Southern style itch with grits-sure fire methods to control atropy and complicating problems (Proceedings)

The combination of clinical diseases observed in pruritic dogs has been a consistent finding over the decades. The occurrence of the atopic dog with flea allergy dermatitis and secondary bacterial pyoderma led to the common expression in th '80's of the Southeastern Triad not that the S.E. has any royalty rights to this combination of clinical problems. Certainly, throughout North America, anywhere fleas are found the triad is observed. The incidence of atopic dermatitis in the Southeastern dog is, without exception, the largest single disease responsible for pruritus. A large proportion of the atopic dogs concurrently have flea allergy (70% or>) and a small percentage may have cutaneous adverse reaction to food (aka food allergy- 15%). Factors related to the preponderance of atopy can only be postulated as there is no single factor responsible in this multifaceted disease. While genetic predilection represents a strong basis for the disease, environmental factors weigh in with near comparable affect. Increasing number of pedigree dogs seems to be an observation although overinterpretation of this finding is cautioned since the owner's of pedigree dogs are those most likely to solicit veterinary attention for their atopic pet. Much understanding of the immunological basis has occurred in the last 25 years with more novel therapeutics becoming part of our daily choice in treating this condition. The development of more refined serum allergy testing has provided veterinarians in all parts of the country to include the option of allergen specific immunotherapy as a choice for the treatment of atopic dermatitis with the expectation of reasonable clinical outcome. Immunological evidence now supports the events that are associated with immunotherapy. Randomized-controlled studies continue to be reviewed with increasing awareness of the outcome of our treatment choice.

Flea allergy continues to be a commonly recognized entity most often associated with atopy and a resurgence observed in the Southeast within the last 8 years. The development of more novel chemicals for flea control has certainly enhanced our success for adequate control although perseverance of the flea as a consequence of many factors assures its survival. While newer products become an asset to our flea control efforts, it does not preclude the need for appropriate history and the continued effort of an integrated approach toward flea control. Maximizing success still requires a complete overview of the problem including the habitat, potential flea population dynamics, pets and non-pets that contribute to the problem as well as the identification of the flea allergic animal. The flea is still a survivor and would do well on one of those reality shows or a sequel to Ironman II.

Bacterial Pyoderma has seen a tremendous change in the past decade with prevalence observed in more than 75% of referral atopic dogs. The recognition of Staphylococcal organism's ability to mutate with resulting resistance is a complex problem with ever increasing incidence. The need for being a good custodian of antibiotic therapy places more responsibility on the practicing veterinarian to follow guidelines to optimize clinical response and minimize the development of resistance factors

The prevalence of yeast dermatitis rounds out the Southeastern Triad for the "Plus One". Three decades ago this condition was only being recognized where today there are cases documented on a daily basis. As with the bacterial pyoderma, malassezia is an opportunist and is almost always observed secondary to a primary disease with atopy being the most common. The occurrence of malassezia is likewise almost always observed with co-existing bacterial infection although it may be observed as an independent facultative pathogen. Research has demonstrated that dogs harboring organisms resulting in disease will likely develop an immediate hypersensitivity reaction to the yeast further potentiating the pruritus associated with metabolic byproducts of the yeast. Recognition and treatment of this component becomes an important part of the overall treatment plan. Microscopic diagnostic evaluation should be performed prior to treatment and during the reassessment. Principles of therapy should be considered similar to the use of antibiotics.

Patterns of pruritus are beneficial in development of a differential diagnostic list. Pruritus affecting the head (face &/or ears), ventrum and extremities include three prominent differentials: 1. Canine atopy 2. Adverse food reaction (food allergy) and 3. Canine scabies. These diseases provide the basis for the evolvement of a basic working list of diseases to initiate diagnostic evaluation. Canine scabies can be easily ruled out despite the lack of disease confirmation from multiple skin scrapings. Dietary trials are usually successful in identifying a diet related problem (remember that the vast majority of food related allergy animals also have concurrent canine atopy). Another concurrent allergic relationship is the presence of flea allergy. The distribution pattern of flea allergy dermatitis in the dog specifically affects the pelvic region with the dorsal lumbar sacral involvement as well as caudal-medial thighs and inguinal area which is quite unique compared to canine atopy. Occasionally food allergy may have the same pattern as flea allergy. Canine atopy does not typically have papules. When they are observed, it is always best to think of concurrent infection first since atopy is less commonly associated with a popular dermatitis.

How to Stay on "Top" of Atopy

The incidence of canine atopic dermatitis has been estimated to be between 3% and 15% of the total canine population. Atopic dermatitis is considered to be a genetically based condition whereby the animal develops an IgE antibody response to environmental proteins resulting in disease, most commonly allergic dermatitis/otiti/conjunctivitis. Access of these proteins is perceived to be primarily via absorption through the skin. The proteins are commonly allergens representing pollens of grasses, trees, and weeds, as well as mold spores, house dust, house dust mite antigen, insects and other miscellaneous environmental substances. Geographic variation is a relevant aspect of the development and presentation of clinical disease. Studies have demonstrated that parasite presence may be a factor encouraging the development of canine atopy. The incidence of atopic dermatitis in dogs may be greater in parts of the country where fleas are more prevalent, as well as increased presence of pollens and other proteins. Other information suggests that viral infections or even vaccination with modified live viral vaccines may augment the production of the specific antibody (IgE) to environmental allergens. The increase in environmental pollutants and indoor allergens has also been postulated as another reason for the increased incidence in the development of atopic dermatitis seen in people. Genetic influence plays an important role in the predilection for this disease and may explain the increased incidence through owner preference for pedigree dogs. In general, atopic dermatitis is a common dermatologic problem observed in the dog.

Pathogenesis of canine atopic dermatitis

The development of canine atopic dermatitis occurs in two stages. The first is considered the sensitization phase of disease development. In this stage, specific proteins (allergens) such as a grass, tree or weed pollen, is absorbed into the skin where a specific cell type (Langerhan's cell) located in the lower part of the epidermis acts as an antigen processing cell and binds the allergen. The allergen then is processed by the Langerhan's cell which migrates from the skin to the regional lymph node where it interacts with T-cells. More specifically, these T-cells are T-helper cells. In addition to the presentation of the allergen protein to the T-helper cells, there is stimulation and proliferation of other memory T-cells and effector T-cells. These T-cells, in turn, interact with B-cells which are used for the production of antibody. During the sensitization stage no disease is observed.

The second stage involves the elicitation of disease. Subsequent exposure to the specific allergen and percutaneous absorption in the sensitized individual, leads to the processing of the allergen by the Langerhan's cell, which again presents the allergen to the immune system already producing specific IgE against the offending allergen. The presentation of the allergen to memory T-helper cells then leads toward the elicitation of cytokines that induce cellular proliferation and IgE production from B-cells (e.g. interleukin 4). The IgE is bound to mast cells and basophils. The mast cells are important in the subsequent development of the clinical signs of the disease through the release of pro-inflammatory mediators. The allergen binds to the specific IgE on the mast cell and the cross-binding of two of the IgE molecules results in this degranulation. Subsequent inflammation is observed as the development of allergic dermatitis and pruritus. Latent reactions may occur as a consequence of the initial immediate reaction.

Clinical features of canine atopic dermatitis

Canine atopic dermatitis is characteristically observed in dogs between six months of age and three years of age where 75% of the animals will initially show the clinical signs. Earlier age of onset has been observed in dogs as young as 2.5 months and dogs have been known to develop symptoms as late as seven years of age. Predominant features of the condition include pruritus affecting the face, legs, feet, ventrum and the ears. Other diseases with similar clinical features include adverse reaction to food (food allergy) and canine scabies. Allergic otitis externa is commonly seen as part of the clinical presentation and is the major primary cause of otitis externa leading to secondary infection in the dog. In addition, ocular changes may also be observed with conjunctivitis, epiphora and possibly secondary complications of infectious conjunctivitis with mucopurulent discharge. Most animals will demonstrate a seasonal pattern before progressing to a non-seasonal (year around) problem. Eventually, as many as 75% will have year around problems. Hair loss is observed through chronic biting, licking, chewing and scratching or by secondary complications.

Early signs of canine atopy are often times not associated with the disease. These may be subtle and have limited evidence of itchiness. Intermittent bacterial infections may be first evidence of the disease presentation. Likewise, ear infections may be signal of underlying canine atopy. Later on more classical symptoms may be observed. Further progression may lead to the complications of secondary infection often characterized by the presence of lesions, such as papules, pustules and macules. Both bacteria (Staphylococcal sp.) and yeast (Malassezia sp.) infections are commonly observed. Evidence of lichenification and hyperpigmentation may be observed in regional areas with chronic dermatitis. Scaling and crusting are common with the development of chronic atopic dermatitis with complications. Occasionally other complications may be seen including demodicosis or dermatophytosis. Secondary ear infections are frequently observed. The clinical features of canine atopic dermatitis with complications may have mimicking features of other conditions. Occasionally, atopy may be observed with pulmonary disease where sneezing or wheezing/coughing may be observed. Coexisting allergic diseases are seen with canine atopy. Flea allergy is observed in flea infested areas in as many as 80% of the cases. Some of the dogs (15-20% ) may also have coexistent adverse reaction to food (food allergy). The diagnosis of canine atopy is made through the historical and clinical examination findings with rule out of other differentials considered.

Treatment for atopic dermatitis

Atopic dermatitis is typically a life-long disease and characteristically intensifies with age showing less responsiveness to commonly used drugs over time. In addition, the development of complicating problems becomes more prevalent. Practical therapy may be separated into four categories: 1) avoidance – often limited; 2) symptomatic glucocorticoid, anti-histamine and EFA therapy; 3)allergen specific immunotherapy; and 4) immunomodulating therapy with cyclosporine. Avoidance techniques have selected usefulness for flea control as well as dietary restriction in cases with coexisting adverse reaction to food.

Symptomatic Therapy:

Symptomatic therapy includes the use of antihistamines, essential fatty acids and glucocorticoids and topical therapy with shampoos, rinses, leave-on conditioners and sprays. Symptomatic therapy requires no knowledge of specific environmental allergens causing the allergic condition. Discussion of this therapeutic approach is listed elsewhere in the notes.

Topical Therapy:

Topical therapy is quite helpful in treating the atopic animal. It not only provides an anti-pruritic affect, it concurrently assists in the removal of surface allergen on the skin before percutaneous absorption may take place. Shampoos are commonly integrated in this treatment approach. They may contain oatmeal, aloe vera, or other antipruritic chemicals such as pramoxine, diphenhydramine, hydrocortisone or triamcinolone. Shampoo therapy is unfortunately limited due to the removal of the product in the rinsing phase of the bath. Rinses and leave-on conditioners or sprays may be more effective because they provide a residual effect. These products may contain colloidal oatmeal, antipruritic chemicals such analgesics, or a glucocorticoid. Their attribute is toward decreasing the need for systemic therapy specifically avoiding increased dependency of glucorticoids. Topical therapy also enhances the targeting of specific regions of pruritus without systemic therapy. Mosturizing agents will improve the dryness frequently observed with allergic dermatitis particularly if a pyoderma is present. I almost always dispense the product Humilac, an oil free humectants to be prepared as a leave on rinse with a solution of 5 capsful to 1 qt. of water. Other leave on conditioners may be integrated after a moisturizing rinse. The use of a cleansing shampoo to remove dirt and oiliness prior to a medicated bath will aid in the effectiveness and extend the use of the more expensive bottle of medicated shampoo. Most animals are committed to a routine of bathing every7-14 days and therefore require a humectant for moisturizing. Antimicrobial shampoos are often indicated during the initial treatment or maintenance of the animal with bacterial pyoderma.

Allergen Specific Immunotherapy:

Allergen specific immunotherapy (ASIT) is commonly known as hyposensitization treatment. The method includes the administration by parenteral therapy using the same proteins to which the animal has known allergic reactivity. Evidence in the dog similar to man demonstrates CD4+ T cells which express the intracellular transcription factor FoxP3 which function as T regulatory cells (T-reg cells) as a result of the allergen immunotherapy. These antigen-induced T-reg cells regulate immune homeostasis with production of cytokines such as IL-10. They also inhibit development of allergic Th2 cells and down-regulate allergic inflammation associated with IgE. They potently suppress total and allergen specific IgE production. IL-10 also increases IgG4 and generates T cell tolerance and regulates antibody isotope formation.

The therapeutic effect of this technique is variable and quite dependent upon the extent and accuracy of identifying specific allergens that are problematic to the given animal. In general, 60-70% of the dogs treated with allergen immunotherapy should demonstrate good to excellent response. These animals classically require integration of antihistamines, essential fatty acids and occasionally glucocorticoid therapy in combination with topical management. Overall, the beneficial effect is significant in those responders making it a very beneficial treatment. This therapy, however, requires identification of offensive allergens causing disease in the respective animal. Treatment is ongoing and is commonly required for the life time of the animal.

Allergy Testing:

Allergy testing is limited to the identification of specific allergens with the anticipation of utilizing this information for allergen immunotherapy. Allergy testing is not used for diagnostic purposes as some normal dogs may show intradermal test reactivity while some atopic dogs may not show reactions to specific testing. Intradermal testing remains the gold standard for allergen identification. False negative reactions are usually the limitation of this procedure as well as the need for drug withdrawal, sedation, and hair removal to perform the procedure.

Serum allergy testing (SAT) has become more popular over time with reputable laboratories providing service for identification of circulating anti-allergen IgE. Different techniques are used by various laboratories and may affect the results. Selection of allergens respective to a given geography may be quite different from one laboratory to another. Selection of a laboratory should be influenced by the array of allergens used in their respective profile. Serum allergy tests may have problems with false positive and false negative findings.

The development of the allergen solution for use as therapy is based upon the results of either a serum allergy test, intradermal test or the combination of both. It is also ideal to submit candidates for allergen immunotherapy at or after one year of age although allergen immunotherapy has been used in younger dogs due to the severity of their problems and after rule out of other diseases. The prospect of immunotherapy should be the only reason for considering allergy testing since it is not valid for disease confirmation or rule out. Due to the excellent safety of this treatment, it is usually administered at home by the pet owner. Oral therapy is being developed for humans but has not been perfected for veterinary administration. The injection schedule is somewhat variable depending upon the laboratory or dermatologist preparing the allergen solution, but classically starts with a dilute solution or two dilute solutions before reaching the more concentrated maintenance vial. The initial injections are given subcutaneously in increasing amounts and progresses from the least concentrated to the most concentrated solutions. Rapid administration of the induction phase of allergen immunotherapy has been developed providing the full induction provided in a 6-8 hours in contrast to 30-40 days. This is known as RUSH allergen immunotherapy. This method requires close observation and preparedness for an allergic emergency although this is unlikely to happen. Maintenance therapy is administered at a dosage and frequency dependent upon the individual response or tolerance of the treatment. Animals administered small amounts more often may respond better than larger amounts with less frequent administration. Injections once weekly or every two weeks or some at a three week interval are also utilized. Decreasing the quantity of allergen administered is necessary when administering more frequently. Animals under 10 kg should be restricted to 0.5 ml. or less at the maximum maintenance dose. Selected animals may require more dilute solution to avoid increased pruritus from the allergen therapy. Modification of the dosage schedules may enhance the response in many cases. Weekly injections of 0.35-0.5 ml of maintenance solution may be preferable to 1.0 ml every 21 days. Injections administered every two weeks may require 0.4 – 0.6 ml and some animals may respond best to a small amount twice weekly (0.15-0.3 ml).

ASIT requires a significant period of time to observe response. This may take as long as 5-7 months but is typically seen between 3-5 months. The attributes of allergen immunotherapy include the development of long term control decreasing the need for adjunctive therapy, in particular glucocorticoids. Allergen specific immunotherapy has a better chance of being effective if started early in the disease progression. It has become the mainstay of treatment alternatives with its appealing response rate and is most cost effective in large dogs in contrast to options such as cyclosporine (Atopica®). It does not, however, eliminate the need for adjunctive therapy in most cases but decreases the intensity of concurrent medication required for control. Flea antigen is not utilized for the treatment of flea allergy where aggressive and persistent flea control is advised. Likewise, dietary allergy is controlled exclusively through the process of avoidance with limited ingredient diets or hypoallergenic diets (hydrolysate diets). Perception of a failure to respond to specific allergen immunotherapy may be related to coexisting problems that have not been identified and treated. These may include complicating infections such as bacterial pyoderma, cutaneous malassezia, dermatophytosis, or demodicosis or related to the other major differentials dietary allergy or canine scabies. Incomplete recognition of offensive allergens may require repeat allergy testing to identify other allergens that may be problematic in a given animal. Inconsistent treatment or treatment regimens that are not optimal may also lead toward failure. The duration of treatment necessary for full assessment would require a full year. Non-responders may represent as many as 25-35% of the animals placed on therapy. Dogs with a large number of allergen reactions may be good responders and should not be perceived as non-candidates for treatment with allergen. Some of the better responders are dogs that have >20-30 allergens identified in their profile. The maximum number of allergens included in a single vial is limited and ranges from 10 – 17 depending on the individual preparing the solution. Animals with larger number of reactions are often placed on multiple vials to include the relevant allergens but remain within the maximum per vial number of allergens.

Modification of immunotherapy should be integrated with intermittent evaluations and modification of the treatment interval and the volume of allergen administered. Integrated adjunctive therapy should be utilized as part of the maintenance regimen. Repetitive bathing with ongoing parasiticidal treatment for flea control is also necessary.

Specific Immunomodulating Therapy – Cyclosporine A

Cyclosporine A (CsA) (Atopica®, Novartis Animal Health) is a chemical that is used in the treatment of humans after receiving organ transplantation. It is a potent immunosuppressant compound that specifically affects the portion of the immune system in which the pathology of atopic dermatitis occurs including the TH2 cells. Cyclosporine is a polypeptide product from a fungus Tolypoladium inflatum. The immunological effects include inhibition of lymphocytes, in particular T-helper lymphocytes. It depresses induction of cytotoxic T-lymphocytes and exhibits suppression of IL-1 & IL-2, macrophage activating factor & gamma interferon. T-lymphocyte proliferation is blocked while there is less effect on B-lymphocytes

As many as 65-70% of atopic dogs treated with CsA may demonstrate appreciable control. CsA is also used in the cat. Typically the drug is administered daily for 30 days then modified to alternate day treatment for the next month with maintenance therapy based upon clinical response and attempt to reduce to the lowest amount necessary to control the clinical signs (e.g. 3 days per week). The dosage is critical for optimal response and should be close to 5 mg/kg/d. Reduced dosage has been achieved with successful response in dogs by integrating ketoconazole at 2.5 mg/kg/day which interferes with the excretory pathway of the CsA. The limitations of this therapy include the cost and adverse effects most often representing GI problems (vomiting and/or diarrhea). Cyclosporine A is used in selective cases typically representing those demonstrating difficult control.

Summary

Atopic dermatitis is common cause of skin disease in the dog particularly in geographic areas with high parasite and allergen exposure. Other conditions need to be evaluated with observation of complicating problems to achieve ultimate success. Diagnosis is based on history, clinical signs, and elimination of other diseases while allergy testing is used predominantly for the identification of allergens to include in the allergen specific immunotherapy. Feline atopy appears to be more common than previously recognized and has options for diagnosis and treatment.