Allergen Profile, Cat, IgE With Component Reflex

Importantly, cat (Felis domesticus) dander allergic individuals are sensitized to a heterogeneous range of cat allergens.^6,16,17 The major cat allergen is the secretoglobin Fel d 1,¹⁶ which accounts for majority all IgE reactivity to cat dander.^18,19 All cat allergens other than Fel d 1 are considered minor allergens because less than 50 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 and Fel d 7.^20-23

Fel d 1

Fel d 1 is produced by the sebaceous glands cat and is found in their saliva.^16,24 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.²⁵ Serum-specific Immunoglobulin E (sIgE) to Fel d 1 is present in up to 95% of patients that test positive for sIgE to cat dander.^{18,21-23,26-33} Early studies showed 60% to 90% of overall allergenic activity to cat dander is directed against Fel d 1.¹⁶ Depending on the population tested, 40% to 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).^21,30,31

A large European study of more than 4,000 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.³² Fel d 1 was the dominant sensitizing cat allergen during the entire childhood in this population.³² Consistent with other studies,^5,28,34 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.³² 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.³² 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 1.³² 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.^32,35

In a longitudinal cohort study of preschool children included during an episode of acute wheeze, the prevalence of sensitization to Fel d 1 increased from 2.8% at early preschool age to 13.9% at age 7.³⁶ Sensitization to cats and dogs in childhood has been shown to predict the persistence of asthma throughout the teen ages¹¹ 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.³⁷ 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.^{2,3,28,32,34,38,39}

Fel d 2

The protein Fel d 2 is cat albumin.⁴⁰ In the context of respiratory allergy, serum albumins are considered to be an uncommon cause of allergic sensitization.^40-42 Sensitization to Fel d 2 has been associated with moderate/severe rhinitis and a diagnosis of asthma in patients sensitized to other cat components.^{3,21,33,43,44} Wisniewski et al. described an association between high levels of sIgE to Fel d 2 and atopic dermatitis in cat-allergic children.⁴⁵ In a study of 266 adolescents and adults, sensitization to Fel d 2 and Fel d 4 was associated with biomarkers of type 2 inflammation (FENO, EOS, total IgE), whereas no associations were found for IgE to cat extract or Fel d 1.⁴³

Serum albumins are major allergens in meat, which underlies their importance as food allergens.⁴² 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.^42,46,47 It is thought that initial environmental exposure to cat albumin causes sensitization that results in subsequent rapid onset of allergic reactions on eating pork.^46,47

Serum albumins from mammals are highly conserved both in amino acid sequence and three-dimensional structure^{20,40,42,48,49} 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.⁴² 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% to 60% of cat dander sensitized patients, depending on the population studied.^{22-24,30,31,50,51} The great majority of patients with sensitization to Fel d 4 are also sensitized to Fel d 1.^29,30 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 4.³¹ 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.⁴³ Wisniewski et al. described an association between high levels of sIgE to Fel d 4 and atopic dermatitis in cat-allergic children.⁴⁵ In a study of 266 adolescents and adults, sensitization to Fel d 4 and Fel d 2 was associated with biomarkers of type 2 inflammation (FENO, EOS, total IgE), whereas no associations were found for IgE to cat extract or Fel d 1.⁴³

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.^20,52,53 Cross-reactivity between Fel d 4 and Can f 2, although the sequential identity observed in their study was less than 22%.⁵⁴ 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. Double-sensitization to cat and dog, and cat and horse, and polysensitization were associated with an increasing prevalence of the cross-reactive lipocalins Fel d 4, Can f 6 and Equ c 1.⁵⁵ Fel d 7 positivity indicates sensitization to furry animals but not specifically to cat.^6,55 Although Fel d 7 is not reliable marker for genuine sensitization, the comparison of sIgE levels may help to diagnose and find a primary sensitizer.^55,56

In a study of 294 children and adults with suspected allergic rhinoconjunctivitis, most patients sensitized to cat only had IgE to Fel d 1 but no or very low levels of IgE to Fel d 2 or 4.⁵⁵ Patients sensitized to both cat and dog more often had IgE to Fel d 4 and Fel d 7 in addition to Fel d 1.

Fel d 7

Fel d 7 is a lipocalin present in cat saliva, lachrymal fluid and on cat hair.⁵⁷ Fel d 7 sensitization is found in 31% to 70% of cat-allergic patients.^21-23,50,59 Basophil activation experiments indicate that Fel d 7 is a highly allergenic molecule.^23,58 The prevalence of Fel d 7 sensitization varies as a function of exposure to cat allergens, atopic status, asthma or allergic rhinitis (AR), ethnicity, cohort selection and geography.^17,23,60 Fel d 7 sensitization is most often found in association with other cat marker allergens Fel d 1 and the lipocalin Fel d 4 in cat-allergic patients.^6,55,56 Fel d 7 sensitization typically co-occurs with Fel d 1 sensitization,²⁷ often developing after Fel d 1 sensitization.³ Fel d 7 shares a high sequence identity (62%) with the major dog allergen Can f 1, giving it high potential for cross-reactivity in dog-allergic patients.

In an Austrian cohort comprising both children and adults, the prevalence of Fel d 7 sensitization was low in cat-monosensitized patients, at 3.8%, but increased to 29% in cat and dog double sensitized patients, and to 59% in cat-, horse- and dog-polysensitized patients.⁵⁵ The prevalence of Fel d 7 sensitization was 47% in Swedish asthmatic patients aged 10 to 35 years with demonstrated cat, dog or horse sensitization and requiring inhaled corticosteroid or antileukotriene treatment.⁴³ In a Swedish cohort of children aged 10 to 17 years investigated for furry animal allergy or sensitization, Fel d 7 sensitization was found in 68% of those experiencing cat-induced respiratory symptoms, but also in 55% of those who did not display such symptoms.²³ Among Lithuanian patients referred to outpatient allergy clinics for allergen multiplex investigations, the reported prevalence of Fel d 7 sensitization was 37%.⁶¹

Apparent monosensitization to Fel d 7 is infrequent in genuine cat-sensitized individuals, usually attributed to cross-reactivity with dog lipocalin Can f 1, explaining the wide variations reported in the literature, from 2% to 20%.^21,43,57,59 

Fel d 7 positivity indicates sensitization to furry animals, but not specifically to cat.^6,55 Although Fel d 7 is not reliable marker for genuine sensitization, the comparison of sIgE levels may help to diagnose and find a primary sensitizer.^55,56

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.^32,55 Sensitization to two or more cat, dog and horse allergen components has been associated with severe respiratory symptoms (severe asthma and rhinitis).^31,33,59 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.^{3,31,34,43,62,63} A cross-sectional cohort study in 269 children found that asthma was significantly associated with sensitization to members of the lipocalin protein family.⁶⁴ 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.⁶³ In adults, poly-sensitization to furry animal allergen components is an important predictor of clinical outcomes of asthma and of asthma severity. ^21,22,43,55

A number of studies suggest that sensitization to minor allergens (Fel d 2, Fel d 4, and Fel d 7) with or without Fel d 1 sensitization is associated with symptoms of asthma.^21,43