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]. 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