Dermatophytosis (“ringworm”) 2012 edition Agent Properties

Transcription

Dermatophytosis (“ringworm”) 2012 edition Agent Properties
Dermatophytosis (“ringworm”) 2012 edition
Agent Properties
In contrast to single-celled yeasts, dermatophytes (literally: “skin plants”) are complex
fungi growing as hyphae and forming a mycelium. They have keratinophilic and
keratinolytic properties. About 40 species belonging to the genera Microsporum,
Trichophyton and Epidermophyton are considered as dermatophytes and they cause
common superficial skin infections in many animal species and humans worldwide.
Dermatophytosis is the most common fungal infection of cats and one of the most
important infectious skin diseases in this species. It is also an important zoonosis: cats
are a main source of infection for man.
Aetiology
Over 90% of feline dermatophytosis cases worldwide are caused by Microsporum canis
[Sparkes et al. 1993a, DeBoer and Moriello, 2006]. Others are caused by infection with
M. gypseum, Trichophyton mentagrophytes, T. quinckeanum, T. verrucosum or other
agents. With the exception of M. gypseum, all produce proteolytic and keratolytic
enzymes that enable them to utilize keratin as the sole source of nutrition after
colonization of the dead, keratinized portion of epidermal tissue (mostly stratum
corneum and hairs, sometimes nails).
By segmentation and fragmentation of the hyphae, dermatophytes produce arthrospores,
which are highly resistant, surviving in a dry environment for 12 months or longer
[Sparkes et al. 1994b]. In a humid environment, however, arthrospores are short-lived.
High temperatures (100°C) destroy them quickly. Arthrospores adhere strongly to
keratin.
Depending on the source of infection and reservoirs, dermatophyte species are classified
into zoophilic, sylvatic, geophilic and anthropophilic fungi.
Epidemiology
M. canis is a typical zoophilic dermatophyte. As this pathogen is isolated from healthy
domestic cats, they are considered the major natural host of M. canis. It was generally
thought that subclinical infections are common, especially in longhaired cats over 2 years
of age. However, the prevalence of M. canis isolation from healthy animals varies greatly
between subpopulations, and in many groups the prevalence is low [Mignon and Losson,
1997]. Therefore, M. canis should not be considered as part of the normal fungal flora of
cats, and isolation from a healthy cat indicates either subclinical infection or fomite
carriage [DeBoer and Moriello, 2006].
Arthrospores are transmitted through contact with sick or subclinically infected animals,
mainly cats, but also dogs and other species. In sick animals, the infected hair shafts are
fragile and hair fragments containing arthrospores are efficient in spreading the infection.
In addition, uninfected cats can passively transport arthrospores on their hair, thereby
acting as a source of infection. Risk factors include introduction of new animals into a
cattery, cat shows, catteries, shelters, mating etc. Indirect contact is important, too;
transmission may occur via contaminated collars, brushes, toys etc. Arthrospores are
easily spread on dust particles. In households with infected cats, the furniture,
wallhangings, clothes and even rooms without access for cats become contaminated
[Brumm 1985].
Outdoor cats, especially in rural areas, can be sometimes infected with agents other than
M. canis dermatophytes. M. gypseum is a geophilic fungus living in soil to which cats are
exposed by digging. T. mentagrophytes and T. quinckeanum are prevalent in small
rodents and their nests, and T. verrucosum is isolated from cattle.
Pathogenesis
Healthy skin acts as an effective physical barrier against fungal invasion. The increased
rate of regeneration of epidermal cells in response to contact with the dermatophyte with
the consequent removal of fungus from the skin surface is another protective
mechanism. As dermatophytes cannot penetrate healthy skin, many cats are merely
passive carriers of the arthrospores or remain subclinically infected. Whether such an
infection will lead to clinical signs depends on endogenous and exogenous factors.
Predisposing factors include young age (first 2 years of life), immunosuppression
(including immunosuppressive treatment), other diseases, nutritional deficits (especially
proteins and vitamin A), high temperature and high humidity [DeBoer and Moriello,
2006]. Any skin trauma resulting from increased moisture, injury by ectoparasites or
scratches due to pruritus, playing or aggressive behaviour, clipping etc. is important for
facilitating infection. In general, poor hygiene is a predisposing factor. In overcrowded
feline groups, social stress may play a role. Thus in catteries or shelters infected with M.
canis, eradication of ringworm may be difficult.
The prevalence of fungal flora was investigated with regard to the potential
immunosuppressive effect of feline immunodeficiency virus (FIV) and feline leukaemia
virus (FeLV). However, the higher prevalence of M. canis in FIV-infected animals
compared with normal cats reported in one survey [Mancianti et al. 1992] was not
observed in another study [Sierra et al. 2000]. The association may be related to
differences in the environment rather than to the retroviral status of the cats [Mignon
and Losson 1997].
The incubation period of ringworm caused by M. canis is 1 to 3 weeks. During this time,
hyphae grow along the hair shafts through the stratum corneum to the follicles where
they produce spores that form a thick layer around the hair shafts. As dermatophytes are
susceptible to high temperatures, they cannot colonize deeper parts of the skin or the
follicle itself. Therefore, the hair grows normally but breaks easily near the skin surface
resulting in hair loss. Several metabolic products of the fungus may induce an
inflammatory skin response and may be observed mainly around the infected area,
forming sometimes ring-like lesions with central areas of healing and papules on the
periphery (“ringworm”).
In many immunocompetent cats living in good conditions these lesions are limited e.g. to
the head, and disappear after several weeks. In immunosuppressed animals, the
outcome may be a multifocal or generalized skin disease with secondary bacterial
infections. On rare occasions, an inflammatory reaction to hyphae induces a nodular
granulomatous lesion involving dermis and draining on the skin surface. These so-called
pseudomycetomas are more often seen in Persian cats, even concurrently with classical
lesions.
The pathogenesis of other dermatophyte infections is similar to that described above.
Immunity
Ringworm rarely recurs, suggesting an effective and long-lasting immunity. Experimental
studies confirm that animals express increased resistance to subsequent challenge by the
homologous fungus. Re-infections may occur, but require a much greater number of
spores, and these subsequent infections are usually cleared more rapidly [DeBoer and
Moriello 2006]. It has been suggested that for the development of full immunity, the
infection must run its natural course, as in cats whose infection was aborted with
antifungal treatment, the delayed type hypersensitivity reactions were often weaker
[Moriello et al. 2003].
Although dermatophyte infection is confined to the superficial keratinised tissues,
humoral and cellular immune responses are induced [Sparkes et al 1993b, 1995].
Prominent activation of T helper type 2 cells and the corresponding cytokine profile leads
to antibody formation followed by chronic disease, whereas activation of Th1 cells
stimulates a cell-mediated response characterized by the cytokines interferon-γ (IFN-γ),
interleukin 12, and IL-2, and leads to recovery [Smith and Griffin 1995, Sparkes et al.
1995, DeBoer and Moriello, 1994]. This implies that cats are protected against reinfection [Sparkes et al., 1993b; DeBoer and Moriello, 1994]. The role of the humoral
response in dermatophytosis is unclear, although specific antibodies could have a direct
fungistatic effect by means of opsonization and complement activation [Sparkes et al.,
1994a]. However, passive transfer of anti-dermatophyte antibodies did not protect mice
against challenge with the homologous fungus in the murine T. quinckeanum infection
model, whereas transfer of lymphoid cells from infected donors conferred protection to
susceptible recipients [Calderon and Hay, 1984].
Clinical signs
In many cats, dermatophytes cause a mild, self-limiting infection with hair loss and
scaling.
The typical presentation of ringworm in cats is regular and circular alopecia, with hair
breakage, desquamation, sometimes an erythematous margin and central healing
[DeBoer and Moriello 2006, Chermette et al. 2008]. The lesions may be quite small, but
on occasions have a diameter of 4-6 cm. Lesions are single or multiple, localised mostly
on the head but also on any part of the body, including the distal parts of the legs and
the tail. Young cats in particular display lesions localised at first to the bridge of the nose
and then extending to the temples, the external side of the pinnae and auricular margins.
Multiple lesions may coalesce. Pruritus is variable, generally mild to moderate, and
usually no fever or loss of appetite is observed [DeBoer and Moriello, 2006; Chermette et
al. 2008].
In some cats, dermatophytosis can present as a papulo-crustous dermatitis (“miliary
dermatitis”) affecting mainly the dorsal trunk.
In immunosuppressed cats, extensive lesions with secondary bacterial involvement are
sometimes associated with chronic ringworm. Such patients demonstrate atypical, large
alopecic areas, erythema, pruritus, exudation and crusts. At this stage, dermatophytosis
may mimic other dermatological conditions. Typical signs may be still visible at the
margins of the lesions [Chermette et al. 2008].
A rare outcome of dermatophyte infection in cats is onyxis and perionyxis, and
exceptionally nodular granulomatous dermatitis (pseudomycetoma) with single or
multiple cutaneous nodules, firm and not painful at palpation [Nuttall et al. 2008].
Fistulisation of these nodules is possible. Intraabdominal dermatophytic
pseudomycetoma occurring as abdominal mass may be a rare complication of laparotomy
in animals with cutaneous dermatophytosis [Black et al., 2001].
Diagnosis
As dermatophytosis can produce lesions similar to other feline skin diseases, it should be
suspected in all cats with any cutaneous disease. Dermatophyte diagnosis should be
undertaken before any treatment.
An inexpensive, simple screening tool for M. canis infection is the Wood’s lamp
examination. However, it is not very sensitive: only about 50% of M. canis strains
fluoresce and other dermatophytes do not at all [Sparkes et al, 1994c]. Furthermore,
debris, scale, lint and topical medications (e.g. tetracycline) can fluoresce and produce
false positive results. For these reasons, Wood’s lamp findings should be confirmed by
direct examination of hairs and/or culture.
Microscopic examination is another simple and rapid method to detect dermatophytes on
hairs or scales. It is recommended to pluck affected hairs under Wood’s lamp
illumination, or from the edge of a lesion. The sample should be cleared with 10-20%
KOH before examination. There are techniques to improve the visualization of fungal
elements on the hair shafts [DeBoer and Moriello, 2006]. Hairs or hair fragments with
hyphae and ectothrix arthrospores are thicker, with a rough and irregular surface.
However, direct microscopic examination may give false positive results, especially if
saprophytic fungal spores are present, or debris is interpreted as fungal elements. Also,
the sensitivity of this technique is only 59% [Sparkes et al, 1993a]; higher sensitivity
(76%) has been achieved by fluorescence microscopy with calcafluor white [Sparkes et
al. 1994c].
Culture on Sabouraud dextrose agar or other media is the gold standard for the detection
of dermatophytes. This method is very sensitive and can determine the species. Samples
(hairs, scales) should be collected from the margin of new lesions after gently swabbing
with alcohol to reduce contamination. If a subclinical infection or passive carriage is
suspected, brushing during 5 minutes with a sterile brush is the best method for
collecting sample material. A brand-new toothbrush is mycologically sterile [DeBoer and
Moriello, 2006]. Several in-office dermatophyte test media showing a colour change
when positive are available and used by practitioners. However, few attempts have been
made to evaluate their performance with veterinary samples [Chermette et al., 2008].
Therefore, suspect colonies must be examined microscopically to confirm presence of a
fungus [DeBoer and Moriello, 2006]. The rapidity of colour change is related to the
incubation temperature and to the number of infected hairs deposited onto the
dermatophyte test medium [Guillot et al. 2001].
PCR has been proposed for the detection of M. canis sequences in suspected material
from animals [Nardoni et al, 2007].
Therapy and disease management
In immunocompetent cats kept under hygienic conditions, isolated lesions disappear
spontaneously after 1-3 months and may not require medication. However, treatment of
such cases will shorten the disease course as well as the risk for other animals and
humans, and of contamination of the environment.
Topical treatment is less effective in cats compared to humans due to poor penetration of
the medicines through the hair coat, lack of tolerance by many cats and the possible
existence of unnoticed small lesions. Thus, therapeutic measures should include a
combination of systemic and topical treatment, maintained for at least 10 weeks.
Generally, cats should be treated not only until the lesions have disappeared, but until
the dermatophyte can no longer be cultured from the hairs on two sequential brushings
1-3 weeks apart.
In catteries and shelters, dermatophyte infection is difficult to eradicate, time-consuming
and expensive. Good compliance with the owner is therefore essential. A treatment
program is necessary, together with complete separation of infected and uninfected
animals, intensive decontamination of the environment and sometimes even interruption
of breeding programs and shows. All animals in the same cattery should be treated . A
far less preferable alternative is to divide the cats into groups and treat according to the
infection status. Special hygiene measures should be taken when handling infected
animals in order to prevent infection of humans (gloves, disinfection of cat scratches or
any other injury).
Topical therapy
In cats with few lesions, hairs should be clipped away from the periphery of lesions
including a wide margin. Clipping should be gentle to avoid spreading the infection due to
microtrauma and mechanical spread of spores. Spot treatment of lesions may be of
limited efficacy; instead, whole-body shampooing, dipping or rinsing is recommended. In
patients with generalized disease, longhaired cats and for cattery decontamination,
clipping the entire cat is useful to make topical therapy application easier and to allow for
better penetration of the drug. This approach limits also spread of the spores. The entire
hair coat, including whiskers, should be gently clipped and all infected hairs should be
wrapped and disinfected before disposal. Chemical or heat sterilization of instruments is
essential. Because of environmental contamination, cats should not be clipped in
veterinary clinics; the best place is in the cat’s own household, where the environment is
already contaminated.
Topical antifungal drugs differ widely in efficacy. One of the most effective procedures is
whole body treatment with a 0.2% enilconazole solution performed twice weekly [DeBoer
and Moriello, 2006]. Local or general side effects are rare provided that grooming is
prevented (Elizabethan collar) until the cat is dry [Hnilica and Medleau, 2002]. Very
effective is also 2% miconazole with or without 2% chlorhexidine as a twice weekly body
rinse or shampoo [Moriello, 2004]. In the USA, lime-sulphur solution is commonly used
[DeBoer and Moriello, 2006].
Systemic therapy
Griseofulvin
In some countries, the fungistatic drug griseofulvin is still used. It is administered orally
for at least 4-6 weeks at 25-50 mg/kg twice daily. It is the classical drug for the systemic
treatment of dermatophytosis [Hill et al. 1995; Foil, 2005]. Griseofulvin is poorly watersoluble; a micronised formulation and administration with fatty meals enhance
absorption. Adverse reactions include anorexia, vomiting, diarrhoea, and bone marrow
suppression, particularly in Siamese, Himalayan and Abyssinian cats. The use of
griseofulvin is contraindicated in kittens younger than 6 weeks of age and in pregnant
animals, as the compound is teratogenic, particularly during the first weeks of gestation.
There are reports suggesting that FIV infection predisposes cats to griseofulvin-induced
bone marrow suppression [Shelton et al. 1990]. Therefore, cats should be tested for FIV
infection prior to griseofulvin therapy. If griseofulvin therapy is chosen, monthly CBCs
should be carried out to detect a possible bone marrow suppression.
Ketoconazole
An alternative to griseofulvin is the fungistatic drug ketoconazole administered orally
2.5–5 mg/kg twice daily [Medleau and Chalmers, 1993]. However, cats are relative
susceptible to secondary effects of this drug which include liver toxicity, anorexia,
vomiting, diarrhoea, and suppression of steroid hormones synthesis. Ketoconazole is also
contraindicated in pregnant animals.
Itraconazole
Though relatively expensive, itraconazole is currently the drug of choice in feline
dermatophytosis [DeBoer and Moriello, 2006]. It is comparable - or superior - in efficacy
to griseofulvin or ketoconazole and is much better tolerated [Moriello, 2004]. The only
adverse reaction occasionally reported was anorexia. Also, the embryotoxicity and
teratogenicity of itraconazole seems to be lower than that of ketoconazole. Nevertheless,
its administration in pregnancy is not recommended [Van Cauteren et al, 1987]. Use in
kittens as young as 6 weeks is possible [DeBoer and Moriello 2006]. Most veterinary
dermatologists will use itraconazole as so-called pulse therapy, which is also suggested
by the manufacturer. This protocol is effective and also reduces the cost of treatment. A
pulse administration of 5 mg/kg/day for one week, every two weeks for 6 weeks has
been suggested [Colombo et al, 2001]. Another study demonstrated that there were
sufficient levels of itraconazole or its metabolite hydroxyitraconazole in the plasma and
the fur of cats with ringworm that had been given three cycles consisting of one week
with treatment (5 mg/kg) and one week without. A 25/30% reduction in levels was
observed after the week without treatment, but the concentrations were still high enough
even two weeks after the last administration [Vlaminck & Engelen, 2004]. These data
illustrate that such a treatment schedule (3 x 7 days of dosing) provides actual coverage
for at least 7 weeks.
Terbinafine
Few data are available concerning the use of the fungicidal drug terbinafine in feline
dermatophytosis [DeBoer and Moriello, 2006]; one report demonstrated its efficacy
[Mancianti et al, 1999] and the dosage of 30-40 mg/kg daily has been suggested
[Kotnik, 2002].
Lufenuron
Lufenuron is a chitin synthesis inhibitor, commonly used for the prevention of flea
infestations in dogs and cats. As chitin is also a component of the fungal cell wall, an
antifungal activity has been suggested [Ben-Ziony and Arzy 2000]. However, no
antifungal effect in cats could be demonstrated in other studies [Guillot et al. 2002,
DeBoer et al. 2003, Mancianti et al. 2009] and lufenuron is not recommended for the
treatment of dermatophytosis [Moriello, 2004].
Other options
In cattle and fur-bearing animals, immunotherapy with anti-dermatophyte vaccines is
believed to reduce the lesions and to accelerate their disappearance [Lund and DeBoer
2008]. Although the therapeutic use of anti-M.canis vaccines has been proposed for cats,
controlled studies demonstrating efficacy of this procedure in cats are hard to find.
Environmental decontamination
Thorough vacuuming and mechanical cleaning is essential to remove infectious material
(no hairs should be visible), especially in households with one or a few cats where
disinfection is impractical and unnecessary. However, in catteries or shelters, disinfection
is important. Most disinfectants labelled as “antifungal” are fungicidal against mycelial
forms of the dermatophyte or macroconidia, but not against arthrospores. Most efficient
against arthrospores are 1:33 lime-sulphur, 0.2% enilconazole, and 1:10 to 1:100
household chlorine bleach [Rycroft and McLay, 1991, DeBoer and Moriello, 2006]. All
surfaces should be mopped with one of these solutions. An enilconazole smoke fumigant
formulation is available in many European countries.
Detailed decontamination procedures as well as the management of infected catteries
and shelters during treatment have been described [DeBoer and Moriello, 2006, Carlotti
et al, 2009].
Vaccination
Although considerable success has been achieved in prophylactic or therapeutic use of
anti-dermatophyte vaccines in cattle and fur-bearing animals, a safe and efficient vaccine
for cats is still lacking [Chermette et al. 2008, Lund and DeBoer 2008].
Only a few efficacy studies on anti-M. canis vaccines (prophylactic or therapeutic) for
cats have been performed and published.
A killed M. canis-cell wall vaccine induced both humoral and cell-mediated immunity in
experimental cats; however, these responses did not protect cats against challenge
[DeBoer and Moriello 1994]. Similarly, M. canis antigens combined with a live
Trichophyton vaccine did not protect against a topical challenge exposure with M. canis
[DeBoer et al. 2002]. Both M. canis recombinant 31.5 kDa keratinase and a M. canis
crude exo-antigen induced high antibody responses and cellular immunity against each of
these antigens in a guinea pig model. [Descamps et al. 2003]. However, these responses
did not protect cats against challenge exposure.
A vaccine consisting of killed M. canis components in adjuvant was licensed in the USA
for feline use. However, in experimental cats, this vaccine did not prevent the
establishment of a challenge infection and did not provide a more rapid cure of an
established infection in vaccinated cats compared to unvaccinated controls [DeBoer et al.
2002]. The product was withdrawn from the market by the manufacturer in 2003
[DeBoer and Moriello 2006].
A commercially developed inactivated M. canis preparation in aluminium hydroxide
adjuvant was tested for prophylactic efficacy in 13 cats [Rybnikář et al. 1997]. Following
two vaccinations, cats developed only minute skin changes at the spore application site,
consisting of scaling and papules, with the skin returning to normal at 28 days postchallenge or less, and fungal cultures were negative at that time. In contrast,
unvaccinated controls developed more severe lesions, which were still present and all
animals were culture positive at day 28. This product has now been replaced on the
market by a preparation that does not contain an adjuvant and hence may or may not
have the same properties [Lund and DeBoer 2008]. Although the manufacturer claims
protection when used prophylactically and a shorter disease course when used in sick
animals, additional data have not been published.
Results of a placebo-controlled-double-blind study performed on 55 cats with severe
dermatophytosis caused by Microsporum canis or Trichophyton mentagrophytes have
recently been published [Westhoff et al. 2010]. An inactivated vaccine containing
antigens of M. canis, M. canis var. distortum, M. canis var. obesum, M. gypseum and T.
mentagrophytes was given three times intramuscularly to sick animals. A trend of
improvement in all cats following therapeutic vaccination has been observed, although it
was not significantly different from that in the placebo treated cats.
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