5 Allergic Diseases (And Differential Diagnoses)

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Chapter 5 5 Allergic Diseases (and Differential Diagnoses)

5.1 Diseases with Possible IgE Involve- tions (combination of type I and type IVb 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). reactioninthecourseof6–12harenewedhy- 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.TheseLPRshavetobedistin- 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),theterm“pseudo”onlyre- sneezing, obstruction) and which can take on flecting the not detectable participation of the thecharacteristicsofdiseaseinintenseor 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 detection 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 ) Filter organ ) Killing of microbes in many patients in the eliciting phase, albeit in ) closeconnectionwithT-cell-mediatedreac- Humidifier 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”)(seeSect.5.1.7on“AllergyandEye”). ) 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.Hesawthehighsummertempera- Clinical stigmata of patients with allergic ture as being the cause although many people rhinitis comprise: calledthedisease“hayfever.”Itwasnotuntil ) “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

5.1.1.2 Symptoms and Pathophysiology In industrialized countries, 10–20% of the population suffer from pollinosis [21]. As first symptoms of allergic rhinitis, sneezing (1–2 min after allergen contact) and early secretion (5 min) develop triggered by a reflex mechanism. In parallel, edema (obstruction) of the mucosa occurs, reaching a maximum after 30 min with itch, a “nasal voice,” disturbance of olfactory and gustatory sensation, sinus complaints, and formation of polyps in the chroniccourseasproductsofhyperplasticrhi- nosinusitis [4, 7, 10, 12]. Aqueous rhinorrhea is due to a cholinergic reflex (possibly via tachykinins) while the symptom of a “blocked nose” is due to vascular dilatation and edema formation. Among the numerous mediators of allergic reactions, histamine plays the most important role in nasal symptoms, but also other mediators have been found in nasal secretions after allergen provocation such as kinins, eicosa- Fig. 5.1. “Allergic salutation” seen typically in children noids, and proteases [1]. with allergic rhinitis (H. Behrendt) 78 5 Allergic Diseases (and Differential Diagnoses)

required. Normally, the diagnosis is done ac- 5.1.1.3 Classification of Different Forms cording to the type of secretion (putrid, milky) of Rhinitis and the rhinoscopic finding. With unilateral In patients with symptoms of rhinitis (itch, symptoms, hemorrhagic secretion and pain- sneezing, secretion, obstruction), other causes fulness, rhinoscopy is obligatory. If the secre- of impaired nasal ventilation have to be exclud- tion is clear or aqueous, further classification ed such as mechanical obstruction, structural into “allergic” and “non-allergic” (also called abnormalities, septum deviation, tumors, for- “vasomotor”) rhinitis is done (Fig. 5.2). eign bodies, atresia, as well as other severe or- While previously allergic rhinitis was clas- gan diseases (cystic fibrosis, Wegener’s granu- sified into seasonal (hay fever) in the spring lomatosis, lepra, or infectious diseases) [6, 19] and summer months and perennial (all year), (Table 5.2). the new WHO classification in the document For the diagnosis of “infectious rhinitis,” Allergic Rhinitis and Its Impact on Asthma usually no detection of an infectious agent is (ARIA) recommends a new classification into “intermittent” (duration of symptoms of less Table 5.2. Classification of rhinitis (according to WHO) than 4 weeks) and “persistent” (symptoms longer than 4 weeks). This new classification, Infectious however, does not replace the practically im- ) Viral ) Bacterial portant distinction between seasonal and pe- ) Others rennial. Allergic Furthermore, the classification of the severi- ) Intermittent ty of allergic rhinitis into “mild,” “moderate,” ) Persistent and “severe” is important. Symptoms like Occupational (allergic, non-allergic) “sleep disturbance,” “impairment of daily ac- ) Intermittent tivities,” “impairment in school or working ) Persistent place,” as well as other impairments in the Drug-induced quality of life are important. ) Acetylsalicylic acid ) Regarding therapy of allergic rhinitis, it is Others important to know that some symptoms such Hormonal as itching, secretion, and sneezing respond Others quite well to antihistamines, while nasal ob- ) NARES (non-allergic rhinitis eosinophilia struction is best treated with corticosteroids. syndrome) This is reflected in the guidelines for therapy of ) Irritants ) Gustatorial rhinitis allergic rhinitis [6]. ) Emotional factors While seasonal allergic rhinitis can mostly ) Atrophic rhinitis be diagnosed with classical allergy diagnosis, ) Gastrointestinal reflux ) in perennial rhinitis sometimes overlaps be- Idiopathic tween allergic (housedust mite allergy) and

Rhinitis

(Secretion: clear/aqueous) (Secretion: putrid/milky)

allergic non allergic infectious (vasomotor)

Hyperreactivity eosinophil Fig. 5.2. Breakdown of without inflammation inflammation rhinitis into its various forms 5.1 Diseases with Possible IgE Involvement 79 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 according 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). ageshouldbementioned! 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 (draughtsofair,coldair,dust)isacommon 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 Thesimplehypothesisthatparticlesizede- bronchopulmonary mycosis, has seen renewed termines deposit and organ manifestation interest (see Sect. 5.4 on “Hypersensitivity (pollen grains with diameters of around 25 µm Pneumonitis”). Interactions between allergic cause rhinitis in the nose, mold spores 5 µm 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 µm 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 Meni`ere, tinnitus, or chronic labyrinthitis, although anecdotal cases Table 5.3. Irritative factors as elicitors of rhinitis have been reported. Tosummarize:Allergicrhinitisisnotane- ) Dust, smoke (particles) ) 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)

References nitis: a common but poorly documented therapy. Allergy 55:11–15 1. BachertC,HauserU,PremB,RudackC,GanzerU 12. Naclerio RM (1997) Pathophysiology of perennial (1995) Proinflammatory cytokines in allergic rhi- allergic rhinitis. Allergy 52:41–44 nitis. Eur Arch Otorhinolaryngol 1 [Suppl]: 13. Nolte D, Renovanz HD, Schumann K (1982) Nase 44–49 und Respirationstrakt. Obere und untere Luftwe- 2. Bachmann W, Bachert C (1984) Quantitative ge als funktionelle Einheit. Dustri, Munich evaluation of rhinomanometric curves. A new 14. Passalacqua G, Bachert C, Davies RJ, Durham SR, simplemethod.LaryngolRhinolOtol63:58–61 et al. (2000) Inhaled and nasal corticosteroids: 3. Bousquet J, Vignola AM, Campbell AM, Michel safety aspects. Position paper. Allergy 55:16–33 FB (1996) Pathophysiology of allergic rhinitis. Int 15. Simons FE (1996) Learning impairment and al- Arch Allergy Immunol 110:207–218 lergic rhinitis. Allergy Asthma Proc 17:185–189 4. Busse WW, Holgate ST (eds) (1995) Asthma and 16. Simons FE (1999) Allergic rhinobronchitis: The rhinitis. Blackwell, Oxford asthma-allergic rhinitis link. J Allergy Clin Im- 5. Canonica GW, Ciprandi G, Pesce GP, Buscaglia S, munol 104:534–540 Paolieri F, Bagnasco M (1995) ICAM-1 on epithe- 17. van Cauwenberge P, Bachert C, Passalacqua G, lial cells in allergic subjects: a hallmark of allergic Bousquet J, Canonica GW, Durham SR, Fokkens inflammation. Int Arch Allergy Immunol 107: WJ,HowarthPH,LundV,MallingHJ,MygindN, 99–102 Passali D, Scadding GK, Wang DY (2000) Consen- 6. Durham SR (1998) Mechanisms of mucosal in- sus statement on the treatment of allergic rhini- flammationinthenoseandlungs.ClinExpAller- tis. European Academy of Allergology and Clini- gy 28 [Suppl 2]:15–16 cal Immunology. Allergy 55:116–134 7. Ellegard E, Karlsson G (1999) Nasal congestion 18. Tas E, Bircher AJ (2001) Therapie der Rhinitis all- during pregnancy. Clin Otolaryngol 24:307–311 ergica. Ther Umsch 58:309–314 8. Heppt W (1998) Zytologie der Nasenschleimhaut. 19. van Wijk RG, de Graaf-in ’t Veld C, Garrelds IM Springer, Berlin Heidelberg New York (1999) Nasal hyperreactivity. Rhinology 37:50–55 9. Malm L, van-Wijk RG, Bachert C (1999) Guide- 20. World Health Organization (2004) Allergic rhinitis lines for nasal provocations with aspects on nasal and its impact on asthma (ARIA). In: Bousquet J, patency, airflow, and airflow resistance. Rhinolo- et al. (eds) Executive summary. WHO (in press) gy 37:133–135 21. Wüthrich B, Schindler C, Leuenberger P, Acker- 10. Mygind N, Dahl R, Pedersen S, Thestrup-Peder- mann-Liebrich U (1995) Prevalence of atopy and sen K (1996) Essential Allergy. Blackwell Science, pollinosis in the adult population of Switzerland Oxford (SAPALDIA study). Swiss Study on Air Pollution 11. Mygind N, Laussen LC, Dahl M (2000) Systemic and Lung Diseases in Adults. Int Arch Allergy Im- corticosteroid treatment for seasonal allergic rhi- munol 106:149–156

5.1.2 Bronchial Asthma A new international definition of an expert group of the NIH [1] is: 5.1.2.1 Definition “Asthma is a chronic inflammatory airway dis- “Asthma is characterized by increased reactivi- ease with participation of numerous inflamma- tyoftheairwaytovariousstimuliwithde- tory cells like mast cells, eosinophils, T lym- creased forced expiration changing in intensity phocytes, neutrophils, and epithelial cells. In either spontaneously or under therapy” (defi- sensitive individuals, inflammation leads to at- nition of the American College of Chest Physi- tacks of wheezing, dyspnea, tightness, and cians1975).Newerdefinitionsstressthebron- cough, especially during nights and early chial hyperreactivity, defining asthma as air- morning hours. These episodes go commonly way disease with bronchial hyperreactivity [1, with generalized but variable increased airway 17, 23, 35, 37]. “Reversible obstructive distur- resistance which is reversible either spontane- bance of ventilation” is the obligatory and cen- ously or following therapy. The airway inflam- tral symptom of bronchial asthma, whereby mation causes increased airway sensitivity two characteristic aspects are crucial: against a variety of different stimuli.” Using this definition, bronchial asthma can be distin- ) Attacks of dyspnea guished in the differential diagnosis from other ) Hyperreactivity of airways against various conditions with dyspnea (Table 5.4). stimuli 5.1 Diseases with Possible IgE Involvement 81

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)aswellasgastrointestinalcomplaints,increased 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]. Inchildren,approximately80%ofasthmaisall- 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 5.5. Classification Grade Term Symptoms FEV1 or PEF of severity in bronchial Day Night (% normal) asthma (German Air- way League) IIntermittent e 2times/week e 2times/ >80% month II Persistent, mild 2 times/week & 80% III Persistent, moderate Daily & 1times/week >60<80% IV Persistent, severe Continuous Frequent <60% 82 5 Allergic Diseases (and Differential Diagnoses)

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. ) a Special forms : Intrinsic asthma responds to a lesser degree to Infection-associated beta-adrenergics, cromoglycate or theophyl- Psychogenic Analgesic (additive) idiosyncrasy (Samter’s 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,animalepithelia,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 Exogenoustoxicirritativefactorsableto 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

Allergen Occupation (examples) Table 5.7. Occupational IgE-mediated and irri- Pollen Agriculture, gardening, floristry tative toxic asthma Storage mites Agriculture Animal epithelia Zoology, laboratory research, bed clothing industry Molds Cheese-making Enzymes Washing powder, bakery Castor oil Agriculture Cotton dust Cotton harvesting Silk Textile industry Coffee (raw) Coffee harvesting Flour and grain dust Bakery, milling, pastry making, agriculture Insect allergens Zoology, food industry, cosmetics Gum arabic Printing Lycopodium Pharmacy Rubber Medical care, health workers Metal salts (e.g., platinum) Metal refinement, catalyzer production Drugs Health workers, pharmacy Colophony Paper production, printing Wood dust Forestry, woodcutting Latex Rubber industry, health personnel Blooming plants Gardening, kitchen Smallchemicals Plastics,varnishes,furnishings,etc. Irritative toxic substances Aliphatic amines Chemical industry Persulfates Chemical industry, hairdressers, photo laboratory Epichlorhydrine Resins, softeners, hardeners Acrylates Plastic industry, dentistry 5.1 Diseases with Possible IgE Involvement 83 via cholinergic irritant receptors leading to In the development and maintenance of bronchial constriction [4, 14, 17, 23, 27]. It is bronchial hyperreactivity, neurogenic factors possible that the well-known exercise-induced play an increasing role (Table 5.8) [14, 19, 27, asthma is caused by cold air or hyperosmolari- 31].Thenervegrowthfactor(NGF)induces ty through water loss and can be improved by neurotransmitters (Table 5.8) influencing neu- mouth protection. So-called psychogenic asth- ronal plasticity of the airway nervous system. ma (see Chap. 7) and infect-allergic asthma al- On the other hand, lymphocytes carry recep- so belong here. Asthma in patients with analge- tors for neurotransmitters or secrete neurotro- sic or additive idiosyncrasy occurs together phins as shown for TH2 cells secreting brain- with polyposis nasi and sinusitis (Samter’s derived neurotrophic factor (BDNF) [24]. triad) (see Sect. 5.7.2). All these stimuli can These mechanisms might help to understand trigger both allergic and intrinsic asthma. the well-known psychosomatic interactions in bronchial asthma (see Chap. 7). The so-called Herxheimer’s triad (mucous 5.1.2.4 Pathophysiology dyscrinia, mucosal edema, and bronchocon- Thereversibleobstructiveventilationdistur- striction) determines the intensity of clinical bance in bronchial asthma develops on the ba- symptoms.Inthesputum,Curschmann’sspira- sis of bronchial hyperreactivity. This is due to les and Charcot-Leyden’s crystals (crystalline inflammatory reactions caused either by aller- forms of lysophospholipase from eosinophils) gen exposure or by other epithelial damage (in- are found. The constriction affects both small fection, toxic agents, etc.) [4, 8, 14, 19, 21, 22, and large bronchi. 23,30,35,43,45](Figs.5.3,5.4). Ventilation and perfusion rate are irregular- ly distributed with a decrease in CO2 pressure (hypocapnia). The airway resistance is increased, the flow rate decreased, and the ventilatory work increases, leading to premature closing of airways and lung emphysema. The intrathoracic gas volume and the functional residual capacity are increased. Characteristic cardial symptoms in bronchial asthma comprise sinus tachycardia, signs of pulmonal hypertension (ECG changes) as well as pulsus paradoxus. Fig. 5.3. Semi-thin-layer preparation of bronchial epi- While previously in asthma the reversibility thelia taken from a patient with bronchial asthma of acute bronchoconstriction was stressed, we viewed under the light microscope (H. Behrendt) know today that in chronic asthma, remodeling of the peribronchial tissue occurs with epithelial damage, and activation of myofibroblasts and fibroblasts (growth factors EGF, IGF, or TGF- q ). This leads to a thickening of the basal membrane together with an increased fibrotic manteling and chronicity of the bronchial obstruction with persistent symptoms and deposits of collagens type I, III, and V [8, 23, 33, 39] (Fig. 5.5).

Fig. 5.4. Semi-thin-layer preparation of muciparous glands taken from a patient with bronchial asthma viewed under the light microscope (H. Behrendt) 84 5 Allergic Diseases (and Differential Diagnoses)

Table 5.8. Neurotransmitters (NT) and receptors in the airways Substance Receptor Function Sensory NT Tachykinins Substance P NK 1 Vasodilation, plasma extravasation, mucus secretion, leukocyte infiltration Neurokinin A NK 2 Bronchoconstriction Neurokinin B NK 3 Autocrine inhibition (?) CGRP CGRP-1 and -2 Vasodilation Bombesin BB1-R, BB2-R Mucus secretion, proliferation VIP VIP1-R, VIP2-R Vasodilation, bronchoconstriction Parasympathic postganglionic NT Acetylcholine (AC) M1 Reflex M2 Inhibition of AC release M3 Bronchoconstriction, mucus secretion M4 ? Sympathic postganglionic NT [ [ Noradrenaline 1, 2 Vasoconstriction q 1 Cardial ino- and chronotropic effect q 2 Bronchodilation q 3 Lipid tissue regulation (?) * * NP 1–6 Long-acting vasoconstriction Opioids q · · -Endorphin 1, 2, µ Autocrine inhibition, mast cell degranula- · · Enkephalin 1, 2,µ tion (?) Proteolytic peptides Endothelin ETA, -B Vasoconstriction Bradykinin B1,B2 Vasodilation, sensory stimulation

Mucus hypersecretion Eosinophil Epithelial Destruction and Remodeling 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- Wer ninghaus)

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 5.9. Diagnostic procedure in allergic bronchial asthma 5.1.2.6 Differential Diagnosis History The most important differential diagnosis of General history, allergy history, personal and family bronchialasthmainadultsischronicobstruc- General examination tive bronchitis, which as persistent obstructive Physical ventilation disturbance leads to chronic ob- Auscultation structive pulmonary disease (COPD) [4, 10, 15, Chest X-ray and sinuses 21, 26, 30, 33]. In some cases, the differential di- Lung function Bronchial dilatation test agnosis from severe chronic asthma may be Unspecific provocation (acetylcholine, exercise, difficult (Table 5.10). The main risk factor for etc.) for bronchial hyperreactivity) COPD is tobacco smoke, but also other indoor Blood count (eosinophils) and routine analysis, air pollutants or occupational toxic exposures total IgE play a role. In contrast to bronchial asthma, Specific tests COPD responds only weakly to pharmacother- Allergen avoidance (if possible) Skin test apy [30]. Steroids and thiotropin are used with RAST moderate effect. Bronchial allergen provocation (if necessary) Differential diagnosis also comprises aller- Additional procedures gic bronchopulmonal aspergillosis as well as Blood gas analysis interstitial lung diseases such as hypersensitiv- In vitro inflammatory parameters (ECP) ity pneumonitis (see Sect. 5.3). Functional la- Sputum ryngospasm, also called “vocal cord dysfunc- Induced sputum Bronchoalveolar lavage (BAL with cytology) tion,” may be triggered by physical and chemi- Exhalation analyses (e.g., NO) cal stimuli and induce wheezing. Among the Additional examinations many forms of sleep apnea syndromes, there ECG are obstructive variants similar to nightly asth- [ 1-Antitrypsin ma attacks. Parasites Tb test 5.1.2.7 Therapy Avoidance Measures. The only causal therapy histamine (0.05–50 mg/ml) [17]. Cholinergic is avoidance of eliciting stimuli including all hyperreactivity is a cardinal symptom of asth- noxious influences. This implies careful allergy ma [40]. diagnosis. Apart from avoidance of occupa- Bronchial provocation tests with allergens tional allergens, avoidance measures in daily need to follow strict indications (see Sect. 4.4). life are of major importance (see Sect. 3.4 on “Aeroallergens”). Items to be avoided include:

Table 5.10. Differential Finding Bronchial asthma COPD diagnosis of bronchial asthma and “chronic Age Childhood, adults Mostly over 50 obstructive pulmonary Allergy Frequent Rarely disease” (COPD) Smoking Rare Almost always Nightly dyspnea Yes A little Symptom-free intervals Yes No Obstruction Central and peripheral Mostly peripheral Eosinophilia (blood and sputum) Frequent Rare Inflation Sometimes reversible Always irreversible Blood gases Normal Abnormal Variability of obstruction Yes No Response to q -adrenergics Good Little Response to steroids Good Little 86 5 Allergic Diseases (and Differential Diagnoses)

Table 5.11. “Unspecific irritation syndrome” (accord- ply behavioral therapy, group therapy, auto- ingtoH.Düngemann) 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,chemicalirritants 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 asthma attacks. Disodium cromoglycate is given ei- feathers in bed clothing, animal or plant mat- therasapowderorasa1%solution(4×daily tresses (horse hair, seaweed), pets (including every 6 h). Ketotifen acts both as a mast cell sta- furs!),carpets,oldupholstery,humidity,moist bilizer and as an antihistamine, has no direct walls,plants(mold),aswellasalldust-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 Dünge- 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].

Allergen-Specific Immunotherapy (Hyposen- Xanthine Derivatives. Xanthine derivatives sitization). In uncomplicated allergic asthma, have been used for decades for bronchospas- allergen-specific immunotherapy is effective molysis [23, 27]. New galenic formulas have de- when started early and with the right indica- creased the problem of the small therapeutic tions [38] (see Sect. 6.3). range of theophylline. If side effects are suspected, the plasma level should be measured Physical Therapy. Adequate breathing tech- and kept between 10 and 20 µg/ml. Average dai- nique and correction of malposition of the tho- lydoseforadultsrangesbetween10and15mg/ rax are important. Training of respiratory ab- kg/day, with higher doses for smokers [46]. dominal and back musculature; connective tissue massage and local heat application; and se- ␤2 Adrenergics. While classical beta-adrener- cretion drainage (deliverance of sputum in the gics (e.g., isoproterenol) often lead to cardial q downward position, etc.) are important [1, 3, side effects due to 1-stimulation (tachycardia), q 11, 20, 25, 38]. selective 2-adrenergics have predominant bronchodilatory effects. Furthermore, they Psychosomatic Consultation. Psychosomatic have mast cell stabilizing properties and can be consultation may help also with regard to used orally or as an aerosol (one to two breaths avoidance of trigger situations and can im- every 4 h), and also in long-term therapy. 5.1 Diseases with Possible IgE Involvement 87

q Long-acting 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. Theatropinederivatesipra- 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- andreversiblegrowthimpairmenthasbeen q phylactically. They can be combined with 2- observed. Topical Glucocorticosteroids can be agonists. combined with long-activity q -agonists.

Secretolysis. Adequate volume replacement Antibiotics. In intrinsic asthma and signs of (2–3 l/day) and humidification of the inhaled infection, short-term antibiotic therapy may be air are important. Furthermore, detergents and helpful. mucolytics are used for secretolysis (acetylcysteine, bromhexine, or ambroxol as well as ethe- Surgical Treatment. Previously surgical mea- ric oils). sures such as vago- or sympathicotomy, cutting of the nervus laryngicus cranialis or resection Glucocorticosteroids. Glucocorticosteroids of the glomus caroticum have been recom- actatdifferentlevelsintheasthmaticreaction: mended,whichtodaydonotplayamajorrole. when given over longer periods they have a Thesideeffectsoftheseoperationsareconsid- bronchodilatory and preventive effect on im- erable; bronchial hyperreactivity can persist in mediate reactions, decrease bronchial hyper- spiteof“denervation”ofthelung[17]. reactivity, inhibit mucous secretion and in- q crease the effect of 2-adrenergics. Through New Immunotherapeutic Approaches. New the anti-inflammatory effect, mucosal edema approachescanbeseeninthedevelopmentof and sputum viscosity will decrease. Systemic monoclonal humanized antibodies against IgE glucocorticosteroids are used in severe asth- (omalizumab) [32]. Antagonists of interleukin- ma, the dose depending upon the severity of 4 (soluble interleukin-4 receptor), adhesion the condition. molecules, tachykinins, as well as antibodies to In status asthmaticus (acute asthma at- other cytokines (anti-interleukin-5 = mepoli- tack), doses of 250 mg up to 2 g prednisolone zumab) are being tested in clinical trials (see q are indicated combined with 2-adrenergics Sect. 6.3). (with nebulizer) and theophylline (with per- fusor). Persistent wheezing over more than Procedures Without Proven Efficacy. Often in 4 h, pulsus paradoxus, persistent tachycardia asthma, so-called unconventional therapies are over 100/min, FEV1 under 1 l/s, and abnormal used such as acupuncture, use of certain bacte- blood gases are signs of an acute asthma at- rial “vaccines,” homeopathy, standard gamma- tack. Immediate hospital admission is indicat- globulins, and others (see Sect. 6.4). ed. Therapy follows the above-mentioned rules; in addition, infusions, oxygen, some- Asthma Schools. The general concept of asth- times anesthesia with mechanical ventilation ma management requires the cooperation of and bronchoscopic removal of secretion are the informed patient. Schooling programs for implied [26]. childrenandadultshavebeenprovenhelpful In cortisone-dependent chronic asthma, and are also paid for by insurance in some usually 40–80 mg prednisolone are given with countries [40] (see also Sect. 6.5 on “Preven- a slow dose reduction (not more than 5 mg/ tion”). Asthmatics may also do sports when week) until a minimal dose is “titrated.” treated properly [47]. Great progress for glucocorticosteroid therapy was achieved through the development of topical steroids (beclomethasone, budesonide, 88 5 Allergic Diseases (and Differential Diagnoses)

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5.1.3 Urticaria and Angioedema

5.1.3.1 Definition Urticariaisadiseasewithoccurrenceofself- 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 vasodilation, edema = increase in capillary permeability, flare = axon reflex). When the reac- Fig. 5.6. Urticariafactitiacausedbytangentialappli- cation of force tion occurs in the subcutaneous tissue, the disease is called angioneurotic or angioedema (also “Quincke’s edema”) (Fig. 5.8). Urticaria comprises several clinical manifestations and maybecausedbyimmunologicalandnon-immune pathomechanisms.

5.1.3.2 Classification Clinically, urticaria can be classified according to: 1.Thecourse:acuteurticaria(<6weeks)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)

Table 5.12. Classification of urticaria according to etio- pathophysiology 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. Quincke’s edema Parasites Mycoses 2. Pathophysiological aspects (Table 5.12): Bacterial and viral infections Neoplasia There are few epidemiological studies regarding the prevalence of urticaria. It seems Enzyme defects Angioneurotic edema that the incidence of urticaria has been con- (C1 inactivator deficiency) stantduringrecentyears[10].Prevalenceof –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 manchildrencomparedtotheEast,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 isthemostcommontypeofur- Stress ticaria; it is estimated that 20–30% of the pop- Depression ulationsufferonceintheirlifefromanepisode Other 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 unclear: Apart from acute infections, allergic Urticariapigmentosa(mastocytosis) 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- acuteurticariacanbeelucidated.Thereisan 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- maticinfluencesaswellasso-called“focusre- 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 festationgiverisetochronicurticaria.Inrecent my patients: “Be glad that you are living today; years, a new concept of autoimmune pathogen- somecenturiesago,youwouldhavebeenburnt esis has been postulated: Autoantibodies as a witch!” against the high-affinity IgE receptor may play Cholinergic urticaria is characterized by the arolewhichcanbefoundinupto50%ofpa- 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 urticaria 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 and sometimes the first stage of anaphylaxis ) Onthesiteofcontact(e.g.,contactcold (see Sect. 5.1.4). urticaria) or Afrequentform(15%ofphysicalurticaria) ) Generalized in a reflex phenomenon (e.g., 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?Skincare,AH 92 5 Allergic Diseases (and Differential Diagnoses)

In the treatment of all forms of physical urticaria, one should warn patients not to do “he- roic self-experiments” (for hardening), since anaphylactic reactions may occur (my first patient with solar urticaria suffered anaphylactic shock in a solarium).

5.1.3.4 Special Forms of Urticaria and Angioedema Contact Urticaria. In these patients, epider- Fig. 5.9. Urticaria induced by cold mal contact of the unlesional skin with eliciting agents (either irritative like nettle, Urtica dioica, or allergenic like latex proteins) leads to occurasafamilialform,orbefoundalong wheal formation, sometimes deteriorating into with cold-sensitive antibodies (e.g., cryoglo- anaphylaxis (“contact anaphylaxis”) [19]. bulinemia, cold hemagglutinins). In dermatohistopathology, neutrophil infiltrates are UrticariaPigmentosa(Mastocytosis). This type found; sometimes ESR is increased. Cold urti- differs from the other urticarias since there are caria can be a sequel of chronic infection (e.g., irreversible long-lasting skin lesions corre- borreliosis). Antihistamines have little effect. sponding to local accumulations of mast cells in High-dose intravenous penicillin has led to the skin. In childhood, isolated mastocytomas improvement without the mechanisms being are common, which after physical stress (hot known [13]. baths or thumb sucking) can trigger generalized Pressure urticaria occurs mostly in young urticaria, sometimes local bulla formation. The men (22–50 years) doing heavy physical work. prognosis is good. There is an immediate type where wheals de- In adulthood, urticaria pigmentosa with velop acutely within minutes up to 1 h and a de- characteristic brownish red disseminated skin layed type which only 4–6 h after pressure ap- lesionsiscommon,whichshowafterrubbing plication (5–10 kg over 10–20 min) elicits urticarial dermographism (Darier’s sign). The massive whealing. Antihistamines have little brownish color is not postinflammatory hyper- effect; dapsone has been tried successfully. pigmentation but corresponds to activation of Light urticaria summarizes all forms of urti- epidermal melanocytes through stem cell fac- caria where the effect of electromagnetic radia- tor (SCF). tion (from X-rays to visible light) induces whe- Mastocytosis may be limited to the skin or aling. The most common form is solar urticar- be found along with systemic involvement ia, where radiation mostly in the UV-A range (bone marrow, gastrointestinal tract). Very elicits whealing. Histamine and mast cell reac- rare are mast cell leukemias or precursors such tions do not seem to play a major role; possibly as “aggressive mastocytosis” with lymphade- direct nerval stimulation takes place (E. Hölzle, nopathy. H. Behrendt, personal communication). Recently cases of “occult mastocytosis” have For therapy, UVA rush-hardening can be been reported where without visible skin le- used in solar urticaria [2]. sions patients were suffering from relapsing ur- Aquagenic urticaria is rare (not to be con- ticaria or anaphylactoid reactions; diagnosis fused with the much more common aquagenic canbemadefromthestronglyelevatedmast pruritus); it has been speculated that a water- cell tryptase level in the serum (see also soluble autoantigen is released from the stra- Sect. 3.1.4). tum corneum and induces histamine release A rare form of mastocytosis is teleangiecta- [11]. Prophylactic skin care prior to water con- siaeruptivamacularisperstans. tact may help. 5.1 Diseases with Possible IgE Involvement 93

Urticaria Vasculitis. Herethesinglewhealsdo not vanish within hours but persist over PROVOCATION 3 12–48 h, being found along with painful large erythematous swellings. Histologically, leuko- INTENSIVE cytoclastic vasculitis as well as immune com- 2 EXAMINATION plex deposits with direct immunofluorescence is found [16, 21]. Urticaria vasculitis some- BASIC 1 timesisaprecursorofautoimmunedisease EXAMINATION such as lupus erythematosus and can be concomitant with petechial bleeding (see Sect. 5.3). Fig. 5.10. Three-step plan for urticaria diagnostics (according to Ring and Przybilla) Hereditary Angioneurotic Edema (HANE). This genetically determined disease is characterized by acute attacks of circumscribed giant apart from possible causal therapy of the path- edema formation especially in the face (eyelids, ological findings detected, symptomatic treat- lips), but also in the genitals without concomi- ment with H1 antihistamines over 1 month is tant urticaria. Sometimes attacks are triggered employed. If – after stopping pharmacotherapy by local trauma (e.g., at the dentist). There is a – new lesions occur, the next step is started. chemical or functional defect of C1-inactivator Eachstepofthethree-stepprogramcomprises (C1-esterase inhibitor) in the complement sys- history, clinical examination, laboratory exam- tem leading to a decrease of C4 and C2 with ac- ination and special test procedures. tivation of the complement and the kallikrein kinin system. HANE is a severe and life-threat- Urticaria Diagnosis: Step 1 (Basic Examination). ening disease (note: laryngeal edema), some- Step 1 comprises basic examinations performed times manifesting only as acute colic-like ab- in all patients with chronic urticaria (Table 5.14). dominal pain (angioedema of the GI tract). In rare cases the disease is acquired in the context Table 5.14. Urticaria diagnosis: step 1 (basic examina- of neoplasia [3]. There is a third form of HANE tion) without detectable C1 inactivator deficiency and a still unknown pathophysiology [3]. History Time course Severe attacks of angioedema have also been Family history (atopy, HANE) observed in patients under angiotensin-con- Contact urticaria verting enzyme inhibitors (ACE inhibitors) Drugs, foods where a pathophysiological role of kallikrein Psychological factors kinin activation has been speculated [15, 16]. Clinical examination Skin lesions Localization Idiopathic Urticaria. The diagnosis “idiopath- Duration of single lesions ic urticaria” only should be made when all oth- Physical tests er (Table 5.12) possible causes have been ex- Dermographism cluded. Diagnosis of chronic urticaria is often Cold/warm,icecubecontact tediousforthephysicianandpatient[4,5,9,10, Exercise (ergometer) 11, 23, 27, 34, 36]. Pressure test Phototesting (minimal erythema dose, MED) Laboratory 5.1.3.5 Diagnosis Blood count, ESR Stool In the diagnosis of chronic urticaria, a three- Serum IgE step program has proven helpful and practical, (C1 inactivator if suspected) increasing the intensity of diagnostic work-up Allergy diagnosis according to the intensity of the disease [27] Atopy screen (Fig. 5.10). Between the single diagnostic steps, Skin prick test with standard food allergens 94 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(Table5.16).Provocationtestsin- nation). In step 2 the history is repeated. In ad- cludesuspectedfoodsaswellasfoodadditives 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 substanceintheprovocationofchronicurti- 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)mayplayarole.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 receptor (Fc 5 RI) of classes IgG 1 and IgG 3 can be detected 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

bodies), immunosuppressive treatment (cyclo- 5.1.3.6 Therapy sporin) or high-dose intravenous immuno- Treatment of acute urticaria is done using H1 globulin G infusions have been effective [9, 23]. antihistamines [25], in severe cases preferably In some patients, alterations of the gastroin- intravenously (dimetinden maleate or clema- testinal flora may induce improvement. Braun- stine fumarate); if the patient does not respond Falco recommended the “Munich scheme” glucocorticosteroids (e.g., 100 mg predniso- with a combination of antibiotic (tetracycline), lone) are given. For severe cases see treatment antimycotic (amphotericin B, nystatin), anthel- of anaphylaxis (Sect. 5.1.4). mintic, and antihistamine followed by restora- In therapy of chronic urticaria, H1 antago- tion of the GI flora with lactobacilli and other nists are the first choice [30]. Often they are not agents [1, 4]. When there is evidence of Helico- dosedadequately[13,30].Obviously,thedose bacter pylori involvement, eradication may be to suppress urticaria has to be higher than helpful. doses applied for hay fever. During the day, There is no specific urticaria diet; however, non-sedating antihistamines should be used if food allergy has been proven, a specific (fexofenadine, loratadine, desloratadine, mizo- avoidance diet is indicated (see Sect. 5.1.5 on lastin, cetirizine, levocetirizine); if people suf- “Food Allergy). fer from nightly attacks the use of classical se- In rare cases of HANE, androgens like dana- dating antihistamines in the evening is an op- zol [3, 24] or stanazolol induce an increase in tion (see also Sect. 6.2 on “Pharmacotherapy”). the decreased C1 inhibitor concentration in se- Antihistamines with a mast cell stabilizing ef- rum. In acute attacks, purified C1 inactivator fect (ketotifen) are sometimes helpful. can be given as a life-saving infusion. Patients Some patients respond better to a combined use of H1 plus H2 antagonists. Doxepin as a tricyclic antidepressant has both H1 and H2 antag- onizing effects. Antihistamines also showing antiserotonin effects may be helpful in some cases of physical urticaria (cold urticaria) (e.g., cyproheptadiene, hydroxyzine), and some cases of cold urticaria can be improved by parenteral penicillin therapy. q 2-Adrenergics (e.g., terbutaline) have been found helpful in some cases of chronic urticaria, as has dapsone [14]. Leukotriene antagonists (Montelukast) have been used with controversial effects [15]; a subgroup of patients has been reported to experience possible improvement [7]. Some studies have also recommended using calcium antagonists especially when flush attacks are predominant [15]. Due to the strong psychosomatic interaction in chronic urticaria, tricyclic antidepressants with antihistamine effects (e.g., opipramol) as well as psychosomatic counseling can be helpful. Systemic glucocorticosteroids should only be used in severe cases together with antihistamines. In very severe cases (sometimes with a positive autologous serum test and autoanti- Fig. 5.11. The “witches’” cauldron of urticaria 96 5 Allergic Diseases (and Differential Diagnoses)

and physicians need to know where they can 14. Juhlin L (1981) Modem approaches to treatment get this preparation! ofchronicurticaria.In:RingJ,BurgG(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. JAmOsteopathAssoc99[Suppl]:1–4 17. Leznoff A, Sussmann GL (1989) Syndrome of idiopathic chronic urticaria and angioedema with References thyroid autoimmunity: A study of 90 patients. J Allergy Clin Immunol 84:66 1. Abeck D, Thomsen S, Plötz 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) UVArush syndrome.Contacturticariatodiethyltoluamide. 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 andacquiredC1-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. MüllerJ,VielufD,RingJ(1993)Schilddrüsenhor- 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 ödem.In:PrzybillaB,BergmannK,RingJ(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, Kövary 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, Bödeker 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 Häufigkeit, 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, HenzBM,ZuberbierT,GrabbeJ(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. Schäfer T, Ring J (1996) Epidemiology adverse against the high-affinity IgE receptor as a cause of food reactions due to allergy and other forms of histamine release in chronic urticaria. N Engl J hypersensitivity. In: Eisenbrand G et al. (eds) 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 5.1 Diseases with Possible IgE Involvement 97

31. Skrebova N, Takiwaki H, Miyaoka Y, Arase S 35. Wüthrich B (1989) Therapie der akuten und (2001) Localized heat urticaria: a clinical study chronischen Urtikaria und des Quincke-Ödems. 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:HenzBM,ZuberbierT,GrabbeJ(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.ZuberbierT,AbererW,GrabbeJ,HartmannK, 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

5.1.4 Anaphylaxis 5.1.4.2 Clinical Symptomatology and Elicitors Clinically, anaphylaxis represents a syndrome 5.1.4.1 Definition of different symptoms involving different or- Anaphylaxisisthemaximalvariantofallergic gans which may develop either alone or simul- immediate-type reaction involving the whole taneously or subsequently. The acute occur- organism. Usually the allergen is transmitted rence is characteristic, and the rapid progres- through the blood (by injection or oral inges- sionwithinafewminutesisaccordingtoroute tion). However, anaphylaxis can also be in- of contact and resorption characteristics. duced after intense contact with the skin or mucous membrane surfaces (contact urticaria, Case Report. Patient M.H., female, 53 years contact anaphylaxis, also by aeroallergens). old, received an infusion of 5% human serum When Richet and Portier (1902) first observed albumin on the 3rd day after colectomy. After a the condition while doing animal experiments few minutes, the patient complained of nausea, on the yacht of the Prince of Monaco and later on and on the face and the trunk patchy wheals de- in Paris, they wanted to name it “condition with- veloped.Atthesametime,tachycardiaandhy- outprotection”[28];thiswas,however,bothlin- potension were present. The doctor starting guistically and pathophysiologically wrong the infusion was still present and stopped the (“withoutprotection”shouldhavebeen“aphyla- infusion after 30 ml and replaced it with physi- xis”). Today anaphylaxis is best translated as “ex- ological saline. The patient became uncon- cessively deviated defense reaction” (“ [ ˆ [ ”=up, scious, blood pressure was no longer measur- over; “ ” r † [ ˇ ” = guardian, protection). able, peripheral pulses were not palpable, and Some authors restrict the term anaphylaxis there was no carotid pulse. Cardiac noises were to IgE-mediated reactions. However, there are no longer audible. Immediate resuscitation in- other mechanisms such as immune complex cluding cardiac massage, artificial respiration, anaphylaxis by circulating IgG or IgM anti- oxygen and volume replacement together with bodies (e.g., against IgA or dextran); further- 500 mg prednisolone i.v. led to a restoration of more, there are non-immunological reactions the cardiac and respiratory function. The pa- leading to identical clinical symptoms (see tient survived this severe anaphylactic reaction Sect. 5.7.2 on “Pseudo-allergy”). Therefore the (grade IV) without sequelae [31]. term “anaphylactoid reaction” is also used as a Forthisexample,humanserumalbuminas clinical entity before pathophysiological inves- elicitor was selected on purpose to show that tigations can be done [31]. practically there is no “a priori” innocent drug Recently, the term anaphylaxis has been de- in allergy! Of course some drugs have a higher fined as also comprising non-immune reac- and some a lower risk of anaphylaxis. In the tions as a “maximal variant of an acute general- United States 100–500 fatalities annually are ized hypersensitivity reaction” [15]. With this attributed to penicillin (see Sect. 6.7 on “Drug definition, the term “anaphylactoid” becomes Allergy”).Apartfromdrugs,foods(e.g.,nuts, superfluous. celery, poppy seeds, rarely also ethanol [25], 98 5 Allergic Diseases (and Differential Diagnoses)

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, Aeroallergensorvapors(e.g.,fishodor)may hoarseness, dysphonia, laryngeal edema, elicit anaphylaxis in highly sensitized individu- cough, bronchospasm, respiratory arrest) alsaswellascontacturticariogens(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 whichwecall“summationanaphylaxis”[21, mayoccur[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].

Grade Skin Abdomen Airways Cardiovascular Table 5.17. Severity system grading of anaphylactic reactions (according to I Itch – – – [30]) Flush Urticaria Angioedema II Itch Nausea Rhinorrhea Tachycardia (>20/min) Flush Cramps Hoarseness Hypotension (>20 mmHg syst.) Urticaria Dyspnea Arrhythmia Angioedema (not obligatory) III Itch Vomitus Laryngeal edema Shock Flush Defecation Bronchospasm Urticaria Cyanosis Angioedema (not obligatory) IV Itch Vomitus Respiratory Cardiac arrest Flush Defecation arrest Urticaria Angioedema (not obligatory) 5.1 Diseases with Possible IgE Involvement 99

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]. (antilymphocyteserum)aswellasdextran 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,oftenturnintomore 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- culatorydisturbanceleadstodecreasedcapil- 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- occurwithanincreaseofmastcelltryptasein 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- areaction[3]. tibodies, the exact mechanisms of amplifica- The mediator release reaction from mast tion are not yet understood, which make it cellsandbasophilsisnotacytolyticprocess 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 symptomatology 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

Drugs (all forms!) Pharmacologic-toxic effects Additives Cramps Foods Syncope (cardial, cerebral) Occupational agents (e.g., latex) Pulmonary embolism Insect venoms Bolus aspiration Aeroallergens Hypoglycemia Contact urticariogens Hyperventilation Seminal fluid Vasovagal reflexes Echinococcal cysts Vocal cord dysfunction Cold, heat, UV radiation Hysterical fit Exercise “Anaphylaxis factitia” (Münchhausen’s syndrome) Summation (infection, stress, exercise, other allergen concomitant exposure, medication as q -blockers, NSAIDs, ACE inhibitors, etc.) that explains why fortunately many sensitized Idiopathic (?) individuals tolerate allergen contact without Underlying diseases: C1 inactivator deficiency clinical incompatibility symptoms! We believe Systemic mastocytosis that many cases of so-called idiopathic anaphylaxis may thus be explaianed [32, 45].

Rare cases of passive transfer of IgE antibodies 5.1.4.5 Diagnosis and Differential Diagnosis via blood transfusion as well as suicide attempts (penicillin-allergic nurse) have been re- The clinical symptomatology of anaphylaxis is ported. Murder has been attempted by eliciting so characteristic that diagnosis usually is not anaphylaxis in the detective literature. Also difficult. Nevertheless several differential diag- anaphylaxis factitia (“Münchhausen’s syn- noses need to be considered (Table 5.19). drome”) exists [I remember the case of a 17- Patients having survived an anaphylaxis year-old girl with repeated severe anaphylactic have to undergo allergy diagnosis! This diag- (gradeIIIandIV)episodesonthebasisofseri- nosticprocedurehasthreeaims: ous somatoform disturbance]. Epidemiology 1. Determination of the eliciting agent of anaphylaxis mostly focuses on the elicitors. 2. Description of the relevant pathomecha- Therateofdrug-inducedanaphylaxisranges nism (e.g., IgE) from 0.001% up to 10% per dose applied [2, 3. Offering of a compatible alternative (see 31]. Rarer reactions have been observed after Sect. 5.7 on “Drug Allergy”). poppy seeds, beer (hops and barley), but also due to ethanol [25]. 5.1.4.6 Prophylaxis and Therapy Theelicitorofanaphylaxismaybetransmit- ted to the organism via the air (fish allergens in For prophylaxis (Table 5.20), abstaining from vapors around fish stores, latex allergens in polypragmatic pharmacotherapy is as impor- rooms decorated with air balloons). The appli- tant as the endeavors of the pharmaceutical in- cation of an ointment on unlesional skin may dustry to produce better and less allergenic elicit contact anaphylaxis in sensitized individ- drugs. uals [33]. In recent years, increasing reports de- Knowledge of possible complications is the scribe patients who only suffer anaphylaxis af- best basis for successful therapy. Being pre- ter combined action of different stimuli, for in- pared for such complications enables one to re- stance, physical exercise, mental or emotional act more quickly. This also implies knowledge stress, acute infection, or concomitant expo- of additives (stabilizers, preservatives, color- sure against other relevant allergens. We call ings, etc.) in drugs against which people can re- this phenomenon “summation” or “augmenta- act. tion anaphylaxis” and think that it may be The question regarding adverse drug reac- much more common than generally suspected. tions in the history allows the risk groups to be Possibly, this type of reaction is the rule and pinpointed. The importance of atopic diathesis 5.1 Diseases with Possible IgE Involvement 101

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 q Avoidance of -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 antagonistsorantihistaminesplussteroids) The treatment of anaphylaxis follows the sever- Emergency set (for self-medication) ityofsymptoms(Fig.5.12).Ifthereactiononly involves the skin (urticaria) with a stable cardiovascular 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 diagnosisiseasy!)glucocorticoidsandepi- 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 q dextran anaphylaxis [17, 29, 31]. with theophylline (0.24–0.48 mg) plus 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 ampule1mlin10mlsalineforslowinfusionof 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 O2 Cyanosis Severity Epinephrine (1:1000) 0,3-1 ml

RR , Tachycardia Glucocorticosteroide 100 mg © Dyspnea Theophylline, 0,24 g i.v. G.I. symptoms

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 IIIIIIIV 102 5 Allergic Diseases (and Differential Diagnoses)

q (1–2 mg) is beneficial [46] in restoring -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 replacement (e.g., crystalloids or hydroxyethyl starch up to 1,000 ml as rapid infusion) is vital. Table 5.22. Emergency equipment for the allergist’s Levarterenol [12], metaraminol, or dopamine office mayalsobeapplied.IngradeIVreactions(car- Tourniquet, disinfectant diac or respiratory arrest), only immediate and adequate resuscitation measures are life-saving Syringes, cannulas, infusion sets, connecting pieces [8] (Table 5.21). In addition to the classical rule of resuscita- Blood pressure, stethoscope 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 bicarbonate, dopamine, lidocaine, possibly atropine, etc.) Beta-adrenergics (e.g., fenoterol, salbutamol) Glucagon (ampules) Spasmolytics (e.g., diazepam) Airway Antigen off Antiemetics (e.g., metoclopramide)

1 Analgesics (tramadol) Breathing + Adrenaline 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: 1–2 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- occasional cases of “late shock,” e.g., second munol 11:251–156 anaphylactic episode after 6–12 h, are danger- 15. Johansson SGO, Hourihane JOB, Bousquet J, Bru- ijnzeel-Koomen, Dreborg S, Haahtela T, Kowalski ous complications [31, 40]. These patients also ML,MygindN,RingJ,vanCauwenbergeP,van represent a risk group for skin testing, which Hage-Hamsten M, Wüthrich B (2001) A revised should only be done under emergency condi- nomenclature for allergy. An EAACI position tions. statement from the EAACI nomenclature task force. Allergy 56:813–824 16. Kleinhans D (1987) Anstrengungs-induzierte Ur- tikaria und Anaphylaxie. Med Klein 82:103–104 References 17. Laubenthal H (1986) Dextrananaphylaxie, Patho- mechanismus und Prophylaxe. Ergebnisse einer 1. Barnard JH (1973) Studies of 400 Hymenoptera multizentrischen Studie. Springer, Berlin Heidel- sting deaths in the United States. J Allergy Clin berg New York Immunol 52:259–264 18. Lockey RF, Benedict LM, Turkeltaub TB, Bukantz 2. Bochner BS, Lichtenstein LM (1991) Anaphylaxis. SC (1987) Fatalities from immunotherapy (IT) N Engl J Med 324:81–88 and skin testing (ST). J Allergy Clin Immunol 3.BrockowK,KiehnM,RiehtmüllerC,VielufD, 79:666–677 Berger J, Ring J (1997) Efficacy of antihistamine 19.LorenzW,DoenickeA,DittmannI,HugP, pretreatment in the prevention of adverse reac- Schwarz B (1977) Anaphylaktoide Reaktionen tions to Hymenoptera venom immunotherapy: a nach Applikation von Blutersatzmitteln beim prospective randomized placebo-controlled trial. Menschen. Verhinderung dieser Nebenwirkung J Allergy Clin Immunol 100:458–463 von Haemaccel durch Praemedikation mit H1- 4. Brown MJ, Brown DC, Murphy MB (1983) Hypo- und H2-Antagonisten. Anaesthesist 26:644 kalemia from beta-2-receptor stimulation by 20. Marone G, Patelle V,Crescanzo A de, Genovese M circulating epinephrine. N Engl J Med 309: (1995) Human heart mast cells in anaphylaxis 1414–1419 and cardiovascular disease. Int Arch Allergy Im- 5. Capurro N, Levi R (1975) The heart as target or- munol 107:72–75 ganinsystemicallergicreactions.CircRes 21. Maulitz RM, Pratt DS, Schocket AL (1979) Exer- 36:520–528 cise-induced anaphylactic reaction to shellfish. J 6. Delage C, Irey HC (1972) Anaphylactic deaths: a Allergy Clin Immunol 63:433 clinicopathologic study of 43 cases. J Forens Sci 22. Meßmer K (1983) Plasma substitutes and indica- 17:525 tions for their use. In: Tinker J, Rapin M (eds) 7. De Soto H, Turk P (1989) Cimetidine in anaphy- Care of the critically ill patient. Springer, Berlin lactic shock refractory to standard therapy. Heidelberg New York, pp 569–575 Anesth Analg 69:264–265 23. Müller U (2001) Spätkomplikationen bei Ana- 8. Eisenberg MS, Mengest TJ (2001) Cardiac resus- phylaxie. In: Ring J, Darsow U (eds) “Allergie citation. N Engl J Med 344:1304–1313 2000: Probleme, Strategien und praktische Kon- 9. Endrich B, Ring J, Intaglietta M (1979) Effects of sequenzen”. Dustri, Munich, pp 249–252 radiopaque contrast media on the microcircula- 24. Pavek K, Wegmann A, Nordström L, Schwander tion of the rabbit omentum. Radiology 132: D (1982) Cardiovascular and respiratory mecha- 331–339 nisms in anaphylactic and anaphylactoid shock 10. Fisher MMD (1986) Clinical observations on the reactions. Klin Wochenschr 60:941–947 pathophysiology and treatment of anaphylactic 25. Przybilla B, Ring J (1983) Anaphylaxis to ethanol cardiovascular collapse. Anesth Intensive Care and sensitization to acetic acid. Lancet 1:483 17:17–21 26. Pumphrey RS (2000) Lessons for management of 11. Fuchs E, Ferlinz R (1986) Allergische Krankhei- anaphylaxis from a study of fatal reactions. Clin ten. In: Wolff HR v, Weihrauch TR (eds) Interni- Exp Allergy 30:1144–1150 stische Therapie, 6th edn. Urban und Schwarzen- 27. Reimers A, Müller U (2000) Behandlung des ana- berg, Munich, pp 275–288 phylaktischen Schocks. Ther Umschau 58:325– 12. Gronemeyer W (1980) Noradrenalin statt Adren- 328 alin beim anaphylaktischen Schock. Dtsch Med 28. Richet C (1904) De l’anaphylaxie ou sensibilite Wochenschr 102:101 croissante des organismes a des doses successives 13. Hannaway PJ, Hoppler GDK (1983) Severe ana- de poison. Arch Fisiol 1:129 phylaxis and drug induced beta-blockage. N Engl 29.RichterW,HedinH,RingJ,KraftD,MessmerK J Med 308:1536 (1980) Anaphylaktoide Reaktionen nach Dextran 14. Hermann K, Ring J (1997) The renin-angiotensin I. Immunologische Grundlagen und klinische Be- system in patients with repeated anaphylactic re- funde. Allergologie 3:9 actions during Hymenoptera venom hyposensiti- 30. Ring J, Messmer K (1977) Incidence and severity 104 5 Allergic Diseases (and Differential Diagnoses)

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Table 5.23. Clinical manifestation of adverse food 5.1.5FoodAllergyandOtherAdverseFood reactions Reactions Skin Panniculitis? 5.1.5.1 Classification and Symptomatology Itching Melkersson-Rosenthal Flushing Syndrome? Adverse food reactions represent an increasing Urticaria Eye and airways Angioedema problem in allergy practice. The clinical symp- Rhinoconjunctivitis Atopic eczema toms range from nausea, vomiting, abdominal Laryngeal edema Lip swelling and swelling pain, gastroenteritis, diarrhea, urticaria, asth- Bronchial asthma of oral mucosa moid complaints, allergic rhinitis to full ana- Stomatitis, glossitis Gastrointestinal tract phylaxis or serum sickness type reactions with (papillitis linguae) Nausea arthralgia and vasculitis [9, 26, 42, 67–70] (Ta- Relapsing aphthae Vomit ing ble 5.23). Immune complex vascu- Meteorism litis Acute gastroenteritis As in all fields of allergology, clinically simi- Purpura pigmentosa Diarrhea lar but pathophysiologically different non-im- progressiva Colitis? Hematogenous (system- munologically elicited conditions (pseudo-al- Cardiovascular system ic) contact dermatitis lergic reactions) need to be distinguished Ta- Anaphylaxis Protein contact dermatitis ble5.24);inthischapter,particularlyenzyme Phototoxic and photo- deficiency (e.g., lactase) as well as toxic effects allergic reactions of contaminants (bacterial toxins) should be Exanthematous eruptions considered. Diseases due to malnutrition will Dermatitis herpetifor- not be covered here [11, 12, 48, 51]. mis Duhring (gluten) 5.1 Diseases with Possible IgE Involvement 105

Table 5.24. Classification of adverse food reactions Mechanism Allergy IgE IgG/M IgA (?) Lympho- Mediator Enzyme Pseudo- cytes release defects allergy/ intolerance Examples Immediate Serum Gluten- Cellular Colorings, Lactase Poisons, reaction sickness sensitive allergy preserva- ) Inherited histamine entero- tives, ) pathy salicylates Secondary Serotonin, ca- Galactokinase techolamines, Gal-1-PO4 psychoactive Uridyltrans- substances ferase Clinical Urticaria, Vasculitis, Diarrhea, Systemic Urticaria, Diarrhea, Anaphylaxis/ symptoms: anaphylax- arthralgia malab- contact angio- malabsorp- anaphylac- (selection) is, diarrhea sorption Contact edema tion toid reaction Colics dermatitis Anaphy- Blood pres- Mental con- Anaphy- Exanthem- laxis sure changes fusion (?) laxis atous (atopic ec- eruption zema) Colitis (?) Diarrhea

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 cow’s milk, hen’s eggs, nuts, spices, garding gene technology and foods are listed in vegetables,cereals,fish,meat,andfruits.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, Cow’s 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 cow’s milk allergic food allergy and other adverse food reactions individuals. This needs to be evaluated using a 1. Diagnostic diets prick test [3]. Allergydietno.1(“allergen-free”):short-term,up Crossreactionsbetweencow’smilkandbeef to 10 days, prior to provocation or after acute or veal are possible but rare (most likely due to reaction BSA). Allergies against horse mare’s 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 Allergydietno.3(“additive-free”):canbegiven over months, basis for provocation with additives pork avoidance in allergic individuals or atopics 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) Hen’s Eggs. Specific IgE antibodies against 3. Therapeutic diets hen’s 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 cow’s milk formula theegg,livetin,apovitillin,andvosvitencanbe Hypoallergenic (oligoantigenic) diet of the mother found, which may play a role in adult hen’s egg during lactation allergics. Cross-sensitizations between hen’s 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”). Cow’s 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- Themostcommonallergensarewheypro- 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. Ve getabl es /Fr uit. 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(seeSect.3.4).Therelevantplantproteins 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)andstronglyhydrolyzedproducts,which ed proteins is the major allergen from birch pol- 5.1 Diseases with Possible IgE Involvement 107 len(Betv1),whichisnotonlypresentinpollen 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 = hen’s 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. selfactsonmastcellsasahistamineliberator. 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 cow’s 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 cognizesoyinthefood(“hiddenallergens”) 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 cow’s some arthropods (housedust mites). milk, hen’s eggs, fish, peanut, etc. Each foreign protein in foods is spe- 5.1.5.3 Pathomechanisms cifically recognized, but induces tolerance 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 cow’s milk and diseases of the gut may play a role in the devel- 108 5 Allergic Diseases (and Differential Diagnoses)

hen’s egg allergy are mostly reversible 2. Exclusion of other possibilities of incompat- during childhood, fish and peanut al- ibility lergies are often lifelong conditions. 3. Demonstration of immunological sensitiza- Type B: Here the sensitization occurs in tion adulthood against aeroallergens with cross-reacting food allergens (see Taking the history for food allergy may be diffi- Sect. 3.4) (celery-mugwort-carrot- cult (e.g., to obtain the recipe for certain spice syndrome). A high percentage dishes). We were able to solve a case of severe ofpollinosispatientsarealsosensi- anaphylaxis after the patient had partaken of tized against foods. “Prinzregententorte”(aBavariandelicacy Type C: The sensitization is acquired orally in withoutnuts)asbeingduetonutallergyonly adulthood (isolated cow’s milk aller- after obtaining the recipe from the pastry mak- gy of the adult with anaphylaxis). er, who had used a coconut-derived lipid for the glazing [60]. Thediagnosticworkupinapatientwithse- 5.1.5.4 Diagnosis vere anaphylaxis after a breakfast including the The diagnostic recommendations for food al- Munich delicacy “white sausage” (obtainable lergy are: from only one special butcher) was successful only by demonstrating chicken meat in the sau- 1. Reproducible elicitation of symptoms by sage (I) in RAST inhibition [54] (Fig. 5.14a,b). the suspected food

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 butcher’s shop was elucidated with the RAST inhibition 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 Cow’s milk and cow’s milk products Day 1 Tartrazine 10–50 mg, PHB ester 500 mg Step 2 Carbohydrates and vegetables Day 2 Color mixture I–II Step 3 Meat ColormixtureI(5mgeach):quinolineyel- Step 4 Poultry and hen’s 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 Foodstobeadded Day 4 Potassium metabisulfite 10–50–100 (–300) mg 1 Tea (fennel) with glucose plus mineral water 5 2Carrots Day Acetylsalicylic acid 50–250–500 3Oats (–1,000) mg 4Potatoes Day 6 Possibly repetition, nitrites, tyramine, pro- 5 Bread (wheat) pionate, other benzoates or colorings, glu- 6Noodles tamate, etc., placebo 7Pears 8Rice 9Soy capsules contain coal, mannose or silicate. 10 Cow’s milk Foods can be blinded with carob and colored 11 Veal juices (blackcurrant). In severe reactions or 12 Beef 13 Pork multiple allergies, food challenges should be 14 Chicken performed under inpatient conditions in order 15 Hen’s 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 pressure, 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 psychosomatic influence [6, 10, 15, 37]. Placebo 110 5 Allergic Diseases (and Differential Diagnoses)

35] with success, but side-effects can occur and 5.1.5.5 Therapy may lead to changes in doses. Of course, during Avoidance is the most important principle in the hyposensitization strict avoidance should be management of food allergy. This may be diffi- kept. After reaching a maintenance dose, natu- cult when basic foods are involved. In patients ralfoodscanbetried.Incow’smilkallergy,for with additive hypersensitivity, knowledge of the instance, a daily dose of 200 ml cow’s milk needs E-numbers is important (Table 5.29). In occa- to be drunk. After longer intervals (5–7 days), sional cases, oral (or even subcutaneous) immu- the effect may be lost. notherapy with allergen extracts after careful al- Therapy and prophylaxis of cow’s milk aller- lergy diagnosis has been attempted [22, 30, 34, gy plays a major role in infants (Table 5.30). A

Table 5.29. Food additives and European (E) numbers Colorings E No. Preservatives E No. Lactoflavin (riboflavin) E101 Sorbic acid E200 Beta-carotene E160a Sodium sorbate E201 Caramel E150 Potassium sorbate E202 Silver E174 Calcium sorbate E203 Gold E175 Benzoic acid E210 Curcumin E100 Sodium benzoate E211 Tartrazine E102 Potassium benzoate E212 Quinoline yellow E104 Calcium benzoate E213 Riboflavin-5-phosphate E106 Ethyl p-hydroxybenzoate E214 Orange yellow S E110 Sodium ethyl p-hydroxybenzoate E215 Carmine (carminic acid, cochineal) E120 Propyl p-hydroxybenzoate E216 Azorubine E122 Sodium propyl p-hydroxybenzoate E217 Amaranth E123 Methyl p-hydroxybenzoate E218 Cochineal red A (Ponceau 4R) E124 Sodium methyl p-hydroxybenzoate E219 Erythrosine E127 Sulfur dioxide E220 Patent blue V E131 Sodium sulfite E221 Indigotin I (indigo carmine) E132 Sodium hydrogen sulfite E222 Chlorophyll E140 Sodium metabisulfite E223 Copper-containing chlorophyll complexes E141 Potassium metabisulfite E224 Brilliant acid green BS (lisamine green) E142 Calcium sulfite E226 Brillant black BN E151 Calcium hydrogen sulfite E227 Vegetable carbon E153 Formic acid E236 Alpha-carotene E160a Sodium formiate E237 Gamma-carotene Calcium formiate E238 Bixin, norbixin (Annatto, Orlean) E160b Propionic acid E280 Capsanthian, Capsorubin E160c Sodium propionate E281 Lycopene E160d Calcium propionate E282 Beta-apo-8’-carotenal E160e Potassium propionate E283 Beta-apo-8’-carotenoic acid ester E160f Biphenyl E230 Xanthophyll E161 Orthophenyl phenol E231 Flavoxanthin E161a Sodium orthophenyl phenol E232 Lutein E161b Thiabendazol E233 Cryptoaxanthin E161c Potassium ascorbate E303 Rubixanthin E161d Tocopherols E306 Violaxanthin E161e Alpha-tocopherol E307 Rhodoxanthin E161f Delta-tocopherol E309 Canthaxanthin E161g Betanin E162 Anthocyanin E163 Aluminum E173 Calcium carbonate E170 Titanium dioxide E171 Iron oxides and hydroxides E172 5.1 Diseases with Possible IgE Involvement 111

Table 5.29. (Cont.) Antioxidants E No. Carriers E No. Propyl gallate E310 Ammonium alginate E403 Octyl gallate E311 Potassium alginate E402 Dodecyl gallate E312 Sodium alginate E401 Butylated hydroxyanisole (BHA) E320 Glycerol E422 Butylated hydroxytoluol (BHT) E321 Pectin E440 Ascorbic acid E300 Sorbitol E420 Sodium L-ascorbate E301 Carrageenan E407 Calcium ascorbate E302 Gum arabic E414 Citric acid E330 Sodium citrate E331 Potassium citrate E332 Calcium citrate E333 Lactic acid E270 Sodium lactate E125 Potassium lactate E326 Calcium lactate E327 Lecithin E322 Glycerides of fatty acids esterified with citric acid E472c Sodium orthophosphate E339 Potassium orthophosphate E340 Orthophosphate E341 6-Palmitoyl-L-ascorbic acid E304 Tartric acid E334 Sodium tartrate E335 Potassium tartrate E336 Sodium potassium tartrate E337 distinction should be made between prophy- For pharmacotherapeutic prevention, mast lactic and therapeutic hypoallergenic formulas cell stabilizers have been used successfully (Table 31). Strongly hydrolyzed products have (oral cromoglycate) [28, 54], possibly also anti- been proven in a large epidemiological study histamines. (GINI) as being equivalent to breast feeding Food-allergic individuals do not have to [3, 61]. spend the rest of their life with appalling re- It is open for discussion whether the addi- strictions and impairment of quality of life. If tion of probiotic lactobacillae with immuno- correctly diagnosed, there are recipes for each modulating effects in the gastrointestinal tract kind of food allergy in order to allow for an plays a role in atopy prevention [27]. agreeable diet [5, 52].

Table 5.30. Hydrolyzed Protein basis Hydrolysis Name Producer cow’s milk formulas for infant food Whey Partial Beba HA Nestlé Aletemil HA Nestlé Strong AlfaréNestle´ Partial Humana HA Humana Partial Nutrition Pepti Milupa Hipp HA Hipp Strong Nutramigen Mead-Johnson Casein Partial Aptamil HA Milupa Soy Strong Pregomin Milupa Carob, amino acids – Sinlac, Neocate Nestlé 112 5 Allergic Diseases (and Differential Diagnoses)

Table 5.31. Statement published by the German Society for Allergology and Clinical Immunology (DGAI) regarding gene technology and food allergy

Many people are worried by the introduction of gene technologically altered foods. In this context, the question 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 prevalence 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 regarding 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 prevention 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 improvement in the declaration not only of additives, but also of food contents, independently of technological procedures. It remains open whether the “gene technologically produced” procedure should be especially 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.

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Häberle M (1987) Klinische und lebensmittelche- gen in transgenic soybeans. N Engl J Med 334: mische Aspekte bei Unverträglichkeits-Reaktio- 688–692 nen auf Salicylat- und Additiva-haltige Lebens- 39. Ortolani C, Ballmer-Weber BK, Hansen KS, et al. mittel. Zbl Haut 153:75–95 (2000) Hazelnut allergy: a double-blind, placebo- 22. Henzgen M, Schlenvoigt G, Diener C, Jäger L controlledfoodchallengemulticenterstudy.JAl- (1991) Nahrungsmittelallergie bei Frühblüher- lergy Clin Immunol 105:577–581 pollinose und deren Beeinflussung mittels Hypo- 40. Pichler WJ, Stich O (1993) Nahrungsmittelaller- sensibilisierung. Allergologie 14:90–94 gien bei Pollensensibilisierungen, part II: Kreuz- 23. Hjorth N, Roed-Petersen J (1976) Occupational reaktionen bei Beifußpollen-Sensibilisierungen. protein contact dermatitis in food handlers. Con- Allergologie 16:494–501 tact Dermatitis 2:28–42 41. Pratschke E (1986) Mediatoren der immunologi- 24. 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5.1.6 Insect Venom Allergy 5.1.6.1 Insect Venoms Allergic reactions against insect venoms are The most important insects honeybee (Apis not infrequent: 0.8–5% of the population react mellifera) and certain wasps (Vespula ger mani- to the venoms of wasps, bees, and hornets with ca, V. vulgaris, Dolichovespula) belong to the systemic allergic symptoms (19% with hype- order of Hymenoptera [12, 29, 34] (Figs. 5.15, rergic local reactions) [31, 33, 47, 49]. In Ger- 5.16). Rarer elicitors are bumblebees (Bombus), many, 10–40 fatalities per year are estimated hornets (Vespa crabro), field wasps (Polistes), with a high “hidden number” of cases of unex- ants (Formicidae), and mosquitos (Diptera). plained cardiac death [2, 11, 37, 52]. Most reac- Insect venoms contain toxic and allergenic sub- tions arise on the basis of IgE-mediated sensiti- stances. zation against insect venoms. Rare cases of im- A painful, itching, or burning sensation mune complex anaphylaxis as well as pseudo- with a surrounding wheal and flare at the sting allergic reactions should be distinguished. site is normal. Moreover, in certain localizations(upperairways)orafteranexcessive 5.1 Diseases with Possible IgE Involvement 115

Arthropoda

Insecta

Hymenoptera

Apidae Vespidae Formicidae

Apis mellifera Bombus Polistinae Vespinae Solenopsis Pogonomyrmex Polistes spp.

Vespa crabo Dolichovespula Vepula vulgaris

Fig. 5.15. Taxonomic classification of the most important Hymenoptera species responsible for insect venom allergies

enzyme in bee venom. Wasp venom also con- tainsantigen5aswellashyaluronidase.There is a marked cross-reactivity between the ven- omsofdifferentspeciesoftheorderVespidae [19, 34, 35, 50, 51]. Hornet venom also contains kinins and acetylcholine.

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 symptomscanbeclassifiedaccordingtoseveri- 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.Apaminhasneurotoxicef- 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)

Contents Molecular Percentage Table 5.32. Contents of weight honeybee and wasp venom Bee venom Proteins Phospholipase A2 15,800 12% Hyaluronidase 45,000 2% Acid phosphatase (allergen B) 49,000 ? Allergen C 105,000 ? Peptides Melittin 2,840 50% Mast cell degranulating peptide 2,593 2% (MCDP) Apamine 2,038 2% Other peptides ? 15% Mediators Histamine 111 1% Leukotriene B4 and C4 336 <0.001% Vespid venom Proteins Antigen 5 25,000 15% Phospholipases ~35,000 10% Hyaluronidase 45,000 2% Proteases ? ? Peptides Kinins ~2,000 ? Mediators Histamine 111 4% Serotonin ~1% Leukotriene B4 and C4 336 ~0.001% Dopamine ~5% Acetylcholinea 5% a Only for Vespa cabro

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 µg/ml and in- Occupations with increased exposure to Hyme- creasing the concentration to 300 µg/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 µg/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 vitro 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 generalized 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 patients with optimal dose increases control of therapeutic efficacy. Severe complications have been observed [3]. Day Conven- Hamburg “Ultrarush” tional schedule

5.1.6.4 Allergen-Specific Immunotherapy 1 0.02 0.001 0.01 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 homogenized honeybee, the asthma improved. 0.8 0.4 100.0 1.0 0.7 Based on this report, a worldwide practice of 4.0 immunotherapy of insect venom allergy with 38.01.0 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].Onlyafteritwasshownthatbee 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 40, 43, 56]. Lichtenstein et al. pioneered the 90.0 100.0 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 butonly5%ofthebeevenomextracttreated 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 venomisproducedbyelectricalstimulationof (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 andneed74millioninsects(=6,000kg). 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 µg every the maintenance dose, intervals are slowly in- 4 weeks is reached. According to a schedule of creasedfrom1,2,3tofinally4weeks. rush hyposensitization with up to four injections 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 nopteravenomsiseffectivein80–100%ofpa- 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.Inourownexperience,only5%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 µg, most of these patients tolerated the subsequent sting challenge [40] (Table 5.35).

Side Effects: Local Reactions. Local reactions occur as swelling with wheal and redness and are observed in most patients, sometimes lasting 6–12 h. The reactions occur mostly during thecourseofthedoseincreaseathighercon- centrations (10–100 µg) and sometimes slow the further increase of dose. Local treatment with moist wraps and topical corticosteroids leads to improvement. Subsequent injections are usually well tolerated. Therapy success

Side Effects: Systemic Reactions. In 3–35% of patients, systemic reactions are observed [39, Starting Maintenance 2 months 1 year 46], which occur more frequently in bee than dose dose Provocation wasp venom allergic individuals [48]. After treatment, immunotherapy is continued with Fig. 5.17. Bee-venom-specific antibodies of the IgE and IgG class demonstrated in two patients undergoing reduceddose(seeSect.6.2).Inpatientswithre- hyposensitization treatment with bee venom extract peated systemic reactions, prophylaxis with H1 antihistamines can be considered [7, 15]. Rare- ly, serum sickness or immune complex reac- Sting Challenge. After reaching the mainte- tions occur [8]; then therapy has to be discon- nance dose and maintaining it over at least tinued. 3 months, sting challenge can be performed with a living insect in emergency conditions (Fig.5.18).Stingchallengerepresentstheonly 5.1.6.5 Therapy Control objective method for evaluation of therapeutic Under allergen-specific immunotherapy, most efficacy [40]. In patients still reacting to sting patients show an increase of specific IgE to- challenge,weincreasethedoseupto200µgev- gether with specific IgG antibodies (Fig. 5.17). ery 4 weeks or shorten the interval (3 weeks). However, in the individual case IgG concentrations do not give reliable prognostic informa- Duration of Treatment. Since there is no reliable tion [3]. Possibly, the ratio sIgG4/sIgE in the prognostic marker which gives solid information immunoblot may be relevant regarding the on the duration of protection, some authors rec- protective effect of immunotherapy [36]. ommend lifelong immunotherapy. International recommendations vary between 3 and 5 years 5.1 Diseases with Possible IgE Involvement 119 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 thehistoryremainsdoubtful.Ifcellulartestsdo 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, additional information about the relevant insect species may be obtained.

Passive Immunotherapy. Intramuscular administration of hyperimmunoglobulin from beekeepers has been proven to be protective and may also enhance efficacy of active immunotherapy [21, 38].

Fig. 5.18. Stingprovocationwithalivinginsect

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, animals, 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 ) Keepcalm!Informpeoplearoundyouaboutyoursituation. ) 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, Kästner 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. Münch 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 tients with this combination come and ask for a 12. Habermann E (1972) Bee and wasp venoms. Sci- 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 Doppelpositivität 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, triple therapy. However, future studies are re- Amodio FJ, Lichtenstein LM (1978) A controlled 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 Independently of immunotherapy, patients 16. Jeßberger B, Habig J, Karl S, et al. (1994) Hyme- 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. Kämmerer H (1941) Fragekasten. Münch 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 höheren Lebensalter. for inhalation or self-injection (in severe cases). Allergo J 2 [Suppl 2]:90–94 19. KingTP,LuG,GonzalezM,QianN,SoldatovaL (1996) Yellow jacket venom allergens, hyaluronidase and phospholipase: Sequence similarity and References antigenic cross-reactivity with their hornet and wasp homologues and possible implications for 1. Albrecht I, Eichler G, Müller U, Hoign´e R (1980) clinical allergy. J Allergy Clin Immunol 98:588–600 Onthesignificanceofseverelocalreactionstohy- 20. Lerch E, Müller UR (1998) Long-term protection menoptera stings. Clin Allergy 10:675 after stopping venom immunotherapy: results of 2. Barnard JH (1973) Studies of 400 hymenoptera restings in 200 patients. J Allergy Clin Immunol sting deaths in the United States. J Allergy Clin Im- 101:606–612 munol 52:259 21. Lessof M, Sobotka AK, Lichtenstein LM (1976) 3. Bauer CP (1986) Stichprovokationen zur Diagno- Protection against anaphylaxis in hymenoptera- stik von Insektengift-Allergien? Allergologie 9:14 sensitive patients by passive immunization. J Al- 4. Benson R, Semenov H (1930) Allergy in its relation lergy Clin Immunol 57:246 tobeesting.JAllergy1:105 22. Lichtenstein LM, Valentine MD, Sobotka AK 5. Benton AW, Morse RA, Stewart JD (1963) Venom (1974) A case for venom treatment in anaphylac- collection from honey bees. Science 142:228 tic sensitivity to hymenoptera sting. N Engl J Med 6. Brehler R (1999) Ultra-Rush-Hyposensibilisie- 290:1223 rung. Allergologie 22 [Suppl 2]:570–571 23. Light WV, Reismann RE, Rosario NA, Arbesman 7. Brockow K, Kiehn M, Riethmüller C, et al. (1997) CE (1976) Comparison of the allergenic proper- Efficacy of antihistamine treatment in the preven- ties of bee venom and whole bee body extract. tion of adverse reactions to Hymenoptera immuno- Clin Allergy 6:293 therapy: A prospective, randomized, placebo-con- 24. Lockey RF (1975) Systemic reactions to stinging trolled trial. J Allergy Clin Immunol 100:458–463 ants. J Allergy Clin Immunol 54:132 5.1 Diseases with Possible IgE Involvement 121

25. Lonsdorf G, Ring J, Burg G (1981) Anaphylakti- bewertenden Punkteschemas gestellt werden. sche Reaktionen nach Insektenstichen. Notfall Allergologie 13:114–119 Medizin 7:409 42.RakoskiJ,MayenburgJvon(1986)DasUltra- 26. Lotter G (1939) Sensibilisierung für Bienengift Rush-Verfahren – eine neue Methode zur Über- durch Typhus-Antitoxin und Desensibilisierung prüfung der Aktualität von Insektengiftallergien. mit Forapin. Münch Med Wochenschr 86:330– Allergologie 9:73–74 331 43.RingJ,LonsdorfG,SchuryW,BurgG(1982)Bie- 27. Loveless MH, Fackler WR (1956) Wasp venom al- nen- und Wespengift-Allergie. Klinik Prophylaxe lergy and immunity. Ann Allergy 14:347 und Therapie. Münch Med Wochenschr 124:587 28. Mauss V (1999) Einfluß von Lebensweise, Popu- 44. Ring J, Gottsmann M, Przybilla B, Eisenmenger lationsdynamik und Abwehrverhalten aculeater W (1986) Tod nach 1000 Bienenstichen. Münch Hymenopteren auf das Stichrisiko für den Men- Med Wochenschr 128:339 schen. Allergologie 22 [Suppl]:542–545 45. Ring J, Przybilla B, Müller U (1997) Insektengif- 29. Mauss V, Treiber R (1994) Betreuungsschlüssel tallergie: Aktuelles für die Praxis. Allergo J 6 für die Faltenwespen (Hymenoptera: Masarinae, [Suppl 1]:571–572 Polistinae, Vespinae) der Bundesrepublik Deutsch- 46. Rueff F, Reißig J, Przybilla B (1997) Nebenwir- land. Deutscher Jugendbund für Naturbeobach- kungen der Schnellhyposensibilisierung mit Hy- tung, Hamburg menopterengift. Allergo J 6 [Suppl 1]:659–664 30. Mueller HL, Schmid WH, Rubinstein R (1975) 47. RueffF,PrzybillaB,FuchsT,GallH,RakoskiJ,Stolz Stinging-insect hypersensitivity. A 20-year old W, Vieluf D (2000) Diagnose und Therapie der Bie- study of immunologic treatment. Pediatrics 55:530 nen- und Wespengiftallergie. Positionspapier der 31. Müller UR (1988) Insektenstichallergie. Klinik, Deutschen Gesellschaft für Allergologie und klini- DiagnostikundTherapie.G.Fischer,Stuttgart sche Immunologie (DGAI). Allergo J 9:458–472 32. Müller U (2001) New development in the diagno- 48. Rzany B, Przybilla B, Jarisch R, et al (1991) Clini- sis and treatment of hymenoptera venom allergy. cal characteristics of immunotherapy with Hy- Int Arch Allergy Immunol 124:447–499 menoptera venoms. A retrospective study. Aller- 33. Müller U, Mosbech H (1993) Position paper: Im- gy 46:251–254 munotherapy with hymenoptera venoms. Allergy 49. Schäfer T, Przybilla B (1996) IgE antibodies to hy- 48 [Suppl 2]:37–46 menoptera venoms in the serum are common in 34. Mumcuoglu Y, Rufli T (1980) Dermatologische thegeneralpopulationandarerelatedtoindica- Entomologie. 12. Apidael Bienen. 13. Vespidae tions of atopy. Allergy 51:372–377 Wespen. Schweiz Rundsch Med 69:1317, 1574 50. Schumacher MJ, Tveten MS, Egen NB (1994) Rate 35. O’Connor R, Peck ML (1978) Venoms of Apidae. and quantity of delivery of venom from honeybee In: Handbook of experimental pharmacology, vol stings. J Allergy Clin Immunol 93:831–835 48. Springer, Berlin Heidelberg New York, p 613 51. Schuberth KC, Golden DBK, Kagey-Sobotka A, 36. Ollert M, Ring J (1999) Prognostische Bedeutung Valentine M, Lichtenstein LM (1981) Evaluation von Immunoblot-Untersuchungen bei Hyme- and treatment of insect sting allergy. In: Ring J, nopterengift-Allergie. Allergologie 22 [Suppl 2]: Burg G (eds) New trends in allergy. Springer, Ber- 578–579 lin Heidelberg New York, p 260 37. Parrish HM (1963) Analysis of 460 fatalities from 52. Settipane GA, Newstead GJ, Boyd GK (1972) Fre- venomous animals in the United States. Am J Med quency of hymenoptera allergy in an atopic and Sci 245:129 normal population. J Allergy Clin Immunol 50:176 38.PrzybillaB,RingJ,GalosiA,GeursenRG,Stickl 53. Stibich AS, Carbonaro PA, Schwartz RA (2001) HA (1986) Bee-venom immunoglobulin for pro- Insect bite reactions: an update. Dermatology phylaxis of anaphylactic reactions during bee 202:193–197 venom immunotherapy (rush hyposensitiza- 54. 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5.1.7 Allergy and the Eye 5.1.7.1 Introduction Allergic eye diseases are sometimes only mar- ginally covered in allergy textbooks, e.g., “rhinoconjunctivitis.” Often, the most common elicitors of allergic conjunctivitis are called “inhalation allergens.”Attempts to classify allergic eye diseases are difficult, partly due to different understandings of diseases as well as lack of knowledgeofhistopathophysiologyofcom- mon conditions. The term “conjunctivitis” – Fig. 5.19. Atopic keratoconjunctivitis used by many allergists as a synonym for type I allergy – only has a descriptive character and is used for clinical conditions of quite different tamines, as well as vasoconstrictors [20]. Rare- pathophysiology; it can be best compared with ly, steroids are necessary. Occasionally, cyclo- the term “dermatitis” in dermatology. oxygenase inhibitors such as ketorolac can help Transparency of the central part of the eye is against itch [20]. the major basic condition for visual function. In cornea, anterior chamber, lens, and vitreous 5.1.7.2.2 Atopic Keratoconjunctivitis body, there are no lymph or blood vessels and no immunocompetent cells. The barrier be- Chronicatopicconjunctivitis(Fig.5.19)often tween blood and chamber fluid as well as blood occurs with other manifestations of atopy and and retina is physiological. The anterior cham- is predominantly observed in medium-aged ber of the eye is an immunologically privileged males;thepathophysiologymaybesimilarto site [2, 5, 6, 11, 14, 21]. Inflammatory reactions that of atopic eczema with increased cellular in- occur mostly in the neighboring tissue, espe- filtrates and high IgE in serum and tear fluid cially conjunctiva, where 90% of the mast cells [6, 9]. The conjunctiva is thickened, rather pale of the eye are situated [2, 20]. and chemotic. Not infrequently, the cornea can be affected, sometimes vascularized. Almost all patients also suffer from intense lid eczema 5.1.7.2 Atopic Eye Diseases with common superinfections. Mast cell stabilizers and glucocorticosteroids are recom- 5.1.7.2.1 Type I Allergic Conjunctivitis mended, generally topically (sometimes also This acute form of allergic conjunctivitis is systemically). classically combined with hay fever, but also in The so-called atopic cataract (prevalence of perennial allergy against airborne allergens up to 25%; in our opinion this has been overes- without nasal symptoms. Pathophysiology cor- timated in the past) is associated with atopic responds to IgE-mediated allergic rhinitis and eczema [2, 21]. This cataract involves the lens allergic bronchial asthma (type I). The clinical epithelium of the anterior lens capsule and can symptoms comprise itching, burning, photo- be clearly differentiated from steroid-induced phobia, immediate hyperemia, and chemosis of posterior subcapsular cataract. the conjunctiva (often aggravated by rubbing) and increased lacrimation. There is no papil- 5.1.7.2.3 Vernal Keratoconjunctivitis lary reaction and no corneal involvement. All the symptoms can be elicited by local hista- This chronically relapsing general conjunctivi- mine application. In animal experiments, this tis occurs predominantly in southern countries typeofallergyisalsocalledocularanaphylaxis oftenseasonallyinspringandsummerandis [2, 6, 22]. Prophylaxis and therapy comprise al- characterized by papillary hyperplasia of the lergen avoidance, mast cell stabilizers, antihis- tarsal upper lid conjunctiva [8]. The disease be- 5.1 Diseases with Possible IgE Involvement 123 gins often before the 10th year and subsides 5.1.7.3 Contact-Allergic Conjunctivitis (Type IV) spontaneously after puberty. In 70–80% of cases, it occurs with other atopic diseases; boys This common form of ocular allergy occurs aremoreoftenaffectedthangirls(3:1).Twoan- with itching, redness and infiltration (some- atomic forms are differentiated: a palpebral times “follicular”) conjunctivitis; often simul- form with typical “cobblestone conjunctivitis” taneous allergic contact dermatitis of the lid of the upper lid and a limbal form (more com- (blepharo-conjunctivitis) is seen. Pathophysio- monincoloredpeopleandAmericanIndians). logically, type IV hypersensitivity correspond- Symptoms are characterized by intense itching to allergic contact dermatitis is present (see ing. Patients feel like “scratching out their Sect. 5.5.2). The most common elicitors are eyes.”Furthermore, burning, redness, swelling, therapeutics (antibiotics, local anesthetics, photophobia and in 50% also corneal involve- preservatives in eyedrops), but also chemicals, ment as superficial keratitis occur. Rarely, ul- cosmetics, and phytoallergens [10, 11, 21]. cus vernalis occurs by loosening of the cornea epithelium through eosinophil products [22]. 5.1.7.4 Blepharitis and Lid Eczema A thick white mucous secretion can be seen containing numerous eosinophils. Histological- The differential diagnosis of blepharitis and lid ly, mast cells are increased, and eosinophils and eczema comprises apart from allergic condi- basophil leukocytes can be found in conjuncti- tions (mostly type IV) and atopic eczema also val epithelium [2]. In the tear fluid, histamine irritative reactions such as cumulative toxic ec- and complement products are elevated [1]. zema (especially when eyedrops or wet wraps There is no clear-cut relation to aeroaller- are applied too frequently), psoriasis, rosacea, gens in spite of sometimes positive prick test seborrheic eczema, as well as infectious dis- results. Therefore, specific immunotherapy eases with inflammatory reactions. mostly remains unsuccessful. As basic therapy, A common disease is microbial-allergic mast cell stabilizers are used, in acute exacer- conjunctivitis: On the basis of an initiating bation steroids, in severe cases even cyclospo- staphylococcal infection, blepharoconjunctivi- rin topically. Occasionally with massive mu- tis occurs with hypersensitivity against bacte- cous secretion, topical administration of muco- rial exotoxins and the formation of conjuncti- lytics (acetylcysteine 10–20%) has been tried. val phlyctena or keratitis marginalis. Incornealinvolvement,surgicalremovalofpa- pillae with subsequent coagulation of the con- 5.1.7.5 Cicatricial Conjunctivitis in Erythema junctiva is helpful. Exsudativum Multiforme or Lyell’s Syndrome 5.1.7.2.4 Giant Papillary Conjunctivitis In rare cases, erythema exsudativum multifor- in Contact Lens Wearers me can occur with massive conjunctival swell- This conjunctivitis is observed in people wearing and cicatricial conjunctivitis (“syndroma ing predominantly soft – sometimes after some muco-cutaneo-oculare Fuchs” or “Stevens- latency also hard – contact lenses as well as Johnson syndrome”). plastic eye prostheses and corresponds clini- In the acute phase, bullous, partly pustular cally and histologically to conjunctivitis verna- changes can be seen, leading to erosions with lis in the early stage. There is no evidence for cicatricial healing. Conjunctiva is affected with atopy. Allergic reactions against unknown al- hyperemia, chemosis, bulla formation, and ul- lergens from contact lenses or cleaning fluid in ceration. Sometimes scarring of the conjuncti- themucusaresuspected[6,17]. va with entropium, trichiasis, and synechia oc- Avoidance of contact lenses is the first step, curs. Secondary disturbance of lacrimation and renewal of contact lenses and changing to and bacterial superinfection lead to severe cor- preservative-free lens fluids (especially en- neal ulcers. The pathophysiology of this reac- zymes!) are recommended. tion is unclear. Apart from a postherpetic form 124 5 Allergic Diseases (and Differential Diagnoses)

(“infect allergy”), drug-induced Stevens-John- high-dose glucocorticosteroids with or without son syndrome has been described with subepi- immunosuppressives, which are sometimes thelial vesiculation, epithelial necrosis, and su- lifelong, are indicated [11, 18, 19]. Enucleation perficial inflammatory reaction [11]. ofthetraumatizedeyeaftertheoccurrenceof A similar condition is observed in toxic epi- sympathetic ophthalmia is rarely helpful. dermal necrolysis (TEN), also called drug- induced Lyell’s syndrome. The pathophysiolo- Endogenous Autoimmune Uveitis. It has been gy is unclear; type III and IV reactions as discussed as to what degree certain forms of well as apoptotic processes are discussed (see endogenous uveitis correspond pathophysio- Sect. 5.7.3 on “Drug Eruptions”). logicallytoanimmunecomplexvasculitis[18]. Early ophthalmologic counseling is the primary recommendation. Hourly nursing with Paraneoplastic Retinopathy. In patients with steroids, topical artificial tears and regular pro- neoplasia or melanoma-associated retinopathy, phylaxis of symblepharon is important; howev- autoimmune processes in the sense of a cross- er, sometimes serious changes cannot be pre- reaction between tumor antigens and retinal vented. Early systemic corticosteroids are con- proteins have been found with the formation of troversial. In cases with corneal involvement antibodies against retinal constituents, leading and opacification, prognosis quoad visum is to disturbance of retinal function. There is little poor. The cornea transplantation in these cases therapy of these conditions, and in occasional is often unsuccessful, synechiolysis shows a cases plasmapheresis has been used. high relapse rate, mucous membrane transplantation is difficult, and sometimes amnion GraftVersusHostReactions. A rare complica- transplants succeed. tion of bone marrow transplantation in leukemia is severe keratoconjunctivitis with opacifi- Ocular (Scarring) Mucous Membrane Pemphi- cation and vascularization of the cornea. goid. The processes in scarring pemphigoid are pathogenetically similar where autoanti- 5.1.7.7 Therapy bodies against basement membrane have been formed.The disease manifests as chronic pro- If possible, treatment should be topical – except gredient scarring conjunctivitis with mostly for the severe autoimmune diseases. Table 5.37 severe corneal complications responding poor- listssomeantiallergiceyedropswithdifferent ly to therapy (local therapy together with sys- drugs. Long-term steroid treatment should be temic immunosuppression with steroids, cyclo- avoided. For lid eczema the new topical calci- phosphamide, dapsone, etc.). neurin inhibitors (tacrolimus and pimecrolimus) (see Sect. 5.5.3) are promising. 5.1.7.6 Eye Diseases of Questionable Allergic Origin Sympathetic Ophthalmia. Sympathetic oph- Table 5.37. Antiallergic eyedrops thalmia is a diffuse granulomatous inflamma- Active substances Flurbiprofen tion of the uvea of both eyes – also of the unlesi- DSCG (disodium Diclofenac cromoglycate) onal eye – as a consequence of a perforating Glucocorticosteroids Lodoxamide trauma or intraocular surgery and represents a Betamethasone Nedocromil Dexamethasone classicautoimmunedisease[12].Theorganism Azelastine Fluorometholone is sensitized against proteins with which the Emedastine Prednisolone Levocabastine immune system because of the privileged ana- Rinaxolone tomical site was previously not in contact. The Non-steroidal anti-inflam- time interval between primary trauma and oc- matory drugs (NSAIDs) currence of sympathetic ophthalmia is variable; Ketorolac 90% of cases occur within 1 year. The resulting Indometacin uveitis may destroy the eye. Therapeutically, 5.2 Allergic Diseases by Cytotoxic Antibodies (Type II) 125

References 12. Fuchs E (1905) Über sympathisierende Entzün- dung. Albrecht v. Graefes Arch Ophthal 61:365 1. Abelson MB, Schaefer K (1993) Conjunctivitis of 13. Hatinen A, Terasvirta M, Fakj JE (1985) Contact allergic origin: immunologic mechanisms and allergy to components in topical ophthalmologic current approaches to therapy. Surv Ophthalmol preparations. Acta Ophthalmol 63:424–426 38:115–132 14. Jay JL (1981) Clinical factors and diagnosis of 2. Allansmith MR (1982) The eye and immunology. atopic keratoconjunctivitis and the effect of treat- Mosby, St. Louis ment with sodium cromoglycate. Br J Ophthal 3. Allansmith MR, Ross RN (1986) Ocular allergy 60:335–340 and mast cell stabilizers. Surv Ophthalmol 15. McGill J (2000) Conjunctival cytokines in ocular 30:229–244 allergy. Clin Exp Allergy 30:1355–1357 4. Anderson DF (1996) The conjunctival late-phase 16. Montan PG, Biberfeld PJ, Scheynius A (1995) IgE, reaction and allergen provocation in the eye. Clin IgE receptors and other immunocytochemical Exp Allergy 26:1105–1107 markers in atopic and nonatopic patients with 5. Bialasiewicz AA (1998) Augenheilkunde. In: Heppt vernal keratoconjunctivitis. Ophthalmology 102: W, Renz H, Röcken M (eds) Allergologie. Springer, 725–732 Berlin Heidelberg New York, pp 262–271 17. Neuhann T (1983) Papillomatös-hyperplastische 6. Bielory L (2000) Allergic and immunologic disor- Konjunktivitis durch Kontaktlinsen. Mbl Augen- ders of the eye, part II: ocular allergy. J Allergy heilkunde 8:46–50 Clin Immunol 106:1019–1032 18. RingI,DechantW,SeifertJ,LundO-E,GretteJ-H, 7. Bonini S, Bucci MG, et al. (1990) Allergen dose re- Stefani FH, Brendel W (1978) Immunosuppres- sponse and late symptoms in a human model of sion with antilymphocyte globulin (ALG) in the ocular allergy. J Allergy Clin Immunol 86/6: treatment of ophthalmic disorders. Ophthal Res 869–876 10:82–97 8. Bonini S, Bonini S, Lambiase A, et al. (2000) Ver- 19. Silverstein AM, O’Connor GR (eds) (1979) Immu- nal keratoconjunctivitis revisited: a case series of nology and immunopathology of the eye. Mas- 195 patients with long-term followup. Ophthal- son, New York mology 107:1157–1163 20.SolomonA,Pe’erJ,Levi-SchafferF(2001)Ad- 9. Foster CS, Rice BA, Dutt JE (1991) Immunopa- vances in ocular allergy: basic mechanisms, clini- thology of atopic keratoconjuncitivitis. Ophthal- cal patterns and new therapies. Curr Opin Aller- mology 98:1190–1196 gy Clin Immunol 1:477–482 10. Friedlaender MH (1988) Contact allergy and tox- 21. Theodore FH, Schlossmann A (1958) Ocular al- icity in the eye. Int Ophthalmol Clin 28/4: 317–320 lergy. Williams & Wilkins, Baltimore 11. Friedlaender MH (1993) Allergy and immunolo- 22.TrocmeSD,AldaveAJ(1994)Theeyeandtheeo- gyoftheeye.Raven,NewYork sinophil. Surv Ophthalmol 39:241–252

AnotherformoftypeIIreactionisthehyper- 5.2 Allergic Diseases by Cytotoxic acute rejection after organ transplantation, me- Antibodies (Type II) diated by specific antibodies [5]. Theoretically, some autoimmune diseases 5.2.1 Mechanisms of Antibody-Mediated also have to be classified under this type of re- Cytotoxicity action when organ-specific antibodies play a The cytotoxic reaction (type II) is mediated by role (certain forms of glomerulonephritis = antibodies with or without complement activa- Masugi nephritis, pemphigus vulgaris, bullous tion directed against markers on hematologic pemphigoid, Goodpasture’s syndrome, auto- cells. The classical type II reaction is the trans- immune hemolytic anemia). fusion reaction (hemolytic reaction caused by Cytotoxic antibodies may destroy cells via natural mostly IgM and complement-binding different mechanisms (Fig. 5.20). antibodies) against foreign blood group anti- ) Complement-mediated cytotoxicity gens [10]. The antigens of the AB0 system differ Binding of the antibody molecule to the by the terminal sugar residue on a common cell surface leads to activation of com- glycolipid (paragloboside) with a terminal fu- plement via the classical pathway with cose (= H-antigen in group 0), to which either subsequent cell lysis (activation of C6 to N-acetyl-D-galactosamine (group A) or D-ga- C9). lactose(groupB)arebound[29]. 126 5 Allergic Diseases (and Differential Diagnoses)

Complement- Target cell + C mediated cytolysis

Antiboy-dependent Killer cell Target cell cellular cytotoxicity (ADCC)

Phago- Target cell Immune phagocytosis cyte Fig. 5.20. Mechanisms of allergic cytotoxicity

14y various drugs, weeks Ax. H. 70 J. sometimes analgetic 0123 ® 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 / µl 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])

) Antibody-dependent cellular cytotoxicity mechanisms such as T-cell-mediated cyto- (ADCC) toxicity (perforin, etc.). Here the antibody acts together with the ) Antibody-dependent phagocytosis (im- so-called killer cell, to which it is bound. mune phagocytosis) These cells represent a subgroup of lym- Here cytotoxic antibodies are bound via phocytes with large granules showing Fc-receptors to the surface of macrophages. neither typical T- nor B-cell characteristics. After binding of antigens on the target cell, The cell destruction follows similar the latter will be phagocytosed. 5.2 Allergic Diseases by Cytotoxic Antibodies (Type II) 127

These mechanisms are best investigated in pe- administration;IgGcanbedetectedonthe ripheral blood cells; however, it is speculated surface of erythrocytes without comple- thattissuedestructioninparenchymatousor- 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- thetargetcellsonlyarelysedthroughsec- 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.”Thismechanismisthemost common form of drug-induced allergic 1. “Hapten” type. Here the drug is bound to cytopenia. The reactions are acute after thecellsurfaceleadingtoanewantigen; 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- sisoccursextravascularlyafterhigh-dose

Fig. 5.22a,b. Clinical manifestations of allergic thrombocytopenic purpura 128 5 Allergic Diseases (and Differential Diagnoses)

ment of a new “autoantigen.” Autoimmune only in 0.7% of patients does anemia develop diseasesofthebloodmaybetriggered [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 thehaptentypeoccurs.ThedirectCoombs’ acuteformmostlyviathehaptenmechanism. 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,andputridtonsillitisdevelopswith 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. nulocytopeniasduetobonemarrowdepres- 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

transfusion of PLA1-positive blood occurring 5.2.2.3 Allergic Thrombocytopenia with high antibody titers against PLA1 [14, 26]. The prototype of allergic hematologic disease Equally important is the exclusion of idiopathic isapronalidpurpura,firstdescribedbyAckro- thrombocytopenic purpura (ITP), where se- yd [1] through an immune complex type reac- rum does not induce platelet changes in nor- tion. Today, the most common elicitors are list- mals. Therapeutically, glucocorticosteroids to- ed in Table 5.40. Figure 5.21 shows a typical gether with high-dose immunoglobulins are course of a thrombocytopenia in allergy given. against quinine [20] in a mixed analgesic prep- Besides allergic and toxic mechanisms, also aration. Clinically, apart from a non-inflamma- enzyme defects can induce bone marrow de- tory purpura (Fig. 5.22a,b), sweating attacks, pression via an idiosyncrasy (see also “Pseudo- dyspnea, fever with shivering, and mucosal allergic Reactions,” Sect. 5.7.3). It has been at- bleeding together with lowered platelet counts tempted to measure this in vitro by the inhibi- aretypical.Thediagnosiscanbeconfirmedin tory effect of certain substances on bone mar- vitro using patients’ serum together with the row stem cells [9]. suspected drug and adding it to a platelet suspension and measuring changes in platelet 5.2.2.4 Heparin-Induced Thrombocytopenia function (e.g., aggregation, serotonin, or platelet factor 3 release) with the adequate controls. The heparin-induced thrombocytopenia (HIT) Treatment consists of immediate withdraw- is of major practical importance. Two types are alofthedrugandhigh-doseglucocorticostero- differentiated [2]: ids together with i.v. immunoglobulins (0.4 g/ HIT 1, spontaneously reversible via inhibi- kg over 5 days) [14]. Sometimes, fresh blood tion of platelet adenylate cyclase activity and transfusion may be indicated. Continuation of without major complications. therapy with vital drugs under systemic gluco- HIT 2, which is more dangerous, developing corticoids has been reported [28]. after 5–14 days and occurring with thrombo- In differential diagnosis, post-transfusion cytopenia,butatthesametimeincreasingthe purpura should be considered developing risk of thrombosis and embolization. Patho- mostly in PLA1-negative women 1 week after physiologically, IgG antibodies against a multi- molecular complex consisting of heparin and platelet factor 4 cause HIT 2 [7, 21]. The size Table 5.40. Drugs eliciting allergic thrombocytopenia and degree of sulfatation of the heparin mole- (selection) cule seem to be crucial in the elicitation of HIT Alprenolol Metamizol 2. The mechanism corresponds to an immune Allylcarbamide Novobiocin complex cytotoxic mechanism through an Fc * (e.g., Sedormid) Para-aminosalicylic acid RII activation. Aminopyrine (PAS) Acetacolamide Penicillamine The strong platelet-stimulating effect leads Acetylsalicylic acid Phenacetin to microparticles from lysed platelets, which Carbamazepine Phensuximide circulate in the blood and enhance thrombosis Cephalotin Phenylbutazone [21]. Quinine and quinidine Procainamide Immediate withdrawal of heparin is the first Chloramphenicol Reserpine Chloroquine Rifampicin step of therapy! Changing to coumarin in the Chlorothiazide Salicylamide first few days is contraindicated since this will Digitoxin Stibophen further increase risk of thrombosis. For thera- Furosemide Sulfonylurea py, low molecular and low sulfatized heparino- Gold salts Tet rac ycline Heparin Thiazide ids may be tried such as danaparoid, recombi- Hydantoin Tolbutamide nant hirudin or a synthetic thrombin inhibitor Isoniazid Trimethoprim argatroban [18, 24]. Levodopa Valproate Meprobamate 130 5 Allergic Diseases (and Differential Diagnoses)

the mechanisms are unclear. Apart from classic 5.2.2.5 Eosinophilia immune complex nephritis (serum nephritis) After certain drugs (Table 5.41), blood eosino- (see Sect. 5.3), specific antibodies against al- philia, sometimes without incompatibility tered renal antigens such as tubular basement symptoms,developspossiblyduetoincreased membrane constituents [8] have been re- interleukin-5 production from T lymphocytes. ported. Rarely, an allergic basis of nephrotic The prognostic relevance is unclear; for safety syndrome (gold, penicillamine, captopril, lithi- reasons, sometimes withdrawal of the drug is um) with positive lymphocyte transformation recommended. has been reported (see also Sect. 5.7.4 on “Drug-Induced Exanthematous Eruptions”). Table 5.41. Drugs inducing eosinophilia Allopurinol Isoniazid References Aminosalicylic acid Kanamycin Cephalosporins Nalidixic acid 1. Ackroyd JF (1952) Sedormid purpura: An immu- Chloral hydrate Nitrofurantoin nological study of drug hypersensitivity. Progr Dacarbazine Penicillamine Allergy 3:531 Digitalis Rifampicin 2. Aster RH (1995) Heparin-induced thrombocyto- Erythromycin Sulfonamides penia and thrombosis. N Engl J Med 332: 1374–1376 3. Belongia EA, Hedberg CW, Gleich GJ (1990) An Eosinophilia Myalgia Syndrome. The patho- investigation into the cause of the eosinophilia genesis of the eosinophilia myalgia syndrome myalgiasyndromeassociatedwithtryptophan (EMS) described in 1989 after intake of L-tryp- use. N Engl J Med 323:357–365 tophan for depression and sleeplessness is not 4. Berg PA, Becker EW (1995) The lymphocyte transformation test – a debated method for the clear. In epidemiological studies comparing evaluation of drug allergic hepatic injury. J Hepa- different batches of the drug, an impurity (peak tol 22:115–118 E) with 1.1 ethylidene-bis-tryptophan was de- 5. Brendel W, Ring J (1980) Transplantationsimmu- termined as elicitor. Apart from scleroderma- nologie. In: Filipp G (ed) Allergologie. Bana- like changes and neuropathy, signs of myositis schewski, Munich, p 436 6. Dukes MNG (1998) Drug-induced hepatic injury. and in 50% autoantibodies with extremely ele- Elsevier, Amsterdam vated eosinophil counts in the peripheral blood 7. Greinacher A, Potzsch B, Amiral J, Dummel V, were observed (1,000–36,000/µl) [3, 27]. Eichner A, Mueller-Eckhardt C (1994) Heparin in associated thrombocytopenia: isolation of the antibody and characterization of a multimolecu- larPF4-heparincomplexasthemajorantigen. 5.2.3 Allergic Cytotoxic Organopathies Thromb Haemost 71:247–251 5.2.3.1 Drug-Induced Hepatitis 8. Jäger L, Merk HF (1996) Arzneimittel-Allergie. Gustav Fischer, Jena After certain drugs, antibodies against liver 9. Kelton JG, Huang AT, Mold N (1979) The use of in vitro techniques to study drug-induced pancyto- cells and constituents (e.g., microsomes, cytopenia. N Engl J Med 301:621 chromeP450isotypes)maydevelopwithcyto- 10. Landsteiner K (1901) Wien Klin Wochenschr 14: toxic effects on hepatocytes detectable in vitro 1132 [4, 11, 12, 17]. Drugs under discussion are halo- 11. Manns M (1989) Autoantibodies and antigens in thane, chlorpromazine, some anticonvulsants, liver diseases – updated. J Hepatol 9:272–280 12. Maria VAJ, Pinto L, Victorino RMM (1994) Lym- thyreostatics, as well as rarely antibiotics (sul- phocyte reactivity to ex-vivo drug antigens in fanomides, erythromycin estolate) [6]. drug-induced hepatitis. J Hepatol 21:151–158 13. Mueller-Eckhardt C (1988) Ex vivo drug antigens. Are drug-induced immunoreactions such as im- 5.2.3.2 Drug-Induced Nephropathy munohemolytic anemia related to genetic control?In:EstabrookRW,LindenlaubE,OeschF, After certain drugs, acute tubular disturbance Weck AL de (eds) Toxicological and immunologi- of the kidney, sometimes occurring with exan- cal aspects of drug metabolism and environmen- thematous drug eruptions, has been reported; tal chemicals. Schattauer, Stuttgart, pp 329–342 5.3AllergicDiseasesduetoImmuneComplexes 131

14. Mueller-Eckhart C, Kuenzlen E, Thilo-Korner D, dependent immune hemolytic anemia. N Engl J Pralle H (1983) High-dose intravenous immuno- Med 313:469–474 globulin for post transfusion purpura. N Engl J 23. Salama A, Mueller-Eckhardt C (1992) Humane- Med 308:287 mediated blood cell dyscrasias related to drugs. 15. Mueller-Eckhardt C, Salama A (1987) Immunhä- Semin Hematol 29:54–63 molytische Anämien durch Medikamente. Dtsch 24. Schiele F, Vuillemenot A, Kramarz P, Kieffer Y, Ärztebl 84:232–234 Anguenot T, Bernard Y, Bassand JP (1995) Use of 16. Neftel KA, Wälti M, Spengler H, Felten A von, recombinant hirudin as antithrombotic treat- Weitzmann SA, Bürgi H, Weck AL de (1981) Neu- ment in patients with heparin induced thrombo- tropenia after penicillins: toxic or immune-medi- cytopenia. Ann J Hematol 50:20–25 ated? Klin Wochenschr 59:877 25. Shulman NR, Aster RH, Leitner A, Hiller MC 17. Pessayre D (1995) Mecanisme de hepatites medi- (1961) Immunoreactions involving platelets. V. camenteuses Gastroenterol. Clin Biol 19:47–56 Posttransfusion purpura due to a complement- 18. Pihusch R (1998) Die Heparin-induzierte Throm- fixing antibody against a genetically controlled bozytopenie. Phlebologie 27:111–116 platelet antigen. J Clin Invest 40:1597 19. Plötz G, et al. Hypereosinophilie-Syndrom. Haut- 26. Shulman NR (1972) Immunologic reactions to arzt drugs. N Engl J Med 286:508–512 20. Raif W, Schubothe H (1979) Durch körperfremde 27. Varga J, Uitto J, Jimenez SA (1992) The cause and Substanzen induzierte immunhämatologische pathogenesis of the eosinophilia-myalgia syn- Erkrankungen. Allergologie 2:192 drome. Ann Int Med 116:140–147 21. Raskob GE, George JN (1997) Thrombotic com- 28. Wanamaker WM, Wanamaker SJ, Celesia GG, et plications of antithrombotic therapy: a paradox al. (1976) Thrombocytopenia associated with with implications for clinical practice. Ann Intern long-term levodopa therapy. J Am Med Assoc Med 127:839–841 235:2217 22. Salama A, Mueller-Eckhardt C (1985) The role of 29. Zweiman B, Patten E (1982) Immunohematologic metabolite-specific antibodies in nomifensine- diseases. J Am Med Assoc 248:2677–2682

Clinical examples are dextran anaphylaxis (see 5.3 Allergic Diseases due to Immune Sects. 5.1.4, 5.7). Complexes

5.3.1 Immune Complex Anaphylaxis 5.3.2 Serum Sickness Binding of antigen by specific antibodies leads Serum sickness was first described by von Pir- to immune complexes which generally have a quet and Schick, giving rise to the term “aller- protective function leading to clearance of the gy” in the following year (see Chap. 1), and rep- antigen from the organism through activation resentstheprototypeofimmunecomplexdis- of the mononuclear phagocyte system [31]. ease[16].Thishasbeenforgottenbysome Furthermore, immune complexes may have a younger allergists. Within 7–14 days after anti- regulating function in immune response, espe- gen administration, circulating antigen anti- cially complexes from anti-idiotype antibodies body complexes [5, 12] lead to complement ac- and antibodies against environmental antigens tivation and activation of Fc * receptors on in- (network theory according to Jerne). flammatory cells with release of mediators and However, circulating immune complexes proteases (Fig. 5.23) and clinical symptoms may induce disease, when by activation of com- suchasfever,urticaria,arthralgia,lymphnode plement or Fc * receptors pathogenic reactions swelling, nephritis, endocarditis, and vasculitis are triggered [17, 28]. [1, 6, 16]. In parallel with the decrease in con- In the sensitized organism (IgG or IgM anti- centration of free antigens and the increase in bodies) antigen administration (mostly paren- concentration of specific antibodies, the clini- terally) may induce anaphylactic immediate re- cal symptoms occur in the phase of circulating actions clinically manifesting sometimes even immune complexes (Fig. 5.24). This principle more acutely and dramatically than IgE-medi- was called “toxic body” by von Pirquet [16]. ated reactions and described under the term Crucial for the elicitation of serum sickness is “immune complex anaphylaxis” [1, 20, 26]. thedoseofantigenapplied;afterhighdosesof 132 5 Allergic Diseases (and Differential Diagnoses)

Antigen Antibody complex

Complement Platelets Macrophages

PMN C5a

Proteases Mast cell- Micro- Serotonin, Cytokines activation thrombi Prostaglandins (IL-1, TNF) Fig. 5.23. Sequelae of the appearance of circulating immune complexes

agnosis and therapy, new problems have aris- Complement en. Major elicitors are drugs, especially xenoge- Vasculitis neic proteins (e.g., antitoxins or antilympho- Arthritis Nephritis cyte antibodies) [18, 19, 25]. Similar symptoms, however, may be observed due to bacteri- Antigen al, viral or tumor antigens. Serum sickness af- free ter insect stings and allergen-specific immuno- antibody therapy has been reported [10]. Serumlevel Circulating immune complexes are detectable under physiological conditions in healthy Immune- complexes individuals (background value of 10–20 µg/ml aggregated gammaglobulin). These clinically silent immune complexes may represent idio- 2 4 6 8 10 12 14 16 18 20 type-anti-idiotype complexes, as shown in Antigen Days healthy volunteers with cytotoxic antibodies Fig. 5.24. Immunologicreactioninapatientwithex- against melanocytes and anti-idiotypic anti- perimentally induced serum sickness (according to F. bodies [14]. Dixon) Commercial plasma protein solutions (human serum albumin, but also unmodified foreign serum in 80–100% of patients serum gammaglobulin) contain a high percentage of sickness can be expected. aggregated proteins able to elicit serum sick- Different types of immune complexes can be ness-like symptoms [19]. By separation of distinguished according to solubility (<106 D= these aggregates, the immunogenicity of xeno- soluble, >106 D = hardly soluble complexes). geneic protein solutions can be decreased and For the mechanism of complement activation, the compatibility dramatically improved [19]. refer to Chap. 2, “Pathophysiology.” Induction of immunological tolerance has The detection of activated complement been demonstrated against xenogeneic anti- products, complement consumption, or circu- lymphocyte globulin successfully using highly lating immune complexes has diagnostic rele- purified monomeric xenogeneic IgG [18]. vance [12, 24, 30]. In serum sickness by animal sera (e.g., snake While serum sickness was a major problem venom), horse IgG has stronger immunogenic- at the beginning of the 20th century (animal se- itythanhorsealbuminasdemonstratedinim- ra as antitoxins), it has almost been forgotten in mune elimination by accelerated elimination in recent decades. However, today with the devel- sensitized organisms [12, 25]. opment of new biologicals of animal origin After serum sickness has subsided, often (monoclonal antibodies from the mouse) in di- positive rheuma factors can be demonstrated 5.3AllergicDiseasesduetoImmuneComplexes 133

(4–6 weeks), which, however, do not contain Table 5.42. Classification of vasculitis according to specificantigeninthecryoprecipitatepossibly 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 Schönlein-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 ) Serum sickness circulating immune complexes in mild antigen ) excess are not eliminated properly by the retic- M. Beh¸cet ) Erythema elevatum et diutinum uloendothelial system and complement activa- ANCA-associated/-mediated tion with local attraction and activation of neu- ) Wegener’s 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.” ) Goodpasture’s 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 ) Takayasu’s arteriitis ) Polymyalgia rheumatica

Fig. 5.25. Leukocytoclastic vasculitis. Postcapillary venules with infiltration of the vessel wall and peri- Fig. 5.26. Demonstration of C3 precipitates in the di- vascular infiltrate with neutrophils (1:650) (reprinted rect immunofluorescent antibody test performed on with the consent of Prof. Dr. H.H. Wolf [32]) a patient with allergic vasculitis 134 5 Allergic Diseases (and Differential Diagnoses)

positsofC3,IgG,andIgMcanbefound.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 pronounced in the lower extremity (hydrostat- ) Hemorrhagic type (corresponding to purpura Schönlein-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) which does not disappear under pressure with Vitamin deficiency (vitamin C, scurvy)

Fig. 5.27. Allergic vasculitis (hemorrhagic type) Fig. 5.28. Allergic vasculitis (papulonecrotic type) 5.3AllergicDiseasesduetoImmuneComplexes 135

Table 5.44. Therapy of immune complex diseases

Antihistamines (H1 and H2 antagonists combined, serotonin antagonists?) Mast cell stabilizers Glucocorticosteroids Inhibitors of neutrophil function (e.g., colchicine, dapsone, clofazemine) Inhibitors of TNF, pentoxiphyllin, infliximab Prostaglandin E2? Plasmapheresis Cytostatics (cyclophosphamide, cyclosporin A)

Cytostatics (cyclophosphamide) can be used as well as immunosuppressives (cyclosporin). Agents with inhibitory effects on neutrophils areusefulsuchascolchicine,dapsone,orclofa- zemine [8, 29]. Possible newer approaches comprise prostaglandin E2 or TNF-inhibiting pentoxyphyllin or infliximab [33].

References

1. Becker EL, Austen KF (1966) Mechanisms of immunologic 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,gastrointestinaltract,andheart) 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.DixonFJ,VasquezJJ,WeigleWO,CochraneCG Therapy. The avoidance of eliciting noxious (1958) Pathogenesis of serum sickness. Arch Pa- agentsaswellastreatmentoftheunderlying thol 65:18 disease is vital (Table 5.44). 7. EisenmannA,RingJ,vonderHelmD,MeurerM, 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 18. Ring J, Seifert J, Lob G, Coulin K, Angstwurm H, 29. Theissen U, Luger TA, Schwarz T (1996) Erfolg- 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 proved compatibility of ALG therapy by applica- immune complexes; techniques and implications. tion of aggregate free globulin. Int Arch Allergy Hosp Pract 15:107 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 natürlicher und künstlicher 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

5.4 Hypersensitivity Pneumonitis eases, hypersensitivity pneumonitis is not a rare disease [6, 7, 12, 13, 17, 34]. (Allergic Alveolitis)

5.4.1 Definition 5.4.2 Clinical Symptoms and Diagnosis Hypersensitivity pneumonitis (exogenous al- The first description dates back to Ramazzini lergic alveolitis) (previously also classified un- (1718) as pneumonia-like disease in merchants der “pneumoconioses”) represents an allergic after contact with grain dust. As allergic dis- disease of the alveoli and terminal bronchi ease, farmer’s lung was classified by Pepys [24] against fine dusty, mostly organic material oc- and bagassosis by Salvaggio [28] in the 1960s curring with precipitating antibodies. Hyper- after first reports by Gronemeyer in 1951. sensitivity pneumonitis has aspects of both An acute and chronic form are distin- type III and IV reactions with lymphocytic and guished.Intheacuteform,4–6hafterexpo- granulomatous reactions. In 2% of airway dis- sure dyspnea with tachypnea, coughing (some- 5.4 Hypersensitivity Pneumonitis (Allergic Alveolitis) 137

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).Thefamilyhistoryofatopyisnega- Weig ht loss 31 % tive.Inthebronchialprovocationtest,thereac- 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. Ver t igo 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 5.47. Differential diagnoses of hypersensitivity times itchy throat), fever, fatigue, myalgia, pneumonitis headache, tightness of the chest, as well as spu- Toxic lung disease tum (sometimes hemoptoe) develop. In the Organic toxic alveolitis auscultation, a fine vesicular noise is heard, (“organic dust toxic syndrome,” ODTS) changing to rough basal noises and the typical Byssinosis end-expiratory rattling noise followed by fi- Harvester’s fever Pig breeder’s fever brotic noises in inspiration (sclerosiphony) Humidifier fever (Table 5.45). Anorganic toxic alveolitis Chest X-ray shows small patches of nodular Metal smoke fever shadows (1–3 mm) and milky opacification. Polymer smoke fever Silo worker’s disease Lung function shows restrictive ventilatory disturbanceaswellasdisturbeddiffusionca- Autoimmune alveolitis pacity (diminished for CO2). Decreased arterial Interstitial lung disease oxygen concentrations are found, especially af- e.g., sarcoidosis ter exercise [34]. Pneumoconioses (berylliosis, asbestosis, silicosis)

Table 5.46. Differential diagnosis between allergic bronchial asthma and hypersensitivity pneumonitis Symptoms Allergic asthma Hypersensitivity pneumonitis Symptoms Wheezing,acuteattacks Dyspnea,fever,cough,generalsymptoms 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)

ODTS HP Table 5.48. Differential diagnosis between Exposure Massive Little to moderate “organic dust toxic syn- Selection All exposed Certain individuals drome” (ODTS) and hy- Course 1 day Days to weeks persensitivity pneumo- Chest X-ray Negative Infiltrates nitis (HP) IgG antibodies ± ++ Lung function Normal to mild restriction Strong restriction BAL 3 d PMIV increased Lymphocytosis

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 hypersensitivity 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 antibodies (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.Theimmunecomplexesthusformed 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, furrier’s 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- diatereaction–theoccurrenceofapapuleafter vascular infiltrates of neutrophil and eosinophil 6–12hupto24hischaracteristic(80%inhy- granulocytes predominate, which transmigrate persensitivity pneumonitis, 50% in exposed through the alveolar walls (type III reaction). In individualswithdemonstrableantibody,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

Alveolar space Interstitium

Antigen IgG

IgG

CD8 B Mo T (CD4) IL-8 TNF

Fig. 5.30. Pathophysiolo- gy of exogenous allergic alveolitis PMN kocytoclastic vasculitis with immunoglobulin The classic example of hypersensitivity and complement deposits in direct immunoflu- pneumonitisisfarmer’slungelicitedbybacte- orescence can be found. Unfortunately, skin ria, especially thermophilic actinomycetes with tests are not often routinely performed since spores between 0.8 and 2 µm in diameter, able allergen extracts are poorly purified and stan- to penetrate alveolar spaces. These microor- dardized; false-positive reactions are common. ganisms are especially dominant in moldy hay Bronchial provocation tests after exposure with high humidity and temperature (45%). (mixing dust or using nebulizers) should be One gram of moldy hay may contain 108 spores performed under inpatient conditions. of Micropolyspora faeni. Farmer’s lung is more common in humid regions in dairy farmers andlatewinterwhenthefreshhayhasalready 5.4.4 Allergens and Common Forms been used. of Hypersensitivity Pneumonitis In central Europe, hypersensitivity pneu- Organic allergens of animal or plant origin, but monitisiscommoninbirdbreederswithanti- also chemicals and drugs, are common elicitors bodies against allergens in bird droppings (but of hypersensitivity pneumonitis (Table 5.50) also feathers, serum, and eggs), mostly gam- [2, 8, 9, 10, 11, 19, 25, 28, 29, 31, 33, 34, 40]. maglobulins and albumin with cross-reactivi- 140 5 Allergic Diseases (and Differential Diagnoses)

Table 5.50. Hypersensitivity pneumonitis: allergens and diseases (according to [34]) Allergen (most common) Diseasea Allergen source Bacteria Micropolyspora faeni, Farmer’s lung Damp hay, grain Thermoactinomyces vulgaris Thermoactinomyces sacchari Humidifier lung Humidifiers and air conditioners “Multiple” microbial agents Water vapor lung bagassosis Moldy sugarcane Tobacco worker’s lung Tobacco leaves Fungal waste Moldy cotton Enzymes Alcalase, maxatase Washing powder lung Enzymes from B. subtilis Fungi Alternaria and others Wood cutter’s lung Moldy wood Alternaria Paper worker’s lung Moldy paper mix Cryptostoma corticale Maplebark lung Moldy maple bark Penicillium frequentans Cork worker’s lung (suberosis) Cork (Portugal) Penicillium casei Cheese washer’s lung Moist cheese storages Penicillium brevicompactum Tomato breeder’s lung Tomatoes Aspergillus clavatus Malt worker’s lung Malt in breweries Aspergillus fumigatus Espartosis Fiber production from esparto grass Streptomyces olivaceus New Guinea lung Straw roofs Cephalosporium trochoderma Textile worker’s lung Textile fibers Botrytis cinerea Winemaker’s lung Grapes Various fungi “Coptic lung” Mummies Pleurotus florida Fungiworker’slung Ediblefungi(oystermushroom) Mixed fungi Fruit farmer’s lung Fruit in cooling rooms Moldy lung Organic waste, moldy cotton Plant allergens Wood fiber Wood dust alveolitis Wood cutting dust Animal allergens Bird dust (feathers, feces, egg) Bird breeder’s lung Bird droppings, bed feathers Bread beetle protein (Sitoph. gran.) Bread beetle’s lung Grain and flour Fish proteins Fish flour lung Miller’s lung Pig epithelium Pig hair lung Animal feeding Rat serum antigens Animal keepers Rat urine Pituitary extracts Pituitary sniffer’s lung Pancreatin Pancreatin powder Pharmaceutical industry Silkworm proteins Silk breeder’s lung Silkworm Crustacea dust Crustacean lung Pearl oyster handling Drugs Nitrofurantoin Hydrochlorothiazide Carbamazepine Amiodarone Phenytoin Gold salts Chemicals Isocyanates Isocyanate alveolitis Plastic production Acid anhydrides Chemicals Plastic, glues Silicon implants a Theterm“alveolitis”shouldbepreferredtothecommonterm“lung” 5.4 Hypersensitivity Pneumonitis (Allergic Alveolitis) 141 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 hypersensitivity 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 ingwork[18].Anewmaskisthe“DustMaster”; 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), medicationis,however,noalternativetoaller- 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 bronchial 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. Bäck 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. 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Rylander R, Malmberg P (1992a) Non-infectious Klein Med 44:1407 fever: inhalation fever or toxic alveolitis? Br J In- 9. Heiner DC, Snears JW, Kniker WT (1962) Multi- dustr Med 49:296 ple precipitins to cow’s milk in chronic respirato- 28. Salvaggio JE, Buechner HA, Seabury H (1966) Ba- ry disease. Am J Dis Child 103:634 gassosis I. Precipitins against extracts of crude 10. Hinojosa M (2001) Stipatosis or hypersensitivity bagasse in the serum of patients with bagassosis. pneumonitis caused by esparto (Stipa tenacissi- AnnInternMed64:748 ma) fibers. J Invest Allergol Clin Immunol 29. Sastre J, Ibanez MD, Lopez M, Lehrer SB (1990) 11:67–72 Respiratory and immunological reactions among 11. Jelke G (1986) Krank durch Fortschritt. Exposi- Shiitake (Lentinus edodes)mushroomworkers. tionelle Besonderheiten bei der exogen-allergi- Clin Exp Allergy 20:13 schen Alveolitis. Allergologie 9:137 30. Schatz M, Patterson R (1977) Immunopathogene- 12. Kroidl RF, Nowak D, Seysen U (1994b) Exogen- sis of hypersensitivity pneumonitis. J Allergy allergische Alveolitis: Probleme und Fehler bei Clin Immunol 60:27 der Begutachtung. Allergologie 17:75 31. Schulz KH, Felten G, Hausen BM, Noster U (1974) 13. Malmberg P, Rask-Andersen A (1993b) Organic Allergy to spores of Pleurotus Florida.Lancet dust toxic syndrome. Semin Resp Med 14:38 I:625 14. Marinkovich VA (1975) Hypersensitivity alveoli- 32. Schultze-Werninghaus G, Rust M (1988b) Asth- tis. J Am Med Assoc 231:944 ma bronchiale und allergische Alveolitis durch 15. McCarthy DS, Pepys J (1971) Allergic broncho- Berufsallergene. Allergologie II:437 pulmonary aspergillosis. Clinical immunology: 33. Seeliger HPR, Sühler H (1975) Farmerlunge beim 1. Clinical features, 2. Skin, nasal and bronchial Tier. Berl Münch Tierärztl Wochenschr 88:163 tests. Clin Allergy 1:261, 415 34. Sennekamp H-J (1998) Exogen allergische Alveo- 16. McSharry C, Banham SW, Boyd G (1985) Effect of litis. 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Am Rev Resp Dis 148:396 simulating cardiac pulmonary edema caused by 38. von Essen S, Robbins RA, Thompson AB (1990) nitrofurantoin. N Engl J Med 273:1185 Organic dust toxic syndrome. Clin Toxicol 28:389 20. Newman-Taylor A, Pickering CAC, Turner-War- 39. Warren CPW (1977) Extrinsic allergic alveolitis: a wick M, Pepys J (1978) Respiratory allergy to a disease commoner in non-smokers. Thorax factor humidifier contaminant presenting as py- 32:567–569 rexia of undetermined origin. Br Med J:II 40. Weck AL de, Gutersohn J, Bütikofer E (1969) La 21. Olenchock SA, May JJ, Pratt DS, et al. (1990) Pres- maladie des laveurs de fromage (“Käsewascher- ence of endotoxin in different agricultural envi- krankheit”): une forme particuli`ere du syndrome ronments. Am J Industr Med 18:279 du poumon de fermier. Schweiz Med Wochenschr 22. Parkers WR (1994) Occupational lung disorders. 99:872 Butterworth, London 41. Westphal O, Lüderitz O (1961) Bacterial endotox- 23. Patterson R (1978d) Studies of hypersensitivity ins. J Med Pharma Chem 4:497 lung disease with emphasis on a solid-phase ra- 42. Wild LG, Lopez M (2001) Hypersensitivity pneu- dioimmunoassay as a potential diagnostic acid. J monitis: A comprehensive review. J Invest Aller- Allergy Clin Immunol 61:216 gol Clin Immunol 11:3–15 5.5 Dermatitis/Eczema 143

ma” in its 1,400 years of history has served a 5.5 Dermatitis/Eczema useful life and is understood by lay people [2, 7, 49, 68]. The earliest definition by Aetius from 5.5.1 Definition and Classification Amida described something like “boiling, foa- The various forms of eczematous skin diseases ming” (ekzeo = I’m boiling) [2]. Interestingly, are the most common skin diseases (approxi- this idea illustrates very well the most modern mately 5–10% of the population). The terms pathophysiology of dermoepidermal inflam- “dermatitis” and “eczema” are often used inter- mation with the subsequent intercellular ede- changeably to describe a disease best defined ma formation (spongiosis). according to Miescher [42] (Table 5.51). Der- The colorful spectrum of eczematous dis- matitis/eczema is characterized by a strong eases may lead to confusion since definitions itching sensation, a relapsing clinical course are given according to variable criteria (mor- and a tendency to chronification. phology, localization, route of contact, kinetics, The following different forms of eczematous etiology, or pathophysiology). It is most unfor- diseases can be distinguished (Table 5.52). In tunate that the term “contact dermatitis” only theUnitedStates,theterm“dermatitis”isoften focusesontherouteofelicitationanddoesnot used identically to “eczema”; some want to stop describetheactualdifferenceinpathophysiol- using the term “eczema” [1]. The name “ecze- ogytoatopiceczema,whichalsocanbeelicited by external contact (see below). Therefore the Table 5.51. Definition of dermatitis/eczema common classification as it is used in most textbooks (Table 5.52) is not very logical. Earli- ) Non-contagious epidermodermitis with typical er the term “vulgar” eczema [28] was used for ) clinical (itch, erythema, papule, seropapule, contact dermatitis; however, this is not an at- vesicle, desquamation, crusting, lichenification in the sense of synchronous or metachronous tractive diagnosis to give a patient today. polymorphism) and Therefore one should focus on the different ) dermatohistological (spongiosis, akanthosis, characteristics between “atopic eczema” and parakeratosis, lymphocytic infiltration into the “contact dermatitis” both pathophysiologically epidermis) manifestation ) mostly on the basis of hypersensitivity and clinically (Table 5.53). In the recent nomenclature consensus of the WAO, a new classification of “dermatitis” was Table 5.52. Classification of dermatitis/eczema proposed, restricting the term “eczema” to the Contact dermatitis forms of what has so far been called atopic ec- ) Allergic zema/dermatitis (Table 5.54). Thus only the al- ) Irritative-toxic lergic (“extrinsic” with IgE involvement) in Atopic and non-atopic eczema contrast to the non-allergic (“intrinsic” with- Seborrheic dermatitis out detection of IgE sensitization) variant Nummular (microbial) dermatitis Unclassified dermatitis should be named “atopic.” The nummular form

Table 5.53. Differences Contact Atopic eczema between contact derma- dermatitis titis and atopic eczema Genetic disposition – + Elicitation (route) Contact ? Psychosomatic influence – ++ Type of allergic reaction IVa I+IVb Antibodies – IgE T cells (elicitation) TH1 TH2 Allergens Haptens Proteins Amplifying cells PMN? EOS, mast cells Role of allergens Established Controversial Diagnosis Patch test Prick, specific IgE, atopy patch test 144 5 Allergic Diseases (and Differential Diagnoses)

Dermatitis Table 5.54. Proposal of a new classification of Eczema Contact dermatitis Other forms dermatitis/eczema (according to WAO Atopic Non-atopic Irritative-toxic Allergic Nummular, 2004; Chap. 1) seborrheic, etc.

Body area Most common Differential diagnosis Table 5.55. Preferable form characteristics of certain forms of dermatitis Dorsum of hands CD AE in various localizations Palms/soles AE CD IT Tinea (AE, atopic eczema; Fingertips AE CD IT CD, contact dermatitis; Scalp SD CD AE Psoriasis IT, irritative-toxic der- External ear SD CD Psoriasis matitis; SD, seborrheic Eyelid AECDSD dermatitis) Lips AE CD IT Oral mucosa IT CD Mamilla AE CD Morbus Paget, scabies Anal IT CD AE Psoriasis Genital IT AE Scabies Lower leg CD AE Venous insufficiency (“stasis dermatitis”?) Post-traumatic IT CE

– 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.Inchildhood,itseemstobeavariantof 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 showing sharp margins and no spreading phenomena.Itoccursinanyindividualwithoutapecu- 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 wives, hairdressers, metal workers, as well as 5.5.2.2 Clinical Manifestations of Classic health personnel. The most important noxious Contact Dermatitis agents are: water, detergents, acids, alkali, solvents, secretions, mechanical factors, etc. A Usually in contact dermatitis, sensitization and subtype can be classified as “exsiccation der- elicitation occur through epidermal contact; matitis” [8] after excessive washing. but there are also systemically elicited forms Allergiccontactdermatitisisduetoanim- (“hematogenous”) where either sensitization munologic reaction of type IVa (sensitized T or elicitation occur via systemic allergen ad- lymphocytes of TH1 type under IL-12 media- ministration [29, 35, 48] mostly via the gut. The tion) [3, 13, 14, 19, 20, 27, 34, 36, 60, 62, 64]. Af- most common elicitors of systemic contact der- ter skin contact, a specific hapten (e.g., chro- matitisaredrugsaswellasfoodsandaromatic mate) is bound to an epidermal carrier protein, substances (flavors). recognized by Langerhans cells [9, 19, 26, 27, Theclinicalsymptoms(Figs.5.31–5.40)in 37, 38, 56, 61, 62] in the epidermis. Metal ions the acute stage are of exsudative character (ery- (e.g., nickel) have been reported as possibly thematous, vesicular, crusted), and in the leading to a structural alteration of the HLA- chronic stage more infiltrative (papules, liche- DR complex [34]. In the regional lymph nodes nification, hyperkeratosis). [61], antigen is presented to T lymphocytes, The most common contact allergens (see which then circulate in the orgnism and after Sect. 3.2.2) are metals (nickel, chromate, co- renewed antigen contact migrate as specifically balt), rubber accelerators (used during vulcani- sensitized T cells to the skin using the skin zation as antioxidants or stabilizers, not rubber homing receptor CLA (cutaneous lymphocyte proteins themselves!), ointment vehicles (e.g., antigen) and secrete or release certain cyto- lanolin, woolwax, emulsifiers, etc.), epoxy res- kines [13, 36, 64]. Apart from Langerhans cells, ins (solvents, hardeners in resins, sensitizing other dendritic cells in the epidermis may be agents mostly are monomers and dimers, not involved during inflammation and tolerance induction [6, 27]. So-called “group allergy” develops when different haptens are transformed by coupling to the carrier into identical substances. “Cou- pling allergy” describes the common phenomenon of concomitant allergic sensitizations against different substances in the same patient duetocommonoccurrenceofallergensinthe environment. The molecular characteristics of contact allergenicity are better understood than that of protein allergens. A crucial characteristic is the Fig. 5.31. Fingertip dermatitis seen in a dentist binding of the hapten to proteins [5, 39], which can occur through electrophil haptens (covalent binding with certain protein structures, e.g., benzochinone), nucleophil haptens (e.g., mercaptobenzothiazole), and lipophil haptens, which directly integrate within the cell membrane (e.g., urushiol from poison ivy). Certain haptens only become immunologically active under UV influence (see Sect. 5.6 on “Photoallergy”). Most contact allergens also have a certain irritative potency. Fig. 5.32. Dyshidrotic hand dermatitis 146 5 Allergic Diseases (and Differential Diagnoses)

Fig. 5.33. Cumulative toxic hand dermatitis Fig. 5.34. Foot dermatitis (allergy to antimycotic medication)

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

Fig. 5.39a,b. Nickel allergy (dermatitis caused by a headband) 5.5 Dermatitis/Eczema 147

a b

Fig. 5.40a,b. Nickel allergy (dermatitis caused by eyeglass frames) the polymers), disinfectants (formaldehyde, parabens), drugs (there is a strong increase in iatrogenic sensitizations through rheuma and venous insufficiency ointments) as well as plants; the most common phytoallergens are sesquiterpenlactones from composites (= Aste- raceae) such as chrysanthemum, arnica, cham- omile, mugwort, as well as chinoid eczemato- gens from exotic woods [5, 30]. There is no allergen cross-reaction to the pollen of the re- spective plants! Contact dermatitis can also be elicited via the air (“airborne contact dermatitis”), which often is confused with photoallergy.

5.5.2.3 The Patch Test Since the first description of the patch test by J. Jadassohn in 1895 [33], the patch test is the classical method for diagnosis of contact dermatitis [4, 10, 15, 18, 20, 52, 55, 56]. The allergen is diluted properly (adequate concentrations have to be determined first in healthy volunteers in order to avoid toxic reactions) in an indifferent vehicle (mostly petrolatum) and fixed to a patch on the skin. Patches either are Fig. 5.41. Positive test reaction to phytoallergens (iris) fixed in aluminum foil or aluminum chambers (Finn chambers). A new technique uses aller- papules, confluent vesicles, erosion), IR = irri- gen-coated thin layer foils (TRUE test, thin lay- tative reaction (Figs. 5.41, 5.42)]. In special er rapid use epicutaneous test) [21]. After 1 or cases, a third reading after 1 or 2 weeks may be 2days,thepatchisremoved.Thetestreaction indicated. is read after 24/48 and after 72 h and graded The open patch test (reading after 20 min) is from0to+++[0=negative,(?)=questionable used in the diagnosis of contact urticaria (see (erythema), + = weakly positive (erythema Sect. 5.1.3). and infiltration, single papules), ++ = strongly The “contact allergy time” (CAT) as the time positive (erythema, infiltrate, papules, and ves- interval needed to become sensitized against icles), +++ = very strongly positive (erythema, neoantigens through epidermal contact deter- 148 5 Allergic Diseases (and Differential Diagnoses)

This requires a high degree of expertise on the part of the physician and cooperation from the patient. Nevertheless, some test reactions remain unexplained when the substance is ubiq- uitous or when the occurrence is unrecognized. In unclear cases, an epidermal provocation test (repeated open application test = ROAT) is used [32]: the substance suspected (e.g., cos- metic) is applied twice daily over 7 days into the elbow flexure, the volar forearm or the cheek. Theopenapplicationavoidstheriskoffalse- positive reactions. Fig. 5.42. Positive epidermal test When there are more than five positive test reactions – except group allergies – “angry back syndrome” should be suspected (see mines the afferent part of the cellular immune above).Substancesshouldberetestedinsingle response quantitatively [11]. small groups, especially in forensic, occupa- Allergic and toxic reactions can be distin- tional situations or if lifesaving drugs are con- guished: toxic reactions are sharply marginat- cerned [8, 59]. ed, reach their maximum earlier (24–48 h) and The selection of substances to be tested fol- arealsopositiveinnormalindividuals lows a careful history. There are standard selec- (>20%). Besides toxic reactions, false-positive tions through national or international contact test results may occur through other factors of dermatitis research groups (ICDRG) and addi- irritation such as adhesive tape irritation, too tional specific “blocks” for special situations high concentrations, allergy against test mate- (occupation, localization, etc.) [4, 5, 8, 10, 18, rials, or concomitant to other very strong reac- 22, 23, 52, 55, 59]. tions (“angry back” or “excited skin syn- Only clear-cut positive and well-defined al- drome”) [12, 40, 42, 44]. Substances with a ten- lergens (no ointment mixtures!) should be doc- dency to elicit false-positive reactions are: umented in the allergy passport! Weakly posi- chromate, formaldehyde, thiomersal, and fra- tive or possibly irritative or “angry back”-in- grance mix. Primary toxic substances may only ducedtestresultsshouldnotbeincludedbe- be tested in very special cases with a clear-cut cause of potential lifelong and forensic conse- history (e.g., tear gas) and in high dilution. quences [8]. However, they should be recorded False-negative test results occur under long- in the files. term glucocorticoid treatment or with too low Particular problems occur with question- concentrations (see Sect. 4.2). External steroid able allergies against dental prosthetic materi- therapy should be stopped 1 week prior to als where often psychosomatic influences play patch tests. On the day of patch testing, no oint- aroleoragainstmetalimplantmaterialsafter ments at all should be applied. Antihistamines, orthopedic surgery (often positive nickel patch beta-adrenergics, and xanthins do not influ- test reactions are not relevant for the implanted ence patch test reactions. Strong UV radiation material situation) as well as against cosmetics should be avoided 4 weeks prior to testing. due to the high number of possible substances Even if carefully performed and read, the re- (Table 5.57). Most common elicitors of cosmet- producibility of patch test reactions (especially ic incompatibility are (in decreasing sequence): of weakly positive reactions) remains unsatis- facial creams, antiperspirants/deodorants, eye factory in some cases [23, 25, 55]. Unfortunate- make-up,nailcosmetics,haircolorings,soap ly, there is no routine in vitro test for type IV al- [45]. The testing of individual products is cru- lergies! cial (Table 5.58). For the evaluation of positive Positive patch test reactions should be eval- patch test reactions, adequate controls are re- uated regarding their relevance for the disease. quired. 5.5 Dermatitis/Eczema 149

Table 5.57. Possible in- Ingredient Examples Possible number gredients of a simple of substances “moisturizer cream” (BHA, butylhydroxyani- Fat Lanolin, paraffin 500 sol) Polyalcohol PEG 20 Emulsifier Tween 1,000 Solvent Alcohol, acetone 30 Thickening Starch, traganth 30 “Moisturizer” Mannit, inositol 50 Color Azo dyes, pigments 500 Preservatives Benzylalcohol, formaldehyde 150 Antioxidants Tocopherol, BHA 40 Fragrance Citronellal, eugenol 3,500 Sum ~6,000

Table 5.58. Recommended concentrations for patch References testing of patient’s cosmetics 1. Ackermann AB, Ragaz A (1982) A plea to ex- Cream Undiluted punge the word eczema from the lexicon of der- Make-up Undiluted matology and dermatopathology. Am J Dermato- Mascara Undiluted pathol 4:315–326 Mascara (dry) Undiluted 2. Aetius von Amida (1549) Tetrabiblos (V.4, Sermo Lipstick Undiluted 1, Kap. 128). Froben, Basel, p 730 Perfume 20 – 100 % 3. Akdis M, Klunker S, Schliz M, Blaser K, Akdis CA Deodorant 20–100% (2000) Expression cutaneous lymphocyte-associ- Hairspray 20 % atedantigenonhumanCD4+ and DC8+ Th2 cells. Hair coloring 10 % Eur J Immunol 30:3533–3541 Hair bleaching 20% (separated!) Nail polish 10 % 4. Bandmann HJ, Dohn W (1967) Die Epicutante- Cold perm materials 2% stung, 2nd edn. Bergmann, Munich To othp aste 2 % 5. Benezra C (1986) Molecular recognition in aller- Soap 1% gic contact dermatitis. In: Ring J, Burg G (eds) Shampoo 1% New trends in allergy II. Springer, Berlin Heidel- berg New York, pp 218–224 6. Bergstresser PR, Tigelaar RE, Dees JH, Streilein JW 5.5.2.4 Therapy (1983) Thy-1 antigen-bearing dendritic cells popu- late murine epidermis. J Invest Dermatol 81:286 Acute dermatitis is treated with moist cooling 7. Bloch I (1911) Der älteste Gebrauch des Wortes “Eczema”. Mh Prakt Dermatol 53:69–71 wraps, lotio alba and short-term topical gluco- 8. Borelli S (1980) Gewerbedermatosen, einschließ- corticosteroids. For long-term success, aller- lich Begutachtung. In: Korting GW (ed) Derma- gen avoidance is crucial. Contact sensitization tologie in Praxis und Klinik, vol II. Thieme, Stutt- is lifelong in most cases. gart Attempts to perform specific hyposensitiza- 9. Braathen LR, Thorsby E (1983) Human epidermal Langerhans cells are more potent than blood tion against contact allergens have been pub- monocytes in inducing some antigen-specific T lished (e.g., by oral administration) without con- cell-responses. Br J Dermatol 108:139–146 vincing success for the clinical routine. Neverthe- 10. Brasch J, Geier J, Schnuch A (1998) Differenzierte less, in many cases “hardening” occurs together Kontaktallergenlisten dienen der Qualitätsver- with adequate skin care. Chronic forms of der- besserung. Hautarzt 49:184–191 11. Burg G, Przybilla B, Bogner J (1986) Contact – al- matitis with hyperkeratotic skin lesions require lergytime.In:RingJ,BurgG(eds)Newtrendsin the use of keratolytics prior to glucocorticostero- allergy II. Springer, Berlin Heidelberg New York, ids. They may be very therapy resistant. In severe pp 230–239 cases of, e.g., dyshidrotic dermatitis, PUVA(pso- 12. Bruynzeel DP (1983) Angry back or excited skin ralen plus UVA) therapy may be helpful. syndrome.Thesis,Amsterdam 13. Cavani A, Albanesi C, Traidl C, Sebastiani S, Giro- The use of new topical immunosuppressants lomoni G (2001) Effector and regulatory T cells in (tacrolimus or pimecrolimus) in these cases allergic contact dermatitis. Trends Immunol 22: may be helpful. 118–120 150 5 Allergic Diseases (and Differential Diagnoses)

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5.5.3 Atopic Eczema faces of infants, while later the large flexures, Atopic eczema is one of the most common in- hands, and neck are most commonly involved. flammatory skin diseases (found in 9–20% of The eczema becomes drier with increasing age, German children!) with a chronic or relapsing the skin shows lichenification, and in adult- course, and strong itching [20, 21, 30, 36, 40, 48, hood excoriated nodules (prurigo-like) 49, 64, 68]. The multitude of names (“atopic (Figs. 5.43–5.51) are common [30, 50]. Unfor- dermatitis,” “neurodermitis diffusa,” “neuro- tunately, atopic eczema – contrary to common dermitis constitutionalis,” “neurodermitis ato- opinion – does not clear regularly before pu- pica,”“prurigo Besnier,”“endogenous eczema,” berty, but two-thirds of affected children will “neurodermatitis,” etc.) reflects the various also suffer from the disease as adults [26] pathophysiological concepts [5, 10, 20, 27, 40, (Fig.5.52).Atopiceczemamayalsofirstappear 48, 49, 65, 68]. We prefer the term “atopic ecze- in adulthood, sometimes even in elderly per- ma” (or “atopic dermatitis”) since it implies sons. neither pathomechanisms (e.g., neurologic ab- Atopic eczema occurs with so-called “stig- normalities) nor routes of contact (exogenous mata” or “minimal variants” [30, 33, 38, 49, 52] or endogenous), but focuses on the familial (Table 5.59, Figs. 5.53, 5.54). There is still con- atopic trait. troversy regarding the primary skin lesion, which is described as erythema, flush, papule, seropapule, or vesicle. In the tradition of St. 5.5.3.1 Clinical Manifestation John or J.W. von Goethe and together with the Atopiceczemamostoftenstartsinchildhood French school [5], we say: “In the beginning or adolescence; sometimes the first manifesta- therewastheitch.”Inmanycasesallskinle- tion is cradle cap in infants (also called “crusta sions can be explained as secondary reactions lactea” because of its similarity with burnt milk to the itch. In children undergoing oral provo- in a pan); it affects the face and extensor sur- cation, I have often observed that they com- 152 5 Allergic Diseases (and Differential Diagnoses)

Fig. 5.43. (left) Atopic eczema in an infant (“cradle cap”)

Fig. 5.44 (right). Atopic eczema in a newborn

Fig. 5.45. (left) Atopic eczema in an older baby

Fig. 5.46. (right) Atopic eczema in a toddler

Table 5.59. Stigmata of atopic eczema plain about itching without any visible skin lesion 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

Fig. 5.47. (left) Itching as the primary symptom of atopic eczema

Fig. 5.48. (right) Atopic eczema on dark skin

b Fig. 49a,b. Elbow eczema 154 5 Allergic Diseases (and Differential Diagnoses)

Fig. 5.50. (left) Atopic eczema on the lower legs and feet

Fig. 5.51. (right) Prurigo form of atopic eczema

Infants Preschool School Adolescents Adults Prevalence children children (%)

I 36,7

II 31,1

III 32,2 Fig. 5.52. Occurrence and course of atopic eczema 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

Fig. 5.53. Ichthyosis handsasastigmaof atopic eczema

Fig. 5.54. Atopic “winter feet”

Table 5.61. Atopic eczema: diagnostic criteria (Ring Table 5.62. Dermatohistopathology in atopic eczema 1982). With four or more positive findings, the diagnosis “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 lymphohistocytic 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- Atopyinpersonalorfamilyhistory 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).Thereisnosignificantassociation IgE receptors [low- and high-affinity (CD23 and between the diagnosis “atopic eczema” and Fc 5 RI)aswellasIgE-bindingprotein] 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% encode for general markers of skin inflamma- Atopy patch test 42 –56 % 69 –92 % tion independent of “atopy.” a Allergen-dependent (related to specific history)

5.5.3.2.2 Increased IgE Production Few diseases are characterized by elevated IgE values in the serum similarly to atopic eczema [36, 40, 42, 48, 49, 68]. These IgE antibodies are directed against environmental allergens, in central Europe in adults most commonly against cat epithelia, housedust mite, and grass pollen, in infants against hen’s eggs and cow’s milk. The evaluation of the relevance of IgE sensitization for the induction or elicitation of eczema may be difficult. It is achieved by careful history and provocation tests. The detection of IgE and IgE- receptors on epidermal Langerhans cells (Fig. 5.56) [6, 12, 55, 66] opens new perspectives for an understanding of the pathogenesis of atopic eczema (Table 5.63). Positive epidermal test reactions induced by typical aeroallergens (e.g., housedust mites) help to show the relevance of an IgE response for the eczematous skin lesions (“atopy patch test,” APT) [16, 46] (Fig. 5.57). Compared to the prick test and RAST, the APT Fig. 5.56. IgE-positive Langerhans cells (reprinted by has a much higher specificity (Table 5.64). permission of T. Bieber) Thereisnodoubtthatforalargegroupof eczema patients, IgE-mediated allergy plays a test reactions (“intrinsic” form or “non-atopic” decisive role in the disease (“extrinsic” form). eczema) [69]. There are, however, (as in respiratory atopy) Recently, in very severe cases of atopic ecze- patients without IgE elevation or positive prick ma, autoantibodies of IgE class against epider- 158 5 Allergic Diseases (and Differential Diagnoses)

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., Kaposi’s 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 aremostprominentintheso-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 not only have proinflammatory activity, but also – as histamine via histamine receptors on lymphocytes – regulatory effects in the immune response (see also Chap. 2), thus favoring IgE production and promoting a “circulus viti- osus” [42]. The well-known psychosomatic interactions fit into this concept very well [10, 18, 45]. Psychologic events may influence the disease positively and negatively through the action of nervous transmitters. In stress or anxiety, the same mediators are liberated as during itch or allergic inflammation (see Chap. 7, “Psyche and Allergy”).

5.5.3.2.5 Dry Skin The phenomenon of “dry skin” is complex in na- Fig. 5.59. Visualization of pruritus with the aid of pos- ture [7, 10, 11, 23] and describes at least three itron emission tomography (PET). The red areas are different dimensions (“rough” versus “smooth”; significantly activated. Motor-associated areas are “fat” versus “lipid-poor”; “moist” versus “water- additionally marked (yellow circles). (From Darsow et poor”); it can be better described as a barrier al. [17]) disturbance of the epidermis. In eczema, the following findings have been shown: 5.5.3.2.6 Itch ) Stratum corneum water content is not Itch and dryness are closely related. Any skin decreased exsiccated too much (e.g., by excessive shower- ) Transepidermal water loss is increased ing) starts to itch and gives rise via scratching ) Epidermal permeability is increased to eczematous lesions. On the basis of “hyper- ) Skin roughness is increased sensitive” skin, patients react more strongly to ) Surface lipids are decreased a variety of stimuli and irritants (e.g., wool). ) Sebaceous glands are smaller Recently, the itch sensation has been visual- ) Ceramidesynthesisisaltered ized with positron emission tomography (PET) ) Microscopically inflammatory reactions [17](Fig.5.59).Atopicitchhasseveralcompo- Therefore, some authors regard “dryness” as a nents, only some of them depending on skin in- minimal inflammatory reaction [59] with the flammation. involvement of keratinocytes [19]. Previously, dryness was interpreted as de- 5.5.3.3 Therapy creased sebaceous gland activity (“sebostasis”); today alterations in intercellular lipid bi- Individual treatment is the major principle, layer are seen as the basis of the epidermal bar- considering the patient’s actual skin character- rier (the “bricks and mortar” model according isticsinthecourseofthedisease[2,11,47]. toP.Elias).Thechemicalbasisisamixtureof There is no “miracle” pill or ointment, nor is ceramides, which are decreased in atopic ecze- there a general diet against atopic eczema! ma and possibly qualitatively altered [7]. Cera- Monomania should be avoided; the disease is mide synthesis follows a subtle balance of dif- neither only allergic nor only sebostatic nor ferentenzymessuchassphingomyelinase, q - only psychologic in origin! glucocerebrosidase, ceramidase, and sphingo- The basis of any therapeutic strategy is care- myelindeacylase [23]. ful dermatologic basic skin care, especially during remission [11]. The individual selection 160 5 Allergic Diseases (and Differential Diagnoses)

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 betweenemulsionandspreadingtypebath 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 basic 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- UVtherapyasadjuvantstrategyhasagood 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 pyiscontroversial[70];however,considering many proinflammatory cytokines is reduced thenewresultswiththeatopypatchtestand [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- theskin.Thetwopreparationsavailableare 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 sometimes require antimicrobial therapy, best done 5.5 Dermatitis/Eczema 161

Table 5.66. Leaflet for patients with (atopic) eczema

) Your disease is based partly on inherited factors which can either lead to eczema, conjunctivitis, rhinitis, or bronchial asthma. This genetic predisposition, however, does not necessarily lead to disease. There is a genetic predisposition to increased hypersensitivity of skin and mucous membranes. ) In eczema, the skin is dry, looks rough, the hair sometimes looks rigid, a variety of factors from the environment (both irritant and allergic) can give rise to the development of eczematous skin lesions (red, itchy, sometimesoozingorcrustedskinlesions),preferablyonthebigflexureselbow,knee,neck,hands,and face. ) The skin of patients with eczema (children and adults) needs constant care. Skin care: ) Avoid too frequent bathing or showering (especially too hot or too foamy)! ) Usealkali-freesoapsorsyndetsforcleaningyourskin(mildproducts). ) When taking a bath or showering, restoration of the skin lipid is important. This can be done by adding a bath oil and/or by creaming after taking a bath or a shower with emollients (lotion, cream, etc.), especially on arms, legs, and hands. ) Take yourself time for skin care every morning and evening. Let the cream penetrate your skin (at least 5 min) before dressing. Don’t change your ointments too often, stick to the products you tolerate. Thus, you can avoid additional allergies. Clothing: ) Avoid wool or irritating textiles. Direct contact to the skin is best tolerated with cotton, silk, or linen. ) Wash underwear before first wearing, especially dark colored products. ) In changing T-shirts on your baby, watch the ears (avoid fissures under the earlobes!). Your favorite sweat- er may scratch your neck where there is no cotton underneath. Then use a silk scarf. ) During acute exacerbations, keep your baby dressed; an uncovered body surface starts itching and will be scratched. Treatment of itch: ) The itch-scratch cycle deserves utmost attention. Often itch is the primary event inducing the new flare. ) Scratching often occurs as a reflex, it is not a matter of will. You should not forbid scratching! Rather treat the itch! ) Keep the nails cut short (scratching occurs also during sleep). ) Itch can be treated topically (anti-inflammatory creams, wet wraps, cooling procedures) or systemically (e.g., antihistamines; the sedating effect of old preparations may be helpful during night time). Topical therapy does less harm to the skin than pronounced scratching! ) Teachers and colleagues should know about the problem. People suffering from intense itch sometimes be- have strangely (most of these children are not “hyperactive/hyperkinetic”). Allergen avoidance: ) According to the results of your allergy diagnosis, avoidance strategies should be implemented. These always have to be specific. Don’t change your apartment into a prison-like environment with only glass and concrete. In housedust mite allergy, the bedroom and the mattress are most important and encasings are helpful. ) Some patients benefit from a longer stay in a different climate (sea level or high altitude; talk about this with your specialist). ) In high-risk families, pets should not be kept for allergy prevention. Tobacco smoke and indoor chemicals (cleaning, hobby activities) should be avoided. Diet: ) There is no general anti-allergy diet. Patients with atopic eczema can principally eat what they want except for those foods detected as elicitors in careful allergy diagnosis including provocation tests. Positive skin prick or blood tests do not necessarily tell you whether this allergy is relevant for your skin disease. You may use these results as markers for self-observation. ) For allergy prevention, newborns from atopic parents should be breast-fed over 3–6 months; solid food should be only introduced after 6 months. If breastfeeding is not possible, use a hypoallergenic formula. ) Avoid ear-piercing in young children (nickel allergy!). ) If you are pollen-allergic wash your hair before going to bed. 162 5 Allergic Diseases (and Differential Diagnoses)

9. Bos JD, Van Leent EJ, Sillevis Smitt JH (1998) The Avoidance millennium criteria for the diagnosis of atopic Diet Balneotherapy dermatitis. Exp Dermatol 7:132–138 Syndets 10. Borelli S, Schnyder UW (1962) Neurodermitis Climate therapy constitutionalis sive atopica, part II: Atiologie, Pathophysiologie, Pathogenese, Therapie. In: UV- Light Creams Miescher G, Storck H (eds) Entzündliche Derma- Ointments tosen I. Handbuch der Haut- und Geschlechts- Pastes krankheiten [Suppl 11/1]. Springer, Berlin Hei- therapy Antipruritics Sonata delberg New York, pp 254–319 Tar for 11. Braun-Falco O, Ring J (1984) Zur Therapie des Antihistamines atopischen Eczemas. Hautarzt 35:447–454 eczema Glococorticosteroids atopic 12. Bruynzeel-Koomen C, Van Wichen DF, Toonstra

ACTH of J, Berrens L, Bruynzeel PLB (1986) The presence 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.CooksonWO,UbhiB,LawrenceR,AbecasisGR, 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.DarsowU,VielufD,RingJfortheAPTStudy Group (1999) Evaluating the relevance of aeroal- References lergen sensitization in atopic eczema with the atopy patch test: a randomized, double-blind mul- 1. Abeck D, Schmidt T, Fesq H, Strom K, Mempel M, ticenter study. J Am Acad Dermatol 40:187–193 Brockow K, Ring J (2000) Long-term efficacy of 17. DarsowU,DrzezgaA,FrischM,MunzF,WeilkeF, medium-dose UVA1 phototherapy in atopic der- Bartenstein P, Schwaiger M, Ring J (2000) Pro- matitis. J Am Acad Dermatol 42:254–257 cessing of histamine-induced itch in the human 2.AbeckD,RingJ(eds)(2002)AtopischesEczema cerebral cortex: a correlation analysis with der- (Neurodermitis) im Kindesalter. Steinkopff, mal reactions. J Invest Dermatol 115:1029–1033 Darmstadt 18. Fartasch M, Abeck D, Werfel T, Diepgen T, 3. Akdis CA, Akdis M, Trautmann A, Blaser K Schmid-Ott G, Ring J, Gieler U (2000) Aktueller (2000) Immune regulation in atopic dermatitis. Stand des interdisziplinären Modellprojektes Curr Opin Immunol 12:641–646 “Neurodermitis-Schulung für Kinder und Ju- 4. Atherton DJ (1981) Allergy and atopic eczema. gendliche”. Hautarzt 51:299–301 Clin Exp Dermatol 6:317–325 19. Giustizieri ML, Mascia F, Frezzolini A, De Pita O, 5. Besnier E (1892) Premiere note et observations ChinniLM,GianettiA,GirolomoniG,PastoreS preliminairespourservird’introductional’etude (2001) Keratinocytes from patients with atopic des prurigos diathesiques (dermatites multifor- dermatitis and psoriasis show a distinct chemo- mes prurigineuses chroniques exacerbantes et kine production profile in response to T cell-de- paroxystiques, du type du prurigo de Hebra). rived cytokines. J Allergy Clin Immunol 107: Ann Derm Syph (Paris) 3,3:634–648 871–877 6. Bieber T (1994) FceR1 on human Langerhans 20. Hanifin JM (1982) Atopic dermatitis. J Am Acad cells: a receptor in search of new functions. Im- Dermatol 8:1–13 munol Today 15:52–53 21. Hanifin JM, Rajka G (1980) Diagnostic features of 7. BleckO,AbeckD,RingJ,HoppeU,VietzkeJ,Wol- atopic dermatitis. Acta Derm Venereol 114: ber R, Brandt O, Schreiner V (1999) Two cerami- 146–148 de subfractions detectable in Cer(AS) position by 22. Herzberg J (1973) Wenig bekannte Formen der HPTLCinskinsurfacelipidsonnon-lesionalskin Neurodermitis. Hautarzt 24:407–501 of atopic eczema. J Invest Dermatol 113:894–900 23. Imokawa G (2001) Lipid abnormalities in atopic 8. Boguniewicz M, Leung DYM (1998) Atopic der- dermatitis. J Am Acad Dermatol 45:S29–32 matitis: A question of balance. Arch Dermatol 24. Jakob T (2002) Mechanismen der Aktivierung 134:870–871 und Mobilisation dentritischer Zellen in der 5.5 Dermatitis/Eczema 163

Haut. Habilitationsschrift, Technische Universi- 43. Ring J (1991) Atopy: condition, disease, or syn- tät München drome? In: Ruzicka T, Ring J, Przybilla B (eds) 25. Jung T (2002) Zytokindysregulation bei atopi- Handbook of atopic eczema. Springer, Berlin scher Dermatitis. Dustri, Munich Heidelberg New York, pp 3– 8 26. Kissling S, Wüthrich B (1994) Dermatitis in 44. Ring J, Bieber T, Vieluf D, et al. (1991) Atopic ec- young adults: personal follow-up 20 years after zema. Langerhans cells and allergy. Int Arch Al- diagnosis in childhood. Hautarzt 45:368–371 lergy Appl Immunol 94:194–201 27. Korting GW (1954) Zur Pathogenese des endoge- 45. Ring J, Schröpl F (1985) Das atopische Eczema. nen Eczemas. Thieme, Stuttgart Medizinisches Hörspiel, Frankfurt (Audio-Kas- 28. Kowalzick L, Kleinheinz A, Weichenthal M, Neu- sette mit Begleitheft) ber K, Köhler I, et al. 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Neuber K (2002) Atopisches Eczema und Staphy- Karger, Basel lococcus aureus.Dustri,Munich 53. Schöpf E, Kapp A, Kim CW (1978) T-cell function 35. Olesen AB (2001) Role of the early environment in atopic dermatitis. Controlled examination of for expression of atopic dermatitis. J Am Acad concanavalin A. Dose-response relations in cul- Dermatol 45:37–40 tured lymphocytes. Arch Dermatol Res 262:37 44 36. Oranje AP (2000) Atopic dermatitis (AD): Evalu- 54. Schultz-Larsen F (1985) Atopic dermatitis. Etio- ation and therapy. Pediatr Dermatol 17:75–83 logical studies based on a twin population. Lae- 37. Platts-Mills TAE, Mitchell EB, Rowntree S, Chap- geforeningens, Copenhagen man MD, Wilkins SR (1983) The role of dust mite 55. Stingl G (2001) IgE-mediated, Fc 5 RI-dependent al- allergens in atopic dermatitis. Clin Exp Dermatol lergen presentation: A pathogenic factor in atopic 8:233–247 dermatitis? J Am Acad Dermatol 45:S517–S520 38.PrzybillaB,RingJ,EndersF,WinkelmannH 56. TaiebA (1999) Hypothesis: from epidermal barri- (1991) Stigmata of atopic constitution in patients er dysfunction to atopic disorders. Contact Der- with atopic eczema or atopic respiratory disease. matitis 41:177–180 Acta Derm Venereol 71:407–410 57.Thestrup-PedersenK,RingJ(1999)Atopicder- 39. Przybilla B, Eberlein-König B, Rueff F (1994) matitis: summary of the 1st Georg Rajka Sympo- Practical management of atopic eczema. Lancet sium 1998 and a literature review. Acta Derm Ve- 343:1342–1346 nerol 79:257–264 40. Rajka G (1989) Essential aspects of atopic derma- 58. Trautmann A, Akdis M, Kleemann D, Altznauer F, titis. Springer, Berlin Heidelberg New York Simon HU, Graeve T, Noll M, Brocker EB, Blase K, 41. Reitamo S, Rissanen J, Remitz A, Granlund H, Akdis CA (2000) T cell-mediated Fas-induced ke- Erkko P, Elg P, Autio P, Lauerma A (1998) Tacro- ratinocyte apoptosis plays a key pathogenetic role lismus ointment does not affect collagen synthe- in eczematous dermatitis. J Clin Invest 106:25–35 sis: results of a single-center randomized trial. J 59. Uehara M (1985) Clinical and histological fea- Invest Dermatol 111:396–398 tures of dry skin in atopic dermatitis. Acta Derm 42. Ring J (1979) Atopic dermatitis: a disease of gen- Venereol (Stockh) [Suppl] 114:8246 eral vasoactive mediator dysregulation. Int Arch 60.ValentaR,SeiberlerS,NatterS,MahlerV,Mossa- Allergy Appl Immunol 59:233–239 beb R, Ring J, Stingl G (2000) Autoallergy: A 164 5 Allergic Diseases (and Differential Diagnoses)

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5.5.4 Topical Glucocorticosteroid Therapy plays a role in the well-known immunosup- Glucocorticosteroids have a central place in the pression and affects wound healing. In fatty tis- treatment of inflammatory skin disease. They sue, lipolysis is enhanced, and in the kidney a can be regarded as the greatest advance in topi- mild mineralocorticoid effect exists, although cal dermatotherapy in the second half of the it is 1,000× weaker than aldosterone. In some 20th century [28]. In Germany in the year 2001, tissues, glucocorticoids induce involution, es- there were 263 different preparations in vari- pecially in lymphatic tissues, the bone and the ous application forms including 70 combina- skin, most likely due to inhibition of DNA syn- tion preparations on the market (systemic sub- thesis. stances not included). Furthermore, gestagenic effects (such as progesterone) have been described as well as psychic alterations (depression, sleeplessness, 5.5.4.1 Mechanisms of Action euphoria, alteration in behavior, and others). Glucocorticosteroids have a variety of well- In the skin, glucocorticosteroids inhibit the known effects due to control of synthesis of proliferation of epidermal, inflammatory, and several enzymes at the chromosome level [2, 5, lipid cells, the synthesis of collagen tissue, the 9, 11]. The steroid is bound to a cytoplasmic re- liberation of mediators from mast cells, and ceptor leading to a conformation change of the pigment formation by melanocytes. They nor- receptor complex [6], which then binds in the malize altered cornification of epidermis cells, nucleus to chromatin and influences the tran- inhibit migration of inflammatory cells, and in- scription of messenger RNA. Steroids may both duce vasoconstriction [5] (Table 5.67). stimulate and inhibit transcription. The exact The anti-inflammatory effect is of particular mechanisms are still not known; however, they interest in dermatology, affecting almost all enhance the activity of RNA polymerases at kinds of inflammation (infectious, allergic, certain positions in the chromatin [2]. physical, chemical, etc.). Apart from formation Glucocorticoids have a variety of metabolic of lipocortin, inhibition of phospholipase plays effects; the best known (hence the name!) af- arolewhichinthecellmembraneisimportant fects the glucose metabolism with the mobili- in the formation of arachidonic acid from zation of muscular glycogen and neoglycoge- phospholipids. From arachidonic acid, highly nesis from amino acids. This protein catabo- active prostaglandins and leukotrienes are lism with a negative nitrogen balance maybe formed[2,4,6].Theanti-inflammatoryeffect 5.5 Dermatitis/Eczema 165

Table 5.67. Action of glucocorticosteroids on skin cells Cells Effects Keratinocytes Inhibition of proliferation Normalization of keratinization Fibroblasts Inhibition of collagen and proteoglycan synthesis a) Pregnane Lymphocytes Inhibition of proliferation and cytokine secretion Granulocytes Inhibition of chemotaxis and activation Mast cells/basophils Inhibition of liberation of vasoactive mediators Vascular system Vasoconstriction Melanocytes Inhibition of pigment formation

Fatty tissue Inhibition of proliferation b) Structure of natural and synthetic Glucocorticosteroides can be shown as inhibitory function on various cells (neutrophils, macrophages, lymphocytes) with additional vasoconstriction. Pharmacologic effects of glucocorticosteroids depend on specific structures in the molecule(Fig.5.61),theintroductionofafluoratom in position 9 [ increases the biological activity, and substitution in position 6 [ increases anti- c) Cortisol inflammatory effects. Esterification, acetonide formationaswellasintroductionofmethylor halogengroupsinpositions16–21leadtoava- riety of topically effective steroid preparations, which have been tested in various experimental systems (e.g., vasoconstriction assay) [1]. Table5.68showsthemostcommontopical glucocorticoids, roughly classified according to pharmacologic potency. d) Diflucortolon-21-valerate New developments with fewer side effects include prednicarbate, methylprednisolonace- ponide, and mometasone furoate. For therapeutic efficacy, dermal resorption of the applied substance is necessary; this can be influenced by certain factors, such as: ) Stratum corneum thickness (tape stripping) ) Age (infant skin has higher permeability) ) Blood flow (increased skin blood flow in- e) Betamethasone-17,21-dipropionate creases resorption) ) Hydration (occlusion increases permeation by a factor of 10!) (Table 5.69) Fig. 5.61. Natural and synthetic glucocorticosteroids as pregnane derivatives [21] 166 5 Allergic Diseases (and Differential Diagnoses)

Table 5.68. Topical glucocorticosteroids of different ) Interaction of drugs (e.g., addition of 3% potency (arbitrary selection) (according to [9, 17, 21]) salicylic acid enhances the steroid penetra- Potency Substance tion) (group) ) Skin metabolism (biotransformation by I= Non-halogenated glucocorticosteroids oxidation, methylation, sulfatation, glucu- Hydrocortisone ronidation, etc.). Fluocortin butylester is Hydrocortisone-17-butyrate hydrolyzed in the skin to the inactive ste- Hydrocortisone acetate roid acid, leading to decreased efficacy, but Desonid Hydrocortisone buteprate also fewer side effects. Methylprednisolone aceponide Prednisolone Prednicarbate 5.5.4.2 Practical Application of Topical II = Weakly fluorinated glucocorticosteroids Glucocorticoids Alclomethasone Clobetasol butyrate Topical glucocorticosteroids have to be indicat- Fluocortin butylester ed. They can suppress inflammation, but rarely III = Moderate glucocorticosteroids are curative, which has to be considered in Betamethasone-17-valerate chronic disease. Betamethasone-17-benzoate Betamethasone-17-pentanoate If there is an indication for topical glucocor- Desoximethasone ticosteroid therapy, the weakest effective prep- Momethasone fuorate arationshouldbeselectedinordertoavoid Triamcinolone-16–17-acetonide side effects. Maximally, apply twice daily, gen- Flumethasone-21-pivalate Fludroxycortide erally once daily (depot in the stratum cor- Fluticasone-17-propionate neum). Occlusion should never be longer than Dexamethasone 12 h to avoid side effects! IV = Strong glucocorticosteroids After 1 week of therapy, the situation should Betamethasone-17–21-dipropionate be monitered by a physician (sometimes even Fluocinolone acetonide Diflorasone-17–21-diacetate daily). If there is no immediate rapid response Diflucortolone-21-valerate within a week, the patient should consult a der- V= Very strong glucocorticosteroids matologist. Amcinonide Long-term steroid therapy never should be Fluocinonide stopped abruptly (rebound phenomenon), Halcinonide slow dose reduction can be done either by Clobetasol-17-propionate changing to a less potent product or, preferably, by interval therapy (3 days steroid, 4 days vehi- Table 5.69. Excretion of hydrocortisone into the urine cle only) [3, 10, 12, 13, 14]. Tachyphylaxis phe- after local administration of 5.2 mg/cm2 in acetone nomena have been observed and may be over- under different conditions (according to [7]) come by changing the product. %ofdose With regard to epidermal proliferation ki- applied netics (with a minimum at 6.00 p.m. in the daily Normal skin 0.46 rhythm), some authors recommend the appli- Under occlusion 4.48 cation of topical steroids in the evening; we fol- After corneal stripping 0.91 low the individual itch intensity. After corneal stripping plus occlusion 14.91 Crucial in the selection of topical steroid preparations is the vehicle [3]. Figure 5.62 ) Skin temperature (increasing temperature shows a rough schedule of critical criteria (clin- increases permeation, part of the occlusion ical course, skin type, body area for the selec- effect) tion of the vehicle) [21]. In chronic inflamma- ) Influence of vehicle (optimal solution of tion, fatty preparations are preferred while the effective agent, but not too high an acute lesions should be treated with solutions affinity to the vehicle) and cooling wraps. In intertrigenous areas, 5.5 Dermatitis/Eczema 167

dry fat

Wraps hydrophilic Fatty Suspensions ointments ointments Lotions (creams) Occlusion Indication Powder Hydropastes

Course

acute subacute chronic

Skin type

Sebostasis Seborrhea

Localization Fig. 5.62. Application forms of topical thera- Extension sites py. Guidelines for selecting the proper ap- Flexor sites plication form for topi- Intertriginous areas cal glucocorticoid therapy 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 (powder 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 glucocorticoids 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)

Table 5.70. Side effects of glucocorticosteroids Systemic administration Endocrinology Diabetes mellitus Catabolic metabolism Osteoporosis Hyperlipidemia Alkalosis (sodium retention potassium excretion) Suppression of pituitary gland (growth suppression in children) Cushing’s syndrome Hypertension Immune system Inhibition of lymphocyte and granulocyte function, 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 Cutispunctatalineariscolli 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

elastic fibers (also vessels) leads to senile elastosis, teleangiectasia, purpura, ecchymosis and striae distensae (Fig. 5.63). A special form of topical corticoid side effect is the so-called perioral rosacea-like dermatitis, developing after long-term application of mostly fluorinated glucocorticoids (especially in atopics) and mostly in the face; it manifests Fig. 5.64. Rosacea-like perioral dermatitis appearing as fine sharp papules and occasional pustules inapatientwhohadusedafluoridatedtopicalgluco- (Fig. 5.64). The indication for steroid treatment corticoid preparation for several weeks 5.5 Dermatitis/Eczema 169 mostly remains trivial or unknown. The anti- Practical Conclusions. Glucocorticosteroids inflammatory effect of the steroid induces im- are, even if applied topically, very active drugs, provement again and again, but is followed by the use of which should be well indicated; it re- heavy rebounds after withdrawal. Therefore, quires experience of skin diseases and steroid the patient will never learn the causal interac- actions and side effects. The good doctor uses tions. Only authoritative guidance of the pa- as little cortisone as necessary and as much in- tient can break this vicious cycle (I tell my pa- different vehicle therapy (emollients, lotio alba, tients: “Your skin is addicted to cortisone and paste, etc.) as possible! we have to perform withdrawal!”). There are also allergic reactions (contact allergy) to cortisone preparations, mostly References against constituents of the vehicle, but also 1. Alpermann HG, Sandow J, Vogel HG (1982) Tie- against the steroid molecule itself. rexperimentelle Untersuchungen zur topischen After intramuscular application of corticoid und systemischen Wirksamkeit von Prednisolon- crystal suspensions, partly irreversible local re- 17-ethylcarbonat-21-propionat. Arzneimittelfor- actions may occur (embolia cutis, lipid or mus- schung/Drug Res 32:633 cular atrophy) (Figs. 5.65, 5.66). 2. Barnes PJ, Adcock I (1993) Anti-inflammatory actions of steroids: molecular mechanisms. Trends Pharmacol Sci 14:436–440 3. Braun-Falco O, Ring J (1984) Zur Therapie des atopischen Ekzems. Hautarzt 35:447–454 4.CarnuccuiR,diRosaM,GuerrasioB,IuvoneT, Sautebin L (1987) Vasocortin: a new glucocorticoid-induced anti-inflammatory protein. Br J Pharmacol 90:443–445 5. Claman WN (1984) Antiinflammatory effects of corticosteroids Immunol. Allergy Practice 4: 317–329 6. Clark CR (1985) Intracellular localisation of steroid receptors. In: Sluyser M (ed) Interaction of steroid hormone receptors with DNA. Ellis Hor- wood, Chichester, pp 7–56 7. Flower RJ, Rothwell NJ (1994) Lipocortin-I: cellu- Fig. 5.65. Lipoatrophy occurring after the intramuscular mechanisms and clinical relevance. Trends lar administration of a glucocorticoid crystalline sus- Pharmacol Sci 15:71–76 pension

Fig. 5.66. Cutaneous atrophy following long- term treatment with a topical glucocorticoid 170 5 Allergic Diseases (and Differential Diagnoses)

8. Guin JD (1984) Contact sensitivity to topical cor- 20. Przybilla B, Ring J (1983) Äußerliche 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, Fröhlich HH (1985) Wirkstoffe in der der- 10. Hornstein OP, Nürnberg 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, Stüttgen 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- tivesandretrospectives.In:RingJ,BurgG(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 tientzündliche Pharmakotherapie. In: Heppt W, 14. Maibach H, Stougthon RB (1973) Topical cortico- Renz H, Röcken 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. Schöpf E (1972) Nebenwirkungen externer Corti- Kontinuierliche versus diskontinuierliche An- coidtherapie. Hautarzt 23:295 wendung. Hautarzt 34:114–117 27. Schöpf 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 Prüfung 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 keratinocytes. J Invest Dermatol 76:211–214

Table 5.71. Terminology of photobiologic reactions 5.6 Photoallergy/Photosensitization Photobiologic Effect of lighta on biological 5.6.1 Classification reaction systems Light incompatibi- Reaction after light exposure Incompatibility reactions in connection with lity exposure to UV light represent a special type Photosensitization Increased sensitivity to light of photobiologic reaction. In the following the by defined endogenous or term“light”isusedfor“non-ionizingelectro- exogenous substances magnetic radiation” in general. When light Photosensitizer Substance inducing photo- reaches the skin, part of the energy is reflect- sensitization ed, another part affecting the organism after Photoallergic Immunologically mediated absorption to body constituents [3, 8, 16, reaction photosensitization 17, 42]. Substances increasing the sensitivity Phototoxic reaction Non-immunologic photo- against light are called “photosensitizers” sensitization (Table 5.71). Photohypersensi- Increased sensitivity against Photosensitization can be either phototoxic tivity light exposure or photoallergic in nature [8, 17, 24, 38]. Photodermatosis Skin disease provoked or Phototoxic effects occur through formation aggravated by light of pyrimidine adducts within the DNA, leading a “Light” in this context means “non-ionizing electro- to cross-links within the double-helix (e.g., magnetic radiation” 5.6 Photoallergy/Photosensitization 171

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) Ye s 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 Vesic ulat ion: 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]. ble5.72),althoughinindividualpatientsthis Photoallergic contact dermatitis is a relatively may be difficult in practice. common form of photohypersensitivity (Fig. 5.67). Some patients under the combined influence 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)orchronically(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)

Suspected systemic photosensitization may be detected by measuring the MED during a systemic administration (oral or parenteral) of a suspected agent, UV irradiation and demonstration of increased photosensitivity [1,9,25].

5.6.3 Photosensitizers Photosensitizing agents are widely distributed in nature. They are found in tar (polyaromatic hydrocarbons, acridine derivatives) or colorings (eosin, fluorescein, methylene blue). Many plants contain photosensitizers (Ta- ble 5.74), giving rise to phototoxic reactions after 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 (dermatitis 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 drugshavebeenshowntoactasphotosensitiz- (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 hardening may be achieved [12, 32, 34]. Umbelliferae 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 areasnotexposedtolight.Thishastobedone (orange), Ruta graveolens, Dictamnus albus onthreesubsequentdayswithdosesof 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

Table 5.75. Photosensitizers in drugs and cosmetics 5.6.4 Diagnosis (examples)

Disinfectants (e.g., halogenated salicylanilides, In the diagnosis of photoallergic or phototoxic hexachlorophen, chlorhexidine, bithionol) reactions, not only the eliciting substance but Antimycotics (buclosamide) also the eliciting wavelength has to be determined [33]. Most of the eliciting wavelengths in Chemotherapeutics (sulfonamides, tetracyclines, nalidixic acid, quinolones) photohypersensitivity are found in the UVA range, but sometimes also in the UVB range or Sedatives (phenothiazine) visiblelight.Withaclear-cuthistoryandnega- Diuretics (hydrochlorothiazide, furosemide) tive test results different wavelengths should be Non-steroidal anti-inflammatory drugs (e.g., used. There is no general concordance between ibuprofen, ketoprofen, piroxicam, diclofenac) the absorption spectrum of a substance and the Antiarrhythmics (quinidine, amiodarone) eliciting wavelength of the adverse reaction. Fragrances (musk ambrette, 6-methylcoumarin) UV radiation penetrates through certain tex- Sunscreen substances (e.g., para-aminobenzoic tiles; affection of covered body areas does not acid, benzophenones, isopropyldibenzoylmethane) exclude photosensitization. A variety of genuine skin diseases can be Antidiabetics (sulfonyl urea) provoked by light which are not currently understood pathophysiologically [24, 28].

Photo-patch Test. The most important tech- niquewithwhichtodiagnosephotoallergicre- actions is the photo-patch test [14, 19, 23, 24, 30], when two samples each of the suspected substance are applied to the back skin. After 24 h the patch over one testblock is removed and the skin radiated with 10 J/cm2 (when radiated with UVB with the half minimal erythema doses). After 48 and 72 h both testblocks are read. Under certain conditions a late reading after 3 weeks (labeling of test areas with a po- laroid camera) is recommended. For quantitative analysis photo-patch- Fig. 5.68. Meadow grass dermatitis caused by furoco- threshold testing can be performed and the se- umarins – in this case by contact with the giant hog- ries of substances is irradiated with increasing weed (Heracleum mantegazzianum) doses (geometric increase) of UV. For differentiation of phototoxic and photoallergic test reactions dermatohistology is sometimes required.

Photo-prick Test. Concordant with the photopatch test, other skin test procedures can be performed with and without irradiation (e.g., in solar urticaria).

Systemic Photo-provocation Test. For evaluation of the clinical relevance of a positive pho- to-patch-test reaction against drugs or foods, a Fig. 5.69. Light-induced drug exanthema following systemic photo-provocation test can be per- the administration of carprofen formed [9, 25, 30]. Before and after systemic 174 5 Allergic Diseases (and Differential Diagnoses)

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 laboratory studies of the photosensitizing potential of 5.6.5 Prophylaxis and Therapy norfloxacin, a 4-quinolone broad-spectrum antibiotic. 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 mediators. 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 describe the sun protection factor for UVB ra- 8. Frain-Bell W (1986) Cutaneous photobiology. 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- stancesinsunscreenscanactasphotoallergens tory peptides by complement in porphyrin-in- ducedphotosensitivity.In:RingJ,BurgG(eds) [38, 39]. Newtrendsinallergy.Springer,BerlinHeidel- 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, Köhler K, titis with transition to persistent light reaction, Ring J (1987) Environmental influences of UVB PUVA therapy as well as UVA1 or small spec- erythema. Photodermatology 4:148–153 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.HölzleE,PlewigG,KriesRv,LehmannP(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. Hölzle E, Neumann N, Hausen B, Przybilla B, drugsorcosmetics,screeningtestsforpossible Schauder S, Hönigsmann 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. Hönigsmann 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, Stüttgen 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) Rötung und Bräunung der Haut 21. Kavli G, Volden G (1984) Phytophotodermatitis. durchUVA.Zuckschnverdt,Munich Photodermatology 1:65–75 3. Eberlein-König 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, Hölzle E, Roser-Maaß E, Hofmann C lergic contact dermatitis from dibenzoylmetha- (1985)Photoallergy.In:RingJ,BurgG(eds)New nes. Photodermatology 3:140–147 trends in allergy. Springer, Berlin Heidelberg 39. Schauder S, Schrader A, Ippen H (1996) Göttinger New York, pp 152–169 Liste 1996. Sonnenschutzkosmetik in Deutsch- 29.PrzybillaB,RingJ,SchwabU,GalosiA,DornM, land, 4th edn. Blackwell, Berlin Braun-Falco O (1987) Photosensibilisierende Ei- 40.SchmidtT,AbeckD,RingJ(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:S23–S28 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 über 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 UVAirradi- 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-König 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

106,000 estimated fatalities in 1994 (the fourth 5.7 Adverse Drug Reactions commonest cause of death in the United States) [4, 31]. 5.7.1 Drug Allergy: General Procedures Apart from severe bullous reactions (Lyell’s syndrome, etc.) (see Sect. 5.7.3), the vasculitic 5.7.1.1 Classification “hypersensitivity syndrome” as well as organ Adversedrugreactionsareunexpectedunde- damage to liver, lung, or kidney, anaphylactoid sired reactions to drugs in normal doses [26] reactions are the most dangerous and most fre- and represent an increasing problem in clinical quently lethal adverse drug reactions. A study medicine. Approximately 3–5% of hospitaliza- fromtheUnitedKingdomreportedamarked tions are due to drug reactions [39], and increase in prevalence of anaphylactic reactions 10–15% of hospitalized patients suffer from leading to hospitalization (1:10,000 in 1995) adverse drug reactions during their hospital [42]. In a hit list of elicitors of fatal anaphylactic stay. reactions, anesthetics, relaxants, antibiotics, Drug allergies are a serious problem: 0.32% and radiographic contrast media are on top. of hospital patients die from adverse drug reac- The frequency of fatal drug allergy is esti- tions in the United States, corresponding to mated to be 1:10,000 [56]; for most drugs aller- 176 5 Allergic Diseases (and Differential Diagnoses)

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 thisholdstrueforproteinsandpeptides(>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:thepenicilloylgroupas“majordeter- 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). Metabolismofdrugsisimportantforthein- 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 ciallytheenzymesofthecytochromeP450sys- 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 alsoplayarolewithmetabolizingenzymes [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.

Table 5.76. Drug allergy: different pathomechanisms Mechanism (type) Symptoms Example I(IgE) Anaphylaxis Penicillin, allergen extracts, insulin II (Cytotoxic) Agranulocytosis Metamizol Anemia Penicillin, cephalosporin Thrombocytopenia Carbamazepine III (Immune complex) Anaphylaxis Xenogeneic serum, dextran Serum sickness Xenogeneic serum, penicillin Vasculitis Allopurinol, phenylbutazone Alveolitis Pituitary extracts, nitrofurantoin IV (Cell mediated) Eczema (also systemic!) Antibiotics, disinfectants Photoallergy Halogenated salicylanilides, nalidixic acid (Fixed drug eruption) Barbiturates, quinine (Maculopapular) Penicillin, gold, barbiturates, q -blockers (Toxic epidermal necrolysis) Sulfonamides, NSAIDs, allopurinol V (Granulomatous) Granuloma Allergen extracts, soluble collagen VI (Neutralizing/stimulating) (Drug-induced LE?) Hydralazine, procainamide Insulin resistance Anti-insulin IgG antibodies 5.7 Adverse Drug Reactions 177

tion himself and needs information from the 5.7.1.3 Risk Factors patient or from colleagues (questionnaires The risk of a drug allergy depends both on the have proven useful). Therefore, every physician characteristics of the substance and on the pa- should carefully document all the symptoms tient(Table5.77).Riskfactorsfromthepatient together with the suspected drug when there is can be seen in underlying diseases (immuno- a suspicion of adverse drug reaction. It is not deficiency, infectious disease, metabolic de- enough to write down the general class of drug fects such as decreased or slow acetylators). (e.g., “penicillin” is often used as a wide term Whether drug allergies are more frequent in for any antibiotic), but the individual sub- atopicsiscontroversial.Moststudieshavenot stance, the brand name, the producer, the for- differentiated according to reaction types and mula, the batch number (especially in intrave- have given controversial results. There is evi- nous solutions and biologicals) should be re- dence that IgE-mediated reactions may be corded. If possible, single substances of combi- more frequent in atopics compared to normals. nation drugs should be documented since the drug content may change over the years under the same brand name (Table 5.78). The allergist Table 5.77. Risk factors for drug allergy also needs the “physician’s desk reference” 1. Risk factors from the drug from previous years! Duration of administration Sometimes the intensity of a reaction can be Frequency of administration evaluated from the treatment given. The time Dose Route of administration course is especially important; some patients Dose of reactive metabolites suffer from a mild anaphylactic reaction, which 2. Risk factors from the patient only becomes serious after administration of Underlying disease (immunodeficiency, metabolic epinephrine. In anesthesia-related complica- disturbance) tions, the anesthesia protocol is of the utmost Age importance for allergy diagnosis. Genetic disposition (polymorphisms, HLA) Atopy (?) According to clinical symptoms, rough in- Previous incompatibility of the same drug formation for suspected pathomechanisms can be found with large overlaps. No single symptom is characteristic for a certain pathomecha- With increasing age and more frequent under- nism (urticaria can be induced by IgE anti- lying diseases, the intensity of clinical symp- bodies,butalsobyimmunecomplexreactions, tomsofdrugreactionsisalsoincreasing. or pseudo-allergic reactions). Sometimes fever reactions occur together with other complaints in the sense of serum 5.7.1.4 General Diagnosis of Drug Allergy sickness; however, they can also be due to toxic The diagnosis of adverse drug reactions follows the same principles used for classical allergy diagnosis: Table 5.78. Important information from the history of adverse drug reactions ) History and clinical symptoms ) Skin test Substance Effective agents, additives ) In vitro diagnostics Brand name, producer ) Administration formula, batch Provocation test number Possible incompatibilities 5.7.1.4.1 History and Clinical Symptoms Reaction type Clinical symptoms History is the most important part of allergy Time course (in surgery also anesthesia protocol!) diagnosis! In most cases of adverse drug reac- Severity tions, however, the allergist has not seen the Therapeutic procedures performed clinical symptoms of the incompatibility reac- 178 5 Allergic Diseases (and Differential Diagnoses)

effects. Hematologic complications are com- possible with confidential cooperation from monincytotoxicreactions(e.g.,allergicagran- 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 reactions. 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- convulsantsaselicitorsareknown.Themecha- 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 3months.Certaindrugsabletoinhibitskinre- 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 lymadeupmoreoftenthanallergenextracts. 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” isthehighvarianceofthetestresults.Inad- Criteria for registration of a substance: verse drug reactions, the problem of standardi- ) Thesubstancecanbeavoided 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) availableforroutinetestsandareonlypossible ) Alternative drug tested in provocation tests in specialized laboratories. ) The allergy passport should contain the following 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 patient’s 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- Themostcommonmistakesinthediagnosis clude the suspected agent from the patient’s 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- ) Wronginterpretationofskintestreactions (especially intradermal) ter administration of acetaminophen in patients ) with a history of anaphylaxis to analgesics. Insufficient precautions for skin tests and provocation tests The evaluation of OPT results can some- ) Wrong interpretation of psychic factors (under- timesbedifficult,especiallywithregardtothe and overestimation) ) Inadequate allergy passport “allergy passport” (Table 5.79). In contrast to ) the procedure for contact allergy and patch test Testing under therapy with antiallergic drugs

Table 5.80. Allergy diagnosis Criterion Score points in adverse drug reaction: 012 Score for inclusion in allergy passport (together with Clinical symptoms (history) Negative Doubtful Clear-cut B. Przybilla). 0–1 point = Provocation test Negative Doubtful Clear-cut no allergy passport, 2 Skin test (epidermal) Negative or (+) + points = “allergy suspicion,” Skin test (cutaneous)a Negative or (+) + ++ 3 or more points = allergy passport necessary a A positive in vitro test may replace a positive cutaneous skin test 180 5 Allergic Diseases (and Differential Diagnoses)

Often doctors advise the patient with adverse Table 5.83. Successful hyposensitization in drug erup- drug reactions: “Just don’t 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: “Don’t press on it again!” Ciprofloxacin Nevirapine Ethambutol Anticonvulsives Rifampicin Carbamazepine 5.7.1.5 Hyposensitization in Drug Allergy Sulfonamides Phenobarbital Cotrimoxazole Cytostatics In spite of multiple alternative substances, it Sulfadiazine Azathioprine may occur that the patient is allergic to a life- 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 induction”) 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 Severeunderlyingdiseasesmayalsorepre- 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 startingdose.Tables5.82and5.83showsuc- withdrawn prior to hyposensitization. cessful schedules for penicillin and insulin. “Hyposensitization” in cutaneous drug eruptions 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 (I–V). The prevalence of all reac- as severe bullous skin diseases (Stevens-John- tions is between 5% and 10% [16]. The inci- son syndrome, Lyell’s 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 penicillin 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 were penicillin mediated (see Sect. 5.1.4). At- Steps Dose (units) Steps Dose (units) 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 (cow’s 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 penicillin G (200,000 U/ml), benzylpenicillin or 5.7.1.6.2 Analgesics benzylpenicillenate (10–2 mM] (minor determinants). 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 GaswellasPPLdecreasesovertheyears. 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 tomsonly(gradeI)therewerepositiveskin 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 thefutureandoffertolerablealternatives.OPT have an additional substitution at the 3-posi- has to be performed under emergency condition of the dihydrothiazine ring. tions.Aslowincreaseindosefrom10%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 startingwith1%or2.5%ofasingledoseisrec- 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- reactionstoinsulin.Granulomatousreactions istic reaction patterns: 40% of our patients rein 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- ferentpyrazolonessuchasmetamizol(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 recombinant insulin is performed as rush hyposensitization (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 reactions 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. 48.0s.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 20.1i.c. 520.0s.c. 0.5 i.c. having been treated with insulin, persisting for 625.0s.c. years and sometimes occurring with antibodies 1.0 i.c. 730.0s.c. against cytoplasmic island cell antigens [57]. 32.0s.c. The clinical symptoms of insulin allergy 4.0 s.c. vary; there are many different types of allergic 6.0 s.c. 5.7 Adverse Drug Reactions 183 used for anticoagulation. Mostly, they are pre- 5.7.1.8 HIV Infection and Drug Allergy pared from mucosa of pig intestine or beef lung. Allergic reactions against heparin may be Adverse drug reactions are a major problem for mediated via different mechanisms (type I to HIV patients, especially exanthematous drug type IV). Anaphylactic reactions are rare but eruptions, which are a hundred times more fre- have been reported (cited by Zürcher and quent in HIV patients than in the general popu- Krebs; Sect. 5.7.3). Cytotoxic reactions in the lation [11]. Maculopapulous eruptions, unspe- sense of heparin-induced thrombocytopenia cific “hypersensitivity syndrome” and rare have been covered in Sect. 5.2. complications such as “metabolic lipodystro- More frequent are local reactions manifest- phy syndrome” have been observed under ing either as the Arthus reaction with leukocy- combined highly active antiretroviral therapy toclastic vasculitis or as a recently more com- (HAART) [38]. monly occurring indurating dermatitis type IV While previously sulfonamides and other reaction [33, 37]. Apart from the exclusion of antimicrobials were the most frequent eliciting allergic sensitization against xenogeneic ani- agents of adverse drug reactions, recently nu- mal proteins, testing is done by prick and intra- cleoside reverse transcriptase inhibitors (e.g., dermaltestsaswellassubcutaneousprovoca- abacavir), non-nucleoside reverse transcription testing. There are considerable cross-reac- tase inhibitors (e.g., delavirdin, efavirenz, ne- tions, sometimes also with low molecular he- virapine, etc.) as well as protease inhibitors parinoids, which should always be tested as (like amprenavir) have become common [38]. possible alternatives. The reasons for the increased prevalence of ex- In some cases, recombinant hirudin (Lepi- anthematous drug eruptions in HIV infections rudin) can be recommended after negative are not clear. Besides the immanent challenge provocation testing in patients with severe due to the multiple pharmacotherapy with heparin allergy and contraindication for cou- drugs to be taken continuously, the use of very marin derivatives. different and new substances with ill-defined side reactions needs to be discussed. Also rather high doses and possible metabolic interac- 5.7.1.7 Rare Drug Reactions tions may be considered as well as the general With the new development of recombinant situationofanoverstimulatedimmunesystem drugs and gene technology, also new side ef- with upregulation of co-stimulatory mole- fects of drugs should be expected such as cules, cell surface receptors, and cytokine se- against: cretion. ) Recombinant drugs ) Monoclonal antibodies (even if hybrids with human immunoglobulin form large parts of the protein and mouse sequences are only small) ) Reactions against viral vectors during gene therapy In the United States, a fatal case in a gene thera- pystudywithadenovirusasthevectorhas been brought to public attention. The precise mechanisms are not clear; overstimulation of the innate immune system with massive secretion of various cytokines, especially interleukin-6andTNF,leadingtoshocklung[acutere- spiratory distress syndrome (ARDS) and multiorgan failure] have been discussed. 184 5 Allergic Diseases (and Differential Diagnoses)

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5.7.2 Pseudo-allergic Drug Reactions The most common drugs eliciting pseudo-allergic 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)

Clinical symptoms Allergy Pseudo-allergy Table 5.85. Mechanisms of different types of Anaphylactic reaction IgE Direct mediator release drug-induced allergy IgG Direct complement activation and pseudo-allergy Neuropsychogenic reflexes (examples) Embolic-toxic reaction Cytotoxic reaction IgG,IgM G6PDHdeficiency Serum sickness, IgG, IgM Shwartzman-Sanarelli phenomenon vasculitis Aggregate-induced reaction Jarisch-Herxheimer reaction Embolia cutis Eczema, exanthema T lymphocytes Phototoxic dermatitis B-cell stimulation (ampicillin), lichen planus (gold) Granuloma Tlymphocytes+ Foreign body granuloma macrophages Organopathy or Autoantibodies Cholestasis autoallergy (drug-induced LE)

Table 5.86. Drugs eliciting pseudo-allergic anaphylactic reactions (examples)

) Radiographic contrast media ) Colloidal volume substitutes ) Gammaglobulins

) ) Antibiotics -1 ) Intravenous anesthetics ) Opioids ) Muscle relaxants ) Local anesthetics ) Cyclooxygenase inhibitors ) Drugs increasing microcirculatory flow RR (mm Hg), pulse (min RR (mm Hg), idiosyncrasy. These patients are often also suffering from nasal polyps and chronic sinusitis (Samter’s triad) [30]. Certain forms of drug-induced hepatopathy possibly may be regarded 500 mg Prednisolone as pseudo-allergic reactions, such as cholestat- ic (phenothiazine, imipramine) or hepatocellu- Minutes lar icterus (amphotericin B, furosemide, isoni- 10 ml HES azid). Hemolytic anemias in patients with specific Fig. 5.70. Clinical symptoms of an anaphylactic reac- enzyme deficiencies (glucose-6-phosphate de- tion following the infusion of hydroxyethyl starch (HES) hydrogenase or glutathione reductase) occur after administration of certain drugs, corresponding to “pseudo-allergic” reactions of tions, neuropsychogenic mechanism reflex re- type II (Table 5.87). actions, and Jarisch-Herxheimer reaction may The pathophysiology of pseudo-allergic re- be mentioned here. For only a few drugs are the actions is variable and not well understood pathomechanisms established. The situation is (Table 5.88): Besides direct complement activa- complicated by the fact that one and the same tion, direct mediator liberation as well as en- drug may elicit both allergic and pseudo-aller- zyme deficiencies, also embolic-toxic reac- gic reactions! Table 5.89 gives some rules for 5.7 Adverse Drug Reactions 187

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

Table 5.88. Examples of possible mechanisms of Direct complement activation pseudo-allergic reac- (Classic) Gammaglobulin (standard) (aggregated tions IgG) Plasmaprotein solutions (aggregated IgG) (Bypass activation) Radiographic contrast media Intravenous anesthetics Direct mediator release Gelatin Radiographic contrast media Relaxants Intravenous anesthetics Antibiotics (polymyxin) (Acetylsalicylic acid?) Enzyme defects C1 inactivator Hereditary angioneurotic edema Glucose-6-phosphate dehydrogenase Hemolytic anemia (cholinesterase) (Succinylcholine incompatibility) Neuropsychogenic reflexes Local anesthetics Embolic-toxic reaction Depot-penicillin (intravascular) Jarisch-Herxheimer reaction Destruction of cells (e.g., syphilis treatment with penicillin) Increase of blood flow Nicotinic acid esters

Table 5.89. Rough crite- Allergy Pseudo-allergy ria for distinction of allergic from pseudo- Sensitization No sensitization allergic reactions Reaction after repeated contact Reaction at first contact Rare (<5%) Frequent (>5%) Typical clinical symptoms “Unspecific” symptoms Low eliciting doses Dose dependent (speed dependent in infusions) Family history sometimes positive Family history negative (exception: enzyme defects) Moderate psychologic influence Strong psychologic influence 188 5 Allergic Diseases (and Differential Diagnoses)

the differentiation of pseudo-allergic and aller- For prophylaxis, antihistamines and gluco- gic reactions (cum grano salis). corticosteroids, beta-adrenergics, antidepres- Inthefollowing,someclinicallycommon sives, as well as hypnotic suggestion have been pseudo-allergic reactions will be discussed. recommended. In a prospective placebo-controlled study of ourown,wewereabletoshowasignificant 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- riskofanRCMreactionintheindividualpa- cussed. The common intravenous gammaglob- tient. Iodine allergy is a type IV reaction in the ulins are chemically or physically modified on senseofaclassicallergiccontactdermatitis 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 antagonistsisaneffectiveprophylaxis. systemic reactions. Therefore, we perform skin Occasional true IgE-mediated reactions to gel- testsasaminimumvariantofprovocationun- atine have been reported [42]. der emergency conditions. The occasional intravenous 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 5.90. Intravenous anesthetics vere anaphylactic reactions, true IgE-mediated Barbiturates Opiates allergies against muscle relaxants have been ) Thiopental ) Morphine observed with cross-reactivity related to the ) Methohexital ) Fentanyl quarternary ammonium group [39]. ) Hexobarbital ) Alfentanil ) ) If a depolarizing relaxant (e.g., succinylcho- Thiobutabarbital Droperidol line) is not tolerated, a non-depolarizing agent Diazepines Others ) ) (e.g., alcuronium) may be tolerated. Diazepam Propanidide Malignant hyperthermia occurs in patients ) Medazolam ) Ketamine ) Etomidate with myopathy due to increased calcium influx ) Althesin and contractility with rapid increase in body temperature without shivering, tachycardia, tachypnea, muscle rigidity, and cardiac arrhyth- tions like hypotension or tachycardia or have mia. The disease is familiar. For diagnosis, central stimulating effects such as ketamine muscle biopsy with in vitro stimulation and and propanidide, or sedative effects like barbi- contractility study is available. Molecular ge- turates. netic tests found a relevant mutation in the rya- Various mechanisms have been discussed to nodin receptor 1 gene (RYR-1) [38]. Effective explain anaphylactic reactions. Besides classic therapy uses the hydantoin derivative dantro- IgE-mediated reactions (barbiturates), pseu- len (1 mg/kg body wt. i.v.), oxygen, and slow re- do-allergic mechanisms with direct comple- duction of body temperature. ment activation and histamine liberation may play a role (especially opioids) [8, 24]. Recently, 5.7.2.7 Local Anesthetics IgE-mediated reactions to opiates and relaxants have been reported [19]. So-called allergic reactions against local anes- A careful history is the mainstay of diagno- thetics are common in the allergist’s office; how- sis of these adverse reactions. The allergist ever, true allergies are rare, except for the type IV needs the cooperation of the anesthetist, who reactions in classic allergic contact dermatitis should record the exact time sequence of the [29].Mostanaphylacticreactionsarenon-im- substances administered! When skin tests are munologic in origin with unspecific symptoms. performed, the histamine-liberating properties Intradermal tests cannot be related to clinical of certain anesthetics need to be considered. manifestation [14]. As pathomechanism, psychoneurogenic reflex mechanisms with vasovagal components have been suggested. In prac- 5.7.2.6 Muscle Relaxants tice, the procedure of “subcutaneous provoca- The most important side effects of muscle re- tion testing” (Table 5.91) is recommended with laxants are: slowly increasing doses under careful observation in emergency conditions subcutaneously. ) Prolonged muscle relaxation The role of preservatives contained in some ) Anaphylactic reaction solutions, especially in larger bottles, has to be ) Malignant hyperthermia Prolonged muscle relaxation mostly is due to a Table 5.91. Local anesthetics: provocation tests, genetic or drug-induced inhibition of cholines- 20-min interval terase (e.g., neostigmine, organophosphates, hexafluronium, quinidine, cyclophosphamide, Prick test aprotinin) or a muscular disease (myasthenia if negative: 1. I.d. 1:10 0.1 ml gravis). 2. S.c. 1:10 0.1 ml Muscle relaxants are direct histamine libera- 3. S.c. Undiluted 0.1 ml tors. It is under discussion whether this proper- 4. S.c. Undiluted 0.5 ml ty is connected with the frequently observed 5. S.c. Undiluted 1.0 ml tachycardia and hypotension. However, in se- 6. S.c. Undiluted 2.0 ml 190 5 Allergic Diseases (and Differential Diagnoses)

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 substances (mostly in ampules). If there is psychologic influence and patients concomitant administration of NSAIDs and alsoreacttoplacebo,weusetheprocedureof 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%ofasthmapatients) 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- hasbeendiscussedaswellasdirectcomple- 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 ASAaswellasotheradditivesandcolorings (see Sect. 5.1.6 on “Urticaria”). Several in vitro diagnostic techniques have Table 5.93. Clinical manifestations of NSAID incompatibility been attempted in ASA idiosyncrasy; however, the observed effects (e.g., histamine release by Eye ) ASA) have also been observed in patients toler- Conjunctivitis atingASA[3,5,27,39].Recentlythecellularal- 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

For therapy, avoidance is the primary prin- 5.7.2.10 Other Pseudo-allergic Reactions ciple: in nasal polyposis polypectomy is indicated; equally infectious sinusitis has to be For the sake of completeness the classical Ja- treated. risch-Herxheimer reaction should be men- By administrations of slowly increasing tioned in a chapter on pseudo-allergic reac- doses of ASA, in some patients “adaptive deac- tions; by cell destruction (penicillin in syphi- tivation” is possible, leading to ASA tolerance, lis), pyrogenic or vasoactive substances may be whichmakesthedailyintakeof500mgor released and activate the complement system. 650 mg ASA necessary [34, 27, 40]. In some pa- After administration (mostly intramuscular) tients a decrease in relapses of nasal polyposis of depot-penicillins occasional pseudo-allergic has been observed [34]. reactions have been observed with central ner- Adaptive deactivation with ASA in patients vous disturbances and cardiovascular symp- with chronic urticaria or anaphylactic reac- toms, which have been called “embolic-toxic re- tions has not been convincingly achieved. actions” (Hoign´esyndrome)[13]. Oily material After the introduction of cyclooxygenase of the depot emulsion may reach the intravasal (COX) 2 inhibitors [10], many people were lumen after injection and lead to microemboli. hopeful of having safe alternatives for patients Whether a direct pharmacologic effect of pro- with ASA idiosyncrasy [6, 31, 36, 37, 45]. There caine – sometimes also contained in these prep- are, however, patients who react particularly to arations– playsapathogenicroleremainsopen. COX 2 inhibitors [12]. COX 2 inhibitors, there- For the mechanisms of ampicillin rash see fore, cannot generally be regarded as safe alter- Sect. 5.7.3. natives in ASA idiosyncrasy. Generally, contaminants and impurities have to be considered whenever an adverse reaction remains unclear. 5.7.2.9 Additives Adverse drug reactions may not only be elicited 5.7.2.11 Therapy and Prophylaxis bytheactivesubstancebutalsobyadditivesin the preparation. Most additives have been The treatment of pseudo-allergic anaphylactic added for galenic reasons (preservatives, anti- reactions follows the principles of anti-anaphy- oxidants, stabilizers, filling substances, etc.); lactic regimens (see Sect. 5.1.4). In unclear however,undesiredingredientsmayalsobe cases and with a history of pseudo-allergic reconsidered [16, 23, 28]. Some may be legal actions the prophylactic administration of his- (such as high molecular residues or small par- tamine H1-andH2-antagonists (intravenously ticles<30µmininfusionsolutions)orillegal 5minpriortothedrug)ororallytogetherwith such as bacterial contaminants or pyrogens glucocorticosteroids (18 h prior to administra- (Table 5.95). tion) is recommended.

Table 5.95. Additivesindrugsaselicitorsofanaphy- lactic reactions (examples) References ) Depot mediators (Penicillin preparations) 1.BrockowK,RingJ(1996)Mechanismsofpseudo- ) Micell formers (Cremophor EL) allergic reactions due to radiographic contrast me- ) Sulfites (Injection solutions, dia. Allergy Clin Immunol Int 8:123–125 local anesthetics) 2.BrockowK,VielufD,PüschelK,GroschJ,RingJ ) Protein stabilizers (Protein solutions) ) (1999) Increased postmortem serum mast cell Benzylalcohol (Injection solutions, tryptase in a fatal anaphylactoid reaction to non- sterile H2Oorsaline) ionic radiocontrast medium. J Allergy Clin Immu- ) Colorings (In tablets) ) nol 104:237–238 Acetate (Dialysis) 3. Capron A, Ameisen J, Joseph M, Auriault C, Tarnel AB, Caen J (1985) New functions for platelets and their pathological implications. Int Arch Allergy Appl Immunol 77:107–114 192 5 Allergic Diseases (and Differential Diagnoses)

4. Conroy MC, de Weck AL (1981) Effect of aspirin cause of hypotension following rapid colloid in- and indomethacin on histamine release from leu- fusion. Arch Pathol Pharm 267:433–439 kocytes of patients with suspected intolerance to 20. Paul E, Gall H-M, Mechlin A, Möller R, Müller I aspirin. Int Arch Allergy Appl Immunol 66 [Suppl (2001) Acetylsalicylic acid (ASA)-augmentation 1]:152–153 in relation to ASA-intolerance. Allergo J 10: 5.CzechW,SchöpfE,KappA(1995)Releaseofsul- 269–272 fidoleukotrienes in vitro: Its relevance in the di- 21. Pierzchalska M, Mastalerz L, Sanak M, et al. (2000) agnosis of pseudoallergy to acetylsalicylic acid. A moderate and unspecific release of cysteinyl leu- Inflamm Res 44:291–295 kotrienes by aspirin from peripheral blood leuco- 6. Dahlen B, Szczeklik A, Murray JJ (2001) Celeco- cytespreludesitsvalueforaspirinsensitivityin xib in patients with asthma and aspirin intoler- asthma. Clin Exp Allergy 30:1785–1791 ance (letter). N Engl J Med 344:142 22. Przybilla B, Ring J (1987) Pseudo-allergische Arz- 7. Denborough MA, Lovell RRH (1960) Anaesthetic neimittelreaktionen: Pathophysiologie und Dia- deaths in a family. Lancet II:362 gnostik. Z Hautkr 62:430–443 8. Doenicke A, Koenig UD (eds) (1983) Immunolo- 23. Ring J (1978) Anaphylaktoide Reaktionen nach gie in Anästhesie und Intensivmedizin. Sertürner Infusion natürlicher und künstlicher Kolloide. Workshops Einbek. Springer, Berlin Heidelberg Springer, Berlin Heidelberg New York New York 24. Ring J, Brockow K (2004) Pseudo-allergische Arz- 9.DukorP,KallosP,SchlumbergerHD,WestGB neimittelreaktionen. In: Schultze-Werninghaus (eds) (1980) Pseudo-allergic reactions, 3 vols. G, et al. (eds) Manuale allergologicum, 2nd edn. Karger, Basel Dustri, Munich (in press) 10. Fitzgerald GA, Patrono C (2001) The coxibs, se- 25.RingJ,ArroyaveCM,FritzlerMJ,TanEM(1978) lective inhibitors of cyclooxygenase-2. N Engl J In vitro histamine and serotonin release by radio- Med 345:433–442 graphic contrast media (RCM). Complement de- 11. Gaetani GF, Luzatto L (1980) Haemolytic reac- pendent and independent release reaction and tions induced by drugs and other agents: the role changes in ultrastructure of human blood cells. of red cell enzyme abnormalities and of abnor- Clin Exp Immunol 32:105–118 malhaemoglobins.In:DukorP,KallosP,Schlum- 26. Ring J, Rothenberger KH, Clauß W (1985) Pre- berger HD, West GB (eds) Pseudo-allergic reac- vention of anaphylactoid reactions after radio- tions; involvement of drugs and chemicals. vol. 2, graphic contrast media in fusion by combined Karger,Basel,pp1–19 histamine H1-andH2-receptor antagonists: re- 12. Grimm V,Rakoski J, Ring J (2004) Selective COX- sults of a prospective controlled trial. Int Arch Al- 2 inhibitors also can elicit symptoms in patients lergy Appl Immunol 78:9–14 with aspirin idiosyncrasy. J Allergy Clin Immu- 27. Ring J, Walz U (1985) Indomethacin enhances in nol (in press) vitro histamine release induced by anti-IgE and 13. Hoign´e R (1962) Allergische und pseudo-allergi- Ca-Ionophore but inhibits C5a-induced release sche Reaktionen auf Penicillinpräparate. Acta reactions from basophils of atopics and normals. Allergol 17:521 Int Arch Allergy Appl Immunol 77:225–227 14.IncaudoG,SchatzM,PattersonR,RosenbergM, 28. Ring J (1992) Pseudo-allergic reactions. In: Ko- Yamamoto E, Hamburger RN (1978) Administra- renblat PE, Wedner HJ (eds) Allergy: theory and tion of local anesthetics to patients with a history practice. Saunders, Philadelphia, pp 243–264 of prior adverse reaction. J Allergy Clin Immunol 29. Ruzicka T, Gerstmeier M, Przybilla B, Ring J 61:339–345 (1987) Allergy to local anesthetics: comparison of 15. Kallos P, Kallos L (1980) Histamine and some patch test with prick and intradermal test results. other mediators of pseudo-allergic reactions. In: J Am Acad Dermatol 16:1202–1208 Pseudo-allergic reactions: involvement of drugs 30. Samter M, Beers RF (1968) Intolerance to aspirin. and chemical, vol. 1. Karger, Basel, p 28 Clinical studies and consideration of its patho- 16. Kleinhans D, Galinsky T (1982) Zur möglichen genesis. Ann Intern Med 68:975–983 Provokation eines Bronchialasthmas und einer 31. S´anchez-Borges M, Capriles-Hulett A, Caballero- Urtikaria durch Natriumdisulfit. Allergologie Fonseca F (2001) NSAID hypersensitivity in the 4:120–121 COX-2 inhibitor era. ACI Int 13:211–218 17.LasserEC,LangJH,LyonSG,HamblinAE,Ho- 32. Schick E, Weber L, Gall H (1996) Delayed hyper- ward MM (1981) Prekallikrein-kallikrein conver- sensitivity reaction to the non-ionic contrast me- sion rate as a predictor of contrast media catas- dium iopromide. Contact Dermatitis 35:312 trophes. Radiology 140:11–15 33. Simon RA (1984) Adverse reactions to drug addi- 18. Lorenz W, Doenicke A (1978) Histamine release tives. J Allergy Clin Immunol 74:623 in clinical conditions. Mt Sinai J Med N Y 34. Stevenson DD (1984) Diagnosis, prevention, and 45:357–386 treatment of adverse reactions to aspirin and 19. Meßmer K, Lorenz W, Sunder-Plassmann L, Klö- nonsteroidal antiinflammatory drugs. J Allergy vekorn WP, Hutzel M (1970) Histamine release as Clin Immunol 74:617–622 5.7 Adverse Drug Reactions 193

35. Stevenson DD, Simon RA (2001) Lack of cross-re- 41. Voigtländer V, Walter E, Siess R, Rother U (1981) activity between rofecoxib and aspirin in aspirin- Acetylsalicylic acid intolerance: a possible role of sensitive patients with asthma. J Allergy Clin Im- complement. Int Archs Allergy Appl Immunol 66 munol 108:47–51 [Suppl 1]:154–155 36. Szczeklik A, Sanak M (2000) Genetic mechanisms 42. Wahl R, Kleinhans D (1989) IgE-mediated aller- in aspirin-induced asthma. Am J Resp Crit Care gic reactions to fruit gums and investigation of Med 161:S142–146 cross-reactivity between gelatine and modified 37. Szczeklik A, Nizankowska E, Sanak M, Swier- gelatine-containing products. Clin Exp Allergy czynska M (2001) Aspirin-induced rhinitis and 19:77–80 asthma. Curr Opin Allergy Clin Immunol 1:27–33 43. Wedi B, Kapp A (2000) Aspirin induced adverse 38. Till G, Rother U, Gemsa D, Gerhardt P (1977) Ak- skin reactions: new pathophysiological aspects. tivierung des Komplementsystems bei Zwischen- Thorax 55 [Suppl 2]:S70–S71 fällen nach Kontrastmittelinjektionen. Verh 44. Wüthrich B (1983) Allergische und pseudo-aller- Dtsch Ges Inn Med 83:1589–1591 gische Reaktionen der Haut durch Arzneimittel 39.VervloetDL,DorP,ArneudA,SenftM,AlaziaM, und Lebensmitteladditiva. Schweiz Rdsch Med Charpin J (1985) Anaphylactic reactions to succi- (Praxis) 72:691–699 nylcholine. Prevention of mediator release by 45. Yoshida S, Ishizaki Y, Onuma K, Shoji T, Nakaga- 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

5.7.3 Exanthematous Drug Eruptions extensor surfaces of extremities [10, 12, 24, 35, 53, 56, 62]. The morphology of exanthematous drug 5.7.3.1 Prevalence eruptions is very colorful. Skin reactions mostly Adverse drug reactions occur preferably on the are not specific but may be elicited through aller- skin. Three percent of all drug treatments give gic, toxic, or infectious processes. There are, how- rise to adverse drug reactions on the skin [3, 10, ever, conditions whichare elicited more frequent- 62], not including contact allergic reactions after ly by certain drugs than by others [10, 60, 62]. external application of topicals (see Sect. 5.5.2). Knowledgeofthesefactsiscrucialinthecausal Exanthematous drug eruptions occur after sys- diagnosis [3, 10, 25, 39, 62] (Tables 5.96, 5.97). temic administration of a drug, manifesting On the other hand, an underlying disease of mostly symmetrically with a predilection of the the patient does influence the occurrence of

Table 5.96. Prevalence of drug-induced allergic skin reactions (from [3]) Prevalence (%) Prevalence (%) Cotrimoxazole 5.90 Trimethobenzamide 0.66 Ampicillin 5.20 Phenazopyridine 0.65 Other semisynthetic penicillins 3.60 Methenamine 0.64 Corticotropin 2.80 Cyanocobalamin 0.62 Erythromycin 2.30 Barbiturate 0.47 Salicylazosulfapyridine 2.10 Glutethimide 0.45 Sulfisoxazole 1.70 Indomethacin 0.44 Penicillin G 1.60 Chlordiazepoxide 0.42 Gentamycin 1.60 Metoclopramide 0.40 Practolol 1.60 Diazepam 0.38 Cephalosporin 1.30 Propoxyphene 0.34 Quinidine 1.20 Isoniazid 0.30 Metamizol (dipyrone) 1.10 Nystatin 0.29 Mercury diuretics 0.95 Chlorothiazide 0.28 Nitrofurantoin 0.91 Furosemide 0.26 Heparin 0.77 Insulin 0.13 Chloramphenicol 0.68 Phenytoin 0.11 Phytonadione 0.09 194 5 Allergic Diseases (and Differential Diagnoses)

Table 5.97. Common elicitors of certain cutaneous drug eruptions: Increased prevalences of drug drug eruptions eruptionsarecommoninHIVinfectionand 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” Theprevalencesofthemostimportanttypesof drugeruptionsfromaFinnishstudyareshown 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 Tet rac yclines 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) Lyell’s syndrome (toxic epidermal Hydantoin necrolysis) 8 Photosensitization 5 Lymphocytic Analgesics (plus alcohol?) Purpura 4 infiltration Lupuserythematosus-likelesions 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 (Schamberg’s 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

Drug-Induced Erythema Nodosum. Erythe- ma-nodosum-like skin lesions may be drug induced (anticonceptives, sulfonamides, phenylbutazone) (Fig. 5.74). In the pathogenesis, immune complexes but also cellular reactions have been discussed.

Lymphohistiocytic Reaction. This is a local- izedreactionmostlyinthefacewithlivid-red infiltrates (Fig. 5.75), sometimes occurring 12–24 h after intake of analgesics together with alcohol. Histologically, perivascular infiltrates Fig. 5.75. Lymphohistiocytic reaction of lymphocytes and histiocytes together with edema of the dermis are characteristic. area after repeated administration. With increasing number of relapses, skin lesions may be more brownish. Specifically sensitized lym- Bullous Drug Eruptions phocytesmaystayoverlongerperiodsoftime Fixed Drug Eruptions. These are sharply mar- inthearea.Patchtestsonlywillbepositivein ginated dark red to livid macules, which can be loco during remission (Fig. 5.78). New investi- blistering with predominant acral localization gations describe an early vascular phase with (hands, feet, glans penis) 24–48 h after drug in- CD4 infiltrates followed by an epidermal phase take (Figs. 5.76, 5.77). The characteristic fea- with CD8 cells and HLA-DR-expressing, partly tureistheoccurrenceonexactlythesameskin destroyed keratinocytes [41]. 5.7 Adverse Drug Reactions 197

Fig. 5.76. Fixed drug-induced exanthema of the oral mucosa

Fig. 5.78. Positive epidermal reaction to patch test in loco during remission (K.H. Schulz)

Fig. 5.77. Fixed drug-induced exanthema following the oral administration of phenylbutazone

Erythema Multiforme. Erythema multiforme- like skin lesions with typical target formations (Fig. 5.79) may be triggered by viral, bacterial infection or drugs. Sulfonamides and barbitu- ratesarecommon,alsotetracyclines.Pathoge- netically, type IV reactions but also immune complex mechanisms are suspected [27]. In the histology, subepidermal blistering is characteristic. A serious complication of erythema multiforme is mucosal involvement (conjunctival, oral, genital) (Figs. 5.80, 5.81) such as in Ste- vens-Johnson syndrome. In rare cases, there is Fig. 5.79. Exudative erythema multiforme 198 5 Allergic Diseases (and Differential Diagnoses)

transition possible into drug-induced Lyell’s syndrome (toxic epidermal necrolysis) (see below). Clinical and dermatopathological characteristics (Table 5.99), however, argue for the individual entity of the different diseases [39, 51].

Toxic Epidermal Necrolysis (Drug-Induced Lyell’s Syndrome). Drug-induced Lyell’s syndrome (“toxic epidermal necrolysis” or “syndrome of burnt skin”) represents the maximal Fig. 5.80. Exudativeerythemamultiformewithmuco- variant of bullous drug eruptions. sal involvement In 1956, Allen Lyell coined the term “toxic epidermal necrolysis” (TEN) for diseases which had been published earlier under different names (Table 5.100). In a retrospective study of 1967, Lyell postulated four subgroups of TEN [34]: drug-induced, staphylococcal-induced, miscellanea (sepsis, viral infections, vaccination, GVH, or malignancy) as well as idiopathic TEN. Today two forms of Lyell’s syndrome can be well differentiated clinically and pathophysiologically (Table 5.101): staphylococcal Lyell’s syndrome, also staphylococcal scalded skin Fig. 5.81. Erosive reaction of the oral mucosa (Ste- syndrome (SSSS) [10, 12, 39], whereas TEN in vens-Johnson syndrome) the actual definition comprises diseases where

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% – – +++ ++

Table 5.100. History and Exfoliative dermatitis Rittershain 1878 terminology of Lyell’s Erythrodermie avec epidermolyses Debr´e 1939 syndrome (from [45]) Toxicoderma bullosum Guszman 1940 Pemphigus aigu febrile Griveaud and Mitarb 1946 Toxic epidermal necrolysis Lyell 1956 Universelle epidermolysis acuta toxica Korting and Holzmann 1960 Syndrome de Lyell Dugois and Mitarb 1961 Syndrom der verbrühten Haut Braun-Falco and Geissler 1962 Lyell’s syndrome Jung and Mitarb 1964 Staphylococcal scalded skin syndrome Melish and Glasgow 1970 Acute disseminated epidermal necrolysis Ruiz-Maldonado 1985 (type III) 5.7 Adverse Drug Reactions 199

Table 5.101. Differences Staphylococcal Drug-induced between staphylococcal and drug-induced History Mostly first episode Sometimes previous Lyell’s syndrome incompatibility (from [28]) Family history S. aureus in family ¶ Drugs Variable Obligatory Age Newborn babies Elderly Skin pain +++ ± Mucosal involvement ++ ++ Conjunctival involvement + ++ Blister formation Subcorneal Junctional

Fig. 5.82a,b. Detachment of large areas of the epidermis in a patient with a drug-induced Lyell’s syndrome the whole epidermis is filled with necrotic keratinocytes in the blister roof [39].

Clinical Symptoms and Dermatopatholo- gy. The clinical symptoms of Lyell’s syndrome are dramatic in nature. After a prodromal phase with fever and unspecific complaints of the upper respiratory tract, often misinterpret- ed as a viral infection, macular eruptions occur, sometimes confluent and leading to large b areas of epidermolysis (Fig. 5.82a,b). Nikolski I and II signs are positive. The patient is “swimming in his own skin.” Mucous membranes are involved, and sometimes hair loss occurs. After successful therapy, skin will heal within 2–4 weeks with large scaling of epidermal components. Finger- and toenails may be lost. Postinflammatory hyperpigmentation is common. Mucosal changes heal more slowly, especially in the eye, giving rise to synechia (Fig. 5.83). Generally, there is a severe disease (highfever!).Throughthefluidloss,hypovole- mia occurs, leading to shock. Superinfection may compromise other organs (pneumonia). Fig. 5.83. Status post-Lyell’s syndrome with scarified Mucosal involvement gives rise to intestinal conjunctival lesions 200 5 Allergic Diseases (and Differential Diagnoses)

bleeding. Toxic changes of the liver (dystrophy, matory changes in the dermis (“empty cori- toxic fattening) and the kidneys (tubular neum”). Monoclonal antibodies may detect an in- crosis, interstitial nephritis) have been decrease 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 formation, early leukopenia, initial renal insufficiency, 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 Schöpf, the risk of drug-in- ell’s syndrome. The entire epidermis with necrotic duced Lyell’s syndrome in the total population keratinocytes is in the blister roof is 0.7 per 1 million inhabitants [53].

SSSS TSS TEN Table 5.102. Comparison between staphylococcal Etiology S. aureus (II) S. aureus (I) Drug (?) scalded skin syndrome Toxin Exfoliatin TSST-1 ? (SSSS), toxic shock syn- Blister formation Subcorneal Subgranular Junctional drome (TSS), and toxic Mucosal involvement ± ++ ++ epidermal necrolysis Organ involvement ++ ++ (TEN)

Fig. 5.86. Drug-induced Lyell’s syndrome. The basement membrane (arrow)remainsintactatthebaseof the continuity boundary. Above the lamina lucida there are cytoplasmic residues of necrotic keratinocy- Fig. 5.85. Histological picture of a staphylogenic Ly- tes (electron microscope magnification: 25,000:1). E, ell’s syndrome: subcorneal blistering epidermis; K, corium; ↑ basement membrane; #, cytoplasmic residue of a necrotic keratinocyte (reprinted with the consent of Prof. Dr. C. Luderschmidt) 5.7 Adverse Drug Reactions 201

Eliciting Drugs. Many textbooks contain “hit Table 5.104. Diagnosis of Lyell’s 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 –Phagetypingandtoxindetection – Blood culture 15 and more different drugs). The danger of “tau- ) tology” following reports from the literature is In vitro diagnosis (e.g., lymphocyte transformation, controls!) evident, leading to increased mentions of certain ) Skin test (after 2–3 months) substances which have been mentioned before. –Patchtest In a study of our own evaluating 306 cases, in – Prick, intradermal (dilution! one substance/ only 67 patients, clear-cut evidence for a suspect- day) ed drug was found (criterion: single or only recently 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 (devil’s 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 isdonethroughanexpertcommitteeleadingto (Fig. 5.87). Local therapy includes early oph- a list of eliciting drugs (Table 5.103). thalmologic counseling for prevention of synechia 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- toozu hoch high sus-ver- phocyte transformation tests have revealed undand sensitizations [54]. We observed positive skin toozu lange long däch-pect- tige ed tests in two out of four tested persons with severe TEN [32, 45]. Looking through the litera- Kortikoidesteroids Pharmakadrugs

Table 5.103. Suspected drugs as elicitors of TEN Sulfon- Sulfonamides amideamid- Aminopenicillins Quinolones Pflas-Ad- hesive ter oderor NSAID- NSAID Chlormezanone Carbamazepine Tape Phenobarbital ExternaTopical Phenytoin Valproic acid NSAIDs Fig. 5.87. Allopurinol Four important “Don’ts” when treating Ly- ell’s syndrome 202 5 Allergic Diseases (and Differential Diagnoses)

Table 5.105. Drug-induced Lyell’s syndrome therapy Inordertoinfluencetheimmunereaction, General measures the following drugs have been tried: Hospitalization in single room, intensive care or ) Cyclophosphamide burn center ) Cyclosporin A Warmth ) 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 Butonlycasereportsorsmallnumbershave Balneotherapy (antiseptics) been published [13, 17, 25, 30, 45, 49, 56, 59]. Metallic foil Debridement of necrotic epidermis The immediate and adequate general therapy is the performance of life-saving measures. Antiseptics (AgNO3, crystal violet, 0.1%, chlorhexidine) 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, tibioticswithunsuspiciousagentsarerecom- 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- timeswitheosinophils.Oftenaso-calledinter- 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- areasofnecrolysis(maximal4daysofhigh-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+naturalkillercells.Majorbasisprotein 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[ )orchemokines 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

Table 5.106. Pathophysiology of various forms of drug eruptions Clinical manifestations Suspected pathomechanism Differential diagnosis Urticarial eruption IgE, serum sickness Focus (infection, tumor) Erythematovesicular Systemic contact Toxic dermatitis, eczema atopic eczema Purpura – Thrombopenic Type II Coagulation defect – Vasculitic Type III Infection, tumor – Purpura chronica progressiva ? – Purpura senilis Cortisone effect Atrophy, vitamin deficiency Macular and maculopapular Type IV? Viral exanthema (special case: ampicillin rash) (B-cell stimulation?) Exfoliative dermatitis, scarlatini- Type IV? Scarlet fever (toxic shock syndrome) form eruption Bullous drug eruption (erythema Type III/type IVc Postherpetic EEM exsudativum multiforme, EEM) Erythema nodosum Type III? Sarcoidosis, infection Fixed drug eruption Type IVc Toxic epidermal necrolysis Type IVc Staphylococcals, scalded Skin syndrome Lichenoid eruption ? Lichen planus Acneiform eruption ? Acne vulgaris Psoriasiform eruption ? Psoriasis vulgaris Lymphohistocytic reaction Type IV Pseudolymphoma

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 complement 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- Lyell’ssyndromewithsubcornealblisters.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, androgens, barbiturates, Drug-induced Lyell’s 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 hydralazine 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

Morphology Example Table 5.109. Skin changes due to drugs Exanthematous drug eruptions (see Table 5.98) (selection) Pruritus Opioids, belladonna, laxatives Sebostasis Retinoids Pigmentary changes Metals (silver, gold, bismuth, mercury), antimalarials (gray-yellow), clofazimine (red), gestagens, estrogens (melasma) Atrophy/striae Glucocorticosteroids Keratoses, tumors Arsenic, cytostatics, levodopa (melanoma?) Nail changes Cytostatics, photosensitization, beta-blockers Alopecia Cytostatics, steroids, anticoagulants, retinoids Skin color changes Chloroquine, mephenesin, bleomycin Hypertrichosis Diazoxide, minoxidil, cyclosporin Iododerma/bromoderma Halogens Palmoplantar pustulosis Lithium Pseudolymphoma Phenytoin, analgesics, menthol Photosensitization See Sect. 5.6 Granuloma See Sect. 5.8 Embolia cutis Antirheumatics, steroids Necroses Coumarin, barbiturates, ergotaminine, see vasculitis allergica (Sect. 5.3) Mucosal changes See Sect. 5.5 5.7 Adverse Drug Reactions 205 heavymetals(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. 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Craven NM (2000) Management of toxic epider- (2001) Toxische epidermale Nekrolysen (Arznei- mal necrolysis. Hosp Med 61:778–781 mittel-induziertes Lyell-Syndrom). Dtsch Med 14. Crowson AN, Magro CM (1999) Recent advances Wochenschr 126:141–144, 177–179 in the pathology of cutaneous drug eruptions. 31. Le Cleach L, Delaire S, Boumsell L, et al (2000) Dermatol Clin 17:537–560 Blister fluid T lymphocytes during toxic epider- 15. Davis JP, Chesney PJ, Wand PJ, LaVenture M mal necrolysis are functional cytotoxic cells 206 5 Allergic Diseases (and Differential Diagnoses)

which express human natural killer (NK) inhibi- drome or toxic epidermal necrolysis. N Engl J tory receptors. Clin Exp Immunol 119:225–230 Med 333:1600–1607 32. Luderschmidt C, Linderkamp O, Ring J (1985) 49. Roujeau J-C, Stern RS (1994) Severe cutaneous Drug-induced toxic epidermal necrolysis (Lyell’s adverse reactions to drugs. N Engl J Med 331: syndrome) in a 4-year-old girl. Eur J Pediatr 1272–1285 14:91–93 50. Ruiz-Maldonado R (1985) Acute disseminated 33. Lyell A (1956) Toxic epidermal necrolysis: an epidermal necrosis types 1, 2, and 3: Study of six- eruption resembling scalding of the skin. Br J ty cases. J Am Acad Dermatol 13:623–635 Dermatol 68:355–361 51. Rzany B, Hering O, Mockenhaupt M, et al. (1996) 34. Lyell A (1967) A review of toxic epidermal necro- Histopathological and epidemiological charac- lysis in Britain. Br J Derm 79:662–671 teristics of patients with erythema exudativum 35. Marghescu S (1978) Allergische Arznei-Exanthe- multiforme major, Stevens-Johnson syndrome me. Pathomechanismus – Klinik – Testung– The- and toxic epidermal necrolysis. Br J Dermatol rapie. Perimed, Erlangen 135:6–11 36. Merk H, Gerecke D (1986) Arzneimittelneben- 52. Sachs B, Merk H (2001) Demonstration and char- wirkungen bei Patienten mit LAV/HTLV-III-In- acterization of drug-specific lymphocyte reactiv- fektion. AIDS-Bericht 2. Grosse, Berlin, pp ity in drug allergies. Allergy Clin Immunol Int 139–142 13:91–98 37. Merk HF, Hertl M (1996) Immunologic mecha- 53. Schöpf E, Stühmer A, Rzany B, Victor N, Zentgraf nisms of cutaneous drug reactions. Semin Cutan R, Kapp JF (1991) Toxic epidermal necrolysis and Med Surg 15:228–235 Stevens-Johnson syndrome. An epidemiologic 38. Merot Y, Saurat JH (1985) Clues to pathogenesis study from West Germany. Arch Dermatol of toxic epidermal necrolysis. Int J Dermatol 127:839–842 24:165–168 54. Schulz KH (1966) Stellenwert und Aussagekraft 39. Mockenhaupt M, Norgauer J (2001) Schwere arz- von Testmethoden bei allergischen Arznei-Exan- neimittelinduzierte Hautreaktionen. Allergologie themen. In: Braun-Falco O, Wolff HH (1979) 24:419–432 Fortschritte der praktischen Dermatologie und 40. Mougdil A, Porat S, Brunnel P, Jordan SC (1995) Venerologie, vol 9. Springer, Berlin Heidelberg Treatment of Stevens-Johnson syndrome with New York, p 71 pooled human intravenous immune globulin. 55. Steigleder GK (1966) Haut. In: Heintz R (ed) Er- Clin Pediatrics 34:47–51 krankungen durch Arzneimittel. Diagnostik, Kli- 41. Murphy GF,Guill´en FJ, Flynn TC (1985) Cytotoxic nik, Pathogenese und Therapie. Thieme, Stutt- T lymphocytes and phenotypically abnormal gart, pp 103–130 epidermal dendritic cells in fixed cutaneous 56. Schulz JT, Sheridan RL, Ryan CM, et al. (2000) A eruptions. Hum Pathol 16:1264–1271 10-year experience with toxic epidermal necroly- 42. Pichler WJ, Yawalkar N (2000) Allergic reactions sis. J Burn Care Rehabil 21:199–204 to drugs: involvement of T cells. Thorax 55 [Suppl 57. Smith CL, Brown I, Torraca BM (1997) Acetylator 2]:S61–S65 status and tolerance of high-dose trimethoprim- 43. Pichler WJ, Zanni M, von Greyerz S, et al. (1997) sulfamethoxazole therapy among patients infect- High IL-5 production by human drug-specific T ed with human immunodeficiency virus. Clin In- cell clones. Int Arch Allergy Immunol 113: fect Dis 25:1477–1478 177–180 58. Todd J, Fishaut M, Kapral F, Welch T (1978) Toxic- 44. Ring J (1987) Diagnostik von Arzneimittel-be- shock syndrome associated with phage-group-I dingten Unverträglichkeitsreaktionen. Hautarzt staphylococci. Lancet II:1116–1118 38:16–22 59. Viard I, Wehrli P, Bullani R, et al. (1998) Inhibi- 45. Ring J (1989) Drug-induced Leyell’s syndrome tion of toxic epidermal necrolysis by blockade of (toxic epidermal necrolysis). In: Pichler WJ, et al. CD95 with human intravenous immunoglobulin. (eds) Progress in allergy and clinical immunolo- Science 282:490–493 gy.Hogrefe&Huber,Toronto,pp455–461 60. Stern RS, Wintroub BU (1999) Cutaneous reac- 46. Ring J, Przybilla B, Gollhausen R (1989) Progres- tions to drugs. In: Freedberg IM, Eisen AZ, Wolff sive pigmentary purpura provoked by a phyto- K, et al. (eds) Fitzpatrick’s dermatology in gener- therapeutic drug containing Echinacea extract. al medicine, 5th edn. McGraw Hill, New York, pp Allergy Clin Immunol News 114:108–109 1633–1642 47. Ring J, Kraus K, Fröschl M, Brunner R, Przybilla 61. Wolff HH, Winzer M (1986) Histopathological B, Burg G, Braun-Falco O (1987) AIDS, HIV-In- patternsofdrugeruptions.In:RingJ,BurgG fektion und allergische Reaktionen. AIDS For- (eds) New trends in allergy II. Springer, Berlin schung 2:643–646 Heidelberg New York, pp 240–253 48. Roujeau JC, Kelly JP,Naldi L, et al. (1995) Medica- 62. Zürcher K, Krebs A (1992) Cutaneous drug reaction use and the risk of Stevens-Johnson syn- tions. Karger, Basel 5.8 Granulomatous Reactions 207

5.8 Granulomatous Reactions

In some textbooks, type IV reactions include both allergic contact dermatitis and tuberculin reactions under the common pathophysiology of sensitized T-lymphocyte reaction with a dif- ference of route of administration (epidermal versus intradermal). The kinetics of tuberculin correspond to a maximum between 48 and 72 h after intradermal administration of allergen to thosewithepidermalpatchtestreactions. Quite different kinetics (3–5 weeks) are characteristic of the lepromin reaction as well as some other granulomatous infectious diseases characterized by typical histopathology with epithelioid cell granulomas [6, 11, 26]. The clear-cut differences in clinical symptomatology, dermatohistopathology, and kinetics [3, 29, 30] justify a separate classification of granulomatous hypersensitivity reactions as type V (see Chap. 1). Granulomatous reactions are inflammatory changes occurring with slow development over 3–5 weeks and long-lasting persistence; histologically, they are characterized by typical epithelioid cell granuloma formation in the upper Fig. 5.88. Multiple circumscribed brownish-red nod- and mid dermis. In the skin brownish-red or ules at the injection site following the repeated intradermal administration of procaine polyvinylpyrroli- livid nodules are characteristic, sometimes done (PVP) to alleviate back pain (from [3]) showing a “lupoid” infiltrate under the diascope [6]. ple brownish-red sharply margined nodules at the injection sites, histologically resembling 5.8.1 Clinical Examples sarcoid granuloma without clinical evidence Common clinical examples of allergic reactions for sarcoidosis (Figs. 5.88, 5.89). Earlier admin- of the granulomatous type V are the zirconium istrations had been tolerated without adverse granuloma after application of zirconium-con- reaction. In the intradermal test, a positive taining deodorants with histologically typical granulomatous reaction was observed [3]. Sim- epithelioid cell granulomas without necrosis ilar granulomas have been described after ad- together with lymphocytic infiltrates with for- ministration of other PVP-containing sub- eign bodies in polarization microscopy [30]. stances [4], whereby often clear storage pro- Rare subcutaneous granuloma formations cesses were evident in contrast to the hypersen- after allergen-specific subcutaneous immuno- sitivity reaction to minute amounts as ob- therapy can equally be classified as type V, es- served in our patient. pecially after application of aluminum hydrox- In dermatological practice, granulomatous ide adsorbed allergen extracts [2]. In some reactions have gained relevance against soluble cases, these granulomas may change into sub- bovine collagen used for the correction of scars cutaneouspseudolymphomas[15]. and wrinkles [7, 8, 12, 16–20, 27, 29]. There- After repeated intradermal administration fore, prior to such treatment, a test injection of procaine polyvinylpyrrolidone (PVP) for needs to be performed, which can lead to clini- back pain, one of our patients developed multi- cally visible nodule formation in 0.3% of the 208 5 Allergic Diseases (and Differential Diagnoses)

Fig. 5.89. Histological examination of the lesions Fig. 5.90. Protruding hard inflammatory lesions fol- showninFig.5.88yieldsthepictureofsarcoidgranu- lowingtheinjectionofsolublebovinecollagenina loma even though there is no clinical evidence of sar- patientwithtypeVallergy(from[29]) coidosis (from [3])

nophenotyping often shows T cells, NK cells, patients [7]. Without this test injection or when and macrophages together with activated fi- sensitization occurs during the first treatment, broblasts. long-lasting persistent granulomatous inflam- The mechanism of activation of NK cells – matory skin reactions may develop at the injec- especially the recently discovered NKT-cell tion site (Figs. 5.90, 5.91) [29]. subpopulation – is not well understood [22]. It seems that NKT cells appear early in the reaction while classic NK cells may stay for a longer 5.8.2 Pathophysiology time at the inflammatory site [23] and mediate Activation of T cells and macrophages for elim- or elicit functions of innate immunity. Among ination of infectious agents plays a major role the various cytokines, especially a member of in immune defense (especially against intracel- the lymphotoxin family, namely LT [ 3, plays a lular microorganisms). When antigen cannot major role in the recruitment of lymphocytes be eliminated totally, this can lead to continu- and macrophages and, thus, the persistence of ous T-cell activation and macrophage reactions granuloma formation [24]. with accumulation of epithelioid cells and for- In the complex interaction between sensi- mation of giant cells. Macrophages which have tized lymphocytes producing certain cytokines taken up bacterial antigens and present those [22] and macrophages, possibly also immune may be destroyed by cytotoxic T cells, as well as complex phenomena (high antibody titers of by natural killer cells in an unspecific manner. the IgG class) may be involved. In the above-de- Therefore, in granulomatous reactions, immu- scribedcaseofbovinecollagenhypersensitivi- 5.8 Granulomatous Reactions 209

flammatory skin diseases such as granuloma anulare, sarcoidosis, Melkersson-Rosenthal syndrome, M. Crohn, Wegener’s granulomatosis, or Churg-Strauss granulomatosis. Some common features of these diseases might be explained by a deposit of a persisting yet unknown antigen. In granuloma anulare in the early phase, signsofvasculitiswithpositiveimmunofluo- rescence[9,14]canbefound.Itisawell-known clinical experience that granuloma anulare sometimes develops after insect stings or minimal trauma and can heal spontaneously after skin biopsy (removal of persistent antigen?). Development of granuloma anulare after injection of soluble collagen has been described [22].Weobservedanexacerbationofscarsar- coidosis under immunotherapy with interferon which had been silent for decades [10].

5.8.3 Therapy Treatment uses glucocorticosteroids (according to the organ manifestation). In granulomatous 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]) drugsaswellasUVA-1irradiationhavebeen 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, chronicstageofextrinsicallergicalveolitis(hy- Huerre M, Marchal G, Cui J, Taniguchi M, Nakau- persensitivity pneumonitis). On the basis of chi H, Fourni´e J-J, Kourilsky P, Gachelin G (1999) these considerations, a hypothetical concept Murine natural killer cells contribute to the granulomatous 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) Häufigste 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– canbeseentogetherwithhightitersofprecipi- 477 tating antibodies, while in the chronic course 4. Bork K, Hoede N (1982) Vortäuschung 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-inducedsilicagranulomaofthegingiva. 28. Cooperman LS, Mackinnon V, Bechler G, Phar- Dermatology 203:177–179 riss BB (1983) Injectable collagen: A six-year clin- 20.McCoyJP,SchadeWJ,SiegleRJ,VanderveenEE, ical investigation. Aesth Plast Surg 9:145–151 Zachary CB, Waldinger TP, Swanson NY (1987) 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-König 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, Masouy´e 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. KlepzigK,RingJ,BurgG(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 FalcoO,BurgG(eds)Fortschrittederprakti- 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

Autoimmune Thyreoiditis. The autoantibody 5.9 Type VI Reactions (Stimulating/ acts like a hormone. Thyreoid-stimulating ac- Neutralizing Hypersensitivity) tivity (long-acting thyroid-stimulating factor, While the pathology of allergic diseases types LATS) was found decades ago in patients with I–V is mainly due to activation of humoral or Hashimoto’s thyreoiditis. These autoantibodies cellular inflammatory systems, the pathologic stimulate specifically the TSH receptor and response of type VI reactions occurs through may elicit a thyreotoxic crisis. As IgG anti- direct interaction of an antibody molecule with bodies they pass through the placenta and may a receptor mediating a signal without inflam- induce reversible thyreotoxicosis in neonates. mation (comparable to a hormone) leading to Myasthenia Gravis. the untoward reaction. Autoantibodies in myas- theniagravisdonotstimulatebuthaveablock- ing effect, directed against the acetylcholine receptor on the motoric endplate of the muscle 5.9.1 Clinical Examples of Autoimmune Diseases [1,9,14]. Thebest-knownexamplesoftypeVIreactions areclassicalautoimmunedisease[2,6,8,9,11]. 5.9 Type VI Reactions (Stimulating/Neutralizing Hypersensitivity) 211

Table 5.111. Direct pathogenic effects of autoantibodies Disease Specificity Clinical symptoms Thyreotoxicosis TSH receptor Stimulation, hormone formation Myasthenia gravis Acetylcholine receptor Blockade, muscle weakness q Antiphospholipid syndrome Cardiolipin/ 2-glycoprotein Thromboembolic complications Pernicious anemiaa ATPase, gastrin receptor Decreased acid production, decreased B12 resorption Male infertility Spermatozoa Agglutination and immobilization of spermatozoa Wegener’s granulomatosis Proteinase III (neutrophil granu- Endothelial damage locytes) Acanthosis nigricans (type B) Insulin receptor Receptor blockade, proliferation Pemphigus vulgaris Desmoglein 3 Bulla formation (acantholysis) a Hematological cytopenias (anemia, thrombocytopenia); see Sect. 5.2

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]. totalserumIgEorinthecourseof 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 nentsofinnateimmunity,e.g.,asoverstimula- 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]

In clinical experimental models, it has been 5.9.3 Stimulating/Neutralizing Reactions known for a long time that IgG antibodies in Classic Allergic Diseases against IgE or IgE receptors may elicit in vitro In a variety of classic allergic diseases with well- andinvivosimilarreactionsasallergen(e.g., known antibody formation against exogenous in vitro histamine release from peripheral ba- allergens, recently autoantibodies of different sophil leukocytes with anti-IgE as positive con- classes against cells or surface receptors autolo- trol). gous with possible pathogenic importance have The positive wheal and flare reaction after been found (Table 5.112). These include: injection of anti-IgE in the passive cutaneous anaphylaxis (PCA) has been known as “reverse anaphylaxis” for a long time [7]. Table 5.112. IgE and autoimmune reactions Thebetterweunderstandthemolecular Autoan- Specificity Disease mechanisms of these reactions, the more it is to tibody be expected that overlaps between type VI and IgG IgE Immunotherapy other allergic reaction types (e.g., type II) will IgG Fc 5 RI Chronic urticaria be detected. IgE Hom s 1–5 (epi- Severe atopic eczema dermal proteins) 212 5 Allergic Diseases (and Differential Diagnoses)

5. Hide M, Francis DM, Grattan CE, Hakimi J, Ko- 5.9.4 Therapy chan JP, Greaves MW (1993) Autoantibodies The existence of a stimulating/neutralizing hy- against high-affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl J persensitivity is not an esoterical-philosophi- Med 328:1599–1604 cal idea but has important practical and thera- 6. King C, Sarvetnick N (1997) Organ-specific auto- peutic implications: In patients with autoanti- immunity. Curr Opin Immunol 9:863–871 bodies against the IgE receptor, chronic urti- 7. Peter HH, Pichler WJ (1996) Klinische Immuno- caria does not respond to antihistamines and logie, 2nd edn. Urban & Schwarzenberg, Munich 8. Roitt IM (1996) Essential immunology, 8th edn. should be treated with cortisone or immuno- Blackwell, Oxford suppressives. 9. Shoenfeld Y, Isenberg D (eds) (1993) Natural au- The skin lesions of patients with atopic ecze- toantibodies. CRC Press, Boca Raton, Florida ma and high IgE autoantibodies against epider- 10. Stadler BM, Miescher S, Horn M, et al. (2001) Al- mal proteins will not improve by allergen lergic manifestations as the results of a condition- al autoimmune response. Int Arch Allergy Immu- avoidance. Active anti-inflammatory or immunol 124:411–413 nosuppressive treatment is indicated. 11. Tan EM (1982) Autoantibodies to nuclear anti- In certain antibody-mediated autoimmune gens (ANA): their immunobiology and medicine. diseases, the intravenous administration of im- Adv Immunol 33:167–240 munoglobulin G in high doses has proven ben- 12. Valenta R, Seiberler S, Natter S, et al. (2000) Auto- allergy: a pathogenetic factor in atopic dermati- eficial [4, 7, 8] (see Sect. 5.2). tis? J Allergy Clin Immunol 105:432–437 13. Venter JC, Fraser CM (1981) The development of monoclonal antibodies to beta-adrenergic recep- References tors and their use in receptor purification and characterization. In: Eisenbarth G, Fellows R (eds) Monoclonal antibodies in endocrine re- 1. Almon RR, Andrew CG, Appel SH (1974) Serum search. Raven Press, New York, pp 119–134 globulin in myasthenia gravis: inhibition of alpha- 14. Vincent A, Mewsom-Davis J (1982) Acetylcholine bungarotoxin binding to acetylcholine receptors. receptor antibody characteristics in myasthenia Science 186:55–57 gravis. I. Patients with generalized myasthenia or 2. Atkinson MA, Maclaren NK (1994) The pathogen- disease restricted to ocular muscles. Clin Exp Im- esis of insulin-dependent diabetes mellitus. N Engl munol 49:257–265 J Med 331:1428–1436 15. Wegmann DR (1996) The immune response to is- 3. Beck K, Hertel J, Rasmussen NG, et al. (1991) Effect lets in experimental diabetes and insulin-depen- of maternal thyroid antibodies and postpartum dent diabetes mellitus. Curr Opin Immunol thyroiditis on the fetus and neonate. Acta Endocri- 8:860–864 nol 125:146:149 4. Chapel H, Haeney M (1993) Essentials of clinical immunology, 3rd edn. Blackwell, Oxford

Table 5.113. “Eco-syndrome”: identical or related syn- 5.10 “Eco-syndrome” (“Multiple dromes Chemical Sensitivity,” MCS) ) “Multiple chemical sensitivity” (MCS) 5.10.1 Classification ) “Multiorgan dysesthesia” ) “Idiopathic environmental intolerance” An increasing number of patients visit the doc- ) “Environmental illness” ) tor because of supposed incompatibility reac- “Allergy to the 20th century” ) “Total allergy syndrome” tions against environmental pollutants with ) “Chronic fatigue syndrome” quite variable complaints, often involving sev- ) “Candidiasis hypersensitivity syndrome” eral organ symptoms which are difficult to re- (“yeast connection”) ) “Wood furnishing syndrome” produce objectively. The patients have often ) undergone an odyssey of visits to various spe- “Living room poison” ) “Toxicopia” cialists, so-called special clinics, or “gurus” without having found help. The problem is well 5.10 “Eco-syndrome” (“Multiple Chemical Sensitivity,” MCS) 213

Table 5.114. Eco-syndrome: common complaints (selection) Neurologic symptoms Skin and mucous membranes General complaints Fatigue, malaise, headache, verti- Itch, burning of the skin, eye irri- Gastrointestinal: nausea, diarrhea, go, concentration disturbance, tation, dry larynx and nose, rhi- obstipation, flatulence, gastric pain sleep disturbance, psychologic norrhea, dyspnea, hair loss Cardiovascular: cardiac pain, anxi- symptoms (confusion, anxiety, ety, tachycardia memory loss, irritability, depression) Flu-like symptoms: mild fever, arthralgia covered in the media and has received attention ) There is immense suffering under different names (Table 5.113). ) Exclusion of other well-defined diseases Themostlysubjectivecomplaintsmaybe From this list it is clear that the diagnosis classified roughly into skin and mucous mem- “MCS”canneverbemadeinaclear-cutfashion 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” wouldbebetter,butitseemstocontradictthe 5.10.2 Differential Diagnoses opinions of the patients, who are convinced of their hypersensitivity. On the other hand, there The“eco-syndrome”partlyhassimilarities 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,isatotallydifferentgroupwith 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 pain 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 building-related illnesses (BRI) (Table 5.115) ) Elicitation of symptoms by a variety of [18, 19, 33]. factors in low dose exposure BRI are well-known and objective diseases, ) Various symptoms manifesting in more and include infectious diseases and allergies. than one organ system and improving after SBS is due to a complex interaction between avoidance of exposure physical, chemical, and biological exposure as ) The complaints cannot be explained by well as psychological factors with occurrence classical examination of subjective complaints in a large number of ) There is a tendency to chronification 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

5.10.3 Pathophysiological Concepts ence of becoming sick from the environment. So Toxicological Concept. Intoxication by envi- it is tempting to look at the environment for elic- ronmental noxious agents is regarded as causal itors of unexplained disturbances. especially by followers of the so-called “clinical ecology” in the United States. Large toxicologic Neurological Concept. Many environmental measurements including biomonitoring of af- noxes have an impact on the nervous system fected individuals, however, have not yet given leading to psychiatric phenomena, concentra- evidence for intoxications by environmental tion disturbance, or fatigue. The low reproduc- noxes [34]. Enzyme defects have been dis- ibility and subjectivity of the complaints may cussed [12, 14]. be the reason that this theory has not yet been proven[1,2,3,7,28,31]. Immunological Concept. Another theory describes damage of the immune system by Olfactoric Concept. Many patients suffer from chemicals leading to disturbance of cellular increasedolfactorysensitivityandbelievethey andhumoralimmunity.However,nodevia- can detect (smell) very low concentrations of tions of immune response were measurable in environmental chemicals as unpleasant odors objective trials [30]. (kakosmia). According to this hypothesis, an olfactoric-hypothalamic-limbic stimulus transfer Allergological Concept. Many patients believe may induce symptoms in the sense of condi- strongly that they are allergic against minute tioned learning and amplification to olfactory amounts of environmental poisons. In our own stimulation [4, 22]. In clinical practice using ol- intensive investigations in approximately 100 factometry, this hypothesis has not been proven. patients, we found objective hypersensitivity phenomena (both allergic and pseudo-allergic Psychiatric Concept. Many physicians believe in nature) in approximately one-third of our pa- that patients with “eco-syndrome” suffer from tients; this could explain some of the complaints; psychiatric disease. Indeed, some cases of true however, rarely were they directed against the endogenous psychoses (schizophrenia, manic- originally suspected environmental noxes [13, depressive reactions, etc.) were present among 23, 24, 25]. The majority of patients have an our patients. One of my first patients, a 35-year- atopic diathesis and are familiar with the experi- old female, believed herself to be allergic against 5.10 “Eco-syndrome” (“Multiple Chemical Sensitivity,” MCS) 215

“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. therespectiveelectromagneticwaves.Inthe 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 verycommoninthe19thcenturyandcalled 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- diagnosissuchas“nervaldisturbance”inthe 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 theinvestigations,whichshouldbeperformed

Table 5.116. Recommendations for the management of patients with “eco-syndrome” ) Since many patients suffer from being neglected or primarily regarded as “psychologic,” a physician-patient relationship based on mutual confidence is most important. This needs time, patience, and talking. ) Theproblemhastobetakenseriously;atthesametime,irrationalexpectationshavetobecalmeddown. ) The examination requires a general understanding of the whole human being and includes the psychosocial aspects as well as possible environmental influences. ) Through cooperation with other disciplines, diseases sometimes disguised under the term “eco-syndrome” have to be excluded, such as: – Infectious diseases (sinusitis, mononucleosis, respiratory infection) – Allergies (rhinoconjunctivitis, atopic eczema, allergic contact eczema, urticaria) – Metabolic toxic diseases (diabetes mellitus, drug abuse, hypo- or hyperthyreoidism) –Malignantneoplasias – Psychiatric disease ) Polypragmatic diagnostics and therapy have to be avoided: – Only recommend measurements when results can be interpreted! – Only recommend acceptable procedures (avoid prophylactic measures in houses and apartments connected with high financial and personal input). – Do not treat laboratory results but individual disease conditions. – Avoid “depoisoning” techniques which may be risky. – Avoid social and human isolation. ) The evaluation of environmental parameters should be done on a strictly scientific basis, e.g. – Objective environmental toxicological dose-response relationships and epidemiological evidence – Allergologic-immunological examinations for detection of allergy or pseudo-allergy – Besides rational recommendations for therapy based on diagnosis of eliciting causes, a supportive atti- tude is crucial including if needed psychologic-psychiatric consultations and therapies. 216 5 Allergic Diseases (and Differential Diagnoses)

with interdisciplinary cooperation. The avoid- Gebefügi 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: ance of allergens, the administration of specific 141–143 diets(e.g.,pseudo-allergicreactionstofood 11. Eikmann T, Herr C (2001) Ein Paradigmenwech- additives), change of living conditions or sel in der Umweltmedizin? Umwelt Forschung psychosomatic or psychiatric counseling (Ta- Prax 6:179–180 12. Fabig K-R (1999) Glutathion-S-Transferase T1 ble5.116).Thereisconsiderableneedforre- und Multiple Chemikaliensensitivität (MCS). search. The major advice I give my co-workers Umwelt Medizin Gesellschaft 12:226–232 in dealing with these patients is: “Take the pa- 13. Gieler U, et al. (1998) Therapeutische Aspekte des tient seriously!” MCS-Syndroms. Umweltmed Forschung Praxis There is no need for pessimism: In a long- 3:3–10 14.GrimmV,RuhdorferS,Eberlein-KönigB,Sche- termfollow-upover2–5yearswefoundthat rer G, Engst R, Ring J (1999) Defizit der Glutathi- two-thirds of our patients had remarkably im- ontransferase bei Patienten mit Öko-Syndrom? proved or were almost symptom free. Allergo J 8 [Suppl 1]:32 15. Hüppe M, Bullinger M (1997) Verfahren zur MCS-Diagnostik. Zusammenfassung und Bewer- tung einer Umfrage. Umweltmed Forschung Prax References 2:291–294 16. IPCS (International Programme on Chemical 1. Abbey SE, Garfinkel PE (1991) Neurasthenia and Safety) (1996) Report of Multiple Chemical Sensi- chronic fatigue syndrome: The role of culture in tivities (MCS) Workshop. Berlin, Inst Arch Occup making of a diagnosis. Am J Psychiatry 148: Environ Health 69:224–226 1638–11646 17. Kofler W (1993) Umweltängste, Toxikopie-Me- 2. Altenkirch H (1995) Multiple chemical sensitivity chanismus, komplexes evolutionäres Coping- (MCS)-Syndrom. Gesundheitswesen 57:661–666 Modell und die Notwendigkeit neuartiger Aufla- 3. Bartenstein PF, Grundwald F, Herholz K, Kuwert gen für genehmigungspflichtige Anlagen. In: Au- T, Tatsch K, Sabri O, Weiller C (1999) Rolle der Po- rand K, Hazard BP, Tretter F (eds) Umweltbela- sitronen-Emissions-Tomographie (PET) und stungen und Ängste. Westdeutscher Verlag, Single-Photon-Emissions-Tomographie (SPECT) Wiesbaden, pp 225–226 bei der sogenannten “Multiple Chemical Sensi- 18. Kröling P (1989) Zur Problematik des “Sick tivity” (MCS). Nuklearmedizin 38:297–301 building”-Syndroms. Allergologie 3:118–129 4. Bell IR, Miller CS, Schwarz GE, et al. (1996) Neu- 19. MolinaC,CaillaudD,MolinaN(1993)Sickbuild- ropsychiatric and somatic characteristics of ing syndrome and atopy. Indoor Air 1:369–373 young adults with and without self-reported 20. Neuhann HF, Wiesmüller GA (1994) Diagnosti- chemical odor intolerance and chemical sensitiv- sche Strategien bei gebäudebezogenen Gesund- ity. Arch Environ Health 51:9–21 heitsstörungen. In: Luftverunreinigung in Innen- 5. BinkleyK,KingN,PoonaiN,SeemanP,UlpianC, räumen. VDI Berichte 1122 Kennedy J (2001) Idiopathic environmental intol- 21. Nixon PGF (1982) “Total allergy syndrome” or erance: Increased prevalence of panic disorder- fluctuatinghypercarbia?LancetI:516 associated cholecystokinin B receptor allele 7. J 22. Österberg OP, Akesson B, Bergendorf U, Karlson Allergy Clin Immunol 107:887–890 B, Seger L (1998) Suprathreshold intensity and 6. Bornschein S, Hausteiner C, Zilker Th, Bickel H, annoyance reactions in experimental challenge to Förstl H (2000) Psychiatrische und somatische toluene and n-butyl acetate among subjects with Morbidität bei Patienten mit vermuteter Multiple long-term solvent exposure. Scand J Work Envi- Chemical Sensitivity (MCS). Nervenarzt 71: ron Health 24:432–438 737–744 23.RingJ,GabrielG,VielufD,PrzybillaB(1991) 7. Bullinger M (1989) Psychological effects of air “Das klinische Ökologie-Syndrom” (“Öko-Syn- pollution on healthy residents – a time-series ap- drom”): Polysomatische Beschwerden bei vermu- proach. J Environ Psychol 9:103–118 teter Allergie gegen Umweltschadstoffe. Münch 8. Cullen MR (1987) The worker with multiple Med Wochenschr 133:50–55 chemical sensitivities: An overview. State Art Rev 24.RingJ,Eberlein-KönigB,BehrendtH(1999) Occup Med 2:655–661 “Eco-Syndrome” (“multiple chemical sensitivity” 9. Derbolowsky J (1999) Die Glaubwürdigkeit wie- – MCS). Zbl Hyg Umweltmed 202:207–218 der herstellen. Zeitschr Umweltmed 7:2–4 25. Ring J, Triendl C, Behrendt H, Borelli S (2000) 10. Eberlein-König B, Przybilla B, Kühnl P, Pechak J, Das Öko-Syndrom (multiple chemical sensitivi- References 217

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