1Clinical Manifestation and Classificationof Allergic Diseases

1.1 History

Allergic diseases have been known for centu-ries, and allergic diseases such as asthma, urti-caria and eczema were described in the ancientmedical literature of China, Egypt, and Greece(Table 1.1) [7, 22, 24]. The first allergic individ-ual in world history might have been the Egyp-tian pharaohMenes, who according to the hi-eroglyphs died in the year 2,641 B.C. after awasp sting [1].

The first family history of atopy syndromewith asthma, rhinoconjunctivitis and atopic ec-zema can be found in the Julian-Claudian impe-rial family of Augustus, Claudius, and Britanni-cus [20] (Fig. 1.1). In the middle ages, rose fe-ver with hay-fever-like symptoms was a well-known entity. Richard III of Englandwas allergicagainst strawberries according to Shakespeare.

Table 1.1. Allergic dis-eases in the ancientmedical literature

Year Author Disease

2698 B.C. Huang Ti Noisy breathing2641 B.C. Hieroglyphs Death by wasp sting (Pharaoh Menes)460 B.C. Hippocrates Hypersensitivity against goats cheese25 B.C. A. Celsus Description of asthma120180 Aretaeus of Kapadokia Term asthma600 Aetius of Amida Term eczema865 Rhazes Rose fever in Persia11351204 Moses Maimonides Treatment of asthma1565 L. Botallus Rose fever in Pavia1783 Philipp Phoebus Hay fever (monography)1802 W. Heberden Summer catarrh1819 J. Bostock Self-description of hay fever1837 J.L. Schoenlein Purpura rheumatica1853 J.M. Charcot Crystals in asthma sputum1886 E. van Leyden Crystals in asthma sputum1868 H.H. Salter Different asthma elicitors1872 H.I. Quincke Angioedema1872 Wyman Autumnal catarrh (from ragweed)

The first clinically exact description of hay feverwas given by John Bostock in 1819. C.H. Black-ley was the first to prove pollen as the cause ofhay fever using skin and provocation tests [2].

The term allergy was born on 24 July 1906in issue no. 30, page 1,457 of the Munich Medi-cal Weekly [18], coined by the Viennese pedia-trician Clemens von Pirquet to differentiate be-tween protective and noxious immunity(Fig. 1.2). Von Pirquet understood allergy asthe specifically altered reactivity of the organ-ism. Linguistically, the term should read al-lourgy since the Greek words [ ; s = dif-ferent and 5 R * ; = work combine in thisway. Von Pirquets definition includes not onlyhypersensitivity reactions, but also decreasedimmune reactions; this aspect has been lost to-day.We define allergy as specific immunologi-cal hypersensitivity leading to disease. A new

Chapter 1

Fig. 1.1. Allergies were already known in ancienttimes. The Roman Emperor Augustus suffered fromatopic syndrome (bronze sculpture, around 14 A.D.,British Museum, London)

consensus of the World Allergy Organization(WAO) on terminology in allergy has beenpublished recently [12].

Fig. 1.2.The word aller-gy made its debut inthe medical literatureon 24 July 1906 in an ar-ticle written by Cle-mens von Pirquet, a pe-diatrician practicing inVienna, for the Mn-chener MedizinischeWochenschrift (MunichMedical Weekly)

Mostly, this hypersensitivity is directedagainst exogenous non-infectious agents. Au-toimmune reactions may be included whenthey are induced through exogenous sub-stances (see Chap 5, Sects. 5.2, 5.7, 5.10).

Table 1.2 lists the historical milestones in thedevelopment and understanding of allergy.

The specialty of allergology saw a major ad-vance in the discovery of immunoglobulin E asthe carrier of immediate type hypersensitivity.IgE seems to be the most important immuno-globulin in allergology; at some congresses,one gains the impression that allergists wouldlike to change their names to IgEologists! Weshould remember, however, that allergic dis-eases include many more clinical entities thanIgE-mediated reactions.

1.2 Clinical Manifestation and Definitionof Allergy

In clinical practice, allergy manifests as variousdifferent conditions such as anaphylactic shock,hay fever, allergic conjunctivitis, urticaria, angi-oedema, serum sickness, allergic vasculitis, hy-persensitivity pneumonitis, contact dermatitis,granulomatous reactions, allergic bronchialasthma, as well as the colorful spectrum of food-or drug-induced adverse reactions [8]. The mostimportant definitions are given in Table 1.3.

2 1 Clinical Manifestation and Classification of Allergic Diseases

Table 1.2. Milestones inallergy research Year Author Condition

1873 Ch. Blackley Skin and provocation tests (grass pollen)1877 P. Ehrlich Mast cells1895 J. Jadassohn Patch test1900 S. Solis-Cohen Suprarenal extracts in asthma/hay fever1902 Ch. Richet, P. Portier Anaphylaxis1903 M. Arthus Local anaphylaxis1903 Th. Smith Anaphylaxis against horse serum1905 von Pirquet, B. Schick Serum sickness1906 von Pirquet Allergy1906 A. Wolff-Eisner Hay fever/urticaria correspond to anaphylaxis1910 W. Dunbar Pollen extract and antiserum (pollantin)1910 H. Dale, Laidlaw Histamine1911 L. Noon, J. Freeman Prophylactic inoculation (hyposensitization)1921 C. Prausnitz, F. Kstner Humoral hypersensitivity is transferable1923 A. Coca, R. Cooke Atopy1924 K.K. Shen, C.F. Schmidt Ephedrine (from Ma Huang)1927 Th. Lewis Triple reaction of histamine1928 W. Storm van Leeuwen House dust allergy/climate chamber1928 H. Kmmerer Allergic diathesis1937 Bovet/Staub Antihistamines (Phenergan)1939 H.H. Donally Food allergens in breast milk1940 M. Loveless Blocking antibodies1941 K. Hansen Shock fragment1949 P.L. Hench, E.C. Kendall Cortisone1952 Z. Ovary Passive cutaneous anaphylaxis (PCA)1953 J.F. Riley, G. West Histamine in mast cell granules1954 W. Frankland First placebo-controlled immunotherapy trial1956 W. Gronemeyer, E. Fuchs Bronchial provocation in routine diagnosis1958 F. Dixon Immune complex reaction1960 B.B. Levine, A. de Weck Penicillin allergy (bivalent hapten)1961 J. Pepys Farmers lung1963 R.R.A. Coombs, P. Gell Type IIV classification1964 L. Lichtenstein, A. Osler Histamine release1966 K. Ishizaka Immunoglobulin E1967 S.G.O. Johansson Immunoglobulin E1967 R. Vorhoorst, F. Spieksma House dust mites1967 R. Altounyan Cromoglycate1969 E. Macher, R. Chase Contact allergy kinetics (mouse)1977 B. Halpern Lymphocyte transformation test in allergy1978 P. Kallos Pseudo-allergy1979 B. Samuelsson Leukotrienes1984 H. Metzger IgE receptor1987 T. Mossmann Th1-Th2 concept1988 V. Coffmann Interleukin-41989 H. Behrendt Allergotoxicology1989 D. Kraft, Baldo Recombinant allergens1987 K. Mullis Polymerase chain reaction (PCR)1987 P. Piper Leukotriene antagonists1996 C. Heusser Anti-IgE in therapy

1.2 Clinical Manifestation and Definition of Allergy 3

Table 1.3. Definitions

Sensitivity Normal response to a stimulus

Hypersensitivi-ty

Abnormally strong response toa stimulus

Toxicity Normal harmfulness of a sub-stance

Intoxication Reaction to normal pharmaco-logical toxicity

Sensitization Development of increased sensi-tivity after repeated contact

Allergy Immunologically mediated hy-persensitivity leading to disease

Idiosyncrasy Non-immunological hypersensi-tivity without relation to thepharmacological toxicity

Intolerance Hypersensitivity in the sense ofpharmacological toxicity

Pseudo-allergy Non-immunological hypersensi-tivity with clinical symptomsmimicking allergic reactions

Table 1.4. Clinical manifestations of allergic diseases in various organs (examples)

Organ Symptomsa Differential diagnosis

Cardiovascular Anaphylaxis, vasculitis Other cases of shock, vasovagal reaction, vasculardiseases

Lung Bronchial asthma, allergic bronchi-tis, hypersensitivity, pneumonitis

Bronchitis, chronic obstructive pulmonary dis-ease, irritative toxic asthma, pneumonia

Upper airways Rhinitis, sinusitis, pharyngitis,laryngeal edema, laryngitis

Vasomotor rhinitis, infection

Eye Conjunctivitis, atopic keratocon-junctivitis, blepharitis, lid edema

Irritation, infectious conjunctivitis rosacea, psori-asis, seborrheic dermatitis, Melkersson-Rosenthalsyndrome

Ear Otitis externa, serous otitis media?tinnitus? vertigo?

Psoriasis, infection, microcirculatory disturbance

Blood Hemolytic anemia, thrombocytope-nia, agranulocytosis

Hematologic disease, toxic reactions

CNS Fever Infectious diseases

(Cramps) Neurological diseases

(Migraine?)

Skin Urticaria, angioedema Hereditary angioneurotic edema

Vasculitis Non-inflammatory purpura

Contact dermatitis and atopiceczema

Other forms of dermatitis

Drug-induced exanthematouseruptions

Viral exanthematous eruptions

Granulomatous reactions Infectious or foreign body granuloma

Oral/genitalmucosa

Gingivostomatitis, erythema multi-forme, vulvovaginitis (aphthae?)

Infection, morbus Behcet

Gastrointestinal Food allergy with nausea, gastritis,enteritis

Malabsorption syndromes, infectious gastroenter-itis, ulcus pepticum, enzyme deficiency

Musculoskeletal Arthralgia Other forms of arthritis and myositis

Kidney Immune complex nephritis Other kidney diseases

a These symptoms can also be elicited by pseudo-allergic mechanisms

4 1 Clinical Manifestation and Classification of Allergic Diseases

Table 1.5. Classificationof pathogenic immune(allergic) reactions(modified after Coombsand Gell [5])

Type Pathophysiology Clinical examples

I IgE AnaphylaxisAllergic rhinitisAllergic bronchial asthmaAllergic conjunctivitisAllergic urticariaAllergic gastroenteritis(Atopic eczema?)

II Cytotoxic Hemolytic anemiaAgranulocytosisThrombocytopenic purpura

III Immune complexes Serum sicknessImmune complex anaphylaxisVasculitisHypersensitivity pneumonitisNephritisArthritis

IV Cellular hypersensitivity Type IVa (TH1) allergic contact dermatitisType IVb (TH2) atopic eczemaType IVc (CD8) drug-induced exanthematouseruptions (purpura pigmentosa progressiva)Bullous drug eruptions

V Granulomatous reactions Granulomas after injections (e.g., bovinecollagen)

VI Stimulating (neutral-izing) hypersensitivity

Autoimmune thyreoiditisMyasthenia gravisReverse anaphylaxisInsulin resistanceChronic urticaria? (subpopulation with auto-antibodies against Fc

5

RI)

Allergies are seen in almost every organ (Ta-ble 1.4). Most frequently, however, it is the skinand the mucous membranes that are involvedand that represent the interface between the in-dividual organism and its environment [127].

1.3 Classification of Allergic Diseases

The multitude of symptoms of allergic diseases(Table 1.4, Fig. 1.3) need a classification. Coombsand Gell [5] were the first to bring some order tothe field of clinical immunology and allergologywhen in 1963 they proposed a classification ofpathogenic immune reactions into four types;this classification has tremendous didactic qual-ities even today. Pathophysiologically oriented,it can be supplemented by the additional type Vcategory for granulomatous and type VI for spe-cific pathogenic antibody effects (stimulating/neutralizing hypersensitivity) (Table 1.5).

Type I. This type comprises IgE-mediated re-actions (classical immediate-type allergic reac-tions), allergic rhinoconjunctivitis, allergicbronchial asthma, urticaria, angioedema, andanaphylaxis. The pathophysiological principleis the release of vasoactive mediators after thebridging of at least two IgE molecules on thesurface of mast cells and basophil leukocytesby the allergen. This reaction does not needcomplement activation. Atopic eczema is char-acterized by elevated serum IgE levels.

Type II. The not so frequent reactions of typeII (mostly hematologic diseases) developthrough the action of cytotoxic antibodies di-rected against surface determinants of cells (af-ter a drug, for instance, has been attached as ahapten to the surface of leukocytes, platelets, orerythrocytes and leads to allergic agranulocy-tosis or thrombocytopenia).

1.3 Classification of Allergic Diseases 5

of a substance

non-immune

AllergyIn -tolerance

Idio-syncrasy

Psycho-neurogenic

reaction

Enviroment-induced disease

Toxicity Hypersensitivity ofthe individuum

immune-mediated

Intoxication,chronic

damage

Irritation,

Fig. 1.3. Classification ofenvironmentally relatedhealth disorders

Type III. Circulating immune complexes mayactivate the complement system as well as neu-trophil granulocytes and platelets. Clinically,one can distinguish two types according to thekinetics: immune complex anaphylaxis as animmediate reaction has been observed in dex-tran anaphylaxis and xenogeneic serum thera-py. A clinically different entity is the conditionof serum sickness, which gave rise to von Pir-quets definition of allergy and accompanies fe-ver, vasculitis, nephritis, arthritis, and urticar-ia as a consequence of deposits of circulatingimmune complexes in moderate antigen ex-cess.

It is questionable whether some forms ofdrug reactions such as erythema nodosum orerythemamultiformewhich accompany vascu-litis and immune-complex deposits may be in-cluded here.

Type IV. Reactions mediated through sensi-tized lymphocytes comprise allergic contactdermatitis, the chronic phase of atopic eczemaand many drug-induced exanthematous erup-tions. Some forms of purpura pigmentosa pro-gressiva can perhaps be mentioned here. Thetuberculin reaction as well as organ transplantrejection follows similar mechanisms. Accord-ing to modern immunology, predominantlyTH1 cells play a role in delayed-type hypersen-

sitivity (DTH), whereas TH2 reactions are im-portant in the early phase of atopic eczema.

Type V. The recently suggested type V catego-ry describes granulomatous reactions (such asafter injection of foreign material) (e.g., zirco-nium or soluble bovine collagen) after25 weeks characterized histologically by epi-thelioid cell granulomas.

Type VI. Pathogenic hypersensitivity reac-tions occurring through the specific antibodyaction have been called stimulating/neutraliz-ing hypersensitivity (I. Roitt) and occur in au-toimmune diseases such as thyreoiditis (LATS,long-acting thyroid-stimulating factor) or my-asthenia gravis with antibodies against the ace-tylcholine receptor in the motoneuron. So-called reverse anaphylaxis after injection ofantibodies (e.g., anti-IgE or antibodies againstthe IgE receptor) might also be mentionedhere; there is some overlap with type II reac-tions.

Generally, it should be stressed that everyclassification is predominantly of a didactic na-ture. In the living organism unlike in a text-book different types of reactions occur andinfluence each other in parallel. In everydaypractice, type I reactions such as allergic rhino-conjunctivitis, allergic asthma, urticaria, and

6 1 Clinical Manifestation and Classification of Allergic Diseases

anaphylaxis as well as type IV reactions such asallergic contact dermatitis are the most impor-tant manifestations of allergy. Atopic eczemacan be regarded as a mixture between type Iand type IV reactions.

References

1. Avenberg KM, Harper DS, Larsson BL (1986)Footnotes on allergy. Pharmacia, Uppsala

2. Blackley C (1873) Experimental researches on thecause and nature of hay fever. Ballie`re, Tindall &Cox, London

3. Bostock J (1819) Case of a periodical affection ofthe eyes and chest. Med-Chir Trans 10:161

4. Cooke RA (1947) Allergy in theory and practice.Saunders, Philadelphia

5. Coombs RRA, Gell PGH (1963) The classificationof allergic reactions underlying disease. In: GellPGH, Coombs RRA (eds) Clinical aspects of im-munology. Davis, Philadelphia, p 317

6. Denburg J (ed) (1998) Allergy and allergic dis-eases. Humana Press, Totowa

7. De Weck A (1997) A short history of allergologi-cal diseases and concepts. In: Kay B (ed) Allergy.Blackwell, Oxford, pp 322

8. Fuchs E, Schadewaldt H (1993) Portraits: KarlHansen. Allergo J 2:8081

9. Fuchs E, Schulz KH (eds) (1987) Manuale Aller-gologicum. Dustri, Mnchen-Deisenhofen

10. Hansen K, Werner M (eds) (1960) Lehrbuch derklinischen Allergie. Thieme, Stuttgart

11. Holgate S, Church M, Lichtenstein L (eds) (2001)Allergy, 2nd edn. Mosby, London

12. Johansson SGO, Bieber T, Dahl R, Friedmann PS,Lanier BQ, Lockey RF, Motala C, Ortega MartellJA, Platts-Mills TAE, Ring J, Thien F, VanCauwen-

berge P,Williams HC (2004) A revised nomencla-ture for allergy for global use. Report of the No-menclature Review Committee of the World Al-lergy Organization, October 2003. J Allergy ClinImmunol 113:832836

13. Kaplan A (ed) (1986) Allergy. Churchill, Livings-tone

14. Kmmerer H (1928) Allergische Diathese. Berg-mann, Munich

15. Kay B (ed) (1997) Allergy and allergic diseases, 2volumes. Blackwell, Oxford

16. Middleton E, Reed CE, Ellis EF (eds) (1998) Aller-gy. Principles and practice, 5th edn. Mosby, St.Louis

17. Mygind N, Dahl R, Pedersen S, Thestrup-Peder-sen K (1996) Essential allergy. Blackwell, Oxford

18. Pirquet C von (1906) Allergie. Mnch Med Wo-chenschr 30:1457

19. Ring J, Behrendt H, Vieluf D (eds) (1997) Newtrends in allergy IV. Springer, Berlin HeidelbergNew York

20. Ring J (1985) Erstbeschreibung einer atopischenFamilien-Anamnese im Julisch-ClaudischenKaiserhaus: Augustus, Claudius, Britannicus.Hautarzt 36:470474

21. Roitt I (1998) Essential immunology, 9th edn.Blackwell, Oxford

22. Schadewaldt H (19801984) Geschichte der All-ergie (4 vols). Dustri, Mnchen-Deisenhofen

23. Schultze-Werninghaus G, Ring J (2001) 50 JahreDeutsche Gesellschaft fr Allergologie und klini-sche Immunologie (DGAI). Allergo J 10:377382

24. Simons E (ed) (1994) Ancestors in allergy. GlobalMed Com, New York

25. Urbach E (1935) Klinik und Therapie der allergi-schen Krankheiten. Maudrich, Vienna

26. Vaughan WT, Black JH (1948) Practice of allergy.Mosby, St. Louis

27. Wahn U, Seger W, Wahn V (eds) (2004) Allergienim Kindesalter, 4th edn. Fischer, Stuttgart

References 7