Pathogenesis and treatment of hyperkeratotic tinea pedis in Japan

mycoses 42, 21–28 (1999)
Accepted: April 20, 1998
Pathogenesis and treatment of hyperkeratotic tinea pedis
in Japan
Pathogenese und Behandlung hyperkeratotischer Tinea pedis in
H. Tanuma
Key words. Tinea pedis, hyperkeratosis, pathogenesis, treatment, Japan.
Schlu¨sselwo¨rter. Tinea pedis, Hyperkeratose, Pathogenese, Behandlung, Japan.
Summary. In this paper, we describe the major
characteristics of hyperkeratotic tinea pedis and
review therapeutic results obtained in the
Department of Dermatology of Kitasato
University Hospital and those reported in the
literature in Japan and abroad.
Zusammenfassung. Es werden die Charakteristika der hyperkeratotischen Tinea pedis
dargestellt und die Therapieergebnisse der Dermatologischen Klinik des Kitasato Universita¨tsklinikums in Japan im Vergleich mit der Literatur
administration of griseofulvin has been mainly
used for the treatment of this type. Today, better
therapeutic results can be expected thanks to the
development of more effective topical antifungal
agents such as butenafine HCl, terbinafine HCl
and lanoconazole, as well as new oral antifungal
agents such as itraconazole and terbinafine.
In this paper, we present therapeutic results
obtained in patients with hyperkeratotic tinea
pedis at the Department of Dermatology of
Kitasato University Hospital, outline the major
characteristics of this disease, and review recent
findings obtained with respect to its mechanisms
on cytokine levels.
In general, tinea pedis is classified into three types:
interdigital, vesicular and hyperkeratotic. In Japan,
the first two types, which are relatively responsive
to topical antifungal agents, account for more than
90% of the total number of patients with tinea
pedis [1–4]. These types are usually cured in 1–3
months. Hyperkeratotic tinea pedis, which is
associated with marked thickening of the plantar
horny layer, is more refractory, and sufficient
therapeutic effects cannot be expected with topical
antifungal agents alone. For this reason, oral
Department of Dermatology, Kitasato University School of
Medicine, Kitasato, Sagamihara, Kanagawa, Japan.
Correspondence: Dr Hiroyuki Tanuma, Department of
Dermatology, Kitasato University School of Medicine, 1-15-1,
Kitasato, Sagamihara, Kanagawa, 228-0829 Japan.
Characteristics of hyperkeratotic tinea
In Japan, hyperkeratotic tinea pedis is generally
understood to be tinea pedis associated with plantar hyperkeratosis. Its definition in other countries
seems to be more ambiguous, and chronic, noninflammatory tinea pedis which shows a tendency
towards hyperkeratosis and is unresponsive to
topical agents is treated as moccasin-type or hyperkeratotic-type tinea pedis [5, 6].
According to Kagawa [7], the major characteristics of hyperkeratotic tinea pedis are as follows:
(1) there is formation of diffuse hyperkeratosis and
desquamative erythema on the sole and the entire
toes; (2) it is chronic and non-seasonal; (3) it is
often accompanied by tinea unguium; and (4) the
causative organism is Trichophyton rubrum.
H. Tanuma
However, hyperkeratotic tinea pedis may also
be caused by other fungi such as T. violaceum and
T. mentagrophytes. The major characteristics of this
disease on reports by different investigators are
presented in Table 1 [10, 11]. On the basis of this
table, the presence of marked hyperkeratosis in
the entire sole and scales in skin sulci and the lack
of seasonal changes in symptoms are essential to
make the diagnosis of hyperkeratotic tinea pedis.
In daily medical practice, it is extremely rare to
encounter patients with true hyperkeratotic tinea
pedis, and this type accounts for only 2–8% of the
total number of patients with tinea pedis [1–4].
Hyperkeratotic tinea pedis, which is often resistant
to treatment, is tinea pedis which, being associated
mainly with hyperkeratosis and presenting a clinical picture very dissimilar to that of athlete’s foot,
is often mistaken as simple chapped skin.
Hyperkeratotic tinea pedis is for convenience’s
sake classified into true, partial and quasihyperkeratotic types [8–11] in order to facilitate determination of the cause and evaluation of therapeutic
efficacy. In our view, only the true type is hyperkeratotic tinea pedis in the strict sense; the partial
type is seen only in limited areas such as the heels
due to chronic exposure to external forces such as
body weight and friction with shoes; quasihyperkeratotic type is formed as a result of recurrent
vesicles in patients with vesicular type tinea pedis.
Although much remains unknown about the aetiology of hyperkeratotic tinea pedis, immune system
impairment is thought to be involved for a number
of reasons: (1) it is more prevalent among the
elderly than vesicular or interdigital tinea pedis;
(2) the causative organism is T. rubrum in most
cases; (3) it is associated with few inflammatory
symptoms; and (4) the main symptom is
Table 2 shows the relationship between various
types of tinea pedis and levels of host-derived
Table 1.
Characteristics of hyperkeratotic tinea pedis
Marked hyperkeratosis is present in the entire sole
Marked scales are present in skin sulci in the foot
Symptoms show little seasonal changes
Itching is slight and no vesicles are seen
Often associated with tinea unguium
The causative organism is T. rubrum in most cases
Table 2. Classification of tinea pedis and hosts’ resistance
against fungi
Granuloma due to trichophyton
3 3 3
Hyperkeratotic tinea pedis
True type
Quasihyperkeratotic type
Partial type
3~3 3
3~3 3*
Vesicular tinea pedis
Interdigital tinea pedis
*Transfer of antifungal substances into the horny layer is
partially insufficient (cited in Takahashi, H. et al., 1993,
[8], with some modifications).
antifungal factors [8]. Patients with true hyperkeratotic tinea pedis are more liable to fungal infections
than patients with quasihyperkeratotic tinea pedis
are more resistant to fungi, and vesicles are sometimes seen in these patients. In patients with
partial-type hyperkeratotic tinea pedis, transfer of
antifungal factors into the horny layer is partially
insufficient, and this allows Trichophyton spp. to
survive in the thick horny layer and cause hyperkeratosis. As reported by Kashima et al. [12], in
patients with candidosis we believe that there are
host-derived anti-Trichophyton factors and that they
prevent Trichophyton spp. from entering into the
thin horny layer, or if it does it causes only vesicles
similar to those seen in patients with ordinary
tinea pedis, and not hyperkeratosis [8].
We have conducted immunohistochemical
evaluations of skin samples from areas affected by
dermatomycosis in order to determine the mechanisms by which it is caused, as well as the
mechanisms by which the body defends itself
against fungi. Factors involved in these mechanisms are thought to include the fungi’s aggressive
factors, the hosts’ defensive factors and environmental factors [10, 13]. Of all these factors, the
hosts’ defensive factors, classified into specific and
non-specific defensive types, are generally
regarded as most important. Specific defensive
factors include cellular and humoral immune factors, whereas non-specific defensive factors include
physiological barriers, inflammatory responses and
phagocytosis. Table 3 shows some of these factors
involved in the defence of the skin against fungi.
In general, hosts show eczema or dermatitis-type
histological responses characterized by increases
in Langerhans cells in the epidermis in affected
areas and the presence of many CD4- and HLADR-positive cells around blood vessels in the upper
mycoses 42, 21–28 (1999)
Hyperkeratotic tinea pedis in Japan
Table 3. Mechanisms by which dermatomycosis occurs
and factors involved in the defence of the body against fungi
I. Fungi’s aggressive factors
1. Adhesive factor (ability to adhere)
2. Proteinases
3. Cellular wall components
4. Others
II. Hosts’ defensive factors
1. Horny layer
2. Epidermal Langerhans cells
3. Keratinocytes
4. Epidermis-derived basic protein components
5. Neutrophils (abscess)
6. Lymphocytes (in particular CD4-positive T cells,
TH1 type)
7. Macrophages
8. Plasma cells
9. Granulomatous reactions
10. Mechanisms for foreign matter expulsion
11. Others
III. Environmental factors
1. Trauma
2. UV rays
3. Drugs (steroids, immunosuppressive drugs, etc.)
4. Others
layer of the dermis [13, 14] in the case of acute
superficial tinea pedis such as tinea corporis, tinea
cruris, interdigital tinea pedis and vesicular-type
tinea pedis. In the case of hyperkeratotic tinea
pedis, hyperkeratosis is marked [14, 15], but epidermal Langerhans cells in affected areas are fewer
than in healthy areas, inflammatory cell infiltration
in the upper dermal layer is slight, and almost no
CD4- or HLA-DR-positive cells are observed [14].
Based on the hypothesis outlined in Fig. 1, we
thought that various cytokines contribute to causing a series of histological responses for defending
the body against fungi. To test this hypothesis, we
determined expression of various cytokines on
mRNA levels by the RT-PCR (reverse transcription-coupled polymerase chain reaction) method
using skin samples obtained from affected areas.
Interferon c (IFN-c) was detected in all patients
with acute superficial tinea pedis [10, 11, 15], and
interleukin 2 (IL-2) and granulocyte–macrophage
Table 4. Expression patterns for various cytokines in
affected skin in patients with superficial dermatophytosis
Tinea corporis and
tinea cruris
tinea pedis
mycoses 42, 21–28 (1999)
Figure 1. Role
superficial dermatophytosis
colony-stimulating factor (GM-CSF) were also
detected in some patients (Table 4). These findings
are consistent with the hypothesis that eczema and
dermatitis-type histological responses observed in
patients with acute superficial dermatophytosis are
delayed hypersensitivity reactions occurring in
response to dermatophyte components and suggest
that, as shown in Fig. 1, dermatophyte metabolites
present in the horny layer act as antigens; that
antigen-related information is transmitted via
Langerhans cells and macrophages, resulting in
the production of IL-2 by locally recruited dermatophyte-specific T cells, their differentiation
and replication, and production of Th1-type cytokines such as IFN-c and GM-CSF; and that
delayed type hypersensitivity reactions occur as a
result of all these events [10, 11, 15]. These
cytokines are thought to mobilize neutrophils and
macrophages and release various antifungal substances, enhancing the hosts’ antifungal defences.
IFN-c not only activates macrophages but promotes the growth of keratinocytes as well [15–17].
Therefore, it is thought to increase the turnover
of epidermal cells and precipitate desquamation,
thereby accelerating elimination of dermatophytes
and enhancing the defence of the body against it.
In the case of hyperkeratotic tinea pedis, however,
no IL-2 or GM-CSF was detected and only IFN-c
was detected in skin samples obtained from
affected areas [11, 15]. Koga [17] found that
H. Tanuma
trichophytin-stimulated production of IFN-c and
IL-2 was markedly decreased in peripheral monocytes from patients with hyperkeratotic tinea pedis
and suggested that the disease becomes chronic
because the causative organism is not efficiently
eliminated for this reason [17].
Hyperkeratotic tinea pedis of the true type
accounts for only 2–8% of the total number of
patients with tinea pedis [1–4]. We suspect that
the number of patients with hyperkeratotic tinea
pedis of the two other types is greatly underestimated, because many of these patients do not seek
treatment and if they do they are simply diagnosed
as having chapped skin in many cases. We estimate
that more than 50% of patients admitted to elderly
persons’ hospitals have hyperkeratotic tinea pedis
of these types. Although one group reported that
the true type accounts for 23.6% of the total [9],
the quasihyperkeratotic type may have been
included in this percentage. Further multicentre
trials will be necessary to more accurately determine the prevalence of each type.
Age and sex
All three types are more prevalent in elderly
patients than vesicular or interdigital tinea pedis
with peaks of prevalence between 50 and 69 years
[8, 9]. There is no sex difference in prevalence.
Duration of illness
The duration of illness is usually very long, regardless of type (1–5 years in general and sometimes
more than 10 years) [9].
Causative organism
The true and partial types are due to T. rubrum in
almost all cases, whereas T. mentagrophytes accounts
for a greater percentage of patients in the case of
quasihyperkeratotic tinea pedis.
Clinical symptoms
As shown in Tables 1 and 2, clinical symptoms
vary to some extent according to type, but plantar
hyperkeratosis, bilateral in 70–80% of patients, is
commonly seen with all three types. All three types
are occasionally associated with slight itching and
do not show any seasonal change. According to
Kasai [18], however, hyperkeratotic tinea pedis
shows a tendency to worsen in winter.
Complications are seen in 36.4% of patients [9],
but no complication is as serious as those associated with tinea unguium [19]. Interdigital and
vesicular-type tinea pedis are seen in about 28%
and 17%, respectively, of patients with hyperkeratotic tinea pedis [8], whereas tinea unguium is
seen in about 50% of these patients.
According to Takahashi et al. [8], imidazole topical
antifungal agents had been used by them in almost
all their patients, and had been ineffective in about
two-thirds of cases.
Oral treatment
Oral administration of griseofulvin has been the
mainstay in the treatment of hyperkeratotic tinea
pedis, because it is often unresponsive to topical
antifungal agents. At present, combination of oral
administration of griseofulvin and topical antifungal agents is the standard therapy. Recently, however, the new oral antifungal agent itraconazole
has come into general clinical use, and oral administration of this agent alone or in combination
with topical antifungal agents seems to be gradually replacing griseofulvin.
Griseofulvin This agent was launched in Japan 35
years ago. Since its effects are fungistatic against
Trichophyton spp., long-term treatment is unavoidable. In general, 375 to 500 mg/day is administered for 3–6 months. A cure is difficult to achieve,
and the recurrence rate is high [20]. It is therefore
recommended that this drug be administered in
combination with topical agents, rather than alone.
Since it is inexpensive and efficacy rates of 70–80%
are reported in patients treated with 500 mg day−1
for 8 weeks [21], this drug can be recommended
as the drug of first choice for economic reasons,
but it must be remembered that treatment must
be prematurely terminated in many cases due to
adverse reactions such as gastrointestinal and hepatic disorders and photosensitivity reactions. In
addition, decreased sensitivity of Trichophyton spp.
to this agent has been reported in some cases [22].
Treatment with other drugs is therefore necessary
in refractory cases.
Itraconazole Owing to its relatively long blood halflife, sufficient plasma and ungual concentrations
can be maintained by once-daily administration
[23, 24]. To ensure good plasma concentrations,
it must be administered immediately after meals.
mycoses 42, 21–28 (1999)
Hyperkeratotic tinea pedis in Japan
In phase II and III clinical trials in Japan [21,
25], efficacy rates of 80% to 90% were obtained
in patients treated with 100 mg day−1 for 8 weeks.
Taking into account the transfer of the drug into
plasma and horny layer in our unit, we now orally
administer it at 100 mg day−1 during the first
month, reduce the dose to 50 mg day−1 thereafter,
and continue the treatment for up to 1 more
month. This treatment regimen has resulted in
good therapeutic outcomes (unpublished data).
Further studies are necessary on various treatment
regimens with this drug, such as intermittent
administration and pulse therapy, as well as its
transfer into the plasma and horny layer.
trial is under way in order to obtain an additional
indication for dermatomycosis. Once-daily oral
treatment is possible with this agent, because high
blood concentrations can be obtained, and its
elimination half-life is long. A overall efficacy rate
of 83.3–100% was obtained for hyperkeratotic
tinea pedis after treatment for 8 weeks at
100 mg/day in phase III clinical trial in Japan [33].
Terbinafine Terbinafine is not expected to cause
hepatic disorders. High blood concentrations can
be obtained when terbinafine is orally administered once a day [26]. Although transfer into the
skin is not as effective as into the blood [27],
concentrations reached in the skin are thought to
be high enough for this drug to be effective [27],
because its effects against dermatophytes are fungicidal [28]. In Japan, a topical version is already
in general clinical use, and an oral version is
expected to be launched in September 1997. The
oral version is expected to be useful for the
treatment of hyperkeratotic tinea pedis and tinea
An overall efficacy rate of 86.8% was obtained
for hyperkeratotic tinea pedis after treatment for
8 weeks at 125 mg day−1 in phase III clinical trials
in Japan [10, 11]. The efficacy rates for the true,
partial and quasihyperkeratotic types were 100%,
86.6% and 80.0% respectively. In other countries,
terbinafine is usually administered at 250 mg
day−1 for 2 weeks, and this treatment regimen is
reported to result in an eradication rate of 86%
and an efficacy rate of 71% [28].
In a double-blind clinical trial in Japan, no
statistically significant differences were observed
between terbinafine and griseofulvin, probably
because 125 mg day−1 of terbinafine was compared with 500 mg day−1 of griseofulvin [10]. In
double-blind clinical trials conducted in other
countries in which terbinafine was administered
at 250 mg day−1, however, it was found to be
significantly superior to griseofulvin [29–32], with
efficacy rates of 75% and 88%, respectively, 6 and
8 weeks after completion of a 2-week treatment.
The incidence of recurrence was also very low
[29–31]. The optimal treatment regimen (dosage
and treatment period) will have to be determined
in Japan taking these foreign findings into account.
Topical treatment Topical therapy has been regarded
as almost ineffective for hyperkeratotic tinea pedis.
However, its therapeutic performance has
improved significantly in recent years because of
the development of new drugs with increased
antifungal activity, transferability and retainability,
use of keratolytic agents, and improvement of
occlusive dressing techniques. The topical treatment regimens in current use at the Department
of Dermatology of Kitasato University Hospital
(Table 5) include monotherapy with antifungal
agents and their combinations with urea ointments
using or not using the occlusive dressing technique.
Fluconazole In Japan, fluconazole was approved for
deep-seated mycosis in 1988. A phase III clinical
mycoses 42, 21–28 (1999)
Others Oral administration of ketoconazole is
approved in some countries but not in Japan
because of hepatic disorders. In Japan and elsewhere, the usefulness of ketoconazole for hyperkeratotic tinea pedis has been not studied in detail.
Monotherapy with antifungal agents Umezawa et al.
[34] obtained a high efficacy rate of 89.2% by
topically applying tioconazole two or three times
a day for 4 weeks, but their patients had tinea
pedis in which hyperkeratosis was a major symptom, and not hyperkeratotic tinea pedis of the true
type. Efficacy rates greater than 80% were also
reported with a 2% ketoconazole cream applied
once or twice a day for 4 weeks [35]. In general,
however, sufficient efficacy cannot be expected
with simple inunction of antifungal agents alone.
In our study [36], the efficacy rate was only 46.7%
Table 5. Topical treatment of hyperkeratotic tinea pedis
in the Department of Dermatology of Kitasato University
Econazole nitrate+10% urea ointment
Tioconazole alone
Bifonazole alone
Bifonazole+10% urea ointment
Bifonazole+10% urea ointment+ODT
Butenafine HCl alone
Butenafine HCl+20% urea ointment
Lanoconazole alone
Lanoconazole+10% urea ointment
Terbinafine HCl alone
Terbinafine HCl+20% urea ointment
H. Tanuma
in patients with hyperkeratotic tinea pedis who
received bifonazole solution once a day by simple
inunction for 12 weeks, a rate considerably lower
than those obtained in patients with interdigital
or vesicular-type tinea pedis. We do not believe
that satisfactory therapeutic results can be
obtained by topical application of conventional
imidazole antifungal agents alone. Recently, a
number of new agents with increased antifungal
potency which are more efficiently transferred to
and retained in affected tissues, such as butenafine
HCl, terbinafine HCl and lanoconazole, have been
developed, and their efficacy for hyperkeratotic
tinea pedis is being evaluated. A butenafine HCl
cream produced high efficacy rates of 41.2–60%
[37, 38] and 81.9% [39], respectively, when
administered 4 and 12 weeks once a day, whereas
a lanoconazole cream produced efficacy rates of
10%, 51.7% and 72.2%, respectively, when administered for 4, 8 and 12 weeks [8]. With lanoconazole, the efficacy rates for the partial and
quasihyperkeratotic types were 80% and 55%,
respectively, but the efficacy rate for the true type
could not be determined because only one patient
was of this type. In our study of a terbinafine HCl
cream, the efficacy rates for the quasi-, partial and
true types were 22.2%, 60.0% and 33.5%, respectively, after 4-week treatment and 93.8%, 100%
and 100% after 12-week treatment [49]. According
to Savin et al. [40], an improvement rate of 79%
was obtained 8 weeks after 2-week treatment twice
a day with a 1% terbinafine cream, but the
improvement rate was 20% lower in cases associated with tinea unguium. However, we believe
that terbinafine is very useful for hyperkeratotic
tinea pedis and plan to conduct further studies on
its efficacy, safety and transfer into the horny layer.
Combinations of antifungal agents and urea ointments
Urea ointments help the horny layer to maintain
water and promote keratolysis. They are also
known to increase percutaneous absorption of
steroids when co-administered with topical steroidal agents in patients with keratosis associated
with inflammation [41]. We often combine topical
antifungal agents with urea ointments in the belief
that the latter alleviates keratosis and enhances
the penetration of the former into the horny layer
[36]. Yamaguchi & Higashiya [42] and Doi &
Umezawa [43] reported efficacy rates of 60–80%
by stratified application of an econazole cream
and a 10% urea ointment. We also obtained
efficacy rates of 85.4–86.7% by combining a bifonazole solution or cream with a 10% urea ointment
for 12 weeks [11, 36]. According to Nishikawa
et al. [38], combination of a butenafine HCl cream
and a 10% urea ointment was effective in 37.5%
and 46.7% of patients after 4- and 8-week treatments, respectively, whereas in our study, combination of a butenafine HCl cream and a 20% urea
ointment resulted in efficacy rates of 50.0%, 69.2%
and 87.5%, respectively, 4, 8 and 12 weeks after
treatment [39]. At present, we are evaluating the
efficacy of combinations of terbinafine HCl or
lanoconazole with a urea ointment.
More recently, mixtures of antifungal agents
and urea ointments have been used to evaluate
their efficacy for hyperkeratotic tinea pedis.
Nakamura et al. [44] obtained an efficacy rate of
33.3% after treatment for 4 weeks with a 151
mixture of a 1% oxiconazole nitrate cream and a
20% urea ointment. At present, we are evaluating
151 and 251 mixtures of bifonazole, butenafine
HCl, terbinafine HCl or lanoconazole and an urea
ointment. Results obtained so far have been
encouraging (unpublished data). ZM-589 is an
investigational new topical antifungal drug (solution) whose active ingredients are tolnaftate (2%)
and salicylic acid (10%) [45, 46]. In experimental
dermatophytosis, it was found to be significantly
more effective than ZM-SA (a drug obtained by
excluding salicylic acid from ZM-859), 1% econazole nitrate solution, 1% cyclopirox olamine solution and 5% exalamide solution (containing 2%
salicylic acid). We therefore expect that more
combination drugs will be developed in the future.
Occlusive dressing technique (ODT) ODT using cream
bases is thought to be more effective than simple
inunction with antifungal agents, because it
enhances maceration of the horny layer and secondary keratin desquamation. However, it causes
discomfort, and hyperhidrotic patients often complain of vesicles and itching, particularly in
summer. Nishimoto & Nakaura [47] reported the
usefulness of a 1% clotrimazole cream administered using ODT. We also obtained favourable
therapeutic results using ODT in combination
with a bifonazole cream and a 10% urea ointment
[11]: cutaneous symptom improvement rates were
31.8%, 58.1%, 77.3% and 82.9%, respectively, 2,
4, 8 and 12 weeks after starting the treatment, and
marked improvement rates were significantly
higher in the ODT group than in the non-ODT
group who received the same combination therapy
at all evaluation time points, indicating that ODT
makes it possible to more quickly improve clinical
symptoms. ODT also increased eradication rates
to 53.3%, 78.6%, 88.6% and 97.1%, respectively,
2, 4, 8 and 12 weeks after starting the treatment
and the usefulness rate to 91.7% 12 weeks after
starting the treatment. We therefore regard ODT
as a very useful administration method.
mycoses 42, 21–28 (1999)
Hyperkeratotic tinea pedis in Japan
At present, oral antifungal drugs such as griseofulvin, itraconazole and terbinafine are useful for
hyperkeratotic tinea pedis in patients who can
orally ingest drugs. In patients who do not respond
to griseofulvin, we recommend the combination
of oral antifungal agents (such as itraconazole and
terbinafine) with topical antifungal agents,
although problems may be encountered in
obtaining reimbursement under the current health
insurance system in Japan. If oral administration
is impossible, various topical application methods,
such as concurrent use of urea ointments and the
use of ODT, are worth trying [48, 49]. In any
case, it is very important to continue treatment
patiently without losing hope.
In the future, we hope to see the development
of more oral and topical antifungal agents with
fewer systemic adverse effects (in particular hepatic
disorders) and interactions with other drugs which
are transferred to skin tissues at higher concentrations. Treatment regimens (dosage, treatment
period, etc.) for existing drugs will also have to be
reviewed in multicentre clinical trials.
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