Diagnostic approach to the pruritic cat Dr Amanda Burrows FANZCVS Animal Dermatology Clinic, Perth Murdoch University, Western Australia

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1 Diagnostic approach to the pruritic cat Dr Amanda Burrows FANZCVS Animal Dermatology Clinic, Perth Murdoch University, Western Australia Introduction Why diagnose? Just let s treat Although it may be tempting to just employ a drug marketed for the treatment of pruritus, there are two main reasons why this is very bad practice: (a) this will not cure the disease, and (b) there is no such thing as a drug without side-effects. So the goal must be to define the cause of the disease as precisely as possible and then to apply treatment tailored to the condition. How do cats manifest pruritus? Cats tend to respond to pruritic stimuli predominantly by licking and rubbing and to a lesser extent scratching. But cats that do scratch tend to induce severe excoriations. The cat has rather typical reaction patterns of miliary dermatitis, self-induced alopecia (either symmetrical or largely ventral), head and neck pruritus, and the eosinophilic granuloma complex (eosinophilic plaques, indolent ulcers and linear (collagenolytic) granulomas) associated with pruritic diseases. 1. Miliary dermatitis Miliary dermatitis is characterised by small, erythematous, crusted papules that are usually nonfollicular in distribution. These are most commonly located on the dorsum but can be anywhere. Miliary dermatitis is not a diagnosis but rather a descriptive term. The differential diagnosis is extensive; the most common being allergies, ectoparasites and infections. Immune mediated diseases such as pemphigus foliaceus may occasionally mimic a miliary dermatitis. 2. Self-induced, symmetrical non-inflammatory alopecia Non-inflammatory alopecia is used to describe an acquired syndrome of multifactorial aetiology resulting in loss of hair over the perineum, proximal ventral and ventro-lateral tail, hind limbs, ventrum, lateral abdomen and distal forelimbs and on rare occasions extends to the lateral thorax. The dorsum is not usually affected and the skin does not appear inflamed. Feline non-inflammatory alopecia may be self-inflicted from licking, biting or pulling the hair as a result of pruritic dermatoses or conditions causing psychogenic disturbances or it may result from spontaneous hair loss due to either epilation of hair or hair shaft fracture. It is critical when presented with this reaction pattern to think about whether the cat is licking the hair out or whether it is falling out. Many owners will think the hair is falling out. Most, if not all, such cases are the result of pruritus or self-trauma due to an underlying problem, and are not related to sex steroids or other hormones. If there is any doubt, perform a trichogram (examine some plucked hairs under the microscope). 3. Eosinophilic dermatoses (Eosinophilic granuloma complex) This is not a specific disease but a reaction pattern which includes a group of disorders affecting

2 both skin and mucous membranes subdivided into eosinophilic ulcer, eosinophilic plaque and eosinophilic (collagenolytic/linear granuloma). 4. Erosive and crusting dermatosis of the face and neck These cases are usually markedly pruritic around the head and neck resulting is alopecia, excoriations and ulceration. There are often severe lesions on the cheeks. It has been suggested that pruritus restricted to the back of the neck may also be due to herpes virus infection of nerve endings following vaccination. Causes of pruritus Causes of pruritus are often classified into primary diseases, able to cause pruritus directly or secondary causes, which are diseases (usually infections) that occur as a consequence of the damage to the skin caused by a primary disease. The diagnosis of chronic pruritus can be complicated by the common occurrence of multiple causes of pruritus being present in the same cat. The possibility of several coexisting primary and/or secondary pruritic diseases should thus be considered. Often a variety of therapeutic or diagnostic trials are indicated to determine the cause of the clinical signs in cats with pruritus. Table 1: Common causes of pruritus in the cat Mechanism Ectoparasites Allergic skin disease Infectious organisms Neoplasia Immune-mediated Psychogenic Aetiological Agent or Disease Notoedres cati Cheyletiella Demodex spp. Otodectes cynotis Sarcoptes scabiei Flea bite hypersensitivity Food hypersensitivity Atopic dermatitis Superficial pyoderma Dermatophytes Malassezia dermatitis Mast cell tumour Epitheliotropic lymphoma Pemphigus foliaceus Cutaneous drug eruptions Diagnostic approach The clinician must decide whether the cat is truly pruritic or if the cat is exhibiting a stereotypic behaviour pattern of excessive grooming (psychogenic dermatitis). The latter condition is rare. Though we can identify several specific causes of pruritus in the cat, bear in mind that in any individual cat the clinical picture may represent a combination of several different aspects. This combination may include both pruritic and behavioural aspects in some cases. The approach to the diagnosis of pruritus is best logically approached by posing a number of

3 diagnostic questions. The clinician will use the information derived from the history and the signalment to rank the likelihood of each of these differential diagnoses. A number of very straightforward in-house diagnostic tests can be used to assist in answering most of the following questions. Step 1. Does this cat have a mite infestation? A coat combing and multiple superficial and deep skin scrapings should be performed to evaluate for ectoparasites (e.g. fleas, Demodex, Cheyletiella, Otodectes, Notoedres and Sarcoptes species). If the tests are positive, the cat should be treated for the specific disease identified. Otitis or pruritus involving the head in any animal is a clear indication for performing an ear smear. This technique is used primarily to find Otodectes cynotis and other species of ear mites. Occasionally Demodex mites may be found in cats. Step 2: Does this cat have a dermatophyte infection? A Wood s lamp examination should be performed. When present, fluorescent hairs should be plucked for fungal culture. If the Wood s lamp examination is negative then a sample should be obtained with a toothbrush and submitted for fungal culture. Step 3. Does this cat have a bacterial or yeast infection? Superficial pyoderma is underdiagnosed in cats. Cutaneous lesions associated with feline superficial pyoderma are most commonly crusted papules, crusts, alopecia, erythema and ulceration/excoriation affecting the face, neck, limbs and ventral abdomen most frequently. Eosinophilic granuloma complex lesions (ulcers, eosinphilic plaques) often have large numbers (moderate to abundant) of intracellular bacteria evident in surface cytology, further supporting the association between eosinophilic granuloma complex lesions and superficial pyoderma. Clinical presentation of feline superficial pyoderma is not readily distinguishable from other feline dermatoses, highlighting the importance of skin surface cytology for diagnosis. Malassezia spp. overgrowth in cats is reported as a marker of serious, underlying diseases, including retrovirus infection and neoplasia. However, feline Malassezia overgrowth is also associated with allergic skin diseases in healthy cats. Cats with Malassezia otitis externa present with pruritus and head shaking and scratching, with accumulation of brown to black exudate and/or cerumen in the external ear canals and mild to moderate inflammation. As in dogs, relapsing infection is common when predisposing factors are not identified or corrected. So where are we up to? Cytology of the skin and external ear canal is the most important test used to determine the presence of bacterial pyoderma and bacterial overgrowth and Malassezia dermatitis. Once these infections are identified they should be treated and eliminated. A thorough diagnostic approach is then indicated to determine the presence of allergies and of secondary and modulating factors that may contribute to the cat s clinical signs. This requires a systematic process. At this stage, I like to determine if fleas are playing a role as a trigger factor in the overall picture. Flea infestation can be overlooked because the fleas are ingested when the cat is pruritic and overgrooming

4 Step 4: Has the cat got flea allergy dermatitis (FAD)? Flea allergy is simply another dose dependent hypersensitivity contingent on the dosage of antigen (flea salivary proteins) injected into the host. The severity of flea allergy is dependent on the magnitude of hypersensitivity elicited in that animal, the number of fleas successfully feeding, plus the amount of antigen injected by fleas during feeding. Since rapid flea kill will reduce antigen access, products that shorten the blood meal duration should diminish antigen access (flea saliva injection) more effectively. In a multi-centre European study of 502 pruritic cats, 29% were diagnosed with flea allergy, while 12% were diagnosed with food allergy and 20% were atopic. All four reaction patterns were identified. Thirty five percent of cats with flea bite allergy presented with miliary dermatitis; 39% with symmetrical, non-inflammatory alopecia and 38% with head and neck excoriations. Eosinophilic granuloma complex (EGC) lesions can occur alone or in combination with other reaction patterns. Fourteen percent of cats with FAD presented with EGC lesions compared to 25% and 26% of food allergic and atopic cats respectively. Twenty five percent of cats with flea allergic cats presented with a combination of reaction patterns. History Acute onset Seasonal Age of onset: no age predilection Response to corticosteroids: good Clinical Lesion Pruritus (overgrooming) Miliary dermatitis (small crusted papules, alopecia, excoriations, crusting, scaling) Symmetrical alopecia Eosinophilic granuloma complex lesions Distribution Dorsal lumbosacral area Tail base Caudomedial thighs Ventral abdomen and flank Head, neck, forelimbs Diagnosis Flea comb: evaluate detritus collected for flea excreta, eggs and fleas. Place debris on a white background, e.g. gauze swab and moisten the flea excreta with water. Blood will leach from flea faeces resulting in a characteristic red-brown staining of the gauze swab. A negative result on flea combing for fleas or flea excreta does not rule out a diagnosis of FAD. Cytology: express a papule to extrude the contents; in FAD, early lesions show a predominance of eosinophils (occasionally basophils) but more chronic lesions are neutrophilic. An eosinophilic papule without bacteria is strongly suggestive of FAD.

5 Flea control trial Nitenpyram (Capstar ) 1mg/kg PO q 24hrs Spinosad (Comfortis ) 50 to 100mg/kg q 14 days Topical indoxacarb (Activyl ) q 14 days Fluralaner (Bravecto for Cats ) q 14 days Assess at Week 6 to 8 The time taken for clinical improvement depends on the severity and chronicity of the disease, the degree of hypersensitivity and the magnitude of the flea challenge. As a general rule the response (or lack thereof) of a therapeutic trial is assessed at the end of four to six weeks but depending on the severity of the disease, it can take up to eight to twelve weeks for these cats to recover. So where are we up to? At this stage the cat is likely to leave hospital with flea control, with or without antimicrobial therapy. If pruritus is moderate to severe then it is likely that you will prescribe a short course of anti-pruritic drug therapy, such as prednisolone. It is important that you explain to the owner that this is a short-term strategy to mask itch and as these drugs is tapered and withdrawn, the itch will recur if the trigger for the pruritus has not been identified. Then it means a more extensive allergy investigation will need to be undertaken, and this may or may not necessitate referral to a dermatologist. The other useful strategy is to make sure that you schedule a follow-up communication from your practice in four to six weeks so you can determine which patients have relapsed and require further attention, rather than waiting for the owner to contact you and tell you that nothing worked. What is next? In cats that have either failed to improve with a flea therapeutic trial and antibiotics and/or relapsed with the tapering or withdrawal of the corticosteroid therapy, we need to institute an elimination diet. Step 5. Does this cat have a food allergy? The most common clinical sign of adverse food reaction in cats is a moderate to severe, nonseasonal, constant pruritus. Cats with food allergy are often clinically indistinguishable from cats with environmental allergies. History Non seasonal, constant, moderate to severe pruritus Not associated with a diet change Age of onset: wide age range: 6 months to 11 years Breed predilection: no breed predilection although Siamese may be overrepresented Sex predilection: nil Response to corticosteroids: variable Clinical: cats Lesions

6 Miliary reaction pattern accompanied by varying erythema, alopecia, erosions and crusting. Non inflammatory, self-induced alopecia Eosinophilic granuloma complex lesions (eosinophilic ulcer and eosinophilic plaques). Malassezia otitis externa Distribution Head and neck including the preauricular, pinnae and periorbital regions Other clinical signs Gastrointestinal tract: vomiting, diarrhea and lymphoplasmacytic colitis Diagnosis Feed a novel home prepared protein and carbohydrate or commercial hydrolysate diet for 8 weeks. A home prepared novel source of protein and carbohydrate is the gold standard for the diagnosis of adverse food reactions. Confirm the diagnosis by demonstrating that the clinical signs recur when feeding a test meal of the cat s previous diet; most dogs relapse within 24 to 72 hours. Do a sequential rechallenge with multiple food sources: feed each of the major food items from the original diet by adding one pure food ingredient to the restrictive diet to determine which individual allergen or allergens is incriminated. What is next? If we have ruled out all of the conditions noted above or if there is only a partial response to a restriction diet, then a diagnosis of atopic dermatitis should be considered. Step 6. Does this cat have feline atopic dermatitis? History Breed: no breed predisposition Age of onset: no age predisposition Response to corticosteroids: good Clinical: Cats Lesions Pruritus Erythema Alopecia, scaling, crusting, hyperpigmentation, excoriations, erosions Non inflammatory, self-induced alopecia Eosinophilic granuloma complex lesions Malassezia otitis externa Distribution Head and neck including the preauricular, pinnae and periorbital regions; limbs (not paws) Diagnosis These clinical reaction patterns are not specific for any particular group of allergens and the final diagnosis of is based on exclusion of other pruritic skin diseases. At this point the clinician has two

7 options: either symptomatic treatment or allergy testing. Which route is taken depends in a number of factors including the severity of the pruritus, age of the cat, financial considerations and what the owner wishes for their pet. In some cases, symptomatic treatment may be recommended at the beginning and then allergy testing performed at some point in the future. Allergy testing Two methods of allergy testing are routinely available for the further investigation of feline atopic dermatitis: intradermal allergy testing (IDAT) and serum in vitro testing (SIVT). The test result is only meaningful if the cat has clinical signs consistent with atopic dermatitis and all other pruritic diseases have been ruled out. They are useful tests if owners wish to consider immunotherapy as a management strategy for the cat with chronic allergic dermatitis. Allergy testing is recommended after a clinical diagnosis of environmental allergies is confirmed in cats where ASIT is indicated and reduction in pharmacotherapy is desirable in a cat with a compliant temperament and a motivated client. Intradermal allergy testing (IDAT) A variety of companies manufacture allergens for IDAT however most dermatologists currently utilise allergens from Greer Laboratories (Lenoir, NC, USA) and dilute according to the manufacturer s recommendations with a final allergen concentration of between 1000 and 1800 PNU/ml (protein nitrogen units/ml) for dogs. There is some evidence that the diagnostic value of intradermal allergy testing for cats improves when higher concentrations of allergens are used; between 6000 and 8000 PNU/ml and when intravenous fluorescein and a Wood s lamp are used to interpret the test reactions. Most veterinary dermatologists test for reactivity against the following antigens: house dust mite and storage mite antigens (Dermatophagoides farinae, Dermatophagoides pteronyssinus, Acarus siro, Tyrophagus putrescantiae); insect body parts/faecal elements (cockroach, moth, ant, houseflies); pollens (from trees, weeds and grasses); moulds (from the household or from crops) and Malassezia. The inclusion of regional allergens (pollens) in the testing kit is based on knowledge of the plants in a particular geographical location. The intradermal allergy test is interpreted by correlating the positive reactions with the patient s history. Clinically relevant reactions can then be used to choose allergens for specific immunotherapy. Intradermal testing is best performed with the cat under sedation in lateral recumbency. Medetomidine (Domitor ) at a dose of 70mcg/kg IM is the preferred sedative. A patch of fur is clipped from the lateral thorax (15cm x 10cm) and the injection sites are marked with a black marker pen. A standard intradermal injection of 0.05mls per allergen is injected intradermally along with the positive (histamine) and negative (saline) control. The reactions are read within 5 minutes. These appear as wheals. The reactions are subjectively graded based on wheal diameter, height, turgidity and erythema and graded from zero to four. A score of zero represents a negative reaction (equivalent to the negative saline control) and a score of four represents a positive reaction that is equivalent to the positive histamine control. Immediately after the test 5mg/kg of 10% fluorescein sodium solution in injected via an intravenous catheter. The reactions are then graded using a subjective evaluation of the intensity of the dye from zero to four. After the testing was completed, sedation was reversed by injecting 0.35mg/kg IM of atipamezole.

8 A positive reaction requires functional cutaneous mast cells and the presence of allergen specific, mast cell bound, reaginic (presumed IgE) antibodies. Allergenic epitopes cause dimeric or trimeric cross-linking of IgE with resultant release pharmacologically reactive substances, such as histamine, serotonin, and various leukotrienes. An immediate reaction is mediated by histamine and neurogenic factors while histamine, prostaglandins and other vasoactive amines are involved in late phase reactions. Intradermal allergy testing 1. Inject allergen into dermis 2. Allergen binds to IgE on mast cell 3. Mast cell degranulates releasing inflammatory mediators Vasodilatation Erythema Wheal formation Reproduced with permission from Dr Peter Hill and Zoetis: Australian Veterinary Dermatology Advisory Panel Guidelines for the Diagnosis and Management of Pruritic Dogs. Allergen solutions are expensive and it would not be cost effective to offer this service unless one or two tests per week were being performed. Practitioners interested in performing this procedure should study for a further qualification in the discipline or undertake residency training Serum in vitro IgE allergy testing (SIVT) In-vitro testing simply requires a blood sample to be collected and sent off to an appropriate laboratory. The serum is assayed for allergen-specific IgE and the results are reported as relative units (the higher the score, the higher the level of IgE). The in-vitro test is interpreted by correlating the positive reactions with the patient s history. Clinically relevant reactions can then be used to choose allergens for specific immunotherapy. The diluted serum sample is added to a plate containing individual wells coated with specific antigens. The types of antigens tested are similar to those used for intradermal allergy testing but there are usually less than in a skin test. If there is any IgE in the serum that is specific for a particular antigen, it binds to it. The bound IgE is then detected by adding an enzyme-linked reagent that can bind to IgE. This is either a monoclonal antibody or a receptor for IgE molecules. A substrate is added that changes colour when it contacts the enzyme attached to the IgE reagent. The degree of colour change is proportional to the amount of IgE that is bound. The colour change is measured by an automated reader and the results are reported as a numerical score. The significance of various scores is indicated by the laboratory.

9 In-vitro measurement of allergen-specific IgE Reproduced with permission from Dr Peter Hill and Zoetis: Australian Veterinary Dermatology Advisory Panel Guidelines for the Diagnosis and Management of Pruritic Dogs. A number of different commercial companies offer tests using different methodologies, such as radioallergosorbent assay (RAST) or enzyme-linked immunoassay (ELISA) that detect IgE to a variety of environmental allergens. The techniques also vary in how they bind to IgE with some using polyclonal, monoclonal or mixed monoclonal anti-ige antibodies and other the Fc Epsilon receptor. The preferred test is the Heska ALLERCEPT assay. The ALLERCEPT TM ELISA assay uses the alpha chain of the high-affinity FcεRI receptor as its detection reagent to ensure specificity for IgE. Preparation of cats for allergy testing Before either of the above tests are performed, it is important that the patient is adequately prepared. Clinicians should ensure that: Other pruritic diseases have been ruled out Anti-pruritic drugs have been withdrawn for a suitable period of time (Table 1) Table 1. Approximate withdrawal times (in weeks) for anti-pruritic drugs before allergy testing. NOTE: These times may vary for individual cats Treatment Intradermal testing In-vitro testing Methylprednisolone acetate injection Daily prednisolone Alternate day prednisolone Topical steroids (including ear and eye 1 0 drops) Antihistamines 1 0 Cyclosporin 0 0 Essential fatty acids 0 0 NOTE: Treatment with methylprednisolone, daily and every other day prednisolone, or cyclosporin for periods longer than 3 months may require longer withdrawal times Which test is better for selecting allergens for ASIT? Veterinary dermatologists are often asked which is the better test. When answering this question, it is important to remember that the tests are not measuring the same thing. In vitro tests merely measure the amount of allergen-specific IgE that is present in the blood. Intradermal allergy testing

10 detects the presence of allergen-specific IgE that is bound to mast cells in the skin. However, intradermal allergy tests also measure mast cell releasability (this can be altered in atopic dermatitis) and the response of the skin to inflammatory mediators. Intradermal allergy tests, therefore, provide a complete functional assessment of some of the pathways that are required to initiate an allergic reaction in the skin. In contrast, in vitro tests only measure one particular point in the pathway. For this reason, most veterinary dermatologists regard intradermal allergy testing as the superior test If it is not possible for a cat to undergo intradermal allergy testing (e.g. if the practice doesn t perform it, there is no local referral centre, the owner doesn t want referral), in vitro tests can be used as alternative to identify allergens for use in immunotherapy. Performance of both tests at the same time is more informative, although it may be cost prohibitive. An increase in the efficacy of the chosen immunotherapy based on the combined test results has not been confirmed in properly controlled studies. Step 7. Does this cat have psychogenic factors contributing to overgrooming? Assessing how often cats with primary pruritic skin disease develop a stereotypic component to their overgrooming as a component of the organic disease process can be challenging. In some cases the initial pruritic trigger may no longer be identifiable but overgrooming has become selfreinforcing. Some individual cats have a temperament that predisposes to this outcome. The possibility of both a pruritic and a psychogenic component, especially in cats with chronic pruritic skin disease. This may account for the partial success seen in some cases with symptomatic anti pruritic therapy. No diagnostic test can confirm a psychogenic disorder. A response to appropriate TCA or SSRI treatment, either with or without conventional anti-pruritic therapy is supportive of this clinical diagnosis. References Favrot, Claude. "Feline Non-Flea Induced Hypersensitivity Dermatitis Clinical features, diagnosis and treatment." Journal of feline medicine and surgery15.9 (2013): Hobi, Stefan, et al. "Clinical characteristics and causes of pruritus in cats: a multicentre study on feline hypersensitivity associated dermatoses."veterinary dermatology 22.5 (2011): Vogelnest LJ, Cheng KY (2013). Cutaneous adverse food reactions in cats: retrospective evaluation of 17 cases in a dermatology referral population ( ). Australian Veterinary Journal (11):