mycoses
Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Original article
Onychomycosis in Israel: epidemiological aspects Rina Segal,1 Avner Shemer,2 Malca Hochberg,3 Yoram Keness,4 Rima Shvarzman,5 Marina Mandelblat,6 Michael Frenkel7 and Esther Segal7 1
Outpatient Dermatology Clinic, Rabin Medical Center, Petah Tikva, Israel, 2Outpatient Dermatology Clinic, Sheba Medical Center, Tel HaShomer, Israel, Outpatient Dermatology Clinic, Hadassa Medical Center, Jerusalem, Israel, 4Clinical Microbiology Laboratory & Outpatient Dermatology Clinic, Emek Medical Center, Afula, Israel, 5Central Laboratories Kupat Holim Leumit, Petah Tikva, Israel, 6Central Laboratories Kupat Holim Macabi, Rehovot, Israel and 7 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 3
Summary
Onychomycosis is a fungal infection treated orally for prolonged periods of treatment, caused primarily by Dermatophytes, Candida species and non-dermatophyte moulds (NDMs). The prevalence of specific aetiology may differ in dependence of environmental, geographic and demographic factors, and may affect management of the infection. The objective of this survey was to analyse epidemiologic parameters of onychomycosis in Israel. Data of a cohort of 27 093 patients were collected from six centres during a 2- and 10-year period. The diagnosis was based on microscopy of KOH/calcofluor mounts of nail scrapings and culture isolation. A positive result indicates isolation of a fungus in culture. Data were analysed for each centre and expressed as range for the whole cohort, using the SPSS v18 software. Analysis included three epidemiologic parameters: fungal aetiology in toe- and fingernails; association with gender; association with age group. Dermatophytes were the major causative agents and Trichophyton rubrum the most frequent isolate. Candida species were more frequent in women fingernails; frequency increased with age and C. parapsilosis the most frequent species. NDMs were isolated at low rate and Aspergillus terreus was the most frequent isolate. This is a first large cohort of onychomycosis patients from Israel analysed by defined epidemiological parameters.
Key words: Onychomychosis, aetiology, epidemiology.
Introduction Fungal skin diseases are among the top 10 most prevalent diseases worldwide and among the most frequent infectious diseases in the developed, as well as in the developing countries.1 Although not life-threatening, these infections are affecting quality of life2 and their therapy may constitute a financial burden. Of the dermal mycoses, onychomycosis is the most problematic infection in current dermatology, and it Correspondence: E. Segal, Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Tel.: +972 (0)3 6409870. Fax: +972 (0)3 6422494. E-mail: [email protected] Submitted for publication 10 September 2014 Revised 27 November 2014 Accepted for publication 5 December 2014
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 133–139
is believed to constitute about 50% of all nail diseases.3 Scher et al. [4] estimate the prevalence of onychomycosis in the general population to be ~10% and in the over 60-year group it may rise to 50%. A recent review5 cites prevalence rates of 23%, 20% and 14% in Europe, Asia and North America respectively. Onychomycosis is difficult to treat, requiring generally, prolonged, systemic oral treatment with anti-fungal agents6,7 due to lack of effective therapeutic topical preparations.6,8 The necessity of management by orally administered systemic drugs and prolonged periods of treatment may result in significant adverse effects.9–11 This may lead to problems of compliance, followed by low rates of therapeutic success and recurrences of infection. An additional complication, in many instances, is lack of a specific microbiological diagnosis of the aetiological agent involved, which may be reflected in a non-suitable treatment.
doi:10.1111/myc.12287
R. Segal et al.
It is generally accepted, that the aetiology of onychomycosis includes, primarily, three fungal groups: the Dermatophytes, Candida species and the nondermatophyte moulds (NDMs).12,13 The Dermatophytes are longtime established aetiological agents of onychomycosis and are the most frequently isolated fungi from this infection.12 Their role as pathogens of the keratinous tissues: skin, hair and nails is not questioned, and isolation in culture is considered as a diagnostic affirmation. In contrast to the Dermatophytes, determination of Candida species as aetiological agents of onychomycosis is more complex and may be controversial. It is believed by some, that Candida species may be considered as mere colonisers in deformed nails or cause infection when there is an underlying compromising background in the patient,14,15 contrary to the recognised pathogenic role of Dermatophytes. Nevertheless, most epidemiological surveys do report the prevalence of Candida isolates, suggesting thereby a role in the infection.16–19 In this context, it should be emphasised that it is of importance to demonstrate the presence of the fungi both directly in the clinical specimen and in culture.18 The NDMs have been recognised as potential agents of onychomycosis much later. The establishment of the role of the NDMs as causative agents is even more problematic,12 since many of these organisms are abundant in the environment and may be considered as contaminants. It is therefore recommended, that mycological diagnosis of NDM onychomycosis be based on repeated demonstration of the same fungus.20 Although Dermatophytes, Candida species and NDMs are universal, the relative prevalence of onychomycosis caused by the different fungi may vary in different geographic areas according to climatic conditions or life style. Thus, epidemiological studies in different geographic areas assessing the specific aetiology involved in onychomycosis in a given area are of importance. The following report comprises an epidemiological study based on a survey of onychomycosis in Israel involving laboratory data from six institutions: hospital outpatient and community dermatological clinics. This large collection of data in Israel, has not been, to the best of our knowledge, reported before.
Materials and methods Collection of data and analysis
Data were collected from laboratories of six centres: four from hospital outpatient dermatology clinics and two from central laboratories of community dermatology clinics.
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The data represent a 2-year period in five of the six centres and a 10-year period in one of the hospital outpatient dermatology clinics. All centres based the diagnosis on laboratory evidence involving direct microscopic observations of KOH/calcofluor mounts of nail scrapings and culture isolation using standard mycological methodology. A positive result indicated in the survey is based on the isolation of a fungus in culture. Data were analysed for each laboratory and expressed as range [%] for the whole cohort. The statistic software used was SPSS v18 (IBM SPSS Statistics, USA). Parameters of data analysis
The analysis of the data included following parameters: 1 Positives/patients. 2 Positives/males vs. females. 3 Positive toenails vs. fingernails in males; Positive toenails vs. fingernails in females. 4 Fungal aetiology – Candida species, Dermatophytes, NDM and mixed aetiology in toe- vs. fingernails in males and females. 5 Data were divided into three age groups: 0–40, 40–60, >60. In each age group analysis included fungal aetiology in toe- vs. fingernails, in males vs. females.
Results Data, percentage of positives in total surveyed population and gender based
Figure 1 shows the sources of the data collected in six institutions over a period of 2 years in five institutions and 10 years in one. The cohort surveyed involved a total of 27 093 patients of which 13 625 were surveyed for 2 years and 13 468 for 10 years. The figure also shows the number of positives in the different institutions. As indicated in the Materials and methods, in this survey a positive result refers to the isolation of a fungus in culture. The cumulative data shown in Fig. 2, reveal that close to 80% of samples demonstrate a correlation between the direct microscopic observation (KOH mount) and culture. The range of positives (Fig. 3a) in the different institutions was between 31% and 74%, with males in the range of 47–75% and females 41–52% (Fig. 3b). This analysis indicates a higher incidence of fungal infection among males than females.
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 133–139
Onychomycosis in Israel
(a)
(b)
Figure 1 The studied cohort: total number of patients and percentage of positives. Th, Bh, Hh, Eh = hospital outpatient dermatology
clinics. Ma, Lu = community dermatology clinics.
Figure 2 Microscopy and culture of specimens in the study.
Diagnosis included direct microscopic observations of KOH/calcofluor mounts of nail scrapings and culture isolation.
Toenails vs. fingernails
The analysis of positives in toenails vs. fingernails (Fig. 3c) revealed a similar cumulative range in both types of nails: 42–76% in toenails; 46.2–71% in fingernails. However, when the analysis was performed in respect to gender (Fig. 3d) it showed a different pattern for males and females. Specifically, in males there was higher frequency of toenail infections (53–65%) and lower in fingernails (34–46%), while in females higher frequency of fingernail infections was noted (42–65%) than in toenails (35–47%). This difference will also be expressed in different fungal aetiology (see later in the text). Fungal aetiology in toenails and fingernails in males and females in different age groups
Three fungal groups are considered as major pathogens causing onychomycosis: the Dermatophyte, the yeast of the Candida genus and the NDM. Table 1 depicts the
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 133–139
fungal aetiology in toenails and fingernails, in females and males, with regard to these three aetiological groups. It can be noted from the Table that most of the infections are found in toenails: 87.8% vs. 12.2% in fingernails. The data reveal also that Dermatophytes are the most frequently isolated fungi from the toenails (89%), while in fingernails it is the genus Candida (65%). Furthermore, Dermatophytes are more frequent in male infections, both in toenails and fingernails (57.8% and 74% respectively). On the other hand, Candida species and NDM species are more frequent aetiological agents of infections in women in the two types of nails (69.2% and 75.6% of Candida in toe-/fingernails; 57% and 75% of NDM in toe/fingernails respectively). In addition, the analysis of the data in our survey, includes as well the aetiology in reference to three different age groups: 60 years (Fig. 4). The analysis demonstrates that the Dermatophytes (Fig. 4a) appear at a higher frequency in toenails than in fingernails in all age groups. Candida species (Fig. 4b) in fingernails are increasing with age, while in the toenails the incidence is low in all age groups. NDM species (Fig. 4c), as indicated above, appear at low incidence both in toe- and fingernails, with no marked differences among the age groups. Specific aetiology data analysis
The analysis of the Dermatophyte group (Fig. 5) reveals the dominance of Trichophyton rubrum in toenails- & fingernails (Fig. 5a and b respectively), in men and women, in all centres of the survey. In male toe- and fingernails, it is almost the sole species, reaching frequency of 97% in some centres. Detailed analysis of the Candida group (Fig. 6) shows that the most
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(a)
(b)
(c)
(d)
Figure 3 Range (%) of fungi in toenails and fingernails of males and females in different centres. (a) Range of total positive cultures in
the different centres; (b) range of positive cultures in males and females in the different centres; (c) range of cultures in toenails and fingernails in the different centres; (d) range of cultures in toenails and fingernails in males and females in the different centres. Toes = toenails; fingers = fingernails. Table 1 Dermatophytes, Candida species and NDM in toe- and fingernails in males and females. % From total positives
In males (%)
Toenails (% from total positives = 87.8%) Dermatophytes 89.6 57.8 Candida spp. 3.9 30.8 NDM 6.5 43.0 Fingernails (% from total positives = 12.2%) Dermatophytes 33.4 74.0 Candida spp. 65.0 24.4 NDM 1.6 25.0
In females (%)
42.2 69.2 57.0 26.0 75.6 75.0
Prevalence of the three major groups of fungal pathogens in nails as expressed by percentage. NDM, non-dermatophytes moulds.
frequent Candida species both in fingernails and toenails (Fig. 6a and b respectively), in males as well as in females, were Candida parapsilosis (up to 75% & 63% and 63% & 56% in male & female fingernails & toenails respectively). The NDM group was characterised by low incidence (toes: 3–9%; fingernails: 1–4%). In the NDM group (Table 2), we found a variety of fungal species. The most frequent species in our survey
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was Aspergillus terreus, mostly in toenails. An interesting association of frequency and gender was noted; namely, A. terreus was isolated, primarily, from female toenails. In summary, our results indicate that: 1 In respect to aetiology – the Dermatophytes are the most common fungi in toenails and the most frequent Dermatophyte species is T. rubrum, Candida species are more frequent in fingernails and the most frequent Candida species is C. parapsilosis, NDM are at low incidence and the most prevalent species is A. terreus. 2 In respect to gender – higher percentage of positives among men than women, among men higher percentage of infected toenails than fingernails, among women higher percentage of infected fingernails than toenails, more NDM infections in female toe and finger nails vs. males. 3 In respect to age – frequency of Candida in fingernails increases with age.
Discussion Onychomycosis related epidemiological surveys, involving studies of prevalence of the different fungal
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 133–139
Onychomycosis in Israel
(a)
(b)
(c)
Figure 4 Fungi in respect to age group. Data were divided into three age groups: 0–40, 40–60, >60. (a) Range (%) of Dermatophytes in each of the three age groups in the different centres; (b) range (%) of Candida in each of the three age groups in the different centres; (c) range (%) of NDM (non-dermatophyte moulds) in each of the three age groups in the different centres.
(a)
(b)
Figure 5 Dermatophyte species in male’ and female’ toenails and fingernails. (a) Range (%) of Dermatophyte species in toenails in the
different centres; (b) range (%) of Dermatophyte species in fingernails in the different centres. T. mentagroph = T. mentagrophytes.
aetiologies in relation to various geographic or demographic parameters, such as gender or age, are important tools to establish the relative proportions of the causative agents in a given geographic area and in defined populations. Our study reported herewith, contains laboratory data from a large cohort of onychomycosis patients (27 093 cases) collected over a period of 2 and 10 years in six hospital outpatient and community dermatological clinics in Israel. It should also be added, that in this survey a positive result refers to the isolation of a fungus in culture, and that close to 80%
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 133–139
of samples demonstrate a correlation between the direct microscopic observation (KOH mount) and culture, thereby giving greater validity to the results. We analysed the data in reference to three major epidemiological aspects: (1) Fungal aetiology – assessment of prevalence of specific fungal etiologies, taking in consideration the differentiation of toenails vs. fingernails; (2) Gender – assessment of association of gender to prevalence of specific fungal etiologies in the two types of nails; (3) Age factor – assessment of association of age with increased susceptibility to develop the infection and prevalence of specific fungal
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(a)
(b)
Figure 6 Candida species in male’ and
female’ toenails and fingernails. (a) Range (%) of Candida species in toenails in the different centres; (b) range (%) of Candida species in fingernails in the different centres. Table 2 NDM in fingernails and toenails in males and females. Fingernails Species Acremonium spp. Alternaria spp. Aspergillus flavus Aspergillus terreus Aspergillus versicolar Aspergillus spp. Chaetomium spp. Cladosporium spp. Fusarium spp. Paecilomyces spp. Penicillium spp. Scopulariopsis spp. Trichosporon asahii Trichosporon mucoids Black moulds
Males
Toenails Females
Males
Females
1
8 5
2
4
17 10 2 40 1 4 1
1
1 1 2
2
1 4
1 2
7 1 3 5
8 2 2 14 1 3 2
Presented data are the number of isolates of each species. NDM, non-dermatophyte moulds.
aetiology, taking in consideration the parameters of gender and two types of nails. As demonstrated in the ‘Results’ we found that Dermatophytes are the most common fungi in toenails and the most frequent Dermatophyte species was T. rubrum. This finding is compatible with the data in literature, indicating that Dermatophytes are the main
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cause of onychomycosis.21 Scher et al. [4] in a recent publication reported that T. rubrum was the most common causative agent of toenail onychomycosis, and its rate was highest in patients over 60. Our Age analysis did not show a marked difference in prevalence of T. rubrum in patients of the over 60-year group, but did show the dominance of T. rubrum in toenails. Dominance of T. rubrum was shown as well by other investigators from different geographic areas.22–25 Candida species were found more frequently in fingernails and the most frequent Candida species was C. parapsilosis. It is of interest that also in a different geographic area C. parapsilosis was found to be the most frequent Candida species in onychomycosis. Fich et al. [26] noted that this species was involved in ~43% of cases, mostly in women, followed by C. guilliermondii and C. albicans. Contrary to this observation, Vasconcellos et al. [22] reported that in their study consisting of institutionalised elderly patients, C. guilliermondii was most frequent, while El Fekih et al. [27] in Tunisia found C. parapsilosis to be the most frequently isolated yeast species. This demonstrates, again, the importance of the different demographic as well as geographic factors affecting prevalence of specific aetiology and emphasises the relevance of such studies. In our study, we found a low incidence of NDMs and the most prevalent species was A. terreus. Our
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 133–139
Onychomycosis in Israel
finding is compatible with that of Fernandez et al. [28] who found 18.5% of the NDMs to be A. terreus. Furthermore, geographic and demographic factors affect the specific mould aetiology and its prevalence, revealing a variety of mould species to be associated with onychomycosis. Morales-Cardona et al. [20] found Neoscyttalidium dimidiatium as the most prevalent mould species in their study, while Tosti et al. [29] and the Monod group [8] consider Fusarium to be the most prevalent. It is rational to assume that the different ecological conditions of the different geographic areas play a role in the specific mould aetiology. In respect to gender, we found a higher percentage of positives among men than women, among men higher percentage of infected toenails than fingernails, among women higher percentage of infected fingernails than toenails, more NDM infections in female toenails and finger nails than in males. Ghannoum and Isham [5] in their recently published review point as well, to the observation that men have higher rates of onychomycosis than women, without indicating a specific reason for this difference. These authors also indicate that age is a risk factor for increased prevalence. We noted this in our study only in respect to Candida in fingernails in women, demonstrated by an increase in the frequency as a function of age. As to other fungal aetiologies our study did not reveal correlations with age, contrary to other studies, as mentioned afore,4 showing increase in dermatophyte infections in over 60 year patients. In summary, we present a comprehensive analysis of a large cohort of onychomycosis patients as to fungal aetiology, in respect to toe- and fingernails, gender and age. To the best of our knowledge, this is a first such study from this geographic area.
References 1
2 3
4
5 6
7
Hay RJ, Johns NE, Williams HC et al. The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions. J Invest Dermatol 2014; 134: 1527–34. Elewski BE. The effect of toenail onychomycosis on patient quality of life. Int J Dermatol 1997; 36: 754–6. Thomas J, Jacobson GA, Narkowicz CK, Peterson GM, Burnet H, Sharpe C. Toenail onychomycosis: an important global disease burden. J Clin Pharm Ther 2010; 35: 497–519. Scher RK, Nakamura N, Tavakkol A. Luliconazole: a review of a new antifungal agent for the topical treatment of onychomycosis. Mycoses 2014; 57: 389–93. Ghannoum M, Isham N. Fungal nail infections (onychomycosis): a never-ending story? PLoS Pathog 2014; 10: e1004105. Gupta AK, Daigle D, Paquet M. Therapies for onychomycosis: a systematic review and network meta-analysis of mycological cure. J Am Podiatr Med Assoc 2014; doi: http://dx.doi.org/10.7547/13-110.1. Gupta AK, Elewski BE, Sugarman JL et al. The efficacy and safety of efinaconazole 10% solution for treatment of mild to moderate onychomycosis: a pooled analysis of two phase 3 randomized trials. J Drugs Dermatol 2014; 13: 815–20.
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Lurati M, Baudraz-Rosselet F, Vernez M et al. Efficacious treatment of non-dermatophyte mould onychomycosis with topical amphotericin B. Dermatology 2011; 223: 289–92. 9 Scher RK, Rich P, Pariser D, Elewski B. The epidemiology, etiology, and pathophysiology of onychomycosis. Semin Cutan Med Surg 2013; 32: S2–4. 10 Verrier J, Bontems O, Baudraz-Rosselet F, Monod M. Oral terbinafine and itraconazole treatments against dermatophytes appear not to favor the establishment of Fusarium spp. in nail. Dermatology 2014; 228: 225–32. 11 Loo DS. Systemic antifungal agents: an update of established and new therapies. Adv Dermatol 2006; 22: 101–24. 12 Hay RJ. Dermatophytosis and other superficial mycoses. In: Mandell GL, Bennett JE, Dolin R (eds), Mandell, Douglas, and Bennett’s. Principles and Practice of Infectious Diseases, Vol. 2, 7th edn. Philadelphia, PA: Elsevier, 2010: 3345–55. 13 Edwards JE. Candida species. In: Mandell GL, Bennett JE, Dolin R (eds), Mandell, Douglas, and Bennett’s. Principles and Practice of Infectious Diseases, Vol. 2, 7th edn. Philadelphia, PA: Elsevier, 2010: 3225–40. 14 Hay RJ. Antifungal therapy of yeast infections. J Am Acad Dermatol 1994; 31: S6–9. 15 Baran R, Hay RJ, Tosti A, Haneke E. New classification of onychomycosis. Br J Dermatol 1998; 139: 567–71. 16 Das NK, Ghosh P, Das S, Bhattacharya S, Dutta RN, Sengupta SR. A study on the etiological agent and clinico-mycological correlation of fingernail onychomycosis in eastern India. Indian J Dermatol 2008; 53: 75–79. 17 Veer P, Patwardhan NS, Damle AS. Study of onychomycosis: prevailing fungi and pattern of infection. Indian J Med Microbiol 2007; 25: 53–56. 18 Ilkit M. Onychomycosis in Adana, Turkey: a 5-year study. Int J Dermatol 2005; 44: 851–4. 19 de Gentile L, Bouchara JP, Cimon B, Chabasse D. Candida ciferrii: clinical and microbiological features of an emerging pathogen. Mycoses 1991; 34: 125–8. 20 Morales-Cardona CA, Valbuena-Mesa MC, Alvarado Z, SolorzanoAmador A. Non-dermatophyte mould onychomycosis: a clinical and epidemiological study at a dermatology referral centre in Bogota, Colombia. Mycoses 2014; 57: 284–93. 21 Baudraz-Rosselet F, Ruffieux C, Lurati M, Bontems O, Monod M. Onychomycosis insensitive to systemic terbinafine and azole treatments reveals non-dermatophyte moulds as infectious agents. Dermatology 2010; 220: 164–8. 22 Vasconcellos C, Pereira CQM, Souza MC, Pelegrini A, Freitas RS, Takahashi JP. Identification of fungi species in onychomycosis of institutionalized elderly. An Bras Dermatol 2013; 88: 377–80. 23 Silva LB, de Oliveira DBC, da Silva BV et al. Identification and antifungal susceptibility of fungi isolated from dermatomycoses. J Eur Acad Dermatol 2014; 28: 633–40. 24 Ghannoum MA, Hajjeh RA, Scher R et al. A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol 2000; 43: 641–8. 25 Sigurgeirsson B, Baran R. The prevalence of onychomycosis in the global population – a literature study. J Eur Acad Dermatol Venereol 2013; 28: 1480–91. 26 Fich F, Abarzua-Araya A, Perez M, Nauhm Y, Leon E. Candida parapsilosis and Candida guillermondii: emerging pathogens in nail candidiasis. Indian J Dermatol 2014; 59: 24–29. 27 El Fekih N, Belghith I, Trabelsi S, Skhiri-Aounallah H, Khaled S, Fazaa B. Epidemiological and etiological study of foot mycosis in Tunisia. Actas Dermosifiliogr 2012; 103: 520–4. 28 Fernandez MS, Rojas FD, Cattana ME, Sosa Mde L, Mangiaterra ML, Giusiano GE. Aspergillus terreus complex: an emergent opportunistic agent of Onychomycosis. Mycoses 2013; 56: 477–81. 29 Tosti A, Piraccini BM, Lorenzi S. Onychomycosis caused by non-dermatophytic molds: clinical features and response to treatment of 59 cases. J Am Acad Dermatol 2000; 42: 217–24. 8
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Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Original article
Onychomycosis in Israel: epidemiological aspects Rina Segal,1 Avner Shemer,2 Malca Hochberg,3 Yoram Keness,4 Rima Shvarzman,5 Marina Mandelblat,6 Michael Frenkel7 and Esther Segal7 1
Outpatient Dermatology Clinic, Rabin Medical Center, Petah Tikva, Israel, 2Outpatient Dermatology Clinic, Sheba Medical Center, Tel HaShomer, Israel, Outpatient Dermatology Clinic, Hadassa Medical Center, Jerusalem, Israel, 4Clinical Microbiology Laboratory & Outpatient Dermatology Clinic, Emek Medical Center, Afula, Israel, 5Central Laboratories Kupat Holim Leumit, Petah Tikva, Israel, 6Central Laboratories Kupat Holim Macabi, Rehovot, Israel and 7 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 3
Summary
Onychomycosis is a fungal infection treated orally for prolonged periods of treatment, caused primarily by Dermatophytes, Candida species and non-dermatophyte moulds (NDMs). The prevalence of specific aetiology may differ in dependence of environmental, geographic and demographic factors, and may affect management of the infection. The objective of this survey was to analyse epidemiologic parameters of onychomycosis in Israel. Data of a cohort of 27 093 patients were collected from six centres during a 2- and 10-year period. The diagnosis was based on microscopy of KOH/calcofluor mounts of nail scrapings and culture isolation. A positive result indicates isolation of a fungus in culture. Data were analysed for each centre and expressed as range for the whole cohort, using the SPSS v18 software. Analysis included three epidemiologic parameters: fungal aetiology in toe- and fingernails; association with gender; association with age group. Dermatophytes were the major causative agents and Trichophyton rubrum the most frequent isolate. Candida species were more frequent in women fingernails; frequency increased with age and C. parapsilosis the most frequent species. NDMs were isolated at low rate and Aspergillus terreus was the most frequent isolate. This is a first large cohort of onychomycosis patients from Israel analysed by defined epidemiological parameters.
Key words: Onychomychosis, aetiology, epidemiology.
Introduction Fungal skin diseases are among the top 10 most prevalent diseases worldwide and among the most frequent infectious diseases in the developed, as well as in the developing countries.1 Although not life-threatening, these infections are affecting quality of life2 and their therapy may constitute a financial burden. Of the dermal mycoses, onychomycosis is the most problematic infection in current dermatology, and it Correspondence: E. Segal, Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Tel.: +972 (0)3 6409870. Fax: +972 (0)3 6422494. E-mail: [email protected] Submitted for publication 10 September 2014 Revised 27 November 2014 Accepted for publication 5 December 2014
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 133–139
is believed to constitute about 50% of all nail diseases.3 Scher et al. [4] estimate the prevalence of onychomycosis in the general population to be ~10% and in the over 60-year group it may rise to 50%. A recent review5 cites prevalence rates of 23%, 20% and 14% in Europe, Asia and North America respectively. Onychomycosis is difficult to treat, requiring generally, prolonged, systemic oral treatment with anti-fungal agents6,7 due to lack of effective therapeutic topical preparations.6,8 The necessity of management by orally administered systemic drugs and prolonged periods of treatment may result in significant adverse effects.9–11 This may lead to problems of compliance, followed by low rates of therapeutic success and recurrences of infection. An additional complication, in many instances, is lack of a specific microbiological diagnosis of the aetiological agent involved, which may be reflected in a non-suitable treatment.
doi:10.1111/myc.12287
R. Segal et al.
It is generally accepted, that the aetiology of onychomycosis includes, primarily, three fungal groups: the Dermatophytes, Candida species and the nondermatophyte moulds (NDMs).12,13 The Dermatophytes are longtime established aetiological agents of onychomycosis and are the most frequently isolated fungi from this infection.12 Their role as pathogens of the keratinous tissues: skin, hair and nails is not questioned, and isolation in culture is considered as a diagnostic affirmation. In contrast to the Dermatophytes, determination of Candida species as aetiological agents of onychomycosis is more complex and may be controversial. It is believed by some, that Candida species may be considered as mere colonisers in deformed nails or cause infection when there is an underlying compromising background in the patient,14,15 contrary to the recognised pathogenic role of Dermatophytes. Nevertheless, most epidemiological surveys do report the prevalence of Candida isolates, suggesting thereby a role in the infection.16–19 In this context, it should be emphasised that it is of importance to demonstrate the presence of the fungi both directly in the clinical specimen and in culture.18 The NDMs have been recognised as potential agents of onychomycosis much later. The establishment of the role of the NDMs as causative agents is even more problematic,12 since many of these organisms are abundant in the environment and may be considered as contaminants. It is therefore recommended, that mycological diagnosis of NDM onychomycosis be based on repeated demonstration of the same fungus.20 Although Dermatophytes, Candida species and NDMs are universal, the relative prevalence of onychomycosis caused by the different fungi may vary in different geographic areas according to climatic conditions or life style. Thus, epidemiological studies in different geographic areas assessing the specific aetiology involved in onychomycosis in a given area are of importance. The following report comprises an epidemiological study based on a survey of onychomycosis in Israel involving laboratory data from six institutions: hospital outpatient and community dermatological clinics. This large collection of data in Israel, has not been, to the best of our knowledge, reported before.
Materials and methods Collection of data and analysis
Data were collected from laboratories of six centres: four from hospital outpatient dermatology clinics and two from central laboratories of community dermatology clinics.
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The data represent a 2-year period in five of the six centres and a 10-year period in one of the hospital outpatient dermatology clinics. All centres based the diagnosis on laboratory evidence involving direct microscopic observations of KOH/calcofluor mounts of nail scrapings and culture isolation using standard mycological methodology. A positive result indicated in the survey is based on the isolation of a fungus in culture. Data were analysed for each laboratory and expressed as range [%] for the whole cohort. The statistic software used was SPSS v18 (IBM SPSS Statistics, USA). Parameters of data analysis
The analysis of the data included following parameters: 1 Positives/patients. 2 Positives/males vs. females. 3 Positive toenails vs. fingernails in males; Positive toenails vs. fingernails in females. 4 Fungal aetiology – Candida species, Dermatophytes, NDM and mixed aetiology in toe- vs. fingernails in males and females. 5 Data were divided into three age groups: 0–40, 40–60, >60. In each age group analysis included fungal aetiology in toe- vs. fingernails, in males vs. females.
Results Data, percentage of positives in total surveyed population and gender based
Figure 1 shows the sources of the data collected in six institutions over a period of 2 years in five institutions and 10 years in one. The cohort surveyed involved a total of 27 093 patients of which 13 625 were surveyed for 2 years and 13 468 for 10 years. The figure also shows the number of positives in the different institutions. As indicated in the Materials and methods, in this survey a positive result refers to the isolation of a fungus in culture. The cumulative data shown in Fig. 2, reveal that close to 80% of samples demonstrate a correlation between the direct microscopic observation (KOH mount) and culture. The range of positives (Fig. 3a) in the different institutions was between 31% and 74%, with males in the range of 47–75% and females 41–52% (Fig. 3b). This analysis indicates a higher incidence of fungal infection among males than females.
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(a)
(b)
Figure 1 The studied cohort: total number of patients and percentage of positives. Th, Bh, Hh, Eh = hospital outpatient dermatology
clinics. Ma, Lu = community dermatology clinics.
Figure 2 Microscopy and culture of specimens in the study.
Diagnosis included direct microscopic observations of KOH/calcofluor mounts of nail scrapings and culture isolation.
Toenails vs. fingernails
The analysis of positives in toenails vs. fingernails (Fig. 3c) revealed a similar cumulative range in both types of nails: 42–76% in toenails; 46.2–71% in fingernails. However, when the analysis was performed in respect to gender (Fig. 3d) it showed a different pattern for males and females. Specifically, in males there was higher frequency of toenail infections (53–65%) and lower in fingernails (34–46%), while in females higher frequency of fingernail infections was noted (42–65%) than in toenails (35–47%). This difference will also be expressed in different fungal aetiology (see later in the text). Fungal aetiology in toenails and fingernails in males and females in different age groups
Three fungal groups are considered as major pathogens causing onychomycosis: the Dermatophyte, the yeast of the Candida genus and the NDM. Table 1 depicts the
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 133–139
fungal aetiology in toenails and fingernails, in females and males, with regard to these three aetiological groups. It can be noted from the Table that most of the infections are found in toenails: 87.8% vs. 12.2% in fingernails. The data reveal also that Dermatophytes are the most frequently isolated fungi from the toenails (89%), while in fingernails it is the genus Candida (65%). Furthermore, Dermatophytes are more frequent in male infections, both in toenails and fingernails (57.8% and 74% respectively). On the other hand, Candida species and NDM species are more frequent aetiological agents of infections in women in the two types of nails (69.2% and 75.6% of Candida in toe-/fingernails; 57% and 75% of NDM in toe/fingernails respectively). In addition, the analysis of the data in our survey, includes as well the aetiology in reference to three different age groups: 60 years (Fig. 4). The analysis demonstrates that the Dermatophytes (Fig. 4a) appear at a higher frequency in toenails than in fingernails in all age groups. Candida species (Fig. 4b) in fingernails are increasing with age, while in the toenails the incidence is low in all age groups. NDM species (Fig. 4c), as indicated above, appear at low incidence both in toe- and fingernails, with no marked differences among the age groups. Specific aetiology data analysis
The analysis of the Dermatophyte group (Fig. 5) reveals the dominance of Trichophyton rubrum in toenails- & fingernails (Fig. 5a and b respectively), in men and women, in all centres of the survey. In male toe- and fingernails, it is almost the sole species, reaching frequency of 97% in some centres. Detailed analysis of the Candida group (Fig. 6) shows that the most
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(a)
(b)
(c)
(d)
Figure 3 Range (%) of fungi in toenails and fingernails of males and females in different centres. (a) Range of total positive cultures in
the different centres; (b) range of positive cultures in males and females in the different centres; (c) range of cultures in toenails and fingernails in the different centres; (d) range of cultures in toenails and fingernails in males and females in the different centres. Toes = toenails; fingers = fingernails. Table 1 Dermatophytes, Candida species and NDM in toe- and fingernails in males and females. % From total positives
In males (%)
Toenails (% from total positives = 87.8%) Dermatophytes 89.6 57.8 Candida spp. 3.9 30.8 NDM 6.5 43.0 Fingernails (% from total positives = 12.2%) Dermatophytes 33.4 74.0 Candida spp. 65.0 24.4 NDM 1.6 25.0
In females (%)
42.2 69.2 57.0 26.0 75.6 75.0
Prevalence of the three major groups of fungal pathogens in nails as expressed by percentage. NDM, non-dermatophytes moulds.
frequent Candida species both in fingernails and toenails (Fig. 6a and b respectively), in males as well as in females, were Candida parapsilosis (up to 75% & 63% and 63% & 56% in male & female fingernails & toenails respectively). The NDM group was characterised by low incidence (toes: 3–9%; fingernails: 1–4%). In the NDM group (Table 2), we found a variety of fungal species. The most frequent species in our survey
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was Aspergillus terreus, mostly in toenails. An interesting association of frequency and gender was noted; namely, A. terreus was isolated, primarily, from female toenails. In summary, our results indicate that: 1 In respect to aetiology – the Dermatophytes are the most common fungi in toenails and the most frequent Dermatophyte species is T. rubrum, Candida species are more frequent in fingernails and the most frequent Candida species is C. parapsilosis, NDM are at low incidence and the most prevalent species is A. terreus. 2 In respect to gender – higher percentage of positives among men than women, among men higher percentage of infected toenails than fingernails, among women higher percentage of infected fingernails than toenails, more NDM infections in female toe and finger nails vs. males. 3 In respect to age – frequency of Candida in fingernails increases with age.
Discussion Onychomycosis related epidemiological surveys, involving studies of prevalence of the different fungal
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(a)
(b)
(c)
Figure 4 Fungi in respect to age group. Data were divided into three age groups: 0–40, 40–60, >60. (a) Range (%) of Dermatophytes in each of the three age groups in the different centres; (b) range (%) of Candida in each of the three age groups in the different centres; (c) range (%) of NDM (non-dermatophyte moulds) in each of the three age groups in the different centres.
(a)
(b)
Figure 5 Dermatophyte species in male’ and female’ toenails and fingernails. (a) Range (%) of Dermatophyte species in toenails in the
different centres; (b) range (%) of Dermatophyte species in fingernails in the different centres. T. mentagroph = T. mentagrophytes.
aetiologies in relation to various geographic or demographic parameters, such as gender or age, are important tools to establish the relative proportions of the causative agents in a given geographic area and in defined populations. Our study reported herewith, contains laboratory data from a large cohort of onychomycosis patients (27 093 cases) collected over a period of 2 and 10 years in six hospital outpatient and community dermatological clinics in Israel. It should also be added, that in this survey a positive result refers to the isolation of a fungus in culture, and that close to 80%
© 2015 Blackwell Verlag GmbH Mycoses, 2015, 58, 133–139
of samples demonstrate a correlation between the direct microscopic observation (KOH mount) and culture, thereby giving greater validity to the results. We analysed the data in reference to three major epidemiological aspects: (1) Fungal aetiology – assessment of prevalence of specific fungal etiologies, taking in consideration the differentiation of toenails vs. fingernails; (2) Gender – assessment of association of gender to prevalence of specific fungal etiologies in the two types of nails; (3) Age factor – assessment of association of age with increased susceptibility to develop the infection and prevalence of specific fungal
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(a)
(b)
Figure 6 Candida species in male’ and
female’ toenails and fingernails. (a) Range (%) of Candida species in toenails in the different centres; (b) range (%) of Candida species in fingernails in the different centres. Table 2 NDM in fingernails and toenails in males and females. Fingernails Species Acremonium spp. Alternaria spp. Aspergillus flavus Aspergillus terreus Aspergillus versicolar Aspergillus spp. Chaetomium spp. Cladosporium spp. Fusarium spp. Paecilomyces spp. Penicillium spp. Scopulariopsis spp. Trichosporon asahii Trichosporon mucoids Black moulds
Males
Toenails Females
Males
Females
1
8 5
2
4
17 10 2 40 1 4 1
1
1 1 2
2
1 4
1 2
7 1 3 5
8 2 2 14 1 3 2
Presented data are the number of isolates of each species. NDM, non-dermatophyte moulds.
aetiology, taking in consideration the parameters of gender and two types of nails. As demonstrated in the ‘Results’ we found that Dermatophytes are the most common fungi in toenails and the most frequent Dermatophyte species was T. rubrum. This finding is compatible with the data in literature, indicating that Dermatophytes are the main
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cause of onychomycosis.21 Scher et al. [4] in a recent publication reported that T. rubrum was the most common causative agent of toenail onychomycosis, and its rate was highest in patients over 60. Our Age analysis did not show a marked difference in prevalence of T. rubrum in patients of the over 60-year group, but did show the dominance of T. rubrum in toenails. Dominance of T. rubrum was shown as well by other investigators from different geographic areas.22–25 Candida species were found more frequently in fingernails and the most frequent Candida species was C. parapsilosis. It is of interest that also in a different geographic area C. parapsilosis was found to be the most frequent Candida species in onychomycosis. Fich et al. [26] noted that this species was involved in ~43% of cases, mostly in women, followed by C. guilliermondii and C. albicans. Contrary to this observation, Vasconcellos et al. [22] reported that in their study consisting of institutionalised elderly patients, C. guilliermondii was most frequent, while El Fekih et al. [27] in Tunisia found C. parapsilosis to be the most frequently isolated yeast species. This demonstrates, again, the importance of the different demographic as well as geographic factors affecting prevalence of specific aetiology and emphasises the relevance of such studies. In our study, we found a low incidence of NDMs and the most prevalent species was A. terreus. Our
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finding is compatible with that of Fernandez et al. [28] who found 18.5% of the NDMs to be A. terreus. Furthermore, geographic and demographic factors affect the specific mould aetiology and its prevalence, revealing a variety of mould species to be associated with onychomycosis. Morales-Cardona et al. [20] found Neoscyttalidium dimidiatium as the most prevalent mould species in their study, while Tosti et al. [29] and the Monod group [8] consider Fusarium to be the most prevalent. It is rational to assume that the different ecological conditions of the different geographic areas play a role in the specific mould aetiology. In respect to gender, we found a higher percentage of positives among men than women, among men higher percentage of infected toenails than fingernails, among women higher percentage of infected fingernails than toenails, more NDM infections in female toenails and finger nails than in males. Ghannoum and Isham [5] in their recently published review point as well, to the observation that men have higher rates of onychomycosis than women, without indicating a specific reason for this difference. These authors also indicate that age is a risk factor for increased prevalence. We noted this in our study only in respect to Candida in fingernails in women, demonstrated by an increase in the frequency as a function of age. As to other fungal aetiologies our study did not reveal correlations with age, contrary to other studies, as mentioned afore,4 showing increase in dermatophyte infections in over 60 year patients. In summary, we present a comprehensive analysis of a large cohort of onychomycosis patients as to fungal aetiology, in respect to toe- and fingernails, gender and age. To the best of our knowledge, this is a first such study from this geographic area.
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2 3
4
5 6
7
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