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Allergy to furry animals: New insights, diagnostic approaches, and challenges

Published:October 02, 2014DOI:https://doi.org/10.1016/j.jaci.2014.08.026
      The prevalence of allergy to furry animals has been increasing, and allergy to cats, dogs, or both is considered a major risk factor for the development of asthma and rhinitis. An important step forward in the diagnosis of allergy to furry animals has been made with the introduction of molecular-based allergy diagnostics. A workshop on furry animals was convened to provide an up-to-date assessment of our understanding of (1) the exposure and immune response to the major mammalian allergens, (2) the relationship of these responses (particularly those to specific proteins or components) to symptoms, and (3) the relevance of these specific antibody responses to current or future investigation of patients presenting with allergic diseases. In this review research results discussed at the workshop are presented, including the effect of concomitant exposures from other allergens or microorganisms, the significance of the community prevalence of furry animals, molecular-based allergy diagnostics, and a detailed discussion of cat and dog components.

      Key words

      Abbreviation used:

      Alpha-gal (Galactose-α-1,3-galactose)
      Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com.
      Allergy to furry animals, cats and dogs in particular, has been recognized for many years and is considered to be a major risk factor for the development of asthma and rhinitis.
      • Perzanowski M.S.
      • Ronmark E.
      • Platts-Mills T.A.
      • Lundback B.
      Effect of cat and dog ownership on sensitization and development of asthma among preteenage children.
      The prevalence of allergy to furry animals
      • Ronmark E.
      • Bjerg A.
      • Perzanowski M.
      • Platts-Mills T.
      • Lundback B.
      Major increase in allergic sensitization in schoolchildren from 1996 to 2006 in northern Sweden.
      and the prevalence of allergic airway disease
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      • Bjorksten B.
      • Lai C.K.
      • Strachan D.P.
      • Weiland S.K.
      • et al.
      Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys.
      have been increasing. Exposure to allergens from these animals is ubiquitous, and the clinician should evaluate all patients with allergic airway disease for sensitization to animal dander.
      • Portnoy J.
      • Kennedy K.
      • Sublett J.
      • Phipatanakul W.
      • Matsui E.
      • Barnes C.
      • et al.
      Environmental assessment and exposure control: a practice parameter—furry animals.
      Allergic sensitization to several mammalian animals is prevalent, which might reflect cosensitization or cross-reactivity.
      • Roberts G.
      • Peckitt C.
      • Northstone K.
      • Strachan D.
      • Lack G.
      • Henderson J.
      • et al.
      Relationship between aeroallergen and food allergen sensitization in childhood.
      In some countries sensitization to furry animals is associated with more severe allergic disease,
      • Nordlund B.
      • Konradsen J.R.
      • Kull I.
      • Borres M.P.
      • Onell A.
      • Hedlin G.
      • et al.
      IgE antibodies to animal-derived lipocalin, kallikrein and secretoglobin are markers of bronchial inflammation in severe childhood asthma.
      which poses extended diagnostic and therapeutic challenges.
      An important step forward in the diagnosis of allergy to furry animals has been made with the introduction of molecular-based allergy diagnostics,
      • Borres M.P.
      • Ebisawa M.
      • Eigenmann P.A.
      Use of allergen components begins a new era in pediatric allergology.
      • Canonica G.W.
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      • Schmid-Grendelmeier P.
      • van Hage M.
      • Baena-Cagnani C.E.
      • et al.
      A WAO-ARIA-GA2LEN consensus document on molecular-based allergy diagnostics.
      which offer new opportunities for improved characterization. One example of novel insights gained by this approach is the differentiation of reactions to meat from patients with pork-cat syndrome.
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      • James H.R.
      • Lane C.J.
      • Matos L.A.
      • Platts-Mills T.A.
      • Commins S.P.
      Initial description of pork-cat syndrome in the United States.
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      • Hosen J.
      • Mozena J.
      • Borish L.
      • Lewis B.D.
      • et al.
      Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose.
      • 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.
      Patients with this syndrome sensitized to albumins from animal dander report symptoms after the consumption of pork because of the cross-reactivity of albumins from different species.
      The workshop on furry animals was convened to provide an up-to-date assessment of our understanding of (1) the exposure and immune response to the major mammalian allergens, (2) the relationship of these responses (particularly those to specific proteins or components) to symptoms, and (3) the relevance of these specific antibody responses to current or future investigation of patients presenting with allergic diseases.

      Definitions

      Allergic sensitization was defined as the presence of specific IgE antibodies to an allergen. Allergy was defined as the occurrence of reproducible symptoms or signs initiated by exposure to a defined stimulus at a dose tolerated by nonallergic persons and mediated by specific immunologic mechanisms (antibody or cell mediated). A component was defined as a molecule (ie, protein or glycoprotein) derived from a given allergen source that is identified by IgE antibodies. Cross-reactivity was defined as the process of IgE antibodies originally developed against a given allergen binding homologous molecules originating from a different allergen source.

      Allergen sources

      Given that most persons in Western societies spend more than 90% of their lives in indoor environments, it is not surprising that indoor allergens play an important role in allergic sensitization and symptoms. In addition to residential environments, exposure to furry animal allergens can occur in schools and occupational and/or leisure environments (eg, animal facilities, stables, pet shops, and farms). The allergen quantities derived from these sources might be clinically significant at the site where the animal is kept or at another site because of passive transfer (Table I). The primary source of cat and dog allergens is thought to be dander coming off the skin,
      • Portnoy J.
      • Kennedy K.
      • Sublett J.
      • Phipatanakul W.
      • Matsui E.
      • Barnes C.
      • et al.
      Environmental assessment and exposure control: a practice parameter—furry animals.
      • Charpin C.
      • Mata P.
      • Charpin D.
      • Lavaut M.N.
      • Allasia C.
      • Vervloet D.
      Fel d I allergen distribution in cat fur and skin.
      whereas for mice and rats, urine is thought to be a more important source.
      • Peng R.D.
      • Paigen B.
      • Eggleston P.A.
      • Hagberg K.A.
      • Krevans M.
      • Curtin-Brosnan J.
      • et al.
      Both the variability and level of mouse allergen exposure influence the phenotype of the immune response in workers at a mouse facility.
      • Sheehan W.J.
      • Rangsithienchai P.A.
      • Muilenberg M.L.
      • Rogers C.A.
      • Lane J.P.
      • Ghaemghami J.
      • et al.
      Mouse allergens in urban elementary schools and homes of children with asthma.
      Table IFurry animals: characteristics of allergen exposures in residential and nonresidential environments
      Data were derived from discussions at the workshop and published data.
      AnimalsPresent in the homeContribution to the microbiomePassive transfer to homes without an animal
      DomesticDustAirborne
       Cats (dander)++ to ++++ to ++?± to ++
      Airborne cat allergen has been measured in homes without a cat.
       Dogs (dander)++ to ++++ to ++Yes± to ++
       Pets
      Guinea pig???
      Hamsters (dander)???Not known
      Rabbits++ to +++?Likely
      Mice (urine)Rare++?Not known
      Rats (urine)Rare+?Not known
       Pests
      Mice (urine)+ to ++++++Likely
      Rats (urine)YesNot known
      LaboratoriesIn the laboratory
       Mice (urine)+++ to +++?Little known
       Rats (urine)+++ to +++?Little known
      Farms and stablesIn stableAt home
       Horses+++Yes?Assumed
       Cows++++ to ++?Rare
      +, Measurable levels but contribution to sensitization or symptoms is less clear; ++, levels consistent with sensitization and symptoms; +++, levels consistently higher than those known to cause sensitization.
      Data were derived from discussions at the workshop and published data.
      Airborne cat allergen has been measured in homes without a cat.

      Cat allergen exposure and allergic sensitization

      For many years, it was assumed that living in a house with a cat increased the risk of allergy. However, in 1999, Hesselmar et al
      • Hesselmar B.
      • Aberg N.
      • Aberg B.
      • Eriksson B.
      • Bjorksten B.
      Does early exposure to cat or dog protect against later allergy development?.
      reported that children who lived in a house with a cat were less likely to be sensitized to cat allergens. This observation has had a major effect and has been confirmed in many, but certainly not all, subsequent studies.
      • Perzanowski M.S.
      • Ronmark E.
      • Platts-Mills T.A.
      • Lundback B.
      Effect of cat and dog ownership on sensitization and development of asthma among preteenage children.
      • Platts-Mills T.
      • Vaughan J.
      • Squillace S.
      • Woodfolk J.
      • Sporik R.
      Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study.
      • Erwin E.A.
      • Wickens K.
      • Custis N.J.
      • Siebers R.
      • Woodfolk J.
      • Barry D.
      • et al.
      Cat and dust mite sensitivity and tolerance in relation to wheezing among children raised with high exposure to both allergens.
      • Custovic A.
      • Simpson B.M.
      • Simpson A.
      • Hallam C.L.
      • Marolia H.
      • Walsh D.
      • et al.
      Current mite, cat, and dog allergen exposure, pet ownership, and sensitization to inhalant allergens in adults.
      • Wegienka G.
      • Johnson C.C.
      • Havstad S.
      • Ownby D.R.
      • Nicholas C.
      • Zoratti E.M.
      Lifetime dog and cat exposure and dog- and cat-specific sensitization at age 18 years.
      A systematic review of recently published articles from birth cohorts and cross-sectional and case-control studies of the association between cat exposure and allergic diseases suggests that early-life cat exposure is likely to protect against allergic disease.
      • Dharmage S.C.
      • Lodge C.L.
      • Matheson M.C.
      • Campbell B.
      • Lowe A.J.
      Exposure to cats: update on risks for sensitization and allergic diseases.
      A recent meta-analysis of pooled results from 11 prospective European birth cohorts concluded that there is no clear evidence for a protective or “harmful” effect of cat ownership on sensitization to animal dander.
      • Lodrup Carlsen K.C.
      • Roll S.
      • Carlsen K.H.
      • Mowinckel P.
      • Wijga A.H.
      • Brunekreef B.
      • et al.
      Does pet ownership in infancy lead to asthma or allergy at school age? Pooled analysis of individual participant data from 11 European birth cohorts.
      These reviews confirm 2 observations: that the very high levels of cat allergens present in a house with a cat do not increase the risk of sensitization and that a large proportion of subjects who become sensitized to cat allergens do not live in a house with a cat. Furthermore, in the review of birth cohorts, the results were similar among children of parents without allergies compared with those among children of parents with allergies, indicating that selection bias did not have a major effect on the results of these studies. However, the issue of selection bias could be more complex; families with the most severe allergy could avoid owning pets, whereas families with mild allergy could be more highly represented among those who have cats at home. If this is the case, the apparent protective effect of cat ownership could be explained in part by the fact that the families with the most severe allergic constitution do not have pets at home.

      Clinical effects of allergen exposure in the sensitized subject

      Several studies have found a strong relationship between allergen exposure in sensitized subjects and allergic airway disease.
      • Apelberg B.J.
      • Aoki Y.
      • Jaakkola J.J.
      Systematic review: exposure to pets and risk of asthma and asthma-like symptoms.
      For instance, cat-sensitized children exposed to cat allergen have increased bronchial hyperreactivity compared with nonexposed children.
      • Nelson H.S.
      • Szefler S.J.
      • Jacobs J.
      • Huss K.
      • Shapiro G.
      • Sternberg A.L.
      The relationships among environmental allergen sensitization, allergen exposure, pulmonary function, and bronchial hyperresponsiveness in the Childhood Asthma Management Program.
      The lung function of dog-sensitized 3-year-old children who are exposed to dog allergens is reduced compared with that of sensitized children without exposure and exposed children without sensitization.
      • Lowe L.A.
      • Woodcock A.
      • Murray C.S.
      • Morris J.
      • Simpson A.
      • Custovic A.
      Lung function at age 3 years: effect of pet ownership and exposure to indoor allergens.
      Sensitization to furry animals has been associated with increased bronchial hyperresponsiveness in adolescents.
      • Bergstrom S.E.
      • Sundell K.
      • Hedlin G.
      Adolescents with asthma: consequences of transition from paediatric to adult healthcare.
      In a population-based study IgE antibodies to 103 allergen molecules were assessed by microarray, and subjects with IgE antibodies to allergen components from furry animals had increased asthma prevalence, higher fraction of exhaled nitric oxide levels, and increased bronchial hyperresponsiveness.
      • Patelis A.
      • Gunnbjornsdottir M.
      • Malinovschi A.
      • Matsson P.
      • Onell A.
      • Hogman M.
      • et al.
      Population-based study of multiplexed IgE sensitization in relation to asthma, exhaled nitric oxide, and bronchial responsiveness.
      Furthermore, a follow-up of children with asthma clearly showed that the probability of remission from age 7 years to age 19 years was significantly reduced if the child had been sensitized to furry animals at age 7 years.
      • Andersson M.
      • Hedman L.
      • Bjerg A.
      • Forsberg B.
      • Lundback B.
      • Ronmark E.
      Remission and persistence of asthma followed from 7 to 19 years of age.
      In addition, exposure to allergens from small furry animals, such as hamsters or mice, has also been associated with symptoms of asthma in sensitized subjects.
      • Niitsuma T.
      • Tsuji A.
      • Nukaga M.
      • Izawa A.
      • Okita M.
      • Maruoka N.
      • et al.
      Thirty cases of bronchial asthma associated with exposure to pet hamsters.
      • Lynch S.V.
      • Wood R.A.
      • Boushey H.
      • Bacharier L.B.
      • Bloomberg G.R.
      • Kattan M.
      • et al.
      Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children.

      Frequencies of allergic sensitization

      In the United States and Europe the prevalence of sensitization to furry animals has increased over the past decades.
      • Ronmark E.
      • Bjerg A.
      • Perzanowski M.
      • Platts-Mills T.
      • Lundback B.
      Major increase in allergic sensitization in schoolchildren from 1996 to 2006 in northern Sweden.
      • Arbes Jr., S.J.
      • Gergen P.J.
      • Elliott L.
      • Zeldin D.C.
      Prevalences of positive skin test responses to 10 common allergens in the US population: results from the third National Health and Nutrition Examination Survey.
      • Linneberg A.
      • Nielsen N.H.
      • Madsen F.
      • Frolund L.
      • Dirksen A.
      • Jorgensen T.
      Increasing prevalence of specific IgE to aeroallergens in an adult population: two cross-sectional surveys 8 years apart: the Copenhagen Allergy Study.
      Age- and sex-adjusted data from a pan-European study published in 2009 found that 26% and 27% of adults were sensitized to cats and dogs (by using skin prick tests), respectively,
      • Heinzerling L.M.
      • Burbach G.J.
      • Edenharter G.
      • Bachert C.
      • Bindslev-Jensen C.
      • Bonini S.
      • 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.
      which could be compared with data from 1992 showing that the frequency of sensitization to cat (by using skin prick tests) was 8.8%.
      • Bousquet P.J.
      • Chinn S.
      • Janson C.
      • Kogevinas M.
      • Burney P.
      • Jarvis D.
      Geographical variation in the prevalence of positive skin tests to environmental aeroallergens in the European Community Respiratory Health Survey I.
      In the United States the frequencies of cat and dog sensitization in subjects aged 6 years and older are 12.1% and 11.8%, respectively.
      • Salo P.M.
      • Arbes Jr., S.J.
      • Jaramillo R.
      • Calatroni A.
      • Weir C.H.
      • Sever M.L.
      • et al.
      Prevalence of allergic sensitization in the United States: results from the National Health and Nutrition Examination Survey (NHANES) 2005-2006.
      A population-based study from Germany (n = 17,641; age, 3-17 years) reported sensitization to dogs of 11.6% and 7.6% and to cats of 9.6% and 6.6% in boys and girls, respectively.
      • Schmitz R.
      • Ellert U.
      • Kalcklosch M.
      • Dahm S.
      • Thamm M.
      Patterns of sensitization to inhalant and food allergens—findings from the German Health Interview and Examination Survey for Children and Adolescents.
      The prevalence of sensitization is modified by the age of the subject, with increasing prevalence throughout childhood
      • Ronmark E.
      • Perzanowski M.
      • Platts-Mills T.
      • Lundback B.
      Different sensitization profile for asthma, rhinitis, and eczema among 7-8-year-old children: report from the Obstructive Lung Disease in Northern Sweden studies.
      • Roberts G.
      • Zhang H.
      • Karmaus W.
      • Raza A.
      • Scott M.
      • Matthews S.
      • et al.
      Trends in cutaneous sensitization in the first 18 years of life: results from the 1989 Isle of Wight birth cohort study.
      • Kim J.
      • Hahm M.I.
      • Lee S.Y.
      • Kim W.K.
      • Chae Y.
      • Park Y.M.
      • et al.
      Sensitization to aeroallergens in Korean children: a population-based study in 2010.
      culminating in peak prevalence during adolescence.
      • Warm K.
      • Backman H.
      • Lindberg A.
      • Lundback B.
      • Ronmark E.
      Low incidence and high remission of allergic sensitization among adults.
      However, it should be emphasized that estimates of the prevalence of sensitization are based on skin tests or in vitro assays with extracts. If the extract's constituents or the strength of the extract changes over time, this could lead to an apparent change in prevalence.

      Determinants for allergic sensitization

      A number of determinants for allergic sensitization to furry animals in the exposed subject have been identified, including factors not directly related to the pet. In particular, the genetic constitution of the exposed subject,
      • Custovic A.
      • Simpson B.M.
      • Simpson A.
      • Kissen P.
      • Woodcock A.
      Effect of environmental manipulation in pregnancy and early life on respiratory symptoms and atopy during first year of life: a randomised trial.
      • Wahn U.
      • Lau S.
      • Bergmann R.
      • Kulig M.
      • Forster J.
      • Bergmann K.
      • et al.
      Indoor allergen exposure is a risk factor for sensitization during the first three years of life.
      the environmental setting,
      • Vartiainen E.
      • Petays T.
      • Haahtela T.
      • Jousilahti P.
      • Pekkanen J.
      Allergic diseases, skin prick test responses, and IgE levels in North Karelia, Finland, and the Republic of Karelia, Russia.
      • von Mutius E.
      • Martinez F.D.
      • Fritzsch C.
      • Nicolai T.
      • Roell G.
      • Thiemann H.H.
      Prevalence of asthma and atopy in two areas of West and East Germany.
      and other environmental exposures, including concomitant exposure to other allergen sources
      • Perzanowski M.S.
      • Ronmark E.
      • Platts-Mills T.A.
      • Lundback B.
      Effect of cat and dog ownership on sensitization and development of asthma among preteenage children.
      • Mandhane P.J.
      • Sears M.R.
      • Poulton R.
      • Greene J.M.
      • Lou W.Y.
      • Taylor D.R.
      • et al.
      Cats and dogs and the risk of atopy in childhood and adulthood.
      and microorganisms,
      • Fujimura K.E.
      • Johnson C.C.
      • Ownby D.R.
      • Cox M.J.
      • Brodie E.L.
      • Havstad S.L.
      • et al.
      Man's best friend? The effect of pet ownership on house dust microbial communities.
      • Ownby D.R.
      • Peterson E.L.
      • Wegienka G.
      • Woodcroft K.J.
      • Nicholas C.
      • Zoratti E.
      • et al.
      Are cats and dogs the major source of endotoxin in homes?.
      have been shown to be important in this connection.
      • Linneberg A.
      • Nielsen N.H.
      • Madsen F.
      • Frolund L.
      • Dirksen A.
      • Jorgensen T.
      Pets in the home and the development of pet allergy in adulthood. The Copenhagen Allergy Study.
      • Olivieri M.
      • Zock J.P.
      • Accordini S.
      • Heinrich J.
      • Jarvis D.
      • Kunzli N.
      • et al.
      Risk factors for new-onset cat sensitization among adults: a population-based international cohort study.
      • Svanes C.
      • Heinrich J.
      • Jarvis D.
      • Chinn S.
      • Omenaas E.
      • Gulsvik A.
      • et al.
      Pet-keeping in childhood and adult asthma and hay fever: European community respiratory health survey.
      Additionally, several determinants directly related to the animal have proved to be of importance, such as the biological activity of the allergen
      • Emara M.
      • Royer P.J.
      • Abbas Z.
      • Sewell H.F.
      • Mohamed G.G.
      • Singh S.
      • et al.
      Recognition of the major cat allergen Fel d 1 through the cysteine-rich domain of the mannose receptor determines its allergenicity.
      and the timing,
      • Almqvist C.
      • Garden F.
      • Kemp A.S.
      • Li Q.
      • Crisafulli D.
      • Tovey E.R.
      • et al.
      Effects of early cat or dog ownership on sensitisation and asthma in a high-risk cohort without disease-related modification of exposure.
      • Ownby D.R.
      • Johnson C.C.
      • Peterson E.L.
      Exposure to dogs and cats in the first year of life and risk of allergic sensitization at 6 to 7 years of age.
      variability,
      • Peng R.D.
      • Paigen B.
      • Eggleston P.A.
      • Hagberg K.A.
      • Krevans M.
      • Curtin-Brosnan J.
      • et al.
      Both the variability and level of mouse allergen exposure influence the phenotype of the immune response in workers at a mouse facility.
      and intensity
      • Platts-Mills T.
      • Vaughan J.
      • Squillace S.
      • Woodfolk J.
      • Sporik R.
      Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study.
      • Lau S.
      • Illi S.
      • Platts-Mills T.A.
      • Riposo D.
      • Nickel R.
      • Gruber C.
      • et al.
      Longitudinal study on the relationship between cat allergen and endotoxin exposure, sensitization, cat-specific IgG and development of asthma in childhood–report of the German Multicentre Allergy Study (MAS 90).
      • Lindfors A.
      • van Hage-Hamsten M.
      • Rietz H.
      • Wickman M.
      • Nordvall S.L.
      Influence of interaction of environmental risk factors and sensitization in young asthmatic children.
      of the allergen exposure. Of particular interest is that there seems to be a tolerance effect with increasing levels of exposure, which could be caused by a modification of the TH2 response
      • Platts-Mills T.
      • Vaughan J.
      • Squillace S.
      • Woodfolk J.
      • Sporik R.
      Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study.
      or induced by concomitant exposures.

       Concomitant exposures

      Prediction of the effects of concomitant exposures to other allergen sources is not straightforward. In one study from northern Sweden, where there are no house dust mites, having a cat at home was associated with a reduced frequency of sensitization to other allergens.
      • Perzanowski M.S.
      • Ronmark E.
      • Platts-Mills T.A.
      • Lundback B.
      Effect of cat and dog ownership on sensitization and development of asthma among preteenage children.
      However, in a study from New Zealand, where children have high exposure to both cat and mite allergens, there appears to be little or no effect of cat ownership on sensitization to dust mite allergens.
      • Erwin E.A.
      • Wickens K.
      • Custis N.J.
      • Siebers R.
      • Woodfolk J.
      • Barry D.
      • et al.
      Cat and dust mite sensitivity and tolerance in relation to wheezing among children raised with high exposure to both allergens.
      With respect to concomitant exposure to microorganisms, it has been shown that in addition to proteins derived from the animal itself, animals can carry significant quantities of endotoxin, pollens, or fungal spores. Although it is possible to measure endotoxin in both cat and dog hair, interpretation of the data on the effects of animals on airborne endotoxin levels is not simple. Cat ownership does not seem to increase endotoxin levels in the home,
      • Platts-Mills J.A.
      • Custis N.J.
      • Woodfolk J.A.
      • Platts-Mills T.A.
      Airborne endotoxin in homes with domestic animals: implications for cat-specific tolerance.
      • Sohy C.
      • Lieutier-Colas F.
      • Casset A.
      • Meyer P.
      • Pauli G.
      • Pons F.
      • et al.
      Dust and airborne endotoxin exposure in dwellings in the Strasbourg metropolitan area (France).
      but cats can act as a vector for Staphylococcus aureus.
      • Abdel-moein K.A.
      • Samir A.
      Isolation of enterotoxigenic Staphylococcus aureus from pet dogs and cats: a public health implication.
      The presence of a dog in the house does increase airborne endotoxin levels.
      • Platts-Mills J.A.
      • Custis N.J.
      • Woodfolk J.A.
      • Platts-Mills T.A.
      Airborne endotoxin in homes with domestic animals: implications for cat-specific tolerance.
      In addition, the microbiome of the dust and the fecal microbiome of children can be altered by the presence of a dog in the house.
      • Fujimura K.E.
      • Johnson C.C.
      • Ownby D.R.
      • Cox M.J.
      • Brodie E.L.
      • Havstad S.L.
      • et al.
      Man's best friend? The effect of pet ownership on house dust microbial communities.
      • Ownby D.R.
      • Peterson E.L.
      • Wegienka G.
      • Woodcroft K.J.
      • Nicholas C.
      • Zoratti E.
      • et al.
      Are cats and dogs the major source of endotoxin in homes?.
      If this has an effect on the development of allergic sensitization in the infant, we assume this would be comparable with the effect of bacterial exposure on children living on a farm and would not be allergen specific.
      • Ege M.J.
      • Mayer M.
      • Normand A.C.
      • Genuneit J.
      • Cookson W.O.
      • Braun-Fahrlander C.
      • et al.
      Exposure to environmental microorganisms and childhood asthma.
      Whether comparable effects can occur with other pets requires further investigation. Clearly, there is a need for more studies directly documenting the effects of pet ownership on the microbiome of homes and their occupants.

       Effect of the community prevalence of pets

      The percentage of homes that report the presence of an animal varies from approximately 5% in Spain to approximately 20% in Sweden and 65% or greater in New Zealand.
      • McBride D.
      • Keil T.
      • Grabenhenrich L.
      • Dubakiene R.
      • Drasutiene G.
      • Fiocchi A.
      • et al.
      The EuroPrevall birth cohort study on food allergy: baseline characteristics of 12,000 newborns and their families from nine European countries.
      • Burr M.L.
      • Limb E.S.
      • Andrae S.
      • Barry D.M.
      • Nagel F.
      Childhood asthma in four countries: a comparative survey.
      In a population-based study on 3400 children in Sweden, at least three quarters of the children who had IgE antibodies to cat had never lived in a house with a cat.
      • Perzanowski M.S.
      • Ronmark E.
      • Platts-Mills T.A.
      • Lundback B.
      Effect of cat and dog ownership on sensitization and development of asthma among preteenage children.
      The quantity of cat allergen in schools is directly related to the number of children in the class who have a cat at home.
      • Almqvist C.
      • Wickman M.
      • Perfetti L.
      • Berglind N.
      • Renstrom A.
      • Hedren M.
      • et al.
      Worsening of asthma in children allergic to cats, after indirect exposure to cat at school.
      Sensitization to cat allergens would only occur in houses without a cat if there were sufficient houses in the community with a cat.
      • Svanes C.
      • Heinrich J.
      • Jarvis D.
      • Chinn S.
      • Omenaas E.
      • Gulsvik A.
      • et al.
      Pet-keeping in childhood and adult asthma and hay fever: European community respiratory health survey.
      If animals are present in a small proportion of homes (eg, <10%), the exposure in homes without a cat might be inadequate to result in a high prevalence of sensitization; by contrast, if animals are present in the majority of homes, the allergen levels in schools or homes without an animal might actually be supraoptimal or sufficient to induce tolerance.
      • Custovic A.
      • Hallam C.L.
      • Simpson B.M.
      • Craven M.
      • Simpson A.
      • Woodcock A.
      Decreased prevalence of sensitization to cats with high exposure to cat allergen.
      At present, there is not sufficient information to predict these effects, and there are very few comparative data between countries about the quantities of cat or dog allergens (dust or airborne) in homes without an animal or in schools.
      Small furry pets, such as rabbits, guinea pigs, and hamsters, have also become increasingly popular over the last 20 years.
      • Phillips J.F.
      • Lockey R.F.
      Exotic pet allergy.
      Up to 5% of US and European households have a small furry animal, but data on allergen quantities in house dust are lacking.

      Immune responses to furry animal allergens in addition to IgE

      The immune response to domestic animal allergens includes T cells and IgE antibodies, as well as different isotypes of antibodies. At present, both the significance of IgE antibodies and the techniques for measuring IgE antibody levels are better established than the techniques for describing any other aspect of the immune response.

       T-cell responses

      After the cloning of Fel d 1,
      • Morgenstern J.P.
      • Griffith I.J.
      • Brauer A.W.
      • Rogers B.L.
      • Bond J.F.
      • Chapman M.D.
      • et al.
      Amino acid sequence of Fel dI, the major allergen of the domestic cat: protein sequence analysis and cDNA cloning.
      a wide range of studies have been carried out on T-cell responses to cat allergens using both the protein Fel d 1 and overlapping peptides derived from Fel d 1.
      • Norman P.S.
      • Ohman Jr., J.L.
      • Long A.A.
      • Creticos P.S.
      • Gefter M.A.
      • Shaked Z.
      • et al.
      Treatment of cat allergy with T-cell reactive peptides.
      • Oldfield W.L.
      • Larche M.
      • Kay A.B.
      Effect of T-cell peptides derived from Fel d 1 on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial.
      • Reefer A.J.
      • Carneiro R.M.
      • Custis N.J.
      • Platts-Mills T.A.
      • Sung S.S.
      • Hammer J.
      • et al.
      A role for IL-10-mediated HLA-DR7-restricted T cell-dependent events in development of the modified Th2 response to cat allergen.
      These studies demonstrated that responses to Fel d 1 are, broadly speaking, of a TH2 type. Furthermore, several groups have identified specific peptides of Fel d 1, which are significant to the response and led to the testing of peptide vaccines based on Fel d 1.
      • Norman P.S.
      • Ohman Jr., J.L.
      • Long A.A.
      • Creticos P.S.
      • Gefter M.A.
      • Shaked Z.
      • et al.
      Treatment of cat allergy with T-cell reactive peptides.
      • Patel D.
      • Couroux P.
      • Hickey P.
      • Salapatek A.M.
      • Laidler P.
      • Larche M.
      • et al.
      Fel d 1-derived peptide antigen desensitization shows a persistent treatment effect 1 year after the start of dosing: a randomized, placebo-controlled study.
      Evaluation of T-cell responses to animal (or other) allergens is not part of the routine assessment of patients presenting with symptoms, and all studies on T-cell responses to Fel d 1 have focused on subjects with positive skin test results. Although it is possible that there are patients who have symptoms related to cat or dog allergen exposure on the basis of a T-cell response without an associated IgE antibody response, this has not been demonstrated.

       IgG antibody responses, including IgG1 and IgG4

      In 1935, it was demonstrated that there are 2 types of antibodies in the sera of patients with hay fever and that the “blocking antibodies” increased with immunotherapy.
      • Cooke R.A.
      • Barnard J.H.
      • Hebald S.
      • Stull A.
      Serological evidence of immunity with coexisting sensitization in a type of human allergy (hay fever).
      Almost all studies have recognized that IgE levels decrease and IgG4 levels increase during subcutaneous immunotherapy.
      • Burks A.W.
      • Calderon M.A.
      • Casale T.
      • Cox L.
      • Demoly P.
      • Jutel M.
      • et al.
      Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report.
      Currently, there are mixed data about the isotypes other than IgE and IgG4, and the data on IgG1 and IgA have to be considered with caution.
      • Janossy G.
      • Gomez De La Concha E.
      • Waxdal M.J.
      • Platts-Mills T.
      The effects of purified mitogenic proteins (Pa-1 and Pa-2) from pokeweed on human T and B lymphocytes in vitro.
      • Platts-Mills T.A.
      Local production of IgG, IgA and IgE antibodies in grass pollen hay fever.
      Many publications report detectable IgG4 antibodies in most allergic and nonallergic subjects in contrast to extensive earlier data. Although the results might not be relevant to the clinical evaluation of patients, they are important to understanding the immune response to cat allergens in those atopic children who live in a house with a cat but do not become symptomatic on exposure to cat allergens.
      • Wegienka G.
      • Johnson C.C.
      • Havstad S.
      • Ownby D.R.
      • Nicholas C.
      • Zoratti E.M.
      Lifetime dog and cat exposure and dog- and cat-specific sensitization at age 18 years.
      Recently, an interesting dissociation of allergen-specific IgE and IgG responses to cat, dog, and horse was reported, indicating that nonsequential class-switch mechanisms are operative in patients with animal allergy and might explain why naturally occurring allergen-specific IgG is not always protective.
      • Erwin E.A.
      • Woodfolk J.A.
      • James H.R.
      • Satinover S.M.
      • Platts-Mills T.A.
      Changes in cat specific IgE and IgG antibodies with decreased cat exposure.
      Measurement of IgG antibodies might also be relevant to understanding why some subjects experience increased symptoms on entering a house with an animal after a period of decreased exposure.

      Clinical considerations in the diagnosis and management of allergy to furry animals

      The management of patients with allergic disease with sensitization to furry animals includes a judgment about (1) exposure to relevant allergens, (2) the effect of that exposure on symptoms, and (3) sound advice about controlling exposure. This includes advice about whether to keep a domestic animal and judgment about whether one allergen in the home is more relevant than another. A good example of this is the common problem of a patient who is sensitized to both mite and cat and is exposed to both allergens. Extract-based diagnosis of sensitization can only provide information about the source in general. Our question here is as follows: How much can identification of sensitization to specific proteins in these extracts contribute to the diagnosis or management of allergic patients?

      Molecular-based allergy diagnostics

      The purification and characterization of allergens started with work on rye grass and ragweed pollen.
      • Johnson P.
      • Marsh D.G.
      ‘Isoallergens’ from rye grass pollen.
      • King T.P.
      • Norman P.S.
      • Connell J.T.
      Isolation and characterization of allergens from ragweed pollen. II.
      This was followed by the purification of Fel d 1 by Ohman et al
      • Ohman Jr., J.L.
      • Lowell F.C.
      • Bloch K.J.
      Allergens of mammalian origin. III. Properties of a major feline allergen.
      in 1974 and has now been extended to hundreds of proteins. The definitions and correct nomenclature for these allergens are by agreement of the International Union of Immunological Societies subcommittee on allergen nomenclature (Table II).

      IUIS Allergen Nomenclature Sub Committee. Allergen nomenclature. Available at: http://www.allergen.org. Accessed January 15, 2014.

      Characterization of allergens has made many different developments possible. These include measurement of class-specific antibodies, production of peptides to test T-cell responses, and development of the mAbs used to measure environmental exposure.
      Table IIPurified and characterized animal allergens
      Component-specific IgE levels can be measured with component-specific IgE assays or by using the Immuno Solid-phase Allergen Chip (ISAC Thermo Fisher Scientific, Uppsala Sweden).
      AnimalMajor allergen
      Airborne measurements of each allergen source have been based on the major allergen.
      Other allergens
      CatFel d 1 (uteroglobin)

      14 + 4 kDa
      Fel d 2 (albumin)
      Albumins have molecular weights of 67 to 69 kDa and can cross-react extensively.


      Fel d 4 (lipocalin)

      Fel d 7 (VEGP)
      von Ebner gland protein.


      Fel d 3 (cystatin)

      Fel d 5w (cat IgA)
      The main epitope on cat IgA and also on cat IgM is the oligosaccharide alpha-gal.


      Fel d 8 (latherin-like)
      DogCan f 1 (lipocalin)

      23-25 kDa
      Can f 2 (lipocalin)

      Can f 4 (lipocalin)

      Can f 6 (lipocalin)

      Can f 3 (albumin)
      Albumins have molecular weights of 67 to 69 kDa and can cross-react extensively.


      Can f 5 (arginine esterase)
      This molecule is a kallikrein.
      Guinea pigCav p 1 (lipocalin)

      20 kDa

      Cav p 2 (lipocalin)

      17 kDa
      Cav p 3 (lipocalin)

      Cav p 4 (albumin)
      HorseEqu c 1 (lipocalin)

      25 kDa
      Equ c 2 (lipocalin)

      Equ c 4 (latherin)

      Equ c 3 (albumin)
      Albumins have molecular weights of 67 to 69 kDa and can cross-react extensively.
      MouseMus m 1 (lipocalin; urinary prealbumin)

      17 kDa
      RatRat n 1 (lipocalin; alpha-2u-globulin)

      17 kDa
      RabbitOry c 1 (lipocalin)

      17-18 kDa
      Ory c 3 (lipophilin)

      19-21 kDa
      Component-specific IgE levels can be measured with component-specific IgE assays or by using the Immuno Solid-phase Allergen Chip (ISAC Thermo Fisher Scientific, Uppsala Sweden).
      Airborne measurements of each allergen source have been based on the major allergen.
      Albumins have molecular weights of 67 to 69 kDa and can cross-react extensively.
      § von Ebner gland protein.
      The main epitope on cat IgA and also on cat IgM is the oligosaccharide alpha-gal.
      This molecule is a kallikrein.
      Allergen components can be classified into separate protein families, and allergens within the same protein family often display cross-reactivity between them. This is particularly clear for the albumins
      • Spitzauer S.
      • Pandjaitan B.
      • Soregi G.
      • Muhl S.
      • Ebner C.
      • Kraft D.
      • et al.
      IgE cross-reactivities against albumins in patients allergic to animals.
      and some lipocalins
      • Saarelainen S.
      • Rytkonen-Nissinen M.
      • Rouvinen J.
      • Taivainen A.
      • Auriola S.
      • Kauppinen A.
      • et al.
      Animal-derived lipocalin allergens exhibit immunoglobulin E cross-reactivity.
      from furry animals.
      Assessment of allergen components can be done either by measuring antibodies to individual components or by using an allergen microarray chip.
      • Canonica G.W.
      • Ansotegui I.J.
      • Pawankar R.
      • Schmid-Grendelmeier P.
      • van Hage M.
      • Baena-Cagnani C.E.
      • et al.
      A WAO-ARIA-GA2LEN consensus document on molecular-based allergy diagnostics.
      • Valenta R.
      • Lidholm J.
      • Niederberger V.
      • Hayek B.
      • Kraft D.
      • Gronlund H.
      The recombinant allergen-based concept of component-resolved diagnostics and immunotherapy (CRD and CRIT).
      The former approach provides quantitative results on a single allergen component, whereas the latter approach allows semiquantitative measurement of IgE antibodies to a large number of components simultaneously. Some allergens are recognized as specific markers of an allergen source,
      • Canonica G.W.
      • Ansotegui I.J.
      • Pawankar R.
      • Schmid-Grendelmeier P.
      • van Hage M.
      • Baena-Cagnani C.E.
      • et al.
      A WAO-ARIA-GA2LEN consensus document on molecular-based allergy diagnostics.
      • Gronlund H.
      • Adedoyin J.
      • Reininger R.
      • Varga E.M.
      • Zach M.
      • Fredriksson M.
      • et al.
      Higher immunoglobulin E antibody levels to recombinant Fel d 1 in cat-allergic children with asthma compared with rhinoconjunctivitis.
      and by identifying these allergens, it is possible to determine which are the sensitizing and which are the cross-reactive allergen sources. Questions regarding the clinical utility of molecular-based allergy diagnostics are summarized in Box 1.

       Secretoglobin Fel d 1: The major cat allergen

      Fel d 1 is the major cat allergen because up to 95% of all patients with cat allergy react to Fel d 1.
      • Gronlund H.
      • Adedoyin J.
      • Reininger R.
      • Varga E.M.
      • Zach M.
      • Fredriksson M.
      • et al.
      Higher immunoglobulin E antibody levels to recombinant Fel d 1 in cat-allergic children with asthma compared with rhinoconjunctivitis.
      • van Ree R.
      • van Leeuwen W.A.
      • Bulder I.
      • Bond J.
      • Aalberse R.C.
      Purified natural and recombinant Fel d 1 and cat albumin in in vitro diagnostics for cat allergy.
      • Ichikawa K.
      • Iwasaki E.
      • Baba M.
      • Chapman M.D.
      High prevalence of sensitization to cat allergen among Japanese children with asthma, living without cats.
      This protein accounts for 60% to 90% of all IgE reactivity to cat dander
      • van Ree R.
      • van Leeuwen W.A.
      • Bulder I.
      • Bond J.
      • Aalberse R.C.
      Purified natural and recombinant Fel d 1 and cat albumin in in vitro diagnostics for cat allergy.
      • Kleine-Tebbe J.
      • Kleine-Tebbe A.
      • Jeep S.
      • Schou C.
      • Lowenstein H.
      • Kunkel G.
      Role of the major allergen (Fel d I) in patients sensitized to cat allergens.
      • Ohman Jr., J.L.
      • Lowell F.C.
      IgE antibody to cat allergens in an allergic population.
      and does not display significant cross-reactivity with other mammalian sources. Fel d 1 is a secretoglobin that is primarily produced in sebaceous, anal, and salivary glands and is mainly present in the epidermis and fur. Fel d 1 is spread to the environment predominantly through airborne dander,
      • Charpin C.
      • Mata P.
      • Charpin D.
      • Lavaut M.N.
      • Allasia C.
      • Vervloet D.
      Fel d I allergen distribution in cat fur and skin.
      • Dabrowski A.J.
      • Van der Brempt X.
      • Soler M.
      • Seguret N.
      • Lucciani P.
      • Charpin D.
      • et al.
      Cat skin as an important source of Fel d I allergen.
      which can be detected both in homes with and those without a cat.
      • Luczynska C.M.
      • Li Y.
      • Chapman M.D.
      • Platts-Mills T.A.
      Airborne concentrations and particle size distribution of allergen derived from domestic cats (Felis domesticus). Measurements using cascade impactor, liquid impinger, and a two-site monoclonal antibody assay for Fel d I.
      The biological role of secretoglobin is unknown. The allergenicity of inhaled Fel d 1 can be increased by its binding to the mannose receptor on dendritic cells, thereby initiating the process of internalization and the production of Fel d 1–specific IgE and IgG1.
      • Emara M.
      • Royer P.J.
      • Abbas Z.
      • Sewell H.F.
      • Mohamed G.G.
      • Singh S.
      • et al.
      Recognition of the major cat allergen Fel d 1 through the cysteine-rich domain of the mannose receptor determines its allergenicity.
      Asthmatic children with cat allergy have higher Fel d 1–specific IgE levels compared with those in children with rhinitis,
      • Gronlund H.
      • Adedoyin J.
      • Reininger R.
      • Varga E.M.
      • Zach M.
      • Fredriksson M.
      • et al.
      Higher immunoglobulin E antibody levels to recombinant Fel d 1 in cat-allergic children with asthma compared with rhinoconjunctivitis.
      which suggests that high IgE levels to Fel d 1 could be a marker of increased asthma risk.
      Recently, another secretoglobin has been isolated from rabbits. The molecule, despite a high structural similarity with Fel d 1, does not display IgE cross-reactivity, probably because of low sequence identity. This protein, Ory c 3, is present on rabbit fur and can be detected in settled airborne dust from houses with a pet rabbit.
      • Hilger C.
      • Kler S.
      • Arumugam K.
      • Revets D.
      • Muller C.P.
      • Charpentier C.
      • et al.
      Identification and isolation of a Fel d 1-like molecule as a major rabbit allergen.

       Lipocalins

      More than 50% of the allergens that have been identified from furry animals are lipocalins.
      • Hilger C.
      • Kuehn A.
      • Hentges F.
      Animal lipocalin allergens.
      These allergens are found in dander, saliva, and urine; the particles they are carried on are sticky; and they easily become airborne, disperse effectively, and are widely present in indoor environments.
      • Virtanen T.
      • Kinnunen T.
      • Rytkonen-Nissinen M.
      Mammalian lipocalin allergens—insights into their enigmatic allergenicity.
      In general, they share sequence identities of only 20% to 30%, but their tertiary structures are highly similar, and several inhibition studies have shown cross-reactivity between lipocalins in conditions of excess inhibitor.
      • Saarelainen S.
      • Rytkonen-Nissinen M.
      • Rouvinen J.
      • Taivainen A.
      • Auriola S.
      • Kauppinen A.
      • et al.
      Animal-derived lipocalin allergens exhibit immunoglobulin E cross-reactivity.
      • 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.
      • Madhurantakam C.
      • Nilsson O.B.
      • Uchtenhagen H.
      • Konradsen J.
      • Saarne T.
      • Hogbom E.
      • et al.
      Crystal structure of the dog lipocalin allergen Can f 2: implications for cross-reactivity to the cat allergen Fel d 4.
      Some lipocalins display much higher sequence identities (about 60%) and cross-react at low doses in a patient-dependent manner. These include Can f 6, Equ c 1, and Fel d 4,
      • Nilsson O.B.
      • Binnmyr J.
      • Zoltowska A.
      • Saarne T.
      • van Hage M.
      • Gronlund H.
      Characterization of the dog lipocalin allergen Can f 6: the role in cross-reactivity with cat and horse.
      • 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.
      as well as Can f 1 and human tear lipocalin.
      • Saarelainen S.
      • Rytkonen-Nissinen M.
      • Rouvinen J.
      • Taivainen A.
      • Auriola S.
      • Kauppinen A.
      • et al.
      Animal-derived lipocalin allergens exhibit immunoglobulin E cross-reactivity.
      Lipocalins are a group of proteins involved as ligand transport proteins with enzymatic activity, participating in cell homeostasis, or both. Lipocalins do not seem to activate dendritic cells,
      • Parviainen S.
      • Kinnunen T.
      • Rytkonen-Nissinen M.
      • Nieminen A.
      • Liukko A.
      • Virtanen T.
      Mammal-derived respiratory lipocalin allergens do not exhibit dendritic cell-activating capacity.
      and the existence of endogenous human lipocalins could be responsible for the generally low T-cell reactivity to lipocalins.
      • Virtanen T.
      • Kinnunen T.
      • Rytkonen-Nissinen M.
      Mammalian lipocalin allergens—insights into their enigmatic allergenicity.

       Cat lipocalin allergens

      Two lipocalin allergens have been identified from cats: Fel d 4
      • Smith W.
      • Butler A.J.
      • Hazell L.A.
      • Chapman M.D.
      • Pomes A.
      • Nickels D.G.
      • et al.
      Fel d 4, a cat lipocalin allergen.
      and Fel d 7.
      • Smith W.
      • O'Neil S.E.
      • Hales B.J.
      • Chai T.L.
      • Hazell L.A.
      • Tanyaratsrisakul S.
      • et al.
      Two newly identified cat allergens: the von Ebner gland protein Fel d 7 and the latherin-like protein Fel d 8.
      Fel d 4 is found primarily in cat saliva and cross-reacts with lipocalin allergens from other animals, mainly Can f 6 and Equ c 1.
      • Nordlund B.
      • Konradsen J.R.
      • Kull I.
      • Borres M.P.
      • Onell A.
      • Hedlin G.
      • et al.
      IgE antibodies to animal-derived lipocalin, kallikrein and secretoglobin are markers of bronchial inflammation in severe childhood asthma.
      • Nilsson O.B.
      • Binnmyr J.
      • Zoltowska A.
      • Saarne T.
      • van Hage M.
      • Gronlund H.
      Characterization of the dog lipocalin allergen Can f 6: the role in cross-reactivity with cat and horse.
      • 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.
      IgE reactivity to Fel d 4 has been found in up to 63% of cat-sensitized subjects.
      • Smith W.
      • Butler A.J.
      • Hazell L.A.
      • Chapman M.D.
      • Pomes A.
      • Nickels D.G.
      • et al.
      Fel d 4, a cat lipocalin allergen.
      High levels of IgE antibodies to Fel d 4 have been associated with atopic dermatitis in children with cat allergy.
      • Wisniewski J.A.
      • Agrawal R.
      • Minnicozzi S.
      • Xin W.
      • Patrie J.
      • Heymann P.W.
      • et al.
      Sensitization to food and inhalant allergens in relation to age and wheeze among children with atopic dermatitis.
      Fel d 7 is not yet widely available for IgE testing but has been reported to bind IgE in 38% of all subjects with cat allergy.
      • Smith W.
      • O'Neil S.E.
      • Hales B.J.
      • Chai T.L.
      • Hazell L.A.
      • Tanyaratsrisakul S.
      • et al.
      Two newly identified cat allergens: the von Ebner gland protein Fel d 7 and the latherin-like protein Fel d 8.
      Fel d 7 and Can f 1 share a high sequence identity (62%), and cross-reactivity between these proteins seems probable.

       Dog lipocalin allergens

      Four of 6 currently identified dog allergens, Can f 1, Can f 2,
      • Konieczny A.
      • Morgenstern J.P.
      • Bizinkauskas C.B.
      • Lilley C.H.
      • Brauer A.W.
      • Bond J.F.
      • et al.
      The major dog allergens, Can f 1 and Can f 2, are salivary lipocalin proteins: cloning and immunological characterization of the recombinant forms.
      Can f 4,
      • 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.
      and Can f 6,
      • Nilsson O.B.
      • Binnmyr J.
      • Zoltowska A.
      • Saarne T.
      • van Hage M.
      • Gronlund H.
      Characterization of the dog lipocalin allergen Can f 6: the role in cross-reactivity with cat and horse.
      • 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.
      are lipocalins. Can f 1 is secreted from canine sebaceous glands and is found in dog hair, dander, and saliva. Airborne levels and particle size distribution of Can f 1 are similar to those of cat allergen
      • Custovic A.
      • Green R.
      • Fletcher A.
      • Smith A.
      • Pickering C.A.
      • Chapman M.D.
      • et al.
      Aerodynamic properties of the major dog allergen Can f 1: distribution in homes, concentration, and particle size of allergen in the air.
      ; it becomes airborne with minimal disturbance, remains airborne for a long time, and can be inhaled into the smaller airways more easily than larger particles, such as mite feces or pollen grains, because of the small size of the particles. Can f 1 is detectable in all homes with a dog and in one third of homes without dogs.
      • Nicholas C.
      • Wegienka G.
      • Havstad S.
      • Zoratti E.
      • Ownby D.
      • Johnson C.C.
      Dog characteristics and allergen levels in the home.
      Fifty percent to 90% of patients sensitized to dog have antibodies to Can f 1. Twenty percent to 33% of dog-sensitized subjects have IgE antibodies to Can f 2; however, all reported patients with antibodies specific for Can f 2 also reacted to Can f 1. The structure of the Can f 2 calyx is very similar to that of Equ c 1 from the horse, but no cross-reactivity was detected between these molecules. Can f 2 shows limited, patient-dependent cross-reactivity with Fel d 4, although only 22% of the sequence is identical.
      • Madhurantakam C.
      • Nilsson O.B.
      • Uchtenhagen H.
      • Konradsen J.
      • Saarne T.
      • Hogbom E.
      • et al.
      Crystal structure of the dog lipocalin allergen Can f 2: implications for cross-reactivity to the cat allergen Fel d 4.
      Can f 4 was reported to bind IgE in around 30% of dog-sensitized subjects.
      • 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.
      Can f 6 has a very similar structure to Fel d 4
      • 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.
      ; it cross-reacts with Fel d 4 and Equ c 1. IgE to Can f 6 have been found in 38% of subjects sensitized to dog.
      • Nilsson O.B.
      • Binnmyr J.
      • Zoltowska A.
      • Saarne T.
      • van Hage M.
      • Gronlund H.
      Characterization of the dog lipocalin allergen Can f 6: the role in cross-reactivity with cat and horse.
      In a selected group of patients with combined sensitization to cats and dogs, IgE to Can f 6 was found in 61%.
      • 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.
      These patterns of cross-reactions probably explain in part the frequently observed pattern of cosensitization between dog, cat, and horse.

       Horse lipocalin allergens

      Two lipocalin allergens, Equ c 1 and Equ c 2, have been identified in the horse.
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      • et al.
      Animal-derived lipocalin allergens exhibit immunoglobulin E cross-reactivity.
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      Hydrophobic interaction chromatography for isolation and purification of Equ.cl, the horse major allergen.
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      • David B.
      • Dandeu J.P.
      cDNA cloning and sequencing reveal the major horse allergen Equ c1 to be a glycoprotein member of the lipocalin superfamily.
      • Bulone V.
      • Krogstad-Johnsen T.
      • Smestad-Paulsen B.
      Separation of horse dander allergen proteins by two-dimensional electrophoresis–molecular characterisation and identification of Equ c 2.0101 and Equ c 2.0102 as lipocalin proteins.
      • Lascombe M.B.
      • Gregoire C.
      • Poncet P.
      • Tavares G.A.
      • Rosinski-Chupin I.
      • Rabillon J.
      • et al.
      Crystal structure of the allergen Equ c 1. A dimeric lipocalin with restricted IgE-reactive epitopes.
      Equ c 1, the major horse allergen, is present in horse dander, the sublingual and submaxillary salivary glands, and urine,
      • Liccardi G.
      • Emenius G.
      • Merritt A.S.
      • Salzillo A.
      • D'Amato M.
      • D'Amato G.
      Direct and indirect exposure to horse: risk for sensitization and asthma.
      and up to 76% of patients with horse allergy react to Equ c 1.
      • Saarelainen S.
      • Rytkonen-Nissinen M.
      • Rouvinen J.
      • Taivainen A.
      • Auriola S.
      • Kauppinen A.
      • et al.
      Animal-derived lipocalin allergens exhibit immunoglobulin E cross-reactivity.
      There is a close structural relationship between Equ c 1 and both Can f 6 and Fel d 4. Among 100 dog-sensitized subjects, Equ c 1 was more frequently recognized than Can f 2, Can f 3, and Can f 6.
      • Nilsson O.B.
      • Binnmyr J.
      • Zoltowska A.
      • Saarne T.
      • van Hage M.
      • Gronlund H.
      Characterization of the dog lipocalin allergen Can f 6: the role in cross-reactivity with cat and horse.
      Sensitization to Equ c 1 has been associated with severe childhood asthma.
      • Konradsen J.R.
      • Nordlund B.
      • Onell A.
      • Borres M.P.
      • Gronlund H.
      • Hedlin G.
      Severe childhood asthma and allergy to furry animals: refined assessment using molecular-based allergy diagnostics.
      The role of Equ c 2 in horse allergy remains to be explored.

      Kallikrein

      Can f 5 is similar to prostatic kallikrein. Antibodies to this allergen have been found in up to 70% of patients with dog allergy, and 38% of these patients did not have antibodies to Can f 1, Can f 2, or Can f 3.
      • Mattsson L.
      • Lundgren T.
      • Everberg H.
      • Larsson H.
      • Lidholm J.
      Prostatic kallikrein: a new major dog allergen.
      Can f 5 is detected in the urine of male animals. No patterns of 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,
      • Weidinger S.
      • Mayerhofer A.
      • Raemsch R.
      • Ring J.
      • Kohn F.M.
      Prostate-specific antigen as allergen in human seminal plasma allergy.
      which suggests that sensitization to Can f 5 could be relevant to seminal fluid allergy.

      Albumins and cross-reactivity of certain cat allergens and related clinical syndromes

      The serum albumins from furry animals are Fel d 2, Can f 3, and Equ c 3 from cat, dog, and horse, respectively. Albumins are minor allergens; around 15% to 35% of patients with cat and dog allergy are sensitized to Fel d 2 and Can f 3, and around 15% to 20% of patients with horse allergy appear to be sensitized to Equ c 3.
      • Spitzauer S.
      • Pandjaitan B.
      • Soregi G.
      • Muhl S.
      • Ebner C.
      • Kraft D.
      • et al.
      IgE cross-reactivities against albumins in patients allergic to animals.
      • van Ree R.
      • van Leeuwen W.A.
      • Bulder I.
      • Bond J.
      • Aalberse R.C.
      Purified natural and recombinant Fel d 1 and cat albumin in in vitro diagnostics for cat allergy.
      • Nilsson O.B.
      • Binnmyr J.
      • Zoltowska A.
      • Saarne T.
      • van Hage M.
      • Gronlund H.
      Characterization of the dog lipocalin allergen Can f 6: the role in cross-reactivity with cat and horse.
      • Spitzauer S.
      • Schweiger C.
      • Sperr W.R.
      • Pandjaitan B.
      • Valent P.
      • Muhl S.
      • et al.
      Molecular characterization of dog albumin as a cross-reactive allergen.
      High levels of IgE antibodies to Fel d 2 have been associated with atopic dermatitis in children with cat allergy.
      • Wisniewski J.A.
      • Agrawal R.
      • Minnicozzi S.
      • Xin W.
      • Patrie J.
      • Heymann P.W.
      • et al.
      Sensitization to food and inhalant allergens in relation to age and wheeze among children with atopic dermatitis.
      In patients with pork-cat syndrome, sensitization to cat was found in patients presenting with food-related or idiopathic urticarial or anaphylactic symptoms.
      • Commins S.P.
      • Satinover S.M.
      • Hosen J.
      • Mozena J.
      • Borish L.
      • Lewis B.D.
      • et al.
      Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose.
      • 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.
      Although most of these patients report reactions to pork, a small number, 10% to 20%, report reactions to beef as well; no cases with reactions to cow's milk have been reported. First there were reports of patients presenting with rapid-onset reactions to eating pork who were also sensitized to cat by using serum assays.
      • 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.
      • Sabbah A.
      • Lauret M.G.
      • Chene J.
      • Boutet S.
      • Drouet M.
      • Drouet M.
      • Sabbah A.
      • Le Sellin J.
      • Bonneau J.C.
      • Gay G.
      • Dubois-Gosnet C.
      Second were reports of patients with urticaria or anaphylaxis developing 3 to 6 hours after eating beef, pork, or lamb.
      • Commins S.P.
      • Satinover S.M.
      • Hosen J.
      • Mozena J.
      • Borish L.
      • Lewis B.D.
      • et al.
      Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose.
      • Morisset M.
      • Richard C.
      • Astier C.
      • Jacquenet S.
      • Croizier A.
      • Beaudouin E.
      • et al.
      Anaphylaxis to pork kidney is related to IgE antibodies specific for galactose-alpha-1,3-galactose.
      • Van Nunen S.A.
      • O'Connor K.S.
      • Clarke L.R.
      • Boyle R.X.
      • Fernando S.L.
      An association between tick bite reactions and red meat allergy in humans.
      Detailed investigation of these groups of patients demonstrated that the allergens involved were cat albumin in the first case and the oligosaccharide epitope on cat IgA (Fel d 5w) in the second.
      • 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.
      • Gronlund H.
      • Adedoyin J.
      • Commins S.P.
      • Platts-Mills T.A.
      • van Hage M.
      The carbohydrate galactose-alpha-1,3-galactose is a major IgE-binding epitope on cat IgA.
      • Hamsten C.
      • Tran T.A.
      • Starkhammar M.
      • Brauner A.
      • Commins S.P.
      • Platts-Mills T.A.
      • et al.
      Red meat allergy in Sweden: association with tick sensitization and B-negative blood groups.
      In patients with pork-cat syndrome, sensitization is thought to be through exposure to a cat, but in the second case bites of several species of ticks have been implicated.
      • Van Nunen S.A.
      • O'Connor K.S.
      • Clarke L.R.
      • Boyle R.X.
      • Fernando S.L.
      An association between tick bite reactions and red meat allergy in humans.
      • Commins S.P.
      • James H.R.
      • Kelly L.A.
      • Pochan S.L.
      • Workman L.J.
      • Perzanowski M.S.
      • et al.
      The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose.
      • Hamsten C.
      • Starkhammar M.
      • Tran T.A.
      • Johansson M.
      • Bengtsson U.
      • Ahlen G.
      • et al.
      Identification of galactose-alpha-1,3-galactose in the gastrointestinal tract of the tick Ixodes ricinus; possible relationship with red meat allergy.
      The oligosaccharide epitope galactose-α-1,3-galactose (alpha-gal) is present on a variety of proteins from nonprimate mammals (Fig 1). The important observation is that sensitization detected with cat extract can be associated with 2 distinct forms of food allergy, as well as with inhalant allergy. These syndromes can only be identified reliably by measuring IgE antibodies to the specific components of the extract. In addition, it is important to realize that cat extracts made in different ways can have very different compositions (Fig 1). The finding that the primary exposure causing sensitization to alpha-gal is from tick bites is an excellent example of the complexity that can occur between the route of exposure (the skin in this case) and associated symptoms (food allergy). Allergy to gelatin can also present clinically as meat allergy. Gelatin is a protein that is most commonly derived from mammals (cow, horse, or pig) and is prepared by cooking skin or connective tissue. Patients occasionally have IgE to the protein, but in addition, some forms of gelatin also carry alpha-gal.
      • Caponetto P.
      • Fischer J.
      • Biedermann T.
      Gelatin-containing sweets can elicit anaphylaxis in a patient with sensitization to galactose-alpha-1,3-galactose.
      This can present as delayed reactions after eating gelatin-containing sweets or marshmallows.
      Figure thumbnail gr1
      Fig 1IgE responses to different cat components can be induced through different routes of exposure and are associated with either inhalant symptoms or 2 forms of food allergy. *Cat IgA and other cat proteins carrying alpha-gal are present as minor constituents of cat dander extracts but are better represented in epithelial extracts. **Fel d 4 is a lipocalin that cross-reacts with Can f 6 and Equ c 1. ‡The albumins all cross-react, but the reactivity between cat and pork albumin is the most consistent.

      Molecular-based allergen exposure measurements

      Currently, all measurements of exposure to mammalian dander allergens are based on the “major allergen” of each species. Thus levels of Fel d 1, Can f 1, and Mus m 1 (from the mouse) have been extensively measured both in floor dust and airborne samples. In addition, measurements of airborne Equ c 1 have been carried out in barns, but very few data are available on homes. The case for measuring other specific proteins in airborne samples is either to further understand the relationship of specific components to allergic disease or to explain why certain allergens do not appear to be related to rhinitis or asthma.
      • Commins S.P.
      • Kelly L.A.
      • Ronmark E.
      • James H.R.
      • Pochan S.L.
      • Peters E.J.
      • et al.
      Galactose-alpha-1,3-galactose-specific IgE is associated with anaphylaxis but not asthma.
      There are some specific allergens that have not been adequately investigated. Two obvious cat allergens are Fel d 2 (cat serum albumin), which is associated with allergic symptoms on eating pork but might not be an inhalant allergen, and Fel d 4 (a lipocalin), which has an uncertain clinical relevance and has not had its presence in airborne samples addressed.
      • 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.
      • Smith W.
      • Butler A.J.
      • Hazell L.A.
      • Chapman M.D.
      • Pomes A.
      • Nickels D.G.
      • et al.
      Fel d 4, a cat lipocalin allergen.

      Conclusions and recommendations

      Although there is clear evidence for the clinical importance of analyzing cat components in relation to both alpha-gal and pork-cat syndrome, we believe that future studies will clarify the clinical utility of molecular-based allergy diagnostics in the management of other patients sensitized to furry animals. The workshop identified 6 areas for future research related to the specific allergens derived from furry animals that could contribute to understanding and managing relevant allergic disease.
      • I.
        Continued comparison of different techniques to detect or measure IgE antibodies to components: By using both microchip and specific component assays, further studies need to be carried out on cohorts that include patients with exposure to different mammals. A major objective of these studies is to identify whether allergens other than the major allergens are relevant to the prevalence or severity of asthma and allergic disease. In addition, these studies will help to confirm the existing syndromes and search for other unexpected syndromes (Table III).
        Table IIIThe arguments for assessing sensitization and exposure to single (components) allergens
        • I.
          Better specificity of the diagnosis of allergy to individual species
          • A.
            For example, cat-specific (Fel d 1) or dog-specific single allergens (or combinations); goal: species-specific allergens for the diagnosis of furry animal allergy
        • II.
          Identification of component-specific sensitivity related to different allergic syndromes:
          • A.
            Albumins: Fel d 2 and nSus s (swine serum albumin) in patients with pork-cat syndrome; also cross-reacts with Can f 3 and Bos d 6
          • B.
            Cat IgA (Fel d 5w): epitope is the glycosylation alpha-gal, which is associated with delayed anaphylaxis to red meat. IgE to alpha-gal is not associated with rhinitis or asthma.
        • III.
          Identification of specific allergens associated with severity of asthma as judged by symptoms or medication use
        • IV.
          Identification of allergens that are important causes of sensitization but present in small quantities in normal extracts (eg, Fel d 7)
        • V.
          Identification of cross-reactive molecules that are clinically significant (eg, Can f 6 and Fel d 4)
      • II.
        Establishment of criteria for diagnosing food-related syndromes related to cat and/or dog sensitization: In particular, these studies will aim to establish panels of allergens that will consistently distinguish the 3 syndromes associated with cat sensitization (Fig 1).
      • III.
        Measurement of airborne cat, dog, or rodent allergens, other than the major allergens, in homes with or without an animal: Although there are obvious allergens that we need to know more about, such as cat albumin (Fel d 2), Fel d 4, Fel d 7, and alpha-gal, there is also room for further evidence about the established major allergens.
      • IV.
        Investigation of the effects of the community prevalence of pets on quantities of cat or dog allergens found in homes or schools without pets: These studies might need to address both levels of airborne allergen and levels in reservoir dust samples. In addition, it would be important to answer whether allergens other than Fel d 1 or Can f 1 can be “passively” transferred. This might also be an area in which multiplex assays for specific allergen components would make testing possible for a large number of samples.
        • Earle C.D.
        • King E.M.
        • Tsay A.
        • Pittman K.
        • Saric B.
        • Vailes L.
        • et al.
        High-throughput fluorescent multiplex array for indoor allergen exposure assessment.
      • V.
        Multicenter study to compare different techniques for measuring isotype-specific antibodies, focusing on IgG1 and IgG4, as well as IgE: This proposal will require establishing protocols for several different techniques and agreeing on the relevant components to be tested, as well as identifying panels of sera with high-titer antibodies and sera that are negative for the relevant antibodies.
      • VI.
        Further definition of T-cell responses associated with different forms of tolerance to cat or dog allergens: These studies will have to address both specific allergens and selected relevant peptides.
      Questions to be resolved regarding the clinical utility of molecular-based allergy diagnostics in patients with allergy to furry animals
      • In which clinical setting? Patients with severe disease only? In multisensitized patients?
      • Are there allergen components that are more specific than extract-based methods for a diagnosis of clinically relevant allergy?
      • Is multisensitization to panallergens, such as lipocalins and albumins, of clinical relevance?
      • Are some allergenic molecules markers of severe (or mild) disease?
      • Is the number of sensitized allergenic molecules relevant for the clinical presentation of the disease?
      • Could patients who are most likely to respond to immunotherapy be identified by using molecular-based allergy diagnostics?
      • Is development of clinical tolerance associated with sensitization to specific allergenic molecules?

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