1. Definitions
Great confusion exists in the terminology used to describe feline eosinophilic skin diseases (ESD). Based on our current understanding of these diseases, new definitions cannot be proposed, however, as definitions are always a good place to start, the following use of the "standard" terminology is proposed (and it will be herein adopted):
The use of the terms eosinophilic plaque (EP), eosinophilic granuloma (EG) and indolent ulcer (IU) should be probably avoided both clinically and histopathologically. These definitions, in fact, represent an inconsistent mixture of clinical and histological terms and they do not exactly define either the clinical or the histopathological aspects of the lesions.
Clinically, lesions should be described as they appear, namely as firm, raised papules and/or, less commonly, plaques, and as sharply demarcated ulcers.
Histological lesions, which are characterised by a perivascular-to-interstitial-to-diffuse predominantly eosinophilic dermal infiltrate, normally with flame figures formation, might be resumed as eosinophilic dermatitis (ED).
The term eosinophilic granuloma complex (EGC) is appropriate to define the clinical-pathological combination of indurate papules-plaques or ulcers with features of ED, normally associated with flame figures. It has been recently proposed to define EGC, together with other feline skin diseases with different clinical appearance and similar histopathological findings, as ESD. However, the delineation of EGC should not be blurred by making eosinophils the central diagnostic criterion and by disregarding the clinical features.
2. Etiopathogenesis of EGC
EGC has been attributed, although not definitely proven, to hypersensitivity reactions to arthropod, food and environmental allergens. Moreover, over the last two decades, several other causes have been proposed for EGC, besides allergic diseases, including viral and bacterial infections, chronic trauma and autoimmune reactions. However, EGC in most cases remains idiopathic.
EGC is commonly reported as a muco-cutaneous reaction pattern triggered by different factors rather than as a specific disease. Nevertheless, it has a distinct clinical-pathological appearance, despite the unknown aetiology, and it therefore deserves to be considered a disease complex in its own right.
The clinical-pathological features of EGC suggest a Th2-mediated delayed type-hypersensitivity against persisting antigens, probably of arthropod origin, in the skin. However, the initial antigenic stimulus that induces massive eosinophil recruitment and degranulation remains unknown.
A study on a closed breeding colony of interrelated specific pathogen-free cats with high incidence of both EG and IU and lack of detectable underlying disorders leaded to the hypothesis of a genetic heritable eosinophil dysregulation predisposing to the development of these lesions. However, the waxing and waning course of the lesions, with spring and summer seasonality, suggests also the presence of possible unrecognised precipitating events. A genetic predisposition would help to explain why only a few cats develop EGC lesions whereas some of the hypothesised underlying stimuli are so largely distributed.
It has been recently hypothesised that the Felis domesticus allergen I (Feld I), the cat allergen contained in feline saliva and hair, might autosensitise cats and contribute to the pathogenesis of EGC. However, this mechanism would explain only pruritic lesions of EGC with self-induced trauma, in fact Feld I needs to penetrate the skin to represent an allergenic stimulus. Moreover, 48 hours after the application of Feld I on the skin surface, eosinophils were lacking in the inflammatory infiltrate.
3. Clinical features of EGC
EGC occurs, in the papular form, as variably alopecic, erythematous, firm (solid oedema), flat-topped, sometimes yellowish, papules and plaques. Single lesions may be located anywhere on the body, including the lower lip and the oral cavity whereas coalescing lesions usually occur on the ventral abdomen, the inguinal region and the inner thighs (ex-EP). When they occur on the caudal thighs or, less commonly, on the lateral trunk they may assume a peculiar (and unexplained) linear configuration (ex-EG). Regional lymphadenopathy is common. EGC may also appear, in the ulcerative form, as reddish-brown to yellowish, glistening, non-bleeding, ulcerated lesions (ex-IU) most commonly occurring on the midline of the upper lip or adjacent to the upper canine tooth.
The ulcerative form of EGC is usually painless and non-pruritic, whereas in the papular form pruritus is variable, from absent to intense, and in this latter case erosions are common. The intense licking showed by some cats with EGC has been interpreted as a clinical sign of pruritus, however, a sensation of burning or pain may not be ruled out. It is worth reminding that self-induced erosions and ulcers are not synonyms of EGC. Why some lesions do not cause any discomfort to the cat whereas others seem to be very pruritic and/or painful remains to be explained.
The course of EGC varies from persistent to recurrent with temporary or definitive self- or treatment-induced-cure. Skin lesions may be insidious in onset and they are identified only when cat's discomfort becomes manifest, especially in the pruritic papular form.
4. Histopathological features of EGC
EGC is characterised histopathologically by epidermal hyperplasia with variable degrees of spongiosis and eosinophilic exocytosis, erosions and/or ulcerations. Necrotising mural eosinophilic folliculitis, furunculosis and/or free dermal hair shafts may be occasionally observed. ED with variable numbers of histiocytes, mast cells and lymphocytes is the histological hallmark. Distinctive dermal deposits of an amorphous to granular eosinophilic debris, the so-called flame figures, both in the form of small depositions and/or in the form of sharply delineated large foci are the common feature of these diseases. In recent lesions flame figures might not be observed, nevertheless, in naturally occurring disease, by the time the biopsy is taken, flame figures are usually present. In presumably older lesions the eosinophil number is reduced, macrophages and multinucleate cells form a palisade around flame figures.
Preliminary electron microscopy studies of skin sections from EGC lesions have shown that feline flame figures are constituted by eosinophils, undergoing both cytolytic and piecemeal degranulation, around ultrastructurally unaltered collagen fibres. Oedema, with separation of collagen bundles, is prominent and macrophages with intracytoplasmic eosinophil granules have been observed. This suggests that collagen is not the target structure for damage in this disease, but it appears to be an innocent bystander, entrapped in the middle of eosinophil granule products and that eosinophil recruitment and degranulation represent the primary event. Moreover, the poor soluble eosinophil cationic proteins presumably provoke the granulomatous reaction around flame figures.
The terms "collagen degeneration" and "collagenolysis" should be therefore avoided to describe histologically flame figures. Moreover, "collagen degeneration" does not obviously represent the cause of the yellowish colour that often characterises clinically EGC, despite what historically assumed.
5. Diagnostic-therapeutic work up of EGC
If EGC is included in the list of differential diagnoses, the following basic diagnostic procedures must be performed:
Skin scrapings and microscopic examination of hairs, scales and cerumen to rule out the presence of mites. The decision to perform dermatophyte culture is taken on individual basis.
Cytological examination of samples obtained by surface impression from eroded-ulcerated lesions and/or by fine needle (23 G) (without aspiration) from papules and/or plaques. Together with eosinophils, variably degenerated neutrophils and intra- and/or extra-cellular bacteria may be observed, especially in impression smears from eroded-ulcerated lesions.
Cutaneous biopsies for histopathological examination.
During anaesthesia for skin biopsy, it might be useful to take blood samples to perform a CBC. Peripheral eosinophilia may be present especially if lesions are of recent onset. The decision to perform bacterial/fungal cultures (from tissue samples), FeLV/FIV testing, biochemistry profile and urinalysis is taken on individual basis.
Once the diagnosis of EGC has been confirmed, based on the clinical-pathological findings, we start the long "non-evidence based" therapeutic trials with:
Simultaneous or sequential treatment with a systemic endectocide and flea control (other pets in contact with the patient must be also treated).
Systemic antibiotics (amoxicillin-clavulanic acid, cefalexin, enrofloxacin) might be prescribed for 3 to 4 weeks especially in case of eroded-ulcerated lesions, when cat's discomfort is serious.
If improvement is observed: maintain flea control and.... wait and see what happens! During the diagnostic-therapeutic work up of EGC we need to always keep in mind that lesions may spontaneously resolve, temporarily or definitely, and that cats "do as they like", independently of our diagnostic-therapeutic efforts!
If no improvement is observed, systemic glucocorticoids may be administered. Prednisone/prednisolone (1-2 mg/Kg every 12 hours) or methylprednisolone acetate (4-5 mg/Kg) are respectively given orally and subcutaneously/intramuscularly. The use of oral triamcinolone (0.5 mg/Kg of every 24 hours) or dexamethasone (0.1-0.2 mg/Kg of every 24 hours) should be reserved for refractory cases.
If lesions improve but frequently relapse or if they do not respond to the above cited treatments, it must be decided if performing an allergic work up or trying pharmacological treatments "alternative" to glucocorticoids. Both ways are quite far from evidence-based dermatology! Before taking a decision we need to consider:
The risk of inducing iatrogenic Cushing's disease
Cat's discomfort
Cat's compliance in taking oral medications
Owner's compliance
Owner's discomfort
The allergic work up may be limited to food trial or it may include allergy testing followed by specific hyposensitisation therapy. After the eventual remission with the privative diet, it is mandatory to re-challenge the cat with the original diet, in fact many cats have been reported not to recrudesce on re-challenge.
Two groups of "alternative" therapies, most of which have been tried in small numbers of cases, only in prospective studies or have been empirically / anecdotally reported as effective, are available.
The first group of "alternative" treatments includes antihistamines and essential fatty acids. These drugs have few reported potential side effects but also few possibilities to work in case of lack of therapeutic efficacy of glucocorticoids.
The second group of "alternative" treatments includes, among others, the following immunomodulatory drugs (CBC, chemistry profile and urinalysis should be periodically checked during therapy):
Cyclosporine A. It is given orally (5-10 mg/Kg every 24 hours) for 4 to 8 weeks then tapered to alternate days. Cyclosporine A is a promising drug to treat EGC, due to its demonstrated ability to inhibit airway eosinophilic inflammation in an experimentally induced feline model of atopic asthma.
Interferon alpha -2a. It may be administered orally (30-60 units/cat per day) for 30 consecutive days, or on alternate weeks. It has been demonstrated that interferon alpha inhibits the release of granule proteins from human eosinophils.
References
1. Aberer, W., Konrad, K., Wolff, K. Wells' syndrome is a distinctive disease entity and not a histologic diagnosis. J Am Acad Dermatol 1988; 18: 105-114.
2. Egesten, A., Calafat, J., Janssen, H. et al. Granules of human eosinophilic leukocytes and their mobilization. Clin Exp Allergy 2001; 31: 1173-1188.
3. Fondati, A., Fondevila, D., Ferrer, L. Histopathological study of feline eosinophilic dermatoses. Vet Derm 2001; 12: 333-338.
4. Leiferman, K. M. Cutaneous eosinophilic diseases. In: Fitzpatrick's dermatology in general medicine. 5th ed. New York: McGraw-Hill, 1999: 1129-1137.
5. Meeusen, E. N. T. Immunology of helminth infections, with special reference to immunopathology. Vet Parasitol 1999; 84: 259-273.
6. Power, H. T., Ihrke, P. J. Selected feline eosinophilic skin diseases. Vet Clin North Am Small Animal Practice 1995; 25 (4): 833-850.
7. Rosenkrantz, W. S. Feline eosinophilic granuloma complex. In: Current Veterinary Dermatology. The science and art of therapy. Griffin, C. E., Kwochka, K. W., Macdonald J. M., eds. St. Louis: Mosby-Year Book, 1993: 319-324.
8. Wisselink, M. A., van Ree, R., Willemse, T. Evaluation of Felis domesticus allergen I as a possible autoallergen in cats with eosinophilic granuloma complex. Am J Vet Res 2002; 63: 338-341.