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5.1 Diseases with Possible IgE Involve- tions (combination of type I and type IV b reac-
ment (Immediate-Type Allergies) tions). Atopic eczema will be discussed in a
separate section (see Sect. 5.5.3).
There are many allergic diseases manifesting in The maximal manifestation of IgE-mediated
different organs and on the basis of different immediate-type allergic reaction is anaphylax-
pathomechanisms (see Sect. 1.3). The most is. In the development of clinical symptoms,
common allergies develop via IgE antibodies different organs may be involved and symp-
and manifest within minutes to hours after al- toms of well-known allergic diseases of skin
lergen contact (immediate-type reactions). and mucous membranes [also called shock
Not infrequently, there are biphasic (dual) re- fragments (Karl Hansen)] may occur accord-
action patterns when after a strong immediate ing to the severity (see Sect. 5.1.4).
reaction in the course of 6 12 h a renewed hy-
persensitivity reaction (late-phase reaction,
LPR) occurs which is triggered by IgE, but am- 5.1.1 Allergic Rhinitis
plified by recruitment of additional cells and
5.1.1.1 Introduction
mediators. These LPRs have to be distin-
guished from classic delayed-type hypersensi- Apart from being an aesthetic organ, the nose
tivity (DTH) reactions (type IV reactions) (see has several very interesting functions (Ta-
Sect. 5.5). ble 5.1). It is true that people can live without
What may be confusing for the inexperi- breathing through the nose, but disturbance of
enced physician is familiar to the allergist: The this function can lead to disease. Here we are
same symptoms of immediate-type reactions interested mostly in defense functions against
are observed without immune phenomena particles and irritants (physical or chemical)
(skin tests or IgE antibodies) being detectable. with clinical symptoms occurring physiologi-
These reactions are called pseudo-allergic re- cally under certain conditions (e.g., secretion,
actions (PARs), the term pseudo only re- sneezing, obstruction) and which can take on
flecting the not detectable participation of the the characteristics of disease in intense or
immune system and not implying psychologi- chronic expression [10, 12]. For these com-
cal phenomena. People can die from pseudo- plaints, the term rhinitis has been accepted
allergic reactions! The term is negatively de- internationally, although the demonstration of
fined; with better techniques allowing the de-
tection of antibodies or sensitized cells, PAR
may turn into true allergy. IgE-mediated drug Table 5.1. Functions of the nose
allergies will be covered together with other ) Airway ) Warming of air
adverse drug reactions (see Sect. 5.7). ) Olfactory sensory ) Air-conditioner
In atopic eczema, IgE antibodies play a role organ ) Body of voice resonance
in many patients in the eliciting phase, albeit in ) Filter organ ) Killing of microbes
) Humidifier
close connection with T-cell-mediated reac-
5.1 Diseases with Possible IgE Involvement 77
inflammation cannot be done in each case. The following mechanisms contribute to the
Therefore, rhinopathy would be a more logical development of nasal hyperreactivity:
term, although it is not often used [3, 4, 10]. Nor- ) Increase in permeability
mal findings and disease conditions overlap in ) Increase in sensitivity of irritant receptors
rhinitis much more often than in asthma. Often ) Increase in number of receptors per cell
the conjunctiva is also affected (rhinoconjunc-
surface
tivitis) (see Sect. 5.1.7 on Allergy and Eye). ) Change of nerval impulses in the CNS
The most common form of allergic rhinitis ) Increase in number of inflammatory cells
and the most frequent atopic disease is pollino- ) Increase in function of effector cells (in-
sis (pollen rhinitis, pollen conjunctivitis, pol-
creased releasability)
len asthma, hay fever, hay asthma, hay rhinitis) ) Hormonal influences (estrogens?)
[19].
The disease was known in Arabic medicine Increased mast cells and basophil leukocytes
and in the late middle ages it was known as rose (especially during late phase reactions) have
fever. The first scientific description dates back been found in the nasal smear in allergic rhini-
to 1819 when John Bostock described his own tis [9].
symptoms. He saw the high summer tempera- Clinical stigmata of patients with allergic
ture as being the cause although many people rhinitis comprise:
called the disease hay fever. It was not until ) Adenoid face
1873 that Charles Blackley, using a skin and ) Permanent mouth breathing
provocation test, proved the disease was caused ) Periorbital halo (allergic shiners)
by pollen. Wolff-Eisner classified the disease in ) Lower lid edema
1906 as being hypersensitivity against pollen ) Allergic greeting (frequent wiping of the
protein (the term allergy had only just been
nose tip) (Fig. 5.1)
introduced) (for literature see Chap. 1). ) Lateral fold in the lower nasal part
Rhinitis
non-allergic mechanisms are observed. All too mechanistic, although of didactic value
forms of rhinitis have in common a hyperreac- [10]. We know that pollen fragments may also
tivity of the nasal mucosa similar to bronchial reach the bronchi.
hyperreactivity in asthma.
In the group of non-allergic vasomotor rhi-
5.1.1.4 Therapy
nitis, two forms may be distinguished accord-
ing to nasal cytology: an inflammatory form The general therapy of allergic rhinitis is cov-
with increased eosinophil granulocytes and the ered in the sections on Immunotherapy
non-inflammatory form. The form of vasomo- (Sect. 6.3.1) and Pharmacotherapy (Sects.
tor rhinitis with increased eosinophils is often 6.2, 6.3) [6]. A characteristic of rhinitis therapy
characterized by strong swelling, formation of is the use of [ -adrenergics as vasoconstrictors
polyps and concomitant acetylsalicylic acid (orally as pseudoephedrine or norephedrine or
[10]. It responds better to antihistamines and topically as naphthazoline, xylometazoline, or
glucocorticosteroids than the non-inflamma- oxymetazoline). The possible adverse reaction
tory form, which is very resistant to therapy of rhinitis medicamentosa after long-term use
and may respond to anticholinergics (ipratro- of topical vasoconstrictors with mucosal dam-
pium bromide). age should be mentioned!
Patients with vasomotor rhinitis show an in- When selecting pharmacotherapy, the clini-
creased reactivity to unspecific irritants (Ta- cal symptoms should be considered. If obstruc-
ble 5.3) with a pathophysiologic correlate of tion is prominent, a combination of antihista-
autonomic nervous system dysregulation mines, vasoconstrictors, and steroids is recom-
corresponding possibly to an extreme variant mended while patients with predominant rhi-
of physiologic reactivity [2, 10, 14]. Dryness norrhea usually respond well to antihistamines
(draughts of air, cold air, dust) is a common and anticholinergics. Mucosal dryness with in-
triggering factor. creased irritability can be treated in perennial
The relationship between allergic rhinitis rhinitis with ointments and inhalations or la-
and otitis media has been discussed. It seems vages.
that with atopics there is an increased risk of In very severe cases of allergic rhinitis, si-
serous otitis media, although the latter cannot nusitis can occur. Recently fungal allergic si-
be regarded as allergic disease. nusitis, a disease corresponding to allergic
The simple hypothesis that particle size de- bronchopulmonary mycosis, has seen renewed
termines deposit and organ manifestation interest (see Sect. 5.4 on Hypersensitivity
(pollen grains with diameters of around 25 m Pneumonitis). Interactions between allergic
cause rhinitis in the nose, mold spores 5 m in rhinitis and diseases of the ear (vestibular or
diameter in the bronchi cause asthma and tube ventilatory disturbances) have been re-
small actinomycete particles below 2 m in di- ported without clear pathophysiological evi-
ameter in the alveoli lead to alveolitis) is surely dence. There is no good evidence for an allergic
mechanism in morbus Meniere, tinnitus, or
chronic labyrinthitis, although anecdotal cases
Table 5.3. Irritative factors as elicitors of rhinitis have been reported.
) Dust, smoke (particles) To summarize: Allergic rhinitis is not a ne-
) Chemical irritants (solvents, alcohol, washing glectable bagatelle condition! It occurs with
powder) systemic symptoms and often represents the
) Kitchen vapors, odors, halogens, formaldehyde, beginning of severe asthma (united airway
ether, etc. disease) [3, 4, 6, 7, 10, 12, 13, 16, 19].
) Change of temperature (especially cold)
) Air draught
) Change of position
) Dryness
) Hormonal influence (e.g., rhinitis in the third
pregnancy trimenon)
80 5 Allergic Diseases (and Differential Diagnoses)
Table 5.4. Differential diagnosis of bronchial asthma orthopnea) with noisy breathing, characteris-
) Mechanical ventilation disturbance (tumors, tic dry noises (wheezing and humming), at-
struma, mediastinal tumors, thymus hyperpla- tacks of coughing and expectoration of a clear
sia, foreign body aspiration) but viscous sputum. The attack often starts
) Disturbance of ventilatory regulation (hyper- with tightness of the chest and a dry cough. Pa-
ventilation) tients have difficulty speaking longer sen-
) Infection (bronchopneumonia, pertussis, acute tences.
epiglottitis [pseudo-Krupp], parasitoses) Through the increasing difficulty in ventila-
) Gastroesophageal reflux tion, respiratory auxiliary muscles are more in-
) Cardiac disease (left ventricular insufficiency tensely used. The suprathoracic veins are often
with pulmonary edema, vitium cordis, coro- filled, and cyanosis may occur. With an in-
nary disease) creased pulse rate, pulsus paradoxus often oc-
) Toxic or drug-induced bronchoconstriction curs. If an asthma attack persists in spite of
) Lung vessel disease (pulmonary embolism, therapy with beta-adrenergics and xanthine
pulmonary hypertension, vasculitis) derivatives for more than 24 h, the term status
) Diseases of larynx and trachea (tracheal steno- asthmaticus (acute severe asthma) is used.
sis, tracheomalacia, acute laryngitis, functional The breathing noises become less pronounced
laryngospasm) (silent lung).
) Other lung diseases (emphysema, fibrosis, Sometimes an asthma attack occurs along
sarcoidosis, interstitial lung disease, alveolitis) with other symptoms of the upper respiratory
) Sleep-apnea syndrome airways (nasal blockage, sneezing, or itching
) Chronic obstructive pulmonary disease (COPD) eyes) as well as gastrointestinal complaints, in-
creased diuresis, or fatigue [35, 36, 45, 46]. In
the chest X-ray, few changes are seen, but in se-
The Deutsche Atemwegsliga (German Airway vere cases increased air with a pronounced in-
League) gives the following definition: Asth- spiratory position of the thorax is seen. In con-
ma is an inflammatory airway disease with trast to lung emphysema, the lung vessels are
bronchial hyperreactivity and variable airway not constricted in bronchial asthma. The char-
obstruction. Typical symptoms are cough and acteristic finding in lung function is obstruc-
attacks of dyspnea, especially during the night tive ventilatory disturbance with increased air-
and early morning, wheezing and clear viscous way resistance and decreased forced expiratory
sputum [46]. volume (FEV1).
Bronchial asthma is the most common aller- The German Airway League has graded
gic lung disease, but can occur without detec- asthma according to severity (Table 5.5) [37,
tion of immune reactions (intrinsic asthma). 46].
In children, approximately 80 % of asthma is all-
ergic in origin, in adults approximately 60 %.
5.1.2.3 Different Forms of Bronchial Asthma
Bronchial asthma can be classified according to
5.1.2.2 Symptomatology
eliciting stimuli, sensitivity of the patient, test
The major clinical symptom of an asthma at- results or other underlying diseases [5, 11, 17,
tack is the sudden dyspnea (also tachypnea or 18, 19, 23, 34, 35, 36, 37]. The best classification
Table 5.6. Forms of bronchial asthma ing. However, eosinophilia in blood and spu-
) Allergic (IgE-mediated, extrinsic) tum is often demonstrable.
) Physical-irritative, chemotoxic Furthermore, asthma can be classified ac-
) Intrinsic (cryptogenic, unknown etiology) cording to prognosis and therapeutic response.
) Special formsa: Intrinsic asthma responds to a lesser degree to
Infection-associated beta-adrenergics, cromoglycate or theophyl-
Psychogenic
Analgesic (additive) idiosyncrasy (Samters triad) line. Sometimes, anticholinergics or ketotifen
Pharmacologic (beta-blockers, histamine are effective; most patients, however, are gluco-
liberators) corticosteroid dependent [17, 20, 35].
Exercise-induced The most important allergens in elicitation
) Mixed forms
of extrinsic asthma are so-called inhalation or
a
These stimuli can trigger both allergic and intrinsic aeroallergens (pollen, animal epithelia, mold
asthma spores, housedust mites, etc.; see Sect. 3.4). The
most important occupational triggers of aller-
follows pathophysiologic criteria (Table 5.6). gic asthma are listed in Table 5.7 [6, 15, 16, 47].
The frequent distinction between extrinsic In the differential diagnosis, allergic alveolitis
(= allergic) and intrinsic (no antibodies de- (hypersensitivity pneumonitis), mostly caused
tected) is not satisfactory since the term in- by organic dusts, should be considered (see
trinsic is ill defined and would be better re- Sect. 5.4).
placed by cryptogenic. Mostly, the so-called Exogenous toxic irritative factors able to
infect-allergic or pathophysiologically unclear trigger and maintain bronchial asthma com-
conditions are included. In intrinsic asthma, prise chemicals [ozone, chlorides, sulfur ox-
the typical signs and symptoms of atopy, such ides, nitric oxides, isocyanates (partly also al-
as increased serum IgE, detection of specific lergic)] and physical stimuli (cold, mechanical
sensitizations in skin tests or RAST, are miss- dust effects, cigarette smoke, etc.), which act
Alveolar
macrophage
Dendritic Basophil
cell
Basalmembrane thickening
Matrix Cell infiltration
Eosinophil Edema
T-Cell
Extravasation B-Cell
Vessel Nerve
Neutrophil
Eosinophil Mast cells
Fig. 5.5. Components of
Mucosal hypertrophy asthmatic inflammation
Bronchial smooth muscle (according to Schultze-
Werninghaus)
5.1.2.5 Diagnosis
histamine, dust, cold air, exercise or hyperven-
The diagnostic procedure in asthma is shown tilation are used [1, 2, 13, 18, 34, 37, 41]. The
in Table 5.9. For allergy diagnosis in general, following test concentrations are used: acetyl-
see Chap. 4. In bronchial provocation tests, un- choline (1.0 100 mg/ml); methylcholine (0.05
specific stimuli like acetyl (or methyl) choline, 50 mg/ml); carbamylcholine (0.05 50 mg/ml);
5.1 Diseases with Possible IgE Involvement 85
Table 5.11. Unspecific irritation syndrome (accord- ply behavioral therapy, group therapy, auto-
ing to H. Dngemann) genic training, etc. (see also asthma schools be-
Physical low).
Temperature change, dust, fog
Chemical Climate Therapy. For rehabilitation of chronic
E.g., exhaust, smog, odors, chemical irritants asthma, climate therapy at sea level (North Sea)
Pharmacodynamic or at high altitude (e.g., Davos, Switzerland)
E.g., histamine liberators, q -blockers, certain has been shown to improve asthma by decreas-
spices, drinks, and drugs ing allergen exposure and unspecific climatic
Infectious diseases effects [7].
Infections of the upper airways
Psychological Mast Cell Blockers. Mast cell stabilizers (e.g.,
Stress, emotional disturbance disodium cromoglycate) act prophylactically
on the mucous membranes in preventing asth-
ma attacks. Disodium cromoglycate is given ei-
feathers in bed clothing, animal or plant mat- ther as a powder or as a 1 % solution (4 daily
tresses (horse hair, seaweed), pets (including every 6 h). Ketotifen acts both as a mast cell sta-
furs!), carpets, old upholstery, humidity, moist bilizer and as an antihistamine, has no direct
walls, plants (mold), as well as all dust-collect- bronchodilating effect but is prophylactically
ing furniture, sprays, and certain humidifiers. effective. Nedocromil sodium has mast cell sta-
In all forms of asthma, the avoidance of non- bilizer and anti-inflammatory properties.
specific stimuli is important, which can lead to
deterioration of any kind of asthma (unspecif- Antihistamines. Histamine H1 antagonists do
ic irritation syndrome according to Dnge- not play a major role in the treatment of asthma
mann [12]) (Table 5.11). (see Sect. 6.2 on Pharmacotherapy).
Finally, therapy of underlying infectious
disease should be mentioned, for instance pu- Leukotriene Antagonists and Inhibitors. In-
trid sinusitis, polypectomy with impaired nose hibitors of lipoxygenase as well as antagonists
breathing, and short-term antibiotic treatment of sulfidoleukotrienes have a place in asthma
after microbiological examination (e.g., Hae- therapy, especially in reducing glucocorticoste-
mophilus influenzae). roids in severe asthma [44].
Long-acting q 2-adrenergics have greatly im- mometasone, triamcinolone). These are also
proved asthma therapy. prophylactically active and allow a reduction of
systemic steroids in steroid-dependent asthma.
Anticholinergics. The atropine derivates ipra- Side effects comprise the possible occurrence
tropium bromide and oxitropium bromide can of candida infection as well as changes in voice
be used as aerosols and act more weakly than quality [28]; in children, a significant but small
q -adrenergics as bronchodilators, also pro- and reversible growth impairment has been
phylactically. They can be combined with q 2- observed. Topical Glucocorticosteroids can be
agonists. combined with long-activity q -agonists.
36. Reinhardt D (ed) (1996) Asthma bronchiale im 43. Virchow JC, Kroegel C, Walker C, Matthyss H
Kindesalter. Springer, Berlin Heidelberg New (1994) Cellular and immunological markers of al-
York lergic and intrinsic bronchial asthma. Lung
37. Schultze-Werninghaus G (ed) (1999) Deutsche 172:313 334
Atemwegsliga: Empfehlungen zur Allergiediag- 44. Virchow JC, Prasse A, Naya I, Summertin A, Har-
nostik bei Atemwegserkrankungen in der Praxis. ris A (2000) Zafirlukast improves asthma control
Pneumologie 48:300 304 in patients receiving high-dose inhaled cortico-
38. Schultze-Werninghaus G (1997) Die Immunthe- steroids. Am J Respir Crit Care Med 62:578 585
rapie (allergenspezifische Hyposensibilisierung) 45. Wahn U, Seger S, Wahn V (eds) (1999) Pdiatri-
bei Asthma bronchiale. Atemw Lungenkrh 23: sche Allergologie und Immunologie, 3rd edn. Ur-
701 707 ban und Fischer, Munich
39. Slavin RG, Reisman RE (eds) Expert guide to al- 46. Wettengel R, Berdel D, Cegla U, et al. (1994) Emp-
lergy and immunology. American College of Phy- fehlungen der Deutschen Atemwegsliga zum
sicians, Philadelphia, pp 23 40 Asthmamanagement bei Erwachsenen und Kin-
40. Szepanski R, Lecheler J (1995) Standard- und dern. Med Klin 89:57 67
Qualittssicherung der Asthmaschulung im Kin- 47. Worth H, Meyer A, Folgering H, Kirsten D, Leche-
des- und Jugendalter. Prv Rehab 7:1 41 ler J, Magnussen H, Pleyer K, Schmidt S, Schmitz
41. Tiffeneau R, Beauvallet M (1945) Production ex- M, Taube K, Wettengel R (2000) Empfehlungen
clusive deffets pulmonaires locaux par inhala- der Deutschen Atemwegsliga zum Sport und kr-
tion daerosol dacetylcholine. Son utilisation perlichen Training bei Patienten mit obstrukti-
comme test dinsufficance respiratoire. Sem Hop ven Atemwegserkrankungen. Pneumologie 54:
(Paris) 21:154 166 61 67
42. Townsley RG (1976) IgE levels and methacholine 48. Wthrich B (1976) Zum Allergenkatalog berufli-
inhalation responses in monozygous and dizy- cher Inhalationsallergien. Berufsdermatosen 24:
gous twins. J Allergy Clin Immunol 57:227 123
5.1.3.1 Definition
Urticaria is a disease with occurrence of self-
vanishing erythematous elevated skin lesions
which disappear and blanch under pressure
(wheals) (Figs. 5.6, 5.7). Identical skin lesions
are observed after injection of histamine into
the skin (Lewis triad: mild redness = local va-
sodilation, edema = increase in capillary per-
meability, flare = axon reflex). When the reac- Fig. 5.6. Urticaria factitia caused by tangential appli-
cation of force
tion occurs in the subcutaneous tissue, the dis-
ease is called angioneurotic or angioedema
(also Quinckes edema) (Fig. 5.8). Urticaria
comprises several clinical manifestations and
may be caused by immunological and non-im-
mune pathomechanisms.
5.1.3.2 Classification
Clinically, urticaria can be classified according
to:
1. The course: acute urticaria (< 6 weeks) and Fig. 5.7. Hive following a histamine injection
chronic urticaria (> 6 weeks). In between
are acute intermittent urticaria (several caria (continuous relapses with short remis-
acute episodes) and chronic relapsing urti- sions of several days).
90 5 Allergic Diseases (and Differential Diagnoses)
Allergic
Foods
Drugs
Aeroallergens
Insect venoms
Plant allergens
Contact urticaria allergens
Others
Toxic-irritative
Insects, plants (Urtica dioica)
Drugs (e.g., opioids)
Enzymes (proteases)
Pseudo-allergic
Acetylsalicylic acid, analgesics
Additives
Colorings
Physical
Mechanical (urticaria factitia, pressure, vibration)
Thermal (cold, heat)
Cholinergic (exercise)
Water
Electromagnetic radiation (e.g., solar urticaria)
Focus reactions
Fig. 5.8. Quinckes edema Parasites
Mycoses
2. Pathophysiological aspects (Table 5.12): Bacterial and viral infections
Neoplasia
There are few epidemiological studies re-
garding the prevalence of urticaria. It seems Enzyme defects
Angioneurotic edema
that the incidence of urticaria has been con- (C1 inactivator deficiency)
stant during recent years [10]. Prevalence of Hereditary
chronic urticaria is estimated at 1 3 % [4, 5, Acquired (neoplasia)
9, 40]; in 1991, after German reunification, Serum carboxypeptidase B deficiency
urticaria was more common in West Ger- Autoimmune diseases
man children compared to the East, follow- Urticaria vasculitis
Systemic lupus erythematosus
ing the pattern of hay fever and asthma Cryoglobulinemia
prevalence (see Sect. 3.3.2).
Psychosomatic conflicts
Acute urticaria is the most common type of ur- Stress
ticaria; it is estimated that 20 30 % of the pop- Depression
Other
ulation suffer once in their life from an episode
of acute urticaria. Mostly, acute urticaria heals Hormonal disturbances
Thyroid function disturbance
spontaneously, and sometimes medical help is Urticaria during menstruation or pregnancy
necessary. The etiopathogenesis often remains
Urticaria pigmentosa (mastocytosis)
unclear: Apart from acute infections, allergic
reactions need to be discussed. Histamine is Idiopathic urticaria
one of the most important mediator substances
[5, 11]. Often acute urticaria occurs after drug
medication during acute infection. In these indication of more intense diagnosis in either
cases the suspected drugs are often tolerated at very severe clinical manifestations (first degree
a later point in time. In up to 50 % no cause for of anaphylaxis), relapses, or when changing in-
acute urticaria can be elucidated. There is an to chronic urticaria.
5.1 Diseases with Possible IgE Involvement 91
When chronic urticaria is subdivided ac- The most common form of physical urti-
cording to pathophysiology (Table 5.12), ap- caria is urticaria factitia (also called dermo-
proximately 5 10 % is allergic in nature, graphic urticaria), when tangentially acting
15 20 % is pseudo-allergic, and 15 20 % is forces in the upper dermis induce histamine re-
triggered by physical stimuli. A large percent- lease. This form is often associated with psy-
age (approximately 50 %) remain etiopatho- chosomatic stress, but is also found in combi-
physiologically unclear (except for the rare nation with IgE-mediated allergy. The occur-
cases of hereditary angioedema). Psychoso- rence of urticaria factitia is variable and some-
matic influences as well as so-called focus re- times directly stress dependent (a female col-
actions are discussed when, e.g., gastrointesti- league of mine only had urticaria factitia on
nal disturbance, chronic infectious disease, au- Thursdays when Prof. Braun-Falco was doing
toimmune disease, neoplasms, or parasitic in- his grand rounds). I sometimes try to console
festation give rise to chronic urticaria. In recent my patients: Be glad that you are living today;
years, a new concept of autoimmune pathogen- some centuries ago, you would have been burnt
esis has been postulated: Autoantibodies as a witch!
against the high-affinity IgE receptor may play Cholinergic urticaria is characterized by the
a role which can be found in up to 50 % of pa- occurrence of small follicular wheals triggered
tients with severe chronic urticaria [9, 12, 28]. by exercise, sweating, or strong psychologic
Chronic urticaria in adults is more frequent stress.
in females (f : m = 2 : 1). The differential diagnosis of chronic urti-
caria comprises localized heat urticaria, where
at the site of heat application (45 50 C) wheals
5.1.3.3 Physical Urticaria
can be triggered [31]. In vitro warming of a ba-
A common subgroup of urticaria is represent- sophil suspension can induce histamine release
ed by the different forms of physical urticaria [32].
(Table 5.13) when specific physical stimuli in- Rather common is exercise-induced urticar-
duce wheals either: ia, which is often connected with food allergy
) On the site of contact (e.g., contact cold and sometimes the first stage of anaphylaxis
(see Sect. 5.1.4).
urticaria) or
) Generalized in a reflex phenomenon (e.g., A frequent form (15 % of physical urticaria)
is cold urticaria (Fig. 5.9), which can rarely
cholinergic urticaria, cold reflex urticaria)
Table 5.13. Classification of physical urticaria (f, frequent; r, rare; vr, very rare; AH, antihistamine; TAD, tricyclic
antidepressant; MS, mast cell stabilizer; GC, glucocorticosteroid)
Elicitor Pathophysiology Therapy
Dermographism (urti- f Psychosomatic influence, summation with IgE AH1 + AH2, TAD, Coun-
caria factitia) seling
Cholinergic (sweating) f Small follicular wheals, frequently psychosomatic AH + anticholinergics
Localized heat vr ? AH
Exercise f Summation with food allergy, anaphylaxis AH, MS
Cold f Rarely familiar, cryoglobulinemia, neutrophil in- AH, penicillin, dapsone
filtrate
Pressure f 4 6 h, neutrophils, ESR elevation AH?, GC, dapsone
Vibration vr Angioedema AH, GC
Electromagnetic radia- r Histamine not involved, specific eliciting wave AH?, photoprotection,
tion (solar urticaria) lengths chloroquine, hardening
Water vr Autoantigens in S. corneum? Skin care, AH
92 5 Allergic Diseases (and Differential Diagnoses)
A careful history taken by experienced aller- autologous serum test (Greaves test) [8, 9, 12,
gists/dermatologists is crucial. Psychosocial 23]. These patients may represent a subgroup
factors should be considered. HANE can be ex- where only systemic steroids or immunosup-
cluded by a careful family history and clinical pression is effective. For the autologous serum
observation (almost never wheals!). In the dif- test, we recommend a serum dilution of 1:100
ferential diagnosis of lid edema, sinusitis or in the intradermal test in order to avoid false-
emphysema of the orbita should also be ex- positive results [23]).
cluded. Examination of thyroid function is also rec-
Physical provocation tests are an essential ommended (4 6 % show disturbed thyroid
part of urticaria diagnosis and comprise prov- function or autoantibodies) [11, 17]. Amplifi-
ocation with cold, warmth, pressure, exercise, cation of in vitro histamine release through
as well as dermographism. Phototests with UV thyroid hormones has been described [22].
light are only done when there is a history of
light urticaria. History should also cover con- Urticaria Diagnosis: Step 3 (Provocation Tests).
tact urticaria [9]. HANE is characterized by a Step 3 comprises provocation testing using dif-
deficiency in C1 inactivator, which can be de- ferent dietary approaches sometimes em-
tected immunochemically, although in 15 % ployed under inpatient conditions in order to
only functionally [3, 15, 24]. standardize other environmental conditions
and guarantee possible emergency therapy for
Urticaria Diagnosis: Step 2 (Intensive Exami- anaphylaxis (Table 5.16). Provocation tests in-
nation). In step 2 the history is repeated. In ad- clude suspected foods as well as food additives
dition, the patient is advised to keep a diary of (oral provocation test for idiosyncrasy, OPTI)
diet and symptom course. A clinical examina- (see Sect. 5.1.5 on Food allergy). The marker
tion search for foci (Table 5.15) is performed substance in the provocation of chronic urti-
in cooperation with the relevant other disci- caria is acetylsalicylic acid; a high percentage
plines. Especially gastrointestinal disturbances (20 30 %) of patients have significant and
(e.g., Helicobacter pylori) may play a role. Urti- partly dramatic exacerbation of skin lesions,
caria vasculitis as the precursor of autoimmune sometimes together with anaphylactoid reac-
disease should be excluded. In the serum, auto- tions [5, 6].
antibodies against the high-affinity IgE recep-
tor (Fc 5 RI) of classes IgG 1 and IgG 3 can be de-
tected by immunoblot or functionally with the Table 5.16. Urticaria diagnosis: Step 3 (provocation
tests)
History
Table 5.15. Urticaria diagnosis: step 2 (intensive ex- Elimination and provocation diets
amination)
Clinical examination
History Skin biopsy with direct immunofluorescence
Diary for diet and symptoms Laboratory
Clinical examination Complement levels
Search for foci (ENT, teeth, gastrointestinal Thyroid hormones and antibodies
tract, thyroid, urology, gynecology, others) Others
Laboratory Allergy tests
Serum and urine analysis (routine) Avoidance diet
Antinuclear antibodies Provocation tests (food challenge)
Antistreptolysin, rheuma factor Oral provocation test for idiosyncrasy (OPTI) with
Others (e.g., cryoglobulins) additives and ASA
Allergy tests Autoimmune diagnostics (Greaves test, anti-
Food allergens (intradermal) bodies against Fc 5 RI)
Drugs (e.g., penicillin)
In vitro tests (RAST)
Possibly open patch test (contact urticaria)
5.1 Diseases with Possible IgE Involvement 95
and physicians need to know where they can 14. Juhlin L (1981) Modem approaches to treatment
get this preparation! of chronic urticaria. In: Ring J, Burg G (eds) New
In solar urticaria and mastocytosis, UV trends in allergy. Springer, Berlin Heidelberg
New York, p 279
hardening (UV-A or PUVA) can be used. 15. Kaplan AP (1981) The pathogenic basic of urti-
The general principle of any kind of urticar- caria and angioedema: Recent advances. Am J
ia management is the elimination of triggering Med 70:755 757
or maintaining factors, which keep the process 16. Kumar SA, Martin BL (1999) Urticaria and angio-
boiling (Fig. 5.11)! edema: diagnostic and treatment considerations.
J Am Osteopath Assoc 99 [Suppl]:1 4
17. Leznoff A, Sussmann GL (1989) Syndrome of idi-
opathic chronic urticaria and angioedema with
References thyroid autoimmunity: A study of 90 patients. J
Allergy Clin Immunol 84:66
1. Abeck D, Thomsen S, Pltz S, Ring J (1999) Die 18. Leznoff A (1998) Chronic urticaria. Can Fam
Biologische Urtikaria-Therapie. Acta Biol Physician 44:2170 2176
38:3 23 19. Maibach HI, Johnson HL (1975) Contact urticaria
2. Beissert S, Stauder H, Schwarz T (2000) UVA rush syndrome. Contact urticaria to diethyltoluamide.
hardening for the treatment of solar urticaria. J Arch Dermatol 111:720 730
Am Acad Dermatol 42:1030 1032 20. Merk H (1992) Urticaria und Rhinitis allergica:
3. Bork K, Witzke G (1989) Long-term prophylaxis In: Hornbostel H, Kaufmann W, Siegenthaler W
with C1-inhibitor (C1INH) concentrate in patients (eds) Innere Medizin in Praxis und Klinik, 4th
with recurrent angioedema caused by hereditary edn. Thieme, Stuttgart, pp 3281 3293
and acquired C1-inhibitor deficiency. J Allergy 21. Meurer M (1981) Urticaria vasculitis. In: Ring J,
Clin Immunol 83:677 Burg G (eds) New trends in allergy. Springer, Ber-
4. Braun-Falco O (1976) Entwicklungen in der Der- lin Heidelberg New York, pp 148 151
matologie. In: Braun-Falco O, Marghescu S (eds) 22. Mller J, Vieluf D, Ring J (1993) Schilddrsenhor-
Fortschritte der praktischen Dermatologie und mone als Amplifikatoren der Histamin-Freiset-
Venerologie, vol 8. Springer, Berlin Heidelberg zung unter Insektengift-Hyposensibilisierung.
New York, p 417 Allergo J 2 [Suppl 2]:77 80
5. Champion RH (1988) Urticaria then and now. Br 23. Ollert M, Ring J (2000) Urtikaria und Angio-
J Dermatol 119:427 436 dem. In: Przybilla B, Bergmann K, Ring J (eds)
6. Doeglas HMG (1975) Reactions to aspirin and Praktische allergologische Diagnostik. Stein-
food additives in patients with chronic urticaria, kopff, Darmstadt, pp 328 334
including the physical urticarias. Br J Dermatol 24. Opferkuch W, Kvary PM, Jaeger U, Echternacht-
93:135 Happle K, Gronemeyer W, Hammar C, Niemczyk
7. Ellis MH (1998) Successful treatment of chronic H, Rieger C (1981) Clinical aspects and therapy of
urticaria with leukotriene antagonists. J Allergy hereditary angioneurotic edema. In: Ring J, Burg
Clin Immunol 102:876 877 G (eds) New trends in Allergy. Springer, Berlin
8. Fiebiger E, Hammerschmid F, Stingl G, Maurer D Heidelberg New York, p 272
(1998) Anti-Fc 5 RI [ autoantibodies in autoimmune- 25. Paul E, Bdeker R-H (1987) Behandlung der chro-
mediated disorders. J Clin Invest 101:243 251 nischen Urticaria mit Terfenadin und Ranitidin.
9. Greaves M (2000) Chronic urticaria. J Allergy Allergologie 10:113
Clin Immunol 105:664 671 26. Ring J, Brockow K, Ollert M, Engst R (1999) Anti-
10. Haas N, et al. (1995) Vergleichende Studie zur histamines in urticaria. Clin Exp Allergy 29
Hufigkeit, Diagnostik und Therapie der Urtika- [Suppl 1]:31 37
ria in einer Hautpoliklinik. Allergologie 18:110 27. Ring J, Przybilla B (1987) Diagnostik der chroni-
113 schen Urtikaria. Med Welt 38:256 259
11. Henz BM (1996) Das Spektrum der Urtikaria. In: 28. Sabroe RA, Grattan CE, Francis DM, Barr RM,
Henz BM, Zuberbier T, Grabbe J (eds) Urtikaria. Kobza Black A, Greaves MW (1999) The autolo-
Klinik, Diagnostik, Therapie. Springer, Berlin gous serum skin test: A screening test for autoan-
Heidelberg New York, pp 1 17 tibodies in chronic idiopathic urticaria. Br J Der-
12. Hide M, Francis DM, Grattan CE, Hakimi J, Ko- matol 140:446 452
chan JP, Greaves MW (1993) Autoantibodies 29. Schfer T, Ring J (1996) Epidemiology adverse
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Med 328:1599 1604 Food allergies and intolerances. DFG, VCH Wein-
13. Illig L, Paul E (1978) Die Stellung der Antihist- heim, pp 40 54
aminika in der Urtikaria-Therapie. Hautarzt 30. Schmutzler W (1997) Histamin als Mediator all-
29:407 ergischer Reaktionen. Allergologie 20:536 542
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31. Skrebova N, Takiwaki H, Miyaoka Y, Arase S 35. Wthrich B (1989) Therapie der akuten und
(2001) Localized heat urticaria: a clinical study chronischen Urtikaria und des Quincke-dems.
using laser Doppler flowmetry. J Dermatol Sci Schweiz Rundschau Med 78:576 581
26:112 118 36. Zuberbier T, Henz BM (1996) Diagnostik der Ur-
32. Schrallhammer-Baenkler S, Ring J, Landthaler M tikaria. In: Henz BM, Zuberbier T, Grabbe J (eds)
(1985) Localized heat urticaria. Arch Dermatol Urtikaria. Klinik, Diagnostik, Therapie. Springer,
Res 277:406 Berlin Heidelberg New York, pp 137 156
33. Toubi E, Blant A, Kessel A, Golan TD (1997) Low 37. Zuberbier T, Aberer W, Grabbe J, Hartmann K,
dose cyclosporin A in the treatment of severe Merk H, Ollert M, Rueff F, Wedi B, Wenning J
chronic idiopathic urticaria. Allergy 52:312 316 (2004) Diagnostik und Therapie der Urtikaria.
34. Warin RP, Champion RH (1974) Urticaria. Saun- Leitlinie der DDG und DGAI. Allergo J (in press)
ders, London
fish, etc.) can elicit anaphylaxis. Insect venom pharynx, or genital mucosa are often the
anaphylaxis will be considered in a separate first symptoms
section (Sect. 5.1.6). ) The respiratory tract (sneezing, rhinorrhea,
Aeroallergens or vapors (e.g., fish odor) may hoarseness, dysphonia, laryngeal edema,
elicit anaphylaxis in highly sensitized individu- cough, bronchospasm, respiratory arrest)
als as well as contact urticariogens (contact ) Abdominal symptoms (nausea, cramps,
anaphylaxis against rubber gloves, ointments, vomitus, defecation, also miction and uter-
or in the open patch test) [33]. Similarly, all the us cramps occur)
elicitors of physical urticaria (see Sect. 5.1.3) ) The cardiovascular system (tachycardia,
may in severe cases lead to anaphylaxis (ana- blood pressure changes not necessarily
phylactic shock in the solarium in solar urti- hypotension, but also transient hyperten-
caria). Finally, so-called idiopathic anaphy- sion has been observed as first symptoms
laxis exists where people suffer repeatedly arrhythmia, shock, cardiac arrest). Primary
from anaphylactic episodes without clear-cut cardiac manifestation in anaphylaxis has
reasons, sometimes following exercise [32, 36]. been observed in ECG changes (T-flatten-
Not infrequently, the combination of differ- ing, supraventricular arrhythmia, AV
ent simultaneously acting stimuli (e.g., exercise block) [20, 24, 43, 44]. Marked changes of
or psychological stress together with certain central-venous pressure are common [39].
otherwise tolerated foods) elicit a reaction During anaphylaxis, myocardial infarction
which we call summation anaphylaxis [21, may occur [1, 6, 24, 31, 34, 43].
32]. Beta-blockers may enhance anaphylaxis
Prodromi of anaphylaxis comprise paresthesia
[13].
on palms and soles, metallic fishy taste, anxi-
Symptoms of anaphylaxis comprise mainly:
ety, sweating, headache, or disorientation.
) The skin (itch, flush, urticaria, angioede- According to the intensity of anaphylactic
ma) and the neighboring mucous mem- symptoms, a severity grading from I to IV has
branes; itchy palms, paresthesia in the proven helpful (Table 5.17) [30].
Autopsy of fatal cases has shown few specific complex anaphylaxis with high concentrations
findings; sometimes there is inflation of the of circulating IgG or IgM antibodies with com-
lung, and pulmonary edema with peribronchi- plement activation and formation of anaphyla-
al eosinophilic infiltrates. Sometimes hemor- toxins. Clinical examples are anaphylactic reac-
rhages in the gastric mucosa as well as hepato- tions after blood products, e.g., in IgA-deficient
splenomegaly are reported [1]. In immune persons after plasma replacement, anaphylaxis
complex anaphylaxis, fibrinoid deposits in the in serum sickness, or after xenogenic proteins
lung have been observed [38]. (antilymphocyte serum) as well as dextran
Some authors define anaphylaxis exclusively anaphylaxis [17, 29, 31, 38].
by the occurrence of cardiovascular symptoms. Besides immunological there are non-im-
For these cases, of course, grade I and II will be mune mechanisms, which will be considered in
missed, which, however, often turn into more Sect. 5.7.2 on Pseudo-allergic Reactions.
severe anaphylaxis at the next contact. Rohrer Neuropsychogenic reflex mechanisms
and Pichler examined 118 patients with cardio- should be considered especially when we know
vascular involvement and found skin symp- that psychic stress alone can lead to increased
toms in 88 %, respiratory reactions in 72 %, and plasma histamine (see Chap. 7 on Psyche and
gastrointestinal symptoms in 44 % [35]. Allergy).
In the end phase of an anaphylactic reaction,
similar mechanisms lead to clinical symptoms:
5.1.4.3 Pathophysiology
postcapillary plasma exudation and microcir-
Classical anaphylaxis is mediated by IgE an- culatory disturbance leads to decreased capil-
tibodies on the surface of mast cells and ba- lary pressure and perfusion [9, 22].
sophil leukocytes, which after bridging with Mast cell dependent anaphylactic reactions
an at least bivalent allergen trigger the secre- occur with an increase of mast cell tryptase in
tion reaction of preformed and newly synthe- the serum (see Chap. 4), which can be detected
sized mediators (see Chap. 2). In spite of our even hours (sometimes also postmortem) after
knowledge of mast cell activation and IgE an- a reaction [3].
tibodies, the exact mechanisms of amplifica- The mediator release reaction from mast
tion are not yet understood, which make it cells and basophils is not a cytolytic process
possible that a healthy individual may be but energy, calcium, and temperature depen-
killed by a few micrograms of an allergen dent and can be inhibited by specific antago-
within minutes. nists (e.g., via cAMP-elevating agents) (see
The extent of mediator release reaction dif- Chap. 2). The concomitant use of beta-blockers
fers between individuals but also in one and the and possibly also angiotensin-converting en-
same individual at different times. The term zyme inhibitors (ACE inhibitors) may lead to
releasability describes this phenomenon. an enhancement of anaphylactic symptoms
Factors influencing releasability comprise cy- [13]. In patients with insect venom anaphylax-
clic nucleotides, cytokines, psychoneurogenic is, we found a significant inverse correlation
(autonomic nervous transmitters, neuropep- between the plasma angiotensin II level and the
tides) and hormonal influences (e.g., thyroid). severity of anaphylactic symptoms in history
Among the cytokines, interleukin-3 has special [14]. Under allergen-specific immunotherapy,
importance in priming mast cells and baso- the previously lowered angiotensin II levels
phils and enhancing releasability. These phe- normalized [14].
nomena are not only of scientific interest, but
gain practical relevance in helping to explain
5.1.4.4 Allergens and Elicitors
the often confusing variability of symptom-
atology underlying the term summation or The most common elicitors of anaphylaxis are
augmentation anaphylaxis (see below). drugs, proteins, foods, aeroallergens, additives,
Apart from IgE, other antibody classes may body fluids, latex, microbial antigens, but also
elicit anaphylactic reactions: There is immune physical factors (Table 5.18).
100 5 Allergic Diseases (and Differential Diagnoses)
Table 5.18. Elicitors of anaphylactic reactions Table 5.19. Differential diagnosis of anaphylaxis
Table 5.20. Prophylaxis of anaphylactic reactions basis of prophylaxis. General rule: The more se-
Exact diagnosis
vere the anaphylactic symptoms to be expected,
Avoidance strategies the sooner they will become manifest! Of course,
Information from the patient (allergy passport) there are exceptions from the rule in the form
Strict indication for pharmacotherapy of tricky late anaphylactic reactions after
Avoidance of q -blockers several hours [31, 41]; often, however, mild
If possible oral administration
Observance of the patient after injection symptoms occur within the first 20 min which
Prophetic testing in selected cases tend to be overlooked.
Hyposensitization (or adaptive deactivation)
Tolerance induction
Hapten inhibition 5.1.4.7 Therapy
Premedication (e.g., with histamine H1 and H2
antagonists or antihistamines plus steroids) The treatment of anaphylaxis follows the sever-
Emergency set (for self-medication) ity of symptoms (Fig. 5.12). If the reaction only
involves the skin (urticaria) with a stable car-
diovascular system, antihistamines may be suf-
as a risk factor is controversial and is probably ficient. In any case, an intravenous catheter
limited to IgE-mediated reactions. should be placed and an infusion prepared.
Only in a few cases is specific prophylaxis If the reaction proceeds (and the differential
possible such as induction of tolerance against diagnosis is easy!) glucocorticoids and epi-
xenogenic immunoglobulin in heterologous nephrine (0.3 mg i.m., in children 0.1 mg/kg
protein therapy [31] or by hapten inhibition in body wt.) should be given, in dyspnea together
dextran anaphylaxis [17, 29, 31]. with theophylline (0.24 0.48 mg) plus q 2-adre-
The combined administration of H1 and H2 nergics.
antagonists or antihistamines together with In fully developed anaphylactic shock, the
glucocorticosteroids is recommended for the general principles of shock therapy are applied
prophylaxis of anaphylactoid reactions after [8, 10, 11, 22, 26, 27, 37, 42]. Epinephrine can be
volume substitutes or radiographic contrast given intravenously (dilute the commercial
media [19] (see Sect. 5.7.2 on Pseudo-allergic ampule 1 ml in 10 ml saline for slow infusion of
Reactions). 1 3 ml under pulse control; if needed, up to
Observation of the patient in the first min- 10 ml and more) or more practically subcuta-
utes after parenteral drug administration is the neously. In patients on q -blockers, i.v. glucagon
Symptoms Treatment
Resuscitation
Cardiac and/or
respiratory arrest ABC-rule
Volume
Shock r it y
ve O2
Cyanosis Se
Epinephrine (1:1000) 0,3-1 ml
Antihistamines i.v.
Urticaria
Flush
Fig. 5.12. Immediate action to be Stop Antigen-(eliciting agent)! i.v. catheter
taken in the event of anaphylactic
reactions of varying severity I II III IV
102 5 Allergic Diseases (and Differential Diagnoses)
(1 2 mg) is beneficial [46] in restoring q -re- ment of grade I and II reactions. Possibly, H2
ceptor responsiveness. For self-medication, antagonists have an additional beneficial effect
epinephrine as autoinjector (Epi-pen or in anaphylaxis [7]. We recommend in severe
Fastject) is recommended. The undoubted anaphylaxis the additional administration of
effect of epinephrine, however, does not guar- high-dose glucocorticosteroids (e.g., 1 g pred-
antee a successful outcome: in spite of early epi- nisolone i.v.), if only to avoid late complications
nephrine, fatal anaphylactic reactions have [31].
been observed [18]. Furthermore, epinephrine The necessary emergency equipment for
may induce severe cardiac arrhythmia until treatment of anaphylaxis is listed in Table 5.22.
ventricular fibrillation occurs especially in el- Patients who have suffered an anaphylactic
derly patients [4, 23, 39, 40, 44]. reaction of grade III and IV should be kept un-
In severe hypotension, intensive volume re-
placement (e.g., crystalloids or hydroxyethyl
starch up to 1,000 ml as rapid infusion) is vital. Table 5.22. Emergency equipment for the allergists
Levarterenol [12], metaraminol, or dopamine office
may also be applied. In grade IV reactions (car-
Tourniquet, disinfectant
diac or respiratory arrest), only immediate and
Syringes, cannulas, infusion sets, connecting
adequate resuscitation measures are life-saving
pieces
[8] (Table 5.21).
Blood pressure, stethoscope
In addition to the classical rule of resuscita-
tion (ABC rule), the treatment of severe ana- Laryngoscope
phylaxis requires the AAC rule (Fig. 5.13) [31]. Guedel and intratracheal tubes (size 0 5 Guedel,
The use of glucocorticosteroids in anaphy- 28 32 Wendel, 3 8 mm intratracheal)
laxis is controversial (see references cited in Oxygen
[31, 34]). Steroids need some time until they act Breathing masks (for children and adults)
(approximately 15 min). They are not as useful Ventilation device (Ambu)
for monotherapy as antihistamines in the treat- Suction pump
ECG (possibly with defibrillator)
Table 5.21. Basic rules of resuscitation Infusion solutions (NaCl, human serum albumin,
hydroxyethyl starch, sodium bicarbonate)
Diagnosis (evaluation of severity, carotid pulses)
Airways (clearing and respiration) Antihistamines (e.g., clemastine, dimetinden, rani-
Oxygen tidine ampules)
Call help (get someone to call) Glucocorticosteroids (e.g., prednisolone hemisuc-
Cardiac massage/respiration cinate 250 mg, triamcinolone 1 g)
Venous catheter plus volume therapy (pressure in- Atropine (0.5-mg ampules)
fusion)
Intubation Theophylline (0.24-g ampules)
ECG (?) Epinephrine (e.g., Suprarenin ampules = epineph-
Defibrillation (?) rine 1:1,000)
Pharmacotherapy (epinephrine, sodium bicarbon-
ate, dopamine, lidocaine, possibly atropine, etc.) Beta-adrenergics (e.g., fenoterol, salbutamol)
Glucagon (ampules)
Spasmolytics (e.g., diazepam)
Airway Antigen off Antiemetics (e.g., metoclopramide)
Breathing Adrenaline1 Analgesics (tramadol)
+
Antihypertensives ( [ -blockers)
Circulation Cortisone2
Antiarrhythmics (lidocaine 2 % ampules, digoxin
1
1:1000: 0.5 ml i.m. or slowly i.v. ampules)
2
e.g. prednisolone: 12 g Calcium ampules, glucose ampules, saline, aqua
dest. ampules
Fig. 5.13. The AAC Rule
5.1 Diseases with Possible IgE Involvement 103
der supervision in hospital at least overnight; zation and sting challenge. Int Arch Allergy Im-
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ijnzeel-Koomen, Dreborg S, Haahtela T, Kowalski
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should only be done under emergency condi- nomenclature for allergy. An EAACI position
tions. statement from the EAACI nomenclature task
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39. Smith PL, Kagey-Sobotka A, Blecker ER, Trayst- 46. Zaloga GP, Delacey W, Holmboe E, Chernow B
man R, Kaplan AP, Gralink H, Valentine MD, Per- (1986) Glucagon reversal of hypotension in a case of
mut S, Lichtenstein LM (1980) Physiologic mani- anaphylactoid shock. Ann Intern Med 105: 65 66
Food allergies manifest frequently on the skin der) as well as between mugwort pollen and
(60 %), the GI tract (20 %), the airways (20 %) spices (anis, curry, etc.) and celery (see
and the cardiovascular system (10 15 %) [29]. Sect. 3.3.4 on Allergens) [1, 57, 67].
Food-induced contact urticaria or contact der- Food allergens may be altered by preparato-
matitis represent special forms. ry procedures (e.g., boiling) [20]. Many aller-
Adverse food reactions are a frequent prob- gens, however, are relatively resistant to pH
lem (Sect. 3.1.2). changes, heat, and proteases.
Few fields of allergology have comparable IgE-inducing food allergens are glycopro-
difficulties with parascientific practices such as teins. Small chemicals may elicit systemic con-
food allergy, especially when patients only suf- tact dermatitis (e.g., nickel, fragrances) [32].
fer from subjective complaints elicited through Elicitors of pseudo-allergic reactions comprise
foods (tension, fatigue, behavioral changes, additives and biogenic amines [29, 31, 39].
etc.). The movement of clinical ecology has
focused interest on so-called allergic reactions Gene Technology and Food Allergy. Gene
against pollutant chemicals especially in foods technology can lead to food changes of allergo-
manifesting as psychiatric diseases [14, 19] (see logical relevance. This can be either as in-
Sect. 5.10 on Eco-syndrome). creased risk as in the introduction of the major
allergen of Brazil nuts into soy [38] or as chance
(production of hypoallergenic rice). The rec-
5.1.5.2 Food Allergens
ommendations of the German Society for All-
The most common food allergens in Central ergology and Clinical Immunology (DGAI) re-
Europe are cows milk, hens eggs, nuts, spices, garding gene technology and foods are listed in
vegetables, cereals, fish, meat, and fruits. Re- Table 5.31.
gional, ethnic-cultural aspects play an impor- In the following, the most important food
tant role as well as age and underlying diseases. allergens are briefly discussed:
Of practical importance are cross-reactions
between different fruits (e.g., apple, peach, Cows Milk. Milk is the secretion product of
cherry) and tree pollen (e.g., hazel, birch, al- the mammary glands of mammals. The species
106 5 Allergic Diseases (and Differential Diagnoses)
Table 5.25. Dietary recommendations employed in can be used for therapy of cows milk allergic
food allergy and other adverse food reactions individuals. This needs to be evaluated using a
1. Diagnostic diets prick test [3].
Allergy diet no. 1 (allergen-free): short-term, up Cross reactions between cows milk and beef
to 10 days, prior to provocation or after acute or veal are possible but rare (most likely due to
reaction BSA). Allergies against horse mares milk (also
Allergy diet no. 2 (allergen-poor): up to 3 weeks, after topical application) can occur.
basis for provocation tests
The common dietary recommendation of
Allergy diet no. 3 (additive-free): can be given
over months, basis for provocation with additives
pork avoidance in allergic individuals or ato-
pics is rarely based on manifest allergy, but is
2. Stepwise diets (diagnostic and therapeutic)
rather of historic, cultural origin.
Stepwise elimination (interval days or weeks)
Stepwise provocation (interval days or weeks)
Hens Eggs. Specific IgE antibodies against
3. Therapeutic diets hens eggs are the best marker of atopy risk in
Specific allergen avoidance
Additive-free diet (hypersensitivity to additives) the newborn (even if the child has been exclu-
Nickel- or fragrance-free diet (in patients with
sively breast-fed); obviously, small amounts of
positive oral provocation test and systemic con- allergens reach the infant through the maternal
tact dermatitis) nutrition and breast milk. The major allergen is
Gluten-free diet (in sprue, dermatitis herpetiformis) ovomucoid (Gal d 1) from the clear part besides
4. Prophylactic diets (general antiallergic diet) ovalbumin (Gal d 2) and ovotransferrin (Gal d
Breastfeeding in infants 3) and lysozyme (Gal d 4). In the yellow part of
Hydrolyzed cows milk formula the egg, livetin, apovitillin, and vosviten can be
Hypoallergenic (oligoantigenic) diet of the mother found, which may play a role in adult hens egg
during lactation allergics. Cross-sensitizations between hens
eggs and poultry meat (chicken, turkey, duck,
goose) have been described.
is important. Plant extracts should not be Cereals. Here we have to distinguish between
falsely called milk (e.g., soy milk). Cows the food and the respiratory allergy (in bakers).
milk contains up to 30 35 g protein/ml, 80 % It is interesting that most asthmatic flour-aller-
of which is casein and 20 % whey protein (be- gic bakers may be able to eat cereals without
ta-lactoglobulin, alpha-lactalbumin, bovine problems. Cross-reactions between different
serum albumin, as well as immunoglobulins). flours are less frequent than between pollen al-
The most common allergens are whey pro- lergens of the same species. The most frequent
teins (beta-lactoglobulins) but also casein, cereal allergy is wheat allergy; patients are not
which is not species-specific and shows cross required to avoid other cereals. In one-fourth
reactions between cattle, goat, sheep, etc. Dur- of patients cross-reactions exist to grass pollen
ing milk preparation, whey proteins remain in and other cereal flours without symptoms of
solution while casein coagulates; in spite of food allergy. Cereals may elicit exacerbation of
this, whey proteins may be present in cheese atopic eczema which may be diagnosed using
or butter as well as casein in whey. Casein is the atopy patch test (see Sect. 5.5.3).
heat-stable, whereas whey proteins are partly
denatured. Vegetables/Fruit. Many patients with pollen
Allergenic proteins may be denatured to dif- allergy are also allergic against fruit and vege-
ferent degrees by hydrolysis, leading to so- tables on the basis of the known cross-reac-
called hypoallergenic infant formulas. The tions (see Sect. 3.4). The relevant plant proteins
term hypoallergenic is not well defined. One exert different functions (hydrolases, carrier
distinguishes between prophylactically hypo- proteins, enzyme inhibitors, stress proteins).
allergenic preparations (a low degree of hydro- One of the most common pathogenesis-relat-
lysis) and strongly hydrolyzed products, which ed proteins is the major allergen from birch pol-
5.1 Diseases with Possible IgE Involvement 107
len (Bet v 1), which is not only present in pollen opment of food allergy perhaps through en-
of different trees (hazel, alder, oak, beech, etc.) hanced resorption as well as absorption-en-
but also in foods (apple, prunes, carrots, nuts, hancing substances (alcohol, spices) or hectic
celery). It is heat-sensitive. Many apple-allergic and excessive monoalimentation (e.g., case of
individuals tolerate apple mousse. Bet v 2 = hens egg allergy after the intake of 24 raw eggs
profillin as a structural protein is heat-stable during a bet) [66].
[13]. Immune reactions play a role in normal gas-
Celery represents a major problem for many trointestinal physiology; this has been shown
food-allergic individuals; minute amounts may in experiments when sensitized dogs digested
elicit severe reactions (anaphylaxis) (e.g., cel- orally applied proteins much better, probably
ery salt in salad). due to gastrin release, stimulated via antigen-
Patients with latex allergy often show cross- presenting cells and T cells in the gastric mu-
sensitization to certain foods such as kiwifruit, cosa and release of cytokines [41]. Gastrin it-
avocado, buckwheat, chestnut, and lychee. self acts on mast cells as a histamine liberator.
Among the legumes, the most common al- It is not yet clear whether allergens need to be
lergens are soy and peanut (peanuts are not absorbed totally in order to elicit food-allergic
nuts!). Severe reactions to minute amounts of reactions. Normally proteins and high molec-
peanut allergen in other foods prepared in the ular weight food constituents are enzymatical-
same machines where peanut butter has been ly digested in the gut. Only the gut of the infant
prepared have been reported. and small child shows a higher permeability.
Soy not only is a relevant allergen for chil- Experimental investigations, however, show
dren (supplement for cows milk) but also for that also in adult organisms, a small percent-
adults. Often, allergic individuals do not re- age of high molecular weight proteins passes
cognize soy in the food (hidden allergens) the gut undigested and with immunologic ac-
(allergic reactions to peas and lentils are rather tivity [53].
rare). Food allergies may develop via different
mechanisms (Table 5.24). The most important
Fish and Seafood. Fish allergy is especially clinical conditions are due to IgE-mediated all-
common in populations on the coast. The first ergic or corresponding pseudo-allergic imme-
chemically defined food allergen was the ma- diate-type reactions [29, 31, 47, 62].
jor allergen of codfish (Gad c 1) [1]. There are Rare forms of IgG- or IgM-mediated reac-
multiple cross-reactivities to other fish but tions manifesting a serum sickness, arthralgia,
rarely to crustaceans and mollusks. The fish or vasculitis and fever can occur [17]. Cellular
allergen is very heat-stable and also volatile hypersensitivity against microbial or mucosal
(patients with severe asthmatic reaction and antigens has been discussed in the pathogene-
anaphylaxis over 50 m distance from a fish sis of ulcerative colitis or m. Crohn [9, 30].
food store). The obvious relationship between the gastro-
While seafood represents a delicacy in some intestinal tract and skin in food allergy has not
countries, it is a basic food for large popula- been explained pathophysiologically. Pichler
tions of the world. The major allergen of [40] distinguishes three types of food allergy:
shrimps (Met e 1) corresponds chemically to a
Type A: The sensitization occurs orally and in
tropomyosin and shows cross-reactivity to
early life; major allergens are cows
some arthropods (housedust mites).
milk, hens eggs, fish, peanut, etc.
Each foreign protein in foods is spe-
5.1.5.3 Pathomechanisms cifically recognized, but induces tol-
erance in normal individuals. In early
Little is known about the mechanism of sensiti-
life, there is a risk of IgE formation in
zation in food allergy [2, 24, 25, 56]. Apart from
the special conditions of immune
the genetic predisposition, acute inflammatory
deviation. While cows milk and
diseases of the gut may play a role in the devel-
108 5 Allergic Diseases (and Differential Diagnoses)
a b
Fig. 5.14a,b. The cause of a severe anaphylactic reaction occurring after a breakfast of Munich white sausage in
a patient who regularly ate white sausage from the same butchers shop was elucidated with the RAST inhibi-
tion test [54]: Chicken allergens (due to the non-declared addition of turkey meat to the sausage meat) proved
to be the culprit!
5.1 Diseases with Possible IgE Involvement 109
Table 5.26. Stepwise diet for adults (according to Ring Table 5.28. Oral provocation test for idiosyncrasy
and Braun-Falco [47]) (OPT1) (according to Ring and Przybilla)
Step 1 Cows milk and cows milk products Day 1 Tartrazine 10 50 mg, PHB ester 500 mg
Step 2 Carbohydrates and vegetables
Day 2 Color mixture III
Step 3 Meat
Color mixture I (5 mg each): quinoline yel-
Step 4 Poultry and hens eggs
low E104, yellow-orange S110, azorubine
Step 5 Fish and seafood
E122, amaranth E123, cochineal red E124
Step 6 Mixed food containing additives
Color mixture II (5 mg each): erythrosin
E127, patent blue E131, iron oxide E172
Table 5.27. Stepwise diet in small children Day 3 Sodium benzoate 50 250 500 mg
Step Foods to be added Day 4 Potassium metabisulfite 10 50 100
(300) mg
1 Tea (fennel) with glucose plus mineral water
2 Carrots Day 5 Acetylsalicylic acid 50 250 500
3 Oats (1,000) mg
4 Potatoes Day 6 Possibly repetition, nitrites, tyramine, pro-
5 Bread (wheat) pionate, other benzoates or colorings, glu-
6 Noodles tamate, etc., placebo
7 Pears
8 Rice
9 Soy capsules contain coal, mannose or silicate.
10 Cows milk Foods can be blinded with carob and colored
11 Veal
12 Beef
juices (blackcurrant). In severe reactions or
13 Pork multiple allergies, food challenges should be
14 Chicken performed under inpatient conditions in order
15 Hens eggs to guarantee optimal standardization and
16 Leguminosae avoidance of additional allergens.
17 Citrus fruits
18 Chocolate, lemonade, sweets Provocation parameters include subjective
and objective complaints (pulse, blood pres-
sure, inspection of the skin, platelet and leuko-
In cases with an unclear history, patients cyte count, sometimes measurement of vasoac-
should keep a diet diary and try to certain tive mediators for, e.g., histamine, ECP, tryp-
avoidance diets [47] (Table 5.25). In parallel, al- tase).
lergy diagnosis in vivo and in vitro should be After oral provocation, alterations of the
done. After avoidance diets (most suspected mucosal surface have been observed on X-ray
substances), provocation diets with a slow rein- [66]. Using intragastral provocation under en-
troduction of different foods (Tables 5.26, 5.27) doscopic control (IPEC), local mucosal reac-
are tried out, which need to be individually tai- tions can be visualized [43]. Similarly, intramu-
lored [6, 21, 47]. cosal allergen injection into the colon (colonic
If necessary, oral provocation tests with allergen application = COLAP) has been per-
foods and food additives should be performed formed [7]. These investigations cannot be rec-
such as the oral provocation test for idiosyn- ommended for routine diagnosis and should
crasy (OPTI) (Table 5.28). Preservatives such as be used for rare cases with unclear test results.
benzoates and sulfites sometimes are not de- From our experience with IPEC, however, we
clared properly and can elicit pseudo-allergic know that double-blind placebo-controlled
reactions (see Sect. 5.1.3 on Urticaria). Sul- food challenge can have false-negative results:
fites are contained especially in dried fruit, In spite of massive erythema and petechial
fruit juice, wine, but also deep-frozen vegeta- bleeding of the gastric mucosa, there were no
bles (e.g., potatoes) and at the salad bar [54]. subjective complaints felt by the patient!
Provocation tests should be done blinded, at
least single-blind, in order to reduce the psy-
chosomatic influence [6, 10, 15, 37]. Placebo
110 5 Allergic Diseases (and Differential Diagnoses)
Table 5.31. Statement published by the German Society for Allergology and Clinical Immunology (DGAI) re-
garding gene technology and food allergy
Many people are worried by the introduction of gene technologically altered foods. In this context, the ques-
tion regarding the risk of food allergy through gene technological procedures is real. The German Society for
Allergology and Clinical Immunology (DGAI), therefore, publishes the following statement:
1. Food allergies are a real and widely prevalent clinical problem, independent of gene technology. The prev-
alence of food allergy in the total population is not precisely known. Estimates range from 2 % to 4 % in
adults and from 5 % to 10 % in childhood. The symptoms of allergic food reactions are multiple and cover
mild reactions (itching, nausea, etc.) up to life-threatening shock conditions (anaphylaxis).
2. In the cultural development of mankind artificial procedures have been used for millennia by which the
nature of possible allergens is changed through technological procedures (e.g., boiling of food). On the
other hand, classical breeding techniques in botany have led to the creation of new species characterized
by a multitude of altered proteins (500 1,000 genes involved); this phenomenon has never led to anxiety
in the general population.
Through the progress in gene technology, for the first time it is exactly known which genes are involved
and how they are altered and expressed in foods. The major novel aspect of this technology is the tremen-
dously improved state of knowledge.
3. Gene technological procedures may lead to changes in foods with possible relevance for allergy; this re-
gards both the risk (e.g., Brazil nut allergen in soy beans) and chance (e.g., hypoallergenic rice).
4. Therefore, it is important prior to the introduction of a novel product to fulfill specific safety criteria re-
garding allergy:
Sequence homology of the altered proteins has to be compared with well-known allergens
Immune reactivity against positive sera or skin test reactions in sensitized individuals has to be tested
Stability against enzymatic digestion has to be studied.
Unless these safety data exist, gene technologically altered products should not be used for the preven-
tion of allergic disease in infants.
One actual problem has to be seen in the fact that the evaluation of immunoreactivity in humans can
only be tested with known allergens in defined sensitized populations. New proteins cannot be tested
in this manner. Here, animal experiments or in vitro models for predictive testing need to be developed.
5. The German Society for Allergology and Clinical Immunology has recommended for many years an im-
provement in the declaration not only of additives, but also of food contents, independently of technologi-
cal procedures. It remains open whether the gene technologically produced procedure should be espe-
cially declared in identical proteins.
6. The German Society for Allergology and Clinical Immunology recommends the presence of persons with
allergological expertise on the relevant committees involved with food production and control.
11. Deutsche Gesellschaft fr Ernhrung (ed) (1995) The role of histamine in wine intolerance. J Aller-
Richtig essen. F+G Rollendruck, Berlin gy Clin Immunol 89:197
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Arthropoda
Insecta
Hymenoptera
Solenopsis Pogonomyrmex
Polistes spp.
Fig. 5.15. Taxonomic classification of the most important Hymenoptera species responsible for insect venom
allergies
5.1.6.2 Symptomatology
Allergic reactions against insect stings have
been known for a long time [26] and range from
hyperergic local reactions to anaphylactic
shock. Strong local reactions also are often IgE
mediated [1], but do not represent an indication
for allergen-specific immunotherapy. They are
Fig. 5.16. The most important Hymenoptera species more frequent in hematologic disease (e.g.,
responsible for insect venom allergies (R. Jarisch)
lymphatic leukemia) [54, 58]. Anaphylactic
symptoms can be classified according to severi-
amount of stings, individuals who are not sen- ty (see Sect. 5.1.4 on Anaphylaxis; Table 5.17).
sitized may be in danger [44]. Table 5.32 shows The severity scale proposed by H.L. Mueller et
the contents of bee and wasp venom [5, 12]. In al. is more complicated in practice [30].
bee venom, the peptide melittin represents the
major product, characterized by a strongly ba-
5.1.6.3 Diagnosis
sic group on one end and a hydrophobic side-
chain on the other end, of the molecule. This History. Often the eliciting insect species can-
detergent effect leads to lysis of cells. Melittin is not be remembered [28, 29]. The severity of the
a weak allergen. Only 3 % of bee-venom-aller- reaction also needs to be determined through
gic individuals are sensitized to melittin. The cooperation with the physician treating the re-
major allergen of bee venom is the enzyme action and the therapy given. The question re-
phospholipase A2. Apamin has neurotoxic ef- garding atopy is important for interpretation of
fects. The phospholipase A2 from wasp venom skin test and RAST results [39]. There are stan-
shows no cross-reaction to the corresponding dardized questionnaires [47].
116 5 Allergic Diseases (and Differential Diagnoses)
Skin Tests. Skin tests (4 weeks after the sting) Table 5.33. Risk factors for insect venom allergy (ac-
are performed under emergency conditions cording to [46])
using endpoint titration with venom extracts Risk factors regarding exposure
(skin prick test beginning with 1 g/ml and in- Occupations with increased exposure to Hyme-
creasing the concentration to 300 g/ml; if neg- noptera (e.g., fruit and pastry workers, firefight-
ative, intradermal tests are performed with ers, forestry workers, agriculture workers, gar-
deners, refuse disposal workers)
0.01 1 g/ml). A second reading after 24 h for Intense outdoor leisure activities (e.g., gardening,
documentation of non-IgE-mediated reactions swimming, tennis, biking, jogging, golf)
is sensible. Beekeeping by the patient himself, neighbors or
family members
In Vitro Allergy Tests. Apart from total serum Motor cycling
IgE, specific IgE possibly also IgG subclasses Risk factors due to underlying disease
against bee and wasp venom is determined Diseases such as cardiovascular disease, asthma,
mastocytosis
[9]. Using cellular tests as in vitro histamine re- Elderly age
lease or basophil activation (CD 63) or CAST High physical or psychological stress
ELISA, additional information can be obtained Medication with q -blockers or ACE inhibitors
[47] (see Chap. 4 on Allergy Diagnosis). (possibly also NSAIDs)
Severe systemic reaction after insect stings
(> severity grade III) in the history
Indication for Allergen-Specific Immunother-
apy. On the basis of history, skin test, and in vi-
tro tests, the indication for immunotherapy is indications, see Sect. 6.3 (Immunotherapy).
evaluated by considering possible ris factors Age alone does not represent a contraindica-
(Table 5.33). Allergen-specific immunotherapy tion [18].
is indicated in patients with an objective gener-
alized systemic reaction and demonstration of Sting Provocation. Sting challenge with hon-
IgE-mediated sensitization. For general contra- eybees or wasps should not be used as a diag-
5.1 Diseases with Possible IgE Involvement 117
nostic instrument in patients prior to allergen- Table 5.34. Dose schedule (in micrograms) for rush
specific immunotherapy! It is an instrument of hyposensitization. The schedule holds true for pa-
tients with optimal dose increases
control of therapeutic efficacy. Severe compli-
cations have been observed [3]. Day Conven- Hamburg Ultrarush
tional schedule
1 0.02 0.001 0.01
5.1.6.4 Allergen-Specific Immunotherapy 0.04 0.01 0.1
(Hyposensitization) 0.08 1.0
0.2 10.0
In 1930, Benson and Semenov reported the 20.0
case of a beekeeper suffering from asthma and 40.0
anaphylaxis while working with bees [4]. After 80.0
immunotherapy with a whole-body extract of 2 0.4 0.1 100.0
0.8 0.4 100.0
homogenized honeybee, the asthma improved. 1.0 0.7
Based on this report, a worldwide practice of 4.0
immunotherapy of insect venom allergy with 3 8.0 1.0
whole-body extracts started with reports of 10.0 4.0
therapeutic effects in up to 75 % of cases [30]. 20.0 7.0
30.0
Early evidence of possible hyposensitization 4 10.0 10.0
with purified bee venom [17, 26] was probably 20.0 40.0
not followed because of anaphylactic complica- 60.0 70.0
tions [10, 27]. Only after it was shown that bee 70.0
5 40.0 100.0
venom and whole-body extracts contain very 50.0
different allergens [23] and that the relevant al- 60.0
lergens are in the venom [22] was hyposensiti- 70.0
zation with venom extracts proposed [9, 14, 22, 6 80.0
90.0
40, 43, 56]. Lichtenstein et al. pioneered the 100.0
work with a double-blind study: From three 8 100.0
groups of 20 patients each, 58 % of the placebo- 15 100.0 100.0
treated, 64 % of the whole-body extract treated, 22 100.0 100.0
but only 5 % of the bee venom extract treated 36 100.0 100.0 100.0
50 100.0 100.0
patients reacted to sting challenge. This study 71 100.0 100.0 (Day 43) 100.0
was only possible through the production of 92 100.0 100.0 (Day 71) 100.0
purified venom extracts in larger amounts. Bee 120 100.0 100.0 (Day 99) 100.0
venom is produced by electrical stimulation of (to be continued every 4 weeks)
bees [5]; wasps have to be killed, operated on,
and the venom sac removed. For 500 g wasp
venom, 250 collectors have to work for 1 year positive allergen solution and increase the dose
and need 74 million insects (= 6,000 kg). by 0.2, 0.4, and 0.8 ml to the next higher con-
The future will show the place of recombi- centration. Ultrarush schedules have been
nant allergens (recombinant phospholipase A2 published [6, 42, 57], increasing the dosis over
from bee venom) in practical allergy [32]. 1 or 2 days. Conventional immunotherapy pro-
There are various methods of allergen-spe- tocols with weekly injections should only be
cific immunotherapy (Table 5.34) by which the performed preseasonally [15]. After reaching
standard maintenance dose of 100 g every the maintenance dose, intervals are slowly in-
4 weeks is reached. According to a schedule of creased from 1, 2, 3 to finally 4 weeks.
rush hyposensitization with up to four injec-
tions a day the maintenance dose can be Therapeutic Efficacy. As demonstrated by
reached in approximately 1 week. sting challenge under emergency conditions,
We start with 0.1 ml of a concentration cor- allergen-specific immunotherapy with Hyme-
responding to 1/100 of the lowest prick test noptera venoms is effective in 80 100 % of pa-
118 5 Allergic Diseases (and Differential Diagnoses)
Systemic anaphylac- Systemic reactions in history (severity grade) Table 5.35. Results of
tic reactions after sting provocation and
sting provocation I II III IV Total severity grades (highest
(severity grade) n (%) n (%) n (%) n (%) individually stated
severity grades) of ana-
None 19 (90.5) 61(78.2) 40 (75.5) 4 (80.0) 125 (79.6) phylaxis in history
I 2 (9.5) 13 (16.7) 6 (11.3) 0 (0) 20 (12.7) (from [30])
II 0 (0) 4 (5.1) 4 (7.5) 1 (20.0) 9 (5.8)
III 0 (0) 0 (0) 3 (5.7) 0 (0) 3 (1.9)
Total 21 (100) 78 (100) 53 (100) 5 (100) 157 (100)
tients. In our own experience, only 5 % showed Spec. IgE Spec. IgG
reactions equally as strong as before immuno- RAST (KU/I)
therapy. When increasing the dose from 100 to Therapy failure
200 g, most of these patients tolerated the sub-
sequent sting challenge [40] (Table 5.35).
at least. In patients with risk factors (systemic Double Sensitizations to Bee/Wasp Venom
reaction after sting challenge, mastocytosis, re- Some patients are positive in skin test and/or
peated anaphylactic reactions to immunother- RAST against both bee and wasp venom and
apy injection), an increase in dose and a longer the history remains doubtful. If cellular tests do
treatment duration is necessary [32, 47]. not give additional information and only one
anaphylactic episode was seen in the history,
we usually use the species with stronger skin or
RAST reactivity for immunotherapy. In unclear
cases, immunotherapy against both Hymenop-
tera species has to be performed. Watching the
kinetics of IgE response immediately after the
sting event (anaphylaxis) and 4 weeks later, ad-
ditional information about the relevant insect
species may be obtained.
Table 5.36. Patient information in honeybee and wasp venom allergy (according to [28, 47])
Avoidance measures
) Repellents (chemical agents) do not give protection.
) Avoid eating of sweets, ice cream, lemonade, fruits in the open, flower picking, presence near dustbins, an-
imals, fallen fruits, as well as fragrance or perfumed cosmetics. After eating, wash hands and wipe mouth.
) Do not drink from bottles or open cans, cover glasses, use straws.
) Do not chase away insects from their food sources, avoid hectic movements.
) Cover your skin by adequate clothing (especially when gardening), avoid going barefoot, open shoes.
When motorbiking wear helmet, gloves, and adequate clothing. Open biking helmets should be covered
with a net.
) On humid warm days, exert extreme caution since insects may be especially aggressive.
) Avoid too loose clothing and dark colors, rather wear light colors.
) Keep apartment windows closed during the day or use insect protection (shutters). Do not open the win-
dow when you have a light on inside in the evening (attractive to hornets).
) Watch out for hidden insects (bed, shoes, etc.).
) Avoid bee and wasp nets and their environs. Nests near your permanent living place should be removed
(by beekeepers or firefighters).
) When you find yourself in the vicinity of insects, avoid hectic movements, withdraw slowly! Do not trem-
ble, never breathe into a nest opening.
) When attacked by bees or wasps, cover your head with arms or clothing. Withdraw slowly. If stung, remove
the sting with a fingernail without emptying the sac. Cover the sting site.
Behavior after being stung
) Keep calm! Inform people around you about your situation.
) Remove sting carefully using the fingernail. Never squeeze the sac.
) Take the drugs from your emergency kit
Immediately after the sting (if not successfully hyposensitized) take:
) Oral antihistamine
) Oral cortisone
) If dyspnea, tachycardia, lip or tongue swelling occur: Inhale epinephrine or use an epinephrine injector.
After allergen-specific immunotherapy, drugs only need to be used when systemic symptoms are observed
120 5 Allergic Diseases (and Differential Diagnoses)
Problems. Rare allergic reactions against oth- 8. De Bandt M, Atassi-Dumont M, Kahn MF, et al.
er insects such as mosquitos, ants, etc., repre- (1997) Serum sickness after wasp venom immu-
sent an increasing problem due to the non- notherapy: clinical and biological study. J Rheu-
matol 24:1195 1197
availability of adequate amounts of purified ex- 9. Forck G, Kstner H, Kalveram C (1981) Insect
tracts. venom tolerance: IgG-blocking antibodies and
There are controversial opinions regarding sting provocation. In: Ring J, Burg G (eds) New
indications for immunotherapy in patients trends in allergy. Springer, Berlin Heidelberg
with HIV infection and other immunodeficien- New York, p 269
10. Fuchs E (1959) Allergie. Mnch Med Wochenschr
cies or with malignancy. While this earlier was 100:1711
regarded as a contraindication the problem 11. Golden DBK, Valentine MD, Kagey-Sobotka A,
was very rare in allergy praxis; however, due to Lichtenstein ML (1982) Prevalence of hymenop-
the increasing allergy prevalence, more pa- tera venom allergy. J Allergy Clin Immunol 69:124
12. Habermann E (1972) Bee and wasp venoms. Sci-
tients with this combination come and ask for a
ence 177:314
decision. We perform allergen-specific immu- 13. Hemmer W, Focke M, Jarisch R (1999) In-vitro-
notherapy if criteria for indication are given Doppelpositivitt gegen Bienen- und Wespengift.
and if known neoplasms have been surgically Allergologie 22 [Suppl 2]:63 64
removed or HIV infection is under control with 14. Hunt KJ, Valentine MD, Sobotka AK, Benton AW,
Amodio FJ, Lichtenstein LM (1978) A controlled
triple therapy. However, future studies are re-
trial of immunotherapy in insect hypersensitivi-
quired to answer these questions. ty. N Engl J Med 299:157
15. Jarisch R (1980) Die Bienengiftallergie (Modell
einer IgE-mediierten Soforttypallergie). Wien
5.1.6.6 Patient Information Klin Wochenschr 92 [Suppl 122]:3
16. Jeberger B, Habig J, Karl S, et al. (1994) Hyme-
Independently of immunotherapy, patients nopterengiftallergie: Hyposensibilisierungsthe-
should be informed about sensible behavior af- rapie trotz vorhandener Kontraindikationen. All-
ter insect stings and also about prevention of ergologie 17:255 260
stings (Table 5.36) [25, 28, 29, 43, 47], especially 17. Kmmerer H (1941) Fragekasten. Mnch Med
about the relevant risk factors [35]. All patients Wochenschr 88:939
18. Kiehn M, Ring J (1993) Hyposensibilisierung mit
should carry with them an emergency kit (see Insektengiftextrakten bei Patienten mit Hyme-
Sect. 5.1.4 on Anaphylaxis) with epinephrine nopterengift-Allergie im hheren Lebensalter.
for inhalation or self-injection (in severe cases). Allergo J 2 [Suppl 2]:90 94
19. King TP, Lu G, Gonzalez M, Qian N, Soldatova L
(1996) Yellow jacket venom allergens, hyaluroni-
dase and phospholipase: Sequence similarity and
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122 5 Allergic Diseases (and Differential Diagnoses)
Antiboy-dependent
Killer cell Target cell cellular cytotoxicity
(ADCC)
Togal
Therapy Prednisone 210 mg
Relapsing, attacks
Symptoms of shivering Purpura
fever, purpura, Sweaten,
epistaxis Dyspnea
39 hematoma
37
Rectal temperature
300 000
200 000
Platelets / l
100 000
50 000 Fig. 5.21. Course of a
thrombocytopenia in-
Megakaryocytes n duced by quinine (in
Thromboaggl. in vitro
Togal). Remission fol-
(Pat.-serum + Chinin) lowed termination of
BSG mm 16/34 6/17 the drug (reprinted
Leukocytes 4 400 with the permission of
Hemoglobin 14.3 Raif and Schubothe
[20])
These mechanisms are best investigated in pe- administration; IgG can be detected on the
ripheral blood cells; however, it is speculated surface of erythrocytes without comple-
that tissue destruction in parenchymatous or- ment products (e.g., C3d).
gans occurs in a similar manner (e.g., hepati- 2. Immune complex type (not to be con-
tis). fused with immune complex reaction of
The most important allergic diseases of the type III!). Here a complex of antibody and
blood (Figs. 5.20 5.22a) are triggered by antigen formed intravascularly with activa-
drugs; similar conditions may also be elicited tion of complement leads to cell destruc-
by infections (especially virus), lymphoprolife- tion [15] most likely via Fc receptors. Since
rative diseases, other neoplasias or idiopathi- the target cells only are lysed through sec-
cally. The complex interaction between drug ondary absorption of immune complexes,
and target cell occurs in different ways (types of this reaction was also called innocent
cytotoxic reaction) [1, 14, 20]: bystander. This mechanism is the most
common form of drug-induced allergic
1. Hapten type. Here the drug is bound to
cytopenia. The reactions are acute after
the cell surface leading to a new antigen;
minute doses. C3d can be detected on the
with or without complement activation,
cell surface [22, 23].
specific antibodies lead to cell destruction
3. Autoimmune type. The drug changes first
(e.g., penicillin, cephalosporins). Hemoly-
the cell surface, leading to the develop-
sis occurs extravascularly after high-dose
a b
ment of a new autoantigen. Autoimmune only in 0.7 % of patients does anemia develop
diseases of the blood may be triggered [23].
(e.g., hemolytic anemia by alphamethyldo- A common diagnostic criterion is the occur-
pa). Autoantibody formation continues rence of hemoglobinemia and hemoglobinuria,
after withdrawal of the drug and does not a hemoglobin decrease with normal MCHB, an
differ from idiopathic autoimmune hemo- increase in indirect bilirubin and a decrease in
lytic anemia of the heat type. haptoglobin. In rare cases, renal insufficiency
or diffuse intravascular coagulation can occur.
Pathophysiologically, mixed forms occur,
5.2.2 Allergic Diseases of the Blood e.g., after nomifensin or cianidanol [13, 22].
Withdrawal of the eliciting drug is the main
5.2.2.1 Allergic Hemolytic Anemia
therapy.
The most important drugs eliciting different
types of allergic hemolytic anemias are listed in
5.2.2.2 Allergic Agranulocytosis
Table 5.38. After high doses of penicillin (over
10 million U/day), slowly developing anemia of Allergic agranulocytosis develops in highly
the hapten type occurs. The direct Coombs acute form mostly via the hapten mechanism.
test is positive. After withdrawal, hemoglobin A few days (in repeated treatments within
normalizes. Antibodies (mostly IgG) do not re- hours) after intake of the eliciting drug (e.g.,
act with normal erythrocytes. Quinine, chlor- aminopyrine, metamizol, sulfonylurea, Ta-
promazine, and isoniazid are the most com- ble 5.39), leukocytes decrease, fever attacks
mon elicitors of hemolytic anemia of the im- occur, and putrid tonsillitis develops with
mune complex type. glossitis, thrush, bronchitis and severe dis-
Alpha-methyldopa, L-dopa, mefenamic ac- ease.
id, as well as methysergide may induce sub- Differential diagnosis comprises toxic gra-
acute heat-autoantibody-mediated anemia. nulocytopenias due to bone marrow depres-
After several months of treatment, 11 % of pa- sion (e.g., cytostatics), which develop slowly
tients develop a positive direct Coombs test; over a subacute chronic stomatitis. A possible
new type of drug reaction has been described
as neutropenia after high toxic doses of penicil-
Table 5.38. Drugs eliciting allergic hemolytic anemia lin (220 550 million U) [16].
(selection) Therapy consists in withdrawal of the drug,
Hapten type high-dose i.v. immunoglobulin, adequate anti-
Penicillin Rifampicin biosis, possibly glucocorticosteroids, and in-
Cephalosporin Cisplatin travenous G-CSF.
Immune complex type
(innocent bystander)
Aminophenazone Melphalan
Acetylsalicylic acid Metamizol Table 5.39. Drugs eliciting allergic agranulocytosis
Butizide Paracetamol (selection)
Quinidine Phenacetin
Aminophenazone Methyldopa
Quinine Rifampicin
Aminopyrine Novobiocin
Chlorpromazine Streptomycin
Aminosalicylic acid Penicillins
Ibuprofen Salicylamide
Quinidine Phenothiazines
Insulin Sulfonamide
Chloral hydrate Phenylbutazone
Isoniazid Sulfonylurea
Chlorpromazine Procainamide
Autoimmune type Diazepoxide Propranolol
Chlorpromazine Latamoxef Ethacrynic acid Mercury diuretics
Glafenin Levodopa Gold salts Salazosulfapyridine
Hydantoin Mefenamic acid Hydantoin Sulfonamide
Ibuprofen Methysergide Metamizol Sulfonylurea
Methyldopa Procainamide Methimazol Thiouracil
5.2 Allergic Diseases by Cytotoxic Antibodies (Type II) 129
PMN C5a
(4 6 weeks), which, however, do not contain Table 5.42. Classification of vasculitis according to
specific antigen in the cryoprecipitate possibly pathophysiology (ANCA, antineutrophil cytoplasmic
antibody)
representing idiotype-anti-idiotype complexes.
The detection of antigen in the disease elicit- Immune complex-mediated
ing immune complexes would be of major diag- ) Purpura Schnlein-Henoch
) Urticaria vasculitis
nostic relevance; however, it is rarely achieved. ) Immune complex vasculitis in infectious disease
(viral, bacterial)
) Drug-induced vasculitis (e.g., sulfonamides)
5.3.3 Allergic (Immune Complex) Vasculitis ) Paraneoplastic vasculitis
) Cryoglobulinemia
Allergic (immune complex) vasculitis is elicit- ) Vasculitis in lupus erythematosus
ed by an immunological type III reaction, when ) Rheumatoid vasculitis
circulating immune complexes in mild antigen ) Serum sickness
) M. Behcet
excess are not eliminated properly by the retic- ) Erythema elevatum et diutinum
uloendothelial system and complement activa- ANCA-associated/-mediated
tion with local attraction and activation of neu- ) Wegeners granulomatosis
trophil granulocytes occurs (experimental ) Microscopic polyangiitis
model of the Arthus phenomenon). Synonyms ) Churg-Strauss syndrome
) Some forms of drug-induced vasculitis
are leukocytoclastic vasculitis, anaphylactic (e.g., thiouracil)
purpura, hypersensitivity angiitis, arterio- Directly antibody-mediated
litis allergica, and vasculitis hyperergica. ) Goodpastures syndrome
Histologically, a perivascular neutrophil infil- ) M. Kawasaki
trate with occasional eosinophils and typical Cell-mediated
) Transplant rejection
leukocytoclasia with nuclear fragments and fi- ) Hemorrhagic pigmentary dermatoses
brinoid degeneration of the vascular wall is ) Other forms of lymphocytic vasculitis
typical (Fig. 5.25). In immunofluorescence or Unknown pathogenesis
immune electron microscopy (Fig. 5.26), de- ) M. Horton
) Takayasus arteriitis
) Polymyalgia rheumatica
posits of C3, IgG, and IgM can be found. Im- the diascope. Punctual extravasations (pete-
mune complex vasculitis should be differenti- chia) or fluctuating hemorrhages (ecchymosis,
ated from other forms of allergic vasculitis suggillation) occur. A pathophysiological clas-
(e.g., with lymphocytic infiltrates as in pro- sification of inflammatory versus non-inflam-
gressive pigmentary purpura) (Table 5.42) [3, matory purpura is helpful (Table 5.43). Platelet
9, 12, 27]. function is normal, and the Rumpel-Leede test
Clinically, three types of allergic vasculitis is positive.
can be distinguished [32]: The exanthema is symmetrical and often
) Hemorrhagic type (corresponding to pur- pronounced in the lower extremity (hydrostat-
pura Schnlein-Henoch) (Fig. 5.27)
) Papulonecrotic type with necrotizing ul- Table 5.43. Inflammatory and non-inflammatory pur-
cers and scarring (Figs. 5.28, 5.29) pura
) Polymorphic nodular type with urticarial,
Inflammatory
maculopapular, and nodular skin lesions Neutrophils: allergic vasculitis
ANCA-associated vasculitis
A special form is urticaria vasculitis with Lymphocytes: progressive pigmentary purpura
long-persisting (> 24 h) wheals with sometimes Granulomatous: granulomatous vasculitis
preceding lupus erythematosus [12, 13, 27] (see Non-inflammatory
Sect. 5.1.3 on Urticaria). Coagulopathy
The cardinal symptom is purpura (Fig. 5.27), Thrombocytopenia
characterized by erythrocyte extravasation, Atrophy (age, corticosteroids)
Vitamin deficiency (vitamin C, scurvy)
which does not disappear under pressure with
Fig. 5.27. Allergic vasculitis (hemorrhagic type) Fig. 5.28. Allergic vasculitis (papulonecrotic type)
5.3 Allergic Diseases due to Immune Complexes 135
References
1. Becker EL, Austen KF (1966) Mechanisms of im-
munologic injury of rat peritoneal mast cells. I.
Fig. 5.29. Allergic vasculitis (necrotic type)
The effect of phosphonate inhibitors on the hom-
cytotropic antibody-mediated histamine release
and the first component of rat complement. J Exp
ic pressure). Erythrocyte sedimentation is ele- Med 124:379 395
vated, and circulating immune complexes can 2. Brostoff J, Challacombe SJ (eds) (1987) Food al-
be detected in the serum. In many cases, sys- lergy and intolerance. Tindall, London
temic manifestations of other organs (kidney, 3. Bruckbauer HR, Ollert M, Ring J (1997) Vaskuliti-
den der Haut. Bay Int 17:166 179
lung, CNS, gastrointestinal tract, and heart) 4. Burden AD, Tillman DM, Foley P, Holme E (1996)
may occur. Eliciting antigens may be viruses IgA class anticardiolipin antibodies in cutaneous
(e.g., hepatitis B), bacteria (e.g., streptococci), leukocytoclastic vasculitis. J Am Acad Dermatol
parasites (e.g., schistosoma), tumors (such as 35:411 415
paraneoplastic syndrome), foods [2, 7] or 5. Cochrane CG, Koftler D (1973) Immune complex
disease in experimental animals and man. Adv
drugs. Immunol 16:185
6. Dixon FJ, Vasquez JJ, Weigle WO, Cochrane CG
Therapy. The avoidance of eliciting noxious (1958) Pathogenesis of serum sickness. Arch Pa-
agents as well as treatment of the underlying thol 65:18
disease is vital (Table 5.44). 7. Eisenmann A, Ring J, von der Helm D, Meurer M,
Braun-Falco O (1988) Vasculitis allergica durch
Symptomatically, glucocorticosteroids are Nahrungsmittelallergie. Hautarzt 39:318 321
used; however, their use is controversial. The 8. Fauci AS (1979) Cyclophosphamide therapy of se-
anti-inflammatory effect may be beneficial; on vere systemic necrotizing vasculitis. N Engl J Med
the other hand, the vasoconstrictive effect and 301:235
the immunosuppressive action may prolong 9. Gross WL, Schmitt WH, Lotti T (1995) ANCA-as-
soziierte Vaskulitiden. Hautarzt 46:511 524
the disease. 10. Hunt HJ, Valentine MD, Sobotha AK, Junginger
Antihistamines are recommended by some JW, Lichtenstein LM (1976) Serum sickness asso-
authors to decrease endothelial permeability. ciated with nonvenom protein in mixed hyme-
136 5 Allergic Diseases (and Differential Diagnoses)
noptera whole body extract. J Allergy Clin Immu- leukocytoclastic vasculitis. Results of a prospec-
nol 57:246 254 tive, randomized controlled trial. Arch Dermatol
11. Jenette CJ, Milling DM, Falk RJ (1994) Vasculitis 131:1399 1402
affecting the skin. Arch Dermatol 130:899 906 23. Scherer R, Wolff HH (1979) Vasculitis allergica.
12. Kohler PF (1983) Immune complexes and allergic Allergologie 2:62
disease. In: Middleton E, Ellis EF, Reed CE (eds) 24. Sedlacek HH (1980) Pathophysiological aspects
Allergy, principles and practice, 2nd edn. Mosby, of immune complex diseases. Klin Wochenschr
St. Louis, pp 167 199 58:543 593
13. Meurer M (1981) Urticarial vasculitis. In: Ring J, 25. Seifert J, Land W, Ring J, Lob G, Brendel W (1978)
Burg G (eds) New trends in allergy. Springer, Ber- Antigen-Eliminationstechnik. Fortschr Med 96:
lin Heidelberg New York, pp 148 151 695 697
14. Morgan AC Jr, Rossen R, Twomey JJ (1979) Natu- 26. Smedegard G, Revenas B, Arfors KE (1979) Ana-
rally occurring circulating immune complexes: phylaxis in the monkey: hemodynamics and
normal serum contains idiotype-anti-idotype blood flow distribution. Acta Physiol Scand 106:
complexes dissociable by certain IgG antiglobu- 191 198
lins. J Immunol 122:1672 27. Soter NA, Austen KF, Gigli I (1974) Urticaria and
15. Ollert, deleted in production arthralgias as manifestations of necrotizing angi-
16. Pirquet C v, Schick B (1905) Die Serumkrankheit. itis (vasculitis). J Invest Dermatol 63:485 490
Deutike, Leipzig 28. Sylvestre DL, Ravetch JV (1994) Fc receptors ini-
17. Ravetch JV (1994) Fc receptors: Rubor redux. Cell tiate the Arthus reaction: Redefining the inflam-
78:533 560 matory cascade. Science 265:1095 1098
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Frick E, Brass B, Mertin I, Backmund H, Brendel reiche topische Anwendung von Cyclosporin A
W (1974) Intensive immunosuppression in the bei Pyoderma gangraenosum. Hautarzt 47:132
treatment of multiple sclerosis. Lancet II:1093 135
19. Ring J, Seifert J, Seiler F, Brendel W (1976) Im- 30. Theofilopoulos AN, Dixon FJ (1980) Detection of
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Appl Immunol 52:227 234 31. van Furth R, Cohn ZA, Hirsch JG, et al. (1972)
20. Ring J (1978) Anaphylaktoide Reaktionen nach The mononuclear phagocyte system: a new clas-
Infusion natrlicher und knstlicher Kolloide. sification of macrophages, monocytes, and their
Springer, Berlin Heidelberg New York precursor cells. Bull Wld Hlth Org 46:845
21. Ruzicka T, Burg G (1987) Effects of chronic intra- 32. Wolff HH, Scherer R (1981) Allergic vasculitis. In:
cutaneous administration of arachidonic acid Ring J, Burg G (eds) New trends in allergy.
and its metabolites. Induction of leukocytoclastic Springer, Berlin Heidelberg New York, pp 140
vasculitis by leukotriene B4 and 12-hydroxyeico- 147
satetraenoic acid and its prevention by prosta- 33. Zhang Y, Ramos BF, Jakschik BA (1992) Neutro-
glandin E2. J Invest Dermatol 88:120 123 phil recruitment by tumor necrosis factor from
22. Sais G, Vidaller A, Jucgla A, Gallardo F, Peyri J mast cells in immune complex peritonitis. Sci-
(1995) Colchicine in the treatment of cutaneous ence 258:1957 1959
Table 5.45. Symptoms and signs of hypersensitivity Blood count shows leukocytosis with devia-
pneumonitis tion, sometimes eosinophilia. The differential
Common cold 91 % diagnosis (Table 5.46) includes bronchial asth-
Dyspnea 85 % ma as type I reaction (sometimes elicited by
Cough 82 % similar exposure) which can be excluded by pre-
Shivering 56 % cipitating antibodies and negative IgE as well as
Sputum expectoration 51 %
Malaise 47 % lung function (no obstructive ventilatory dis-
Tightness of chest 42 % turbance). The family history of atopy is nega-
Weight loss 31 % tive. In the bronchial provocation test, the reac-
Nightly sweating 29 % tion occurs after 4 6 h as diffusion disturbance.
Headache 25 %
Nausea 19 % More difficult to diagnose are chronic
Loss of appetite 18 % courses characterized by dry coughing, general
Rhinitis/pharyngitis 15 % malaise, weight loss, sometimes increased ESR,
Myalgia 14 % leukocytosis and hypergammaglobulinemia.
Vertigo 12 %
Hemoptoe 8%
In the X-ray, signs of lung fibrosis are found.
Auscultatory noises 73 % Patients are often treated for long periods as
Fever 40 % having common cold, bronchitis, etc. Other
Leukocytosis 76 % differential diagnoses are listed in Table 5.47.
CRP elevation 72 %
ESR elevation 46 %
Table 5.46. Differential diagnosis between allergic bronchial asthma and hypersensitivity pneumonitis
Symptoms Allergic asthma Hypersensitivity pneumonitis
Symptoms Wheezing, acute attacks Dyspnea, fever, cough, general symptoms
Latency <1 h 6 12 h
Duration (after exposure) Mostly hours Days
History of atopy Positive Negative
Chest X-ray, acute Lung inflation Infiltrates
Chronic Emphysema Fibrosis
Lung function Obstructive diffusion disturbance Restrictive diffusion disturbance
Skin test Immediate reaction (20 min) Type III reaction (8 24 h)
Serology RAST+ Precipitating antibodies +
Bronchial provocation testa Immediate reaction Delayed reaction (4 12 h)
a
Note the different parameters of lung function disturbance
138 5 Allergic Diseases (and Differential Diagnoses)
Table 5.49. Diagnostic criteria for hypersensitivity infiltrates (type IV reaction) with the beginnings
pneumonitis (German Society for Allergology and of granuloma formation and multinuclear giant
Clinical Immunology) [3]. For diagnosis of hypersen-
sitivity pneumonitis, criteria 1 3 plus 1 additional cells are observed (see Sect. 5.8).
criterion have to be positive In chronic conditions, fibrotic changes are
typical.
1. Allergen exposure During bronchoalveolar lavage, a decreased
2. Symptoms of alveolitis
3. IgG/IgA antibodies CD4/CD8 ratio with increased lymphocytes of
4. Pathologic lung function (diffusion, hypoxemia) the TH1 secretion type is typical. Sometimes
5. Typical chest X-ray infiltrates TH2 can be found [4]. In direct immunofluores-
6. Typical BAL findings cence, deposits of immunoglobulins in alveolar
7. Positive bronchial provocation
walls have been observed [1, 6, 34].
In the blood, a high concentration of IgG an-
tibodies (mostly as precipitins in immunodif-
Toxic irritative processes through endotoxins fusion) against eliciting allergens can be de-
or other irritants in organic materials can in- tected. The immune complexes thus formed
duce bronchoalveolar diseases [7, 11, 13, 20, 21, and deposited lead to activation of macro-
22, 27, 34, 38, 41] (Table 5.48): byssinosis in cot- phages, maintaining further inflammatory
ton wool workers, grain dust (harvesting dust) processes. It is interesting that non-smokers
disease, flax or hemp workers lung. In these have a higher incidence of hypersensitivity
cases, no relevant sensitization can be demon- pneumonitis, possibly due to inhibition of
strated immunologically or in provocation macrophage functions in smokers [16, 39].
tests. Silo workers disease through toxic effects Antibodies may also be detected by comple-
of nitric gases, furriers disease with foreign ment fixation [30, 32, 34] or using indirect im-
body granulomas around animal hair in lung munofluorescence (e.g., bird feathers) or en-
tissue as well as autoimmune alveolitis (in lu- zyme or radioimmunoassays.
pus erythematodes or scleroderma) need to be The interpretation of antibody results is dif-
differentiated (see the diagnostic criteria for ficult since they also may be found in healthy
hypersensitivity pneumonitis of the German exposed individuals, although in lower concen-
Society of Allergology and Clinical Immunolo- trations. More detailed investigations (long-
gy as well as the German Society for Pneumolo- term follow-up) and accidental autopsies of
gy in Table 5.49). possibly asymptomatic exposed persons have
yielded evidence that in many cases a clinically
latent, but minimal form of alveolitis may be
5.4.3 Pathophysiology
present in these individuals.
There are three phases in the histological chang- In the skin test sometimes after an imme-
es (Fig. 5.30): In the acute phase (4 30 h), peri- diate reaction the occurrence of a papule after
vascular infiltrates of neutrophil and eosinophil 6 12 h up to 24 h is characteristic (80 % in hy-
granulocytes predominate, which transmigrate persensitivity pneumonitis, 50 % in exposed
through the alveolar walls (type III reaction). In individuals with demonstrable antibody, 10 %
the further course (30 h to weeks), mononuclear in non-exposed controls). Histologically, leu-
5.4 Hypersensitivity Pneumonitis (Allergic Alveolitis) 139
Alveolar epithelium
Vessel
Antigen
IgG
IgG
CD8 B
Mo T (CD4)
IL-8 TNF
ties between various bird species (budgerigar, hypersensitivity pneumonitis through hay dust
parrot, canary, etc.) [6, 34, 37]. The fine dust of or isocyanates.
dry pigeon feces seems to be especially aller- In this context, other forms of mold allergy
genic. In Germany, there are an estimated together with an infection occurring in the pa-
110,000 pigeon breeders. The prevalence of hy- ranasal sinuses should be mentioned such as
persensitivity pneumonitis is estimated at the recently described allergic fungal sinusi-
0.2 10 % of exposed individuals. In the United tis (see also Sect. 5.1.1 on Rhinitis).
Kingdom, 12 % of the population is supposed
to keep birds (mostly budgerigars) without
5.4.6 Therapy of Hypersensitivity Pneumonitis
alarming figures of high prevalences of hyper-
sensitivity pneumonitis. A study from the is- Strict allergen avoidance is the primary com-
land of Gotland revealed among farmers a mandment. Prophylactic measures include re-
10 100 times higher prevalence of IgE-mediat- duction of allergen concentrations through
ed allergic diseases (especially against house- constructing better and drier storage rooms.
dust and storage mites) than hypersensitivity With air masks, the amount of inhaled allergen
pneumonitis [36]. can be reduced. The airstream helmet with an
In preparing lists of allergens and corre- airflow passing through a filter can be used dur-
sponding diseases, it has to be considered that ing work [18]. A new mask is the Dust Master;
not infrequently several allergens of various or- there are also half-masks (3M Co.). In highly
igin (bacteria, fungi, parasites) are involved to- sensitized individuals, a change of occupation
gether in the elicitation of the disease (e.g., hu- or cessation of the exposed work is the only way.
midifier lung) (Table 5.50). Glucocorticosteroids may reduce the symp-
Rare cases are observed under treatment toms of hypersensitivity pneumonitis. Doses
with pituitary gland extracts, in the preparation between 40 and 60 mg prednisolone (in chil-
of pancreatin, in fungi farming, under nitrofu- dren 0.2 mg/kg body wt.) are given; steroid
rantoin treatment (3 weeks after beginning), medication is, however, no alternative to aller-
with ACE inhibitors, or with silicon implants. gen avoidance!
Hypersensitivity pneumonitis can also oc- For therapy control, measurement of vital
cur in animals (e.g., horses) [33]. capacity, diffusion capacity, and O2 partial
pressure under exercise are recommended.
The efficacy of cromoglycate is controver-
5.4.5 Allergic Bronchopulmonary Mycosis
sial. Allergen-specific immunotherapy in hy-
The disease of allergic bronchopulmonary my- persensitivity pneumonitis is contraindicated.
cosis (mostly aspergillosis) needs to be distin- In severe cases, cytostatics and immunosup-
guished from hypersensitivity pneumonitis; it pressives are given [34, 42].
develops mostly on the basis of a chronic bron-
chial asthma and consists of a combination of
type I and III allergy together with intrabron- References
chial colonization with molds. Relapsing lung
infiltrates in patients with allergic bronchial 1. Allen DH, Basten A, Woolcock AJ (1977) Studies of
asthma are characteristic [35]. In the diagnosis, cell and humoral immunity in birdbreeders hyper-
precipitating antibodies together with specific sensitivity pneumonitis. Am Rev Resp Dis 115:45
2. Bck O, Lindgren R, Wiman LG (1974) Nitrofuran-
IgE antibodies, dual skin reactions, as well as toin induced pulmonary fibrosis and lupus syn-
positive demonstration of molds in the sputum drome. Lancet I:930
culture are relevant [34]. Other diseases due to 3. Bergmann KC, Costabel U, Knape H, Kroidl R,
aspergilli are aspergillus pneumonia as well as Mller-Wening D, Repp H, Rust M, Schwarz H,
aspergilloma. Sennekamp J (1990b) Empfehlungen zur Diagno-
sestellung einer exogen-allergischen Alveolitis.
Besides allergic bronchopulmonary myco- Allergologie 13:111
sis, there are true combinations of type I and III 4. Boyd G, McSharry C, McLeod K, Sriram S, Boyd F
reactions such as exogenic allergic asthma and (1999) Lymphocyte responses in pigeon breeders
142 5 Allergic Diseases (and Differential Diagnoses)
with extrinsic allergic alveolitis/hypersensitivity 24. Pepys J (1994) Farmer lungs a needle in a hay-
pneumonitis (EAA/HP) are predominantly T stack, and Pandoras box. Allergy Clin Immunol
helper 2-type. Am J Resp Crit Care Med 159:A742 News 6:68
5. Doerr W (1953) Pneumokoniose durch Getreide- 25. Pepys I, Jenkins P, Festenstein G, Gregory P, Lacey
staub. Virchows Arch Pathol Anat 324:263 M, Skinner F (1963) Farmers lung. Thermophilic
6. Fink JN (1992) Hypersensitivity pneumonitis. actinomycetes as a source of farmers lung hay
Clinics in chest Medicine 13:303 antigen. Lancet II:607
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5.5 Dermatitis/Eczema 143
also called dysregulative microbial [31] is Table 5.56. Clinical and histological distinctions be-
still not well understood in its pathophysiolo- tween irritative-toxic and allergic contact dermatitis
gy. In childhood, it seems to be a variant of Irritative-toxic Allergic
atopic eczema.
Clinical characteristics
Whether seborrheic dermatitis [65], first Margin Sharp Spreading
defined by Unna, really represents this type of Polymorphism + +++
inflammation or rather a superficial skin infec- Kinetic Decrescendo Crescendo
tion (e.g., P. ovale) is under discussion [20]. Pain ++ +/
Contact dermatitis and atopic eczema are Itch + +++
the most common forms, followed by nummu- Histology
lar, seborrheic and other forms of dermatitis. Spongiosis 0 +++
Exocytosis ++ ++
One can also classify according to localiza- Vesiculation Non-spongiotic Spongiotic
tion (e.g., hand, lower leg dermatitis) for prac- Keratinocyte
tical reasons. The prevalence of certain forms necrosis ++ 0
differs according to localization (Table 5.55). Eosinophils 0 +
Neutrophils + 0
The entity of stasis dermatitis is controver- Mononuclear
sial. infiltrates + +
Clinical subtypes are dyshidrotic dermati- Edema + 0
tis (pompholyx), which often turns when in
chronification into hyperkeratotic-rhagadi-
form dermatitis [4, 17, 46, 58]. titis) develops after irritation, usually show-
ing sharp margins and no spreading phenome-
na. It occurs in any individual without a pecu-
5.5.2 Contact Dermatitis liar genetic disposition. Special forms are dia-
per dermatitis in infants and intertrigo. The
5.5.2.1 Pathophysiology
chronic (cumulative-toxic) form develops
Contact dermatitis can be either due to toxic or more slowly in disposed individuals (frequent-
to allergic mechanisms (Table 5.56). Acute tox- ly atopics) and is due to skin barrier distur-
ic contact dermatitis (irritant contact derma- bance; it occurs most commonly in house-
5.5 Dermatitis/Eczema 145
Fig. 5.33. Cumulative toxic hand dermatitis Fig. 5.34. Foot dermatitis (allergy to antimycotic med-
ication)
Fig. 5.35. Irritative contact dermatitis due to artificial Fig. 5.36. Allergy to coins containing nickel
application of a disinfectant
Fig. 5.37. Dermatitis caused by excessive licking of the lips Fig. 5.38. Contact stomatitis
a b
a b
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25. Gollhausen R, Ring J, Przybilla B (1987) Der itera- 43. Miescher G (1962) In: Marchionini A (ed) Hand-
tive Test zur Unterscheidung kontaktallergischer buch der Haut- und Geschlechtskrankheiten,
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28. Halter S (1959) Das vulgre Eczema. In: Gottron 46. Odia S, Vocks E, Rakoski J, Ring J (1996) Success-
A, Schnfeld W (eds) Dermatologie und Venero- ful treatment of dyshidrotic hand eczema using
logie, vol III/1. Thieme, Stuttgart tap water iontophoresis with pulsed direct cur-
29. Happle R (1994) Paraptisches Eczema. Hautarzt rent. Acta Derm Venereol 76:472 474
45:1 3 47. Rietschel RL, Fouler JF (2001) Fishers contact
30. Hausen B, Vieluf I (1998) Allergie-Pflanzen. dermatitis, 5th edn. Lippincott-Williams, Phila-
Pflanzen-Allergene. Ecomed, Landsberg delphia
31. Hornstein OP (1986) Anmerkungen und Vor- 48. Ring J (ed) (1990) Endogenous and exogenous
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zemakrankheiten. Z Hautkr 61:1281 1296 49. Ring J ((1996) Zum Wandel des Eczema-Begreif-
32. Hannuksela M, Salo H (1986) The repeated open fes: Klassisches versus atopisches Eczema. Z
application test (ROAT). Contact Dermatol 14: Hautkr 10:752 756
211 227 50. Rmpp H (1982) Chemielexikon, 8th edn.
33. Jadassohn J (1895) Verhandl Dtsch Derm Gesell- Franckhsche Verlagshandlung, Stuttgart
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34. Kapsenberg ML, Bos JD, Wierenga EA (1992) U, Frstermann AB, Reske-Kunz (1998) Involve-
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munol 10:61 69 matosen. Dustri, Munich
52. Rycroft RJG, Menne T, Frosch P (eds) (1995) Text- 60. Scott P (1993) IL-12: initiation cytokine for cell-
book of contact dermatitis. Springer, Berlin Hei- mediated immunity. Science 260:496 497
delberg New York 61. Silberberg I, Baer RI, Rosenthal SA (1974) The
53. Schfer T, Bhler E, Ruhdorfer S, Weigl L, Wes- role of Langerhans cells in contact allergy. I. An
sner D, Filipiak B, Wichmann HE, Ring J (2004) ultrastructural study in actively induced contact
Epidemiology of contact allergy in adults. Allergy dermatitis in guinea pigs. Acta Derm Venereol
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54. Schnuch A, Geier J, Uter W, et al. (1997) National 62. Stingl G (1980) New aspects of Langerhans cell
rates and regional differences in sensitization to function. Int J Dermatol 19:189
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titis 37:200 209 Budapest
55. Schnuch A, Aberer W, Agathos M, Brasch J, 64. Traidl C, Merk HF, Cavani A, Hunzelmann N
Frosch PJ, Fuchs T, Richter G (2001) Leitlinien der (2000) New insights into the pathomechanisms of
Deutschen Dermatologischen Gesellschaft (DDG) contact dermatitis by the use of transgenic mouse
zur Durchfhrung des Epikutantests mit Kontak- models. Skin Pharmacol Appl Skin Physiol
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56. Schulz KH, Fuchs T (1993) Der Epikutantest. Ma- 65. Unna PG (1887) Seborrhoeal eczema. J Cutan GU
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pp 1 39 66. Uter W, Schnuch A, Geier J, et al. (1998) Epidemi-
57. Schuler G, Steinman RM (1985) Murine epider- ology of contact dermatitis. The information net-
mal Langerhans cells mature into potent immu- work of Department of Dermatology (IVDK) in
no-stimulatory dendritic cells in vitro. J Exp Med Germany. Eur J Dermatol 8:36 40
161:526 546 67. Willan (1808) On cutaneous diseases. Johnson,
58. Schwanitz HJ (1986) Das atopische Palmoplanta- London
reczema. Springer, Berlin Heidelberg New York
Table 5.59. Stigmata of atopic eczema plain about itching without any visible skin le-
sion and start scratching, and only 15 20 min
Sebostasis (dry skin)
Ichthyotic palms/soles later do eczematous changes occur. For the di-
Linear grooves on the fingertips agnosis of atopic eczema, classically the criteria
Atopy lid fold (Dennie-Morgan) of Hanifin and Rajka [21] (Table 5.60) are cited,
Rarefication of lateral parts of eyebrows (Hertoghe) but are rarely used in practice.
Cap-like temporal hair growth (small distance
between lateral eyebrow and temporal scalp hair)
Facial pallor with periorbital halo
White dermographism
Delayed blanch after acetylcholine
5.5 Dermatitis/Eczema 153
b
Fig. 49a,b. Elbow eczema
154 5 Allergic Diseases (and Differential Diagnoses)
I 36,7
II 31,1
III 32,2
Fig. 5.52. Occurrence
and course of atopic ec-
zema at different ages
Years (modified according to
2 6 14 20
[26])
Table 5.60. Diagnosis of atopic eczema: criteria of Hanifin and Rajka [21] (three major and minor criteria each
have to be positive)
Major Itch Minor Mamillar eczema
criteria Typical morphology and distribution criteria Cheilitis
(lichenification in flexures of adults, (cont.) Relapsing conjunctivitis
face and extensor surfaces of children) Dennie-Morgan fold
Chronic relapsing eczema Keratoconus
Personal and family history of atopy Subcapsular cataract
Periocular halo
Minor Sebostasis Facial pallor
criteria Ichthyosis Facial erythema
Ichthyotic palm/sole Pityriasis alba
Keratosis follicularis Folding in the neck
Type I sensitization (prick test) Itch when sweating
Elevated total serum IgE Wool and solvent incompatibility
Early onset of disease Perifollicular accentuation
Tendency to cutaneous infections Adverse food reactions
(Staph. aureus, HSV) Dependence of environmental and
Tendency to unspecific hand and foot psychological factors
eczema White dermographism
5.5 Dermatitis/Eczema 155
Table 5.61. Atopic eczema: diagnostic criteria (Ring Table 5.62. Dermatohistopathology in atopic eczema
1982). With four or more positive findings, the diag-
nosis atopic eczema can be made (note that by this Acute
criterion, the diagnosis atopic eczema is possible Acanthosis, hyperkeratosis, parakeratosis
without history or laboratory tests for atopy) Spongiosis, exocytosis, mild dermal lymphohisto-
cytic infiltrate
Eczema morphology (age-dependent)
Chronic-lichenified
Itch
Acanthosis, enlarged rete ridges, hyperkeratosis,
Typical localization (age-dependent)
parakeratosis, dense dermal infiltrate (mononucle-
Atopy stigmata
ar cells), increased mast cells, increase in capillar-
Atopy in personal or family history
ies and thickening of capillary walls, endothelial
IgE sensitization
cell hyperplasia, fibrosis
Table 5.61 shows our diagnostic criteria from Atopic Dermatitis ETFAD [71], has proven
1982: with four out of six positive parameters, valuable (Fig. 5.55).
the diagnosis atopic eczema can be made. Simi- In dermatohistology, patterns differ be-
larly in the 1990s, the UK-refined criteria tween acute and chronically lichenified lesions
[64] or the Millennium criteria [9] were de- (Table 5.62) [59].
veloped.
Particular manifestations of eczema com-
5.5.3.1.1 Genetics
prise so-called sandbox dermatitis, atopic
winter feet, and patchy lichenoid infiltrates Atopic eczema, allergic bronchial asthma, and
of Kitamura-Zazagawa-Takahashi and others allergic rhinoconjunctivitis are genetically
[20, 22, 30, 38, 48, 49], some of them also in- closely linked [52]. Sixty percent of patients
cluded under minimal variants (for instance, with eczema have other atopic diseases in their
infra-auricular fissures). For the determination family history. The concordance rate of homo-
of severity of actual eczematous skin lesions, zygous twins is 85 % compared to 30 % in het-
the SCORAD (scoring system atopic dermati- erozygous twins [54]. Inheritance is multifac-
tis), developed by the European Task Force torial: IgE formation in general (total IgE), the
156 5 Allergic Diseases (and Differential Diagnoses)
Fig. 5.55. SCORAD (scoring for atopic dermatitis) index for assessing the severity of eczema
5.5 Dermatitis/Eczema 157
specificity of IgE antibodies and organ ma- Table 5.63. Langerhans cells, IgE and atopic eczema
nifestations are influenced separately (see IgE on Langerhans cells
Sect. 3.1). There is no significant association
IgE receptors [low- and high-affinity (CD23 and
between the diagnosis atopic eczema and Fc 5 R I) as well as IgE-binding protein]
HLA haplotypes [15]. Housedust mite allergen (Der p 1) next to IgE in
doublestaining on Langerhans cell surface
5.5.3.2 Pathophysiology Langerhans cells may present allergen via IgE
5.5.3.2.1 Genetics T-cell clones from atopy patch test reactions show
TH2 characteristics and allergen specificity
Recently, a close link of infantile atopic eczema Particularly increased expression of Fc 5 R I in atop-
with a gene on chromosome 3q21 was reported ic eczema in lesional skin (contrary to contact der-
[31]. A second genome screen revealed an asso- matitis and other inflammatory skin diseases)
ciation with loci on chromosomes 1q21, 17q25,
and 20p [15]. While the genes for the costimu- Table 5.64. Comparison of different allergy tests in
latory CD80/86 molecules are found in the re- atopic eczema (Darsow et al. [16])
gion of chromosome 3q21, the other loci do not
Test Sensitivitya Specificity
reveal known relations to atopy. It is interesting
that all four gene loci are also linked to psoria- Skin prick test 69 82 % 44 53 %
sis [15]. It may be speculated that these genes RAST 65 94 % 42 64 %
Atopy patch test 42 56 % 69 92 %
encode for general markers of skin inflamma-
a
tion independent of atopy. Allergen-dependent (related to specific history)
Fig. 5.57. Atopy patch test (APT) Fig. 5.58. Atopic eczema with massive superinfection
by Staphylococcus aureus
mal proteins (Hom s 1) have been detected breaking up of intercellular E-cadherin junc-
[60]; we see an increasing dynamic of eczema tions, while desmosomes stay intact and the in-
elicitation and maintenance via TH2 over TH1 flammatory edema induces the picture of spon-
to IgE autoantibodies, explaining the phenom- giosis [3, 58].
ena of chronification and resistance to therapy.
5.5.3.2.4 Autonomic Nervous System
5.5.3.2.3 Disturbed T-Cell Regulation Dysregulation
Patients with eczema are often suffering from Many patients show a dysbalance in autonomic
infections of fungal, bacterial, or viral origin nervous system reactivity [27], mostly in the
(e.g., Kaposis varicelliform eruption, or ecze- sense of decreased q -adrenergic and increased
ma herpeticum as well as increased staphylo- [ -adrenergic and cholinergic reactivity [3, 42]
coccal colonization and infection of the skin; (see also Stigmata). In a Japanese study, pa-
Fig. 5.58). Increased TH2 reaction occurs with tients with atopic eczema less frequently had
decreased TH1 phenomena [14, 25, 53], which hypertension than normals [Uehara, personal
are most prominent in the so-called hyper-IgE communication).
syndrome, which in its dermatological mani- The imbalance of enhancing and inhibitory
festation may be regarded as a maximal variant influences on mediator secretion can lead to an
of atopic eczema [49]. increased releasability of mediator secreting
Recent phenomena of spongiosis have been cells in atopic eczema. Patients with atopic ec-
elucidated: activated CLA-positive T cells in the zema have increased plasma histamine levels as
skin secrete beside other cytokines Fas-ligand, well as enhanced releasability of other media-
leading to apoptosis of keratinocytes and tors (e.g., leukotriene) [44]. These mediators
5.5 Dermatitis/Eczema 159
of emollients (different for different body areas Table 5.65. Atopic eczema: irritants and elicitors
and different individuals) including bath or Physical Mechanical stimuli, dryness,
showering oils (a distinction should be made UV radiation, temperature
between emulsion and spreading type bath Chemical Detergents, solvents, acids,
oils) is critical; avoid showering at too hot a alkali
temperature or for too long. Pharmacological Vasoactive substances (alcohol,
Acceptance by the patient is important; nicotine, amines)
many patients do not like ointments which are Infectious Superantigens
too greasy although their skin looks very dry. Psychological Stress, emotional conflict
Hydrophilic ointments (unguentum emulsifi-
cans aquosum) have been found helpful as ba-
sic vehicles. with disinfectants (clioquinol, triclosan, gen-
Consistent avoidance of all eliciting factors tian violet). In severe cases, systemic antibiotic
detected during the diagnostic work-up is cru- or antimycotic (in head and neck dermatitis)
cial (irritants, allergens, infection, food reac- treatment may help.
tions) [36, 39, 47]. The inflamed skin manifest- Wet wraps (moist pyjamas), cooling
ing as eczema is treated with anti-inflammato- baths, topical steroids, lotio alba, and systemic
ry drugs, preferably with topical glucocortico- antihistamines are used against severe itching
steroids in the acute phase (see Sect. 5.5.4). (see Sect. 6.3.2 on Pharmacotherapy).
A new method of anti-inflammatory treat- The well-known psychosomatic interac-
ment of atopic eczema without glucocorticoids tions in atopic eczema sometimes require care-
is available with the new topical immunosup- ful psychosomatic counseling of the patient
pressives or calcineurin antagonists, which act and relatives [10, 18, 45].
topically. These substances (tacrolimus and pi- UV therapy as adjuvant strategy has a good
mecrolimus) inhibit like cyclosporin A activa- effect with different modalities, especially as
tion of calcineurin phosphatase in T cells and long-wave UVA-1 [1, 28, 29].
also mast cells and basophil leukocytes by Unsaturated fatty acids have been recom-
binding to a cytosolic immunophyllin (cyclo- mended as well as traditional Chinese herbs [2]
phyllin, FK506 binding protein or macrophyl- or leukotriene antagonists [13].
lin 12). The intracellular signal transduction is The role of allergen-specific immunothera-
thereby inhibited and the transcription of py is controversial [70]; however, considering
many proinflammatory cytokines is reduced the new results with the atopy patch test and
[41, 57, 69]. (see also Sect. 6.3.2). the clear-cut role of allergy in some patients, it
In contrast to glucocorticosteroids, these should be investigated by control studies.
substances do not have atrophogenic effects in There is no need for desperation or pessi-
the skin. The two preparations available are mism when we look at the spectrum of thera-
tacrolimus in a relatively fatty ointment in peutic modalities available for atopic eczema
0.1 % and 0.03 % concentrations as well as the (Fig. 5.60). All these treatment modalities re-
more aqueous cream pimecrolimus in a 1 % quire the active cooperation of the informed
cream. The place of these new compounds in patient over months and years (Table 5.66).
the management of atopic eczema will be seen Therefore, eczema school programs have
in the years to come. been developed, which after adequate training
For prophylaxis, avoidance of irritants and (eight atopic eczema academies in Germany)
allergens (Table 5.65) also includes recommen- are offered in an interdisciplinary setting (al-
dations for breast feeding of the newborn infant, lergy, dermatology, pediatrics, nutritionists,
the use of encasings at home or rehabilitation psychosomatics) for children, parents, and
under climatic therapy conditions (e.g., North adults [18].
Sea, high altitude in Davos, Switzerland) [10].
Frequent superinfections of the skin some-
times require antimicrobial therapy, best done
5.5 Dermatitis/Eczema 161
therapy eczema
Sonata
Tar 11. Braun-Falco O, Ring J (1984) Zur Therapie des
for
Antihistamines atopischen Eczemas. Hautarzt 35:447 454
Glococorticosteroids 12. Bruynzeel-Koomen C, Van Wichen DF, Toonstra
atopic
ACTH J, Berrens L, Bruynzeel PLB (1986) The presence
of
Mast cell blockers of IgE molecules on epidermal Langerhans cells
Anticholinergics in patients with atopic dermatitis. Arch Dermatol
Antimicrobial Terapy Res 278:199 205
Hyposensibilization 13. Carucci JA, Washenik K, Weinstein A, Shupack J,
Immunmodulants Cohen DE (1998) The leukotriene antagonist za-
Immunsuppressives firlukast as a therapeutic agent for atopic derma-
Cytokines
titis. Arch Dermatol 134:785 786
Psychopharmaca
Behavioral Therapy 14. Cooper KD, Stevens SR (2001) T cells in atopic
Psychotherapy dermatitis. J Am Acad Dermatol 45:510 512
15. Cookson WO, Ubhi B, Lawrence R, Abecasis GR,
Whalley AJ, Cox HE, et al. (2001) Genetic linkage
Fig. 5.60. Therapeutic keyboard
of childhood atopic dermatitis to psoriasis sus-
ceptibility loci. Nat Genet 27:372 373
16. Darsow U, Vieluf D, Ring J for the APT Study
Group (1999) Evaluating the relevance of aeroal-
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eral vasoactive mediator dysregulation. Int Arch 60. Valenta R, Seiberler S, Natter S, Mahler V, Mossa-
Allergy Appl Immunol 59:233 239 beb R, Ring J, Stingl G (2000) Autoallergy: A
164 5 Allergic Diseases (and Differential Diagnoses)
pathogenetic factor in atopic dermatitis? J Aller- 66. Wollenberg A, Wen S, Bieber T (1999) Phenoty-
gy Clin Immunol 105:432 437 ping of epidermal dendritic cells clinical appli-
61. Wahlgren CF, Scheynius A, Hagermark O (1990) cations of a flow cytometric micromethod. Cyto-
Antipruritic effect of oral cyclosporin A in atopic metry 37:147 155
dermatitis. Acta Derm Venereol 70:323 329 67. Wright S, Burton JL (1982) Oral-evening-prim-
62. Wakim M, Alazard M, Yajima A, Speights D, Sax- rose-seed oil improves atopic eczema. Lancet
on A, Stiehm E (1998) High dose intravenous im- 2:1120 1122
munoglobulin in atopic dermatitis and hyper-IgE 68. Wthrich B (1975) Zur Immunpathologie der
syndrome. Ann Allergy Asthma Immunol 81: Neurodermitis constitutionalis. Huber, Bern
153 158 69. Wthrich B (ed) (1999) The atopic syndrome in
63. Werfel T (2000) Allergenspezifische T-Zell-Ant- the third millennium. Karger, Basel
wort bei Eczemakrankheiten. Dustri, Munich 70. Zachariae H, Cramers M, Herlin T, Jensen J, Krag-
64. Williams HC (ed) (2000) Atopic dermatitis. The balle K, Ternowitz T, Thestrup-Pedersen K (1985)
epidemiology, causes and prevention of atopic ec- Non-specific immunotherapy and specific hypo-
zema. Cambridge University Press, Cambridge sensitization in severe atopic dermatitis. Acta
65. Wise F, Sulzberger MB (1933) Footnote on prob- Derm Venereol (Stockh) [Suppl] 114:48 54
lem of eczema, neurodermatitis and lichenificati- 71. Stalder R, Taieb A, et al. (1993) Consensus Report
on. In: Wise F, Sulzberger MB (eds) The 1933 Year of the European Task Force on Atopic Dermatitis.
book of dermatology and syphilology. Year Book Severity scoring of atopic dermatitis: the SCO-
Publishers, Chicago, pp 38 39 RAD index. Dermatology 186:23 31
dry fat
Course
acute
subacute
chronic
Skin type
Sebostasis
Seborrhea
Localization
Fig. 5.62. Application
forms of topical thera- Extension sites
py. Guidelines for se-
lecting the proper ap- Flexor sites
plication form for topi-
Intertriginous areas
cal glucocorticoid ther-
apy according to the Dyshidrosis
clinical course and the
location and condition Hairy areas
of the affected skin area
greasy ointments need to be avoided, whereas avoid instability of emulsions, loss of efficacy,
on the extensor surfaces and in chronic lesions and incompatibilities between substances. Many
they are indicated. companies offer the vehicle ointment alone in
Corticoid preparations are available in all addition to the steroid-containing compound.
forms: greasy ointment (no water), water in oil
ointments, oil in water (creams), lotio (suspen-
5.5.4.3 Side Effects of Topical Glucocorticosteroids
sion mixtures), lotion (milk), gel, paste (pow-
der in ointment), alcoholic solutions (tinctu- The most relevant side effects of topical steroid
ra), plasters, sprays, foams, etc. The vehicles therapy are listed in Table 5.70. The risk of sys-
comprise substances of mineral (petrolatum, temic steroid therapy generally is much higher.
paraffin), animal (wool wax alcohols), plant However, sometimes after very intense topical
(oils, wax, starch), and synthetic origin (pro- steroid application (especially under occlu-
pylene glycol) together with emulsifiers, pre- sion) systemic side effects may occur [5, 9, 11,
servatives, fragrances, etc. These constituents 16, 17, 21].
are important for potential contact allergy. Almost all undesired side effects of corti-
Combination preparations of glucocorti- coids are somehow related to the desired phar-
coids with antibiotics or antimycotics should macological effect and therefore in most cases
be considered critically and only in occasional dose dependent. Disturbance of ostiofollicular
cases are they indicated. The ex iuvantibus keratinization leads to comedo formation and
practice often prevents correct diagnosis. steroid acne. Inhibition of proliferation and re-
For individual prescriptions of mixtures, the generation of the epidermis induces thinning
galenic compatibility has to be considered to and atrophy. The degeneration of collagen and
168 5 Allergic Diseases (and Differential Diagnoses)
Systemic administration
Endocrinology
Diabetes mellitus
Catabolic metabolism
Osteoporosis
Hyperlipidemia
Alkalosis (sodium retention potassium excretion)
Suppression of pituitary gland (growth suppres-
sion in children)
Cushings syndrome
Hypertension
Immune system
Inhibition of lymphocyte and granulocyte func-
tion, immunosuppression
Gastrointestinal
Peptic ulcer
Neurological
Myopathy
Neuropathy
Psychic alteration
Ophthalmological
Cataract
Glaucoma
Thromboembolic complication
Anaphylactoid reaction (very rare)
Topical application on skin Fig. 5.63. Striae distensae after long-term application
Striae distensae of glucocorticoids
Atrophy
Fatty tissue atrophy
Embolia cutis (after i.m. crystal suspension)
Increased photosensitivity
Pseudo-anetoderma
Cutis punctata linearis colli
Teleangiectasias
Rubeosis steroidica
Pigment changes
Perioral rosacea-like dermatitis
Granuloma gluteale infantum
Hypertrichosis
Purpura and ecchymosis
Acne
Hair loss
Infection
Disturbance of wound healing
Contact allergy
8. Guin JD (1984) Contact sensitivity to topical cor- 20. Przybilla B, Ring J (1983) uerliche Behandlung
ticosteroids. J Am Acad Dermatol 10:773 782 mit Glukokortikosteroiden. Med Monatsschr
9. Hatz H (1998) Kortison und Kortikoide. Deut- Pharm 6:192 205
scher Apothekerverlag, Stuttgart 21. Ring J, Frhlich HH (1985) Wirkstoffe in der der-
10. Hornstein OP, Nrnberg E (eds) (1985) Externe matologischen Therapie, 2nd edn. Springer, Ber-
Therapie von Hautkrankheiten. Pharmazeuti- lin Heidelberg New York
sche und medizinische Praxis. Thieme, Stuttgart 22. Schaefer H, Zesch A, Schalla W, Stttgen G (1980)
11. Kaiser H (1977) Cortisonderivate in Klinik und Pharmakokinetik externer Glucocorticoide. All-
Praxis. Thieme, Stuttgart ergologie 3:194
12. Kligman AM (1986) Topical steroids: Perspec- 23. Schell H, Hornstein OP (1980) Endogener Korti-
tives and retrospectives. In: Ring J, Burg G (eds) solrhythmus und Epidermisproliferation. Akt
New trends in allergy. II. Springer, Berlin Heidel- Derm 6:27 33
berg New York, pp 342 352 24. Schleimer RP (1993) An overview of glucocorti-
13. Lubach D, Kietzmann M (1992) Dermatokortiko- coid anti-inflammatory actions. Eur J Clin Phar-
ide Pharmakologie und Therapie. In: Marghes- macol 45 [Suppl]:1
cu S, Wolff HH, Zaun H (eds) Kohlhammer, Frei- 25. Schmutzler W (1999) Antiallergische und an-
burg tientzndliche Pharmakotherapie. In: Heppt W,
14. Maibach H, Stougthon RB (1973) Topical cortico- Renz H, Rcken M (eds) Allergologie. Springer,
steroids. Med Clin N Am 57:1253 Berlin Heidelberg New York, pp 160 174
15. Marghescu S (1983) Externe Kortikoidtherapie: 26. Schpf E (1972) Nebenwirkungen externer Corti-
Kontinuierliche versus diskontinuierliche An- coidtherapie. Hautarzt 23:295
wendung. Hautarzt 34:114 117 27. Schpf E (1980) Kortikosteroide in der Dermato-
16. Miyachi Y (1982) Adrenal axis suppression logie. Allergologie 3:306
caused by a small dose of a potent topical cortico- 28. Sulzberger MB, Witten VH (1952) The effect of
steroid. Arch Dermatol 118:451 topically applied compound F in selected derma-
17. Niedner R, Ziegenmeyer J (eds) (1992) Dermati- toses. J Invest Dermatol 19:101
ka Therapeutischer Einsatz, Pharmakologie 29. Wendt H, Frosch PJ (1982) Klinisch-pharmakolo-
und Pharmazie. Wiss Verlagsgesellsch, Stuttgart gische Modelle zur Prfung von Corticoidexter-
18. Poulsen J, Rorsman H (1980) Ranking of gluco- na. Karger, Basel
corticoid creams and ointments. Acta Derm Ve- 30. Wilckens T (1995) Glucocorticoids and immune
nereol 60:57 function: hormonal dysfunction. Trends Phar-
19. Ponec M, Kempanaar SA, DeKloet ER (1981) Cor- macol Sci 16:193 197
ticosteroids and cultured human epidermal kera-
tinocytes. J Invest Dermatol 76:211 214
Table 5.72. Differential diagnosis of phototoxic and Table 5.73. Classification of photohypersensitivity
photoallergic reactions diseases
Phototoxic Photoallergic Photoallergic reactions
Photoallergic contact dermatitis
Mechanism: Persistent light reaction (?) (chronic actinic der-
Direct cell damage Immunologic matitis)
sensitization
Possibly photoallergic reactions
Manifestation after first contact: Light-urticaria (solar urticaria)
Yes No Polymorphic light eruption
Flare up of earlier involved skin Phototoxic reactions
areas: Acute and chronic light damage
No Yes Phototoxic dermatitis
Morphology: Metabolic diseases (porphyria, Hartnup-syn-
Erythema: drome, etc.)
+++ + (Questionable: hydroa vacciniforme, Mallorca acne)
Edema: Light-provoked dermatoses
++++ +++ Lupus erythematosus
Papules/papulovesicles: Morbus Darier (dyskeratosis follicularis)
+/ ++ Porokeratosis
Vesiculation: Herpes simplex
+++++ + Lichen planus
Spreading phenomena: Psoriasis
++ Atopic eczema (?)
Margination of skin lesions: Pityriasis rubra pilaris
Sharp Not sharp
Dermatohistology:
Sunburn cells in epidermis: bolic disturbances or enyzme defects (e.g., var-
+ ious forms of porphyria) with endogenous
Spongiosis:
+
photosensitizers or contact with exogenous
photosensitizers (e.g., weeds in dermatitis pra-
Kinetics: tensis or drugs).
Decrescendo Crescendo
Photoallergic reactions manifest mostly as
photoallergic contact dermatitis. Photohyper-
psoralen phototoxicity) or via oxygen radicals sensitivity reactions with an unknown elicitor
affecting cell membranes [8, 15, 42]. (Table 5.73) comprise some forms of solar urti-
Photoallergic reactions are due to immuno- caria and so-called polymorphic light eruption
logical sensitization directed against a new (lay people often call it sun allergy), which
photoallergen induced by action of UV radia- differs from patient to patient in morphology,
tion. Theoretically, phototoxic and photoaller- but is rather monomorphous in the individual
gic reactions can be well differentiated (Ta- patient [2, 3, 13, 24, 28, 36].
ble 5.72), although in individual patients this Photoallergic contact dermatitis is a relatively
may be difficult in practice. common form of photohypersensitivity (Fig.
5.67). Some patients under the combined influ-
ence of light and photoallergen develop a chroni-
5.6.2 Clinical Manifestations of Photo-
fication, the so-called persistent light reaction,
hypersensitivity
occurring with thickened erythematous licheno-
Photohypersensitivity reactions should be dis- id plaques and a strong itching or burning pain.
tinguished from well-known adverse reactions Persistent light reaction is characterized by a
induced by UV radiation, either acutely (sun- general increase in photosensitivity in different
burn) or chronically (atrophy, elastosis, carci- parts of the UV spectrum. Persistent light reac-
nogenesis), which occur dose dependently in tion can further develop into chronic actinic der-
all individuals with normal sensitivity. Hyper- matitis (actinic reticuloid), which may some-
sensitivity against UV light may occur in meta- times turn into cutaneous lymphoma [8, 17, 24].
172 5 Allergic Diseases (and Differential Diagnoses)
5.6.3 Photosensitizers
Photosensitizing agents are widely distributed
in nature. They are found in tar (polyaromatic
hydrocarbons, acridine derivatives) or color-
ings (eosin, fluorescein, methylene blue).
Many plants contain photosensitizers (Ta-
ble 5.74), giving rise to phototoxic reactions af-
ter epidermal contact or after oral intake [26,
43]. The furocoumarins contained in many
etheric oils or fragrances in cosmetics (Brelo-
que dermatitis) are also the active agents in the
elicitation of meadow grass dermatitis (derma-
titis pratensis) [21, 26] (Fig. 5.68). Chlorophyll
derivatives have been described as inductors of
Fig. 5.67. Photoallergic contact eczema photodermatoses [18].
Various drugs (mostly after systemic ad-
In patients with persistent light reaction the ministration) act as photosensitizers (Ta-
minimal erythema dose (MED) is generally de- ble 5.75). Photosensitizers eliciting clear-cut al-
creased, mostly in the UVB but also in the UVA lergic reactions are also called photoaller-
range. Rarely there is also hypersensitivity gens. In the office the distinction is often diffi-
against visible light. These patients develop in- cult, since many photoallergens also have pho-
flammatory skin lesions after exposure to light, totoxic potential.
independent of allergen contact. Recently non-steroidal anti-inflammatory
In the rare solar urticaria, UV radiation drugs have been shown to act as photosensitiz-
(mostly UVA) is the elicitor. The detection of ers, especially the propionic acid derivatives
the eliciting wavelength is important. In photo- (Fig. 5.69) [25, 32, 35, 39].
provocation tests 0.2 5.0 J/cm2 UVA will elicit
reactions within 10 20 min. Anaphylactic
shock in the solarium has been described. By Table 5.74. Photosensitizors from plants
pretreatment with other wavelengths harden-
Umbelliferae
ing may be achieved [12, 32, 34]. Heracleum, Angelica, Daucus carota (carrot),
In polymorphic light eruption photoprovo- Ammi majus, Apium graveolens (celery), Pastinaca
cation may be possible in previously involved,
Rutaceae
but at the time of testing symptom-free, skin Citrus bergamia (bergamot), Citrus sinensis
areas not exposed to light. This has to be done (orange), Ruta graveolens, Dictamnus albus
on three subsequent days with doses of Moraceae
3 60 100 J/cm2 UVA or UVA1, or 3 1.5 Ficus carica (fig)
MED UVB or UVA+UVB. Leguminosae
The very rare disease of hydroa vaccinifor- Psoralea corylifolia
mia can sometimes be treated with UVA; the Rosaceae
cause is unknown, vitamin B deficiency has
Compositae
been discussed.
5.6 Photoallergy/Photosensitization 173
administration of the suspected substance var- 4. Epstein S (1939) Photoallergy and primary pho-
ious areas are irradiated at different time inter- tosensitivity to sulfanilamide. J Invest Dermatol
vals (e.g., 50 J/cm2 UVA). 2:43 51
5. Ferguson J, Johnson BE (1993) Clinical and labo-
ratory studies of the photosensitizing potential of
5.6.5 Prophylaxis and Therapy norfloxacin, a 4-quinolone broad-spectrum anti-
biotic. Br J Dermatol 128:185 195
Information from the patient and recommen- 6. Fjellner B (1981) Experimental and clinical pruri-
dations for careful sun exposure are the basis of tus. Studies on some putative peripheral media-
tors. The influence of ultraviolet light and trans-
any treatment. Avoidance of elicitation agents cutaneous nerve stimulation. Thesis, Stockholm
is crucial. In patients with unknown photosen- 7. Fotiades J, Soter NA, Lim HW (1995) Results of
sitizers the selection of the sunscreen is very evaluation of 203 patients for photosensitivity in a
important. Most of the commercial sunscreens 7.3-year period. J Am Acad Dermatol 33: 597 602
8. Frain-Bell W (1986) Cutaneous photobiology.
describe the sun protection factor for UVB ra-
Oxford University Press, New York
diation only (rarely also for UVA), which, how- 9. Galosi A, Przybilla B, Ring J, Dorn M (1984) Sy-
ever, is the decisive wavelength for most pa- stemische Photoprovokation mit Surgam. Aller-
tients with photosensitization. One should gologie 7:143 144
know that many of the common light filter sub- 10. Gigli I, Lim HW (1981) Release of proinflamma-
tory peptides by complement in porphyrin-in-
stances in sunscreens can act as photoallergens
duced photosensitivity. In: Ring J, Burg G (eds)
[38, 39]. New trends in allergy. Springer, Berlin Heidel-
In patients with polymorphic light eruption berg New York, p 5848
as well as chronic photoallergic contact derma- 11. Gollhausen R, Przybilla B, Galosi A, Khler K,
titis with transition to persistent light reaction, Ring J (1987) Environmental influences of UVB
erythema. Photodermatology 4:148 153
PUVA therapy as well as UVA1 or small spec- 12. Hasei K, Ichihashi M (1982) Solar urticaria. De-
trum UVB (311 nm) can be used as condition- terminations of action and inhibition spectra.
ing [13, 15, 28]. In experimental models inhibi- Arch Dermatol 118:346 350
tory effects of UV radiation on allergy-relevant 13. Hlzle E, Plewig G, Kries R v, Lehmann P (1987)
reactions have been demonstrated [3, 6, 22, 32]. Polymorphous light eruption. J Invest Dermatol
88:32 38
Prior to the production of new substances as 14. Hlzle E, Neumann N, Hausen B, Przybilla B,
drugs or cosmetics, screening tests for possible Schauder S, Hnigsmann H, Bircher A, Plewig G
photosensitizing properties should be per- (1991) Photopatch testing: The 5-year experience
formed. There are various in vivo (guinea pig, of the German, Austrian and Swiss photopatch
rat, mice) and in vitro procedures (Candida al- test group. J Am Acad Dermatol 25:59 68
15. Hnigsmann H, Stingl G (eds) (1986) Therapeu-
bicans inhibition test, photohemolysis test) [5, tic photomedicine. Karger, Basel
12, 14]. We have detected the photosensitizing 16. Horio T (1975) Chlorpromazine photoallergy.
properties of non-steroidal anti-inflammatory Arch Dermatol 111:1469 1471
drugs using a photo-basophil-histamine-re- 17. Ippen H (1973) Photochemie der Haut. In: Herr-
lease test [31, 35]. mann F, Oppen H, Schaefer H, Stttgen G (eds)
Biochemie der Haut. Thieme, Stuttgart, p 146
18. Jitsukawa K, Suizu R, Hidano A (1984) Chlorella
photosensitization, a new phytophotodermato-
sis. Int J Dermatol 23:263
References 19. Jung EG (1981) Die belichtete Epikutantestung.
Akt Derm 7:163 165
1. Bergner T, Przybilla B (1992) Photosensitization 20. Jung EG, Hardmeier T (1967) Zur Histologie der
caused by ibuprofen. J Am Acad Dermatol photoallergischen Testreaktion. Dermatologica
26:114 116 135:243 252
2. Breit R (1987) Rtung und Brunung der Haut 21. Kavli G, Volden G (1984) Phytophotodermatitis.
durch UVA. Zuckschnverdt, Munich Photodermatology 1:65 75
3. Eberlein-Knig B, Fesq H, Abeck D, Przybilla B, 22. Kripke ML (1986) Photoimmunology, the first
Placzek M, Ring J (2000) Systemic vitamin C and decade. Curr Probl Dermatol 15:164 175
vitamin E do not prevent photoprovocation test re- 23. Lehmann P (1990) Die Deutschsprachige Ar-
actions in polymorphous light eruption. Photo- beitsgemeinschaft Photopatch-Test (DAPT). Haut-
dermatol Photoimmunol Photomed 16:50 52 arzt 41:295 297
5.7 Adverse Drug Reactions 175
24. Lischka G, Jung EG (1982) Lichtkrankheiten der histamine and leukotriene release from peripher-
Haut, 2nd edn. Perimed, Erlangen al human leukocytes. Int Arch Allergy Appl Im-
25. Ljunggren B, Bjellerup M (1986) Systemic drug munol 82:344 346
photosensitivity. Photodermatology 3:26 35 36. Ring J, Przybilla B (1990) UV irradiation and al-
26. Ljunggren B (1990) Severe phototoxic burn fol- lergy. Allergologie 12(Suppl EAACI):75 79
lowing celery ingestion. Arch Dermatol 126: 37. Ruzicka T, Walter JF, Printz MP (1983) Changes in
1334 1336 arachidonic acid metabolism in ultraviolet irra-
27. Maurer T (1983) Contact and photocontact aller- diated hairless mouse skin. J Invest Dermatol
gens. A manual of predictive test methods. Dek- 81:300 303
ker, New York 38. Schauder S, Ippen H (1986) Photoallergic and al-
28. Plewig G, Hlzle E, Roser-Maa E, Hofmann C lergic contact dermatitis from dibenzoylmetha-
(1985) Photoallergy. In: Ring J, Burg G (eds) New nes. Photodermatology 3:140 147
trends in allergy. Springer, Berlin Heidelberg 39. Schauder S, Schrader A, Ippen H (1996) Gttinger
New York, pp 152 169 Liste 1996. Sonnenschutzkosmetik in Deutsch-
29. Przybilla B, Ring J, Schwab U, Galosi A, Dorn M, land, 4th edn. Blackwell, Berlin
Braun-Falco O (1987) Photosensibilisierende Ei- 40. Schmidt T, Abeck D, Ring J (1998) Photoallergic
genschaften nicht-steroidaler Antirheumatika im contact dermatitis due to combined UVB-(4-me-
Photopatch-Test. Hautarzt 38:18 25 thylbenzylidene camphor/octyl methoxy-cinna-
30. Przybilla B (1987) Phototestungen bei Lichtder- mate) and UVA-(benzophenone-3/butyl-metho-
matosen. Hautarzt 38:S23S28 xy-dibenzoylmethane) absorber. Dermatology
31. Przybilla B, Schwab-Przybilla U, Ruzicka T, Ring J 196:354 357
(1987) Phototoxicity of non-steroidal antiinflam- 41. Schulz KH, Wiskemann K, Wolf K (1956) Klini-
matory drugs demonstrated in vitro by a photo- sche und experimentelle Untersuchungen ber
basophil-histamine-release test. Photodermatol- die photodynamische Wirksamkeit von Phenoti-
ogy 4:73 78 azinderivaten, insbesondere Megaphen. Arch
32. Przybilla B, Ring J, Eberlein B (1988) Inhibition of Klin Exp Dermatol 202:285 298
in vitro basophil histamine release by UVA irradi- 42. Terui T, Okuyama R, Tagami H (2001) Molecular
ation. J Allergy Clin Immunol 83:302 events occurring behind ultraviolet-induced skin
33. Przybilla B, Bergner T (1992) Diagnostik von inflammation. Curr Opin Allergy Clin Immunol
lichtallergischen Exanthemen im erscheinungs- 1:461 467
freien Intervall. Hautarzt 43:100 101 43. Wessner D, Hofmann H, Ring J (1999) Phytopho-
34. Przybilla B, Eberlein-Knig B (2000) Photoprovo- todermatitis due to Ruta graveolens applied as
kationstests. In: Przybilla B, Bergmann K, Ring J protection against evil spells. Contact Dermatitis
(eds) Praktische allergologische Diagnostik. 41:232 233
Steinkopff, Darmstadt 44. Wucherpfennig V (1931) Biologie und praktische
35. Ring J, Przybilla B, Ruzicka T (1987) Nonsteroidal Verwendbarkeit der Erythemschwelle des UV.
antiinflammatory drugs induce UV-dependent Strahlentherapie 40:201 243
gy prevalences are lower (0.1 1 %). Some Coombs and Gell) (Table 5.76). In order to elicit
groups of drugs, however, have a higher risk an allergy, the drug has to be immunogenic;
(over 2 %), e.g., foreign proteins (xenogeneic this holds true for proteins and peptides (> 7
protein, allergen extracts, organ extracts, vac- amino acids). Low molecular drugs are haptens
cines, transfusions, enzymes, and hormones) and need binding to body carrier proteins to
and antibiotics (penicillin, ampicillin, sulfon- gain immunogenicity. The chemical basis of
amides, erythromycin). It is unlikely that there sensitization is known for very few drugs; for
are drugs which under guarantee will never penicillin, we know the critical antigenic deter-
elicit an allergy! Anaphylactoid reactions to minants: the penicilloyl group as major deter-
corticosteroids have been reported. Precise minant (that is most frequent, not most dan-
studies to compare the prevalences of side ef- gerous!) and the minor determinants (less
fects are difficult to perform. The term fre- frequent) of penicillenate and penicillamine
quent implies different aspects such as an ac- [62]. Similar molecules can show cross-reac-
tual increased prevalence of side reactions tions; small molecules can elicit a reaction
(relative percentage) as well as an absolutely when they have capacity for at least divalent
increased usage of the drug (absolute num- binding to the antibody molecule.
bers). Metabolism of drugs is important for the in-
The classification of adverse drug reactions duction of incompatibility reactions. In the
can be done according to clinical symptoms balance between activation and detoxification,
(e.g., anaphylactoid reaction, fever, exanthem- disturbances may be crucial, involving espe-
atous eruption, organ disease) and suggested cially the enzymes of the cytochrome P450 sys-
or proven pathomechanism time course kinet- tem as well as N-acetyltransferase (NAT) [34,
ics (acute 0 60 min, subacute 1 24 h, delayed 35]. In cutaneous drug reactions, keratinocytes
or accelerated for more than 24 h) (according to also play a role with metabolizing enzymes
[23]). [45].
For the frequency of sensitization, the route
of administration is essential: the risk of allergy
5.7.1.2 Pathophysiology
induction increases in the following sequence:
Drug allergies can be classified like all other oral, intravenous, intramuscular, subcutane-
allergic diseases (modified classification of ous, and topical.
effects. Hematologic complications are com- possible with confidential cooperation from
mon in cytotoxic reactions (e.g., allergic agran- the pharmaceutical industry (confidentiality
ulocytosis) (see Sect. 5.2). Central nervous agreement!) and the informed patient.
symptoms (cramps, paresthesia, cognitive fail- In pseudo-allergic reactions skin tests are
ure) are seen in pseudo-allergic reactions (e.g., usually negative; they should, however, be per-
with local anesthetics). formed in order to detect rare true allergies and
In the literature, a hypersensitivity syn- in order to avoid dramatic immediate type reac-
drome is described as a very severe drug reac- tions.
tion with sepsis-like symptoms, high fever with
or without skin involvement and frequent hy-
5.7.1.4.3 In Vitro Diagnosis
pereosinophilia in the peripheral blood. Anti-
convulsants as elicitors are known. The mecha- The development of reliable in vitro tests for al-
nism of these reactions in earlier textbooks lergy diagnosis of adverse drug reaction is a
also called drug fever is not clear. Lympho- major endeavor in research in order to save pa-
cyte transformation tests may be helpful [5]. tients from having to undergo unnecessary
provocation tests. Unfortunately, only for a few
drugs (e.g., penicillin) are standardized RAST
5.7.1.4.2 Skin Test
procedures available for routine diagnosis.
Two to 3 weeks after remission of symptoms or Besides RAST, IgE-mediated reactions may
withdrawal of systemic glucocorticoid or anti- be detected by in vitro histamine release, sulfi-
histamine therapy, skin tests should be per- doleukotriene formation (CAST-ELISA) [63]
formed, if possible not later than after or basophil activation (CD63) from peripheral
3 months. Certain drugs able to inhibit skin re- leukocytes after stimulation with the suspect
actions should be withdrawn (see Sect. 4.2). drug. In these tests, the problem of hapten cou-
Skin tests stay positive over longer periods of pling to protein is inherent.
time compared to in vitro tests. However, they The diagnosis of non-IgE-mediated reac-
also bear the risk of systemic reactions. Fatali- tions requires the measurement of other anti-
ties after simple scratch tests in highly sensi- body classes, e.g., with passive hemagglutina-
tized patients have been reported [14]. tion, immunodiffusion, or specific RIA or EIA
The general problem of all drug allergy tests assays. Immune complex anaphylaxis due to
is the haptenic nature of the low molecular sub- dextran is mediated by high titers of specific
stances which have to bind in the body to pro- IgG antibodies against dextran (see Sect. 5.3).
teins to gain antigenic properties. Therefore, In this model, the importance of time points for
real progress in the field of drug allergy is only taking blood samples for investigation has
possible when haptens can be coupled to high been elucidated. The highest antibody titers
molecular carriers, for instance penicillin to were found in serum samples drawn prior to
penicilloyl polylysine (PPL) [62]. the administrations of the drug [46]; immedi-
Prior to testing of unknown substances, ately after the clinical reaction, antibody titers
concentrations used need to be evaluated care- were markedly reduced or not measurable; on-
fully [51] in order to avoid toxic reactions. The ly after several days or weeks were antibodies
choice of solvent in water-insoluble drugs is again increased. The retrospective asservation
important. Drug test solutions should be fresh- of samples (laboratory or blood bank) may be
ly made up more often than allergen extracts. decisive for final diagnosis!
Positive test reactions should be evaluated to- Some authors recommend the lymphocyte
gether with controls in healthy volunteers (in transformation test (LTT) as an in vitro test
order to exclude irritative reactions). for adverse drug reactions [5, 40, 53]. In our
Patch tests with topical preparations must experience, the LTT can be helpful in the diag-
include vehicles and other ingredients. In posi- nosis of cell-mediated reactions while immedi-
tive reactions the single substances need to be ate-type reactions only rarely show reliable re-
tested in adequate concentrations; this is only sults.
5.7 Adverse Drug Reactions 179
A major difficulty of all cellular procedures Table 5.79. Documentation for an allergy passport
is the high variance of the test results. In ad- Criteria for registration of a substance:
verse drug reactions, the problem of standardi- ) The substance can be avoided
zation (vehicle, concentration, metabolites, ) The clinical relevant sensitization usually per-
controls) causes difficulty; many procedures sists over longer periods
) High allergenic potency
(e.g., use of liver microsomes) [34] are not ) Risk of systemic reactions (anaphylaxis)
available for routine tests and are only possible ) Alternative drug tested in provocation tests
in specialized laboratories. ) The allergy passport should contain the follow-
ing information:
) Location and date, name of the allergist
5.7.1.4.4 Provocation Test ) Clinical symptomatology and severity of the
adverse reaction
The provocation test, e.g., the exposure of the ) Eliciting substance
) Information regarding the diagnostic test pro-
patient to the specific relevant substance under cedures
controlled conditions, often remains the only ) Tested alternatives (e.g., information regarding
reliable method in the diagnosis of adverse the dose tolerated in OPT)
drug reactions; this holds especially true for
pseudo-allergic reactions [43, 48]. results (only clear-cut positive patch test reac-
Prior to the provocation test, the other diag- tions are recorded in the allergy passport!), we
nostic procedures need to be performed in or- also document the so-called allergy suspi-
der to gain information about the intensity of cion in adverse drug reactions (Table 5.80).
the patients sensitization. Any provocation test However, in the allergy passport, both test re-
bears a certain risk and has to be performed sults and diagnostic considerations should be
with the utmost caution (sometimes under in- documented (e.g., suspicion by history, skin
patient conditions). test positive, RAST positive) [60]. So-called
In the diagnosis of adverse drug reactions, prophetic testings (without a history of adverse
oral provocation is the commonest test. The reactions) are rarely indicated.
oral provocation test (OPT) should not only in- The most common mistakes in the diagnosis
clude the suspected agent from the patients his- of adverse drug reactions are listed in Table 5.81.
tory but also a selection of standard substances
as possible alternatives. The recommendation
Table 5.81. Common mistakes in the diagnosis of ad-
of an alternative drug on the basis of the litera- verse drug reactions
ture only without actual proof of tolerability in
an OPT may be dangerous [43, 48]. ) Insufficient history
) Wrong substance tested
For example, we have observed several ) Wrong test procedure
sometimes severe anaphylactoid reactions af- ) Wrong interpretation of skin test reactions
ter administration of acetaminophen in patients (especially intradermal)
) Insufficient precautions for skin tests and prov-
with a history of anaphylaxis to analgesics.
ocation tests
The evaluation of OPT results can some- ) Wrong interpretation of psychic factors (under-
times be difficult, especially with regard to the and overestimation)
allergy passport (Table 5.79). In contrast to ) Inadequate allergy passport
) Testing under therapy with antiallergic drugs
the procedure for contact allergy and patch test
Often doctors advise the patient with adverse Table 5.83. Successful hyposensitization in drug erup-
drug reactions: Just dont take this drug any tions
more. This advice is as intelligent as the rec- Antibiotics Virostatiics
ommendation for a patient with abdominal Penicillin Zidovudine
pain: Dont press on it again! Ciprofloxacin Nevirapine
Ethambutol
Anticonvulsives
Rifampicin
Carbamazepine
5.7.1.5 Hyposensitization in Drug Allergy Sulfonamides Phenobarbital
Cotrimoxazole
In spite of multiple alternative substances, it Cytostatics
Sulfadiazine
may occur that the patient is allergic to a life- Azathioprine
Dapsone
6-Mercaptopurine
saving drug and the possibility of hyposensiti- Antimycotics Carboplatin
zation should be discussed. This has been done Itraconazole
Other
successfully for various drugs although the Antiparasitics Allopurinol
mechanism of this hyposensitization (also Pyrimethamine Insulin
called adaptive deactivation or tolerance in-
duction) is by no means clear.
Principally, one has to distinguish between locytosis, thrombocytopenia, anemia). Maybe
anaphylactic reactions and cutaneous drug this should be reconsidered after future studies
eruptions. The best experiences date from im- using granulocyte colony-stimulating factor
mediate reactions to penicillin, antibiotics and (G-CSF) or erythropoietin as emergency treat-
insulin (Table 5.82). Hyposensitization can be ment.
performed orally or intravenously. In patients Severe underlying diseases may also repre-
with anaphylaxis, the dose increase is done at sent a contraindication. In suspected IgE-me-
15 30 min intervals. According to the severity diated allergy, beta-blocking agents and angio-
of the history, 0.1 1 of a usual dosis is the tensin-converting enzyme inhibitors should be
starting dose. Tables 5.82 and 5.83 show suc- withdrawn prior to hyposensitization.
cessful schedules for penicillin and insulin.
Hyposensitization in cutaneous drug erup-
tions usually does not induce lasting tolerance. 5.7.1.6 Adverse Reactions to Special Drugs
After renewed administration, the drug has to
5.7.1.6.1 Penicillin and Betalactam
be carefully started with a low dose.
Antibiotics
Contraindications for drug hyposensitiza-
tions comprise severe and life-threatening con- Penicillin allergy may manifest in many reac-
ditions without adequate possible therapy such tion types (IV). The prevalence of all reac-
as severe bullous skin diseases (Stevens-John- tions is between 5 % and 10 % [16]. The inci-
son syndrome, Lyells syndrome, necrotic vas- dence of anaphylactic reactions is approxi-
culitis), severe organopathies (hepatitis, ne- mately 1 %, of lethal cases 1:50,000. Regarding
phritis), as well as cytotoxic reactions (agranu- the common use of penicillin (80 million peni-
cillin administrations per year in the United
Table 5.82. Schedule for hyposensitization in penicil- States), this is a great practical problem: 32 of
lin allergy (oral) 43 fatal anaphylactic reactions in the US army
Steps Dose (units) Steps Dose (units)
were penicillin mediated (see Sect. 5.1.4). At-
tempted suicide through the elicitation of ana-
1 100 9 24,000 phylaxis by a penicillin-allergic individual has
2 200 10 48,000 been reported [55]. Often penicillin allergy is
3 400 11 80,000
4 800 12 160,000 observed after the first therapeutic administra-
5 1,600 13 320,000 tion of penicillin; here sensitization may have
6 3,200 14 640,000 occurred unnoticed via food (cows milk,
7 6,400 15 1,000,000 chicken, etc.), conjunctival prophylaxis at birth
8 12,000
or penicillin-containing wound ointments. A
5.7 Adverse Drug Reactions 181
positive reaction against Penicillium notatum creasing doses with the utmost caution [54].
in the standard allergy test is not of relevance Fortunately, penicillin can be replaced for most
for penicillin allergy! indications by alternative antibiotics. Very spe-
The skin test (always begin with a prick or cial indications remain: streptococcal endocar-
scratch!) is performed with penicilloyl polyly- ditis, life-threatening Pseudomonas infection,
sin (PPL) in a concentration of 50 nM/ml to sepsis with serratia or neurosyphilis.
500 nM/ml (major determinant) as well as pen-
icillin G (200,000 U/ml), benzylpenicillin or
5.7.1.6.2 Analgesics
benzylpenicillenate (102 mM] (minor deter-
minants). Anaphylactoid reactions after analgesics repre-
If negative, intradermal tests are started: sent the major problem in allergy due to the
PPL 25 250 nM/ml, penicillin G 10 1,000 U/ wide use of these drugs. They may be elicited
ml. via different mechanisms: opiates are direct
The frequency of positive skin test reactions histamine liberators. The most commonly used
in patients with a history of penicillin allergy is agents in mild analgesics are salicylates, pa-
approximately 30 %. Negative skin tests do not ra-aminophenol derivatives, pyrazolones, as
exclude penicillin allergy; positive tests do not well as other contents like vitamins or codeine
100 % predict adverse reactions at the next pen- [28, 43, 59]. Combination drugs are commonly
icillin administration! However, the risk of used in many countries as well. The identifica-
penicillin allergy in patients with a positive tion of the eliciting substance is the major aim
skin test is significantly higher (30 %), while of allergy diagnosis. Skin test procedures have
provocation tests in patients with a negative limited sensitivity. However, strongly positive
skin test in spite of a positive history have only (+++) prick reactions often have diagnostic
shown 3 % positive reactions [20]. The experi- relevance. Intradermal reactions are more dif-
ence with RAST is similar: a positive RAST ficult to evaluate; adequate controls are crucial!
does not necessarily imply adverse reactions, Positive skin test reactions after codeine- or
and negative RASTs do not exclude allergy [29]. opioid-containing analgesics are a sequel of di-
In the single patient, the synopsis of skin test, rect histamine liberation. Rarely, IgE-mediated
in vitro test results, and history should be eval- reactions against opiates have been reported
uated in a risk-benefit consideration towards (e.g., morphine) [19].
the desired therapeutic effect. Penicillin allergy The relevance of positive prick tests in-
is not life-long. Skin test studies in penicillin- creases with increasing severity of the anaphy-
allergic patients show that allergy to penicillin lactoid reaction in history. Twenty-five percent
G as well as PPL decreases over the years. of patients with grade III anaphylactic reac-
Penicillin and cephalosporins of the first tions (shock) had positive prick test reactions
generation have shown a cross-reactivity of in our study, while in patients with skin symp-
10 %; this does not hold true for the newer toms only (grade I) there were positive skin
cephalosporins (third generation]. tests in only 7 % [43].
q -Lactam antibiotics (penicillin and cepha- For most cases, OPTs are required for final
losporin) differ by various side chains of the q - diagnosis to avoid life-threatening reactions in
lactam ring structure whereby cephalosporins the future and offer tolerable alternatives. OPT
have an additional substitution at the 3-posi- has to be performed under emergency condi-
tion of the dihydrothiazine ring. tions. A slow increase in dose from 10 % via
While 10 years ago the most frequent IgE-me- 50 % to 100 % of a usual single dose of a sub-
diated sensitizations were due to the penicilloyl stance has been proven useful; in very severe
group, in recent years the spectrum has changed reactions (e.g., propyphenazone anaphylaxis)
towards an increasing number of reactions to starting with 1 % or 2.5 % of a single dose is rec-
minor determinants and amoxicillin [34]. ommended. Provocation tests have to be per-
If penicillin treatment is life-saving, hypo- formed blinded and placebo controlled in or-
sensitization can be attempted with slowly in- der to avoid psychosomatic interactions. The
182 5 Allergic Diseases (and Differential Diagnoses)
results of OPT with analgesics show character- reactions to insulin. Granulomatous reactions
istic reaction patterns: 40 % of our patients re- in patients allergic to surfen at the injection site
acted to acetylsalicylic acid with concomitant need to be mentioned. Maybe the lipatrophy
reactions to other analgesics. These patients sometimes observed after insulin injection is
had negative skin tests and possible pseudo-al- also immunologically mediated [18, 57].
lergic mechanisms. In contrast, 50 % of pa- Almost half of patients under insulin treat-
tients only reacted to pyrazolone compounds, ment form antibodies of IgE and IgG class
with occasional positive skin reactions sug- against insulin without clinical incompatibility.
gesting allergic mechanisms. It was interesting Sometimes high titers of neutralizing IgG anti-
that there was no cross-reaction between dif- bodies against insulin give rise to insulin resis-
ferent pyrazolones such as metamizol (dipyro- tance [18], a phenomenon that may be classi-
ne) and propyphenazone [43]. Eight percent of fied under type VI reactions (see Table 5.76).
our patients also reacted to para-aminophenol Anaphylactic reactions to insulin represent
derivatives such as acetaminophen. The com- the major problem; for diagnosis, skin tests
mon practice of avoiding OPTs and just recom- (start with 0.01 U in a prick or 0.0001 U intra-
mending acetaminophen as alternative is not dermally) as well as RAST and histamine re-
justified. lease are used.
We use a standard block of analgesics for When insulin allergy is diagnosed, the indi-
OPT comprising acetylsalicylic acid (ASA), cation for insulin therapy should be evaluated.
acetaminophen, dipyrone, propyphenazone, If this is given, hyposensitization under inpa-
tramadol, ibuprofen, and sometimes nefopam tient conditions can be attempted (see above).
or dextropropoxyphen. For the special prob- If the patient has received insulin within the
lem of ASA idiosyncrasy, see Sect. 5.7.3. previous 24 h, the dose is reduced to one-tenth
It should be stressed that with other sub- of the last dose and increased daily by 5 U.
stances suspected in a mixed preparation these If the last insulin injection dates back fur-
also have to be tested including also additives. ther, hyposensitization with human recombi-
nant insulin is performed as rush hyposensiti-
zation (Table 5.84). The starting dose repre-
5.7.1.6.3 Insulin
sents 1/100 of the last positive prick test con-
With increasing purity of insulin preparations, centration.
the previously frequent incompatibility reac-
tions have become rare. Insulin of different
5.7.1.6.4 Heparin
species shows pronounced cross-reactivity.
Even after the introduction of recombinant hu- Heparin and heparinoids are glucosaminogly-
man insulin, allergic reactions have been ob- cans (molecular weight 3,000 to 40,000) and are
served. The unusual route of administration
(subcutaneous), possible impurities, additives
(depot substances such as protamine, zinc, pre- Table 5.84. Schedule of rush hyposensitization in in-
servatives such as surfen, phenolcresol, or glyc- sulin allergy
erin acetate), as well as unphysiological molec- Day Dose Adminis- Day Dose Adminis-
ular structures (aggregates of insulin) have tration tration
been discussed [57]. A genetic association with 1 0.0001 i.c. 4 8.0 s.c.
HLA-D 3 has been suggested. 0.001 i.c. 12.0 s.c.
Interestingly, some patients with type I diabe- 0.01 i.c. 16.0 s.c.
tes have insulin autoantibodies, without ever 2 0.1 i.c. 5 20.0 s.c.
having been treated with insulin, persisting for 0.5 i.c.
6 25.0 s.c.
years and sometimes occurring with antibodies 1.0 i.c.
7 30.0 s.c.
against cytoplasmic island cell antigens [57]. 3 2.0 s.c.
The clinical symptoms of insulin allergy 4.0 s.c.
6.0 s.c.
vary; there are many different types of allergic
5.7 Adverse Drug Reactions 183
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(1998) Declining morbidity and mortality among gie. In: Fuchs E, Schulz KH (eds) Manuale aller-
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5.7.2 Pseudo-allergic Drug Reactions The most common drugs eliciting pseudo-al-
lergic anaphylactic reactions are radiographic
5.7.2.1 Definition and Elicitors
contrast media, local anesthetics, i.v. anesthet-
Adverse reactions mimicking clinically allergic ics, volume substitutes, acetylsalicylic acid, and
diseases without detectable immunologic sen- other non-steroidal anti-inflammatory drugs
sitization are called pseudo-allergic reac- (Table 5.86). The case of a severe anaphylactic
tions [9, 13, 15, 28]. In principle, pseudo-aller- reaction after infusion of a colloid volume sub-
gic reactions exist for all types of allergic reac- stitute (hydroxyethyl starch HES) is shown in
tions (see Table 5.85); the most frequent pseu- Fig. 5.70.
do-allergic reactions, however, are immediate- Asthma and urticaria are the most common
type reactions resembling anaphylaxis [23]. clinical manifestations of acetylsalicylic acid
186 5 Allergic Diseases (and Differential Diagnoses)
) Intravenous anesthetics
) Opioids
) Muscle relaxants
) Local anesthetics
) Cyclooxygenase inhibitors
) Drugs increasing microcirculatory flow
Table 5.87. Drugs and other substances able to induce hemolysis in patients with enzyme deficiency (from [11])
Glucose-6-phosphate dehydrogenase deficiency Glutathione reductase deficiency
Drug Food Drug Other substances
Primaquine Fava beans Nitrofurantoin Nitro solvent
Atebrin Leguminosae Primaquine Thallium
Anilin derivatives Red- and black currants Resochin
Acetanilide Azulfidine
Naphthalene and derivatives Dapsone (DADPS)
Phenylhydrazine Chloramphenicol
Acetylphenylhydrazine Phenacetin
Methylene blue Pentazolidine
Phenacetin Coumarin
Aminopyrine
p-Aminosalicylic acid
Sulfones and Sulfonamides
Chloramphenicol
Vitamin K and analogues
Azulfidine
Dimercaprol
the differentiation of pseudo-allergic and aller- For prophylaxis, antihistamines and gluco-
gic reactions (cum grano salis). corticosteroids, beta-adrenergics, antidepres-
In the following, some clinically common sives, as well as hypnotic suggestion have been
pseudo-allergic reactions will be discussed. recommended.
In a prospective placebo-controlled study of
our own, we were able to show a significant
5.7.2.2 Radiographic Contrast Media
prophylactic effect of a combined H1 and H2 an-
The majority of adverse reactions after radio- tagonist intravenous pretreatment (clemastine
graphic contrast media (RCM) are non-immu- + cimetidine 5 min prior to RCM infusion)
nologic in origin. Occasional cases of true aller- [26].
gy have been published. In recent years, late or
delayed reactions (4 8 h) after RCM infusion
5.7.2.3 Plasma Protein Solutions
have been reported, which may correspond to a
true type IV reaction (positive patch tests) [1, After intravenous injection of standard gam-
32]. RCM are direct histamine and serotonin lib- maglobulin, severe anaphylactic reactions may
erators [25] as well as complement activators occur; therefore, these preparations are only
[38]. Interactions with the coagulation and kalli- applied intramuscularly. Gammaglobulin ag-
krein-kinin system have been reported [17, 28]. gregates present in the solutions activate the
While 20 years ago toxic effects of ionic con- complement system via the classic pathway (re-
trast media as well as high osmolarity were verse immune complex reaction). Protein ag-
considered pathophysiologically important, we gregates are also present in other plasma pro-
now know that even after non-ionic solutions tein solutions and severe systemic reactions
with physiological osmolarity, severe side reac- have been observed [23]. The liberation of ki-
tions (even fatalities) may occur. nins and kinin-activating substances present in
There is no reliable method of predicting the some human serum albumin batches is dis-
risk of an RCM reaction in the individual pa- cussed. The common intravenous gammaglob-
tient. Iodine allergy is a type IV reaction in the ulins are chemically or physically modified on
sense of a classic allergic contact dermatitis the Fc part, thus preventing aggregate forma-
and is not primarily linked to anaphylactic re- tion and complement activation. Therefore,
actions after iodinated RCM, where iodine is they are generally well tolerated.
bound within the benzoic acid ring structure!
Occasional cases of systemic contact dermatitis
5.7.2.4 Gelatine Volume Substitutes
may be elicited by iodine since in some RCM
solutions minute amounts of free iodine (pico- After infusion of gelatine volume substitutes
gram range) have been detected. especially the urea-linked modification using
According to our experience, the risk of an di-isocyanate (Haemaccel) a dose- and
RCM reaction is not increased in atopics or pa- speed-dependent histamine liberation has
tients with other drug reactions. Only in pa- been described [8, 19]. Anaphylactic reactions
tients with a clear-cut history of severe anaphy- after gelatine infusion were very frequent in the
lactic reactions after RCM infusion is the risk 1980s (up to 30 %!), but have been reduced by
significantly elevated to 30 % (normal individ- better production with lower isocyanate con-
uals around 10 %) (cited in [24]). centrations. Pretreatment with histamine H1
Some patients may react to a prick test with and H2 antagonists is an effective prophylaxis.
systemic reactions. Therefore, we perform skin Occasional true IgE-mediated reactions to gel-
tests as a minimum variant of provocation un- atine have been reported [42].
der emergency conditions. The occasional in-
travenous provocation testing with RCM is a
5.7.2.5 Intravenous Anesthetics
matter of clinical research.
Uncontrolled test injections of small vol- Intravenous anesthetics (Table 5.90) have phar-
umes may elicit severe anaphylactic reactions. macological effects, giving rise to complica-
5.7 Adverse Drug Reactions 189
Table 5.92. Local anesthetic (LA) incompatibility: Table 5.94. Hypothetical concepts for pathophysiolo-
reverse placebo provocation (in patients reacting to gy of ASA idiosyncrasy
placebo and psychological influence)
) Cyclooxygenase inhibition leads to diminished
Procedure Patient protective prostaglandins
information ) Cyclooxygenase inhibition leads to increased
formation of lipoxygenase products
1. Skin test Open ) Cyclooxygenase 1-inhibition is decisive
2. S.c. provocation with LA 1 with LA ) Direct release of vasoactive mediators
3. S.c. provocation with LA 2 another LA ) Activation of complement system
4. S.c. provocation with NaCl another LA ) Activation of coagulation and/or kallikrein-
5. S.c. provocation with LA 1 NaCl kinin system
6. S.c. provocation with LA 1 LA 1 ) Increased platelet reactivity
) Immune reaction against ASA metabolites or
impurities
evaluated by testing preservative-free sub-
stances (mostly in ampules).
If there is psychologic influence and patients concomitant administration of NSAIDs and
also react to placebo, we use the procedure of allergen can lead to increased reactions (ASA
reverse placebo provocation (Table 5.92), giv- augmentation [20]) (see Sect. 5.1.4 on Ana-
ing the patient verum under the label place- phylaxis).
bo. If the local anesthetic then is well tolerated, The most prominent feature of analgesic idi-
the patient is completely informed and the same osyncrasy (sometimes also called intolerance
procedure is repeated on the next day openly. syndrome [20, 40] is the lack of immunologic
cross-reactivity with other chemically related
substances. However, there are pharmacologic
5.7.2.8 Acetylsalicylic Acid and Non-steroidal
cross-reactivities with similarly acting sub-
Anti-inflammatory Drugs (NSAIDs)
stances, e.g., other NSAIDs, but also chemicals
Toxic effects of NSAIDs such as gastric irrita- such as food colorings (tartrazine) and preser-
tion and inhibition of platelet aggregation need vatives (see Sect. 5.1.5 on Food Allergy).
to be differentiated from pseudo-allergic hy- For diagnosis the provocation test is most
persensitivity reactions with variable manifes- important (see Sect. 5.7.1). Caveat: with too
tation (Table 5.93). high doses of ASA, patients with aspirin-asth-
The pathomechanism of acetylsalicylic acid ma may develop acute severe asthma attacks!
(ASA) idiosyncrasy (15 % of asthma patients) We recommend beginning according to the in-
has not yet been clearly elucidated. Direct me- tensity of symptoms in the history with
diator liberation [3, 4, 5, 15, 21, 27, 36, 40, 41] 5 50 mg ASA and increasing doses at 2-h inter-
has been discussed as well as direct comple- vals to 100, 200 500 and eventually 500 mg.
ment activation, platelet stimulation and a shift Patients with chronic urticaria often react to
in eicosanoid metabolism (Table 5.94). The ASA as well as other additives and colorings
(see Sect. 5.1.6 on Urticaria).
Several in vitro diagnostic techniques have
Table 5.93. Clinical manifestations of NSAID incom-
patibility been attempted in ASA idiosyncrasy; however,
the observed effects (e.g., histamine release by
Eye ASA) have also been observed in patients toler-
) Conjunctivitis
ating ASA [3, 5, 27, 39]. Recently the cellular al-
Respiratory tract lergen stimulation test (CAST) has been fa-
) Rhinitis
) Sinusitis vored, when after stimulation with C5a, PAF or
) Asthma F-Met-Leu-Phe increased leukotriene secretion
Urticaria and angioedema is measured in patients with chronic urticaria
and a positive ASA provocation test [5, 43]. Di-
Anaphylactic reaction
rect stimulation with ASA in vitro, however,
Photodermatosis
has yielded controversial results [5, 21, 43].
5.7 Adverse Drug Reactions 191
4. Conroy MC, de Weck AL (1981) Effect of aspirin cause of hypotension following rapid colloid in-
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5.7 Adverse Drug Reactions 193
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38. Till G, Rother U, Gemsa D, Gerhardt P (1977) Ak- skin reactions: new pathophysiological aspects.
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Dtsch Ges Inn Med 83:1589 1591 gische Reaktionen der Haut durch Arzneimittel
39. Vervloet DL, Dor P, Arneud A, Senft M, Alazia M, und Lebensmitteladditiva. Schweiz Rdsch Med
Charpin J (1985) Anaphylactic reactions to succi- (Praxis) 72:691 699
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choline. J Allergy Clin Immunol 75:150 wa H, Amayasu H (2000) Selective cyclo-oxyge-
40. Virchow C (ed) (1986) Analgetika, Asthma. Medi- nase 2 inhibitor in patients with aspirin-induced
dact 6. Programmed, Frankfurt asthma. J Allergy Clin Immunol 106:1203 1204
Table 5.97. Common elicitors of certain cutaneous drug eruptions: Increased prevalences of drug
drug eruptions eruptions are common in HIV infection and
Morphology Elicitor (examples) AIDS (sulfonamides, etc.) while in early stages
of HIV, IgE-mediated reactions may be dimin-
Urticarial see Sect. 5.1.3 on Urticaria
eruptions and Sect. 5.1.4 on Anaphylaxis ished [36, 47].
Erythematovesi- see Sect. 5.5.2 on Dermatitis
cular eruptions 5.7.3.2 Clinical Classification of Exanthematous
Purpura/hemor- see Sect. 5.2 on Cytotoxic Drug Eruptions
rhagic eruptions Reactions and Sect. 5.3 on
Immune Complex Reactions The prevalences of the most important types of
drug eruptions from a Finnish study are shown
Erythema Barbiturates
multiforme Sulfonamides
in Table 5.98.
Hydantoin
Hydralazine Urticarial Drug Eruptions. These represent
Carbamazepine mostly allergic reactions due to IgE-mediated
Diuretics phenomena (urticaria, anaphylaxis) (see
NSAIDs
Sects. 5.1.3, 5.1.4) or IgG/IgM immune com-
Erythema Anticonceptives plexes as serum sickness (after 8 14 days!) (see
nodosum Halogens
Sulfonamides Sect. 5.3.2).
Macular and Penicillin Erythematovesicular Drug Eruptions. These
maculopapular Ampicillin
Allopurinol correspond clinically to systemic contact der-
Sulfonamides matitis whereby the allergens are administered
NSAIDs systemically (e.g., sulfonamides, metal ions)
Exfoliative Antiepileptics (see Sect. 5.5.2).
dermatitis Phenylbutazone
Heavy metals (e.g., arsenic) Hemorrhagic Drug Eruptions. Some exan-
Fixed drug Barbiturates thematous drug eruptions may become hemor-
eruption Analgesics rhagic in nature when they are very intense or
NSAIDs
Tetracyclines
Sulfonamides
Table 5.98. Prevalence of clinical types of drug erup-
Anticonceptives
tions in 446 patients (from Kauppinnen and Stubb
Hydantoin
[26])
Laxants
Metronidazole Type Number of
patients
Lichenoid drug Thiazides
eruptions Phenothiazine Macular und maculopapular
Captopril eruptions 189
Gold Fixed eruptions 92 (16 multi-
Sulfonamides locular)
Acneiform drug Steroid hormones Urticaria/angioedema 57
eruptions Halogens Eczema 47
Lithium Erythema multiforme 18
Isoniazin Stevens-Johnson syndrome 8
Vitamins (B) Lyells syndrome (toxic epidermal
Hydantoin necrolysis) 8
Photosensitization 5
Lymphocytic Analgesics (plus alcohol?) Purpura 4
infiltration Lupus erythematosus-like lesions 2
Psoriasiform Beta-blockers Erythema nodosum 1
eruptions Gold salts Fever 5
Lithium Total 436
5.7 Adverse Drug Reactions 195
Fig. 5.71. Clinical manifestation of purpura chronica Fig. 5.72. Measles-like drug exanthema following the
progressiva (Schambergs disease) oral administration of penicillin
due to hydrostatic pressure (legs). There is, ble (CD8 cells), which can be demonstrated
however, primary drug-induced purpura cor- as delayed-type reactions in the intradermal
responding to cytotoxic reactions (allergic or patch test [14, 35, 42, 54]. Infectious dis-
thrombocytopenic purpura) (see Sect. 5.2) or eases (measles, rubeola) are a differential di-
as immune complex vasculitis (see Sect. 5.3). agnosis.
Purpura chronica progressiva (M. Scham- A special problem is ampicillin exanthema,
berg) is characterized by small petechial bleed- which occurs in 10 % of ampicillin-treated pa-
ings with a reddish-brownish (Cayenne pep- tients and is probably due to unspecific B-cell
per) skin lesion and is elicited by drugs (bro- stimulation as it occurs with certain viral infec-
mide carbamide) or additives (Fig. 5.71). tions (e.g., Epstein-Barr virus). Infection and
Histologically, lymphocytic infiltration drug effect may potentiate in the example of in-
around the vessels is seen; sometimes patch fectious mononucleosis where 90 100 % of
tests are positive. Some authors regard progres- ampicillin-treated patients develop ampicillin
sive pigmentary purpura as the vascular type rash (almost pathognomonic).
IV reaction ( dermatitis of the vessels) [35].
Exfoliative Dermatitis. Some drugs elicit gen-
Macular and Maculopapular Drug Eruptions. eralized exfoliative dermatitis (Fig. 5.73) rang-
These are the most common exanthematous ing up to erythroderma (e.g., sulfonamides,
drug eruptions with histologically perivascu- antimalarials, penicillin, mercury-containing
lar lymphocytic infiltrates. The skin lesions diuretics, barbiturates). The pathomechanism
manifest 8 12 days after the first treatment is not clear; in the differential diagnosis, toxic
(Fig. 5.72), in repeated treatment much faster. shock syndrome should be considered [15, 23,
Pathogenetically, a type IVc reaction is proba- 58].
196 5 Allergic Diseases (and Differential Diagnoses)
Fig. 5.73. Drug exanthema: exfoliative dermatitis Fig. 5.74. Drug-induced erythema with nodosum-like
skin lesions
Table 5.99. Clinical characteristics of various bullous drug eruptions (according to [39]). SJS, Stevens-Johnson
syndrome; TEN, toxic epidermal necrolysis
Extent Target lesions Macules Large Mucosal
(% body surface) erythemas involvement
Erythema multiforme < 10 % ++
SJS < 10 % (atypical) + ++
SJS/TEN (mixed) 10 30 % (flat) ++ ++
TEN with macules > 30 % (flat) +++ + ++
TEN > 10 % +++ ++
bleeding. Toxic changes of the liver (dystrophy, matory changes in the dermis (empty cori-
toxic fattening) and the kidneys (tubular ne- um). Monoclonal antibodies may detect an in-
crosis, interstitial nephritis) have been de- crease in monocytoid cells in the epidermis
scribed as well as endocarditis, myocarditis, or [20, 51], which is in the blister roof (Fig. 5.84),
central nervous involvement (cerebral edema, in contrast to staphylococcal scalded skin syn-
encephalomalacia) [11]. drome with subcorneal blistering (Fig. 5.85, Ta-
In dermatopathology, there is necrosis of ble 5.102). The blister formation is junctional
the whole epidermis with only minimal inflam- with the destruction of basal cells (Fig. 5.86).
Higher age groups are more often affected
with female sex predilection (2:1). Rarely, there
is a history of allergy. In France, a linkage to the
HLA haplotypes A2, B12, and DR4 has been
found [49].
Prognostic infaust factors include advanced
age, late hospitalization, extent of blister for-
mation, early leukopenia, initial renal insuffi-
ciency, as well as increased glucosemia. Lethal-
ity is around 30 % in spite of the availability of
most modern therapeutic modalities (15 50 %
in the literature) [45].
Fig. 5.84. Histological picture of a drug-induced Ly-
According to Schpf, the risk of drug-in-
ells syndrome. The entire epidermis with necrotic duced Lyells syndrome in the total population
keratinocytes is in the blister roof is 0.7 per 1 million inhabitants [53].
Eliciting Drugs. Many textbooks contain hit Table 5.104. Diagnosis of Lyells syndrome
lists based on the literature, naming sulfon- ) Dermatological examination
amides, analgesics, CNS-active drugs such as ) Blister cryosection
barbiturates and phenytoin besides many other ) Biopsy (immunochemistry)
drugs. The causal relation is difficult and some- ) Asservation of serum (for later investigation)
) Bacteriological swabs (skin, mucosa, specific
times arbitrary. Often, drugs are administered si- foci)
multaneously (especially in elderly patients with Phage typing and toxin detection
15 and more different drugs). The danger of tau- Blood culture
) In vitro diagnosis (e.g., lymphocyte transfor-
tology following reports from the literature is
mation, controls!)
evident, leading to increased mentions of certain ) Skin test (after 2 3 months)
substances which have been mentioned before. Patch test
In a study of our own evaluating 306 cases, in Prick, intradermal (dilution! one substance/
day)
only 67 patients, clear-cut evidence for a suspect-
ed drug was found (criterion: single or only re-
cently introduced drug or proved by reexpo- ture, there is no evidence that a careful skin test
sure). However, we have seen a patient who react- (prick or patch test) may induce generalized
ed to carbamazepine, which he had been taking TEN symptoms.
over 4 years as a single drug prior to TEN [45]. Rarely oral provocation has been tried [28]
In a critical evaluation, there is no totally successfully. Many authors, however, do not rec-
safe drug. We observed a case elicited by a herb- ommend it. If there is an indication, one should
al tea (devils claw) as well as cases elicited by use an extremely low starting dose (1/1,000 of a
eyedrops (Borelli, personal communication), single dose and lower) and apply only one sub-
isoproterenol powder or tonic water [11, 18, 45]. stance per day under inpatient conditions.
In Germany, the documentation center for
severe cutaneous reactions has been recording Therapy of TEN. Therapy consists of general,
for 10 years all bullous drug eruptions occur- local, and systemic procedures (Table 5.105), as
ring in Germany. Evaluation and classification well as the observation of certain items to avoid
is done through an expert committee leading to (Fig. 5.87). Local therapy includes early oph-
a list of eliciting drugs (Table 5.103). thalmologic counseling for prevention of syn-
echia with hourly application of eyedrops!
Diagnostic Procedures in TEN. Besides the
clinical and dermatopathological diagnosis
(Table 5.104), allergy tests may be helpful in
single cases. Positive skin tests or in vitro lym- too
zu hoch
high sus-
ver-
phocyte transformation tests have revealed und
and
sensitizations [54]. We observed positive skin too
zu lange
long dch-
pect- tige
ed
tests in two out of four tested persons with se-
vere TEN [32, 45]. Looking through the litera-
Kortikoide
steroids Pharmaka
drugs
Table 5.105. Drug-induced Lyells syndrome therapy In order to influence the immune reaction,
General measures
the following drugs have been tried:
Hospitalization in single room, intensive care or ) Cyclophosphamide
burn center
Warmth
) Cyclosporin A
Special bedding ) Thalidomide as TNF inhibitor
Fluid, electrolytes, colloid replacementa ) Intravenous immunoglobulin G
Nutrition through gastric tube ) Protease inhibitors (ulinastatin)
Withdrawal of suspected drugs
Plasmapheresis?
) Plasmapheresis
Local therapy But only case reports or small numbers have
Balneotherapy (antiseptics) been published [13, 17, 25, 30, 45, 49, 56, 59].
Metallic foil
Debridement of necrotic epidermis
The immediate and adequate general thera-
Antiseptics (AgNO3, crystal violet, 0.1 %, chlor- py is the performance of life-saving measures.
hexidine) Due to pathophysiologic considerations and
Antibiotic gaze (furantoin, povidone iodine) possible involvement of microbial toxins as
Covering (polyurethane)
Mucosal care (oral mucosa, genitals)
well as the avoidance of sepsis, prophylactic an-
Eye prophylaxis (scleral lenses, artificial tears, tibiotics with unsuspicious agents are recom-
hourly) mended by some authors.
Avoid suspected topicals!
No adhesive tape!!
Systemic drug therapy 5.7.3.3 Pathophysiology of Cutaneous
In the acute phase (prior to necrolysis) glucocorti- Drug Eruptions
costeroids
(e.g., days 1 4: 1,000, 250, 100, 20 mg prednisolone) While urticarial reactions may often be due to
Caveat: high-dose long-term treatment! IgE-mediated or pseudo-allergic reactions,
Antibiotics thrombocytopenic purpura represents a cyto-
If sepsis is suspected or leukopenia (prophylactic?)
Choice of not suspected agents (e.g., cephalospo-
toxic reaction, hemorrhagic vasculitic phe-
rins, imipenem) nomena an immune complex reaction. The
Heparin (thrombosis prophylaxis) mechanisms of the colorful spectrum of exan-
Central analgesics (selection according to history) thematous drug eruptions, however, are not
a Not only according to the rule of 9 but controlled well established (Table 5.106).
according to excretion, body weight, urine, and se- In dermatopathology, superficial perivascu-
rum electrolytes, etc. lar mononuclear cell infiltrate is seen some-
times with eosinophils. Often a so-called inter-
Systemic glucocorticosteroids are controversial face dermatitis with lymphocytes at the der-
[30, 49, 50]. We give steroids only in the early ex- moepidermal junction is seen [61].
anthematous phase prior to appearance of large Immunohistochemistry shows a predomi-
areas of necrolysis (maximal 4 days of high-dose nant T-cell (CD3+) infiltrate with both CD4
therapy). If epidermolysis has occurred, gluco- and CD8 cells. CD1a+ dendritic cells and CD68
corticosteroids may rather have a negative effect. macrophages are also increased as well as
Avoidance of the eliciting drug is the focus CD56+ natural killer cells. Major basis protein
of immediate treatment as well as general life- from eosinophils can be detected.
saving measures. Activated T cells are also CLA positive and
According to the extent of bullous erosive may maintain inflammatory reactions through
skin lesions, patients may be treated in special cytokines (IL-5, IL-6, TNF [ ) or chemokines
institutions for burn injury or intensive care (eotaxin, RANTES) [19, 36, 43].
units. Volume replacement, parenteral nutri- Furthermore, cytotoxic T cells may directly
tion, temperature application, and special bed- destroy keratinocytes either via Fas/Fas ligand
ding (Clinitron) are crucial. Medium-severe (rather unlikely) or more probably via a cyto-
cases have been treated successfully isolated toxic mechanism through perforin and granzy-
under hygienic conditions in a single room. me B.
5.7 Adverse Drug Reactions 203
The role of proinflammatory cytokines is sup- Table 5.107. Toxic epidermal necrolysis: pathophysio-
ported by the common coincidence of concom- logical concepts
itant infections in the eliciting phase. It may be Immunologic reactions
that different cell populations (CD4 or CD8 Allergy (type II): antibodies or cytotoxic T cells
cells) with different activation mechanisms in- against keratinocytes?
duce different clinical symptoms. The metabo- Allergy (type III): immunoglobulin and comple-
ment deposits
lism of the drug via different routes (acetyla- Allergy (type IV): positive patch tests and lympho-
tion, glutathione transferase, cytochrome P450, cyte transformation
etc.) is important [22, 37]. Graft versus host reaction: altered self?
Table 5.107 lists some possible immunologic Monocyte-mediated cytotoxicity?
and non-immunologic reactions which play a Combination of infection and drug
Photosensitization
role in the pathogenesis of TEN (hypothetical). Non-immunologic reaction
Animal experiments have shown similarities Pharmacotoxicity in enzyme deficiency
between GVH and TEN [38]. Enzyme activation
The differential diagnosis between TEN and Activated oxygen species
Combination: virus/drug?
toxic shock syndrome (TSS) may be difficult Combination: UV/drug?
[23, 58]. TSS is defined by: fever, exanthema Microbial toxins (prodromi through toxin, inter-
(diffuse, sometimes with erythroderma or ve- leukin-1)?
siculation), mucous membrane involvement,
hypotension, multiorgan affection, as well as
exclusion of other infectious diseases [15]. The staphylococcal toxin of TSS (TSST-1) in-
TEN and TSS have some things in common: duces necrosis in the stadium granulosum in
prodromi, certain laboratory findings (liver animal experiments with keratinocyte necrosis
enzymes), mucosal involvement, multiorgan in contrast to the exfoliatin of staphylococcal
affection. However, in the majority of TSS pa- Lyells syndrome with subcorneal blisters. Der-
tients, no large epidermolysis occurs, but rath- matologically, TEN can be clearly differentiat-
er desquamative exfoliative dermatitis (espe- ed from other bullous drug eruptions (Ta-
cially palmoplantar) after 8 10 days (similar to ble 5.108).
scarlet fever).
204 5 Allergic Diseases (and Differential Diagnoses)
Table 5.108. Dermatopathological patterns of bullous Table 5.110. Genuine skin diseases provoked by drugs
drug eruptions
Acanthosis nigricans Gestagens
Fixed drug eruption
Acne vulgaris Androgens, gestagens
Vacuolar degeneration of basal keratinocytes
Single cell keratinization Bullous pemphigoid Furosemide, salazosul-
Single cell necrosis fapyridine
Superficial and deep perivascular infiltrate
Dermatitis herpeti- Halogens, progesterone
(lymphohistiocytic and neutrophils)
formis
Erythrocyte extravasate
Pigment incontinence Lichen planus Gold, arsenic, quinine,
sulfonamides
Erythema multiforme
Vacuolar degeneration of basal keratinocytes Lupus erythematosus Hydralazine, isoniazid,
Single cell keratinization procainamide, phenyto-
Single cell necrosis in, phenylbutazone
Interface dermatitis
Pemphigus vulgaris D-Penicillamine
Superficial perivascular infiltrate (lymphohistiocytic)
Erythrocyte extravasate Porphyria cutanea tarda Alcohol, analgesics, an-
drogens, barbiturates,
Drug-induced Lyells syndrome (toxic epidermal
contraceptives, sulfon-
necrolysis)
amides
Complete necrosis of epidermis
Junctional blister formation
Little inflammatory infiltrates (empty corium)
Possibly thrombi in dermal vessels fonamides, lupus erythematosus by hydral-
azine and procainamide, or psoriasiform drug
eruptions by beta-blockers (Table 5.110).
Many cases are characterized by mucosal
5.7.3.4 Special Forms of Drug-Induced
membrane involvement only (stomatitis me-
Skin Diseases
dicamentosa) [2]. These conditions need to be
After intake of some drugs, specific dermato- distinguished from contact-allergic reactions
logic symptoms may be induced (Table 5.109). (against dental prostheses) as well as the toxic
Some genuine dermatoses may be provoked effects of some drugs as cytostatics. Drugs in-
by drugs such as lichen planus by gold and sul- ducing stomatitis medicamentosa include
heavy metals (mercury, gold), antibiotics (sul- (1980) Toxic-shock syndrome: Epidemiologic
fonamides, chloramphenicol, streptomycin), features, recurrence, risk factors and prevention.
local anesthetics, hypnotics (barbiturates, hy- N Engl J Med 303:1429 1435
16. Fellner MJ, Prutkin L (1970) Morbilliform erup-
dantoin), and analgesics (phenylbutazone, tions caused by penicillin. A study by electron
aminopyrine) [2]. microscopy and immunologic tests. J Invest Der-
matol 55:390 395
17. French LE, Tschopp J (2000) Fas-mediated cell
death in toxic epidermal necrolysis and graft-ver-
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5.8 Granulomatous Reactions 207
Fig. 5.89. Histological examination of the lesions Fig. 5.90. Protruding hard inflammatory lesions fol-
shown in Fig. 5.88 yields the picture of sarcoid granu- lowing the injection of soluble bovine collagen in a
loma even though there is no clinical evidence of sar- patient with type V allergy (from [29])
coidosis (from [3])
5.8.3 Therapy
Treatment uses glucocorticosteroids (accord-
ing to the organ manifestation). In granuloma-
tous reactions of the skin, intralesional steroids
Fig. 5.91. Granulomatous infiltrate surrounding streaky or occlusion treatment should be tried [3, 6,
eosinophilic material (injected collagen) seen in the 29]; also cytostatic therapy, tuberculostatic
histological preparation (from [29])
drugs as well as UVA-1 irradiation have been
used.
ty, a high IgG antibody antititer against bovine
collagen was found [29].
A concomitant or subsequent following of References
immune complex reaction and granulomatous
inflammation also is characteristic for the 1. Apostolou I, Takahama Y, Belmant C, Kawanos T,
chronic stage of extrinsic allergic alveolitis (hy- Huerre M, Marchal G, Cui J, Taniguchi M, Nakau-
persensitivity pneumonitis). On the basis of chi H, Fournie J-J, Kourilsky P, Gachelin G (1999)
these considerations, a hypothetical concept Murine natural killer cells contribute to the granu-
lomatous reaction caused by mycobacterial cell
may be suggested: Persistent antigen induces walls. Proc Natl Acad Sci USA 96:5141 5146
after an initial type III reaction with vasculitis 2. Baumgarten C (1978) Hufigste Nebenwirkungen
a strong activation of macrophages, leading fi- bei der spezifischen Hyposensibilisierung. Aller-
nally to granulomatous inflammation. In hy- gologie 1:223 228
persensitivity pneumonitis in the early phase 3. Bode U, Ring J, Schmoeckel Chr (1984) Granulom-
bildung nach intrakutaner Applikation von Pro-
changes similar to leukocytoclastic vasculitis cain-Polyvinylpyrrolidon (PVP). Hautarzt 35:474
can be seen together with high titers of precipi- 477
tating antibodies, while in the chronic course 4. Bork K, Hoede N (1982) Vortuschung maligner
the histologic pattern of granulomatous in- Tumoren durch nicht deklariertes PVP in Arznei-
flammation develops (see Sect. 5.4 on Hyper- mitteln. Hautarzt 33:373 377
5. Boros DL (1981) The role of lymphokines in gran-
sensitivity Pneumonitis). ulomatous inflammations. Lymphokines 3:257
It is tempting to speculate about the patho- 281
physiology of some other granulomatous in- 6. Braun-Falco O, Plewig G, Wolff HH (1998) Derma-
210 5 Allergic Diseases (and Differential Diagnoses)
tologie und Venerologie, 4th edn. Springer, Berlin 18. Kuhn K, Timpl R (1984) Collagens. Molecular and
Heidelberg New York antigenic structure. In: Myelofibrosis and the bi-
7. Castrow FF II, Krull E (1983) An injectable colla- ology of connective tissue, p. 45. Liss, New York
gen implant update. J Am Acad Dermatol 9: 19. Lombardi T, Kuffer R, Dubrez B (2001) Polishing-
889 893 paste-induced silica granuloma of the gingiva.
28. Cooperman LS, Mackinnon V, Bechler G, Phar- Dermatology 203:177 179
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9. Dahl M, Ullmann S, Goetz RW (1977) Vasculitis in Immune responses to bovine collagen implants. J
granuloma anulare. Arch Dermatol 113:463 467 Am Acad Dermatol 16:955 960
10. Eberlein-Knig B, Hein R, Abeck D, Engst R, Ring 22. Rapaport M (1984) Granuloma annulare caused
J (1999) Cutaneous sarcoid foreign body granulo- by injectable collagen. Arch Dermatol 120:837
mas developing in sites of previous skin injury af- 23. Raupach B, Kaufman S (2001) Immune responses
ter systemic interferon-alpha treatment for to intracellular bacteria. Curr Opin Immunol
chronic hepatitis C. Br J Dermatol 140:370 372 13:417 428
11. Eder M, Gedigk P (1986) Lehrbuch der allgemei- 24. Roach DR, Briscoe H, Saunders B, France MP, Ri-
nen Pathologie und pathologischen Anatomie. minton S, Britton WJ (2001) Secreted lymphoto-
Springer, Berlin Heidelberg New York xin-alpha is essential for the control of an intra-
12. Ellingsworth LR, DeLustro F, Brennan JE, Sawa- cellular bacterial infection. J Exp Med 193:
mura S, McPherson J (1986) The human immune 239 246
response to reconstituted bovine collagen. J Im- 25. Roitt I, Delves P (2001) Essential immunology,
munol 36:877 882 10th edn. Blackwell, Oxford
13. Harms M, Masouye I, Saurat JH (1990) Silica 26. Sandritter W, Beneke G (1984) Allgemeine Patho-
granuloma mimicking granulomatous cheilitis. logie. Schattauer, Stuttgart
Dermatologica 181:246 247 27. Sellem PH, Caranzan FR, Bene MC, Faure GC
14. Kleinhans D, Knoth W (1977) Immunhistoche- (1987) Immunogenicity of injectable collagen im-
mischer Fibrin-Nachweis beim Granuloma anu- plants. J Dermatol Surg Oncol 13:1199 1202
lare. Arch Dermatol Res 258:231 234 28. Shelley WB, Hurley HJ (1960) The pathogenesis
15. Klepzig K, Ring J, Burg G (1987) Pseudolymphom of silica granulomas in man: A nonallergic colloi-
nach Hyposensibilisierung. Allergologie 10:432 dal phenomenon. J Invest Dermatol 34:107 123
16. Kligman AM, Armstrong RC (1986) Histologic 29. Schurig V, Konz B, Ring J, Dorn M (1986) Granu-
response to intradermal zyderm und zyplast lombildung an Test- und Behandlungsstellen
(glutaraldehyde crosslinked) collagen in humans. durch intrakutan verabreichtes, injizierbares
J Dermatol Surg Oncol 12:351 357 Kollagen. Hautarzt 37:42 45
17. Konz B (1983) Injizierbares Kollagen. In: Braun- 30. Shelley WB, Hurrley HJ (1958) The allergic origin
Falco O, Burg G (eds) Fortschritte der prakti- of zirconium deodorant granulomas. Br J Derma-
schen Dermatologie und Venerologie, vol. 10, pp tol 70:75 82
193 198. Springer, Berlin Heidelberg New York
Other Autoimmune Diseases. Similar mecha- ) IgG antibodies against platelet factor 4 in
nisms can be found in a variety of other autoim- heparin-associated thrombocytopenia (see
mune diseases although the actual pathogenic Sect. 5.2)
role of autoantibodies has not been proven for ) Anti-IgE antibodies in patients with high
each disease entity (Table 5.111) [4, 6, 7, 8, 15]. total serum IgE or in the course of
allergen-specific immunotherapy [10]
) Antibodies against the high-affinity IgE
5.9.2 Stimulating Hypersensitivity in Bacterial
receptor (Fc 5 R I) in some patients with
Infection
chronic urticaria and positive skin reaction
Some authors regard the severe acute disease of to autologous serum [5]
multiorgan failure occurring in certain bac- ) IgE autoantibodies against epidermal pro-
terial infections as hypersensitivity of compo- teins (Hom s 1 5) in patients with very
nents of innate immunity, e.g., as overstimula- severe atopic eczema and high serum IgE
tion of macrophages and endothelial cells by levels [12]
endotoxin (lipopolysaccharide S = LPS) or un- ) In severe asthma, antibodies against the
specific T-cell activation by superantigens of q -adrenergic receptor have been described
Gram-positive organisms. [13]
covered in the media and has received attention ) There is immense suffering
under different names (Table 5.113). ) Exclusion of other well-defined diseases
The mostly subjective complaints may be
From this list it is clear that the diagnosis
classified roughly into skin and mucous mem-
MCS can never be made in a clear-cut fashion
brane symptoms, neurologic and general
since certain criteria are not defined exactly
symptoms (Table 5.114) [2, 8, 13, 15, 24, 31, 34].
(what are classical examinations or other
Many patients have fear of the environment
well-defined diseases?).
and apply excessive avoidance behavior with
Since the factors suspected are not only
chemicals, foods, drugs, fragrances, etc. The
chemicals, but also physical factors (e.g., elec-
most common name for this condition today is
tromagnetic radiation, radioactive radiation),
multiple chemical sensitivity (MCS); it has to
an expert committee of the WHO has proposed
be remarked that in most of these patients, this
the term idiopathic environmental intoler-
sensitivity is not objectively measurable. The
ances (IEI) [16].
term supposed multiple chemical sensitivity
would be better, but it seems to contradict the
5.10.2 Differential Diagnoses
opinions of the patients, who are convinced of
their hypersensitivity. On the other hand, there The eco-syndrome partly has similarities
are patients who objectively suffer from multi- with some differently defined but also environ-
ple hypersensitivity against various chemicals, ment-associated conditions:
namely patients with multiple drug allergies. ) Chronic fatigue syndrome (virus infections
This, however, is a totally different group with
like EBV, HHV 6, etc., are discussed) [1].
objective signs and symptoms. ) Fibromyalgia syndrome with muscle pain
When in the early 1980s we saw the first pa-
in the center and disturbed pain regulation
tients with these conditions we suggested the
with possible disturbance in serotonin
term eco-syndrome as a working diagnosis
metabolism.
for patients suffering from mostly subjective ) Candida syndrome with mainly irritable
symptoms affecting different organ systems
bowel symptoms and candida phobia and
who are convinced that the disease is due to en-
immune weakness.
vironmental noxes.
The definition of MCS (according to Cullen) Complaints related to indoor exposure com-
[8] is: prise the sick building syndrome (SBS) and
) Elicitation of symptoms by a variety of building-related illnesses (BRI) (Table 5.115)
[18, 19, 33].
factors in low dose exposure
) Various symptoms manifesting in more BRI are well-known and objective diseases,
and include infectious diseases and allergies.
than one organ system and improving after
SBS is due to a complex interaction between
avoidance of exposure
) The complaints cannot be explained by physical, chemical, and biological exposure as
well as psychological factors with occurrence
classical examination
) There is a tendency to chronification of subjective complaints in a large number of
people employed in one building.
214 5 Allergic Diseases (and Differential Diagnoses)
Table 5.115. Differential diagnosis between building-related illness (BRI), sick building syndrome (SBS), and
eco-syndrome
Building-related illness Sick building syndrome Eco-syndrome (MCS)
Occurrence Clearly building-associ- At least 10 20 % of persons Individual complaints
ated, individual or sever- employed in a building are
al persons affected
Symptoms Objective (e.g., infection, Mucous membrane and skin Many organ systems in-
allergy) irritations, neurologic com- volved, diffuse psychologic
plaints and physical complaints
Pathophysiology Monocausal: Multifactorial (physical, Unknown (only hypotheses)
) Infectious chemical, psychological)
) Irritative-toxic
) Allergic
Risk factors Atopy, higher age, immu- Atopy, air conditioning, Atopy
nosuppression occupation in low social
grade
Female : male 1:1 Predominantly female Predominantly female
Psyche Not prominent Psychosomatic-psychiatric Strong psychosomatic
factors, not causal involvement
Radio Free Europe; this highly intelligent ploration a history of sexual abuse in early
woman had previously been totally psychologi- childhood [23, 29].
cally normal and healthy and only then was diag- In interdisciplinary expert committees,
nosed as having schizophrenia. In intensive in- mostly no one feels responsible: the toxicolo-
vestigations comprising allergy and consulta- gist sees psychological phenomena, the psychi-
tions together with exposure challenges, it was atrist thinks of allergies, and the allergist dis-
not possible to elicit the observed symptoms by cusses toxicological effects.
the respective electromagnetic waves. In the Although the definition and etiopathophy-
course of our diagnostic activities, finally the di- siology of eco-syndrome are controversial
agnosis of schizophrenia was ascertained. The and ill understood, something needs to be done
majority of patients, however, do not suffer from for the affected patients, who suffer consider-
psychiatric disease [10, 13, 16, 26, 27, 31, 32]. ably.
It cannot be excluded that environmental
Psychosomatic Concept. The symptoms of noxes in low concentrations have true effects
eco-syndrome are very similar to a condition which are not yet measurable at this time or are
very common in the 19th century and called not yet understood. Exposure of patients with
neurasthenia [1]. Anxiety reactions, dispro- atopic eczema in stable remission to low con-
portional conflict coping, as well as somatiza- centrations of formaldehyde in indoor air led
tion disturbance in hidden depression are fac- to objectively measurable changes of transepi-
tors [5, 6, 15, 17, 21, 25, 27, 31, 36]. It is impor- dermal water loss, e.g., a disturbance of barrier
tant for the patient to gain a socially acceptable function of the skin without subjective com-
diagnosis such as nerval disturbance in the plaints of the patients [10].
19th century and allergy today, which are
easier to bear than psychiatrization.
5.10.4 Management of Patients with
Similar to neurasthenia, eco-syndrome af-
Eco-syndrome
fects mainly females (2.5:1 female-male ratio).
Some of our patients reported after careful ex- Therapy of the condition follows the results of
the investigations, which should be performed
with interdisciplinary cooperation. The avoid- Gebefgi I, Kleinschmidt J, Ring J (1998) Influ-
ance of relevant elicitor factors is crucial, be it ence of airborne nitrogen dioxide or formalde-
in the treatment of underlying diseases (e.g., hyde on parameters of skin function and cellular
activation in patients with atopic eczema and
chronic cholecystitis, ostemyelitis), the avoid- control subjects. J Allergy Clin Immunol 101:
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3:3 10
There is no need for pessimism: In a long-
14. Grimm V, Ruhdorfer S, Eberlein-Knig B, Sche-
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proved or were almost symptom free. Allergo J 8 [Suppl 1]:32
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