ACRAL MANIFESTATIONS OF FUNGAL INFECTIONS

Zekayi Kutlubay1, MD*, Gürkan Yardımcı2, MD, A. Serda Kantarcıoğlu3, PhD,

Server Serdaroğlu1, MD.

Abstract
Fungal infections, which are named according to the body site involved, can
affect any skin area, the fingernails or the toenails. Numerous fungal agents are
responsible for both superficial and deep fungal diseases. Dermatophytes and
Candida spp. are the most common causative organisms on the surface of the hands,
feet and nails of patients with superficial fungal diseases; however, while deep fungal
infections of the skin are less commonly seen compared to superficial fungal diseases,
their incidence is increasing worldwide because of cross-border travel. Most
superficial fungal diseases are diagnosed clinically, but sometimes direct microscopic
examination with potassium hydroxide and fungal culture may be necessary for
diagnosis, especially in patients suspected of having tinea incognito. In cases of
superficial fungal infections except for onychomycosis and tinea incognito, topical
treatments are usually sufficient and effective, but systemic treatments may be
required in recalcitrant cases. Deep fungal diseases may resemble each other
clinically; therefore the organism must be identified with laboratory methods and
should be treated for a long period. We want to review the most important clinical,
diagnostic and therapeutic aspects of fungal diseases. This paper covers fungal
problems encountered both in hospitals and in general practice.

Introduction
Fungal infections can affect different anatomic locations on the body and
different layers of the skin such as superficial cutaneous, subcutaneous and deep
tissues, as well as the nail plate and/or nail bed. 10% of patients referred to outpatient
clinics complain of fungal infections. Superficial fungal infections are generally
caused by various fungal organisms like dermatophytes, Candida spp. and Malassezia
spp. Dermatophytes are a group of fungi that can invade keratin-bearing structures of
the skin and nails. The infections caused by the dermatophytes are called
dermatophytosis or tinea. Subcutaneous and deep fungal infections have different
clinical manifestations unlike superficial infections.1-4
Dermatophytes, which typically exist in three genera (Trichophyton,
Microsporum, and Epidermophyton), are the most common causes of fungal
infections in the United States (U.S.).2-4 There are approximately 50 species of
dermatophytes that cause infections in humans and they are divided into three groups
according to their living space: antropophilic, zoophilic, and geophilic. While
zoophilic and geophilic dermatophytes can cause more acute and inflamed infections,
antropophilic dermatophytes mostly create more mild clinical manifestations. The
inflammatory response of the host is determined by the natural immunity of the fungi,
and the deep invasion of the organism is a factor that increases the inflammation. The
antibodies and the delayed cellular immune response play roles together in the
inflammatory process. The severity of inflammation is related to the age, gender,
health condition, current medication, and genetic predisposition of the host.2 This
paper reviews commonly seen acrally distributed cutaneous fungal infections.

Superficial Fungal Infections

Tinea Manuum
It is described as a fungal infection of the hand or hands. There are several
clinical aspects. The most common appearance is diffuse hyperkeratosis of the palms
and fingers. Half of the cases present unilateral involvement (Figure 1). Flexural
creases are characteristically involved.5 Tinea manuum occurs more in adults than in
children and usually appears as a unilateral involvement coexisting with bilateral
tinea pedis.3 This dermatophytic infection known as ‘the two-feet-one-hand
syndrome’ was first described by Celaleddin Muhtar Özden (Djelaleddin Moukhtar)
and published in the national journal in 1936. 6 He identified a form of Trichophyton
on the palms and soles, also known as “Trichophytie Palmaire et Plantaire”. Later, he
also applied microscopic examination and cultured the organism. But the mechanism
behind why only one hand is involved remains unclear. 7 Both dorsal and palmar
aspects of the hand can be affected. The clinical features of the dorsal aspect of the
hand are quite similar to tinea corporis, whereas tinea infection of the palm is similar
to the keratotic form of tinea pedis. 4 Typically, tinea manuum presents as mild
erythema and diffuse scaling of the palmar surface of the hand. The patients with
tinea manuum may suffer from itching.3 Tinea manuum is mostly found together with
moccasin type tinea pedis. On the palms and fingers, a diffuse hyperkeratosis exists,
mostly only on one hand. T. rubrum, T. mentagrophytes, and E. floccosum are the
main causative agents.8 In addition to skin manifestations, the involvement of the
nails of the affected hand may be seen and these findings may help in diagnosis. It
should be distinguished from some inflammatory diseases such as contact dermatitis,
dyshidrotic dermatitis, atopic dermatitis and psoriasis.3 According to some authors, if
several or all the nails of both hands are involved, especially proximal white
onychomycosis subtype, patients should be considered for the possibility of
immunosuppression.9
Tinea manuum, as with most superficial dermatophyte infections except for
hair-bearing areas, can be treated with topical antifungals such as ketoconazole,
econazole, oxiconazole, sulconazole, clotrimazole, terbinafine, ciclopirox, and
butenafine.3,10,11 Although nystatin is not effective in treating dermatophyte infections,
it is primarily effective against Candida spp. Topical antifungals are available as
creams, gels, sprays, and powders. Twice daily application is recommended to the
affected areas and one to two cm outwards until resolved. Systemic therapy is rarely
required.3 De Doncker et al. reported that itraconazole 2x200mg daily for one week
was very effective.12 Schuller et al. also reported that itraconazole both 100mg/4
weeks and 400mg/1 week treatment regimens were effective, well-tolerated and safe
for the treatment of tinea manuum.13 Aste et al. reported the first case of tinea
manuum bullosa caused by Trichophyton (T.) verrucosum treated with terbinafine
250 mg once daily for one month.14
During pregnancy, topical antifungals are much safer than oral antifungals.
The category B topical antifungals such as oxiconazole, clotrimazole, naftifine,
butenafine, terbinafine, ciclopirox, and nystatin can be preferred in the treatment of
tinea manuum.15
To prevent tinea manuum, patients should be told to pay attention to hygiene,
wash their hands more frequently, not to touch feet or nails infected by fungi, and to
treat tinea pedis before it is too late.7

Tinea Pedis
Tinea pedis, generally known as “athletes’ foot”, is the most common
dermatophytic infection that usually affects intertriginous areas and the plantar
surface of the foot.16,17 It is an infection with world-wide distribution. It is found more
often in adults than in prepubertal children.3 Males are more affected than females.4
It is closely related to increased contact with swimming pools, athletic shoes, sports
equipment, locker rooms, and households.3,16 In addition to these environmental
factors, the presence of certain diseases such as psoriasis or atopic dermatitis
increases the risk of tinea pedis.18 The pathogen organisms are antropophilic
dermatophytes such as T. rubrum, T. mentagrophytes (antropophilic strains),
Epidermophyton (E.) floccosum, and T. tonsurans.3,18 The most frequently detected
dermatophyte in patients with tinea pedis is T. rubrum.19 T. mentagrophytes have
different species, but only T. interdigitale (previously called T. mentagrophytes var.
interdigitale) and T. mentagrophytes can be involved in tinea pedis. T. interdigitale is
almost strictly antropophilic, but T. mentagrophytes is primarily zoophilic and can
cause inflammatory types of tinea pedis.18 T. tonsurans is the most common causative
organism in children with tinea pedis and its prevalence is increasing in adults. 3,18 In
addition to these dermatophytes, non-dermatophyte molds such as Neoscytalidium
dimidiatum that is endemic in Africa, Asia, the Caribbean, Central and South
America, and several states in the United States can result in treatment-resistant tinea
infections of the feet.18
The incidence of tinea pedis has been increasing over the past 30 years.18 It is
estimated to affect 30-70% of the population. 20 However, the etiology and
pathogenesis of tinea pedis is still uncertain. Ozturk et al. reported that antioxidant
defense of lesional skin was higher compared to non-lesional skin in patients with
interdigital types of tinea pedis.21 Miraloglu et al. also reported that there was a
possible link between oxidative stress and imbalance of trace element status in
lesional areas of tinea pedis patients. 22 When these studies are considered, it is
thought that there might be a relationship between tinea pedis and oxidative stress ;
however, there is not yet enough data to prove this interrelation.
There are four major clinical forms known as interdigital, moccasin,
inflammatory, and ulcerative types.3 The clinical appearance is not pathogen-
specific.23 Although most patients are asymptomatic and unaware that the disease is
present, some patients may suffer from severe itching, malodor, and pain if it is
complicated by bacterial superinfection. The interdigital type of tinea pedis is the
most common form characterized by scaling, erythematous and macerated skin with
fissures in the interdigital web spaces.3,16 The most commonly affected interdigital
area is between the third or fourth toes. It is closely related to warm, humid
environments and hyperhydrosis.17,18 HIV/AIDS, organ transplantation,
chemotherapy, immunosuppressive drugs like steroids, and parenteral nutrition etc.
are the most important factors that decrease a patient’s resistance to dermatophyte
infection.
The causative agents responsible for most cases are T. rubrum and E.
floccosum. Some severe macerated cases can develop with Gram positive (such as
Staphylococcus (S.) aureus and A. streptococci) and/or Gram negative (such as
Escherichia (E.) coli, Klebsiella spp., Pseudomonas (P.) aeruginosa, and Proteus spp.)
bacterial secondary infection that is termed dermatophytosis complex.18,23 Moccasin
type is the second most common form of tinea pedis characterized by diffuse
erythema and scaling of the heels, and plantar and lateral surfaces of the feet. The
causative dermatophyte is typically T. rubrum. Most cases are asymptomatic but
rarely dense hyperkeratotic scales and fissures may be seen. Concurrently, it may be
associated with tinea manuum and called ‘two-feet-one-hand syndrome’. If left
untreated, onychomycosis can develop.16,18 The inflammatory type of tinea pedis, also
known as the dyshidrotic type, is usually transmitted from animals and is
characterized by vesicules, pustules and blisters on the medial foot. This form is a
less common presentation of tinea pedis and T. mentagrophytes is mostly detected.
Lesions that clinically show as small, superficial, pruritic vesicles on erythematous
areas and exfoliations of the stratum corneum with scaling may be painful (Figure
2).3,18,23 The ulcerative type of tinea pedis is rarely seen and is characterized by
extensive erosions and ulcers in the interdigital areas. Most cases have concurrent
systemic diseases like diabetes mellitus, immunosuppression, and peripheric vascular
disease. Patients with the ulcerative type of tinea pedis may progress to develop
cellulitis, lymphangitis and fever.3,18
Diagnosis is obtained clinically, but Woods light examination, direct
microscopic examination and fungal culture may be useful for diagnosis. The role of
Woods light examination is far lower than microscopic examination in the diagnosis,
because most dermatophytes do not fluorescence, but this method may be rather
useful in distinguishing from erythrasma caused by Corynebacterium
minutissimum.4,17,18 The direct microscopic examination, which can be done easily
and quickly, is highly specific and sensitive for dermatophyte identification. Material
should be scraped from an active area of the lesion in cases of suspected tinea pedis.
Skin scrapings should ideally be collected from the peripheral raised border.
Subsequently, potassium hydroxide (KOH) solution 10-20% is dropped and
examined under a microscope. Apart from KOH, tetraethylammonium hydroxide
(TEAH) can be used as an alternative. Discovery of fungal hyphae is enough to start
treatment. Fungal culture is not performed routinely, but if we are not sure of the
diagnosis or in the case of treatment resistance, this method should be used.
Sabouraud dextrose agar (SDA), which contains 4% peptone, 1% glucose, agar, and
water, is the most commonly used isolation medium for dermatophytosis. Cultures
are incubated at temperatures of 26-320C, optimally at 280C, for three or four
weeks.17,23,24 As molecular techniques, PCR and mass spectrometry can also be used.
The Dermatophyte Test Strip is an alternative diagnostic test that may be used as a
supplementary method for detecting dermatophytes when direct microscopy cannot
be performed.25
Tinea pedis should be distinguished from other infectious and non-infectious
feet diseases shown in Table 1.
Table 1. Differential Diagnosis of Tinea Pedis3,18,23

Infectious diseases Non-infectious diseases

Candidal infection  Dyshidrotic dermatitis

Pitted keratolysis  Contact dermatitis

Impetigo  Atopic foot dermatitis

Erythrasma  Plantar psoriasis

 Palmoplantar keratoderma of the

Gamborg-Nielsen type

Tinea pedis can be treated effectively with both topical and systemic
antifungals,16 but The American Academy of Dermatology recommends topical
therapy for the initial treatment of uncomplicated dermatophyte infections of the
skin.26 ; however,, topical treatment is often inadequate for interdigital tinea pedis,
and systemic antifungals may be necessary in some patients with moccasin and
inflammatory types. If bacterial coinfection is present, a systemic antibiotic should be
added to antifungal therapy. Patients should be analyzed for hepatotoxicity if
necessary.16 The azole class includes econazole, oxiconazole, sertaconazole,
ketoconazole, sulconazole, and clatrimazole; and the allylamine class includes
naftifine, butenafine, and terbinafine.27 Ketoconazole, itraconazole, terbinafine,
griseofulvin, and fluconazole may be preferable options as systemic therapy if the
topical therapy fails or an inadequate effect is suspected. Griseofulvin is slightly less
effective than itraconazole and terbinafine. Fluconazole, which is used as a single
dose per week, provides an advantage in terms of patient compliance. 17,28 Terbinafine
250mg/day has been used for tinea pedis with a duration of 2-6 weeks. Itraconazole
may be used with different doses and durations such as 100mg/day for one month,
200mg/day for 2-4 weeks, and 400mg/day for one week. Fluconazole is mostly used
as 150mg/week for 2-6 weeks. Griseofulvin is suggested as 660 or 750mg/day for 6-8
weeks. Ketoconazole regimen of 200-400mg daily for 4-8 weeks may be used but its
hepatic side effects limit its use for tinea pedis. 11 Schuller et al. reported that both
itraconazole 100mg/4 weeks and itraconazole 400mg/1 week treatment regimens
were effective, well-tolerated and safe in the treatment of tinea pedis.13
Apart from these treatments, in recent years some topical antifungal agents have
been developed for treatment of tinea pedis. Luliconazole is a new antifungal agent
that received clearance by the Food and Drug Administration (FDA) in the U.S. in
2013. Interdigitale tinea pedis caused by T. rubrum and E. floccosum can be treated
with luliconazole that should be applied once daily for two weeks. 27 In one
trial,luliconazole cream 1% was safe, well-tolerated and effective in patients with
interdigital tinea pedis.29 Naftifine is another new topical antifungal drug approved
by the FDA for interdigital tinea pedis. It should be applied once daily for two
weeks.27 Additionally, another report revealed a novel two-step kit that includes a
topical solution (0.5% climbazole and 14% glycolic acid) and a cream (0.5%
climbazole and 2% urea) was found to be effective, well-tolerated, and safe in the
treatment of moderate and severe tinea pedis.20 Although topical corticosteroids
should not be used for long periods in the treatment of tinea pedis because of the
possibility of fungal proliferation, it may be preferred in patients with severe
symptoms in the initial phase of treatment.17 Foot baths containing green tea
polyphenols were also found to be effective in improving symptoms of interdigital
tinea pedis.30 Photodynamic therapy has a destructive effect on fungi and may be
effective in the treatment of superficial mycosis like tinea pedis.31

Onychomycosis
Onychomycosis is commonly seen as a superficial fungal nail infection that is
caused by dermatophytes, yeasts and non-dermatophyte molds.32 If the causative
agents are dermatophytes, it is called ‘tinea unguium’. It is more common in adults
than children, but the incidence in children is increasing. In children, there is usually
a history of tinea pedis and/or onychomycosis in the first-degree relatives.
Approximately three-quarters of onychomycosis cases are caused by dermatophytes,
commonly T. rubrum, T. mentagrophytes and E. floccosum.3,17 In In addition to the
dermatophytes, non-dermatophyte fungi such as Candida, Aspergillus, Scopulariopsis
brevicularis, Scytalidium dimidiatum, and Fusarium are responsible for the infection
in 5% to 15% of patients with onychomycosis. 16,33 Aspergillus spp. And
Scopulariopsis brevicularis were reported as the most common opportunistic molds in
patients with onychomycosis .34 In addition to these, two other groups reported
phaeohyphomycosis of the ungual apparatus and onychomycosis due to Onychocola
canadensis, which can be seen very rarely.35,36
It is estimated to affect approximately 12% of the U.S. population. 37,38
According to ‘Foot Check Study’, the prevalence of onychomycosis among Germans
is 12.4%.23; however, in the 0 to 18 age group that is accepted as the pediatric
population (previously, it was under the age of 15) for onychmycosis it is less
common than in adults. Its prevalence ranges from 0.2% to 2.6% among children.
One group reporte onychomycosis in children represented 2.3% of all
onychomycoses between 1999 and 2009. Exactly why this infection is less common
in children than in adults is unknown but it is thought to be due to faster nail growth,
smaller surface areas available for exposure to onychomycotic pathogens, lack of
cumulative trauma, and reduced environmental exposure to public places.39

There are numerous risk factors for onychomycosis that are shown in Table 2.
Table 2. Risk Factors for Onychomycosis.16,17,38,40
 Genetic susceptibility  Obesity
 Male sex  Cancer
 Wearing occlusive shoes  Smoking
 Poor foot hygiene  Prolonged water exposure
 Advanced age  Immunocompromised hosts
 Family history  Trauma
 The presence of some underlying  Diabetes mellitus
conditions such as tinea pedis, nail  Poor venous and lymphatic
psoriasis, and nail damage drainage.

Onychomycosis is found more often in toenails (Figure 3) than fingernails.17

The fungal infection of the nail unit may be a reservoir for tinea pedis. Approximately
30-40% of the patients with onychomycosis also have tinea pedis, especially the
interdigital form.38 Clinically, onychomycosis can be divided into five different
appearances: distal lateral subungual onychomycosis (DLSO), proximal subungual
onychomycosis, superficial white onychomycosis, Candidal onychomycosis, and total
dystrophic onychomycosis. The most common type both in adults and in children is
DLSO. This type begins from the free edge of the affected nail and spreads
proximally towards the proximal nail fold. It is clinically characterized by yellow to
white discoloration on the nail plate and subungual hyperkeratosis due to subungual
debris. The most common agent causing this clinical situation is T. rubrum. Proximal
subungual onychomycosis begins from the proximal area of the affected nail and then
spreads distally. This form is usually found in HIV-positive patients. Periungual
inflammation may be present. The fingernails and the toenails are equally affected. T.
rubrum is the most common pathogen. Superficial white onychomycosis begins with
white and soft areas on the nail plate, and gradually spreads to the entire nail surface.
It is caused mainly by T. mentagrophytes. Toenails are the primary targets.
Inflammation is minimal. Candidal onychomycosis is another entity and Candida
albicans is the most commonly seen pathogen. The organism invades the nail plate
directly and has three subtypes. Candida paronychia presents with inflammation of
the proximal and lateral nail folds, and is also called a “whitlow”. As a consequence
of the invasion of the nail matrix, transverse depressions (Beau’s lines) can occur.
Candidal granuloma is another uncommon subtype mostly seen in
immunocompromised patients. The lateral and the proximal nail folds create a
pseudoclubbing appearance. Candidal onycholysis can be described as separation of
the distal nail plate from the nail bed. Total dystrophic onychomycosis means the
total destruction of the nail plate, which can occur as an end stage of all the
onychomycosis patterns. Generally the main pathogens are T. mentogrophytes, T.
rubrum, Candida species and E. floccosum. The disease often begins from the lateral
sides of the nail plate, which changes in color. The diagnosis should be verified
before treatment. KOH and fungal culture have low sensitivity; periodic acid Schiff
(PAS) staining has high at 90-95%.3,41-43
Onychomycosis should be distinguished from some conditions such as nail
psoriasis, subungual warts, pachyonychia congenita, trachyonychia, chronic
paronychia, and traumatic, medication-induced, or postinfectious onycholysis and the
diagnosis should be confirmed by histpathologic examination or fungal culture in
suspected cases.3 The characteristic histological features include subungual
hyperkeratosis, neutrophilic infiltrate, parakeratosis, hemorrhage, and serum crusts.
The ventral aspect of the nail plate is the area most affected by the fungi. PAS and
Gomori methenamine silver (GMS) stains should be performed for onychomycosis,
because nail unit psoriasis may resemble onychomycosis and fungal hyphae should
be shown for proper treatment.33
 If mild to moderate onychomycosis (<50% of distal end affected) is present,
topical therapy can be preferred. Two topical medications formulated as lacquers are
approved for use in onychomycosis as monotherapies. Ciclopirox nail lacquer 8%
solution should be applied once daily for 48 weeks and reported mycologic cure rates
range from 33% to 67% during this period. Amorolfine 5% nail lacquer should be
applied once or twice weekly for 6-12 months and mycologic cure rates are reported
as 60-76%. Drugs used for systemic therapy are the same as with tinea pedis.
Suggested dosage of terbinafine is 250mg/day for 12 weeks (toenails) and six weeks
(fingernails only). Itraconazole can be used at 200mg twice daily for one week as
pulse therapy (followed by three weeks without the drug) using two pulses
(fingernails) or three pulses (toenails). Fluconazole is frequently preferred as 150-
300mg once weekly for 3-6 months (fingernails) or 9-12 months (toenails).
Griseofulvine and ketoconazole are often avoided because of lower efficacy (for
griseofulvine) and high potential hepatic adverse effects (for ketoconazole). 11
Efinaconazole is a new triazole antifungal that has been developed specifically for the
topical treatment of onychomycosis, especially the distal lateral subungual type. 44,45 It
has been shown that efinaconazole 10% solution applied once daily may be effective
in the treatment of onychomycosis.27,46-48 Tavaborole is a drug approved by the FDA
in July, 2014 for the treatment of toenail onychomycosis. According to clinical trials,
tavaborole topical solution 5% may be an alternative to other drugs that are applied
topically.27,46,49,50 Luliconazole, which is another promising drug in the treatment of
onychomycosis, does not yet have sufficient clinical data and further trials are
needed.51 Nail plate excision and matricectomy are only rarely performed in selected
cases.16,52
In recent years, various laser devices include neodymium-doped yttrium
aluminum garnet (Nd:YAG), diode, carbon dioxide (CO2), and Erbium:glass
(Er:Glass) have been used as an alternative modality for onychomycosis. Their
mechanism of action is not yet exactly known. Most of the reported trials are about
Nd:YAG lasers. The Nd:YAG lasers were the first medical devices designed
specifically for the treatment of onychomycosis, but the outcomes are still
contradictory.53 In one study, a temporary improvement in the appearance of the
target nail was observed in 78% of patients and the affected area of the nail plate was
reduced by at least 50% from the baseline in 46% of patients,54 but another group
found the 1064nm Nd:YAG laser was not an effective treatment for onychomycosis. 55
In two clinical trials .56 and .57, fractional CO2 laser and topical antifungal agents were
found to be effective treatments for onychomycosis. It was observed that the
combination of fractional CO2 laser and photodynamic therapy can be effective in the
treatment of onychomycosis in the study reported.58

Tinea Incognito
Tinea incognito, which was first described59 in 1968, is a cutaneous fungal
disease induced by topical and/or systemic steroids, calcineurin inhibitors and other
immunosuppressive agents.60,61 The prolonged use of these drugs can cause tinea
incognito because of the rapid proliferation of fungal organisms. Characteristic
clinical findings are often not observed62,63; therefore, it may resemble various skin
conditions such as psoriasis, pyoderma and contact dermatitis in cases of involvement
of the hands and feet.64 The typical tinea lesions are suppressed, active borders and
scales are diminished and nodules are detected in the physical examination (Figures
4, 5). Tinea lesion becomes more extensive, pustular, pruritic, and painful. Mycologic
confirmation with laboratory testing such as skin biopsy with PAS stain, KOH test
and fungal culture is recommended before antifungal therapy.60,61 Systemic
antifungals such as terbinafine, itraconazole and fluconazole are preferred and the
patients should be warned regarding the discontinuation of steroids.62,63

Erosio Interdigitalis Blastomycetica

Erosio interdigitalis blastomycetica (EIB) is a superficial candidal infection
that affects the areas between the fingers (Figure 6). The most common organism is
Candida albicans. The patients with EIB are usually individuals who work in humid
environments such as cooks, barmen, barmaids, dentists, and stewards. It clinically
represents as white and macerated skin erosions on a pink and moist background.
Some patients suffer from pain.2

Chronic paronychia
Chronic paronychia is a disease that affects periungual skin and the proximal
part of the nail of the fingernails. Until recently, Candida albicans was thought to play
a role in the etiology but today it is believed to be a form of hand dermatitis.
Disrupted barrier function is very important for the development of the disease. If the
disrupted barrier function is improved again, isolated Candida species may disappear
in many patients. It has been reported that methylprednisolone aceponate cream 1% is
more effective than oral itraconazole 200mg/day or terbinafine 250mg/day in patients
with chronic paronychia. All patients should be informed about reducing contact of
the hand with water and the importance of restoring the barrier function.2

Tinea Nigra
Tinea nigra is a superficial mycosis caused by Hortaea werneckii. 65,66 It was
first observed by Alexandre Cerqueira in 1891, in Bahia (Brazil). Tinea nigra is
usually seen in tropical and subtropical climates, and affects those under the age of
20, especially females.65,67,68 Eccrine glands are the most affected structures. The
fungus exhibits lipophilic adhesion to human skin; it is exclusively found in the
stratum corneum. Tinea nigra most often occurs in pediatric and adolescent
populations. After a 10 to 15-day-incubation period, light brown to black sharp
marginated painless single or multiple macules appear. 69,70 It is an asymptomatic
infection that presents as brown to black macules, single or multiple, with well-
defined borders. Palmoplantar areas are the most common sites but it may be seen in
any parts of the body. Generally, unilateral involvement occurs. Melanocytic lesions
such as malignant melanoma and melanocytic naevus and exogenous pigmentations
may be similar to tinea nigra. Diagnosis should be confirmed with direct microscopic
examination after clarification with KOH or fungal culture. Scanning electron
microscopy can be useful in the diagnosis of tinea nigra. 65,67,68 Although spontaneous
cures may occasionally occur, various topical antifungals such as isoconazole,
ketoconazole, bifanazole, terbinafine, Whitfield’s ointment, and butenafine can be
effective in the treatment of tinea nigra.66,68,71,72

Deep Fungal Infections

Cutaneous and subcutaneous fungal infections may develop following trauma
or hematogenous shedding in both immunocompetent and immunocompromised
patients. Transcutaneous trauma, fissuration or lacerations allow an entrance for the
fungal agents. If they adopt the host with adverse immunologic reaction, the infection
starts. Apart from endemic areas, they have been increasingly reported in various
regions of world.73,74
Mycetoma, also known as Madura foot, is a deep mycosis caused by
eumycetes (fungi) and actinomycetes (filamentous bacteria). This infection results in
a granulomatous inflammatory response in the deep dermis and subcutaneous tissue
that can extend to the underlying bone. Individuals living in tropical and subtropical
regions are more affected. Eumycotic mycetomas were more common in northern
India, but the incidence of actinomycetomas is increasing. The most common
eumycetic organisms include Madurella, Pseudallescheria, Acremonium, and
Leptosphaeria, while Actinomadura, Streptomyces and Nocardia are commonly seen
among actinomycetic organisms. Bacterial actinomycetomas caused by Nocardia
species are most common in Central America and Mexico. In other parts of the world,
the most common organism is an eumycetoma agent, Madurella mycetomatis. Most
lesions locate on the lower extremities. 74,75 Mycetoma is clinically characterized by
papules, nodules, perilesional edema, formation of sinus tracts, and discharge of
purulent exudate containing grains (Figure 7).76 In some publications, it has been
reported that it occurs more frequently in men than in females. It is most commonly
seen on the foot. Advanced disease causes periostitis, osteomyelitis and bone
destruction. Other body parts that come into contact with the soil may also be
affected. The disease may spread via lymphatics or along the facial planes. Blood
borne spread may also occur. Lymphatic spread is more common in actinomycetoma
than in eumycetoma. According to sinus formation and deep connecting tracts, the
disease may spread extensively. As imaging techniques CT Scan, USG, X-Ray and
MRI may be helpful for the diagnosis. The most used stains are Hematoxylin and
Eosin (H&E) for the microscopic identification. Immuno-fluorescent antibody and
immuno-histochemistry techniques can be used to improve the histological
identification of the organisms and host reactions. Histologically,
pseudoepitheliomatous hyperplasia is observed. The grains represent tightly packed
colonies of organisms. The thickness of filaments allows a differentiation of
eumycotic and actinomycotic mycetomas. In addition to surgical excision,
itraconazole, voriconazole and posaconazole may be effective in the treatment of
mycetoma, but recurrence can be seen. The most successful treatment option for
eumycetomas is itraconazole 200 mg twice daily. 73,74 Chufal et al. reported that a
combination of amikacin, cotrimoxazole and rifampicin along with regular surgical
debridement had a good clinical response.75
Sporotrichosis is a subcutaneous fungal disease caused by Sporothrix (S.)
schenckii found in decaying vegetation, sphagnum moss and soil. Most commonly
affected areas are the face and extremities in immunocompetent patients. The
pathogen creates a granulomatous formation including neutrophilic infiltration. The
disease is usually seen in farmers/gardeners following an injury from a rose thorn or
splinter. The initial lesion becomes an erythematous papule, which then turns into a
verrucous plaque. A single papule occurs approximately three weeks after inoculation
of the agent by skin injury. ; however,, the interval from injury to apparent infection
may be as long as six months.73,77,78 The clinical presentations include
lymphocutaneous, fixed cutaneous, disseminated and extracutaneous sporotrichosis.
Approximately 75% to 80% of cases represent the lymphocutaneous form of
sporotrichosis. In this form, the initial lesion mostly resolves, and is followed by the
formation of new nodules along lymphatic vessels that is referred to as sporotrichoid
pattern. Fixed cutaneous form, also known as localized cutaneous, is characterized by
one to two lesions in the affected area.79 Multifocal or disseminated cutaneous
sporotrichosis is a very rare form in which there is no predisposing factor for
immunosuppression. Mostly traumatic implantation or sometimes hematogeneous
spread play a role. Extracutaneous sporotrichosis is seen in immunocompromised
patients. Direct microscopy is rarely useful for identification of the agents because S.
schenckii is very rarely present in infected tissues. Fluorescent-labeled antibodies
staining sometimes helps to recognize the cigar shaped yeast forms. 80,81 Itraconazole,
terbinafine, potassium iodide and local hyperthermia can be effective for treating
sporotrichosis. Itraconazole is the drug of choice for cutaneous disease. Amphotericin
B is the drug of choice for systemic disease, although more recent literature indicates
that itraconazole or terbinafine may replace amphotericin B. Potassium iodide is the
third drug of choice for cutaneous disease.73,79,82
Cryptococcosis is mostly caused by Cryptococcus neoformans and
Cryptococcus gattii. The fungus is an encapsulated yeast. Primary cutaneous
cryptococcosis by direct skin inoculation is an uncommon entity unrelated to the
patient’s immune status and may present a sporotrichoid pattern. There is often a
history of trauma or exposure to soil or birds preceding the development of the
lesion.73,83-85 Although the main sites of the infection are the central nervous system,
blood, and lung, skin involvement can also occur. In most patients, skin lesions
develop after hematogenous dissemination, but occasionally cutaneous
cryptococcosis occurs alone without systemic involvement and is known as primary
cutaneous cryptococcosis. Cryptococcosis is more frequently seen in
immunocompromised individuals such as those who are HIV-positive or solid organ
transplant recipients. Immunosuppression causes brain, meningeal and lung invasion
and secondary skin lesions due to the inhalation of fungal propagules.
Maculopapules, pustules, ulcers, and abscesses are reported in the lower extremities
in disseminated patients. Fluconazole may be effective in primary cutaneous
cryptococcosis, but disseminated patients should be treated with amphotericin B and
flucytosine followed by fluconazole.73,79,86
Choromoblastomycosis is a rare, chronic granulomatous fungal infection that
is characterized by plaques, nodules or verrucous and exophytic lesions on the skin
and subcutaneous tissue. The most common pathogens are Fonsecaea pedrosoi,
Fonsecaea compacta, Phialophora verrucosa, and Cladophialophora carrionii.
Unprotected areas on the distal extremities are the most commonly affected. After
inoculation, the disease progresses slowly and spontaneous resolution is not observed
unless treated.87,88 In general, the disease remains localized to the area of the initial
infection or neighboring skin, but lymphatic and hematogenous dissemination may
occur, causing metastatic lesions. Annular lesion resolves centrally with scarring.
Some lesions create multinodular mass. It may rarely appear as a phagedenic ulcer on
the face.89,90 Clinically, it resembles the other deep fungal mycosis, atypical
mycobacteriosis, cutaneous tuberculosis, leishmaniasis, squamous cell carcinoma,
and sarcoidosis.87 The characteristic histological features of chromoblastomycosis
include microabscesses and pseudoepitheliomatous hyperplasia.91 Surgical excision
may be effective on its own if the lesions are small and non-advanced, but advanced
disease should be treated with physical methods such as surgical excision,
cryotherapy and electrocautery and pharmacologic agents such as itraconazole,
terbinafine, fluocytosine, amphotericin B, and posaconazole. Recurrences still occur
frequently.73,87,91,92
Lobomycosis is a chronic granulomatous infection of the skin and
subcutaneous tissues caused by the fungus Lacazia loboi (previously known as Loboa
loboi). Lobomycosis occurs in Central and South America. Most characteristic
lesions are asymptomatic firm keloid-like nodules and papules, which are verrucous
or ulcerative.89 In physical examination, shiny, atrophic and discolored skin is
observed. Lesions occur at the side of a local trauma especially located on the
extremities, trunk and face. Histologically, thick-walled, yeast-like cells are
connected by thin, tube-like bridges. The most effective treatment is the surgical
excision of the lesion with wide margins.93,94
Histoplasmosis is another deep fungal infection. The causative organism is
Histoplasma capsulatum var. capsulatum. The environmental reservoir is soil
contaminated by the feces of birds, fowl and bats. Most skin lesions begin from the
primary pulmonary focus. Disseminated disease in immunocompromised patients
presents with mucocutaneous erosion and ulcers. Histopathologically, yeast is located
within the cytoplasm of macrophages. In order to identify the fungi, PAS or
methenamine silver staining can be applied. Itraconazole, or amphotericin for severe
or diffuse disease, are the usual treatments.95
Blastomycosis is an endemic fungal infection caused by the dimorphic fungus
Blastomyces dermatitidis. It is transmitted by inhaling spore-laden dust. Person-to-
person transmission does not occur. The presentation of clinical blastomycosis for
most patients is pneumonia with an alveolar or mass-like infiltrate by radiography. ;
however,, the disease can present with extra pulmonary signs such as erythematous
verrucous or ulcerative lesions similar to pyoderma gangrenosum. Extra pulmonary
manifestations are present in 25-40% of cases. Immunocompromised patients present
with disseminated disease involving bones, the central nervous system and skin. Skin
lesions are more common on the face, neck and extremities. Early in the disease
course, the lesions are sharply demarcated papules or pustules or subcutaneous
nodules. Nodules can ulcerate or purulate.74 Within a few weeks to months, the
primary lesions evolve into ulcers. Typically, the border is arciform or serpiginous
and contains numerous tiny pustules. Centrally healed lesions show scarring. The skin
lesions are described as "chancriform" and are accompanied by nodular lymphangitis.
Microscopically, broad based budding and double contoured walls separate
blastomycosis from the other systemic fungal infections.96
Coccidioidomycosis (also known as valley fever) results from inhaling the
spores (arthroconidia) of the Coccidioides species (Coccidioides immitis or
Coccidioides posadasii). The infection is mostly asymptomatic. On the other hand,
flu-like symptoms can be the only presentation. Depending on the host immunity, the
organism can disseminate. The cutaneous lesions may appear as abscesses,
granulomas, ulcers or discharging sinuses, hypersensitivity reactions such as
erythema multiforme and erythema nodosum, toxic erythema. PAS and silver
methenamine stains are helpful in identifying immature spherules with
endospores.89,97

Paracoccidioidomycosis occurs by inhaling the conidia deriving from the soil.

The main organism of paracoccidioidomycosis is Paracoccidioides brasiliensis, which
targets mucous membranes, lymph nodes and internal organs. The pulmonary
involvement is the most common clinical presentation. Lesions must be distinguished
from histoplasmosis and tuberculosis. Later reactivation results in chronic infection of
the skin and oral mucous membranes. On the other hand, disseminated disease causes
mucocutaneous lesions such as ulceration or painful verrucous eruption. Perforation
of the palate or nasal septum may be seen. Lymphadenopathies are common in
patients with buccal involvement. Hematogenous or lymphatic spread results in
subcutaneous abscesses. The histological examination shows granulomatous reaction
and pseudoepitheliomatous hyperplasia similar to blastomycosis. Multiple narrow-
based buds resemble “mariner’s wheel”.89,98
Primary cutaneous mucormycosis located on the hands is rarely reported by
direct inoculation after penetrating trauma. The causative microorganisms are
Rhizomucor, Absidia, and Rhizopus. Their invasion pattern is angioinvasive causing
necrotic skin lesions. Diabetes mellitus and immunosuppression are the main
predispositions. Primary infection can be rhino-orbito-cerebral, pulmonary,
gastrointestinal or cutaneous. Pathological examination highlights broad, non-septate,
90° branching hyphae.99,100
Aspergillosis has non-specific cutaneous manifestations. Aspergillus (A.)
fumigatus and A. flavus are the main responsible organisms (Figure 8). Primary
cutaneous involvements occur subsequently after skin maceration and secondary
involvement dissemination of primary lung infection caused by inhalation of conidia.
In advanced disease, ulcerative lesions and additionally kidney, heart, and central
nervous system problems can be detected. Important histological findings are 45°
dichotomous branching of hyaline, septate hyphae.101,102
Phaeohyphomycosis is the other deep fungal infection that has non-specific
cutaneous manifestations like papules, pustules, nodules and ulcers. Causative
organisms should be identified with laboratory tests. Fungal culture on Sabouraud
agar is the gold standard for diagnosis. ; however,, while itraconazole and fluconazole
can be effective in the treatment of mild or moderate cases, these drugs should be
combined with amphotericin B in severe and disseminated cases.73,79

Non-Dermatophytic Mold Infections of Nails

Dermatophytes are usually assumed to be the principal causative agents of
abnormal nails. ; however,, dermatologists are frequently faced with treatment failure,
and microbiologists are often confronted with failure to isolate dermatophytes in
culture. This may be due to a possible infection by non-dermatophyte molds,
including Scitalidium species, Scopulariopsis, Fusarium, Acremonium, and
Aspergillus spp. In many of these cases, colonization by non-dermatophyte molds
may frequently be observed. It is important to differentiate the etiologic agent ;
however,, the presence of incidental non-dermatophyte contaminants or secondary
colonizers does not usually affect the treatment outcome.74,89