Ann Allergy Asthma Immunol xxx (2016) 1e6

Contents lists available at ScienceDirect

Review

Dog allergen immunotherapy: past, present, and future

Derek M. Smith, MD; and Christopher A. Coop, MD
Department of Allergy/Immunology, Wilford Hall Ambulatory Surgical Center, San Antonio, Texas

A R T I C L E I N F O A B S T R A C T

Article history: Objective: To review the published medical literature on dog allergy immunotherapy and discuss prior
Received for publication October 1, 2015. clinical trials, important allergens, extract specifics, and potential future treatment options for dog allergy
Received in revised form November 25,
relevant to the clinical allergist.
2015.
Data Sources: MEDLINE search was performed using the terms dog, immunotherapy, and allergy limited to
Accepted for publication December 2, 2015.
human studies from any period. Articles cited in selected studies also were reviewed for appropriateness of
inclusion into this review.
Study Selections: Publications were included that were original research and fit the topic of dog allergen
immunotherapy, specifically articles that investigated prior effectiveness and safety of dog allergen immu-
notherapy, dog extracts, identification of dog allergens, and current prescribing trends among allergists.
Results: Two hundred fifteen articles were initially identified and 60 were reviewed in complete detail for
inclusion in this review. The primary focus was placed on the 17 clinical trials that investigated the safety
and efficacy of dog immunotherapy and the 19 studies that explored and defined the complex allergenic
profile of dog extracts.
Conclusion: The medical literature on the use of dog extract immunotherapy in patients with hypersensitivity
to dog shows poor and conflicting results of clinical efficacy, which has been attributed to poor-quality extracts
and the inherent complex allergenic profile of dogs that remains without a clearly dominant allergen.
Published by Elsevier Inc. on behalf of the American College of Allergy, Asthma & Immunology.

Introduction room air filters,8 and even breeding “hypoallergenic” dogs9 or

consistently altering their natural hair length.10 All these methods
According to the American Pet Products Association, dogs
can lower allergen levels but have failed to resolve the issue of
currently live in more than 54.4 million US homes, and studies have
dog allergy. Therefore, the allergist is presented with the
shown that Can f 1 is nearly ubiquitous in public places.1 Domes-
option of recommending dog immunotherapy to help ameliorate
ticated dogs initially fulfilled a pragmatic role for people, for pro-
patients’ symptoms. This article reviews the current evidence on
tection or for agricultural use, but now serve a more emotional role
which to base this decision.
of companionship. With this paradigm shift, dogs have moved in-
doors and constant exposure is associated with the development
and exacerbation of allergic disease. For the patient with dog al-
Early Clinical Studies
lergy, avoidance is clearly the best treatment modality, but this
frequently does not occur even in settings beyond occupational After the advancement in protein extraction methods in the
allergy. The sensitization rate is reported as high as 10% of all people early 1960s, it was hypothesized that the role of immunotherapy
in Westernized countries,2 and this rate varies by country, time would expand far beyond pollens in the treatment of allergic dis-
period, and atopic predisposition.3e5 As such, great efforts have ease. Soon after, reports were published about symptomatic
been made in determining ways to minimize dog allergen levels in improvement for patients with dog allergy after immunotherapy
the home without removing the dog. Specific trials have looked at with the newest form of dog extract. The oldest report of successful
frequent washing of the dog,6 using high-efficiency particulate air- dog immunotherapy was a presentation by Gould11 in 1963, who
filtered vacuum cleaners,7 using high-efficiency particulate air reported a case series of 11 patients with dog allergy whose
symptoms were alleviated after being treated with dog extracts. In
1967, Tuft and Torsney12 reported that 13 of 17 patients (76%) with
Reprints: Derek M. Smith, MD, Allergy/Immunology, 2200 Bergquist Drive, Suite 1,
dog allergy had improved tolerance to dog exposure after immu-
Lackland AFB 78236; E-mail: [email protected].
notherapy, and Scherr13 reported improved tolerance in 25 of 27
Disclosures: Authors have nothing to disclose.
Disclaimer: The opinions or assertions herein are the private views of the authors patients (93%) treated with dog extracts. However, no placebo in-
and are not to be construed as reflecting the views of the Department of the Air jection or blinding controlled these trials and the improvement was
Force or the Department of Defense. based solely on subjective symptom scores.

http://dx.doi.org/10.1016/j.anai.2015.12.006
1081-1206/Published by Elsevier Inc. on behalf of the American College of Allergy, Asthma & Immunology.
2 D.M. Smith and C.A. Coop / Ann Allergy Asthma Immunol xxx (2016) 1e6

Although these early results were encouraging, clearly there measurements and symptom scores or allergen-specific broncho-
was a need to improve the quality of evidence to support the use of provocation testing were noted.
dog allergen immunotherapy. As more data accumulated, the At the end of the initial 12 months, the blinding code was broken
excitement for the effectiveness of this therapy began to wane. In and the 4 patients with dog allergy receiving placebo were offered
1968, Brown and Wolfe14 prospectively compared immunotherapy immunotherapy for 3 years (a total of 11 patients). After 2 years of
with alum-precipitated dog extracts with the previous standard immunotherapy, no significant change in outcomes was noted
aqueous extracts in 50 patients with dog allergy. The 2 groups compared with just 1 year of treatment.20 At completion of 3 years,
showed less convincing results because only 11 of 38 patients (29%) symptom scores improved in 4 of 9 patients (44%) and allergen-
in the alum group and 4 of 12 patients (33%) in the aqueous group specific bronchoprovocation testing (mean provocation concen-
experienced any subjective improvement. No comparable control tration that caused a decrease in forced expiratory volume in 1
group was available to evaluate for potential placebo effects. To second of 20% of 0.2 mg/mL) and skin prick testing (mean wheal
refute these negative results, Tuft and Torsney15 reported addi- from 5.9 to 4.2 mm) results significantly improved, whereas
tional information in 1976 regarding their continued experiences nonspecific histamine bronchoprovocation testing failed to show a
with dog immunotherapy with an additional 67 patients. A total of meaningful decrease in bronchial hyperreactivity. All improve-
62 of 84 patients (74%) subjectively reported increased tolerance to ments were noted in the first year and failed to improve further
dogs, but there were no objective end points or placebo control with additional treatment duration. There was no significant
group with which to compare these results. change in specific IgE when comparing pretreatment with
post-immunotherapy values, and the diminutive increase in
allergen-specific bronchoprovocation tolerance was unlikely to be
First Double-Blinded Placebo-Controlled Trial
clinically relevant.21
To aid in clarifying these conflicting data, the first randomized, For patients who had received 3 years of dog immunotherapy, a
double-blinded, placebo-controlled trial regarding the effective- 5-year follow-up evaluation was completed. Of the final 11 patients
ness of dog immunotherapy was published in 1984 and involved 27 who had received dog immunotherapy, 9 patients responded to the
children with asthma and dog allergy. Fifteen patients were placed symptom questionnaire, 6 agreed to the allergen challenge, 7
on dog dander extracts and 12 received placebo injections con- agreed to the histamine challenge, and 7 agreed to additional blood
taining histamine. The patients’ responses were evaluated by testing for IgE and IgG4. Three of the 4 patients who noted symp-
bronchial and conjunctival provocation challenges and symptom tomatic improvement at the end of the 3-year study maintained
scores. After 12 months of immunotherapy, 12 of 15 patients (80%) this improvement 5 years later, whereas 1 patient noted worsening
had improved tolerance to the conjunctival challenge compared after discontinuing immunotherapy. Five of the 6 patients who
with 2 of 12 (17%) who received placebo, 6 of 15 patients (40%) had underwent allergen-specific bronchoprovocation testing experi-
improved tolerance to dog allergen bronchoprovocation compared enced an increase in sensitivity 5 years after the cessation of
with 2 of 12 (17%) who received placebo, and 8 of 15 patients (53%) treatment compared with their bronchoprovocation testing results
had improved by subjective symptoms compared with 6 of 12 (50%) at the end of 3 years of immunotherapy. Specific IgG4 had
who received placebo. The only statistically significant difference decreased and specific IgE remained low at levels comparable to the
for immunotherapy compared with placebo was noted to the end of 3 years of treatment. There was no correlation with the
conjunctival challenge because there was no difference in symptom changes in immunoglobulin levels, bronchoprovocation threshold,
scores.16 Early laboratory methods of comparing specific immu- and symptom scores.22 The 2 major limitations of this study were
noglobulin (Ig) E did not significantly change, but specific IgG that it was likely underpowered to find a difference in the pre-
increased significantly. The overall lack of improvement in asthma defined outcomes and that after the first year of treatment, there
was postulated to be due to poor extract quality or confounding was no longer a placebo group with which to compare further
allergens, such as cat, for which this study did not control.17 results. The lack of efficacy noted and lack of placebo with which to
compare the results lead to a study conclusion that does not
support the use of dog immunotherapy.
The “Landmark” Dog Immunotherapy Trial
Notably, the parallel cat immunotherapy arm showed a statis-
After further refinement in pet dander extracts, the landmark tically and clinically significant difference in specific allergen and
trial in dog allergy immunotherapy occurred in Denmark and initial nonspecific histamine bronchoprovocation. Speculation continued
results were published in 1986. This study compared 7 patients that these findings most likely resulted from potency differences
with asthma and dog allergy (and 15 with cat allergy) with 17 between the cat and dog extracts. The lower local and systemic side
patients receiving placebo injections. The primary outcomes of effect profile in the dog group also coincided with this theory, but
investigation were symptom scores, bronchoprovocation testing similar immunologic changes in IgE and IgG levels in the dog and
reactions to dog allergen extract and histamine,18 skin prick testing cat groups suggest otherwise.
reactions, specific IgE level, and specific IgG and IgG4 levels.19 At the
end of 12 months of therapy, 4 of 7 patients (57%) with dog allergy
Further Dog Immunotherapy Clinical Studies
reported improvement in symptoms and could tolerate roughly 3
times more conjunctival allergen (determined not to be statistically Subsequent studies evaluated different hypotheses of why dog
significant) but could not tolerate additional histamine levels by immunotherapy did not exhibit robustly successful results. Previ-
bronchoprovocation. Skin prick testing to dog extracts showed ously it had been proposed that only the late response is improved
significantly decreased wheal diameter throughout the study in all with therapy; however, a 1988 study showed that after immuno-
patients who received immunotherapy. Specific IgE levels therapy, 3 of the 5 patients experienced complete inhibition of their
increased significantly in all patients receiving cat or dog immu- immediate response and 1 patient with the dual response experi-
notherapy during the first 9 months of therapy but began to enced ablation of early and late responses.23 In 1989, another
decrease in the following 3 months in adults, whereas they Danish study aimed to evaluate the effects of dog or cat immuno-
continued to increase in children, which could be secondary to therapy in addition to maximal medical therapy alone (because it
the effect of immunotherapy or natural exposure to allergen. was deemed unethical to stop all other treatments) in 27 children
Specific IgG and IgG4 levels also significantly increased in all with asthma. A statistically significant difference was found in an
patients. Importantly, no correlations between any laboratory increased tolerance of dog allergen during bronchoprovocation
 D.M. Smith and C.A. Coop / Ann Allergy Asthma Immunol xxx (2016) 1e6 3

testing, suggesting the utility of combining immunotherapy with cross-reactive allergens with cat were noted, but no breed-specific
medical therapy to improve outcomes.24 allergens were identified. Because dogs phenotypically vary wildly,
In 1989, a Swedish study aimed to elucidate the effectiveness of it was still assumed that different breeds would have unique anti-
dander immunotherapy with another new, more potent extract in gens. In 1980, a study into breed specifics noted that dander was
patients with continuous dog exposure. After 3 months, skin prick more allergenic than serum for all breeds. This study concluded
testing and conjunctival challenges were significantly decreased that the variations in skin testing among breeds could be due to
with little further improvement for the duration of the 12 months. qualitative or more likely quantitative differences in extracts
These findings confirmed the effectiveness of immunotherapy in because no breed-specific allergens were identified.33
patients with continued allergen exposure.25 An additional study in In 1983, Uhlin et al34 characterized a poodle and Alsatian
1992 treated patients with cat and dog allergies with immuno- dandruff extract, noting 29 different antigens and 24 separate al-
therapy to cat and dog extracts. The investigators theorized that the lergens. These 2 breeds were chosen because poodle appeared to
lack of response to dog immunotherapy in several past studies have higher dander allergen levels, whereas Alsatians had higher
could be due to concomitant allergens for which they were not serum allergen levels. When combined, these 2 breeds would
receiving therapy. Unfortunately, patients with dog allergy treated theoretically produce a more balanced and potent extract. In 1985,
with dog and cat allergens had no decrease in bronchial hyperre- data analysis of the landmark clinical study noted 16 total antigens
activity to histamine or dog extract.26 in their dog extract being used for treatment. IgE was noted to bind
In 2006, Lent et al27 sought to determine the most effective dose to up to 5 different allergens per patient. IgE also was discovered to
of dog immunotherapy by following immunologic markers at bind most often to Ag 2 (DSA), Ag 6, and Ag 13.35
differing doses of Can f 1 up to 15 mg, a dose noted to be the most In 1986, the International Union of Immunological Societies
effective dose in an antecedent study involving cat extract. Because sought to standardize the allergen nomenclature system. Highly
conventional dog extract had previously been reported to contain 5 purified allergens would be designated using the first 3 letters in
mg/mL of Can f 1, it was determined that only acetone-precipitated the genus name, followed by the first letter in the species name in
(AP) dog extract (reported by the manufacturer to contain up to italics, followed by a roman numeral. This numeral was intended to
165 mg/mL) was potent enough to reach these therapeutic levels. represent the chronologic order in which the molecules were
Twenty-seven patients received cluster immunotherapy for 5 identified with the following 2 major exceptions. The major
weeks, with interest in the outcomes of skin prick test positivity, allergen would normally be assigned “I” regardless of its order of
nasal challenge, serum specific IgE, and IgG4. After immuno- identification and structurally homologous allergens from different
therapy, a dose-dependent response was noted in suppression of species would be given the same number (eg, Der p I and Der f I).36
skin prick testing and an increase in IgG4, but, importantly, there This intervention was not immediately universally accepted but
was no change in symptoms scores after nasal challenge. The was pivotal to ameliorating the confusion about allergens and
investigators concluded that the dog immunotherapy is “likely eliminating redundancy of research. In 1994, the italics were
effective” because many of the same immunologic parameters were deemed unnecessary and the roman numerals were switched to
similar as the antecedent Fe d 1 dosing trial (which did show Arabic numerals, producing the current format.
clinical efficacy). In 1988, Lindgren et al37 attempted to equalize the different
The validity of following immunologic parameters, specifically extracts of 8 breeds of dogs in terms of crude protein content to
the decrease in IgE or increase in IgG4 alone, as a surrogate for correct for quantitative differences caused by serum allergens and
clinical efficacy was questioned in several earlier studies because to discover any qualitative differences. With this correction, the
changes in immunologic markers did not correspond to symptoms study did notice that some allergens were found only in certain
or provocative testing results.17,19e22,24,25 A subsequent study in breeds and that DSA appeared to represent only a weaker allergen
2013 noted similar IgG4 levels in patients sensitized to dog and in to which only 18% of patients allergic to dog showed skin test
patients asymptomatic to dog exposure. This trial provided further positivity. It also noted that approximately 15% of patients showed
evidence to question relying on immunologic parameters alone as a a significant difference in skin test results based on specific breed,
surrogate marker for clinical efficacy.28 but these differences did not correlate to symptom scores. These
The published trial data do support safety of subcutaneous dog differences do not appear to have been pursued further. In 1989,
immunotherapy. Overall, the systemic reaction rate reported for Ford et al38 performed a similar study using sera from British and
these dog immunotherapy trials was 0% to 0.3% in subjects Finnish patients allergic to dog and found no difference in allergen
receiving dog extracts.14e16,19,20,23e25,27 binding based on the geographic location of the patients. Twenty-
one separate allergens were identified, notably Ag 8, which was
found primarily in dander and bound IgE in 63% of patients. Ag 8
Early Dog Allergens and Extracts
was in fact the same allergen as the previously named Ag 13,
After dog immunotherapy gained awareness in the 1960s, ef- providing another example of the confusion among antigens and
forts began to understand the complex antigenic and allergenic the value of adhering to the standardized nomenclature.
profile of dog extracts. As early as 1971, reports noted that the
potency of different extracts could vary by up to 1,000-fold and that
Extract Research after Nomenclature Standardization
different breeds appeared to have a different profile of allergens.29
Dog serum albumin (DSA) was identified in 1973 as an important In 1991, Schou et al39 sought to further characterize Ag 8/13 and
allergen, but it also was noted that there were likely other impor- named it Can f 1 according to the new nomenclature system. Can f 1
tant allergens. As expected, albumin levels were confirmed to be was described as having a molecular weight of 22 to 25 kDa. In the
much higher in epithelial extracts compared with hair extracts.30 study, 24 of 26 patients (92%) with dog allergy had a positive skin
Two years later, Ohman et al31 explained the frequent finding of prick reaction to purified Can f 1, but only 16 of 23 patients (70%)
cat co-sensitization in patients allergic to dog using IgE inhibition demonstrated specific IgE by immunoblotting, and Can f 1
studies that showed common allergens between dogs and cats. accounted for only 56.5% of IgE binding in pooled sera from patients
In 1977, Blands et al32 characterized the extracts of 6 different allergic to dog. These data confirm the importance of Can f 1 but
dog breeds and found 21 distinct antigens. DSA and antigen (Ag) 13 also indicate the role of other allergens. Another study by Ford and
were major allergens with IgE binding in more than 50% of symp- Kemeny40 in 1992 noted a dander-specific allergen at 21 kDa,
tomatic patients, and there were 6 minor allergens. Significant naming it Ag X initially but then noting the similarity in size and
4 D.M. Smith and C.A. Coop / Ann Allergy Asthma Immunol xxx (2016) 1e6

binding (78% total) to the Ag 8 of Lindgren et al and the Ag 13 of of 140 C dry heat. In 2009, the stability and compatibility of AP and
Blands et al. It was agreed that the allergen was likely the same as conventional dog extracts were investigated in different time,
the previously named Can f 1. temperature, and mixing conditions.49 Can f 1 levels remained at
Once Can f 1 was determined to be an important dog allergen, 94% to 119% and Can f 3 retained 79% to 94% potency for 3 days
efforts began to determine its best natural source to improve the when kept between 21 C and 45 C, showing standard shipping
potency of the extracts. Can f 1 levels in 4 commercially available methods without refrigeration are acceptable for extracts. These
extract sources (dander, hair and skin scrapings, skin scrapings, and extracts also were mixed with molds and insects (cockroach and
whole skin) were compared in 1994 using different in vivo and fire ant) and refrigerated for 15 months. As expected, the extracts
in vitro testing techniques. It was discovered that dander was the with 50% glycerin retained their potency, whereas the extracts with
best source. Subsequent evaluation showed that Can f 1 is a lip- no more than 10% glycerin showed significant degradation. The
ocalin that is produced on tongue epithelia, explaining why Can f 1 effects of combining dog extracts with cat dander, pollens, or dust
is found in the skin and saliva41 but not in the urine or feces. This mite was not determined.
testing showed that Can f 1 is typically accompanied by a distinct
19-kDa lipocalin named Can f 2. The source of Can f 2 is the parotid Newest Identified Dog Allergens
gland and the highest content is in extracts made from dander.42
A 1991 article investigating Can f 1 also mentioned dog allergen 2 A plethora of new information regarding dog allergens has been
(Can f 2), noting IgE binding to this allergen in 34% of patients with published in the past 5 years (Table 1). In 2009, prostatic kallikrein,
symptoms to dog exposure. Can f 2 was noted to be positive only in a 28-kDa protein, was identified (and named Can f 5) as a major dog
patients also positive to Can f 1, but not all patients positive to Can f 1 allergen because it bound IgE in 70% of patients with allergy. As a
were sensitized to this molecule. However, it was noted that Can f 1 prostatic protein, it is found only in male dog urine and exhibits
and Can f 2 were found in all commercial cat extracts, suggesting cross-reactivity to human prostate-specific antigen, providing a
contamination or cross-reactivity.43 The structure of Can f 2 was potential explanation for the development of semen hypersensi-
ultimately revealed by crystallography in 2010. The structure is tivity from dog allergen exposure. Interestingly, 38% of patients
similar to Fe d 4, likely explaining some of this observation.44 reacted only to Can f 5 and not to Can f 1, 2, or 3, suggesting that
In 1994, Spitzauer et al45 continued investigating DSA, the 66- to some individuals are selectively allergic to male dogs.50 In 2010,
69-kDa allergen with approximately 35% IgE binding (subsequently Can f 4, an 18-kDa protein,was characterized as a lipocalin and it
named Can f 3), and its cross-reactivity with other mammalian was reported to bind 35% of patients’ IgE. As a lipocalin, it was
albumins. This investigation was conducted by producing frag- found to be cross-reactive with cow dander.51 In 2012, Can f 6 also
ments of recombinant albumin. Because mammalian albumins are was more fully characterized as a 20-kDa lipocalin reported to bind
similar, Fe d 2 and Can f 3 exhibited cross-reactivity, further IgE in 35% of patients with dog allergy. As another lipocalin, it was
explaining cat co-sensitization in individuals allergic to dog. found to be cross-reactive to cat and horse.52 In 2013, dog saliva was
reported to contain Can f 1, 2, 4, and 6 (all known dog lipocalin
allergens), suggesting its potential role for use in extract
Variability of Dog Extracts
manufacturing.53
To complicate matters, a 1996 report noted that the major dust “Major” allergen studies have their own inherent errors because
mite allergens, Der p 1 and Der p 2, were detectable in all com- allergens were initially described as major if they bound IgE in
mercial dog extracts at a median concentration of 5.8 ng/mL. This more than 90% of patients. However, this number was subsequently
level could explain skin test positivity to dogs in the absence of decreased to more than 50% because very few allergens qualified.
allergic sensitivity to dogs. Can f 1 levels in these extracts ranged Also, testing methods to prove IgE binding vary among studies and
from 3.8 to 170 mg/mL. This study illuminated the possibility of false sample size has varied greatly in different studies, with a smaller
positives with skin prick testing for dog allergy.46 sample inherently creating less precise rates. Thus, it is clear that
In 2001, Meiser and Nelson47 compared the newest AP dog extract there are several important dog allergens, but no dominant
to the traditional aqueous dog extract in 123 consecutive patients allergen. Ultimately, the only “major” allergen is the one to which a
receiving skin testing and noted that 59 of 123 patients (48%) tested particular patient is sensitized!
positive to AP dog. Only 35 of 123 patients (28%) tested positive to
conventional dog extracts. All patients who tested positive to con- Current Prescribing Trends
ventional extracts also were positive to AP dog, with a significantly
larger mean wheal diameter. These data perpetuated questions A nationwide survey in 2006 showed the perspective of how
about false negatives because 24 of 59 patients (41%) who tested allergists across the United States were integrating these conflicting
positive to AP dog tested negative to conventional dog extracts. and confusing data and using them in daily practice. Other types of
physicians prescribing immunotherapy were excluded. Responses
showed the maintenance weight-to-volume ratio varied widely
Stability of Dog Extracts
from 1:10 to 1:1,000, with the most common concentration being
A study by Cain et al48 in 1998 showed that Can f 1 was relatively 1:100 (24.3%). Despite the paucity of clinical evidence, most aller-
thermostable, with 50% of the allergen remaining after 60 minutes gists believe that dog immunotherapy will provide at least some

Table 1
Described allergens of Canis familiaris

Allergen (previous names) Molecular weight (kDa) Biologic activity Sensitization rates (%) Major cross-reactive allergens

Can f 1 (Ag 13, Ag 8, Ag X) 23e25 Lipocalin 50e70 Unknown

Can f 2 19 Lipocalin 30 Fe d 4
Can f 3 (dog serum albumin, Ag 2) 66e69 Albumin 35 Fe d 2
Can f 4 16e23 Lipocalin 35 Bos d 2
Can f 5 28 Prostatic kallikrein 70 Human prostate-specific antigen
Can f 6 20 Lipocalin 35 Fe d 4, Equ c 1

Abbreviation: Ag, antigen.

 D.M. Smith and C.A. Coop / Ann Allergy Asthma Immunol xxx (2016) 1e6 5

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