In this study, 59/103 dogs (57%) had good or excellent responses to RESPIT. Similar rates have been reported in studies evaluating AIT effectiveness [5, 15–17, 19, 20]. Therapeutic extracts are likely to be imperfectly matched with dogs’ actual sensitivity with both AIT and RESPIT, perhaps accounting for the similarity in response rates.
The efficacy of immunotherapy using uniform allergen mixtures has been evaluated in two randomized controlled trials in atopic dogs, both reported only in abstract form with limited details or analysis [10, 11]. In a 12-month study of 78 dogs, Garfield found a 76% good to excellent response (>51% resolution of pruritus) to a uniform mixture of 32 aqueous allergens [10]. This was not significantly different from the response of those dogs that received either of two doses of AIT based on IDT findings. In contrast are the findings of an 8-month trial of 30 dogs in which a uniform mixture of four alum-precipitated allergens (house dust, dog dander, human dander, and grass mix) was compared to AIT. The median improvement in clinical scores (pruritus and lesion severity) was 70% in the AIT group and 18% in the group that received the uniform mixture of allergens [11]. The discrepancy in response rates between the latter study versus those of Garfield and the present study may reflect differences in the number or type of allergens in the uniform mixtures and their formulations (alum-precipitated vs. aqueous).
Beneficial effects of immunotherapy with imperfectly matched or unrelated allergens have also been reported in cats and humans [12, 21, 22]. In a feline asthma model, eosinophilic airway inflammation responded to AIT with allergens matched to experimental sensitization, but also to immunotherapy with imperfectly matched or unrelated allergens [21]. Cats dually sensitized to both Bermuda grass allergen and house dust mite given AIT to either allergen displayed decreased eosinophilic airway inflammation and higher levels of CD4+ CD25+ FoxP3+ Treg cells compared to placebo-treated cats. Differences were found in the immunological responses of cats given sensitivity-matched allergens versus those given unrelated allergens. Cats monosenesitized to Bermuda grass allergen displayed evidence of lymphocyte hypoproliferation during immunotherapy with Bermuda grass allergen, whereas Bermuda grass sensitized cats displayed lymphocyte hyperproliferation with house dust mite immunotherapy. The authors concluded that sensitizing allergens and those used in AIT need not be identically matched in order to provide a clinical benefit. Analogous findings have been reported in humans sensitive to both birch and grass pollen [22]. Sublingual immunotherapy with either birch or grass pollen led to clinical improvement and lower nasal eosinophil counts during both pollen seasons, although the improvement was greater when both were given.
Whereas perfectly matching an atopic dog’s clinical sensitivity is the objective of AIT, the mechanism of action of RESPIT may be both allergen-specific and non-specific. Phylogenetically related allergens frequently cross react on IDT in atopic dogs [23]. About 30 major groups of cross-reactive botanical proteins have been identified [24]. The RESPIT extract used in this study contained 20 allergens representing a spectrum of botanically related allergen groups and house dust mites. RESPIT may imperfectly match an atopic dog’s actual sensitivities, but include some allergen-specific epitopes as well as panallergens (e.g. profilins, polcalcins, and non-specific lipid transfer proteins) common to distinct allergen groups. Although panallergens are widely distributed in nature with highly conserved amino acid sequence regions, structures, and functions, their clinical significance in human allergy is unclear [24, 25].
In the present study, the median duration of therapy at the time of the D270+ evaluation was 12 months and the majority of D270+ evaluations (74/103) occurred between 9 and 15 months after beginning RESPIT (Fig. 2). The slight correlation between the days until D270+ and response classification, and the moderate correlation between the total length of therapy and response classification at D270+ likely reflect pet owners’ higher level of compliance when satisfied with their dogs’ response. The calendar month during which D270+ evaluations took place did not correlate with the response to RESPIT (Fig. 1). Taken together, these findings suggest that the possible confounding variable of seasonality did not account for the clinical improvement detected in this study.
Similar to a number of retrospective studies of AIT in atopic dogs [5], these results suggest that a dog’s response to RESPIT cannot be predicted from their age, weight, gender, or from the seasonality of their signs. The relatively low number of dogs of any given breed did not allow for rigorous analysis of the possible correlation of breed and response classification. Neither D0 pruritus severity nor lesion severity significantly correlated with the response classification. The dataset did not allow for precise reporting of the duration of clinical signs prior to RESPIT therapy.
For many pet owners, pruritus is the most important burden of canine atopic dermatitis [26]. Pruritus severity was scored with the validated visual analog scale [10], however, lesion severity was scored with an ad hoc scale (LSI). The third iteration of the canine atopic dermatitis extent and severity index, the only validated lesion severity scale available when the data collection began, was not practical for routine use in a clinical setting [27].
Immunotherapy with irrelevant allergens could, in theory, lead to the development of clinical sensitivity. This outcome may occur with either RESPIT or AIT with imperfectly matched allergens. However, this study found that the prevalence of adverse reactions to RESPIT (2.4%) was at the low end of the wide range reported for AIT (5–50%) [4, 5]. In a small study, immunotherapy with irrelevant allergens did not lead to the development of clinical signs of atopic dermatitis in normal dogs [28].
In children with rhinitis or asthma who are sensitive to house dust mite, AIT may have a tolerogenic effect, preventing the sensitization to additional allergens by inducing a shift from a TH2 to a TH1 allergen response [29]. Irrelevant allergens that are prescribed in either AIT or RESPIT may also confer some degree of non-specific allergen tolerance. This could explain, in part, why the reported success rates of AIT are similar when utilizing a variety of allergy testing techniques and assays that exhibit poor agreement with one another [9].
A limitation of this study was the open, retrospective design, similar to most studies on the effectiveness of AIT [5]. A placebo-controlled trial could provide a higher level of evidence concerning the efficacy of immunotherapy, but may suffer from a high rate of non-compliance during a long-term study. Forty-three percent of dogs were lost to follow up by 12 months in the prospective study of AIT by Willemse [16]. A second limitation of our study was that only 36% of the dogs initially identified met the inclusion criteria, which required a follow-up examination after 270 days of therapy. In the current study, dogs that continued to receive RESPIT prescribed by their primary care veterinarian but did not return for the D270+ examination were excluded. Allowing telephone interviews for follow-up, as have some retrospective studies of AIT [15, 20], may have resulted in excluding fewer dogs, but would not have allowed for consistent scoring of pruritus and lesion severity.
