Efficacy of diagnostic testing for allergen sensitization in canine atopic dermatitis: a systematic review

Introduction: Canine atopic dermatitis (CAD) is an important cause of quality of life in dogs and their owners. There are different diagnostic tools to evaluate sensitization to allergens in CAD; however, there is little information to evaluate the clinical usefulness of these tests.

Methods: A systematic review aiming to assess the accuracy of allergen sensitization tests in CAD patients was performed. The search was planned, executed, and reported following PRISMA standards. The OVID®/MEDLINE, PubMed®, SciELO, and Redalyc databases were searched to find relevant studies comprising “diagnostic method” (OR test OR diagnosis OR method OR diagnostic OR paraclinic=) AND (atopic = OR hypersensitivity* OR allergen* OR “allergic reaction*” OR atopy) AND (dermatitis OR eczema OR scratching OR prurit = OR erythema OR rash OR edema) AND (canine OR dog* OR bitch* OR pupp*) search. Defined relevant articles were systematized, and content was analyzed via Atlas TI Scientific Software Development Software.

Results: The groups of diagnostic tests included the intradermal test (IDT), serologic-specific allergen test (SAT), skin prick test (SPT), and patch test. Combining the results from all the search engines and deduplicate elimination, yielded 928 eligible citations published between 1963 and 2024, and the 72 articles that met the eligibility criteria were included in the qualitative synthesis evaluating SAT (n = 36), IDT (n = 37), SPT (n = 2), and patch tests (n = 1) reporting the use of 136 different allergens. Favrot’s clinical criteria were applied in 41.6% of the studies (30/72), with no previous consensus on the case definition for CAD.

Discussion: The results of the review indicate that there is little information available to establish the diagnostic performance of the tests, which makes it difficult to make a recommendation regarding their use. In this systematic review they identified gaps in current knowledge that suggest the need for future research to standardize allergenic extracts, define cutoff points in serological tests, and consider environmental, geographic, and demographic variables. These findings provide a solid basis for improving the diagnosis and management of CAD and guiding future research in this field. Further studies are needed to adequately establish the diagnostic performance of the tests and their actual clinical usefulness.

Introduction

The skin, the largest and most visible body organ, is a significant concern in veterinary consultation. Dermatopathies account for nearly 30% of general consultations in dogs (1). These conditions are often frustrating for both veterinarians and pet owners, as they impact an animal’s quality of life and appearance, which are particularly important to pet owners (2). Pruritus is the primary reason for dermatological consultations in dogs, with allergic conditions such as flea allergy dermatitis, food hypersensitivity, and atopic dermatitis being the most prevalent underlying causes (1). Pruritus (3) and several behavioral problems (4) account for the most critical findings affecting the quality of life of canine atopic dermatitis (CAD) patients.

Atopic dermatitis is a common condition in both humans (called AD) (5) and dogs (called CAD) (6, 7), with an estimated prevalence of 10–15% and a high tendency for relapse (8). This disease is defined as a complex, multifactorial inflammatory syndrome in which the skin is the primary exposure route. While similar and divergent pathophysiological mechanisms have been identified in humans and canines, dogs are frequently used as experimental models for studying human AD (9).

The primary underlying cause of AD appears to be a type-1 hypersensitivity reaction driven by mechanisms mediated by IgE. This mechanism is observed in humans (5) and 40–90% of canine cases (7, 10). Inflammation is triggered by normally innocuous environmental proteins and antigens, commonly called allergens (6, 8). An allergen triggers an exaggerated inflammatory response in susceptible individuals. This response leads to the production of IgE antibodies and the release of proinflammatory mediators, resulting in allergic symptoms such as itching, hives, and respiratory difficulties. Allergens are classified on the basis of similarities in their molecular structure and allergenic potential (11).

Reactivity to common epitopes grouped in allergen mixtures used in dermabrasion test extracts has been proposed. However, variations in the concentrations of individual allergens and their fractions in most allergen identification tests raise concerns about the reliability of these mixtures for diagnostic purposes and for the formulation of allergen-specific immunotherapies (12, 13). Co-sensitization can occur when an individual is sensitized to multiple allergens simultaneously, usually through cross-reactivity. This phenomenon arises when the immune system recognizes similar protein structures in related or unrelated allergens, provoking an inflammatory response.

The diagnosis of CAD is predominantly based on the widely recognized Favrot’s clinical criteria (14). These consist of two set of findings: Set 1: (i) Affected ear pinnae. (ii) Affected front feet. (iii) Age at onset <3 years. (iv) Chronic or recurrent infections (Mainly related to Malassezia yeast, and Staphylococcus pseudintermedius). (v) Corticosteroid-responsive pruritus. (vi) Mostly indoor. (vii) Non-affected dorso-lumbar area. And (viii) Non-affected ear margins. Set 2: (i) Affected front feet. (ii) Affected ear pinnae. (iii) Age at onset <3 years. (iv) Mostly indoor. (v) Non-affected dorso-lumbar area. (vi) Non-affected ear margins. And (vii) Pruritus sine material at onset (14).

This diagnostic approach requires meeting at least 5 out of 8 specified criteria (2), providing a sensitivity of 85% and a specificity of approximately 80% for identifying the syndrome. Notably, no significant predisposition has been reported regarding breed, age, or sex (15). Accordingly, the Favrot’s criteria are critical but not exclusive for CAD definitive diagnosis, for which Anamnesis, the CADESI score, and Pruritus Visual Assessment Score (PVAS), must be considered. Finally, diagnostic test must provide data to the most probable allergen the dog is allergic to.

Diagnostic tests for AD include methods such as dermabrasion to the epidermal level (prick test—SPT) or the dermal layer (intradermal skin test—IDT), which use a standardized panel of allergens to evaluate the patient’s reactivity against them (16). In dogs, IDT is the test of choice (17), whereas in humans, SPT is preferred because of its lower cost, faster interpretation, greater safety, higher specificity, and reduced pain (18). The serologic-specific allergen test (SAT), which measures specific IgE levels in the blood in response to common allergens, has also been documented and evaluated for CAD diagnosis. However, the results have been inconsistent, and there is no consensus on its reliability (17, 19). Another approach, the patch test, involves the epicutaneous application of allergens to assess cellular hypersensitivity to food and environmental allergens. This test aims to replicate the immune changes observed in natural lesions. However, its results remain controversial, particularly for food allergens (20, 21).

These diagnostic techniques have the potential to be useful for (1) supporting the clinical diagnosis of CDA, (2) establishing environmental restriction measures, (3) selecting extracts for allergen-specific immunotherapy, and (4) determining the prognosis of clinical control or remission. However, it is necessary to define the diagnostic performance of the tests for each outcome to establish their clinical utility (e.g., sensitivity, specificity, predictive values, and kappa index). Considering these challenges, our objective was to systematically compile and analyze the existing evidence from studies investigating the allergens utilized in CAD diagnosis, aiming to provide clarity and insights into this complex diagnostic process.

Methods

This systematic review was planned, executed, and reported in accordance with PRISMA standards (22). The research question, methodology for conducting literature searches, study inclusion/exclusion criteria, and checklists for relevance screening, baseline characterization, methodological assessment, and data extraction from relevant primary research were all conducted on the basis of a preestablished and pretested protocol.

Search strategy

Our goal was to evaluate the diagnostic performance of the available tests for CAD. The initial search took place on June 11, 2024. Four search databases (i.e., OVID®/MEDLINE, PubMed®, SciELO, and Redalyc) were searched. The topic was divided into components, and the search terms used to find relevant studies on the platforms were (“diagnostic method” OR test OR diagnosis OR method OR diagnostic OR paraclinic=) AND (atopic = OR hypersensitivity* OR allergen* OR “allergic reaction*” OR atopy) AND (dermatitis OR eczema OR scratching OR pruritus = OR erythema OR rash OR edema) AND (canine OR dog* OR bitch* OR pupp*).

Eligibility screening

The inclusion criteria were limited to original articles published in peer-reviewed journals and written in English, Portuguese, French, or Spanish. The publication year and country of origin were not restrictive factors. The initial citation selection process involved evaluating the titles by two authors (RMR and MSGD), who selected citations on the basis of their potential relevance to the study topic. Two authors subsequently screened the list of citations chosen on the basis of their abstracts, following the inclusion and exclusion criteria established during the title screening phase. Afterward, two authors thoroughly reviewed the full texts of the remaining citations to ensure that they contained relevant data to address the research question. Kappa coefficients were calculated for each selection stage to assess agreement. Detailed scrutiny of each full text’s materials, methods, and results sections was conducted, with any conflicts resolved through author consensus. The World Association of Veterinary Dermatologists (WAVD) proceedings from 1989 to 2020 were available on its website.¹ These proceedings were manually examined for any published primary studies. Additionally, as a final step, two authors manually searched the references cited in the pertinent articles identified during full-text screening, a process commonly referred to as snowballing, to uncover additional published sources.

To ensure eligibility, the articles defined as relevant were systematized, resulting in emerging categories and subcategories. A content analysis was developed via the Software Atlas TI Scientific Software Development GmbH (ATLAS.ti 24 Windows, 2022–2024). Subsequently, groups of diagnostic tests (i.e., IDT, SAT, SPT, and patch test) were assessed through an intentional coding analysis. Three recent articles were selected at the researchers’ discretion (23–25) to search for the most frequent concepts that would be considered trends. From there, the discriminated codes were obtained and served as a basis for the comprehensive review of the relevant articles. After all applicable publications were compiled, a descriptive summary was provided that considered the information of interest by groups of diagnostic tests.

Risk of bias assessment

To assess the methodological quality of the included studies, a qualitative risk of bias evaluation was performed based on adapted domains from the QUADAS-2 tool, which is specifically designed for studies of diagnostic accuracy. The domains considered were: patient selection, index test, reference standard, and flow and timing. Two reviewers independently evaluated each study for potential sources of bias, and discrepancies were resolved by consensus.

Results

The bias assessment revealed a high risk of bias in several domains across the included studies. Most studies (68/72) did not clearly define a reference standard for confirming CAD, increasing the likelihood of misclassification bias. Approximately 70% of the studies did not report blinding of test interpreters, leading to potential detection bias. Additionally, considerable variability in allergen concentrations and test protocols contributed to methodological heterogeneity. Only 41.6% (30/72) of studies applied Favrot’s clinical criteria, raising concerns regarding case definition and applicability. These findings suggest a moderate to high risk of bias in the body of evidence, which should be considered when interpreting the diagnostic value of allergen tests for CAD.

The electronic search, which combines results from all search engines and, after deduplication, yielded 928 eligible citations possibly associated with the subject of this systematic review. The citations to be reviewed were published between 1963 and 2024. After the titles were read, 641 were considered unrelated (agreed upon by two reviewing authors). The final number of citations by title screening was 287 (retained by at least one reviewer). After the abstracts of the articles were read, 145 were excluded (by both authors), and 142 original articles remained for the full-text review. Sixty articles were reviewed in full text and kept for data extraction after 82 articles were dismissed during this phase. The snowballing strategy was applied through the reference lists of the 59 definitive articles, and 90 citations were retained after title screening. After the abstracts were screened, 26 studies were retained. The final selection of articles from the snowballing method yielded 11 results. In addition, two more articles were detected through the proceedings of the WAVD. The final number of articles that met the eligibility criteria and were included in the qualitative synthesis was 72. The file with the systematic process of collecting and selecting citations is available as Supplementary material (SM1). Figure 1 describes the protocol and the selection of relevant articles. All the articles were written in English. Studies were performed in the United States (n = 11), the United Kingdom, Japan, Brazil (n = 6, each), the Netherlands, Korea, Thailand (n = 4, each), Spain, Germany (n = 3, each), Austria, Norway, Poland (n = 2, each), Australia, China, Colombia, France and Italy (n = 1, each).

Figure 1

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow chart (22), which describes the progress of the citations through the systematic review. OA, Open Access.

The first relevant article was published in 1982, and the most recent article was published in 2023. Citations were published in 31 journals and 18 countries, of which only three were nonseasonal countries (e.g., Brazil, Colombia, and Thailand). The results for the SAT, IDT, SPT, and patch tests corresponded to 36, 37, 2, and a single relevant study, respectively, reporting the use of 136 different allergens and considering relevant articles that addressed two or more diagnostic tests for CAD.

For SAT reports, 19 out of 36 articles (52.7%) reported positive reaction values in optical densities of variable cutoff points; 4 out of 36 (11.1%) reported in ELISA Units; 3 out of 36 (8.3%) used Top Screen and Immunodot values; and 10 out of 36 (24.7%) reported not reaction units (Table 1). For IDT reports, a high variability of cutoff point to define positive reactions was found, with a single report out of 37 (2.7%) reporting not positive reaction definitions (Table 2). Finally, for SPT reports, the two reports found reported different positive cutoff procedures and scales (Table 3).

Table 1

Table 1. The study features when a serologic specific allergen test (SAT) was considered in the diagnosis of canine atopic dermatitis (n = 36).

Table 2

Table 2. The study features when an intradermal skin test (IDT) was considered in the diagnosis of canine atopic dermatitis (n = 37).

Table 3

Table 3. The studies featured when the prick test (SPT) was considered in the diagnosis of canine atopic dermatitis (n = 2).

Tables 1–4 display the information extracted from the four diagnostic test groups. Since 2010, Favrot’s clinical criteria (14) have been applied in 41.6% of studies (30/72); before this report, there was no consensus on the case definition for CAD. The five most represented breeds included mixed, Labrador, German Shepperd, Shih Tzu, and Boxer. However, the breed of almost 500 out of 2,096 dogs was not specified. All remaining and well-known dog breeds are represented in Figure 2. Table 1 presents a detailed feature of selected articles reporting a serologic-specific allergen test (SAT) for CAD diagnosis. The Sensitivity, Specificity and Positive or Negative predictive comparison values between studies that met the criteria for these analyses are presented in Table 5. Finally, the available data for allergen prevalence according to allergen reactivity of CAD patients against mites, insects, trees, and molds, is presented in Table 6.

Table 4

Table 4. The patch test was used for the diagnosis of canine atopic dermatitis (n = 1).

Figure 2

Figure 2. Distribution of dogs in the selected studies according to breed. Nomenclature according to the Fédération Cynologique Internationale (https://www.fci.be/en/nomenclature).

Table 5

Table 5. SAT (specific allergen serological test) comparison table.

Table 6

Table 6. Table of allergen prevalence according to allergen reactivity in canine atopic dermatitis.

Discussion

This systematic review describes the available literature on factors related to the diagnosis of allergens associated with CAD, a disease of complex etiology. Identifying specific clinical criteria is the cornerstone of CAD diagnosis. To identify allergens related to CAD provides the clinician with additional therapeutics to offering accurate therapeutic plans to their patients. Diagnostic tests with high reliability, specificity, repeatability, and sensitivity are needed as diagnostic alternatives for clinicians to achieve a more accurate diagnosis of the allergens involved. One of the most critical findings of this work was the failure to find a gold standard parameter. Another limitation in evaluating diagnostic performance is the heterogeneous concentrations of allergens used in dermabrasion tests, mode of preparation, and source of extraction.

For the SPT, which has been used regularly for several years in the diagnosis of allergens in human medicine, only two studies have evaluated the diagnostic performance of CAD in case-control studies. The findings of the two studies are contradictory, so SPT does not have enough references to judge its accuracy, making it necessary to conduct more studies on the subject since, owing to its easy design and application, it could be a useful tool in diagnosing allergens responsible for CAD crises. On the other hand, the measurement of serum IgE concentrations, which is often widely accepted in human AD allergen diagnosis, also presents a range of variations as complementary diagnoses of CAD. In addition, their results must be analyzed in the context of the patient’s clinical signs at a given time. The same doubts exist about IgE testing, as no evidence-based medical criteria were found. In this context, human dermatology has achieved an important consensus for diagnosing allergens associated with AD, but we still have a long way to go in CAD.

This systematic review identified 72 studies published between 1982 and 2023 in which microbial and nonmicrobial allergens were identified. In addition to IDT, SPT, the patch test, and ST, the study by Sævik et al., a combination of ELISA and intradermal injections of allergens to detect Ig-E-mediated reactivity in atopic dogs, revealed no concordance between serological and dermal tests and IgE positivity in the diagnosis of allergens related to CAD (26). Sasaki et al. used a crude allergen extract from Japanese cedar pollen to assess reactivity against it via IDT in dogs (27).

The results of this systematic review highlight the actual limitations in defining the utility of diagnostic tests to identify allergens in CAD patients. This discussion has taken place in the medical and scientific community, and the results of our systematic review did not answer the research question, which was intended to identify diagnostic tests that could be considered consistent, reliable, sensitive, and specific for CAD.

The role of immunoglobulins in the pathogenesis and diagnostic criteria for CAD has not been fully elucidated (28). Mueller et al. reported no statistically significant differences in the IgA concentration in skin washings between atopic and clinically healthy dogs (28). In contrast, Noli et al. reported a lack of IgE reactivity of serum from atopic dogs against Dermatophagoides pteronyssinus-derived allergens (Der p I, Der p II), and D. farinae antigens Der f I, and Der f II, which seem unlikely to be major allergens in dogs with CAD. However, the serum of atopic dogs reacts to a 90 kDa polypeptide of D. farinae, according to Western blot analysis (29). Hämmerling, evaluating IgE and the IgGa subclass in atopic dermatitis dogs, concluded that finding DP- and DF-related IgE renders this IG isotype more relevant than IgGa in detecting DA-related allergens (30).

Willense et al., and Moya et al. reported IgE and the IgG 1, IgG 2 subclasses against fractions of Der f 2 and Der f 1, Der f 18 in a lesser proportion; the IgG1 subclass seems to distinguish both IgE and House Dust Mites Allergens (HDMs) in CAD (31, 32). IgE reactivity against HDMs is more common than IgG reactivity in CAD (33). However, several factors must be considered when interpreting the results that affect their titer. Day and Corato reported heterogeneous IgG subclass reactivity against the most common allergens related to atopic dermatitis in dogs (34). Interestingly, helminth parasite infestation stimulates IgG production against IgE epitopes and decreases their levels in atopic dogs concomitantly infected by helminths and acari (35). Some patterns of IgE sensitization in dogs have been described in humans (e.g., Der f 18) (35), and the positive results of dermabrasion tests with concordant allergy-specific IgE levels in atopic dogs in Brazil are evidenced by the high prevalence of dust mites in Sao Paulo (24). For some authors, total IgE tests are unreliable and do not differentiate CAD (36). Jang et al. reported no significant differences in allergen reactivity between IDT and SAT (37).

Cross-reactivity has been reported in CAD dogs against plant allergens (38) and HDMs (DF and DP) (39), as well as with invertebrates and storage mites (Tyrophagus putrescentiae) with DF (40). Dogs sensitized to grass pollen often react to other allergens, particularly DF (24, 38, 39), and there is apparent sensitization between related allergen groups (house dust/storage mites, epidermis/fibers, trees, weeds, grass pollen, and molds) (41, 42).

The predominant sensitization against HDMs was common in several seasonal and nonseasonal countries reported from 1983 to 2023 (1–26, 28–31, 33–40, 43–76), indicating a consensus on a higher prevalence of HDMs than other allergenic groups, followed by plant pollen (39), animal allergens and molds, except for the study by Jung Kim et al., which described a higher prevalence of mold (77) (related to closed spaces, climatic changes that can influence findings).

Allergens have been described in HDMs, especially DFs, with high and low molecular weights classified as major and minor allergens according to their allergenic potential. Among the major allergens, the following have been reported: chitinase (Der f15) (48) and Der f 18, with greater sensitization in CAD (84.6%) than in human DA (50%) (48). Minor: In the Der 1 and 2 groups, approximately 50% of CAD dogs were sensitized to Der 1 and Der 2 in a study in Japan (40), and little importance in CAD has been reported (47), similar to the Der p I, Der p II, Der f 1, and Der f 2 (48) fractions. They were also described as irrelevant in the study by Noli et al. (29). Der f 1 is the major allergen in humans, and Der f 2 in SAT in CAD is poorly recognized by IgE (53). Other studies reported a high prevalence (86.7% in humans and 94.1% in dogs) (40). Khantavee et al. reported five major DF fractions (Der f Alt a 10, EF1-α, the gelsolin-like allergen Der f 16, Der f 28 and Der f 2) and Der f 3, Der f 10, Der f 20, and Der f 32 as minor allergens (33). Exposure to furniture and textiles has been associated with DF sensitization via the Zen 1 fraction, which strongly correlates with the crude DF extract in the SAT (62).

Geographical variations accounting for the prevalence and diversity of allergens (humidity and temperature in HDMs) should be taken into account (67), reflecting exposure factors (50). There are allergens specific to each region, including Japanese cedars (JCs) and pollen in Japan (38). Rumex acetosa (sorrel) in Italy (61), the pollen of some weeds in Thailand (23), and Cynodon dactylon in Brazil (57). In addition, environmental and surrounding conditions increase the prevalence of certain storage mites, as reported in Portugal (65), Brazil (T. putrescentiae, Lepidoglyphus destructor, and Blomia tropicalis) (53), and Thailand (23), where IgE titers increased during the rainy season (23). Air currents affect pollen distribution (39), although indoor aeroallergen deposition is independent of seasonality (42).

There are discrepancies between SATs (43) and various IgE measurement techniques lacking quality control and providing different results when the same sample is analyzed simultaneously with other equipment and methods (59). There is intra- and interlaboratory variability, so a quality assurance program (reliability) is needed (52).

Thirty-seven out of the 72 articles evaluated were related to IDT: only five studies reported sensitivity and specificity measurements (Table 5). Considering the positivity cutoff point as a determinant of these values is important. The positivity cutoff points for SAT do not have a consensus, ranging from OD >0.15 (44) to OD >0.250 (26, 49); other reported 50 EAU (56), or units were not reported (46).

Lowering cutoff point arbitrarily increases the probability of false positives (decreasing the test’s specificity). On the contrary, raising cutoff point affects the sensitivity and the possibility of false negatives. Standardizing this evaluation according to the techniques used and the allergens evaluated (allergenic potential) is essential (26). Cross-reactivity should be reduced with inhibitors of carbohydrate cross-reacting determinants (CCDs) (60). The study of allergenic fractions with allergenic potential detected by specific IgE would increase the effectiveness and greater reliability of the tests, mitigating false positives. IgG1, which reacts against DF and DP, was also reported as the predominant IgG subtype in a set of atopic dogs (33).

Threshold concentrations (positive nonirritating reactions) in IDT in dogs have been reported to be similar to those in humans (66). Standardized extracts for human medicine are often effective in CAD (78). Some studies define thresholds for certain allergens (values expressed in Protein Nitrogen Units, PNU): grasses, weeds, trees, molds and insects (1,750 PNU/mL), flea allergens (1:500 w/v), DPs (250 PNU/mL), DFs and T. putrescentiae (100 PNU/mL), epidermis (all at least 1,250 PNU/mL), human dander (300 PNU/mL), the optimal concentration of histamine (positive control) at 1:10,000 w/v. (76), Irritability at 1:10,000 w/v for DF and DP; 1,000 PNU for dust (36); and highly concentrated pollen extracts of 1,000–1,500 PNU (66). It has also been shown that mixed allergen extracts (26) in HDMs and house dust result in false negatives and low sensitivity and specificity. Individual DF and DP extracts, not house dust, are indicated (75).

IDT usually exhibits high sensitivity and specificity in detecting allergens in dogs with CAD (26). However, these values may vary depending on the allergen and concentration used. There is no clear consensus on the optimal allergen concentrations for IDT, which may affect the accuracy and reproducibility of the results. Some studies have evaluated different allergen concentrations and reported that higher concentrations may increase sensitivity and the risk of false positive reactions (36, 76). Interpretation of IDT results can be subjective and can vary among raters. Scales from 0 to 4 assess papule size, turgor, and erythema. Standardizing interpretation methods to reduce variability and improve comparability between studies and clinical settings is crucial.

Most of the works found in this systematic review reported prevalence values of mixtures or individual allergens without homogeneity in concentrations on the basis of the definition of a case or disease as CAD. The current clinical criteria were established in 2010 by Favrot (14), who issued eight clinical criteria, more than five of which had a sensitivity of 85% and a specificity of 80%. Assuming these criteria as a case definition, the previous prevalence would be reconsidered (because of the possibility to have been included nonatopic individuals), and therefore, false-positive results would have been obtained (Table 5).

Cross-reactivity between related allergens can complicate the interpretation of IDT results (38, 39, 42). Identifying and considering these factors when allergens are selected for testing are important. Co-sensitization to multiple allergens is common in dogs with AD (41), which may influence allergen choice (67). Allergen prevalence can vary significantly by geographic region, highlighting the importance of tailoring allergen panels to local conditions. Factors such as humidity and temperature can affect allergen sensitivity and should be considered when interpreting IDT results (61).

Standard protocols for performing and interpreting the IDT, including allergen concentration and interpretation criteria, are needed. Combining subjective and objective methods may yield more reliable IDT results (79). Longitudinal studies have been conducted to assess the long-term effectiveness of IDT and IDT-based immunotherapy. The inclusion of new relevant allergens in different geographic regions should be investigated to improve the accuracy and utility of IDT.

The study by Carmona et al. revealed a moderate sensitivity of 66% for SPT and a high specificity of 100% (80), in parallel with the study by Fleischman and Morris (25), where the intradermal test (IDT) and the SPT were compared, with a low sensitivity of 47% and a high specificity of 92.1% for the latter. SPT does not require sedation, is less invasive and comfortable for the animal, is less expensive than IDT, and has high specificity, reducing the probability of false positives. It appears to have moderate to low sensitivity, limiting its usefulness. However, the low reactivity to allergen mixtures (used in both studies) due to the dilution of individual components must be considered, which can result in false negatives. The interpretation of the results can be subjective and vary between evaluators, as with IDT. The agreement between the SPT and the IDT in the Fleischman and Morris (25) study was moderate (Cohen’s kappa value = 0.424), suggesting that both methods may complement each other. Studies should be conducted in larger and more diverse populations to validate the findings and improve the generalizability of the results with individual allergens instead of mixtures by increasing the reactivity and accuracy of the SPT; additionally, protocols for the performance and interpretation of the SPT should be developed and standardized to reduce variability and improve the comparability of results. Panels of new allergens relevant to different geographical regions should be included (25).

In the study by Olivry et al., an extract of D. farinae was used (500 μg per patch) (81). The presence of visible erythema, edema, induration, and vesiculation at the application site was evaluated. Macroscopic observations of skin inflammation were compared with microscopic observations. The study was conducted with a small, nonrepresentative sample. We wondered whether individual extracts should be used instead of mixtures with different standardized concentrations, considering irritant thresholds. Studies should be designed with more individuals and diverse races to validate the findings and compare the system evaluated with other diagnostic and treatment methods to evaluate its relative effectiveness.

In the study by Sævik et al., intradermal injections of sera from allergen-positive dogs were performed via ELISA. On the other hand, the challenge test involves the controlled administration of a specific allergen to the patient to observe whether an allergic reaction occurs (26), using a crude allergen extract from Japanese cedar pollen in dogs. The challenge test fell into disuse owing to the risk of adverse reactions and has been replaced by dermabrasion tests (27).

Given the gaps in knowledge, this manuscript proposes bringing together world experts in veterinary allergology to agree on critical points and issuing a general guide as a starting point for new research with internal and external validity, reproducibility, and comparative capacity. It is necessary to clearly and reliably define prevalence tables and statistical association measures to support the diagnosis of CAD. We urge the execution of studies with significant sample sizes, diverse racial groups, and sexual parity, considering the factors mentioned earlier, such as the environment, seasonality, humidity, temperature, and geographic variations in the prevalence of allergens (67).

Advantages and limitations of systematic review

Our systematic review has several strengths. We followed a structured approach anchored in a clearly defined research question previously documented and validated by systematic reviews from health field experts. Our extensive literature search spanned numerous sources, including general databases, search engines, journals, and conference proceedings, enabling us to capture data as far back as 1949. By excluding geographic and time-based limitations, we aimed to reduce potential biases. Additionally, the extracted information was rigorously organized; one author prepared a matrix of findings, which a second author subsequently reviewed to ensure accuracy across studies of varying quality and methodology. As a limitation, 21 relevant documents identified through abstract screening were not available as open access, so they could not be fully processed as complete texts to determine their definitive relevance, and we did not consider gray literature. To mitigate this, we employed snowballing techniques.

Finally, this manuscript presents a detailed, comprehensive, and transparent systematic review of allergen diagnostic methods for CAD, following PRISMA standards. The methodology used in the review, including exhaustive search and content analysis with Atlas TI software, ensures the robustness and reproducibility of the findings. This includes the evaluation of multiple databases and the application of rigorous inclusion and exclusion criteria. Different diagnostic methods are compared, providing a clear overview of their advantages, limitations, and relative effectiveness. We report sensitivity and specificity data from relevant studies, which helps the scientific community understand the gaps in knowledge and scientific rigor to improve the accuracy of these diagnostic methods. The most common allergens used in the studies were identified and reported, which could guide future research. We highlight the application of Favrot’s clinical criteria in 41.6% of the studies since 2010 (14), highlighting the importance of these criteria in defining CAD cases. We identified gaps in current knowledge that suggest the need for future research to standardize allergenic extracts, define cutoff points in serological tests, and consider environmental, geographic, and demographic variables. These findings are valuable to the scientific community, as they provide a solid basis for improving the diagnosis and management of CAD and guiding future research in this field.

Conclusion

Even though most scientist and practitioners consider IDT as the standard test to diagnose allergen sensitization in CAD patients, our results suggest caution must be kept when considering the available tests as a gold standard to identify allergen sensitization in dogs affected by CAD. Current methods have advantages and limitations. There is no consensus on antigen concentrations, no standardized cutoff points for SAT positivity have been defined, and there is no laboratory regulation or monitoring. Favrot’s clinical criteria have been applied in 41.6% of studies since 2010, highlighting their importance in defining CAD cases. A total of 136 different allergens used in the studies were identified, providing a basis for future research and clinical practice. The development and standardization of allergenic extracts for diagnostic testing are crucial, ensuring the consistency and comparability of results between different studies and laboratories. Studies that consider environmental, geographic, and demographic variables should be conducted to better understand how these factors affect the prevalence and severity of CAD. We urge further studies to evaluate the efficacy and applicability of the Favrot’s criteria in different populations and settings. Longitudinal studies should be conducted to better understand the progression of CAD and the long-term effectiveness of different diagnostic methods and treatments and to further explore co-sensitization and cross-reactivity between different allergens to improve the accuracy of diagnostic tests and the formulation of specific immunotherapies. Investigate the impact of CAD on the quality of life of dogs and their owners and how different diagnostic methods and treatments can improve these aspects. These proposals may help advance the knowledge and management of CAD, improving the diagnosis and treatment of this condition.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors without undue reservation.

Author contributions

RM-R: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing, Conceptualization. MG-D: Investigation, Supervision, Validation, Writing – review & editing. JS: Supervision, Writing – review & editing, Formal analysis, Validation. NC-V: Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing, Methodology. JM-E: Conceptualization, Data curation, Investigation, Writing – original draft, Writing – review & editing, Funding acquisition, Project administration, Supervision.

Funding

The author(s) declare that financial support was received for the research and/or publication of this article. This work was funded by the Universidad de Antioquia through the call for consolidation of research groups 2023-2024 (RM-R, NC-V, JS, JGM-E). MSG-D was funded by Universidad CES and Bivett.

Acknowledgments

Research Activities of World Class research group in the University of Antioquia (Grupos Minciencias Categoría A1 y A) is supported by “Estrategias de Sostenibilidad para grupos de Investigación” Calls 2021 and 2023. OHVRI Research Group, Group of Clinical and Experimental Allergy, and CENTAURO Research Group, are supported by these University of Antioquia internal Calls. INCA-CES Research group scientific activities are supported by Universidad CES.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The authors declare that Gen AI was used in the creation of this manuscript. During the preparation of this work, the authors used OpenAI ChatGPT (October 2023 version, https://chat.openai.com/) to improve the readability and language of the manuscript. After using this tool, the authors reviewed and edited the content as needed and took full responsibility for the content of the published article. Several Grammarly reviewing sessions were applied before submitting the final version of the manuscript.

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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fvets.2025.1551207/full#supplementary-material

Footnotes

1. ^https://wavd.org/

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Glossary

AD - Human Atopic Dermatitis

ASIS - Allergen-specific IgE serology

BU - Bethesda Unit

CAD - Canine Atopic Dermatitis

CADESI - Canine Atopic Dermatitis Extent and Severity Index

CCDs - Carbohydrate Cross-Reacting Determinants

CMG Immunodot - ELISA test using allergen-specific anti-canine IgE monoclonal antibodies.

Der f 15, Der f 18 - Dermatophagoides farinae-derived Major allergens. Each one are the major allergens of the American house dust mites.

Der f 1, Der f 2, Der f 18 - Dermatophagoides farinae-derived Minor allergens. Each one are the major allergens of the American house dust mites.

Der p I, Der p II, - Dermatophagoides pteronyssinus-derived allergens (major allergens of the American house dust mites).

DF - Dermatophagoides farinae

DP - Dermatophagoides pteronyssinus

EAU - ELISA Absorbance Units

ELISA - Enzyme-Linked Immunosorbent Assay

HDM - House Dust Mites Allergens

IDT - Intradermal Test

IgE - Immunoglobulin type E

IgG - Immunoglobulin type G

IgG1 - Immunoglobulin type G subclass 1

IgG2 - Immunoglobulin type G subclass 2

MWD - Mean Wheal Diameter

NE - Nitrogen Equivalents

OD - Optical Density

PNU - Protein Nitrogen Units

PNV - Predictive Negative Value

PPV - Predictive Positive Value

PVAS - Pruritus Visual Analog Scale

SAT - Serologic-specific Allergen Test

SD - Standard Deviation

Sens - Sensitivity

Spec - Specificity

SPT - Skin Prick Test

w/v - Weight-to-volume Ratio