
Figure 6a.3 KOH,
T. rubrum
,
T. mentagrophytes
.
Figure 6a.4
T. rubrum
and
T. mentagrophytes
colonies.
Figure 6a.5 PAS and GMS stained sections of onychomycosis.
Chapter 06b
Figure 6b.1 Onychomycosis due to yeasts: groups of spores (some of them budding) and pseudo‐hyphae invading the ventral part of the nail plate.
Figure 6b.2 Onychomycosis due to molds: thin, perforating filaments arising from irregular hyphae penetrate the nail plate perpendicularly.
Figure 6b.3 Ventral nail plate in a longitudinal nail biopsy stained with PAS. Psoriasiform onychomycosis due to dermatophytes: numerous regular, straight, septate, hyphae that tend to run parallel to the nail surface.
Chapter 06c
Figure 6c.1 Dermoscopy of DSO shows white‐yellow longitudinal spikes directed to the proximal fold.
Figure 6c.2 Dermoscopy of dermatophytoma showing an irregularly round discoloration under the nail plate, with yellow‐orange homogeneous matte color, connected with the distal margin by a longitudinal yellow‐white band.
Figure 6c.3 Dermoscopy of the distal nail margin in fungal melanonychia, showing accumulation of whitish and brown‐black scales under the detached nail plate.
Figure 6c.4 Dermoscopy of WSO shows large, white‐to‐yellow, friable patches irregularly spread on the nail surface.
Figure 6c.5 Dermoscopy of total onychomycosis showing a grossly friable nail plate with yellow‐white scales and distal irregular termination.
Clinical case Figure 6c.1a
Clinical case Figure 6c.2a
Clinical case Figure 6c.1b
Clinical case Figure 6c.2b
Chapter 08
Figure 8.1 Two patients (a and b) with onychomycosis. Both are treated with a standard 12‐week course of terbinafine, 250 mg daily. Although both patients show good response to treatment, only patient (a) is cured at the end of follow‐up. Microscopy/culture. D dermatophyte, – negative, + positive.
Figure 8.2 Examples of patients with lateral edge involvement.
Figure 8.3 Examples of patients with thick hyperkeratotic nails. It is logical that it can be difficult to treat patients with a thick nail plate or subungual hyperkeratosis, as it is likely that it is more difficult for the drug to reach sufficient concentration in thick hyperkeratotic nails.
Figure 8.4 Examples of patients with onycholysis. It is logical that it can be difficult for a topical or systemic drug to penetrate a layer of air.
Figure 8.5 Examples of patients with matrix involvement.
Figure 8.6 Examples of patients with dermatophytoma and spikes.
Chapter 09d
Figure 9d.1 Severe onycholysis due to onychomycosis in an old woman.
Figure 9d.2 Severe subungual hyperkeratosis on the great toenail (dermatophytoma).
Figure 9d.3 Yellow spikes.
Figure 9d.4 Lateral involvement of the plate (lateral disease).
Figure 9d.5 Blackish discoloration due to
Scopulariopsis brevicaulis
.
Figure 9d.6 Dual action nail clippers.
Figure 9d.7a Onychomycosis involving the whole plate with extensive onycholysis.
Figure 9d.7b After debridement with dual action nail clippers.
Figure 9d.8 (a) Debridement with nail clippers; (b) after debridement; (c) gentle curettage of the subungual debris; (d) vigorous rubbing of the bed with a wet gauze; (e) final aspect.
Figure 9d.9 (a) Onychomycosis with yellow spikes; (b) urea past applied to the plate; (c) application of the ergonomic dressing; (d) dressing completed.
Figure 9d.10 (a) Detachment of the plate from the bed with the elevator; (b) clipping away the detached nail plate; (c) hemostasis with Monsel’s solution.
Chapter 09f
Figure 9f.1 Schematic illustration of onychomycosis relapse and re‐infection.
Figure 9f.2 The asymmetric gait nail unit syndrome (AGNUS) with the characteristic foot deformation is a frequent cause of misdiagnosis and wrong antifungal treatment.
Figure 9f.3 Onychomycosis of the big toenail due to
Fusarium oxysporum
.
Figure 9f.4 Onycholytic big toenail with culture‐proven
Aspergillus glaucus
.
Figure 9f.5
Scytalidium dimidiatum
infection of the big toenail.
Figure 9f.6 Onychomycosis in a male patient aged 90 years with severe arterial impairment.
Figure 9f.7 Extremely thick subungual hyperkeratosis and severe nail destruction in a male patient with the one‐hand two‐feet syndrome.
Figure 9f.8 Hypertrophic nail dystrophy with fungal infection after ingrown nail surgery
alio loco
.
Figure 9f.9 Refractory onychomycosis in a big toenail surrounded by nail folds on all four sides. The nail cannot grow forward, thickens, and becomes onycholytic.
Figure 9f.10 Recalcitrant onychomycosis in a previously operated on big toe.
Figure 9f.11 Posttraumatic single digit onychomycosis in a young woman. This infection developed five months after a crush trauma. Repeated direct microscopy and cultures were negative; histopathology of the nail revealed an invasive onychomycosis.
Figure 9f.12 Onychomycosis of the big toe with a yellow streak. This phenomenon is also called dermatophytoma as it harbors huge amounts of very thick‐walled arthrospores and short filaments.
Chapter 10
Figure 10.1 Chemical structure of albaconazole [12].
Figure 10.2 Chemical structure of posaconazole [16].
Figure 10.3 Chemical structure of methylene blue [52].
Chapter 11
Figure 11.1 Onychomycosis of the toenails in a diabetic patient. Besides of the clinical features of vascular impairment a chronic ulcer on the ventral part of right foot.
Figure 11.2 Nail dystrophy and onychomycosis in a soccer player. Observe the worst condition of the right big toenail where the trauma is more frequent.
Figure 11.3 Total dystrophic onychomycosis caused by
T. rubrum
in patients with HIV infection.
Figure 11.4 Nail psoriasis, onycholysis, and onychomycosis due to
Candida
species of the fingernails.
Figure 11.5 Onychomycosis of the toenails in a patient with tuberculoid leprosy.
Chapter 12
Figure 12.1 Perpendicular orientation.
Figure 12.2 Parallel orientation.
Figure 12.3 Incurvated nail border.
Figure 12.4 Nail removal.
Figure 12.5 Nail bed erythema.
Guide
Cover
Table of Contents
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Onychomycosis
Diagnosis and Effective Management
Edited by
Dimitris Rigopoulos, MD
Andreas Sygros Hospital
Greece
Boni Elewski, MD
University of Alabama at Birmingham
USA
Bertrand Richert, MD, PhD
Université Libre de Bruxelles
Belgium
This edition first published 2018© 2018 John Wiley & Sons Ltd
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The right of Dimitris Rigopoulos, Boni Elewski, and Bertrand Richert to be identified as the authors of editorial material in this work has been asserted in accordance with law.
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Library of Congress Cataloging‐in‐Publication Data
Names: Rigopoulos, Dimitris, editor. | Elewski, Boni, editor. | Richert, Bertrand, editor.Title: Onychomycosis: diagnosis and effective management / edited by Dimitris Rigopoulos, Boni Elewski, Bertrand Richert.Other titles: Onychomycosis (Rigopoulos)Description: Hoboken, NJ: Wiley, 2018. | Includes bibliographical references and index.|Identifiers: LCCN 2018000517 (print) | LCCN 2018000729 (ebook) | ISBN 9781119226499 (pdf) | ISBN 9781119226505 (epub) | ISBN 9781119226536 (cloth)Subjects: | MESH: OnychomycosisClassification: LCC RL170 (ebook) | LCC RL170 (print) | NLM WR 475 | DDC 616.5/47–dc23LC record available at https://lccn.loc.gov/2018000517
Cover Design: WileyCover Image: Top two images courtesy of Roderick Hay; Bottom image courtesy of Eckart Haneke
List of Contributors
Aurora AlessandriniDepartment of Internal Medicine, Geriatrics and Nephrology Division of Dermatology University of Bologna Bologna, Italy
Josette AndréHead of Department Dermatology and Dermatopathology Lab CHU Saint‐Pierre, CHU Brugmann and Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles Brussels, Belgium
Jane S. BelletAssociate Professor of Pediatrics and Dermatology Duke University School of Medicine Durham, NC, USA
David de BerkerBristol Dermatology Centre University Hospitals Bristol Bristol, UK
Francesca BruniDepartment of Experimental, Diagnostic and Specialty Medicine, Division of Dermatology University of Bologna Bologna, Italy
Theresa CanavanDepartment of Dermatology University of Alabama at Birmingham Birmingham, AL, USA
Nilton Di ChiacchioDermatology Clinic, Hospital do Servidor Público Municipal de São Paulo São Paulo, Brazil
Nilton Gioia Di ChiacchioDermatology Clinic, Hospital do Servidor Público Municipal de São Paulo; and Department of Dermatology Medicine School of ABC São Paulo, Brazil
Luisa ChristensenDepartment of Dermatology University Hospitals Cleveland Medical Center Cleveland, OH, USA
Lauren DabakaroffDivision of Podiatric Medicine and Surgery Icahn School of Medicine at Mount Sinai New York, NY, USA
C. Ralph Daniel, IIIClinical Professor of Dermatology University of Mississippi; and Clinical Professor of Dermatology University of Alabama in Birmingham Jackson, MI, USA
Boni ElewskiDepartment of Dermatology University of Alabama at Birmingham Birmingham, AL, USA
Mahmoud A. GhannoumCenter for Medical Mycology University Hospitals Cleveland Medical Center Case Western Reserve University Cleveland, OH, USA
Aditya K. GuptaDepartment of Medicine, University of Toronto School of Medicine, Toronto; Mediprobe Research Inc., London, Ontario, Canada
Eckart HanekeDepartment of Dermatology, Intelspital University of Bern, Bern, Switzerland; Dermatological Practice “Dermaticum,” Freiburg, Germany; Centro Dermatologia “Epidermis,” CUF Porto Instituto Matosinhos, Portugal; and Department of Dermatology, University Hospital, Ghent, Belgium
Anna Q. HareDepartment of Dermatology Oregon Health and Science University Portland, OR, USA
Roderick J. HaySkin Infections Clinic, Dermatology Department, King’s College Hospital NHS Trust, London, UK
Dimitris IoannidesFirst Dermatology Department Aristotle University of Thessaloniki Greece
Pauline LecerfDermatology Department, CHU Brugmann – Saint‐Pierre – HUDERF Université Libre de Bruxelles, Brussels Belgium
Shari R. LipnerWeill Cornell Medicine, New York, NY, USA
Austin John MaddyDepartment of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
Bryan C. MarkinsonDepartment of Orthopedic Surgery/Department of Dermatologic Surgery Icahn School of Medicine at Mount Sinai New York, NY, USA
Tyrone A. MayorgaNew York College of Podiatric Medicine New York, NY, USA
Bianca Maria PiracciniDepartment of Experimental, Diagnostic and Specialty Medicine, Division of Dermatology University of Bologna Bologna, Italy
Christos PrevezasSecond Department of Dermatology and Venereology, National and Kapodistrian University of Athens, Medical School Attikon University Hospital Greece
Phoebe RichDepartment of Dermatology, Oregon Health and Science University, Portland, OR, USA
Bertrand RichertDepartment of Dermatology, Brugmann Saint‐Pierre and Queen Fabiola Children’s University Hospitals, Université Libre de Bruxelles, Brussels Belgium
Dimitris RigopoulosFirst Department of Dermatology and Venereology National and Kapodistrian University of Athens Medical School, Andreas Sygros Hospital Greece
Adam I. RubinDepartment of Dermatology, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania Philadelphia, PA, USA
Iman SalemCenter for Medical Mycology University Hospitals Cleveland Medical Center Case Western Reserve University Cleveland, OH, USA
Richard K. ScherWeill Cornell Medicine New York, NY, USA
Avner ShemerSheba Medical Center, Tel Hashomer Ramat Gan; and Tel Aviv University Tel Aviv, Israel
Bárður SigurgeirssonDepartment of Dermatology Faculty of Medicine, University of Iceland Reykjavík, Iceland
Elena SotiriouFirst Dermatology Department Aristotle University of Thessaloniki Greece
Michela StaraceDepartment of Experimental, Diagnostic and Specialty Medicine, Division of Dermatology University of Bologna Bologna, Italy
Antonella TostiDepartment of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
Ioanna TriantafyllopoulouFirst Department of Dermatology and Venereology National and Kapodistrian University of Athens Medical School, Andreas Sygros Hospital Greece
Sarah G. VersteegMediprobe Research Inc., London Ontario, Canada
Casey WangDepartment of Dermatology University of Alabama at Birmingham Birmingham, AL, USA
1The History of Onychomycosis
Bárður Sigurgeirsson
Department of Dermatology, Faculty of Medicine, University of Iceland, Reykjavík, Iceland
1.1 Introduction
The modern history of medical mycology is relatively short (Table 1.1). It was Agostino Bassi (1773–1856) who in 1836 described the muscardine disease of silkworms which was caused by a fungus that would be named eventually Beauveria bassiana in his honor [1]. The clinical aspects of dermatomycoses have been known for a much longer time. Aulus Cornelius Celsus (c. 25 BC to c. 50 AD) recognized inflammatory tinea and described the first kerion celsi, a name still used today [2]. At that time, no microscopic knowledge existed and therefore the study of diseases was purely based on clinical findings. Favus and sycosis were already known in ancient times (the word means tinea in Egyptian).
Table 1.1 Early development of medical mycology and onychomycosis.
Year
Author
Comment
References
1835
Bassi
Discovers that muscardine disease of silkworms is caused by a fungus
[
1
]
1837
Remak
Observes microscopic structures appearing as rods and buds in crusts from favic lesions. Does not publish his observations, but allows his findings to be cited in a doctoral thesis of Xavier Hube
Not published [
3
]
1839
Schönlein
Communicates the fungal nature of dermatomycoses
[
4
]
1841–1844
Gruby
Unware of Remek’s and Schönlein’s findings, he describes clinical and microscopic characteristics of the causative agent of favus
[
5
–
8
]
1853
Meissner
Discovers that onychomycosis is caused by fungi
[
9
]
1854
Virchow
First to use the name onychomycosis for this new disease
[
10
]
Johannes Schönlein was the first to understand the fungal nature of dermatomycoses [4]. Sabouraud began his scientific studies of the dermatophytes around 1890, culminating in the publication of his classic volume, Les Teignes, in 1910 [11]. No specific antifungal drugs existed until after World War II.
1.2 The History and Discovery of Onychomycosis
A German medical student, Georg Meissner (19 November 1829 to 30 March, 1905) was the first to describe the fungal nature of onychomycosis in 1853 (Figure 1.1) [9]. It was Meissner later who became famous for discovering the tactile instrument of the skin (Meissner’s corpuscle). Meissner described accurately both the clinical and mycological form of onychomycosis [9]. He also included drawings of the clinical appearance of the disease (Figure 1.2). He described how he softened the nail by using sodium hydroxide, and it is important that to remember that at that time microscopes were still very simple and dyes were not used. Meissner also described and drew filamentous fungi and spores (Figure 1.3).
Figure 1.1 The first page from Meissner’s paper where he describes his discovery of the fungal nature of onychomycosis.
Figure 1.2 Meissner’s original clinical drawings of infected nails.
Figure 1.3 Meissner’s original drawings of the microscopic appearance of onychomycosis.
Most scholars give Meissner the honor of having discovered onychomycosis [12], although the fungal nature of onychomycosis had been suspected earlier. In a letter to the editor of The Boston Medical and Surgical Journal(today N Engl J Med) “On Fungus Ulcer of the Toe, or That Disease Usually Styled Inverted Toe Nail”, J.P. Leonard describes various methods for treating onychomycosis [13].
Onychomycosis and tinea pedis usually go hand in hand. It is hard to imagine that the first case of tinea pedis was described only 129 years ago by an Italian dermatologist, Celso Pellizzari [14]. Most of the early reports on onychomycosis and tinea pedis are from Europe [15]. The first reported case of tinea pedis in the United States was noted in Birmingham, Alabama, in the 1920s [16].
World War I troops returning from battle may have transported Trichophyton rubrum to the United States [16]. The first case of toenail onychomycosis presented in the United States is from 1937, when Montgomery presented a 28‐year‐old woman with onychomycosis before the Manhattan Dermatologic Society on 14 December 1937 [17]. However “mycotic conditions of the nails” were described much earlier in the United States and Guy and Jacob in 1923 recognized hyperhidrosis as a risk factor for onychomycosis and tinea pedis. They also understood that “injury is a definite factor; mycotic conditions of the nails, especially, often date from injury” [18]. In a personal case series from 1927, White reported on 1013 patients diagnosed with “fungus diseases of the skin” between 1910 and 1925 [19]. Only three patients were diagnosed in 1910 and 147 in 1925. Out of these 1013 patients, 23 (2.3%) had onychomycosis and 341 (33.7%) had tinea pedis [19].
The history of onychomycosis is short and parallels that of tinea pedis and the invasion of dermatophyte T. rubrum into the Western world [20]. T. rubrum is today the major cause of onychomycosis worldwide [21].
T. rubrum originated from West Africa and the Eastern world. The native populations of these areas did not develop tinea pedis or onychomycosis, probably because they mainly walked barefoot [22]. When the colonialists and soldiers arrived, wearing boots, which caused hyperhidrosis and maceration of the feet, it was easy for T. rubrum to find a new home. During the late eighteenth and early nineteenth centuries, there was increased urbanization and traveling. The great wars (World War I and II and the Vietnam War) may have contributed further to the spread of T. rubrum. Modern lifestyle with leisure travel and the “health boom” with frequent use of gyms and shared bathing facilities may have helped further with the dramatic increase of onychomycosis that we have seen during the past 100 years.
1.3 The Early Epidemiology of Onychomycosis
Onychomycosis is so common today that every dermatologist examines several cases a week or even several a day. On the other hand, during the nineteenth and early twentieth centuries onychomycosis was a very rare disease.
Julius Heller, a German dermatologist (1864–1931), published a book on nail diseases which he simply named Diseases of the Nails (Die Krankheiten der Nägel). It was first published in 1900 [23], and a second edition came out in 1927 [24]. This book can be considered the bible of nail diseases at that time.
In his book, Dr. Heller writes: “I myself pay close attention to the nail diseases and have, despite large nail medical material, at most seen 7–8 cases between 1896 and 1923” (one case every 4–5 years). What a contrast to the modern dermatologist, who can see several cases in a single day. Despite this, Heller’s clinical description is impeccable and also includes photographs (Figure 1.4).
Figure 1.4 Clinical photographs of patients with onychomycosis.
Source:[24]. Reproduced with permission of Springer.
The famous dermatologist Jean Darier collected material from 3000 cases of dermatomycoses. In this material there were only three patients with onychomycosis [25].
Dr. Sabouraud, considered by many to be the father of modern mycology, noted in 1910 in his classic monograph that out of 500 patients with superficial fungal infections only one (0.2%) had onychomycosis [11]. This is in great contrast to recent laboratory series, where more than 50% of the subjects have onychomycosis [26].
In the United States, Dr. Milton Foster looked at immigrants in 1915 on Ellis Island and found 101 cases out of 521 366 (0.02%) immigrants examined with onychomycosis (cited in Heller [24]). White, in 1902, examined 485 patients with nail disease and found eight with onychomycosis, or 1.6%, [27]. This is far from the figures seen today where at least 50% of patients with nail diseases have onychomycosis.
Onychomycosis was rare at the start of the 20th century but has increased dramatically during the last century. Krönke comments in his thesis that onychomycosis rose sharply in Germany after World War I [28]. This is understandable and likely, because of poor hygienic conditions during the war and close‐quarter living [29].
Data on the changes in prevalence of onychomycosis do not exist. However, by examining the ratio between onychomycosis and all other mycoses, one can predict the changes in prevalence of onychomycosis. Also, in hospital series that exist, there is information about all cases seen at these hospitals and how many of these had onychomycosis. In Figure 1.5 the ratio over time of onychomycosis compared to all other superficial mycoses is shown. In this figure it is interesting to see that the increase in prevalence of onychomycosis goes hand in hand with the increase of T. rubrum (data from [21] and a personal database from the literature). Single‐center data over long periods, on the prevalence of onychomycosis, are rare. One of the best series is from Mexico [30]. It is obvious that this single‐center data shows the same trend (Figure 1.6) as the accumulated data (Figure 1.5) and further supports dramatic increase of onychomycosis, mostly due to an increase in T. rubrum, during the last 100 years.
Figure 1.5 The percentage of patients with onychomycosis out of all other mycoses (dashed line, % on left y‐axis). The percentage of T. rubrum out of all other fungi (solid line, % on right y‐axis).
Figure 1.6 The percentage of patients with onychomycosis out of all other mycoses from Mexico [30] (dashed line). The percentage of T. rubrum out of all other fungi (solid line).
Source: Reproduced with permission of Oxford University Press.
1.4 History of Treatment of Onychomycosis
The medical treatment of onychomycosis has changed considerably over the past 150 years from the crude topical treatments (Table 1.2) to the current use of active and specific antifungal agents. When the fungal nature of onychomycosis was discovered, there were not many treatment options (Table 1.3). Treatment was almost exclusively topical. The mechanism of action was nonspecific. Historically, several topical antifungal agents have been used in the treatment of onychomycosis; however, the evidence for their effectiveness is based on very limited data or anecdotal reports. The following treatment was presented by Wigglesworth in the Boston Medical and Surgical Journal (later N. Engl. J. Med), based on a case he saw at the St. Louis Hospital in Paris:
To treat true onychomycosis the nail should be thinned by scraping with a bit of glass, and then wet frequently with corrosive sublimate (mercuric chloride) one gramme in two hundred of water, which is about three times as strong as one would use it upon the skin or hair [31].
Table 1.2 Change prevalence of onychomycosis over time. Myc = Mycological series. Shows the ratio of onychomycosis patients to other patients with superficial mycoses. Pat = Patient series. Pat nail = Series of patients with nail disease. Shows the ratio of patients with onychomycosis to patients visiting a clinic or hospital. Pop = Population series. Shows the ratio of patients with onychomycosis to the general or otherwise defined population.
Author
Year
Country
Comment
Type
%
References
Anderson
1873
UK
11 000 consecutive patients with skin diseases Of these, 178 had superficial fungal infections but no cases of onychomycosis were discovered
Pat
0
[
32
]
Bulkley
1875
US
Analyzed 1000 patients with skin disease 300 ha ds superficial fungal infection but no cases of onychomycosis were found
Pat
0
[
33
]
Block
1888
Germany
3000 patients with skin disease 300 with superficial fungal infections 2 with onychomycosis
Myc
0.7
[
34
]
Arnozan
1889
France
3700 patients with skin diseases 11 cases of onychomycosis
Pat
0.3
[
35
]
Heller
1900
Germany
Dr. Heller writes: “I myself pay close attention to the nail diseases and have, despite large nail medical material, at most seen 7–8 cases between 1896 and 1923” (case every 4–5 years)
Pat
?
[
23
]
White
1902
US
Examined 485 patients with nail disease and found 8 with onychomycosis
Pat nail
[
27
]
Crocker
1905
US
Out of 1000 patients with skin dieses, 2 had onychomycosis
Pat
0.2
Cited in Heller [
24
]
Sabouraud
1910
France
Only 1 case of onychomycosis amongst 500 patients with superficial fungal infections
Myc
0.2
[
11
]
Foster
1915
US
Looked at immigrants on Ellis Island and found 101 onychomycosis cases out of 521 366 (0.02%) immigrants
Pop
0.02
Cited in [
24
]
Wirz
1923
Germany
2898 patients with superficial mycoses
Myc
0.14
[
36
]
Darier
1928
France
Only 3 cases of onychomycosis amongst 3000 patients with a superficial fungal infection
Myc
0.1
[
37
]
Krönke
1935
Germany
Single‐center epidemiological study between 1919 and 1934 Total of 273 258 patients with skin disease 91 cases of onychomycosis were found Male/female ratio was 1.5
Myc
2.2
[
28
]
Boedyn
1938
US
Single‐center mycological study during the year 1935 106 cases diagnosed with a superficial mycosis 5 with onychomycosis
Myc
4.7
[
38
]
Zündel
1939
Germany
133 cases of superficial mycoses 13 with onychomycosis
Myc
10
[
39
]
Mu
1939
China
Between 1925 and 1938, 36 847 patients were seen 6006 cases of superficial mycoses were diagnosed 113 patients had onychomycosis
Myc
1.9
[
40
]
Perpignano
1939
Italy
Superficial mycoses in the province of Cagliari 2107 superficial mycoses were diagnosed
Myc
0.6
[
41
]
Grimmer
1954
Germany
134 cases of superficial mycoses between 1952 to 1954 60 with onychomycosis
Myc
44
[
42
]
Langer
1957
Germany
1705 cases of superficial mycoses between 1955 to 1956 441 with onychomycosis
Myc
26
[
43
]
Kriester
1967
Germany
Between 1956 and 1965, 188 590 patients were seen 6,113 cases of superficial mycoses were diagnosed
Myc
56
[
44
]
Götz
1938 (pub 1952)
Germany
Single‐center mycological study during the year 1935 106 cases diagnosed with a superficial mycosis one with onychomcyosis
Myc
0.1
[
45
]
Grimmer
1939 (published 1954)
Germany
128 cases of superficial mycoses 13 with onychomycosis
Myc
10
[
42
]
Götz
1949 (published 1952)
Germany
Single center mycological study during the year 1949 537 cases diagnosed with a superficial mycosis 58 with onychomycosis
Myc
1
[
45
]
Table 1.3 The history of onychomycosis treatment.
Year
Author
Treatment
Reference
1853
Meissner
Discovers that onychomycosis is caused by fungi, but does not offer any treatment options
[
9
]
1870
Neumann
Remove the lamellae of nail substance, which are readily detached by applying solutions of caustic potash (potassium hydroxide), corrosive sublimate (mercuric chloride), Ol. Terebinth (oil made from the turpentine tree)
English translation [
47
]
1880
Wigglesworth
To treat true onychomycosis the nail should be thinned by scraping with a bit of glass, and then wet frequently with corrosive sublimate (mercuric chloride) one gramme in two hundred of water, which is about three times as strong as one would use it upon the skin or hair
[
31
]
1907
Whitfield
Whitfield’s ointment, which combined a weak antifungal, benzoic acid, with a keratolytic, salicylic acid shows some effect
[
48
]
1944
Woolley
First azole discovered
[
49
]
1951
Hazen and Brown
Nystatin discovered
[
50
]
1958
Gentles
Griseofulvin discovered. It is synthesized of the mold fungus
Penicillium griseofulvum
and was found to be active orally in the treatment of dermatophyte infections
[
51
–
53
]
1977
Heeres
Ketoconazole, the first oral azole becomes available
[
54
]
1978
Richardson
Development of fluconazole starts
[
55
]
1983
Polak
Topical amorolfine discovered
[
56
,
57
]
1984
Hay
Itraconazole discovered Has broader spectrum compared to fluconazole
[
58
]
1991
Ryder
Discovered in 1983, it is closely related to naftifine Terbinafine was licensed in Europe in 1991
[
59
,
60
]
1991
Abrams
Topical ciclopirox discovered
[
61
,
62
]
2014
Del Rosso
Topical efinaconazole becomes available
[
63
]
2014
Ciaravino
Topical tavaborole becomes available
[
64
]
2017
Sigurgeirsson
Several new antifungals in development
[
65
,
66
]
This treatment is representative for what was available during the late 19th century and the beginning of last century.
In 1907 Whitfield’s ointment was discovered. It contains benzoic acid, with a keratolytic, salicylic acid and showed some antifungal effect. Not very much happened until the time of World War II, when developments in treatment started to focus on drugs with more specific antifungal activity. The first of these were derivatives of undecylenic acid such as tolnaftate, which was one of the first inhibitors of squalene epoxidase, which plays a key role in the biosynthesis of ergosterol in the fungal cell membrane [46].
In 1958, griseofulvin was discovered. This is a metabolic product derived from several species of Penicillium, which was first isolated from Penicillium griseofulvum. Its activity, which is fungistatic, is largely restricted to dermatophyte infections. Treatment duration for onychomycosis is very long.
In the early 1970s, the first azole antifungals were introduced, whose mode of action was targeted on the formation of the fungal cell membrane at the step of inhibition of 14‐α demethylase [65]. Ketoconazole, the first oral azole, became available in 1977. It was the first broad‐spectrum oral antifungal drug.
The discovery of ketoconazole succeeded by fluconazole and itraconazole. Both had far fewer side effects. Terbinafine was discovered in 1991 and is today considered the gold standard of treatment for onychomycosis [66]. Topical efinaconazole was licensed in 2014 and seems more promising compared to previously marketed topical antifungals. At the present time, several antifungal drugs are in development.
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2Epidemiology of Onychomycosis
Mahmoud A. Ghannoum,1* Iman Salem,1 and Luisa Christensen2
1Center for Medical Mycology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA
2Department of Dermatology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
2.1 Introduction and Background
Onychomycosis is a fungal nail infection either caused by a dermatophyte (tinea unguium) or by other non‐dermatophyte filamentous fungi or Candida spp. [1]. The incidence of onychomycosis in the United States is about 10%, preferentially affecting the elderly [2, 3]. Onychomycosis is distributed worldwide with high demographic and ethnic variations in its etiological agents [1]. Trichophyton rubrum is the main causative organism in North America, being responsible for 90% of toenail onychomycosis [4]. Among the predisposing factors for onychomycosis are aging, genetic predisposition, and medical disorders such as diabetes, HIV infection, chronic renal failure, iatrogenic immunosuppressive status, and peripheral vascular disease. Other factors include the excessive use of occlusive footwear, concurrent nail disorder or deformity, repeated nail micro trauma, various sport activities, and other concurrent tinea infections [5–7]. This chapter aims to discuss the incidence, etiology, and risk factors of onychomycosis.
2.2 History of Onychomycosis
Charif and Elewski studied the epidemiology of superficial dermatomycoses including onychomycosis in the United States and Europe, reporting that the introduction of the disease was parallel to the translocation of its main causative organism, T. rubrum, to Europe early in the last century (1908) [8]. The ancestry of this species was found in southeast Asia, west Africa, Indonesia, and north Australia, where it was known as an etiological agent of tinea corporis. The spread of the disease was facilitated through the increase and ease of population migration from these endemic regions to Europe. The disease outbreak in the United States coincided with World War I, which assisted the transmission of T. rubrum from Europe to North America [8].
2.3 Incidence of Onychomycosis
Onychomycosis accounts for 23% of all foot diseases and approximately half of inflammatory nail conditions (48%), with toenails being affected 10.6 times more often than fingernails [9, 10]. The incidence of onychomycosis differs widely among different demographics, though this could be attributed to variations in screening methods. Some studies reported an onychomycosis prevalence as high as 14, 20, and 23% across North America, East Asia, and Europe, respectively [11]. However, most of the epidemiological data from different observational studies estimated an incidence range between 2 and 10% in developed countries. A meta‐analysis conducted by Sigurgeirsson and Baran studied the epidemiology of onychomycosis in different European and North American populations and revealed a prevalence of 4.3% in the general population, with a male preponderance. This percentage is increasing multi‐fold in certain populations, reaching 20% in patients above the age of 60 and more than 50% in diabetics [3, 12–14].
The incidence of onychomycosis has progressively risen over the last decade, which could be attributed to an increase in the number of immunocompromised cases. This increase may be due to several factors, including induction by iatrogenic agents, the wider use of systemic antibiotics and immunosuppressive drugs, or the rise in the number of HIV‐infected patients and diabetics [2].
2.4 Etiology of Onychomycosis
Onychomycosis can be caused by dermatophytes (tinea unguium), non‐dermatophytic molds, or yeast. While dermatophytes account for the majority of onychomycosis cases in temperate Western countries, non‐dermatophytic filamentous fungi and yeast are more commonly implicated in countries with a humid and hot climate [4]. The causative organisms have different entry sites, resulting in different clinical variants of onychomycosis. For instance, T. rubrum and Epidermophyton floccosum usually infect the distal and lateral parts of the nail, while T. soudanense usually manifests as endonyx subungual disease. T. mentagrophytes and non‐dermatophyte molds normally invade the superficial layer of the nail plate causing superficial white onychomycosis (SWO). By contrast, Candida spp. invade the subcuticular space, eventually resulting in proximal nail dystrophy [3, 5].
2.4.1 Tinea Unguium
Depending on the source of infection, the causative dermatophyte can be anthropophilic (human reservoir), zoophilic (transmitted from animals), or geophilic (found in soil). The three main anthropophilic genera responsible for human‐to‐human transmission of tinea unguium are Trichophyton, Epidermophyton, and some Microsporum spp. (Box 2.1). These fungi are keratinophilic organisms, characterized by a high affinity to keratinized tissues such as nails and stratum corneum. The primary causative organism accountable for about 90% of mycotic nail infections is T. rubrum[4], which has superseded T. interdigitale as the main cause of tinea unguium in Europe since the 1950s. T. rubrum has been isolated from 76 and 91% of onychomycosis cases in Belgium and Germany, respectively [15–17]. A large‐scale study conducted by Ghannoum et al. likewise revealed the dominance of T. rubrum isolated from onychomycosis in North America, followed by T. mentagrophytes[18]. The organism is more likely to be transmitted between infected family members through the common use of private bathrooms. The spread of these organisms could also be attributed to the increase of sports facilities, including swimming pools, spas, gyms, and fitness centers, where the primary sources of infection are showers and mats. Similarly, practices that involve prolonged contact with moist environments, such as walking barefoot or the excessive use of occlusive footwear, are important modes of transmission. Sharing of nail care equipment such as scissors, clippers, and emery boards in nail salons also contributes to the spread of infection. [4, 15–18]. Other less commonly involved dermatophytes include E. floccosum, M. gypseum, T. violaceum, T. tonsurans, T. soudanense (believed to be an African variant of T. rubrum), and T. interdigitale. Anthropophilic dermatophytes more frequently involve the toenails (80%), while zoophilic dermatophytes predominantly affect the fingernails [1, 4, 15–18].
Box 2.1 Etiology of onychomycosis in the United States.
Tinea Unguium
Epidermophyton floccosum (+)
Microsporum canis (+)
Trichophyton mentagrophytes (++)
Trichophyton rubrum (+++)
Trichophyton tonsurans (+)
Candida Onychomycosis
Candida albicans (++)
Candida guilliermondii (+)
Candida lusitaniae (+)
Candida parapsilosis (+++)
Candida tropicalis (+)
Non‐Dermatophyte Mold Onychomycosis
Acremonium spp. (+++)
Aspergillus flavus (+)
Aspergillus fumigatus (+)
Aspergillus terreus (+)
Aspergillus versicolor (+)
Fusarium spp. (+++)
Scopulariopsis spp. (++)
Scytalidium spp. (+)
2.4.2 Candida Onychomycosis
Candida spp. account for approximately 5–10% of all cases of onychomycosis. The commonly involved species are C. albicans, C. guilliermondii, and C. parapsilosis (Box 2.1), which frequently coexist with T. interdigitale. Candida onychomycosis is the primary cause of onychomycosis in patients with chronic mucocutaneous candidiasis. They are more common in women, occurring more frequently in fingernails. These fungi are particularly common in occupations associated with frequent immersion or exposure of hands to water, and therefore predominantly manifested in the dominant hand, especially the fourth and fifth fingers [1].
2.4.2.1 Onychomycosis Caused by Non‐Dermatophyte Molds
Unlike dermatophytes, none of these molds, with the exception of Neoscytalidium spp., is keratophilic and are in most cases secondary contaminants to an already diseased nail plate. However, some geophilic molds, including N. dimidiatum (previously known as Scytalidium dimidiatum or Hendersonula toruloidea), some Aspergillus spp., and Scopulariopsis can primarily invade the nail plate. Others include Acremonium spp., Fusarium spp., and Onychocola canadensis (Box 2.1). Onychomycosis caused by non‐dermatophyte molds predominantly infect the toenails and are more common in elderly men. Non‐dermatophytes are responsible for between approximately 5 and 20% of onychomycosis cases in the United Kingdom and North America, respectively. However, the determination of their true involvement in nail disease is challenging, as it is often difficult to distinguish whether the non‐dermatophyte is the primary causative agent or a secondary invader. Onychomycosis caused by non‐dermatophytes tends to occur more frequently in certain populations, including immunocompromised patients. Unlike tinea unguium, onychomycosis caused by non‐dermatophytes is commonly not contagious. However, it usually exhibits a more recalcitrant course, resulting in poorer therapeutic outcomes in most cases [1, 4, 15–18].
2.5 Risk Factors of Onychomycosis
A systematic review conducted by Gupta and colleagues estimating the risk of developing onychomycosis among special populations revealed the highest incidence of the disease among dialysis patients (11.93%), caused mainly by dermatophytes [19
