BRITISH VETERINARY DERMATOLOGY STUDY GROUP AUTUMN MEETING l NOVEMBER 2012 Feline Dermatology ...... Radisson SAS Manchester Sat 10th / Sun 11th November 2012

AUTUMN PROCEEDINGS

2012Proceedings sponsored by BRITISH VETERINARY DERMATOLOGY STUDY GROUP AUTUMN MEETING

Radisson SAS Manchester Sat 10th / Sun 11th November 2012

Sponsors

Diamond: Virbac

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Silver: Dermoscent®; made in France by LDCA and distributed in the UK by Vet Direct

The B.V.D.S.G. committee and members would like to thank our sponsors for their generosity and support of this meeting Proceedings designed and printed by Taproom Images for the British Veterinary Dermatology Study Group. Proceedings Editor: Sarah Warren BVetMed MSc (Clin. Onc.) CertVD MRCVS, Regional Veterinary Dermatologist, CVS. Mildmay Veterinary Centre, Winchester Tel: 01962 854088 Fax: 01962 870844 E: [email protected]

© British Veterinary Dermatology Study Group. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, photocopying, electronic, mechanical, recording or otherwise, without the prior permission of British Veterinary Dermatology Study Group. 1 BVDSG Autumn Meeting – November 2012 Feline Dermatology Programme Saturday 10th November 2012

MORNING SESSION

0830 - 0900 Registration

0900 - 0945 Feline reaction patterns - cats are not small dogs Craig Griffin

0945 - 1030 Fleas and other little critters: Ectoparasites in cats Craig Griffin

1030 - 1115 COFFEE AND COMMERCIAL EXHIBITION

1115 - 1245 Breed related infections and oddities in cats Ross Bond

1245 - 1400 LUNCH

AFTERNOON SESSION

1400 - 1445 Feline Mycobacterial diseases Danièlle Gunn-Moore Speaker - Kerry Simpson

1445 - 1530 Feline Cowpox Virus and Upper Respiratory Tract diseases Danièlle Gunn-Moore Speaker - Kerry Simpson

1530 - 1615 COFFEE AND COMMERCIAL EXHIBITION

1615 - 1715 AGM

1800 - 1900 Drinks, dinner from 1900

2 BVDSG Autumn Meeting – November 2012 Feline Dermatology Programme continued Sunday 11th November 2012

MORNING SESSION

0900 - 0945 Allergic skin conditions Craig Griffin

0945 - 1030 Autoimmune skin diseases Craig Griffin

1030 - 1115 COFFEE AND COMMERCIAL EXHIBITION

1115 - 1200 Feline cutaneous bacteriology and pyoderma Anita Patel

1200 - 1245 Endocrine, paraneoplastic and dermatoses related to systemic disease Craig Griffin

1245 - 1400 LUNCH

AFTERNOON SESSION

1400 - 1445 Neurology related skin diseases in the feline patient Claire Rusbridge

1445 - 1530 Abstracts

1530 - 1600 COFFEE AND COMMERCIAL EXHIBITION

1600 - 1645 Behavioural factors in feline dermatological disease Sarah Heath

3 CONTENTS

Feline reaction patterns - cats are not small dogs 5 Craig Griffin

Fleas and other little critters: Ectoparasites in cats 9 Craig Griffin

Breed related infections and oddities in cats 15 Ross Bond

Feline Mycobacterial diseases 25 Danièlle Gunn-Moore

Feline Cowpox Virus 37 Danièlle Gunn-Moore

Upper Respiratory Tract diseases 39 Danièlle Gunn-Moore

Allergic skin conditions 55 Craig Griffin

Autoimmune skin diseases 61 Craig Griffin

Feline cutaneous bacteriology and pyoderma 65 Anita Patel

Endocrine, paraneoplastic and dermatoses 73 related to systemic disease Craig Griffin

Neurology related skin diseases in the feline patient 79 Claire Rusbridge

Abstracts 85

Behavioural factors in feline dermatological disease 87 Sarah Heath

4 FELINE REACTION PATTERNS - CATS ARE NOT SMALL DOGS

Craig E. Griffin, DVM, DACVD,Animal Dermatology Clinic, San Diego, California, USA www.animaldermatology.com

A reaction pattern is the way the skin reacts to a specific insult or inflammation. This reaction pattern can occur on a gross or microscopic level. At the microscopic level this leads to the development of dermatopathologic interpretation based on pattern analysis. Each pattern is associated with a differential of common and less common causes. At the gross level this leads to clinical differentials.This is often based on the specific physical findings and the lesions that are clinically present. In cats there are a number of distinctive physical findings and lesions that can be associated with specific reaction patterns.There are also some conditions that have been given specific disease identities but are actually groups of lesions that can be associated with a variety of different diseases. Two examples of this include the eosinophilic granuloma complex and miliary dermatitis. Both have even been described as specific diseases but can consist of various types of lesions that are associated with a variety of underlying causes or specific diseases.For example, eosinophilic granuloma complex can present with three different clinical and histopathologic forms (upper lip ulcers, eosinophilic plaques and eosinophilic granulomas). This complex can be due to insect, dietary and environmental allergies, infectious agents, and genetic or hereditary factors. The hereditary mode of transmission was evaluated in a group of specific pathogen free cats.1 In this study 25 related cats with eosinophilic granuloma complex showed all forms of the disease and no underlying etiology could be detected suggesting an inherent metabolic abnormality or aberrant self-directed inflammatory response. Why these three lesions have been seen together is usually attributed to the underlying disease. However it may relate to something more basic; reaction patterns to pruritus. Another classic pattern in the cat is "barbered" alopecia which results from excessive licking.The licking can occur as a result of grooming behavior or from pruritus.This discussion will focus on barbered alopecia, eosinophilic plaques and lip ulcers which may share a similar underlying cause - pruritus and damage from the tongue - and lead to a common secondary problem, pyoderma.

BARBERED ALOPECIA

Barbered alopecia is when there is hair loss due to breaking of the hair (loss of hair length not hair growth) near the surface of the skin by licking. In some cases there may be areas with complete hair loss which reflects not just licking but the cat pulling the hair out. In these cases owners may note tufts of hair in the environment. Often the skin is not grossly inflamed though the excessive licking is still due to pruritus. Some cats will hide this grooming behavior and owners will not be aware of why the hair loss is occurring. Determining that the hair loss is from excessive licking is still simple.The skin may be rolled or folded and the margin examined for short stubbles or broken hairs which is relatively easy to visualize. It can also be detected by rubbing the skin with your fingers against the normal pattern of hair growth and feeling the broken hairs. There are two major causes of this type of alopecia. Most commonly the licking is in response to pruritus.The less common reason is the cat has developed excessive grooming behavior unrelated to any skin problem, referred to as psychogenic alopecia though the cat may also be licking due to deeper pain. An uncommon example of deep pain is when cats lick hair just off the abdomen in relation to cystitis. So the first goal in cats with barbered alopecia is to determine if the licking behavior is due to pruritus or not. One clue that indicates pruritus and not self grooming behavior is when the cat is pruritic in areas that it does not or cannot groom. In these situations the cat most likely scratches or rubs against objects. Scratching and even some rubbing may result in linear excoriations and ulcerations from the claws. Another clue is when there is inflammation in the skin. Though sometimes inflammation can result from the grooming it is associated more with pruritus. Another clue used to help is to try and determine if the cat has had other behavioral problems which raise the suspicion that the excessive grooming is also behavioral. One study of 21 cats that had been diagnosed and referred to a behaviorist for psychogenic dermatitis revealed that allergic skin disease was most often the cause.2 Food allergy was diagnosed in 12 (57%) with psychogenic dermatitis only likely in 2 cases. Once the barbered alopecia is determined to be from pruritus then allergic disease is the most likely cause with about 52% of non flea induced allergic cats likely having it.3 Though the author is not aware of any study this does not appear as common in allergic dogs. 5 LIP ULCERS

Classic feline indolent ulcers initially occur on the upper lip near the median raphe or adjacent to the canine teeth. Initially there will be erosion and only with chronicity will a proliferative tissue response develop.This is an important distinction as some cases will have a swollen lip first that later ulcerates and that is a different problem. Lip ulcers not swelling are described as an early lesion when cats are experimentally induced to develop flea allergy dermatitis.4 This occurred in 5 of 8 cases and the histopathology of the early lip ulcer was neutrophilic with bacterial "colonization" in contrast to the allergy sites that were eosinophilic.This also fits the controversy that lip ulcers can vary their histopathologic findings from suppurative, eosinophilic to granulomatous. One case was presented where flea allergy likely induced a lip ulcer that then failed to respond to numerous treatments but eventually responded completely to antibiotic therapy.5 My theory is that lip ulcers start as cheilitis from trauma induced while licking. Even some normal cats have cytologic findings from lips with neutrophils.6 The lips may look normal but microscopic damage likely occurs with normal grooming or eating.When there is excessive licking then the trauma may become much more significant and occasionally lead to cheilitis. Once the eroded inflamed lip becomes infected then a lip ulcer occurs. Not only does that stimulate a fibrous tissue response but also eosinophilia. One study did not show a significant response clinically to oral antibiotic therapy but there was a marked reduction in the number of infected fields cytologically.6 Cases were also improving and the problem is that lip ulcers take time to respond but generally are antibiotic responsive. How many lip ulcers are a form of pyoderma? Most are in my experience.

EOSINOPHILIC PLAQUE

Overzealous grooming or licking in some cats may also result in erosions or even ulcers. When erosions are induced from licking the lesions tend to be more oval or circular and may appear more in groups.When the erosions are chronic and or infected then the dermis thickens and the lesions become plaques.This is another way cats and dogs are very different. When cats develop superficial pyoderma the response often involves eosinophils.The eosinophils may even be found phagocytosing bacteria. The classic eosinophilic plaque most often represents superficial pyoderma in cats. A blinded study showed as significant a response of eosinophilic plaques to antibiotic therapy.6 However a retrospective review of superficial pyoderma in cats showed only 4 of 55 presented with eosinophilic plaques.7

FELINE PYODERMA

Pyoderma and bacterial folliculitis in the dog are considered to be very common problems yet in the cat are described as rare or very uncommon in textbooks on small animal dermatology. A study in France of 783 feline derm cases evaluated between 1992 and 1997 diagnosed pyoderma in 4.7%.8 Pyoderma does occur in cats and is not rare and similar to dogs is most often a secondary problem.5 Pyoderma plays a role in feline allergic diseases and as a secondary perpetuating factor in other skin diseases. One study showed 92% of cats with superficial pyoderma were pruritic.7 There are two reasons I believe pyoderma was not readily recognized in cats.The first is that they do not present with pustules, the classic lesion of pyoderma in the dog. Second is pyoderma may not be recognized as much in the cat because in contrast to dogs when an allergic cat with pyoderma has its allergies effectively treated the pyoderma may resolve.

Clinical presentations of feline pyoderma are quite variable.For most recognized syndromes there is no age, sex or breed predilections.The more common cases are the superficial pyoderma though occasionally a folliculitis will be found on histopathology. As discussed eosinophilic plaques and lip ulcers may represent pyoderma. Other lesions that may be seen include superficial crusts over erosions or papules, moist erythematous erosions, linear crusted erosions and ulcers, moist erythematous plaques. Linear excoriations from scratching that have widening ulcerative crusting margins are typically spreading pyoderma. Other cases develop more typical crusted papules and these cases are sometimes referred to as unresponsive cases of miliary eczema. In addition some feline acne and some eosinophilic granuloma have responded to antibiotic therapy. Another syndrome that is often frustrating to treat but has been reported doxycycline responsive is feline plasma cell pododermatitis.9 Whether this represents "pyoderma" or not has not been established.

6 The diagnosis of pyoderma is based on the demonstration of organisms and neutrophils in the cutaneous lesions.This is most often accomplished by cytological examination of direct smears from the lesions, or less commonly on histopathologic examination of representative lesions. One study evaluated blinded cytology from 9 control cats and 9 cats with eosinophilic cutaneous plaques (ECP) and 8 eosinophilic lip ulcers (ELU). Of the 9 control cats sampled, 0/180 oil immersion fields from skin were infected. Conversely 143/160 (89.4%) day 0 ECP fields from 9 cats were infected. Only 12/180 (6.7%) fields from the upper lip mucosa of control cats were infected, while 129/160 (80.6%) day 0 ELU fields from 8 cats were infected. All 9 ECP and all 8 ELU lesions showed evidence of bacterial infection in at least one field, while none of the 9 normal cats showed skin infection and 3/9 showed mucosal infection. Preferably there will be intracellular bacteria as well and occasionally intracellular bacteria may be seen in macrophages or eosinophils. Some of these cases likely reflect secondary pyoderma and may be more prevalent in cats with chronic skin diseases that have been treated with long term or repetitive glucocorticoid therapy.

Treatment is best accomplished with systemic antibiotic therapy. Therapy is more difficult than in the dog for several reasons. Many cats are more difficult to medicate and the incidence of vomiting or diarrhea is somewhat higher. Table one lists some antibiotics commonly used.

TABLE 1

Key Drug Dose Range Route/Frequency Comments Amoxicillin trihydrate/ 62.5mg/cat<7kg PO Well tolerated, bid dose clavulanate potassium 125mg/cat>7kg Q12h affects compliance Cefovecin 8mg/kg Subq Improves compliance, two Q 14 days treatments preferred Clindamycin HCL 11-22mg/kg PO Sometimes better in thick Q24h scarred lesions Doxycycline HCL 10mg/kg PO Make liquid or give Q24h water following dose Marbofloxacin 2.75-5.5mg/kg PO Preferred fluoroquinolone Q24h with lower potential retinal concerns

REFERENCES

1. Power, H. and P. Ihrke, Selected feline eosinophilic skin diseases.Vet Clin North Am Small Anim Pract, 1995. 24(4): p. 833-845. 2. Waisglass,S., et al. Evaluation of 21 cats with presumptive diagnosis of psychogenic alopecia. in Nt Am Vet Derm Forum. 2006. Palm Springs. 3. Hobi, S., et al., Clinical characteristics and causes of pruritus in cats: a multicentre study on feline hypersensitivity-associated dermatoses.Vet Dermatol, 2011. 22(5): p. 406-13. 4. Colombini, S., et al., Induction of feline flea allergy dermatitis and the incidence and histopathological characteristics of concurrent indolent lip ulcers. Vet Dermatol, 2001. 12(3): p. 155-61. 5. Wildermuth, B.E., C.E. Griffin, and W.S.Rosenkrantz, Feline pyoderma therapy. Clin Tech Small Anim Pract, 2006. 21(3): p. 150-6. 6. Wildermuth, B.E., C.E. Griffin, and W.S.Rosenkrantz, Response of feline eosinophilic cutaneous plaque and eosinophilic lip ulcers to amoxicillin-clavulonate (Clavamox) therapy: a randomized, double blind placebo controlled prospective study. Submitted to Vet Derm, 2010. 7. Yu, H.W. and L.J. Vogelnest, Feline superficial pyoderma: a retrospective study of 52 cases (2001-2011). Vet Dermatol, 2012. 23(5): p. 448-e86. 8. Bourdeau, P. and F.Fer, Characteristics of the 10 most frequent feline skin disease conditions seen in the dermatology clinic at the National Veterinary School of Nantes. Vet Dermatol, 2004. 15(s): p. 63. 9. Bettenay, S.V., et al., Prospective study of the treatment of feline plasmacytic pododermatitis with doxycycline. Vet Rec, 2003. 152(18): p. 564-6.

7 NOTES

8 FLEAS AND OTHER LITTLE CRITTERS, ECTOPARASITES IN CATS Craig E. Griffin, DVM, DACVD,Animal Dermatology Clinic, San Diego, California, USA www.animaldermatology.com

FLEAS

Ctenocephalides felis (C felis) is the species that usually infests both dogs and cats. It has been subdivided into four subspecies with C felis felis most prevalent. Fleas are an important aspect of disease in cats. A study evaluated why animals presented to 20 small animal practices in the UK, primarily in the months of March, April, June through September and December.There were 1043 cats presented, of those 154 cats had a dermatologic complaint and 22 (2.10% of cases, 14.28% of dermatologic diagnoses) had fleas or flea allergy dermatitis. Another study in the United Kingdom was conducted at 31 general practices for one five day work week in July of 2005.1 Every case was examined for evidence of flea infestation or flea allergy. In cats 318 (21.09%) of 1508 had evidence of fleas which was found in 318 of 1508 cats.This was significantly higher than what was found in dogs. Skin lesions compatible with FAD were seen in 121 (8.02%) and flea or FAD was 22.28%. There was a wide variation reported with one clinic in Wales having no cases with flea evidence in dogs or cats. The incidence in the remaining clinics varied from 12.6% to 38.5% of cats. It is also important to realize that even if fleas do not appear to be a problem in cats they still may be due to their role as a vector in spreading a variety of infectious diseases, but in the cat the most notable are Bartonella henselae and Rickettsia felis. One study in an experimental controlled setting showed the monthly use of 10% imidacloprid - 1% moxidectin topically prevented spread of B henselae.2 Six treated cats housed next to six 6 infected and flea infested cats remained uninfected while 6 control cats housed on the other side of the infected cats all became infected. Five of six cats had seroconverted positive within 84 days. In ticks there are studies showing those variable times (4-24 hours) of tick attachment and feeding is required for the spread of some diseases.3-5 and the times are different for different diseases.We do not know how long or how many fleas must feed to successfully transmit disease these cat diseases.This information would allow us to be able to determine more accurately if goal five was possible in flea endemic areas.

FLEA ALLERGY DERMATITIS

No age breed or sex predilection has been shown. Hobi et al reported on 146 cats diagnosed with flea allergy dermatitis based on compatible lesions and response to flea control. The mean age of onset was 4.4 years and the ratio of indoor to outdoor cats was 49/73 which is in contrast to atopic cats with a 46/42 ratio. Seasonality was reported in only seen in 9% of these cases.Fleas can induce a variety of lesions in the cat and all these may not really be allergy mediated. For example some cats respond with twitching and itching in response to the fleas that twitch following nitenpyram therapy. Other cats may develop barbered alopecia just from "chasing down" fleas while removing them or have a psychogenic alopecia from the presence of fleas without actual allergy. However the most classic flea lesion associated with allergy is miliary dermatitis. Hobi et al found this in 35% of cases but this was less than the 39% that had barbered alopecia and 38%with erosions and ulcerations on the face and neck. Miliary eczema is typified by focal, small 1-5mm, crusted papules. Depending on the stage the lesions may appear as erythematous or hyperpigmented macules or papules. As alopecia may be absent or mild these lesions may be difficult to see and it is often stated they are felt more readily than they are seen. Experimental studies in cats have shown a variety of changes. Erythema and wheals develop in 15 minutes to hours and papules generally occur by 24 hours.6 Another study did not describe papules but reported 8of 8 cats developed miliary dermatitis of the head and neck while 5 had self induced alopecia of the abdomen.7 Four developed lip ulcers but on histopathology eosinophils were not noted in these lesions though present in all other lesions biopsied. No papules, erythema or wheals are described on the abdomen.7 Eosinophilic granuloma complex lesions were seen in 20(14%) of 146 cases. The lesions may be seen virtually anywhere on the body and the pattern is used to suggest which associated

9 causes are more likely as these lesions are not specific for flea allergy but may also be seen with atopic disease, food allergy, folliculitis, cheyletiella and dermatophytosis.The dorsal lumbar, groin and caudal thigh areas are often affected, as in the dog but that pattern is not as typical and only one of these areas may be affected even without the dorsal lumbar area. Cervical lesions more dorsal but all around the neck is another common area affected in feline FAD and some cases will have generalized disease. Hobi et al reported the four most common affected sites as rump/tail (53%), abdomen (50%), head/face 42% and neck (36%).

TREATMENT

Treatment for flea allergy dermatitis is achieved by limiting flea bites to a small enough level that flea allergy dermatitis is not triggered. If this cannot be achieved then drugs to control the allergic inflammation will be needed whenever the flea exposure cannot be controlled. Drugs most commonly used for this purpose are systemic glucocorticoids and ciclosporin which will be discussed in the allergy and autoimmune section. Allergen specific immunotherapy and antihistamines are infrequently effective.

FLEA CONTROL

Effective flea control to an owner and to some degree the veterinarian depends on what the actual desired goal is and how observant the owner is.Just over 50% of owners of dogs and cats with evidence of flea disease were aware their pet had fleas.1 Different goals and aspects related to achieving the goals are listed in table 1. Effective control of flea populations and achieving the desired goal requires an understanding of many aspects of flea biology, flea allergy and the role fleas play in other allergic skin diseases and contagious disease.8-11 A complete discussion is beyond the scope of this presentation. See Table 1.

The advent of newer more effective flea control products has been both beneficial and detrimental to clinical practice. Most clients can control fleas effectively with the regular monthly use of topical or systemic flea products on all dogs and cats in the house that contain one of the following: dinotefuran, fipronil/methoprene, imidicloprid, indoxacarb, selamectin, spinetoram, spinosad. They may be more effective when combined with the systemic insect growth regulator lufeneron or topical pyriproxyfen. What is important is that the use of the products on all pets in the home environment will result in no fleas in the house.This may take several months of regular and compliant use. In addition when one wants to really rule out flea allergy then the affected cat should remain indoors in the flea free environment nearly all the time if not 100%. This is part of the criteria when one uses aggressive flea control to rule out fleas as a cause of the dermatitis. After the 30 day trial the cat may be allowed outside and if it flares then better flea control will be needed. For the flea allergic cat preventing flea bites as much as possible may be essential for control. This means limiting bites by having a flea free environment and killing newly acquired fleas as fast as possible to minimize biting. Outdoor and indoor outdoor cats are not as likely to be confined to flea free environments and the speed of kill may become more critical. It is also important to consider the duration of the speed of kill between treatments. If potential exposure is going to be on limited short term occasions then nitenpyram is the most rapid flea killing systemic product available, with the drawback of short half life. This means there is only one day duration. Table 2 reviews some flea products used for flea allergic cats.

10 TABLE 1 GOALS AND CHALLENGES OF FLEA CONTROL

Goal Difficulty Challenge Achieve by Factor*

Family members 1 No hot spots in house Some degree of insecticides in house not bitten by fleas and or enough pets present to handle flea burden Intermittent flea products applied to pets

Prevention of flea 2 No viable flea eggs deposited Indoor only pets infestation in house in house or development of eggs to adults in house Regular use of indoor flea treatments with insect growth regulators or long acting multi stage cidal products.

Some use of highly efficacious adulticides on all pets with insect growth regulator or that kills fleas fast enough to prevent egg production.

Owners believe fleas 2 No household infestation Same as above though depends on are controlled and not see skin disease owner and pets present as if allergic or fleas on pet pets in house may be same as difficulty 4

Elimination of 3 No household infestation Regular consistent use of effective "flea problem" and continuous on animal adulticides on all dogs and cats, and noted on pets adulticide control of main outdoor environment pets spend time in or limited time outside.

Control of flea 4 Decrease number of flea As above but may need very rapid allergy dermatitis bites below level of allergen killing adulticide and or prevent needed to induce FAD and exposure to flea hot spots. May have secondary trauma from to limit time outside or where pet goes excessive biting in "flea season"

Prevention of 4 Minimize flea bites below As above but may require even more allergy flare ups in flea allergy threshold and control as FAD may be flaring mildly atopic +/- FAD dogs from adding to pruritic/allergic but what it contributes to atopic is load in atopic dermatitis enough to aggravate that disease.

Prevention of 5 Prevent flea bites (duration Do not allow pet to enter flea infested disease transmission and burden to induce disease environment or if does enter need with hematogenous parasites effective repellent unknown so to be sure complete prevention required)

*Difficulty factor - 1 easiest to achieve, 5 most difficult requiring diligent control and flea bite prevention measures

Resistance to some flea products has been seen in the past. The cat flea has been described as the most resistant of the flea species, and to more types of products. Integrated pest management decreases the probability of this developing to the newer products now being used extensively 9,11.The international imidacloprid flea susceptibility monitoring program developed an invitro assay to test for the development of flea resistance.There evaluations of natural strains of fleas from around the world have shown little

11 resistance12,13. Complete resistance has not been described to the new insecticides though strains of fleas that are less susceptible have. A study in Japan has shown resistance to imidacloprid in naturally occurring flea population. More work is needed in this area.

Compliance is still a key component of a successful flea control program. Even the newer products require regular use to prevent the development of viable eggs from being laid. Therefore to assure that the flea life cycle is broken owners must be diligent about proper application of these products at correct intervals.The optimum control will utilize integrated pest management as the most effective way to eliminate multiple stages of the flea life cycle and decrease the chance of resistant strains of fleas develop.This involves the use of different ingredients or techniques on pets and in the environment. In severely infested environments, effective control may take 4-8 weeks to achieve. Once flea control is achieved, clients may find that only one or two aspects of flea control are sufficient for maintenance, but the long term use of an integrated pest control plan is optimum.

TABLE 2 SELECTED FLEA CONTROL PRODUCTS FOR CATS Chemical Brand/ Treatment Speed Kill Important facts Name Manufacturer Regimen Dinotefuran/ Vectra Cats Monthly 100% 6 hoursA Over 95% at 6 hours for 29 daysA Pyriproxyfen/ and Kittens/ topical Summit Vet Pharm Fipronil or Frontline or Monthly 100% 48 hoursB 7 days 100% at 48 hours and over 99% Fipronil / Frontline Plus/ topical at 24 hour through day 14B. Methoprene Merial 28 days Ks1 86.4% at 48hC. Very Significant reduction flea feeding for 7 daysD Imidacloprid Advantage/ Monthly up Over 98% at 6 7 days 100% at 24 hoursB. Bayer to weekly hoursA 90% at 12 hour for 29 daysA topical spot 28 days Ks1 72.6% at 48hC application Very Significant reduction flea feeding for 14 daysD Indoxacarb Merck Monthly 100% at 8 hour 14 days 100% at 8 hour and 100% at 12 topical hour for 21 days and 100% at 24 hours for 35 days Lufenuron Program/ Monthly oral Not adulticidal 100% effective over 30 days Novartis and long effective for whole Animal Health acting injection month preventing for cats. egg development Nitenpyram Capstar/ Oral systemic 100% dead in 3 hours Blood consumption ceased 15 minutes Novartis therapy. To but only one day after fleas applied to treated catD Animal maintain levels Health q24h in cats Selamectin Revolution/ Monthly 100% at 48h but 7 day 100% at 24hours and 21 days over Pfizer topical over 99% at 12 90% at 12 hoursB administration hourB 28 days Ks1 99% at 48hC which is Very Significant reduction flea feeding absorbed for 28 daysD systemically Spinetoram Assurity/ Topical 100% in 12 hour Elanco monthly Spinosad Comfortis/ Monthly oral Elanco systemic

12 TABLE 2 REFERENCES

(A) Murphy, M., C.A. Ball, and S. Gross, Comparative in vivo adulticidal activity of a topical dinotefuran versus an imidacloprid-based formulation against cat fleas Ctenocephalides felis) on cats.Vet Ther, 2009. 10(1-2): p. 9- 16. (B) Dryden, M.W., et al., Comparative speed of kill of selamectin, imidacloprid, and fipronil(S)-methoprene spot-on formulations against fleas on cats.Vet Ther, 2005. 6(3): p. 228-36. (C) Dryden, M., et al., Efficacy of a topically applied spot-on formulation of a novel insecticide, metaflumizone, applied to cats against a flea strain (KS1) with documented reduced susceptibility to various insecticides.Vet Parasitol, 2008. 151(1): p. 74-79. (D) McCoy, C., A.B. Broce, and M.W. Dryden, Flea blood feeding patterns in cats treated with oral nitenpyram and the topical insecticides imidacloprid, fipronil and selamectin. Vet Parasitol, 2008. 155(3-4): p. 293-301.

DEMODEX

Apparently there are three species of demodex mites that cause dermatologic disease in cats.14,15 Demodex cati, Demodex gatoi and a third still unnamed mite that has been seen in the UK, Germany, USA and Japan.14, 16-18 Demodex cati is most common and is a long slender mite that is follicular oriented and causes alopecia and follicular disease. It most commonly is associated with immunosuppressed cats such as seen with Felv/FIV, progestational or glucocorticoid drugs and with papillloma virus.19 The unnamed mite has also been seen in cats treated with glucocorticoids. Demodex gatoi is not associated with other diseases and appears to be regionally found with relatively high incidence in some areas. Compared to Demodex cati this mite is shorter in length with a broad based blunted abdominal segment. This mite is a surface dweller in contrast to the normal follicular orientation of classic demodex, D. cati or canis. It also appears to be somewhat contagious as outbreaks have been described.18, 20, 21. In some households the mite is more readily found in pets with milder disease as it appears intense pruritus may remove mites.This has led to the speculation that the clinical disease is partly a hypersensitivity reaction. Since grooming excessively may remove the mites the diagnosis may be made by fecal flotation examination. Clinically there may be minimal disease and pruritus or intense pruritus.20 Pruritus is the main symptom though scale may also occur. Hair loss due to excessive grooming occurs and may involve the abdomen, forelegs (especially elbows), head and neck or rear legs. As such it mimics allergic disease or psychogenic dermatitis. In cats that are excessively grooming mites may be more difficult to find though in mildly affected non-pruritic cats they are usually present in abundant numbers. Scraping other normal or mildly affected cats in a household may lead to a diagnosis. Individual itchy cats have anecdotally been diagnosed with fecal flotation. Therapy though not routinely effective has been successful with lime sulfur dip as well as ivermectin 1mg/4-5kg eod.

TROMBICULOSIS

There are numerous species of chigger mites that will infest dogs and cats but most commonly in Europe is Neotrombicula(Trombicula)Autumnalis. The adult form is a scavenger and does not infect pets. Certain locations are more heavily infested than others and reports of animals in certain areas.There are anecdotal reports of clients knowing that certain fields or wooded areas are more likely to cause an infestation. The red, six legged larvae will parasitize animals.The mites cause lesions most often where the body will touch the ground such as head, pinna, paws though neck and ventrum may also be affected. Lesions can consist of small mildly pruritic papules to intensely pruritic papules. Crusting may be seen and secondary excoriations may occur. If one looks closely or magnifies the lesions the small red larvae may be visualized. Due to the life cycle the disease is most often seen in late summer or fall. Treatment is generally successful with fipronil spray and selamectin was also shown effective with all mites dead within two days of treatment.22,23 This may be a good preventative for animals that may be prone to reinfestation though not study has been reported on long term prevention.

13 REFERENCES

1. Bond, R., et al., Survey of flea infestation in dogs and cats in the United Kingdom during 2005.Vet Rec, 2007. 160(15): p. 503-506. 2. Bradbury, C.A. and M.R. Lappin, Evaluation of topical application of 10% imidacloprid-1% moxidectin to prevent Bartonella henselae transmission from cat fleas. J Am Vet Med Assoc, 2010. 236(8): p. 869-73. 3. Piesman, J., et al., Duration of adult female Ixodes dammini attachment and transmission of Borrelia burgdorferi, with description of a needle aspiration isolation method. J Infect Dis, 1991. 163(4): p. 895-7. 4. Thorner, A.R., D.H. Walker, and W.A. Petri, Jr., Rocky mountain spotted fever. Clin Infect Dis, 1998. 27(6): p. 1353- 9; quiz 1360. 5. Piesman, J., Experimental acquisition of the Lyme disease spirochete, Borrelia burgdorferi, by larval Ixodes dammini (Acari: Ixodidae) during partial blood meals. J Med Entomol, 1991. 28(2): p. 259-62. 6. Bond, R., M.J. Hutchinson, and A. Loeffler, Serological, intradermal and live flea challenge tests in the assessment of hypersensitivity to flea antigens in cats (Felis domesticus). Parasitol Res, 2006. 99(4): p. 392-397. 7. Colombini, S., et al., Induction of feline flea allergy dermatitis and the incidence and histopathological characteristics of concurrent indolent lip ulcers. Vet Dermatol, 2001. 12(3): p. 155-61. 8. Carlotti, D.N. and D.Jacobs, Therapy, control and prevention of flea allergy dermatitis in dogs and cats. Vet Dermatol, 2000. 11(2): p. 83-98. 9. Blagburn, B.L. Flea and tick control: Ensuring efficacy while minimizing resistance. in Western Veterinary Conference. 2004. Las Vegas: Advanstar Veterinary Healthcare Communications and Bayer Healthcare LLC. 10. Dryden, M.W. Understanding persistent and recurrent flea problems. in Western Veterinary Conference. 2004. Las Vegas: Advanstar Veterinary Healthcare Communications and Bayer Healthcare LLC. 11. Dryden, M.W. and A. Brace, Integrated flea control for the 21st century. Comp cont educ, 2002. 24 (supplement 1): p. 36-39. 12. Rust, M., Advances in the control of Ctenocephalides felis (cat flea) on cats and dogs. Trends in Parasitology, 2005. 21(5): p. 232-236. 13. Bayer Healthcare, B.H.L. and B. Blagburn (2008) Monitoring flea susceptibility to imidicloprid. spotlight on research Volume, 1-3 14. Löwenstein, C., et al., Feline demodicosis caused by concurrent infestation with Demodex cati and an unnamed species of mite. Vet Rec, 2005. 157(10): p. 290-292. 15. Beale, K., Feline demodicosis: a consideration in the itchy or overgrooming cat. J Feline Med Surg, 2012. 14(3): p. 209-13. 16. Chesney, C.J., An unusual species of demodex mite in a cat. Vet Rec, 1988. 123: p. 671-673. 17. Kano, R., et al., Feline demodicosis caused by an unnamed species. Res Vet Sci, 2011. 92(2): p. 257-8. 18. Newbury, S., K. Moriello, and H. Steinberg. An outbreak of Demodex gatoi and an unnamed Demodex mite in an open admission animal shelter. in Nt Am Vet Derm Forum. 2001. Palm Springs. 19. Neel, J.A., et al., Deep and superficial skin scrapings from a feline immunodeficiency virus-positive cat. Vet Clin Pathol, 2007. 36(1): p. 101-104. 20. Beale, K.M. Feline Non-inflammatory Alopecias (VET-89). in Western Veterinary Conference. 2004. Houston, TX, USA: Gulf Coast Veterinary Dermatology & Allergy. 21. Saari, S.A., et al., Demodex gatoi-associated contagious pruritic dermatosis in cats--a report from six households in Finland. Acta Vet Scand, 2009. 51: p. 40. 22. Nuttall, T.J., et al., Treatment of Trombicula autumnalis infestation in dogs and cats with a 0.25 per cent fipronil pump spray. J Small Anim Pract, 1998. 39(5): p. 237-9. 23. Leone, F. and F. Albanese, (Abst) Efficacy of selamectin spot-on formulation against Neotrombicula autumnalis in eight cats. Vet Derm, 2004. 15 (supp1)(s1): p. 49.

14 BREED RELATED INFECTIONS AND ODDITIES IN CATS Ross Bond, Dept. Veterinary Clinical Sciences, Royal Veterinary College, Hawkshead Lane, North Mymms Herts AL9 7TA

INTRODUCTION

This section reviews fungal infections and selected, unrelated skin diseases that occur in three main types of cats: Persian, Sphynx and Rex cats. Dermatophytosis caused by Microsporum canis may present in Persian cats typically with follicular signs or rarely as a granulomatous panniculitis.Persian cats are also prone to an idiopathic facial dermatitis. Sphynx cats and Devon Rex cats are commonly affected by Malassezia dermatitis and rarely by urticaria pigmentosa.

IDIOPATHIC FACIAL DERMATITIS IN PERSIAN CATS

Subsequent to some anecdotal reports of a syndrome of facial dermatitis in Persian and Himalayan cats, Bond et al reviewed the case records of 13 Persian cats with similar historical, clinical and clinicopathological features (Bond 2000). Eight male and 5 female Persian cats aged between 10 months and 6 years (median 2.5 years), each from separate households in the south-east of England, were studied. Both light and dark-coated cats were affected. Each cat was presented with a history of progressive, predominately facial skin disease of 3 months to 4 years duration (median 12 months). The age at onset reported by the owners ranged from 4 months to 5 years (median 12 months). The first abnormality noted by the owners was the presence of a black material which matted the hairs of the periocular, perioral or chin areas. Pruritus was not reported early in the course of the disease. However, the affected areas became progressively inflamed and pruritus became moderate or severe, despite a variety of symptomatic treatments. Affected cats were otherwise reported to be in good general health. At the time of first presentation, all cats were routinely fed on standard commercial diets.

Similar clinical signs were seen in each case. A black waxy material which matted the distal portions of the hair was present in a symmetrical pattern on the face of each cat. In most cases, the chin, perioral and periocular areas were affected. Erythema and exudation were often observed in the facial folds but the lesions were clearly present in non-intertriginous areas. Moderate to severe erythema was observed in the areas of exudation and also in the preauricular area. A bilateral erythematous otitis externa with accumulation of black waxy material within the external ear canal was seen in 7 cats. Excoriations were observed in severely affected cases. Five cats had a bilateral mucoid ocular discharge. Apart from a submandibular lymphadenopathy which was present in 5 cats, general physical examinations showed no other abnormalities.

Microscopic parasites and dermatophytes were not observed in skin scrapings and dermatophytes were not isolated from samples from the 11 cats which were cultured, but bacteria and Malassezia yeasts were commonly found in cytological preparations. A range of bacteria, including Staphylococcus intermedius, streptococci and Gram- negative rods were isolated from all 9 cats that were swabbed.

Beneficial effects were not seen in the eight cats fed restricted diets. Intradermal tests were negative in each cat tested. A peripheral eosinophilia was observed in 4 cases; eosinophil counts in these cats ranged from 2.3 to 13.1 × 109 L-1 (normal range 0-1.5 × 109 L-1). Lymphopenia was observed in 2 cats (0.1 and 0.5 × 109 L-1 [normal range 1.5-7.0 × 109 L-1]) but biochemical abnormalities were not found.

Histopathological examination of skin biopsy specimens showed marked acanthosis (9 out of 9 cases biopsied) with crusting which often included sebum. Hydropic degeneration of basal cells (9 cases) and occasional dyskeratotic keratinocytes (8 cases) were found; dyskeratoses were particularly marked in the follicular epithelium. A superficial dermal infiltrate comprised of eosinophils (8 cases), neutrophils (8 cases), mast cells (7 cases), histiocytes and occasional melanophages (9 cases) was observed; the infiltrate was usually intense. Sebaceous glands appeared enlarged (8 cases), especially in areas of marked acanthosis. Less common features included mild dysplasia of the epidermis, exocytosis of eosinophils and neutrophils which occasionally formed subcorneal pustules without acantholysis, ulceration and focal luminal folliculitis. 15 Topical and environmental flea treatments were administered to twelve cats without apparent benefit. Twelve cats received glucocorticoid therapy, either alone or in combination with other drugs but in no case was the response complete.Three owners reported that the response to oral glucocorticoids provided by their local veterinarians had been better earlier in the course of the disease.

Systemic antibacterial therapy (cephalexin, enrofloxacin, co-amoxyclav) was given to 12 cats, either alone or in combination with other drugs. Seven of the cats failed to respond and five showed partial improvements. In three cases which appeared to benefit from antibacterial therapy, further courses were considered to be less helpful. Partial reductions in pruritus and exudation were seen in three out of four cats that received ketoconazole orally at 10 mg/kg once daily but in no case was the response complete. One cat from which both M. pachydermatis and Gram-negative bacteria had been isolated showed a good initial response to thrice weekly shampoos with a 2% miconazole / 2% chlorhexidine product (Malaseb); however, this product was withdrawn subsequently as its application appeared to induce irritation.

Although the black material could be removed from hair and skin with various topical products in those cats which permitted washing, the owners consistently reported that it accumulated again within 1-3 days of treatment.

Duration of follow-up ranged from 2 to 28 months. In no case could the disease be maintained in complete remission. Four cats were euthanased because of uncontrolled severe pruritus. Five of the cats received maintenance glucocorticoid therapy which reduced the severity of the disease to "tolerable" levels. Of these, one cat received depot injections of methylprednisolone acetate at 5 week intervals and four cats were given alternate day therapy with oral prednisolone at doses of 1 mg.kg-1 (3 cats) and 3 mg.kg-1 (one cat). Two of these cats were receiving concurrent daily topical antibacterial therapy with fucidic acid (Fucidin gel, Leo Laboratories Ltd) and mupirocin (Bactroban, Beecham), and one, intermittent treatments with cephalexin given orally at 15 mg.kg-1 bid.

Subsequent to this original report, others have reported varying success with calcineurin inhibitors; either topical tacrolimus or oral ciclosporin.

The aetiology of the apparent syndrome of facial skin disease in these Persian cats is unclear. A number of potential causes have either been excluded or are most unlikely. Ectoparasitic infestation and dermatophytosis seem most unlikely as microscopic parasites and dermatophytes were not found in any case.The initial clinical sign of accumulation of a black waxy material without pruritus is not suggestive of a hypersensitivity disorder.

Whilst feline acne is a relatively poorly defined condition affecting the face of cats, the clinical features of the subject cases do not closely resemble those described for acne. Comedo formation, a principal feature of acne, was not observed clinically. Papules, pustules and furuncles, features seen in more severe acne cases, were also not observed. Acne is often restricted to the chin and lip commisures whereas lesions were more extensive in the subject cats.Feline acne is characterised histopathologically by comedones, cystic follicles and dilated sebaceous gland ducts, associated with either minimal inflammation or varying degrees of folliculitis, granulomatous perifolliculitis or sebaceous adenitis; these were not the principal features observed in biopsy specimens taken from the subject cats.Foil (Foil 1995) considers marked pruritus to be a feature which excludes feline acne from the differential diagnosis of head pruritus in the cat, although White et al. (White 1997) reported pruritus in 10 out of 25 cases.

The widespread nature of skin lesions, the young age at onset, the lack of pruritus, and the histopathology (orthokeratotic hyperkeratosis, papillomatosis and a mild lymphocytic perivascular dermatitis) of hereditary primary seborrhoea reported by Paradis and Scott (Paradis 1990) differentiates these two disorders. Pedigrees were not available for all the cats in this study but the authors have received anecdotal reports of very similar cases in two Persian cats which were known to be littermates (A. Patel, personal communication), and a genetic basis seems likely.

Although M. pachydermatis and a range of potentially pathogenic bacteria were isolated from many of the cats, the lack of complete response to antifungal and antibacterial therapy suggests that microbial infection was not

16 the sole cause of the skin lesions. However, the partial responses seen in some of the cats suggest that concurrent infection was an occasional complicating factor in this syndrome. Since the original paper was written, ciclosporin therapy has been anecdotally reported to be of occasional benefit in affected cats.

The nature of the black material seen adherent to the hair is uncertain but it may represent a sebaceous gland product. Although sebaceous hyperplasia was present histologically in all cases, sebaceous glands are frequently large in the facial region in healthy cats. Further studies in which sebaceous gland size in affected cats are compared with biopsies from healthy cats are required to confirm the degree of sebaceous hyperplasia.

Gross et al describe features that are similar to those seen in our case series (Gross and others 2005a). They report severe acanthosis and moderate spongiosis of the epidermis and hair follicles, accompanied by neutrophil and eosinophil exocytosis, and parakeratotic and neutrophilic scale/ crust. Scattered individual keratinocyte apoptosis (without lymphocyte satellitosis) and basal cell vacuolation is seen but true interface dermatitis is not present. Overall the features are not specific and must be interpreted with the clinical context.

In summary, young Persian cats may present with a progressive, apparently idiopathic, predominately facial skin disease which is characterised clinically by the presence of a black material which adheres to the skin surface and, ultimately, by moderate or severe pruritus.The condition is diagnosed by a combination of clinical and histological features.The aetiology is unknown and a consistently successful treatment has not been identified.

URTICARIA PIGMENTOSA-LIKE DERMATITIS IN DEVON REX AND SPHYNX CATS.

In 1996, Vitale et al reported that three young-adult Sphynx cats that shared a common grandsire presented with a widespread macular and papular eruption on the head, neck, limbs and trunk (Vitale and others 1996). A linear configuration of the lesions was noted in two cats. Histologically, these lesions reflected a perivascular to diffuse subcutaneous and dermal infiltrate of well-differentiated mast cells.The clinical and histological features were considered similar to those of urticaria pigmentosa in humans.

In 2004, Noli et al reported a similar presentation in 5 unrelated Devon Rex cats (Noli and others 2004). Two of the five cats had a linear lesion distribution on the ventro-lateral trunk. The cats were otherwise healthy. Two cats that received oral prednisolone responded to anti-inflammatory doses but relapsed when the drug was withdrawn, and another two cats responsed to EFA supplementation. These authors proposed the name 'papular eosinophilic/mastocytic dermatitis'. In 2012, Columbo et al reported a further 3 cases in Devon Rex cats with concurrent dermatophytosis; antifungal therapy led to a resolution of all skin lesions (Colombo and others 2012). These authors concluded that dermatophytosis should always be carefully investigated in cats presenting with signs suggestive of urticaria pigmentosa-like dermatitis.

Sphynx and Devon Rex cats are genetically-related and the apparent breed association strongly suggests a genetic component in the pathogenesis of this disorder.

SEBORRHOEIC DERMATITIS CAUSED BY M. PACHYDERMATIS IN DEVON REX AND SPHYNX CATS.

Four Rex mutations, each with subtle phenotypic differences in their soft, plush and wavy hair coats, have been reported in domestic cats, with the designations of Devon, Cornish, German and Oregon reflecting the place of origin (Robinson 1971, 1972). Mating studies have indicated that all are inherited as autosomal recessive traits, and that the Devon, Cornish and Oregon Rexes are genetically-independent, whereas the Cornish and German Rex mutants may be identical or closely similar (Robinson 1971, 1972).

Four Rex mutations, each with subtle phenotypic differences in their soft, plush and wavy hair coats, have been reported in domestic cats, with the designations of Devon, Cornish, German and Oregon reflecting the place of origin (Robinson 1971, 1972). Mating studies have indicated that all are inherited as autosomal recessive traits, and that the Devon, Cornish and Oregon Rexes are genetically-independent, whereas the Cornish and German Rex mutants may be identical or closely similar (Robinson 1971, 1972). 17 Dermatitis associated with Malassezia spp. in cats is most often reported in association with endocrine and metabolic diseases, neoplasia, and infection with feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV) (Forster-Van Hijfte and others 1997, Godfrey 1998, Mauldin and others 2002, Sierra and others 2000). A recent report also suggested that Malassezia spp. overgrowth may occur in association with feline allergic skin diseases (Ordeix and others 2006), in a manner analogous to that commonly reported in dogs. It is the author’s clinical impression that Devon Rex cats (DRC) are predisposed to a seborrhoeic dermatitis associated with Malassezia spp. yeasts, although this observation is not mentioned in standard textbooks of veterinary dermatology (Gross and others 2005b, Scott and others 2001). In a study of Malassezia carriage in the claw folds of 46 cats of various breeds, the yeast was identified in 18 out of 31 Domestic short-haired (DSH) and Persian cats, but notably in all 15 DRC sampled (Colombo and Cornegliani 2000).

A group of 30 DRC were examined clinically and sampled quantitatively for Malassezia spp. carriage (Åhman and others 2007a). Nine DRC had greasy seborrhoea (seborrhoea oleosa) at multiple sites. In eight cases, it involved the axilla, groin, ventral neck and feet. One of these cats, in addition, had severe, generalised seborrhoea sicca. The ninth cat had greasy seborrhoea affecting the ventral neck and head. All eight cats with axilla and groin involvement, had alopecia and either hyperpigmentation or a reddish-brown surface discoloration of the skin at these sites.Three of these cats also were erythematous in the axilla and groin. Furthermore, in all these eight cats, there was a greasy, tightly adherent brown exudate on the claws and, or in the claw folds of multiple digits, accompanied by a dark, greasy exudate that matted the hairs on the palmar and plantar aspects of the interdigital skin.

One of the nine seborrhoeic DRC had non-seasonal, generalised pruritus and had been previously reported to show a partial (approximately 50%) reduction in pruritus following fortnightly treatments with a miconazole and chlorhexidine shampoo (Malaseb, VetXX, Thame, U. K.). The remaining eight cats reportedly did not display pruritic behaviour and none had received previous treatment for skin disease; indeed, all the owners of non- pruritic cats considered the presenting signs to be normal or near-normal for the breed.

Malassezia spp. yeasts were isolated from 18 out of 21 healthy DRC, and from all 9 seborrhoeic DRC. M. pachydermatis was predominantly isolated, and this species accounted for all Malassezia spp. isolates recovered from the axilla, groin, ear and anus. Malassezia slooffiae was isolated from the claw fold of five healthy and three seborrhoeic DRC. In four healthy DRC, only Malassezia slooffiae was recovered from the claw fold, whereas it was isolated in combination with M. pachydermatis in the one healthy DRC and three seborrhoeic DRC.

M. pachydermatis was isolated at a significantly higher frequency from the left axilla (P=0.02), right axilla (P=0.01), left groin (P=0.01) and claw fold (P=0.0001) of seborrhoeic DRC when compared with healthy DRC, whereas no significant difference was found between the frequencies of isolation of M. pachydermatis from the left ear, right groin and anus.The frequency of isolation of lipid-dependent Malassezia spp. from the claw fold did not vary significantly between healthy and seborrhoeic DRC. The population sizes of M. pachydermatis in the seborrhoeic DRC were significantly greater (P= or <0.001) in the axillae, groin and claw fold when compared with the healthy DRC, whereas populations in the ear and anus were comparable between the two groups.Whilst large numbers of Malassezia spp. yeasts were isolated from the eight DRC with greasy exudation, the single seborrhoeic DRC with dry scaling without greasy exudation yielded only one colony of M. pachydermatis from the right groin.

Treatment of Malassezia pachydermatis- associated seborrhoeic dermatitis with oral itraconazole was investigated in six Devon Rex cats (Åhman and others 2007b). Cats were examined and cutaneous populations of Malassezia were determined using contact plates and a swab-wash method before and after 21 days of pulse treatment with itraconazole (5 mg.kg-1 once daily, 7 days on, 7 days off, 7 days on). Before treatment, all cats had greasy seborrhoeic dermatitis involving the axillae, groin, claw folds and palmar and plantar interdigital skin, and two cats had similar lesions on the ventral neck. After treatment, there was a significant (P < 0.05) reduction in overall clinical scores and in scores at all individual sites assessed, except for interdigital skin (P=0.068). Population sizes of M. pachydermatis in the left and right axilla, left and right groin and palmar interdigital skin were significantly (P < 0.05) reduced, whereas the reduction in claw fold counts did not reach significance (P = 0.068). The dramatic reduction in yeast counts and the associated marked clinical improvement of the seborrhoeic dermatitis provides important pilot data on the potential value of oral itraconazole in the management of seborrhoeic dermatitis associated with Malassezia pachydermatis in Devon Rex cats. 18 Carriage of Malassezia spp. yeasts was investigated in 33 healthy Cornish Rex cats (CRC) and compared with carriage in Devon Rex (DRC) and Domestic short-haired (DSH) cats (Bond and others 2008). Samples were obtained by swabbing the left external ear canal, anus and claw fold of digit III of the left fore foot, and by sampling the axilla and groin using contact plates.Yeasts were grown on modified Dixon's agar incubated at 32oC for 7 days. Malassezia species were isolated from 90 % of the Devon Rex cats, but from only 39 % of the CRC and 50 % of the DSH cats. M. pachydermatis accounted for 121 of 141 Malassezia spp. isolates. Five CRC were colonised by M. pachydermatis alone, one CRC yielded only M. nana, and one cat yielded only M. slooffiae, whereas five CRC were colonised by both M. pachydermatis and M. nana and another yielded M. pachydermatis, M. slooffiae and M. nana. M. nana was primarily isolated from the ear canal, whereas M. slooffiae was most often isolated from the claw. Both the frequencies of isolation and population sizes of M. pachydermatis at all sites sampled in the CRC were comparable to those of 10 healthy DSH cats.Populations of M. pachydermatis in the left axilla and left and right groin in the CRC were significantly lower when compared with counts in a group of 21 healthy DRC, a breed with very similar coat characteristics to CRC but which are prone to seborrhoeic dermatitis caused by M. pachydermatis.

Carriage of Malassezia spp. yeasts in healthy Sphynx cats was compared with that in Devon Rex (DRC), Cornish Rex (CRC) and Domestic short-haired (DSH) cats (Volk and others 2010). Swab samples from the external ear, anus and claw folds, and contact plate samples from the axillae and groins, were incubated on modified Dixon's agar at 32oC for 7 days. Malassezia species were isolated from all 18 Sphynx cats; M. pachydermatis accounted for 118 of 140 isolates. Of 20 isolates of M. nana, 16 were recovered from the ear canal. M. slooffiae was isolated from the claw fold of one cat and the left groin of another.The high counts of M. pachydermatis obtained from the axillae, groins and claw folds of the Sphynx cats exceeded those of healthy DSH, CRC and DRC; axillary populations were comparable to those of seborrhoeic DRC. These data support recent reports from Sweden of high Malassezia spp. colonisation in Sphynx cats (Ahman and Bergstrom 2009).

DERMATOPHYTOSIS IN CATS

The dermatophytes consist of a group of fungi that are adapted to digest keratinous debris, and when pathogenic are normally located in the epidermal stratum corneum, hair shaft or claw. The species that are adapted to animal hosts are termed 'zoophilic' but these occasionally spread to in-contact humans, or to other animal species.The soil-adapted 'geophilic' dermatophytes sometimes affect veterinary species where there is outdoor husbandry or activity. Microsporum spp. and Trichophyton spp. account for the majority of animal disease, and the human-adapted 'anthropophilic' species such as Epidermophyton floccosum and T. tonsurans only rarely transfer from humans to animals (Brilhante and others 2006, Terreni and others 1985).

M. canis is a zoophilic dermatophyte probably best adapted to the cat. It was the most frequent cause of feline dermatophytosis in surveys from the United Kingdom (Sparkes and others 1993a), Italy (Iorio and others 2007), southern USA (Lewis and others 1991) and Brazil (Brilhante and others 2003), and is also a very common cause of canine dermatophytosis. Strains adapted to infect horses were previously termed M. equinum (Graser and others 2008).

In general, younger animals are most susceptible to dermatophytosis (Pascoe 1979, Sparkes and others 1993a). This may reflect a lack of specific immunity acquired after first exposure but also innate immune mechanisms, such as the quantity and nature of sebaceous lipids in the epidermis (Hay 1992). M. canis infection in veterinary species (and humans) often reflects contact with infected cats, or contaminated environment or fomites (Cafarchia and others 2006). Asymptomatic carrier cats are especially risky for humans since no precautions are taken to prevent potential transfer; although such cats may progress to develop overt infection and more abundant arthrospore shedding (Sparkes and others 1994). Infected cats have been shown to cause substantial environmental contamination and a significant airborne load of viable fungal elements, whereas dogs are of lesser importance in this regard (Mancianti and others 2003). Arthrospores of M. canis can remain viable in the environment for 18 months, representing a reservoir for new or re-infection (Sparkes and others 1994). Cats are more prone to dermatophytosis than dogs, and long-haired and pedigree cats seem at particular risk (Sparkes and others 1993a). Dermatophytosis should be suspected in any animal showing lesions comprising combinations of alopecia,

19 erythema, papules, scaling and crusting. In cats, the classical lesion is well-demarcated with active inflammation at the periphery, commonly on the face or limbs. Depending on the size and duration of the lesion, there may be central crusting or central healing. Lesions of the nasal planum, footpads and claws are possible but infrequently reported. The lesions of M. canis dermatophytosis, typically patches of alopecia with erythema and grey scales or crusts, are often much less inflamed and thickened than those caused by T. mentagrophytes . Areas of relative healing may have a shiny appearance.Kerion, a nodular form of dermatophytosis with deep, suppurant, inflammatory lesions, is occasionally seen. Cats with dermatophytosis may also present with a widespread papular and crusting eruption ('miliary dermatitis'), recurrent chin acne, dermatophyte pseudomycetoma (mainly in Persians) or as clinically normal carriers.

The contagious and zoonotic nature of dermatophytosis obliges veterinarians to maintain a high index of suspicion of this disease. An accurate and early diagnosis is also important because of the length, complexity, potential toxicity and cost of treatment required. The goal in diagnosing dermatophytosis is to prove invasion of the epidermis and or hair shaft by a dermatophyte.The principal diagnostic methods are Wood's lamp examination, direct microscopy, culture and biopsy.The first three of these tests should be considered complimentary and should be routinely performed. Biopsy can be useful in unusual presentations and the results may surprise the clinician when another diagnosis is suspected. None of the above is always reliable. As in human medicine, a combination of direct microscopy, Wood's lamp examination, culture, and sometimes histopathology, is required for optimum sensitivity and specificity (Sparkes and others 1993b).

The histopathological features of dermatophytosis in veterinary species are variable but commonly include a nodular, pyogranulomatous pattern targeting infected hair follicles, and, or a superficial perivascular dermatitis. Rare cases of 'dermatophyte pseudomycetoma' are characterized by granulomatous panniculitis with aggregates of fungal elements.

The normal course of mammalian dermatophytosis is self-cure within 1-4 months, although certain individuals, particularly long-haired cats, may fail to clear the infection efficiently. The contagious and zoonotic nature of this disease makes treatment mandatory for small companion animals. A combination of topical and systemic therapy, along with clipping of the hair is generally the optimal approach in small companion animals, although systemic therapy is rarely given in farm animals and horses. Confining the animal to an easily cleaned room during treatment limits environmental contamination.

Topical therapy is of particular value in targeting fungal elements within the stratum corneum of the interfollicular epidermis, and on the surface of hairs, thus reducing contamination and the risk of spread, but cannot be expected to access fungal elements deep within hair shafts (Borgers and others 1993). Thus, topical therapy should normally be considered to be an important adjunctive measure that should be combined with systemic therapy in the majority of cases (DeBoer and Moriello 1995). Several clinical trials have demonstrated that combination of topical and systemic therapy with griseofulvin is superior to systemic therapy alone in cats with M. canis dermatophytosis (Mason and others 2000, Paterson 1999, Sparkes and others 2000). Miconazole / chlorhexidine shampoos and lime sulfur dips are useful adjuncts for the treatment of more generalized cases in cats (Newbury and others 2007, Paterson 1999, Sparkes and others 2000) . Enilconazole is not licensed for use in cats and there are conflicting reports on its safety in this species (de Jaham and others 1998, Hnilica and Medleau 2002).

Systemic therapy is routinely needed in haired veterinary species because hyphae and arthrospores penetrate deep within the hair follicles and hair shafts. Griseofulvin was the most commonly used systemic treatment for dermatophytosis in small animals, although it is no longer licensed in for animal use in many countries.The principal alternatives to griseofulvin for systemic therapy of dermatophytosis are ketoconazole and itraconazole. Itraconazole is expensive but may be generally safer that ketoconazole, which may cause anorexia, vomiting and hepatotoxicity. Itraconazole is now licensed for use in cats with M. canis dermatophytosis using an alternate week dosing schedule, reflecting its incorporation into stratum corneum and hair (Vlaminck and Engelen 2005).

Preliminary studies indicate potential for use of terbinafine in the treatment of canine and feline dermatophytosis but this requires further assessment (Moriello 2004). A report of dramatic therapeutic

20 efficacy of lufenuron, an inhibitor of chitin synthesis widely used in flea control, in canine and feline dermatophytosis (Ben-Ziony and Arzi 2000) has been discounted by subsequent controlled studies (Moriello 2004).

For environmental decontamination, the use of disinfectants alone is not adequate (Moriello 2009). All gross debris should be moved by vacuuming and dusting of surfaces, followed by a thorough wash of all surfaces with water and detergent. In homes, the only products that were safe and practical to use in the home are hypochlorite bleach (but obviously only on selected surfaces) and enilconazole environmental spray.

REFERENCES

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Åhman, S., Perrins, N. & Bond, R. (2007b) Treatment of Malassezia pachydermatis-associated seborrhoeic dermatitis in Devon Rex cats with itraconazole - a pilot study. Vet Dermatol 18, 171-174

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24 FELINE MYCOBACTERIAL INFECTIONS Danièlle Gunn-Moore Speaker: Kerry Simpson Professor of Feline Medicine BVM&S Cert VC PhD FACVSc University of Edinburgh (Feline Medicine) MRCVS RCVS Specialist in Feline Medicine

INTRODUCTION

Several species of mycobacteria can cause disease in veterinary species, being either primary pathogens, or becoming pathogenic under certain circumstances.

Tuberculosis can be caused by a number of different, but closely related, bacteria. Relevant members of the tuberculosis complex group include Mycobacterium (M.) tuberculosis, M. bovis and M. microti. M. tuberculosis causes over 90% of tuberculosis in man, but rarely infects other mammals, except for dogs. M. bovis is the main cause of tuberculosis in cattle. It can also infect various other mammals, including humans, dogs, cats, deer, llama and pigs. M. microti causes tuberculosis in voles and cats (in the latter it was previously termed M. microti-like and has culture characteristics between M. tuberculosis and M. bovis).

Other potentially pathogenic mycobacteria include M. avium which causes mycobacteriosis in birds, and can also infect man, dogs and cats.This is a member of the M. avium-intracellulare complex (MAC) and these organisms are mainly ubiquitous saprophytes. M. lepraemurium, which causes leprosy in rats, and a similar, or possibly the same, organism may be one of the causes of feline leprosy. Other opportunistic (or atypical) non-tuberculous mycobacteria (NTM) are usually saprophytes, but a number of species have been reported to cause disease in cats.These include M. chelonae-abscessus, M. fortuitum / peregrinum group, M. smegmatis, M. phlei, M. genavense, M. simiae, M. thermoresistible, M, flavescens, M. xenopi, M. alvei and M. terrae complex.

Mycobacterial syndromes seen in cats therefore include tuberculosis, feline leprosy and NTM mycobacteriosis. All three syndromes have been reported in the UK, where the majority of cases appear to be cutaneous in nature. All three syndromes can present with nodules, draining tracts and/or ulceration. In some cases, the disease may become generalised secondary to skin inoculation, but only occasional cases present with primary systemic disease.Where systemic disease is seen, infection with a member of the tuberculosis group or a MAC organism is most likely, although occasional cases have been seen with NTM. In many cases of feline mycobacteriosis, infection can be related to percutaneous injury, contamination via soil or the presence of devitalised tissue.These factors tend to be reflected in the distribution of the lesions.

It is difficult to determine just how common each of the infections are: however, our recent studies revealed that in Great Britain feline mycobacterial infections are far from rare; being reported in ~1% of feline tissue samples submitted to diagnostic laboratories for routine histopathology (with ~0.3% being Ziehl Neelsen (ZN)-positive). In addition, over a four year period to December 2008, 339 ZN-positive feline samples were received by the Veterinary Laboratories Agency (VLA) for culture; M. microti was identified in 19%, M. bovis in 15%, M. avium in 7%, M. malmonoense in 1%, unclassified mycobacterium in 4%, and the samples failed to culture in 53%. A positive culture was only gained in 45% of samples in part because the culture system used by the VLA is optimised for the growth of M. bovis and other members of the tuberculosis complex group. Many of the NTM would not have been identified by this system and even with optimised systems are exceedingly difficult to grow.

TUBERCULOSIS

CLINICAL BACKGROUND: EPIDEMIOLOGY AND AETIOPATHOGENESIS:

In cats, tuberculosis has classically been described as being caused by M. bovis. Historically, infection resulted from the ingestion of milk from tuberculous cattle.With the reduction of tuberculosis from the national herd,

25 and the pasteurisation of milk, there has been a marked decline in the prevalence of the disease seen in cats.

Currently, tuberculosis in cats is recognised infrequently. When it is diagnosed it is usually caused by infection with either the cattle form of the infection (M. bovis) or the vole form (M. microti). Of the recent cases of tuberculosis in the UK 61% was found to be caused by M. microti and 39% by M. bovis. Infection of cats with M. tuberculosis is incredibly rare, probably because cats are naturally very resistant to it. (Interestingly, this is quite different from the picture seen in humans; where over 90% of cases result from infection with M. tuberculosis, approximately 1% is caused by M. bovis, and disease due to M. microti is incredibly rare).

The current epidemiology of tuberculosis in cats is unclear. Few cases are believed to relate to direct infection from cattle.This is because when tuberculosis is gained by drinking contaminated cows milk the infection settles within the cat's intestines, and disease results in diarrhoea and weight loss. It is probably because almost all cows' milk is now pasteurised that this type of tuberculosis is very rare. The tuberculosis that we now see most frequently in cats affects their skin; where it causes ulcers and masses that fail to heal. This is often associated with lymphadenopathy, especially of the submandibular lymph nodes, and some cases show only lymphadenopathy. In chronic cases, where the infection has spread to the cat's lungs, they may develop a soft cough and/or dyspnoea.

It is important to try to determine how cats are becoming infected. If we look into possible risk factors we find that most of the cats are keen hunters, regularly catching small rodents. Interestingly, studies have shown that in the UK wild mice and voles can carry M. microti, and the same species and a wide range of other animals in the salvatic reservoir (e.g. foxes, stoats, moles, rats and deer) can carry M. bovis. It is therefore most likely that cats become infected by hunting small wild rodents.This also accounts for the distribution of the skin lesions seen on these cats, which occur most frequently on the face and legs, i.e. the areas most likely to be bitten when playing with prey. In some areas of Britain M. bovis has become endemic in badgers. While cats and badgers rarely interact directly, there may be a potential risk for cats to become infected via local environmental contamination. M. bovis can also be endemically present in many other species of free-ranging wildlife, e.g. deer; so the risk of feline infection may vary in each country dependent on the likely interaction between these species and domestic cats.

All members of the tuberculosis complex pose potential zoonotic risks. However, to date, there have been no reported cases of cats passing tuberculosis onto humans. By far the greatest tuberculosis risk to humans is spending time with infected humans or, less frequently, handling infected cattle. M. tuberculosis and M. bovis can both cause reverse zoonoses and there have been a small number of cases where humans have infected their cats (with M. bovis).

PREDISPOSITION:

Most cases of feline tuberculosis are probably sub-clinical in nature. Infection usually occurs after protracted exposure, e.g. repeated exposure to infected small mammals, living on a farm housing tuberculous cattle, or living for prolonged periods with infected humans or poultry. In Great Britain tubercle group mycobacterial infections have a geographical distribution, with M. bovis being found in cats in the South West of England (co- incident with the area of the country where cattle and badger are infected with M. bovis), while M. microti is found in the South East of England, the North of England and the South of Scotland. Tuberculosis is seen mainly in adult cats (median age for M. bovis is 3 years, while for M. microti it is 8 years); and interestingly, is seen most commonly in males. No evidence of classical immunosuppression has been found as those cats tested for FIV and FeLV have usually been negative. However, we have shown that these cats have low serum vitamin D concentrations which may play a role in the effectiveness of their macrophages in fighting these infections.

CLINICAL SIGNS:

Depending on the route of infection, affected cats may present with systemic signs related to the alimentary, and/or respiratory tracts, or with localised disease affecting the skin. Currently, the most usual presentation for tuberculosis in cats is the cutaneous form, with respiratory and alimentary forms being seen less frequently.

26 In the cutaneous form the lesions probably arise from infected bite wounds, local spread or haematogenous dissemination to the skin. The lesions often involve the face, extremities, tail base or perineum, i.e. "fight and bite sites". Less frequently they involve the ventral thorax. They generally take the form of firm, raised, dermal nodules, ulceration, or non-healing wounds with draining sinus tracts. Extension of granulomatous tissue may in some cases involve the subcutaneous structures, muscle and/or bone. Skin lesions are commonly associated with either local or generalised lymphadenopathy. On occasion, submandibular or prescapular lymphadenopathy may be the only clinical finding.

In rare cases where the infection is acquired through inhalation, tubercles arise in the lungs and/or hilar lymph nodes and affected cats present with weight loss, anorexia, dyspnoea and coughing. However, pulmonary infection occurs more frequently, secondary to haematogenous spread from cutaneous lesion so the infection is more typically interstitial (but eventually spreading to bronchial), so the changes are more diffuse and the cats typically only show dyspnoea.

In the alimentary form, tubercles arise in the intestines and/or mesenteric lymph nodes. Affected cats commonly develop intestinal malabsorption and present with weight loss, anaemia, vomiting and diarrhoea. Occasionally tubercles arise in the tonsils, resulting in signs of oropharangeal disease.

A range of clinical signs may be seen with disseminated disease.These include splenomegaly, hepatomegaly, pleural or pericardial effusions, generalised lymphadenopathy, weight loss and fever. Lameness may result from bone involvement. Granulomatous uveitis and signs referable to central nervous system involvement have been seen in some cases.

DIAGNOSTIC TECHNIQUES:

NON-SPECIFIC TESTS:

A thorough evaluation of the patient is necessary to assess the extent of local infection and the degree of systemic involvement. Changes in serum biochemistry and haematology, if present, are non-specific and vary with the severity of the disease. However, hypercalcaemia has been seen in a number of cases and appears to correlate with a poorer prognosis.Radiography can be useful in the appraisal of lung involvement. However, changes are very variable and include tracheo-bronchial lymphadenopathy, interstitial or miliary lung infiltration, localised lung consolidation, or pleural effusion. Abdominal radiography may reveal hepato- or splenomegaly, abdominal masses, mineralised mesenteric lymph nodes, or ascites. Bone lesions tend to consist of areas of bony lysis and sclerosis, osteoarthritis, discospondylitis or periostitis.

SPECIFIC TESTS:

The recently developed interferon-gamma test is showing promise for detecting members of the tuberculosis complex. Other specific tests for the diagnosis of tuberculosis have been investigated in cats, but have generally proved less helpful, although newer tests for specific serum antibody responses are still being developed. Unlike other species, cats do not react strongly to intra-dermally administered tuberculin and the results from intra- dermal skin testing are unreliable.

To confirm mycobacterial involvement, aspirates and/or biopsy samples of affected tissue should be stained with ZN stain or other specific special stains.The number of acid fast bacilli seen within affected macrophages may be variable, depending on the species of mycobacteria involved, the location of the granuloma and, probably most importantly, the nature of the cat's immune response. While finding acid fast bacilli confirms the presence of mycobacteria, it is important to identify the organism (by culture or PCR) to determine the exact species involved. Once the species has been identified it is possible to evaluate zoonotic risk, potential sources of infection, and feasible treatment options. Unfortunately, many samples that are seen to have ZN positive organisms fail to culture positive, and even those that do often take two-three months. While molecular PCR techniques are now available, and can be considered where tissue for culture is not available, they are expensive, and have still to be perfected (see end for details).

27 CORRECT HANDLING OF BIOPSY MATERIAL:

In practice, this usually involves taking a biopsy from a case where mycobacterial disease is only one of a large number of possible differential diagnoses. If in-house facilities are available for ZN staining, this can be performed on aspirates or biopsy impression smears. However, in most cases biopsy material must be sent to a veterinary diagnostic laboratory. It is practical to collect the biopsy, cut it into four pieces, fix one in formalin for histopathological examination and ZN staining and, pending results, place two in a sterile container and freeze them. Where other bacterial infections are suspected, the fourth sample should be sent unfixed for routine bacterial culture and ZN staining. If the sample is found to have ZN positive organisms, one of the frozen pieces can be sent for specialist culture (by the VLA and/or a Mycobacterial Reference Laboratory; see end of text for addresses), while the last sample is kept in case further investigation is needed. This is advisable for all enlarged lymph nodes and cutaneous/subcutaneous nodules in cats.

Until the organism has been properly characterised, it should be considered a potential human pathogen.

Whenever handling potentially tuberculous material it is necessary to take certain precautions. In the UK, the law dealing with material KNOWN to be tuberculous is very exact and requires the use of specialist laboratories. However, the law relating to material taken from animals where tuberculosis is only one of a number of possible differentials is less stringent. In the latter case routine aseptic practices are generally adequate, although gloves should be worn when handling either the biopsy site or the biopsy material.

Under the Tuberculosis Orders currently in force in England, Wales, and Scotland, the identification of M. bovis in clinical or pathological samples taken from any mammal (except humans) is notifiable to the VLA (see end of text for the address). This, of course, includes domestic cats and other felines. The same Orders impose a duty on any veterinary surgeon who suspects tuberculosis in a domestic cat to immediately notify the Divisional Veterinary Manager at the local office of the State Veterinary Service. When a confirmed case is euthanased it is advisable to have the body cremated. For DEFRA Guidance notes on Tuberculosis in cats go to: CatsTBbriefing (VIPER23 App Y5)_March 08 update.doc

HISTOPATHOLOGY:

Histopathology of affected tissue generally reveals granulomatous inflammation, with foamy macrophages containing variable numbers of acid fast bacilli.

MANAGEMENT:

Interim Management: Deciding to treat a case of suspected feline tuberculosis is always contentious. Before undertaking treatment it is important to address a number of points: l Consider the potential zoonotic risk. All members of the affected cat's household must be involved in any decision making.Particular consideration should be given to those individuals most susceptible to the infection, e.g. household members with HIV infection, or those undergoing chemotherapy or organ transplantation. We strongly advise against treatment where such individuals may be exposed to an infected cat. We also advise against treatment if the affected cat has generalised disease, respiratory tract involvement, or extensive draining cutaneous lesions; any of these findings may increase the risk of transmission. l Where the cat is a suitable candidate, it should be emphasised that treatment is long-term and difficult to maintain given patient non-compliance, the inherent toxicity of some of the drugs and the financial costs involved. In some cases the drugs may at best suppress the disease and indefinite treatment may be required. Uncomplicated cutaneous disease appears to carry the most favourable prognosis. l Tailoring treatment is difficult as sensitivity testing does not always correlate with in vivo results. l Surgical excision of small cutaneous lesions may be considered, but is successful in only a few cases. Debulking larger lesions risks wound dehiscence and local recurrence of infection.

28 Pending a definitive diagnosis, interim therapy with a fluoroquinolone has previously been recommended. However, this should only be considered in cases of localized cutaneous infection. It is more sensible to recommend that double or triple therapy be initiated (Table 1). This not only gives the best chance of clinical resolution, but also decreases the potential for the mycobacteria to develop resistance to the fluoroquinolone. This is an important consideration since generating drug resistance will be detrimental not only to the individual cat, but may also endanger human patients.

Before deciding on continued treatment it is ideal to know exactly which form of mycobacteria is responsible. This is because it is strongly inadvisable to continue treating a cat with M. tuberculosis or disseminated M. bovis (and UK and Scottish law dictates that M. bovis infection is notifiable). Unfortunately, in many cases it is not possible to culture organisms from tissue samples that have been seen to have positive ZN staining. Because of this is it essential to counsel owners very carefully, making them aware of all of the potential risks and complications.

TREATMENT OF CHOICE:

Ideally, anti-tuberculosis treatment should consist of an initial and a continuation phase.The initial phase usually requires at least three drugs and lasts for two months, while the continuation phase requires two drugs and lasts for perhaps a further four months, depending on the type and extent of the disease. In those cats where triple therapy is not feasible, treatment should still involve at least two drugs and should be given for a minimum of six to nine months.

Traditionally, the rifampicin-isoniazid-ethambutol combination has been considered the most effective regime for the treatment of tuberculosis in animals. However, some newer and less toxic drugs are worth appraisal. The fluoroquinolones, e.g. marbofloxacin, have potential in the treatment of feline tuberculosis, as well as NTM mycobacteriosis.The newer fluoroquinolone, pradofloxacin may also be useful, and it has a wider efficacy. Clarithromycin is a modern macrolide which is used in the treatment of human tuberculosis; it appears to be effective in cats with mycobacterial infection, especially when given in combination with rifampicin and/or another antibiotic as per culture e.g. marbofloxacin or doxycyclin. A potentially useful once daily alternative to clarithromycin is azithromycin, although it may not be as effective. To date, the only side effect seen with clarithromycin treatment has been pinnal or more generalised erythema which resolves on discontinuation of the drug. From clinical experience gained over the past 15 years we recommend treatment consisting of an initial phase of rifampicin-fluoroquinolone-clarithromycin/azithromycin, followed by a continuation phase of rifampicin and either fluoroquinolone or clarithromycin/azithromycin (Table 1). For ease of administration all three once-daily medications can be given as liquids and placed in a single syringe prior to oral administration, or given as tablets with all three being given together after being placed in a single gelatin capsule. Alternately, where oral medication proves too difficult, an oesophagostomy tube may be placed (through which the liquid medications can be given) and left in place for the duration of the treatment.

In cases where resistance develops, the rifampicin-isoniazid-ethambutol combination may be considered. If necessary, ethambutol can be substituted with dihydrostreptomycin or pyrazinamide. However, where M. bovis has been confirmed, pyrazinamide is not recommended due to the organism's natural resistance. Rifampicin and isoniazid are more effective and less toxic than ethambutol and dihydrostreptomycin and consequently are more appropriate choices if only two drugs are required.

PROGNOSIS:

The prognosis depends on the type of mycobacteria involved, and the extent and severity of the infection. While many cases, especially those caused by M. microti infection, have responded favourably to treatment, and have achieved apparent cure or long-term remission, the prognosis should always be stated as guarded.

29 FELINE LEPROSY SYNDROME

CLINICAL BACKGROUND: EPIDEMIOLOGY AND AETIOPATHOGENESIS:

Infection with M. lepraemurium is largely assumed as the organism cannot be cultured using standard techniques. However, recent reports from Australia show that feline leprosy can take one of two different forms and that while disease in younger cats does appear to be caused by M. lepraemurium; the disease seen in older cats appears to be caused by a novel, but as yet undefined, mycobacterial species. Infection is believed to be gained by the introduction of the organisms through bite wounds from rodents. However, this is not proven and it is also possible that infection is gained via soil contamination of cutaneous wounds. As yet, there is no known zoonotic potential for this disease.

PREDISPOSITION:

There is no breed or gender predisposition but adult cats are more often affected. The prevalence of feline leprosy is higher in areas with a temperate maritime climate, e.g.Australia, New Zealand, Europe (UK, the Channel Islands,The Netherlands), western Canada and western parts of the USA (California, Oregon).

CLINICAL SIGNS:

Feline leprosy is primarily a cutaneous syndrome: single or multiple nodules, which may be haired, alopecic or ulcerated, may be seen on the head, limbs and occasionally the trunk. They are non-painful and freely mobile. Regional lymphadenopathy may be present but systemic disease is rare. In Australia this disease appears to have two different forms: one type affecting young cats, which initially develop localised nodular, often ulcerated, lesions on the limbs, which progress rapidly, while the other type affects older cats, which develop more generalized skin involvement with no ulceration and a slower clinical progression.

DIAGNOSTIC TECHNIQUES:

Cytology and histopathology (with the use of special stains) are the major methods of diagnosis. In young cats there are typically few acid fast organisms present. However, in older cats the lesions often contain large numbers of acid fast organisms, which can be clearly seen within macrophages. Culture is usually unrewarding, but should be performed in all suspect cases as the clinical signs and histopathology of feline leprosy can mimic those of feline tuberculosis. Molecular PCR techniques are currently being investigated and do show promise.The diagnostic approach discussed previously for tuberculosis should be followed.

MANAGEMENT:

Interim management: The minimum of a fluoroquinolone (Table 1.) should be used pending diagnosis. Treatment of choice: Surgical removal of small nodules is recommended. Clofazamine (Table 1.) has been used in a limited number of cases where surgical removal was difficult. Dapsone is considered too toxic for use in cats.

PROGNOSIS:

The prognosis is good and spontaneous resolution may occur.

30 DISEASE CAUSED BY NON-TUBERCULOUS MYCOBACTERIA (NTM)

CLINICAL BACKGROUND: EPIDEMIOLOGY AND AETIOPATHOGENESIS:

This syndrome is caused by saprophytic, usually non-pathogenic, organisms which are found in soil, water and decaying vegetation. The "fast growing" representatives of this mycobacterial group are most commonly implicated in feline skin disease. However, as our ability to recognise the implications of "bite site" lesions improves, along with our access to the expertise of the specialist laboratories, slow growing variants are being recognised more frequently, as they are in human medicine.

The following organisms have been implicated in causing this syndrome; MAC, M. chelonae-abscessus, M. fortuitum / peregrinum group, M. smegmatis and M. phlei. Other NTM that have also been found causing disease in cats include M. genavense, M. simiae, M. thermoresistible, M. flavescens, M. xenopi, M. malmoense, M. alvei and M. terrae complex. All of these organisms can cause disease through contamination of cutaneous wounds and are particularly pathogenic if inoculated into adipose tissue. Entry through the gastrointestinal or respiratory tracts is rare.

PREDISPOSITION:

In general, cats appear to be at greater risk of infection with this group of mycobacteria than most other domestic species. Adult cats with a hunting or fighting lifestyle are more likely to be affected. Certain breeds of cat appear to be predisposed to infection with MAC organisms, including Siamese, Abyssinian and Somali breeds. Disease appears to be more common in tropical and subtropical areas of the world. However, difficulties associated with diagnosis may influence its true prevalence. Unlike the situation in humans, immunosuppression has only been found in a small number of the affected cats.

CLINICAL SIGNS:

Many of the different species of NTM produce similar clinical syndromes.The most common of which is typified by panniculitis, where multiple, punctate draining tracts occur with a "salt and pepper shaker" appearance.These are associated with subcutaneous nodules and coalescence produces large areas of ulcerated, non-healing tissue. Affected areas can be extremely painful. The inguinal fat pads, flanks and the tail base are affected most frequently. However, any area may be affected if it is prone to injury (and has sufficient subcutaneous fat). The lesions may be exacerbated by surgery and dehiscence associated with satellite lesions is common. Other cases may present with single or multiple cutaneous lesions which may be haired or alopecic, ulcerated or not, and/or adherent to underlying tissue. Although systemic spread is rare, fever, anorexia and reluctance to move may be seen. Primary pulmonary infection with M. fortuitum and disseminated infections with M. smegmatis and M. xenopi have been reported and may have arisen from non-cutaneous routes of entry.

DIAGNOSTIC TECHNIQUES: HISTOPATHOLOGY:

Pyogranulomatous panniculitis and/or dermatitis is seen and should automatically warrant a search for mycobacteria. These organisms are difficult to identify in histopathological sections even when acid fast stained, but the use of modified Fite's or rapid ZN methods will increase the sensitivity of detection.

CULTURE:

Culture from a biopsy specimen is the diagnostic test of choice. Some of the organisms are relatively easy to grow on Lowenstein Jensen media, but molecular PCR techniques are also currently being investigated.

31 MANAGEMENT:

Interim management: The minimum of a fluoroquinolone is suggested while waiting for culture.

TREATMENT OF CHOICE:

This is controversial and evaluation of the individual case is required. Ideally, antimicrobial therapy should be determined by culture and sensitivity.The fluoroquinolones, e.g. marbofloxacin, have potential in the treatment of NTM mycobacteriosis. However, they often do not appear to be effective against MAC infection, except possibly when some of the newer preparations are used, e.g. pradofloxacin or moxifloxacin. When treating MAC infections the best results have been gained when clarithromycin has been included in the treatment regimen. Clarithromycin appears to be effective in cats with mycobacterial infection, especially when given in combination with rifampicin and/or another antibiotic as per culture e.g. doxycyclin. A potentially useful once daily alternative to clarithromycin is azithromycin, although it may not be as effective.

Different species of NTM have differing sensitivity patterns. One paper showed M. chelonae-abscessus and M. fortuitum were sensitive to amikacin (100%), cefoxitin (94%), ciprofloxacin (75% - presume other fluoquinolones are similar), clarithromycin (71%) and doxycycline (29%). M. smegmatis is usually sensitive to fluoquinolones, and M. xenopi may be sensitive to fluoquinolones, clarithromycin, rifampicin and clofazimine. It is possible that double or triple therapy with a combination of fluoquinolone, clarithromycin or azithromycin, and/or rifampicin should be considered as for the tuberculosis syndromes (Table 1.). A new fluoquinolone, pradofloxacin, has an extended spectrum of activity and has been shown to have activity against some NTM; and it has been suggested that it could be combined with doxycycline to treat M. smegmatis, and with clarithromycin to treat M. fortuitum. Antibiotic therapy should be continued for protracted periods of time, i.e. six to twelve weeks. Surgical intervention should be radical and planned with the same precision as removing a locally invasive neoplasm. Antibiotic therapy in combination with surgery has been recommended.

PROGNOSIS:

Prognosis is poor to guarded. The prognosis deteriorates further when there have been previous unsuccessful attempts at surgery.

32 TABLE 1. Potentially useful drugs for the treatment of feline and canine mycobacterial disease (see text for information on potential drug combinations and treatment duration). Uses Drug Dose Interval Toxicity mg/kg hours 1st line tx for TB + Marbofloxacina 2 PO 24 Retinal degeneration? NTM Pradofloxacin 10 PO 24 1st line tx for TB, Rifamp(ic)inb 10-15 PO 24 Hepatotoxicity, induction of liver MAC + NTM (Max enzymes, discoloration of body 600mg/d) fluids, generalised erythema + pruritus, teratogenic, poor palatability 1st line tx for TB, Clarithromycinbc 5-15 PO 12 Pinnal or generalised erythema, leprosy + NTM hepatotoxicity? GI signs? Azithromycinb 5-15 PO 24 2nd line tx for TB Isoniazidb 10-20 PO 24 Hepatotoxicity, peripheral neuritis, (Max seizures, acute renal failure. 300mg/d) As above Prophylaxis for TB 10 PO 24 2nd line tx for TB Dihydro 15 IM 24 Ototoxicity. -streptomycinb 2nd line tx for TB Pyrazinamidebd 15-40 PO 24 Hepatotoxicity, GI signs. 2nd line tx for TB Ethambutolb 10-25 PO 24 Optic neuritis. Tx for leprosy, Clofazaminebe 4-8 (occ. ~10) 24 Hepatotoxicity, G-I signs, discoloration NTM + MAC PO Max 25 of body fluids, photosensitization, total pitting corneal lesions 2nd line tx for Doxycycline 5-10 PO 12-24 G-I signs, oesophagitisf NTM + MAC Amikacinb 10-15 IV, 24 Nephrotoxic, ototoxic IM, SC

Cefoxitinb 20-30 IV, 6-8 Pain on injection IM, SQ IM, SCpo

TABLE 1 REFERENCES tx - treatment, TB - tuberculosis, NTM - non-tuberculous mycobacteria, MAC - M. avium-intracellulare complex, PO - per os, IM - intramuscularly, SC - subcutaneously.aThe authors recommend using a fluroquinolone that is not enrofloxacin when treating cats as the latter has been associated with retinal degeneration. Most fluroquinolones are not effective against MAC infections. bThese drugs are not licensed for use in pets. cParticularly useful when treating MAC infections. dNot effective against M. bovis infection. eCan be difficult to obtain. fGive with food or give water after the medication to avoid oesophageal injury. Second line treatments for tuberculosis should be reserved for resistant infections. Drugs licensed for human use can be obtained by veterinary prescription from larger chemists as long as all aspects of cascade prescribing have been considered.

33 REFERENCES AND FURTHER READING: l Baral, R.M., Metcalfe, S.S., Krockenberger, M.B., Catt, M.J., Barrs, V.R., McWhirter,C., Hutson, C.A., Wigney, D.I., Martin, P., Chen, C.A., Mitchell, D.H. and Malik, R. (2006) Disseminated Mycobacterium Avium infection in young cats: overrepresentation of Abysinian cats. JFMS 8, 23-44 l Beccati, M., Peano, A. and Gallo, M.G. (2007) Pyogranulomatous panniculitis caused by Mycobacterium alvei in a cat. JSAP, 48, 664 (letter) l Bennett A, Lalour S, Swartz T, Gunn-Moore DA. Radiographic Changes in Cats with Mycobacterial Infections. JFSM (2011) 13(10): 718-24 l Cavanagh R, Begon M, Bennett M, Ergon T, Graham IM, De Haas PE, Hart CA, Koedam M, Kremer K, Lambin X, Roholl P, Soolingen Dv D. (2002) J Clin Microbiol. Mycobacterium microti infection (vole tuberculosis) in wild rodent populations. 40(9):3281-5 l Delahay RJ, Smith GC, Barlow AM, Walker N, Harris A, Clifton-Hadley RS, Cheeseman CL. (2007) Bovine tuberculosis infection in wild mammals in the South-West region of England: a survey of prevalence and a semi-quantitative assessment of the relative risks to cattle.Vet J.173(2):287-301 l Greene,C.E. and Gunn-Moore, D.A. Mycobacterial infections. In: Infectious Diseases of the Dog & Cat, 3rd edition, Greene,C.E. (ed.). W.B. Saunders Co., Philadelphia, PA, 2006; pp.462-477 l Greene,C.E. & Gunn-Moore, D.A. "Mycobacterial Infections". In: Infectious Diseases of the Dog and Cat. Ed. Greene,Fourth Edition, 2012. C.E., Saunders, W.B., Philadelphia, pp 495-510. l Govendir M, Norris JM, Hansen T, et al. (2011) Suseptibility of rapidly growing mycobacteria and Nocardia isolates from cats and dogs to pradofloxacin. Vet Micro: 153: 240-245 l Gunn-Moore, D.A. "Mycobacterial infections in cats and dogs" In: Textbook of Veterinary Internal Medicine, 7th Edition, Eds. S. Ettinger & E. Feldman, 2010. C.E., Saunders, W.B., Philadelphia, pp. 875-881 l Gunn-Moore, D.A., Jenkins,P.A. and Lucke, V.M. (1996) Feline tuberculosis: a literature review and discussion of 19 cases caused by an unusual mycobacterial variant. Vet. Rec. 138, 53-58 l Gunn-Moore, DA, McFarland, S, Brewer J, Crawshaw, T, Clifton-Hadley RS, Kovalik M, Shaw, DJ. Mycobacterial disease in cats in Great Britain: 1 bacterial species, geographical distribution and clinical presentation of 339 cases. JFSM (2011) 13: 934-944 l Gunn-Moore, DA, McFarland, S, Brewer J, Crawshaw, T, Clifton-Hadley RS, Schock A, Shaw, DJ. Mycobacterial disease in cats in Great Britain: 2 histopathology, treatment and outcome of 339 cases. JFSM (2011) 13: 945-952 l Gunn-Moore, DA, Gaunt, C, Shaw, DJ. Incidence of mycobacterial infections in cats in Great Britain: estimate from feline tissue samples submitted to diagnostic laboratories. Transboundry Emerging Diseases, 2012, In Press l Jang,S.S. and Hirsh, D.C. (2002) Rapidly growing members of the genus Mycobacterium affecting dogs and cats.JAAHA. 38, 217-220 l Lalor SM, Mellanby RJ,Friend EJ, Bowlt KL, Berry J, Gunn-Moore D. Domesticated Cats with Active Mycobacteria Infections have Low Serum Vitamin D (25(OH)D) Concentrations. Transbound Emerg Dis. (2012) 59(3):279-81 l Malik, R., Hughes, M.S., Martin, P. and Wigney, D. Feline leprosy syndromes. In: Infectious Diseases of the Dog & Cat, 3rd edition, Greene,C.E. (ed.). W.B. Saunders Co., Philadelphia, PA, 2006; pp.477-480 l Malik, R., Hunt, G.B., Goldsmid, S.E., Martin, P., Wigney, D.I. & Love, D.N. (1994) Diagnosis and treatment of pyogranulomatous panniculitis due to Mycobacterium smegmatis in cats. J Sm An Pract. 35, 524-530 l Malik, R., Martin, P. Wigney, D. and Foster, S. Infections caused by rapidly growing mycobcateria. In: Infectious Diseases of the Dog & Cat, 3rd edition, Greene,C.E. (ed.). W.B. Saunders Co., Philadelphia, PA, 2006; pp.482-488 l Meeks, C. Levy,J.K., Crawford, P.C. and others. (2008) Chronic disseminated Mycobacterium xenopi in a cat with idiopathic CD4+ T-lymphopenia. JVIM, In press. l Monies,B., Jahans, K. and de la Rue, R. (2006) Bovine tuberculosis in cats.Vet. Rec.158, 245-256 (letter) l Mundell, A.C. Mycobacterial skin diseases in small animals. In: Kirk's Current Veterinary Therapy, XII. Bonagura, J. (Ed.). W.B. Saunders, Philadelphia, PA, 1995; pp.662-625 l Rhodes,S.G., T.J. Gruffydd-Jones,D.A.Gunn-Moore and K.Jahans. An Interferon-gamma test for Feline Tuberculosis.Vet Rec (2008) 162: 453-455 l Rhodes,S.G., T.J. Gruffydd-Jones,D.A.Gunn-Moore and K.Jahans. Adaptation of IFN-gamma ELISA and ELISPOT for the diagnosis of feline tuberculosis.Veterinary Immunology and Immunopathology (2008) 124(3-4): 379-84 34 l Rhodes SG, Gunn-Moore DA, Boschiroli L, Schiller I, Esfandiari J, Greenwalr R, Lyashchenko KP. Comparative study of IFN and antibody tests for feline tuberculosis.Veterinary Immunology and Immunopathology (2011) 144: 129-134 l Rüfenacht S, Bögli-Stuber K, Bodmer T, Bornand Jaunin V, Gonin Jmaa DC, Gunn-Moore DA. Feline Mycobacterium microti infection: a case report and literature review. JFSM (2011) 13: 195-204 l Studdert, V.P. & Hughes, K.L. (1992) Treatment of opportunistic mycobacteria infections with enrofloxacin in cats. JAVMA 201, 1388-1390

USEFUL ADDRESSES IN THE UK:

Danièlle Gunn-Moore, Professor of Feline Medicine, University of Edinburgh Small Animal Hospital, Easterbush Veterinary Centre, Roslin, Midlothian, Scotland, EH25 9RG Tel: 0131 650 765 Email: [email protected]

Please contact the author to discuss any case in more detail. We are currently trying to collate all of the cases in cats in the UK so that we can gain a better understanding of the presentation, causes, and treatment responses of the condition. We are also investigating the possible role of faulty Vitamin D metabolism in these cats and would love to receive 1-2ml of serum (and 0.5ml EDTA if at all possible) from any affected case so we can continue this work.

All potential cases should be reported to the VLA. The VLA is currently willing to undertake mycobacterial culture free of charge in cases where the history, clinical signs and/or histopathological findings are suggestive of mycobacterial infection. Please contact the TB Diagnostic Laboratory prior to sending samples to ensure appropriate samples are submitted, and enclose case details when submitting samples:

TB Diagnosis Section (SEB2), Veterinary Laboratories Agency (DEFRA) - Weybridge, Wood Lane, New Haw, Addlestone, Surrey, KT15 3NB Tel: 01932 357471

For IFN-g blood testing 1.5-2ml of heparinised blood is needed. Under Home Office regulations we are only allowed to request a blood sample from those cats where a blood sample is already being taken for some other blood test. Send sample in a well padded envelope marked with do not refrigerate to:

Dr. Shelley Rhodes Service not currently available - sorry TB Research Group Stewart Stockman Building,Veterinary Laboratories Agency, Addlestone, Surrey KT15 3NB Tel: 01932 357471 / 01932 359588 Fax: 01932 357406

For culture of samples that have failed to grow for VLA or for more extensive Mycobacterial culture the reference laboratories in Cardiff and Leeds have extensive experience of handling samples from cats.There will be a charge (generally ~£100 but it varies on how difficult the organism is to grow); please contact the laboratory prior to sending samples to ensure appropriate samples are submitted:

Regional Centre for Mycobacteriology (PHLS), Llandough Hospital, Penlan Road, Penarth, Cardiff CF64 2XX Tel: 02920 716408

35 National Mycobacterium Reference Laboratory (NMRL) HPA National Mycobacterium Reference Laboratory Abernethy Building, Institute of Cell and Molecular Science (ICMS), 2 Newark Street, London E1 2AT Tel: 020 7377 5895 Fax: 020 7539 3459 Director: Professor Francis Drobniewski Email: [email protected]

Where it is impossible to collect a sample for culture, it may be possible to confirm the presence of mycobacteria and whether or not the organism is a member of the tuberculosis complex by PCR test performed on formalin-fixed tissue (although a fresh unfixed tissue sample is always referred). However, the tests are expensive, and culture is preferable. [Costs as of April 1 2007: Routine Tb PCR and mycobacterium detection £159+vat; identification of atypical mycobacterium a further £130.50+vat; cost of differentiating members of the tuberculosis complex a further £213+vat]. Results are usually available within a week of specimen receipt. Please contact the NMRL (see above) or the laboratory below prior to sending samples to ensure appropriate samples are submitted:

Dr Deborah Gascoyne-Binzi Principal Clinical Scientist, Leeds Teaching Hospitals Trust, Department of Microbiology, The General Infirmary, Great George Street, Leeds LS1 3EX Tel: 0113 392 3929 (Laboratory: 0113 392 8797) Fax: 0113 343 5649 Email: [email protected].

36 FELINE COWPOX VIRUS INFECTION Danièlle Gunn-Moore Speaker: Kerry Simpson Professor of Feline Medicine BVM&S Cert VC PhD FACVSc University of Edinburgh (Feline Medicine) MRCVS RCVS Specialist in Feline Medicine

AETIOLOGY:

Infection is seen in domestic cats and cheetahs, rodents, humans, cattle, dogs, elephants and foals. Although cowpox virus infects cattle, they are not implicated as a source of infection for cats. Cats infected with cowpox are usually hunters of bank voles (Clethrionomys glareolus), field voles (Microtus agrestis) and wood mice (Apodemus sylvaticus) which are known to carry the infection. The infection can occasionally be found in the house mouse (Mus domesticus). Affected rodents do not usually show signs of infection. The prevalence of cowpox in cats is low but varies geographically. There is no age, breed or sex predilection. Infection is seen throughout Europe (Austria, Belgium, France, Germany, The Netherlands, and Norway) and the western states of the former Soviet Union. Disease is most common from July to November (when rodents are most common), but can occur any time.

CLINICAL SIGNS:

Virus enters the skin through a bite wound usually on the cat's head, neck or limb. Infection becomes apparent after a few days as a small ulcerated nodule.This may be followed by secondary bacterial infection, causing cellulitis and/or abscessation. The virus multiplies in the lungs, nasal passages and lymphoid tissues for ~5 days producing a transient viraemia. The mouth, nasal passages, lungs and gut may be affected with oral and gastrointestinal ulceration, nasal discharge, pneumonia and diarrhoea. Signs of viraemia are usually mild and include serous to mucopurulent discharge, pyrexia, depression and poor appetite.

Numerous skin lesions may appear 10 days to several weeks later.These are oval to circular ulcerated papules and plaques up to 1 cm in size, and may occur on any part of the body. Pruritus is not a feature. The plaques are covered with crust material which separate as the infection resolves; there may be residual scarring and alopecia. Infection usually resolves over 6-8 weeks. If the cat is immunosuppressed (glucocorticoids, FIV, FeLV) severe generalised systemic infection and focal to fulminant necrotizing pneumonia may develop.

DIAGNOSIS:

A positive antibody titre is supportive of recent infection (previous 6 months). Titres may be positive 7- 14 days after initial exposure. Crust material from skin lesions can be sent in a sterile container for analysis; PCR (quick and sensitive); viral culture (takes 3- 10 days); or electron microscopy (where it is available). Skin biopsies show characteristic changes on histopathologic examination.

TREATMENT:

The lesions usually heal (albeit slowly) without intervention. Secondary bacterial infection may require broad- spectrum antibiotics. Severe cases may require hospitalisation and fluid therapy. Severe cases with respiratory involvement have a poor prognosis unless treated with interferon (Feline IFNω- Virbagen 0.5-1 M IU/kg SQ q24h, 3x), plus O2, covering antibiotics (e.g. amox-clav, 'quinolone, clinida), analgesia and, potentially, inhaled steroids. Avoid glucocorticoids (unless IFN is also given) because the clinical signs may become much worse.

SPREAD OF INFECTION:

Cat-to-cat transmission may occur and cowpox can be an occasional zoonosis, especially to very young or elderly immunosuppressed people, or individuals with severe (especially atopic) skin disease.The virus can survive for months at room temperature and is resistant to many disinfectants (hypochlorite-based products are effective).

37 REFERENCES

Veterinary Record 1986;118:387-390 Poxvirus infection in the domestic cat: some clinical and epidemiological observations M Bennett, CJ Gaskell, RM Gaskell, D Baxby and TJ Gruffydd-Jones

Acta Virol. 1992 May;36(3):329-31. Experimental infection of domestic cats by cowpox virus. Zhukova OA, Tsanava SA, Marennikova SS.

Vet Rec. 1983 Feb 19;112(8):164-70. Natural and experimental pox virus infection in the domestic cat. Gaskell RM, Gaskell CJ, Evans RJ, Dennis PE, Bennett AM, Udall ND, Voyle C, Hill TJ.

Arch Virol. 1989;104(1-2):19-33. Studies on poxvirus infection in cats. Bennett M, Gaskell RM, Gaskell CJ, Baxby D,Kelly DF.

38 UPPER RESPIRATORY TRACT DISEASE Danièlle Gunn-Moore Speaker: Kerry Simpson Professor of Feline Medicine BVM&S Cert VC PhD FACVSc University of Edinburgh (Feline Medicine) MRCVS RCVS Specialist in Feline Medicine

ACUTE URT DISEASE - CAT 'FLU'

AETIOLOGY

Cat 'flu' is the common name used to describe infectious acute URT disease. It is frequently seen in unvaccinated cats and kittens, particularly when they are kept in large groups, either in private homes, or rescue centres.While the disease can be caused by a number of different organisms, over 80% of cases are caused by infection with either feline calicivirus (FCV), feline herpes virus (FHV-1, previously called feline rhinotracheitis virus), or both. Other organisms may also be involved, including feline coronavirus (FCoV), reovirus, Influenza A virus (rarely), mixed bacteria; Bordetella bronchiseptica, Pasturella multocida and Mycoplasma species, Chlamydophila felis (formerly Chlamydia psittaci) and, rarely, Streptococcus equi subspecies zooepidemicus. Many cases of cat 'flu' involve infection with a number of different organisms. Environmental factors, such as poor ventilation, high humidity, and over-crowding may exacerbate the problem.

Factors involved in cat 'flu': l Feline herpes virus (FHV-1) l Feline calicivirus (FCV) l Feline coronavirus (FCoV) l Reovirus l Bordetella bronchiseptica l Pasturella multocida l Mycoplasma species l Chlamydophila felis l (Streptococcus equi subspecies zooepidemicus) l (Rarely; Influenza A virus - either from humans or birds) l Poor ventilation, high humidity, dusty environment, over-crowding.

FHV-1 is a labile DNA virus of a single serotype and consistent pathogenicity that is readily destroyed outside the host. The most important source of this virus is clinical cases. However, most cats recovered from FHV-1 infection become long-term latent carriers, and can shed virus intermittently, typically in response to stress, concurrent disease or following the use of corticosteroids.

FCV is an RNA virus with variable virulence and pathogenicity that is more resistant within the environment and to disinfection. Clinical cases are also the most important source of the virus. However, asymptomatic carriers are common as most cats shed FCV for at least a month following infection, ~50% are still shedding by 75 days, and 10-25% of recovered cats may become long-term viral carriers (sometimes for months or years) and may either shed virus continually or excrete virus intermittently, again usually under the influence of stress, concurrent disease or following the use of corticosteroids.

B. bronchiseptica is a Gram-negative coccobacillus that can act as a respiratory pathogen in a number of species, including pigs, dogs (where it is one of the causes of kennel cough), cats and humans (particularly when immuno-compromised). It can cross-species and has potential zoonotic risk. Affected cats may remain persistently infected and shed bacteria.

C. felis has a special predilection for the conjunctiva and, in the UK up to 30% of cats with conjunctivitis are infected with this pathogen. It is an obligate intracellular bacterium with Gram-negative characteristics.While some strains of Chlamydia may be zoonosic, C. felis is not generally believed to be. Affected cats may remain persistently infected and shed bacteria long-term.

39 PATHOGENESIS

Most of the organisms that typically cause cat 'flu are transmitted by aerosol and/or direct contact of eyes, noses and mouths. FHV-1 replicates in the epithelial cells of the nasal epithelial cells, tonsils, conjunctiva, and trachea. It causes local necrosis of mucosa and leads to a serous and subsequently mucopurulent discharge. Infiltration of the mucosa with neutrophils commonly occurs, as does secondary bacterial infection. FCV targets similar cells but more often causes oral ulceration and ulceration of the external nares. Ulceration may involve the tongue, hard palate, soft palate and pharynx. These ulcers form from vesicles which burst due to tissue necrosis and cellular infiltration with neutrophils. An acute synovitis can occur occasionally (resulting in limping syndrome) as can an alveolitis (leading to interstitial pneumonia). Recently, highly pathogenic strains of FCV has arisen (in USA and UK), where they causes very severe disease, including jaundice, subcutaneous oedema and vasculitis, and a very high level of mortality (see below).

CLINICAL SIGNS

Clinical signs of cat 'flu are most frequently observed in young cats although any age group can be affected. The incubation period is around 6 days. Morbidity is high while mortality should be low with appropriate treatment. Clinical disease may be more serious in some pure bred cats.

Sneezing is typically the first clinical sign observed. This is followed by a serous ocular and nasal discharge which rapidly becomes mucopurluent due to secondary bacterial infection. Affected cats are usually depressed and pyrexic. Conjunctivitis can cause the eyelids to become 'sticky' leading to closure or, in the case of FHV-1, keratitis and corneal ulceration. The nose may block leading to a total loss of olfaction and mouth breathing. Ulceration of the oral cavity leads to salivation and loss of appetite. Coughing and dyspnoea are seen less commonly, and tend to be associated with FHV-1 and B. bronchiseptica.While none of the infections cause specific clinical signs C. felis is particularly associated with conjunctivitis, which may initially be unilateral, FHV-1 tends to cause more severe disease than FCV, with more prominent conjunctivitis, perfuse nasal discharge, and obvious coughing, and FCV (except for the newly recognised severe strains) tends to be associated with milder clinical signs, and oral ulceration. Oral ulceration can also be seen with FHV-1, and both VS-FCV and FHV-1 can result in skin ulceration, either on the face or limbs. Abortions may result from generalised disease and debility, or be caused by the organisms themselves (FHV-1 and C. felis).

The severity of infection may be associated with several factors, including the age, breed and vaccine status of the cat, which organisms are present and how virulent they are, the nutritional status and health status of the cat, and the presence of FeLV and FIV. Clinical signs should resolve within 2-3 weeks. However, chronic disease, often called chronic rhinitis or 'snufflers', can occur and may continue for months or years. Chronic disease may be linked to immuno-suppression associated with FIV and FeLV.

Clinical signs of cat 'flu': l Sneezing l Conjunctivitis l Ocular and nasal discharge - initially serous progressing to mucopurulent l Ulceration of the tongue and mouth l Excessive salivation l Inappetence l Depression l Fever l Coughing l Limping syndrome (FCV - due to acute viraemia and localization of the virus and/or immune complexes in the joints: affected cats typically also show lethargy and pyrexia) l Jaundice, swollen face, collapse and death (new highly pathogenic strains of FCV that causes vasculitis - see later section VS-FCV)

40 DIAGNOSIS l A presumptive diagnosis is usually made on the presence of typical clinical signs and a history of possible exposure to causal organisms.While different organisms tend to produce characteristic clinical signs in the laboratory situation, in mixed natural infections it is not usually possible to determine which organisms are involved from clinical signs alone.That said, FHV-1 tends to cause more severe disease than FCV, with more prominent conjunctivitis, perfuse nasal discharge, and obvious coughing. FCV tends to be associated with milder clinical signs, and oral ulceration. C. felis is usually associated with conjunctivitis, which may initially be unilateral. B. bronchiseptica may cause coughing, and is generally seen when kittens are kept in over-crowded conditions. l Nasal or oropharyngeal swabs can be taken for isolation and culture or PCR (in the case of FHV-1, C. felis and Mycoplasma). Care should be taken when interpreting the results since FHV-1 is shed only intermittently, and FCV shedding may result from infection with either pathogenic or non-pathogenic field strains of virus, or vaccine virus. Bacteriology is generally of little value unless the diagnostic laboratory is instructed to look for specific agents e.g. B. bronchiseptica, Mycoplasma spp., or C. felis. It is advisable to speak to the laboratory prior to collecting the samples since specific transport media may be required. l Serology can be used to determine whether or not a cat has been previously exposed to FCV or FHV-1. However, it is of limited value since most cats have usually been vaccinated. A rising titre against C. felis may be detected in unvaccinated cats. l C. felis may be detected as intranuclear inclusion bodies in Giemsa-stained conjunctival smears around 7 days post infection.

TREATMENT

Treatment usually involves symptomatic therapies and good nursing care. l ANTIBIOTICS - ideally, where specific organisms are detected, antibiotics should be selected by culture and sensitivity. If not, a safe broad-spectrum antibiotic, that is active against bacteria commonly found in the feline oropharynx, should be given for 2-3 weeks. e.g amoxycillin-clavulanic acid or a cephalosporin. Since affected cats typically find swallowing painful it is often better to use syrups or parenteral administration (where available) rather than tablets or capsules. Where B. bronchiseptica, Mycoplasma spp., or C. felis have been detected give doxycycline 10mg/kg/day, or oxytetracycline at 20mg/kg q8h, plus an ophthalmic tetracycline ointment. Oral tetracycline should not be used in kittens as it will discolour the teeth. ALL of the cats in the unit should be treated at the same time, and the treatment should be continued for two weeks AFTER clinical signs have resolved. Oral doxycycline should always be followed by a syringe of water to ensure the medication has passed down into the stomach and so reduce the risk of oesophageal stricture formation. Alternative antibiotics include fluroquinolones and azithromycin (5-10 mg/kg PO q24h for 3 days, then twice weekly - which can be a good choice for kittens as it comes in a syrup). l NUTRITIONAL AND FLUID SUPPORT - this usually entails giving intravenous fluids and often the placing of a feeding tube. Care should be taken when placing naso-oesophageal tubes as the cat's nasal turbinates are already inflamed. Oesophageal feeding tubes are therefore preferred. Cats should be encouraged to eat by use of warmed tempting food. Consider appetite stimulants: cyproheptadine (Periactin) @ 0.1-0.5mg/kg PO q8-12 hours or mirtazapine @ 1/8 of a 15mg tablet PO q3 days. Diazepam is no longer used because of its association with fatal idiosyncratic hepatic necrosis. l SUPPORTIVE NURSING CARE - it is important to keep the cat's eyes and nose clean, and its coat groomed. l MULTIVITAMINS - anorexia can result in a lack of certain vitamins, especially B12. This can in turn exacerbate anorexia. Supplementation can be beneficial, e.g. B12 @ 125-250 ug/cat q7days SC.

41 l OCULAR ANTI-INFLAMMATORY DRUGS - for use when ocular signs cause significant pain and/or inflammation. However, they can slow the healing of corneal ulcers. Ocufen (flubiprofen) 0.3 mg/ml apply 2-3x daily; Ketoralac 5 mg/ml solution, apply 2-3x daily; (£2-3/drop as single use vials in the UK). l MUCOLYTICS - mucolytics may help to ease respiratory tract congestion; e.g. bromhexine (Bisolvon) @ 3mg/cat IM q24 hours, or 1mg/kg PO q24 hours. l NEBULISED AIR - the use of steam or nebulised air can help to clear the airways.Where necessary, bronchodilators can be added to the air current. l DECONGESTANTS - intranasal oxymetazoline (Afrazine) may give temporary relieve to nasal congestion @ 1 drop/nostril q12 hours for 48 hours maximum. l ANTIVIRALS - although cat 'flu' is usually caused by FCV or FHV-1, specific antiviral therapy is rarely used. Where FHV-1 infection is present, famcyclovir may be given at 62.5-125 mg/cat PO q8-24h for 1-3 weeks (Malik et al, JFMS 2009, 11(1):40-48); or oral L-lysine may be beneficial @ 200 mg q12-24h, PO with food, as this may help to reduce clinical signs and viral shedding (although new data on this looks less promising). l TOPICAL ANTIVIRALS - while studies have shown that these may help to reduce FHV-1 viral shedding and clinical signs (trifluridine >> idoxuridine > vidarabine >> acyclovir), their use is often limited by their availability, cost, need for frequent administration, and ability to cause local irritation. Suggested treatment: trifluorothymidine 1% eye drops given q1-2h for 24h then 6x daily for 3 weeks may improve ocular condition. Recently, cidofovir has gained favour, being non-irritant and only needing to be given q12h: 0.5% solution q12h, but is expensive and needs reformulation. l INTERFERON - while many non-specific immune stimulants are currently available, few have proven efficacy and safety. Perhaps most studies have been performed with recombinant feline interferon (Virbagen Omega Virbac), which can act as an antiviral at high doses and a non-specific immune stimulant at lower doses. However, the most effective dose has yet to be determined; suggested doses range 1x103-5x106 M IU/cat IV, SQ or PO q24h, for 5 days or more; a practical dose is 5x104 IU PO or SQ q24h). (Minimum purchase 2x10 M IU vials (~ £80: or 5x10 M IU vials at ~£200) - dilute 1 vial in 100 of saline, aliquot into 10ml volumes, freeze for up to a year. Defrost as required, dilute if required, keep refrigerated for up to 2 weeks). Alternately, recombinant human interferon alpha (hrIFN ) can be obtained as 3, 5 or 10M IU, which can then be diluted in one litre of saline, aliquoted into 1ml volumes, and frozen for up to a year. It can then be defrosted as required, diluted to the appropriate concentration, and kept refrigerated for up to 2 weeks. It is usually given @ 1-30 IU, PO, q24h. Given parenterally at high doses it will cause toxicity and induce antibody production. l TOPICAL IFN - IFN diluted in saline IFN has been shown to be safe (up to 1 M IU/ml), and has a dose-dependent anti-FHV- 1 effect at >100 IU; suggested dosage is 10 M IU + 20 ml normal saline ? 1 drop per eye 5x daily for 7-10 days, then 2x daily for another 3 weeks. l DO NOT use corticosteroids, especially systemically.

42 PREVENTION AND CONTROL

To reduce respiratory disease within a group of cats it is necessary to address infectious and non-infectious causes.This may require instigating a suitable vaccination and/or isolation programme, treating with suitable antibacterial agents, improving ventilation, and reducing over-crowding. l Introduce a suitable vaccination program (see below) l Decrease stocking density l Increase air flow l Ensure good sneeze barriers are present between separate groups of cats l Improve overall hygiene, and use suitable disinfectant (ideally 1:32 bleach as some stains of FCV may not be killed as easily as the FCV-F9 vaccine strain that tends to be used as a standard and virus may therefore persist in the environment for several days to several weeks on dried surfaces, or longer in colder damp conditions) l Have individual cats give birth and then wean their kittens in isolation l Have a suitable quarantine facility and quarantine all incoming cats for 3 weeks l Stop breeding - kittens are most susceptible to infection l In colonies known to be free of infection should use inactivated vaccines only, and only introduce cats that have been tested to be free of infection

VACCINATION

Vaccines against FCV and FHV-1 include attenuated live and inactivated vaccines given SC, and in the US, attenuated live intranasal vaccines. Initial vaccination should start at 8-9 weeks of age with a second vaccination at 12 weeks, and possible a third vaccination at 16 weeks (in kittens with persistent maternally derived immunity [MDA]). While boosting is often given annually new guidelines suggests that after the booster at 1 year, boosting more frequently than once every 3 years is not always needed. Where available, intranasal vaccines are particularly useful when a rapid onset of protection is required, and a single dose may be sufficient to overcome MDA and induce immunity so these vaccines can be particularly useful in kittens during a 'flu outbreak. In addition, intranasal vaccines may stimulate cross protection against other pathogens (e.g. B. bronchiseptica). While these vaccines are generally effective there are a number of concerns, particularly with FCV vaccines: l Vaccination fails to produce a sterilizing immunity so it can only protect against the development of clinical signs of disease, not against infection itself.This is why there has been little change in the overall prevalence of FCV infection since the introduction of vaccination: 10-40%, depending on the nature and size of the population sampled, with large groups of random-source cats living in colonies and shelters usually having a higher chance of being infected. l There are concerns over the relative risks and merits of live verses inactivated vaccines.For example, live vaccines may lead to clinical signs of disease following vaccination (particularly if a vaccine designed for parenteral administration becomes aerosolised or deposited on the cat's coat and is then licked off and enters the cat via the oro-nasal route). In addition, live vaccine virus can persist within a colony of cats, gaining the potential to mutate and so become pathogenic.While it was previously believed that live vaccines tended to generate superior immune responses to those seen with inactivated vaccines, with modern advances in vaccine development this is no longer necessarily the case, as has been shown with Merial Purevax, which can give fast effective immunity within one week of vaccination. However, inactivated vaccines are more likely to require the incorporation of an adjuvant, and the potential role of these substances in the development of injection-site sarcomas is still of concern. l Since field strains of FCV mutate and develop over time (particularly in response to immune pressure resulting from vaccination), there is concern about the ability of traditional vaccines, for example FCVF9 and FCV255, to protect against current field strains.Recent studies looking at the in vitro neutralisation of field strains of FCV by antisera raised against FCV vaccine strains have produced variable results.For example, in 1 study FCVF9 was shown to neutralise 87.5% of UK field isolates compared to 75% with FCV255. However, in a separate study, FCVF9 and FCV255 neutralised only 20 and 21% or 37 and 56%, respectively, while the newer vaccine strains FCVG1 or FCV431 neutralised 29 and 70% or 67 and 87%, of field strains respectively.

43 A third study found FCVF9 to neutralise 25%; FCV255 24%; FCVG1 81%; FCV431 85%. While a fourth found FCV255 to neutralise only 23%, but when it was combined with FCVDD1 this increased to 70%. Unfortunately, it is very difficult to directly compare the results from the different studies.This is because they used different experimental protocols and different field strains (with variable percentages of ill cats included, and strains from different countries). That said, while the older vaccines are still to some extent broadly cross- reactive, it is better to develop vaccines with broader heterologous protection, for example, by incorporation a number of different FCV strains.

Vaccines against C. felis include attenuated live and inactivated vaccines given SC. Initial vaccination should start at 8-9 weeks of age with a second vaccination at 12 weeks and boosting should be annually. Mild signs of infection may occur post vaccination when using live vaccines. Pregnant queens should not be vaccinated. Vaccination is usually only considered when a unit has an identified C. felis problem.

The vaccine against B. bronchiseptica is live attenuated, and given intranasally. Initial vaccination should start at 8- 9 weeks of age with a second vaccination at 12 weeks and boosting should be at least annually. Mild signs of infection may occur post vaccination. Pregnant queens should not be vaccinated. Vaccination is usually only considered when a unit has an identified B. bronchiseptica problem.

VIRAL SYSTEMIC - FCV DISEASE (VS-FCV)

Cases of severe systemic haemorrhagic-fever disease due to particularly pathogenic strains of FCV were first seen in the US in 1998, and similar cases have been seen in the UK since 2003, and in France. Clinical signs become apparent within 1-5 days of infection and affected cats show a range of clinical signs, including upper respiratory disease (oculo-nasal discharge, oral ulcers), pneumonia, peripheral oedema and skin sloughing (typically affecting the head and limbs) which is due to peripheral vasculitis, and systemic vasculitis with disseminated intravascular coagulation that can result in multiple organ failure and death (see below). The mortality can be >50% even in previously healthy, vaccinated cats, with adult cats suffering significantly higher morbidity and mortality than kittens (which may only show more classical signs of 'flu). The duration of disease from first signs to death is typically from 4-9 days, but occasional cases have been more protracted.

CLINICAL SIGNS OF VS-FCV: l Anorexia, lethargy, depression l Pyrexia (can be >105oF/40.6oC) (~80%) l Subcutaneous oedema and ulcerative dermatitis - particularly on the nose, lips, pinnae, around the eyes, and distal limbs and fluid may ooze from the affected areas (>50%) l Mouth ulcers (~50%) l Nasal discharge (~30%) l Severe respiratory distress: pulmonary oedema and/or pleural effusion* (~20%) l Ocular discharge (~10%) l Jaundice* (~10%) l Gastrointestinal signs: vomiting, diarrhoea l Signs of coagulopathy: petechiae, ecchymosis l Sudden death * These signs are associated with a poor prognosis.

Laboratory investigation may reveal changes in serum biochemistry (moderate hypoproteinaemia, and increases in total bilirubin and creatinine kinase), a mild neutrophilia and lymphopenia, non-regenerative anaemia, and severe coagulopathy. Necropsy typically confirms the external changes and may reveal severe pancreatitis with saponification of the peripancreatic fat, necrotizing or interstitial bronchopneumonia, and/or hepatocellular, lymphoid and splenic necrosis.

Potential differential diagnoses include pancreatitis/vasculitis/sepicaemia, e.g. causes by Salmonella, Streptococcus equi subspecies zooepidemicus, Influenza A virus, E. coli, and potentially Mycoplasma species or Toxoplasmosis. 44 Diagnosis of VS-FCV may be suspected when a number of in-contact cats show clinical signs as described above, and are found to be positive for FCV by virus isolation (typically from pharyngeal swabs). However, there is currently no way of confirming the diagnosis as all outbreaks have been caused by viral strains of differing sequences so a genetic test has not been developed. Finding that the cat is shedding FCV may help in the diagnosis but it is always possible that the cat is ill because of another reason (e.g. severe pancreatitis), but is concurrently shedding either a normal field or vaccine strain of FCV. Immunohistochemistry to detect the presence of FCV within tissue biopsies can be helpful in indicting the presence of the virus within the pathological lesions.

Most outbreaks have involved the introduction of a cat from a rescue centre immediately prior to the disease spreading rapidly within the veterinary practice, shelter or private home. It has therefore been suggested that crowded, high-stress environments, such as found in shelters, may contain high levels of viral biodiversity (i.e. many different FCV strains which can lead to sequential re-infection, rare persistently FCV-infected cats [which enable progressive evolution of FCV within an individual cat], and even cats infected with more than one FCV strain [which raise the possibility of viral recombination]). This, plus high levels on non-neutralising immunity, may select for highly contagious and virulent viral strains. Under these conditions viral variants that are capable of replicating faster and to higher titres will be more likely to be transmitted and positively selected for. Once selected, these strains can then spread rapidly. Cats growing up in these environments and kittens born to infected mothers within these environments will tend to have matched immune responses so can suppress viral replication and at most develop only minimal clinical signs. However, when these viruses gain assess to populations that have not been previously exposed to them (e.g. veterinary practice or another home) this can result in an outbreak of VS-FCV. VS-FCV is believed to result from increased viral pathogenicity and altered cell tropism (invasion of epithelium and endothelium), and altered host cytokine response.This results in systemic vascular compromise, multi-organ failure, haemorrhage, shock and death.

The infection can be easily spread by cat handlers and fomites (oro-nasal secretions, skin-ooze from areas of ulceration, faeces and urine) and infection may still manage to spread despite the introduction of strict isolation and barrier nursing. Asymptomatic and recovered carrier animals also exist. Somewhat inexplicably, all outbreaks have so far been self-limiting, have typically involved <100 cats, and resolved within 2 months.

Traditional FCV vaccinations (containing FCVF9 or FCV255) offer little protection against VS-FCV (although very recently vaccinated cats may be slightly less likely to become ill). However, a recent study revealed that Merial Purevax (containing FCVG1 and FCV431) protected against VS-FCV strains from Europe, and there have been two vaccines generated against VS-FCV strains by Fort Dodge and one by Boehringer Inglheim in the US. One of these by FD (FCV2280) offered no protection against European VS-FCV isolates, which underlines the problem of strain variation between the different VS-FCV strains meaning that protection against other VS-FCV strains cannot be assumed. The other vaccine by FD (FCVDD1) has been combined with their classical FCV vaccine (FCV255) and in a recent publication this bivalent vaccine gave protection against European and US VS-FCV strains (at the time of writing this is not currently available in Europe). Boehringer Ingelhein have recently released a bivalent inactivated FCV vaccine in the US that also offers protection against VS-FCV (Fel-O-Vax CaliciVax).

All suspicious cases should be handled with strict hygiene and quarantine precautions, ideally treated away from the veterinary practice (to reduce the risk of nosocomial infection), and kept in isolation until they have been shown to have stopped shedding virus (which may take a few weeks). To prevent the infection spreading it is important to trace all in-contact cats and to quarantine all potential suspects.

TREATMENT:

While nothing has been published a pragmatic approach would consist of high dose interferon (to suppress viral replication [and suppress the excessive immune response which can be so damaging] IFN 0.5-2.5x106 M IU/kg IV q24h, for 3 days), plus IV fluids, covering antibiotics, analgesia, supportive care and, if needed, systemic corticosteroids.

45 CHRONIC URT DISEASE

CAUSES l Chronic post-viral rhinitis / idiopathic chronic rhinitis: The majority of cases of chronic URT disease are defined as chronic post-viral rhinitis/sinusitis. The initial viral infection causes damage to the nasal mucosa, which allows secondary infection with oro-pharyngeal bacteria, and hence the establishment of chronic osteomyelitis of the turbinate bones. However, since it is usually not possible to detect FHV-1 or FCV at this late stage of disease, the condition should perhaps more correctly be termed chronic idiopathic rhinitis. Bacteria commonly cultured from these cases include Pasturella, and in the case of rhinosinusitis, Pseudomonas l Chronic primarily bacterial rhinitis: Occasional cases have been seen associated with Pseudomonas, Mycoplasma, B. bronchiseptica, or Mycobacteria species. l Fungal rhinitis: Cryptococcus neoformans infection is seen world wide; however it is rare in the UK. Infection with Aspergillus spp. is seen even less commonly. Saprophytic fungi (e.g. Alternaria spp.) have caused occasional cases of fungal rhinitis. These are typically associated with plant material that has become lodged in the nasopharynx. l Allergic rhinitis: Allergic rhinitis has occasionally been diagnosed in cats, and may be more common than we appreciate.Typical allergens include cat-litter dust, certain aerosol sprays, and cigarette smoke. In some cases, allergic rhinitis may occur concurrently with 'feline asthma'. l Nasopharyngeal polyps: These inflammatory polyps are usually associated with chronic inflammation of the middle ear, from where they are believed to originate.While they are usually seen in young cats, they can be seen in cats of all ages. Nasopharyngeal polyps usually cause obstructive URT disease.When they extend into the caudal nasopharynx they may also cause dysphagia or gagging.When they extend from the middle ear into the outer ear they may cause ear pain, otitis externa and otorrhoea. l Nasonasal polyps: Nasonasal polyps originate within the nasal chambers. They arise secondary to chronic inflammation. Since their mucosa is very friable they may be associated with epistaxis. l Nasopharyngeal stenosis: This is seen when an inflammatory membrane develops across the caudal nasopharynx. It usually arises secondary to chronic inflammation. l Neoplasia: The most common tumours of the nasal cavity are lymphoma (LSA) and adenocarcinoma. Other tumours that may be seen in this location include undifferentiated carcinoma, squamous cell carcinoma (SCC), fibrosarcoma, and chondrosarcoma. Tumours may arise secondary to chronic inflammation. The author has seen nasal LSA develop in cats that have had chronic idiopathic (lymphocytic/plasmacytic) rhinitis. One cat, which had chronic idiopathic rhinitis, later developed nasonasal polyps, then undifferentiated carcinoma. l Foreign body: Intranasal foreign bodies typically consist of plant material, and usually enter via the nasopharynx. Fungal spores associated with the plant material may occasionally lead to a secondary fungal rhinitis.Removal of the foreign body, and any associated fungal cast, usually results in a good recovery. l Trauma: Trauma is usually caused by road traffic accidents or cat fights.Road traffic accidents may cause hard palate separation, the generation of oro-nasal fistulae, or damage to the maxillary bones. Cat fights occasionally result in the loss of teeth within the opponent's nose, or maxillary bone fractures.This type of damage may in turn 46 lead to infected sequestra. l Dental disease: Severe peridontal disease or tooth fracture can result in the generation of an oronasal fistula. l Congenital defects: Cleft palate, defects of the external nares or nasal septum can all result in chronic URT disease. l Laryngeal - Paralysis / Trauma / Oedema / Polyp / Granulomata / Neoplasia: Laryngeal disease is seen far less frequently than rhinitis.Paralysis is seen most commonly secondary to neck trauma. While tumours of the larynx are uncommon, they are usually of similar types to those seen in the nose or pharynx, with SCC and LSA being seen most often.

DIAGNOSIS

Diagnosis of URT disease, as with all diagnostic investigations, relies on a combination of knowing the signalment of the patient (i.e. its age, sex and breed), gaining a complete medical history, performing a thorough physical examination, and then undertaking selected further investigations.

The signalment can be of help since congenital detects will usually cause clinical signs within a few days of birth. However, cat 'flu' is seen most frequently in older kittens, and neoplasia is seen most typically in old cats. While the breed rarely has a bearing on URT disease, the author has seen nasonasal polyps most frequently in Oriental breeds of cat.

From the history it is important to determine; l what type of environment the cat lives in l what other animals it lives with l where it has previously lived l whether or not it has been vaccinated, and if so, with what and when l whether there is any history of previous illness, facial trauma, dental disease or ear infections l at what age signs of URT developed l what was the pattern of onset of clinical signs l were other animals from the same household affected l did the cat ever have cat 'flu' (remember - chronic post-viral rhinitis is the most common cause of chronic URT disease) l how has the disease progressed l have the clinical signs ever responded to previous treatments l is there a history of dysphagia or dysphonia?

PHYSICAL EXAMINATION

The main signs of URT disease are sneezing, nasal discharge and difficulty in breathing.The exact nature of the discharge, whether both sides of the nose are affected, and the presence of other clinical signs are dependent on the nature of the underlying disease, and on the presence of any other illness the cat may have.

Particular points to look out for include: l The presence of nasal discharge, and whether it is bilateral or unilateral. Some diseases tend to show unilateral signs (e.g. foreign bodies, or neoplasia), while others more often cause bilateral signs (e.g. chronic post-viral rhinitis). While the nature of discharge can be helpful (e.g. haemorrhage is seen commonly with neoplasia, fungal infections and nasonasal polyps), it can be misleading (e.g. haemorrhage can occasionally be seen with foreign bodies, or severe chronic post-viral rhinitis). l The character of breathing, and whether or not the breathing is noisy when the cat breathes through its mouth,

47 may help to localise disease to the nasal area or the larynx. Generally, disease in the URT causes inspiratory dyspnoea. The breathing is more stertorous (snoring) when disease is in the nose, but more stridorous (high pitched and harsh) when disease affects the larynx. Both nostrils should be checked for deformity, obvious obstruction and presence of airflow. Dysphonia may be associated with laryngeal disease. l Facial examination may reveal a lack of symmetry or facially swelling (most typically associated with neoplasia or fungal infections). Facial pain and resentment of facial examination is common among cats with URT obstruction, especially those with intranasal foreign bodies, or polyps. In Siamese cats the facial hair overlying the inflamed nasal chambers may become de-pigmented. l Ocular examination should involve assessment of the periocular area, the anterior and posterior chambers, and the retina. Examination may reveal a serous ocular discharge resulting from tear duct damage associated with previous URT viral disease, or occasionally associated with cancer within the nose. Previous FCV, FHV-1 or C. felis infections can result in chronic conjunctivitis, which in the case of FHV-1 infection may also result in keratitis.Retinal lesions may be seen associated with intranasal neoplasia or fungal rhinitis. l Aural examination may reveal evidence of painful or infected ears associated with inflammatory polyps. l General body condition and body weight. Cats with URT obstruction often have a poor appetite and so experience a degree of weight loss. Marked weight loss is more suggestive of neoplasia, fungal disease or severe systemic disease. l Cats with chronic URT disease frequently have mild to moderate submandibular lymphadenopathy. If submandibular lymphadenopathy is marked, or if lymph nodes elsewhere in the body are also affected, neoplasia, mycobacteriosis or fungal infections are most likely to be the cause. l Kidneys should be assessed for size and shape since nasal LSA may be associated with renal LSA.

Since different diseases can present very similarly it is important not to over-interpret the presence of a particular clinical sign. A few general rules usually hold true, e.g. facial deformity with associated pain, especially if accompanied by a unilateral nasal haemorrhage or marked lymphadenopathy, is usually suggestive of nasal neoplasia or fungal infection. However, a lack of these findings does not rule out these diagnoses, and some cases of nasal LSA cause bilateral nasal obstruction and little nasal discharge of any kind. Also, although post-viral rhinitis usually presents with chronic bilateral purulent discharge, it can also present with unilateral discharge, sometimes blood tinged and occasionally with frank haemorrhage.

FURTHER INVESTIGATIONS:

Assessment of serum biochemistry, haematology, and FeLV/FIV status will help to gain an overall picture of the cat's health.

Attempts to make a diagnosis from nasal swabs taken from a conscious cat are rarely successful (unless C. neoformans is detected). If C. neoformans is detected its presence should be confirmed by culture and/or serology. Bacteria detected in this manner usually represent only secondary contaminants.

The detection of FHV-1 or FCV by oro-pharyngeal swab and viral culture or PCR is rarely helpful. Vaccinated cats and cats that have been previously infected with FCV may also be shedding virus. Since FHV-1 is shed only intermittently, failure of its detection does not negate against it playing a significant role in disease.

It is usually only by performing a detailed examination of the URT (for which the cat has to be anaesthetised), taking radiographs (CT or MRI investigation*), and collecting samples for microbiological and histopathological examination, that a definitive diagnosis may be made.These procedures are performed under general anaesthesia; anaesthesia is induced, the mouth and larynx are examined as the cat is intubated, radiographs are taken, and then the nasopharynx and nasal chambers are examined. The investigations can be performed under

48 the same anaesthetic.Radiographs, or any advanced imaging, should be taken before the introduction of flushing solutions, an endoscope, or biopsy instruments since these procedures may result in haemorrhage that will alter the radiographic appearance.

*Where it is available advanced imaging can be very useful in the investigation of URT disease. Because CT enables detailed visualisation of boney detail as well as soft tissue structures it is often of more use than MRI.

RADIOGRAPHIC INVESTIGATIONS:

To prevent head movement radiographic investigations should be performed with the cat under general anaesthetic.When taking the radiographs it is advisable to remove the endotracheal tube to prevent it obscuring essential details. The investigation should include: l Whole skull radiographs (lateral and VD views) - to assess the overall structure of the skull, the frontal sinuses, the size and content of the pharynx, etc. l Intraoral view - to assess the nasal chambers and the maxillary dental arcade. l Open mouth view - to assess the tympanic bullae. l Lateral oblique views - to look for the presence of dental disease and to highlight the tympanic bulla.

Lateral oblique view Open mouth view Intraoral views

Radiographs should be assessed for the presence of dental disease, evidence of middle ear infection, obstruction of the nasopharynx by soft tissue, soft tissue density within the frontal sinuses, loss of integrity of the nasal septum, and loss of turbinate detail. Whether the loss of turbinate detail is unilateral or bilateral, and its position within the nasal chambers may help to localise the disease.The loss of turbinate detail may be due to an overall loss of turbinate bone, or an overlying increase in soft tissue.While the nature of the change should be assessed, it is rarely specific. An overall loss of turbinate bone may be seen with chronic destructive post-viral rhinitis, neoplasia, reaction to a foreign body, or fungal rhinitis. An overlying increase in soft tissue may be seen with chronic post-viral rhinitis, neoplasia, nasonasal polyps and allergic rhinitis.

PHYSICAL EXAMINATION l Teeth, hard palate, soft palate, oro-pharynx and tonsils: This examination is performed under general anaesthesia, preferably with a gently cuffed endotracheal tube in place.The teeth, hard and soft palates, oro-pharynx and tonsils are examined visually and digitally for signs of disease. l The nasopharynx: The caudal nasopharynx is then examined using a dental mirror and a bright light, or a retroflexed bronchoscope. If the soft palate needs to be drawn forward to improve visualisation this should be done by placing 'stay sutures' though its caudal margin, or using atraumatic tissues forceps (not Alice tissue forceps). Any unusual findings should be biopsied.

49 l The rostral nasal chambers: Prior to investigating the nasal chambers it is important to pack the caudal oro-pharynx with surgical swabs. This is done because even minor trauma to the nasal mucosa can result in significant haemorrhage. It is important to prevent this blood from entering the trachea. For this reason it is also advisable to use a gently cuffed endotracheal tube.While the rostral nasal chambers can be assessed using an auroscope fitted with a small cone, this approach generally affords very poor visualisation. Where available, a narrow rigid rhinoscope/arthroscope is more suitable, and in large cats may even permit biopsies to be collected with endoscope guidance.When using either a rhinoscope or taking blind biopsies it is important that the instrument is measured against the animal's face, and marked with a tape tag at the distance from the tip of the nose to the medial canthus of the eye on the same side.This prevents iatrogenic damage to the brain when the instrument is introduced into the nose.

SAMPLE COLLECTION:

Samples for cytological and microbiological examination can be collected by a number of methods. Pros and cons exist for each of the methods. l Direct swabs: While direct nasal or pharyngeal swabs are non-invasive they rarely yield useful information (see earlier section in "further investigations"). l Direct aspirates/flushes: Flushing sterile saline through the nasal chambers may help to clear away mucus and debris, and the resultant flush can be used for analysis. Unfortunately, analysis of this fluid is likely to detect only surface contaminants. l Traumatic flush: A traumatic flush entails scarification of the intranasal mucosa at the same time as flushing the nose with saline.While the cellular yield is increased using this technique, the cellular detail is generally poor and the risk of haemorrhage considerable. l Forced flush: A forced flush is performed after firmly packing the caudal pharynx, then forcing approximately 10ml of saline up one nostril while holding the other nostril shut. This technique can be used to dislodge foreign bodies, inspissated pus, necrotic debris, and occasionally, tumours or polyps.The solid tissue collects on the pharyngeal swabs.The procedure should be performed carefully, as excessive force may flush material through the cribriform place if it has already been damaged by local pathology. l Pinch biopsies: Pinch biopsies are most easily collected using endoscopic biopsy grabs or crocodile biopsy forceps. Only in very large cats can the biopsies be endoscopically guided. Blind biopsies are usually adequate, provided that 2-3 samples are collected from each side of the nose. l Nasal core biopsy: Nasal core biopsies can be collected by cutting down a 16 gauge over-the-needle IV catheter, and using it like an 'apple corer' to collect a nasal biopsy. l Surgery: The most representative and diagnostic biopsies will be gained during surgical exploration of the nose.

HAEMORRHAGE:

While many methods of sample collection have been devised it is important to remember that the larger the biopsy sample, the better the chance of an accurate diagnosis, but the greater the risk of haemorrhage. Since nasal investigations frequently result in bleeding it is recommended that patients have their clotting times 50 checked prior to beginning the procedure, especially if they have shown epistaxis. If intra-operative haemorrhage does occur the intranasal instillation of ice-cold saline or adrenaline may help, along with packing of the pharynx and closing the nostrils.

SUBMISSION AND NON-SPECIFIC FINDINGS:

Samples should be submitted for cytology/histopathology (where appropriate staining for fungi and/or mycobacteria), aerobic and anaerobic culture and a non-fixed sample can be sent for Mycoplasma PCR. Unfortunately, the collection of suitable samples does not always lead to a definitive diagnosis. Since most cases of chronic URT disease result from chronic post-viral damage, many of the tests will give negative or non- specific results, at best confirming the presence of chronic-active inflammation. A diagnosis of chronic post- viral rhinitis is usually a diagnosis of exclusion.

TREATMENT

When undertaking the treatment of a cat with chronic URT disease it is helpful (where possible) to differentiate between the possible underlying causes (see diagnosis). This allows for the correct treatment to be given and a prognosis to be considered. However, since most cases of chronic URT disease result from chronic post-viral damage, it is important to remember that the likelihood for full recovery is poor.

Where a specific disease is diagnosed, specific treatment should be given: l Nasopharyngeal polyps can be removed by gentle traction, pulling the polyp towards the oro-pharynx, followed by a short course of corticosteroids to reduce inflammation. To reduce the risk of recurrence inflammatory material can also be removed from the middle ear.This is usually achieved via an ipsilateral ventral bulla osteotomy, but this is only required if the polyps are recurrent. l Nasonasal polyps can be surgically resected, as can the inflammatory membrane of nasopharyngeal stenosis (a condition which can also be resolved by balloon dilation and/or stent placement). l Foreign bodies can be removed. Local infection can be reduced by curettage. Following foreign body removal, especially where local damage is extensive, a long course of antibiotics is recommended (e.g. 6-8 weeks). l Fungal rhinitis should be treated with antifungal drugs (e.g. itraconazole, fluconazole, ketoconazole, and/or amphotericin B, and these drugs may need to be given for 2-18 months depending on the severity of disease). l Laryngeal paralysis can be ameliorated by performing a unilateral 'laryngeal tie-back'. Any underlying cause should be determined and corrected. l Post-viral rhinitis/idiopathic rhinitis is rarely curable.The emphasis is on management not cure. Many of the therapeutic options discussed in the section on treatment of cat 'flu' also apply here (see earlier section).

- Antibiotics - While antibiotics rarely result in a cure, their strategic or long-term use can reduce the severity of clinical signs, and so improve the cat's quality of life. A good response is sometimes gained using a long course of antibiotics (6-8 weeks), starting immediately following intranasal investigations.Recently findings suggest that a long course of doxycyclin or azithromycin may be particularly good choices, especially when Mycoplasma and/or Bordetella are present. - Anti-inflammatory agents - While safety is an issue, recent studies have suggested that meloxicam may be a particularly good choice. - Interferon - as for acute flu. - Famcyclovir - where chronic FHV-1 is involved famcyclovir may be useful when given at 62.5-125 mg/cat PO q8-24h for 1-3 weeks (Malik et al, JFMS 2009, 11(1):40-48). - Intranasal live modified FHV-1 & FCV vaccines (where available) may act as immunotherapy and help in some cases. - Inhaled corticosteroids - These can help in the general reduction of inflammation, and can be particularly useful

51 in cases of allergic rhinitis (for more information see the section on Treatment of Chronic Bronchopulmonary Disease). - Leukotriene receptor antagonists: e.g. Zafirlukast or Montelukast. No published trials on the use of this type of drug in cats with chronic URT disease have been published. While it has been suggested that they may help in some cases see section on Treatment of Chronic Bronchopulmonary Disease before considering their use. - Therapeutic flush - A therapeutic flush entails adding an antibiotic, antiseptic or other therapeutic agent (e.g. IFN) to the intranasal flush. This may have beneficial effects when performed at the end of a nasal investigation. - Nasal curettage - While this procedure results in a degree of improvement in some cases, other cases benefit little. Also, the procedure is not without risk, and can be very painful. This procedure should not be undertaken lightly, and post-operative analgesics are essential. - Frontal sinus ablation, trephination and irrigation - These procedures may be considered where inflammation has extended into the frontal sinuses.Response to these procedures is not always favourable and post-operatively the cat's can be in considerable pain. Analgesics are essential.

AeroKat Spacers can be obtained from: USA: Martin Foley, Vice President, Advanced Product Design, Trudell Medical International, 725 Third Street, London, Ontario, Canada N5V 5G4 Phone: +1 519 455 7060 ext 2203 Fax: +1 519 455 6478 Email: [email protected] www.aerokat.com

UK: Jon Slattery, Managing Director, BreathEazy Ltd 154 Worcester Road, Malvern, Worcestershire WR14 1AA, United Kingdom Tel: +44 845 680 8975 Fax: +44 845 680 8976 E-Mail: [email protected] Web: www.breatheazy.co.uk

AeroKat is stocked by VSS Co Ltd, NVS, Centaur and Dunlops

Other helpful sites for owners and vets are: www.felineasthma.co.uk www.fritzthebrave.com http://www.felineasthma.org http://groups.yahoo.com/groups/felineasthma/

REFERENCES AND FURTHER READING

Ali A, Daniels JB, Zhang Y, et al. (2011) Pandemic and seasonal human influenza virus infections in domestic cats: prevalence, association with respiratory disease and seasonality patterns. J Clin Micro, 49(12): 4101-4105 Blum S, Elad D, Zukin N,Lysnyansky I, Weisblith L, Perl S, Netanel O, David D. (2010) Outbreak of Streptococcus equi subsp. zooepidemicus infections in cats.Vet Microbiol. 2010 Jan 11. [Epub ahead of print] Boothe,D.M. and McKiernan, B.C. (1992). Respiratory therapeutics. Veterinary Clinics of North America: Small Animal Practice 22: 1231-1258 Bradley A, Kinyon J, Frana T, Bolte D, Hyatt DR, Lappin MR (2012) Intranasal administration of a modified live feline herpes virus 1 and feline calicivirus vaccine induces cross protection against Bordetella bronchiseptica. JVIM 26(3): 784-785 (Abstract ID-8) Cohn LA, DeClue AE, Cohen RL, Reinero CR. (2010) Effects of fluticasone propionate dosage in an experimental model of feline asthma. JFMS, 12(2):91-6. Corcoran, B.M., Foster,D.J. and Luis Fuentes, V. (1995). Feline asthma syndrome: A retrospective study of the

52 clinical presentation in 29 cats. Journal of Small Animal Practice 36: 481-488 Drazenovich TL et al. (2009) Effects of dietary lysine supplementation on upper respiratory and ocular disease and detection of infectious organisms in cats within an animal shelter. AJVR, 70(11): 1391-1400 Dye, J.A. (1992) Feline bronchopulmonary disease. Veterinary Clinics of North America: Small Animal Practice 22: 1187-1201 Dye, J.A., McKiernan, B.C., Rozanski, E.A., Hoffmann, W.E., Losonsky, J.M., Homco, L.D., Weisiger, R.M. and Kakoma, I. (1996). Bronchopulmonary disease in the cat: historical, physical, radiographic, clinicopathologic, and pulmonary function evaluation of 24 affected and 15 healthy cats. Journal of Veterinary Internal Medicine 10: 385-400 Fenimore A, Fankhauser J, Carter K, Hawley JR, Lappin MR (2012) Treatment of chronic rhinitis in shelter cats with a parenteral alpha-interferon or an intranasal feline herpesvirus 1 and feline calicivirus vaccine. JVIM 26(3); 784 (Abstract ID-7) Hawkins, E.C., Kennedy-Stoskopf,S., Levy,J., Meuten, D.J., Cullins, L., DeNicola, D., Tompkins,W.A. and Tompkins, M.B. (1994). Cytologic characterization of bronchoalveolar lavage fluid collected through endotracheal tube in cats. American Journal of Veterinary Research 55: 795-802 Lecuyer, M., Dube, P-G., DiFruscia, R., Desnoyers, M. and Lagace, A. (1995). Bronchoalveolar lavage in normal cats. Canadian Veterinary Journal 36: 771-773 Mandelker, L. (2000). Experimental drug therapy for respiratory disorders in dogs and cats. Veterinary Clinics of North America: Small Animal Practice 22: 1087-1099 McCarthy, G. and Quinn, P.J. (1989). Bronchoalveolar lavage in the cat: cytologic findings. Canadian Journal of Veterinary Research 53: 259-263 Moise,N.S., Wiedenkeller,D., Yeager, A.E., Blue,J.T. and Scarlett, J. (1989). Clinical, radiographic, and bronchial cytologic features of cats with bronchial disease: 65 cases (1980-1986). Journal of the American Veterinary Medicine Association 194: 1467-1473 Padrid, P.A. (2000). Feline asthma - diagnosis and treatment. Veterinary Clinics of North America: Small Animal Practice 30: 1279-1293 Padrid, P.A., Feldman, B.F., Funk, K., Samitz, E.M., Reil, D. and Cross,C.E. (1991). Cytologic, microbiologic and biochemical analysis of bronchoalveolar lavage fluid obtained from 24 cats. American Journal of Veterinary Research 52: 1300-1307

FCV REFERENCES

Abd-Eldaim M et al. Genetic analysis of feline caliciviruses associated with a hemorrhagic-like disease. JVetDiagInvest 2005, 17: 420-429 Addie D,Poulet H, Golder MC, McDonald M, Brunet S,Thibault JC, Hosie MJ. Ability of antibodies to two new caliciviral vaccine strains to neutralise feline calicivirus isolates from the UK. Vet Rec. 2008 Sep 20;163(12):355-7. Coyne KP,Jones BR, Kipar A, Chantrey J,Porter CJ, Barber PJ, Dawson S, Gaskell RM, Radford AD. Lethal outbreak of disease associated with feline calicivirus infection in cats.Vet Rec. 2006 Apr 22;158(16):544-50. Coyne KP, Dawson S,Radford AD, Cripps PJ,Porter CJ, McCracken CM, Gaskell RM. Long-term analysis of feline calicivirus prevalence and viral shedding patterns in naturally infected colonies of domestic cats.Vet Microbiol. 2006 Nov 26;118(1-2):12-25. Coyne KP,Reed FC,Porter CJ, Dawson S, Gaskell RM, Radford AD.Recombination of Feline calicivirus within an endemically infected cat colony. J Gen Virol. 2006 Apr;87(Pt 4):921-6. Coyne KP, Gaskell RM, Dawson S,Porter CJ,Radford AD. Evolutionary mechanisms of persistence and diversification of a calicivirus within endemically infected natural host populations. J Virol. 2007 Feb;81(4):1961-71. Foley J et al. Virulent systemic feline calicivirus infection: local cytokine modulation and contribution of viral mutants. JFMS 2006, 8: 55-61 Gore TC, Lakshmanan N,Williams JR, Jirjis FF, Chester ST, Duncan KL, Coyne MJ, Lum MA, Sterner FJ. Three-year duration of immunity in cats following vaccination against feline rhinotracheitis virus, feline calicivirus, and feline panleukopenia virus.Vet Ther. 2006 Fall;7(3):213-22. Hill RJ. Duration of immunity (DOI) and booster vaccination--dealing with the issue at practice level in the UK. Vet Microbiol. 2006 Oct 5;117(1):93-7.

53 Huang C, Hess J, Gill M, Hustead D. A dual-strain feline calicivirus vaccine stimulates broader cross- neutralization antibodies than a single-strain vaccine and lessens clinical signs in vaccinated cats when challenged with a homologous feline calicivirus strain associated with virulent systemic disease. J Feline Med Surg. 2010 Feb;12(2):129-37. Hurley KF et al. An outbreak of virulent systemic feline calicivirus disease. JAVMA 2004, 224(2): 241-249 Lappin MR, Andrews J, Simpson D,Jensen WA. Use of serologic tests to predict resistance to feline herpesvirus 1, feline calicivirus, and feline parvovirus infection in cats. J Am Vet Med Assoc. 2002 Jan 1;220(1):38-42. Mouzin DE, Lorenzen MJ, Haworth JD, King VL. Duration of serologic response to three viral antigens in cats. J Am Vet Med Assoc. 2004 Jan 1;224(1):61-6. Pedersen NC et al. An isolated epizootic of hemorrhagic-like fever in cats caused by a novel and highly virulent strain of feline calicivirus.VetMicrobiol 2000, 73: 281-300 Porter CJ,Radford AD, Gaskell RM, Ryvar R, Coyne KP, Pinchbeck GL, Dawson S. Comparison of the ability of feline calicivirus (FCV) vaccines to neutralise a panel of current UK FCV isolates. J Feline Med Surg. 2008 Feb;10(1):32-40. Poulet H, Jas D, Lemeter C, Coupier C, Brunet S. Efficacy of a bivalent inactivated non-adjuvanted feline calicivirus vaccine: relation between in vitro cross-neutralization and heterologous protection in vivo. Vaccine. 2008 Jul 4;26(29-30):3647-54. Radford AD, Dawson S, Coyne KP,Porter CJ, Gaskell RM. The challenge for the next generation of feline calicivirus vaccines.Vet Microbiol. 2006 Oct 5;117(1):14-8. Radford AD et al. Feline calicivirus.VetRes 2007, 38: 319-335 Schorr-Evans EM et al. An epizootic of highly virulent feline calicivirus disease in a hospital setting in New England. JFMS 2003, 5: 217-226 Schultz RD. Duration of immunity for canine and feline vaccines: a review. Vet Microbiol. 2006 Oct 5;117(1):75-9. Schultz RD,Thiel B, Mukhtar E, Sharp P, Larson LJ. Age and long-term protective immunity in dogs and cats.J Comp Pathol. 2010 Jan;142 Suppl 1:S102-8. Scott FW, Geissinger CM. Long-term immunity in cats vaccinated with an inactivated trivalent vaccine. Am J Vet Res. 1999 May;60(5):652-8. Stursberg U, Zenker I, Hecht S, Hartmann K, Schulz BS. Use of propentofylline in feline bronchial disease: prospective, randomized, positive-controlled study. J Am Anim Hosp Assoc. 2010 Sep-Oct;46(5):318-26.

54 ALLERGIC SKIN CONDITIONS Craig E. Griffin, DVM, DACVD, Animal Dermatology Clinic, San Diego, California, USA www.animaldermatology.com

INTRODUCTION

In one study of 1043 cats presenting to general veterinary practices in the United Kingdom preventative health care was the most common reason for presentation followed by dermatologic disease in 17%. In this study the most common reason for dermatologic presentation was cutaneous swellings (36%), followed by pruritus and otitis (19%). In another study the most common dermatologic problem in cats was itchy skin disease.2 In the United States allergic skin disease was the fifth most common feline claim at Veterinary Pet Insurance in 2011 .3 Most often itchy cats have allergic skin disease, with relative incidences of most notable being 29-43% fleas and flea allergy dermatitis, 20-22.5% atopic dermatitis and 12.-22.5% adverse food reactions. 2,4

ATOPIC AND FOOD ALLERGIC DERMATITIS

Atopic disease is becoming more commonly recognized in the cat and similar to the dog the skin form, atopic dermatitis, is the most common and may result from percutaneous absorption of allergen. Atopy is a type I, IgE-mediated allergic disease caused by environmental allergens.The environmental allergens are not commonly diagnosed by practitioners due to the difficulty in performing intradermal skin testing in the cat and the perceived safety of glucocorticoids. Serum in vitro testing is preferred by some dermatologists though normal cats may also react.5-10 However favorable response to ASIT suggests the test has value.7,8 .House dust mite is the most common environmental allergen. House dust mites are found where cats live and their level in a house has even correlated with the presence of cats. 11

Atopy has different manifestations and we believe it most commonly presents as atopic dermatitis though atopic rhinitis, conjunctivitis, otitis and asthma have been reported. However this has not really been proven and the cat appears to have more respiratory disease with atopy. A study evaluated 42 cats that had intermittent or continuous wheezing and dyspnea with eosinophilic lung infiltrates and no other detectable cause for their wheezing diagnosed as asthma. Of those, 50% had normal skin and 50% had skin disease, mainly barbered alopecia from excessive licking6 The atopic dermatitis cat similar to the dog is characterized by subclinical inflammation in the skin that usually results in pruritus.The majority of the lesions seen are the result of pruritus or secondary infections. However sometimes the inflammation will leave a sign in the form of hyper or hypo pigmentation. Eosinophilic granuloma complex and miliary dermatitis may also be seen in atopic dermatitis cases and how often this represents pyoderma has not been well evaluated. Recently a scoring system was developed for allergic cats, the (SCORing Feline Allergic Dermatitis; SCORFAD).12 My problem with the scale is one and likely two of the lesions being scored often represent pyoderma and when severe enough will impact response to allergic therapies.13,15. Therefore they should be eliminated prior to or at the onset of drug trials for feline allergic disease. Unfortunately or fortunately, once fleas and pyoderma are eliminated miliary eczema often resolves or becomes very mild.

Patterns for atopic dermatitis in the cat are not as well established nor as helpful as in the dog. The abdomen, groin and forelegs are the most common pattern I recognize but generalized pruritus, facial and head pruritus and even pruritic chin with acne have been seen with atopic dermatitis. In addition flea allergy and food allergy may affect all the same places.4 The dorsal lumbar area is significantly associated with flea allergy and in contrast to the dog not as often affected in food allergy.4 The face and head is more often associated with food allergy but only by a small margin. However the study by Hobi did not differentiate head / face pruritus that was sharply marginated at the level of the pinnae. I believe this is more helpful but still not a definitive sign. Another sign is otitis externa which is seen more with atopic dermatitis. Certainly there is a lot more work to be done regarding food and atopic dermatitis in cats, even regarding how often they coexist. We do have evidence that gastrointestinal signs are more common in food allergy.4 Unfortunately with outdoor cats and litter boxes owners are often not as aware about gastrointestinal signs in cats as dogs, though one sign often not evaluated that should be is flatulence.16 Food allergic cats do have more flatulence than atopic cats. 55 Borborygamus has not been evaluated but should be as it also seems more common in food allergic cats, though still infrequent. In one study of cats with chronic gastrointestinal disease 25% of those considered food sensitive had concurrent dermatitis and 40% of ten cats with GI disease and skin disease had food sensitivity. 17 It is also more common in Siamese cats though any breed may be affected. The pruritus, lesions and pattern cannot be as definitively differentiated visually from many other diseases, especially adverse food reactions, Demodex gatoi, Otodectes or Cheyletiella and even some cases of flea allergy or flea induced irritation. Psychogenic alopecia also has to be considered in the differential and can be difficult as stress and anxiety are known aggravators of atopic disease in humans and likely cats as well. Atopic dermatitis should be considered in any seasonally pruritic disease, but it can also present with year round signs. A tentative diagnosis of atopic dermatitis requires ruling out other differentials, in particular food and flea allergy and in certain geographic areas Demodex gatoi.This usually requires a period of confinement while diet trials and aggressive flea control are done.The definitive diagnosis requires demonstration of allergen specific IgE or positive intradermal testing as well as ruling out the other compatible differential diagnoses. Intradermal testing cats is more difficult than in the dog and also reactions are often slight and harder to interpet. This has left many practitioners and specialists frustrated in cases that have been well worked up and appear to be classic atopic dermatitis cats.The author is a consultant for Veterinary Allergy Reference Laboratory and has utilized this test as well as intradermal testing for instituting ASIT in cats with atopic dermatitis and atopic asthma. I prefer the VARL test over IDT in many cases because I have had more positives in suspect atopic cats while irrelevant positives appear to be less common in cats as compared to dogs.Though positive in other pruritic disease in normal cats it is therefore not diagnostic. Similar to the literature about 70% of the cats respond to ASIT. In many cats ASIT ends up being preferred by the owner because they find giving injections at home more convenient than oral medications.This also may be the best way to confirm a diagnosis. RULE OUTS Flea control was discussed in another section but is generally done in conjunction with a diet trial as both require the cat being confined indoors. Demodex gatoi is ruled out by trial lime sulfur dips for three weeks DIET TRIAL

Diagnosis requires elimination diet trials and provocation testing.The home cooked diet is extremely difficult in cats. A new protein and carbohydrate as the only food source is the primary goal. In general commercial diets are preferred for making a diagnosis.The newest trend in commercial hypoallergenic diets is the use of hydrolyzed protein sources. TABLE 1 Hydrolyzed Commercial Manufacturer Main Protein Carbohydrate Fat Diets in the United States HA Feline Purina Veterinary Purina Hydrolyzed soy, Rice starch Canola and corn Diets chicken and chicken oils liver Hypoallergenic Feather Royal Canin Hydrolyzed feather Corn starch Chicken fat, (hopefully for cats soon) copra, soya and fish oil Hypoallergenic HP Feline Royal Canin Hydrolyzed soy Rice Chicken fat, vegetable and fish oils ZD Feline canned Hill’s Hydrolyzed chicken Corn starch Vegetable oil liver ZD Feline Low Allergen dry Hill’s Rice protein, Rice Soybean oil brewer's rice, hydrolyzed chicken and hydrolyzed chicken liver The theory behind these diets is that food allergy is generally to large complex proteins or glycoproteins. By hydrolyzing foods to sizes smaller than this the diet will no longer be allergenic.There is work in humans to suggest this is the case however little documentation of this has been done in dogs and none in cats. Additionally if some of our food reaction cats are not allergic in pathogenesis then this theory of low molecular weight protein may not apply even though it could be true in true allergic induced disease. Other options are commercial diets that are formulated with the major protein and carbohydrate source being ones the pet was not previously being fed. The problem with these is the backordering and possibility of ingredient contamination.18

PROVOCATION TESTING

The true confirmation of food adverse reaction requires that feeding the offending diet can induce symptoms (provocation testing). After symptoms have improved significantly or been eliminated the pet should be challenged with the diet being fed prior to the diet trial. If there is no increase in symptoms then all other treats etc should be fed. Each challenge should be given only until a recurrence is obvious to the client or for 7 days. If there is no recurrence after 7 days that food is not likely to be the problem. One study evaluated food sensitivity in 55 cats with chronic gastrointestinal disease that was not attributed to any infectious, neoplastic, metabolic, viral or obstructive disease.17 Of these 55 cats, 27 responded favorably to restricted protein and rice diets fed for 4 weeks. However only 16 were able to be confirmed food sensitive by provocation testing as 11 stayed improved when challenged with their original diet. If there is a recurrence of symptoms, which most commonly is just an increase in pruritus, then the elimination diet is again fed until the symptoms again resolve. This will usually occur rapidly if the exacerbation is noted in the first two or three days on the challenge. With true allergy I suspect symptoms recur rapidly and in my experience most well confirmed food allergies are worse in one or two days.The next step is to try and determine what ingredients the pet is allergic to. Many clients are resistant to this proposal until I explain the value for them. Some pets will develop new allergies and by doing multiple challenges the client will not have to start totally over to determine what else the pet can eat. Additionally by knowing what foods the pet is not sensitive to more feeding options become available.This is particularly helpful for the long-term management of the case especially when multiple pets are in the household.

TREATMENTS FOR ALLERGIC DERMATITIS

Therapy for atopic dermatitis has traditionally relied on corticosteroid therapy partly because cats are often described as being "resistant" to the adverse effects.Though controlled studies have not been reported it is accepted that the incidence is probably lower that in the dog and humans but adverse effects do still occur. In fact my impression is that cats are more susceptible than dogs to diabetes mellitus from chronic glucocorticoids.There are also significant numbers of atopic cats that do not respond well therefore alternative therapies are still being sought. Alternatives to consider include antihistamines, fatty acids, allergen specific immunotherapy and ciclosporin.

If glucocorticoids are used many owners and clinicians prefer long acting injectable forms. If they are only used three times year approximately every four months then Depomedrol may be given IM at 4 mg/kg. Though systemic glucocorticoids are considered safer in cats than dogs, they still may cause serious adverse reactions and iatrogenic hyperadrenocorticism can and does occur. In the largest retrospective study of iatrogenic hyperadrenocorticism, twelve cases that met all the inclusion criteria were found at a teaching hospital during a 3.5 year time frame.19 Diabetes mellitus, polyphagia, polydipsia, cutaneous changes, muscle wasting, pot belly, curled pinna, steroid hepatopathy, and elevated liver enzymes may all be seen in cats on glucocorticoids. Elevations in alkaline phosphatase are very rare, as cats do not make a steroid induced isoenzyme, and the half life is much shorter than in the dog Herpes virus proliferation and disease may be aggravated, made more severe or induced by glucocorticoid administration.20,21 In one study looking at 271 cats diagnosed with congestive heart failure, 12 were associated with and attributed to corticosteroid therapy.22 Studies in normal cats suggests this is due to volume expansion from hyperglycemia and not elevated blood pressure.23 In another study, seven cats treated with dexamethasone 0.55mg/kg q24h routinely demonstrated

57 elevated fructosamine, glucosuria and decreased insulin sensitivity.24 One cat developed icterus by day 40, and curling of the pinna, a sign of iatrogenic hyperadrenocorticism, by day forty-eight. It is certain that glucocorticoids are not benign drugs in the feline, and they should be used with caution and in ways to minimize risk.

A variety of glucocorticoids and doseage regimens have been recommended for cats see table 2. My favorites are oral methylprednisolone and triamcinolone though due to variation in responses I have used all those in table 1 as well as prednisone which is variably absorbed in cats.25 A recent study showed that this is about ten times stronger than medrol and once daily dosing is effective in reducing remission in 94% of cases when dosed at 0.09 to 0.26 mg/kg once daily.26 Over 2/3 of the cases will stay in remission at eod dosing with a mean of 0.08mg/kg which appears to be a relatively safe dose.The equivalent median medrol doses were 1.41mg/kg daily and 0.54mg/kg eod with response rates of 88% and about 2/3 at eod.

TABLE 2: GLUCOCORTICOIDS AND INDUCTION DOSAGES

Steroid Route Dose per injection or for 4-7 Post induction dose 4 -7 days day induction Dexamethasone tablets PO 0.05 to 0.15 mg/kg q24h 0.05 to 0.1mg/kg q48h Dexamethasone sodium phosphate PO or 0.05-0.15mg/kg q24h 0.05 to 0.15 mg/kg q48h Subq Methylprednisolone acetate IM 20-30mg/cat IM NA Methylprednisolone tablets PO 1-2mg/kg q 24h 1-2mg/kg q48h Prednisolone tablets PO 2-3 mg/kg q24h 1-3mg/kg q48h Triamcinolone acetonide IM or 5mg/cat IM NA Subq Triamcinolone tablets PO 0.1-0.2mg/kg q24h 0.1-0.2mg/kg q48h

*All oral glucocorticoids are tapered after the induction to every other day dosing (EOD) and then over time to the lowest effective EOD dose.

Antihistamines may be helpful in treating atopic cats though I do not see the 50% response rate that some have reported. My favorite two are chlorpheniramine at 2 mg q12h and cyproheptadine 2mg q12h. I have heard of or seen limited response to amitriptyline 10 mg once to twice a day, clemastine .67 mg once a day, and allegra. Cetrizine 5mg q 12-24h is considered by some to be more valuable because of its inhibition of eosinophil migration.

Allergen specific immunotherapy has been utilized for years in the management of atopic dermatitis in dogs but its use in cats has lagged behind. In dogs it is described as a mainstay of therapy. Part of the relatively lower use of ASIT in cats may reflect that the cat is perceived as "relatively resistant" to the adverse effects of glucocorticoids, it is too expensive a therapy, or that there is less availability of tests to determine the formula for ASIT in cats. However there are reasons to prefer this method of therapy. It is the only therapy that may cure the problem or prevent the development or disease progression. Other treatments are treating symptoms or the effects of the disease. Many cats actually tolerate subcutaneous injections better than oral medications and the less frequent administration usually required is also helpful for most clients. It has been shown to be efficacious in cats and may even be more effective than in dogs.7,8 The shots can be administered at home and to date there have been few if any serious side effects or reactions reported. Additionally I have actually come to prefer a serum in vitro test for cats which is in contrast to the dog, therefore what I consider the best way to test cats for what allergens to treat with is more available to practitioners. The protocol I use in cats is different than that used in dogs. Often cats end up on smaller volume injections

58 that many clients find easier to administer as well. The initial schedule I use is in table 1 with vial one consisting of up to 12 items. Each item is 1 ml at 1,000-2,000 PNU per ml. Vial 2 is the same 12 items but the concentration is 10,000 - 20,000 PNU per ml. If there are less than 12 items then they are all increased equally in volume until there is 12 cc. Once maintenance is reached the final volume and interval between shots is determined by each patient's response. If there is an increase in pruritus or symptoms then I decrease to the last dose that caused no reactions.

TABLE 3 DAY 1 0.1CC DAY15 0.2CC DAY3 0.2 DAY17 0.3 DAY5 0.3 DAY19 0.4 DAY7 0.4 DAY21 0.5 DAY9 0.6 DAY23 0.5 DAY11 0.8 DAY25 0.5 DAY13 1.0 DAY30 phone call 0.5 ml at 5 at five day intervals

Reactions in cats are rare and serious reactions such as angioedema, or anaphylaxis have not been reported in the literature, nor have I personally had this happen to one of my patients. However I am aware of an anecdotal report from one veterinarian. In this case it sounded as if the cat had respiratory distress and collapsed appearing to have died but then shortly later got up and acted fine. Interestingly the owner never took the cat to the veterinarian so that this reaction can be confirmed as to type. I also have had one case that had symptoms compatible with intestinal anaphylaxis as seen in the dog.

The newest treatment being utilized for atopic cats as well as idiopathic eosinophilic granuloma complex is ciclosporin. Ciclosporin has been used for years in cats undergoing renal transplantation. Recently Atopica® for Cats by Novartis was released for treating allergic cats.There are also a number of reports about the benefits of ciclosporin for a variety of skin diseases in cats which often were likely allergic in origin.27,29 There are studies of feline asthma that report the use of the drug at 10mg/kg/bid, administered with food.30 The dose in allergic cats is 7mg/kg once daily.31 This is an effective therapy with 78% of cats becoming comfortable on treatment. Tapering is possible in about 2/3 of cases. Generic and compounded ciclosporin formulations are not equivalent or as effective.32 The mode of action of ciclosporin involves the inhibition of T-cell activation and the synthesis of various cytokines especially interleukin-2 (IL-2) and inhibits T-cell proliferation and the formation of cytotoxic lymphocytes. Ciclosporin is also thought to inhibit, via suppression of calcium- mediated signal transduction, mast cells and IgE-mediated immediate and LPR reactions, although in one study of human AD the opposite was found although the patients improved. Numerous studies have demonstrated influences on mast cells, Langerhans cells, keratinocytes, eosinophils and lymphocytes. Ciclosporin has immunosuppressive and antiproliferative effects rather than cytotoxic or myelotoxic effects.The drug is available as Atopica Feline a liquid formuation with a dose syringe based on the cats weight. Adverse reactions and concern for Toxoplasmosis will be discussed in the autoimmune presentation.

REFERENCES 1. Hill, P.B., et al., Survey of the prevalence, diagnosis and treatment of dermatological conditions in small animals in general practice.Vet Rec, 2006. 158(16): p. 533-539. 2. Bourdeau, P. and F.Fer, Characteristics of the 10 most frequent feline skin disease conditions seen in the dermatology clinic at the National Veterinary School of Nantes. Vet Dermatol, 2004. 15(s): p. 63. 3. www.petinsurance.com. Top ten reasons pets visit vets. 2011 [cited 2011; 2007 survey of claims]. 4. Hobi, S., et al., Clinical characteristics and causes of pruritus in cats: a multicentre study on feline hypersensitivity-associated dermatoses.Vet Dermatol, 2011. 22(5): p. 406-413. 5. Schleifer,S.G. and A. Willemse, Evaluation of skin test reactivity to environmental allergens in healthy cats and cats with atopic dermatitis. Am J Vet Res, 2003. 64(6): p. 773-778. 6. Trimmer, A., et al. Response of feline asthmatics to allergen specific immunotherapy: A prospective double-blinded placebo controlled study. in North American Veterinary Dermatology Forum. 2005. Sarasota, Florida.

59 7. Halliwell, R.E., Efficacy of hyposensitization in feline allergic diseases based upon results of in vitro testing for allergen- specific immunoglobulin E. J Am Anim Hosp Assoc, 1997. 33(3): p. 282-8. 8. Bettenay, S., Response to hyposensitization in 29 atopic cats, in Advances in Veterinary Dermatology, K. Kwochka, T. Willemse, and C. von Tscharner, Editors. 1998, Butterworth Heinemann: Oxford. p. 517-518. 9. Kadoya, M., Y. Momoi, and T. Iwasaki, Comparison of intradermal test and antigen-specific IgE test in 22 cases of feline allergic dermatitis. Vet Dermatol, 2004. 15(s): p. 37. 10. Diesel, A. and D.J. DeBoer, Serum allergen-specific immunoglobulin E in atopic and healthy cats: comparison of a rapid screening immunoassay and complete-panel analysis.Vet Dermatol, 2011. 22(1): p. 39-45. 11. Loft, K.E. and E.J.Rosser, Jr., Group 1 and 2 Dermatophagoides house dust mite allergens in the microenvironment of cats. Vet Dermatol, 2012. 21(2): p. 152-8. 12. Steffan, J., et al., Responsiveness and validity of the SCORFAD, an extent and severity scale for feline hypersensitivity dermatitis.Vet Dermatol, 2012. 23(5): p. 410-e77. 13. Wildermuth, B.E., C.E. Griffin, and W.S.Rosenkrantz, Feline pyoderma therapy. Clin Tech Small Anim Pract, 2006. 21(3): p. 150-6. 14. Yu, H.W. and L.J. Vogelnest, Feline superficial pyoderma: a retrospective study of 52 cases (2001-2011).Vet Dermatol, 2012. 23(5): p. 448-e86. 15. Wildermuth, B.E., C.E. Griffin, and W.S.Rosenkrantz, Response of feline eosinophilic plaques and lip ulcers to amoxicillin trihydrate-clavulanate potassium therapy: a randomized, double-blind placebo-controlled prospective study. Vet Dermatol, 2012. 23(2): p. 110-118. 16. Guilford, W.G., et al., Food sensitivity in cats with chronic idiopathic gastrointestinal problems. J Vet Intern Med, 2001. 15(1): p. 7-13. 17. Guilford, W.G., et al., Food sensitivity in cats with chronic idiopathic gastrointestinal problems. J Vet Intern Med, 2001. 15: p. 7-13. 18. Raditic,D.M., R.L. Remillard, and K.C. Tater, ELISA testing for common food antigens in four dry dog foods used in dietary elimination trials. J Anim Physiol Anim Nutr (Berl), 2011. 95(1): p. 90-7. 19. Lien, Y.-H., H.-P. Huang, and P.-H. Chang, Iatrogenic hyperadrenocorticism in 12 cats. J Am Anim Hosp Assoc, 2006. 42(6): p. 414-423. 20. Nasisse, M.P., et al., Experimental ocular herpesvirus infection in the cat. Sites of virus replication, clinical features and effects of corticosteroid administration. Invest Ophthalmol Vis Sci, 1989. 30(8): p. 1758-1768. 21. Stiles, J. and R. Pogranichniy, Detection of virulent feline herpesvirus-1 in the corneas of clinically normal cats. J Feline Med Surg, 2008. 10(2): p. 154-159. 22. Smith, S.A., et al., Corticosteroid-Associated congestive heart failure in 12 cats. Intern J Appl Res Vet Med, 2004. 2(3): p. 159-170. 23. Ployngam, T., et al., Hemodynamic effects of methylprednisolone acetate administration in cats. Am J Vet Res, 2006. 67(4): p. 583-587. 24. Lowe, A.D., et al., Clinical, clinicopathological and histological changes observed in 14 cats treated with glucocorticoids. Vet Rec, 2008. 162(24): p. 777-783. 25. Graham-Mize, C.A., E.J.Rosser Jr, and J. Hauptman, Absorbtion, bioavailability and activity of prednisone and prednisolone in cats, in Advances in Veterinary Dermatology, A. Hillier, A. Foster, and K. KW, Editors. 2005, Blackwell Publishing: Ames p. 152-158. 26. Ganz, E.C., et al., Evaluation of methylprednisolone and triamcinolone for the induction and maintenance treatment of pruritus in allergic cats: a double-blinded, randomized, prospective study. Vet Dermatol, 2012. 23(5): p. 387-e72. 27. Robson, D.C. and G.G. Burton, Ciclosporin: applications in small animal dermatology. Vet Dermatol, 2003. 14(1): p. 1-9. 28. Nakazato, A., et al. Administration of ciclosporin A to cats with allergic dermatitis: improvement of clinical signs and decrease of peripheral eosinophils in an open pilot study. in Nt Am Vet Derm Forum. 2006. Palm Springs. 29. Noli, C. and F. Scarampella, A prospective pilot study on the use of ciclosporin on feline allergic diseases. Vet Dermatol, 2004. 15(s): p. 33. 30. Padrid, P., Feline asthma: pathophysiology and treatment. Waltham Focus, 1999. 9: p. 17-22. 31. King,S., et al., A randomized double-blinded placebo-controlled study to evaluate an effective ciclosporin dose for the treatment of feline hypersensitivity dermatitis.Vet Dermatol, 2012. 23(5): p. 440-e84. 32. Umstead, M.E., et al., Accuracy and precision of compounded ciclosporin capsules and solution.Vet Dermatol, 2012. 23(5): p. 431-e82.

60 AUTOIMMUNE SKIN DISEASES Craig E. Griffin, DVM, DACVD, Animal Dermatology Clinic, San Diego, California, USA www.animaldermatology.com

Autoimmune skin diseases are much less common in cats than dogs.The proof that they are autoimmune is generally lacking as the exact antigen targeted is unknown for most. It is believed that cats develop bullous pemphigoid, lupus erythematosus, mucus membrane pemphigoid and pemphigus complex.1-8 For all of these but pemphigus, the number of cases is very limited making characterisation of the disease impossible.

In general the autoimmune diseases in cats tend to be facial and cause erythematous erosive or ulcerative disease.The distal extremities and digits or pads may be affected, a feature that should raise the index of suspicion for autoimmune disease. Since all are rare except pemphigus foliaceus, only that disease will have clinical findings presented in detail.

Pemphigus foliaceus is by far the most common autoimmune disease in cats. Single cases of pemphigus vulgaris and pemphigus erythematosus have been reported.9-13 Several studies have been published with the largest reporting on 57 cases.10 It is unknown what induces pemphigus though similar to dogs some cases occur in cats with prior history of drugs or skin disease most often allergic. Some PF cats even have seasonal exacerbations and have been misdiagnosed at least initially as allergic. One had concurrent leishmania.14

No breed or sex predisposition has been documented for feline PF. Disease onset has varied from < 1yr to 17 yrs, with a median of 5 years.10 Pustular lesions are not often seen except when pads are involved. Erythematous based erosions and focal crusting lesions are most common. These areas often develop alopecia as the crusts fall off. The pinnae, nasal area, and face are most often affected. Lesions may also be seen around the areolae though this was not described in the largest case series. Lesions often extend to involve other body regions, especially the claw folds in 30% of cases.10 This presents as a refractory paronychia. Lesions may be bilateral symmetric or slightly asymmetrical. Pruritus is mild-severe in about 80% of cases, and animals are often lethargic, febrile and anorectic.

Diagnosis is made by histopathology, with subcorneal or intracorneal pustules regarded as the most significant finding. All are neutrophilic, with some having significant eosinophils.The outer root sheath is involved in one third of cases, and the pustules, where seen, may span from 1-15 follicular units.10 Acantholytic cells are a highly significant finding, and 39 cases in the above series had >20 acanthocytic cells per high power field. Immunological studies have not been routinely performed, and so there is no data on their utility as diagnostic aids.

The prognosis for this disease in cats is quite good. Although in an earlier report, azathioprine was used successfully for induction therapy this is not recommended by this author and severe fatal reactions have been reported. Follow up was possible in 44 cases in one study and only 4/44 cats died from their disease or treatment-related causes during this period.10 Since some cases of feline pemphigus may be cured the treatment has 4 main phases.These phases are 1. Induction of remission, 2. Transition, 3. Maintenance and 4. Determining cure.

INDUCTION PHASE

The initial therapy used in treating immune mediated dermatoses is to stop the inflammation and suppress the immunologic response against the skin. Higher doses of drugs are usually needed for this phase of therapy. If the induction therapy is not effective in a timely manner for the chosen class of drugs and the disease, then the induction treatment should be immediately changed.

61 TRANSITION PHASE

This phase involves tapering the drugs used to minimize the long-term side effects, risks of adverse reactions and cost. When combinations of medications are prescribed, the first drugs to be tapered are those with greater likelihood of adverse effects.When control of the disease and side effects have reached levels acceptable to both the client and clinician, then tapering of more expensive drugs or drugs that require more monitoring expenses can begin. All medications are slowly tapered until there is a recurrence of clinical signs. If no recurrence is seen then the case may be determined cured.

MAINTENANCE PHASE

Maintenance is reached after recurrence or exacerbation of the disease occurs in the transition phase. Once recurrence is noted, medication doses are raised again sufficiently to reinduce remission and then doses are maintained at the level reached prior to the recurrence.Thus, maintenance doses are the lowest doses that result in a stable degree of disease that is acceptable to the client and clinician. After one year of maintenance therapy, tapering is repeated, and some cases may remain cured even though they had flared at the end of the transition phase.

DETERMINING CURES

Many immune mediated dermatoses have been recognized where cases are put into remission and treated for a period of time then go off medications and remain disease free.These "Cures" may be achieved at the end of the transition phase or after the maintenance phase has persisted for a period of time. Cats that have been in the maintenance phase for 8- 12 months should consider having their medications stopped or go through a new transition phase to see if they have become cured. This may occur in some cases but if they had severe recurrences that were harder to get back into remission then this should not be considered again.

The treatment regimens most often employed are prednisone or prednisilone (4-5mg/kg) or triamcinolone (0.6- 2.0mg/kg). The latter appears to be the most effective with a lower incidence of side effects.For maintenance, triamcinolone is used at 0.6-1.0 mg/kg every 2-7 days, or prednisone at 2.5-5.0mg/kg every 2-3 days. If steroids alone are not effective then concurrent ciclosporin or chlorambucil are usually added. The glucocorticoids are discussed in the allergy section.

CICLOSPORIN

Ciclosporin has been approved for the treatment of allergic dermatitis in cats but has also been used to treat autoimmune diseases in cats. It is generally used in conjunction with a glucocorticoid unless the cat developed diabetes then it may be used a sole therapy. One retrospective study showed it had superior steroid sparing effect and controlled 5/6 cases of feline pemphigus foliaceus without the need for long term glucocorticoid and could be used as sole therapy in some cats with PF.13 The liquid formulation comes as 100mg/ml and once opened has a shelf life of 11 weeks. It is initially dosed at 7mg/kg daily until a good response is seen which if does not occur in 4 weeks you can increase the dose to 10mg/kg daily or bid.. Generally it is given with a meal but that is not essential. Once a response is seen the treatment is tapered to eod and if remission is maintained for a month then further tapering may occur. Some cases have tapered to eod then lower mg/kg dose even though they could not go to less frequent dosing. Similar to dogs, adverse reactions of vomiting and diarrhoea are most common but not a limiting factor in most cases. It appears liver hepatotoxicity and kidney disease are very rare but hepatic lipidosis has been seen so making sure cats are not losing weight rapidly or anorectic on the medication is important and something owners should be counselled about. Gingivitis or gingival hyperplasia may occur as well as upper respiratory infections.There has been some concern about serious reactions to ciclosporin. In the 6 pemphigus cats treated with ciclosporin one did die from lymphoma and one systemic mycobacterium avium infection.13 There are rare reports of systemic fatal Toxoplasmosis and it is believed this most likely occurs in cats that have never been exposed to Toxoplasma until after being on

62 ciclosporin. However two cases for sure and likely two others did have Toxoplasmosis prior to being put on ciclosporin. In addition the problem appears to be much more common in male cats 11,13 and the only case to survive was female.15 Over half the cases develop signs by 30-60 days after being put on ciclosporin or exposure to Toxoplasmosis. Pretesting titers of Toxoplasma may not be that helpful but since cases may become positive while on therapy it may be worth monitoring. All systemic cases present with respiratory disease so owners need to watch for coughing, dyspnea or lethargy. It is strongly recommended to try to limit hunting in cats on ciclosporin even if seropositive prior to initiating therapy. The incidence in either case appears to be very low. Titers are monitored in cats kept on the drug long term and if IgM titers develop appropriate therapy is indicated. The cases I have had generally are asymptomatic so testing should be routine and not just in cats showing symptoms.

CHLORAMBUCIL

Chlorambucil (Leukeran, Glaxo Wellcome) is an alkylating agent that functions by affecting the cross linking of DNA. It is considered less toxic and slower acting than other alkylating agents. It is dosed at .1 -.2-mg/kg q 24h to 48h. It is available in a 2 mg non-scored coated tablet, making dosing in cats easier.You can give the average daily dose daily to eod. Myelosuppression is a concern and complete blood cell count and chemistry monitoring is recommended. Initially every two weeks then once stable it may be less frequent. Other side effects include vomiting, diarrhea and anorexia 16.The author will use chlorambucil as the drug of choice in feline pemphigus when glucocorticoids do not work or are not tolerated. 10,17

REFERENCES

1. Olivry, T., et al., Laminin-5 is targeted by autoantibodies in feline mucous membrane (cicatricial) pemphigoid.Vet Immunol Immunopathol, 2002. 88(3-4): p. 123-9. 2. Olivry, T., et al., Novel feline autoimmune blistering disease resembling bullous pemphigoid in humans: IgG autoantibodies target the NC16A ectodomain of type XVII collagen (BP180/BPAG2). Vet Pathol, 1999. 36(4): p. 328-35. 3. Olivry, T. and H.A. Jackson, Diagnosing new autoimmune blistering skin diseases of dogs and cats. Clin Tech Small Anim Pract, 2001. 16(4): p. 225-9. 4. Murayama, N., H. Takahashi, and T. Hizume, A feline case study suspected of systemic lupus erythematosus. Jpn J Vet Dermatol, 2005. 11(2): p. 61-64. 5. Lusson, D., B. Billiemaz, and J.L. Chabanne, Circulating lupus anticoagulant and probable systemic lupus erythematosus in a cat. J Feline Med Surg, 1999. 1(3): p. 193-6. 6. Kalaher, K. and D.W. Scott, Discoid lupus erythematosus in a cat. Feline pract, 1991. 19: p. 7. 7. Pedersen, N.C. and J. Barlough, Systemic lupus erythematosus in the cat. Feline pract, 1991. 19: p. 5. 8. Werner, L.L. and N.T. Gorman, Immune-mediated disorders of cats. Vet Clin North Am Small Anim Pract, 1984. 14(5): p. 1039-64. 9. Olivry, T., A review of autoimmune skin diseases in domestic animals: I - Superficial pemphigus.Veterinary Dermatology, 2006. 17(5): p. 291-305. 10. Preziosi, D.E., et al., Feline pemphigus foliaceus: a retrospective analysis of 57 cases. Vet Dermatol, 2003. 14(6): p. 313-21. 11. Manning, T. and e. al, Pemphigus diseases in the feline: Seven case reports and discussion. J Am Anim Hosp Assoc, 1982. 18: p. 433. 12. Greek, J.S., Feline Pemphigus foliaceus: A retrospective of 23 cases. Proc Annu Memb Meet Am Acad Vet Dermatol Am Coll Vet Dermatol, 1993. 9: p. 27. 13. Irwin, K.E., K.M. Beale, and V.A. Fadok, Use of modified ciclosporin in the management of feline pemphigus foliaceus: a retrospective analysis. Vet Dermatol, 2012. 23(5): p. 403-e76. 14. Rufenacht, S., et al., Two cases of feline leishmaniosis in Switzerland.Vet Rec, 2005. 156(17): p. 542-5. 15. Griffin, C.E. Toxoplasmosis update and current thoughts. in WCVD Novartis Animal Health Symposium. 2012. Vancouver. 16. Rosenkrantz, W.S., Immunomodulating drugs in dermatology, in Current Veterinary Therapy X: Small Animal Practice. 1989, W. B. Saunders Co: Phildelphia. p. 570. 17. Rhodes, K. and N. Shoulberg, Chlorambucil: Effective therapuetic options for the treatment options for the treatment of feline immune-mediated dermatoses.Feline pract, 1992. 20: p. 5. 63 NOTES

64 FELINE CUTANEOUS BACTERIOLOGY AND PYODERMA Anita Patel BVM, DVD, MRCVS, RCVS Recognised Specialist in Veterinary Dermatology Dermatology Referrals

INTRODUCTION

Compared to published studies on cutaneous bacteriology in healthy dogs and those with skin lesions, similar studies in cats are few in number. Similarly, there is much information on the classification (i.e. superficial vs. deep) and on sub-classifications (based on anatomical site, lesion type and or distribution) of canine pyodermas1, but information on feline pyodermas is still scarce and the classification in dogs cannot be extrapolated to cats as they tend to show reaction patterns rather than specific lesions, or infection in specific sites. Furthermore cats tend not to exhibit the lesions, such as pustules, follicular papules, epidermal collarettes and lichenification that are frequently seen in canine pyodermas.

CUTANEOUS BACTERIOLOGY

For many years Staphylococcus aureus and S. simulans were reported as the most isolated organisms from feline skin2, 3. Some years later S. pseudintermedius (previously known as S. intermedius) was reported as the most frequently isolated coagulase-positive organism from healthy feline skin4.With advances in techniques for isolation and identification, reports of organisms found on feline skin also changed. Staphylococcus felis a coagulase-negative species was first described in 1989 5, 6 and it was suggested that the previously reported S. simulans may have actually been S. felis because the two have similar biochemical properties, except for differences in mannose fermentation, phosphatase reaction and bacitracin sensitivity.

A later study7, reported on the prevalence of cutaneous staphylococci in three groups of cats; feral cats, healthy pet cats and pet cats with skin lesions. Sixteen different staphylococcal species were identified from the samples obtained. Staphylococcus felis (35%) was isolated from all three populations and there was no significant difference between the three groups (p>0.05) suggesting that this species may be a resident Staphylococcus of cats. S. pseudintermedius (20%) was the most common coagulase-positive species isolated and was derived mainly from lesions and multiple sites on cats with skin lesions suggesting it may play a role in perpetuating skin disease in cats.The isolation rate for S. aureus was 2 % and MRSA was not isolated in healthy cats, nor in those with skin lesions.

S. felis has also been isolated from saliva and conjunctivae of cats 8,9,10. The most recent report on isolation of coagulase-positive staphylococci was part of broader study involving mainly humans and their house hold pets which included dogs and cats 11. In this study the isolation rate of S. aureus was 4.3%, MRSA was 0% and S. pseudintermedius was 1.2%.

Overall the isolation rates of staphylococcal organisms from healthy cat skin remain very low, which may be due to low adherence of bacteria to cat skin. This supposition is supported by a study reporting low in vitro staphylococcal adherence to feline corneocytes, when compared to canine and human ones 12.

FELINE PYODERMA

Rather than use the canine classifications, a more appropriate classification system for feline pyoderma would be based on the types of lesions present 13 . Crusted papules, plaques, scaling, excoriations and ulcerations are associated with superficial infection, whereas abscesses, non-healing draining nodules, ulcers and cellulitis are associated with deep pyoderma. In my experience the micro-organisms responsible for the superficial infections are those that are part of the cutaneous microenvironment, while those responsible for deep infections are usually introduced to the skin and subcutis as a result of trauma. 65 SUPERFICIAL PYODERMA

The lesions, crusted papules, plaques, scaling, excoriations and ulcerations, are confined to the epidermis, dermis and the follicular epithelium. In the literature these lesions in cats have been described as acne, superficial juvenile pustular dermatitis, superficial pyoderma, and superficial folliculitis.

DEEP PYODERMA

When the infection has invaded the dermis and the subcutaneous tissue, either via a ruptured follicle, or a penetrating wound, it is described as deep pyoderma. The lesion types of such cases seen in cats include abscesses, furuncles, non-healing draining nodules, ulcers and cellulitis.

PATHOGENESIS

S. felis was first identified from clinical specimens and has subsequently been implicated in the pathogenesis of otitis externa 14, paronychia 15 and miliary dermatitis 16 in single cases.

As part of a dissertation17 the potential role of staphylococci in the pathogenesis of pruritic skin lesions, which included papulocrustous lesions, otitis externa, excoriations, ulcerations and alopecia, in cats was studied. This was done by identifying staphylococci from the lesions and other sites on nine affected cats and monitoring response to antibacterial therapy based on sensitivity testing18 .Following a full dermatological examination and appropriate investigations, the underlying causes (flea allergic dermatitis, atopic dermatitis, adverse food reaction, contact allergic dermatitis, otoacariasis) were identified in all but one case.

Five out of the nine cats with skin lesions given antibacterial agent (generally co-amoxiclav) and flea control, for periods of between 2-8 weeks, responded to the treatment and did not require any additional drugs. Two cats showed moderate improvement, but lesions were still evident after 2 weeks and two cats failed to respond at all. Complete resolution of lesions within two weeks of starting treatment with co-amoxiclav implies a secondary role for staphylococcal skin infections in cats with self-induced dermatitis. S. pseudintermedius was also isolated from lesions and nares of three cats. In those three cases, response to antimicrobial treatment was favourable. S. felis was isolated from 3 affected cats. Interestingly the same staphylococcal species was isolated both from the nostril and from the lesion in all but one case.This finding was further tested and confirmed using pulsed field gel electrophoresis to compare the specimens taken from one of the cats.

A more recent randomized double-blinded placebo controlled study19 evaluated the response of feline eosinophilic plaques and lip ulcers to amoxicillin-clavulanate therapy. Swab and tissue biopsy samples were obtained for aerobic culture. Multiple organisms were isolated in each cat and those from the swab sample were not identical to those from the tissue culture. A total of 17 staphylococcal isolates were obtained from the eosinophilic plaques. S. aureus and S. pseudintermedius were isolated in 6 out of 9 cats (12 isolates in total) and coagulase-negative staphylococci were isolated in 3 cats (total 5 isolates). Other species included Pastuerella multocida (2 isolates), Streptococcus canis (2 isolates), Streptococcus viridans (2 isolates) Pseudomonas aeruginosa (2 isolates), enteric species (one each) and Pseudomonas stutzeri (one isolate). A total of 21 staphylococcal isolates (20 coagulase-positive and 1 coagulase-negative) were obtained from the lip ulcers from swab and tissue samples. Other species included Pastuerella (8 isolates), Streptococcus suis (1), Streptococcus canis (1), non-haemolytic streptococcus (1), Corynebacterium spp (1), Pseudomonas spp (1), Neisseria like bacterium (1). Staphylococcal organisms were the predominant species isolated.

In this study the investigators evaluated response to amoxicillin-clavulanate treatment at a mean dose of 13.4mg/kg by measuring changes in lesion size using digital photography. All four cats in the treated group with eosinophilic plaques showed at least a 70% improvement while all 5 cats in the placebo-controlled group showed no improvement. In the group of cats with lip ulcers only 2 out of the 5 cats in the treatment group improved by more than 70%.

66 Both, the findings of the unpublished part of the dissertation 17 and the more recent study 19 show that lesions such as papulocrustous lesions, plaques, ulcers and excoriations can be infected with both coagulase-positive and coagulase-negative staphylococci and other bacteria. These organisms are likely play a role in perpetuating the lesions, as was demonstrated by the response to antibacterial treatment.

The organisms implicated in perpetuating skin lesions may be introduced during excessive grooming, due to parasitic and allergic skin diseases, or due to systemic diseases such as exfoliative dermatitis associated with thymoma, paraneoplastic alopecia, diabetes mellitus and other immunosuppressive diseases.The relationship between the presence of the organisms and the lesions has been shown by the response to antibacterial treatment, where a reduction in size, or resolution, of lesions has been demonstrated as a result of treatment.

Pasteurella multocida is generally found in the oral cavity and the respiratory tract. This organism is generally associated with cat bite abscesses, but is also implicated as a secondary invader in superficial pyoderma 20.

Deep pyoderma in cats is generally associated with organisms introduced into the skin through penetrating wounds, commonly resulting from a fight. Therefore the organisms associated with these infections are generally those that are found in the oral cavity.They include aerobic bacteria Pasteurella multocida, staphylococcal species, E. coli, Pseudomonas spp, beta haemolytic Streptococci; and anaerobic organisms such as Bacteroides, Arcanobacterium spp, and Clostridium spp. In most cases the infections lead to abscess formation and in some cases cellulitis 21.

Saprophytic bacteria introduced through wound contamination include Nocardia spp, Rhodococcus equi and mycobacteria 23, 24, 25, 26, 27. These bacteria cause pyogranulomatous to granulomatous dermatitis in both immunocompetent and immunosuppressed cats.The organisms develop a number of strategies to survive within the host tissue.

CLINICAL SIGNS

The clinical signs and the distribution of lesions associated with superficial infections vary between individuals. The lesions include crusted papules plaque, scaling, alopecia, excoriations and ulcerations.These may be present as what are referred to as miliary lesions, eosinophilic plaques, granulomas or indolent (rodent) ulcers. More than one of these signs can be seen on individual animals. Comedones, hyperpigmentation, follicular papules and epidermal collarettes are very rarely seen in cats.

Acne, another reaction pattern has been associated with hypersensitivity, demodicosis, and dermatophytosis and as a primary keratinization defect in some breeds such as Burmese and Persian cats, is usually also associated with secondary bacterial infections. Comedones and black exudate adherent to the skin on the chin and lower lips are the predominant finding in these cases.

Paronychia and pyonychia are often associated with bacterial infections secondary to immunosuppression, trauma, autoimmune diseases, and foreign bodies. Signs include swelling, erythema, purulent or waxy exudate around the claws. Single or multiple claws are involved depending on the underlying cause.

A general physical examination may elucidate signs that are consistent with an underlying systemic disease (i.e. hyperthyroidism, diabetes mellitus, internal neoplasia and viral diseases).

The clinical signs associated with deep pyoderma include abscesses, cellulitis, draining furuncles and sinuses, nodules and non-healing ulcers. Abscesses and cellulitis are very common and occur anywhere on the body, but are mainly seen on the face, neck and the tail base.They appear as a soft fluctuant swelling, which is usually painful and on close examination bite wounds, or scabs, may be found under tufts of matted hair. In some cases these swellings rupture and a purulent discharge is seen. Cellulitis is mainly seen in distal limbs, as a diffuse painful swelling and, depending on the duration of the disease, the skin may be red to blackish in appearance and may be devoid of hair. Systemic signs include pyrexia, inappetence and malaise.

67 Bacterial furunculosis is an uncommon presentation in cats but can occur. It presents as papules, pustules, ulcerations and draining fistulas with varying degrees of pain and pruritus.The lesions can occur anywhere, but are most frequently seen on the chin regions and have sometimes been described as acne.

Non-healing lesions, nodules, ulcers and draining tracts, are mainly seen in cases associated with saprophytic bacteria (Nocardia, Rhodococcus equi, Arcanobacterium), which have gained entry through wounds contaminated with soil, or other debris. Lesions develop slowly over a period of weeks to months and often are unresponsive to routine treatment used for abscesses and superficial infections.They range from single circumscribed nodules to multiple ill-defined swellings with draining fistulae and punctate ulcers. Lesions can occur anywhere on the body, but the most common sites are the abdominal, thorax and rump regions.The discharge varies from purulent to haemopurulent and may or may not contain granules.

The condition may be pruritic and or painful. Peripheral lymphadenopathy may be a feature in some cases. In some cases systemic illness may be associated with the infection, especially with certain etiological organisms. Systemic signs, for instance respiratory signs associated with pyothorax, anorexia, weight loss, weakness, pyrexia and lethargy may be present, depending on whether the infection has disseminated to internal organs, or not. Hypercalcemia is associated with granulomatous infections in cats 28.

DIAGNOSTIC TESTS

Unlike in dogs, a diagnosis of superficial pyoderma in a cat cannot be based on history, clinical signs and the distribution of lesions alone. Cytological examination of smears, cultures, histopathology and response to treatment should be used to both diagnose and to assess the role of bacterial infections in any individual case.

CYTOLOGY

Direct impression smears, or tape-strip preparations stained with modified Wrights stain (Diff-Quik) usually provide clues on the pathogenic process involved. The smears may show neutrophils and intracellular cocci or rods suggesting a bacterial infection. The presence of eosinophils and neutrophils with cocci suggest an infection with a concurrent allergic disease.The presence of large bacteria, especially coccal organisms, suggests microbial overgrowth and is mainly seen in immunosuppressed cats.

For deep pyoderma fine needle aspirates from nodules and impression smears from draining sinuses are examined. They usually reveal a pyogranulomatous inflammation, which is characterised by a mixture of neutrophils and macrophages, whereas granulomatous inflammation is characterised by macrophages. In some cases organisms may be visible within the macrophages, or within lipid vacuoles, or giant cells, in smears stained with a modified Wright's stain (Diff Quik), or they may require Gram-staining, or an acid-fast stain such as Zeihl-Neilson stain. The absence of visible organisms on direct smears, or histology, does not rule out infectious causes.

CULTURE

For superficial lesions that fail to respond to first line treatment culture should be performed as MRSA and MRSP may be involved. For superficial lesions swab samples are taken, but for deep pyoderma and ulcers tissue biopsy samples should be obtained using an aseptic technique. Identification of the organism on culture provides a definitive diagnosis. Many require specific culture media and aerobic, or anaerobic, conditions for growth and therefore the laboratory should be warned when submitting the sample.

68 SKIN BIOPSIES

Histological findings range from mild to severe neutrophilic and/or eosinophilic superficial perivascular and/or ulcerative dermatitis, interstitial dermatitis, periadnexal dermatitis, perifolliculitis and luminal folliculitis. Bacteria may be visible in the focal, or multifocal crusts on the ulcerated surface, or in the stratum corneum. In the author's experience the latter is a more common histological finding than presence of pustules, or follicular pathology. Histological changes associated with eosinophilic dermatitis and paraneoplastic syndromes may be evident, giving an indication of the associated primary disease.

Deep pyoderma is histologically seen as a nodular to diffuse dermatitis and/or panniculitis patterns composed of coalescing granulomas, or pyogranulomas.The inflammatory cells are macrophages, neutrophils and small number of lymphocytes.The infectious organism may be visible in cytoplasmic vacuoles, or within clear spaces surrounded by neutrophils and macrophages. In other cases, especially with actinobacillosis, Arcanobacterium pyogenes infection (actinomycosis) and staphylococcal infections, club-colonies consisting of a central core of organisms surrounded by radial array of eosinophilic material - the Splendore- Hoeppli phenomenon 29 - may be evident. The morphology of the organism and special stains such as the Brown and Brenn's Gram tissue stain and modified acid fast stains give an indication of the causative organism and provides useful information for the microbiologist.

RESPONSE TO TREATMENT

Ultimately the significance of staphylococci, or other organisms, involved in superficial infections depends on the response to appropriate antibacterial treatment. Bearing in mind that the bacterial infection is likely to be a perpetuating factor in superficial skin lesions, rather than a cause, the associated primary disease must also be identified and treated concurrently, if the recurrence of lesions is to be avoided. The duration of treatment should be individualised based on cytological findings performed at each visit, lesion size and level of pruritus. The underlying aetiology, which is present in most cases, should be identified and managed appropriately.

OTHER INVESTIGATIONS

Non-healing draining nodules are uncommon and can occur when there is systemic disease, therefore haematological, biochemical and serological tests for immunosuppressive diseases, such as feline immunodeficiency virus and feline leukaemia virus, should be performed. Additional screening tests for systemic involvement could include survey radiography and ultrasonography.

TREATMENT

Systemic treatment is best for superficial bacterial infections, given the propensity of cats to lick off most topical medications and the difficulty in bathing them. There are a number of factors to consider before deciding on the actual antibiotic preparation to prescribe. Unlike dogs, very few cats will eat food with medication in it and some drugs may cause the cat to froth and salivate, after which it is impossible to administer the preparation. Therefore the ability and the willingness of the owner to administer the medication may well be the key to the choice of drug. In feline cases therefore the therapy needs to be individualised to suit both the owner and the patient.

There are a few reports 18,30 on the antibacterial susceptibilities of the staphylococci found on cats and the drugs and doses recommended for the treatment of superficial pyoderma based on these reports in Table 1. Staphylococcal resistance to penicillin and amoxicillin appears to be common in the USA and the UK and therefore should be not used as a first line of treatment, however due to regional differences they may be useful in other regions. Bear in mind that poor response to beta lactam antibiotics may be an indication of MRSA or MRSP. Treatment should always be carried out for 7-14 days beyond clinical cure if infection alone, or until there is no further change in lesion size or cytological evidence of infection is absent.

69 Underlying diseases should be investigated and treated. In most cases it is best to monitor progress much more frequently in cats than in dogs, as in some cases concurrent anti-inflammatory treatment is required. In particular, in cases with eosinophilic dermatitis concurrent treatment is required for the resolution of the lesions.

Successful treatment for non-healing nodules and ulcers depends on a number of different factors, which include: the number and site of the lesions, the immune status of the cat and whether there is systemic involvement or not. The prognosis in cats with widespread lesions, or with an underlying disease, is guarded.

Complete wide margin surgical excision of the infected tissue is the most successful treatment for single lesions. If there is widespread involvement, surgical debulking together with long courses of antibiotics is recommended. Choice of antibiotic for saprophytic infections should be based on culture and sensitivity result and treatment should be continued for at least 4 weeks beyond clinical cure.

TABLE 1:

Antibiotics for superficial and deep pyoderma in cats (NB those for mycobacterial infections are not included in this table)

Antibiotic Dose Route of administration

bid (every 12 hours) PO (oral) IM (intramuscular)

sid (every 24 hours) SC (subcutaneous)

Co-amoxiclav 12.5-25mg/kg bid PO, IM, SC

Cephalexin 15-20mg/kg bid PO

Cefadroxil 20mg/kg bid PO

Cefovecin 8mg/kg every 2 weeks SC

Clindamycin 5.5mg/kg bid PO

Doxycycline * 5-10mg/kg sid PO

Enrofloxacin * 5-20mg/kg sid PO, SC

Marbofloxacin * 2-5mg/kg sid PO

Pradofloxacin 3mg/kg sid PO

Lincomycin 20mg/kg bid PO

Oxytetracycline 10-30mg/kg bid PO

Trimethoprim-Sulphadiazine 15-30mg/kg bid PO

* Useful for deep pyoderma based on the identification of the causative organism and sensitivity to the agent.

70 REFERENCES

1. Scott DW, Miller WH, Griffin CE: Small Animal Dermatology, ed 6, Philadelphia, 2001, WB Saunders 2. Krogh HV & Kristensen S: A study skin diseases in dogs and cats: II. Microflora of the normal skin of dogs and cats, Nord Vet. Med 1976; 28: 459-463 3. Devriese LA, Nzuambe D, Godard C: Identification and characterisation of staphylococci isolated from cats, Vet Microbiol 1984; 9: 279-285 4. Cox HU, Hoskins JD, Newman SS,Turnwald GH, et al: Distribution of staphylococcal species on clinically healthy cats, Am J of Vet Res 1985; 46: 1824-1828 5. Igimi S, Kawamura S,Takahashi E et al: Staphylococcus felis, a new species from clinical specimens from cats, Int J Syst Bacteriol 1989; 39: 373-377 6. Igimi S, Atobe H, Tohya Y, et al Characterisation of the most frequently encountered staphylococcal species in cats,Vet Microbiol 1994; 39: 255-260 7. Patel A, Lloyd DH, Lamport AI: Prevalence of feline staphylococci with special reference to Staphylococcus felis among domestic and feral cats in the south-east of England, In Thoday KL, Foil CS, Bond R editors, Advances in Veterinary Dermatology 2002; 4: 85-91 8. Lilenbaum W, Esteves AL, Souza GN: Prevalence and susceptibility of staphylococci isolated from saliva of clinically normal cats, Lett Appl Microbiol 1999; 28: 448- 9. Lilenbaum W, Nunes EL, Azeredo MA, Prevalence and antimicrobial susceptibility of staphylococci isolated from the skin surface of clinically normal cats, Lett Appl Microbiol 1998; 27: 224 10. Espinola, MB, Lilenbaum W: Prevalence of bacteria in the conjunctival sac and on the eyelid margin of clinically normal cats, J Small Anim Pract 1996; 37: 364- 364-366 11. Hanselman BA, Kruth SA, Rousseau J,Weese JS: Coagulase positive staphylococcal colonization of humans and their household pets, Can Vet J 2009; 50: 954-958 12. Wooley KL, Kelly RF,Fazakerley J,Williams NJ, Nuttall TJ, McEwan NA: Reduced in vitro adherence of Staphylococcus species to feline corneocytes compared to canine and human corneocytes,Vet Dermatol 2008; 19: 1-6 13. Patel A Bacterial pyoderma in Consultations in Feline internal medicine ed August JR 2006 Vol 5 Elsevier Saunders 251-259 14. Higgins R, Gottchalk M: Isolation of Staphylococcus felis from cases of external otitis in cats, Can Vet J 1991; 32: 312-313 15. Aarestrup FM, Jacobeson MJ: Bacterial paronychia caused by Staphylococcus felis in cats, Dansk Vet 1993; 76: 1066-1067 16. Patel A, Lloyd DH, Howell SA et al: Investigation into the potential pathogenicity of Staphylococcus felis in a cat, Vet Rec 2002; 150: 668-669 17. Patel A, A study on feline staphylococci in England, RCVS diploma dissertation 2002. 18. Patel A, Lloyd DH, Lamport AI: Antimicrobial resistance of feline staphylococci in south-eastern England, Vet Dermatol 1999; 10: 257-261 19. Wildermuth BE, Griffin CE, Rosenkrantz WS: Response of eosinophilic plaques and lip ulcers to amoxicillin trihydrate-clavulanate potassium therapy: a randomized, double blinded placebo-controlled prospective study, Vet Dermatol 2012; 23, 110-118 20. Hoshuyama S, Furusawa S,Kanoe M et al: Detection and partial characterisation of Pasteurella multocida found in feline skin lesions, Microbios 1995; 83:161 21. Love DN,Jones RF, Bailey M et al: Isolation and characterisation of bacteria from abscesses in the subcutis of cats, J Med Microbiol 1979; 12: 207-212 22. Reinke SI, Ihrke PJ,Reinke JD et al: Actinomycotic mycetoma in a cat, J Am Vet Med Assoc 1986; 189: 446-448 23. Wilkinson GT: Cutaneous Nocardia infection in a cat, Feline Pract 1983; 13: 32 24. Fairley RA, Fairley NM: Rhodococcus equi infections in cats,Vet Dermatol 1999; 10: 43-46 25. Patel A: Pyogranulomatous skin disease and cellulitis in a cat caused by Rhodococcus equi, J Small Anim Pract 2002; 43: 129-132 26. Malik R, Martin P, Mitchell DH, et al: Subcutaneous granuloma caused by Mycobacterium avium complex infection in a cat, Aust Vet J 1998; 76: 604-607 27. Malik R, Wigney DI, Dawson D, et al: Infection of the subcutis and skin of cats with rapidly growing mycobacteria: a review of microbiological and clinical findings, J Feline Med and Surg 2000; 2: 35-48

71 28. Mealy KI, Willard MD, Nagode LA, et al: Hypercalcemia associated with granulomatous disease in a cat, J Am Vet Med Assoc 1999; 215: 959 29. Yager JA, Wilcock BP: Actinomycosis, actinobacillosis, nocardiosis, botryomycosis (staphylococcal pseudomycetoma), In: Colour Atlas and text of surgical pathology of the dog and cat, London, 136, 1994, Mosby Year Book. 30. Medleau L, Blue JL: Frequency and antimicrobial susceptibility of staphylococcal sp. isolated from feline skin lesions, J Am Vet Med Assoc 1988; 193: 1080-1081

72 ENDOCRINE, PARANEOPLASTIC AND DERMATOSES RELATED TO SYSTEMIC DISEASE

Craig E. Griffin, DVM, DACVD, Animal Dermatology Clinic, San Diego, California, USA www.animaldermatology.com

ENDOCRINE DERMATOSES

The incidence of feline endocrine dermatoses is different from dogs. Dogs and cats both have a significant incidence of diabetes mellitus, but most cases do not have associated skin disease.When they do occur dogs develop metabolic epidermal necrosis which is even rarer in cats. Xanthoma, fragile skin syndrome and demodex have been seen in cats with diabetes mellitus but not dogs. In contrast to dogs feline hyperthyroidism is relatively common but feline hypercortisolism and sex hormone dermatoses are rare. Acquired hypothyroidism is exceptionally rare.

THYROID DISEASE

Though hyperthyroidism was not recognized until the late 70's it is considered relatively common.1,2 This apparent increase in incidence may relate to the disease partly being diet induced due to a variety of ingredients that may be in foods, particularly canned. One study also associated regular flea control product use to hyperthyroidism.3 It usually occurs in older cats, mostly over 10. Generally there is no breed or sex predilections though some have shown females predisposed. It does not typically cause skin disease though some cats will be excessive groomers and alopecia and matting of the fur have been described. Additionally some cats have a dry, scaly, unkempt hair coat. Macronychia or onychauxia (hypertrophy of the claw) may also be seen in some cases though this appears to be an uncommon finding.The disease does not usually present to veterinary dermatologists as the most common and obvious presenting signs are weight loss, polyphagia, polyuria and polydipsia. Cats may also exhibit nervousness, agitation, increased vocalization and heat intolerance. Some cases will have vomiting, anorexia and lethargy. Many cats have tachycardia and most have a palpable thyroid nodule. Diagnosis is confirmed with the presence of elevated serum thyroxin (T4) concentrations. Generally I have referred cases to internists for treatment though recently it has been shown that diets low in iodine may be effective in treatment as well. Hill's Prescription Diet® y/d®Feline is a therapeutic food with dietary iodine levels below 0.32 ppm dry matter basis (DMB). Thyroid levels return to normal in 2-3 months when cats are fed only this diet.

Hypothyroidism unless induced when treating hyperthyroidism is quite rare. It has occurred as a congenital disease in cats that have stunted growth and dry coats. It is rarely diagnosed in adult cats which may have dry scaly skin and poor hair coat. Feline alopecia with cutaneous atrophy is a presentation that has been most often associated with endocrine disease, particularly of the adrenal gland. The cutaneous atrophy may become as severe as to result in fragile skin that easily tears. The primary differential, especially with easily torn skin, is hypercortisolism though it may also occur with adrenal tumors that produce excessive levels of sex hormones, hepatic neoplasia or hepatic lipidosis. Two cases were also reported with multiple endocrine neoplasia both had alopecia and cushings though one case may also have lost hair from paraneoplastic alopecia.4 In two cases an adrenal gland tumor was confirmed, cortisol response testing did not support a diagnosis of hypercortisolism and serum concentrations of progesterone were increased compared with a normal cat.5,6 In one case surgical removal of the tumor was associated with normalization of the hormone abnormalities and clinical improvement with hair growth. This suggests the progesterone type hormones are most likely responsible for inducing lesions similar to hypercortisolism. A case with similar findings was reported in association with phenytoin administration in one cat, and in this case was reversible.

73 ADRENAL DISEASE

Hypercortisolism is rare in the cat and results from excessive production of cortisol from the adrenal glands due to either an ACTH secreting pituitary tumor or functional adrenal tumor about 20%.7 It occurs in older cats and more often in females. Most cats are insulin resistant and 80% are diabetic.8 The clinical signs: polydipsia, polyuria, polyphagia, weight loss, muscle wasting and abdominal enlargement or pot belly. Cutaneous changes that may be seen include: unkempt hair coat or symmetrical or patchy alopecia, seborrhea, comedones and hyperpigmentation. A sometimes striking feature is the cutaneous atrophy which may result in easily torn skin and lacerations.These cats are also predisposed to bacterial infection so clinical signs of pyoderma, recurrent abscesses, urinary tract infection and respiratory infections may also be observed. Calcinosis cutis does not appear to occur in cats. Diagnosis is made by a combination of ACTH response testing which should include pre and post progesterone as well as cortisol levels.The test is performed with an intramuscular dose of 125 µg of Cortrosyn® and serum samples taken at baseline, 30 and 60 minutes post Cortrosyn. A post-ACTH cortisol of > 410 nmol/l at either 30 or 60 minutes after administration is consistent with a diagnosis of hypercortisolism but up to 50% of cats will have normal values.That is why low dose dexamethasone suppression (LDDS) test may be needed if the ACTH is normal even if the progesterone is elevated. LDDS is done with dexamethasone at 0.1mg/kg IV.Post samples are done at 4 and 8 hours. Cortisol concentration greater than 41 nmol/l at 8 hours is seen in most hypercortisolism cats. Other lab abnormalities that may be seen include increased alanine transferase, hypercholesterolemia, hyperglycemia and low blood urea nitrogen (BUN). Sometimes there will be an increased alkaline phosphatase but cats do not make steroid induced hepatic isoenzyme so the values may be normal or only mildly elevated. When an adrenal tumor is present adrenalectomy is the preferred treatment and some cats with adrenal hyperplasia may respond to trilostane or lysodren.

PARANEOPLASTIC DERMATOSES

FELINE PARANEOPLASTIC ALOPECIA

Paraneoplastic cutaneous syndromes are dermatoses secondary to cancer and develop after a malignancy but also follow a parallel course. Based on a case where the skin disease resolved following surgery then returned with growth of metastatic lesions, this feline cutaneous syndrome meets the essential criteria for a true paraneoplastic cutaneous disease.9 The pathophysiology of this syndrome is unknown, as is the case in many human cutaneous paraneoplastic diseases. A similar condition has not been described in human or canine dermatology, making this a unique feline syndrome. The alopecia is generally seen in cats over 10 years of age, but has been described in cats as young as 7.5. There is no sex or breed predilection described. This alopecia syndrome occurs in cats with internal malignancy, most commonly pancreatic or bile duct carcinomas. Liver metastasis is frequently present at the time of diagnosis. One case with compatible cutaneous histopathology was described that had multiple endocrine tumors in addition to a pancreatic carcinoma.4 Lesions occur with the presence of the tumor, and in one case resolved with tumor removal and reoccurred with tumor recurrence.The tumor does not involve the skin, and generally endocrine changes are not present. Clinically, cats present with a 2-week to 10-month history of alopecia. Most cases generally evolve rapidly, with lesions occurring and spreading over much of the body within weeks, not several months.The majority of reported cases die or are euthanized within 8 weeks of developing the initial alopecia. Alopecia begins acutely and typically starts with clumps of hair loss from the ventrum and then spreads to the legs and eventually the face.The pinna and top of the head are generally spared or affected late in lesion progression. Though dorsal complete alopecia is uncommon, poor, dry hair and thinning hair coat may be present. Focal areas of erythema may be present, and often there is characteristic shiny skin in areas where cats excessively groom. Scale, which may appear as large sheets, will be seen in many cats; some focal crusting may also be seen. Crusting and a brown-black waxy to crusty debris tend to be associated with secondary Malassezia dermatitis. In one retrospective histopathologic study of 550 feline skin specimens biopsied, Malassezia was found in 15 cases, with 11 cases having generalized or multifocal disease; 7 of those had changes consistent with this syndrome and died within 2 months.10 The authors suggest the finding of Malassezia in feline skin biopsies, especially from cases with multifocal disease, warrants concern for paraneoplastic alopecia. Hair may be easily epilated

74 from all over the body. The footpads and less frequently nasal planum may be affected. The normal thickened epidermis becomes shiny, smooth, and soft, and occasionally foot pads become crusted and fissured, which can lead to pain and reluctance to walk. The black waxy material is typically associated with Malassezia dermatitis.

Hematologic and biochemical results are not indicative of underlying neoplasia. Skin biopsy is a preferred diagnostic test and typically will reveal changes highly suggestive of this syndrome, with the major differential being hypercortisolism. Paraneoplastic alopecia may have differentiating features from hypercortisolism including the presence of acanthosis and parakeratosis and lack of trichilemmal keratin. Radiographic and ultrasonographic studies may be helpful but usually fail to reveal an abdominal mass. The diagnosis is usually made during exploratory laparotomy. Most cats have had a pancreatic carcinoma of either acinar cell or pancreatic duct origin, and metastasis to the liver has often occurred, but if not, resection of the mass is the treatment of choice.The prognosis is grave because metastasis to the liver or lungs has usually occurred by the time a diagnosis is made, although early surgical intervention may be curative. So far, this has not been reported in published literature, because recurrence was seen from metastatic lesions.

FELINE THYMOMA-ASSOCIATED EXFOLIATIVE DERMATITIS

Exfoliative dermatitis and eventual alopecia has been reported in cats in association with thymoma.11,13 The etiology is unknown and it has been speculated that the disease may be similar to erythema multiforme or be autoimmune, mediated by auto reactive cytotoxic T lymphocytes from the thymus that cause direct damage to keratinocytes.This disorder begins as non-pruritic scaling and mild erythema on the head and pinnae. Progressively, the lesions spread over the rest of the body with intensification of scaling and development of alopecia. Brown, waxy, keratosebaceous debris accumulates between the digits, in the nail beds and in the ear canals. Crusts and ulcers may also develop.The appearance of pruritus is usually associated with secondary overgrowth of Malassezia spp. On skin histopathology, the most characteristic finding is a cell-poor hydropic interface dermatitis wherein multifocal areas of hydropic degeneration of basal cells and apoptotic keratinocytes are found in the epidermis and the infundibular region of hair follicles.This histological appearance is quite similar to what is seen in graft versus host disease. In thoracic radiographs, the presence of a variably sized mass in the cranial mediastinum, occasionally accompanied by pleural effusion, is suggestive of the diagnosis. CT scans may be more effective in staging the tumor but are not able to help differentiate the type of mass present.14 Ultrasound-guided cytology (small mature lymphocytes and/or abnormal epithelial cells) and histopathology are the preferred way to confirm what the mass is. Since feline thymomas are usually benign tumors, surgical removal is in general curative, carrying a good prognosis with a median survival of almost 2 years and another report of 74% having a three year survival rate.15 Radiation therapy may also be palliative for non resectable tumors.

SYSTEMIC DISEASE RELATED

SUPERFICIAL NECROLYTIC DERMATITIS

This disease is also called hepatocutaneous syndrome, metabolic epidermal necrosis, necrolytic migratory erythema and glucagonoma syndrome.The disease has rarely been seen in cats.11, 16-18 This skin disease is essentially a marker for chronic end stage liver disease that may be associated with pancreatic glucagon secreting tumors, Cushings and diabetes. One cat was shown to also by hypoaminoacidemia, similar to dogs with this syndrome.17 The most common lesions are hyper/parakeratosis of the footpads that may be associated with fissures, erythema erosions, ulcerations and pain. Other areas exposed to pressure may also be affected. The lesions are usually sharply marginated and the crusts are generally adherent and not readily removed. These lesions most often are perioral, especially the muzzle and lip margins.They are also commonly found periocular, around the genitals, on the elbows and the distal extremities. Ultrasound may show a pancreatic neoplasm but most commonly there are liver changes.The liver appears like honeycomb or Swiss cheese with hypoechoic areas surrounded by highly echogenic borders. A liver biopsy will usually reveal areas of parenchymal collapse surrounding nodular regeneration. Many cases die or are euthanized within months of diagnosis. Not enough cats have been reported, none where current canine treatments, including intravenous

75 amino acids with hepatic support have been tried to determine if some cases may have over a year of good response as happens in some dogs. Treatment should include high quality protein as well as managing the secondary infections. Support for the liver may also be helpful and denosyl as well as colchicine has been reported helpful. A high quality high protein diet supplemented with egg whites, liver, dried whey containing supplements, zinc and essential fatty acids should be fed. If the diet change and managing infections does not result in significant improvement then intravenous amino acids should be recommended. Human amino acid parenteral solutions are used and generally are 8-10% amino acids.The author uses Free Amine III 8.5% --B. Braun Medical Inc. or Aminosyn 10% Crystalline Amino Acid Solution - Abbott Laboratories at 24 ml/kg slowly over 6- 8 hours through a large central vein daily for 2-3 days. If there is no response to these then the prognosis is grave. If there is a favorable response then the goal is to maintain the improvement with oral protein or amino acid supplements. In some cases a second or third parenteral amino acid infusion is given one to several weeks after the initial therapy. Long term the prognosis is grave as the vast majority of dogs will eventually succumb or be euthanized for liver failure.

XANTHOMAS (XANTHOMATOSIS AND XANTHOGRANULOMA)

Xanthomas are generally histiocytic granulomatous lesions associated with the deposition of lipoproteins in the skin. Lipoproteins are composed of triglycerides and cholesterol surrounded by phospholipids, cholesterol and apoproteins.The skin lesions represent pooling of these lipid materials and their phagocytosis by macrophages. The mechanism is unknown but one theory is that trauma damages vascular permeability resulting in leakage of the lipoprotein which is elevated in the plasma. The lesions are seen most often in association with diabetes, progestational drug therapy or primary hyperlipoproteinemia in cats fed high fat diets.19 Not enough cats have been reported, especially with the diet responsive form of xanthomas, to establish any predisposed signalment factors. The disease has also been reported once in a dog with pancreatitis.The lesions seen are typically yellow to reddish or pink papules, plaques and nodules.They may ulcerate but do not drain though hemorrhage has been noted in some cases. Alopecia is variable as well as pruritus. Lesions may occur in areas of pressure or trauma with most descriptions involving face, head, pinnae, neck and distal extremities, especially over boney prominences. Clinical lesions are suggestive of an infiltrative disorder and then confirmed with dermatopathology. Nodular to diffuse infiltrates of foamy macrophages and histiocytes are found. There may be organized granuloma formation, fibroplasia or the presence of cholesterol crystals.Fasting serum triglyceride and cholesterol levels should be performed and will be elevated in the diet responsive cases. Treatment may consist of changing the diet to low fat or in some cases just discontinuing high fat treats may result in the resolution of the lesions. Controlling diabetes and discontinuation of progestational drugs has also been effective when associated with lesion development.

REFERENCES

1. Greco,D.S., Diagnosis of congenital and adult-onset hypothyroidism in cats. Clin Tech Small Anim Pract, 2006. 21(1): p. 40-4. 2. Scott-Moncrieff, J.C., Thyroid disorders in the geriatric veterinary patient. Vet Clin North Am Small Anim Pract, 2012. 42(4): p. 707-25, vi-vii. 3. Olczak, J., et al., Multivariate analysis of risk factors for feline hyperthyroidism in New Zealand. N Z Vet J, 2005. 53(1): p. 53-8. 4. Roccabianca, P., et al., Multiple endocrine neoplasia type-I-like syndrome in two cats.Vet Pathol, 2006. 43(3): p. 345- 352. 5. Rossmeisl, J.H., Jr., et al., Hyperadrenocorticism and hyperprogesteronemia in a cat with an adrenocortical adenocarcinoma. J Am Anim Hosp Assoc, 2000. 36(6): p. 512-7. 6. Boord, M. and C. Griffin, Progesterone Secreting Adrenal Mass in a Cat with Clinical Signs of Hyperadrenocorticism. J Am Vet Med Assoc, 1999. 214(5): p. 666-669. 7. Bruyette, D. Feline Adrenal Disease: Exploring the unexplored. in Western Vet Conf. 2010. Las Vegas. 8. Scott-Moncrieff, J.C., Insulin resistance in cats. Vet Clin North Am Small Anim Pract, 2010. 40(2): p. 241-57. 9. Tasker,S., et al., Resolution of paraneoplastic alopecia following surgical removal of a pancreatic carcinoma in a cat. J Small Anim Pract, 1999. 40(1): p. 16-19.

76 10. Mauldin-Daniel, E.A., D.O. Morris, and M.H. Goldschmidt, Retrospective study: the presence of Malassezia in feline skin biopsies. A clinicopathological study. Vet Derm, 2002. 13(1): p. 7-13. 11. Turek, M., Cutaneous paraneoplastic syndromes in dogs and cats: a review of the literature. Vet Dermatol, 2003. 14(6): p. 279-296. 12. Rosenbaum, M.R. Two cases of feline paraneoplastic skin disease: paraneoplastic alopecia and thymoma-associated exfoliative dermatitis. in Proceedings of the 19th AAVD/ACVD annual meeting. 2004. Kansas City, Mo: Hill's Pet Nutrition. 13. Rottenberg, S., C. von Tscharner, and P.J.Roosje, Thymoma-associated exfoliative dermatitis in cats. Vet Pathol, 2004. 41(4): p. 429-433. 14. Yoon, J., et al., Computed tomographic evaluation of canine and feline mediastinal masses in 14 patients. Vet Radiol Ultrasound, 2004. 45(6): p. 542-546. 15. Zitz, J.C., et al., Results of excision of thymoma in cats and dogs: 20 cases (1984-2005). J Am Vet Med Assoc, 2008. 232(8): p. 1186-1192. 16. Patel, A., T. Whitbread, and P. McNeil, A Case Of Metabolic Epidermal Necrosis In A Cat. Vet Dermatol, 1996. 7(4): p. 221-227. 17. Kimmel, S.E., W. Christiansen, and K.P. Byrne, Clinicopathological, ultrasonographic, and histopathological findings of superficial necrolytic dermatitis with hepatopathy in a cat. J Am Anim Hosp Assoc, 2003. 39(1): p. 23-7. 18. Byrne, K., Metabolic epidermal necrosis-hepatocutaneous syndrome. Vet Clin North Am Small Anim Pract, 1999. 29(6): p. 1337-1355. 19. Vitale, C. and e. al, Diet-induced alterations in lipid metabolism and associated cutaneous xanthoma formations in 5 cats, in Advances in Veterinary Dermatology III, K.W. Kwochka and e. al, Editors. 1998, Bitterworth-Heinemann: Boston. p. 241.

77 NOTES

78 NEUROLOGY RELATED SKIN DISEASES IN THE FELINE PATIENT Clare Rusbridge BVMS PhD DECVN MRCVS, Stone Lion Veterinary Hospital, 41 High Street, Wimbledon, SW19 5AU veterinary-neurologist.co.uk; [email protected]

THE NEUROANATOMY OF ITCH

Itch is a protective sensation similar to pain, hypothesized to have evolved to protect against small clinging threats such as insects and plant spines that would not be effectively removed by the nociceptive withdrawal response. It is mediated by a specialised subset of small unmyelinated C-fibres. Mast cell degranulation after injury or inflammation releases histamine and serotonin which bind to specific pruritogenic receptors on cutaneous nerve endings and initiates itch signalling action potentials 1.The release of histamine also results in a cascade of release of other inflammatory mediators which augment inflammation and ultimately up-regulates neuronal pathways.This up-regulation is one of the reasons why antihistamines have limited benefit in conditions such as atopy and no benefit in neuropathic itch. Some itch C fibres also respond to heat stimuli, perhaps explaining why heat worsens many itch sensations and cooling gives some relief 1.

The cell bodies of the "itch" neurons are located in the peripheral nervous system ganglia which are located just outside the central nervous system - for example the dorsal root ganglia of spinal nerves and the trigeminal ganglion. The ganglia are relays sending central axons via the spinothalamic tract to the brain's itch processing centres that lead to conscious and unconscious itch perceptions, and the emotions, and actions that these evoke1.The brain areas implicated in processing itch include the periacqueductal grey matter, cingulate gyrus and primary somatosensory cortex.

NEUROPATHIC ITCH - SCRATCHING MORE THAN THE SURFACE.

Itch can be classified according to origin 2. Cutaneous or pruritoceptive itch originates in the skin and is caused by pruritogens such as histamine. In contrast, neuropathic itch is defined by diseased or malfunctioning pruritic neurons (central or peripheral) firing action potentials out of proportion or even completely independent of any pruritogenic stimuli. Neuropathic itch often does not often respond to antihistamines, corticosteroids or other medications effective for conventional itch. Injury from scratching is common however extension into deeper tissues is not and if this occurs is suggestive of neuropathic itch especially if a pruritogenic cause cannot be identified. In the majority of cases this type of injury has not only intractable itch but also a sensory loss that permits scratching to continue to the point of self-injury 2,3

The anatomical overlap between itch and pain perception means that neurological diseases that cause neuropathic pain can potentially cause neuropathic itch. Just as patients with neuropathic pain can have allodynia (pain evoked by non-noxious stimulus) patients with neuropathic itch can have alloknisis, i.e. itch evoked by lightly touching the surrounding skin 4 (Table 1). However there are some important differences - in particular opioids will alleviate neuropathic pain to some degree however they can worse or even cause neuropathic itch 1.

79 TABLE 1 PAIN AND ITCH, AN EXPLANATION OF COMMON TERMS PAIN / ITCH CHARACTERISTICS Nociceptive pain Information about tissue trauma transmitted by normal nerves to the central nervous system. Neuropathic pain A clinical syndrome of pain due to abnormal somatosensory processing in the peripheral or central nervous system. The spectrum may include spontaneous pain, paresthesia, dysthesia, allodynia, or hyperpathia Neuropathic itch A clinical syndrome of pruritus due to abnormal somatosensory processing in the peripheral or central nervous system. Neuralgia Pain in distribution of nerve or nerves Hyperpathia Increased pain from stimuli which are normally painful Allodynia Pain from a stimulus that is not normally painful. Examples Touch - pain from touch e.g. collar Thermal - pain from draft of warm or cold air on the skin. Location allodynia (ephapse) - pain in area distinct from location of stimulus Dynamic mechanical allodynia - pain from a lightweight moving mechanical stimulus (e.g. soft brush moved back and forth) Kinesthetic (motion) allodynia- pain from motion (usually called kinesthetic dysesthesia because the feeling evoked by such movement is dysesthetic burning) Hyperalgesia Used by some instead of allodynia. Means "pain in the area stimulated" and can include nociceptive as well as neuropathic pain. Alloknisis Itch from a stimulus that is not normally itchy Paresthesia. A spontaneous or evoked abnormal sensation (not unpleasant) Dysesthesia A spontaneous or evoked unpleasant abnormal sensation. It is usually associated with burning, but is difficult to describe because the patient has never felt this sensation before developing neuropathic pain. The message perceived by the brain is one of "tissue destruction" with burning the most prominent component (Berg, 2001)

NEUROPATHIC ITCH AND MUTILATION SYNDROMES IN THE CAT

Itch and pain are subjective sensations meaning that neuropathic itch syndromes are difficult to diagnose in animals however there are a number of conditions and syndromes which are highly suggestive.

PRURITUS ASSOCIATED WITH BURNS AND SCARS

Sensory receptors are overexpressed on the ends of regenerating axons which is a potential cause of the itching that often accompanies scar formation. Unusually this is self-limiting however recalcitrant itching secondary to burns is occasionally recognised and neuronal mechanisms are implicated due to the lack of response to conventional treatment.

NERVE / NERVE ROOT / GANGLION INJURY

Damage to sensory nerves can result in mutilation syndromes presumably as a consequence of the cat experiencing unpleasant sensations combined with sensory loss. Examples include brachial plexus avulsion, cauda equina injuries, sciatic nerve entrapment/damage following orthopaedic surgery and trigeminal lesions.

80 Phantom itch perceived in an amputated limb or other missing body part is theoretically possible but rarely recognised in cats.This is due to over-expression of sensory reception in neuromas that can form at the distal ends of transected nerves.

SPINAL NEUROPATHIC ITCH

Various intramedullary lesions have been shown to cause neuropathic itch in both humans and animals, attesting to the importance of the spinal cord as an itch-modulating centre. Intramedullary cavernous hemangiomas have been particularly associated with neuropathic itch in humans and it has been suggested that dorsal horn location, gliosis and hemosiderin deposition are risk factors 5.The author has yet to diagnose a spinal neuropathic itch in a cat. In the dog the classic cause is syringomyelia which is also characterised by dorsal horn location and gliosis.The author has also treated cases of mutilation in dermatomes corresponding to spinal cord infarction/ haemorrhage as a consequence of Angiostrongylus infection.

FELINE IDIOPATHIC ULCERATIVE DERMATOSIS

Feline idiopathic ulcerative dermatosis is a rare condition of unknown pathogenesis characterised by a scratching induced deep ulcer on the neck or between the shoulder blades where no underlying puritogen or exciting cause can be determined. The author proposes that this may be a neuropathic itch syndrome.The location has prompted the hypothesis that it may be triggered by a reaction to a subcutaneous injection or vaccine. Herpes virus is a classic cause of neuropathic itch in humans. However unvaccinated cats have also developed feline idiopathic ulcerative dermatosis.The location of itch may not be directly related to the cause. Preliminary evidence in suggests that itch, like the other body senses, is not equally distributed along the body surface and in humans neuropathic itch is more likely to develop on the face, head and neck than lower on the body. Some have suggested that this is simply because this area is more easily assessable and more easily mutilated. Some cases of feline head and neck pruritus also have neuropathic itch like characteristics including scratching induced ulcer similar to trigeminal trophic syndrome in humans.

FELINE OROFACIAL PAIN SYNDROME (FOPS)

The disease is most likely a neuropathic pain disorder similar to trigeminal neuralgia. Predilection to the Burmese cat (all colours) and their crosses suggests a hereditary susceptibility for some cases. It is characterised by face and tongue mutilation and affected cats are most commonly presented with exaggerated licking and chewing movements, with pawing at the mouth. More severe cases have mutilation of tongue, lips and buccal mucosa. Predisposing factors are stress and oral lesions - in particular erupting permanent teeth, dental disease, (especially periodontal disease and dental resorptive lesions) and mouth ulceration. The condition can also be triggered by routine dental treatment, including dental extraction. A recent study found that for 1 in 5 cases, environmental factors influenced FOPS and individuals with poor social coping strategies in multi-cat households appear to be more vulnerable to this condition. There is no definite diagnostic test for this disease and the diagnosis is made on the basis of appropriate signalment, elimination of other explanations and identification of contributory causes. Until discomfort can be controlled mutilation should be prevented by using an Elizabethan collar and / or paw bandaging or "Soft Claws". Any dental disease should be appropriately treated. Analgesia should be provided (see below). Environmental factors (as above) should also be addressed. It is essential that there is appropriate distribution of the five essential feline resources - food, water, resting places, latrines and points of entry and exit into the territory. The cat should also have a private area(s) and the ability to hide and elevate in order to control stress. Use of commercially available feline facial pheromone F3 can be useful.

81 FELINE HYPERAESTHESIA SYNDROME.

Feline Hyperesthesia Syndrome is an enigmatic condition which some argue is not a single disease but manifestation of clinical signs which can have many underlying causes including skin disease or a compulsive disorder.There is also an argument that it may be a syndrome of neuropathic itch. It has been referred to as "rolling skin syndrome," self-mutilation syndrome", "twitchy cat disease" or "atypical neurodermatitis". It is reputed to be more common in Siamese, Burmese, Himalayan and Abyssinian cats and is said to more commonly appear between 1-4 years. Commonly described signs include: dilated pupils; appearing to be annoyed with, twitching or biting at the tail; rippling skin on the back just above the tail; sensitive to touch around the tail and spine; and personality change. There may be self-mutilation characterised by biting, licking, chewing, and plucking of the hair and the cat may be difficult to distract during an episode.The personality of the cats is often described as highly aroused (anxious, and/ or aggressive, restless, constantly wandering and pacing) and the behaviour may be provoked by petting /stroking and may be more likely when anxious or stressed. Diagnostic work up of affected cats includes ruling out all other possible explanations in particular skin disease. A full dermatology work up especially allergy testing should be performed. It is worth videoing the episodes for review by a neurologist as an important differential is complex partial seizures. Investigation for spinal diseases should be performed however it is often unrewarding. A full investigation should also include retroviral testing as chronic FeLV has been associated with a myelopathy with clinical signs that included abnormal vocalization, hyperesthesia, and paresis progressing to paralysis. As these episodes can be precipitated by environmental stress it is important to spend time questioning the owner about possible contributory factors and finding out about the ways in which owners have reacted to the behaviour in the past. For many owners the sight of their cat behaving in an "odd" manner can be very distressing and repeated attempts to interrupt the behaviour can inadvertently lead to increasing levels of arousal and a subsequent worsening of the behavioural symptoms. Any underlying or contributory causes should be treated especially skin disease and environmental stress. If all other explanations have been ruled out then it may be worth a trial of anti-epileptic drugs and in some cases medication for compulsive disorder may be considered (see below). However it can be difficult to know if a positive response to medication indicates that the aetiology is seizures, neuropathic pain syndrome or an altered neurochemical balance.

MANAGEMENT OF NEUROPATHIC ITCH AND MUTILATION SYNDROMES.

Unfortunately in cats very little information is available about what is the most appropriate treatment. Treatment is anecdotal and/or based on what was effective with the last case! Neuropathic pain and itch is typically refractory to conventional analgesic or anti-pruritic therapy and because the aetiology is complex often poly-pharmacy is more likely to be successful that monotherapy.

In general we can describe the progression of acute itch/pain into chronic neuropathic itch/pain as taking place in five steps. Drugs based on different mechanisms of action can be used to target each step.

1. ACTIVATION OF GLUTAMATE RECEPTORS Glutamate transmitter release results in increased activation of spinal receptors and increased neuronal excitability.Release of the glutamate is calcium channel dependent. Anti-epileptic drugs such as gabapentin and pregabalin target these altered calcium channels, and inhibit their function [6].

2. ACTIVATION OF THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR In the spinal cord, release of peptides and glutamate activates the NMDA receptor, which, in concert with other spinal systems, generates a persistent pain state.Wind up 1 and long term potentiation 2 are key processes related to chronic activation of NMDA receptors. Wind-up is induced by C and A-delta fibre inputs and, once produced, enhances all responses, including those from low threshold inputs.Ketamine blocks the NMDA receptor complex and potentially may be useful for topical treatment in the cat but this is an unexplored possibility.

82 3. TEMPORAL SUMMATION (WIND-UP AND FURTHER WIND-UP) If the nociceptive input continues, neuronal responses remain elevated, resulting in a cascade of detrimental neuronal overactivity. By this process weak stimuli may evoke pain, if repeated or if their duration is prolonged.

4. GLIAL ACTIVATION

5. CORTICAL REORGANIZATION Spinal cord neurons that become hyperexcitable, as a result of the mechanisms described above, show reduced thresholds to normal sensory inputs, greater evoked responses to such input, increased receptive field sizes 3 and on-going stimulus independent activity.These processes are all important factors in the pathogenesis of allodynia, alloknisis, hyperalgesia and spontaneous itch /pain. Over-active neurons in the central nervous system can be inhibited via drugs that target neural cells directly such as antidepressants, anti-epileptics, GABAergic agonists (benzodiazepines) and, for pain, opioids. A common feature of these drugs is that their targets are ion channels and receptors on nerve endings (synapses).

ANTIEPILEPTIC DRUGS

The author has used several anti-epileptic drugs successfully for the management of several neuropathic itch / pain syndromes.There are no licenced agents for cats and doses are that used in epilepsy (see BSAVA formulary or similar). Phenobarbital is often useful for FOPS or feline hyperaesthesia syndrome. Gapapentin or pregabalin can be useful for spinal cord, nerve root and ganglion related syndromes.The authors recently managed a case of Feline idiopathic ulcerative dermatosis with Topiramate.The case had not made any response to other drugs including corticosteroids, phenobarbital and gabapentin.

1. Wind-up pain is a mechanism leading to chronic pain via the constant bombardment of the second order neurons in the dorsal horn of the spinal cord. 2. Long-term potentiation is a long-lasting enhancement in signal transmission between two neurons as a consequence of stimulation 3. The receptive field of a sensory neuron is a term originally coined by the famous neurophysiologist Sherrington to describe an area of the body surface where a stimulus alters the firing of that neuron. In neuropathic pain / itch repetitive painful stimulation / itch results in an expansion of the receptive fields.

ANTIDEPRESSANTS

Tricyclic antidepressants such as amitriptyline have "dirty" pharmacology, which is perhaps the reason for their efficacy in pain states with complex pathophysiology. Pharmacologically dirty drugs, which bind to multiple receptors, tend to be more effective for neuropathic pain but have more potential adverse effects.The therapeutic effect of the classical tricyclic antidepressants is mediated by their inhibition of the reuptake of noradrenaline and of serotonin. However, they also interact with the muscarinic acetylcholine receptor, the histamine-1 receptor, the alpha-1 adrenergic receptor and sodium ion channels 6.The more receptors that are triggered then the greater the biological effect. If only one receptor in a complicated network is influenced then this impact will ultimately be neutralized. If multiple sites are affected then the network is more likely to be broken and for longer.There have been some anecdotal reports that amitriptyline is effective for FOPS and/or feline hyperaesthesia syndrome. However as with all pharmacologically "dirty" drugs this could be effective for multiple reasons. Serotonin-selective reuptake inhibitors also have the ability to relieve itch.

83 TOPICAL THERAPY?

A great variety of drugs can be applied as topical formulations.Topical treatment has the advantage that it is relatively cheap and associated with less systemic effects.Topical therapy is commonly utilised and is often effective for human neuropathic itch / pain for example lidocaine or capsaicin patches/creams for management of herpes and AIDS skin lesions. Some pain clinics will compound creams including 5% and 10% amitriptyline and 10% racemic ketamine.The possibility of topical therapy could be considered for localised lesions in feline patients.

BOTOX THERAPY?

Several papers report efficacy for subcutaneous injection of botulinum toxin type A for focal neuropathic itch which is independent of its effects at the neuromuscular junction to weaken muscles1. Botulinum toxins also reduce C-fiber secretions that potentiate neurogenic inflammation and itch. The high cost of botulinum toxin limits this theoretical therapy.

REFERENCES

1. Oaklander, A.L., Common neuropathic itch syndromes. Acta Derm Venereol, 2012. 92(2): p. 118-25. 2. Twycross, R., et al., Itch: scratching more than the surface. QJM, 2003. 96(1): p. 7-26. 3. Oaklander, A.L., Neuropathic itch. Semin Cutan Med Surg, 2011. 30(2): p. 87-92. 4. Akiyama, T., et al., Mouse model of touch-evoked itch (alloknesis). J Invest Dermatol, 2012. 132(7): p. 1886- 91. 5. Dey, D.D., O. Landrum, and A.L. Oaklander, Central neuropathic itch from spinal-cord cavernous hemangioma: a human case, a possible animal model, and hypotheses about pathogenesis.Pain, 2005. 113(1-2): p. 233-7. 6. Anand, S., Gabapentin for Pruritus in Palliative Care. Am J Hosp Palliat Care, 2012. 7. Pancrazio,J.J., et al., Inhibition of neuronal Na+ channels by antidepressant drugs. J Pharmacol Exp Ther, 1998. 284(1): p. 208-14.

84 COMPARISON OF FIPRONIL/(S)-METHOPRENE (FSM) AND SPINOSAD (SPN) IN CONTROLLING FLEAS IN CLIENT-OWNED DOGS IN NORTH AMERICA.

M Dryden1, W Ryan2, A Rumschlag3, D Snyder3, L Young3 1Kansas State University, Manhattan, KS; 2Ryan Mitchell Associates LLC, Westfield, NJ; 3Elanco Animal Health, Greenfield, IN

Spinosad [SPN] is available as an oral formulation, with laboratory studies demonstrating a high level of efficacy, and monthly administrations providing >99% control of fleas in client-owned dogs (Robertson-Plouch et al, 2008; Blagburn et al, 2010; Wolken et al, 2012). Similar outcomes have been reported in laboratory studies of experimentally infested dogs treated with a low-volume topical formulation containing fipronil/(s)- methoprene (FSM). Field reports indicate that FSM provides effective flea control, although in some cases, low flea numbers have persisted following monthly applications (Beugnet et al, 2011; Dryden et al, 2011a,b,c). To monitor the ongoing performance of these products in the field for clearing natural flea infestations, an investigator/assessor-blinded, randomised, multi-site clinical study was initiated to compare the flea control provided by monthly treatments with either FSM or SPN.

MATERIALS AND METHODS:

Objectives were based on one primary dog (>10 fleas) per household. Within each clinic, households were blocked according to: a) whether they were single- or multiple-pet households, and then b) on owner-reported pruritus score of the primary dog. Within blocks, households were randomized to FSM or SPN groups. Owners were instructed to avoid any additional on-pet or environmental flea control measures. Dogs were required to be "indoor", sleeping and spending at least 50% of the time within the household. Households with additional mammalian pets (eg ferrets, rabbits) or more than 4 dogs and cats were excluded. A single treatment with FSM or SPN (30-60 mg/kg) (Comfortis® Chewable Tablets for Dogs, Elanco Animal Health) was dispensed on days 0, 30 and 60 for at-home administration to each household pet. In households where the primary dog received SPN, other dogs received the same product and cats received spinetoram (Assurity®, Elanco Animal Health); where the primary dog received FSM (Frontline® Plus, Merial), other dogs and cats received the appropriate formulation of the same drug.The level of flea control in primary dogs was assessed on the number of flea free dogs (using whole body counts), reduction in mean flea counts per treatment group and improvement in owner-scored pruritus on days 30, 60 and 90. Flea counts for non-primary household pets were assessed on days 0 and 90.

RESULTS:

From July through December 2011, 10 clinics across the southern United States enrolled a total of 128 primary dogs, of which 55 FSM allocated dogs and 58 SPN dogs completed the study. For primary dogs, there was no statistically significant difference between the treatment groups in mean baseline flea counts and pruritus scoring. On day 90, 95% and 38% of dogs were flea free in the SPN (N=58) and FSM (N=55) groups respectively. Mean pruritus scores in the SPN group decreased from 6.67 on day 0 to 0.92 on day 90 and in the FSM group from 6.33 to 3.83 on the same days. No owners of dogs in the SPN group reported lack of efficacy in controlling fleas. From day 30 onwards, all assessments (number of flea free dogs, reduction in pruritus and reduction in mean flea counts) were greater for SPN than for FSM (p<0.0002). Flea count reductions in non-primary pets were parallel to the reductions observed in primary dogs. Both treatments were well tolerated by all dogs on the study. 85 CONCLUSIONS

In this evaluation of flea control in client owned dogs, both FSM and SPN were well tolerated. The dose of SPN used in this study (30 - 60 mg/kg) is below or in the lower half of the dose range recommended for use in Europe (45 - 70 mg/kg). Nonetheless, SPN provided a high level of consistent flea control in client-owned dogs, regardless of challenge and is consistent with earlier results reported from Europe and the United States (Robertson-Plouch et al, 2008; Wolken et al, 2012), thus suggesting direct relevance to any geography in which dogs and cats are maintained as household pets.The authors are unaware of any comparable field report using FSM, although there is similarity to earlier field monitoring reports from the south-eastern USA. The continuing high counts in some FSM-treated dogs, in this study somewhat higher than in the earlier monitoring studies, warrants further investigation. This is particularly so from the perspective of assessing the value of (s)- methoprene in helping to suppress flea challenge, and in determining whether the counts were due to difficulties in client compliance with the application directions.While laboratory assessments can be helpful in explaining the field behaviour of flea control products, decisions on their utility in the hands of clients are better based on the outcome of field performance studies.

REFERENCES

Beugnet, F., Doyle,V., Murray, M., Chalvet-Monfray, K., 2011.Comparative efficacy on dogs of a single topical treatment with the pioneer fipronil/(S)-methoprene and an oral treatment with spinosad against Ctenocephalides felis. Parasite.18, 325-331.

Dryden, M.W., Payne,P.A., Vicki, S., Kobuszewki, D. 2011a. Efficacy of Topically Applied Dinotefuran Formulations and Orally Administered Spinosad Tablets Against the KS1 Flea Strain Infesting Dogs. Intern J Appl Res Vet Med. 9(2): 123-128.

Dryden, M.W., Payne,P.A., Smith, V., Riggs,B., Davenport, J., Kobuszewski, D., 2011b. Efficacy of dinotefuran-pyriproxyfen, dinotefuran-pyriproxyfen-permethrin and fipronil-(S)-methoprene topical spot-on formulations to control flea populations in naturally infested pets and private residences in Tampa, FL. Vet Parasitol. 182, 281- 286

Dryden, M., Carithers, D., McBride, A., Riggs,B., Smith, L., Davenport, J., Smith, V., Payne,P., Gross,S.J., 2011c. A comparison of flea control measurement methods for tracking flea populations in highly infested private residences in Tampa FL, following topical treatment of pets with Frontline Plus (fipronil/(S)- methoprene). Intern J Appl Res Vet Med. 4, 356-367

Robertson-Plouch, C., Baker, K.A., Hozak, R.R., Zimmermann, A.G., Parks,S.C., Herr, C., Hart, L.M., Jay, J., Hutchens,D.E., Snyder,D.E., 2008. Clinical field study of the safety and efficacy of spinosad chewable tablets for controlling fleas on dogs.Vet Ther. 9, 26-36.

Wolken, S., Franc, M., Bouhsira, E., Wiseman, S., Hayes,B., Schnitzler,B., Jacobs,D.E., 2012. Evaluation of spinosad for the oral treatment and control of flea infestations on dogs in Europe.Vet Rec. 170, 99-103.

86 BEHAVIOURAL FACTORS IN FELINE DERMATOLOGICAL DISEASE Sarah Heath BVSc DipECAWBM (BM) CCAB MRCVS, Behavioural Referrals Veterinary Practice, 10, Rushton Drive, Upton. Chester CH2 1RE Email: [email protected]

INTRODUCTION:

The concept of behavioural dermatology may be relatively new but the importance of consideration of emotional factors in human dermatology is well recognised. It is estimated that emotional factors are a significant consideration in the management of one third of human dermatological cases. Some authors have explained the importance of emotion in terms of the common embryonic history of the skin and the central nervous system and the resulting potential for effects of psychoneuroendocrinoimmunological mediators on the CNS, immune system and skin with resulting physical signs such as pruritus, flushing and sweating.There is also the suggestion that cutaneous contact and stimulation during postnatal development may substantially influence cell growth and differentiation, CNS maturation, neurosensory responses, immune function and the incidence of behavioural disorders in a variety of species (Virga 2003). The two way nature of the relationship between emotional state and mucosal integrity warrants consideration of emotional influences in primary dermatological disorders and the potential for dermatological changes to influence emotional state. In addition the potential for behavioural disturbance to result in self-inflicted dermatological lesions also needs to be considered. Feline dermatology is a complex subject in its own right and unravelling the histories of these cases can be something of a challenge in general practice. One aspect that is often overlooked is the behavioural perspective, but the potential role of emotional factors in feline dermatological cases should not be underestimated.

GATHERING A COMPREHENSIVE HISTORY:

In order to establish the possible involvement of behavioural factors it is important to incorporate questions about the cat's social and physical environment into the history taking process. Information about resource distribution and availability of natural feline coping strategies, such as hiding and elevation, within the home will help to form an understanding of the potential for environmentally induced stress. Information about people, other species and other cats in the household or neighbourhood will help to establish whether social stress could be a contributory factor. It is important to realise that inter-cat tension can present in both active and passive forms. Owners will often be aware of overt hostility between cats in the home, or active aggression between felines in the local neighbourhood, but more subtle signs of conflict may go unnoticed. The use of eye contact and physical positioning to prevent other cats from having access around the home is commonplace in feline society and in many cases the use of video recording enables owners to watch interactions more carefully and identify some of these insidious forms of feline conflict. In some cases passive inter-cat tension may be identified when overt behavioural problems, such as indoor toileting or marking, occur as a result but in others the behavioural consequences are not as clearly identified and behaviour such as chronic over grooming can go unnoticed for some time. Indeed these cases may not be identified until obvious skin lesions or hair loss occur and a dermatological investigation is requested.

THE INFLUENCE OF SOCIAL STRESS:

In multi-cat households it is not unusual for there to be more than one social group co-existing under the same roof. However, these situations pose potential problems in terms of chronic stress when the owners fail to identify the groupings and try to treat all of the cats as part of one large feline community. Cats find it difficult to share resources with individuals from outside their social group and yet many multi-cat households provide

87 just one feeding and watering station, one litter tray and one or two resting locations and expect all of the cats to share. In many cases the cats learn to tolerate this enforced proximity to unrelated individuals but the resulting suppression of normal behaviour patterns can result in chronic stress which eventually manifests itself in the form of medical symptoms such as hair loss.

RESOURCE DISTRIBUTION:

When cats are expected to share feeding stations owners commonly misinterpret their willingness to come together at meal times as a sign that they are happy with each other's company but in reality what is happening is that the cats suppress their behavioural reactions through necessity. After all the provision of food is controlled by the owner and if meals are only provided twice a day in a set location the cats will have to overcome any feline tension in order to gain access to the vital resource of nutrition. When cats are transferred onto a more natural self service system of feeding, in which food is provided at a variety of feeding stations around the house, owners often comment on how their pets are never seen eating side by side anymore. They also note that the cats develop favoured feeding stations, which they do not share, and in many cases owners become aware of the fact that the cats are more relaxed around the home. Alterations to feeding practice are not the only ways in which feline tension can be alleviated and increasing the availability of other essential resources, such as latrines and resting areas, will have similar effects.

THE IMPORTANCE OF THE ENVIRONMENT:

Ensuring that cats have better access to natural coping strategies such as hiding and elevation is an important part of establishing emotional control. Access to the three-dimensional aspects of the home can be provided by way of cat aerobic centres, strategic shelving and access to tops of furniture and can contribute to a significant decrease in feline tension. Provision of feline scent signals which indicate that the home is safe and secure can be useful in treating situations of inter-cat hostility and in situations where problems of hair loss are identified within multi-cat households the installation of pheromone diffusers can be a useful adjunct to any medical treatment.

THE FUNCTION OF GROOMING:

Grooming is an important feline behaviour, in terms of coat care and parasite control but also has a crucial role in social communication and in regulation of emotional responses.Related individuals, and those living as part of one social grouping, will engage in mutual grooming, referred to as allogrooming, which serves to exchange scent signals between individuals and establish a common identity. Individual cats will also groom themselves as a means of reducing emotional tension and coping with stress and when they do so the aim of the grooming response is to return the cat to a state of emotional homeostasis. In situations of short term stress this mechanism is highly effective and the grooming remains within acceptable limits, but when the stress is more chronic and unavoidable in nature the grooming can become excessive and hair loss and skin damage can result.

PRIMARY EMOTIONAL DISORDERS:

Inter-cat tension is not the only possible behavioural factor to consider in feline dermatology cases and in situations where cats are living harmoniously with their feline neighbours and housemates, or have limited interaction with other cats, there may be other potential sources of emotional disturbance which should be investigated. Cats can suffer from a range of fear and anxiety related behaviour problems resulting in emotional disturbance which in turn exacerbate or induce dermatological presentations. It can be therefore be helpful to collect information about individuals' reactions to people, places and noises as well as other cats. If the onset of the dermatological signs has been sudden it is sensible to ask questions about alterations in lifestyle as well as changes to the cat's physical and social environment. Various factors are involved in the development of

88 emotional disorders and gathering information about the cat's early life experiences and about the temperament of its parents may be beneficial. Individuals that have not received adequate socialisation and habituation have been shown to have less well developed coping strategies for dealing with stress in adulthood, and kittens that have been fathered by tom cats that do not carry the so called "boldness trait", have also been shown to cope less effectively with emotional challenge.

INFLUENCE OF EMOTIONAL STATE ON MEDICAL CONDITIONS:

It is important to remember that some of the physical causes of dermatological changes in the cat may also have a behavioural dimension. For example hair loss over the lower abdomen and medial thighs may be indicative of feline lower urinary tract disease, a pathological condition with a well-established link to behavioural and emotional factors. Stress resulting from inter-cat tension has been identified as a potential contributory factor in cases of interstitial cystitis and when conflict between feline housemates results in restricted access to water stations within the home the influence of behaviour on this condition is further compounded. Treatment in these cases will obviously involve resolution of the urinary tract disease as well as the dermatological signs and behavioural therapy to resolve the underlying anxiety will also need to be considered.

PRIMARY DERMATOLOGICAL CONDITIONS:

A substantial number of chronic dermatoses in humans have been shown to be affected by emotional stress, including acne, urticarial, atopic dermatitis and psoriasis. In the veterinary context conditions including atopic dermatitis and chronic inflammatory dermatoses also warrant investigation in terms of the potential influence of emotional state.The potential for triggering or exacerbation of pruritus and the resulting behaviours of itching, scratching and licking, by emotional stress needs to be considered.

In cases where hair loss is combined with over-sensitivity of the skin and the onset of behavioural changes, such as aggression, the complex medical condition of feline hyperaesthesia syndrome should feature in the list of differentials.The presence of rippling skin in association with minimal stimulation is one of the characteristic signs of this condition and behavioural symptoms can vary from low-grade irritability to overt aggression. Signs of frustration, including mounting of inanimate objects and dashing uncontrollably around the house, may also be evident. Successful treatment of feline hyperaesthesia syndrome often involves medication with tricyclic antidepressants or serotonin reuptake inhibitors, but potential stressors within the cat's environment should also be identified in order to offer a long-term approach to controlling the condition and behavioural therapy will be an important component of the treatment strategy. Cure is seldom achievable in these cases and owners need to be aware that symptoms are likely to reoccur when the cat is under stress.

MULTIFACTORIAL CASES:

One particular condition that may present with dermatological symptoms related to self induced trauma around the face and particularly the mouth is feline orofacial pain syndrome.This condition has been primarily recognised in the Burmese, although cases have been reported in other breeds such the Burmilla and Siamese and the condition has been identified in small numbers of domestic shorthair.The clinical signs are characterised by exaggerated licking and chewing movements, with pawing at the mouth. Affected cats can severely mutilate their tongue and or lips.The episodes may be triggered by mouth movements e.g. eating or grooming and some cases appear to be associated with oral disease e.g. dental disease. Others may be associated with systemic or environmental stress.These cases highlight the need for co-operation between veterinary disciplines and particularly between those working in dentistry, dermatology, neurology and behavioural medicine.

89 CONCLUSIONS:

When cats are presented with signs of skin irritation, skin lesions and hair loss it is obviously important to consider common dermatological conditions before assuming that the physical signs have a purely behavioural origin. However, it is also important to remember that there is a potential for interplay between emotion and the skin which is of a bilateral nature. Primary dermatological conditions can be affected by emotional stress but equally primary behavioural conditions can result in secondary self-induced dermatological signs. In addition emotional disturbance may be exacerbated by concurrent dermatological disorders which adversely affect normal behaviour patterns. Social and emotional factors can play an important role in cases of feline dermatology both directly and through their influence on stress coping strategies and systemic disease. Treating the medical symptoms, while failing to address underlying sources of emotional conflict and stress, increases the likelihood of recurrence. In addition it can significantly decrease the effectiveness of treatment in these cases. Behaviour modification can therefore be an essential element of the management plan for dermatological cases.

FURTHER READING

Heath S E (2005) Feline compulsive disorders in Bowen J and Heath S E Behaviour Problems in Small Animals Published by Elsevier pp 181 -182

Heath S E (2005) An overview of feline social behaviour and communication in Bowen J and Heath S E Behaviour Problems in Small Animals Published by Elsevier pp 29-30

Mege C (2008) Skin conditions associated with behavioural disorders in Guaguere E and Prelaud P A Practical guide to Feline Dermatology Translated by Craig M Published by Merial pp 17.1-17.11

Overall K L (2005) Mental Illness in Animals - the need for precision in terminology and diagnostic criteria in McMillan F D Mental Health and Well Being in Animals Published by Blackwell Publishing pp 137-139

Virga V (2003) Behavioral dermatology The Veterinary Clinics - Small Animal Practice 33: 231-251

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