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Chapter 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 B.C. 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.

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

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

Year

Author

Disease

2698

B.C.

Huang Ti Hieroglyphs Hippocrates A. Celsus Aretaeus of Kapadokia

“Noisy breathing” Death by wasp sting (Pharaoh Menes) Hypersensitivity against goat’s cheese Description of asthma Term “asthma”

2641

B.C.

460 B.C.

25 B.C.

120 –180

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)

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1 Clinical Manifestation and Classification of Allergic Diseases

Manifestation and Classification of Allergic Diseases Fig. 1.1. Allergies were already known in ancient times.

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

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

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.

[8]. The most important definitions are given in Table 1.3. Fig. 1.2. The word “aller- gy”

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)

1.2 Clinical Manifestation and Definition of Allergy

3

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 1 -Th 2 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

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1 Clinical Manifestation and Classification of Allergic Diseases

Table 1.3. Definitions

Sensitivity

Normal response to a stimulus

Hypersensitivi-

Abnormally strong response to

ty

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 a

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-

Irritation, infectious conjunctivitis rosacea, psori- asis, seborrheic dermatitis, Melkersson-Rosenthal syndrome

junctivitis, blepharitis, lid

edema

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

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

Infection, morbus Beh¸cet

mucosa

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

1.3 Classification of Allergic Diseases

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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 5 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).

6

1 Clinical Manifestation and Classification of Allergic Diseases

Enviroment-induced disease

Toxicity of a substance Hypersensitivity of the individuum non- immune- immune mediated Irritation, In- Psycho-
Toxicity
of a substance
Hypersensitivity of
the individuum
non-
immune-
immune
mediated
Irritation,
In- Psycho-
Idio-
Intoxication,
tolerance
neurogenic
syncrasy
chronic
reaction
damage
Allergy

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

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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.

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