Some of the most common clinical complaints in veterinary medicine have an underlying allergic basis or share similar pathomechanisms of disease. Clients often ask why we are seeing so many pets with allergies in our generation. Several factors have changed from the days where the farm dog who was fed table scraps, kept in an outdoor doghouse and never vaccinated never developed allergic dermatitis. The closing genetic pool of popular dogs, housing pets indoors as part of a family group, and development of multivalent vaccines are three factors that will result in up to 8 out of 10 members of a litter developing allergies and being constantly kept above their allergic threshold while the other 2 members of the same litter display no signs of allergic disease.

Genetics

Nuttall (2012) and Bizikova et al. (2015) summarized from the results of multiple studies that the development of allergic disease may be attributable to complex alterations in up to 54 genes (e.g., Canis familiaris chromosome 5 [CFA5], plakophilin 2 [PKP2], PTPN22, cytochrome P450 26B1, TSLP, PROM1 and RAB3C gene, etc.) that are involved in innate immunity and inflammation, cell cycle, apoptosis, barrier formation and transcription regulation. Shaw et al. (2004) estimated the heritability rate of allergic dermatitis in Labrador and Golden Retrievers from a study in the United Kingdom to be approximately 47%. They determined that mating of two allergic individuals can lead to 70–80% of the litter being affected with allergic dermatitis, while mating one allergic and one non-allergic will result in only 30–40% being predisposed to developing allergies. Hence, it stands to reason that purebred dogs are most predisposed as breeding non-clinical carrier pairs may result in a significant percentage of the litter being affected. The breeds with the highest number of diagnosed atopic animals are, in no particular order: Boxer, Chihuahua, Yorkshire Terrier, Chinese Shar-Pei, West Highland White Terrier, Lhasa Apso, Shih Tzu, Dalmatian, Pug, Boston Terrier, Golden Retriever, Labrador Retriever, Cocker Spaniel, Bull Terrier, Bichon Frisé, Tibetan Terrier, English and French Bulldogs.

Genome-wide association studies have shown that allergic tendencies also vary with breeds within different geographical locations and may explain differences in clinical presentations and response to treatment.

Understanding the genotype will allow clinicians to better predict which treatment options work better in certain breeds and which breeds may not respond as well. Ideally, genotyping will help to identify young dogs with an atopic tendency so that implementation of environmental management and minimization of immunostimulation will help to reduce their risk of developing clinical atopic dermatitis.

Practice Tip: Outcross

Based on the above information, a breeding strategy of outcrossing allergic breeding stock (breed an allergic to a non-allergic) may help dilute and lower allergic tendencies closer to that of mating of two non-allergic individuals (0–11%).

Environment

Allergens are introduced into the body via four main routes: inhalation, injection, ingestion and percutaneous absorption across a defective epidermal barrier. Individuals with allergic tendencies respond to commonly encountered substances in a hyper-reactive manner as a result of alteration to their ancestral microbiome. Feehley et al. (2012) summarized that in humans, sanitation, antibiotic use, endoparasiticides, high fat (Western) diets, cesarean birth, formula feeding (devoid of transforming growth factor-[sic]) all alter normal immune system maturation decreasing immunoglobulin A (IgA) and T regulatory cell (Treg) production, leading to a shift toward the allergic T helper 2 cells (Th2) and their pro-allergic cytokines. This is highlighted by the increased prevalence of allergies in urbanized regions of Western society in compared to individuals in rural environments with two or more pets/animals. The beneficial effects of good bacteria and other microorganisms have been termed the “hygiene hypothesis” by Strachan in 1989. Rook et al. (2003) modified the concept of “hygiene hypothesis” to “old friends hypothesis,” focusing more on the positive effect of “friendly” microbes that interact with regulatory systems and keep our immune system in balance, and that sterilization may lead to chronic inflammatory diseases ranging from asthma and eczema to even more debilitating conditions such as type 1 diabetes, multiple sclerosis, some types of depression and cancer.

Supporting the notion of “old friends hypothesis,” Hesselmar et al. (2013) found 3x less eczema at 1.5 and 3 years of age in children whose parents sucked their soothers to clean them in comparison to those that had their pacifiers boiled or rinsed with tap water. Based on differences in salivary microbiota between the groups, the authors concluded that oral commensal microbes were transferred from parents that helped establish “old friends” in their immune environment shifting them away from allergic tendencies.

They also noted that natural childbirth provided additive protection as compared to children born by cesarean section.

Environmental contributions to atopic dermatitis dogs have also been investigated. Similar to humans, a reduced risk for developing atopic dermatitis was noted in puppies being fed a noncommercial (and possibly microbe-rich) diet during lactation, in dogs that had an endoparasite burden, and in dogs living in northern rural environments with low annual rainfall.

Research, mainly done in humans, reveals that exposure to house dust mites and storage mites may result in damage to the epidermal barrier and promotion of inflammation. For instance, release of mite proteases increases epithelial permeability by degrading occludins, claudin and the tight junction protein zonula occludens as well as mite cysteine allergens facilitating the actions of serine proteases by degrading α1-antitrypsin compromising the epidermal barrier and resulting in increased percutaneous absorption of environmental allergens.

Non-IgE dependent mechanisms by which mites promote inflammation include the release of mite serine proteases that are potent activators of protease-activated receptor 2 (PAR-2) in human keratinocytes and lung epithelial cells, and may directly induce mast cell, basophil and eosinophil degranulation with the subsequent release of IL4 that stimulates a T-helper-2 response. Studies in dogs have also revealed the release of inflammation promoting granulocyte macrophage colony-stimulating factor (GM-CSF), IL-8/CXCL8 and tumour necrosis factor alpha from a canine keratinocyte cell line in response to mite antigens. Dust mite proteins also inhibit a T-helper-1 response by removal of the α-chain of the IL-2 receptor, an impairment of IL-12 secretion thus shifting the balance toward a T-helper-2 response.

Not only do mites release proteases but insect, fungal, and pollen extracts also have proteolytic activity that degrade tight junction proteins and enhance the development of a T-helper-2 response. Oxidative stress induced by environmental allergens can also result in the release of IL-8, IL-6 and tumour necrosis factor promoting inflammation. Lastly, smoke exposure has been correlated with an increased incidence of atopic dermatitis in dogs; the exact mechanism is still under investigation.

Practice Tip

Try to avoid sterilizing our pets’ environments during puppyhood by allowing natural birth and nursing when possible, and perhaps considering a later date of puppy sale so that natural mechanisms of immune defense can be passed along from the bitch via grooming and lactation.

If this is not possible, the use of probiotics may be warranted in those dogs may not have had natural exposure beneficial bacteria and for those dogs with greater tendencies toward allergic disease. An excellent review by Özdemir et al. in 2013 presented several mechanisms by which probiotics help to modulate the immune response including:

1.  Maturing gut barrier by probiotic regulation in intestinal epithelium and upregulation of host immune responses

2.  Immunomodulation of the Th1/Th2 balance, IgE and cytokine production

3.  Anti-inflammatory effects on serum inflammatory parameters

4.  Development of tolerogenic dendritic cells

5.  Immunoregulation by T regulatory (Treg) cells

6.  Lymphocyte subpopulations shift from CD4/CD25 to CD8

7.  Toll-like receptor (TLR) stimulation

The authors also compiled numerous studies in humans that exist supporting the use of probiotics taken by individuals to help minimize clinical signs with existing allergies, as well as perinatal probiotics to prevent allergies in predisposed families.

Marsella in 2009 evaluated the efficacy of Lactobacillus rhamnosus strain GG for the alleviation or prevention of clinical signs of atopic dermatitis (AD) in genetically predisposed dogs. Two adult Beagles were bred twice, with a year between breedings. Lactobacillus rhamnosus GG was administered to the bitch during the second pregnancy and to the puppies of the second litter from 3 weeks to 6 months of age.

In comparison to the non-treated group, the second litter treated with probiotics had a significantly lower serum titer of allergen-specific IgE and milder reaction to intradermal testing, compared with the first litter. Hence, early exposure to Lactobacillus rhamnosus GG (LGG) significantly decreases allergen-specific IgE and partially prevents atopic dermatitis in the first 6 months of life. In a three-year follow-up after discontinuation of probiotics, Marsella et al. (2012) noted that early exposure to probiotics had long-term clinical and immunological effects.

A pilot randomized double blinded placebo-controlled evaluation by Yamazaki et al. (2019) evaluated Enterococcus faecium SF68 (FortiFlora®) as adjunctive therapy for adult atopic dogs that were controlled on oclacitinib (Apoquel®) over a 12-week supplementation period. The expectations were that concurrent use of probiotics would result in an oclacitinib dose reduction in the treated patients. Unfortunately, both the treated and placebo group were not able to reduce their use of oclacitinib during the study despite supplementation. As well, there were no significant difference in CADESI-04 and PVAS scores any of the 21 treated or placebo-controlled client-owned dogs with atopic dermatitis. Interestingly, patients in the placebo group responded better most likely due to more aggressive topical management of secondary infections. Perhaps other strains or probiotics (e.g., Lactobacillus acidophilus 21 [Ygia14®]) may provide better immune modulatory effects and increased production of bioactive metabolites that can inhibit cell-to-cell communication in pathogenic bacteria to prevent and treat the infection that may contribute to inflammatory response in atopic patients. Other products that contain the refined and concentrated bioactive metabolites also show promise.

When evaluating research on probiotics, realize that mixed results in atopic patients may stem from the disease/condition that is being treated or prevented, the severity of the disease, the study design, the length of the study, compliance of the owners, the probiotic strain-specific effects and the quality of the probiotics. In a review by Weese et al. (2011) of 25 probiotics on the human and veterinary market, only two products provided accurate bacterial content and label accuracy—Prostora (IAMS) and FortiFlora (Purina)—both veterinary products. Several other veterinary probiotics were not assessed (Florentero [Candioli], Juvita Pro-B [Zoetis], Ygia 14 [Ygia]), however, the study does highlight the need for owners to scrutinize the product quality before embarking on a long course of supplementation.

Vaccinations

Vaccines stimulate the production of protective antibodies against common bacteria and viruses. Unfortunately, stimulation of the immune system at the time of vaccination can also results in sensitization to food antigens (Tater et al. 2005) and environmental allergens (Frick et al. 1983; HogenEsch et al. 2002) in allergy-prone dogs. Scott-Moncrieff et al. (2002) also demonstrated that vaccines resulted in an increased production of anti-thyroglobulin antibodies, which in turn may lead to hypothyroidism.

Practice Tip

I therefore take precautions when vaccinating patients with allergic tendencies as follows:

1.  Vaccinate outside of the pet’s allergy season (e.g., midsummer or wintertime=lowest allergen load)

2.  Move to a 3-year rotating vaccination protocol with labeled and licensed 3-year vaccines

3.  If not able to move to 3-year rotation, split-up vaccine injections by 2–4 week intervals (i.e., give rabies vaccine by itself, and follow 4 weeks later with the next set of vaccines)

4.  Consider titers in dog with severe reactions to vaccine as sanctioned by the World Small Animal Veterinary Association (VacciCheck [Biogal Laboratories] and the other is called TiterChek [Zoetis])

5.  Consider pre-/post-vaccination use of anti-inflammatory medication to prevent reactions

6.  If vaccinating in a peak allergen season, consider minimizing exposure to environmental allergens (e.g., keep puppies in a “clean room”—no carpet or plants, use of HEPA filters, isolate indoors, etc.)

Diet

Currently the top food producing food allergens in North America includes beef, dairy, lamb, wheat, corn, chicken and rice. Potential reasons that our pets are recognizing these common proteins found in most commercial dog foods may be a result of vaccine-induced sensitization to dietary antigens during the puppy booster series. Tater et al. have demonstrated that allergen-specific IgE levels increase to food antigens being fed in allergy-prone dogs immuno-stimulated by prophylactic vaccines for at least three (3) weeks post-vaccination and subside to normal pre-vaccination levels in 8–9 weeks. Imani et al. proposed that human vaccines induce the expression of IgE mRNA through the activation of an antiviral protein kinase. In a large Swedish study, Nooedtvet et al. in 2007 noted that feeding a home-made diet to the bitch during lactation was found to decrease the likelihood of her offspring developing canine atopic dermatitis by 50% in three high-risk breeds, namely West Highland White Terriers, Boxers, and Bull Terriers. Whether it was due to a reduction in allergen load or perhaps the presence of bacteria that promoted the “hygiene hypothesis” has yet to be elucidated.

Practice Tip

Based on the potential for sensitization to foods being ingested at the time of booster vaccinations during puppyhood, I typically advise the lactating bitch and puppies a homecooked “sacrificial protein” be fed during this stage of a dog’s life especially in breeds with a predisposition toward allergies. Once the pet reaches adulthood and vaccines occur annually or less frequently, then switch to a different protein source; for example, start with a lamb-based diet in puppyhood, then move to a fish-based diet into adulthood.

After puppyhood, only alter the pet’s diet when signs of adverse food reactions are noted to help preserve the pool of future novel protein sources.

Allergy Prevention Recommendations and Puppy Pack

1.  Outcross allergic breeding stock

2.  Avoid caesarean section when possible

3.  Allow puppies to nurse for as long as possible

4.  Avoid over-sterilization of the puppies internal and external environment

5.  Minimize allergen exposure the week after each booster vaccinations

6.  Minimize over-stimulation with vaccines

7.  Feed a homecooked sacrificial protein during puppyhood to both the lactating bitch and mature pups

8.  Puppy pack recommendations for dogs with allergic tendencies:

a.  Epidermal barrier repair products

b.  Omega 3 and 6 fatty acids (dietary and supplemental)

c.  Mild cleansing shampoo to be used with cool to cold water

d.  Probiotics (use only reliable veterinary source)

Using these strategies will help to minimize development of allergic disease in our pets. Obviously, clinical signs can develop despite these efforts. The earlier the treatment including allergen specific immunotherapy to address environmental allergens after the patient has experienced an entire allergy season, the more favourable the long-term outcome.

References

1.  Bizikova P, et al. Review: role of genetics and the environment in the pathogenesis of canine atopic dermatitis. Vet Dermatol. 2015;26(2):95–e26.

2.  Feehley T, et al. Microbial regulation of allergic responses to food. Semin Immunopathol. 2012:34(5):671–688.

3.  Frick OL, et al. Immunoglobulin E antibodies to pollens augmented in dogs by virus vaccines. Am J Vet Res. 1983;44:440–445.

4.  HogenEsch H, et al. Effect of vaccination on serum concentrations of total and antigen-specific immunoglobulin E in dogs. Am J Vet Res. 2002;63:611–616.

5.  Hesselmar B, et al. Pacifier cleaning practices and risk of allergy development. Pediatrics. 2013;131(6):1829–1837.

6.  Imani F, et al. Infection of human B lymphocytes with MMR vaccine induces IgE class switching. Clin Immunol. 2001;100:355–361.

7.  Marsella R. Evaluation of Lactobacillus rhamnosus strain GG for the prevention of atopic dermatitis in dogs. Am J Vet Res. 2009:70(6):735–740.

8.  Marsella R, et al. Early exposure to probiotics in a canine model of atopic dermatitis has long-term clinical and immunological effects. Vet Immunol Immunopathol. 2012;146(2):185–189.

9.  Nuttall T. Update on the immunopathogenesis of canine atopic dermatitis. In: Proceedings from the 7th WCVD. 2012:275–284.

10.  Nødtvedt A, et al. A case-control study of risk factors for canine atopic dermatitis among Boxer, Bull Terrier and West Highland White Terrier dogs in Sweden. Vet Dermatol. 2007; 18(5):309–315.

11.  Özdemir Ö, et al. Preventative and therapeutic probiotic use in allergic skin conditions: experimental and clinical findings. Biomed Res Int. 2013:932391. doi:10.1155/2013/932391.

12.  Rook GA, et al. Innate immune responses to mycobacteria and the downregulation of atopic responses. Curr Opin Allergy Clin Immunol. 2003;3(5):337–342.