Position statement: Recommendations on the diagnosis and treatment of Malassezia folliculitis.

Malassezia is a lipophilic yeast that is a part of the human mycobiome. Malassezia folliculitis appears when the benign colonization of the hair follicles, by the Malassezia yeasts, becomes symptomatic with pruritic papules and pustules. Although Malassezia folliculitis is common in hospital departments, diagnosing and treating it varies among dermatologists and countries. The European Academy of Dermatology and Venereology Mycology Task Force Malassezia folliculitis working group has, therefore, sought to develop these recommendations for the diagnosis and management of Malassezia folliculitis. Recommendations comprise methods for diagnosing Malassezia folliculitis, required positive findings before starting therapies and specific treatment algorithms for individuals who are immunocompetent, immunocompromised or who have compromised liver function. In conclusion, this study provides a clinical strategy for diagnosing and managing Malassezia folliculitis.

Critical synthesis of available data in Malassezia folliculitis and a systematic review of treatments.

Folliculitis is an inflammatory process involving the hair follicle, frequently attributed to infectious causes. Malassezia, an established symbiotic yeast that can evolve to a skin pathogen with opportunistic attributes, is a common source of folliculitis, especially when intrinsic (e.g. immunosuppression) or extrinsic (high ambient temperature and humidity, clothing) impact on the hair follicle and the overlying skin microenvironment. Our aim was to critically review the pathophysiology and clinical characteristics of Malassezia folliculitis, to describe laboratory methods that facilitate diagnosis and to systematically review treatment options. Malassezia folliculitis manifests as a pruritic, follicular papulopustular eruption distributed on the upper trunk. It commonly affects young to middle-aged adults and immunosuppressed individuals. Inclusion into the differential diagnosis of folliculitis is regularly oversighted, and the prerequisite-targeted diagnostic procedures are not always performed. Sampling by tape stripping or comedo extractor and microscopic examination of the sample usually identifies the monopolar budding yeast cells of Malassezia without the presence of hyphae. However, confirmation of the diagnosis with anatomical association with the hair follicle is performed by biopsy. For systematic review of therapies, PubMed was searched using the search string "(malassezia" [MeSH Terms] OR "malassezia" [All Fields] OR pityrosporum [All Fields]) AND "folliculitis" [MeSH Terms] and EMBASE was searched using the search string: 'malassezia folliculitis.mp OR pityrosporum folliculitis.mp'. In total, 28 full-length studies were assessed for eligibility and 21 were selected for inclusion in therapy evaluation. Conclusively Malassezia folliculitis should be considered in the assessment of truncal, follicular skin lesions. Patient's history, comorbidities and clinical presentation are usually indicative, but microscopically and histological examination is needed to confirm the diagnosis. Adequate samples obtained with comedo extractor and serial sections in the histological material are critical for proper diagnosis. Therapy should include systemic or topical measures for the control of the inflammation, as well as the prevention of recurrences.

Causality evaluation of bacterial species isolated from patients with community-acquired lower leg cellulitis.

INTRODUCTION: Lower leg cellulitis is a diffuse inflammation of the cutaneous connective tissue following invasion of microorganisms and with potential to recur. The causative agent is not routinely identified in clinical practice, and the empirical therapy initiated primarily targets the 'conventional' disease pathogens, Streptococcus pyogenes and Staphylococcus aureus. OBJECTIVE: To evaluate at case level, the role of bacterial species isolated from lesional skin in the pathogenesis of community-acquired lower leg cellulitis. METHODS: Two sampling methods (superficial swab and biopsy) were applied to isolate bacterial species from 40 patients hospitalized for first (N = 24 cases) and recurrent (N = 16 patients) lower leg cellulitis episodes. Subsequently, a clinical-laboratory heuristic algorithm was employed to interpret causality associations of isolated species with disease episodes at case level. RESULTS: In 37/40 cases (92.5%), at least one bacterial species was identified with either sampling method. The number of different species/specimen isolated from superficial swabs compared to punch biopsies was significantly more (P < 0.001). A causative agent was identified in 16 cases (40%); it was a 'conventional' pathogen in seven patients and strains belonging to one of six 'non-conventional' pathogens in nine cases. There was no concordance in the spectrum of isolated pathogens with the two sampling methods (kappa-index = 0.028). Another four species may have participated in five patients as co-pathogens in mixed infections. There was also no difference in microbiological disease features between patients with first and recurrent cellulitis episodes. CONCLUSIONS: The application of a clinical-laboratory causality algorithm coupled with pooled culture results of more than one sampling methods in patients with lower leg cellulitis is anticipated to permit the identification of responsible bacterial species at case level and offer incentive for therapeutic intervention studies.

Intralesional bevacizumab as in-add adjuvant to immunocryosurgery for locally advanced basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is a tumour that relies mainly on aerobic energy assimilation for growth and depends on an extensive microvascular network to support adequate oxygen supply. In this tumour, higher expression levels of vascular endothelial growth factor (VEGF) has been described to correlate with increased microvessel density and more aggressive biologic behaviour. OBJECTIVE: To report feasibility and effectiveness of intralesional bevacizumab, an anti-VEGF antibody, as an in-add adjuvant to immunocryosurgery (cryosurgery sessions during daily topical imiquimod application) for the treatment of locally advanced BCC. METHOD: Seven patients (six uncontrollable or extensive local disease; one tumour unresponsive to repeated immunocryosurgery) were treated with 1­3 sessions of intralesional injections of bevacizumab (25 mg) at the day of cryosurgery during ongoing immunocryosurgery. Follow-up after treatment was 18­48 months. RESULTS: In 4/7 cases tumours cleared completely and 3/7 remained relapse free during follow-up. A relapsed tumour and a further case that did not clear after repeated immunocryosurgery cycles were excised with significantly reduced burden of surgery. Finally, two cases with previously locally uncontrollable BCC tumours regressed significantly and stabilized. CONCLUSION: In-add intralesional bevacizumab is a feasible and potentially effective addition to minimally invasive schemes for the treatment of locally advanced BCC.

Phospholipase activity after ß-endorphin exposure discriminates Malassezia strains isolated from healthy and seborrhoeic dermatitis skin.

BACKGROUND: Phospholipase activity and its induction by ß-endorphin have been associated with pathogenic Malassezia pachydermatis animal isolates. OBJECTIVE: To evaluate Malassezia phosholipase activity in human isolates from seborrhoeic dermatitis (SD) and healthy controls before and after ß-endorphin exposure. METHODS: Eighty-four volunteers with or without SD (N = 41) were sampled. Isolated Malassezia strains were incubated in Dixon's medium with and without 100 nmol/L ß-endorphin. Subsequently, phospholipase activity was assessed in egg-yolk agar and the results were compared employing Wilcoxon sign test for paired data, chi-squared test and multinomial logistic regression analysis. RESULTS: A total of 64 Malassezia strains were isolated. SD strains tended to have decreased phospholipase activity before (P = 0.057) and increased after exposure to ß-endorphin (P = 0.061) compared to isolates from healthy skin. Phospholipase activity after ß-endorphin exposure related to basal enzyme activity as a measure of per strain phospholipase inducibility by ß-endorphin did not depend on Malassezia species (P = 0.652). However, this latter biochemical trait discriminates strains isolated from SD lesional and healthy skin (P = 0.036). CONCLUSION: ß-endorphin exposure modifies the in vitro phosholipase activity in Malassezia species isolated from SD lesional skin. This is in accordance with emerging evidence that enhanced local lipase activity is involved in the pathogenesis of SD.

Malassezia-derived indoles activate the aryl hydrocarbon receptor and inhibit Toll-like receptor-induced maturation in monocyte-derived dendritic cells.

BACKGROUND: The aryl hydrocarbon receptor (AhR) is a nuclear receptor and transcriptional regulator with pleiotropic effects. The production of potent AhR ligands by Malassezia yeasts, such as indirubin, indolo[3,2-b]carbazole (ICZ), tryptanthrin and malassezin, has been associated with the pathogenesis of seborrhoeic dermatitis and pityriasis versicolor. Antigen-presenting cells in the skin can encounter microbes in the presence of these bioactive metabolites that could potentially modulate their function. OBJECTIVES: To study the effects of the aforementioned naturally occurring ligands on AhR activation and Toll-like receptor (TLR)-induced maturation in human monocyte-derived dendritic cells (moDCs). METHODS: These indoles were screened for AhR activation capacity in moDCs employing CYP1A1 and CYP1B1 induction as read out and for their effects on the function of moDCs after TLR-ligand stimulation. RESULTS: Indirubin and ICZ were the most potent AhR ligands and were selected for subsequent experiments. Concurrent exposure of moDCs to indirubin or ICZ together with TLR agonists significantly augmented the AhR-mediated CYP1A1 and CYP1B1 gene expression. Additionally, mature DCs that were subsequently stimulated with AhR ligands showed increased AhR target gene expression. Moreover, these ligands limited TLR-induced phenotypic maturation (CD80, CD83, CD86, MHC II upregulation) of moDCs, reduced secretion of the inflammatory cytokines interleukin (IL)-6 and IL-12, and decreased their ability to induce alloreactive T-lymphocyte proliferation. CONCLUSIONS: These results demonstrate that AhR agonists of yeast origin are able to inhibit moDC responses to TLR ligands and that moDCs can adapt through increased transcription of metabolizing enzymes such as CYP1A1 and CYP1B1.

Drug-induced bullous pemphigoid in diabetes mellitus patients receiving dipeptidyl peptidase-IV inhibitors plus metformin.

BACKGROUND: Preclinical data and reports of adverse skin reactions in patients treated with dipeptidyl peptidase-IV inhibitors (gliptins) have increased awareness towards skin-targeting side-effects of these anti-hyperglycaemic drugs. Bullous pemphigoid (BP), sometimes drug-induced, is the most commonly acquired autoimmune blistering dermatosis in western countries, typically a disease of the elderly people with significant morbidity and excess mortality. OBJECTIVE: To report the development of BP in five diabetics under gliptin (4 vildagliptin, 1 sitagliptin) plus metformin in fixed-dose drug combinations. CASE REPORTS: From March to August 2010 six out of nine newly diagnosed BP patients in our Department were type 2 diabetics. Five of them were on gliptin plus metformin (three different trade preparations) for 2-13 months prior to BP onset. In all cases BP was controlled after withdrawal of the suspected medication and relatively mild therapeutic interventions. In two cases the eliciting role of the preceding treatment is supported by evidence at the level 'probable/likely' according to the WHO-UMC algorithm. CONCLUSIONS: This is the first report of drug-induced BP as a group adverse event of the gliptins plus metformin combination therapy for glycaemia control in type 2 diabetes mellitus patients.

Could Malassezia yeasts be implicated in skin carcinogenesis through the production of aryl-hydrocarbon receptor ligands?

UNLABELLED: Malassezia yeasts are found on the skin of all humans and many warm-blooded animals. In vitro they have the ability to synthesize potent ligands (indolo[3,2-b]carbazole, malassezin and indirubin) of the aryl-hydrocarbon receptor (AhR; synonym: dioxin receptor) when the sweat contained L-tryptophan is used as the single nitrogen source. The production of these AhR-ligands has been associated with pathogenic strains of a certain Malassezia species (Malassezia furfur) but recent evidence shows that this property is widely distributed in almost all currently known Malassezia species. AhR is associated with carcinogenesis and the potential connection of these ubiquitous skin symbionts, and putative pathogens, with skin neoplasia should be evaluated mainly focusing on mechanisms related to the distinctive ability of the yeast to produce potent AhR ligands. HYPOTHESIS: Synthesis of available pertinent data show a possible link between Malassezia produced AhR ligands and skin carcinogenesis, particularly of basal cell carcinoma (BCC). BCCs are almost exclusively observed in animal species colonized by Malassezia. In humans and animals there is overlapping in the skin regions colonized by this yeast and affected by BCC. The potent AhR ligands synthesized by pathogenic Malassezia strains could contribute to tumor promotion by: modification of the UV radiation carcinogenesis, alterations in the salvage/survival of initiated tumor cells, inhibition of cell senescence, interaction with vitamin D metabolism, promotion of immune tolerance and finally pro-carcinogenic modulation of cell cycle progression and apoptosis.

Immunocryosurgery for basal cell carcinoma: results of a pilot, prospective, open-label study of cryosurgery during continued imiquimod application.

BACKGROUND/AIM: Theoretical considerations support the combination of cryosurgery and topical imiquimod to treat basal cell carcinomas (BCC). The aim of the present study was to test the feasibility and efficacy of 'cryosurgery during continued imiquimod application' ('immunocryosurgery') to treat 'high-risk-for-recurrence' BCCs. METHODS: Thirteen patients with 21 biopsy-proven tumours (4 of 21 relapses after prior surgery) were included. After 2-5 weeks (median, 3) of daily 5% imiquimod cream application, the tumours were treated by liquid N(2) cryosurgery (spray, two cycles, 10-20 s) and imiquimod was continued for additional 2-12 weeks (median, 4). The outcome after at least 18 months of follow-up (18-24 months) is currently reported. RESULTS: Nineteen of 21 tumours responded promptly to immunocryosurgery; two tumours required additional treatment cycles to clear. Thus, the clinical clearance rate was 100%. Only 1 of 21(5%) tumour relapsed after at least 18 months of follow-up (cumulative efficacy: 95%). CONCLUSIONS: 'Immunocryosurgery' is a promising non-surgical combination modality to treat 'high-risk-for-recurrence BCCs'. Initial evidence is suggestive of an at least additive effect of the two combined modalities. Further studies comparing immunocryosurgery directly with cryosurgery and imiquimod monotherapies will confirm the reported results.