Canine atopic dermatitis

Canine Atopic Dermatitis (CAD) is a complex and multiform pathology with many possible manifestations. Recent researches revealed new mechanisms on its pathogenesis that are important for improving the approach and management of the disease. In fact, CAD is influenced by the interaction of genetic and environmental factors, by abnormalities of the immune system, by its interaction with the nervous system and by defects in the epidermal barrier. After flea dermatitis, CAD is the most common skin disease in cats and dogs. The pathogenesis of CAD is very complex and not yet fully understood.
The fundamental immunological principle in the pathogenesis of CAD is an alteration of the lymphocyte response to antigens with the production of IgE antibodies. CAD was therefore considered a disease that began “inside the body” (immune system) with “external” influences: allergens, irritants, bacteria and yeasts that could bring out and / or worsen symptoms. New information has recently been gained suggesting how other factors may contribute to the pathogenesis of the disease.
First, a clinical form called “Atopic-like Dermatitis” was identified in which the clinical symptoms are identical to those observed in CAD, but in which it is not possible to detect the presence of allergen-specific IgE using classic diagnostic methods. Therefore, in CAD, an anomaly of the immune system with the production of IgE is not always evident or at least it is not demonstrable.
These and other mechanisms, still being studied today, involve the epidermis and are considered as “external” factors. Therefore, it is currently believed that CAD could begin as an “external” defect (of the epidermal barrier) and, subsequently, lead to an alteration of the immune response resulting in skin inflammation capable of self-feeding.

Clinical symptoms and diagnosis of canine atopic dermatitis

It is essential to emphasize that the diagnosis of CAD is a clinical diagnosis and is based on a specific path that includes:

• medical history,
• clinical examination,
• differential diagnosis

Anamnesis

The careful and detailed collection of anamnestic data is very important to guide the diagnosis.
Useful indications can be obtained from a detailed interview with the owner regarding the environment in which the animal lives, clinical history, presence or absence of itching and response to therapies.
Breed predisposition for CAD may vary by geography, but some breeds (West Highland White terrier, Boxer, Bulldog) are listed as particularly susceptible, while others (German Shepherd, Golden retriever, and Labrador retriever) appear to be predisposed only in some geographical areas.
The age of onset of CAD is reported in most cases (75%) between 6 months and 3 years of age.
Itching is the main symptom and may initially be unrelated to injury. Itching must always be present with typical breech localizations, on the muzzle and on the ventral surfaces of the body. Initially, the itch may be seasonal (42 -75% of cases), but it can worsen and persist throughout the year. In many cases, the symptoms present throughout the year worsen with the arrival of the spring / summer season.
Both any cortisone-based therapies and the patient’s response to them should be carefully evaluated, as most animals respond adequately to these treatments, at least initially. In chronic cases, the response to these treatments is usually low, due to the development of secondary infections.
Equally important is the environment in which the animal lives, since it has been seen that 82% of atopic dogs live most of their time indoors. This suggests that prolonged exposure to house mites can trigger or worsen clinical symptoms.

Clinical examination

Without obvious symptoms it can be difficult to diagnose CAD, although erythema and itching are always present and often represent the first clinical symptoms.
Small erythematous papules (considered the primary lesions of CAD) are rarely found, because they escape the attention of the owner and the vet often has to evaluate a complicated or neglected situation in which most of the lesions are the consequence of self-trauma and/or secondary infections.
Secondary lesions mainly involve the muzzle, the periocular regions, the concave surface of the auricle, the ventral region of the neck, the armpits, the groin, the abdomen, the perineum, the flexor surfaces and the medial aspect of the extremities with alterations of the hair and skin (alopecia, discoloration or hyperpigmentation of the hair, lichenification). Often in the patient not all the mentioned areas are involved at the same time, except in the chronic phase.
Symptoms such as seasonal conjunctivitis and otitis externa may also be observed, while respiratory symptoms rarely occur.
A critical role is played by secondary infections. Bacterial staphylococcal and yeast infections of the genus Malassezia can help maintain and aggravate the inflammatory and itchy state. It has recently been shown that some toxins produced by staphylococci can directly activate T lymphocytes by stimulating them to release pro-allergic cytokines and thus favoring the persistence of allergic processes. Low levels of anti-staphylococcal IgE exclude a hypersensitivity reaction, but the identification of some major allergens of Malassezia pachidermatis has shown the presence of specific hypersensitivity reactions towards yeast in dogs.

Differential diagnosis

As indicated above, CAD is a clinical diagnosis and should never be ascertained without excluding other dermatological diseases that may be similar or overlapping or associated with it. CAD should therefore be diagnosed after the exclusion of other pathologies.
It is therefore important to take into account and exclude allergic flea dermatitis, adverse food reactions, the presence of ectoparasites (Sarcoptes, Demodex, Cheyletiella) and dermatophyte skin infections.
Flea allergy dermatitis is often overlapping on CAD, is highly itchy and typically localized in the dorsal-lumbar region and base of the tail. It is therefore always advisable to implement flea treatment and environmental control.
Skin scrapings and cultures should be performed to exclude the presence of Sarcoptes, Demodex, Cheyletiella and dermatophyte infections, followed by targeted treatments in case of positivity.
The adverse skin reaction to food deserves a separate discussion.
Recently, the International Task Force on Canine Atopic Dermatitis indicated that adverse skin reactions to food can occur in some individuals in the form of CAD and that food components can aggravate CAD in individuals hypersensitive to these allergens.
Adverse skin reactions to food can be divided into two categories: based on type I and IV hypersensitivity and non-immune-mediated (food intolerance).
The symptoms and presentation of the lesions of the adverse skin reaction to food are very similar to those of CAD with some possible variations: itching does not normally have a seasonal course; it can be of variable intensity and often does not respond to cortisone treatments. In many cases there is recurrent external otitis which, in some cases, may be the only symptom present. Gastrointestinal symptoms such as vomiting and diarrhea may be present. The adverse skin reaction to food can occur at any age. The only way to diagnose it is to use a “hypoallergenic” elimination diet.

The itch threshold

The itch threshold concept can be useful for understanding the development of the clinical manifestations of CAD and is linked to the presence of a multitude of stimuli that can contribute to the onset of itching. The activation and sensitization of nerve fibers by substances released by the degranulation of mast cells and the release of mediators by inflamed keratinocytes can lower the sensitivity threshold to itching, that is the level of nerve stimulation necessary to determine the appearance of the manifestation.
Therefore, each animal tolerates a certain level of itchy stimulus without showing scratching, while if the stimulus exceeds the individual limit it will trigger itchy symptoms. Factors contributing to exceeding the limit can be environmental, secondary infections, flea infestation, food allergy and environmental allergen load.The itch threshold concept can be useful for understanding the development of the clinical manifestations of CAD and is linked to the presence of a multitude of stimuli that can contribute to the onset of itching. The activation and sensitization of nerve fibers by substances released by the degranulation of mast cells and the release of mediators by inflamed keratinocytes can lower the sensitivity threshold to itching, that is the level of nerve stimulation necessary to determine the appearance of the manifestation.
Therefore, each animal tolerates a certain level of itchy stimulus without showing scratching, while if the stimulus exceeds the individual limit it will trigger itchy symptoms. Factors contributing to exceeding the limit can be environmental, secondary infections, flea infestation, food allergy and environmental allergen load.

Diagnostic criteria for CAD

Over the years, various lists of diagnostic criteria have been proposed to identify the most common symptom and clinical features that can guide the diagnosis of CAD. Initially human developed diagnostic criteria were adapted by Willemse and then revised by Prelaud. More recently, new criteria for the diagnosis of dog atopic dermatitis were proposed and validated by Favrot in 2010:

• onset of clinical symptoms under 3 years of age,
• stay of the dog mainly inside the house
• itch response to glucocorticoids
• itching begins in the absence of lesions
• involvement of the distal portion of the forelimbs
• involvement of the auricles
• the margins of the ears are not involved
• absence of involvement of the back-lumbar area

The association of the presence of five criteria has a sensitivity of 85% and a specificity of 79% in differentiating dogs with CAD from dogs with chronic or recurrent itching not affected by CAD.
However, it should always be considered that these criteria are not absolute and that if they were strictly applied, one in 5 cases could be incorrect. It is also important to consider that clinical symptoms and lesions are not always present in all classic body areas and that the use of diagnostic criteria is useful for an initial address and cannot be used alone, but in clinical in-depth investigations.

“Allergy” test

It is important to repeat that CAD is a clinical diagnosis, which is achieved thanks to the combination of criteria closely associated with the disease and the exclusion of possible differential diagnoses.
The “allergy tests” for the detection of allergen-specific IgE cannot therefore be used as a primary diagnostic criterion. Numerous clinically healthy dogs can have positive reactions to the test and an appreciable number of dogs with clinical symptoms compatible with CAD are negative for all types of “allergic tests” (Atopic-like dermatitis).
These tests can be used to select the allergens to be included in the allergen-specific immunotherapy formulation. They can also confirm that the disease is associated or not with the presence of allergen-specific IgE and can address environmental interventions to limit allergen exposure.
The most recently acquired serological tests measure allergen-specific IgE present in patient serum or plasma samples; the test is based on the ELISA principle (Enzyme-Linked ImmunoSorbent Assay): allergens adhered to the bottom of the well bind any allergen-specific IgE present in the sample. Then, with the addition of a conjugate (poly-monoclonal antibody or the high affinity receptor for the Fc fragment of the IgE), the allergen-IgE-antibody immunocomplex is formed which is highlighted by enzymatic staining. The results are calculated by comparison with a calibration curve.
Several correlation studies have been performed between ELISA and intradermal reaction (considered as the golden standard) with results varying from study to study. With both methods of analysis, many factors can influence the results and among these many concern the reproducibility of the tests, which can be linked to the non-standardization of the allergens used in both techniques, or to the lack of standardization of reading and interpretation of the results (subjective in skin test and arbitrary for each individual laboratory in the serological test).
Some serological test manufacturers are voluntarily carrying out quality control and standardization procedures in laboratories that use their tests to increase the reliability of analytical techniques.
In conclusion, it can be said that the results of an “allergy test” only indicate that the animal has IgE antibodies to the allergen in question and that they must always be evaluated and interpreted in the light of the animal’s clinical and environmental history.