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An Easier Way to Diagnose and Manage Otitis Externa in the Real World (Parts 1 and 2)

Paul Bloom, DVM, DACVD, DABVP Allergy, Skin and Ear Clinic for Pets

Livonia, MI

It is important to understand that ear disease is only a symptom (no more specific than “pruritus”). As Dr Flemming Kristensen stated “A patient showing ear problems is a dermatology case until proven otherwise”. It is appropriate therefore to approach the diagnosis of ear disease just as you would for any other skin disease.

Obtaining a detailed history is an important first step in trying to identify the underlying cause of the ear disease. Specific questions that should be asked include:

1. When did the symptoms first occur? This is an important question, because many owners will only tell you when this current episode of symptoms occurred, not the very first time it occurred;

2. Other than the problem the owner presents the patient for, you must ask all owners if the dog has EVER had problems with excessive licking, scratching, chewing, biting or rubbing. Has the dog ever had ear problems before this episode? If so, when, with what medication and what was the response to treatment;

3. Where does the dog live- indoor, outdoors, both? Describe the environment, especially the outdoor environment; 4. Is the dog on heartworm and flea preventative? If so, what product, how often is it administered and is it year round or

seasonal? 5. Are there any other pets in the household? If so, what kind and are they symptomatic. If they are cats, do they go

outside? ; 6. Are any of the humans in the household showing “new” skin problems? If so, what kind; 7. Do they board the dog, take him to obedience school, training or to the groomers? If so, when was the last time? ; 8. Do they know if the parents of the dog or any siblings have ear or pruritic skin problems? If so, what was done and

what was the response? ; 9. What does the dog eat? 10. How do the ears seem today- is today’s presentation the best, worse or average since the problem began? 11. Do you notice if the symptoms were better, worse or no different or not sure between the different seasons.

After reviewing signalment and thoroughly questioning the owner, the next step is to do a complete physical examination – be sure to note any constitutional signs that may be present that could explain the ear problem (eg fever associated with pemphigus, lethargy associated with vasculitis, etc)

This is followed by a complete dermatologic examination. Because ears are really just skin attached to the skull many diseases that affect the ears frequently will be affect the rest of the skin and vice versa. Therefore even when a dog is presented only for otic pruritus you still need to examine the rest of the body. And the opposite also holds true, when a dog is presented for truncal pruritus be sure to do an otic examination. .

In order not to miss an abnormality, an otic exam should be done in a systematic manner beginning with the pinna. You should note any alopecia, erythema, ulceration, crusting, scaling or swelling. Then palpate the canals for pain, calcification or thickening. This is followed by an otoscopic examination of the ear canals. Due to the curve in the external ear canal, the ear canal must be straightened in order to see the horizontal canal and the tympanic membrane. This is accomplished by placing the tip of the cone of the otoscope in the opening of the external ear canal. As you advance the cone is proximally you need to pull the pinna laterally (outward). By “stretching” the pinna laterally into a straight line horizontally the ear canal becomes straight and allows examination of the horizontal canal and the tympanic membrane

The presence, degree and location of inflammation, ulceration & proliferative changes should be noted (i.e. cobblestone hyperplasia). Describing the size of both the vertical and horizontal canals along with the type, location and quantity of debris or exudate should also be included in the medical record. Next it should be documented whether the tympanic membrane is visualized. If it is not, then note why the membrane is not seen- is it due to swelling in the ear canal, the presence of a ceruminolith or is there debris in the proximal horizontal canal obstructing the view? Sometimes it is because the animal is too painful to allow deep examination of the ear canal. If you can visualize the tympanic membrane (TM) you need describe if it is normal in appearance or not. Changes that may be noted include discoloration or bulging.

It is important to then evaluate for concurrent middle or inner ear disease. This is because dogs with chronic recurrent otitis externa (OE) may have concurrent otitis media (OM). This step may require heavy sedation or general anesthesia. Evidence of middle ear involvement include a ruptured TM or an abnormal appearing TM (i.e. thickened, change in lucency (opaque), bulging or discolored).

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Horner’s syndrome (damage to sympathetic innervation); keratoconjunctivitis sicca (damage to the parasympathetic component of the facial nerve) and facial nerve paralysis may be present in cases of OM due to the close association of the respective nerves to the middle ear. Deafness may also be present with OM.

Some veterinarians will have their staff collect ear cytology samples prior to examining the ear (as a time saver) but this makes it more difficult to evaluate the true appearance of the ear canal. Debris may be pushed into the horizontal canal thereby limiting visualization of the tympanic membrane due to the compacting of debris in the canal.

Now diagnostics and treatment needs to be pursued. The first step is to identify and treat the primary (underlying) cause(s) of the ear disease. These would include:

1. Parasitic (including Demodex, Otodectes, Sarcoptes); 2. Foreign bodies; 3. Hypersensitivities (atopy- NOTE OE may be the ONLY symptom in 3-5% of the environmentally triggered atopic

dermatitis cases and it may be UNILATERAL!!; it may be seen in cutaneous adverse food reactions where it too may be the ONLY symptom in up to 20% of the cases and also may be unilateral or flea allergy dermatitis. In cases of FAD there should be involvement of the posterior 1/3 of the body in addition to the OE;

4. Allergic or irritant contact dermatitis; 5. Endocrinopathies, keratinization or sebaceous gland disorders leading to an altered lipid layer in the epidermis, alteration in

normal keratinization or glandular function; idiopathic seborrhea (is there such a disease?); 6. Autoimmune or immune mediated diseases (eg pemphigus complex, vasculitis- note these diseases involve the pinna >>>

canals); 7. Zinc responsive dermatosis (will involve more than the pinna); 8. Juvenile cellulitis; 9. Immunosuppressive diseases (distemper, FeLV, FIV, parvo virus); 10. Neoplasia (adenoma, adenocarcinoma) ; 11. Dermatophytosis (affects the pinna rather than the ear canal).

In addition to identifying the primary cause, secondary factors must be addressed if possible. Secondary factors don’t cause ear disease but increases the risk of developing ear disease and may make successful treatment more difficult. Secondary factors are: anatomical factors (eg- long pendulous ears in the Basset Hound or stenotic ear canals in Shar Peis); excessive moisture in ears (swimming); and iatrogenic trauma (plucking hairs from the ear canals, cleaning ear canals with cotton tip applicators).

Lastly perpetuating factors must be identified and treated. These factors don’t initiate the problem, but will cause the disease to continue, even with the elimination of the primary factor, once it has been established until these factors have also been addressed. Perpetuating factors include:

1. Bacteria (cocci most commonly Staphylococcus intermedius (acute infections), beta hemolytic streptococci and rods most commonly E. coli, Pseudomonas spp (chronic infections); Proteus spp, Klebsiella spp and Corynebacterium spp);

2. Fungi (Malassezia pachydermatis (which may cause a hypersensitivity reaction so that small numbers may be significant) ; 3. Progressive pathological changes; 4. Otitis media; 5. Contact hypersensitivity/irritant; 6. Treatment errors (most commonly due to under treating the infection).

Laboratory tests are a necessary component to the proper workup of a case of canine ear disease. CBC, serum chemistry profile, urinalysis, skin scrapings, fungal culture, endocrine testing and skin biopsies may be necessary depending on what the differential diagnoses are for that patient.

Cytologic examination of a roll swab sample should be performed on any exudate. The numbers & type of bacteria, yeast and inflammatory cells should be quantitated. In cases of OE the question of what is an abnormal number of organisms, per oil field, has not been settled. Depending on the study, cutoff numbers, per oil immersion field, that differentiates between normal and abnormal ears ranges from >1 Malassezia to >4 Malassezia and from >1 bacteria to >10 bacteria. It is the author’s opinion that the number of organisms present to be considered significant is not just a “number”. The author doesn’t perform cytology on normal ears – it is only done if the ears that are inflamed or have exudate. Therefore ANY organism seen will be considered significant and will be treated as part of the therapy regardless of the number present. As for follow-up cytologies, the only time cytology is performed during therapy is when the ear is not clinically improving OR if the initial cytology had rods. If there is a mixed population of organisms present at the initial examination without rods and the ear is clinically normal at the recheck examination, follow-up cytology is not performed.

Bacterial culture and susceptibility (c/s) should only be rarely, if ever, performed in cases of OE. If a c/s is performed, it should be done in conjunction with cytology. One reason that the author doesn’t perform cultures in OE cases is that with a culture the

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susceptibility is based on systemically achieved antibiotic levels (measured in microgram/ml) not topically. Since topical medication has a 1000 fold higher concentration (milligrams/ml) the resistance reported on the culture can’t be extrapolated to topical therapy.

Other concerns include poor reproducibility of c/s results when culturing the ear. In a study where two samples were taken for bacterial c/s from the same location in the external ear canal of dogs who had otitis externa, there were different bacterial isolates identified 20% of the time and the same isolate with different susceptibility patterns another 20% of the time. Eleven percent of the P. aeruginosa isolates had different susceptibility patterns. A second study took triplicate samples and sent the samples to 3 different laboratories. There were 18 samples that had Pseudomonas spp. Identified. All three laboratories only agreed on the presence of Pseudomonas in 15 (83.35) of the ears while 2 agreed on 2 (11.1%) of the samples and on one occasion (5.5%) only 1 laboratory identified Pseudomonas but none

There are a few possible reasons for these discrepancies. These include:

of the samples had identical patterns of antibiotic susceptibility. A 3rd study was performed in which duplicate samples were sent to the same lab1. Seventy percent of the Pseudomonas aeruginosa had different susceptibility profiles.

1. Multiple strains with different susceptibilities 2. Single strain with heteroresistances

In both of the cases the selection of which colonies are selected to be tested for susceptibility may vary from technician to technician. . A 3rd study was performed in which duplicate samples were sent to the same lab. Seventy percent of the Pseudomonas aeruginosa had different susceptibility profiles.

These results should give you great pause as to the reliability of cultures. The author will only take a culture in cases of OE when there are proliferative changes present AND there are numerous rods present on cytology AND the dog has failed to respond to empirical antimicrobial therapy. This is a very uncommon scenario. This approach is supported by a study in which the author evaluated if there was any correlation between topical antibiotic selection, in vitro bacterial antibiotic sensitivity and clinical response in 16 cases of canine otitis externa complicated by Pseudomonas aeruginosa. For these cases empirically selected topical antibiotic therapy was dispensed after collecting bacterial cultures from the affected ears. All dogs had Pseudomonas aeruginosa isolated on culture. In 10 cases, the antibiotic selected was deemed to be resistant based on the culture, yet 8/10 responded to the selected antibiotic. One of the 10 resistant cases needed to have a second antibiotic selected to successfully treat the infection. This supports the observation that there is no value to performing cultures in cases of canine otitis externa.

The MIC (broth microdilution technique) method is the “gold standard” for culture technique therefore if a c/s is submitted, the MIC method should be used to determine the susceptibility of the organism(s) rather than the disc diffusion method (Kirby-Bauer). This is because the disk-diffusion susceptibility test (DDST) is only semi quantitative. This means that the drug concentration achieved in the agar surrounding the disc can be roughly correlated with the concentration achieved in the patient’s serum. It will only report the organism’s susceptibility (susceptible, intermediate or resistant) based on an approximation of the effect of an antibiotic on bacterial growth on a solid medium. Tube dilution (MIC) is quantitative, not only reporting SIR but also the amount of drug necessary to inhibit microbial growth. The MIC is reported as the amount of antibiotic (in µmg/ml) necessary to inhibit 90% of the tested bacteria (the lowest concentration in the tube that is clear). This allows a clinician to not only decide susceptible or resistant but also the proper dosage and frequency of administration of the antibiotic. Note that if the MIC for the bacterial isolate is reported to be susceptible, there is a greater likelihood of successful treatment (cure) than if the isolate was classified as resistant. Treatment failure is still possible due to other drug or patient factors such as the location of the infection and the immunologic status of the host. If the MIC value is in the intermediate category, therapy with this drug at the usual dose will likely be unsuccessful in establishing a cure. However, successful therapy is possible when doses higher than the label dose is used or if the drug is concentrated in the affected organ (eg urine) or is used topically (ear). If the MIC is in the resistant category, treatment failure is more likely because of resistance mechanisms or inadequate drug concentrations. Lastly not only does the MIC method indicate susceptibility, but it also implies the relative risk of emerging resistance and thus the need for a high dose.

The other limitation to the Kirby-Bauer results in regards to Pseudomonas susceptibility is the discrepancy between it and MIC. In two studies, Kirby-Bauer underestimated P. aeruginosa sensitivity to enrofloxacin (when compared with MIC) whereas in 2 other studies Kirby-Bauer overestimated enrofloxacin susceptibility. Since Pseudomonas infections is one of the most common reasons cultures are performed in cases of otitis externa, and enrofloxacin is a commonly used antibiotic for this infection, this inability to properly identify susceptible vs resistance to enrofloxacin is an important limitation in using Kirby-Bauer testing..

With the information gathered above, the treatment is directed toward the primary cause(s) (eg parasiticidal treatment, food trial, intradermal testing and allergen specific immunotherapy, etc) and perpetuating factors. Ear cleaning is performed in the clinic with a bulb syringe, AuriFlushTM system or by retrograde tube flushing (under anesthesia). If on the initial examination the ear canals are swollen and painful, ear cleaning may not be performed on the first visit, preferring to use topical glucocorticoids (GC) and systemic GC for 10-14 days to decrease the swelling. Once the swelling has decreased it will be much easier to examine the ear canals and visualize the TM.

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Cleaning agents contain substances that soften and emulsify wax and lipids. This initial cleaning is necessary in order to remove debris that may interfere with the effectiveness of topical agents and to reduce inflammatory debris (bacterial toxins). The author doesn’t usually have the owner do cleaning after the initial exam since it seems that many owners have trouble with just medicating the ear, let alone cleaning too. Many of the cleaners have a low pH leading to discomfort if used in an inflamed ear. A study comparing 2 ear cleaners (original formulation and then a new formulation) noted that in 38% of the cases with the old formulation and 37.5% of the cases with the new formulation dogs had a moderate to marked avoidance to having the cleaner instilled. This behavior was believed to be due to either a reaction to the ear cleaner or just overall animal irritability. Also the base in the otic ointments/suspensions (mineral oil, liquid paraffin) acts as a ceruminolytic agent. In addition, a recent study calls into question whether any of the ear cleaners have any ceruminolytic activity. In this study the ceruminolytic activity of 13 ear cleansers was evaluated using a standardized synthetic cerumen (SSC) that mimics the composition and texture of canine cerumen. Of the tested products only Cerumene®, Epiotic® and Vet Solutions Ear Cleaner® are available in the US. The test products were incubated with mild agitation for 20 min with 500 mg of SSC previously compacted at the bottom of a test tube. Ceruminolytic activity was then assessed by quantifying the SSC removed by decantation. Overall, Otoclean® (OT) was most efficacious, reaching an activity of 86–90% followed by Netaural® (NET) with a 39%, Specicare® (SP) with a 23% and Cerumene® (CE) with an 8% ceruminolytic activity. None of the other products displayed any ceruminolytic activity. It was concluded that, in the experimental conditions used in this study, only 1/13 products had significant ceruminolytic activity. Please note that the company that manufactures OT funded this study A follow up study by Robson, et al using Australian and US products revealed that 15/24 cleaners had <5% efficacy while only 6/24 ear cleaners had >80% efficacy-none of which are available in the US

There is frequently a discussion of the ototoxicity of agents put into ears. Remember that it is inner ear damage, specifically vestibular and/or cochlear damage that occurs with ototoxic agents, not middle ear damage. In order for a drug to cause damage to the inner ear it must either get to the inner ear hematogenously or by traveling thru the middle ear and entering the inner ear thru the vestibular (oval) or cochlear (round) window(s).

In humans because ofloxacin otic solution (Floxin Otic®) is the only topical agent to be labeled by the U.S. Food and Drug Administration (FDA) for use when the tympanic membrane is perforated, oral antibiotics have traditionally been used in this situation. However, according to otolaryngologists because the risk of cochlear damage with the use of other topical medications seems quite small, perforation alone is not an indication for oral antibiotics.

The opinion of this author is that the concern for ototoxicity due to topical medications is overstated. This position is supported by a consensus panel on reviewing the use of ototopical antibiotics. In their report they stated “There have been very few irrefutable cases of ototoxicity reported (after proper use of a topical otic preparation). Under many circumstances, it is difficult to separate the underlying disease process, which is also known to cause ototoxicity, from ototopical drug use.” They go on to state “For more than 40 years, the most common treatment has been aminoglycocide combination drops. A longstanding debate over the safety of these drops centers on ototoxicity. Even though the theoretical risk exists, there have been few reported cases in the literature, considering the millions of doses given”.

The author has only seen one ototoxic reaction that was suspected to be due to a topical agent and in that case the TM was intact! Therefore, agents are chosen more for their effectiveness than the concern about ototoxicity, especially since there are very few agents that have been proven to be safe in cases of a ruptured TM. It is more important to get rid of the infection than to avoid (effective) drugs because of ototoxicity concerns. Also, just because the TM is intact doesn’t mean that the barrier function is complete, therefore, even in the presence of an intact TM it is possible to get drugs into the middle/inner ear.

After ear cleaning topical agents are dispensed. The author prefers ointments over drops because of the impression that ointments get the drugs to the region of the tympanic membrane better than drops do (this may be a volume issue more than the formulation- it has been reported that it takes 1.0 cc of medication to get down to the TM in a medium sized (40 pound) sized dog - personal communication). The other advantage of ointments is that the base vehicle in the otic ointments (mineral oil/liquid paraffin) acts as a ceruminolytic agent.

Most topical products contain a combination of glucocorticoids, antibacterial and antifungal agents. Antibacterial agents used topically include:

1. Broad spectrum agents (gram positive and negative organisms) – a. Aminoglycocides

i. Decreased effectiveness in an acidified ear ii. Inactivated by purulent debris (so they must be put in a clean ear) ii. Examples of first line

a. Neomycin b. Gentamicin – note injectable water based gentamicin is non toxic even if the dog has

a ruptured tympanic membrane- this has not been studied when using commercial ear products that contain more than just gentamicin.

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iii. Silver sulfadiazine - inactivated by purulent debris so they must be put in a clean ear. It needs to be compounded to a 1% solution

a. Spectrum also includes yeast b. Inactivated by purulent debris so they must be put in a clean ear

2. Narrow spectrum agents (gram negative rods) – most are reserved for resistant gram negative infections a. Polymyxin B - inactivated by purulent material b. Fluoroquinolone –- decreased effectiveness in an acidified ear

i. Never a first line choice ii. Enrofloxacin

iii. Orbifloxacin c. Extended-spectrum penicillins (anti- Pseudomonas penicillins)

i. Susceptible to beta lactamase ii. Penetrate Pseudomonas cell wall better than other antibiotics

iii. Increase gram negative activity but less activity gram positive and anaerobes compared to other penicillins

iv. Carboxypenicillin a. Ticarcillin

v. Ureidopenicillins a. Piperacillin b. More effective against Pseudomonas than are the Carboxypenicillin

d. Aminoglycocide i. Amikacin and tobramycin

a. Gram negative bacteria (including some Pseudomonas) have less resistance to amikacin or tobramycin then gentamicin or neomycin

b. Decreased effectiveness in an acidified ear c. Inactivated by purulent debris so they must be put in a clean ear

Antifungal agents used include thiabendazole (anecdotally reported to have poor efficacy against Malassezia- is it volume related?), nystatin, clotrimazole 1%, miconazole 1 or 2%, posaconazole 0.1% and ketoconazole 1 or 2%

When gram negative organisms are present treatment of OE should include EDTA. To understand the action of ethylenediaminetetraacetic acid (EDTA) solution we need to review some microbiology. A capsule surrounds bacteria. Under the capsule is the cell wall that contains peptidoglycans. Under the cell wall is the cytoplasmic membrane (plasma membrane, cell membrane). The cytoplasmic membrane surrounds the cytoplasm and nuclear body. Gram negative have 2 additional layers. The outer most is the outer cell membrane that lies between the capsule and the cell wall. The outer cell membrane is composed of lipopolysaccharides. The other additional layer is between the cell wall and cytoplasmic membrane, called the periplasmic space. This space contains a variety of enzymes and other proteins that help digest and move nutrients into the cell. Gram positives do not have the outer cell membrane (and therefore no lipopolysaccharides) or a periplasmic space but do have a thick layer of peptidoglycans in the cell wall (vs. gram negatives which only have a thin layer). Note the peptidoglycans are the site of action for beta-lactam antibiotics.

Topical EDTA solution has a direct bactericidal action against bacteria by chelating metal ions important for the integrity of the bacterial cell wall. EDTA also stimulates the release of outer cell membrane lipopolysaccharides (LPS), proteins, and other cell contents. The end result of these actions is the leakage of cell solutes leading to cell death and better drug penetration and antimicrobial activity. Note - since EDTA stimulates the release of LPS from the outer membrane it is less effective at inhibiting gram-positive than gram-negative bacteria because gram-positive bacteria lack an outer membrane.

Pseudomonas bacteria have an efflux pump that is mediated by the MEX gene. This protein pumps the drugs out the bacteria, rendering the antibiotic ineffective. EDTA blocks this pump thereby allowing the antibiotic to accumulate in the bacteria.

To maximize its bactericidal activity it is essential for EDTA to be in an environment with an alkaline pH. Appropriate pH (8.0) is maintained by combining it with buffers such as tromethamine (TRIS) hydrochloride. This alkaline pH also decreases the bacterial MIC for an aminoglycocide or a fluoroquinolone. It is therefore useful to use TrisEDTA prior to instilling either of these antibiotics. Two commercial veterinary preparations are available - TrizEDTA®, (Dechra) or Tris Flush® (Sogeval). The ear canal should be filled with the solution prior to instilling the topical antibiotic (15-30 minutes before is ideal). This is done q 12 hrs. EDTA is used primarily for treatment of otitis externa and/or media caused by gram-negative organisms especially Pseudomonas.

A product made by Dechra, TrizChlor® contains 0.15% chlorhexidene in addition to the trisEDTA. The combination of these 2 ingredients is beneficial due to the synergistic effect between EDTA and chlorhexidene. The addition of the chlorhexidene extends the antimicrobial spectrum to include cocci in addition to the rods. There are 2 studies that support the effectiveness of this combination. The limitations of these studies are they in vitro studies and they used a 30 minute contact time. Whether these results can be repeated in vivo has not been studied. Since the author uses this product in combination with other topical agents, it is impossible to draw an accurate conclusion.

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In regards to safety of the chlorhexidene in otic products, a study reported the effects of instilling 0.2% chlorhexidene into the ear canals of dogs with experimentally ruptured tympanic membranes. In this study, 0.2% chlorhexidene was instilled in greyhound’s ear canals bid for 21 days. At the end of the study there were neither clinical vestibular signs nor BAER changes noted. THIS DOESN’T APPLY TO CATS!!!. A study instilling 0.05% chlorhexidene once every other day for 3 treatments into the middle ear of cats concluded that even this concentration of chlorhexidene may cause hearing loss in a cat. The authors did a subsequent study in which they evaluated vestibular effects of infusing chlorhexidene into the middle ear of cats. That study concluded that exposure of the middle ear to even dilute concentrations of chlorhexidene (0.05%) were likely to cause vestibular disturbances.

Any otic cleaner that contains EDTA-Tris would be appropriate to use when otitis externa/media is complicated by both rod shaped bacteria and Malassezia. Some contain ketoconazole. An unanswered concern about using ketoconazole chronically as a maintenance treatment is whether (when?) resistance will to ketoconazole will develop. Also acidifying the ear canal is one of the best treatments/prevention for Malassezia otitis and these products alkalinize the ear.

GC's are an essential component of topical treatment. Successful treatment of OE frequently requires topical GC and in fact the author has seen cases resolve where the only change in therapy was the addition of topical GC. GC are antipruritic, anti-inflammatory, decreases glandular secretions (cerumen), decreases pain and swelling and decreases hyperplasia- all properties that can help restore the normal barrier function to the epithelium of the ear canal. When using topical GC it is best to begin with the most potent form and if GC are needed long term go to less potent (and less side effects) forms (in decreasing potency- mometasone>betamethasone= hydrocortisone aceponate > fluocinolone> triamcinolone>dexamethasone> prednisolone> hydrocortisone). Note- even though hydrocortisone aceponate is classified as an intermediate potent glucocorticoid, equal to that of betamethasone 17-valerate, it has an improved benefit/risk ratio due to its decrease incidence of skin atrophy. REMEMBER topical steroids are systemically absorbed and can lower thyroid hormone concentrations; elevate liver enzymes, suppress the hypothalamus- pituitary-adrenal axis and even cause pu/pd.

The author has rarely used systemic antibiotics when treating OE. This approach is supported by the previously mentioned consensus panel who stated “In most cases of uncomplicated AOE, topical antibiotics are the first-line treatment choice. There is no evidence that systemic antibiotics alone or combined with topical preparations improve treatment outcome compared with topical antibiotics alone”.

In addition systemic antibiotics increase the risks of adverse effects and enhancing the environment for the production of resistant organisms. In humans it has been reported to increase the time to clinical cure and do not improve outcomes compared with a topical agent alone in uncomplicated otitis externa, In humans systemic antibiotics are recommended to be used only when the infection has spread beyond the ear canal, or when there is uncontrolled diabetes, immunocompromise, a history of local radiotherapy, or an inability to deliver topical antibiotics.

Systemic antibiotics or antifungal agents are used only if otitis media with bacteria, other than Pseudomonas (see below about Pseudomonas), or Malassezia are present on cytology, compliance and follow up has been good and topical treatment has been unsuccessful (very rare occurrence). Once again this approach is supported by the consensus panel (for humans) in which they state “The initial therapy o otherwise normal, healthy patients with CSOM (chronic suppurative otitis media)… should consist of ototopical drops and thorough cleaning of the canal.”

Empirical choices for cocci include cephalosporins, amoxicillin–clavulanic acid, clindamycin and potentiated sulfas. Empirical choices for rods include cephalosporins, amoxicillin–clavulanic acid (use TID vs. BID for gram negative organisms) and potentiated sulfas. Fluoroquinolones should be reserved for culture-proven resistant gram-negative rods. The antifungal agents that the author prefers include ketoconazole (5 to 10 mg/kg sid, given with food to enhance absorption), fluconazole (10 mg/kg sid), and itraconazole (5 mg/kg sid).

If the OM infection is due to Pseudomonas it is unlikely that systemic antibiotics will be useful. This is because systemic administration of antibiotics, including the fluoroquinolones, can’t exceed the MIC for P. aeruginosa in the ear canal. Since P. aeruginosa is the most common pathogen associated with OM in dogs, systemic administration of antibiotics will only select for more resistant organisms. Since it has been documented in humans that high drug concentration may be achieved in the middle ear when topical antibiotics are used, in cases of OM, topical treatment is the author’s mainstay therapy.

Systemic glucocorticoids are used if the ear canals are edematous, ulcerated and/or stenotic. Even proliferative changes may decrease with steroid administration since secondary edema may be present. Prednisone at 0.25-.50 mg/# bid for 7-14 days is dispensed and a reassessment is made in 7-14 days. At that time if the canals are completely open and the ulcers are healed, the prednisone can be discontinued. If the ears are better but not normal then make a clinical decision is made whether to maintain or decrease the dose for another 7-14 days. Again reassessment should be done in 7-14 days. If the ear canals are not opened by this second recheck, a total ear canal ablation with a bullae osteotomy would most likely need to be performed.

Specific scenarios

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1. Acute otitis (and/or infrequent) externa treatment overview. It is important to differentiate whether this is a first time occurrence, a recurrence or an unresolved infection. The only way to know this is to do follow-up examinations on ALL cases of OE. Remember that the absence of symptoms is not synonymous with resolution of the disease. This means that owners are unable to determine whether the infection is resolved and the dog must be rechecked. If this is the first episode, discuss the possible predisposing, primary and perpetuating causes and foreshadow that additional testing may be necessary in the future. In this situation, begin with eliminating easily diagnosed primary causes (foreign bodies, parasites, masses, etc). During the examination be sure to evaluate the status of the tympanic membrane. Perform a cytology to identify secondary infections. Treatment should be directed toward both the infectious component and the inflammatory component. Treatment should be for 7-14 days, unless using Easotic® (Virbac). At the end of the treatment, while still on therapy, a recheck examination should be performed!! Traditionally once the OE has clinically resolved the author has treated cases for an additional 7 days. More recently the author has begun to use a product with a unique delivery system- Easotic® (Virbac). When using this product, the dog is only treated for 5 days, in contrast to the 7-14 day schedule as previously mentioned, and then rechecked. The author has found this product to be very effective- most likely due to better compliance. Unless contraindicated, a topical GC containing product should be used as part of the therapy. The author prefers ointments over drops when treating otitis externa. Since all the otic ointments contain steroids and an antimicrobial agent, the author uses a combination product.

a. In cases of an acute infection there are a variety of products that are effective and would be appropriate to dispense (note most products will contain a combination of 3 of these drugs- antifungal, antibiotic and steroid). Typical ingredients include miconazole polymyxin B, prednisolone, nystatin,neomycin sulfate, thiostrepton, triamcinolone acetonide , gentamicin, hydrocortisone aceponate, betamethasone valerate and clotrimazole.

b. The only time this is altered is if there are heavy rods or just rods present, which is very rare in this scenario. In that case the author would use TrisEDTA, silver sulfadiazine and either gentamicin or polymyxin B (see below – Pseudomonas)

c. If the dog is painful, systemic GC and analgesics (tramadol, gabapentin and/or Tylenol with codeine) are added to the treatment.

2. If initially TM the is not visible due to swelling of the ear canals oral prednisone ½-1mg/#/day for 10-14 days will be added to the topical treatment. Because of the potency of fluocinolone or mometasone, Synotic® (fluocinolone with DMSO) and/or Mometamax® (mometasone) will be included in the therapy. Many times an analgesic is added as previously described (NO NSAID!).

a. A recheck examination will be performed in 10-14 days. If the TM is visible and the swelling resolved, then only the prednisone can be stopped. All the other treatment should be continued.

b. If the TM is not visible but the swelling has resolved, then an ear lavage via FEVO under general anesthesia should be performed.

c. If at the 10-14 day recheck the TM is not visible and the swelling has NOT resolved, continue the prednisone for another 10-14 days and then recheck.

i. If the ear canals are still narrowed at the next recheck, perform (or refer) a total ear ablation with a bullae osteotomy.

3. In cases of chronic (recurrent and/or unresolved) otitis externa, it is essential to determine if it is recurrent or unresolved. If it is unresolved is it because of owner compliance? If it is poor compliance then this problem must be resolved! If it is recurrent (or unresolved with good owner compliance) in addition to the above, a very aggressive search is performed to identify and treat the primary, perpetuating and secondary factors. Treatment should be for a minimum of 30 days. As above, GC will be an important component of therapy.

a. If there is only yeast, then the depending on what products have already been used, consider using clotrimazole 1%, miconazole 2%, 0.1% posaconazole or 2% ketoconazole lotion compounded with dexamethasone 0.1%.

b. If cocci are the only organism present then use gentamicin, mupirocin or 5% cefazolin (1 gm vial mixed with20 cc Triz-Edta plus).

c. If rods +/- cocci are present then use-Triz-Edta (+/- chlorhexidene if cocci are present) along with gentamicin or polymyxin B and silver sulfadiazine

d. Because of the association of the use of fluoroquinolones and the development of MRSA, and E.coli, the author rarely uses fluoroquinolones for the treatment of otitis externa. This concern is supported by many different sources. In the BSAVA “Guide to the Use of Veterinary Medicines” it discusses the prudent use of

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antimicrobial agents. In regards to all fluoroquinolones (FQ) it states “that in all species fluoroquinolones and third- and fourth-generation cephalosporins should be used judiciously and never considered as first-choice options”. The concern with using FQ is that, according to information from the CDC website, “a major limitation of fluoroquinolones is that resistant mutants can be selected with relative ease, leading to relapse and treatment failure”. In addition it has been observed that there is a significant association between total fluoroquinolone use within human hospitals and percentage of S. aureus isolates that were MRSA and between total fluoroquinolone use in the community and percentage of E. coli isolates that were fluoroquinolone-resistant E. coli. Association between fluoroquinolone exposure and the induction of mecA-positive S. aureus (MRSA) and the increase in the resistance index for methicillin resistance has been noted. Lastly it has been widely reported that there is an association between FQ use and clinically significant MRSA

i. The only time the author will use enrofloxacin or orbifloxacin is when the infection has failed to respond to the author’s aggressive therapy. The author prefers the later product due to the inclusion of steroids in the lotion. If using the former, dexamethasone should be added to achieve a final concentration if 0.1% dexamethasone.

Pseudomonas infections are especially challenging because of Pseudomonas’ intrinsic multidrug resistance (MDR). Many of the clinically relevant resistance mechanisms in Pseudomonas aeruginosa are attributed to synergy between its outer membrane that has a very low permeability to drugs and the presence of an active drug efflux pump (MEX). Because of the intrinsic MDR, Pseudomonas infections successful treatment must be aggressive before other resistance develops.

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Canine Cutaneous Adverse Food Reactions: Diagnosis and Treatment

Paul Bloom, DVM, DACVD, DABVP Allergy, Skin, and Ear Clinic for Pets

Livonia, MI

Initially, the ACVD task force on canine atopic dermatitis (cAD) defined cAD as a genetically-predisposed inflammatory and pruritic skin disease, most commonly associated with IgE antibodies to environmental allergens. cAD has now been recognized as a multifaceted disease associated with exposure to various offending agents such as environmental and food allergens. This author believes that the later definition should be used when discussing cAD.

It is important to remember that there are many other causes for pruritus in the dog other than cAD such as ectoparasites, cutaneous neoplasia (epitheliotropic lymphoma), bacterial pyoderma, etc. so canine pruritus is not always due to cAD.

In veterinary medicine the criteria for diagnosing cAD has evolved over time. Historically 1 of 2 sets of criteria have been used for making the diagnosis of cAD, The problem with these previous criteria is the former was never validated while the later had a limited sample size. The most current guideline was proposed by Favrot. Please note that before applying these criteria to a pruritic dog, other causes of pruritus, such as ectoparasites or infectious causes, need to be ruled out. You shouldn’t use these criteria alone to make a diagnosis of cAD. History, physical examination, diagnostic testing and response to treatment should also be included in your evaluation.

The criteria used to establish a diagnosis of cAD include 1. Onset of signs under 3 years of age 2. Dog living mostly indoors 3. Glucocorticoid-responsive pruritus 4. Pruritus sine materia at onset (i.e. alesional pruritus) 5. Affected front feet 6. Affected ear pinnae 7. Nonaffected ear margins 8. Nonaffected dorso-lumbar

Using these criteria, if 5 criteria are matched, and ectoparasites and infectious causes have been ruled out, the sensitivity and specificity are about 85% and 79% respectively. This means that using only these criteria, a wrong diagnosis will be made about 20% of the time.

Once you have established a diagnosis of cAD it is important to identify triggers that may cause the cAD to flare up. Triggers include

1. Environmental allergens 2. Food allergens 3. Ectoparasites 4. Infectious (bacterial, Malassezia)

This lecture is going to focus on food allergens as the trigger. Food allergy (FA) is recognized as a potential cause of various dermatological and gastrointestinal (GI) signs in the dog and cat.

The exact incidence of FA is unknown. However, the term “allergy” is often used indiscriminately. Acquaintance with exact terminology is important when dealing with FA.

An adverse food reaction (food sensitivity) as defined by the American Academy of Allergy and Immunology and the National Institute of Allergy and Infectious can be divided into two categories: immunological and non-immunological reactions. Food allergy (food hypersensitivity) implies an immunological reaction following food intake. Food intolerance (FI) is due to a non-immune mediated reaction. Food idiosyncrasy, food toxicity, food poisoning, anaphylactic food reaction, pharmacological and metabolic food reactions are all forms of FI.

Cutaneous clinical signs of an adverse food reaction (CAFR) are identical to that of environmental triggered cAD. The only clue that the dog may have a CAFR is that there MAY be GI signs present. In regards to an environmental trigger, the only definitive clue is if the dog has a history of seasonal symptoms.

An elimination diet trial (EDT) is the ONLY diagnostic tool that is useful in dogs with suspected adverse reactions to food. In vitro testing, biopsies, intradermal skin testing and gastroscopic food sensitivity testing are not reliable for diagnosing CAFR. Be aware that an EDT doesn’t give any information about the underlying immunologic mechanism. Although FI can also be identified with an elimination diet it is generally accepted that most of the animals with adverse reactions to food do suffer from CAFR if cutaneous signs are present. In regards to serum testing for CARF remember that identifying food can ONLY be established via properly performed food

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trials. Serum testing and intradermal testing for CAFR in dogs have been universally determined to have poor specificity and sensitivity. Supporting this position was a poster presented at the 8th annual World Congress of Veterinary Dermatology. At this meeting there was a poster presented titled “Inaccuracy of hair and saliva test for allergies in dogs”. The objective of the project was to determine if the Immune IQ test (Vet DVM, Boulder, CO) could reliably differentiate between samples from allergic dogs, non-allergic dog, fake dog fur or tap water. In this study, they took “samples” from fur/saliva from a known atopic/food allergic dog (n = 10), fur/saliva from a normal, non-allergic dog (n = 10), fake fur from a realistic appearing stuffed toy animal (n = 5), tap water (n = 5) and submitted it for laboratory testing. The laboratory tested for 128 food and environmental allergens. Results were reported as red (things to avoid), yellow (caution) or green (not a problem). The results revealed that the Immune IQ test results could not differentiate between allergic dogs, non-allergic dogs, and a stuffed animal! Another interesting fact that reminds us that a food trial must be performed to diagnosis CAFR is the statement that veterinary reference laboratory makes on their submission form for food allergy testing. It states that XXX, “in agreement with the ACVD, does NOT recommend IgE testing for food. A compliant exclusionary diet trial, followed by a provocative re-challenge, is recommended for animals suspected of suffering from adverse reactions to foods”.

The first step in performing an EDT is to identify 1 protein and 1 carbohydrate that the dog has not previously eaten and feed that to the dog for 60 days. No other food, treats, flavored medications, etc. should be fed during the EDT. The dog is then re-examined 30 and 60 days after beginning the EDT. If symptoms resolve, the dog is then “challenged” with his original diet, expecting exacerbation of the pruritus within 14 days if the dog has CAFR. If symptoms recur within 14 days of feeding the original diet, the dog should be fed the EDT once again and the symptoms should resolve.

What diet should be used to diagnosis CAFR? The choices are a commercial novel protein, a hydrolyzed limited antigen or a home cooked diet. A diet can only be “hypoallergenic” if the animal was never exposed to the food components before. The identification of what is truly a novel protein for any given individual is determined by a very detailed dietary history. Because of the enhanced complexity of pet foods, it has become more difficult to compose a suitable elimination diet.

Regardless of what type of diet is used to diagnose CAFR there are several potential pitfalls to avoid. A common mistake made during food trials is using flavored heartworm preventative. This was reported in an abstract in which there were 12 dogs with natural occurring CAFR to either soy or corn. The author fed a flavored heartworm preventative (Interceptor). fed to each dog. This preventative contained pork liver and soy. A clinical score (CS) was assigned based on the severity of skin and otic disease. After 1 pill 10/12 dogs had an increase in CS. In 5/12 dogs the values peaked on day 2 post challenge while in 5/12 dogs it occurred on day 5.

Another problem is the use of supplements or medications during the food trial. In a study the authors tested 7 supplements for the presence of soy, pork, or beef antigens. Three were flavored OTC products and 4 were veterinary therapeutics. All OTC test products produced ELISA results in agreement with their ingredient lists. ELISA testing of veterinary therapeutic products did not agree with either their ingredient lists or product inserts because of the presence of other ingredients not listed. In 1 product, the “artificial beef flavor” was made using pork liver and 1 arthritis product listed “natural flavors” which was determined to be a spray-dried digest derived from pork liver. Another potential problem identified was administering supplements/medications that were in a gelatin capsules. This is because the gelatin is derived from beef or pork. This lead the authors to recommend that veterinarians contact manufacturers of oral therapeutics prior to prescribing them during a dietary elimination trial to determine the other ingredients in those products that may not be listed on the ingredient list or product insert.

Mislabeling is not limited to supplements. A study was done using 12 dog foods (eleven novel protein diets and one hydrolyzed diet) from five different manufacturers, both international and Italian, for potential contamination by animal origin ingredients that were not mentioned on the label. The food was analyzed using both the official method (microscopy to identify bone fragments of different zoological classes (mammalian, avian and fish) and by polymerase chain reaction (PCR) for the identification of DNA of animal origin. In 2/12 samples the results of both analyses match the ingredients listed on the label. In the remaining 10 samples, microscopy detected bone fragments from 1 or 2 u nlabeled zoological classes. In 6/10 samples, there were undeclared avian fragments, 5/10 had fish and 4/10 had mammalian fragments. In two samples, microscopy analysis identified a contamination that would have otherwise passed unobserved if only PCR had been used. However, PCR identified the DNA of undeclared zoological class in 2 samples. The conclusion by the authors was that dogs might fail to respond to commercial limited antigen diets because such diets are contaminated with potential allergens. Both PCR and microscopy analysis are required to guarantee the absence of undeclared animal sources in pet foods. Lastly a study by Okuma et al collected 52 commercial dog and cat food products from southern California and on line. They tested the foods for the presence of eight meat species (bovine, caprine, ovine, chicken, goose, turkey, porcine, and equine) using real-time polymerase chain reaction (PCR). Of the 52 products, 31 were labeled correctly, 20 were potentially mislabeled because they either (1) contained meat species that were not included on the product label (16) and/or (2) did not contain meat species that were included on the product label (7) - note some food had both problems. One food contained a non-specific meat ingredient that could not be verified. Pork was the most common undeclared meat species detected.

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There was also a trend to substitute lower cost ingredients, such as poultry meats, for higher cost ingredients, such as beef and lamb. These studies support the position that before ruling out a n AFR, a novel protein home-made diet trial should be p e r f o r m e d .

A retrospective study added additional evidence to support the statement that a homemade diet is superior to commercial diets in diagnosing CAFR In this retrospective study reporting CAFR in cats, the author evaluated cases presented to a dermatology referral service for possible CAFR. Seventeen cats were diagnosed with having CAFR. Home prepared elimination diets were completed by 16 cats; 8 cats with a final diagnosis of CAFR failed to respond to a minimum 6-week commercial hydrolyzed protein diet but did respond to the home-made diet. Of the 13 cats in which their final dietary management was reported, 6 cats could not tolerate any commercial dry foods, but did tolerate select canned foods; 7 cats could consume commercial dry foods, with 4 maintained on commercial hypoallergenic diets and 3 with other commercial restricted protein diets.

As previously discussed, an appropriate elimination diet should contain 1 new, highly digestible protein or a diet that contains hydrolyzed proteins. Ideally a homemade diet (HMD) should be fed. This is the type of diet the author uses. A HMD consists of one novel protein and one novel carbohydrate. The protein usually is rabbit, venison, goat, ostrich, emu or alligator. White or sweet potatoes, oats, quinoa or rutabaga are appropriate carbohydrate sources. It is mixed 1 part meat and 3 parts carbohydrate and the dog is given 1-2 cups of the mixture/10#. HMDs should not include ANY other ingredients. The dog must not ingest any other food, treats, tidbits, etc. including items used to hide medication in. Avoiding gelatin capsules should be attempted. This may be difficult because some medications only come in a capsular form (e.g. modified cyclosporine). The problem with HMDs is that they are nutritionally inadequate for growth and maintenance therefore they are not using in growing dogs or for long term maintenance. Because they are not very calorically dense most animals will lose weight on these diets. If a dog has a body score of 4/9 or less, this author does not use a HMD. Although a HMD is not nutritionally balanced nor complete, supplements are not necessary, nor used, during the short test period. When a HMD is given during a prolonged time, it is recommended to consult a veterinary nutritionist to formulate a balance diet.

Although the gold standard for diagnosing CAFR is a HMD there are circumstances where the author will use a commercial diet instead. Examples include owners who will not cook for the dog, if the dog doesn’t tolerate HMDs (typically because of weight loss but some dogs will become lethargic on them or have GI disturbances). They are not fed to growing dogs.

Commercial novel protein diets (NPDs) can be used to diagnosis CAFR and can be used long term to maintain a dog with CAFR. A variety of NPDs are available for dogs. These diets are readily available but do not have a 100% negative predictive value (false negatives occur 25-50% of the time). Several studies have demonstrated the problems associated with NPD. In the first study, they fed dogs with proven CAFR either venison/rice, chicken/rice or catfish/rice commercial dog food. When fed the venison dog food 85% of the dogs with CAFR reacted while 52% and 47.5% reacted to chicken and catfish dog food respectively. More recently 3 of 4 over the counter (OTC) dog foods that didn’t list soy on their ingredients list had soy identified via ELISA testing. More disturbing was the study that reported 3 out of 4 OTC dog foods that specifically stated “NO SOY” had soy found when ELISA testing was performed. Note that in the same study 2 of 3 hydrolyzed soy diets had intact soy identified.

Commercial hydrolyzed protein diets (HPDs) contain proteins that been enzymatically hydrolyzed to smaller molecules. This reduces the MW of the original protein which leads to a decrease in the antigenicity and allergenicity of the protein. This means that the molecules are too small to evoke a cross binding between IgE on the surface of the mast cell. This prevents degranulation of the mast cell and IgE-mediated (Type I) hypersensitivity. This is a key point because if the CAFR in that dog is not caused by IgE (which is believed to be the more common scenario) but by some other mechanism (e.g. type IV which is a T cell driven disease) the size of the molecule doesn't not matter and the diet will be ineffective. The optimal MW of a protein hydrolysate in dogs has not been agreed upon. Hand et al states that an ideal molecular weight of less than 10,000 Daltons, while Cave states that if the protein size is reduced to less than 6,000 Daltons in size, it should reduce binding to IgE and increase digestibility. However, Verlinden et al. states that peptides over 4,500 Daltons could still can start the immunologic reaction which contributes to the allergic reaction. In addition, these diets are only partially hydrolyzed. This means that only a percentage of the protein is hydrolyzed- there is still some intact protein remaining. In the humans, peptides with a MW as low as 3000 Da are still capable of an allergic reaction. Free AA are not allergenic, but are not suitable in foods because of their bitter taste, high osmolarity (leading to diarrhea) and very high costs. As with the NPD, HPD are not able to diagnose CAFR in all dogs- they probably miss about the same percentage as the NPD.

Recently a study evaluated whether the molecular weight of peptides present in three different hydrolysed foods [Royal Canin Ultimino (Royal Canin; Aimargues, France), Purina HA (Nestle Purina PetCare; Meaux, France) and Hill’s z/d Low Allergen (Hill’s Pet Nutrition; Sophia-Antipolis, France)] matches with the producers’ claims and if peptides are recognized by IgE. The results showed that in all 3 diets there were several high molecular-weight (HMW) proteins ranging from 15 kDa to 60 kDa. This study further demonstates that even highly hydrolysed hypoallergenic foods may still contain immunoreactive HMW proteins. Further studies are required to determine the clinical relevance of these findings but it is a concern that these HMW proteins may impact the success rates of some elimination diets.

Regardless of which diet is used there are a few points to discuss. The first issue is how long to feed the diet. The following is based on the best evidence available as of December 14, 2014 and is information gathered from 209 dogs with CAFR. After 3 weeks

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on the diet approximately 50% of the dogs will have achieved a complete or marked reduction (>50%) of pruritus. After 5 weeks 85 % of dogs had responded partially or completely and by 8 weeks >95% had responded. Less than 5% needed 9-13 weeks. Information gathered from 40 cats with CAFR revealed that it took approximately 4 weeks (50% of the cats), 6 weeks (80%) and 8 weeks (90%) on the diet to achieve a remission. As in dogs, by 13 weeks 100% had either partially or completely responded. Remember if at any point the pruritus has completely resolved, the diet can be “challenged” at that time, there is no need to extend the special diet any further.

Veterinarians are frequently asked by owners which ingredients cause the most reactions? The answer depends on the study. In 265 dogs reported collectively by 12 different studies, beef, dairy products, and wheat accounted for two thirds of reactions. Reactions to corn, pork, rice, and fish were rarely reported in dogs. In the April 2013 issue, Veterinary Dermatology a letter to the editor reported the most common ingredients causing CAFR in 330 dogs- beef, dairy, chicken and wheat accounted for 78% of the reactions. Of 56 cats reported collectively by 10 studies, beef, dairy products, and fish accounted for 80% of reactions.

More recently a literature search (limited to 1985-2015) for canine or feline food allergy in CAB Abstracts and Web of Science revealed that of the 297 dogs included in the selected studies the most frequently reported food allergens involved in dogs were beef (102 dogs, 34 %), dairy products (51 dogs, 17 %), chicken (45 dogs, 15 %), wheat (38 dogs,13 %) and lamb (14, 5 %). Other less commonly reported offending food sources were soy (18 dogs, 6 %), corn (13 dogs, 4 %), egg (11 dogs, 4 %), pork (7 dogs, 2 %), fish and rice (5 dogs each, 2 %). In cats the food sources most frequently causing CAFR in were beef (14 cats, 18 %), fish (13 cats, 17 %), chicken (4 cats, 5 %), wheat, corn and dairy products (3 cats each, 4 %) and lamb (2 cats, 3 %). Egg, barley and rabbit were also reported as offending allergens in individual cats.

The problem with any of these retrospective studies is that the offending allergens listed reflects pet feeding habits in the preceding decades, and these allergens could change once new pet foods become fashionable and used more frequently. Note that many owners believe that food additives (dyes and preservatives) are common causes of food allergy in dogs, yet there has not been even 1 published case report documenting this

Maillard reactant products are formed when proteins are cooked with carbohydrate. They can increase or decrease the allergenicity of proteins, depending on the food component. This phenomenon may explain the apparent increase in allergenicity of proteins in commercial pet foods compared to fresh proteins. Because of this, the author suggests that when preparing the HMD, the protein and carbohydrate should be cooked in separate pots.

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Quick, Easy, and Profitable Dermatologic Tests for Small Animal Practice

Paul Bloom, DVM, DACVD, DABVP Allergy, Skin, and Ear Clinic for Pets

Livonia, MI

Protocols are useful in helping to diagnose and treated many different disorders. Part of any good protocol should be a minimum data base (MDB). In addition to signalment, history, etc in veterinary dermatology, laboratory testing should be a component of this data base. Just as you may have a standard set of tests for diarrhea you should have a standard set of tests for dermatology cases. Because practitioners get busy, sometimes collection of this minimum data base is overlooked. By training technicians to perform the tests this potential problem can be avoided. Instructing technicians to perform these tests on every pruritic animal ensures that this will be done on every case.

Tests can be separated into immediate and delayed tests. For a pruritic dog or cat all the immediate tests should be performed. Which of the delayed tests should be performed will varying based on the results of these tests.

Immediate tests include 1. Skin scrapings ** 2. Impressions smears ** 3. Ear cytologies ** if ear disease is present 4. Fine tooth combing ** 5. Hair plucks/trichograms

Delayed tests would include 1. Skin biopsies 2. Woods lamp and fungal culture 3. Bacterial culture and susceptibility 4. CBC, serum chemistry profile and urinalysis 5. Adrenal function tests 6. Thyroid profile 7. Dietary elimination food trial 8. Intradermal testing (or serum testing) and allergen specific immunotherapy

** Component of MDB

Equipment The equipment needed is very basic and include

1. #10 scalpel blade- dulled by scratching the frosted part of a glass slide 2. Mineral oil 3. Frosted 4. Clippers

glass slides and cover slips

5. Microscope 6. Minitip culturettes 7. Needle and syringes 8. Woods lamp +/- derm duet 9. Punch biopsy 10. Lidocaine/bupivicaine/sodium bicarbonate

Skin scraping Let’s begin with skin scrapings. Before performing skin scrapings you should ask the following questions

1. What technique do I use (broad superficial or deep scrapings or both) 2. Where do I need to skin scrape? 3. What lesions should be scraped?

The answers to these questions depend on which parasite you suspect. If you suspect a superficial mite (Sarcoptes, Notoedres, Demodex gatoi (cats), Demodex cornei (dogs) Cheyletiella) then broad superficial scrapings should be performed. Deep skin scrapings should be performed when Demodex canis or cati is suspected. (Table 1)

When performing superficial scrapes be sure to scrape from appropriate areas. For Sarcoptes you will be more successful if you scrape pinnal edges, the elbows, ventral chest and hocks. In addition any popular, crusted or erythematous lesion should be scraped.

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For any of the superficial mites, broad scraping should be performed. Remember that mites associated w/hypersensitivity (eg Sarcoptes, Cheyletiellai) may be difficult to find due to their low numbers so be sure to take multiple (10-15) sites. In contrast to demodex, all scrapes can be placed on 1 or 2 slides because the quantity of mites present is not important, they are either found or not.

When performing a deep skin scrape for demodex (this applies mostly to dogs) there are a few pitfalls to avoid. By avoiding these errors the diagnosis and your management of demodex will improve.

These include 1. Failure to squeeze the skin prior to scraping. Squeezing helps express the Demodex from the hair follicles 2. Failing to record location of scrapes; 3. Failing to record numbers & stages present; 4. Failing to record whether the mites are alive or dead; 5. Failing to clip hair at skin scrapings sites (if it is a recheck appointment, the hair may be regrowing preventing proper

sample collection); 6. Failure to squeeze the skin prior to scraping to try 7. Failure to recognize that lesions that are granulomatous & fibrotic, especially on the paws may have demodex that are

hard to demonstrate on skin scrapings and a skin biopsy may be necessary to diagnosis; 8. Failure to sedate dogs if the feet are to be scraped 9. Failing to scrape hyperpigmented areas even if they are not alopecic; 10. Failing to scrape areas with comedones even if they are not alopecic 11. Failing to scrape if a dog only has greasy seborrhea (especially along the dorsum). A long body type of demodex mite

has been identified (Demodex injai). This mite lives in the sebaceous glands of the dog's skin, and thus, is commonly associated with "greasy coats" rather than the moth eaten or pustular appearance that we are used to seeing.

12. Failing to take broad superficial skin scrapes even if demodex is the only parasite you suspect. There is a short bodied demodex mite (Demodex cornei), which lives on the surface of the skin layer. Note that there may be a low number of these mites found because of the superficial location of the mites allowing removal by the animal.

Cytology Cytologic examination is another very commonly performed procedure in dermatology that should be performed on any dog or cat presented w/skin or ear disease. Cytology is used to identify the presence (and/or type) of:

1. Bacterial or fungal organisms (Malassezia); 2. Neoplastic cells; 3. Inflammatory cells; 4. Abnormal cells (eg acantholytic keratinocytes associated w/pemphigus foliaceus)

When the skin is scaly, a superficial skin scraping can be useful. A very small amount of mineral oil is placed on a #15 scalpel blade to help keep the scale on the blade once it has been collected. The lesion is scraped a few times, and the material collected is placed on a microscope slide, stained (see below about staining samples), and examined microscopically at 40X and 100X.

Direct smears can be collected by a variety of ways. Impression (touch) smears are useful when there is an erosion, ulcer, crust, moist or greasy lesion. To perform an impression

smear, a slide is firmly applied to a lesion and, in most cases, is then gently moved back and forth a few times to increase the yield. Some people will use slides that are “sticky” on one side. These slides are reported to increase the yield of sample collected but the author finds that a standard slide works quite well. The slide is then processed and examined as described below.

If the lesion is fluid filled (eg pustule, papule) but is too small for a fine needle aspirate, “lance” the lesion with a 25 gauge needle, gently squeeze the lesion and then do an impression smear of any material expressed. When sampling crusts, lift the crust and rub both the underside of the crust and the surface of the skin.

Roll smears (swabs) are used when it would be difficult to get a slide into the affected area. This could be the face fold, the interdigital space on cats and small dogs and the ear canals in all dogs and cats. A cotton tipped applicator is gently rubbed back and forth across the lesion and then the material from the applicator stick is rolled back and forth on the slide. If the lesion is scaly, applying a small amount of mineral oil to the swab can help with collection. The sample is rolled onto a microscope slide, stained and examined as previously described.

A fine needle aspirate is performed when a solid or fluid filled mass or lesion is present. A 22-25 gauge needle attached to a 12 cc syringe is placed into the lesion and suction is applied by pulling back the plunger of the syringe (½ to ¾ of the way). The syringe plunger is pulled back and released a few times. Don’t aspirate aggressively enough that you get blood contaminating the sample (you should not see blood in the hub of the needle). After aspirating one spot, stop aspirating and redirect the needle in the mass w/o pulling out and repeat the aspiration. This can be repeated 2 or 3 times on each sampling attempt. The needle is disconnected from

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the syringe, the syringe is filled w/air and the needle is placed back on the syringe. The material is then ejected from the needle by compressing the plunger. If the lesion is a fluid filled you only have to pull back far enough to get a sample into the syringe. Note- Measuring and noting the location of the masses is valuable for monitoring progression and/or response to treatment.

Regardless of the collection technique (except when using the tape prep) historically the author would heat fix the sample, using a cigarette lighter, and then wait a minute or so to allow it to cool. The slide was then stained w/a modified Wright stain (Diff Quik®). There are 3 jars in the Diff Quik® kit. The first jar is a fixative containing methanol, the second contains buffered xanthene dye, which stains the cells and organisms red and the third contains a buffered thiazine dye (methylene blue) which stains the cells and organisms purple. After drying, the slide would then be examined.

A more rapid and equally effective method is to bypassed both the fixative step and the second step (eosin) and directly go to the 3rd step using the methylene blue only. It doesn’t appear to hinder the identification of bacteria, yeast or inflammatory cells except for eosinophils. If using the tape prep I will put a drop on stain on the slide and then place the tape, sticky side down, over the stain and examine.

Ear cytologies are performed to identify mites, infectious agents and inflammatory cells. A cotton tip applicator is used to collect the samples prior to instituting therapy. Results of the cytology help direct appropriate therapy (presence of infectious agents would indicate the need for antimicrobial therapy). I will also perform ear cytologies during therapy if either the ear(s) are not responding to treatment OR if there were rods or WBC’s on the initial cytology regardless of the appearance of the ear. If the initial cytology revealed yeast and/or cocci and the looks normal at the recheck examination I don’t cytology it since I don’t expect to sterilize the ear canal- in fact the treat for eliminating certain bacteria (eg enterococcus) may be just discontinue the antibiotic and allow restoration of the normal microbiome.

A few tips when examining your sample. 1. For skin cytologies

a. For bacteria look in 10 fields and record a range (eg 0-5, 5-10, 10-20 etc) – be sure to note if they are cocci or rods, if WBC’s are present or not and if the bacteria are intracellular or extracellular

b. For Malassezia look in 20-25 fields (unless they are ID sooner). Report them as negative/+0 if NO Malassezia is found, +1 if 1 or 2 organisms are found (total #) in all the fields examined and there were never more than 1 in a field, report a +2 if there are more than 1 organism in a field or 1 organism q 3-4 oil fields – treat any case w/a +2 and consider treating even if +1. In fact the ACVD now recommends either reporting Malassezia as either present or absent.

2. For ear cytologies a. There is no universal agreement as to what are normal number of cocci or Malassezia from an ear cytology

i. Because the host reaction to the organism is as important as the number, ANY organism seen in a diseased ear will be treated as part of the therapy regardless of the number present

b. Inflammatory cells or rod shaped bacteria are never present in a normal ear. Fine tooth combing Combing of the hair with a fine tooth comb (“flea comb”) is a method that can be useful in finding fleas and other ectoparasites (ticks, lice and Cheyletiella). You may also detect military lesions on cats that were not appreciated on your physical examination. Trichogram (“hair plucks”) Veterinarians are frequently presented w/animals that have hair loss. In establishing the diagnosis of the hair disease, signalment, history (constitutional signs present or not?) and physical examination (eg pot belly, enlargened liver, etc) are important components in establishing a diagnosis. There are times that even w/this information the cause of the alopecia has not been established. A trichogram, which is a microscopic evaluation of plucked hairs, may be a useful tool to help identify the underlying cause.

If the alopecia is post traumatic (pruritus) or due to fragile hairs (eg dermatophytosis) the distal end of the hairs will be broken (or if the dog/cat gets haircuts). If the hair loss is spontaneous (eg endocrinopathy) the tips are tapered.

Hair plucks can also be useful in ruling in (but not ruling out) demodicosis. Other ectoparasites may also be identified such as Cheyletiella or lice.

Follicular cast can also be identified w/hair plucks. Follicular casts refers to the accumulation of keratin debris that adheres to the hair shaft as it extends out of the hair follicle. This finding indicates a follicular keratinization disorder which occurs w/vitamin A responsive dermatosis (rare- but if occurs would be a Cocker Spaniel most likely), follicular infections (demodex, dermatophyte, bacterial), Malassezia dermatitis,sebaceous adenitis, endocrinopathy (hyperadrenocorticism, hypothyroidism) or primary seborrhea such as ear margin seborrhea.

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Skin biopsies Skin biopsies are an easily performed outpatient procedure. The author will perform a skin biopsy for:

1. Any skin disease that is not responding to what should be effective therapy; 2. Any skin disease that may be potentially neoplastic; 3. Any skin disease that may be a cutaneous marker for a systemic disease (eg 4. hyperkeratotic footpads associated with metabolic epidermal necrolysis); 5. Any skin disease that may be autoimmune or immune mediated; 6. Any nodular disease; 7. Any skin disease that appears unusual; 8. Any skin disease that requires expensive or potentially toxic therapy

The 2 methods used to biopsy the skin are the punch technique and the elliptical, incisional biopsy. For punch biopsies, the author usually will use a 6 mm punch biopsy instrument. When using this instrument, DO NOT include

normal tissue in the sample- only the lesion. If biopsying the edge of a lesion then perform an incisional biopsy. The author uses elliptical, incisional biopsy with a scalpel blade for lesions that are alopecia, ulcerated, erosive or are suspected to

involve the subcutaneous tissue (eg panniculitis). For subcutaneous lesions, a punch sample may not get subcutaneous tissue and therefore may miss important lesions. This type of biopsy has one end of the sample in normal tissue and 1 end in the middle of the abnormal. The biopsy should be elliptical and request the laboratory to section the sample from tip to tip. This technique allows the evaluation of the formation of the lesion- from normal to very affected skin- it allows a “story to be told” about the lesion

Sites should NOT be shaved or scrubbed prior to collection since this may remove very valuable information. The hair may be partially clipped to visualize the lesion better, but in order to avoid traumatizing the skin, at least ¼ inch length of hair should remain. Bacterial cultures In the past, bacterial cultures were not frequently performed in dogs with skin disease since Staphylococcus intermedius was the most common bacterial pathogen and had a predictable susceptibility profile. Unfortunately it isn’t that simple any more. Staphylococcus intermedius, Staphylococcus pseudintermedius, Staphylococcus lugdunensis or Staphylococcus delphini Staphylococcus schleiferi subsp. Schleiferi, Staphylococcus schleiferi subsp. coagalens, and Staphylococcus aureus all w/variable susceptibilities (methicillin resistant, multidrug resistant, combination) are now associated w/pyoderma in dogs. The need for bacterial culture and susceptibility testing in the dog or cat has become more frequent. Indications for bacterial culture would include the presence of:

1. Nodules; 2. Deep draining tracts; 3. A bacterial infection of the skin (confirmed by identifying intracellular bacteria and degenerative neutrophils) that fails

to respond to appropriate antibiotic therapy; 4. Suspicion of an uncommon bacterial infection (atypical mycobacteria, nocardia, actinobacillus); 5. Suspicion of an anaerobic infection (gas pocket formation);

A few tips when dealing w/a bacterial culture (see table 1 for more details) 1. Use a Mini-Tip Culturette (Becton Dickinson Microbiology Systems) to pin point the sample 2. Taking samples from 2 or 3 lesions (if possible) will increase the likelihood of identifying all pathogens 3. Do cytology concurrently 4. When selecting a lesion to culture – from best to worse - pustule >papule>crust>epidermal collarette 5. If you are sampling a crust- lift the crust and swab the underside of the crust and the surface of the skin under the crusts

with a the culturette. 6. For an epidermal collarette lift the edge of the collarette- if you are not able to do this then clip the hair w/scissors to

expose the collarette then take a the culturette swab and gently roll it across the collarette 3 to 4 times. 7. Have the lab do susceptibility testing use the tube dilution (MIC) rather than disc diffusion (Kirby-Bauer)

Wood’s Lamp examination and fungal culture for dermatophytes Dermatophyte infection is a common problem in cats and young animals of all species. Proper collection of the specimen is critical in identifying this infection. The first step is to examine the animal with a Wood’s lamp. You should let the Wood’s lamp warm up for at least 10 minutes, and then shine the light on the hair coat looking for apple-green glow to the entire hair shaft. Remember crusts may glow as may some topical medications. A positive test is suggestive of dermatophytes, but you need to culture the hair to confirm this. Please note that a negative test does not rule out dermatophytosis, in fact you should only use the lamp to guide in selecting hairs to pluck for culture not as a tool to rule out dermatophytosis.

Prior to collection, the suspected skin lesion should be gently cleaned if grossly contaminated. Mild soap (not antimicrobial) and water may be used. Allow the site to dry before collecting the sample. Using a sterile hemostat, you should pluck the hairs near the

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base so that you can get close to the bulb. Also scrape a small amount of scale/crust from the edge of the lesions. This will increase the success rate of identifying dermatophyte infections. If there are diffuse lesions or you are screening a cat for infection, a Mackenzie toothbrush method is used. To perform the toothbrush method, take a sterile toothbrush and rub it over the entire lesion from the margins to the center. Then take a sterile hemostat and remove the hairs/scale from the tooth brush and inoculate the culture plate.

Once a media is inoculated, close the cover and place the culture plate in a plastic bag or “pencil box” with a sponge to prevent dehydration of the media which can inhibit growth of organisms. In contrast to previous recommendations the sample does not need to be placed in a darkened area and it doesn’t need to be incubated- it should be left at 77-86O F. PUT IT IN A PLACE WHERE IT WILL BE EXAMINED DAILY.

If submitting to a reference lab, just take the sample and place it in a red top tube and send that to the reference lab.

If you are doing the culture in house, be sure to check it DAILY and record the findings. It is important to note when the media changes color w/respect to colony growth. A large amount of growth w/small color change (contaminant) is interpreted differently than a small amount of growth & large color change to RED (dermatophyte). The color of colony is important in determining contaminant vs. dermatophyte, as is microscopic examination of macroconidia. To get the sample for microscopic examination, apply sticky side of clear acetate tape to the culture media where the growth has occurred. Then stain the sample with Lactophenol cotton blue

By microscopically examining the sample you can speciate the dermatophyte. By speciating the dermatophyte you can tell the source of the infection (see below). This is done by identifying macroconidia. The descriptions of the different macroconidia are available in many text books or on line.

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Simplified Diagnosis and Management of Autoimmune Skin Diseases- Including Immunosuppressive Therapy

Paul Bloom, DVM, DACVD, DABVP Allergy, Skin, and Ear Clinic for Pets

Livonia, MI

The diagnosis of ANY skin disease is based on obtaining a detailed history, evaluating clinical findings (identification of primary lesions, distribution of lesions), laboratory testing and therapeutic trials. For autoimmune skin diseases (AISD) the most beneficial diagnostic tool is histopathologic evaluation. Pemphigus In pemphigus, the immune system is directed to inappropriately attack the desmosomes. Desmosomes are spot like sites of intercellular contact and attachment between keratinocytes.

Pemphigus foliaceus (PF) is the most common form of pemphigus and is probably the most frequently diagnosed autoimmune skin disease (AISD) affecting cats and dogs1,2

1

. Other forms of pemphigus that will be seen in practice include pemphigus erythematosus (PE) and panepidermal pemphigus (PPP). In general, PF is a disease of young to middle aged animals with a mean age of onset of 4 years old. Sixty five percent of the dogs have the disease before 5 years of age. PF has been reported in numerous breeds with Chow Chows and Akitas being at increased risk in the author’s practice. There is no gender predilection in dogs ,2.

In the author’s experience, even though there are three forms of PF reported in the literature- spontaneous pemphigus, drug-related (both drug induced (no genetic predisposition) and drug triggered (genetic predisposition) and a form that is associated with chronic skin disease, it is rare to have cases in which the dog has had chronic skin disease. In fact, there is no evidence to support that claim. Cases that occur spontaneously are by far the most common.

Historically, the owner may report that the lesions wax and wane or are progressive. The progression of the disease may be slow, especially cases with only facial involvement, or the dog may develop acute eruptions (most commonly associated with generalized disease). With the generalized form the dogs frequently will be febrile, may have limb edema and have constitutional signs. Pruritus with any form varies from non-existent to moderately intense.

There are 3 primary distribution patterns of PF -facial (most common) form which involves the bridge of the nose, nasal planum, periorbitally, pinnae (especially in cats); a footpad form (cats may present only with paronychia) and a generalized form where lesions usually begin on the face and then spread. Note that there is a subset of dogs that have generalized disease from the onset.

The lesions progress from an erythematous macule⇒ pustule⇒ collarettes⇒ erosions ⇒ yellow brown crusts. Because there is involvement of the hair follicles, multi-focal to diffuse alopecia is frequently present. The primary lesions of PF are large nonfollicular

Differential diagnosis would include any pustular, crusting and scaling disease such as: pemphigus erythematosus; zinc responsive dermatosis (especially with foot pad involvement); metabolic epidermal necrosis (especially with foot pad involvement); bacterial and fungal (dermatophytosis) infections; demodicosis, DLE (facial/nasal form); erythema multiformae; mycosis fungoides; Leishmaniasis; and sebaceous adenitis.

pustules (there are also follicular pustules present) especially involving the bridge of the nose, footpads, nasal planum or pinnae (cats may have lesions around the nipples). This contrasts with pustules associated with a bacterial pyoderma in which the pustules are follicularly oriented. The pustules that are present in a bacterial pyoderma usually involve the ventral abdomen and/or trunk and are much smaller than those seen with PF. In cats and dogs with PF, secondary lesions are more commonly seen than the pustules. These lesions include epidermal collarettes (uncommon), yellow brown crusts and erosions. These animals may be systemically ill, have distal limb edema, fever, lethargy and/or lymphadenopathy.

Diagnosis A cytologic prep of a pustule or crust should be performed. Microscopic findings would include acantholytic keratinocytes, either individually or in clusters, surrounded by NON-degenerative

1 Scott DW, Miller WH, Griffin CE Chapter 9 - Immune-Mediated Disorders, Muller & Kirk's

neutrophils and/or eosinophils- bacteria should not be seen. Histopathology is the only definitive means to diagnose pemphigus. An intact pustule (or if none are present, a crusted lesion) should be biopsied. Infectious diseases that produce proteases, such as a bacterial pyoderma or a dermatophyte infection (Trichophyton

Small Animal Dermatology. 6th ed. Philadelphia: WB Saunders; 2001:667-779. 2 Willemse T. Auto-immune dermatoses. In: Guaguere E, Prelaud P, eds. A Practical Guide to Feline Dermatology. Merial. 1999: 13.1-13.7.

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mentagrophytes), can breakdown the intracellular glycoproteins (desmoglein) leading to acantholysis. Because these infectious diseases mimic PF histologically, you should request special stains for both bacteria (gram stain) and fungi (GMS, PAS) anytime a there is a histopathologic diagnosis of PF. Prognosis PF may be drug related, either drug-induced or drug-triggered3,4

A study at NCSU

. The drug-induced form PF is caused by a drug and upon removal of the drug, sometimes with a short course of immunosuppressive treatment, the disease resolves. Drug-triggered PF occurs when a drug stimulates a genetically predisposed individual to develop PF. Typically, this form of PF must be managed long term, like idiopathic PF. Currently there is no way to identify which cases of drug related PF are drug induced and which ones are drug triggered. In fact, there is no test that can be used to predict how well a case of PF will respond to treatment.

5 revealed that 6 of 51 dogs (11.7%) with PF were weaned off all medication and stayed in remission for >1 year. Recognizing that PF is a sunlight aggravated disease; it was interestingly the dogs in this study were from areas (NC or Sweden) with high UV light exposure. In this report the dogs took 1.5–5 months of therapy before the disease was in remission. The drug(s) were then slowly tapered and then all therapy was stopped. The total duration of immunosuppressive therapy varied between 3 and 22 months. These dogs stayed in remission for the entire follow up period (1.5–6 years after treatment). Supporting this finding is a study from the University of Pennsylvania that reported that 10% of their cases went into long-term remission after weaning off medication.6

This study performed at the University of Pennsylvania suggests that dogs with PF survived longer when given antibiotics (usually cephalexin) in addition to their immunosuppressive regimen. This contrasts with the author’s clinical observation that if dogs with PF do develop a concurrent pyoderma it only occurs AFTER being placed on immunosuppressive therapy. Supporting the author’s observations is a study from CSU that reported that there was no difference in survival when antibiotics were part of the initial treatment.

7

In the study from University of Pennsylvania the survival rate was approximately 40% with 92% of the deaths occurring by 1 year. Other researchers have reported having a long-term survival rate of approximately 70%.

Cats may have a better prognosis than dogs with this disease. In the same report from the University of Pennsylvania, only 4/44 cats treated died (from their disease or therapy) during the study period. In the author’s practice, survival at 1 year also exceeds 90%. In addition, a significant number of the cats are eventually able to have all medications discontinued without suffering a subsequent relapse. Treatment Managing any AISD takes frequent rechecks and alertness to complications associated with immunosuppressive therapy such as demodicosis, dermatophytosis and bacterial pyoderma. Interestingly the author has rarely seen a dog with PF that had a secondary pyoderma at initial presentation. It is more common to develop after beginning immunosuppressive therapy. If a patient was controlled and then has a relapse or if the patient has been improving and suddenly worsens, there are 2 possibilities. The PF (which does wax/wane) is flaring up OR that the dog developed a secondary infection due to immunosuppression. If the new lesions are folliculocentric you must also rule the big 3 folliculocentric infections – bacteria, demodex and dermatophyte. Skin scrapings, Wood’s light examination (screening test) and impression smears are the minimum data based that should be performed when a dog is presented with these lesions. Whether you need to do a fungal culture now depends on the how frequently you see dermatophytosis in your practice and what is seen on cytology (acantholytic keratinocytes, cocci, demodex mites). If dermatophytosis is commonly seen

3Marsella R. Canine pemphigus complex: Pathogenesis and clinical presentation. Comp on Cont Ed for the Pract Vet. 22(6):568-572, 2000 4Rosenkrantz WS. Pemphigus foliaceus. In: Griffin CE, Kwochka KW, MacDonald JM, eds. Current Veterinary Dermatology. St. Louis: Mosby-Year Book. 1993: 141-148 5 Olivry T., et al. Prolonged remission after immunosuppressive therapy in 6 dogs with pemphigus foliaceus. Vet Dermatol 2004;15(4):245. 6Gomez SM, Morris DO, Rosenbaum MR, et.al. Outcome and complications associated with the treatment of pemphigus foliaceus in dogs:43 cases (1994-2000). JAVMA 2004;224(8):1312-16. 7 Mueller RS, Krebs I, Power HT, et.al. Pemphigus Foliaceus in 91 Dogs J Am Anim Hosp Assoc 2006 42:189-96

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in your practice, then a fungal culture should be performed. Otherwise a fungal culture and a repeat skin biopsy can be considered second tier tests to be performed if the case doesn’t respond to appropriate therapy (eg antibiotics)

In addition to the treatment options listed below, shampoo therapy should be included for symptomatic treatment of the crusting dermatitis. Pending biopsy results, if intracellular cocci are seen on cytology the author will dispense cephalexin (10-15 mg/# bid-tid), unless there is a suspicion that it is a case of cephalexin induced PF. If only extra cellular cocci are seen, then topical shampoo therapy with an antiseptic (eg chlorhexidene, benzoyl peroxide, etc)

Treatment must be individualized for each patient since there is no “best” treatment that works in all PF patients.8,9

There may be regional differences in how aggressively PF needs to be treated. Some of this may be due to the differences in the gene pools of the patients. But since PF is a sunlight aggravated disease, it also may be related to the differences in sun exposure. Regardless of the locale, sun avoidance should be part of the treatment for PF.

This is why monitoring the progress of the disease closely by PHYSICALLY examine the dog or cat is critical for successful management of PF. It is especially important to recheck the patient prior to any adjustment in medication. When devising a treatment plan, be sure to consider the severity of the disease so that the treatment side effects are not worse than the disease itself.

Because diet has been implicated as a cause of PF (endemic) in humans, the author will review the dietary history and consider dietary modification if the initial response to therapy is poor. The ingredients implicated in human endemic PF contain thiols (eg garlic, onion), isothiocynates (mustard, horseradish), phenols (food additives) and/or tannins (tea, bananas, and apples).

Vitamin E (400-800 IU bid) and essential fatty acids may be used as part of the treatment since these nutrients have anti-inflammatory properties and anti-oxidant activities.

For mild or localized disease, a tetracycline with niacinamide may be used. This is because tetracycline family and niacinamide (T/N) have a variety of anti-inflammatory & immunomodulating properties the combination has been used in treating a variety of immune mediated skin diseases, such as discoid lupus erythematosus, vesicular cutaneous lupus erythematosus (idiopathic ulcerative dermatosis of collies and Shelties), lupoid onychodystrophy, pemphigus erythematosus, German Shepard Dog metatarsal fistulae, sterile panniculitis, sterile periadnexal granulomatous dermatitis (idiopathic sterile granuloma-pyogranuloma syndrome), vasculitis, dermatomyositis and cutaneous histiocytosis10

Traditionally tetracycline was the drug used from the tetracycline family but when it became unavailable then doxycycline was used. But with the increasing occurrence of methicillin resistant staphylococcus infections, using antibiotics for immunomodulating properties has become a concern, this is especially true for doxycycline because it is considered a second line antibiotic in the treatment of bacterial pyoderma in the dog. Studies in humans have failed to show any evidence that sub-antimicrobial doxycycline treatment (20 mg bid for 9 months) exerted an effect on the composition, or doxycycline resistance level, of either the fecal or the vaginal microflora.

. The author may use this combination for any of the previous mentioned diseases if the disease is relatively mild. If any of these diseases fail to respond well to immunosuppressive therapy, T/N may also be added to the therapy in dogs.

11 Additional studies in humans using 40 mg for 16 weeks revealed that a subantimicrobial doxycycline dose (40 mg) had a minor ecological effect on the oropharyngeal and intestinal microflora. 12 A third study in humans revealed that long-term oral administration of 40 mg of doxycycline once daily results in no antimicrobial resistance.13 A study was performed on beagle dogs that revealed that doxycycline at 2 mg/kg daily appeared to be an appropriate subantimicrobial regimen for dogs with periodontitis. 14

8 Olivry T. Canine pemphigus folicaeus: an update on pathogenesis and therapy In: Clinical

It appears as though this dosage may be suitable for long-term treatment of gelatinolytic inflammatory diseases.

Programme Proceedings of the Fifth World Congress 222-227 9 Rosenkrantz WS. Pemphigus: Current Therapy. Vet Dermatol 2004:15[2]:90-98 10 White SD, Rosychuk RAW, Reinke SI, et al. Tetracycline and niacinamide for treatment of autoimmune skin disease in 31 dogs. J Am Vet Med Assoc 1992; 200:1497-1500 11 Walker, C., Preshaw, P. M., Novak, J., Hefti, A. F., Bradshaw, M. and Powala, C. (2005), Long-term treatment with sub-antimicrobial dose doxycycline has no antibacterial effect on intestinal flora. Journal of Clinical Periodontology, 32: 1163–1169. 12 Rashid MU, Panagiotidis G, Bäckström T, et al. Ecological impact of doxycycline at low dose on normal oropharyngeal and intestinal microflora. Int J Antimicrob Agents 2013 Apr; 41(4) :352-7 13 Preshaw PM, Novak MJ, Mellonig J, et al. Modified-release subantimicrobial dose doxycycline enhances scaling and root planing in subjects with periodontal disease. J Periodontol 2008;79:440–452 14 Kim SE, Kim S, Jeong M, Lee Y, Ahn JT, Park YW, Ahn JS, Lee E, Ryu DY, Seo K. Experimental determination of a subantimicrobial dosage of doxycycline hyclate for treatment

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Whether that is true for other inflammatory or immune mediated diseases has not been studied. Based on these 4 studies, the author’s concern about antimicrobial resistance and the lack of any evidence based studies supporting any other dose, the author now will use doxycycline at 2 mg/kg sid (or 1 mg/kg bid). On the limited number of cases that have been treated it appears this dose is effective.

The dosage niacinamide in dogs <10 kg is 250 mg of each, q 8 hours. For dogs >10kg - 500 mg of niacinamide q 8 hours is administered. If there is a clinical response, which may take a few months, the frequency of administration may be slowly decreased (q 6 months or so) Side effects are rare but they include vomiting, anorexia, lethargy, diarrhea and elevated liver enzymes.

Glucocorticoids (GC) are the main stay of therapy for AISD. They may be applied topically or administered systemically depending on the severity of the disease and the amount of the body involved. Since some cats can't metabolize inactive prednisone to the active form, prednisolone, ONLY PREDNISOLONE should be used in cats. In dogs either prednisone or prednisolone may be used. The author has seen cases of feline PF, which were well controlled on prednisolone, but when prednisone was dispensed relapsed, only to go back into remission once the cat was placed back on prednisolone- all at the exact SAME dosage and frequency.

The most potent topical GC (veterinary product) is a product containing fluocinolone acetonide (Synotic®). For localized disease, the author will apply this product bid until clinical remission (not to exceed 21 days) and then tapered slowly over the next few months. Be sure to have the owners wear gloves when applying this product. If this treatment is unsuccessful the one of the following systemic therapies will be instituted.

In dogs with more extensive disease or those that fail topical therapy, prednisone or prednisolone is administered at 1 mg/# bid for 4 days then ½ mg/# bid for another 10 days. The dog is rechecked every 14 days. If the disease is in remission, the dose is decreased 25% at each recheck examination. The author defines “remission” as the absence of any active lesions (no pustules and any crusts that are present are easily removed with the underlying epidermis appearing pink rather than erosive). DON’T TAPER THE DOSE TOO QUICKLY. The goal is to maintain the dog on 0.25 mg/# or less every other day of prednisone/prednisolone. If this is not achievable, then azathioprine is added to the therapy (see below). Some dermatologist will use the combination therapy from the onset, but because at least 75% of the dogs in the author’s practice can be maintained on just GC and there are additional risks and costs associated with this drug the author considers this a second-tier therapy 7. Only if the dog fails to respond to GC, or can’t be managed with every other day administration, will the author add azathioprine to the therapy.

For cats, ONLY prednisolone is used and in fact only prednisolone is stocked in the author’s pharmacy- this is to avoid the inadvertent administration of prednisone to a cat. The dose for cats is 1 mg/# bid for 14 days. From that point forward the management of the cat with prednisolone is the same as the dog. If the disease is not controlled with prednisolone, then CHLORAMBUCIL (see below) is added to the therapy NOT AZATHIOPRINE!!!

If an animal fails to respond to prednisolone other immunosuppressive agents (see below) will be added to the therapy Animals on chronic GC, regardless of dose should have a CBC, serum chemistry profile, urinalysis every 6 months. The

urinalysis is performed to identify proteinuria due to the steroid administration. There is no benefit to doing a urine culture if the dog or cat are asymptomatic since you will identify animals with asymptomatic bacteriuria which doesn’t need/should be treated. There is no evidence to the author’s knowledge that leaving a dog on cyclosporine or steroids with asymptomatic bacteriuria will lead to pyelonephritis. In a consensus statement, the ACVIM states that “treatment may not be necessary in animals that have no clinical signs of UTI and no evidence of UTI based on examination of urine sediment.”15 In humans they don't treat asymptomatic bacteriuria except in pregnant women or type 1 diabetic patients or if undergoing a urologic procedure in which mucosal bleeding is anticipated16

Azathioprine (AZA) is an antimetabolite that is a competitive inhibitor of purine. Purine is necessary for DNA formation, so in the presence of AZA, defective DNA is formed preventing cell replication. It has a lag phase of four to six weeks before it reaches its full effectiveness. The drug is administered concurrently with GC. The initial dose of azathioprine is 1.0 mg/# sid. Once remission is achieved, and the dog is either off GC, or the lowest dose of GC has been obtained, AZA is then tapered every 60-90 days. Usually the author will decrease the frequency, not the dose of azathioprine, first decreasing it to every other day and then if the disease is still in remission, to every 72 hours. A CBC, platelet count, serum chemistry profile is performed every 14 days for 2 months, then q 30

. In humans, no recommendation can be made for screening for or treatment of asymptomatic bacteriuria in renal transplant or other solid organ transplant recipients.

of periodontitis in Beagles Am J Vet Res. 2013 Jan;74(1):130-5 15 Weese, J. Scott, et al. "Antimicrobial use guidelines for treatment of urinary tract disease in dogs and cats: antimicrobial guidelines working group of the international society for companion animal infectious diseases." Veterinary medicine international 2011 (2011). 16 Nicolle, Lindsay E., et al. "Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults." Clinical Infectious Diseases (2005): 643- 654.

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days for 2 months then q 3 months for if the dog is on azathioprine. Potential adverse effects include anemia, leukopenia, thrombocytopenia, hypersensitivity reactions (especially of the liver) and/or pancreatitis. AZA should not be used in cats- it may cause irreversible bone marrow suppression.

Chlorambucil (CAL) is used in cats and in dogs who failure to respond to azathioprine or can’t tolerate it. The protocol/precautions/monitoring for CAL is the same as w/AZA. The induction dose is 0.1-0.2 mg/KG

Cyclosporine A (CSA), a calcineurin inhibitor, has been used orally at a dose of 5 mg/kg sid in cases of PF with poor results in dogs

/day. Note it too may have a 4-6-week lag effect.

17. Recently the author has used CSA at 5 mg/kg sid- bid with success either as monotherapy or as steroid sparing agent. There have been anecdotal reports of successful treatment of PF in cats (especially nail bed form) with CSA. Recently topical tacrolimus has been reported to be effective in the treatment of facial PF and PE18

Sulfasalazine (SSZ) is a sulfa that has both anti-inflammatory and/or immunomodulatory properties due to its prostaglandin synthetase and leukotriene inhibition. In the past it has been used for the treatment of colitis but more recently it has been used for neutrophilic vasculitis. SSZ is metabolized by colonic bacteria to 5-aminosalicylic acid (5ASA) and sulfapyridine (SP). SP is well absorbed, metabolized in the liver, and excreted by the kidney while 5-ASA is much less well absorbed. Because SSZ is metabolized to aminosalicylic (“aspirin”) this drug should be used cautiously in cats. The biggest concern with this medication is the possibility of developing irreversible keratoconjunctivitis sicca. This appears to be an idiosyncratic reaction that occurs more in smaller dogs but may occur in any dog. It is essential that you warn the owner that if the eyes become red or they notice an ocular discharge or squinting to contact you immediately so that you can do tear testing. Other side-effects associated with this drug include anemia, KCS and hepatotoxicity so a CBC, serum chemistry profile and Schrimer tear test are performed every 14 days for 2 months, then q 30 days for 2 months then q 3 months for if the dog is on SZA. In cases of neutrophilic vasculitis that fail SZA treatment w/dapsone may be effective, however, dapsone appears to be more toxic than SZA. The dose is 20-50 mg/kg tid (maximum 1 gm/dose), usually beginning with 20-30 mg/kg tid. Once the disease is in remission, the dose is slowly tapered

. The author has limited experience with this product.

Specific treatment approach-

If the disease is not responding to the above treatment, CONFIRM that the diagnosis is correct (be sure to have ruled out dermatophytosis, demodicosis and bacterial pyoderma) then, changing to either dexamethasone or triamcinolone may be helpful. Use 0.05-0.1 mg/# bid of either drug, as the starting dose, and then taper as previously discussed.

for mild cases of facial PF (or cases of pemphigus erythematosus), a topical glucocorticoid is used and/or T/N. For generalized forms, or in cases with severe facial and/or footpad involvement, prednis(ol)one should be used as described above. If the disease is in remission at each recheck, the steroids are tapered as previously described. If the disease is not in remission at the first 14 day recheck or it can’t be kept in remission with steroids at a dose of <0.25 mg/# q 48 hrs, then either azathioprine (dogs) or chlorambucil (cats) is added to the treatment.

As a “rescue” treatment for refractory cases of PF, high dose GC pulse therapy has been reported to be successful. Pulse therapy is followed by ½ mg/# bid of prednisolone and then taper as described previously. There are 2 protocols for pulse therapy:

1. 11 mg/kg of methylprednisolone sodium succinate (mixed w/250 ml of D5W) IV sid x 3-5 days 19

2. 10 mg/kg once daily for 3 days of prednisone ORALLY

20

Discoid lupus erythematosus (DLE) The approach to diagnosing DLE is the same as PF- signalment, detailed history, physical findings, histopathology changes and response to therapy. In the dog, DLE is the 2nd most common autoimmune skin disease1. The author has never recognized it in a cat. It has been suggested that there is no age predilection, but in the author’s experience it seems to be more common in young to middle aged-dog. Collies, Shelties, German shepherd dogs, Siberian huskies and Brittany spaniels are at risk breeds1.

Clinical findings include depigmentation, erythema, erosions, crusts and alopecia. When the nasal planum is first affected there is loss of its normal cobblestone appearance and it develops a slate gray appearance. Depigmentation, erythema, erosions and crusts

17 Olivry T, Rivierre C, Murphy KM. Efficacy of cyclosporine for treatment induction of canine pemphigus foliaceus. Vet Rec 2003;152(2):53-54 18 Griffies JD, Mendelsohn CL, Rosenkrantz WS et al Topical 0.1% tacrolimus for the treatment of discoid lupus erythematosus and pemphigus erythematosus in dogs. Veterinary Dermatology, 2002; 13: 211–229 19 White SD, Stewart LJ, Bernstein M. Corticosteroid (methylprednisolone sodium succinate) pulse therapy in five dogs with autoimmune skin disease. J Am Vet Med Assoc 1987;191(9):1121-1124. 20 Olivry T, Murphy KM, Bizikova P. Immunosuppression of canine pemphigus foliaceus with traditional vs. pulse oral glucocorticoid protocols: preliminary comparisons of treatment outcome (abstr). Vet Dermatol 2008;19:51.

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may occur over time. DLE usually begins on the nasal planum and may process to involve the bridge of the nose. It may also involve the lips, periocular region, pinnae, and genitalia. Dogs affected with DLE are not clinically ill.

Differential diagnoses may include mucocutaneous pyoderma

A better way to approach cases of nasal dermatitis that presents clinically as the “typical” DLE is to recognize that is a reaction pattern rather than a disease. This reaction pattern (lymphoplasmacytic lichenoid nasal dermatitis) may be antibiotic responsive (MCP) or may require immunomodulating therapy (DLE). Since the biopsy findings will be identical in both cases as will the physical findings, if “DLE” is a differential, a 30-day trial of a cephalosporin prior to biopsy should be administered.Error! Bookmark not

defined.

, pemphigus complex, cutaneous drug reaction, erythema multiformae, cutaneous lymphoma, uveodermatologic syndrome, SSC, solar dermatitis/collie nose and systemic fungal infections., ,ucocutaneous pyoderma (MCP) (the author feels a better name is “antibiotic responsive dermatitis” since bacteria are not seen histologically) is a crusting disease that may affect the lips, nasal planum (exclusively), the bridge of the nose, periocular region, genitals or anus. Clinically it is indistinguishable from DLE. There is no identifiable cause for this disease and the diagnosis is based on the signalment (adult dog, most commonly in German Shepard Dogs (or mixes)), clinical appearance and distribution of the lesions and most importantly response to antibiotic therapy. In the past MCP was differentiated from DLE based on histopathologic findings. DLE was diagnosed when a lichenoid lymphocytic to lymphoplasmacytic interface dermatitis with hydropic degeneration and/or individual necrotic keratinocyte involving the basal cell layer, pigmentary incontinence and a thickened basement membrane was present. Mucocutaneous pyoderma would be diagnosed histologically when a lichenoid plasmacytic to lymphoplasmacytic infiltration was present without an interface change and without basal cell damage. HOWEVER, this criterion has been called into question with a study that reported that histologically mucocutaneous pyoderma and DLE are indistinguishable! In that study, dogs were separated, based on histologic findings, into 3 groups, ones with lymphocytic lichenoid interface dermatitis with hydropic degeneration; ones with plasmacytic lichenoid dermatitis, and lastly ones with a mixture of the first 2 patterns- lymphoplasmacytic lichenoid, interface dermatitis with hydropic degeneration. The authors then evaluated whether the group responded to antibiotics or immunomodulating therapy. There was no statistical difference when histopathologic features were compared between the 2nd and 3rd groups! The author now believes that all cases of canine nasal dermatitis should have a 30-day course of cephalexin prior to immunomodulating therapy- in fact prior to biopsy a 3-4-week course of a cephalosporin is appropriate and may establish a diagnosis without needing to biopsy the lesion!

Diagnosis Dogs with DLE/MCP are clinically healthy and are normal hematologically and serologically (including a negative ANA). Historically the histopathologic changes consistent w/DLE/MCP included a lymphocytic to lymphoplasmacytic lichenoid interface dermatitis w/hydropic degeneration of basal keratinocytes. Scattered apoptotic keratinocytes may also be present. Failure to respond to a 30-day course of a cephalosporin is also required to differentiate the antibiotic responsive form vs the immune mediated responsive form. Treatment When treating dogs with DLE it is important to avoid aggressive therapy since it is primarily a cosmetic disease. Occasionally the lesions seem to bother the dog because of pruritus. It is therefore important to treat cases in proportion to the severity of the symptoms. Be sure that the therapy is not worse than the disease. The author treats this disease in a stepwise progression with each step added to the previous therapy except where noted. The steps are as follows: Cephalexin 10-15 mg/# bid- tid for 30 days (since DLE and MCP are indistinguishable); if the dog does not respond to the cephalexin, and a biopsy has not been performed, then a nasal biopsy needs to be done. If the diagnosis of LPLD is confirmed but the dog has not responded to cephalexin, then the cephalexin is discontinued and the following treatment is begun, sun avoidance, sun screens and vitamin E and omega 3 fatty acids. Depending on the severity, either topical steroids (if localized and very mild) or oral niacinamide and doxycycline (mild to moderate disease) are begun as previously described. If after 60 days, of using topical therapy the dog doesn’t respond to this treatment and the next step is to try oral niacinamide and doxycycline. If after 60 days, there is no response, or from the onset the disease is moderate to severe, then stop the doxycycline and niacinamide (if receiving it) and begin systemic prednisolone (anti-inflammatory doses) that is slowly weaned over a period of months to achieve the lowest possible dose. If that is ineffective, first confirm the diagnosis before going to immunosuppressive therapy. If the diagnosis is confirmed and the previous therapies are ineffective, then begin treatment as you did for pemph

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What’s New about Demodicosis in Dogs? Paul Bloom, DVM, DACVD, DABVP Allergy, Skin, and Ear Clinic for Pets

Livonia, MI

The mite Demodex spp., which belongs to the Class Arachnida, Order Acarina, lives in hair follicles of all mammals. Demodex canis is the dog follicular mite while in cats it is D. felis (in cats). In dogs Demodex injai is found within sebaceous glands and ducts. D. cornei and gatoi live in the stratum corneum of dogs and cats respectively . They complete their life cycle in about 30 days and the adults will survive for about 21 days. The life cycle of demodex is that an egg (fusiform shaped) develops into 6 legged larvae that then develops into an 8 legged nymph (differentiated from an adult by it lack of an “armor-like” breastplate). This nymph then matures into an adult.

Neonates are thought to acquire mites from their dam/queen via direct skin-to-skin contact during nursing. Direct transmission, other than from dam/queen to the pup/kitten, only occurs with D. gatoi in cats.

In a normal animal the mite does not cause any symptoms. However in some dogs it may cause either localized or generalized disease. There is no universally accepted definition of localized vs generalized disease but recently it has been suggested that with localized disease there are no more than four lesions with a maximum diameter of to 2.5 cm .. Demodicosis is also categorized based on age of onset- those less than 12 months of age (18 months in large or giant breeds .) are considered juvenile onset while older dogs are considered adult onset .. The prognosis is excellent for the localized form either in puppies or adult dogs while the generalized form carries a more guarded prognosis.

Demodex causes disease when there is an overgrowth of the commensal mites either associated with a genetic defect (juvenile onset) or immune suppression (adult onset). In the adult dog, hyperadrenocorticism (iatrogenic or spontaneous), hypothyroidism, leishmaniasis, or chemotherapy are the most identifiable causes of adult onset generalized demodicosis .. Note that contrary to what was previously taught, “dogs with adult onset demodicosis have cancer or some other very serious life threatening disease”, in the author’s experience, idiopathy is the rule not the exception. In a retrospective study, less than 50% of the adult onset generalized demodicosis cases had an identifiable underlying cause. .

The lesions associated with demodicosis include non pruritic alopecia, scaling, follicular casts, follicular papules/pustules (if a secondary bacterial infection is present), comedones, crusts, erythema, hyperpigmentation, and lichenification. Pruritus is variable but is mild except in cases with a secondary bacterial folliculitis.

Lesions frequently involve the face and/or forelegs and may progress to affect other body sites. Since the lining of the external ear canal is epidermis, demodicosis may cause a bilateral ceruminous otitis externa. As the disease progress dogs may develop a deep bacterial folliculitis and furunculosis and draining tracts. In those cases peripheral lymphadenopathy, lethargy and fever are commonly present. In some patients their presentation is exclusively pododemodicosis. In these cases a deep bacterial folliculitis and furunculosis is frequently present and the feet are swollen and painful leading to lameness.

In contrast to D.canis and cornea, D. injai tends to be associated with a greasy hair coat on the dorsum of the trunk. Many times alopecia is not present and only a low number of mites may be found on skin scrapings. It has been reported that terriers, especially wire haired fox terrier and West Highland white terrier, are at risk of developing this form of demodicosis. ., ., .

Since demodicosis is a folliculocentric disease it will look identical to follicular lesions caused by a bacterial pyoderma and dermatophytosis. Because of the similarity in appearance these folliculitides, clinical appearance is not an acceptable method to rule-in or rule-out demodicosis. Superficial (for D.cornea) and deep skin scrapings (for the other species of demodex) are the most reliable and cost effective method to diagnose demodicosis. In medium or long haired dogs, clip a small “window” in the hair coat to get easier access to the skin and to prevent the loss of the scraped material into the surrounding hair. Skin scrapings are performed with a No. 10 scalpel blade after dulling the blade on the frosted end of the microscope slide.

To perform a deep skin scraping it is best to squeeze the skin prior to and during the scraping to push the mites out of the hair follicles. Scrape the skin in the direction of hair growth until capillary bleeding occurs. When lesions are present on the face or paws the animal should either be sedated before scraping or a hair pluck/trichogram may be performed in an awake animal. Hair plucks are performed with mosquito hemostat forceps that grasp and pull out hairs. It is best to collect hairs from the leading edge of the lesion. To increase your yield, squeeze the skin as you are plucking the hairs and be sure to collect a large number of hairs (50–100). Take the collected hairs and lay them on a slide containing a drop of mineral oil and add a cover slip. Sample multiple sites in each patient. Trichograms, or in cases of pustular demodicosis examination of the exudate, will detect Demodex mites in about 85% and 100% of dogs respectively with demodicosis. If the trichogram is negative but other sites are positive, sedation and skin scrapings of the feet should be performed since the mites may be present even if the feet appear alesional. It has been the author’s experience that pododemodicosis, if present, is usually the hardest component of generalized demodicosis to resolve and so should be used as one of the monitoring sites.

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Recently it has been reported that applying tape to a skin lesion and then squeezing the skin is as an effective way to identify demodex mites in dogs. A study was performed to confirm this observation. Specifically the study was to evaluate and compare the sensitivities of acetate tape impression deep skin scraping for the diagnosis of canine demodicosis. They concluded that squeezing the skin followed by acetate tape prep was found to be as sensitive as deep skin scraping for the diagnosis of canine demodicosis. Unfortunately the author has not had the same experience. So if you want to do it as a screening test, in difficult to handle dogs or sensitive locations on the dog, be sure to follow it with deep skin scrapings (with sedation if needed) if the tape prep is negative.

Be sure to collect samples from multiple sites and note the site that the sample is collected from since localized disease is treated differently than generalized disease. When examining the slides you need to evaluate for the approximate number of each stage that is present (eggs, larva, nymph and adults). Also note how many of the mites alive vs are dead. These results will be important to compare to future skin scrapings as you are monitoring the dog’s response to therapy. With effective treatment a decreasing number of immature mites and the disappearance of eggs should occur. The number of live mites should also decrease. In all cases of demodicosis be sure to perform an examination of an otic swab. Otodemodicosis is identified by collecting roll swabs from each ear using a cotton swab that has been dipped in mineral oil. The sample collected is place onto a glass slide that also has a drop of mineral oil on its surface. A cover slip is applied and then the sample is examined. .

If samples are collected as described it would be extremely uncommon to miss the presence of demodex mites. Occasionally this may occur, even with properly performed skin scrapings and hair plucks, if the dog has scarring due to chronic disease or because of the thickness of their dermis (therefore the deeper depth of their hair follicle making expulsion of the mite more difficult) (i.e. Shar-Peis)Error! Bookmark not defined.. If demodicosis is strongly suspected, but no mites are found on skin scrapings and hair plucks, skin biopsy is recommended to rule in or rule out their presence.

How to treat a dog with demodicosis depends on whether it is localized or generalized. In cases of localized demodicosis, less is best. In many cases, especially juvenile onset, the disease will spontaneously resolve within a couple months. Miticidal therapy is not required unless the disease becomes generalized. Since the progression of localized disease to more generalized form is not influenced by whether the localized form is treated or not, treatment of localized disease is not necessary. However, in the author’s practice “benign” topical treatment is prescribed. This is done so that if the disease does progress, the owner feels that something had been done to try to prevent for occurring. Topical therapy with benzoyl peroxide shampoo and/or gel can theoretically be helpful due to its antibacterial properties and follicular flushing activity. Due to its suppressive effect on the immune system you should avoid using any steroid containing product (topically or systemically) in patients with demodicosis (localized or generalized). Ensuring a proper diet and intestinal deworming program should also be part of the treatment of dogs with demodicosis. To evaluate the effectiveness of treatment, a follow up examination, including repeating skin scrapings, should be performed in 30 days.

Treating a dog with generalized demodicosis requires much more aggressive therapy than localized. Multimodal therapy, a common approach that is used to treat other diseases (eg arthritis, atopic dermatitis or congestive heart failure) will be necessary when treating generalized demodicosis. Acaricidal therapy and treating secondary bacterial infections if present is required for both adult and juvenile onset disease. In adult onset cases attempts should be made to identify and treat the underlying systemic disease.

Dogs with juvenile onset generalized demodicosis, in addition to the above mentioned treatment should be neutered. This is important not only to prevent the propagation of this genetic defect but also estrus may trigger recurrence of clinical disease ..

As mentioned previously, in cases of adult onset generalized demodicosis attempts should be made to identify and treat the underlying disease. Evidence shows that successful treatment of an underlying cause increases the likelihood that adult onset demodicosis can be cured.. In the author’s practice, diagnostics performed in cases of adult onset generalized demodicosis include a CBC, serum chemistry profile and a urinalysis. Depending on the age of onset, abdominal ultrasound and thoracic radiographs may be included in the minimum data base. Because of the influence that bacterial pyoderma or generalized demodicosis has on evaluating thyroid or adrenal gland disease, evaluation of these organs is delayed until any secondary bacterial infection has been resolved and the demodicosis has improved or is in remission.

Specific treatment of generalized demodicosis is outline in table 1. This table is the result of the most recent consensus guidelines written by an international group of dermatologists. The author has indicated in bold the approach used in his practice. However other therapies have come to the forefront since these guidelines have been published. Specifically the isoxazoline class of ectoparasiticides (fluralaner, afoxolaner and , sarolaner). These products have a broad spectrum of insecticidal and acaricidal activity. Besides their efficacy against fleas and ticks, there are limited studies reporting the effectiveness of these drugs against a variety of mites including demodex, sarcoptes and otodectes. Given their ease of use and safety many practitioners are using these products as a first line treatment for canine demodicosis. The following is the most current information concerning these products effectiveness against canine demodicosis

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Fluralaner (Bravecto)- a study was done in 2015 that compared the efficacy of oral Bravecto™ (fluralaner) with the efficacy of topically applied Advocate/Advantage multi® (imidacloprid/moxidectin) for the treatment of generalized demodicosis (GD) in dogs21

Also in 2015 another study evaluating the efficacy of fluralaner for the treatment of canine demodicosis was reported

. In this study 16 dogs, all over 12 months of age that had been diagnosed with generalized demodicosis, were randomly assigned to being treated with either 1 dose of fluralaner or 3 doses (q 28 days) of imidacloprid/moxidectin. Dogs were examined (and had skin scrapings) at the beginning of the study and then every 28 days for 12 weeks. The results revealed a 99.8% reduction in mite numbers on Day 28 and 100% on Days 56 and 84 after 1 dose of fluralaner. Mite numbers in the dogs treated topically on three occasions at 28-day intervals with imidacloprid/moxidectin were reduced by 98.0% on Day 28, by 96.5% on Day 56 and by 94.7% on Day 84. The biggest drawback in this study was that the dogs were only followed up for 12 weeks so that we don’t know the relapse rate. Since juvenile onset GD has a higher success rate than adult onset GD it would have been beneficial to stratify the dogs into 2 groups based on age of onset.

22

Because fleas are a concern in the authors practice and many of these dogs need frequent bathing initially the author used a combination of ivermectin daily and 1 dose of Bravecto every 3 months. Note that it has been shown that the concurrent administration of fluralaner and ivermectin (0.3 mg/kg) does not alter the pharmacokinetics of either compound . Based on the plasma pharmacokinetic profile and the clinical observations, there is no evident interaction between fluralaner and ivermectin, and co-administration does not increase the risk of ivermectin associated neurotoxicity. The response to this combination was less than that of the studies previously discussed so this practice has been discontinued. It is theorized that because Bravecto is a selective inhibitor of arthropod γ-aminobutyric acid- and l-glutamate-gated chloride channels and ivermectin’s mechanism of action is that it enhances the effects of

. One hundred sixty three dogs of different breeds with GD. Animals were divided into two age groups based on age at presentation: group one, 2–18 months (62.6%) and group two, over 2 years of age (37.4%). Dogs were treated with fluralaner (25 mg/kg) orally, twice three months apart. Skin scraping and/or hair plucking were performed 1, 2 and 3 months after the first fluralaner administration. The overall response to therapy was 100%. The majority of dogs (87.1%) had negative skin scrapings at the 30 day exam (note that this was an abstact so they didn’t state if the negative skin scraping was only in reference to live mites or to any stage or fragment of a mite). Twenty-one individuals (12.9%) (all belonging to group two) needed two months after the initial fluralaner administration to achieve negative scrapings. As with the previous study, no long term follow up was performed so relapse rate is unknown. Note even though the drug insert states that the dog needs to be > 6 months old to administer fluralaner the label in Europe states it should not be used on puppies less than 8 weeks old and /or dogs weighing less than 2 kg. The FOI sheet states that it is not a safety issue, that the margin of safety in 8 week old puppies is adequate but substantial evidence to support a12-week duration of effectiveness in dogs less than 6 months of age has not been demonstrated.

glutamate at the invertebrate-specific glutamate-gated chloride channel, with minor effects on gamma-aminobutyric acid receptors.

Afoxolaner has also been studied for treatment of generalized demodicosis. A 3 month study was performed in which 16 dogs with generalized demodicosis were divided into 2 treatment groups.23

21 Fourie, J. J., et al. (2015). "Efficacy of orally administered fluralaner (Bravecto) or topically applied imidacloprid/moxidectin (Advocate(R)) against generalized demodicosis in dogs." Parasit Vectors 8: 187

In the first group the eight dogs were treated w/afoxolaner (NexGard® ) at the label dose but given every 14 days (days 0, 14 and 28) and then 1 monthly treatment (day 56). The other 8 dogs were treated with topical imidacloprid/moxidectin (Revolution/Advocate®, Bayer) at the same treatment interval. The mite reduction is listed below

22 Karas-Tecza J, Dawidowicz J Efficacy of fluralaner for the treatment of canine demodicosis , Veterinary Dermatology,2015; 26, 307 23 Beugnet F, Halos L, Larsen D, de Vos C: Efficacy of afoxolaner for the treatment of canine generalised demodicosis. Parasite 2016 Vol 23 (14) pp. 1-8.

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There were statistically significantly fewer mites found on Days 28, 56, 84 in the afoxolaner group. The authors concluded that afoxolaner given orally every 2 weeks for 3 treatments, then monthly is highly effective against generalized demodicosis, within 2 months BUT a few things to point out= The study states that On Day 84, no live mites were recorded for any dog in the Nexgard_-treated group- the key word is LIVE mites. This is apparent because later in the article it states that a significant portion of the afoxolaner treated dogs (7/8) had no mites in their skin scrapings at Day 84. So I interpret this to mean that at day 84 there were still mites present on the 1 dog treated with Nexgard, perhaps dead or maybe fragments of the mite. This impression is further supported by the statement that “in the present study, seven out of eight NexGard_-treated dogs had two successive negative skin scrapings at a one-month interval, indicating that treatments at appropriate intervals can provide remission of the disease”. So the key to this is that there needs to be 2 consecutive negative skin scrapes to declare the demodicosis in remission so not all dogs were in remission. Other issues are they didn’t say how old the dogs the dogs were other than > 6 months of age – it is important to stratify the groups into adult and juvenile onset since the later is in general more difficult to get in remission and in fact juvenile onset generalized demodicosis may self cure. They didn’t state if any of the dogs had previously been treated for demodex- only that they had not received an ectoparasiticide or macrocyclic lactone for at least 12 weeks prior to Day 0, as far as it could be reasonably established by verbal communication with the owners. Lastly they didn’t state how long the dogs had generalized demodicosis before entering into the study..

There was another study24 using afoxolaner for the treatment of generalized canine demodicosis that involved 4 dogs- ages 8 months to 10 years of age. All dogs had been affected for at least 2 months. These dogs were treated at label dose on day 1 then at 4 weeks and 8 weeks after the initial dose. There was a reduction of live mites by week 4. All 4 dogs were negative for live mites 8 and 12 wks after treatment. The problems with this study are the same as the previous study using afoxolaner other than it did state that the dogs were affected for at least 2 months with generalized demodicosis. The author reported that at the time of preparation of the paper, 6 months after the initiation of treatment with afoxolaner, all four4dogs remain clinically free from clinical signs of demodicosis. The problem is that it has been shown that clinical remission is not the same as parasitic remission – the later be required to state that the dog is in remission and can only be determined by skin scrapings.25

Sarolaner was recently studied

Note that the product insert contains a caution about use in dogs with a history of seizures.

26

24 Chavez, F: Case Report of Afoxolaner Treatment for Canine Demodicosis in Four Dogs Naturally Infected with Demodex Canis Journal of Applied Research in Veterinary Medicine, The 14(2):123-127-January 2016

where it was compared to topical imidacloprid-moxidectin for the treatment of generalized demodicosis. Sixteen dogs over the age of 6 months were entered into the study. The dogs were divided into 2 groups- group 1 was treated w/sarolaner orally on days 0, 30 and 60 while the other group was treated with the topical imidacloprid-moxidectin weekly. Efficacy for sarolaner based upon live mite counts was 97.1% and 99.8% on Days 14 and 29, respectively and 100% on all subsequent days. For the topical therapy group efficacy based upon live mite counts was 84.4%, 95.6% and 99.7% on Days 14, 29, and 44, respectively and 100% on all subsequent days. Limitations of this study were they only followed up for 30 days after the last treatment so we don’t know the relapse rate. Since juvenile onset GD has a higher success rate than adult onset GD it would have been beneficial to stratify the dogs into 2 groups based on age of onset. They didn’t state if any of the dogs had previously been treated for demodex and lastly they didn’t state how long the dogs had generalized demodicosis before entering into the study..

25 Medleau, L., Ristic, Z. And Mcelveen, D. R. (1996), Daily Ivermectin For Treatment Of Generalized Demodicosis In Dogs. Veterinary Dermatology, 7: 209–212 26 Six, R. H., et al. (2016). "Efficacy of sarolaner, a novel oral isoxazoline, against two common mite infestations in dogs: Demodex spp. and Otodectes cynotis." Vet Parasitol 222: 62-66.

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Two studies have evaluated the efficacy of doramectin in the treatment of generalized demodicosis.27,28 Both studies used a dose of 0.6 mg/kg body weight given every 7 days; in the first study the drug was administered by subcutaneous injection to 23 dogs and in the second it was administered orally to 29 dogs. Administration subcutaneously appeared to be marginally more effective but the cohort size in each case was relatively small and thus caution needs to be exercised in the interpretation of results. It has been shown that subcutaneous injection of doramectin results in slower drug absorption and greater bioavailability of the drug compared to oral administration29 A study therefore was performed in which 400 dogs with generalized demodicosis were treated using weekly s.c. injections of doramectin at a dose rate of 0.6 mg/kg body weight.30

It is interesting that when you look at any of the treatment protocols it seems none are 100% effective so the bottom line is to start with the easiest, safest and least expensive treatment and if that is ineffective to try another treatment.

Results revealed that 66.7% of the dogs over the age of 4 achieved remission by having two consecutive negative skin scrapings while the overall remission rate based on intent to treat was 86.3% This may be a good option for those dogs in which people are unable to give oral ivermectin due to the taste of the ivermectin.

Remember, regardless of the selected treatment, miticidal therapy should be followed up with skin scrapings since dogs may look normal clinically but still have active disease (as determined by the presence of mites on skin scrapings) . treatment must be continued beyond clinical resolution. Parasitic cure is defined as multiple negative skin scrapings, including lack of dead or fragmented mites, on 3 consecutive monthly visits. Skin scrapings should be used to determine the therapeutic end-point. This end point is reached when the dog looks normal clinically and skin scrapings have been performed monthly ALL areas that have EVER been positive on skin scraping and have been negative for 3 consecutive visits. If during a visit the skin scraping is positive, it is important to compare the number of live and dead mites and the number of each stage of the mite life cycle to the previous visit. An indication of effective treatment is that during therapy the number of live mites found on skin scrapings and the number of immature mites should be reduced from the previous visit. If this doesn’t occur, therapy should be re-examined and possibly changed.

Diagnosis and treatment of demodicosis is an important concept that all small animal practitioners should feel comfortable with. By taking time to thoroughly examine and evaluate the dog, and spending time explaining the disease to the owner, the outcome will usually be successful. Table 1- Summarized treatement of canine demodicosis * (Items in bold are the author’s preferences) Treatment of a dog with severe generalized disease

1 Perform cytology and if there is evidence of a deep bacterial skin infection or the dog has been treated previously with antibiotics a bacterial culture and sensitivity. With inflammatory cells and bacteria present, appropriate oral antibiotic therapy is required. 2 Use topical therapy with chlorhexidene or benzoyl peroxide shampoo weekly to possibly twice weekly. (Unless amitraz is being applied) 3 There are several treatment options for the treatment of canine demodicosis. The best option will depend on the legalities pertaining to the use of veterinary pharmaceutical products in the country of residence, the finances of the owner and the clinical situation. However, independent of the treatment specifics the dog should be neutered because dogs in need of mite treatment should not be allowed to breed, and the disease may relapse in cycling bitches.

a. Ivermectin at an oral dose of 0.3–0.6 mg⁄ kg (0.4 mg/kg) or moxidectin at 0.2–0.5 mg⁄ kg p.o. daily are further options. Note- many herding breed dogs have a genetic predisposition to adverse drug reactions involving ivermectin due to a defective MDR-1 gene. This gene is responsible for pumping drugs out of the mammalian’s brain. When this gene is defective, drugs accumulate in the brain leading to adverse events. Gene testing for the defect can help eliminate at risk dogs but there are a number of dogs with adverse effects to ivermectin and an intact MDR-1 gene due to alternative mechanisms. Thus adverse events may still occur in dogs w/normal MDR-1 genes. Therefore with both drugs, a gradual increase from an initial dose of 0.05 mg⁄ kg to the final dose (of 0.4 mg/kg) within a few days is recommended to identify dogs that cannot tolerate those drugs. Monitoring for neurological adverse effects should occur throughout the course of therapy. Ivermectin is the treatment of choice in the author’s practice.

b. Amitraz weekly or every 2 weeks in a concentration of (0.025–0.06% can be used. Dogs with a medium to long hair coat need to be clipped, and skin should stay dry between rinses to avoid washing off

27 Murayama N, Shibata K, Nagata M. Efficacy of weekly oral doramectin treatment in canine demodicosis. Vet Rec 2010; 167:63–64. 28 Johnstone IP. Doramectin as a treatment for canine & feline Demodicosis. Aust Vet Pract 2002; 32: 98–103. 29 Gokbulut C, Karademir U, Boyacioglu M, et al. Comparative plasma dispositions of ivermectin and doramectin following subcutaneous and oral administration in dogs. Vet Parasitol 2006; 135: 347–354 30 Hutt, J. H., et al. (2015). "Treatment of canine generalized demodicosis using weekly injections of doramectin: 232 cases in the USA (2002-2012)." Vet Dermatol 26(5): 345-349, e373.

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the drug. Rinsing should be performed in well-ventilated areas. The author only uses this therapy if the dog has failed to respond to ivermectin or is a herding breed. Please note that amitraz is EPA registered and doesn’t EVER allow any off label use (label states 1 bottle/2 gallons every 14 days)

c. Milbemycin oxime may be administered orally at a dose of 1–2 mg⁄ kg ⁄ day. Moxidectin orally (see below) is in the milbemycin family, is much less expensive than milbemycin, and is used if the dog fails to respond to ivermectin (again a non herding breed)

d. Moxidectin as a spot-on in combination with imidacloprid may be used weekly.

e. Doramectin weekly at 0.6 mg⁄ kg p.o. or SQ is a possible treatment. A gradual increase from an initial dose of 0.1 mg⁄ kg to the final dose seems prudent to identify dogs that cannot tolerate the drug and will show neurological adverse effects.(SEE PREVIOUS DISCUSSION ABOVE ABOUT PO VS SQ)

This spot-on formulation has a markedly higher success rate in dogs with milder disease or juvenile onset

So to summarize- this report states that “There is good evidence for the efficacy of weekly amitraz rinses and daily oral macrocyclic lactones such as milbemycin oxime, ivermectin and moxidectin for the treatment of canine demodicosis.” Other recommendations are

Dogs should be evaluated monthly, and treatment should be continued until 3 consecutive visits with multiple negative skin scrapings have been achieved. Treat secondary bacterial infections Factors predisposing to demodicosis, such as malnutrition, endoparasites, endocrine disease, neoplasia and chemotherapy, should be identified and corrected to maximize response to therapy. * Modified from - Mueller, R. S., Bensignor, E., Ferrer, L. et al Treatment of demodicosis in dogs: 2011 clinical practice guidelines. Veterinary Dermatology, 2012; 23: 86

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Beyond Allergies: Diseases of the Nasal Planum

Ashley Bourgeois, DVM, DACVD Animal Dermatology Clinic

Milwaukie, OR

The nasal planum is a unique area of the skin. A nose print is so unique it can be used as a “fingerprint” to distinguish individuals. The epidermis of the nasal planum is very thick (up to 1.5 mm) when compared to other skin (between 0.1 to 0.5 mm). One very important distinguishing feature of the nasal planum is the lack of glands and hair follicles.

Diseases affecting the nasal planum appear very similar and can clinically be indistinguishable from each other. Histopathology is a key diagnostic tool for differentiation of these diseases. Majority of diseases of the nasal planum (especially immune mediated) are described in dogs compared to cats. It is much more common for cats to have a neoplastic process on the nasal planum (particularly squamous cell carcinoma) than any other etiologic categories. Immune mediated diseases

Discoid lupus erythematosus This non-systemic disease is photo aggravated so lesions tend to occur in areas of the body with more sun exposure. This can also lead to waxing and waning of lesions.1,2 Predisposed breeds include Australian shepherds, collies, Shetland sheepdogs, Siberian huskies, border collies and German Shepherds.

Lesions usually occur on the dorsal nasal planum, junction of the nasal planum to the haired skin and ventral aspects of the alar folds. Early lesions appear as loss of normal cobblestone texture and pigment (slate gray or bluish color change). Erosions, ulceration and crusting develop in chronic cases. Lesions can spread to the dorsal muzzle, eyelid margins and concave pinnae. Cases with unusual distributions such as distal limbs, footpads and perianal region have been reported.3

Histopathology reveals an interface dermatitis with hydropic degeneration of basal cells, pigmentary dermatitis, apoptotic keratinocytes and thickening of the basement membrane zones.

Treatment includes sun avoidance, doxycycline/minocycline and niacinamide, essential fatty acids, corticosteroids and 0.1% tacrolimus.2

Pemphigus erythematosus/Foliaceus These two forms of the pemphigoid complex are clinically indistinct from one another when solely affecting the nasal planum. Many clinicians even consider these pathologies different stages/severities of the same disease.4 Predisposed breeds include Akitas, Chows, Dachshunds, Newfoundlands, Doberman pinschers, cocker spaniels and Australian sheepdogs.

Clinical signs often include nasal depigmentation with ulcerations and crusting over the dorsal muzzle and extending to the nasal planum. Classic signs for pemphigus foliaceus may also be present such as pustules, erosions or yellow crusting on the face, ears or trunk. Paw pads may also become crusted and painful (sometimes causing limping).

In recent years, it has been discovered that desmocollin-1 (interdigitating portion of the desmosome) is the primary target of autoantibodies in this disease in dogs.5 Contradictory to human medicine where desmoglein-1 is the primary autoantibody target.

Examination of intact pustules or crusting by cytology can reveal acantholytic cells. These cells are rounded and deeply staining keratinocytes. Histopathology reveals intragranular or subcorneal pustule formation with acantholytic keratinocytes. Since certain species of dermatophyte can also cause acantholysis, a PAS stain can be requested to assure an infectious organism is not present. Though clinically dermatophyte should not affect the nasal planum itself due to lack of hair follicles.

Corticosteroids at immunosuppressive doses are the hallmark treatment for the pemphigus complex. Other treatment options include azathioprine, doxycycline/minocycline and niacinamide, mycophenolate, leflunomide and tacrolimus for more localized lesions (especially nasal planum).

Reactive cutaneous histiocytosis Cutaneous histiocytosis is a benign disease caused by reactive proliferation of activated dermal antigen-presenting dendritic cells.6 This disease is limited to the skin and subcutis but can be multifocal.

Lesions appear as multiple, alopecic, erythematous dermal to subcutaneous nodules affecting the face, ears, nose, neck, trunk and extremities. Some dogs will have infiltration of the nasal planum leading to respiratory signs (snoring, stridor, etc). Collies and Shetland sheepdogs are predisposed. However, the disease has been reported in many breeds. Dogs also tend to be middle-aged to older.

Histopathology reveals granulomatous inflammation with nodular to diffuse deep dermal infiltrates of histiocytes, lymphocytes and neutrophils. Special stains are often necessary to rule out deep infectious diseases due to the type of inflammation.

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Spontaneous remission can occur. Dogs are usually readily responsive to immunosuppressive medications when deemed necessary. Medications such as corticosteroids, doxycycline/minocycline and niacinamide, essential fatty acids and vitamin E have been successfully used. Anecdotally, cyclosporine appears to be a great long term option for patients with relapsing cutaneous lesions.

Erythema multiforme (EM) This is a rare disorder which is classified as a specific inflammatory reaction pattern in the skin and mucous membranes. There are several suspected etiologies including drugs, vaccinations, nutraceuticals and viruses. The pathogenesis of EM is incompletely understood but thought to be a T lymphocyte-mediated hypersensitivity reaction that creates a cellular immune response directed against various keratinocyte-associated antigens.

Clinical signs include erythematous macules to papules or plaques that spread peripherally along the trunk or limbs and may include mucous membranes. Larger erythematous plaques often create serpiginous to annular “target-like” lesions which are characteristic of this disease.7

Histopathology reveals hydropic interface dermatitis with prominent single-cell apoptosis of keratinocytes of all levels of the epidermis. Many cases of EM will resolve with simple removal of the triggering etiology. But some cases require medical intervention with immunosuppressive medications such as corticosteroids, azathioprine and cyclosporine.

Uveodermatologic Syndrome (Voyt-Koyanagi-Harada-like Syndrome) This is a very rare disorder of cell-mediated hypersensitivity to melanin and melanocytes. Akitas are the most predisposed breed with Chows, Samoyeds and Siberian huskies also at risk.8

The disease is more common in young to middle-aged dogs. Uveitis is the primary sign and is an ocular emergency requiring aggressive therapy to preserve vision. Skin lesions include depigmentation of the nose, lips and eyelids.

Histopathology shows lichenoid interface dermatitis with large histiocytes. Therapy requires ongoing topical ocular and systemic immunosuppressive therapies (such as corticosteroids and azathioprine). Cornification disorders

Nasal hyperkeratosis This disease tends to occur in older dogs with excessive hyperkeratotic tissue develops at the junction of the dorsal nasal planum and haired skin of muzzle. Treatment includes topical moisturizing agents and possible flushing of the nasolacrimal ducts.

Hereditary nasal parakeratosis of the Labrador Retriever This disease is a result of an autosomal recessive trait in Labrador retrievers causing a hyperkeratotic condition of the dorsal aspect of the nasal planum at a young age (6-12 months). It is a cosmetic disease where keratin becomes tightly adherent. The thickness of the keratin band usually thickens as the dog ages. Focal or diffuse decreased pigmentation may occur. In severely affected cases, fissures, erosions and ulcers can be seen.

Histopathologic findings include mild to marked parakeratotic hyperkeratosis, moderate lymphocytic and neutrophilic exocytosis and multifocal serous lakes in the upper epidermis.

This is a lifelong condition and rate of progression is variable. If the dog is comfortable then no treatment is necessary. Oral/topical corticosteroids or tacrolimus can be used if discomfort develops. Hydration and moisturization are beneficial for maintenance (such as 60% propylene glycol). Miscellaneous diseases

Vitiligo This is an acquired disease associated with melanocyte destruction. Leukoderma and leukotrichia can be strikingly evident on the face and nasal planum. It is believed this disease has a genetic predisposition due to strong breed associations.

Onset of lesions occur in young adulthood. Predisposed breeds include Rottweilers and Doberman pinschers. Histopathology reveals normal epidermis and dermis except for lack of melanocytes and mild lymphocytic interface dermatitis. This is a cosmetic disease and no treatment is needed.

Proliferative arteritis of the nasal philtrum This disease is clinically distinct with solitary, circumscribed ulcerative lesions of the nasal philtrum (the rest of the nasal planum is spared). The hallmark breed for this disease is the Saint Bernard. Though the disease has been reported in Labrador retrievers, Newfoundlands and Samoyeds. Dogs tend to be young adults (2-6 years) at age of onset. Intermittent arterial bleeding can occur and even evolve into severe bleeding requiring surgical intervention.

Histopathology of deep dermal arteries and arterioles reveal proliferative arteritis with stenosis of the vessel. Medical therapy includes topical/oral corticosteroids and/or tacrolimus.

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Neoplastic diseases Epitheliotropic cutaneous lymphoma

The disease is usually T-lymphocyte in origin. This neoplastic disease can appear as solely depigmentation of the nasal planum or can involve generalized disease. Older animals (9-12 years) are affected with erythroderma, plaques or multifocal tumors. Peripheral lymphadenopathy may be present. Pruritus is variable from mild to severe.

Histopathology reveals epitheliotropic atypical lymphocytes. Prognosis is grave. Referral to an oncologist is recommended for this disease. Lomustine (CCNU), with or without prednisone, is effective. Essential fatty acids have also been recommended as an adjunctive therapy.

Squamous cell carcinoma (SCC) This is a common malignant neoplasm in which the tumor cells show keratinocyte differentiation. Development of SCC is associated with chronic sun exposure, lack of pigment and a thin hair coat. Solar-induced squamous cell carcinoma commonly occurs on the lightly pigmented skin of the nose, eyelid and pinnae of cats (between 9-14 years). White cats have a 13 times greater risk of developing SCC than cats of any other colors.9 Lesions can be seen on the nasal planum of older dogs. However, lesions are more likely to occur on the trunk, limbs, scrotum, lips and anus. Histopathology reveals irregular masses or cords of keratinocytes that proliferate downward and invade the dermis. Findings include keratin “pearls”, mitoses, atypia and keratin formation.

These tumors are slow to metastasize and are locally invasive. Over 80% of tumors are found on the head (usually involving the nasal planum) in cats. Surgical removal of the affected area (even if nosectomy is required) is primary treatment. Other options include cryotherapy, radiation therapy, photodynamic therapy and intralesional chemotherapy. Other diseases There are various other diseases that can affect the nasal planum such as infectious (fungal, bacterial, etc) etiologies, sterile pyogranulomatous syndrome, contact allergy, etc. Biopsies +/- tissue cultures are the most definitive diagnostic tools to differentiate these various diseases and the ones listed above. Also, examining for lesions on other anatomical regions of the pet can heighten suspicion of particular diseases. References

1. Goo M, Hong I, Yang et al. Discoid Lupus Erythematosus (DLE) in a Spitz dog. J of Vet Med and Sci 2008. 70: 633-5. 2. Griffies J, Mendelsohn C, Rosenkrantz W et al. Topical 0.1% tacrolimus for the treatment of discoid lupus erythematosus and pemphigus

erythematosus in dogs. J Am Anim Hosp Assoc 2004. 40: 29-41. 3. Gerhauser I, Strothmann-Luerssen A, Baumgartner W. A case of interface 4. perianal dermatitis in a dog: is this an unusual manifestation of lupus 5. erythematosus. Vet Pathol 2006. 43:761–4. 6. Olivry T: A review of autoimmune skin diseases in domestic animals: I—Superficial pemphigus. Vet Dermatol 2006. 17:291–305. 7. Bizikova P, Dean G, Hashimoto T et al. Cloning and establishment of canine desmocollin-1 as a major autoantigen in canine pemphigus

foliaceus. Vet Immun and Immunopath 2012. 149: 197-207. 8. Palmeiro BS, Morris DO, Goldschmidt MH, et al. Cutaneous reactive histiocytosis in dogs: a retrospective evaluation of 32 cases. Vet

Dermatol 2007. 18:332–40. 9. Nemec A, Zavodovskaya R, Affolter VK et al.. Erythema multiforme and epitheliotropic T-cell lymphoma in the oral cavity of dogs: 1989

to 2009. J of Small Anim Pract 2012. 53: 445-52. 10. Vercelli A, Taraglio S. Canine Vogt-Koyanagi-Harada-like syndrome in two Siberian husky dogs. Vet Dermatol 1990. 1: 151–8. 11. Clarke RE: Cryosurgical treatment of feline cutaneous squamous cell carcinoma. Aust Vet Pract 1991; 21: 148-53.

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Diagnosing and Treating Dermaphytosis Ashley Bourgeois, DVM, DACVD

Animal Dermatology Clinic Milwaukie, OR

Dermatophyte is a word derived from Greek origin meaning “skin plants”. This is a common label for a group of fungus that commonly cause skin disease in animals and humans. Three fungi cause most lesions in dogs and cats: Microsporum canis, Microsporum gypseum and Trichophyton mentagrophytes. Incidence and prevalence can vary with climate and natural reservoirs. There is a higher incidence in hot, humid climates. Outdoor cats and dogs are also more predisposed.1 Transmission Secreted proteases from dermatophytes are considered key factors involved in adherence and invasion of superficial cornified skin layers and keratinized epidermal appendages.2 Transmission occurs by contact with infected hair and scales of the fungal elements on animals, the environment or fomites. Fomites can include items such as combs, clippers, bedding and cages. These can be especially important in environments where multiple animals are present (grooming, transportation or housing situations). For example, visitors to catteries and multi-cat households can be at high risk to introduce organisms.

Various species of dermatophytes can be acquired from different sources. M. canis is most commonly related to exposure to a cat.1 M. gypseum inhabits soil environments and exposure is usually from animals digging and rooting in contaminated areas. T. mentagrophytes is usually acquired directly or indirectly by exposure to reservoir hosts (usually rodents). Pathophysiology of infection Dermatophytes can only survive in keratin. They are found in the outer cornified layers of the skin and within hairs. The infective portion of the organism is the arthrospore. This is formed by segmentation and fragmentation of fungal hyphae. These can be carried by dust particles, air currents, fomites and ectoparasites.

There are three stages in the infective process: 1) adhesion of arthroconidia to corneocytes 2) conidial germination 3) fungal invasion of the keratin network.

Decontamination of the environment is important since arthrospores can remain infectious in the environment for months (up to 18 months for M. canis). Host defenses There are several ways a normal animal will protect itself from dermatophyte infection. Desquamation and physical barrier are the first lines of defense. Sebaceous and apocrine glands secrete materials with fungistatic properties. Fungal pathogen-associated molecular patterns (PAMPs) active synthesis of chemotactic factors result in an influx of neutrophils and macrophages that have ability to kill fungal pathogens. Hence, pyogranulomatous inflammation is often seen with dermatophyte infections.

T helper type 1 (Th-1) cell-mediated immunity seems to be effective in clearing fungal infections. Infections are more easily established in young, elderly or immunocompromised animals and humans. Once recovered from

dermatophytosis an individual usually has at least partial immunity to reinfection. Resistance can vary in degree and duration, the individual, host species, species of dermatophyte and site of original infection. Experimentally inducing a second infection is possible but requires a greater number of spores or more occlusive conditions. The infection may also clear up sooner with secondary infections. Clinical findings A “classic” lesion is a circular erythematous and alopecic lesion that has fine follicular papules, scale and crusts around the periphery. However, signs and symptoms can be highly variable due to host-fungus interactions and various degrees of inflammation. Though pruritus is usually minimal it can also be marked if concurrent ectoparasitism, allergy or pyoderma is present.

Canine Lesions can be single or multifocal. On dogs, it can be seen symmetrically on the muzzle. It may appear to mimic certain autoimmune skin diseases such as pemphigus foliaceus. However, since dermatophyte organisms feed off keratin the nasal planum should not be affected (while autoimmune diseases will affect this region).

Distribution tends to affect the face, pinnae, paws and tail. Yorkshire terriers are predisposed to M. canis and T. mentagrophytes. Jack Russell Terriers are also predisposed to T. mentagrophytes.

A unique presentation of canine dermatophyte is a kerion. This is an exudative, well-circumscribed nodular type of furunculosis that develops multiple draining tracts. It is often associated with T. mentagrophytes.

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Feline Cats often have one or more irregular areas of alopecia with or without scale. Hairs will appear broken and frayed. Comedones may form from follicular hyperkeratosis. Widespread pruritic, exfoliative erythroderma can also occur. Lesions most commonly occur on the head, pinnae and paws. Generalized dermatophyte infection is more common in cats than dogs.

A unique presentation in cats is referred to as pseudomycetoma.3 This presents as one or more subcutaneous nodules that are ulcerated and discharging. They are located on the dorsal trunk or tail base. This phenomenon has only been reported in Persians from M. canis. Diagnosis Several differential diagnoses are possible since the clinical appearance is variable. These include staphylococcal pyoderma, demodicosis, pemphigus foliaceus, flea bite hypersensitivity, food hypersensitivity and neoplasia. Therefore, being familiar with different diagnostic tests is important.

A Wood’s lamp may be used to screen for certain species of dermatophytes but false negatives and positives are possible. The lamp should emit long wave UV-A light of approximately 360 nm. When a true positive occurs, an apple green fluorescence should occur when M. canis is present due to a water-soluble chemical metabolite (pteridine).1 These metabolites are only produced by fungi that have invaded actively growing hair. To avoid false positives, make sure to evaluate individual hair shafts for fluorescence. False positives can occur with keratin, topical medication and carpet fibers. The best use of Wood’s lamp is to select fluorescing hair to use for fungal culture or microscopic examination.

Trichography may reveal hyphae or arthrospores in 40-70% of cases. Mineral oil is used to remove and suspend hairs for microscopic evaluation. The hair will appear swollen, frayed and irregular. The definition between the cuticle, cortex and medulla is lost. Infections tend to be ectothrix and conidia may be identified in chains on the outside of the hairs.

Cytology usually reveals pyogranulomatous inflammation +/- fungal hyphae or spores. Often a secondary bacterial infection is identified.

Fungal culture

Although colonies grown on DTM may provide adequate macroconidia, some cases may require SDA without the extra ingredients to find them. When speciating under the microscope lactophenol blue should be used. M. canis will have spindle-shaped macroconidia with thick walls, a terminal knob and 6-15 cells per macroconidia. M. gypseum have ellipsoidal macroconidia with thin walls, no terminal knob and 4-5 cells per macroconidia. T. mentagrophytes produce cigar-shaped macroconidia with thin smooth walls. There may be globose microconidia present singly or in grape-like clusters.

is one of the most reliable diagnostic tests and allows speciation of the dermatophyte.4 Dermatophyte test medium (DTM) is the most commonly used. It is Sabouraud dextrose agar (SDA) with cycloheximide, gentamicin and chlortetracycline added to help reduce contamination. Hairs and scales can be plucked or a Mackenzie toothbrush technique can be used for diffuse selection (especially useful for asymptomatic carriers). A scalpel blade can be used to scrape fine pieces of the claw onto culture if they are affected. Dermatophytes will first use protein with alkaline metabolites which turns the medium from yellow to red. Therefore, the color change must occur at the same time the colony is first visible. Dermatophyte colonies are never green, brown, gray or black.

Histopathology can be useful in nodular forms such as a kerion or pseudomycetoma. However, can also be used in diffuse cases. Folliculitis or furunculosis will be present with fungal arthrospores or hyphae encircling the hair shafts. Sometimes these organisms can be hard to identify so a Periodic acid-Schiff (PAS) stain can be used. Trichophyton spp. can cause marked epidermal and follicular acantholysis which can be easily confused with pemphigus foliaceus.

Polymerase Chain Reaction (PCR) identification can be helpful. However, a positive PCR does not necessarily indicate active infection.1,5 Dead fungal organisms and non-infected fomite carriers can still be detected on PCR. But a negative PCR in a treated cat is compatible with cure.

Dermoscopy

may be a useful clinical tool with or without concurrent use of a Wood’s lamp to identify hairs for culture.6 It is a noninvasive tool that is widely used in human medicine. Cats uniquely have opaque, slightly curved or broken hair with a homogenous thickness (“comma hair”) when infected with dermatophytosis.

Therapy If topical therapy is indicated then rinses or shampoo may be preferred since the entire body surface can be treated. Rinses are often done twice weekly and include lime sulfur 2%, miconazole 2% plus chlorhexidine 2% and enilconazole 0.2%.7 Chlorhexidine as a sole product has not been shown to be effective.

If multifocal or diffuse lesions are present then systemic antifungal therapy is warranted. Itraconazole (5-10 mg/kg q24 hours), fluconazole (5-10 mg/kg q24 hours) and terbinafine (20-30 mg/kg q24 hours) have been shown to be the safest and most effective treatments for dermatophytosis. Griseofulvin is effective and use to be commonly used for dermatophytosis treatment. However, serious adverse effect (such as myelosuppression) have been recognized and it is no longer recommended.

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Treatment should be continued until complete resolution of clinical signs and 2-3 negative fungal cultures are obtained one month apart. Fungal cultures can continue to be positive for several weeks after clinical cure. It may take several months to achieve remission. Environmental disinfection Disinfection of surfaces requires mechanical removal of all debris (vacuuming and sweeping), washing with a detergent and application of a disinfectant to kill any residual spores.1 The most common disinfectant includes sodium hypochlorite (household bleach) at a ratio from 1:10 to 1:100. However, it should be prepared at least once weekly and stored in a dark opaque container to maintain chlorine. Accelerated hydrogen peroxide contains surfactants and chelating agents that reduce metal content. It has been shown to be effective against M. canis and Trichophyton spp.1

If bedding, clothing and towels are washable then mechanical washing at any water temperature at the longest was cycle is effective. Accelerated hydrogen peroxide can be sprayed on the surface of the washing machine and dryer to assure there is no contamination. References

1. Moriello K, Coyner K, et al. Diagnosis and treatment of dermatophytosis in dogs and cats. Vet Dermatol 2017. 28: 266-303. 2. Bagut ET, Baldo A, et al. Subtilisin Sub3 is involved in adherence of Microsporum canis to human and animal epidermis. Veterinary

Microbiology 2012. 160: 413-419. 3. Chang SC, et al. Dermatophytic pseudomycetomas in four cats. Vet Dermatol 2011. 22(2): 181-7. 4. Kaufmann R, Blum S, et al. Comparison between point-of-care dermatophyte test medium and mycology laboratory culture for diagnosis

of dermatophytosis in dogs and cats. Vet Dermatol 2016. 27: 284-e68. 5. Cafarchia C, Gasser R, et al. An improved molecular diagnostic assay for canine and feline dermatophytosis. Med Mycol 2013. 51: 132-

144. 6. Dong C, Angus J, et al. Evaluation of dermoscopy in the diagnosis of naturally occurring dermatophytosis in cats. Vet Dermatol 2016. 27:

275-e65. 7. Newbury S, Moriello KA, et al. Use of itraconazole and either lime sulphur or Malaseb Concentrate Rinse to treat shelter cats naturally

infected with Microsporum canis: an open field trial. Vet Dermatol 2010. 22: 75-79.

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How to Differentiate Crusty Cats Ashley Bourgeois, DVM, DACVD

Animal Dermatology Clinic Milwaukie, OR

Two of the most important aspects in assessing dermatology cases in dogs and cats are the ability to accurately describe and recognize primary and secondary skin lesions along with obtaining an accurate history. Many primary and secondary lesions are easily distinguishable from each other. However, crusts and scales can be difficult to distinguish and often happen concurrently in the same patient. Scale Scale is an accumulation of loose fragments of the epidermal stratum corneum. Scale can appear as a fine powder, large flakes, grease or dry, loose or adherent and may be various colors from white, silver, yellow brown or grey. When larger flakes are present, abnormalities in keratinization (including overproduction) or desquamation (abnormal retention) may be the underlying cause. Most scaling disorders in cats result from chronic inflammation and are usually due to secondary issues. Crust A crust is an accumulation of dried exudate, serum, pus, blood and/or other cells that adhere to the skin surface. Crusts often appear thick when associated with haired regions. This is due to the hair and crust becoming tightly adherent. Like scale, crust can be variable in color. They can range from reddish-brown to yellow. Like scales, crusts are often associated with inflammation, excoriation and pruritus. Crusts are often due to secondary issues. Pruritus As with many dermatology cases, the presence of pruritus can affect the diagnostic plan. Identifying pruritus in cats can be difficult due to their independent nature. Owner assessment can be influenced by the amount of time the owner spends with the cat and how the owner defines itchiness. Overgrooming is often overlooked as being a sign of “itch”. A trichogram can be very informative to help determine if a cat is licking excessively. Hairs may be plucked from regions of hypotrichosis and microscopically evaluated for signs of trauma. Hairs with tapered ends are normal. Broken and blunted follicular tips suggest overgrooming.

The diagnostic plan for cats with scales or crusting would be consistent with a routine work-up of most cases of feline dermatologic disease. Diagnostic testing can include skin scraping, flea combing, cytology, dermatophyte culture, Wood’s light examination and skin biopsies. Finally, if all other pruritic disorders have been ruled out, appropriate work-up for allergic skin disease should be pursued.1 Parasitic mites

Notoedres cati Notoedric mange in cats is caused by the Sarcoptid mite, Notoedres cati. Like other Sarcoptic mites, these burrowing mites live in the epidermis and are obligate parasites. This means their entire life cycle is on the host, like Sarcoptes scabiei in dogs. This is a highly contagious mite and appears to occur more often regionally in the United States. Clinically, crusts initially develop on the face and medial proximal edge of the pinnae with subsequent secondary clinical signs including erythema, scaling and pruritus. The affected areas may spread to involve the rest of the body over time. Skin scrapings may reveal all stages of mites, including eggs, nymphs, larvae and adults. These mites are generally much easier to find than their counterpart in the dog.

Otodectes cynotis A Psoroptid mite named Otodectes cynotis accounts for 50-80% of cases of otitis externa in cats.2 Otodectes mites are obligate parasites but not especially host specific. These mites may cause disease and be transmitted to dogs and small mammals in the environment. These mites live predominately in the ear canal and occasionally on the face, neck or body. They cause disease both by direct mechanical irrigation and by hypersensitive reactions. Classic clinical signs include generally young age of onset (although any age may be affected) with a typical black brown ceruminous discharge that is usually bilateral. Pruritus can be severe with erosions and significant crusting on the face and ears from excoriations. This disease should be differentiated from relapsing Malassezia otitis externa associated with hypersensitivity reactions. Chronic relapsing cases of Otodectic mange are unlikely. Cats with recurrent ear disease require investigation into underlying allergic skin disease. O. cynotis mites are generally easy to find by direct examination of the ear canal with a hand held or video otoscope or direct smears of ceruminous debris on a microscope slide with mineral oil. Skin scrapings of affected body parts may be more difficult for mite identification.

Demodex cati Demodectic mange caused by the mite Demodex cati is a relatively uncommon disease in the cat. Pathology occurs due to proliferation of these mites within the hair follicle or sebaceous glands.3 The life cycle and stages of these mites are similar to

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Demodex canis in dogs. Localized or generalized conditions can occur. Localized presentations are often limited to the head, eyelids and face or as a ceruminous otitis externa. These may be self-limiting or require topical, but rarely systemic, therapy. The generalized form of the disease is more common although still quite rare. Burmese and Siamese cats are reported to be over-represented. Clinical lesions include alopecia, erythema, scale and crusting. Pruritus is variable. Generalized disease is often seen in association with underlying metabolic immunosuppression such as FeLV/FIV, diabetes mellitus, hypercortisolism (either spontaneous or iatrogenic) and neoplasia. Therapy for this condition is predicated upon resolution and control of the underlying disorder with appropriate miticidal therapy such as ivermectin. Chronic management is usually necessary.

Demodex gatoi Another demodectic mite recognized in cats is Demodex gatoi. This short-bodied Demodex mite lives in the epidermal pits of the stratum corneum. The life cycle of this mite is less understood. However, they are suspected to live their entire life in the superficial layers of the skin. This condition can present as either non-pruritic cases of alopecia and scale with crusting to intense pruritus and significant crusting with excoriations and trauma. The abdomen, lateral thorax and medial aspect of the legs are generally affected. These mites appear to have geographic epizootic infestations in some areas of the United States, specifically southern states and areas of higher humidity. The mites can be easily missed on skin scraping because cats can remove them while overgrooming due to pruritus. Fecal flotation may be helpful in finding these mites in cases when the skin scrapings are non-diagnostic. Additionally, scraping along the margins of the areas of hair loss may increase mite yield. Routine miticidal treatments and anti-parasiticidal medications are generally ineffective. Most cases will only respond to lime-sulfur baths or rinses performed weekly to twice weekly.

Cheyletiella blakei This particular species of mite is specific to feline patients. However, there are other species of Cheyletiella (including C. yasguri and C. parasitovorax) that may infest the cat. These mites live on the skin surface and feed on cutaneous debris. They are more often diagnosed in young cats but adults can be affected and sometimes asymptomatic. Cheyletiella present a zoonotic concern as it can trigger a pruritic papular rash in humans. Often called “walking dandruff”, these mites are slightly larger and can be visualized as moving white spots in severely affected cats. Infestation will create significant scaling. Skin scraping or tape preparations can identify the mite. Cheyletiella is generally easily killed by most topical flea control products such as selamectin. Bacterial pyoderma Superficial bacterial pyoderma is often undiagnosed and in many cases untreated in cats. These secondary infections associated with primary skin disease in the cat are actually quite common. Crusted papular eruptions or miliary dermatitis are the most common presentation for folliculitis in the cat. However, large areas of erythematous and erosive dermatoses can also be associated with large numbers of bacterial organisms. Bacterial infections are generally considered a secondary complication of underlying disease, but management of the bacterial component can be a critical factor in achieving control and remission of the primary disease.4 Dermatophytosis Dermatophytosis is most commonly caused by Microsporum canis in the cat. It is a common skin disorder that has a pleomorphic presentation. It can be characterized by either scale or crusting. Contact with the naturally infective stage, the arthrospore, is the route of infection.5 This is most commonly associated with contact of an infected animal or in environments containing infected cats. Normal grooming behavior may be an important first line of protection but the most commonly affected animal are ones that are young, older or immune compromised due to poor nutrition, ectoparasitic concerns or metabolic disease. In most healthy cats, spontaneous remission occurs and treatment goals should be aimed at reducing environmental contamination and zoonotic potential. Topical therapy such as lime sulfur dips or enilconazole can be used in more mild cases. Treatment options for systemic therapy include the use of itraconazole, fluconazole or terbinafine when needed. Pemphigus foliaceus Pemphigus foliaceus (PF) is the most common autoimmune disease in cats. While primary lesions of PF in the cat are vesicobullous or pustular these lesions are fragile and transient. Crusting is the most predominately recognized sign. Crusted lesions are generally found on the face, pinnae, and periocular areas as well as around the nipples. In addition, purulent discharge around individual or multiple claw folds can be a common manifestation of this condition in cats. The claw fold disease is a distinct difference to the clinical presentation of PF in the dog. This disease can have a waxing and waning course. It may respond transiently to injectable corticosteroids and is often misdiagnosed as an allergic skin disease. Pruritus is variable. Cytology can be suggestive of PF with the finding of acantholytic keratinocytes, however histopathology is needed for definitive diagnosis in most cases. Acantholytic cells in the cat can occasionally be challenging to isolate on cytology or histopathology and evaluation of multiple sectioning samples may need to be requested. Focusing on lesions with heavy crusting can increase the diagnosis yield. Treatment with corticosteroids, cyclosporine, or chlorambucil is the most commonly used therapy for this condition.6 Prognosis is generally good although some cases can be challenging to achieve remission.

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Exfoliative dermatoses Exfoliative (or shedding of keratinocytes in scales) dermatoses can occur in the cat and has been associated with several different disorders. The scale produced in these disorders tends to be large and sheet-like. There may or may not be associated erythema. In cats, disease triggers can be associated with topical agents, FeLV/FIV infection, erythema multiforme, or toxic epidermal necrolysis.

A well-recognized syndrome in the cat is associated with the presence of a thymoma. Systemic signs may include lethargy, weight loss and anorexia. Larger masses may be associated with respiratory signs or regurgitation. Exfoliative reaction is generally observed at the head and neck initially with progression caudally. Thoracic radiographs or ultrasound should be diagnostic for the mass. Skin biopsy demonstrates cell poor interface dermatitis with exocytosis of lymphocytes onto the surface or follicular epithelium. Surgical excision of the thymoma is curative. Paraneoplastic dermatosis Paraneoplastic dermatosis is a syndrome presenting with progressive alopecia and scale. It is seen in association with malignant internal neoplasia. This syndrome is recognized in older cats with no breed or sex predilection. Pancreatic and bile duct malignancies are the most commonly associated cancers. Often the primary tumor and liver metastasis are not detected at the time of diagnosis. The neoplastic process does not involve the skin directly but is a manifestation of the internal disease. The alopecia has an acute onset and large areas of hair are sloughed initially from the ventral abdomen and then the limbs and paws.7 The surface of the skin often has a “shiny” appearance and the remaining hair is of poor quality and easy to epilate.

Generalized large sheets of scale are often noted in association with the clumps of hair falling out. Secondary colonization with Malassezia organisms can be observed with a dark brown discharge on the surface of the skin. Skin biopsy reveals cutaneous histopathologic changes suggestive of the syndrome but can be nonspecific. Ultimately ultrasound, imaging or exploratory laparotomy are necessary for definitive diagnosis. Because metastasis is often present at the time of diagnosis, prognosis is grave. References

1. Ravens P, Xu B, et al. Feline atopic dermatitis: a retrospective study of 45 cases (2001-2012). Vet Dermatol 2014. 25: 95-e28. 2. Yang C, Huang H. Evidence-based veterinary dermatology: a review of published studies of treatments for Otodectes cynotis (ear mite)

infestation in cats. Vet Dermatol 2016. 27: 221-e56. 3. Guaguere E, Muller A, et al. Feline demodicosis: a retrospective study of 12 cases. Vet Dermatol 2004. 15: 34. 4. Yu H, Vogelnest L. Feline superficial pyoderma: a retrospective study of 52 cases (2001-2011). Vet Dermatol 2012. 23: 448-e86. 5. Moriello K, Coyner K, et al. Diagnosis and treatment of dermatophytosis in dogs and cats. Vet Dermatol 2017. 28. 266-e68. 6. Simpson D, Burton G. Use of prednisolone as a monotherapy in the treatment of feline pemphigus foliaceus: a retrospective study of 37

cats. Vet Dermatol. 24: 598-e144. 7. Caporali C, Albanese F, et al. Two cases of feline paraneoplastic alopecia associated with a neuroendocrine pancreatic neoplasia and a

hepatosplenic plasma cell tumour. Vet Dermatol 2016. 27: 508-e137.

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Improving Epidermal Barrier Function to Manage Allergies Ashley Bourgeois, DVM, DACVD

Animal Dermatology Clinic Milwaukie, OR

The skin is an anatomical and physiological barrier between the environment and the microflora of the skin. The stratum corneum (SC) provides a barrier for the skin. It is the outermost region of the epidermis and is composed of ‘bricks’ (i.e. flattened, protein-enriched corneocytes) and ‘mortar’ (i.e. intercellular lipid-enriched layers). The SC in mammalian skin is essential to the health of the skin by retaining water and solutes essential for physiological homeostasis and protects the individual from physical, chemical and biological stresses.

The epidermal barrier is created by epidermal cornification, the end point of epidermal differentiation. An effective epidermal barrier requires intricate organization and formation of the keratin intermediate filaments and the intercellular lipids together with tight regulation of desquamation. The SC consists of a sheet of corneocytes embedded in an intercellular lipid matrix and is the primary barrier against pathogen entry. It is also largely responsible for the regulation of water loss from the body (transepidermal water loss (TEWL)) and is also able to withstand physical forces.

Lipids are very important in barrier function, water retention, cohesion and desquamation of corneocytes and control of epidermal proliferation and differentiation. Ceramides are the most important lipid component for the lamellar arrangement of the stratum corneum. Ceramides are composed of polyunsaturated fatty acids (such as the omega-6 linoleic acid contained in sunflower oil) and sphingosines.

An effective epidermal barrier requires intricate organization and formation of the keratin intermediate filaments. Filaggrin (FLG) is a keratin filament-associated protein necessary for organization of the keratin intermediate filaments. It comes from profilaggrin in the keratohyalin bodies of the granular layer. FLG and keratin both undergo proteolysis during cornification and form acidic substrates that are hygroscopic (trap water) and affect pH dependent enzymes involved with desquamation. Lower or defective FLG reduces the ability of the epidermis to trap water, and increases rate of breakdown of the cornified layer by causing premature breakdown of the corneodesmosomes that hold the corneocytes together. These epidermal components form an effective flexible epidermal barrier against the penetration of environmental irritants, allergens and infections and TEWL and desiccation.

Profilaggrin, the precursor protein of FLG, is the major constituent of keratohyalin granules in the SG. Profilaggrin (encoded by the FLG gene) is an insoluble, large, highly phosphorylated, histidine-rich protein, which contains arranged FLG repeats (10–12 repeats in humans) that are flanked on either side by two partial FLG repeats and N- and C-terminal domains. The N- and C-terminal domains in profilaggrin are thought to be important in processing of profilaggrin to FLG monomers during epidermal differentiation.1

The cornified cell envelope is a 15-nm-thick layer of proteins (in humans) located on the inner surface of the keratinocyte plasma membrane. The cornified cell envelope is formed by the assembly of several precursor proteins, including involucrin, loricrin, envoplakin, periplakin and small proline-rich proteins. Transglutaminases in the epidermis are thought to be responsible for the assembly of the precursor proteins that form the cornified cell envelope. Among the three subtypes of transglutaminases, transglutaminase-1 is known to be a membrane-located transglutaminase in the epidermis. Transglutaminase-1 is synthesized in the epidermis as an inactivated precursor protein, which is later processed by cathepsin D for activation.1

Evidence obtained through genetically engineered mice suggests that the assembly of cornified cell envelope proteins is crucial for the normal desquamation process and the structural and mechanical integrity of corneocytes in the epidermis, even though targeted ablation of single protein genes did not cause lethal or life- long cutaneous abnormalities.

There is insufficient evidence supporting the use of topical formulations containing essential fatty acids (EFA), essential oils, or complex lipid mixtures for improvement of coat quality, barrier function or any other clinically relevant benefit in dogs with atopic dermatitis (AD). Some lipid-based topical emollient products appear effective in human AD and several products are under development and evaluation in the veterinary field.

In recent studies, ceramides, free fatty acids and cholesterol have all been found to be lower in the skin of untreated dogs with atopic dermatitis than in normal dogs. Topical treatment with sphingolipid emulsion resulted in significant increase in values for cutaneous ceramides detectable after just three weeks of topical therapy in atopic dogs. The normalization of lipids showed also a relationship with normalization in ultrastructure.2

Topical application of ceramides can be beneficial in allergic patients and but may require multiple applications per week. It is important to stress that the benefits are not immediate and may be best used in combination with other treatment modalities.

Essential fatty acid (EFA) therapy has been considered for skin barrier repair. An open study that used a spot-on once a week and a spray daily containing essential oils and unsaturated fatty acids for eight weeks showed decreased clinical scores and pruritus significantly in both groups with no difference between groups.3

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There are many other products on the market labelled for skin barrier repair ranging from ceramide precursors (phytosphingosines) to combinations of humectants. Although the theory behind the use of these products is reasonable, very few studies have been completed and most information is anecdotal. Humans The importance of addressing skin dryness in humans with AD has been long supported. A direct relationship exists between skin dryness and disease severity in AD patients. Both moisturizers and emollients have been shown to improve the skin barrier and clinical signs. Skin barrier creams increase the time between flare-ups and reduce relapses by about one-third compared with no treatment. Skin care has also a preventative function. Early implementation of emollient therapy decreases the frequency of development of AD in high-risk children to 15%, compared with 30–50% when no skin care is done.1

There is significant evidence for both innate and acquired defects of the epidermal barrier in atopic humans and dogs. It is thought that in humans and dogs that inherited innate barrier function defects are a significant primary risk factor for atopic dermatitis.1 In the past it was thought IgE-mediated early and late-phase hypersensitivity reactions to airborne allergens were the issue. The current theory suggests that in the acute phase of the disease, epidermal barrier defects facilitate contact of environmental (and possibly microbial) allergens with epidermal immune cells.

The significance of a defective epidermal barrier is that it loses water through the skin resulting in itchy dry skin with loss of skin flexibility, increased penetration of irritants and potential allergens, especially house dust mites and a lowered ability to prevent microbial colonization. Dust mite proteases have also been reported to directly trigger inflammation in the epidermis potentially leading to interference with barrier homeostasis, and to cleave tight junctions. With increased allergen penetration, there is increased exposure of the immune system (via Langerhans cells), thereby increasing the likelihood of development and IgE-mediated exacerbation of cutaneous inflammation.

The terms moisturizers and emollients are frequently used interchangeably. Moisturizers typically contain water as the main ingredient mixed with humectants to hydrate the stratum corneum. While emollients classically contain some form of lipid. Water itself can contribute to dryness and worsen the skin barrier, because prolonged contact with water can disrupt the stratum corneum and water rapidly evaporates after application. Watery lotions can worsen the skin barrier and predispose to development of AD.

Therefore, ointments or thick creams rather than watery lotions are preferred in humans with AD. Ingredients used in skin repair include combinations of petrolatum, vegetable oils, glycerin and urea. Petrolatum has an immediate

barrier-repairing effect and is used in many over-the-counter products. Paraffin oil and vegetable oils penetrate the upper layers of the stratum corneum, and this is paralleled by a decrease in TEWL with the most effective occlusion seen with petrolatum.

Skin barrier dysfunction exists in AD and may increase the risk of allergic sensitization. Decreased ceramides and abnormal stratum corneum ultrastructure have been described. An increase in free and protein-bound glycosylceramides suggests an abnormality in metabolism of ceramides. A significant decrease and altered metabolism of sphingosine-1-phosphate are described in lesional atopic skin compared with healthy skin. All these studies emphasize the relevance of exploring skin barrier repair in veterinary medicine. Dogs In dogs, the skin barrier is often assessed by TEWL, although the reliability of this methodology is questionable. A relationship between deficiency of ceramides and an increase in TEWL has been described, while a relationship between disease severity and skin barrier dysfunction measured by TEWL has yet to be proven in dogs.1 While it is reasonable to speculate that restoration of lipid deficiency should improve skin barrier function, it is still largely unknown whether skin barrier repair would directly translate into an improvement of clinical signs.

Topical application of ceramides, free fatty acids and cholesterol (Allerderm spot-on; Virbac Animal Health) improves the ultrastructure of the stratum corneum and increases the number of lipid lamellae.2 Three weeks of topical application led to an increase in ceramide content and decrease in glucosyl-ceramides. Normalization of protein-bound lipid content was also observed.

While these two studies showed a positive effect on lipid composition, demonstration of clinical benefit is still limited. An open study in dogs with chronic AD showed clinical improvement with twice-weekly application for 12 weeks, with a significant improvement of erythema noticeable after 6 weeks.4 Although these results are promising, the impact of this study is limited by the small number of patients and the lack of a control group. A yet unpublished double-blinded, placebo-controlled study, applying the same emulsion three times weekly for 4 weeks, reported a significant decrease of clinical signs when compared with the control group, although the results on TEWL were mixed.5 The lack of significant improvement in TEWL may be an indication of poor reliability of TEWL measurements rather than lack of skin barrier amelioration in light of the ultrastructural studies, although the ultrastructural studies did not evaluate the correlation between ultrastructure and TEWL measurements.

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Oral administration of essential fatty acids for two months also improved the ultrastructure and increased the lipid content in the skin of atopic dogs.6 This feature was observed with both free and protein-bound lipids. No evaluation of the correlation with clinical improvement was reported.

Evidence to support the topical application of phytosphingosine is currently lacking. A blinded, randomized controlled trial in atopic dogs using a phytosphingosine-containing shampoo (Douxo calm; Sogeval Laboratories Inc) or a phytosphingosine-containing shampoo plus spray with similar ingredients or a control shampoo containing antiseptics, fatty acids and complex sugars (Allermyl; Virbac Animal Health) showed clinical improvement in all groups.7 No significant difference was found between groups. As all the interventions were theoretically able to affect the skin barrier, it is unknown whether using phytosphingosine provides extra benefit compared with any emollient or simple bathing. No assessment of skin barrier function was done in this study.

A preliminary study evaluating anti-inflammatory doses of oral prednisolone versus cyclosporine in dogs with AD failed to report a significant effect of time or group for TEWL after four weeks. Clinical signs improved in both groups, but TEWL was not correlated with clinical improvement. On the contrary, successful allergen-specific immunotherapy was correlated with decreased TEWL when compared with atopic dogs that did not respond to allergen-specific immunotherapy.8

Skin barrier repair is a promising approach to the management of canine AD. This approach could prove to be very beneficial when initiated early on in life and could possibly alter the course and minimize development of allergic sensitization. However, this approach needs to be evaluated carefully because the choice of the wrong ingredients could have negative long-term effects and ultimately worsen an already impaired skin barrier. Thus, large controlled studies are still needed to identify the best treatment and the long-term effects on skin barrier function. Conclusion In summary, the treatment of AD must be individualized for each patient. Treatment of chronic AD is most challenging and should identify flare factors, elimination of these factors, optimization of skin care, reduction of skin lesions and pruritus and prevention of recurrence of signs after remission. Not all topical treatments will be suitable for every patient; topical drugs will not be equally effective for, or tolerated by, every dog or cat. References

1. Marsella R. Fixing the skin barrier: past, recent and future – man and dog compared. Vet Dermatol 2013. 24:73-6. 2. Inman A, Olivry, T. Electron microscopic observations of the stratum corneum intracellular lipids in normal and atopic dogs. Vet Path

2001. 38: 720-23. 3. Tretter S, Mueller R. The influence of topical unsaturated fatty acids and essential oils on normal and atopic dogs. J Am Anim Hosp Assoc

2011. 47: 236-40. 4. Fujimura M, et al. Spot-on skin lipid complex as an adjunct therapy in dogs with atopic dermatitis: an open pilot study. Vet Med Int 2011.

281846. 5. Marsella R, et al, Investigations on the effects of a topical ceramide and free fatty acid solution (Allerderm Spot-on) on clinical signs and

skin barrier function in dogs with atopic dermatitis: a double blinded, randomized, controlled study. Vet Dermatol 2012. 23: (Suppl) abstract.

6. Popa I, et al. Analysis of epidermal lipids in normal and atopic dogs, before and after administration of an oral omega-6/0mega-3 fatty acid feed supplement. A pilot study. Vet Res Commun 2011. 35: 501-9.

7. Bourdeau P, et al. Evaluation of phytosphingosine-containing shampoo and microemulsion spray in the clinical control of allergic dermatoses in dogs; preliminary results of a multicenter study. Vet Dermatol 2007. 18: 177-8.

8. Cornegliani L, et al. Transepidermal water loss in healthy and atopic dogs, treated and untreated; a comparative preliminary study. Vet Dermatol 2012. 23: 41-4.

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Otoscopy Techniques and Ear Canal Masses Ashley Bourgeois, DVM, DACVD

Animal Dermatology Clinic Milwaukie, OR

Ear disease can account for up to 15% of all veterinary case presentations. Treatment of secondary infections is necessary in cases of otitis. However, identifying the underlying cause is essential to prevent recurrence. Any dog or cat presenting with a unilateral otitis presentation needs a thorough otoscopic examination to rule out the presence of a foreign body or mass within the external ear canal or middle ear.

There are several different types of otoscopes and techniques that can be used to diagnose and, potentially, treat ear masses. Otoscopy In addition to detailed history, physical examination, and ear canal cytology, otoscopy is part of a diagnostic minimum database, and can diagnose several conditions that create deeper ear canal disease such as neoplasia or foreign bodies.

Handheld otoscopy Otoscopes must have a strong light and power source, combined with at least 10× magnification that allows focusing within the normal length of the ear canal. Avoid using a battery-operated otoscope that has significantly lost power or light, which results in a diminished view of the deep ear canal.

Either a traditional diagnostic otoscope or surgical otoscope head may be used. The benefits of surgical otoscopes include enhanced manipulation and angulation within the ear canal and passage of instruments into the ear canal with concurrent visualization.

Various sizes of otoscopic cones (3mm being the most common) are ideal to properly examine ear canals based on patient size. This is also important if traction avulsion is attempted through an otoscopic cone as the largest diameter possible will allow better visualization especially if working near the tympanic membrane to prevent puncture.

Fiberoptic video-enhanced otoscopy (FVEO) Advancement of fiberoptics, improved lighting, and miniaturization of video cameras, combined with rigid endoscopy, has led to development of fiberoptic video-enhanced otoscopy (FVEO). FVEO, despite its expense to purchase and maintain, is extremely beneficial for improved diagnostics, therapy and client education.1

The camera within the fiberoptic tip significantly magnifies and improves visualization of the ear canal. FVEO also facilitates permanent recordings via picture or video of the ear canal—including debris, foreign bodies, and masses—which can be shared with clients and other veterinarians.

Compared with handheld otoscopy, FVEO allows thorough flushing with water or saline, providing better visualization and magnification. Also, observation of fine details, such as small tears of the tympanic membrane, consequently recognized as air bubbles extruding from the middle ear cavity through the tympanic membrane.1

General anesthesia is preferred for more aggressive flushing procedures, as placement of an endotracheal tube prevents aspiration of fluids (ie- those that may pass through a ruptured tympanic membrane into the middle ear, through the auditory canal, and into the posterior pharynx). For greatest safety, inflate the endotracheal tube cuff and pack the pharynx with gauze, which is removed prior to anesthetic recovery.

Otoscopic tools Ear loops or curettes can be helpful for breaking up debris adhered together in the deep ear canal or to the wall. Either tool can be placed down a handheld otoscope to allow better visualization.

Infant feeding tubes or red rubber catheters can be used for deep ear flushes. An 8F catheter can be placed down a handheld otoscope which allows for more fluid and pressure. A typical port on a FVEO unit will only accompany up to a 5F catheter. Combination flushing and suction units (such as EarIgator [MedRX]) contain a handpiece with buttons that allow the operator to switch back and forth between irrigation and suction. The pressure of flushing and suction can be altered based on need. These units attach to a 5F tube allowing magnified visualization of the tip of the catheter to prevent disruption of the tympanic membrane if intact.

Polypropylene catheters are more rigid than red rubber catheters. A 5F polypropylene catheters can be used through FVEO to perform a myringotomy if needed. Myringotomies are useful to drain fluid from the middle ear, relieving pressure and instilling medication.2 The end of the catheter should be cut to a point to provide a sharp end for puncturing.

For removing ear masses, tools such as biopsy forceps and polypectomy snares can be used with the FVEO unit to allow more complete removal with enhanced visualization.

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Ear masses Externally the more common clinical signs are odor extruding from the ear, pain, pruritus and discharge at the entrance of the ear canal or medial pinna. Rarely, with more aggressive tumors, vestibular signs (tilting the head, circling, difficulty blinking, etc) may be noted.

The external ear canal and middle ear cavity of a dog or cat can develop benign or malignant tumors. Tumors primarily arise from the apocrine or ceruminous glands that line the ear canal. The most common ear neoplasms originate from ceruminous glands.3 Tumors are more commonly seen in middle-aged to older animals. It is more common for inflammatory polyps to be identified in younger animals.

Inflammatory polyps (aka nasopharyngeal polyps) Non-neoplastic inflammatory masses thought to arise from the mucosa of the middle ear or auditory tube. Much more common to occur in cats compared to dogs. The mass arises from a small pedicle that enlarges as it extends into the external ear canal and/or pharynx. Most commonly occur in young cats but have been reported in older cats. Unique to other ear canal masses, upper respiratory disease can occur (nasal discharge, sneezing, dyspnea, etc).4

Histopathology reveals loose fibrovascular tissue covered by stratified squamous or ciliated columnar epithelium. There is also mixed inflammatory infiltrates such as lymphocytes, plasma cells, macrophages and neutrophils.5

Ceruminous gland adenocarcinomas Arising from ceruminous glands in the external ear canal which secrete cerumen (ear wax). These neoplastic masses are locally aggressive and are capable of invading nearby structures such as the bones of the skull. Tumors (especially chronic masses) have the potential to metastasize to local lymph nodes, salivary glands and lungs. In dogs and cats, malignant adenocarcinomas are more common than benign adenomas.6

Ceruminous gland adenomas These are benign tumors that do not metastasize or invade tissues. However, even a benign growing mass can compress the ear canal and lead to secondary infections and pain.

Feline ceruminous cystomatosis Lesions appear as multiple nodules or vesicles in the external ear canal, external orifice and concave pinnae. Cats with a chronic history of recurrent otitis externa may be predisposed.7 They range from dark blue to black in color. If nodules are punctured then a yellow to brown fluid can be expressed. This disease is more common in middle-aged cats. Abyssinians and Persians are over-represented.

Histopathology reveals cystic glands grouped into clusters. In chronic cases, secretory material may undergo mineralization. Distended ceruminous glands are lined by a single layer of epithelial cells. Most appropriate treatment is vaporization through laser surgery.

Miscellaneous tumors Rarely, other cancers can occur in ear canals such as squamous cell carcinomas, etc. Other benign tumors include papillomas, basal cell tumors, etc. Treatment The most effective treatment of ear canal tumors is complete surgical excision. In most cases a total ear canal ablation with bulla osteotomy is required. With less invasive masses (such as small inflammatory polyps) more conservative surgical procedures may be attempted without complete removal of the ear canal.

Traction avulsion may be attempted through a handheld or video otoscopy unit. However, owners should be advised that complete removal of the mass cannot be guaranteed as a base or stalk can be left behind. Conclusion Otoscopy is an extremely useful tool to uncover underlying etiologies of otitis externa/media. Whether allowing more aggressive flushing of the ear canal or removal of a mass, there are several benefits and tools that can be used with handheld and video otoscopy. The best treatment for an ear mass is removal (whether complete through surgery or partial through traction avulsion) with histopathology for identification in case further treatment or monitoring is warranted. References

1. Bourgeois A, Rosenkrantz W. Otitis Externa Series Part 1: Diagnosis of Otitis Externa. Today’s Veterinary Practice 2014. 4: 14-18. 2. Palmeiro B, Morris D, Wiemelt S, et al. Evaluation of outcome of otitis media after lavage of the tympanic bulla and long-term

antimicrobial drug treatment in dogs: 44 cases (1998-2002). J Am Vet Med Assoc 2004. 225 : 548–553. 3. London C, Dubilzeig R, Vail D, et al. Evaluation of dogs and cats with tumors of the ear canal: 145 cases (1978-1992). J Am Vet Med Assoc

1996. 208: 1413–1418.

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4. Anders B, Hoelzler M, Scavelli T, et al. Analysis of auditory and neurologic effects associated with ventral bulla osteotomy for removal of inflammatory polyps or nasopharyngeal masses in cats. J Am Vet Med Assoc 2008. 233: 580–585.

5. De Lorenzi D, Bonfanti U, Masserdotti C, et al. Fine-needle biopsy of external ear canal masses in the cat: cytologic results and histologic correlations in 27 cases. Vet Clin Pathol 2005. 34: 100–105.

6. Moisan P, Watson G. Ceruminous gland tumors in dogs and cats: a review of 124 cases. J Am Anim Hosp Assoc 1996. 32: 448–52. 7. Gross TL, et al: Sweat gland tumors. In Skin Diseases of the Dog and Cat, Clinical and Histopathologic Diagnosis, Ames, Iowa, 2005,

Blackwell Science, pp 665–694.

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Pyoderma: Updates on Use of Systemic Antimicrobials

Ashley Bourgeois, DVM, DACVD Animal Dermatology Clinic

Milwaukie, OR

Methicillin is a semi-synthetic, penicillinase-resistant penicillin that was developed to avoid penicillin resistance mediated by staphylococcal penicillinases. Penicillinases are bacterial enzymes that deactivate both natural penicillins (penicillin G and V) and aminopenicillins (e.g. ampicillin and amoxicillin) by breaking the core structure of these β-lactam antibiotics. Staphylococcus aureus developed resistance to methicillin by acquisition of mecA, a gene encoding a specific penicillin-binding protein (PBP2a) with low affinity to all β-lactams, including cephalosporins.1 The term “methicillin-resistant” Staph (MRS) has been used to indicate strains that are resistant to beta-lactams. MRS may express co-resistance to any combination of other drug classes, including aminoglycosides, fluoroquinolones, lincosamides, macrolides, tetracyclines, potentiated sulfonamides, chloramphenicol, and rifampicin.2 When a MRS strain expresses co-resistance to at least two additional antimicrobial classes, it may be referred to as “multidrug resistant” (MDR), and the term extensively drug resistant (XDR) may be used if the strain is non-susceptible to all but two or fewer antimicrobial classes.3 Both MDR and XDR strains have emerged worldwide amongst clinical MRS isolates from dogs and cats.4

Staphylococcus pseudintermedius, S. schleiferi (including the coagulase-negative variant) and S. aureus are the primary pathogens encountered in small animal dermatologic practice. Clinical isolates of all three species commonly express methicillin resistance and multidrug resistance. In addition, several other species of coagulase-negative Staphylococcus (CoNS) have been reported to cause skin and soft tissue infections. The pathogenic potential of any CoNS isolate obtained from a secondary skin lesion or a contaminated body site should be interpreted considering the clinical disease process (urgency, co-morbidities, risk for adverse reactions to specific antibacterial drugs) and with respect to any other pathogenic species of bacteria that may be co-isolated with it.

MRS infections have been on the rise in both human and veterinary medicine. With the increasing resistance comes challenges on how to manage and treat these cases. It is important that pet owners be informed when their dog has MRS infection, especially if the isolate is identified as MRSA in repeated bacterial cultures or if the owner is immunosuppressed. One study looked at whether pet dogs and cats and humans, when living in close contact, shared colonizing strains of MRS. One hundred and seventy-one veterinary dermatology practice staff and their respective pets (258 dogs and 160 cats) were screened for MRSA, MRS pseudintermedius (MRSP) and MRS schleiferi (MRSS). Human samples yielded 6 MRSA, 9 MRSP, and 4 MRSS isolates, whereas animal samples yielded 8 MRSA, 21 MRSP, and 2 MRSS isolates. Genetically identical strains, as determined by pulsed-field gel electrophoresis, were isolated from five people and their respective pets: MRSA in two people/three pets and MRSP in three people/four pets. There were no demographic or epidemiologic factors statistically associated with either human or animal carriage of MRS, or with concordant carriage by person–pet pairs. However, the MRSA isolation rate for people in this study (3.5%) exceeded that documented for the general US population (0.84%).5

The prevalence rates of MRS in dogs ranges from 0.58 to 30%, but comparison of studies is difficult due to differences in the populations sampled; healthy vs diseased, hospitalized vs outpatients and sites of sample collections.6-9 Risk factors for the development of MRS in dogs appear to be related to the use of previously used antibiotics, previous hospitalization, living in an urban environment and older age of the affected animal.8 One study looked at the prevalence of methicillin resistance between a primary care hospital and a veterinary referral university hospital and there was no difference between the isolates of MRS, however previous antimicrobial therapy was an important risk factor for the isolation of MRS at both sites.10 Topical therapy Topical therapy, using antibacterial agents with proven anti-staphylococcal efficacy, is the recommended treatment for any surface and superficial pyoderma involving MRS, particularly those with localized lesions, and for otitis and superficial wound infection. A systematic review of topical therapy for canine skin infections concluded that there was good evidence to support the use of shampoos containing 2-3% chlorhexidine and to a lesser extent of benzoyl peroxide in bacterial skin infections.11 Other topical actives with efficacy include miconazole, fusidic acid , mupirocin and polymyxin B. Topical therapy should be used as the sole on-animal antibacterial treatment for surface and superficial infections whenever a pet and owner can be compliant. Although many specialists and practitioners recommend systemic antimicrobial therapy for superficial pyoderma with or without added topical medication, this recommendation should be questioned due to increasing antimicrobial resistance. Newer studies have provided evidence that topical therapy as the sole antibacterial treatment can be effective in superficial pyoderma, providing opportunity to reduce the need for systemic therapy.

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Sodium hypochlorite (bleach) has been a disinfectant that is commonly used in human and veterinary hospitals. There are general recommendations regarding the use of bleach bathing for decontamination of humans with MRS infections used at 2.5 microliters/ml (which equates to approximately one-quarter to a half cup of bleach per bathtub). It is often used at a slightly higher concentration at 1:10 dilution it veterinary medicine with no big issue. This is used as a soak twice weekly (up to daily in severe cases) and has generally resulted in good efficacy with control of colonization in association with other therapies. Generalized xerosis of the skin is the only commonly seen side effect. A study tested 12 isolates of MRSP strains obtained from a clinical laboratory with various concentrations of bleach (6.15%). The results showed that all strains had a minimum bactericidal concentration of 1:32 but most isolates showed MIC between 1:64 and 1:128.12 Topical bleach sprays and rinses have become increasingly utilized in our practices with generally good response. These are often used 2-3 times weekly as adjunctive therapy.

Mupirocin is available in a polyethylene glycol ointment base. It functions by inhibiting bacterial protein synthesis and has excellent tissue penetration. It should not be used on mucosal surfaces or in areas where large amounts of polyethylene glycol can be absorbed due to potential for nephrotoxicity. Mupirocin is an antibiotic derived from fermentation of Pseudomonas fluorescens that specifically and reversibly binds to iso-leucyl transfer RNA synthetase in bacteria. This binding causes interrupted bacterial protein synthesis and inhibited bacterial RNA synthesis. Because of the intracellular mechanism of action, mupirocin can be used topically for treatment of multidrug-resistant Staphylococcus spp., even methicillin-resistant strains. The drug is particularly effective in localized lesions or in spot treating individual lesions that are not responding completely to appropriate topical and systemic therapy.

Nisin is marketed in the US as a dairy teat wipe (Wipe Out [ImmuCell Corporation]) for prevention of bovine mastitis, and for its ability to control common bacterial pathogens including some methicillin-resistant Staphylococcus spp. A recent study looked at nisin as sole therapy and as combined therapy with systemic antibiotics in canine pyoderma. In the nisin-only treatment group there was some benefit in dogs with S. pseudintermedius. In the group treated with nisin and antibiotics, the topically treated group with nisin had their S. pseudintermedius lesions clear more rapidly than a non-nisin antibiotic-treated group. The study suggested efficacy in treating some dogs with bacterial pyoderma and warrants further evaluation.13 They are particularly effective in short-coated breeds or in areas where lesions are readily accessible with the wipe such as the groin. Systemic therapy For deep pyodermas, widespread superficial infections and animals that are not amenable to topical therapy, systemic treatment is indicated. Susceptibility test results should always be considered to make treatment decisions once MRS has been identified.

Some general principles should be kept in mind: 1. Beta-lactam antibiotics should not be used for MRS infections, irrespective of the susceptibility report. Although third

generation cephalosporins have a broader spectrum of efficacy than first generation cephalosporins, they do not have efficacy against MRS as shown for cefovecin and cefpodoxime.14

2. Be careful when interpreting clindamycin susceptibility as inducible resistance has been reported in MRSA and MRSP associated with certain sequence types.15 Erythromycin-clindamycin-D-zone testing is recommended prior to treatment to avoid treatment failure, particularly with MRSA.16

3. Resistance to the tetracyclines is mediated by four different genes and the genes most commonly expressed by S. pseudintermedius are tet(M) and tet(K). Strains which possess only tet(K) maintain susceptibility to minocycline but not to other tetracyclines. The newly approved canine breakpoints for doxycycline are also reasonable for minocycline susceptibility. Tetracycline may be used as an option for testing susceptibility to doxycycline, but canine specific MIC or disc-diffusion breakpoints should always be used.17

4. Empirical choice of fluoroquinolones should be avoided, particularly when an MRS is suspected. For the first-generation fluoroquinolones, the disparity in resistance rates between MRSP and methicillin-susceptible S. pseudintermedius (MSSP) is striking,18 and fluoroquinolone use has been associated with increased rates of MRSA in human hospitals.19

5. Good evidence for recommendations on treatment duration is sparse and specific dose assessment for treatment of MRS has not been published. In the absence of such data, current published advice on the duration of treatment (three weeks for superficial pyoderma or one week beyond clinical resolution and four to six weeks for deep pyoderma or two weeks beyond clinical resolution) remain the standard.20,21

Some of the antibiotics that are used at the Animal Dermatology Clinics for MRS include: Clindamycin

Clindamycin (Antirobe®, Zoetis) is a lincosamide. Unlike penicillin and cephalosporin, it does not have a beta-lactamase enzyme. Therefore, bacteria that produce these enzymes can be susceptible to clindamycin, making it an option for some MRS pyodermas. As listed above be careful when interpreting clindamycin susceptibility as inducible resistance has been reported in MRSA and MRSP associated with certain sequence types. It is bacteriostatic, and resistance problems can occur. It has high oral bioavailability and a

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large volume of distribution. Therefore, it penetrates tissues well. It can be a good antibiotic for deep scarring pyodermas but it should be used at a higher dose 11 mg/kg q12 hrs. One study showed efficacy at 15 to 20 mg/kg q 24 h, making it more client-friendly. Side effects are minimal but include gastrointestinal events.22

Doxycycline Doxycycline has been used for MRS, however the break-points for determining sensitivity to doxycycline are changing: if the minimum inhibitory concentration is greater than 0.5 to 1 mcg/mL, or if tetracycline is resistant and zone of the doxycycline inhibition is less than 25mm, then failure of therapy is more likely even if a culture indicates sensitivity. It also seems to have nonspecific anti-inflammatory effects that have been seen with the tetracycline family of medications, making it a good choice in deep scarring pyodermas, especially those complicated by free hair shaft foreign bodies. The dosage is 5 to 10 mg/kg q12-24 hrs. Vomiting, esophagitis, and esophageal ulceration have been reported, and doxycycline should not be given to patients with dysphagia or diseases accompanied by vomiting. Liquid formulations are preferred particularly in cats. Use of tetracycline during tooth development can lead to tooth discoloration and dental hypoplasia. There are good reports of its use in canine and feline acne.23

Sulfonamides The trimethoprim-potentiated sulfonamides have good efficacy for some MRS infections. Major advantages are reduced expense with generics and twice-a-day dosing. The major disadvantages are its association with drug reactions, keratoconjunctivitis sicca, and thyroid gland hypoplasia. Cutaneous reactions include macular–papular eruptions, erythema multiforme, toxic epidermal necrolysis, and vasculitis; noncutaneous reactions include blood dyscrasias, keratoconjunctivitis sicca, nonseptic arthritis, and polysystemic immune complex disease. This last disorder is common in Dobermans and thus is contraindicated in this breed. The potentiated sulfonamide ormetoprim-potentiated sulfadimethoxine (Primor®, Zoetis) has major advantages of once-a-day dosing and less potential for keratoconjunctivitis sicca and other drug reactions than trimethoprim-potentiated sulfonamides.

Chloramphenicol Chloramphenicol is a bacteriostatic antibiotic but is a highly effective antibiotic for MRS. Dosing in dogs is ~ 35-50 mg/kg PO q8 hrs, with the lower end of the range recommended in larger breed dogs. It should be used limitedly in cats but reports list dosing in cats at 15mg /kg q12 hrs. Adverse reactions include vomiting, diarrhea, anorexia, and depression. Rarely exercise intolerance, weakness, and tachycardia. The idiosyncratic reversible muscle weakness is seen more in larger breed dogs after a few weeks of therapy. This can sometimes necessitate the need to discontinue the drug. Bone marrow suppression could be seen with prolonged and/or high doses (reversible with discontinuation of drug). Cats are more sensitive to bone marrow suppression than dogs. It should be handled with caution. Powder should not be inhaled and hands should be washed after handling tablets. Reported to cause aplastic anemia in humans when ingested. Clients should handle with gloves to avoid inadvertent ingestion.

Rifampin Rifampin is another antibiotic used for MRS infections and can penetrate scarred, walled-off areas of infection. Rifampin (5–10 mg/kg q 24 hrs) is a bactericidal antibiotic that not only has excellent tissue penetration but is also capable of killing Staphylococcus species intracellularly. A disadvantage of rifampin is the potential for hepatotoxicity, and it is contraindicated in dogs with preexisting liver disease. Rifampin will commonly produce orange-colored urine due to a metabolite. To monitor for potential toxicity, complete blood counts and liver screens should be performed done every 2 weeks.

Amikacin Amikacin is well tolerated by most dogs but must be given by subcutaneous injection (15-20 mg/kg once daily) and does present the risk for renal toxicity. However, the incidence of this is extremely rare. It is recommended to perform frequent monitoring of urine for casts and repeated blood analysis of blood urea nitrogen (BUN) and creatinine. In most cases, weekly urinalysis can evaluate cast formation, proteinuria, and a drop in specific gravity. Urinalysis is more sensitive than BUN or creatinine to amikacin-induced renal toxicosis. References

1. Berger-Bachi B, Rohrer S. Factors influencing methicillin resistance in staphylococci. Arch Microbiol 2002;178:165. 2. Kadlec K, Schwarz S. Antimicrobial resistance of Staphylococcus pseudintermedius. Vet Dermatol 2012;23:276-e55. 3. Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an

international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012;18:268-81. 4. Detwiler A, Bloom P, Petersen A, et al. Multi-drug and methicillin resistance of staphylococci from canine patients at a veterinary teaching

hospital (2006-2011). Vet Quarterly 2013;33:60-67.. 5. Morris, D., et al., Human and animal risk factor analysis for cross-transmission of methicillin-resistant staphylococci between veterinary

dermatology practice staff and their respective pets (abst). Veterinary Dermatology, 2009. 20(3): p. 220. 6. Ruscher, C., et al., Prevalence of Methicillin-resistant Staphylococcus pseudintermedius isolated from clinical samples of companion

animals and equidaes. Vet Microbiol, 2009. 136(1-2): p. 197-201. 7. Kawakami, T., et al., Antimicrobial susceptibility and methicillin resistance in Staphylococcus pseudintermedius and Staphylococcus

schleiferi subsp. coagulans isolated from dogs with pyoderma in Japan. J Vet Med Sci, 2010. 72(12): p. 1615-9.

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8. Nienhoff, U., et al., Methicillin-resistant Staphylococcus pseudintermedius among dogs admitted to a small animal hospital. Vet Microbiol, 2011. 150(1-2): p. 191-7.

9. Morris, D.O., et al., Screening of Staphylococcus aureus, Staphylococcus intermedius, and Staphylococcus schleiferi isolates obtained from small companion animals for antimicrobial resistance: a retrospective review of 749 isolates (2003-04). Vet Dermatol, 2006. 17(5): p. 332-7.

10. Eckholm, N.G., et al., Prevalence of and risk factors for isolation of meticillin-resistant Staphylococcus spp. from dogs with pyoderma in northern California, USA. Vet Dermatol, 2013. 24(1): p. 154-e34.

11. Mueller RS, Bergvall K, Bensignor E et al. A review of topical therapy for skin infections with bacteria and yeast. Vet Dermatol 2012; 23: 330-341.

12. Parisier et al. An invitro study to determine the minimal concentration of sodium hypochlorite (bleach) required to inhibit methicillin resistant Staphylococcus pseudintermedius strains isolated from canine skin. Veterinary Dermatology 2013: 24(6): 632-e157.

13. Frank LA, Kirzeder EM, Davis JA, et al. Nisin impregnated wipes for the treatment of canine pyoderma and surface bacterial colonization. In: Proceedings of the North American Veterinary Dermatology 24th Forum. Savannah (GA); 2009. p. 215.

14. Liu YC, Huang WK, Cheng DL. Antibacterial activity of cefpodoxime in vitro. Chemotherapy 1997; 43: 21-26. 15. Chanchaithong P, Prapasarakul N. Occurrence and characterization of inducible clindamycin resistance in canine methicillin-resistant

Staphylococcus pseudintermedius. Vet J 2015. pii: S1090-0233(15)00342-1. 16. Lewis II J, Jorgensen JH. Inducible clindamycin resistance in staphylococci: Should clinicians and microbiologists be concerned? Clin

Infect Dis 40: 280-285. 17. Maaland MG, Papich MG, Turnridge J, et al. Pharmacodynamics of doxycycline and tetracycline against Staphylococcus

pseudintermedius: Proposal of canine-specific breakpoints for doxycycline. J Clin Microbiol 2013; 51: 3547–3554. 18. Morris DO, Rook KA, Shofer FS, et al: Screening of Staphylococcus aureus, S. intermedius, and S. schleiferi isolates obtained from small

companion animals for antimicrobial resistance: A retrospective review of 749 isolates (2003-2004). Vet Dermatol 2006;17:332. 19. Knight GM, Budd EL, Whitney L et al. Shift in dominant hospital-associated methicillin-resistant Staphylococcus aureus (HA-MRSA)

clones over time. J Antimicrob Chemother 2012; 67: 2514-2522. 20. Beco L, Guaguere E, Lorente Mendez C, et al. Suggested guidelines for using systemic antimicrobials in bacterial skin infections (2):

antimicrobial choice, treatment regimens and compliance. Vet Record 2013;172:156-60. 21. Hillier A, Lloyd DH, Weese JS, et al. Guidelines for the diagnosis and antimicrobial therapy of canine superficial bacterial folliculitis

(Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases). Vet Dermatol 2014. 22. Bloom, P.B. and E.J. Rosser, Efficacy of once-daily clindamycin hydrochloride in the treatment of superficial bacterial pyoderma in dogs. J

Am Anim Hosp Assoc, 2001. 37(6): p. 537-42. 23. Bensignor, E. and E. Guaguere, Treatment of canine acne with doxycycline: an open trial. Vet Dermatol, 2004. 15(s): p. 43.

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The Ins and Outs of Immunotherapy Ashley Bourgeois, DVM, DACVD

Animal Dermatology Clinic Milwaukie, OR

Allergen specific immunotherapy (ASIT) is a treatment for atopic dermatitis in dogs and cats where extracts of allergenic substances are administered in gradually increasing amounts to lessen the allergic status of the patient. It is the only proven treatment for allergies that works by reversing the underlying immunopathogenesis of the disease instead of simply covering up the clinical signs with various anti-inflammatory therapies. However, it is an inexact science that relies on the expertise of the clinician and the cooperation of the patient and client. Success rates for ASIT are well established by multiple studies in humans and animals via both the subcutaneous route and the sublingual route. Mechanisms of action After performing allergy testing of an individual to identify allergic triggers, ASIT is selected as a specific and tailored therapy for each individual patient. The mechanism of action for ASIT involves exposing specific allergens to the immune system to induce tolerance. Multiple mechanisms are involved and several theories exist in how immunotherapy works. There is a large increase in allergen-specific IgG during successful immunotherapy and it is theorized that the IgG competes with IgE for allergen binding, preventing the allergen from cross-linking mast cell-bound IgE and is associated with immunologic tolerance. The “immune deviation” theory stresses that the observed effects are related to effects of the ASIT on T-helper lymphocyte subsets. In this theory, the normal (non-allergenic) response is a T-helper 1 (Th1) response. When the allergen reaches the immune system, Th1 lymphocytes produce cytokines such as interleukin (IL)-2 and interferon (INF)-gamma and include production of anti-inflammatory cytokines and the induction of T-regulatory cells. These cytokines direct B lymphocytes to differentiate towards cells that produce IgG antibodies. In allergic responses, the lymphocyte response is instead T-helper 2 (Th2). In this case, the Th2 lymphocytes produce cytokines such as IL-4, -5, and -13 among others. These cytokines direct B lymphocytes to differentiate towards cells that produce IgE antibodies and stimulate inflammation resulting in an allergic response. The immune response exists in a kind of balance between Th1 and Th2 and many things can potentially influence which response predominates. Modulating this IgG/IgE balance and deviating it towards the IgG bias is one target of ASIT. Regulatory T-cells help to modify Th1 and Th2 responses directly and indirectly through cell-cell contact and cytokines.

There are differences in mechanism of action between the route of intentional exposure to allergens in subcutaneous immunotherapy (SCIT) and the sublingual immunotherapy (SLIT). SCIT involves injection of the allergens directly into the body while SLIT allows for uptake of allergens placed under the tongue via dendritic cells and T-cells. Dendritic cells of the mucosa present the antigen to T-cells directly inducing an effector response. Dendritic cells then migrate to regional lymph nodes where they prime naïve T-cells and induce regulatory T-cell function. Routes of immunotherapy Subcutaneous immunotherapy (SCIT) has been used in humans for over 100 years and is supported by well-controlled studies showing its effectiveness with both environmental and venomous allergens. Conventional immunotherapy has generally involved use of aqueous extracts given by subcutaneous injection. These are manufactured in a saline vehicle with phenol used as a preservative. Extracts require refrigeration to maintain their potency.

Sublingual immunotherapy (SLIT) has also been used in humans for over 50 years with a growing body of support for its effectiveness as well. SLIT is much more commonly used in Europe than in the US and Australia and 80% of ASIT in Europe is administered via the sublingual route. Allergens for SLIT are also dissolved in saline but the diluent is commonly a mixture of saline and glycerin 50:50. The addition of glycerin provides greater stability allowing longer shelf life and less need for refrigeration.

There are many similarities between SCIT and SLIT. Both are formulated in induction and maintenance vials. Concurrent medications do not appear to interfere with efficacy and are often used initially. Mechanisms of action can be different via the route of exposure and may affect efficacy. SCIT consists of phenol-saline based extracts while SLIT formulations use a glycerin base to stabilize and allow uptake through the oral mucosa. The glycerin preserved extracts are protected from degradation by proteases and are stable at room temperature. The other main difference is dosing frequency. SLIT formulations are typically administered daily for the duration of therapy while SCIT injections are administered in tapering dosages and can be used weekly to every other week in most patients. Clients that travel or have inconvenient schedules to accommodate multiple daily dosing may not be compatible with SLIT therapy. Some clients who are “needle-phobic” or patients that are resentful of injections may benefit from SLIT therapy.

The importance of mold reactors or fungal allergens is another variable. Mold allergens may inactivate aqueous pollen allergens through protease activity. This reaction does not apparently occur in glycerin-stabilized formulation of SLIT therapy. Some clinicians recommend separate vials, which involve multiple injections if patients have significant mold allergies and are relevant in their

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clinical condition. In this case SLIT may be a better approach for these patients. Although little data is available regarding safety or reactions in dogs and cats it seems to be less common in the SLIT route of allergen administration even in patients that have previously had adverse reactions to the subcutaneously injected allergens.

Choosing the route of immunotherapy involving either SLIT or SCIT does not alter the diagnostic approach that should be taken. The initial work-up and management of the patient to eliminate parasitic concerns, cutaneous adverse food reactions as well as secondary infectious causes is critical in arriving at a diagnosis of atopic dermatitis. Once you have arrived at a tentative diagnosis of atopic dermatitis then allergy testing is performed. Assessing the ingredients of the allergy vaccine involves careful evaluation of the results as well as assessment and questioning of the owner as to the history of exposure, likelihood of exposure and knowledge of the cross reactivity of allergens from the various botanical groups of related weeds, trees and grasses. This will exclude the tendency to include irrelevant positives that may dilute the effects of the relevant allergens. Conventional induction versus RUSH induction Generally, a slow increase in concentration of allergy vaccine is used in conventional induction protocols and can be done in a 2- or 3-vial set. These injections are done at set intervals over a 2-4 week period until the maximum dosage is reached and then maintenance injection concentrations are given every 1-3 weeks depending on response and tolerance. The frequency of injections can be decreased when improvement is noted. There are many varying protocols and schedules and no particular schedule has been noted to be more effective than another.

Occasional reactions occur but are generally uncommon. If reactions such as vomiting, diarrhea, lethargy, increased pruritus, urticaria, weakness or anaphylactic reactions occur, then the dosage may need to be reduced or pre-treatment with antihistamines or corticosteroids may be indicated. A recent study reported the incidence of reactions including pruritus, urticarial and angioedema/anaphylaxis from assessing a database of logged calls from veterinarians who had ordered ASIT from an allergy vaccine company in the US. During a one year period 1,730 allergy vaccine treatment sets had been ordered (1,679 canine and 51 feline patients). No cats and 27 dogs had reported allergic reactions. “New” sets of allergens were reported to have been given in 25 of the 27 reported reactions while “refill” sets were reported in the other two. Seven dogs reacted to the induction vial (lower concentration) while 18 reacted to the maintenance vials. Reactions appeared most commonly in boxers (4/90 or 4.40%), English Bulldogs (9/212 or 4.25%) and pugs (2/90 or 2.22%).1

An alternative to conventional “ramped” induction of immunotherapy has emerged as a method of induction in humans and animals. Termed “rush” immunotherapy, this approach allows the escalation phase to be performed rapidly (in one day) as the patient is hospitalized and increasing dosages of the vaccine are administered at preset times (30-minute intervals) so that the entire induction phase is completed in 6-8 hours. Blood pressure, temperature, heart rate and general demeanor are monitored during the escalation phase. Once the initial day of induction is completed, the maintenance phase is continued as with conventional immunotherapy induction. Generally, response rates are comparable to conventional protocols although it is suggested that response may occur more rapidly. There are many advantages to the “rush” protocol since it avoids the need for more frequent injections initially. It also allows for a closer monitoring of the patients for any anaphylactic type reactions.

Rush immunotherapy has been reported to be a safe and effective therapy in multiple studies. One study showed that 7/30 dogs had increased levels of pruritus that required discontinuation of the procedure, but the levels of pruritus resolved with administration of anti-inflammatory dosages of corticosteroids and those dogs were switched to standard induction protocols.2 The same group reported their results to a rush induction using alum-precipitate allergens and in that case only one dog of 20 exhibited vomiting while the others tolerated the induction with no adverse reactions.3

Safe rush protocols have also been established the cat in a published report.4 This protocol gave progressively increasing injections of allergens to an average of 7500 PNU/ml (maintenance dosage). The cats were pre-medicated with 1.5 mg of triamcinolone and injections were given every 30 minutes for 5 hours. Two of the cats exhibited mild pruritus that resolved spontaneously but no other adverse effects were noted. Efficacy of immunotherapy Multiple retrospective studies and anecdotal reports over many years have shown the benefits of immunotherapy and most studies report the rates of good to excellent response between 60-70% in dog.5 A recent double-blinded placebo controlled study from France evaluated the success of allergen specific immunotherapy in dogs that were sensitized to house dust mite and at least five aeroallergens. This study showed statistically significant improvement by 12 months as compared to the placebo group. This is the first reported double-blind placebo controlled study that confirms the benefit of allergen specific immunotherapy in dogs. No controlled studies have been done to determine the success of immunotherapy in cats.

Studies on SLIT in animals are just now being more widely reported. Several studies over the past few years have shown variable results. One study in an experimental model of canine AD failed to show evidence of efficacy of orally administered allergen in laboratory beagles experimentally sensitized to dust mite. However in this study the allergen was fed to the dog rather than applied to

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the mucosa.6 Another open trial of atopic canine clinical patients with dust mite allergy treated with SLIT reported clinical benefit in 80% of dogs and that clinical benefit was usually accompanied by measurable immunologic changes including increases in allergen-specific IgG and decreases in allergen-specific IgE.7 Finally a multi-center open trial of 217 dogs, reported approximately 60% response to SLIT therapy including 50% of dogs that had previously failed to respond to SCIT.8 Given that the mechanism of action can be different, it stands to reason that some patients that fail SCIT could possibly improve with SLIT. Multiple investigators have reported this phenomenon anecdotally. Some patients may be more likely to respond to the oral challenge and many dermatologists are now offering this as an option for patients that fail conventional SC immunotherapy. Discrepancy of results as in human trials are likely related to many of the same problems including variability in protocols for dosing frequency, vehicle and preparation. Altering immunotherapy Once immunotherapy has been instituted manipulation of the frequency and/or dosages of the injections is often done by the dermatologist during the maintenance phase. Attempts to improve efficacy is the most common reason for altered protocols. There are two rationales for altering the protocols in this situation. If the patient achieves improvement when the injection is given but the response does not last until the next injection is due then increased frequency can be attempted to achieve better control throughout the inter-injection interval. A thorough history from the owner during the initial stages of the induction and maintenance are important to ascertain situations where the pet improves with the injection and then worsens as the time interval increases. In other patients that have shown little to no response to the immunotherapy over a six-month time frame increasing frequency or dosing may be initiated.

Adverse reactions are the other rationale to adjust immunotherapy. For SCIT, the most common adverse reaction leading to adjustments are increased pruritus following an injection (generally within 30-60 minutes) or worsening of signs after ASIT is initiated. Less commonly dogs may become increasingly pruritic in areas that had not been a focus prior to starting therapy. For these cases if a reaction is not severe, it is recommended to temporarily stop injections for 5-7 days to see if the pruritus decreases or resolves. Reduction in the injection volume by 50% is recommended in mild reactions but even more drastic reductions may be indicated in more severe reactions. If a patient has a suspected reaction careful history taking and exam are important to determine if the reaction is truly to the vaccine injection or simply worsening of clinical disease

For those on SLIT, reactions are uncommon, but do occur. Reactions may include general increases in pruritus, especially focused at the face or muzzle. These may occur at any time but anecdotally appear to be more common when changing from a less concentrated vial to a more concentrated one. If worsening pruritus is suspected to be caused from the SLIT, the dosing can be temporarily discontinued. If pruritus improves it would be expected in a fairly short period of time. It can then be re-initiated while decreasing the amount administered.

Another reason to alter therapy where more than 12 reactions are detected on the allergy testing methodology. If no response is noted after 6-12 months in cases of immunotherapy with one set then a second set of allergens can be introduced. The original set is continued at a maintenance level and the new set is begun with the induction protocol. Concurrent therapy Reactions indicating that adjustments are needed often occur early in immunotherapy and concurrent treatments that may obscure observations of the response to ASIT can be a problem. Since most patients take time to respond to immunotherapy, concurrent therapy with glucocorticoids, cyclosporine, oclacitinib and other anti-pruritic therapies are often used for the comfort of the patient. Unfortunately, these therapies can sometimes make it difficult to determine the patient’s initial responses to immunotherapy and the subsequent need for any adjustments. Avoidance of these therapies or use at the lowest possible dosing or frequency (while not always practical or possible) should be encouraged when possible. Concurrent infection management and topical therapy can often provide adequate control to preclude the need for systemic anti-pruritic medications in some cases. References

1. Griffin CE, et al. Prospective survey of reported reactions to allergen specific immunotherapy injections. Proceedings of the North American Dermatology Forum 2015. Nashville, TN.

2. Mueller, RS, Bettenay SV. Evaluation of the safety of an abbreviated course of injections of allergen extracts (rush immunotherapy) for the treatment of dogs with atopic dermatitis. Am J Vet Res 2001. 62:307-10.

3. Hobi S, Mueller R, Efficacy and safety of rush immunotherapy with alum-precipitated allergens in canine atopic dermatitis. Tierarztl Prax Ausg K Kleintiere Heimtiere 2014. 42:167-173.

4. Trimmer, AM, et al. Allergen specific immunotherapy protocol in feline atopic dermatitis: a pilot study of four cats. Vet Dermatol 2005. 16:324-29.

5. Miller W, Griffin, C, Campbell K. Muller and Kirk’s Small Animal Dermatology 7th edition. Elsevier, St. Louis, MO 2013. p 383. 6. Marsella, R, Tolerability and clinical efficacy or oral immunotherapy with house dust mites in a model of canine atopic dermatitis: a pilot

study. Vet Dermatol 2011. 21:566-71.

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7. DeBoer D. et al. Changes in mite-specific IgE and IgG levels during sublingual immunotherapy (SLIT) in dust mite-sensitive dogs with atopic dermatitis (abstract). Proceedings of the European Society of Veterinary Dermatology Meeting. Firenze, Italy, September 2010.

8. DeBoer, D. Morris, M., Multicentre open trial demonstrates efficacy of sublingual immunotherapy in canine atopic dermatitis (abstract). Vet Dermatol 2012. 23(Suppl 1): 65.

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The Pros and Cons of Immunosuppressive Drugs in Dermatology Ashley Bourgeois, DVM, DACVD

Animal Dermatology Clinic Milwaukie, OR

Immunosuppression is the interference of a developing immunologic response. Most immunosuppressive drugs work by affecting specific stages in the cell cycle. The response of cells to the drug varies depending on their stage in the cell cycle. In general, the most sensitive cells are those that are rapidly proliferating which can account for some side effects.

There are two main types of immunosuppressive drugs: non-specific inhibitors of cell division and drugs that specifically block the activation of T cells. Corticosteroids Corticosteroids are absorbed into cells by passive diffusion and bind to high affinity cytoplasmic glucocorticoid receptors.1 Also, the production of IκBα is stimulated which blocks processes such as cytokine synthesis and T-cell responses. Effects of corticosteroids on immunity include inhibiting inflammatory mediators, modifying protein/carbohydrate/fat metabolism and inhibiting effects of lymphocytes.2

Duration of action of synthetic corticosteroids can be determined by structure of the drug molecule which affects the potency and dose. However, in a clinical setting the route of administration and water solubility of the carrier substance usually plays a bigger role in duration of action. For example, injectable methylprednisolone acetate (Depo-medrol®; Zoetis) is poorly water soluble and slowly absorbed. Therefore, it can give continuous low levels of corticosteroid for several days to weeks.

Metabolism occurs in the liver through oxidation and excretion is through the kidneys. Corticosteroids are often the first line treatment in small animals for pruritic dermatoses and autoimmune disorders. For dogs, antipruritic dosing of prednisone: 0.5 to 1.0 mg/kg/day; anti-inflammatory dosing: 1 to 1.5 mg/kg/day; immunosuppressive dosing: 2 to 6 mg/kg/day. Cats require significantly higher doses than dogs. Different steroids have different potencies. In general, the following milligrams are approximately equivalent to 5 mg of prednisone: 4 mg of methylprednisolone, 0.5-0.75 mg of triamcinolone and 0.5-0.75 mg of dexamethasone.

General side effects of corticosteroids include hyperglycemia, fat redistribution, pendulous abdomen, skin atrophy, poor wound healing, hepatopathy, alopecia, calcinosis cutis, panting, polydipsia, polyphagia, etc. Complete blood count (CBC), serum chemistry and urinalysis (UA) should be performed every 6 months for monitoring. Azathioprine This is a steroid-sparing agent that is usually not used as a sole therapy.1 Azathioprine is a phase specific cytotoxic agent that specifically affects the S phase of the cell cycle (proliferating cells).3 The active metabolite (6-mercaptopurine) inhibits enzymes that are necessary for purine synthesis.4,5 This inhibits B and T lymphocytes and production of macrophages.

The drug is metabolized in the liver and excreted in the urine. This is often the first cytotoxic drug that is selected for many immune-mediated diseases. Clinically it can be used for pemphigus foliaceus, pemphigus vulgaris, vasculitis and erythema multiforme. The dose is 2mg/kg or 50 mg/m2 q24 hours for 1-4 weeks and then reduce to every other day. Azathioprine should be avoided in cats, dogs with liver disease and concurrently with allopurinol.

Azathioprine has a lag time of 4-8 weeks so results will not be seen immediately. Side effects include gastrointestinal upset, myelosuppression, hepatotoxicity and pancreatitis. Monitoring includes CBC and liver values every 2 weeks for a total of 8 weeks. Then, every 1-2 months until maintenance is reached and every 6 months for life. If values are abnormal then discontinue drug until normalized. Then, a lower dose may be restarted. Cyclophosphamide Cyclophosphamide is a nitrogen mustard derivative that is converted by oxidase enzymes in the liver to active metabolites. The drug forms crosslinks between DNA strands at the guanine N-7 positions.3,5 This is an irreversible mechanism that leads to cell death.

It is widely distributed into tissue and well absorbed orally. Metabolism is through the liver and excretion is through the kidney. The drug is not used very commonly used in veterinary dermatology. Clinical uses have been reported for mycosis fungoides, pemphigus vulgaris, dermatomyositis and vasculitis.

The dose is 1.5-2 mg/kg or 50 mg/m2 q48 hours and may further be reduced as remission is achieved. Side effects include myelosuppression, gastrointestinal upset and hemorrhagic cystitis. Monitoring includes CBC, serum chemistry and UA every 2 weeks for the first 8-12 weeks. Then, every 3-6 months as maintenance.

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Lomustine (CCNU) An alkylating agent that is cell cycle non-specific and inhibits DNA and RNA synthesis. Lomustine is absorbed completely from the gastrointestinal tract and can appear in the plasma within 3 minutes of administration. It is metabolized in the liver and excreted through the kidneys. The drug is highly lipid soluble causing wide distribution to tissue and may penetrate the blood-brain barrier.

Clinical uses include mycosis fungoides (epitheliotropic lymphoma), mast cell tumors and histiocytic sarcomas.6 The dose is 50-90 mg/m2 every 2-6 weeks. Side effects include myelosuppression, hepatotoxicity, renal toxicity and gastrointestinal toxicity. Monitoring should include CBC with platelets one week after dosing and prior to the next dose. Chemistry (specifically liver values) should be checked before each treatment. Cyclosporine This drug is a calcineurin inhibitor which inhibits inflammatory mediators such as interleukin (IL)-2, IL-6 and IFN-γ by T cells.5 Availability of the drug can vary widely based on the form of the drug. Vegetable-oil based formulations should be avoided due to low bioavailability from the large molecular mass. Microemulsion forms (such as Atopica®; Elanco) have improved bioavailability. Drug is metabolized in the liver and intestine via cytochrome P450 enzymes. Therefore, one should be cautious to use this medication with other drugs that utilize cytochrome P450 enzymes such as the azole family. Excretion is through bile.

This drug is used to treat a variety of diseases such as atopic dermatitis, pemphigus foliaceus, sterile nodular panniculitis, erythema multiforme, alopecia areata, perianal fistulas and sebaceous adenitis. The dosing starts at 5 mg/kg q24 hours for dogs and 7 mg/kg q24 hours in cats. However, it can be increased up to 10 mg/kg in both species if there are no gastrointestinal side effects. Cyclosporine can have a lag time of 2-4 weeks to show full effect.

The primary side effect is gastrointestinal upset. However, hirsutism, gingival hyperplasia and lymphoplasmacytoid dermatitis can also occur. Cats can be more predisposed to toxoplasmosis while on cyclosporine so the drug if usually limited to cats with no potential rodent exposure. CBC and serum chemistry should be performed every 6 months if used long term. Tacrolimus A calcineurin inhibitor like cyclosporine but inhibits a different binding protein. It is more potent than cyclosporine and absorbs well into the epidermis.1 The drug is used via topical administration due to potency. It is metabolized in the liver and mostly excreted through bile like cyclosporine.

Clinical uses include discoid lupus erythematosus, pemphigus foliaceus, vasculitis and perianal fistulas. It is commercially formulated as a 0.1% ointment and can be found in most human pharmacies. Instruct owners to use a thin layer to the affected area as the ointment can be expensive. Topical side effects are minimal but could include local irritation. No systemic monitoring is required. Doxycycline/Niacinamide Doxycycline is a broad-spectrum antibiotic which reversibly binds to the 30s ribosomal subunit. This has anti-inflammatory and immunomodulating effects due to blocking translation. Niacinamide is a water-soluble B vitamin which inhibits histamine release. Doxycycline is well absorbed after oral administration. It is excreted into the urine and feces via non-biliary routes in an inactive form. Niacinamide is metabolized in the liver and excreted in the urine.

Clinical uses of combining these two drugs include discoid lupus erythematosus, sterile pyogranulomatous disease, symmetrical lupoid onychodystrophy and vasculopathies.1 Doxycycline can be used at doses of 5-10 mg/kg q12-24 hours. Niacinamide can be dose at 250mg q8-12 hours for dogs under 10kg and 500mg q8-12 hours for dogs over 10kg. It can take up to 6-8 weeks to see the full effect of this combination.

Side effects include gastrointestinal upset with either drug. Niacinamide may increase liver enzymes. CBC and serum chemistry annually is usually sufficient. Chlorambucil This drug is cell cycle non-specific and acts on rapidly dividing cells. Chlorambucil causes cross-linking of two complementary DNA strands.5 This prevents separation of DNA strands for transcription and leads to apoptosis. Metabolism occurs in the liver and excretion is through the urine.

Chlorambucil is usually used in conjunction with corticosteroids. In cats, it is often used in place of azathioprine as a steroid-sparing agent for diseases such as pemphigus foliaceus and severe refractory cases of feline eosinophilic granuloma complex. The dose is 0.1-0.2 mg/kg q24-48 hours.

Chlorambucil side effects include myelosuppression and hepatotoxicity. Monitoring is similar to azathioprine. CBC and chemistry should be done every 2 weeks for the first 8 weeks. Then, every 3-6 months while on maintenance.

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Mycophenolate Mycophenolate is metabolized in the liver to mycophenolic acid (active form). Mycophenolic acid blocks the synthesis of guanine which is in the de novo pathway of purine synthesis.1,5,8 Therefore, DNA and RNA synthesis are blocked. This is cytotoxic to cells such as T and B lymphocytes.3 However, the drug does not affect cells that can utilize the purine salvage pathway such as myeloid cells. Primarily excreted through the kidney.

It has been used clinically for diseases such as pemphigus foliaceus and systemic histiocytosis. The dose is 22-40 mg/kg daily divided into q8-12hour dosing. Side effects include myelosuppression and gastrointestinal upset. CBC and chemistry should be performed every 2-4 weeks for the first 2-3 months. Then, every 6 months for maintenance. Leflunomide Leflunomide is considered a disease-modifying anti-rheumatic drug which inhibits pyrimidine synthesis.9 It has antiproliferative effects on antibody synthesis by interfering with cell cycle progression. It can also antagonize the effects of IL-3, IL-4 and TNF-α. Metabolism occurs in the gastrointestinal mucosa and liver. It is excreted in urine and bile.

It has been used to treat pemphigus foliaceus and reactive histiocytosis. The dose is 2-4 mg/kg q24 hours. Contraindications include hepatopathy and renal disease. CBC and chemistry should be checked 4 weeks after starting therapy. Then, every 6 months for life. References

1. Rosenkrantz, WR. Immunomodulatory and Immunosuppressive Therapy. Procedures of the ACVD Resident Education Forum 2009. 2. Jacomini LC, Da Silva NA. Drug interactions: a contribution to the rational use of synthetic and biological immunosuppressants. Rev Bras

Reumatol 2011. 51:161-174. 3. Stern DK, Tripp JM, Ho VC, Lebwohl M. The use of systemic immune moderators in dermatology: an update. Dermatol Clin 2005: 259-

300. 4. Kidd LB et al. Thiopurine methyltransferase activity in red blood cells of dogs. J Vet Intern Med 2004: 214-8. 5. Marder W, McCune WJ. Advances in Immunosuppressive Therapy. Seminars in respiratory and critical care medicine 2007. 28: 398-417. 6. Heading KL, Brockley LK, Bennett PF. CCNU (lomustine) toxicity in dogs: a retrospective study (2002-07). Aust Vet J 2011. 89: 109-16. 7. Ransom JT. Mechanism of action of mycophenolate mofetil. Ther Drug Monit 1995. 17: 681-4. 8. Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus 2005. 14: 2-8. 9. Gummert JF, Ikonen T, Morris RE. Newer Immunosuppressive Drugs: A Review. J Am Soc Nephrol 1999. 10: 1366-1380.

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Managing Canine Otitis: Essentials to Diagnosis and Treatment

Lynette Cole Bayer Sponsored Content Provider

STEP 1: Identify the primary cause of the otitis. Primary causes of otitis externa include parasitic diseases, hypersensitivity disorders, foreign bodies, disorders of keratinization, juvenile cellulitis, autoimmune diseases, neoplasia, and polyps. These are the conditions or disorders that initiate the inflammatory process within the ear canal. In a retrospective study evaluating 100 dogs with acute and chronic-recurrent otitis externa, the most common primary cause

STEP 2: Identify the predisposing factors of otitis. Predisposing factors facilitate the inflammation by permitting the external ear canal microenvironment to be altered allowing pathogenic or opportunistic bacteria to become established. These factors may include variation in ear conformation (pendulous pinnae, hair in the ear canal, congenital stenosis of the ear canal), moisture in the ear, and inappropriate prior therapies. Question the owner about previous treatments, the use of cotton-tipped applicators, or hair removal from the ears. It is important to eliminate as many of these factors as possible, realizing that some of these, such as ear conformation, cannot be changed.

of the otitis was due to allergic dermatitis (n=43 dogs). On the other hand, in the cat, the most common causes of recurrent otitis externa are polyps, parasites (e.g. Otodectes cynotis) and allergies.

STEP 3: Identify the perpetuating factors of otitis. Perpetuating factors sustain and aggravate the inflammatory process and prevent resolution or worsen an already present otitis externa. Bacterial and yeast infections, otitis media, and progressive pathologic changes (e.g. hyperplasia) are perpetuating factors of otitis externa, which need to be identified and controlled.

STEP 4: Treat the present otic infection with topical ear cleaning and drying agents, topical antimicrobial agents and topical glucocorticoids (if needed). If the ears are stenotic and hyperplastic, systemic glucocorticoids are indicated as well. Treat any other concurrent skin conditions (e.g. superficial bacterial pyoderma, yeast dermatitis). Otic preparations that are ointment/suspension-based may not be as effective as those that are solution/emulsion-based, if the ears are stenotic or hyperplastic, as may be the case in those patients with chronic otitis externa, but may be utilized if the ears are not stenotic or hyperplastic.

STEP 5: Recheck the patient in three to four weeks to assess response to therapy, by performing an otic examination and otic cytology in addition to the general examination. This step is so critical to the management of otitis. If the patient is responding, initiate a food trial, if the otitis and pruritus (if present) is non-seasonal. In cases of seasonal otitis and pruritus, where other causes of the otitis and pruritus have been ruled out, a diagnosis of atopic dermatitis is made, and allergy testing or symptomatic therapy are initiated. If, however, the ears have not responded, go to Step 6: and schedule a deep ear flush, to clean the ears and evaluate the patient for concurrent otitis media. In dogs with recurrent ear infections of 6 months or longer, up to 82% of these dogs may have concurrent otitis media, with 70% having an intact but abnormal tympanic membrane.

STEP 6: A short course (two to three weeks) of glucocorticoids should be utilized prior to the deep ear flush to decrease inflammation and stenosis of the horizontal and vertical ear canals. The deep ear flushing procedure is best done under general anesthesia in order to completely clean the ear. Once the animal is under anesthesia, prior to the deep ear flush, radiographic imaging of the tympanic bulla is performed to stage the ear disease, remembering that normal radiographic imaging does not rule out otitis media. Next, the external ear canal is soaked for 10 minutes with a non-ototoxic ceruminolytic ear cleaner, like Cerumene. The ear is then flushed with warm sterile isotonic saline using a bulb syringe to remove large debris and exudate. This is followed by flushing with warm sterile isotonic saline using an 8 French polypropylene urinary catheter attached to a 12 cc syringe passed through an otoscopic cone. Once the ear is clean, the tympanic membrane is evaluated with an otoscope or video otoscope. If the tympanic membrane is not intact, cytology and bacterial C/S is performed from the middle ear cavity. This may be performed using the hand-held otoscope or the video otoscope. Using a hand-held otoscope, a sterile otoscopic cone is inserted into the horizontal ear canal and a sterile pediatric-size swab is passed into the middle ear cavity. The first swab is used for C/S. A second swab is passed into the middle ear for cytological analysis. If the video otoscope is used, an open-end 3 1/2 French Tom cat catheter or 5 Fr polypropylene urinary catheter attached to a 12 cc syringe is placed through the port of the otoendoscope. Warm sterile isotonic saline is flushed into the middle ear cavity and aspirated back, the first sample for cytology, and the second sample for culture. Then the middle ear is flushed repeatedly with warm sterile isotonic saline to flush the middle ear cavity. If the tympanic membrane is intact, appears abnormal, and otitis media is suspected, a myringotomy is needed to obtain samples for cytology and bacterial C/S, and to flush the middle ear cavity. In the dog, an intact tympanic membrane does not rule out the possibility of otitis media. Using a hand-held otoscope, a sterile otoscopic cone is inserted into the horizontal ear canal and the tympanic membrane is visualized. Using a sterile swab, an incision is made into the caudoventral quadrant of the tympanic membrane, specifically the pars tensa. The swab used for the myringotomy incision is submitted for bacterial C/S. A second swab is inserted into the original incision and the sample obtained is used for cytological analysis. If the video otoscope is used to perform the myringotomy, an open-end 3 1/2 French Tom cat catheter or 5 Fr polypropylene urinary catheter is placed through the port of the otoendoscope, and is used to make the incision. Saline is

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flushed into the middle ear cavity and aspirated back using a 12 cc syringe attached to the catheter, and the first sample is for cytology, and the second sample is submitted for bacterial C/S. The normal tympanum heals in 21 to 35 days. Therefore, if the ear is kept free of infection after the myringotomy procedure, the tympanic membrane should heal. Possible complications of ear flushing and myringotomy are Horner’s syndrome, facial nerve paralysis, vestibular disturbances, and deafness. Owners should understand these complications and sign a consent form prior to the procedure. After the otic flush, it is important that the patient is sent home on empiric topical and systemic therapy based on cytology, and the oral antibiotic treatments (only needed if dog has infectious otitis media) may be modified once the cultures have been completed. Ointment or suspension-vehicle otic products should be avoided if a myringotomy was performed or if the tympanic membrane was torn or ruptured. As discussed in step 5, if the patient has non-seasonal otitis and pruritus, a food trial is commenced while in cases of seasonal otitis and pruritus, a diagnosis of atopic dermatitis is made, and allergy testing or symptomatic therapy are initiated.

STEP 7: Recheck the patient three to four weeks after the ear flush to monitor the response to otic treatments as well as to the food trial (if a food trial was performed). In most cases of chronic otitis externa, where continual inflammation and stenosis have occurred along with increased cerumen production, which may alter epidermal migration, some type of maintenance otic therapy is required, such as a cleaning and drying agent, to keep the ear canal free of wax build up.

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Managing Canine Otitis: So Many Treatment Options, How Do I Choose?

Lynette Cole Bayer Sponsored Content Provider

Once an otic infection has been diagnosed, treatment may include topical as well as systemic therapy. At each recheck, the patients response to treatment should be monitored, cytology performed, and products changed accordingly. In the majority of the cases of infectious otitis externa, topical therapy alone is sufficient. In those ears with severe infections, or those that have long-standing chronic otitis externa, the addition of a systemic antimicrobial agent may be required to clear the infection that is present in the ear tissue as well as in the lumen of the ear canal. For those dogs with infectious otitis externa and otitis media, topical and systemic antimicrobial therapy is usually required.

Topical otic preparations usually contain various combinations of glucocorticoids, antibiotics, and/or antifungals in a vehicle base. Selection of the active ingredient needed in the product for topical use should be based on cytology. It is important to remember that C/S results indicate the plasma level of an antimicrobial agent. The advantage of topical therapy is that you can achieve 100 to 1000 times the plasma level of the antimicrobial agent by administering it topically. The patient’s progress while on these medications should be monitored cytologically at each re-evaluation and the topical therapy adjusted accordingly.

None of the commercially available otic topical treatments or the extra-label otic preparations are labeled for use with a non-intact tympanic membrane. However, most all of these products have been used to treat otic infections in dogs with otitis media. Always warn the owner of the possibility of neurological signs of ototoxicity while administering topical medications when the tympanic membrane is not intact. The otic topicals that I will not use in the ear with a non-intact tympanic membrane are those in an ointment or suspension base.

Glucocorticoids are antipruritic, anti-inflammatory, and antiproliferative. During the acute stage of otitis, the ear canal becomes edematous and erythematous. As the inflammation progresses, the dermis becomes infiltrated with a mixed population of cells. Apocrine glands dilate and become hyperplastic, which leads to excessive cerumen production. Therefore, glucocorticoids are beneficial in decreasing the pain, pruritus, stenosis, and edema associated with otitis. In addition, they are effective in decreasing sebaceous and apocrine secretions. They are usually in combination with other agents but may be beneficial when used alone in allergic cases of otitis and some ceruminous otitis cases. It is important to use the lowest potency glucocorticoid at the lowest frequency needed to control the otitis to prevent iatrogenic hyperadrenocorticism. Examples include Cort/Astrin Solution (Vedco) and Synotic (Zoetis).

Topical aminoglycosides such as neomycin and gentamicin have good activity against gram-positive and gram-negative otic pathogens for treatment of acute otitis externa. Gentamicin and neomycin are available in many combination products, some which contain an antifungal and glucocorticoid such as Tresaderm (Merial), Otomax Ointment (Merck), Mometamax Suspension (Merck), Panolog Ointment (Zoetis), easOtic Suspension (Virbac). Another aminoglycoside, tobramycin, is available as an ophthalmic solution and is very effective against Pseudomonas otitis infections, especially in those cases of chronic otitis externa: Tobramycin Ophthalmic Solution (generics)

Fluoroquinolones have a broad spectrum of antibacterial activity against gram-negative and gram-positive bacteria and are found in Baytril Otic Emulsion (Bayer) and Posatex (Merck).

Polymyxin has excellent in vitro activity against Pseudomonas with resistance rarely developing but is inactivated in purulent debris so the ear needs to be kept clean during treatment. Products containing polymyxin B are Neomycin, polymyxin B, and hydrocortisone (generics) and Surolan (ELANCO).

Florfenicol has been available for a number of years as a fast-acting, long-lasting injectable antibiotic for treatment of bovine respiratory disease. Recently, two new otic medications have been approved for the treatment of bacterial (Staphylococcus pseudintermedius) and yeast (due to the addition of terbinafine in the products). They also contain a topical glucocorticoid. These otic products are Claro (Bayer) and Osurnia (ELANCO).

Tris-EDTA is a topical product that enhances the activity of topical antibiotics against otic pathogens by decreasing stability and increasing the permeability of the cell wall of gram-negative bacteria. There are numerous products containing Tris-EDTA: Triz-EDTA (Dechra), TrizUltra (with ketoconazole) (Dechra), TrizChlor (with chlorhexidine) (Dechra), Mal-A-Ket Plus TrizEDTA Flush (with ketoconazole and chlorhexidine) (Dechra) and T8Keto (with ketoconazole) (Bayer).

Antifungal agents are used in cases of otitis caused by Malassezia or Candida. Ingredients that are active against yeast include nystatin (Panolog), thiabendazole (Tresaderm), miconazole (generics, Surolan, easOtic), ketoconazole (TrizUltra, T8keto), posaconazole (Posatex), clotrimazole (Otomax, Mometamax), and terbinafine (Claro, Osurnia).

An extra-label topical preparation containing enrofloxacin may be formulated using 1 part of the injectable enrofloxacin (22.7 mg/ml) added to 4 parts of an appropriate vehicle (Cort/Astrin for example) or 1 part injectable enrofloxacin to 1 part miconazole to 1

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part injectable dexamethasone (2 mg/kg). Topical enrofloxacin appears to be very effective for treatment of Pseudomonas otitis infections. Silver sulfadiazine 1% (Silvadene) is available in a cream formulation. One part of the Silvadene cream can be mixed with 1 part TrizChlor prior to application in the ear and has been shown to be very effective against resistant Pseudomonas. For inflamed ears with yeast otitis without a bacterial component a topical antifungal such as miconazole may be mixed 1:1 with dexamethasone.

So how would one decide which topical products to choose? Start with the chronicity of the otitis, the results of the otic examination, and otic cytology. The results of cytological examination of otic exudate are the basis for the selection of the active ingredient. Otic preparations that are ointment/suspension-based may not be as effective as those that are solution/emulsion-based, if the ears are stenotic or hyperplastic, as may be the case in those patients with chronic otitis externa, but may be utilized if the ears are not stenotic or hyperplastic or in animal with acute otitis externa. First line topical otic medications should be selected for those cases of acute or occasional otitis externa, while second-line otic medications, such as those containing fluoroquinolones, should be reserved for cases of bacterial otitis due to Pseudomonas otitis externa or those chronic infections that have not responded to first-line topical otic antimicrobials.

Systemic antimicrobial therapy for infectious otitis externa and otitis media is controversial. In dogs with end-stage otitis externa and concurrent otitis media, bacterial organisms may be isolated from the exudate in the lumen of the vertical ear canal and middle ear cavity as well as from the tissue from these sites. Therefore, most agree that systemic antibiotics (based on culture and susceptibility testing) are indicated in patients with otitis media, patients with severe proliferative chronic otitis externa, patients with ulcerative otitis externa, patients where inflammatory cells are seen cytologically (indicating deeper skin involvement) and in patients where owners cannot administer topical therapy. The selection of systemic antimicrobial agent must be made based on C/S from the external ear (for otitis externa) and middle ear (for otitis media). However, therapy may be initiated based on cytologic results while awaiting the results of the C/S.

Indications for systemic antifungal agents are similar to those above for bacterial infections and include patients with yeast otitis media, patients with severe yeast otitis externa, or in patients where owners cannot administer topical therapy. However, otic yeast infections require topical therapy in addition to systemic therapy for resolution. Both ketoconazole (5 mg/kg q24h) and itraconazole (Sporanox 5 mg/kg PO q24h or pulse-dosed 2 days on and 5 days off) have been used in dogs for treatment of yeast otitis.

Systemic glucocorticoids are used to decrease stenosis, edema, and hyperplasia of the vertical and horizontal ear canal to allow a complete otic examination as well as allow proper cleaning of the ear. They are also indicated in cases of allergic otitis externa. In older patients, or those with concurrent diseases, it may be necessary to perform bloodwork prior to starting the patient on glucocorticoids. Initially, 0.5-1 mg/kg q24h orally may be needed, followed by a low-dose, alternate day dosing schedule. The lowest dose needed should be administered to prevent the occurrence of side effects with the end goal to discontinue the systemic glucocorticoid.

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Managing Canine Otitis: Solving Those Difficult Cases

Lynette Cole Bayer Sponsored Content Provider

Acute Otitis Externa Topical Otic Treatments-First Line Otic Topicals

Product Options Otic Exam Rods, cocci, yeast OR rods

and yeast OR rods cytologically

Cocci and yeast OR cocci only cytologically

Yeast cytologically

Minimal to no stenosis or hyperplasia

easOtic Suspension Mometamax

Suspension Otomax Ointment Tresaderm Solution

Claro Otic Solution easOtic Suspension Mometamax Suspension Osurnia Otic Gel Otomax Ointment Tresaderm Solution

Claro Otic Solution easOtic Suspension MalAcetic Ultra Otic

Flush Mal-A-Ket plus

TrizEDTA Flush Miconazole Lotion Miconazole

Lotion/dexamethasone extra-label

Mometamax Suspension Osurnia Otic Gel Otomax Ointment Tresaderm Solution TrizUltra + Keto Flush T8Keto Flush

Moderate to severe stenosis or hyperplasia

Tresaderm Solution Claro Otic Solution Osurnia Otic Gel Tresaderm Solution

Claro Otic Solution MalAcetic Ultra Otic

Flush Mal-A-Ket plus

TrizEDTA Flush Miconazole Lotion Miconazole

Lotion/dexamethasone extra-label

Osurnia Otic Gel Tresaderm Solution TrizUltra + Keto Flush T8Keto Flush

Chronic Otitis Externa Topical Otic Treatments-Second Line Otic Topicals Product Options Rods, cocci, yeast OR cocci

and yeast OR rods and yeast cytologically

Cocci only OR rods only cytologically Yeast only cytologically

Minimal to no stenosis or hyperplasia

Baytril (2.27% injectable)/miconazole lotion/dexamethasone Solution extra-label

Posatex Suspension Surolan Suspension

Baytril (2.27% injectable): CortAstrin Solution: extra-label

Baytril (2.27% injectable)/dexamethasone/saline Solution extra-label

Baytril Otic Emulsion Posatex Suspension Surolan Suspension

Claro Otic Solution easOtic Suspension MalAcetic Ultra Otic

Flush TrizEDTA Flush Miconazole Lotion Miconazole

Lotion/dexamethasone: extra-label

Mometamax Suspension Osurnia Otic Gel Otomax Ointment Surolan Suspension Tresaderm Solution TrizUltra + Keto Flush

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T8Keto Flush

Moderate to severe stenosis or hyperplasia

Baytril (2.27% injectable)/miconazole lotion/dexamethasone Solution: extra-label

Baytril (2.27% injectable): CortAstrin Solution: extra-label

Baytril (2.27% injectable)/dexamethasone/saline Solution: extra-label

Baytril Otic Emulsion

Claro Otic Solution MalAcetic Ultra Otic

Flush TrizEDTA Flush Miconazole 1% lotion Miconazole 1%

Lotion/dexamethasone extra-label

Osurnia Otic Gel

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Alopecia: What to Do When the Thyroid is Normal

Thomas Lewis, DVM, DACVD Dermatology for Animals

Tempe, AZ

When a canine patient presents to a veterinarian with the complaint of hair loss, we are ingrained to investigate the dog’s thyroid and cortisol levels. When these tests reveal normal thyroid and adrenal gland function, a second tier of differential diagnosis needs to be considered.

There are typically several phases to the hair cycle. Anagen is when the follicle is in an active growing stage. Catagen is a transition phase between anagen and telogen which is the resting phase. Exogen is the shedding of the hair. Breeds in which anagen is the predominant phase will have minimal shedding but require regular grooming or cutting of the hair. Examples are poodles, Old English sheepdogs, Angora rabbits and humans. Breeds in which telogen is predominant will exhibit continuous or seasonal shedding. Labrador retrievers have continuous shedding while malamutes will be more seasonal with their shedding. Clients and others will use the term “blow the coat” to describe this dramatic shedding.

As with many dermatological abnormalities, signalment and history can be important when determining the cause of hair loss. Questions regarding age of onset, sex of the patient, reproductive history, and medical history prior to onset of the alopecia are all potentially relevant.

When examining a patient with alopecia, the clinician should evaluate for the presence or absence of inflammation and look for lesions suggestive of pruritus with hair barbering. Changes in skin or coat color or texture might prove helpful diagnostically. Note the pattern; is the alopecia bilaterally symmetrical suggestive of hormonal or congenital abnormalities, or is there asymmetry or focal or multifocal lesions suggestive of infection of the skin or follicle. Lesions such as papules, pustules, crust or scale are also important to note and typically suggest an inflammatory cause to the hair loss, and/or secondary bacterial infection of the follicle. Approach to hair loss diagnostics A Trichogram, or hair pluck, is a vastly under-utilized diagnostic tool when evaluating a patient with hair loss. The technique involves plucking a group of hairs with a hemostat and placing the hair on a glass slide which has a drop of oil to hold the hairs in place. The microscope diaphragm should be closed. The hair shaft should be evaluated, is there breakage at the tip suggesting broken or barbered hairs? The presence of melanin clumping should be noted, as well as the shape of the hair bulb and the stage of hair growth. With practice a clinician can identify ectothrix hyphae of dermatophytes, and demodex mites can also be found with trichograms. Congenital and heritable causes of alopecia Examples of congenital or heritable alopecia include the well-known alopecic dog breeds such as the Mexican hairless (Xoloitzcuintle), Chinese crested, as well as the lesser-known American Hairless terrier and Inca hairless dogs. Cats with heritable alopecia include the Sphinx, Donskoy, Bramble cat, Dossow and Peterbald. In these breeds, the hairlessness is thought to have an autosomal dominant mode of inheritance, and some individuals may also have features of ectodermal dysplasia or may also exhibit abnormal dentition, glandular formation and/or function.

Black hair follicular dysplasia is an uncommon condition where the alopecia is confined to the black haired portions of the coat. The early clinical appearance may be broken or dull appearing hair which later develops more obvious alopecia and scaling. The condition is thought to be an autosomal recessive trait and susceptible breeds include Bearded collie, Saluki, Border collie, King Charles spaniel, Jack Russell terrier, Gordon setter and Yorkshire terriers. The diagnosis can be supported with a trichogram which reveals clumping of melanin in the hair shaft and confirmed with histopathology showing large clumps of melanin within the melanocytes of the hair matrix as well as atrophic or distorted hair follicles.

Color dilution alopecia affects blue, gray, fawn and red coats (aka “dilute coats) with clinical signs occurring between 3-24 months of age. These individuals typically have full hair coats as puppies and young adults. Alopecia is thought to be due to abnormal transfer of pigment into the hair which results in broken hairs and subsequent alopecia. Trichogram and histopathology findings are identical to that of black-haired follicle dysplasia, and no effective therapy exists for either condition.

Other even more uncommon or rare congenital or hereditary causes of alopecia will be shown during the lecture including melanoderma and alopecia in Yorkshire terriers, “Bald thigh syndrome” in greyhounds, and breeds with hair cycle abnormalities leading to alopecia such as Irish water spaniels and Portuguese water dogs.

Immune-mediated alopecia One of the more common immune-mediated causes of alopecia is sebaceous adenitis. Breeds which are predisposed include the Standard poodle, Samoyed, Akita, Havanese, German shepherd, vizsla and dachshund. Clinically the condition may be generalized

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and symmetrical, or more focal or multifocal. There is often a change in both the color and texture of the skin and coat, and the clinicians should note the presence of follicular casts. Pruritus is variable. On histopathology the pathologist will see inflammation around sebaceous glands or even more commonly complete absence of these glands. Because the hair loss can be symmetrical, and dramatic in long-coat breeds, the disorder is frequently misdiagnosed as hypothyroidism.

Other rare immune-mediated causes of hair loss will be shown including alopecia areata, alopecia universalis, and canine familial dermatomyositis.

Hypothyroidism. The first test usually called for with symmetrical alopecia is resting thyroid. Thyroid hormone influences cell cycle kinetics of the hair bulb, and low thyroid levels leads to decrease proliferative activity. Thyroid receptors are found on sebocytes, cells of the outer root sheath and dermal papilla. With hypothyroidism the alopecia is a result of slower elongation of the hair shafts (prevention of anagen) and hair cycle arrest. Clinically the hair coat may appear dull and brittle, with nonpruritic, non-inflammatory and symmetrical truncal alopecia, although alopecia may be first noted in areas of wear or failure to regrow post-clipping. In some breeds such as boxers and Doberman pinschers, hair retention may lead to a “bleached out” appearance. Average age of onset is between 6-10 years of age, and dermatologic changes are seen in approximately 60-80% of cases. Other clinical signs include lethargy, weight gain, mental dullness and myxedematous changes (tragic facial expression). It is important to differentiate between true hypothyroidism and euthyroid sick syndrome, and to keep in mind the drugs that will interfere with thyroid levels when testing. An in depth discussion of thyroid testing is beyond the scope of these notes and lecture.

Hyperadrenocorticism (Cushing’s disease) is the second most common endocrine disorder resulting in alopecia in the dog. In addition to symmetrical alopecia, other cutaneous abnormalities can include thin skin, comedones, hair color changes (bleaching) and hyperpigmentation. Non-dermatologic clinical signs include PU/PD, polyphagia, muscle wasting and pot-belly formation, excessive panting and lethargy. The diagnosis and treatment of Cushing’s disease is beyond the scope of this presentation.

Alopecia X is yet a different endocrine abnormality resulting in alopecia. The exact etiology is unknown, but thought to be related to imbalance of adrenal gland steroid hormone intermediates such as 17-hydroxyprogesterone. Plush coated breeds are predisposed such as Pomeranians, Alaskan malamutes, Chow chows, Keeshonds, Samoyeds, Siberian huskies. Age of onset can be younger than other endocrinopathies, often between 1-3 years of age. Initially loss of guard hairs results in a dry, dull coat which progresses to hair loss, especially in frictional areas, that becomes more wide-spread. The underlying skin may become scaly or hyperpigmented. The diagnosis is generally one of exclusion. Histopathology will show the classic changes of an endocrinopathy, but may also have features of follicular dysplasia or flame follicles. The sex-hormone stimulation test available at the University of Tennessee can also help rule out other sex-hormone disorders. Since this condition is not known to cause other systemic illness (unlike hypothyroidism or Cushing’s disease), conservative therapy is called for. Melatonin and flax seed oil with lignans may cause regrowth in about 40% (caution with diabetics). Mitotane and Trilostain can cause hair growth but have a higher risk of side effects.

Transdermal absorption of topical sex hormones. A growing cause of alopecia in dogs is being recognized due to accidental or unintended, transcutaneous absorption of human topically applied hormone replacement cream. This is often a testosterone cream for males or more commonly a combination cream (progesterone and/or estrogen and/or testosterone) for female application. In our experience the affected dogs are usually smaller (less than 15 kg) and have direct exposure to the human skin where the sex hormone replacement has been applied. The resulting alopecia in dogs is usually “patchy” and hyperpigmentation may also be seen. Other clinic signs have included onset of sexual behavior, enlarged nipples, or estrous like behavior in females. The diagnosis is based on history and the University of Tennessee sex-hormone panel can also confirm abnormal sex hormone levels. It is critical to question owners about exposure to exogenous sex-hormone replacement products in dogs with abnormal blood levels, especially before expensive imaging or invasive exploratory surgeries.

Pattern alopecia, aka pattern baldness, is a non-inflammatory, non-pruritic, slowly progressive alopecic dermatosis which most commonly affects the convex pinna, periaural areas, ventral trunk and caudal thighs, usually in a bilateral symmetrical pattern. Breeds most commonly affected include Boston terrier, boxer, Chihuahua, dachshund, Italian greyhound, miniature pinscher and whippet. No affected therapy is known, although there are anecdotal reports of melatonin having some efficacy.

Traction alopecia can develop after application of a hair clip or rubber band that is too tight, causing disruption of cutaneous blood flow and follicular atrophy. The alopecia is localized, typically on the dorsum of the head.

Flank alopecia, aka seasonal flank alopecia, cyclic flank alopecia or recurrent flank alopecia is a localized, potentially seasonally recurring, non-inflammatory alopecia which is often accompanied with hyperpigmentation. Some consider this another variation of Alopecia X. It is often bilateral but not necessarily symmetrical. Melatonin and Flax seed oil with lignans is the normal recommended therapy, but this has variable and sometimes poor efficacy.

Post-vaccination panniculitis occur most commonly, but not limited to, a rabies vaccination. Lesions are most commonly alopecic patches at or near the injection site, but can be wide spread, and even multiple sites. Alopecia may be noted 2-4 months after an injection and small dogs (under 10 kg) are predisposed. Topical tacrolimus and systemic pentoxifylline are therapeutic options.

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Chemotherapy induced hair follicle dystrophy is caused by chemotherapeutic agents which affect cell division, resulting in impaired mitotic and metabolic processes in actively growing hair follicles. Hair loss begins 7-10 days following initiation of treatment and is most dramatic within 1-2 months. Breeds with hair follicle in which anagen is the dominant stage (poodles, Old English sheepdogs and terriers) are at increased risk.

Post-clipping alopecia is a term to describe failure of regrowth within 3 months of clipping. “Plush coated” breeds are at higher risk such as the Alaskan malamute, American eskimo, chow chow, pomeranian, samoyed, Siberian husky and keeshond. Because complete regrowth can occur within a year, it is also speculated these breeds normally have a very slow hair growth rate.

Paraneoplastic alopecia is a rare syndrome which is most commonly associated with pancreatic malignancy. The alopecia is generally acute with rapid onset spreading over the entire body and is accompanied with a characteristic shiny skin and large scale.

Telogen Effluvium results from a stressful occurrence (pregnancy, shock, drugs and anesthesia) which results in abrupt premature cessation of growth and synchronization of hair follicles into catagen and then telogen. Hair loss typically occurs within 1-3 months of insult a trichogram may help identify large numbers of telogen follicles. The condition will spontaneously resolve.

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Derm Emergencies Thomas Lewis, DVM, DACVD

Dermatology for Animals Tempe, AZ

Dermatology “emergencies” can range from irritated or inflamed skin which is disturbing the patients and owners quality of life, to truly life threatening dermatological disorders.

Pruritus/pyotraumatic dermatitis: One of the more common reasons for a patient to be presented on an urgent or critical basis is intense pruritus and/or pyotraumatic dermatitis (aka “hotspot”). Clinically the pruritus is often acute and may progress into secondary Staphylococcal or Malassezia dermatitis due to the self-trauma. Underlying causes of the pruritus are oftentimes flea allergy although mites, atopy and food allergy can also be a cause of the initial pruritus. Clinically these patients are pruritic or even painful with rapidly enlarging areas of erythema, alopecia and exudative dermatitis. Lesions are most common on the trunk, tail base, lateral thigh, neck and face. Lesions on the lateral face are known to be associated with a deeper bacterial folliculitis and furunculosis. Treatment includes finding the underlying cause of the pruritus, aggressive parasite control. It can be helpful to clip/clean lesion with dilute chlorhexidine or dilute betadine although pain control +/- sedation may be needed. Topical antibiotic/steroid products are indicated and usually systemic steroids. Systemic oclacitinib would also be indicated for 7-10 days and is a good alternative to corticosteroids. If lesions include papules, pustules or thickened skin, or if the lesion is on the lateral face, a 3-4 week course of oral antibiotics is indicated.

Otitis +/- Aural hematoma: Otitis most commonly is due to a primary allergic trigger (parasite, food, atopy) and less commonly due to hypothyroidism, keratinization disorders and foreign bodies such as foxtails. Once the pinnae and ear canal are inflamed, they are often complicated by secondary bacterial or Malassezia infection. Factors which perpetuate the otitis include thickening of skin, stenosis of the canal and otitis media. Even though identification and treatment of the secondary infection gets much of the attention when dealing with otitis, it is more important for the emergency clinician to also deal with the inflammation and pain which is present. This usually requires topical and systemic steroids with the dose and duration based on the severity of the inflammation. Control of the secondary infections are always based on cytology (one cannot treat ear disease without a microscope) and not odor, texture of the exudate, or other factors. Ultimately identification and control of the underlying allergic disease will lead to successful prevention of recurring otitis but this may not be the focus of an emergency visit. Corticosteroids are also useful when dealing with an auricular hematoma. Some clinicians advocate immediate surgical intervention of an ear hematoma, but it is also possible in the short-term to drain the hematoma with an 18 or 20 gauge needle attached to an appropriate sized syringe and aspirate the fluid within the hematoma. Surgi-sox® Dogleggs head wrap can be useful in reducing trauma from head shaking and then surgical correction can be performed once the otitis externa is controlled. Recently this author has been using a CO2 laser to make multiple small puncture type incision on the medial pinna with success.

Juvenile cellulitis (aka puppy strangles, juvenile pyoderma, or juvenile sterile granulomatous dermatitis and lymphadenitis) is a granulomatous and pustular disorder of the face, pinnae and submandibular lymph nodes. The cause is uncertain although the favorable response to steroids suggests an immune mediated component, while breed predisposition suggests a heritable component may also be involved. Patients with juvenile cellulitis tend to be young (3 weeks to 6 months) and multiple members of a litter may be affected. Breeds which seem over represented include golden retriever, dachshund, Labrador retriever, Gordon setter, beagle and pointers. Patients present with facial swelling, pustules and papules on the eyelids, lips, muzzle, bridge of the nose and medial pinnae. Patients are frequently febrile, and often have submandibular lymphadenopathy. The lesions can fistulate, drain and produce crust. The diagnosis is based on the clinical features and ruling out other causes of folliculitis including demodicosis, deep pyoderma, dermatophytosis and drug reactions. Cytology of a pustule (or crust) show pyogranulomatous cellular infiltrate with no bacteria. Histopathology helps confirm the diagnosis, but the distinct presentation of this condition often makes histopathology unnecessary after the infectious causes mentioned above have been ruled out. Corticosteroids are essential in the treatment of juvenile cellulitis, with a starting dose of 1-2 mg/kg/day until lesions are inactive. A slow taper over the next 6-12 weeks is then indicated. Relapses are rare unless the prednisone is tapered too quickly. Doxycycline may have some steroid-sparring affects, but keep in mind the age of the patient and potential for staining of the teeth.

Urticaria and Angioedema: It is not uncommon for patients to present on an emergency basis with acute swelling of the face. The pathogenesis is thought to be a Type I and or Type III hypersensitivity disorder. Clinical signs include erythematous wheals (which disappear on diascopy), edematous swelling of face and ventral neck, and variable pruritus. An extensive list of triggers should be explored including adverse reactions to foods, drugs, vaccines, insects, intestinal parasitism, skin parasites, infection and atopy. Treatment includes identification of triggering factor if possible, along with antihistamines IM, glucocorticoids IV, IM, SQ, PO and epinephrine in severe cases.

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Post-grooming furunculosis: The pathogenesis is thought to be due to short coated breeds being predisposed with mechanical trauma from vigorous grooming. Other causes or in longer-coated breeds being due to contaminated shampoos applied at grooming. Patients typically present 24 to 48 hours post grooming with the dorsal midline being most severely affected. Lesions include marked erythema, induration, pustules (hemorrhagic), papules, furuncles, ulcers and draining tracts. Patients are usually febrile and initially may mimic spinal pain. The diagnosis is based on the history, physical exam and cytology findings showing a marked pyogranulomatous inflammatory response with intercellular rod-shaped bacterial organisms. If rods are seen, a culture for sensitivity testing is indicated. Histopathology reveals a deep pyogranulomatous to suppurative inflammation with folliculitis, furunculosis, panniculitis and cellulitis; bacteria may or may not be seen. Treatment is with systemic antibiotics based on culture, but fluoroquinolones are a good first empirical choice while results are pending. Pain management with Tramadol or NSAIDs may also be indicated.

Sterile pustular erythroderma of miniature schnauzers (aka superficial suppurative necrolytic dermatitis, Schnauzer syndrome) is a rare cutaneous and visceral disease with an unknown etiology. It can be due to adverse drug reactions, or unusual allergens or immunogens, especially components of shampoos or other topical chemical products, especially “herbal” topical products. Even though usually seen in miniature schnauzers, other breeds have been recognized with similar clinical presentations. Patients present with localized erythematous macules and papules with coalescing edematous plaques with crust. Lesions usually spread rapidly, become painful, and the patients become obviously ill with fever, anorexia. Patients may have hypoalbumenemia and a neutrophilic leukocytosis. The prognosis can be poor and patients can die without aggressive supportive treatment as would be appropriate for a burn patient.

Erythema multiforme (EM) is considered to be a host specific, cell-mediated hypersensitivity reaction induced by various antigens including drugs, chemicals, infections, neoplasia and even food allergy. Many are idiopathic. Toxic epidermal necrolysis (TEN) is considered to be a more severe manifestation of EM. As the name suggest, EM can present with a variety of cutaneous lesions ranging from erythematous macules to slightly raised papules which spread peripherally and clear centrally. Urticarial plaques, vesicles, bullae, ulcers can occur, and lesions most commonly affect the ventrum, mucocutaneous junctions, pinnae and footpads. With TEN lesions are even more extensive and can include full thickness necrosis of the epidermis. Both can be acute onset and life threatening and the presumptive diagnosis is based on history and physical examination and confirmed with histopathology. Treatment includes identifying and treating the underlying cause if possible. Any suspect drugs should be discontinued if possible. Mild cases may spontaneously resolve within 2-4 weeks but immunosuppressive treatment may be needed for severe or refractory cases. Corticosteroids, cyclosporine and pentoxifylline at immunosuppressive doses are this author’s first treatment of choice, but keep in mind severe cases may require supportive therapy including hospitalization. Glucocorticoid use is controversial with TEN and patients should ideally be referred to a facility skilled with the treatment of intensive care.

Necrotizing fasciitis (aka “flesh eating” infection, Toxic shock syndrome) is a fulminant, rapidly progressive, life threatening infection of fascial and SQ tissues which in dogs is usually caused by Streptococcus canis (Group G streptococcus). Fascial tissue infection may occur if the normal skin barrier is compromised such as with a penetrating wound or blunt trauma. Tissue destruction and extension occurs due to bacterial exotoxins and proteases, resulting in localized erythema, edema, swelling, heat, marked pain with subsequent sloughing. A malodorous discharge may develop in the SQ tissue leading to the term “Murky dishwater.” The limbs and trunk are most commonly affected and patients are febrile, lethargic and tachycardic. The diagnosis should be suspected based on the clinical presentation combined with cytological findings of pairs or chains of gram positive coccoid bacteria. A positive “finger test” is where the SQ tissue is easily separated from fascia by blunt dissection. Early tissue culture and sensitivity is critical and successful treatment hinges on early and complete surgical debridement. Limb amputation may be required. Medical treatment alone is usually not successful due to poor antibiotic penetration of affected areas and continued production of bacterial exotoxins. It is recommended to start a combination of penicillin, aminoglycoside and clindamycin pending culture results, and also to avoid fluoroquinolones as they may induce bacteriophages encoding superantigen genes thus increasing bacterial virulence. Pain control with opioids is also important for these patients but one should avoid NSAIDS as they may enhance disease progression via neutrophils inhibition. Intensive supportive, nutritional and hemodynamic therapies similar to care for a severe burn patient are essential.

Thermal burn: Superficial burns affecting the epidermis only lead to painful erythematous desquamation which heals in 3-5 days via re-epithelialization. Partial to full thickness burns affects the epidermis and varying degrees of the dermis and sub cutis, resulting in blister, edema, and eschar formation if the entire dermis is involved. Burns can be caused by strong chemicals, electric currents, solar and microwave radiation and heat (fire, boiling liquids, heating pads, dryers). Damage from solar or heat can be hidden by fur and not become evident for a week post injury when necrotic skin appears, thus making history important with any necrotic lesion. Treatment is similar as for toxic epidermal necrolysis.

Vasculitis is an inflammatory disorder of blood vessels which is usually due to immune complex deposition in vessel walls, therefore any antigenic stimulation can trigger vasculitis. The clinical presentation consists of purpura, necrosis, punctate ulcers,

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alopecia, crusting and erosions most often on the ears, tail tip and footpad. The diagnosis is confirmed with histopathology. Therapy includes finding and treating the underlying cause when possible and immunosuppressive therapy. Pentoxifylline is an important immune modulating drug which is usually indicated with vasculitis.

Pemphigus foliaceus may present in an emergency setting and the challenge is for the busy emergency clinician to not assume the lesions are due to a bacterial pyoderma since the primary lesion of pemphigus is a superficial pustule, which then leads to secondary crust, scale and alopecia. With generalized skin disease, fever, lethargy, depression, limb edema, lymphadenopathy may occur. Cytology of a pustule can be very helpful in distinguishing pemphigus (with acantholytic keratinocytes seen on cytology) vs pyoderma (which will reveal intercellular coccoid bacteria) but of course the diagnosis is confirmed with histopathology. On an emergency basis, treatment with oral or injectable corticosteroids would be indicated (after the biopsy) but if the diagnosis is confirmed, additional therapy with azathioprine, cyclosporine, or mycophenolate can have significant steroid-sparring affects.

Eosinophilic furunculosis of the face is seen in dogs and is often suspected to be due to insect or arachnid envenomation although in practice, the cause in most cases remains speculative. Patients present with an acute onset erythematous papular eruption of the bridge of the nose which leads to alopecia, erosions and ulcers, with serous and hemorrhagic crusting. Differential diagnosis would be nasal bacterial furunculosis or pemphigus complex, but cytology should show eosinophils without bacteria or acantholytic keratinocytes. Treatment with systemic corticosteroids over 2-4 weeks usually leads to resolution.

Feline mosquito bite hypersensitivity is an uncommon, seasonal dermatosis in cats that predominantly affects the bridge of the nose, pinnal, and footpad areas. Initially after the bite a focal wheal may develop, which progresses to a popular eruption with serous crusting, alopecia and potentially erosions or ulcers. Black skin seems overly predisposed for unknown reasons, and is obviously seasonal and correlates with mosquito season. Treatment involves keeping the patient inside, especially dawn to dusk and topical and or systemic corticosteroids.

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Diagnostic Workup and Therapy of the Allergic Dog Thomas Lewis, DVM, DACVD

Dermatology for Animals Tempe, AZ

Immunotherapy, Oclacitinib, IL-31 mAb, Corticosteroids,

Cyclosporine, Topical therapy, Fatty Acids (including diet), and

Infection control

Challenge withFormer Diet

Atopy

PruritusResolves

Pruritus Persists

Food Trial &Parasite

Treatment

No

YesPrimary Lesion

Skin ScrapingsDTM &

Cytology

Non-seasonalOr Unsure

u tus Flea Allergy

PruritusPersists

Seaso a

Pruritus Persists

Pustules = Pyoderma, Pemphigus Foliaceous, Dermatophytosis, Demodex

Papules = Pyoderma, Parasite Hypersensitivity, Demodex, Dermatophytosis, Neoplasia, Viral

Plaques = Pyoderma, Dermatophytosis, Acanthocheilonema, Neoplasia,Calcinosis Cutis, Viral, Keratinization disorder

Nodules = Deep Pyoderma, Neoplasia, Sterile Granuloma,Deep Fungal

C Idi

Ap Thomas

Pruritus Flares, Indicates Food

Hypersensitivity

Pruritus doesn’t Flare, Indicates

Parasite Hypersensitivity

Approach to the pruritic patient When faced with a pruritic dog in an exam room, the practitioner may feel he or she is faced with a hopeless array of possibilities as to the cause of the pruritus. One way to approach these cases is by following a flowchart, such as the one handed out during this lecture. The flowchart emphasizes the importance of obtaining a thorough history regarding each patient as well as performing essential diagnostic tests such as skin scrapings for mites, skin cytology for bacteria, yeast and inflammatory cells, and dermatophyte cultures to identify infections on every pruritic pet. Depending on history, seasonality, and response to treatment of parasites and infections, further assessment with skin biopsy or culture, hypoallergenic diet trial, or allergy testing may be warranted. These notes are intended to aid in the process of obtaining an accurate diagnosis as to the cause of the pruritus.

The first question to ask an owner with a pruritic patient is to determine if there is a seasonal recurrence of the pruritus. If so, this tends to limit the possibilities to either flea allergy or atopic dermatitis. Many times, especially if this is a new patient, the owner and veterinarian may not know, in which case the minimum data base should be a skin scraping and DTM culture, along with cytology if any primary lesions are present. This should all be performed during the initial examination. If lesions such as papules, pustules, plaques, nodules or crust are present, cytology is always indicated to investigate the cause of these lesions. Remember primary allergic disease rarely elicits the formation of any of these primary lesions. If cytology or scrapings reveal findings such as mites,

Refer, Repeat FoodTrial, Biopsy

Immunotherapy, Oclacitinib, IL-31 mAb, Corticosteroids,

Cyclosporine, Topical therapy, Fatty Acids (including diet), and

Infection control

Challenge withFormer Diet

Atopy

PruritusResolves

Pruritus Persists

Food Trial &Parasite

Treatment

No

YesPrimary Lesion

Skin ScrapingsDTM &

Cytology

Non-seasonalOr Unsure

Pruritus Atopy, Flea Allergy

PruritusPersists

Seasonal

Pruritus Persists

BiopsyCulture

LesionsPersist

Antibiotics

Biopsy

Pustules = Pyoderma, Pemphigus Foliaceous, Dermatophytosis, Demodex

Papules = Pyoderma, Parasite Hypersensitivity, Demodex, Dermatophytosis, Neoplasia, Viral

Plaques = Pyoderma, Dermatophytosis, Acanthocheilonema, Neoplasia,Calcinosis Cutis, Viral, Keratinization disorder

Nodules = Deep Pyoderma, Neoplasia, Sterile Granuloma,Deep Fungal

Cytology

PruritusClears

LesionsClear

Food Allergy, Hypothyroid,

Cushing's, Atopy,Idiopathic Recurring

Pyoderma

Approach to PruritusThomas P. Lewis II, DVM, DACVD

Dermatology for Animals

Pruritus Flares, Indicates Food

Hypersensitivity

Pruritus doesn’t Flare, Indicates

Parasite Hypersensitivity

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neoplastic cells, or infectious causes of dermatitis, then these conditions will obviously need to be treated. Often times an allergic patient will present with concurrent secondary bacterial or Malassezia dermatitis, which exacerbates the pruritus and needs to be addressed.

If pruritus resolves after dealing with secondary infection, then non-pruritic causes of infections such as endocrinopathies, food allergy or idiopathic recurring pyoderma should be considered. If pruritus remains despite treatment of any secondary infection, then a food trial and empirical treatment of ectoparasites would be indicated. If pruritus persists despite a food trial and parasite treatment trial, the patient should be considered as atopic. Notes on food allergy and food trials are provided as additional notes. Parasite treatment regiments have improved significantly with the arrival of the Isoxazoline family of drugs. Three are currently available, and even though they are all off-label for the treatment of demodicosis and scabies, these products are proving to be a very reliable, safe and effective way to treat the ectoparasites which cause pruritus in dogs and cats.

When a practitioner finds primary lesions, and cytology fails to give answers consistent with infectious causes, then a biopsy may be appropriate. Diseases such as sebaceous adentitis, T-cell (epitheliotropic) lymphoma, and sterile granulomatous diseases may mimic allergic disease but can be distinguished on histopathology. Biopsies of erythematous, pruritic skin without other primary lesions is generally not appropriate use of owners’ funds, as histopathology will only reveal a pattern of inflammation consistent with a hypersensitivity reaction. In most cases, the astute clinician should be able to determine this without the aid of histopathology.

If the clinician is finding coccoid bacteria from cytology samples, then obviously a Staphylococcus bacterial infection should be assumed and treated either systemically, or topically, or both. With the rise in methicillin-resistant Staphylococcus (MRS) infections, if improvement is not seen after empirical therapy, a culture and sensitivity should be performed. Because the vast majority of patients suffering from bacterial infections (resistant or not) are due to underlying allergic diseases, the clinician should feel even more motivated to identify and treat the underlying cause o f these secondary infections. Most owners, once educated of the rise in MRS and need to determine the underlying etiology of these infections, will become more compliant and motivated to find the causes as well.

It is also important to remember that many allergic patients will have multiple “triggers” to their allergy, with as many as 40% of the allergic patients being allergic to both food and environmental allergens. Such a patient is also going to be the one which has a more severe reaction when exposed to fleas or other ectoparasites. In this case, it is necessary to address and control multiple causes of pruritus, which will require extra time in the exam room to educate the client of these factors. Such a patient may require control of ectoparasites, secondary bacterial or Malassezia dermatitis, food allergy, and atopic dermatitis before the pruritus is truly controlled and the patient stable. In an ideal situation such a patient would be controlled with dietary restrictions, topical antimicrobial shampoo therapy, and allergy specific immunotherapy. Older patients, or patients with short-term seasonal pruritus may be better candidates for antipruritic or anti-inflammatory medications such as corticosteroids, oclacitinib, cyclosporine, or IL-31 monoclonal antibody therapy. Food allergy Food hypersensitivity, food intolerance and other adverse reactions to food (ARF) could be the subject of a carrier of study. Food hypersensitivity in the dog and cat can cause a myriad of effects on several different systems of the body, with the integument and digestive system being most commonly affected. This article will hopefully give insight into how ARF will affect the skin in dogs and cats.

Because food hypersensitivy can be the manifestation of a type I, III or IV hypersensitivity reaction, the onset of clinical signs can range from minutes to days after ingestion of the offending allergen. In humans the allergen usually has a molecular weight above 12,000 Daltons, although this has not been confirmed in domestic animals, where the offending allergen may be smaller. A number of studies published over the years have listed the most common food allergens in dogs and cats. Summarizing these reports has led many dermatologists to conclude that animals have the potential or ability to become allergic to any food stuff to which they are exposed, especially proteins. In a 1996 report (Jeffers) from the United States, the most common allergens were beef, chicken, chicken egg, cow milk, wheat, soy and corn. In this report 80% of the dogs reacted to just one or two items although there are reports of dogs allergic to as many as nine food items. Additional published reports will list fish, rice and potato as foods known to cause adverse reactions. The food items most commonly known to cause ARF in cats include chicken, fish and dairy products. A few minutes spent reading ingredient labels of most commercial cat foods will show these are the most common ingredients used in formulating the diets.

One common misconception by clients and many veterinarians is that food allergy is more likely to develop only after a recent diet change. In fact when food allergies develop the offending allergen has often been fed for over two years, and some patients will eat the same protein for many years before the allergy develops. To further complicate the workup of a suspect food allergic patient is the recognition that some patients will have cross reactions between related food ingredients. This phenomenon is well recognized in human medicine as well. Examples include patients allergic to chicken who will not tolerate duck or turkey. Some patients allergic to

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beef will cross-react or show clinical signs when exposed to other ruminants, such as lamb or venison. Fortunately not all food allergic patients will have cross reactions, but some will, which further complicates the workup of these patients Food hypersensitivity in dogs No age or sex predisposition is known to exist regarding the development of food allergy in the dog, but as many as 50% of food allergic patients may exhibit clinical signs at less than a year of age. There may be a higher rate of food allergy in “allergic breeds” such as the Cocker spaniel, Springer spaniel, Labrador retriever, Miniature schnauzer, Shar Pei, West Highland white terrier, Wheaten terrier, German Shepherd, and Golden retriever. Three breeds of dogs this author associates with a higher rate of food allergy are German Shepherds, Rhodesian ridgebacks, and the Shar Pei dog. Clinical signs are variable but nonseasonal pruritus, otitis, and dermatitis are frequently seen in dogs suffering from a food allergy. Sometimes the clinical signs are as simple (or vague) as recurring pyoderma or a nondescript keratinization disorder (seborrhea). Food allergy should always be considered as a cause for any patient with recurring urticaria, and eosinophilic vasculitis has also been associated with ARF.

In general the clinical signs of food allergy are non-seasonal, although they could be episodic if due to sporadic treat administration. It is also possible for the effects of a food allergy to be low or subclinical (below a pruritic threshold) and only with the addition of environmental allergens will the patient flare.

Any dog with a non-seasonal pruritic dermatosis should have food allergy ruled out as a contributing cause of the skin disease. In addition there are several other clues which may raise the index of suspicion that a patient is suffering from a food allergy. One is the pattern of skin disease. Food allergies are known to commonly affect the “ears and rears” of the patient. Another potentially useful clue is the response to corticosteroids. Atopic dermatitis is usually responsive to corticosteroids at anti-inflammatory doses. While some patients with a food allergy will be very steroid responsive, some will not, and when the pruritus is not steroid responsive, food allergy should be considered. Nearly half of this authors patients will have gastrointestinal manifestations of their ARF. Dramatic GI signs include vomiting and diarrhea, but it may be as subtle as flatulence or frequent (more than 2/day) bowel movements. Rarely reported clinical signs of ARF include seizures and respiratory signs including bronchitis, rhinitis and chronic obstructive pulmonary disease, all of which have been recognized by this author. Feline food allergy No age or sex predisposition has been reported or recognized in food allergic cats. White (1989) reported the offending allergen had been fed on average over two years. Siamese and Siamese crosses may be a breed predisposed to food hypersensitivity. The classic or hallmark clinical sign for food allergy in the cat is pruritus, especially of the head. Others will manifest as “self induced alopecia”, or any manifestation of the eosinophilic granuloma complex. Diagnostic tests The diagnosis of food allergy in the dog and cat remains a challenge. Unfortunately as of 2017 the only method to accurately identify patients which suffer from food allergy is by performing an elimination diet trial for sufficient time while controlling all concurrent allergies and secondary infections. This is easier said than done. Both intradermal allergy testing and serology testing for food allergies remain unreliable with both false positive and false negative reactions occurring.

Three types of diets are available and useful in a veterinary dermatology setting. Novel protein and hydrolyzed protein diets are useful for the diagnosis and long-term management of a food allergic patient. The trend has been for manufactures to utilize hydrolyzed diets over novel proteins in both human and veterinary medicine. Therapeutic diets are formulated with higher and “balanced” levels of omega 3 &6 fatty acids, as well as skin barrier enhancement and are most useful for the atopic patient. They will not necessarily be formulated with novel proteins. Most of the major manufactures of prescription dog food now provide a line of “hypoallergenic” foods. There is no foolproof “works every time” test diet. Choosing the “best” diet to feed a suspected food allergic patient requires careful and detailed questioning of the client regarding previous and current diets, treats, and flavored medications. Once that information is known, the practitioner must choose a diet that 1) consists of proteins to which the patient has not had exposure 2) with minimal chance of cross reactions with previously fed proteins 3) that the patient will eat 4) and that the client is able and willing to feed. Because of all these factors, rabbit, kangaroo, and occasionally fish have been the novel proteins of choice for the majority of our suspected food allergic patients. Unfortunately these are becoming more limited regarding availability. Many novel protein diets now also include hydrolyzed proteins (such as soy). The clinician should also have confidence the manufacturer of the food has truly kept the food limited to what is stated on the label, and not allowed contamination with other feeds or proteins.

In addition to determining which product is appropriate for the test diet, it is also necessary to counsel the owners on what to avoid feeding. We frequently deal with situations where the owners have fed an appropriate test diet, but continued to feed treats and protein based supplements. Some of our food allergic patients will flare, or continue to exhibit clinical signs simply from beef or pork based additives in chewable medications.

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As already mentioned, hydrolyzed diets are now the predominant hypoallergenic products available in veterinary medicine. Hydrolyzed chicken and soy based products are currently the most common options from the major manufactures. Several published studies have reported the majority of patients fed hydrolyzed diets have improvement in clinical signs, even if they are allergic to the parent protein. Yet other studies show up to 50% of food allergic patients flare or fail to improve on a hydrolyzed diet. In 2010 Olivry summarized all of the various (and sometimes conflicting) articles on the subject and concluded hydrolyzed diets not be used if the patient could potentially be hypersensitive to the parent (non-hydrolyzed) protein. For these reasons, the International Committee of Allergic Disease in Animals (ICADA) has recommended hydrolyzed diets not be used as a test diet in animals with previous exposure the parent protein. However a small study published in 2016 reported a cross-over study of ten dogs allergic to poultry. In this study dogs were fed a hydrolyzed chicken liver and cornstarch (Hills z/d®) with a poultry feather hydrolysate with cornstarch (Royal Canin Ultamino®). In this particular study, 4 of the 10 dogs flared when fed the hydrolyzed chicken liver product, but none of the ten dogs flared or reacted negatively to the feather hydrolysate. Authors speculated the reason for these results could include differences in allergenicity due to a different degree of protein hydrolysis (a smaller size of hydrolysate), or a difference in protein composition of poultry feathers vs. liver. Another possibility could be related to the presence of residual peptides of larger size in z/d that were not hydrolyzed. It is reported that 3% of the protein in Hills z/d® is larger than 10kDa.

Recently a new prescription diet (BLUE Natural Veterinary Diet® HF) has been marketed to veterinarians with hydrolyzed salmon. This product also includes potato, pea starch and pea protein. Initial independent ELISA studies of purity submitted by this author revealed no detection of beef, poultry, soy or pork. Although unlikely to resolve clinical signs of every food allergic patient, it is nice to have an additional option to offer a finicky pet (or pet owner!). In practice, this product appears to be performing comparable to Royal Canin Ultamino®.

There is a plethora of over the counter novel proteins which claim to be restricted in their protein sources. The veterinarian and client need to read labels closely to insure they are consistent with the goals of the food trial, or management of the food allergic patient. Because of price and convenience these OTC foods are often preferred by the client. Unfortunately close scrutiny and evaluation has revealed many of the OTC “novel protein diets” contain several ingredients not listed on the label. Raditic et al (2011) published an evaluation of four popular OTC venison diets which were tested for soy, beef and chicken. Three of the four diets contained soy, beef and/or chicken, and the fourth contained rice protein. For this reason using prescription diets from reputable companies with stringent quality control remains the diet of choice for determining if a patient is food allergic. Once the food allergic patient is stable one can always “work backwards” and challenge the patient with an OTC novel protein diet and monitor for a flare. Whereas improvement on a diet may require weeks, most dogs flare within days if not hours.

One will find variable recommendations regarding the length of time necessary to see improvement once the patient is placed on the hypoallergenic diet, with some recommending a twelve week diet trial. In this authors experience it is rare for a food allergic patient to not show measurable improvement within 4-6 weeks, therefore six weeks is our normal recommended length. Requiring a client and patient to struggle on for 12 weeks without seeing improvement in clinical signs can cause many owners to lose faith with the entire process, leading to abandonment of the food trial and possibly seeking out a different opinion. It may require more than six weeks for the maximum improvement to be seen, but at least the patient is improving during the process which provides encouragement to continue the trial.

During the food trial it is very important to minimize the other causes of pruritus which will interfere with the ability of the client and veterinarian to determine the success or failure of the food trial. Zealous flea control in flea endemic areas is necessary. Monitoring and treating secondary infections (pyoderma and Malassezia) are also necessary. These infections are often times the reason a food trial is being performed in the first place, so it is not uncommon to treat the patient with appropriate antimicrobial therapy for potentially the first half of the food trial. Further counseling is then needed to insure the medications are not administered in a “treat”.

At times a client will desire to utilize a diet cooked at home. In these cases the challenge is to find a novel protein which fits the previously discussed criteria that is available and not cost prohibitive. I typically will utilize white or sweet potato as the carbohydrate. If the patient has not had exposure to fish, I might recommend tilapia as the protein source. We recommend a ratio of one part protein and 2 parts carbohydrate. Since this diet is intended to be used as a test diet and not long-term maintenance, we do not attempt to balance the diet with various micronutrients. If the patient is to be fed a home-cooked diet long-term then we will suggest a resource such as www.balanceit.com for advice regarding a proper balance of nutrients. There are several new companies providing frozen or freeze dried novel exotic proteins for feeding dogs or cats which may provide alternative options for clients.

One last pitfall for successfully implementing an effective food trial is the “unbelievers” at home whom cannot comprehend the detriment a little snack can have. Small children who drop food and other dogs at home eating different diets can also provide challenges the owner will have to overcome. The cost of the prescription diets can also be an obstacle in performing a food trial. Supplementing the diet with home cooked ingredients which are already allowed (such as potato) can help buffer the cost of the food trial and is preferable to OTC foods. Flavored medications have become an increasingly common challenge to overcome when

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enforcing a food trial. Many flavored medications contain beef and pork protein. I have observed patients flare from their once monthly flavored heart worm preventative. Glucosamine chondroitin is another potential allergen commonly administered.

It is not uncommon for an atopic dog or cat to have multiple triggers for their disease, with both food and environmental allergens playing a role. The clinician trying to sort out these multiple triggers will also sometimes have to make compromises when developing a comprehensive treatment plan for the pruritic patient. Feeding a large dog such as a Labrador retriever a novel prescription diet long-term may leave nothing else in the budget for control of the environmental triggers. In such cases I will frequently recommend some of the OTC fish based diets in an attempt to find an OTC food that will not trigger the food allergy, and possibly provide some supportive care for the atopic dermatitis due to the omega three fatty acids. This of course assumes the patient is not allergic to fish, and that there are not other protein contaminants in the food not listed on the label.

Even though we utilize handouts to help educate clients on the principles of the food trial, we do not rely on them alone. It requires time to properly educate a client on how to perform the food trial. We will schedule a follow up from one of our office staff after a few days of initiating the trial, as well as after 4-6 weeks of starting the trial to schedule a recheck so that progress, or lack thereof, can be assessed. Atopic therapy task force Atopy or Atopic dermatitis continues to be one of the most common dermatological disorders afflicting both dogs and cats. At our referral dermatology specialty practice, 75% of our patients have atopic dermatitis as one of the final diagnosis. The problem is so common and severe that many drugs have been utilized in an attempt to offer relief to the suffering patient. The challenge for the clinician is to try and find the right balance between all of the therapy options, their cost, efficacy and safety. The disease continues to generate research, with new therapies being developed. The International Task Force on Atopic Dermatitis, later changed to the International Committee on Allergic Diseases of Animals (ICADA), initially developed guidelines in 2010 for the treatment of atopic dermatitis which involve a multifaceted approach including

• Treatment of acute flares • Attempt to ID and avoid all triggers of flare • Improve skin & coat hygiene • Treat ongoing pruritus with drug therapy • Allergen specific immunotherapy should be offered when feasible

The diagnosis of atopic dermatitis is not based on any laboratory or skin test but is based on a combination of signalment, history, clinical signs and the ruling out other causes of inflammatory skin. Obtaining a certain and complete diagnosis for the pruritic patient can be challenging, but is a necessity if efficient and effective care is to be delivered.

When attempting to effectively help a patient with atopic dermatitis it is necessary to understand the pathogenesis of the disease, and teach the client these basic concepts.

• In dogs, atopic dermatitis is known to be an inherited type 1 hypersensitivity reaction to percutaneously absorbed antigens

• Epidermal barrier defects contribute to the pathogenesis • Bacterial and yeast infections provide additional antigens which may exacerbate pruritus

I try and simplify options with clients and explain there are many options for the treatment of atopic dermatitis, including supportive therapy, corticosteroids, cyclosporine, oclacitinib, canine atopic dermatitis immunotherapeutic and allergen specific immunotherapy (desensitization). The challenge for the clinician is how best to utilize and balance these options. Allergen specific immunotherapy is covered in more detail in a separate lecture. These therapies are frequently used in combination in order to obtain synergistic effects, which is an important concept to teach clients. In order to use less of the “big guns” clients must administer more intensive supportive therapy.

Supportive therapy is always a good place to start when treating a “mildly” affected atopic patient and includes antihistamines, essential fatty acids, bathing, restoration of the epidermal barrier, control of secondary infections, and potentially topical anti-inflammatory products.

A number of antihistamines have been utilized to control pruritus in dogs. Good clinical trials with placebo controls show the benefits of reducing pruritus ranging from zero to 30%. Many dermatologists will utilize antihistamines as part of the ongoing maintenance control of atopic dermatitis, but recognize their limited value when treating an acute or intense flare. Antihistamines which we currently recommend at our practice include cetirizine, amitrpytilline, clemastine, diphenhydramine, and chlorpheniramine. Most are available in generic formulation, and are over the counter, which helps keep the cost low. I usually try 2-3 different antihistamines, but expectations need to be realistic in understanding the value of these drugs may be in their steroid sparring effects. Remind owners to avoid formulas which contain decongestants and pain relief products.

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There are many published reports regarding efficacy of essential fatty acids (EFAs) for the treatment of atopic dermatitis. Unfortunately many of these studies failed to control, or account for the amount of EFAs in the diet which makes interpretation and comparison of these studies difficult. Most dermatologist support the use of EFAs in the treatment of chronic atopic dermatitis. Despite claims to the contrary, currently it is the position of the ICADA that there is no evidence of superiority of any particular EFA combination, dosage, ratio or formulation (including enriched diets) to improve skin and coat quality. As with antihistamines, EFAs are not adequate as a single therapy for atopic dermatitis except in mildly affected patients. I recommend minimizing other oils or fats such as olive oil or animal fat to minimize competition for absorption of the EFAs.

Improvement of the epidermal barrier has recently been getting more investigation and implementation. Simply bathing the atopic patients has many benefits including physical removal of antigens, reduction of bacterial and yeast populations, repair of epidermal barrier defects and the anti-pruritic effects of cool water cooling hot inflamed skin.

Despite the widespread belief that frequent baths will dry out the skin, in the experience of this author, a client cannot over bathe an allergic dog. The biggest drawback of frequent baths is the concern of washing away some of the topically applied flea control products. In such case, recommendation of flea control products which are not washed off or waterproof are appropriate. Drugs in the Isoxazoline family are proving to be effective and waterproof (given orally or topically).

A plethora of OTC and prescription antipruritic shampoos are available with ingredients including oatmeal, corticosteroids, diphenhydramine, pramoxine, lidocaine and coal tar just to name a few. It is the feeling of this author that the higher cost and short-term benefit of these products usually do not justify their use. Instead, at our practice we utilize products with antiseptic and epidermal restoration effects. Knowledge of any and all infections of the skin should influence the choice of antimicrobial shampoo. Chlorhexidene, triclosan with ethyl lactate, or benzoyl peroxide are chosen for most allergic patients prone to recurring pyoderma. If the skin is oily, or the infection is deeper than a superficial folliculitis, ethyl lactate or benzoyl peroxide is chosen since they are more potent “degreasers” and have follicle flushing activity. Shampoos with climbazole, miconazole or ketoconazole are chosen if the skin is infected only with Malassezia, otherwise a shampoo with multiple ingredients may be needed for a mixed infection of bacteria and yeast. We will utilize products containing Tris-EDTA with 4% chlorhexidine, particularly when dealing with methicillin resistant Staphylococcal infections of the skin.

The final “goal” of shampoo therapy is to repair or restore the epidermal barrier. Products marketed for this function include ceramide and phytosphingosine, many of which also contain chlorhexidine. I encourage the clinician to find a chlorhexidine containing shampoo with an antifungal and barrier replacement ingredient that lathers well and make it a foundation of your treatment recommendation for atopic dermatitis.

Simple management techniques can be employed to reduce overall allergen load on the skin surface. In addition to frequent baths, the coat can be wiped down on a daily (or more often) basis in an attempt to wipe off allergens. Keeping the hair coat short can reduce the “dust mop” effect of a longer coat. Wearing T-shirts and boots or socks can act as a physical barrier to the allergens.

The fourth recommendation of the ICADA is to “treat ongoing pruritus with drug therapy.” I will generally have a lengthy and detailed conversation with the client and explain both short and long-term benefits and side effects of corticosteroids, oclacitinib, IL-31 monoclonal antibody, and cyclosporine. The pros and cons of corticosteroids are well known to veterinarians and most clients. Cyclosporine (CSA) can certainly help many pruritic allergic patients, but can be one of the more expensive therapies to maintain except in very small patients. It also commonly causes GI disturbance and cannot be tolerated. There are also potential concerns with abnormal infections, gingival hyperplasia, and perhaps increased incidence of neoplasia secondary to cyclosporine. One scenario where CSA still excels is when the chronic inflammation has resulted in deep induration, scar tissue, and or granulomatous response. Examples of pruritus associated with end-stage otitis or proliferative pododermatitis are cases where CSA should be considered before some of the other newer alternatives.

The release a few years ago of a newer and exciting medication to treat ongoing pruritus is oclacitinib (Apoquel™) which became commercially available in 2014, with the author having used the medication in clinical trial settings since 2009. The advantages of oclacitinib include its rapid onset of efficacy and low incidence of side effects. One of the frustrations of oclacitinib is that for some patients, the efficacy does not last for the full 24 hours after the once daily dosing regimen has been started. We frequently receive calls from both clients and veterinarians about resuming twice daily dosing. I personally am strongly opposed to this as the safety profile of the drug changes with twice daily administration long-term. Concerns of increased infection and neoplasia would have to be discussed if twice daily dosing on a long-term basis is going to be recommended by a veterinarian. Apoquel is not approved for use in dogs less than one year of age. As with all the other options for treating atopic dermatitis, oclacitinib does not adequately control pruritus in all our patients either, so the veterinarian and client are required to consider what additional therapies are needed in addition to oclacitinib to find the best “balance” between drugs, efficacy and safety.

Canine Atopic Dermatitis Immunotherapeutic (Cytopoint™) is an injectable IL-31 monoclonal antibody which is administered subcutaneously to the dog. It is labeled for use every 4-8 weeks and in our experience will show benefit in 85% of the canine population. It has a few advantages over oclacitinib, namely having no age restriction, nor is its use contraindicated with any other

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preexisting or concurrent medical entity. When Apoquel is not controlling pruritus for the entire 24 hours, it would be rationale to administer Cytopoint.

Both oclacitinib and IL-31 monoclonal antibody therapy can be effective in both treating an acute flare, and/or for long-term use of treating the pruritus. As mentioned earlier, when significant inflammation is present (particularly with otitis externa and pododermatitis) this author finds corticosteroids and/or cyclosporine to be more effective at controlling the inflammation and corresponding pruritus. Cytopoint™ in particular can have limited anti-inflammatory effects, and administering this product when significant inflammation exists can be disappointing for both the patient and client. Again a rational combination of products may be required in some of these more severely affected patients.

Even though the final recommendation of the Task Force is “allergy specific immunotherapy (ASIT) should be offered when available”, it seems that with the popularity of drugs such as oclacitinib, and now Cytopoint™, this option has been cast aside by many practitioners, or only considered if or when these drugs fail. It is the opinion of this author and of the International Committee of Allergic Disease in Animals that this is a mistake, particularly in young or middle aged patients who might otherwise expect to receive a lifetime of drug therapy. For many atopic patients ASIT can become one of the easier, safer, more cost effective therapies. It can be the only effective therapy that is not a drug, and the only therapy which may address the immune dysfunction directly and cure the patient. The utilization of sublingual immunotherapy instead of the more traditional injectable immunotherapy has also led to many atopic patients benefiting from immunotherapy more quickly, easily and safely. For ASIT in any form (sublingual or injectable) to be its most efficacious, the clinician will require skills relating to the formulation of allergens, prioritizing positive test results, and teaching the client how to monitor the process. An in-depth discussion of these skills is beyond the scope of this text.

References Olivry T, DeBoer DJ, Favrot C et al Treatment of canine atopic dermatitis: 2010 clinical practice guidelines from the International Task Force on Canine Atopic Dermatitis. Veterinary Dermatology 2010; 21: 1-16 Olivry T, DeBoer DJ, Favrot C et al Treatment of canine atopic dermatitis: 2015 updated guidelines from the International Committee on Allergic Diseases of Animals (ICADA) BMC Veterinary Research (2015) 11:210 Jeffers JC. Et al: Responses of dogs with food allergies to single-ingredient dietary provocation. JAVMA 1996 Paterson S: Food hypersensitivity in 20 dogs with skin and gastrointestinal signs. J Sm An Practice 1995 Mueller R. Tsohalis J. Evaluation of serum allergen-specific IgE for the diagnosis of food adverse reactions in the dog. Veterinary Dermatology 1998 9, 167–171. Olivry T, Bizikova P. A systematic review of the evidence of reduced allergenicity and clinical benefit of food hydrolysates in dogs with cutaneous adverse food reactions. Veterinary Dermatology 2010, 21,32-41 Raditic DM, Remillard RL, Tater KC. ELISA testing for common food antigens in four dry dog foods used in dietary elimination trials. Journal of Animal Physiology and Animal Nutrition 95 (2011) 90–97 Bizikova P, Olivry T. A randomized, double-blinded crossover trial testing the benefit of two hydrolyzed poultry-based commercial diets for dogs with spontaneous pruritic chicken allergy. Veterinary Dermatology 2016, 27, 289-293