Onychomycosis Incidence in Type 2 Diabetes Mellitus Patients

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1 Mycopathologia (2008) 166:41 45 DOI /s Onychomycosis Incidence in Type 2 Diabetes Mellitus Patients Patricia Manzano-Gayosso Æ Francisca Hernández-Hernández Æ Luis Javier Méndez-Tovar Æ Yanni Palacios-Morales Æ Erika Córdova-Martínez Æ Elva Bazán-Mora Æ Rubén López-Martinez Received: 26 July 2007 / Accepted: 11 March 2008 / Published online: 29 March 2008 Ó Springer Science+Business Media B.V Abstract The onychomycosis incidence was determined in 250 type 2 diabetes mellitus (T2DM) patients who were registered at the Internal Medicine Service from a Mexico city General Hospital throughout a year (January December 2006). Out of the total of studied T2DM patients, 93 (37.2%) showed ungual dystrophy and from these, in 75.3% a fungal etiology was corroborated. Out of 70 patients, 34 were men and 36 women, with an average of 63.5 years. Correlation between T2DM evolution time and onychomycosis was significant (P \ 0.01). Distal-lateral subungual and total dystrophic onychomycosis were the most frequent clinical types (55.1% and 33.7%, respectively). Fifty-eight fungal isolates were obtained; 48.6% corresponded to dermatophytes, Trichophyton P. Manzano-Gayosso (&) F. Hernández-Hernández E. Córdova-Martínez E. Bazán-Mora R. López-Martinez Laboratorio de Micología Médica, Departamento de Microbiología y Parasitología, Facultad de Medicina, UNAM, Ciudad Universitaria, Mexico, CP 04510, DF, Mexico angelesmg@liceaga.facmed.unam.mx L. J. Méndez-Tovar Unidad de Investigación Médica en Dermatología y Micología Dr. Ernesto Macotela, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, Mexico, DF, Mexico Y. Palacios-Morales Servicio de Medicina Interna, Hospital General Dr. Darío Fernández Fierro, ISSSTE, Mexico, DF, Mexico rubrum being the first species (37.1%). All these strains corresponded to two morphological varieties: yellow and typical downy. From the yeast-like isolates, 12 corresponded to Candida spp., firstly C. albicans and C. parapsilosis; three to Cryptococcus spp. (C. albidus, C. uniguttulatus and C. laurentii); two Trichosporon asahii; and only one to Pichia ohmeri. Six non-dermatophytic molds were isolated: two Chrysosporium keratinophylus, two Scopulariopsis brevicaulis, one Aspergillus fumigatus, and one Acremonium sp. The fungal mixture corresponded to T. mentagrophytes with C. guilliermondii; T. mentagrophytes with C. glabrata; T. rubrum with C. glabrata; T. rubrum with P. ohmeri. Keywords Candida Dermatophytes Diabetes mellitus Onychomycosis Introduction Onychomycosis are common diseases within the general population, where these represent from 18% to 40% of nail diseases [1]. However, in adults over 60 years old the disease is 40% more frequent [2] and in type 2 diabetes mellitus (T2DM) patients it increases 2.5 times [3]. In these patients onychomycosis diagnosis is overestimated since this population commonly presents ungual dystrophy related with the elderly and some diabetes complications such as peripheral vascular disease and neuropathy [4]. According to Gupta

2 42 Mycopathologia (2008) 166:41 45 et al. [3] 33% of diabetic patients present onychomycosis frequently associated with tinea pedis. López- González and Mayorga [5] found similar data. Among the fungi causing onychomycosis, dermatophytes are the most frequent (38 80% of cases), followed by yeasts (10 24%) and non-dermatophytic molds (8 14%) [6 8]. Trichophyton rubrum is the most common isolated species followed by T. mentagrophytes (20%). On the other hand, Álvarez et al. [6] found that from 299 onychomycosis patients, Candida albicans was the number one etiological agent followed by T. rubrum. Among the non-dermatophytic molds, Fusarium was the most prevalent. Four onychomycosis clinical types have been described: distal-lateral subungual (D-LSO), proximal subungual (PSO), white superficial (WSO) and total dystrophic (TDO) onychomycosis. The first clinical type is the most common and the last one seems to be a mixture of all the other onychomycosis types [9, 10]. In diabetic patients another clinical form has been described, and is named Candida onychomycosis characterized by paronychia [11]. In Mexico, as in other countries, diabetes is a great public health problem and according to the national chronic disease survey reported by Membreño et al. [12], the prevalence of diabetes mellitus is 7.2% in general population and, T2DM corresponds to 90% of the cases. This disease is the first cause of hospital admission. In spite of the fact that other authors have not found a significant difference between onychomycosis incidence in the general population and diabetic patients, the latter frequently show vascular and sensibility disorders, resulting in small traumatic lesions which represent the access for bacteria and fungi infections. We conducted a descriptive and observational study aiming to determine the onychomycosis incidence, evolution time, clinical forms, and etiological agents in T2DM patients. Materials and Methods Patients Two hundred and fifty T2DM patients admitted in the Department of Internal Medicine at the General Hospital Dr. Darío Fernández Fierro ISSSTE, in Mexico city, during a 1-year period (January December 2006) were studied. The following data were obtained from each patient: gender, age, occupation, T2DM evolution time and complications; onychomycosis clinical types and evolution time; cutaneous lesions suggestive of fungal infection, and previous antifungal treatment. Fungal Cultures In the patients with any kind of ungual dystrophy (onycholysis, paronychia, or pachyonychia), a mycological study was performed. Nail scrapings were taken in three consecutive days and microscopically examined after 15% potassium hydroxide treatment; samples were inoculated in ten different points on Sabouraud dextrose agar plates with and without antibiotics (Bioxon). The cultures were incubated at 28 C and examined daily for 15 days. Identification of Dermatophytes and Other Keratinophilic Fungi Identification of isolated fungi was based on morphological characteristics and some physiological tests depending on genus and species. Dermatophytes and other keratinophilic fungi were grown on bromcresol purple milk solids glucose agar, on lactrimel agar, 1% peptone agar, Christensen-urea agar, 5% NaCl agar; hair perforation test was also performed [13]. Identification of Yeasts Yeast species were identified by using germ tube production, morphology on cornmeal agar, colonial pigmentation on chromogenic medium (CHROMagar Candida) [14], Christensen-urea agar and Staib agar, and the assimilation of carbohydrates by commercial identification systems (API 20C AUX (biomeriux) and YBC card (Vitek)). Isolates identified as C. albicans were studied by means of other tests such as chlamydoconidia production on three media (Staib [15], casein [16], and tobacco agar [17]) and growth at 45 C[18]to differentiate it from C. dubliniensis. The Pearson Test (SSPS Program, version 12) was applied when it was necessary to establish comparisons. Values of P B 0.05 were considered to be significant. Percentages of different factors (gender, clinical types, etiological agents versus T2DM) in patients were also obtained.

Mycopathologia (2008) 166:41 45 43 Results From the 250 T2DM patients, 93 (37.2%) presented ungual dystrophy. Seventy patients (75.

3 Mycopathologia (2008) 166: Results From the 250 T2DM patients, 93 (37.2%) presented ungual dystrophy. Seventy patients (75.3%) had onychomycosis confirmed by three different positive samples for direct examination and culture of nail scrapings. Among 70 patients, 34 were males and 36 females. The average age was 63.5 years. From 70 T2DM patients, 28 presented onychomycosis associated with other medical conditions, such as peripheral vascular disease (13), diabetic dermatopathy (six), cellulitis (five), diabetic foot (three), and peripheral neuropathy (one). Concerning the relationship between the T2DM evolution time and onychomycosis, in most of the cases the last started after the diabetes was diagnosed, and this event was statistically significant (P \ 0.01) (Table 1). The clinical localization of onychomycosis in the 70 patients was in toenails (56) and in fingernails (11). Infections of both fingernails and toenails were observed in three cases. Table 2 shows the observed clinical types of onychomycosis, predominating both D-LSO (48.6%) and TDO (31.4%). Figure 1 shows a case of white superficial onychomycosis. Twenty seven patients had associated tinea pedis, two had tinea mannum, and one tinea corporis. Out of the 70 onychomycosis-t2dm patients, 58 fungal isolates were obtained (82.8%): 34 dermatophytes (48.6%), 18 yeasts (25.6%), and six other nondermatophytic molds (8.6%); in four cases a mixture of two species was found. Table 3 shows the different isolated species correlated with the onychomycosis clinical types previously mentioned. Out of the 34 dermatophyte-positive cultures, T. rubrum was predominant (37%), corresponding only to two morphological varieties: yellow and typical downy. This dermatophyte was the only species inducing all the onychomycosis clinical types. The yeast-like isolates of the genus Candida were identified as C. albicans and C. parapsilosis in similar number. Table 1 Correlation between T2DM and onychomycosis evolution time in 70 hospitalized patients T2DM (years) Range Average 13.5* 10* * P \ 0.01 Onychomycosis (years) Table 2 Onychomycosis clinical types observed in 70 T2DM patients Clinical type Toenails Fingernails Total Percentage D-LSO TDO PSO WSO D-LSO, distal-lateral subungual onychomycosis; PSO, proximal subungual onychomycosis; WSO, white superficial onychomycosis; TDO, total dystrophic onychomycosis Fig. 1 A white superficial onychomycosis case caused by T. rubrum, in a 68-year-old male patient, with an evolution of 7 years. Lesion consists of transverse leuconychia with a single band Other yeast-like isolates corresponded to genera Cryptococcus, Trichosporon, andpichia. Fourmixed fungal species were also observed: two T. rubrum with C. glabrata; one T. mentagrophytes with C. guilliermondii; and one T. rubrum with P. ohmeri.noneofthe isolates firstly identified as C. albicans was differentiated as C. dubliniensis. Discussion Onychomycosis is a public health problem in patients over 60 years old, whose incidence is considered between 40% and 60% [2, 3, 19], and this is increased with age. According to some authors, onychomycosis

4 44 Mycopathologia (2008) 166:41 45 Table 3 Isolates obtained from 70 onychomycosis and T2DM patients correlated with clinical types Fungi Isolates Percentage Clinical types TDO DLSO PSO WSO Dermatophytes Trichophyton rubrum Trichophyton mentagrophytes Trichophyton tonsurans Epidermophyton floccosum Subtotal Yeasts Candida albicans Candida parapsilosis Candida guilliermondii Candida glabrata Candida lipolytica Candida zeylanoides Pichia ohmeri Cryptococcus albidus Cryptococcus uniguttulatus Cryptococcus laurentii Trichosporon asahii Subtotal Non dermatophytic molds Chrysosporium keratinophilus Scopulariopsis brevicaulis Aspergillus fumigatus Acremonium spp Subtotal Total is more frequent in diabetic patients than in general population, especially in those suffering from sensibility disorders in soles, in toes, and in nails, conditions that could induce pressure necrosis of the skin by constrictive footwear [20, 21]. Gupta et al. [3] reported that a third part of the diabetic patients with pachyonychia presented onychomycosis. However it is not well defined whether this onychomycosis is more frequent in diabetic patients than in general population. In the present study the onychomycosis incidence was 28% in T2DM patients, similar to that reported by other authors [3, 5, 22]. In other works, it seems that in these patients the T2DM was not the only risk factor for onychomycosis, since the ungual dystrophy was associated with other feet medical conditions. In our study, 40% of T2DM patients presented another associated clinical condition. In contrast to other works [3, 22, 23] the T2DM patient onychomycosis in our study was predominant in toenails and the distribution was similar in both female and male genders. As in other studies, the predominant onychomycosis clinical types were D-LSO (48.6%) and TDO (31.4%) [9, 10, 24]. Without considering the etiological agent, in most cases the clinical features were similar. In our work, as well as in others, dermatophytes were the most frequent agents (48.6%), T. rubrum being the first one followed by Candida spp. [11, 20]. In some studies, Candida spp. are the most frequent onychomycosis causal agents in T2DM patients. A remarkable result in our study was to find that six of the onychomycosis cases were caused by Cryptococcus non neoformans, Pichia sp., and Trichosporon sp. It is possible that these yeasts are more frequently involved

5 Mycopathologia (2008) 166: in onychomycosis than previously supposed, as reported by Méndez-Tovar et al. [25]. Mügge et al. [26] found 3% non-dermatophytic molds in onychomycosis patients, but this frequency can vary from 1.4% to 17.6% (8.6% in the present work) depending on different authors [27, 28]. In this work, the pathogenic role of these non-dermatophytic fungi was established based on three criteria: (a) ungual dystrophy; (b) abundant hyphae and/or yeasts on direct examination in three consecutive nail samples; (c) positive culture in three consecutive nail samples. According to data obtained from the patients, onychomycosis developed 3.5 years after T2DM was detected. This event was significant by Pearson test. In addition, in 60% of cases the T2DM was the only risk factor to develop the onychomycosis. Therefore, in this work a relationship between the presence of onychomycosis and the T2DM as a risk factor was established. Acknowledgment We wish to acknowledge Ricardo Orozco for his technical assistance in the translation of this document. References 1. Pardo-Costello V, Pardo OA. Diseases of the nails. Springfield, IL: Charles C. Thomas; Elewski BE, Charif MA. Prevalence of onychomycosis in patients attending a dermatology clinic in northeastern Ohio for other conditions. Arch Dermatol 1997;133: Gupta AK, Konnikov N, MacDonald P, Rich P, Rodger NW, Edmonds MW, et al. Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: a multicentre survey. Br J Dermatol 1998;139: Perez MI, Kohn SR. Cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol 1994;30: López González V, Mayorga J. Frecuencia de onicomicosis podal y tiña de los pies en 100 pacientes diabéticos tipo 2. Dermatología Rev Mex 2002;46: Alvarez MI, González LA, Castro LA. Onychomycosis in Cali, Colombia. Mycopathologia 2004;158: Ilkit M. Onychomycosis in Adana, Turkey: a 5-year study. 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J Am Podiatr Med Assoc 1997;87: McCarthy DJ, Boyko EJ, Smith DG. Cutaneous manifestations of the lower extremities in diabetes mellitus. In: Kominsky S, editor. Medical and surgical management of the diabetic foot. St. Louis: Mosby; p Arenas R, Rubalcaba Priego J, Leyva Santiago J, Álvarez Zavala B, Fabian San Miguel G, Rubalcaba Priego MA, et al. Onicomicosis y diabetes mellitus tipo 2. Frecuencia en 143 pacientes ambulatorios. Dermatología Rev Mex 1999;43: Piérard GE, Piérard-Franchimont C. The nail under fungal siege in patients with type II diabetes mellitus. Mycoses 2005;48: Romano C, Gianni C, Difonzo EM. Retrospective study of onychomycosis in Italy: Mycoses 2005;48: Méndez-Tovar LJ, Anides-Fonseca A, Vázquez-Hernández A, Galindo-González M, Díaz-Madrid M, Berdón-Castro A, et al. Micosis observadas en cinco comunidades mexicanas con alto grado de marginación. Gac Méd Méx 2006;142: Mügge C, Haustein UF, Nenoff P. Causative agents of onychomycosis-a retrospective study. 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