1 Clinical Manifestation and Classification of Allergic Diseases

1 Clinical Manifestation and Classification

of 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 ancient medical 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 pharaoh Menes, who – according to the hi- eroglyphs – died in the year 2,641

after a wasp sting [1].

The first family history of atopy syndrome with 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 England was allergic against strawberries according to Shakespeare.

Table 1.1. Allergic dis- eases in the ancient medical literature

Year Author Disease

2698

Huang Ti “Noisy breathing”

2641

Hieroglyphs Death by wasp sting (Pharaoh Menes) 460

Hippocrates Hypersensitivity against goat’s cheese 25

A. Celsus Description of asthma

120 – 180 Aretaeus of Kapadokia Term “asthma”

600 Aetius of Amida Term “eczema”

865 Rhazes Rose fever in Persia

1135 – 1204 Moses Maimonides Treatment of asthma

1565 L. Botallus Rose fever in Pavia

1783 Philipp Phoebus Hay fever (monography)

1802 W. Heberden “Summer catarrh”

1819 J. Bostock Self-description of hay fever 1837 J.L. Schoenlein Purpura rheumatica 1853 J.M. Charcot Crystals in asthma sputum 1886 E. van Leyden Crystals in asthma sputum 1868 H.H. Salter Different asthma elicitors

1872 H.I. Quincke Angioedema

1872 Wyman Autumnal catarrh (from ragweed)

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

The term “allergy” was born on 24 July 1906

in 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” as

the specifically altered reactivity of the organ-

ism. Linguistically, the term should read “al-

lourgy” since the Greek words “ [ † † ; s” = “dif-

ferent” and “ 5 R * ; ˆ ” = “work” combine in this

way. Von Pirquet’s definition includes not only

hypersensitivity reactions, but also decreased

immune reactions; this aspect has been lost to-

day. We define allergy as “specific immunologi-

cal hypersensitivity leading to disease.” A new

Fig. 1.1. Allergies were already known in ancient times. The Roman Emperor Augustus suffered from atopic syndrome (bronze sculpture, around 14

, British Museum, London)

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

Fig. 1.2. The word “aller- gy” made its debut in the medical literature on 24 July 1906 in an ar- ticle written by Cle- mens von Pirquet, a pe- diatrician practicing in Vienna, for the Mün- chener Medizinische Wochenschrift (Munich Medical Weekly) Mostly, this hypersensitivity is directed against exogenous non-infectious agents. Au- toimmune reactions may be included when they are induced through exogenous sub- stances (see Chap 5, Sects. 5.2, 5.7, 5.10).

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

The specialty of allergology saw a major ad- vance in the discovery of immunoglobulin E as the 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 would like to change their names to “IgEologists”! We should remember, however, that allergic dis- eases include many more clinical entities than IgE-mediated reactions.

1.2 Clinical Manifestation and Definition of Allergy

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

2 1 Clinical Manifestation and Classification of Allergic Diseases

Table 1.2. Milestones in

allergy research Year Author Condition

1873 Ch. Blackley Skin and provocation tests (grass pollen)

1877 P. Ehrlich Mast cells

1895 J. Jadassohn Patch test

1900 S. Solis-Cohen Suprarenal extracts in asthma/hay fever 1902 Ch. Richet, P. Portier Anaphylaxis

1903 M. Arthus Local anaphylaxis

1903 Th. Smith Anaphylaxis against horse serum 1905 von Pirquet, B. Schick Serum sickness

1906 von Pirquet Allergy

1906 A. Wolff-Eisner Hay fever/urticaria correspond to anaphylaxis 1910 W. Dunbar Pollen extract and antiserum (pollantin) 1910 H. Dale, Laidlaw Histamine

1911 L. Noon, J. Freeman Prophylactic inoculation (hyposensitization) 1921 C. Prausnitz, F. Küstner Humoral hypersensitivity is transferable 1923 A. Coca, R. Cooke Atopy

1924 K.K. Shen, C.F. Schmidt Ephedrine (from Ma Huang) 1927 Th. Lewis Triple reaction of histamine 1928 W. Storm van Leeuwen House dust allergy/climate chamber 1928 H. Kämmerer Allergic diathesis

1937 Bovet/Staub Antihistamines (Phenergan) 1939 H.H. Donally Food allergens in breast milk 1940 M. Loveless Blocking antibodies

1941 K. Hansen Shock fragment

1949 P.L. Hench, E.C. Kendall Cortisone

1952 Z. Ovary Passive cutaneous anaphylaxis (PCA) 1953 J.F. Riley, G. West Histamine in mast cell granules

1954 W. Frankland First placebo-controlled immunotherapy trial 1956 W. Gronemeyer, E. Fuchs Bronchial provocation in routine diagnosis

1958 F. Dixon Immune complex reaction

1960 B.B. Levine, A. de Weck Penicillin allergy (bivalent hapten)

1961 J. Pepys Farmer’s lung

1963 R.R.A. Coombs, P. Gell Type I–IV classification 1964 L. Lichtenstein, A. Osler Histamine release 1966 K. Ishizaka Immunoglobulin E 1967 S.G.O. Johansson Immunoglobulin E 1967 R. Vorhoorst, F. Spieksma House dust mites 1967 R. Altounyan Cromoglycate

1969 E. Macher, R. Chase Contact allergy kinetics (mouse)

1977 B. Halpern Lymphocyte transformation test in allergy 1978 P. Kall´os Pseudo-allergy

1979 B. Samuelsson Leukotrienes

1984 H. Metzger IgE receptor

1987 T. Mossmann Th

-Th

concept 1988 V. Coffmann Interleukin-4 1989 H. Behrendt Allergotoxicology 1989 D. Kraft, Baldo Recombinant allergens

1987 K. Mullis Polymerase chain reaction (PCR)

1987 P. Piper Leukotriene antagonists

1996 C. Heusser Anti-IgE in therapy

Table 1.3. Definitions

Sensitivity Normal response to a stimulus Hypersensitivi-

ty Abnormally strong response to a 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 the pharmacological toxicity Intolerance Hypersensitivity in the sense of

pharmacological toxicity Pseudo-allergy Non-immunological hypersensi-

tivity with clinical symptoms mimicking allergic reactions

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

Organ Symptoms

Differential diagnosis

Cardiovascular Anaphylaxis, vasculitis Other cases of shock, vasovagal reaction, vascular diseases

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-Rosenthal syndrome

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 atopic eczema

Other forms of dermatitis

Drug-induced exanthematous eruptions

Viral exanthematous eruptions

Granulomatous reactions Infectious or foreign body granuloma Oral/genital

mucosa Gingivostomatitis, erythema multi-

forme, vulvovaginitis (aphthae?) Infection, morbus Beh¸cet 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. Classification of pathogenic immune (“allergic”) reactions (modified after Coombs and Gell [5])

Type Pathophysiology Clinical examples

I IgE Anaphylaxis

Allergic rhinitis

Allergic bronchial asthma Allergic conjunctivitis Allergic urticaria Allergic gastroenteritis (Atopic eczema?)

II Cytotoxic Hemolytic anemia

Agranulocytosis

Thrombocytopenic purpura III Immune complexes Serum sickness

Immune complex anaphylaxis Vasculitis

Hypersensitivity pneumonitis Nephritis

Arthritis

IV Cellular hypersensitivity Type IVa (TH1) allergic contact dermatitis Type IVb (TH2) atopic eczema

Type IVc (CD8) drug-induced exanthematous eruptions (purpura pigmentosa progressiva) Bullous drug eruptions

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

VI “Stimulating” (“neutral- izing”) hypersensitivity

Autoimmune thyreoiditis Myasthenia gravis Reverse anaphylaxis Insulin resistance

Chronic urticaria? (subpopulation with auto- antibodies against Fc

RI)

Allergies are seen in almost every organ (Ta- ble 1.4). Most frequently, however, it is the skin and the mucous membranes that are involved and that represent the interface between the in- dividual organism and its environment [1 – 27].

1.3 Classification of Allergic Diseases

The multitude of symptoms of allergic diseases (Table 1.4, Fig. 1.3) need a classification. Coombs and Gell [5] were the first to bring some order to the field of clinical immunology and allergology when in 1963 they proposed a classification of pathogenic immune reactions into four types;

this classification has tremendous didactic qual- ities even today. Pathophysiologically oriented, it can be supplemented by the additional type V category 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, allergic bronchial asthma, urticaria, angioedema, and anaphylaxis. The pathophysiological principle is the release of vasoactive mediators after the bridging of at least two IgE molecules on the surface of mast cells and basophil leukocytes by the allergen. This reaction does not need complement activation. Atopic eczema is char- acterized by elevated serum IgE levels.

Type II. The not so frequent reactions of type

II (mostly hematologic diseases) develop

through the action of cytotoxic antibodies di-

rected against surface determinants of cells (af-

ter a drug, for instance, has been attached as a

hapten to the surface of leukocytes, platelets, or

erythrocytes and leads to allergic agranulocy-

tosis or thrombocytopenia).

of a substance

non- immune

Allergy In -

tolerance

Idio- syncrasy Psycho-

neurogenic reaction

Enviroment-induced disease

Toxicity Hypersensitivity of

the individuum

immune- mediated

Intoxication, chronic damage Irritation,

Fig. 1.3. Classification of environmentally related health disorders

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

It is questionable whether some forms of drug reactions such as erythema nodosum or erythema multiforme which accompany vascu- litis and immune-complex deposits may be in- cluded here.

Type IV. Reactions mediated through sensi- tized lymphocytes comprise allergic contact dermatitis, the chronic phase of atopic eczema and many drug-induced exanthematous erup- tions. Some forms of purpura pigmentosa pro- gressiva can perhaps be mentioned here. The tuberculin reaction as well as organ transplant rejection follows similar mechanisms. Accord- ing to modern immunology, predominantly TH1 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 as after injection of foreign material) (e.g., zirco- nium or soluble bovine collagen) after 2 – 5 weeks characterized histologically by epi- thelioid cell granulomas.

Type VI. Pathogenic hypersensitivity reac- tions occurring through the specific antibody action 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 of antibodies (e.g., anti-IgE or antibodies against the IgE receptor) might also be mentioned here; there is some overlap with type II reac- tions.

Generally, it should be stressed that every

classification is predominantly of a didactic na-

ture. In the living organism – unlike in a text-

book – different types of reactions occur and

influence each other in parallel. In everyday

practice, 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 as allergic contact dermatitis are the most impor- tant manifestations of allergy. Atopic eczema can be regarded as a mixture between type I and type IV reactions.

References

1. Avenberg KM, Harper DS, Larsson BL (1986) Footnotes on allergy. Pharmacia, Uppsala 2. Blackley C (1873) Experimental researches on the

cause and nature of hay fever. Balli`ere, Tindall &

Cox, London

3. Bostock J (1819) Case of a periodical affection of the 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 classification of allergic reactions underlying disease. In: Gell PGH, 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 3 – 22

8. Fuchs E, Schadewaldt H (1993) Portraits: Karl Hansen. Allergo J 2:80 – 81

9. Fuchs E, Schulz KH (eds) (1987) Manuale Aller- gologicum. Dustri, München-Deisenhofen 10. Hansen K, Werner M (eds) (1960) Lehrbuch der

klinischen 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 Martell JA, Platts-Mills TAE, Ring J, Thien F, Van Cauwen-

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 Clin Immunol 113:832 – 836

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

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

15. Kay B (ed) (1997) Allergy and allergic diseases, 2 volumes. 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. Münch Med Wo-

chenschr 30:1457

19. Ring J, Behrendt H, Vieluf D (eds) (1997) New trends in allergy IV. Springer, Berlin Heidelberg New York

20. Ring J (1985) Erstbeschreibung einer “atopischen Familien-Anamnese” im Julisch-Claudischen Kaiserhaus: Augustus, Claudius, Britannicus.

Hautarzt 36:470 – 474

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

Blackwell, Oxford

22. Schadewaldt H (1980 – 1984) Geschichte der All- ergie (4 vols). Dustri, München-Deisenhofen 23. Schultze-Werninghaus G, Ring J (2001) 50 Jahre

Deutsche Gesellschaft für Allergologie und klini- sche Immunologie (DGAI). Allergo J 10:377 – 382 24. Simons E (ed) (1994) Ancestors in allergy. Global

Med 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) Allergien

im Kindesalter, 4th edn. Fischer, Stuttgart