Summary

Fel d 4 is a lipocalin found in cat saliva, dander and urine. In cat allergic patients, Fel d 4 is a major allergen, with detectable sensitization in up to 70% of patients, occurring mainly in association with secretoglobin Fel d 1. Fel d 4 belongs to a subgroup of lipocalins with clinically relevant cross-reactivity comprising Equ c 1, Can f 6, and Cav p 6 from horse, dog, and guinea pig respectively. Fel d 4 sensitization is associated with persistent type 2 inflammation. Fel d 4 sensitization is clinically relevant as a marker of polysensitization to furry animals and of 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 [2-5].

Fel d 4 sensitization was initially reported in 63% of cat-allergic patients, although typically with low IgE levels [6]. Later studies showed that Fel d 4 sensitization can be found in both symptomatic and asymptomatic individuals. The prevalence of Fel d 4 sensitization varies as a function of exposure to cat allergens, atopic status, asthma or allergic rhinitis (AR), ethnicity, cohort selection, and geography [5, 7, 8]. In randomly selected populations, the prevalence of Fel d 4 sensitization was 4.1% in children aged 5 – 9 years and 2.1% in individuals aged 16 – 75 years, respectively in Switzerland and Sweden [4, 9]. Among atopic Dutch children as young as 0-4 years, the prevalence of Fel d 4 sensitization was 10% in the absence of AR symptoms but increased to 20% in those with symptomatic AR [7]. These figures almost doubled, at 20% and 35% respectively, when the whole cohort comprising children aged 0 to 18 years was considered [7]. In asthmatic patients from a Swedish cohort aged 16-75, the prevalence of Fel d 4 sensitization was 12.1% [4]. In adult European patients with demonstrated cat allergy, the prevalence of Fel d 4 sensitization was 41% - 52% [3, 10]. Finally, in a Swedish cohort of children aged 10 – 17 years investigated for furry animal allergy or sensitization, Fel d 4 sensitization was found in 70% of those experiencing cat-induced respiratory symptoms, but also in 50% of those who did not display such symptoms [8].

In an Austrian cohort comprising both children and adults, the prevalence of Fel d 4 sensitization was low in cat skin prick test (SPT)-monosensitized patients, at 9.2%, but increased to 81% in cat and horse double sensitized patients, and to 85% in cat, horse, and dog polysensitized patients [11].

Among patients referred to outpatient allergy clinics for allergen multiplex investigations, the reported prevalence of Fel d 4 sensitization varied widely, e.g. 5.3% in a Czech cohort and 19% in a Lithuanian one [12, 13].

Similar findings were reported in a Korean cohort of 238 adults, with Fel d 4 sensitization found in 49/206 (24%) of cat extract-sensitized individuals [14].

Apparent monosensitization to Fel d 4 is infrequent, reported at 1.2 -1.6% [12, 15].

Environmental characteristics                       

Source and tissue

Fel d 4 belongs to the lipocalin protein family, one of the most important groups of mammalian allergens [16]. Lipocalins are synthesized in secretory glands and are excreted in skin, urine, saliva, sweat and sebum [2, 17]. They are readily conveyed by airborne particles, explaining their presence in homes and public places.

Fel d 4 was characterized from cat salivary glands, where it is produced and secreted into saliva, subsequently spreading to fur through grooming [6, 18]. Salivary concentrations of Fel d 4 are higher than those of Fel d 1 (7.6 µg/mL versus 2.5 µg/mL) while fur and urine contained less Fel d 4. Cat age, sex, neutering and hair length were not associated with significant variations of Fel d 4 amounts, except for lower salivary Fel d 4 concentrations in neutered (2µg/mL) compared to non-neutered (17 µg/mL) female cats [18].  

Risk factors

Cat ownership, exposure to cats, and atopy are associated with an increased risk of becoming sensitized to cat allergens, including Fel d 4 [1, 7]. 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 4 sensitization [11].

Horse riding was proposed as a risk factor for Fel d 4 cross-sensitization following primary sensitization to Equ c 1 [11].

Clinical relevance

Specific molecules

Fel d 4, a lipocalin showing cross-reactivity with Equ c 1 from horse, Can f 6 from dog, and Cav p 6 from guinea pig, indicates sensitization to furry animals, but not specifically to cat [11, 17].

Cross-reactive molecules

Fel d 4 along with Equ c 1, Can f 6, and Cav p 6 belong to a subgroup of lipocalins with established clinically relevant cross-reactivity [17].

In a study of 273 cat-sensitized patients, 98 (38.7%)  were sensitized to Fel d 4, of which 63 were considered a primary sensitization and 35 due to cross-reactivity with Can f 6 [11].

Disease severity

As reviewed in the “Worldwide distribution” section, an increased prevalence of Fel d 4 sensitization has been consistently reported in symptomatic cat allergic patients, compared to asymptomatic sensitization.

Fel d 4 is most often found in association with other mammalian allergens, notably with the cat marker allergen Fel d 1 in cat-allergic patients, and with Equ c 1 without Fel d 1 in horse-allergic patients [11, 17]. Polysensitization to lipocalins, including Fel d 4, is associated with an increased risk of allergic disease and symptom severity. From a pathophysiological viewpoint, Fel d 4 sensitization is associated with persistent type 2 inflammation, which is a major contributor to atopic diseases [19].

Allergic asthma

Fel d 4 sensitization has been associated with symptoms of asthma [20]. In a Swedish population-based cohort aged 16-25 years, Fel d 4 sensitization carried an odds risk (OR) of 11 (CI95 6-19) for having asthma, higher than Fel d 1 (OR 4.9), and was also associated with an increased risk of rhinitis and concomitant asthma and rhinitis [5]. In the same study, Fel d 4 sensitization was associated with a lower OR for having controlled asthma, defined as an ACT score greater than 19, in comparison with Fel d 1 sensitization [5].

In a study of 195 adolescents from the general population, sensitization to Fel d 4 was associated with rhinoconjunctivitis and wheeze [21]. Similarly, Fel d 4 sensitization was found to be strongly associated with asthma in a cohort of 19-year old students [22]. Fel d 4 sensitization was also associated with asthma diagnosis in multiple other studies, with a prevalence of 42-55% in patients with a history of rhinitis or asthma [23-25].

Asthma symptoms were elicited by cat exposure in 40% of patients with Fel d 4 and Fel d 1 cosensitization, compared to only few of the mono-sensitized patients. Additionally, in cat-sensitized patients an intermediate to high level sensitization to Fel d 4 was significantly more common in the asthmatic patients [26].

Asthmatic pediatric patients with IgE to Fel d 2 serum albumin, Fel d 4 and Fel d 7 lipocalins are more likely to have persistent type 2 inflammation [19]. A study of 94 schoolchildren showed that patients with severe asthma displayed sensitization to Fel d 4 and two or more other pet allergens preferentially over those with mild or controlled asthma [27]. A cross-sectional study conducted in 269 children found that asthma was significantly associated with sensitization to members of the lipocalin family [16]. In addition to lipocalin polysensitization, demonstration of Fel d 4 IgE among a cluster of 27 molecules from 12 plant, animal, and fungal protein families was most strongly associated with pediatric asthma and decreased lung function [28].

Higher exhaled nitric oxide and increased bronchial responsiveness were reported in adults with detectable sensitization to both Fel d 4 and cat extract compared to subjects sensitized to the extract alone. Furthermore, detectable sensitization to Fel d 4 was associated with an increased risk of developing asthma and rhinitis over a 12-year follow-up, highlighting the predictive value of Fel d 4 and other component resolved diagnosis for disease severity [29].

Atopic Dermatitis 

Higher levels of IgE antibodies against Fel d 4 have been associated with AD in cat-allergic infants and children [30, 31]. In a Japanese cohort of 304 young children included at a median age of 13 months with AD and/or food allergy symptoms but not asthma, Fel d 4 was the second most frequent cat allergen sensitization, with IgE detected in 9.9%  at entry and in 15.7% at the end of the 2-year follow-up (29% and 33% of all cat-sensitized children at the respective time points); however, Fel d 4 sensitization did not predict the development of asthma during the study interval [32].

Molecular aspects

Biochemistry

Fel d 4 is a 22 kDa protein belonging to the lipocalin family of animal allergens, capable of efficient airborne dissemination and comprising most mammalian allergens [17]. Lipocalins display an internal cavity for binding hydrophobic ligands, which are pheromones or odorants in the case of mammalian lipocalins [17].

Isoforms, epitopes, antibodies

As of April 22, 2024, a unique isoallergen, Fel d 4.0101, has been included in the World Health Organization (WHO) and International Union of Immunological Societies (IUIS) Allergen Nomenclature [33].

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 [17]. Clinically relevant cross-reactivity between Fel d 4, Equ c 1, Can f 6, and Cav p 6 is supported by high sequence identity (53-67%) in addition to the conserved 3-dimensional conformation [17].

Fel d 4 and Can f 6 share 80% sequence similarity and 67% protein identity; specific IgE binding is highly overlapping between these two allergens [20, 34-36]. However, Fel d 4 and Can f 6 also contain epitopes that are not shared, resulting in non cross-reactive IgE antibodies which bind only Can f 6 or Fel d 4 and can co-exist with Fel d 4 – Can f 6 cross-reactive IgE in the same patient [36].

Shared epitopes have been demonstrated among otherwise non cross-reactive lipocalins, this observation being relevant for the documented Fel d 4 and Can f 2 cross-reactivity [37].

Diagnostic relevance              

Disease Severity

In line with the literature review presented in the above section of “Clinical Relevance”, Fel d 4 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, 5, 10, 11, 14, 15, 17, 19, 21-28, 30-32]. Fel d 4 sensitization has also shown predictive value for the development of asthma over a 12-year period [29].

At the clinical laboratory level, the demonstration of Fel d 4 sensitization is more frequent and displays higher IgE levels in individuals experiencing cat-related allergic symptoms [1, 7, 11, 15], in patients with asthma, AR, AD, as well as in individuals from the general population displaying symptoms such as rhinoconjunctivitis and wheeze .

In line with other pet molecular allergens, the demonstration of specific IgG to Fel d 4 is not useful for the diagnosis of cat, horse, or dog allergy [38].

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 [7, 8]. In contrast, Fel d 4 cross-reactivity with Equ c 1 and Can f 6 is illustrated in cases of primary sensitization to horse and/or dog, when Fel d 1 cosensitization is lacking [17].

AIT Prescription

Lipocalins including Fel d 4 are not currently considered as adequate options for molecular therapeutic approaches, due to their cross-reactivity [17, 39].

Explained results                    

Allergen information

Fel d 4 is a major cat allergen belonging to the lipocalin family, secreted in cat saliva, spread through grooming on the fur, and readily disseminated indoors. Fel d 4 sensitization is associated with persistent type 2 inflammation.

Clinical information

Fel d 4 sensitization, both on its own and within complex sensitization profiles, is associated with the diagnosis and symptom elicitation of asthma and allergic rhinitis, with a diagnosis of atopic dermatitis, and in some studies with decreased lung function and the long-term prediction of asthma development.

Cross reactivity

Fel d 4 exhibits clinically relevant, extensive cross-reactivity with related lipocalins Equ c 1, Can f 6, and Cav p 6 from horse, dog, and guinea pig.

Author: Dr. Joana Vitte

Reviewed by: Dr. Magnus Borres