Malassezia-Associated Skin Diseases, the Use of Diagnostics and Treatment

Abstract

Yeasts of the genus, Malassezia, formerly known as Pityrosporum, are lipophilic yeasts, which are a part of the normal skin flora (microbiome). Malassezia colonize the human skin after birth and must therefore, as commensals, be normally tolerated by the human immune system. The Malassezia yeasts also have a pathogenic potential where they can, under appropriate conditions, invade the stratum corneum and interact with the host immune system, both directly but also through chemical mediators. The species distribution on the skin and the pathogenetic potential of the yeast varies between different Malassezia related diseases such as head and neck dermatitis, seborrheic dermatitis, pityriasis versicolor, and Malassezia folliculitis. The diagnostic methods used to confirm the presence of Malassezia yeasts include direct microcopy, culture based methods (often a combination of morphological features of the isolate combined with biochemical test), molecular based methods such as Polymerase Chain Reaction techniques, and Matrix Assisted Laser Desorption/Ionization—Time Of Flight mass spectrometry and the chemical imprint method Raman spectroscopy. Skin diseases caused by Malassezia are usually treated with antifungal therapy and if there are associated inflammatory skin mechanisms this is often supplemented by anti-inflammatory therapy. The aim of this paper is to provide an overview of Malassezia related skin disease, diagnostic methods and treatment options.

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published: 20 March 2020
doi: 10.3389/fcimb.2020.00112
Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 1March 2020 | Volume 10 | Article 112
Edited by:
Salomé LeibundGut-Landmann,
University of Zurich, Switzerland
Reviewed by:
Peter Mayser,
University of Giessen, Germany
Philipp Peter Bosshard,
University Hospital Zürich, Switzerland
Cheryl Kit Mun Leong,
Institute of Medical Biology
(A∗STAR), Singapore
*Correspondence:
Ditte M. L. Saunte
disa@regionsjaelland.dk
†Member of European Academy of
Dermatology and Venereology Task
Force of Mycology
‡Member of the International Society
for Human and Animal Mycology
working group on Malassezia
Epidemiology and Pathobiology
Specialty section:
This article was submitted to
Fungal Pathogenesis,
a section of the journal
Frontiers in Cellular and Infection
Microbiology
Received: 16 January 2020
Accepted: 28 February 2020
Published: 20 March 2020
Citation:
Saunte DML, Gaitanis G and Hay RJ
(2020) Malassezia-Associated Skin
Diseases, the Use of Diagnostics and
Treatment.
Front. Cell. Infect. Microbiol. 10:112.
doi: 10.3389/fcimb.2020.00112
Malassezia-Associated Skin
Diseases, the Use of Diagnostics and
Treatment
Ditte M. L. Saunte 1,2
*†, George Gaitanis 3,4†‡ and Roderick James Hay 5†
1Department of Dermatology, Zealand University Hospital, Roskilde, Denmark, 2Department of Clinical Medicine, Health
Sciences Faculty, University of Copenhagen, Copenhagen, Denmark, 3Department of Skin and Venereal Diseases, Faculty of
Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece, 4DELC Clinic, Biel/Bienne, Switzerland,
5St. Johns Institute of Dermatology, Kings College London, London, United Kingdom
Yeasts of the genus, Malassezia, formerly known as Pityrosporum, are lipophilic yeasts,
which are a part of the normal skin flora (microbiome). Malassezia colonize the human
skin after birth and must therefore, as commensals, be normally tolerated by the
human immune system. The Malassezia yeasts also have a pathogenic potential where
they can, under appropriate conditions, invade the stratum corneum and interact with
the host immune system, both directly but also through chemical mediators. The
species distribution on the skin and the pathogenetic potential of the yeast varies
between different Malassezia related diseases such as head and neck dermatitis,
seborrheic dermatitis, pityriasis versicolor, and Malassezia folliculitis. The diagnostic
methods used to confirm the presence of Malassezia yeasts include direct microcopy,
culture based methods (often a combination of morphological features of the isolate
combined with biochemical test), molecular based methods such as Polymerase
Chain Reaction techniques, and Matrix Assisted Laser Desorption/Ionization—Time
Of Flight mass spectrometry and the chemical imprint method Raman spectroscopy.
Skin diseases caused by Malassezia are usually treated with antifungal therapy and
if there are associated inflammatory skin mechanisms this is often supplemented
by anti-inflammatory therapy. The aim of this paper is to provide an overview of
Malassezia related skin disease, diagnostic methods and treatment options.
Keywords: Malassezia, folliculitis, head and neck dermatitis, seborrheic dermatitis, pityriasis versicolor
INTRODUCTION
Yeasts of the genus, Malassezia, formerly known as Pityrosporum, are lipophilic yeasts, which
are a part of the normal skin flora (microbiome). The genus Malassezia belongs to the phylum
Basidiomycota (class Malasseziomycetes) and the genus consists at present of 17 species (Grice
and Dawson, 2017; Theelen et al., 2018). It is the most prevalent fungal genus of the healthy
skin, but these yeasts also demonstrate a pathogenic potential where they can, under appropriate
conditions, invade the stratum corneum. They interact with almost all the cellular constituents
of normal epidermis, including keratinocytes, Langerhans cells, melanocytes as well as the host
immune system, both directly but also through chemical mediators (Glatz et al., 2015; Grice and
Dawson, 2017). Malassezia colonize the human skin after birth and must therefore, as a commensal,

Saunte et al. Malassezia-Associated Skin Diseases
be normally tolerated by the human immune system. Depending
on sampling technique and diagnostic methods they have been
isolated from 30 to 100% of newborns (Ayhan et al., 2007; Nagata
et al., 2012).
Malassezia species are dependent on exogenous lipids because
they lack fatty acid synthase genes, except M. pachydermatis
(Glatz et al., 2015). This explains their distribution on seborrheic
skin areas (face, scalp and thorax), but they have been detected
from most body sites except the feet (Grice and Dawson,
2017). There is also a correlation between species diversity and
anatomical sampling site (Grice and Dawson, 2017; Theelen et al.,
2018).
The species distribution on the skin varies between different
Malassezia related diseases, but their worldwide distribution
may also differ (Grice and Dawson, 2017). For example, M.
sympodialis considered the most prevalent species in Europe and
M. restricta and M. globosa the most predominant species in
Asia. The difference in the species distribution may not only be
revealed by differences in geographic specificity but may also
be due to a difference in diagnostic methods used. Most of the
European studies used culture-based methods whereas Asian
countries generally have applied molecular based methods and
as some Malassezia species are slow-growing and more fastidious
in culture, such as M. restricta, this particular species in culture
may be overgrown by a more rapid-growing Malassezia species
as e.g., M. sympodialis (Kohsaka et al., 2018).
Skin diseases caused by Malassezia are usually treated with
antifungal therapy and if there are associated inflammatory
skin mechanisms this is often supplemented by anti-
inflammatory therapy. Different Malassezia species have
shown various antifungal susceptibility patterns (Prohic
et al., 2016; Theelen et al., 2018). It may therefore
occasionally be important to identify the Malassezia species
in order to choose the most sensitive antifungal drug
although this poses immense practical problems in resource
poor settings.
The aim of this paper is to provide an overview of the
Malassezia related skin diseases Head and neck dermatitis,
seborrheic dermatitis, pityriasis versicolor, and Malassezia
folliculitis, their diagnostic methods and treatment options.
DIAGNOSTICS
Different sampling methods have been used to confirm the
presence of Malassezia yeasts in skin conditions and these
include tape stripping, skin scraping, swabs, and contact plates
(Darabi et al., 2009). Direct microcopy is used frequently in
clinical settings (Saunte et al., 2018) as it can be used to
detect fungal elements after application of potassium hydroxide
and adding a dye such as e.g., Parker ink, methylene blue,
lactophenol blue, May-Grunwald-Giemsa, Gram staining or a
fluorescence dye such as Calcofluor white and Blancophor
(Rubenstein and Malerich, 2014; Tu et al., 2018). Malassezia is
Abbreviations: AD, atopic dermatitis; M, Malassezia; HND, Head and neck
dermatitis; PCR, Polymerase Chain Reaction; PV, pityriasis versicolor; SD,
seborrheic dermatitis.
recognized by the detection of characteristic unipolar budding
yeasts and in the case of pityriasis versicolor these are
accompanied by short hyphae (the so-called spaghetti and
meatballs appearance). Hyphae are not detected in head and
neck dermatitis and rarely seen in Malassezia folliculitis or
seborrheic dermatitis/dandruff. Even though it is possible to see
differences in the shape of the Malassezia yeasts cells as e.g.,
the globose cells of M. globosa or the sympodial budding of
M. sympodialis, accurate species identification is not possible
by direct microscopy. For this, different in vitro methods have
been applied.
The initial isolation usually employs Dixon’s or Leeming-
Notman agar and growth at 32–35◦C under aerobic conditions.
Daily evaluation of the cultures is required to observe the
presence of mixed species colonies, which are needed to be
separated using needle sampling of the colonies and/or multiple
dilutions before subculturing. Identification to species level is
achieved by evaluation of the different lipid assimilation profile
of the Malassezia species (Guého et al., 1996; Mayser et al.,
1997) in combination with microscopic morphological features.
However, the variations revealed by this conventional mycology
approach are not sufficiently specific for the identification of the
current expanded Malassezia species, as there is a common lipid
profile overlap between species (Cafarchia et al., 2011; Theelen
et al., 2018). Although these culture-based methods are time-
consuming and it is difficult to separate closely related species
characteristics of each strain.
For this reason during the last five decades molecular based
methods (Arendrup et al., 2013) as well as methods that identify
the chemical imprint of the different species e.g., different
Polymerase Chain Reaction (PCR) techniques, Matrix Assisted
Laser Desorption/Ionization—Time Of Flight (MALDI-TOF)
mass spectrometry (Kolecka et al., 2014; Diongue et al., 2018;
Honnavar et al., 2018; Saunte et al., 2018) and or Raman
spectroscopy (Petrokilidou et al., 2019) have been applied to
achieve fast and accurate fungal identification.
Discrepancies in the epidemiological data generated by
culture and molecular based Malassezia identification methods
are well-known and probably reflect differences in growth
rate, where the fast growing species may overgrowth slower
ones in culture based methods and because molecular based
methods are considered to be more accurate (Soares et al., 2015;
Prohic et al., 2016). Additionally, species identification using
molecular based methods is dependent on reliable “databases” for
sequence comparison.
Antifungal susceptibility of Malassezia species using
agar and broth dilution methods (Clinical & Laboratory
Standards Institute and European Committee of Antimicrobial
Susceptibility Testing assays) with lipid supplementation has
been studied (Cafarchia et al., 2012; Leong et al., 2017; Peano
et al., 2017; Rojas et al., 2017). In vitro antifungal resistance
have been demonstrated in different strains, but as there is
no reference procedure for antifungal susceptibility testing
the strains may appear susceptible under other test conditions
(Peano et al., 2017; Rojas et al., 2017).
Despite the current knowledge of Malassezia species’
association and contribution to skin disorders, the mechanisms
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Saunte et al. Malassezia-Associated Skin Diseases
TABLE 1 | Malassezia associated diseases and their possible pathogenesis, main diagnostics and differential diagnosis.
Disease Possible pathogenesis Main diagnostic Examples of differential
diagnosis
Head & neck dermatitis Type-I hypersensitivity to Malassezia Clinical
Skin prick test
Malassezia spp. specific IgE
(Atopy patch test)
Contact dermatitis
Steroid induced dermatitis
Seborrheic dermatitis Colonization with Malassezia that triggers
irritant dermatitis
Clinical
Biopsy shows psoriasiform, spongiotic
dermatitis without intraepidermal pustules
Rosacea
Sebopsoriasis
Systemic lupus erythematois
Tinea capitis
Zinc deficiency
Contact dermatitis
Pityriasis versicolor Malassezia infection Clinical
Direct microscopy with unipolar budding
yeast and hyphae (spaghetti and
meatballs)
Vitiligo
Pityriasis alba
Chloasma
Nummular dermatitis
Malassezia folliculitis Invasion of the pilo-sebaceous with
Malassezia
Histopathology
Direct microscopy with unipolar budding
yeast (rarely hyphae)
Acne
Steroid acne
Bacterial folliculitis
Eosinophilic folliculitis
Pustular drug eruptions
Lymphomatoid papulosis
underlying their change from a commensal to pathogen are
still to be further elucidated. Furthermore, there is a need for
standardization of species diagnostic methods and antifungal
susceptibility testing.
MALASSEZIA-ASSOCIATED SKIN
DISEASES
Even though Malassezia is a part of the human microbiome it is
also involved in the pathogenesis of head and neck dermatitis,
seborrheic dermatitis, pityriasis versicolor, and Malassezia
folliculitis. It interacts with both the innate and acquired skin
immune systems and thereby causes immune reactions under
certain conditions. It is possible to detect IgG and IgM antibodies
against Malassezia in most individuals, but healthy persons are
usually not sensitized as is the cases with atopic dermatitis
patients. The sensitization can in atopic dermatitis (AD) patients
cause a type I hypersensitivity reaction contributing to redness,
itching and further scaling in the seborrheic areas of the
head and neck, the so-called head and neck dermatitis (Glatz
et al., 2015; Kohsaka et al., 2018). In seborrheic dermatitis
(Faergemann et al., 2001) the inflammatory reaction that leads
to the development of seborrheic dermatitis seems to be an
irritant non-immunogenic stimulation of the immune system
that leads to complement activation and local increase in
NK1+and CD16+cells. Pityriasis versicolor is an infection
which involves proliferation of the organisms and activation of
the formation of hyphae to cause superficial invasion of the
stratum corneum.
In Malassezia folliculitis the yeasts invade the pilo-sebaceous
unit leading to a dilatation of the follicles with large number of
Malassezia cells. If the follicular walls rupture this results in a
mixed inflammatory infiltrate and clinical inflammation.
HEAD AND NECK DERMATITIS
Epidemiology and Pathogenesis
Head and neck dermatitis is a subtype and difficult to treat form
of atopic dermatitis, which is generally seen in post-pubertal
atopic dermatitis patients. The prevalence of atopic dermatitis
among adults in industrialized countries is 1–3% and it affects
10–20% of children (Brodská et al., 2014). It is thought to be
due to a type I hypersensitivity reaction to Malassezia antigens
(Table 1). The antigens e.g., M. globosa protein (MGL_1304) and
its homologs from M. sympodialis (Mala s 8) and M. restricta
(Mala r 8) have all been implicated in the pathogenesis of
head and neck dermatitis and show different histamine releasing
activity (Kohsaka et al., 2018). The Malassezia (antigen) proteins
are found in sweat and the disease is therefore triggered by
sweating (sometimes referred to as sweat allergy) (Hiragun et al.,
2013; Maarouf et al., 2018). IgE antibodies against Malassezia is
found in up to 27% of children and 65% of adults with atopic
dermatitis (Glatz et al., 2015).
Malassezia’s interaction with the skin immune system is
thought to be both humoral and cell-mediated and it contributes
to and accentuates the pre-existing skin inflammation in AD
(Brodská et al., 2014). It is suggested that an increased pH,
which is higher in AD patients, may contribute to allergen release
by Malassezia. The disturbed skin barrier in AD allows both
Malassezia allergens as well as cells to penetrate the epidermis
and hereby introducing them to toll-like receptor 2 on dendritic
cells and keratinocytes. A release of pro-inflammatory cytokines
and Malassezia spp.- specific IgE antibodies is produced through
T cell mediated activation of B cells and through dendritic cells
and mast cells and this contributes to the skin inflammation.
Furthermore, autoreactive T cells may cross react and sustain
skin inflammation (Glatz et al., 2015).
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Saunte et al. Malassezia-Associated Skin Diseases
FIGURE 1 | (A,B) Head and neck dermatitis. (A) Neck with erythema and discrete skin scales. Arrows indicate the area. (B) Skin scales, erythema (arrows) and
excoriation (square) of neck and cheek.
Clinical Presentation
The clinical manifestations of head and neck dermatitis are
typically erythematous involvement of the eyelids, forehead and
neck; sometimes the changes are wheal-like (urticarial) (Maarouf
et al., 2018). Affected areas are itchy and there is often scaling
giving the appearances of an eczema flare (Figures 1A,B).
Diagnosis
The diagnosis is based upon the clinical picture and may be
supported a positive type I allergic reaction to Malassezia and a
positive skin prick test with Malassezia spp. –specific extract is
found in 30–80% of adult atopic dermatitis (Glatz et al., 2015).
A study by Devos and van der Valk found that all AD patients
with head and neck dermatitis had increased Malassezia-spp.
specific IgE as compared with only 13.6% of AD patients without
head and neck dermatitis (Devos and van der Valk, 2000). A
commercial and standardized kit (ImmunoCAP R
m70, Phadia)
is available for measuring Malassezia spp.-specific serum IgE
(Glatz et al., 2015). The use of atopy patch test shows diverse
results (Brodská et al., 2014). In two different studies (Ramirez
De Knott et al., 2006; Johansson et al., 2009) there was no
correlation between IgE and atopy patch test for Malassezia,
whereas Johansson et al. (Johansson et al., 2003) found that
atopic patch test was positive in 30% of AD patients without
head and neck dermatitis and in 41% of patients with head and
neck dermatitis.
Treatment
Head and neck dermatitis can be treated using anti-inflammatory
medications, antifungals or a combination.
The main purpose of the antifungal treatment is to reduce
the skin colonization thereby reducing the amount of allergen
causing the type I hypersensivity. It has been shown that AD
patients with head and neck dermatitis treated with anti-fungals
(itraconazole) show decreases in the total Malassezia specific
IgE, eosinophil count as well as improving clinical severity
scores (Ikezawa et al., 2004).
The clinical improvement is usually seen within the
first week(s) and the daily regimen is often continued
for 1–2 months followed by a twice weekly regimen to
prevent relapse (Darabi et al., 2009). Systemic antifungals
are useful in severe cases or when treatment failure after
topical therapy.
Furthermore, in AD patients repair of the impaired skin
barrier and a reduction of the inflammation with e.g., calcineurin
inhibitors or topical steroids are very useful (Nowicka and
Nawrot, 2019). It is not clear if the reduction of the inflammation
is more important than reducing skin colonization of Malassezia
for two reasons. First of all the treatment responses to
hydrocortisone combined with placebo shampoo compared with
miconazole-hydrocortisone cream and ketoconazole shampoo
are not significantly different (Broberg and Faergemann, 1995).
Secondly, some antifungals have anti-inflammatory properties
(inhibit IL-4 and IL-5 production) (Kanda et al., 2001).
SEBORRHEIC DERMATITIS
Epidemiology and Pathogenesis
Seborrheic dermatitis is an inflammatory dermatosis with a
predilection for anatomical areas with high sebaceous gland
concentration such as the midface, chest, back, and scalp.
Seborrheic dermatitis located on the scalp and dandruff should
be considered as representing different ends of a disease
severity spectrum (Grimalt, 2007). Therefore, for scalp disease
the term seborrheic dermatitis/dandruff complex is suggested
to encompass the scaling both with inflammation (seborrheic
dermatitis) and without inflammatory component (dandruff).
As dandruff is extremely common and practically all adults are
affected at some point in their life, we will note only relevant
data in the pathogenesis section that help us to understand
seborrheic dermatitis.
Seborrheic dermatitis is a relative common dermatosis
and few recent meticulous studies have addressed the point
prevalence of this disease. Thus the point prevalence of
seborrheic dermatitis in 161,269 working individuals in Germany
(Zander et al., 2019) was recorded to be 3.2% with seborrheic
dermatitis being three times more common in men than in
women. Also, seborrheic dermatitis prevalence increased with
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Saunte et al. Malassezia-Associated Skin Diseases
FIGURE 2 | (A,B) Seborrheic dermatitis. (A) Peri-nasal skin and upper lip with erythema and greasy skin scales. (B) Erythema and greasy skin scales of the chest and
a close-up (square) of an area with erythematous lesions.
age (2.0% in <35 years; 3.6% in 35–64 years; 4.4% ≥65 years)
and there was an association with other fungal diseases such
as tinea pedis, onychomycosis and pityriasis versicolor. The age
dependence of seborrheic dermatitis is probably responsible for
the increased prevalence (14.3%) recorded in the Rotterdam
study (Sanders et al., 2018a) as the median age of patients was
67.9 years. These robustly acquired data confirm the association
of seborrheic dermatitis with gender (two-fold increase in men),
season (increased in winter) and generalized xerosis cutis. A
darker skin phenotype was a protective factor for seborrheic
dermatitis. Whether this was due to difficulty in recording
erythema in darker skin types or the fact that it represents a
different barrier function in these skin phenotypes is a matter of
debate. Nevertheless seborrheic dermatitis was also commonly
diagnosed in 2.1% of young Korean male army recruits (Bae
et al., 2012) (93.3% of cohort between 19 and 24 years of
age), supporting the generally suggested prevalence of seborrheic
dermatitis between 2 and 8% (Palamaras et al., 2012).
It well established that seborrheic dermatitis prevalence is
significantly increased in subgroups of patients such as those
with Human Immunodeficiency Virus (HIV) infection, where
it is associated with low CD4 counts (Lifson et al., 1991)
as well as neurological patients. These include those with
Parkinson’s disease (Skorvanek and Bhatia, 2017) patients as
well as patients with spinal cord injury on which seborrheic
dermatitis appears above the level of injury (Han et al., 2015),
pointing toward brain-skin axis involvement. In the light
of the recent implication of Malassezia yeasts in pancreatic
ductal carcinoma development (Aykut et al., 2019), these
epidemiological observations point to future research areas
(Laurence et al., 2019). The understanding of the pathogenesis
of seborrheic dermatitis is limited by the overlap with other
conditions such as psoriasis (sebopsoriasis), the indistinct
borders between seborrheic dermatitis and dandruff and the
absence of a robust severity scoring system. Thus, findings in
dandruff pathophysiological changes that are generated from
scalp are not necessarily applicable to facial seborrheic dermatitis.
Likewise only recently markers to differentiate the overlapping
cases of psoriasis and seborrheic dermatitis (sebopsoriasis)
have been developed. These include immunohistochemistry
markers that address clinical and pathological indistinct
cases of sebopsoriasis (Cohen et al., 2019). Additionally,
seborrheic dermatitis patients do not share susceptibility loci
with psoriasis patients (Sanders et al., 2018b). Regarding the
implication of Malassezia yeasts in the pathogenesis of seborrheic
dermatitis and dandruff there are characteristic and persistent
findings that link seborrheic dermatitis or dandruff associated
Malassezia strains with the respective conditions. Thus M. furfur
strains isolated from seborrheic dermatitis lesions produce,
in vitro, significantly more bioactive indolic substances as
compared to strains isolated from healthy skin (Gaitanis et al.,
2008). These substances [i.e., indirubin, 6-formylindolo[3,2-
b]carbazole (FICZ), indolo[3,2-b]carbazole (ICZ), malassezin,
and pityriacitrin] are also found on seborrheic dermatitis skin
and correspond to the most active aryl-hydrocarbon receptor
ligands known (Magiatis et al., 2013). As a marker of their
clinical significance, indirubin is used as a potent local treatment
for psoriasis (Lin et al., 2018), while there are ongoing
clinical trials that evaluate aryl hydrocarbon receptor ligands
applied locally for this disease (https://clinicaltrials.gov/ct2/
show/NCT04053387). Likewise, the irritating effect on the skin
through a compromised permeability barrier function (Turner
et al., 2012) of free fatty acids (DeAngelis et al., 2005) and
squalene peroxides (Jourdain et al., 2016) produced by Malassezia
lipases as a result of its nutritional needs, are key players, at
least, in the pathogenesis of dandruff. Accordingly, the skepticism
expressed (Wikramanayake et al., 2019) on the implication of
Malassezia yeasts in seborrheic dermatitis can be a useful starting
point for future research toward the better understanding of
seborrheic dermatitis pathogenesis.
Clinical Presentation
Seborrheic dermatitis presents with erythema, small papules
and sometime pustules overlayed with greasy, white to yellow
scales. The areas of predilection include the nasolabial folds
and the upper lip close to the nostrils (Figure 2A), the
eyebrows and the root of the nose, the pre- and retro
auricular areas, the sternum (Figure 2B) and less often the
back. Scalp seborrheic dermatitis/Dandruff does not involve
the whole scalp, rather it appears as patchy areas of erythema
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Saunte et al. Malassezia-Associated Skin Diseases
and scaling. Involvement of the eye presents as seborrheic
dermatitis blepharitis.
Diagnosis
The diagnosis of seborrheic dermatitis is mostly clinical. The
typical cases are straightforward in their recognition while
some confusion can be created when there is co-existence
with rosacea or late-onset acne. In rosacea the involvement of
“convex” anatomical areas (nose, cheeks) and the evaluation of
precipitating factors is of help. In acne the lesions are located
in the hair follicles, scaling unless receiving therapy is not
prominent and the prevailing lesions are comedones, papules
and pustules.
Biopsy should be restricted to difficult to diagnose
cases and the appearances are mostly described as a
psoriasiform, spongiotic dermatitis without intraepidermal
pustules (Table 1). Routine cultures for identification and
characterization of Malassezia species involved to a case of
seborrheic dermatitis are not currently suggested. Hopefully
in the future, our understanding of seborrheic dermatitis
pathogenesis could be associated with identification of virulence
factors of Malassezia yeasts. This could possibly lead to the
development of therapy guided by the pathogenetic mechanisms
(tryptophan metabolism, enzyme production) of the case related
Malassezia strain.
Treatment
The patient should be informed that seborrheic dermatitis can
be a chronic, recurring condition and side-effects of long-term
treatment should be weighed against the potential gain. This
mostly pertains to topical steroids that are used in clinical
practice to rapidly reduce erythema (Gupta and Versteeg,
2017). When long-term control of the inflammatory response in
seborrheic dermatitis is required topical use of the calcineurin
inhibitors tacrolimus and pimecrolimus is advised (Ang-Tiu
et al., 2012). Safety regarding carcinogenicity of these substances
is extrapolated from data in atopic dermatitis and does not seem
a reason of concern (Cook and Warshaw, 2009). The use of
topical antifungals (ketoconazole, ciclopirox) is supported by
recent systematic reviews (Okokon et al., 2015) and given their
high efficacy and improved safety they should be included in
relevant therapeutic schemes. Also it should be stressed that
both pimecrolimus and tacrolimus have antifungal action against
Malassezia yeasts (Sugita et al., 2006) so at least part of their
activity in seborrheic dermatitis can be attributed to this. A
variety of alternative or natural product treatments are also
suggested for seborrheic dermatitis (Gupta and Versteeg, 2017)
while a recent suggestion is the use of formulations that restore
the barrier function of the skin (Purnamawati et al., 2017) and
definitely formulations that restore the barrier function of the
skin will be a useful addition to treatment (Wikramanayake et al.,
2019). Furthermore various salts are also efficient, like lithium
succinate, which seems to interfere with the availability of the
prerequisite lipids for Malassezia growth (Mayser and Schulz,
2016). Systemic antifungals are suggested for resistant or rapidly
relapsing cases of seborrheic dermatitis (Gupta et al., 2014).
PITYRIASIS VERSICOLOR
Epidemiology and Pathogenesis
Pityriasis versicolor is a mild, chronic infection of the skin
caused by Malassezia yeasts, characterized by discrete or
confluent, scaly, dark or depigmented patches, mainly
on the upper trunk but this can extend to the neck,
abdomen and other sites, although the peripheries are
usually spared.
Pityriasis versicolor occurs in both tropical, where it may be
very common, and temperate climates and affects both genders
equally. However, lesions in temperate areas are often noticed
after a visit to a warmer environment. It is commonest in teen-
agers and young adults but can occur at any age. Data on global
prevalence is not available, however in tropical climates, the
condition is more common than in temperate zones, and in
one study from Bahia, Brazil 40% of the population of some
areas was affected (Santana et al., 2013). Although there are
reports of an association between pityriasis versicolor and a
number of other underlying conditions, it generally occurs in
otherwise healthy individual although patients with idiopathic
and iatrogenic Cushing’s syndrome are more susceptible (Finding
et al., 1981). It does not appear to be more common in the
acquired immune deficiency syndrome (AIDS) (Mathes and
Douglass, 1985).
A striking feature of most cases of pityriasis versicolor is the
presence of hyphae in lesions. But the reasons for hyphal growth
are still unknown. The activation of the MGL_3741 gene which
encodes the enzyme Dihydroxy acid dehydratase (DHAD) in
M. globosa has been implicated as it is present in lesional but
not non-lesional skin (Aghaei Gharehbolagh et al., 2018) Lack
of inflammation in lesions of pityriasis versicolor is noticeable
although there is evidence of interaction between Malassezia
species in this condition and innate and acquired immunity
(Brasch et al., 2014) T-cell inhibition by a lipid component
associated with the yeast cell wall has also been reported (Kesavan
et al., 1998) which may partially explain the lack of clinically
significant inflammation.
The mechanism for the typical pigmentary changes seen
in pityriasis versicolor is still not understood, although
electron microscopy shows abnormally large melanosomes
in hyperpigmented lesions (Figure 3A), and smaller-than-
normal melanosomes in hypopigmented ones (Figure 3B).
Depigmentation has been explained on the production of
dicarboxylic acids produced by Malassezia species (e.g., azaleic
acid) causing competitive inhibition of tyrosinase and perhaps
a direct cytotoxic effect on hyperactive melanocytes (Nazzaro-
Porro and Passi, 1978). M. furfur produces pigments and
fluorochromes with tryptophan as sole nitrogen source. They
(i.e., malassezin, pityriacitrin, pityrialacton, pityriarubins) may
explain some clinical phenomena of pityriasis versicolor
(depigmentation. fluorescence, lack of sunburn in pityriasis
versicolor alba) (de Hoog et al., 2017).
The Malassezia species mainly identified in pityriasis
versicolor lesions are M. globosa and also M. sympodialis and
M. furfur.
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Saunte et al. Malassezia-Associated Skin Diseases
FIGURE 3 | (A,B) Pityriasis versicolor. (A) Hyperpigmented maculae on the back and a close-up of the lesion (square). (B) Hypopigmented maculae and a close-up of
the lesion (square).
Clinical Presentation
The primary lesions are well demarcated macules, which may
be slightly erythematous and covered by fine scales which may
only be noticeable after scratching the lesional surface. These co-
alesce to form scattered patches of hypo- or hyperpigmentation
(Figures 3A,B). Itching is very mild. The sites most commonly
affected are the upper trunk, but there is often spread to
the upper arms, the neck and the abdomen. Lesions in the
axillae and groins, and on the thighs and genitalia occur, and
extension down the forearms on to the backs of the hands;
these atypical forms of pityriasis versicolor may be associated
with oval yeast forms seen in direct microscopy. Another rare
but well documented variant is one where there is marked
atrophy or anetoderma-like change in the skin that follow
infection (Tellechea et al., 2012). Pityriasis versicolor is a chronic
infection if left untreated. In some patients, lesions recur rapidly
and may not respond well to treatment. Such cases, while not
common, are seen regularly. Some have been associated with
the presence of the organism, M. japonica, and raised IgE levels
(Romero-Sandoval et al., 2017).
Vitiligo and chloasma are normally distinguishable from
pityriasis versicolor by their complete absence of scaling.
Diagnosis
Under filtered ultraviolet (Wood’s) light, the scaly lesions
may show pale yellow fluorescence. Direct microscopy shows
coarse mycelium, fragmented into short filaments, together with
spherical, thick-walled yeasts. Occasionally, only oval yeasts may
be seen (see above). The characteristic appearance on microscopy
has been described as “spaghetti and meatballs” (Table 1).
Detection of Malassezia species by culture or molecular methods
from skin scrapings is of no diagnostic value, and does not
form part of the diagnostic investigation of pityriasis versicolor.
Dermoscopy, although useful in confirming the scaling, does not
identify specific diagnostic features (Mathur et al., 2019).
Treatment
The first line treatment is topical antifungal therapy. The topical
azole antifungals work well in pityriasis versicolor, and there is
no significant difference in results achieved by different azoles.
The usual time to recovery is 2–3 weeks. A practical problem
with the use of topical antifungals is the difficulty of applying
creams to a wide body surface area. An alternative solution to
this is ketoconazole shampoo which is lathered into the skin
in a shower and then washed off after 3–4 min, and although
it has not been fully evaluated in pityriasis versicolor, two or
three applications of the shampoo appear to clear most infections.
Terbinafine 1% cream, but not oral terbinafine, is also effective.
Another approach is the application of 2.5% selenium sulfide in a
detergent base (Selsun R
shampoo). It is applied to all the affected
areas and left overnight. Alternatives include 50: 50 propylene
glycol in water. The latter has also been used intermittently as
long-term suppressive therapy to prevent relapse (Faergemann
and Fredriksson, 1980).
Oral itraconazole is also very effective in cases of pityriasis
versicolor 100 mg daily for 10 days (Delescluse, 1990) although
it is usually given in extensive or recalcitrant cases. Fluconazole
has also been used.
Whatever medication is given patients should be warned that
normalization of pigmentation may take several months after the
end of treatment.
MALASSEZIA FOLLICULITIS
Epidemiology and Pathogenesis
Malassezia folliculitis is an inflammatory condition caused by
Malassezia yeasts involving the pilo-sebaceous unit.
Predisposing factors includes immunosuppression (e.g.,
immunosuppressive medication, broad spectrum antibiotics,
diabetes, HIV, hematological malignancies), occlusion and
sweating (Tragiannidis et al., 2010; Prohic et al., 2016).
It is more frequent in, or after visiting, tropical areas or
hotter climates because of humidity and high temperatures
(Tragiannidis et al., 2010).
The most prevalent species associated with Malassezia
folliculitis are M. globosa, M. restricta and M. sympodialis (Akaza
et al., 2009; Ko et al., 2011; Durdu et al., 2013; Prohic et al., 2016).
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Saunte et al. Malassezia-Associated Skin Diseases
FIGURE 4 | (A,B) Malassezia folliculitis. (A) Erythematous paplues and pustules on the chest of a male and a close-up of a papule (square). (B) On the chest of a
woman and a close-up of a papule (square).
Clinical Presentation
The typical presentation is monomorphic, approximately 2–
4 mm, erythematous itchy papules or papulopustules on the
chest (Figures 4A,B), back, upper arms, neck and face; some
patients have concomitant pityriasis versicolor or seborrheic
dermatitis (Hald et al., 2014). Malassezia folliculitis, especially in
adolescent, may be misdiagnosed as acne or bacterial folliculitis,
but comedones are absent and itching is a common symptom
(Hald et al., 2014; Tsai et al., 2019). The itching may be less
pronounced in immunosuppressed patients (Hald et al., 2014).
Diagnosis
The diagnosis is based upon the clinical picture and symptoms
supported by mycological detection and response to antifungal
therapy (Prohic et al., 2016). Histopathology can be used to
differentiate Malassezia folliculitis from other types of folliculitis
such as e.g., bacterial, eosinophilic or pustular drug eruptions.
In Malassezia folliculitis invasion and dilatation of follicles with
large number of Malassezia conidia (and rarely hyphae) is seen
and inside the follicle there is a reticular pattern of keratin
plugging in the majority of patients (An et al., 2019). The
follicular walls may rupture resulting in a mixed inflammatory
infiltrate of neutrophils, lymphocytes and histiocytes in the
dermis. Direct microscopy on skin scraping and the content
of pustules treated with KOH (and a dye) will detect unipolar
budding yeast, rarely hyphae (Table 1). In a study by Tu et al.
Gram staining has been shown to have a sensitivity and specificity
of 84.6 and 100% as compared with a final diagnosis of Malassezia
folliculitis when two of three criteria was met: 1. Typical clinical
presentation, 2. Biopsy with Malassezia in inflamed hair follicle,
3. Treatment response to antifungal therapy (Tu et al., 2018). This
suggests that direct microscopy which is both rapid, simple and
non-invasive is an alternative to histology. Nevertheless, direct
microscopy is not species specific as are culture- or molecular-
based methods and it does not reveal location of the fungus in
relation to the follicle.
Other diagnostic methods includes Wood’s lamp which
fluorescence yellow-green when the lesions is illuminated,
reflectance confocal microscopy and optical coherence
tomography (Rubenstein and Malerich, 2014; Andersen
et al., 2018).
In clinical settings initial diagnosis based upon the
combination of symptoms such as itch, clinical picture with
monomorphic papulopustules without comedones supported
by direct mycological detection by microscopy is sufficient to
initiate therapy while awaiting histopathology results. The direct
microscopy is important to differentiate Malassezia folliculitis
from bacterial folliculitis.
Treatment
Systemic itraconazole 100–200 mg daily has been used for 1–
4 weeks with a clinical treatment effect of 69–100% (Parsad
et al., 1998; Durdu et al., 2013; Suzuki et al., 2016; Tsai
et al., 2019) and fluconazole 100−200 mg daily for 1–4 weeks
with a clinical effect of 80% (Rhie et al., 2000). Combination
of systemic antifungals and topical antifungals (Abdel-Razek
et al., 1995; Prindaville et al., 2018) or tretinoin/bensylperoxide
(Ayers et al., 2005) is also useful. Topical therapies which
have proven useful for the treatment of Malassezia folliculitis
include azoles (Back et al., 1985; Rhie et al., 2000; Suzuki
et al., 2016; Prindaville et al., 2018; Tsai et al., 2019), selenium
sulfide once daily for 3 days then weekly (Back et al., 1985)
and propylene glycol 50 % twice daily (Back et al., 1985).
Systemic antifungal monotherapy is thought to be more efficient
than topical monotherapy, but in a small study (N=44)
comparing ketoconazole cream twice daily with oral itraconazole
100 mg daily an improvement and treatment respond was
noted in both groups although the topical treatment required
a longer treatment course (Suzuki et al., 2016). Topical therapy
may therefore be useful and considered in patients as a
prevention measure or in patients with contraindication for
systemic therapy.
Recurrence is common after treatment is completed, and
maintenance therapies such as weekly topical or monthly oral
antifungals have been used as prevention measures (Levy et al.,
2007; Rubenstein and Malerich, 2014).
Alternative treatment options include photodynamic therapy
(Lee et al., 2010, 2011).
Currently, there is no internationally approved treatment
guideline for the management of Malassezia folliculitis.
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Saunte et al. Malassezia-Associated Skin Diseases
CONCLUSION
The Malassezia yeasts are complex fungi which are part of
the normal skin microbiome. They have pathogenic potential
and are able to cause skin related diseases through different
mechanisms: an activation of the immune system as in head
and neck dermatitis, an eczematous/inflammatory reaction as
in seborrheic dermatitis, an infection of stratum corneum as
in pityriasis versicolor or a colonization (invasion) with a
large number of Malassezia yeasts of the pilo-sebaceous unit
as in Malassezia folliculitis. To support the clinical suspicion
of the association between Malassezia and disease, a broad
spectrum of techniques is used for the confirmation of the
presence of Malassezia yeasts or for the detection of pathogenetic
mechanisms such as Malassezia related type I allergy. Traditional
direct microscopy, culture on lipid enriched media, biochemical
tests and histopathology but also newer molecular based
methods can be used for the detection of Malassezia yeast.
For confirmation of type I allergy to Malassezia a specific IgE
testing or prick testing is useful. A positive treatment response
to antifungals, backed by reduction or temporary elimination
of the organisms is highly suggestive, if not confirmatory, of a
Malassezia etiology, but there are other variables such as the host’s
general condition and the species involved. Further investigative
work that helps to delineate the disease mechanisms and the role,
if any, of other members of the skin microbiome in the process
is needed.
ETHICS STATEMENT
For patients providing clinical photos a written consent
was obtained.
AUTHOR CONTRIBUTIONS
DS, GG, and RH planned, wrote, and contributed to the critical
review of the manuscript.
FUNDING
This publication was made possible by a grant from the
Department of Dermatology, Zealand University Hospital,
Roskilde, Denmark.
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Conflict of Interest: DS was paid as a consultant for advisory board meeting by
AbbVie, Janssen, Sanofi, and Leo Pharma. Leo Pharma and received speaker’s
honoraria and/or received grants from the following companies: Abbvie,
Galderma, Astellas, Novartis and Leo Pharma during the last 3 years.
The remaining 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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Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 11 March 2020 | Volume 10 | Article 112