Allergy 2001: 56: 813–824 Copyright # Munksgaard 2001 Printed in UK. All rights reserved ISSN 0105-4538

Position paper A revised nomenclature for allergy An EAACI position statement from the EAACI nomenclature task force

This report has been prepared by an EAACI task force representing the five S. G. O. Johansson1, EAACI Sections and the EAACI Executive Committee composed of specialists J. O’B Hourihane2, J. Bousquet3, that reflect the broad opinion on allergy expressed by various clinical and basic C. Bruijnzeel-Koomen4, S. Dreborg5, specialties dealing with allergy. The aim of this report is to propose a revised T. Haahtela6, M. L. Kowalski7, nomenclature for allergic and related reactions that can be used independently of N. Mygind8, J. Ring9, target organ or patient age group. The nomenclature is based on the present P. van Cauwenberge10, knowledge of the mechanisms which initiate and mediate allergic reactions. M. van Hage-Hamsten1, However, the intention has not been to revise the nomenclature of nonallergic B. Wu¨thrich11 . 1Department of Medicine, Unit of Clinical and Allergy, Karolinska Hospital, Stockholm, Sweden; 2Allergy and Inflammation Sciences Division, University of Southampton, Southampton, UK; 3Service des Maladies Respiratoires, Hoˆpital Arnaud de Villeneuve, Montpellier, France; 4Department of , State University Hospital, Utrecht, The Netherlands; 5Voksentoppen, Oslo, Norway; 6Division of Allergy, Skin and Allergy Hospital, Helsinki University Central Hospital, Helsinki, Finland; 7Department of Clinical Immunology and Allergy, Faculty of Medicine, Ło´dz, Poland; 8Department of Respiratory Diseases, University Hospital of Aarhus, Aarhus, Denmark; 9Klinik und Poliklinik Dermatologie/ Allergologie, Technische Unviersita¨tMu¨nchen, Munich, Germany; 10Department of Oto-Rhino- Laryngology, University Hospital, Ghent, Belgium; 11Department of Dermatology, Allergy Unit, University Hospital, Zurich, Switzerland

Prof. S. G. O. Johansson Department of Medicine Unit of Clinical Immunology and Allergy Karolinska Hospital, L2:03 SE-171 76 Stockholm Sweden

Accepted for publication 26 June 2001

Introduction and treatments have had a great impact on the provision Allergic reactions can express themselves in many of medical care to allergic patients. Doctors in all different organs and in any age group. Allergic diseases community- or hospital-based specialties are faced with have a significant effect on the emotional and social patients who have, or suspect they have, an allergic health of patients and their families. The high prevalence disorder underlying their medical presentations. To of allergic diseases and improved diagnostic procedures avoid being misunderstood by patients and colleagues,

813 Johansson et al. physicians should adopt very clear designations of the allergic reactions introduced by Gell & Coombs in allergic disorders and adhere to this nomenclature in 1968 (25) (the familiar types I–IV ) has their professional and public communications. been useful. However, too much emphasis has been In the early 1920s, Coca & Cooke (20) introduced the given to the supposedly distinct and mutually exclusive term ‘‘atopy’’ to designate some phenomena of hyper- roles of antibodies and immunocompetent cells. This sensitiveness in man. They considered ‘‘atopy’’ to be all dichotomy is not consistent with our present knowledge of the following: of the dynamic immune response, as orchestrated by dendritic cells and T helper cells, and mediated by 1) hereditary effector cells of several types, antibodies, chemokines, 2) limited to a small group of patients and cytokines. The last two groups have been mostly 3) different from ‘‘’’ in referring to a lack identified since Gell & Coombs produced their classi- of protection, and from ‘‘allergy’’ meaning an fication of allergic reactions. Therefore, a revised altered reactivity nomenclature is much needed. 4) ‘‘qualitatively an abnormal response’’ occurring In 1968, the WHO International Reference Center for only in particular individuals (atopics) Immunoglobulins decided that enough critical data were 5) clinically characterized by hay fever and bronchial available to announce the presence of a fifth immuno- globulin isotype, IgE (12). The classical ‘‘reaginic 6) associated with immediate-type (wheal-and-flare) activity’’ could be linked to IgE (41, 82). Whether skin reactions. other types of tissue-sensitizing activity present in At this time, they were evidently unaware of the work animals, such as short-term sensitizing antibody (67), that Prausnitz & Ku¨stner (73) published in 1921 about occur also in man is still not settled. the passive transfer of immediate hypersensitivity in In the mid-1970s, classical, IgE-mediated allergic man by serum. In their original definition of ‘‘atopy’’, reactions to inhalant were termed by Pepys Coca & Cooke included only allergic and ‘‘atopic allergy’’ (69). The term ‘‘atopic’’ is today used bronchial asthma. Wise & Sulzberger proposed the synonymously with ‘‘IgE-mediated’’ by most doctors term ‘‘atopic ’’ to denote ‘‘confusing types of and scientists involved in allergy. However, others, localised and generalised lichenification, generalised especially pediatricians and dermatologists, also con- neurodermatitis or manifestation of atopy’’ (93). sider ‘‘atopy’’ a constitutional trait. They find ‘‘atopy’’ Coca and Grove investigated atopy further (21), to be a clinically useful term since IgE-mediated allergy throwing light on certain important aspects but reaching is common in children and young adults, and often runs some curious conclusions (70). They reported the in families. presence of heat-labile ‘‘bodies’’, which they called Typical allergic symptoms include asthma, rhino- ‘‘reagins’’ by virtue of their similarity in this respect to conjunctivitis, gastrointestinal symptoms, and charac- the heat-labile reagins (complement) of the Wassermann teristic skin lesions, generally referred to as ‘‘atopic reaction. They concluded that it is ‘‘advisable for the diseases’’ (for the new nomenclature of some of these present to avoid the term ‘antibodies’ ’’, because there diseases, see below). Typically, an atopic patient was ‘‘no evidence that these bodies appeared as the develops a spectrum of ‘‘atopic diseases’’ with age, result of immunological stimulation’’. sometimes referred to as ‘‘the atopic march’’. During the In the following decades, many population studies, first years, gastrointestinal and eczematous skin symp- particularly those by Schwartz (81) and by Schnyder toms, often caused by food allergens, predominate. (80), and follow-up studies of children first seen with Asthma and rhinitis to inhalant allergens develop later. infantile eczema (60, 83) demonstrated the classic atopic Atopy is inherited. For example, the risk of a child diseases and the close association of asthma, hay fever, developing an IgE-mediated allergy is 40–60% if both perennial rhinitis, , and food parents are atopic. This risk used to be 5–10% if neither in such infants. It was later shown that serum IgE levels parent was atopic (49), but the percentage is increasing. (42) are increased, on average, in ‘‘atopic dermatitis’’ In ‘‘highly atopic’’ children, IgE sensitization and atopic (46, 64), and that this serum IgE increase is related to the diseases develop early in life. Associations between increase of IgE specific against several environmental several gene loci and asthma, high IgE levels, and other allergens (35, 96, 107). However, it was also observed conditions have been reported (10, 52). However, so far, that in moderate or mild forms, and even in a few cases no specific genetic markers for atopy have been of severe ‘‘atopic dermatitis’’ without coexistent asthma identified. The most likely explanation is that atopy is or rhinitis, the IgE values may lie in the normal range a polygenic disorder. (79, 106). Some individuals that cannot be described as atopic The field of allergy has developed rapidly during the escape sensitization to common allergens in childhood last 50 years. Knowledge about immunologic mechan- and adolescence, but develop IgE-mediated allergy later isms and pharmacologic effects has improved our in life when exposed to high doses of , often understanding (61). The classical nomenclature for together with some adjuvant, such as tobacco smoke

814 Allergy nomenclature

(66). This situation is illustrated by many cases of immune protection against bacterial and viral infec- occupational allergy (74), as to laboratory animals such tions, and Th2 cells protect the body from helminth as mice (90), enzymes such as a-amylase (11, 101), infestations and perhaps also maintain pregnancy (37). Bacillus subtilis protease (95), and houseplants such as It should be remembered that cells and mediators of the Ficus benjamina (7, 78). There are some indications that, immune system are also found in biopsies of inflamma- in addition to the IgE trait, atopy includes some kind of tory sites, as immunologic reactions are of course target organ sensitivity, as shown, for example, by the involved in mediating and initiating inflammatory as adverse effect of exercise in some patients, the finding of well as allergic responses. Inflammatory reactions, nonallergen-specific bronchial hyperreactivity in especially the Th2-driven ones, are also involved in the patients with allergic asthma, and the disturbed barrier immune defense, as against helminths, and function of atopic skin. can be stimulated by bacterial and viral infections. Without a genetic marker, the atopic individual Various types of inflammatory reactions, especially cannot be identified before developing allergen-specific eosinophilic inflammation, are of fundamental impor- IgE sensitization. However, it is not widely appreciated tance in allergic reactions. Thus, the presence in the by nonspecialists in allergic disease that the presence of tissue or circulation of increased numbers of eosino- IgE antibodies does not necessarily mean clinically phils, IL-5, or even polyclonal IgE without significant active disease, although such antibodies represent a risk antibody activity does not necessarily indicate an in the appropriate circumstances; for example, allergen allergic reaction. On the other hand, the presence of exposure and a concomitant promoter such as infection IgE antibodies to classical allergens is always the sign of or exercise. In addition, the presence of IgE antibodies a potentially significant allergic reaction. may have a predictive value. Several groups have found The same cytokines and interleukins of the Th2 system that even without symptoms, the presence of IgE are involved in both the beneficial and harmful effects. antibodies to hen’s egg white in infants predicts the In addition, various substances can act as adjuvants and development of atopic symptoms before 7–10 years of polyclonal IgE stimulants. One example is the enter- age (31, 62). otoxins of Staphylococcus aureus, sometimes referred to In a typical case of atopy, the dose of inhalant allergen as ‘‘superantigens’’, that seem to be capable of necessary to induce sensitization and symptoms is stimulating eosinophilic inflammation and a polyclonal extremely low. Estimates based on counts IgE response in ‘‘atopic dermatitis’’ (53) and also in indicate an annual dose of a few micrograms (57), and typically nonallergic nasal polyps (8). Other examples sensitization to cat allergen Fel d 1 can occur (88) at are cigarette smoke (26), cytomegalovirus (CMV) levels around 25 ng/g of dust. Levels of animal allergens infection (63), and graft versus host disease (GVHD) in the air of public buildings such as schools have been (76). Similarly, the microscopic and immunologic found to be in the ng/m3 range, i.e., about the same level appearance of the bronchial mucosa is similar in the of exposure as to . biopsies of both classical allergic asthma (previously IgE-mediated mechanisms are often involved in also referred to as extrinsic or exogenous asthma) and allergies to insect venom (58, 59), usually in the same nonallergic asthma (previously referred to as intrinsic or frequency as in individuals that cannot be described as endogenous asthma) (16, 38). The same is true also of atopic, and to certain drugs (87). An IgE involvement, allergic and nonallergic rhinitis (6) and different kinds of with markedly raised serum levels of IgE and the eczema/dermatitis (5, 51, 79, 89). presence of specific IgE antibodies, has been detected in In the following paragraphs, we propose that helminth infestations (36, 43, 77), and it is thought that ‘‘hypersensitivity’’ be used as an umbrella term (see the beneficial function of IgE is related to our defense below), and that the term ‘‘allergy’’ be reserved for against helminth parasites. However, more studies are clinical reactions in which an immunologic mechanism is needed to explain the entire possible range of beneficial proven or strongly implicated. The term ‘‘atopy’’, functions of IgE. discussed above, has also been revised. We propose The IgE antibody response may represent a remark- that the term ‘‘atopy’’ be used to describe a familial or ably large proportion of the IgE pool; in some cases of personal tendency to develop allergen-specific IgE on , as much as 50–60% of IgE in a serum exposure to environmental allergens, and to suffer sample can be recovered as antibody to the pollen typical allergic symptoms. allergen (44). However, in other cases, e.g., IgE- mediated ‘‘atopic’’ dermatitis, the polyclonal produc- tion is considerable, and the IgE antibody can represent as little as 2% or less of the total IgE production (99, 1 Hypersensitivity 106). There has been a tendency during the last couple of According to the currently favored hypothesis of how decades to use the word ‘‘allergy’’ to describe not only the immune system is controlled, there is a balance allergy as defined below but all kinds of unexpected between Th1 and Th2 helper cells. Th1 cells promote reactions in the skin and mucosal surfaces. These include 815 Johansson et al.

Figure 1. all kinds of controversial adverse reactions to food and tivity’’ and ‘‘multiple chemical sensitivity’’ (27), as well food additives (17, 65), side-effects to drugs, psycholo- as reactions attributed to amalgam in tooth fillings (55) gical reactions blamed on environmental factors and electromagnetic waves, should not be called (‘‘allergy to electricity’’) (54), behavioral disorders, hypersensitivity. and others. We propose to use the term nonallergic hypersensitiv- We propose that the term hypersensitivity be used as ity when immunologic mechanisms cannot be proven, as the ‘‘umbrella’’ term to cover such reactions (Fig. 1), in hypersensitivity to (84). The term ‘‘pseudo- and that its definition should be as follows: allergy’’, introduced many years ago (22) and still occasionally used in some European countries, should Hypersensitivity causes objectively reproducible symptoms or be abandoned. signs, initiated by exposure to a defined stimulus at a dose The term ‘‘nonallergic hypersensitivity’’ embraces tolerated by normal subjects. many different disorders. However, it is not within the remit of this group to classify these entities. This definition does not accommodate classical responses to infection, , or toxic reac- tions. It is important that the hypersensitivity reaction 2 Atopy be reproducible in the sense that there is reasonable evidence from history, examination, or investigation of We propose that the definition of atopy should be as follows: a link between the symptoms and the environmental factors to which the patients attribute their symptoms. Atopy is a personal or familial tendency to produce IgE In this context, ‘‘reproducible’’ does not mean, for antibodies in response to low doses of allergens, usually example, that a food provocation test of a patient in the proteins, and to develop typical symptoms such as asthma, doctor’s office must be positive at any time. The old rhinoconjunctivitis, or eczema/dermatitis. term ‘‘idiosyncrasy’’ is no longer needed. Furthermore, hypersensitivity must be distinguished from hyper- We propose that the terms atopy and atopic be reactivity, which is an exaggerated normal response to a reserved to describe this clinical trait and predisposition, stimulus. and not be used to describe diseases. The first As a consequence of this stringent definition of manifestations of atopy in a child are often ‘‘allergic’’ hypersensitivity, many entities within the field of symptoms, such as diarrhea, wheezing, and skin rashes, ‘‘environmental medicine’’, such as ‘‘total drug sensi- and only later can the responsible IgE antibody be

816 Allergy nomenclature

isotype. The serum concentration is often high enough to allow detection of the antibody, historically termed ‘‘precipitin’’, as a precipitate in gel when allowed to react with the corresponding antigen. There is a relation between degree of exposure and antibody concentration. Similarly, the presence in serum of IgA, IgM, and especially IgG antibodies, as a result of exposure but Figure 2. without any obvious pathogenic role, has also been reported to food antigens, such as those of cow’s milk detected. The term atopy should be used with caution and hen’s egg (39). In the same way, antigen-specific until IgE sensitization can be documented. Allergic lymphocytes can often be found by using the antigen- symptoms in a typical atopic individual may be referred specific lymphocyte stimulation test (50, 71). to as atopic, as in atopic asthma. However, in general, Some individuals with high IgG antibody levels as a IgE-mediated asthma should not be called ‘‘atopic result of chronic inhalation of large amounts of certain asthma’’, and the same applies to the other clinical protein-containing material, such as Actinomyces and manifestations. Nor can a positive skin prick test or the molds (farmer’s lung) and bird droppings (pigeon presence of IgE antibody per se be a criterion for atopy. breeder’s disease), may exhibit symptoms from the Such patients should be referred to as ‘‘skin prick test airways, often referred to as ‘‘alveolitis’’, upon exposure. positive’’ and ‘‘IgE sensitized’’, respectively. We propose that the term allergic alveolitis be used for such diseases. Allergy can also be cell-mediated, as in allergic , in which immunologically sensitized 3.1 Allergy lymphocytes play a major role. Similar immunologic Allergy is a hypersensitivity reaction initiated by mechanisms seem to be important in celiac disease (29) immunologic mechanisms. and in non-IgE-associated ‘‘atopic dermatitis/eczema’’ Allergy can be antibody- or cell-mediated. In most (see below). Therefore, we propose that non-IgE- patients, the antibody typically responsible for an mediated allergic reactions be subdivided into those in allergic reaction belongs to the IgE isotype and these which the reaction is initiated predominantly by patients may be said to suffer from IgE-mediated allergy mechanisms associated with allergen-specific antibodies (Fig. 2). It must be noted that not all IgE-associated other than IgE, and those in which a cellular response is allergic reactions occur in atopic subjects; see the disease predominant. classifications below. In non-IgE-mediated allergy, the antibody may belong to the IgG isotype, as in anaphylaxis due to immune complexes containing dextran (32) and the classical, 3.2 Allergens now rare, previously referred to as a type Antigens stimulating hypersensitivity mediated by an III reaction (25), whereas both IgE and IgG antibodies immunologic mechanism (defined above as ‘‘allergy’’) are found in allergic bronchopulmonary aspergillosis are referred to as allergens. Most allergens reacting with (ABPA) (68). IgE and IgG antibodies are proteins, often with Inhalation of large amounts of protein, as in mold, carbohydrate side chains (1, 56), but in certain grain dust, etc., stimulates the immune system to circumstances pure carbohydrates have been considered produce antibodies mainly of the IgG, IgA, and IgM to be allergens (2, 24). In rare instances, a low- molecular-weight chemical, such as isocyanates and anhydrides acting as haptens, is still referred to as an allergen for IgE antibodies (47). Certain drugs are recognized by T cells in a MHC-restricted way. In the case of allergic contact dermatitis, the classical allergens are low-molecular-weight chemicals, such as chromium, nickel, and formaldehyde, which act as haptens and react with T cells.

Nomenclature of allergic diseases Classifications of the common allergic diseases are Figure 3. presented below. We have used a similar scheme to

817 Johansson et al.

Figure 4. present each disease to encourage uniform description Figure 5. of these related diseases, often found together in a particular individual. to eye-drops has been reported (40). It is not clear at the moment whether other non-IgE-mediated forms of can be defined. 4 Rhinitis Persistent allergic conjunctivitis is divided into subgroups that have distinct morphologic appearances The symptoms resulting from an immunologically (4). Both ‘‘vernal keratoconjunctivitis’’ and ‘‘atopic mediated hypersensitivity reaction in the nose should keratoconjunctivitis’’ are in part explained by IgE- be called allergic rhinitis (Fig. 3). If we wish to highlight mediated reactions and may be classified as subgroups the role of IgE, the term IgE-mediated rhinitis or of IgE-mediated conjunctivitis (Fig. 4). IgE-mediated allergic rhinitis should be used. It is not ‘‘Atopic keratoconjunctivitis’’ is the ocular manifes- clear whether non-IgE-mediated forms of allergic tation of ‘‘atopic dermatitis’’, and the term ‘‘atopic’’ is rhinitis can be defined further (97). It might be useful used here in a similar way as in ‘‘atopic dermatitis’’. All to distinguish between subgroups of IgE-mediated other forms of conjunctivitis should be listed under rhinitis depending on the duration of the symptoms. nonallergic conjunctivitis and named according to the The WHO document ‘‘Allergic Rhinitis and its Impact recommendations of specialists in the field. on Asthma’’ (ARIA) recommends that the old terms ‘‘seasonal’’ and ‘‘perennial’’, which are not useful where climatic seasons are perennial, should be replaced by 6 Asthma the terms intermittent allergic rhinitis and persistent allergic rhinitis, respectively. However, in describing Allergic mechanisms are of importance in about 80% of symptoms during the pollen season in a case of pollen- childhood asthma (3, 28) and in about 40–50% of the induced allergic rhinitis, the old term ‘‘seasonal allergic adult form (48). We propose to use the term allergic rhinitis’’ is valid. asthma (Fig. 5) as the basic term for asthma mediated All other forms of rhinitis should be subsumed under by immunologic mechanisms. When there are indica- nonallergic rhinitis, which is sometimes referred to as tions of IgE-mediated mechanisms, the term should be ‘‘hyperreflectory rhinopathy’’, including such entities as IgE-mediated asthma. IgE antibodies can initiate both aspirin hypersensitivity, infectious reactions, side-effects an immediate and a late asthmatic reaction. However, of systemic drugs, and abuse of topical decongestants. It as in other allergic disorders, T-cell-associated reactions is not the aim of the present task force to consider the seem to be of importance in the late and delayed details of the nomenclature for such disorders outside the reactions. Today, it is not still clear whether other forms field of allergy (Fig. 3). of allergic asthma can be defined. Other nonimmuno- logic types of asthma should be called nonallergic asthma. The old terms, ‘‘extrinsic’’, ‘‘intrinsic’’, ‘‘exo- genous’’, and ‘‘endogenous’’ should no longer be used 5 Conjunctivitis to distinguish between the allergic and nonallergic Conjunctivitis often accompanies rhinitis. It is therefore subgroups of asthma. logical to use a nomenclature for conjunctivitis that is structured in the same way as for rhinitis. IgE-mediated conjunctivitis (Fig. 4), a subgroup of allergic conjuncti- 7 Skin diseases vitis, may be divided into intermittent and persistent Unlike the respiratory tract, where the symptomatology allergic conjunctivitis as in the subdivision of allergic of allergic diseases is rather uniform, a variety of rhinitis. Whenever necessary, the term allergic con- different diseases with distinctly different pathogenic junctivitis may be combined with allergic rhinitis, as in mechanisms is manifested in the skin. Here we will allergic rhinoconjunctivitis. Conjunctival contact allergy consider only the most common allergic skin diseases,

818 Allergy nomenclature namely, urticaria, angioedema, allergic contact eczema/ dermatitis, atopic eczema/dermatitis, and exanthema- tous drug eruptions. Allergic diseases manifesting as purpura or vasculitis, as well as allergic granulomatous skin reactions, will not be discussed. Since urticaria and angioedema often represent the first symptoms within the spectrum of ‘‘anaphylaxis’’, they will be discussed there. The terms eczema and dermatitis are used inter- changeably in the literature, although some authors prefer to call the more acute cases dermatitis, whereas the term eczema is applied to the more chronic forms. Figure 6. We have not distinguished between eczema and dermatitis in the present discussion. In the current literature, eczema/dermatitis is sub- It has been suggested that early signs and symptoms divided into contact eczema/dermatitis (irritant or of the skin can be seen in individuals predisposed to allergic), atopic eczema/dermatitis, nummular eczema/ ‘‘atopic diseases’’ long before the disease itself becomes dermatitis, and seborrheic eczema/dermatitis. The manifest (the so-called stigmata or symptoms of minor pathogenesis of nummular and seborrheic eczema/ criteria) (30, 102). Thus, in current dermatology, dermatitis is largely unknown. These and other ‘‘atopy’’ is a clinical diagnosis, and a patient can be nonallergic skin disorders will not be further discussed. called ‘‘atopic’’ without knowledge of skin prick tests or the presence of IgE antibodies in his serum. Since the aim of this task force is to harmonize the 7.1 The atopic eczema/dermatitis syndrome (AEDS) allergy-relevant definitions in the various fields, we need Reaching a consensus on the definitions of the a new term for ‘‘atopic eczema/dermatitis’’. In some dermatologic aspects of allergy has been the most countries (France, Germany, Switzerland, and Austria), difficult issue for the nomenclature task force. The the term ‘‘neurodermatitis’’, or ‘‘neurodermitis’’, has current term for eczematous hypersensitivity reactions been used, mainly by lay people. Other synonyms, such in the skin, analogous to rhinitis in the nose and asthma as ‘‘diathetic prurigo’’ (15), ‘‘prurigo Besnier’’ (13), in the lung, is ‘‘atopic eczema/dermatitis’’. The term ‘‘endogenous eczema’’, ‘‘exudative eczematoid’’, ‘‘atopic dermatitis’’ consists of two words to allow ‘‘asthma-eczema’’ and many others, are not suitable definition of one distinct form of eczema/dermatitis (see for international use. A compromise would be to use the above). In this designation, the modifier ‘‘atopic’’ has a term ‘‘constitutional eczema’’ proposed by Wu¨thrich different meaning (92, 105) than atopy as defined above. (98), since it reflects the familial occurrence and the However, as Rajka has stated (75), ‘‘This . . . is an presence of the characteristic signs and symptoms unfortunate choice of term, even when it is considered independent of IgE. However, during a transition in the light of the definition [of ‘‘atopy’’] . . . by Coca in period, it may be useful to highlight the well-accepted 1953 (19). The flaw lies in the conclusion from recent view that ‘‘atopic dermatitis’’ is not one, single disease experience that the disease can no longer be considered but rather an aggregation of several diseases with a typical atopic disease.’’ However, it is even more certain clinical characteristics in common (94). confusing that one of the four major classical criteria We propose to use the term atopic eczema/dermatitis (30) for the diagnosis of ‘‘atopic eczema/dermatitis’’ is syndrome to describe what is currently referred to as atopy, as defined above. Thus, it is possible to select ‘‘atopic eczema/dermatitis’’. patients with ‘‘atopic eczema/dermatitis’’ in whom there is no evidence of IgE-associated mechanisms (79, 105). This internal contradiction and inconsistency must be addressed in the near future, however entrenched and familiar the current terminology may be. To describe ‘‘atopic eczema/dermatitis’’ as ‘‘extrinsic’’/‘‘intrinsic’’ in analogy with the superseded characterization of asthma would not be in accordance with the revised nomen- clature that we propose. In addition, antigen-specific T-cell responses (91) and autoallergic phenomena have been described in the IgE-associated subgroup of the disease (86). Such a case would then incorrectly be classified as ‘‘extrinsic’’, a term which is not appropriate for an autoimmune disorder (Fig. 6). Figure 7.

819 Johansson et al.

Allergic AEDS (Fig. 6) would be dominated by the IgE-associated subgroup, i.e., those cases of the present ‘‘atopic dermatitis’’ in which the clinical selection is based on Hanifin & Rajka’s criterion, ‘‘family history of or simultaneous occurrence of symptoms of atopy’’ (75). Since this is the only immunologically well-defined subgroup, one should always, when appropriate, use the term IgE-associated AEDS. Because less is known about the precise role of IgE antibodies initiating the disease than in other allergic diseases, the word ‘‘associated’’ is provisional. Another subgroup seems Figure 8. to include cell-mediated forms (33). It is characterized by positive atopy patch tests to aero- and food allergens or allergen-specific T cells in the peripheral blood or in contact eczema/dermatitis. It is usually an occupational skin biopsies, but in the absence of IgE sensitization. disorder, as when caused by exposure to bovine serum The term allergic, T-cell-associated AEDS might be proteins in butchers, or to flour in bakery workers when appropriate. The term nonallergic AEDS should replace linked to severe AEDS of the hands (34, 103). the term ‘‘intrinsic/cryptogenic variants’’. In the future, all these subgroups may be better defined, as by immunologic characteristics, in a way similar to the classification of bullous skin disorders on microscopic 8 Reactions to food, drugs, and venoms findings. There are situations in which organ-based classification 7.2 Urticaria is not adequate. Certain allergen sources give rise to hypersensitivity reactions that are more difficult to ‘‘Acute urticaria’’ may have a very rapid onset and classify by the proposed system. The main reason might disappearance and is linked to considerable pruritus. We be a different multisystem response pattern when an propose the term allergic urticaria to denote urticaria individual is exposed to very high allergen/antigen mediated by immunologic mechanisms. When the dosages (milligram to gram) via mucosal membranes, as disease is related to IgE-mediated reactions, the term by food and drugs, or by injection (microgram to IgE-mediated urticaria should be used (Fig. 7). ‘‘Chronic milligram), as by Hymenoptera venoms and drugs. urticaria’’ should be referred to as nonallergic urticaria Moreover, individuals with a less obvious tendency to until proven to be mediated by immunologic mechan- mount an IgE antibody response will do this after a isms. Sometimes IgE-mediated urticaria can develop large, often repeated high dose of allergen stimulation. locally after topical contact with the allergen, as on the The clinical reaction covers a wide range of symptoms, hands of a latex-allergic individual wearing latex gloves often starting locally and sometimes developing into a (72, 85) or in a dog-allergic individual licked by a dog. general reaction, i.e., anaphylactic shock. Then the term should be allergic contact urticaria, either Subjects with rhinitis and asthma due to pollen IgE-mediated or non-IgE-mediated, and the correspond- allergy may have symptoms on oral exposure to often ing, nonimmunologic form should be termed nonallergic unstable food allergens, which may show structural contact urticaria. similarities to pollen allergens. There are several examples of this ‘‘’’ (23, 45, 65), 7.3 Contact eczema/dermatitis such as reaction to birch pollen and apple or hazelnuts The term contact eczema/dermatitis describes hypersen- (23, 104) and to mugwort pollen and celeriac or celery sitivity reactions in the skin occurring under special circumstances after close contact with low-molecular- weight chemicals or irritants. When these reactions are mediated by immunologic mechanisms, predominantly cellular (Th1) related, the term should be allergic contact eczema/dermatitis. When there is no immune mechan- ism involved, irritant/toxic contact eczema/dermatitis is the best term. A subgroup of contact eczema/dermatitis, protein contact eczema/dermatitis, is probably an IgE-asso- ciated reaction due to resorption of proteins through damaged skin. It may be referred to as allergic protein contact eczema/dermatitis or IgE-associated protein Figure 9.

820 Allergy nomenclature

Figure 10. Figure 11.

(9, 100). Therefore, these food allergies can present with (58), i.e., several micrograms of major allergens per symptoms in other organ systems that do not justify a sting, an amount similar to the annual dose of inhaled diagnosis of anaphylaxis (see below). pollen allergen. This is probably the reason for almost the same prevalence of atopy among patients with IgE 8.1 sensitization to venom as in the normal population (14). We propose that any venom hypersensitivity reaction We propose that an adverse reaction to food should be called food hypersensitivity (Fig. 8). When immunologic (Fig. 10) mediated by immunologic mechanisms be called allergy, as in bee venom allergy. To highlight the mechanisms have been demonstrated, the appropriate term is food allergy, and, if the role of IgE is highlighted, role of IgE antibody, we may use a term such as IgE-mediated bee venom allergy. A term such as the term is IgE-mediated food allergy. All other nonallergic venom hypersensitivity reactions, previously sometimes referred to as ‘‘food bee should be used to denote other reactions. intolerance’’, should be referred to as nonallergic food hypersensitivity (17, 65). Severe, generalized allergic reactions to food can be classified as anaphylaxis (see below). 9 Anaphylaxis The term ‘‘anaphylaxis’’ is applied in various regions 8.2 Drug allergy and by various physicians to different clinical entities The side-effects of drugs of the type discussed here and immunologic mechanisms. Some doctors confine should be referred to as drug hypersensitivity (Fig. 9). application of the term ‘‘anaphylaxis’’ to reactions in When immunologic mechanisms have been shown, which critical hypotension is evident – ‘‘anaphylactic either antibody or cell mediated, the reactions should be shock’’ – with an IgE-mediated mechanism. Others referred to as drug allergy. By adding the adjective extend its application beyond anaphylactic shock to immediate/late or delayed, we can both describe the include severe, life-threatening attacks of broncho- onset of symptoms and indicate the probable mediating spasm. Still other clinicians use it to describe any mechanisms, IgE and lymphocytes (71), respectively. If generalized or systemic allergic reactions, even if we wish to highlight the role of IgE antibody in a hypotension and severe bronchospasm are absent. We reaction, it may be called IgE-mediated drug allergy. All propose the following broad definition: other reactions should be referred to as nonallergic drug hypersensitivity. Such reactions may have identifiable Anaphylaxis is a severe, life-threatening, generalized or associations, such as G6PD deficiency, or unknown systemic hypersensitivity reaction. mechanisms. A positive intradermal skin test or a weak The reaction usually develops gradually, most often (<3 mm) skin prick test is not an objective or sufficient measure of an immunologic reaction – for example, starting with itching of the gums/throat, the palms, or compare direct mediator release by certain neuropep- the soles, and local urticaria; developing to a multiple tides and basic secretagogues such as compound 48/80 organ reaction often dominated by severe asthma; and (18) – and should not be accepted as the only evidence culminating in hypotension and shock. Hypotension for a possible immunologic mechanism. and severe bronchospasm do not have to be present for a reaction to be classified as anaphylaxis. The term allergic anaphylaxis (Fig. 11) should be 8.3 Insect sting allergy used when an immunologic mechanism can be shown to As with drugs, individuals stung, for example, by a be important, as in an IgG , comple- Hymenoptera insect are exposed to large quantities ment-related, or immune cell-mediated mechanism, or

821 Johansson et al. when the role of IgE is unclear. An anaphylactic Acknowledgments reaction mediated by IgE antibodies, such as peanut- We thank the following colleagues who have kindly acted as active induced food anaphylaxis or bee venom-induced test panels and discussion partners during the development of this anaphylaxis, may be called IgE-mediated anaphylaxis. document: Sergio Bonini, Carlos Cafarelli, Per Djupesland, Philippe All other situations, which are much less common, Eigenmann, Alexander Kapp, Gunnar Lilja, Magnus Lindberg, Luis Garcia Marcos, Per Montan, Hermann Neijens, Lennart Nordvall, should be referred to as nonallergic anaphylaxis. The Arnold Oranje, Harald Renz, Timo Reunala, Frank Riedel, Joanna term ‘‘anaphylactoid’’ should not be used. G. M. Rijntjes, Magnus Wickman, and Sven O¨ hman.

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