Übersichtsarbeit
César Bimbi
Malassezia beyond tinea versicolor: the newest wolf in sheep’s clothing pathogen?
Malassezia jenseits Tinea versicolor: das neueste Pathogen als Wolf im Schafspelz?
Keywords | Summary | Correspondence | Literature
Keywords
Schlüsselworte
Summary
Malassezia (M) yeasts are lipophilic commensals and part of the healthy human skin flora, although they may play a role as opportunistic cutaneous pathogens, being a well-known cause of pityriasis versicolor (PV), the prototypical Malassezia-associated skin infection. Recent data has shown new pathogenic potential of Malassezia which under insufficiently understood conditions may be implicated in exacerbations of inflammatory dermatoses, especially on a clinical variant of atopic dermatitis (AD) and some other dermatological and systemic diseases previously unrelated to this yeast. Although there is no evidence that Malassezia species invade the skin, there actually is evidence that their antigens might penetrate a previously damaged epidermis and interact with cells that take part in the skin’s immune system, thus inducing the production of a variety of cytokines which may trigger flares of certain dermatoses. The purpose of this article is to discuss clinical cases reflecting the spectrum of pathogenic interactions of Malassezia fungus with human skin.
Zusammenfassung
Malassezia (M)- Hefen sind lipophile Kommensalen und Teil der Flora der gesunden Haut. Anderseits spielen sie eine Rolle als opportunistische kutane Pathogene wie bei der prototypischen M-Infektion der Haut, der Pityriasis versicolor. Rezente Daten zeigen neue Aspekte des pathogenetischen Potentials von M, z.B. bei der Exazerbation entzündlicher Dermatosen, z.B. bei klinischen Varianten des atopischen Ekzems sowie einiger anderer Dermatosen und Systemerkrankungen. Obwohl es keine Daten gibt, die eine Invasion von M-Spezies in die Haut belegen, können Antigene durch eine geschädigte Haut penetrieren und mit Immunzellen in Wechselwirkung treten. Dieser Umstand könnte die Freisetzung von Zytokinen auslösen, welche die Exazerbation vom Dermatosen triggern könnten. In diesem Artikel werden wir klinische Fälle diskutieren, die das klinische Spektrum pathogener Wechselwirkungen von M mit humaner Haut illustrieren sollen.
César Bimbi 1, Daiane Flores Dalla Lana 2, Georgia Kyriakou 3, Uwe Wollina 4
1 Private Clinic, Dermatologia Medica & Laser Clinic, Porto Alegre, Rio Grande do Sul, Brazil.
2 Post-Graduate Program in Pathology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Brazil.
3 Department of Dermatology, University General Hospital of Patras, Rion, Greece.
4 Department of Dermatology and Allergology, Städtisches Klinikum Dresden, Academic Teaching Hospital, Dresden, Germany
Introduction
The genus Malassezia comprises 17 species of basidiomycetous yeasts that are part of the human skin microbiota [1]. These lipid-dependent commensals appear on human skin shortly after birth, being usually tolerated by the immune system. Currently, it has been strongly hypothesized that the complex interaction of constituents of the yeast wall, its metabolic products and secreted enzymes may hurt skin barrier function and interact with cells that take part in the skin immune system (keratinocyte subpopulations, dendritic cells, macrophages, eosinophils, and neutrophils) resulting in symptomatic inflammatory skin reactions previously unrelated to Malassezia (2). Interaction with the host immune system may occur both directly or through chemical mediators [3].
Recent data has shown new pathogenic potential of Malassezia beyond tinea versicolor in AD. A wide variety of M. related allergens are detectable in AD patients, but not in healthy individuals. AD also affects animals, especially dogs quite often, and have long been recognized there as induced by Malassezia yeasts. There are some common clinical signs of M. infections in dogs and humans, since metabolic products like indoles modify the function of melanocytes and dendritic cells in both races. After being present for some time, “versicolor” phenomena may be seen in canines as the animal skin darkens due to excessive pigmentation and also a reddish-brown discoloration appears on the claws [4].
Case Presentation
Case 1- A healthy, immunocompetent 17-year-old adolescent girl was referred to our clinic with a 2-year history of a previously diagnosed facial acne. Unexpectedly, the treatment with topical clindamycin solution and oral lymecycline did not improve the disease. Her second complain was an itchy rash on the trunk that had been diagnosed as urticaria. Examination showed individual follicular papules on the cheeks and grouped follicular micro-pustules over the back. A diagnosis of Malassezia folliculitis was made after the scraping of lesions on both sites examined under direct microscopy (KOH) showed the presence of a large number of yeasts. By the first week of itraconazole 200mg/day, both facial and trunk lesions began to regress (Fig. 1 a, b).
Case 2 – A 15-year-old adolescent girl, who was otherwise healthy, was seen with a five-month history of monomorphic papules and pustules over her back. Examination showed disseminated pruritic folliculitis lesions and abundant furfuraceous desquamation, somehow mimicking Darier disease for the hyperkeratotic papules grouped in seborrheic areas which resulted in a “dirty“ appearance (Fig. 2). Synthetic fabric clothes use in summer season was noticed. Scraping of the lesions on both sites revealed furfuraceous desquamation. A microscopic potassium hydroxide (KOH) preparation revealed the presence of large number of yeasts. Itraconazole 200 mg/day for 20 days and topical ketoconazole 2% ointment associated with zinc-pyrithione shampoo cleared folliculitis in 3 weeks.
Case 3 – An otherwise healthy 55-year-old woman presented with a 2-year history of a widespread itchy skin rash on her back. Symptoms worsened in hot weather and usually improved in winter. She had been using topical corticosteroids for an “allergy“ diagnosis. At first glance, a case of urticaria could be considered except for the presence of scaling on the affected skin (Fig. 3a). A simple scraping of the macules resulted in abundant visible flaking and a 30% KOH preparation revealed thick-walled spherical yeasts cells and pseudo-hyphae, forming the characteristic “spaghetti and meatballs” feature. Disappearance of the rash followed treatment with itraconazole 200 mg / day for 15 days (Fig. 3b).
Case 4 – An otherwise healthy and immunocompetent 50-year-old woman presented with an asymptomatic rash of well-demarcated areas of atrophic patches confined to her back and displaying slightly raised keratotic rim forming porokeratosis-like designs. The presence of fine scaling overlying the areas of atrophy was noted. There was no prior treatment of these lesions. Skin scrapings were examined at direct microscopy (KOH) and large number of yeasts were seen. Our patient had a complete recovery following treatment with systemic itraconazole 200 mg / day which led to the rapid disappearance of the lesions (Fig. 4).
Case 5 – A 32-year-old woman came to the office with an itchy facial eruption to which corticosteroid creams had been prescribed but no improvement was noted. She had a history of asthma episodes. The initial clinical impression suggested an irritant-type contact dermatitis, but there was an abundant production of a fine dusty scaling. Scraping and microscopy cleared diagnosis showing thick-walled spherical yeasts cells and pseudo-hyphae. Itraconazole 200 mg/ day led to the disappearance of the patient’s lesions (Fig. 5 a, b).
Discussion
Malassezia yeasts are a well-recognized cause of pityriasis (tinea) versicolor and folliculitis, but very recent in-depth studies brought more evidence of its influence on inflammatory skin diseases previously unrelated to this fungus. The patients of cases 1 and 2 illustrates common factors predisposing Malassezia growth and subsequent infection; that is, being adolescent, living in a hot and humid country and an excessive sweating. Malassezia colonization of the skin increases in summer. Cases 1, 2, 3 are the result of erroneously prescribed topical steroids and antibiotics fueling the spread of the fungus. An inflammatory itchy rash was so intense to the point of being simulative of urticaria. Disseminated Malassezia eruptions are associated with conditions altering microbiota balance, such as prolonged antibiotic or corticosteroid use. In this regard, there have been reports of Malassezia secondary infection in previous steroid acneiform eruptions [5]. The presence of tiny follicular pustules localized in the trunk and associated with acneiform facial rash after systemic or topical administration of steroids should raise high level of suspicion of Malassezia folliculitis [6]. In this case, there will be superiority of antifungal therapy over other antibiotic-based acne treatments. Itraconazole 200 mg/ day led to the disappearance of our patient’s lesions.
Atrophying pityriasis versicolor is the diagnosis of the patient of case 4 and represents the sequelae of an idiosyncratic T cell-mediated response to Malassezia, since TH1 cytokines regulate histiocytes (source of elastases), which result in epidermal atrophy. Moreover, an association with topical corticosteroids use has been suggested by some case reports. This is a rare variant of PV in which lesions appear atrophic and simulative of conditions such as anetoderma, atrophoderma, porokeratosis, patch-stage mycosis fungoides, acrodermatitis atrophicans and atypical pityriasis rosea [7].
Head and neck dermatitis (HND) is a variant of eczema affecting atopic patients as in Case 5. There is growing evidence of Malassezia spp. playing a role in the development of AD [8]. Interestingly, M. is an already well-established cause of canine AD, being a routine diagnosis in general veterinary practice [9]. The precise impact of Malassezia on the immunology of AD is open to further research, but there are some theories on its pathogenic mechanisms. Natural killer cells may regulate dendritic cells in the skin of AD patients and Malassezia seems to disturb this normal interaction [10]. Recently, Japanese researchers have identified an antigen secreted by Malassezia globosa showing high histamine-releasing activity of this antigen on human basophils of AD patients and coined it as MGL_1304. This antigen has been demonstrated as an exacerbation factor of AD and also a strong trigger of cholinergic urticaria (CholU) flares, since serum levels of anti-MGL_1304 IgE of patients with both AD and CholU were significantly higher than those of normal controls [11]. This finding could explain the so-called “sweat allergy” episodes, a term frequently heard from patients who experience worsening of symptoms during physical activity. Since Malassezia-specific IgE antibodies are detected in high levels in the sweat, this finding suggests a triggering mechanism of excessive sweating on atopic dermatitis flares.
HND is suspected as a type I hypersensitivity reaction to Malassezia-released compounds on the complex fungus-host interaction. M. antigens effects on epidermal cell lineages having immune functions and a previous dysfunctional skin barrier would result in cytokine production.
Malassezia on the skin might also be responsible for some other reactive skin diseases. Palmoplantar pustulosis (PPP) is a chronic skin disease of difficult control and insufficient knowledge regarding its pathogenesis displaying similarities with palmoplantar psoriasis and pompholyx. Pustules in PPP are assumed to be sterile but a recent study performed PCR analysis in the pustules and identified fungal DNA bands related to Malassezia spp. in more than 40% of the samples [12].
The suspicion of Malassezia yeasts playing a role in the induction of basal cell carcinoma (BCC) have come from the interactive analysis of some facts. First, M. furfur may synthesize potent ligands of the aryl-hydrocarbon receptor (AhR) which are associated with carcinogenesis induction [13, 14]. On the other hand, veterinary medicine observations show BCC incidence almost exclusively affecting animal species colonized by Malassezia and also those dog breeds offering anatomical conditions (long pendulous ears) for Malassezia overgrowth are the most affected. Furthermore, canine BCCs usually develop on the same head and neck region that is also the niche of Malassezia.
The objective of this article is to overview the pathogenic potential and to encourage etiologic suspicion based on the broad clinical spectrum of M. related skin diseases. Our cases also showed that superficial fungal presence seems not to be routinely investigated and, as a result, diagnosis escapes. Suspected Malassezia-associated dermatitis may be quickly diagnosed since the fungus is easily detected with a microscope. Prick testing, Malassezia-specific IgE testing, IgG and IgM antibodies against Malassezia may also be useful in cases of AD, HND, and CholU. Direct microscopy revealed multiple hyphae in all our cases. The microscope used to be an indispensable tool in any dermatological office a few decades ago and now it’s certainly the time for this valuable tool to retrieve its place. Most of these infections are gratifyingly simple to treat. A range of topical and systemic therapies are effective. All our patients responded to oral itraconazole 100 mg daily for 5 to 20 days, topical imidazoles once daily for 3 weeks and ketoconazole, pyrithione-zinc or selenium sulfide shampoos. Predisposing factors need to be corrected, especially disturbed epithelial barrier function. Associated inflammatory symptoms may be supplemented by anti-inflammatory therapy.
Malassezia has always been considered as a very low virulence fungus, somehow limited to trivial superficial summer infections. There is now growing evidence that this fungus might be implicated in more serious diseases. Malassezia’s role beyond the skin has emerged and an association with Crohn’s disease [15] and pancreatic ductal carcinoma has also been reported [16]. Neonatal cephalic pustulosis (a pustular eruption on young babies that resembles infantile acne) to Malassezia pachydermatis fungemia in critically ill neonates has been recently described [17].
While more in-depth investigations are still needed, the latest studies make this once-innocent and naïve fungus an indeed serious candidate to be nominated as the newest wolf in sheep’s clothing pathogen.
Conclusion:
Constituents of the yeast wall (lipid cover), its metabolic products (indoles) and secreted enzymes (lipases, phospholipases) may hurt skin barrier function and affect keratinocytes resulting in symptomatic inflammatory skin reactions previously unrelated to Malassezia as palmoplantar pustulosis, cholinergic urticaria and head and neck subtype of atopic dermatitis.
Worsening of symptoms during physical activity may raise suspicion of “sweat allergy”, since Malassezia-specific IgE antibodies are detected in high levels in the sweat. This suggests a triggering mechanism of excessive sweating for atopic dermatitis and cholinergic urticaria (CholU) patients, although this theory still remains under investigation.
Malassezia specific IgE testing or prick testing and a positive treatment response to antifungals may be regarded as confirmatory role of Malassezia etiology.
Abbreviations
AD, atopic dermatitis; M, Malassezia; HND, Head and neck dermatitis; PCR, Polymerase Chain Reaction; PV, pityriasis versicolor; SD, seborrheic dermatitis. (CholU) cholinergic urticaria; (BCC) basal cell carcinoma
Korrespondenz-Adresse
César Bimbi, MD
R. 24 de Outubro
111 - Sala 502 – Independência
Porto Alegre – RS
BR-90510-002
cbimbi@terra.com.br
Conflict of Interests
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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