Chapter 1

Clinical Manifestation and Classification

of Allergic Diseases

1.1 History
Allergic diseases have been known for centuries, and allergic diseases such as asthma, urticaria and eczema were described in the ancient
medical literature of China, Egypt, and Greece
(Table 1.1) [7, 22, 24]. The first allergic individual in world history might have been the Egyptian pharaoh Menes, who according to the hieroglyphs 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 eczema can be found in the Julian-Claudian imperial family of Augustus, Claudius, and Britannicus [20] (Fig. 1.1). In the middle ages, rose fever with hay-fever-like symptoms was a wellknown entity. Richard III of England was allergic
against strawberries according to Shakespeare.

Table 1.1. Allergic diseases in the ancient

medical literature

The first clinically exact description of hay fever

was given by John Bostock in 1819. C.H. Blackley 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 Medical Weekly [18], coined by the Viennese pediatrician Clemens von Pirquet to differentiate between protective and noxious immunity
(Fig. 1.2). Von Pirquet understood allergy as
the specifically altered reactivity of the organism. Linguistically, the term should read allourgy since the Greek words [ ; s = different and 5 R * ; = work combine in this
way. Von Pirquets definition includes not only
hypersensitivity reactions, but also decreased
immune reactions; this aspect has been lost today. We define allergy as specific immunological hypersensitivity leading to disease. A new

Year

Author

Disease

2698 B.C.
2641 B.C.
460 B.C.
25 B.C.
120 180
600
865
1135 1204
1565
1783
1802
1819
1837
1853
1886
1868
1872
1872

Huang Ti
Hieroglyphs
Hippocrates
A. Celsus
Aretaeus of Kapadokia
Aetius of Amida
Rhazes
Moses Maimonides
L. Botallus
Philipp Phoebus
W. Heberden
J. Bostock
J.L. Schoenlein
J.M. Charcot
E. van Leyden
H.H. Salter
H.I. Quincke
Wyman

Noisy breathing
Death by wasp sting (Pharaoh Menes)
Hypersensitivity against goats cheese
Description of asthma
Term asthma
Term eczema
Rose fever in Persia
Treatment of asthma
Rose fever in Pavia
Hay fever (monography)
Summer catarrh
Self-description of hay fever
Purpura rheumatica
Crystals in asthma sputum
Crystals in asthma sputum
Different asthma elicitors
Angioedema
Autumnal catarrh (from ragweed)

1 Clinical Manifestation and Classification of Allergic Diseases

Mostly, this hypersensitivity is directed

against exogenous non-infectious agents. Autoimmune reactions may be included when
they are induced through exogenous substances (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 advance in the discovery of immunoglobulin E as
the carrier of immediate type hypersensitivity.
IgE seems to be the most important immunoglobulin 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 diseases include many more clinical entities than
IgE-mediated reactions.

1.2 Clinical Manifestation and Definition

of Allergy
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].

In clinical practice, allergy manifests as various

different conditions such as anaphylactic shock,
hay fever, allergic conjunctivitis, urticaria, angioedema, serum sickness, allergic vasculitis, hypersensitivity pneumonitis, contact dermatitis,
granulomatous reactions, allergic bronchial
asthma, as well as the colorful spectrum of foodor drug-induced adverse reactions [8]. The most
important definitions are given in Table 1.3.

Fig. 1.2. The word allergy made its debut in

the medical literature
on 24 July 1906 in an article written by Clemens von Pirquet, a pediatrician practicing in
Vienna, for the Mnchener Medizinische
Wochenschrift (Munich
Medical Weekly)

1.2 Clinical Manifestation and Definition of Allergy

Table 1.2. Milestones in
allergy research

Year

Author

Condition

1873
1877
1895
1900
1902
1903
1903
1905
1906
1906
1910
1910
1911
1921
1923
1924
1927
1928
1928
1937
1939
1940
1941
1949
1952
1953
1954
1956
1958
1960
1961
1963
1964
1966
1967
1967
1967
1969
1977
1978
1979
1984
1987
1988
1989
1989
1987
1987
1996

Ch. Blackley
P. Ehrlich
J. Jadassohn
S. Solis-Cohen
Ch. Richet, P. Portier
M. Arthus
Th. Smith
von Pirquet, B. Schick
von Pirquet
A. Wolff-Eisner
W. Dunbar
H. Dale, Laidlaw
L. Noon, J. Freeman
C. Prausnitz, F. Kstner
A. Coca, R. Cooke
K.K. Shen, C.F. Schmidt
Th. Lewis
W. Storm van Leeuwen
H. Kmmerer
Bovet/Staub
H.H. Donally
M. Loveless
K. Hansen
P.L. Hench, E.C. Kendall
Z. Ovary
J.F. Riley, G. West
W. Frankland
W. Gronemeyer, E. Fuchs
F. Dixon
B.B. Levine, A. de Weck
J. Pepys
R.R.A. Coombs, P. Gell
L. Lichtenstein, A. Osler
K. Ishizaka
S.G.O. Johansson
R. Vorhoorst, F. Spieksma
R. Altounyan
E. Macher, R. Chase
B. Halpern
P. Kallos
B. Samuelsson
H. Metzger
T. Mossmann
V. Coffmann
H. Behrendt
D. Kraft, Baldo
K. Mullis
P. Piper
C. Heusser

Skin and provocation tests (grass pollen)

Mast cells
Patch test
Suprarenal extracts in asthma/hay fever
Anaphylaxis
Local anaphylaxis
Anaphylaxis against horse serum
Serum sickness
Allergy
Hay fever/urticaria correspond to anaphylaxis
Pollen extract and antiserum (pollantin)
Histamine
Prophylactic inoculation (hyposensitization)
Humoral hypersensitivity is transferable
Atopy
Ephedrine (from Ma Huang)
Triple reaction of histamine
House dust allergy/climate chamber
Allergic diathesis
Antihistamines (Phenergan)
Food allergens in breast milk
Blocking antibodies
Shock fragment
Cortisone
Passive cutaneous anaphylaxis (PCA)
Histamine in mast cell granules
First placebo-controlled immunotherapy trial
Bronchial provocation in routine diagnosis
Immune complex reaction
Penicillin allergy (bivalent hapten)
Farmers lung
Type IIV classification
Histamine release
Immunoglobulin E
Immunoglobulin E
House dust mites
Cromoglycate
Contact allergy kinetics (mouse)
Lymphocyte transformation test in allergy
Pseudo-allergy
Leukotrienes
IgE receptor
Th1-Th2 concept
Interleukin-4
Allergotoxicology
Recombinant allergens
Polymerase chain reaction (PCR)
Leukotriene antagonists
Anti-IgE in therapy

1 Clinical Manifestation and Classification of Allergic Diseases

Table 1.3. Definitions
Sensitivity

Normal response to a stimulus

Allergy

Hypersensitivity

Abnormally strong response to

a stimulus

Immunologically mediated hypersensitivity leading to disease

Idiosyncrasy

Toxicity

Normal harmfulness of a substance

Non-immunological hypersensitivity without relation to the

pharmacological toxicity

Intoxication

Reaction to normal pharmacological toxicity

Intolerance

Hypersensitivity in the sense of

pharmacological toxicity

Sensitization

Development of increased sensitivity after repeated contact

Pseudo-allergy

Non-immunological hypersensitivity with clinical symptoms

mimicking 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, vascular

diseases

Lung

Bronchial asthma, allergic bronchitis, hypersensitivity, pneumonitis

Bronchitis, chronic obstructive pulmonary disease, irritative toxic asthma, pneumonia

Upper airways

Rhinitis, sinusitis, pharyngitis,

laryngeal edema, laryngitis

Vasomotor rhinitis, infection

Eye

Conjunctivitis, atopic keratoconjunctivitis, blepharitis, lid edema

Irritation, infectious conjunctivitis rosacea, psoriasis, seborrheic dermatitis, Melkersson-Rosenthal

syndrome

Ear

Otitis externa, serous otitis media?

tinnitus? vertigo?

Psoriasis, infection, microcirculatory disturbance

Blood

Hemolytic anemia, thrombocytope- Hematologic disease, toxic reactions

nia, agranulocytosis

CNS

Fever

Infectious diseases

(Cramps)

Neurological diseases

(Migraine?)
Skin

Oral/genital
mucosa

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

Gingivostomatitis, erythema multiforme, vulvovaginitis (aphthae?)

Infection, morbus Behcet

Gastrointestinal Food allergy with nausea, gastritis,

enteritis

Malabsorption syndromes, infectious gastroenteritis, ulcus pepticum, enzyme deficiency

Musculoskeletal Arthralgia

Other forms of arthritis and myositis

Kidney

Other kidney diseases

Immune complex nephritis

These symptoms can also be elicited by pseudo-allergic mechanisms

1.3 Classification of Allergic Diseases

Table 1.5. Classification
of pathogenic immune
(allergic) reactions
(modified after Coombs
and Gell [5])

Type Pathophysiology
I

II

III

IV

V
VI

Clinical examples

IgE

Anaphylaxis
Allergic rhinitis
Allergic bronchial asthma
Allergic conjunctivitis
Allergic urticaria
Allergic gastroenteritis
(Atopic eczema?)
Cytotoxic
Hemolytic anemia
Agranulocytosis
Thrombocytopenic purpura
Immune complexes
Serum sickness
Immune complex anaphylaxis
Vasculitis
Hypersensitivity pneumonitis
Nephritis
Arthritis
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
Granulomatous reactions Granulomas after injections (e.g., bovine
collagen)
Stimulating (neutral- Autoimmune thyreoiditis
izing) hypersensitivity Myasthenia gravis
Reverse anaphylaxis
Insulin resistance
Chronic urticaria? (subpopulation with autoantibodies against Fc 5 RI)

Allergies are seen in almost every organ (Table 1.4). Most frequently, however, it is the skin
and the mucous membranes that are involved
and that represent the interface between the individual 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 qualities even today. Pathophysiologically oriented,
it can be supplemented by the additional type V
category for granulomatous and type VI for specific pathogenic antibody effects (stimulating/
neutralizing hypersensitivity) (Table 1.5).

Type I. This type comprises IgE-mediated reactions (classical immediate-type allergic reactions), 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 characterized 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 directed against surface determinants of cells (after a drug, for instance, has been attached as a
hapten to the surface of leukocytes, platelets, or
erythrocytes and leads to allergic agranulocytosis or thrombocytopenia).

1 Clinical Manifestation and Classification of Allergic Diseases

Enviroment-induced disease

Toxicity
of a substance

Hypersensitivity of
the individuum

nonimmune

Irritation,
Intoxication,
chronic
damage

In tolerance

Psychoneurogenic
reaction

immunemediated

Idiosyncrasy

Type III. Circulating immune complexes may

activate the complement system as well as neutrophil granulocytes and platelets. Clinically,
one can distinguish two types according to the
kinetics: immune complex anaphylaxis as an
immediate reaction has been observed in dextran anaphylaxis and xenogeneic serum therapy. A clinically different entity is the condition
of serum sickness, which gave rise to von Pirquets definition of allergy and accompanies fever, vasculitis, nephritis, arthritis, and urticaria as a consequence of deposits of circulating
immune complexes in moderate antigen excess.
It is questionable whether some forms of
drug reactions such as erythema nodosum or
erythema multiforme which accompany vasculitis and immune-complex deposits may be included here.
Type IV. Reactions mediated through sensitized lymphocytes comprise allergic contact
dermatitis, the chronic phase of atopic eczema
and many drug-induced exanthematous eruptions. Some forms of purpura pigmentosa progressiva can perhaps be mentioned here. The
tuberculin reaction as well as organ transplant
rejection follows similar mechanisms. According to modern immunology, predominantly
TH1 cells play a role in delayed-type hypersen-

Allergy

Fig. 1.3. Classification of

environmentally related
health disorders

sitivity (DTH), whereas TH2 reactions are important in the early phase of atopic eczema.
Type V. The recently suggested type V category describes granulomatous reactions (such as
after injection of foreign material) (e.g., zirconium or soluble bovine collagen) after
2 5 weeks characterized histologically by epithelioid cell granulomas.
Type VI. Pathogenic hypersensitivity reactions occurring through the specific antibody
action have been called stimulating/neutralizing hypersensitivity (I. Roitt) and occur in autoimmune diseases such as thyreoiditis (LATS,
long-acting thyroid-stimulating factor) or myasthenia gravis with antibodies against the acetylcholine receptor in the motoneuron. Socalled 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 reactions.
Generally, it should be stressed that every
classification is predominantly of a didactic nature. In the living organism unlike in a textbook different types of reactions occur and
influence each other in parallel. In everyday
practice, type I reactions such as allergic rhinoconjunctivitis, allergic asthma, urticaria, and

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and type IV reactions.

13.
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