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Allergen Profile, Cat, IgE With Component Reflex

CPT: 86003

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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

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.1 Cats are an important source of indoor allergens and are considered to be a major risk factor for the development of allergic rhinitis and asthma.2-7 A significant proportion of atopic subjects (about 20-40%) are sensitized to cat allergens.8,9 Cats are dominant sensitizers in young adults with asthma10 and IgE titers to cat proteins correlate with disease severity.3 Further, sensitization to these pets in childhood predicts persistence of asthma throughout the teen ages.11,12 Recent studies have shown that the majority of individuals who are sensitized to cats do not have a cat in their home.13,14

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.6 sIgE is necessary but not sufficient for eliciting an allergic response and thus generating a definitive diagnosis of allergic disease. 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 use of purified or recombinant allergens in the serologic assessment of individuals who suffer reproducible hypersensitivity reactions with exposures to an allergen at a dose tolerated by non-allergic individuals.6 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.15 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.


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

Importantly, cat (Felis domesticus) dander allergic individuals are sensitized to a heterogeneous range of cat allergens.6,16 The major cat allergen is the secretoglobin Fel d 1,16 which accounts for majority all IgE reactivity to cat dander.17,18 All cat allergens other than Fel d 1 are considered minor allergens because less than fifty percent of cat dander sensitized individuals test positive for sIgE to these proteins. The minor cat allergens for which we have the most clinical data are the serum albumin, Fel d 2 and the lipocalin, Fel d 4.

Fel d 1

Fel d 1 is produced by the sebaceous glands cat and is found in their saliva.16,19 This a thermostable protein is therefore present in large concentrations on skin surface and fur of cats as a result of grooming.20 Cats are the only mammals for which a secretoglobulin is the primary sensitizer for allergic disease. No comparable protein has been characterized in other species. Since Fel d 1 does not have significant IgE cross-reactivity with other mammalian proteins, Fel d 1 positivity is considered to denote cat specific sensitization.20 Serum-specific Immunoglobulin E (sIgE) to Fel d 1 is present in approximately 95% of patients that test positive for sIgE to cat dander.18,21-26 Early studies showed 60-90% of overall allergenic activity to cat dander is directed against Fel d 1.16 Depending on the population tested, 40-70% percent of Fel d 1 sIgE positive patients are not sensitized to any other cat component routinely measured (Fel d 2 and Fel d 4).23,24

A large European study of more than 4000 children eight years old and younger (the ABAMSE/MeDALL study) reported that sIgE reactivity to the three cat allergen molecules tested (Fel d 1, Fel d and Fel d 4) increased with age.25 Fel d 1 was the dominant sensitizing cat allergen during the entire childhood in this population.25 Consistent with other studies,5,21,27 the ABAMSE/MeDALL study found that testing for sIgE to Fel d 1 was comparable to testing for sIgE to cat allergen extract in diagnosing cat allergy.25 This study also found that sIgE to Fel d 1 in young children was more predictive of cat allergy at 16 years of age than measuring sIgE to cat allergen extract.25 In the ABAMSE/MeDALL population, less than ten percent of patients were positive for Fel d 2 and/or Fel d 4 and not Fel d 1.25 Testing for sIgE to Fel d 1 directly, without testing for sIgE to cat dander extract would have caused a small number of cases with non-typical sensitization profiles (about 5-10%) to be missed.25,28

Sensitization to cats and dogs in childhood has been shown to predict the persistence of asthma throughout the teen ages 11 and cat dander has been shown to be a dominant sensitizer in young adults with asthma.10 In a population-based study of 963 19-year-old Swedes, levels of sIgE to Fel d 1 were found to be strongly associated with the prevalence, severity, and persistence of asthma.29 This finding was consistent with a other studies that have found that increased Fel d 1 sIgE levels can serve as a prognostic marker of future cat allergy and allergic asthma.2,3,21,24,25,27,30,46

Fel d 2

The protein Fel d 2 is cat albumin.31 In the context of respiratory allergy, serum albumins are considered to be an uncommon cause of allergic sensitization.31-33 Sensitization to Fel d 2 has been associated with moderate/severe rhinitis and a diagnosis of asthma in patients sensitized to other cat components.3,26,34 Wisniewski et al. described an association between high levels of sIgE to Fel d 2 and atopic dermatitis in cat-allergic children.35

Serum albumins are major allergen in meats, which underlies their importance as food allergens.33 Most albumin sensitized patients tolerate well-cooked meat or milk as serum albumins are thermolabile. Cross-reactivity between cat and pork albumin is thought to be responsible for allergic reactions after ingestion of pork in cat-allergic individuals in a condition referred to as pork-cat-syndrome.33,36-37 It is thought that initial environmental exposure to cat albumin causes sensitization that results in subsequent rapid onset of allergic reactions on eating pork.36,37

Serum albumins from mammals are highly conserved both in amino acid sequence and three-dimensional structure31,33,38 and are thought to play a significant role as cross-reacting allergens in individuals sensitized to several types of animal dander. Monosensitization to Fel d 2 or to the dog albumin, Can f 3, is very rare. The occurrence of specific IgE to Fel d 2 without sensitization to Fel d 1 could be a marker of cross-reactivity to another animal and not primary sensitization to cat.33 As sensitization to cat and/or dog serum albumins is almost always seen in combination with specific IgE directed against major allergens, the clinical relevance of serum albumins is still undefined.

Fel d 4

Fel d 4, a lipocalin protein, is the second most frequent sIgE sensitizing component of cat dander and is positive in 30-60% of cat dander sensitized patients, depending on the population studied.23,24,39 The great majority of patients with sensitization to Fel d 4 are also sensitized to Fel d 1.23,24 A study involving 696 Swedish children reported that current asthma and asthma symptoms following contact with cats were associated with co-sensitization to Fel d 1 and Fel d 4.24 Levels of IgE to Fel d 4, but not Fel d 1 or cat extract, were independently associated with Β-Eos count (P = .009) and total IgE in young asthmatics.34 Wisniewski et al. described an association between high levels of sIgE to Fel d 4 and atopic dermatitis in cat-allergic children.35

Many individuals that test positive for sIgE to cat dander also test positive for sIgE to dander from other mammals. 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. This cosensitization is explained, in part, by to the fact that Fel d 4 has up to 60% amino acid sequence identity with lipocalins from other mammals including Can f 6 from dog, Equ c 1 from horse and other lipocalins from mouse, rabbit and rat.40,41 Cross-reactivity between Fel d 4 and Can f 2, although the sequential identity observed in their study was less than 22%.42 Many patients with measurable sIgE to Fel d 4 also test positive for these other, cross-reactive components making it sometimes difficult to discern the extent to which the presence of sIgE to one or more of these components represents true clinical sensitization or simply cross-reactivity. Fel d 4 positivity in Fel d 1 negative patients suggest that cat is not the primary sensitizer.

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).24,26 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.3,24,27,34,43,44 A cross-sectional cohort study in 269 children found that asthma was significantly associated with sensitization to members of the lipocalin protein family.45 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.44 A recent study of unselected adults revealed that sensitization, particularly poly-sensitization, to furry animal allergen components is an important predictor of clinical outcomes of asthma and eosinophilic markers of asthma severity.46


Footnotes

1. 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
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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
8. Heinzerling L, Frew AJ, Bindslev-Jensen C, et al. Standard skin prick testing and sensitization to inhalant allergens across Europe—a survey from the GALEN network. Allergy. 2005 Oct;60(10):1287-1300.16134996
9. Heinzerling LM, Burbach GJ, Edenharter G, et al. GA(2)LEN skin test study I: GA(2)LEN harmonization of skin prick testing: novel sensitization patterns for inhalant allergens in Europe. Allergy. 2009 Oct;64(10):1498-1506.19772515
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. Grönlund H, Saarne T, Gafvelin G, van Hage M. The major cat allergen, Fel d 1, in diagnosis and therapy. Int Arch Allergy Immunol. 2010;151(4):265-274.19844127
17. Kleine-Tebbe J, Kleine-Tebbe A, Jeep S, Schou C, Løwenstein H, Kunkel G. Role of the major allergen (Fel d I) in patients sensitized to cat allergens. Int Arch Allergy Immunol. 1993;100(3):256-262.7680928
18. van Ree R, van Leeuwen WA, Bulder I, Bond J, Aalberse RC. Purified natural and recombinant Fel d 1 and cat albumin in in vitro diagnostics for cat allergy. J Allergy Clin Immunol. 1999 Dec;104(6):1223-1230.10589005
19. 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
20. Chan SK, Leung DYM. Dog and Cat Allergies: Current State of Diagnostic Approaches and Challenges. Allergy Asthma Immunol Res. 2018 Mar;10(2):97-105.29411550
21. Grönlund H, Adédoyin J, Reininger R V, et al. Higher immunoglobulin E antibody levels to recombinant Fel d 1 in cat-allergic children with asthma compared with rhinoconjunctivitis. Clin Exp Allergy. 2008 Aug;38(8):1275-81.18477016
22. Ichikawa K, Iwasaki E, Baba M, Chapman MD. High prevalence of sensitization to cat allergen among Japanese children with asthma, living without cats. Clin Exp Allergy. 1999 Jun;29(6):754-761.10336590
23. 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
24. 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
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. Uriarte SA, Sastre J. Clinical relevance of molecular diagnosis in pet allergy. Allergy. 2016 Jul;71(7):1066-1068.27108666
27. 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
28. Bonnet B, Messaoudi K, Jacomet F, et al. An update on molecular cat allergens: Fel d 1 and what else? Chapter 1: Fel d 1, the major cat allergen. Allergy Asthma Clin Immunol. 2018 Apr 10;14:14.29643919
29. 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
30. Wickman M, Lupinek C, Andersson N, et al. Detection of IgE Reactivity to a Handful of Allergen Molecules in Early Childhood Predicts Respiratory Allergy in Adolescence. EBioMedicine. 2017 Dec;26:91-99.29221963
31. Chruszcz M, Mikolajczak K, Mank N, Majorek KA, Porebski PJ, Minor W. Serum albumins-unusual allergens. Biochim Biophys Acta. 2013 Dec;1830(12):5375-5381.23811341
32. 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
33. 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
34. Tsolakis N, Malinovschi A, Nordvall L, et al. Sensitization to minor cat allergen components is associated with type-2 biomarkers in young asthmatics. Clin Exp Allergy. 2018 Sep;48(9):1186-1194.29575179
35. Wisniewski JA, Agrawal R, Minnicozzi S, et al. Sensitization to food and inhalant allergens in relation to age and wheeze among children with atopic dermatitis. Clin Exp Allergy. 2013 Oct;43(10):1160-1170.24074334
36. Hilger C, Kohnen M, Grigioni F, Lehners C, Hentges F. Allergic cross-reactions between cat and pig serum albumin. Study at the protein and DNA levels. Allergy. 1997 Feb;52(2):179-187.9105522
37. Posthumus J, James HR, Lane CJ, Matos LA, Platts-Mills TA, Commins SP. Initial description of pork-cat syndrome in the United States. J Allergy Clin Immunol. 2013 Mar;131(3):923-925.23352634
38. Spitzauer S, Pandjaitan B, Söregi G, et al. IgE cross-reactivities against albumins in patients allergic to animals. J Allergy Clin Immunol. 1995 Dec;96(6 Pt 1):951-959.8543754
39. Smith W, Butler AJ, Hazell LA, et al. Fel d 4, a cat lipocalin allergen. Clin Exp Allergy. 2004 Nov;34(11):1732-1738.15544598
40. 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
41. Hentges F, Leonard C, Arumugam K, Hilger C. Immune responses to inhalant Mammalian allergens. Front Immunol. 2014 May 21;5:234.24904583
42. 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
43. 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
44. 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
45. 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
46. 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
47. Grönlund H, Saarne T, Gafvelin G, van Hage M. The major cat allergen, Fel d 1, in diagnosis and therapy. Int Arch Allergy Immunol. 2010;151(4):265-274.19844127

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