Retraining the hypersensitive immune system with regionally-specific immunotherapy

A comprehensive look at allergen immunotherapy (AIT) in dogs and cats, including regionally-specific immunotherapy (RSI).

Pruritus and otitis externa are two of the most common presenting complaints in small animal practice. Both are most often secondary to allergic dermatitis. When caring for a patient with allergic dermatitis, your complementary goals should be to control the pruritus, and manage the underlying allergic triggers. This article reviews the uses of allergen immunotherapy (AIT) in dogs and cats.Example of atopic dermatitis

Establishing a diagnosis of atopic dermatitis

Most cases of allergic dermatitis in dogs and cats are triggered by fleas (flea allergy dermatitis), ingested proteins (food hypersensitivity), or environmental allergens (atopic dermatitis). The steps to making a diagnosis of atopic dermatitis should be familiar:1

Diagnose canine atopic dermatitis based on these clinical features

  1. Take a thorough dermatological history
  2. Rule out flea allergy dermatitis with appropriate flea control
  3. Rule out food hypersensitivity with a limited ingredient diet trial
  4. Rule out other pruritic dermatoses as indicated (e.g. skin scrapings for mites)
  5. Rely on clinical features to establish a clinical diagnosis (see sidebar).

Treating the cause of atopic dermatitis

Recommending routine flea control is automatic for most of us, especially when the dorsal lumbar area is affected or fleas are evident. Veterinarians practicing integrative medicine are accustomed to discussing limited-ingredient, raw and home-prepared diets to address underlying food hypersensitivity.

Addressing the underlying causes of atopic dermatitis (AD) is more complex. Depending on your comfort level with chronic immunomodulating therapeutics, you may offer Apoquel, Cytopoint, Atopica, or prednisone as long-term treatment options for AD. But are you missing an opportunity to target the underlying causes of the problem?

Allergen immunotherapy (AIT) is described as the only treatment for AD that can result in partial or complete remission by addressing the underlying cause.2 Most studies evaluating the effectiveness of AIT in dogs with AD have been retrospective, but they report a success rate of 60% to 70%.3 Because testing and treatment protocols for AIT in dogs and cats are not standardized, there is still a great deal of uncertainty regarding optimal allergen dosing, mixture, and administration. For instance, while some studies suggest that including fewer allergens is desirable, others have concluded that including 11 to 20 allergens is most effective.4 Effectiveness of regionally-specific immunotherapy for the management of canine atopic dermatitis

Regionally-specific immunotherapy (RSI) extracts are formulated with reference to the geographic distribution and prevalence of important aeroallergens, rather than an individual dog or cat’s allergy test results. The commercially-available regionally-specific immunotherapy product, RESPIT®, is standardized for nine geographic regions of the United States, and is available for either subcutaneous injection or oromucosal administration. The injectable formulations each contain 20 allergens; the oromucosal formulations contain 22. (See sidebar on p. X for an example of one regional RESPIT® formula.)

The common triggers of AD in pets are pollens, dust mites, and mold spores. Within these groups, certain allergens are more significant than others depending on their prevalence, allergenicity, and degree of cross-reactivity between individual pollens. Veterinary dermatologists consider this information when deciding which allergens to include in allergy tests or in therapeutic extracts.5

Retraining the immune system

The objective of AIT is to retrain the pet’s immune system to tolerate natural exposure to the offending allergens. The mechanisms by which tolerance is achieved remain unclear in dogs and cats, but may include altering the responses of antigen presenting cells, regulatory T cells, and B cells, and influencing the expression of cytokines, especially IL-10.6 While there are no known contraindications to AIT in dogs and cats, it is most often recommended for patients that have clinical signs for six months or more throughout the year.

Allergen ingredients in the California mixture of RESPIT® Oromucosal Spray

Selecting allergens for immunotherapy

The starting point for AIT is making a clinical diagnosis of AD, based on the pet’s history, clinical signs, and by ruling out differential diagnoses. Traditionally, a pet’s allergen sensitivity is then determined by the primary care veterinarian with serum IgE testing, or a veterinary dermatologist with intradermal testing (IDT). This forms the basis for formulating an individual pet’s therapeutic allergenic extract.1 More recently, several companies have begun marketing hair and/or saliva sensitivity testing (often directly to pet owners).

The significance of allergy test reliability

What do we know about the reliability of serum allergy testing, IDT, and hair/saliva sensitivity testing? It is clear that each method produces false positive and false negative readings for individual allergens and that they generally don’t agree well with each other.1 The agreement between four serum allergy testing laboratories on replicate samples was found to be poor.7 Some of the hair/saliva tests have even been shown to report positive sensitivities to saline, water, and nylon “hair” from stuffed animals.8.9 And, although IDT is sometimes referred to as the gold standard in canine allergy testing, it is itself imperfect, relying on subjective interpretation and having unproven test-retest repeatability.10

The reported differences between allergy tests are not insignificant and introduce substantial variability to allergen formulation. If you are selecting five allergens from a list of 50, there are 2,118,760 possible combinations. For even just ten allergens, the number of possible combinations is over ten billion. And for an extract that contains 15 of 50 possible allergens, the number balloons to a quadrillion combinations, exceeding the number of stars in the Milky Way galaxy!

If your rationale for performing an allergy test is to perfectly match a pet’s prescription to his actual sensitivity, your chances of doing so based on an imperfect test is extremely low. The practical effects of this was brought to light in the previously referenced study comparing treatment recommendations of four serum allergy testing laboratories;7 85% of all the individual allergens recommended for nine dogs’ prescriptions were recommended by only one of the four laboratories. All four laboratories agreed on just 1/261 (0.4%) of the AIT ingredient recommendations.

Immunotherapy with imperfectly matched allergens

While perfectly matching a therapeutic allergen extract to a pet’s sensitivity is a noble aspiration of allergy test-based immunotherapy, there is evidence in dogs, cats, and humans that immunotherapy with imperfectly matched allergens is also effective. A total of 57% of dogs receiving RSI had a good to excellent response in a retrospective study.11 Similar results were reported in a double-blinded study comparing a stock mixture of allergens to IDT-based AIT.12  Placebo-controlled studies of both IDT-based AIT and RSI are needed. In a model of asthmatic cats, allergens given for AIT did not need to match the sensitizing allergens in order to provide a clinical benefit.13 In humans sensitive to both birch and grass pollens, sublingual AIT with either pollen individually produces clinical improvement and lower nasal eosinophil counts during both distinct pollen seasons.14

The mechanism of action of RSI may be both allergen-specific and non-specific. Phylogenetically related allergens often cross-react on IDT in atopic dogs.15 There are about 30 major groups of cross-reactive botanical proteins. Although imperfectly matching a dog’s sensitivities, RSI may include some allergen-specific epitopes as well as panallergens (e.g. profilins, polcalcins, and non-specific lipid transfer proteins) common to distinct allergen groups. These panallergens are widely distributed in nature with highly conserved amino acid sequence regions, structures, and functions.16 Comparison of Injectable and Oromucosal RESPIT®

Oromucosal or injectable RSI?

Once you make the diagnosis of AD and prescribe RSI, you have the choice of injectable or oromucosal spray formulations (see table on page xx). For the commercially-available product, each of the nine regional U.S. formulations includes 18 pollen and two dust mite allergens. The oromucosal versions also contain two common mold spores, Alternaria and Cladosporium.

The two routes of administration stimulate somewhat different aspects of the immune system, but are of similar efficacy. Anecdotal reports suggest that oral immunotherapy may control signs of AD more quickly than subcutaneous immunotherapy.17 However, no rigorous studies in dogs or cats comparing the two have been published. A possible advantage of subcutaneous AIT administration is that the frequency of injections can be reduced once a response is achieved, whereas ongoing daily administration is recommended when using the oromucosal route.

Concomitant therapy

Scratching, biting, and excessive grooming are what usually prompt your client to seek care for their dog or cat with atopic dermatitis, and you’ll want to control the pruritus while retraining the immune system with AIT. I’ll routinely prescribe Apoquel or Cytopoint for several months while beginning AIT. You may also choose to continue integrative medicine options during this time.

Avoidance therapy

Ideally, we would love to accurately identify aeroallergen triggers of atopic dermatitis and keep our patients away from them. However, there is only limited evidence that avoidance therapy is effective for managing AD in dogs or cats.2 In an uncontrolled study undertaking house dust mite control measures in the homes of dogs with mite sensitivity, clinical improvement was noted.18 Given the uncertainty surrounding allergy testing and the impracticality of avoiding pollen allergens, avoidance therapy is an ancillary measure, at best. For dogs, regular bathing may help by removing in-contact allergens.

Adverse reactions

Adverse reactions to AIT, including RSI, are uncommon and most often present as an increase in pruritus and, less commonly, urticaria. These are usually manageable with dose reductions and/or pre-medicating with an antihistamine. Anaphylactic shock due to AIT is rare in dogs and cats. When pet owners are administering AIT at home, it is good practice to have them observe the pet for 60 minutes after subcutaneous AIT administration. The oromucosal route of administration is associated with fewer adverse reactions and is preferred by this author for dogs with a history of urticaria.

Outcome

Improvement in patients receiving AIT is measured by a reduction in pruritus and less frequent and severe clinical signs, including secondary pyoderma, Malassezia dermatitis, and otitis externa. The regular use of a pruritus visual analog scale (vetrespit.com/resources/PVAS.pdf ) and a skin lesion scoring index (atopiscore.com) is helpful in monitoring improvement.

Many dogs or cats will show improvement in the first three to six months, but a one-year trial is often recommended. Most studies evaluating AIT report that about 20% of dogs have an excellent response, and 40% have a good response (a greater than 50% reduction in signs and concomitant medications).6,11 The variable response rate may relate to the choice of allergens, route of administration, or the fact that AD has a complex pathogenesis that is somewhat different from patient to patient in different stages of the disease.

Pets that have responded during the first year are often treated for at least two more years. The dosing frequency of subcutaneous AIT is often reduced over time to every two to four weeks, but oromucosal AIT is usually maintained at once daily, as much as possible. After several years, I may discontinue AIT on a trial basis. However, AIT has traditionally been regarded by most authors as a lifelong therapy for dogs and cats.

Disclosure statement

* The author of this publication developed RESPIT® and has a financial interest in RESPIT, LLC. For more information, visit vetrespit.com.

**This article is peer reviewed

 

References

1Hensel P, Santoro D, Favrot C, Hill P, Griffin C. “Canine atopic dermatitis: detailed guidelines for diagnosis and allergen identification”. BMC Vet Res. 2015;11:196.

2Olivry T, Sousa CA. “The ACVD task force on canine atopic dermatitis (XIX): general principles of therapy”. Vet Immunol Immunopathol. 2001;81(3-4):311-6.

3DeBoer DJ. “The future of immunotherapy for canine atopic dermatitis: a review”. Vet Dermatol 2017;28: 25–e6.

4Griffin CE, Hillier A. “The ACVD task force on canine atopic dermatitis (XXIV): allergen-specific immunotherapy”. Vet Immuno and Immunopath 2001 81:363-383.

5Hillier A, DeBoer DJ. “The ACVD task force on canine atopic dermatitis (XVII): intradermal testing”. Vet Immunol Immunopathol. 2001;81(3-4):289-304.

6Loewenstein C, Mueller RS. “A review of allergen-specific immunotherapy in human and veterinary medicine”. Vet Dermatol. 2009;20(2):84-98.

7Plant JD, Neradelik MB, Polissar NL, Fadok VA, Scott BA. “Agreement between allergen-specific IgE assays and ensuing immunotherapy recommendations from four commercial laboratories in the USA”. Vet Dermatol. 2014;25(1):15-e6.

8Bernstein JA, Tater K, Bicalho RC, Rishniw M. “Hair and saliva analysis fails to accurately identify atopic dogs or differentiate real and fake samples”. Vet Dermatol. 2019;30:105-e28.

9Coyner K, Schick A. “Hair and saliva test fails to identify allergies in dogs”. J Small Anim Pract. 2019;60(2):121-5.

10Ferrer-Canals G, Plant JD, Beale KM, Fadok V. “Reliability of intradermal allergy tests in dogs with atopic dermatitis”. NAVDF 2009 Abstracts. Vet Dermatol. 2009;20(3):228.

11Plant JD, Neradilek MB. “Effectiveness of regionally-specific immunotherapy for the management of canine atopic dermatitis”. BMC Vet Res. 2017;13(1):4.

12Garfield R, Editor. “Injection immunotherapy in the treatment of canine atopic dermatitis: comparison of 3 protocols”. Annual Meeting of the American Academy of Veterinary Dermatology and American College of Veterinary Dermatology; 1992; Montreal, Canada.

13Reinero C, Lee-Fowler T, Chang C-H, Cohn L, DeClue A. “Beneficial cross-protection of allergen-specific immunotherapy on airway eosinophilia using unrelated or a partial repertoire of allergen(s) implicated in experimental feline asthma”. Vet J. 2012;192(3):412-6.

14Marogna M, Spadolini I, Massolo A, Zanon P, Berra D, Chiodini E, et al. “Effects of sublingual immunotherapy for multiple or single allergens in polysensitized patients”. Ann Allergy Asthma Immunol. 2007;98(3):274-80.

15Buckley L, Schmidt V, McEwan N, Nuttall T. “Cross-reaction and co-sensitization among related and unrelated allergens in canine intradermal tests”. Vet Dermatol. 2013;24(4):422-e92.

16Hauser M, Roulias A, Ferreira F, Egger M. “Panallergens and their impact on the allergic patient”. Allergy Asthma Clin Immunol. 2010;6(1):1.

17DeBoer DJ, Morris M. “7th World Congress of Veterinary Dermatology Abstracts, Multicentre open trial demonstrates efficacy of sublingual immunotherapy in canine atopic dermatitis”. Vet Dermatol. 2012;23(s1):64.

18Swinnen C, Vroom M. “The clinical effect of environmental control of house dust mites in 60 house dust mite-sensitive dogs”. Vet Dermatol. 2004;15(1):31-6.

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