e231 Fel d 7

Summary

Fel d 7 is a lipocalin present in cat saliva, lacrymal fluid, and on cat hair. Fel d 7 sensitization is found in 31-54% of cat-allergic patients, mainly in association with secretoglobin Fel d 1. Fel d 7 belongs to a subgroup of lipocalins with clinically relevant cross-reactivity with Can f 1 from dog. Fel d 7 sensitization by itself and within complex patterns of sensitization to lipocalins is associated with persistent type 2 inflammation, and an increased risk of asthma, allergic rhinitis, and atopic dermatitis.

Epidemiology

 Worldwide distribution

Cat allergens are among the most important sensitizers and causes of IgE-mediated allergic disease worldwide, due to high rates of cat ownership, frequent indoor presence of cats, and the demonstrated dissemination of cat allergens in schools and in homes without cats [1]. Sensitization rates to cat extracts are high in both asymptomatic and symptomatic individuals [1].

The prevalence of sensitization to cat extract and allergens increases during childhood, reaching a peak in teenagers and young adults, then slowly decreases in adults and elderly individuals [2, 3].

Fel d 7 sensitization is most often found in association with other mammalian allergens, notably with the cat marker allergen Fel d 1 and the lipocalin Fel d 4 in cat-allergic patients, and with Can f 1 without Fel d 1 in dog-allergic patients [4, 5].

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 [1, 2, 6].

Fel d 7 sensitization was initially reported in 37% of cat-allergic patients, although typically with low IgE levels, and in 8% of cat-tolerant individuals [7].

Later studies confirmed that Fel d 7 sensitization can be found in both symptomatic and asymptomatic individuals.

In adult European patients with demonstrated cat allergy, the prevalence of Fel d 7 sensitization was 31% - 54% [3, 8, 9]. Similar findings were reported in a Korean cohort of 238 adults, with Fel d 7 sensitization found in 67/206 (33%) of cat extract-sensitized individuals [10].

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 [4].

The prevalence of Fel d 7 sensitization was 47% in Swedish asthmatic patients aged 10-35 years with demonstrated cat, dog or horse sensitization and requiring inhaled corticosteroid or antileukotriene treatment [11].

In a Swedish cohort of children aged 10 – 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 [6].

Among Lithuanian patients referred to outpatient allergy clinics for allergen multiplex investigations, the reported prevalence of Fel d 7 sensitization was 37% [12].

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% [7, 9-11].

Environmental characteristics

Source and tissue

Fel d 7, a homologue of von Ebner gland proteins described in various mammals, is a secreted protein first identified from a cat tongue DNA library containing the lingual salivary glands [7]. Despite no Fel d 7 expression being evidenced in the princeps study from other salivary, skin, or anal cDNA libraries, Fel d 7 allergen was present in cat saliva and cat hair, while it was lacking from cat pelt [7]. The estimated contribution of Fel d 7 to total protein content of cat saliva and cat hair was less than 0.5% [7]. Fel d 7 was also demonstrated in the cat tear film proteome [13].

Like other lipocalins, Fel d 7 is readily conveyed by direct contact with cats and through airborne particles, explaining their presence in homes and public places.

Risk factors

Cat ownership, exposure to cats, and atopy are associated with an increased risk of becoming sensitized to cat allergens, including Fel d 7 [1]. While Fel d 1 is ubiquitous and can act as a primary sensitizer even in individuals who do not own a cat, cat ownership may be a risk factor for primary Fel d 7 sensitization [4, 9]. In dog-sensitized patients, dog ownership was not associated with an increased risk of Can f 1 – Fel d 7 cross-reactivity [4].

Clinical relevance

Specific molecules

Fel d 7, a lipocalin showing cross-reactivity with Can f 1 from dog, indicates sensitization to furry animals, but not specifically to cat [4, 5].

Cross-reactive molecules

Fel d 7 belongs to a subgroup of lipocalins which also contains Can f 1, with established clinically relevant cross-reactivity [5].

Disease severity

As reviewed in the “Worldwide distribution” section, an increased prevalence of Fel d 7 sensitization, especially in association with other cat and/or dog allergens, is reported in symptomatic cat and/or dog allergic patients, compared to asymptomatic sensitization. In addition, polysensitization to multiple lipocalins, including Fel d 7, is associated with an increased risk of symptom severity. The ability of Fel d 7 to induce IgE-dependent degranulation was demonstrated in basophil activation tests, with higher potency than other cat allergens [6, 14], while its association with persistent type 2 inflammation and more severe respiratory symptoms was addressed in a Swedish cohort of children and young adults [11].

Allergic asthma and allergic rhinitis

An early cross-sectional study in 269 children reported that asthma was associated with sensitization to the lipocalin protein family [15].

In a cohort of 266 Swedish children with well-characterized asthma and sensitization to furry animals, detectable IgE to Fel d 7 and/or Fel d 4 in addition to Fel d 1 were associated with a significantly increased number of recent asthma attacks and overall worse asthma control [11]. In the same study, Fel d 7 + Fel d 4 cosensitization was independently associated with an increased fraction of exhaled nitric oxide (FeNO) and with increased concentrations of circulating total IgE [11]. These biomarkers point to persistent type 2 inflammation, which is a major contributor to atopic diseases, in conjunction with Fel d 7 sensitization.

Current asthma and current allergic rhinitis were also associated with lipocalin (Fel d 7 and Fel d 4) sensitization in Swedish adults aged 16-75 years [9]. In this study, concomitant Fel d 1 and Fel d 7 sensitization was the most frequent pattern in individuals with allergic rhinitis (32%).

Finally, a study investigating the efficacy of subcutaneous immunotherapy reported that 42% of patients with a history of rhinitis/asthma tested positive to recombinant Fel d 7 in skin prick tests [16].

Atopic Dermatitis 

In a Russian cohort of cat-allergic adults, AD symptoms were associated with Fel d 7 sensitization in over 50% of patients [8].

Molecular aspects                  

Biochemistry

Fel d 7 is a 17.5 kDa protein belonging to the lipocalin family of animal allergens, capable of efficient airborne dissemination and comprising most mammalian allergens [5]. Lipocalins display an internal cavity for binding hydrophobic ligands, which are pheromones or odorants in the case of mammalian lipocalins [5].

Isoforms, epitopes, antibodies

As of April 30, 2024, a unique isoallergen, Fel d 7.0101, has been included in the World Health Organization (WHO) and International Union of Immunological Societies (IUIS) Allergen Nomenclature [17].

Cross-reactivity due to structural similarity

Lipocalins as a family are characterized by low sequence identity (20-30%) but conserved 3-dimensional conformation, which allows selective cross-reactivity [5]. Clinically relevant cross-reactivity between Fel d 7 and Can f 1 is supported by high sequence identity (63%) in addition to the conserved 3-dimensional conformation [5]. IgE binding inhibition studies showed that Fel d 7 cross-reacts with dog dander extracts [7].

IgE binding is highly overlapping between Fel d 7 and Can f 1 [7, 18]. However, Fel d 7 and Can f 1 also contain epitopes that are not shared, resulting in non cross-reactive IgE antibodies which bind only Fel d 7 or Can f 1 and can co-exist with Fel d 7 – Can f 1 cross-reactive IgE in the same patient [18].

Diagnostic relevance              

Disease Severity

In line with the literature review presented in the above section of “Clinical Relevance”, Fel d 7 sensitization has been associated with respiratory symptoms and disease severity on its own, in association with Fel d 1 sensitization, and within a phenotype of lipocalin or wider polysensitization [1, 2, 4, 5, 8-11].

At the clinical laboratory level, the demonstration of Fel d 7 sensitization is more frequent and displays higher IgE levels in individuals experiencing cat-related allergic symptoms, in patients with asthma, AR, AD, as well as in individuals from the general population displaying symptoms such as rhinoconjunctivitis and wheeze [1, 4, 9].

Serum concentrations of Fel d 7-specific IgE were significantly higher in asthmatic patients with higher FeNO and higher blood eosinophil counts, exhibiting a positive association with these inflammatory biomarkers, as well as with airway hyperresponsiveness and a trend to decreased lung function [11].

Cross- Reactivity

Fel d 1 cat-related clusters of sensitization, including Fel d 4, Fel d 7 and Fel d 2, are considered to be driven by Fel d 1 and correspond to genuine sensitization to cat [6]. In contrast, Fel d 7 cross-reactivity with Can f 1 is illustrated in cases of primary sensitization to dog, when Fel d 1 cosensitization is lacking [5]. Comparison of the concentrations of serum specific IgE to Fel d 7 and to Can f 1 may help identify the primary sensitizer, since virtually all patients with higher levels of IgE to Fel d 7 were cat owners in an Austrian cohort, while most of those with higher levels of IgE to Can f 1 were dog owners [4]. Overall, the cross-reactivity between Fel d 7 and Can f 1 explains why Can f 1 cannot be used as a marker allergen for dog sensitization in case of concomitant cat sensitization [5].

Importantly, irrespective of the primary sensitizer, Fel d 7 sensitization is associated to an increased risk of cat and dog-induced symptoms [1, 14].

AIT Prescription

Lipocalins including Fel d 7 are not currently considered as adequate options for molecular therapeutic approaches, due to their cross-reactivity [5, 19].

Explained results                   

Allergen information

Fel d 7 is a minor cat allergen belonging to the lipocalin family, secreted in cat saliva, spread through grooming on the fur, and readily disseminated indoors. Fel d 7 sensitization is associated with persistent type 2 inflammation.

Clinical relevance

Fel d 7 sensitization, both on its own and within complex sensitization profiles, is associated with the diagnosis and symptom elicitation of asthma and allergic rhinitis, and in some studies with decreased lung function and with a diagnosis of atopic dermatitis.

Cross reactivity

Fel d 7 exhibits clinically relevant cross-reactivity with related lipocalin Can f 1 from dog. In cat-sensitized patients, Fel d 7 cross-reactivity prevents the use of Can f 1 as a marker allergen for genuine dog sensitization.

Author: Dr. Joana Vitte

Reviewed by: Dr. Magnus Borres