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Allergen Profile, Dog, IgE With Component Reflex

CPT: 86003

Expected Turnaround Time

4-5 days


Related Documents


Specimen Requirements


Specimen

Serum


Volume

1 mL


Minimum Volume

0.5 mL (Note: This volume does not allow for repeat testing.)


Container

Gel-barrier tube


Storage Instructions

Room temperature


Stability Requirements

Temperature

Period

Room temperature

14 days

Refrigerated

14 days

Frozen

3 months

Freeze/thaw cycles

Stable x3


Test Details


Use

The diagnostic assessment of allergy starts with the patient’s clinical history and examination and is followed by an extract-based analysis to confirm the presence of specific IgE (sIgE) antibody.1,2 sIgE is necessary but not sufficient for eliciting an allergic response and thus generating a definitive diagnosis of allergic disease.1 Testing utilizing allergenic extracts does not lend itself to the differentiation of primary sensitization from a cross-reactivity-driven response because of the complexity of the extracts. Extracts contain most of the extractable allergenic components from the suspected sensitizer. However, it is often not possible to predict the relative risk of having a systemic allergic reaction using an extract-based diagnostic test. Component Resolved Diagnostics (CRD) refers to the diagnostic use of purified or recombinant allergens in the clinical assessment of individuals who suffer reproducible hypersensitivity reactions with exposures to an allergen at a dose tolerated by non-allergic individuals.2-4 This approach offers advantages over the use of a complete extract, especially in polysensitized individuals, given its usefulness for distinguishing between sensitizations specific to singular species and sensitizations due to cross-reactivity.3

Sensitization to dog dander is an important risk factor for rhinoconjunctivitis and asthma.1 Allergic rhinitis and asthma are chronic inflammatory diseases leading to restrictions in the patient's quality of life and high costs for health care systems. Both diseases are associated with the presence of specific IgE (sIgE) against aeroallergens.4 Dogs are an important source of indoor allergens and are considered to be a major risk factor for the development of allergic rhinitis and asthma.2,5-9 A significant proportion of atopic subjects (about 20-40%) are sensitized to dog allergens. Dogs are dominant sensitizers in young adults with asthma12 and IgE titers to dog proteins correlate with disease severity.6 Further, sensitization to dogs in childhood predicts persistence of asthma throughout the teen ages.13,14


Limitations

Allergen-specific IgE assays do not demonstrate absolute positive and negative predictive values for allergic disease. Clinical history must be incorporated into the diagnostic determination. Although the use of component resolved IgE testing may enhance the evaluation of potentially allergic individuals over the use of whole extracts alone, it cannot yet replace clinical history and oral food challenge in most cases. Sensitization against thus far unidentified determinants that are not found in the whole extract or in components might cause symptoms in rare cases.


Methodology

Thermo Fisher ImmunoCAP® Allergen-specific IgE


Additional Information

Unlike cat allergy, which is almost entirely attributable to sensitization to its major allergen, Fel d 1, the sensitization profile for dog allergy is more heterogeneous.15 A number of allergen molecules have been described in dogs (Canis familiaris).2 Can f 1 and Can f 2 belong to the lipocalin family; Can f 3 is a serum albumin; and Can f 5 is a prostatic kallikrein from male dog urine. Can f 1 and Can f 5 have been classified as major allergens as their sensitization frequencies in dog dander sensitized patients are about 55% and 70%, respectively.16-21 While Can f 2 and Can f 3 are considered minor allergens (< 50% sensitization rate),16-19 the measurement of sIgE to these components has been shown to add diagnostic value.17

Can f 1

Can f 1 is a lipocalin protein produced by the salivary glands of dogs.15 Can f 1 cross-reactivity with the human tear lipocalin has been reported.15,22 Can f 1 also displays some cross-reactivity with cat component Fel d 723,24 and may contribute to symptoms in cat as well in dog-allergic patients. A recent study found that 64% of cat dander sensitized individuals were Can f 1 IgE positive, with 32% of those individuals monosensitized to Can f 1.21 In Can f 1 sensitized individuals, sensitization to cat may be excluded by a negative test to Fel d 1.24

A large European study of more than 700 children eight years old and younger (the ABAMSE/MeDALL study) reported that sIgE reactivity to the five dog allergen molecules tested (Can f 1, Can f 2, Can f 3, Can f 5 and Can f 6) increased with age.25 This study found that sIgE to Can f 1 was superior to sIgE to dog allergen extract in diagnosing dog allergy. This study also found that sIgE reactivity to Can f 1 in childhood predicted the development of dog allergy in adolescence significantly better than IgE reactivity to dog allergen extract. Furthermore, IgE reactivity to Can f 1 was the only parameter that independently could predict future symptoms to dog.25

Can f 2

Can f 1 and Can f 2 have common epitopes and most of the patients allergic to Can f 2 are co-sensitized to Can f 1.21 Sensitization to Can f 2 without Can f 1 sensitization is very rare.6,21,18,26-28 Because Can f 2 has little sequence identity or cross-reactivity to proteins of other mammals sIgE to this protein suggests dog-specific sensitization.27 Structures of Can f 2 and Equ c 1 are quite similar; however, they do not show cross-reactivity.17 Asthmatic children sensitized to Can f 2 have been shown to be at a greater risk of having more severe symptoms.6,29

Can f 3

Can f 3, dog serum albumin, is a highly cross-reactive minor allergen detected in 15% to 35% of dog-sensitized patients.7,16 Serum albumins are abundant in saliva and dander and are highly cross-reactive molecules, although they are generally considered to be minor allergens.30 Allergic sensitization to furry animals may be induced not only by direct/indirect exposure but also by a cross-reaction mechanism involving some families of allergenic proteins. Cross sensitization to other furry animals via initial allergy to Can f 3 may play a role in the progression to polysensitization and clinical allergies to other animals. Uriarte et al found that sensitization to albumins was associated with more severe respiratory symptoms.28

Can f 5

Can f 5 is a prostatic kallikrein that was original isolated from the urine of male dogs.31 Since this protein is produced in significant quantities only by non-neutered, male dogs,32 it has been suggested that mono-sensitization to Can f 5 may correlate with allergic sensitivity to male and not female dogs.16,33 Antibodies to Can f 5 have been found in up to 70% of patients with dog allergy18,19,28,31,34 and approximately a third of Can f 5-positive, dog dander-sensitized patients did not have antibodies to Can f 1, Can f 2, or Can f 3.31

No patterns of Can f 5 cross-reactivity to allergens from other furry animals have been identified. However, cross-reactivity to human prostate-specific antigen, the major allergen in seminal plasma, has been reported.7,35,36 Some studies have implicated sensitization to Can f 5 in cases of human seminal plasma allergy.37-39

In a population-based study on 963 19-year-olds where associations with asthma symptoms, diagnosis, and treatment were examined, Perzanowski et al found that IgE antibodies to Can f 5 (and Fel d 1) were each associated with current asthma.40 Sensitization to Can f 5 was also recently measured among children with severe asthma who, compared with children with controlled asthma, had an IgE response to more than 3 animal-derived allergen molecules, of which Can f 5 was one.6,29

Sensitization to Multiple Components

Multiple sensitization to cat and dog allergens during childhood has been associated to the development of subsequent allergy to dogs and cats.25 Sensitization to two or more cat, dog, and horse allergen components has been associated with severe respiratory symptoms (severe asthma and rhinitis).18,28 Poly-sensitization to multiple cat or dog components has been shown to be a risk marker for asthma in children and has been associated with increased bronchial inflammation in severe asthmatic children and young adults.6,18,29,41,42 A cross-sectional cohort study in 269 children found that asthma was significantly associated with sensitization to members of the lipocalin protein family.42 Nordlund et al reported that a specific IgE response in children to more than three animal-derived components was more common among uncontrolled severe asthmatics compared to children with controlled asthma.29 A recent study of unselected adults revealed that sensitization, particularly poly-sensitization, to furry animal allergen components is an important predictor of severity and clinical outcomes of asthma.44


Footnotes

1. Käck U, Asarnoj A, Grönlund H, et al. Molecular allergy diagnostics refine characterization of children sensitized to dog dander. J Allergy Clin Immunol. 2018 Oct;142(4):1113-1120.e9.29852259
2. Matricardi PM, Kleine-Tebbe J, Hoffmann HJ, et al. EAACI Molecular Allergology User’s Guide. Pediatr Allergy Immunol. 2016 May;27 Suppl 23:1-250.27288833
3. Liccardi G, Bilo MB, Manzi F, Piccolo A, Di Maro E, Salzillo A. What could be the role of molecular-based allergy diagnostics in detecting the risk of developing allergic sensitization to furry animals? Eur Ann Allergy Clin Immunol. 2015 Sep;47(5):163-167.26357003
4. Eiringhaus K, Renz H, Matricardi P, Skevaki C. Component-Resolved Diagnosis in Allergic Rhinitis and Asthma. J Applied Lab Med. 2019 Feb;3(5):883-898.10.1373/jalm.2018.026526
5. Perzanowski MS, Ronmark E, Platts-Mills TA, Lundback B. Effect of cat and dog ownership on sensitization and development of asthma among preteenage children. Am J Respir Crit Care Med. 2002 Sep 1;166(5):696-702.12204868
6. Konradsen JR, Nordlund B, Onell A, Borres MP, Grönlund H, Hedlin G. Severe childhood asthma and allergy to furry animals: refined assessment using molecular-based allergy diagnostics. Pediatr Allergy Immunol. 2014 Mar;25(2):187-192.24460778
7. Konradsen JR, Fujisawa T, van Hage M, et al. Allergy to furry animals: new insights, diagnostic approaches, and challenges. J Allergy Clin Immunol. 2015 Mar;135(3):616-625.25282018
8. Eder K, Becker S, San Nicoló M, Berghaus A, Gröger M. Usefulness of component resolved analysis of cat allergy in routine clinical practice. Allergy Asthma Clin Immunol. 2016 Nov 15;12:58.27891156
9. Gergen PJ, Mitchell HE, Calatroni A, et al. Sensitization and Exposure to Pets: The Effect on Asthma Morbidity in the US Population. J Allergy Clin Immunol Pract. 2018 Jan - Feb;6(1):101-107.e2.28694047
10. Liccardi G, Salzillo A, Calzetta L, Piccolo A, Menna G, Rogliani P. Can the presence of cat/dog at home be considered the only criterion of exposure to cat/dog allergens? A likely underestimated bias in clinical practice and in large epidemiological studies. Eur Ann Allergy Clin Immunol. 2016 Mar;48(2):61-64.26934742
11. Liccardi G, Calzetta L, Baldi G, et al. Allergic sensitization to common pets (cats/dogs) according to different possible modalities of exposure: an Italian Multicenter Study. Clin Mol Allergy. 2018 Feb 2;16:3.29434523
12. Patelis A, Janson C, Borres MP, Nordvall L, Alving K, Malinovschi A. Aeroallergen and food IgE sensitization and local and systemic inflammation in asthma. Allergy. 2014 Mar;69(3):380-387.24397423
13. Andersson M, Hedman L, Bjerg A, Forsberg B, Lundbäck B, Rönmark E. Remission and persistence of asthma followed from 7 to 19 years of age. Pediatrics. 2013 Aug;132(2):e435-442.23897917
14. Bjerg-Bäcklund A, Perzanowski MS, Platts-Mills T, Sandström T, Lundbäck B, Rönmark E. Asthma during the primary school ages - prevalence, remission and the impact of allergic sensitization. Allergy. 2006 May;61(5):549-555.16629783
15. Nilsson OB, van Hage M, Gronlund H. Mammalian-derived respiratory allergens - implications for diagnosis and therapy of individuals allergic to furry animals. Methods. 2014 Mar 1;66(1):86-95.24041755
16. Mattsson L, Lundgren T, Olsson P, Sundberg M, Lidholm J. Molecular and immunological characterization of Can f 4: a dog dander allergen cross-reactive with a 23 kDa odorant-binding protein in cow dander. Clin Exp Allergy. 2010 Aug;40(8):1276-1287.20545700
17. Nilsson OB, Binnmyr J, Zoltowska A, Saarne T, van Hage M, Grönlund H. Characterization of the dog lipocalin allergen Can f 6: the role in cross-reactivity with cat and horse. Allergy. 2012 Jun;67(6):751-757.22515174
18. Bjerg A, Winberg A, Berthold M, Mattsson L, Borres MP, Rönmark E. A population-based study of animal component sensitization, asthma, and rhinitis in schoolchildren. Pediatr Allergy Immunol. 2015 Sep;26(6):557-563.26059105
19. Basagana M, Luengo O, Labrador M, et al. Component-Resolved Diagnosis of Dog Allergy. J Investig Allergol Clin Immunol. 2017 Jun;27(3):185-187.28570224
20. Smith DM, Coop CA. Dog allergen immunotherapy: past, present, and future. Ann Allergy Asthma Immunol. 2016 Mar;116(3):188-193.26774974
21. Ukleja-Sokołowska N, Gawrońska-Ukleja E, Żbikowska-Gotz M, et al. Analysis of feline and canine allergen components in patients sensitized to pets. Allergy Asthma Clin Immunol. 2016 Nov 30;12:61.27956908
22. Saarelainen S, Rytkönen-Nissinen M, Rouvinen J, et al. Animal-derived lipocalin allergens exhibit immunoglobulin E cross-reactivity. Clin Exp Allergy. 2008 Feb;38(2):374-381.18070162
23. Apostolovic D, Sánchez-Vidaurre S, Waden K, et al. The cat lipocalin Fel d 7 and its cross-reactivity with the dog lipocalin Can f 1. Allergy. 2016 Oct;71(10):1490-1495.27289080
24. Hilger C, van Hage M, Kuehn A. Diagnosis of Allergy to Mammals and Fish: Cross-Reactive vs. Specific Markers. Curr Allergy Asthma Rep. 2017 Aug 22;17(9):6428831729
25. Asarnoj A, Hamsten C, Wadén K, et al. Sensitization to cat and dog allergen molecules in childhood and prediction of symptoms of cat and dog allergy in adolescence: a BAMSE/MeDALL study. J Allergy Clin Immunol. 2016 Mar;137(3):813-821.e7.26686472
26. Hilger C, Swiontek K, Arumugam K, Lehners C, Hentges F. Identification of a new major dog allergen highly cross-reactive with Fel d 4 in a population of cat- and dog-sensitized patients. J Allergy Clin Immunol. 2012 Apr;129(4):1149-1151.22104604
27. Madhurantakam C, Nilsson OB, Uchtenhagen H, et al. Crystal structure of the dog lipocalin allergen Can f 2: implications for cross-reactivity to the cat allergen Fel d 4. J Mol Biol. 2010 Aug 6;401(1):68-83.20621650
28. Uriarte SA, Sastre J. Clinical relevance of molecular diagnosis in pet allergy. Allergy. 2016 Jul;71(7):1066-1068.27108666
29. Nordlund B, Konradsen JR, Kull I, et al. IgE antibodies to animal-derived lipocalin, kallikrein and secretoglobin are markers of bronchial inflammation in severe childhood asthma. Allergy. 2012 May;67(5):661-669.22339365
30. Liccardi G, Asero R, D'Amato M, D'Amato G. Role of sensitization to mammalian serum albumin in allergic disease. Curr Allergy Asthma Rep. 2011 Oct;11(5):421-426.21809117
31. Mattsson L, Lundgren T, Everberg H, Larsson H, Lidholm J. Prostatic kallikrein: a new major dog allergen. J Allergy Clin Immunol. 2009 Feb;123(2):362-368.19135239
32. Portnoy J, Kennedy K, Sublett J, et al. Environmental assessment and exposure control: a practice parameter–furry animals. Ann Allergy Asthma Immunol. 2012 Apr;108(4):223.e1-15.22469456
33. Schoos AM, Bønnelykke K, Chawes BL, Stokholm J, Bisgaard H, Kristensen B. Precision allergy: Separate allergies to male and female dogs. J Allergy Clin Immunol Pract. 2017 Nov - Dec;5(6):1754-1756.28499775
34. Curin M, Swoboda I, Wollmann E, et al. Microarrayed dog, cat, and horse allergens show weak correlation between allergen-specific IgE and IgG responses. J Allergy Clin Immunol. 2014 Mar;133(3):918-921.e6.24406070
35. Weidinger S, Mayerhofer A, Raemsch R, Ring J, Köhn FM. Prostate-specific antigen as allergen in human seminal plasma allergy. J Allergy Clin Immunol. 2006 Jan;117(1):213-215.16387609
36. Basagaña M, Bartolomé B, Pastor C, et al. Allergy to human seminal fluid: cross-reactivity with dog dander. J Allergy Clin Immunol. 2008 Jan;121(1):233-239.18061650
37. Basagaña M, Bartolome B, Pastor-Vargas C, Mattsson L, Lidholm J, Labrador-Horrillo M. Involvement of Can f 5 in a case of human seminal plasma allergy. Int Arch Allergy Immunol. 2012;159(2):143-146.22653399
38. Kofler L, Kofler H, Mattsson L, Lidholm J. A case of dog-related human seminal plasma allergy. Eur Ann Allergy Clin Immunol. 2012 Apr;44(2):89-92.22768730
39. Tanaka M, Nakagawa Y, Kotobuki Y, Katayama I. A case of human seminal plasma allergy sensitized with dog prostatic kallikrein, Can f 5. Allergol Int. 2019 Apr;68(2):259-260.30181013
40. Perzanowski MS, Ronmark E, James HR, et al. Relevance of specific IgE antibody titer to the prevalence, severity, and persistence of asthma among 19-year-olds in northern Sweden. J Allergy Clin Immunol. 2016 Dec;138(6):1582-1590.27430609
41. Prosperi MC, Belgrave D, Buchan I, Simpson A, Custovic A. Challenges in interpreting allergen microarrays in relation to clinical symptoms: a machine learning approach. Pediatr Allergy Immunol. 2014 Feb;25(1):71-79.24131308
42. Patelis A, Gunnbjornsdottir M, Alving K, et al. Allergen extract vs. component sensitization and airway inflammation, responsiveness and new-onset respiratory disease. Clin Exp Allergy. 2016 May;46(5):730-740.26243058
43. Schoos AM, Kattan JD, Gimenez G, Sampson HA. Sensitization phenotypes based on protein groups and associations to allergic diseases in children. J Allergy Clin Immunol. 2016 Apr;137(4):1277-1280.26581917
44. Nwaru BI, Suzuki S, Ekerljung L, et al. Furry Animal Allergen Component Sensitization and Clinical Outcomes in Adult Asthma and Rhinitis. J Allergy Clin Immunol Pract. 2019 Apr;7(4):1230-1238.e4.30594587

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