Chapter 6 6 Allergy Prevention and Therapy

6.1 General Concept of Allergy The next causal therapeutic option is - Treatment specific immunotherapy (hyposensitization), whereitispossibletochangetheabnormal The most efficient causal method of allergy treat- pathologic immune reaction into normal im- mentistheavoidanceoftheelicitingallergen munity. (Fig. 6.1). This underlines the immediate impor- The final aim of any treatment is that the pa- tance of careful allergy diagnosis. There are few tientwillbefreeofsymptoms.Thesinglesteps disciplines in medicine in which diagnosis and in the general concept of allergy treatment do therapyareascloselyconnectedasinallergolo- not exclude each other! Also during allergen- gy. Note: “Not every cold in summer is hay fever, specific immunotherapy, symptomatic treat- not every cold in winter is a viral infection!” menthastobegiven.Table6.1showsthemost Allergen avoidance comprises not only the important steps of a treatment strategy ranging avoidance of pets, sanitizing measures in the from allergen avoidance to psychosomatic apartment, anti-housedust mite strategies, but counseling or psychotherapy. also the elimination of unspecific irritants, as After prophylactic treatment with mast cell well as dietetic regimens in food allergy; finally stabilizers (e.g., cromones), anti-inflammato- changes in occupation as well as rehabilitation ry strategies are the most important symp- treatments in an allergen-poor climate (North tomatic treatment. Here glucocorticosteroids Sea, high altitude as in Davos, Switzerland) are in first place, and these have gained much have to be considered. in efficacy and safety by the development of

Level of action Procedure Table 6.1. General con- cept of allergy treat- Allergen exposure Avoidance (e.g., apartment, mite protection, rehabili- ment tation in occupational allergy, climatic therapy, diet) Pathogenic immune Allergen-specific immunotherapy (hyposensitiza- reaction tion), immunosuppression, immunomodulation Inhibition of mediator Mast cell stabilizers release Inhibition of Glucocorticosteroids inflammation Receptor antagonists Histamine (sedating, non-sedating) Leukotrienes Leukotriene antagonists, lipoxygenase inhibitors Specific therapy at Bronchodilation, secretolysis, physical therapy, skin organ level care, restoration of disturbed barrier Psyche Antidepressives, psychotherapy, psychosomatic counseling 6.1 General Concept of Allergy Treatment 219

Allergen source / carrier

Antigen Allergen/Elicitor

Antibodies / T cells

Mediator secreting cells

Mediators

End organs

Fig. 6.1. General concept Symptoms / Disease of allergy treatment (points of intervention) topicalproductsformucousmembranesand al” or “complementary” therapeutic proce- skin. dures have gained a high degree of popularity Antagonists of proinflammatory mediators in many countries, but rarely show evidence- are the most commonly used antiallergic based efficacy. Depending on the definition drugs. Apart from antihistamines, also antago- of “complementary,” some procedures (e.g., nistsofleukotrienesorinhibitorsoflipoxyge- autogenic training, Kneipp’s hydrotherapy) can naseshouldbementioned. be supplementary in some conditions (see Finally, the specific therapy at the diseased Sect. 6.4). organ – in asthma bronchodilation, secretoly- The novel experimental therapeutic con- sis, physical therapy, in eczema skin care, anti- cepts which are undergoing clinical trials may microbial treatment, and restoration of im- be the therapeutic options of the future and paired barrier function – is crucial. should not be called “complementary.” Allergic reactions show a well-known inter- action with psychologic factors; therefore, psy- chosomatic counseling may be important. Phytopharmacological preparations are used in allergy treatment and “unconvention- 220 6 Allergy Prevention and Therapy

Table 6.2. Histamine H receptor antagonists 6.2 Antiallergic Pharmacotherapy 1 Classic antihistamines New less sedating 6.2.1 Inhibition of Histamine Synthesis Alimemazine antihistamines Bamipine Previously, substances inhibiting histidine de- Clemastine Cetirizine carboxylase and thereby the synthesis of hista- Cyproheptadine Desloratadine Dexchlorpheniramine Ebastine mine were recommended (e.g., tritoqualine). Dimetinden Fexofenadine Flavonoids may have a similar action. Studies Diphenhydramin are in progress. Doxylamine Levocetirizine Hydroxyzine Loratadin Meclozine Mizolastine 6.2.2 Mast Cell Stabilizers Mequitazine Terfenadine These substances are able to inhibit the release of mediators on the surface of mast cells and pete with histamine on the H1 receptor and can basophil leukocytes most likely by acting on be further distinguished in different pharma- the calcium channel [30]. The best known sub- cologicalgroups(Fig.6.2).ThesidechainsR1 stance is disodium cromoglycate (DSCG) [3], and R2 contain aromatic or heteroaromatic which is used in different galenic formulations ring structures. Furthermore, mention should for the conjunctiva, the nasal mucosa, the be made of tricyclic systems, which are deriva- bronchial tract, and the gastrointestinal tract. tives of phenothiazine. Cromones are also used in veterinary medicine The most commonly used so-called classic (obstructive bronchitis in racehorses). Another antihistamines are not totally specific and cromone is . Cromoglycates can on- apart from also show antagonis- ly be used topically on the mucosal surface. tic effects with other receptors such as acetyl- They do not penetrate the epidermis and are choline, serotonin, and dopamine. Due to anti- not absorbed from the gut. Neither systemic cholinergic effects, some antihistamines are treatment nor topical skin treatment is possi- contraindicated in glaucoma, urinary reten- ble. tion,aswellasinpatientsundertreatmentwith Someotherdrugswhichalsohaveantihista- monoaminooxidase (MAO) inhibitors. mine properties act as mast cell stabilizers like Sedation is the most common side effect, ketotifen [29] and oxatomide. Ketotifen not on- which may be welcome under some conditions ly is effective against allergen-induced but also (againstitchduringthenight).Thereare,how- against bronchoconstriction due to platelet-ac- ever, paradoxical reactions especially in chil- tivating factor and is able to influence bronchi- dren, who show signs of hyperactivity after an- al hyperreactivity over longer periods of time. tihistamines. Sedation is especially undesired in patients who have to be well oriented in their occupa- 6.2.3 Antihistamines tion [8, 9]. Therefore, the development of the Since the first antihistamine (Bovet and Staub newnon-sedatingH1 antagonists (Table 6.2) is [10]), a multitude of H1 antagonists (in Germa- one of the major advances of allergy therapy ny more than 50 preparations are on the mar- [37, 39, 42]. Most of the substances are also ket) have been developed (Table 6.2); they com- available for children in liquid form.

– Ethylendiamine-Type: X = N-Atom – Colamine-Type: X = O-Atom – Propylamine-Type: X = C-Atom Fig. 6.2. Classification of the H1 antagonists 6.2 Antiallergic Pharmacotherapy 221

In severe cases of chronic urticaria or for miracle drugs. The history of leukotriene an- prophylaxis of anaphylactoid reactions, the tagonistsisagoodexampleoftheadvances combined administration of H1 and H2 antago- made in practical medicine: From the charac- nists (see Sect. 5.1.4 on “Anaphylaxis”) has terization of the substance in 1979 by Samuel- been recommended. son until the first practically available antago- The topical use of antihistamines as antipru- nist for the patient, there was a time lag of al- ritics (e.g., after insect stings) is controversial. most 20 years in spite of very intensive research The possible beneficial effect of some antihista- being carried out. mine gels is most likely due to the alcoholic ve- hicle more than the drug. LTB4 Antagonists The search for LTB4 antagonists was not as suc- cessful although a variety of substances have 6.2.4 Leukotriene Inhibitors been tried in experimental and clinical trials Leukotrienesareamongthemostactiveproin- (e.g., LY293111, Lilly, CGS25019C, Novartis, BI- flammatory mediators and have principally IL284BS, Boehringer-Ingelheim). These sub- two quite different effects: LTB4 is chemotactic stanceshaveaneffectininvitroandinexperi- for neutrophil and eosinophil granulocytes, mental models, but have produced controver- and the sulfidoleukotrienes LTC4, LTD4, and sial results in clinical trials. LTE4 have a long-acting bronchoconstrictory effect (previously called “slow-reacting sub- 6.2.5 Glucocorticosteroids stance of anaphylaxis SRS-A”). Glucocorticosteroids (GC) play a central role in antiallergic treatment since almost all inflam- 6.2.4.1 Lipoxygenase Inhibitors matory phenomena elicited during an allergic By inhibiting 5-lipoxygenase (5-LO), reduction reaction may be inhibited. GC act after passive of both LTB4 and sulfidoleukotriene is possi- penetration through the cell membrane and ble. Specific 5-LO inhibitors (e.g., zileuton, gen- binding to a GC receptor in the cytoplasm, leuton) may be distinguished from inhibitors which is normally protected by heat-shock pro- of an interaction between 5-LO- and the “5-li- teins from dimerization. The novel complex poxygenase-activating protein FLAP” (e.g., then enters into the nucleus and binds to the MK886, BAYx1005) [35]. promoter region of certain genes (GC-respon- Zileuton is used against asthma in the United sive elements) inducing the well-known cata- States; it has to be given 3–4 times per day and bolic effects by increased transcription. At the can induce disturbance of liver function. It af- same time, GC bind to intracellular regulator fects allergen-induced bronchoconstriction and proteins (transcription factors NF-κBoracti- decreases the use of cortisone in asthmatics. vator protein 1AP1) and inhibit mRNA forma- tion.Thisisthebasisofanti-inflammatoryand in allergy therapy desired effects [5, 21, 22, 33] 6.2.4.2 Leukotriene Antagonists (Table 6.3). Sulfidoleukotriene Antagonists In practice, the distinction between system- Several companies have developed specific an- ic and topical GC therapy is essential. The most tagonists of sulfidoleukotrienes such as: important and unpleasant side effects of corti- sone occur after long-term systemic treatment, ) Zafirlukast (Astra-Zeneca) which is necessary for severe asthma, autoim- ) Montelukast (MSD) mune disease, or rare cases of chronic urticar- ) Pranlukast (in preparation, ONO) ia. Side effects of topical GC on the skin are cov- These substances inhibit allergen-induced ered in Sect. 5.5.4. bronchoconstriction [6, 20, 28]. In the aller- Side effects of inhalatory GC comprise gist’s office, however, while they can reduce hoarseness, oropharyngeal candidosis, and cortisone use in severe asthma, they are no dysphonia(the“smoky”voiceofapopsinger). 222 6 Allergy Prevention and Therapy

Table 6.3. Glucocorticosteroid effects on transcription Table 6.5. [ -Sympathicomimetics of various genes (according to Barnes [5]) Topical Systemic preparations Increased transcription Indanazoline [ 2-Adrenoceptors Lipocortin IL-1 receptor II Tet r yzoline IL-1 receptor antagonist Tramazoline Inhibition of transcription Cytokines (IL-1–-6, IL-11, IL-13, TNF [ , SCF, GM-CSF) Chemokines (IL-8, RANTES, eotaxin, MIP-1 [ , arations. (epinephrine) has its main MCP-1, MCP-3) indication in anaphylactic shock (see Sect. 5.1.4). COX1 and COX2 Today for treatment of mucosal swelling, syn- Phospholipase A2 Adhesion molecules thetic drugs, mostly imidazole derivatives, are Neurokinin receptors used (Table 6.5). All these substances should only Endothelin1 be given over a short time period since the muco- sal epithelium may be damaged through the va- Table 6.4. Glucocorticosteroids for inhalation soconstriction (“privinism”). Apart from solutions and sprays, some pa- dipropionate tients with very sensitive nasal mucosa prefer -21-isonicotinate the application of an ointment or gel (e.g., oxy- Fluocortinbutyl metazoline or tramazoline). For mucosal care, vehicle preparations, some of them containing -17-propionate vitamins in emollients, are used. Triamcinolonacetonide Mometasonfuroate ␤ Combination: 6.2.6.2 2-Adrenergics Fluticasone-17-propionate q and salmeterol 2-Adrenergics act especially in the bronchial tract as dilatory substances (Table 6.6) with re- duced cardiac side effects. They also show mast- It is surprising that the respiratory mucosa ob- cell-blocking activity, inhibit edema formation, viously is more resistant to atrophy-inducing enhancemucociliarytransport,anddecrease GC effects than the skin. the risk of infection. Most substances are avail- Table6.4liststheavailableinhalativeGC, able for inhalation as well as systemic treat- which can also be combined successfully with ment.Theadvantageofinhalatorytherapycan q other drugs such as 2-adrenergics. Further be seen in the lower dosage, fewer systemic side improvement can be seen through the develop- effects, and rapid onset of action. Disadvan- ment of substances with fewer side effects (e.g., tages are sometimes wrong use by the patient fluocortinbutyl, which is rapidly inactivated by and the tendency to overdose. For children, q unspecific esterases, loteprednoletabonate or 2-adrenergics are available in liquid form. cyclesonide). After long-term administration q Table 6.6. Selective 2-adrenoceptor agonists of inhalative GC in childhood, reversible growth retardation may occur. Systemic Inhalation, short-acting Bambuterol Fenoterol Clenbuterol Salbutamol Reproterol Terbutaline 6.2.6 Sympathicomimetics Salbutamol Pirbuterol [ Terbutaline Prosaterol 6.2.6.1 -Adrenergics Tolbuterol Bitolterol Thepreviouslyverycommon [ -sympathicomi- Inhalation, long-acting metics adrenaline und and their de- Formoterol fumarate rivatives are only available in combination prep- Salmeterol xinafoate 6.2 Antiallergic Pharmacotherapy 223

Newer developments comprise the long-act- Circadianrhythmshouldbeconsidered[27, q ing 2-agonists salmeterol and formoterol as 34].Manypreparationsareinslowrelease q well as mixed 2 +dopaminereceptorantago- form. Also combination preparations of the- nists (Viozan, in development). ophylline, diprophylline, and proxyphylline are available. Newer developments can be seen in selective PDE-IV inhibitors, which are under- 6.2.7 Anticholinergics going clinical trials. Cholinergic hyperreactivity is the major char- acteristic of patients with bronchial asthma. 6.2.9 Secretolytics Clinically useful anticholinergics are the mus- carine receptor antagonists atropine sulfate, at- These substances are able to split the very large ropine methylnitrate, as well as the more recent molecules (>1 million kDa) of mucus in the substances , oxitropium bronchial mucosa by cutting disulfide bridges bromide, and tiotropium. One hundred years and increasing water retention, which also in- ago, “asthma cigarettes” containing atropine duces expectoration [16]. In animal experi- were used for the treatment of asthma (stramo- ments, blockade of in vitro allergen tachyphy- nium cigarette according to Trousseau). laxis after pretreatment with acetylcysteine Anticholinergics have a place, especially for [14]mayleadtoanincreaseinasthmaticreac- intrinsic (cryptogenic) asthma as well as non- tions; however, this has not been investigated allergic vasomotor . Side effects are so far in humans. dryness of the mucous membranes, which Most important in secretolysis is adequate needs special care. fluidintake(seeSect.5.1.2on“Asthma”),which also humidifies the inspiratory air. 6.2.8 Phosphodiesterase Inhibitors 6.2.10 Preparations with Doubtful Efficiency Since the 1920s, xanthine derivatives – espe- cially theophylline – have been used as bron- Apart from therapeutic modalities which are chodilators. The non-selective inhibition of evidence based, many procedures are com- phosphodiesterase is responsible for the poor monly used in the treatment of allergy diseases compatibility. The poor solubility in water re- where the efficacy has not really been proven. quires the addition of complex-forming agents The immunomodulating substance inosiplex such as ethylenediamine or glycine. Certain so- may have mast-cell-stabilizing activity [37]. lutions also contain sulfites, which may elicit The peptide N-acetyl-aspartyl-glutamic acid severe asthma attacks in hypersensitive pa- (Rhinaaxia) has antagonistic effects against tients (see Sect. 5.1.5 on “Food Allergy”). Some some lipoxygenase metabolites. Pharmacologi- solutions contain carbamoylphenoxyacetic ac- cally, calcium preparations are ineffective; id (= salicylamide-o-acetate sodium), which however, they are widely used by general prac- doesnotseemtoshowcross-reactivitytoace- titioners and patients [16, 26]. Phytotherapeu- tylsalicylic acid in patients with ASA idiosyn- tic substances comprise Echinacea extracts, ex- crasy. tracts from Ginkgo biloba, benzyl mustard oil, Side effects of xanthine derivatives are nau- as well as homeopathic therapy using Cardio- sea, headache, anxiety, and sleeplessness; an spermum, Chelidonium, Galphimia glauca, etc. adequate dosage is mandatory requiring effi- (see Sect. 6.4). cient monitoring of blood levels between 10 and 20 µg/ml. Certain factors influence theoph- 6.2.11 New Developments ylline metabolism (e.g., in small children and infants, as well as after certain other medica- New developments in pharmacotherapy of al- tions like phenytoin or barbiturates, or in lergic diseases comprise calcium antagonists, smokers); with concomitant use of erythromy- flavonoids, indolbenzodiazepines, possible in- cin or other antibiotics, metabolism is slower. hibitors of synthesis of mediators or antago- 224 6 Allergy Prevention and Therapy

nists of vasoactive mediators (e.g., AHR 5333, Table 6.7. Antipruritic therapy C11949, ICI 204 219, Sch 37 224, neurotropin) Central nervous action [20] as well as antiallergic substances from on- Patient education (itch-scratch cycle) ion extracts [13] or fish oil (see Sect. 6.3 for im- Systemic: H1 antagonists (sedating), sometimes munotherapy). combined with H2 antagonists, cholestyramine, opiate antagonists, acetylsalicylic acid (polycy- themia vera), tricyclic antidepressants Acupuncture, TENS 6.2.12 Antipruritic Treatment Stress reduction 6.2.12.1 General Introduction Action on the skin Patient education (skin care) Itch is an untoward sensation inducing the urge Elimination of provocation factors (, in- to scratch (Fig. 6.3). There is no better modern festation) Unspecific topical therapy (capsaicin, polidocanol, definition.Itchisthemostcommonandmost doxepine) crucial – impairing quality of life – symptom of Physical treatment (UVB, PUVA, cooling) allergic skin diseases [7, 12]. Similar to pain, Steroids only when indicated for underlying disease itch is a sensation with strong subjective com- ponents and individual variants. Itch is mediat- ed via a subpopulation of demyelinated C-fi- Recently, it has been possible to visualize the bers and differs qualitatively also in peripheral itch sensation by positron emission tomogra- and central nervous conduction from pain. phy (PET) [11] (see Sect. 5.5.3). Small children and infants often cannot clearly In the treatment of itch, one distinguishes describe itch; infants only learn to scratch be- between central and peripheral mechanisms of tween the 3rd and 6th months of life. action (Table 6.7). Each antipruritic treatment The basis of each antipruritic treatment is modality has to be integrated into a general the avoidance of specific and non-specific concept of treatment of the underlying disease. provocation factors (see other chapters of this book). There are various qualities of itch which 6.2.12.2 External Treatment of Itch differconsiderablyascanbeseenonthe scratch reaction: In the treatment of acutely itching dermatoses, the application of cold (stimulation of A · fi- ) “Wheal”itchinurticaria(neverexcoriated bers) is effective, e.g., using wet wraps (“wet until bleeding, but only rubbed) pyjamas”), lotio alba, or menthol. Antihista- ) “Eczema” itch in atopic and contact derma- mines do not have an effect when used exter- titis (superficial excoriations) nally. Possibly the tricyclic antidepressant do- ) “Prurigo” itch (extremely itchy nodules, xepin with combined H and H antagonistic which are dug out while scratching) 1 2 actionmayalsobeusedtopically[4,15].The long-known topical local anesthetic Thesit can beusedasalotionorinacream.Itchontheba- sis of disturbed nerval functions (e.g., in zoster neuralgia) can be treated with capsaicin lead- ing to depletion of sensory nerve endings. In prurigo itch due to internal diseases (liver, kid- ney), UV treatment (UVB) has proven helpful.

6.2.12.3 Systemic Antipruritic Treatment The most commonly used systemic antipruri- tics are antihistamines, which are especially ef- Fig. 6.3. Representation of itching in a drawing by a fective in urticaria. In eczema, antihistamines teenage allergy patient show a limited effect, and classic antihista- 6.2 Antiallergic Pharmacotherapy 225

Table 6.8. Systemically Substance Dose/day Remarks acting antipruritics Antihistamines Sedative preparations – Dimetindenmaleate 3×1–2mg – Alimemazine 3×5 mg Max. 50–100 mg/day ASS 3×500mg Inpolycythemiavera Cholestyramine 8–16 g In renalem and hepatic pruritus CyclosporinA 5mg/kg Inatopiceczema(caveat:nephrotoxi- city!) Doxepine 3×10–25 mg Tricyclic antidepressant Mycophenolatmofetil 1–2 g In atopic eczema, immunosuppressive Ondansetron 2–3×8mg Serotoninantagonist Opiate antagonists – Naloxone 0.8 mg s.c. In primary biliary cirrhosis –Naltrexone 25–50mg – Nalmefen 2×5 mg Caveat: opiate withdrawal Propofol 10-mg bolus Experimentally used in cholestasis Rifampicin 1–2×300mg Incholestasis;caveat:toxicity mines with sedative properties may be helpful 6.2.13 Antiallergic Pharmacotherapy especially when given intravenously as infu- and Pregnancy sion in acute itch crisis (e.g., dimetinden) (Ta- ble 6.8). Thereislittleinformationregardingtherisks Antipruritic therapy has to be supported by of antiallergic drugs during pregnancy. Most other measures such as adequate cutting of fin- producers therefore recommend using the ut- gernails, soft gloves, as well as covering itching most care. From long-lasting experience and q skin areas with fatty-moist bandages (e.g., Tu- wide international use, 2-adrenergic aerosols bifast). Chronic itch can be treated using be- as well as topical glucocorticosteroids are con- havioral therapy (itch diary, “scratch device”) sidered fairly safe [23]. Fenoterol has been used [1,2,35]. after the 16th week as a tocolytic. Systemic glu- In urticarial itch, antihistamines are effec- cocorticosteroids over a short period are well tive. In eczema, antihistamines with sedating tolerated. components like doxylamine succinate, dime- Due to forensic considerations, antihista- tinden maleate, clemastine, and hydroxyzine minesshouldbeusedonlyinselectedcases. are preferred [2, 35, 39]. In 10–15% of chil- Drugs which have been in worldwide use for dren, after antihistamines paradoxical reac- decades against hyperemesis gravidarum also tions leading to hyperactivity may occur. Then have antihistamine action. another antihistamine may be used; possible overdosage should be considered. Antihista- mines should only be given during acute References phases of exacerbation, especially at night and in adequate dosing. In acute itch crises dime- 1. Abeck D, Ring J (1998) Etablierte medizinische tinden maleate should be given intravenously! Therapieansätze. In: Ring J (ed) Neurodermitis. In a double-blind study using the combined Expertise zur gesundheitlichen Versorgung und Vorsorge bei Kindern mit atopischem Ekzem. Eco- H1 antagonist promethazine and the H2 antago- med, Landsberg, pp 93–105 nist cimetidine in 21 young adults with atopic 2. Abeck D, Werfel S, Brockow K, Ring J (1997) Die eczema, there was no additional effect of cimet- Behandlung des atopischen Ekzems im Kindesalt- idine [17]. er. Hautarzt 48:379–383 3. Altounyan REC (1967) Inhibition of experimental asthma by a new compound disodium cromogly- cate – “Intal”. Acta Allerg (Kbh) 22:487–489 4. Anonymous (2000) Doxepin cream for eczema? Drug Ther Bull 38:31–32 226 6 Allergy Prevention and Therapy

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bility to different secretagogues and secretion in- der praktischen Dermatologie und Venerologie. hibitors. Int Arch Allergy Appl Immunol 77: Springer, Berlin Heidelberg New York, pp 177–178 437–440 39. Simons KI, Simons FER (1996) H1-receptor an- 41. Weinberger MM, Bronsky EA (1974) Evaluation tagonists: Pharmacokinetics and clinical phar- of oral bronchodilator therapy in asthmatic chil- macology. In: Simons FER (ed) Histamine and dren. J Pediatr 84:421 H1-receptor antagonists in allergic disease. Dek- 42. Woodward JK, Munro NL (1982) Terfenadine, the ker, New York, 175–213 first non-sedating antihistamine. Arzneimittel- 40. Wassilew SW (2000) Serotoninantagonisten bei forschung/Drug Res 32:1154–1159 Pruritis. In: Plewig G, Degitz K (eds) Fortschritte

6.3 Immunotherapy munotherapy.” However, immunotherapy also includes many other therapeutic options like 6.3.1 Allergen-Specific Immunotherapy the use of antibodies (= immunoglobulins), (Specific Hyposensitization) immunosuppression, as well as the increasing- ly used immunomodulating therapy with bio- 6.3.1.1 Definition and History logicals (cytokine antagonists, receptor antag- The classic causal treatment option in allergo- onists, anti-IgE, etc.). The term “allergen-spe- logy is specific hyposensitization (previously cific immunotherapy” (specific hyposensitiza- “desensitization”), also called allergen-specific tion) characterizes a well-described therapeu- immunotherapy, where the relevant allergen is tic procedure in certain indications. administered repeatedly in increasing doses Hyposensitization has been used for almost until reaching a so-called maintenance dose or 100 years in clinical allergology (Table 6.9) remission of symptoms. since Noon and Freeman, who continued This maintenance dose is either the dose Noon’s work after his death, with so-called leading to complete remission or marked im- “prophylactic inoculations” of pollen were able provement or the dose which is tolerated by the to cure hay fever [23, 50, 65]. patient over a longer period of time without Early precursor treatments of hyposensiti- side effects. This procedure has some similarity zation can be found in antiquity when King to active immunization (= vaccination), but Mithradates tried to protect himself against differs in principle (vaccination = protective poisoning by eating very low amounts of in- induction of immunity against infectious dis- creasing doses of toxic substances (he died by ease). Some authors use the broader term “im- the sword). In modern times, homeopathy as

Table 6.9. History of allergen-specific immunotherapy (specific hyposensitization) (literature cited in [51] and [65])

Immunization against hay fever Curtis 1900 Passive immunization (“pollantin”) against pollen toxin Dunbar 1903 Decrease of local reactions after increased administration of xenogeneic serum v. Pirquet 1906 Antianaphylaxis (“Desensibilization”) Besredka 1907 Intranasal immunization Scheppegrell 1909 Horse serum treatment of conjunctivitis Stancueanu and Nita 1909 “Prophylactic inoculation” Noon and Freeman 1911 “Hyposensitization” Cooke 1922 Blocking antibodies (blood transfusion) Cooke 1935 Specificity of blocking antibodies Loveless 1940 First controlled trial Bruun 1949 Allergoid (formaldehyde) Marsh and Lichtenstein 1970 Allergoid (glutaraldehyde) Johansson et al. 1974 T-cell peptides Norman 1965 Recombinant PLA2 in insect venom allergy Müller et al. 1998 Role of IL-10 and IgG4 Akdis and Blaser 2000 228 6 Allergy Prevention and Therapy

well as vaccination can be seen as precursors of Table 6.10. Possible mechanisms of action of allergen- hyposensitization. The early authors using hy- specific immunotherapy posensitization in hay fever were convinced IgG antibodies (subclass IgG4?) that the clinical symptoms were due to a pollen – Blocking antigen-specific toxin. – IgE synthesis-inhibitory In 1935 Cooke described blocking anti- – IgE receptor-inhibitory Secretory antibodies (IgA, possibly IgG) bodies in the serum of hyposensitized patients, Hapten inhibition whowereabletosuppressimmediateallergic Induction of B-cell tolerance skin reactions (cited in [51]). Only in the 1970s Inductionofsuppressorcells was the long-known principle in vaccination of – Soluble factors – Ag-/isotype-specific using toxoids as better compatible prepara- Anti-idiotypic antibodies tions also used in allergology in the develop- Tachy phylaxis ment of “allergoids,” i.e., modified allergens Decrease of releasability producing a strong immunogenic action with Switch of TH2 to TH1 reactivity Induction of T-cell tolerance (anergy) fewersideeffects.Currently,glutaraldehyde-or Increase of IL-10 formaldehyde-treated allergens are used as all- ergoids [51, 76]. increasing concentrations which can be char- acterizedinvivoandinvitrobytheirblocking 6.3.1.2 Mechanism of Action of Hyposensitization activity of certain IgE-mediated reactions In spite of its practical use over a long period, (Fig. 6.4). the exact mechanisms of action of this thera- In the first weeks of allergen-specific immu- peutic option are only known as hypothetical notherapy, both IgE and IgG antibodies in- concepts (Table 6.10). crease; while IgE decreases within the next few months,IgGstayshigh.However,intheindi- vidual case, the antibody pattern does not al- IgG-Blocking Antibodies ways follow this schedule [57] as has been There is no doubt that during subcutaneous hy- shown in insect venom allergy [30, 57, 72]. posensitization, IgG antibodies are formed in Maybe locally produced blocking antibodies in Antibody concentration in Serum Antibody concentration

Fig. 6.4. Typical course of the IgE and IgG anti- body concentrations during a hyposensitiza- Hyposensitization (months) tion therapy. s-IgG, spe- cific IgG; t-IgE, total IgE 6.3 Immunotherapy 229 themucousmembranearecrucial.Especially TH2-Th1 Balance theIgG4subclassseemstoberelevant[9]. Apart from a direct blocking effect, IgG anti- The most important effect of allergen-specific bodies may also inhibit IgE synthesis, possibly immunotherapy seems to be the successful cor- via a Fc * receptor. Gammaglobulin therapy has rectionofthedeviatedimmuneresponsefrom been used in certain allergies [60]. By adminis- TH2 to “normal” TH1 [9, 20, 21, 35, 36, 48], tration of specific hyperimmunoglobulin G, al- which can be measured as cytokine secretion or lergic reactions can be inhibited as in bee ven- isotypeantibodypattern.Allergendoseand om allergy [39, 56]. immunologic milieu (microenvironment) seem to be crucial. Low doses preferably induce IL-4 and TH reactivity with IgE formation, while Anti-idiotypic Antibodies 2 high doses such as during specific hyposensiti- Theantigen-bindingsiteoftheantibodymole- zation lead to IgG4 antibodies and a TH1 secre- cule is the hypervariable region, the personal tion pattern [3, 9]. Specific hyposensitization identity card (individual specificity) of an anti- follows the rules of the “mass-effect law” as body molecule. Against this idiotypic struc- does the process of allergy development (ac- ture, antibodies may be produced as anti-idio- cording to K. Blaser). typic antibodies. Possibly, this idiotype-anti- At the beginning of hyposensitization, T-cell idiotype network (according to N. Jerne) has anergy develops: neither TH1 nor TH2 cyto- physiologic importance in the regulation of im- kines are formed after allergen stimulation, mune response and also in hyposensitization. whileB-cellsproduceIgG4antibodies.Thisan- ergy is probably due to IL-10 and reversible [3]. In the TH milieu, interferon- * induces further Decrease of Releasability of Mediator- 1 IgG4 formation. In a TH milieu together with Secreting Cells 2 high concentrations of IL-4, TH2 reactivity is The releasability of mediator-secreting cells al- strengthened. This explains the much better so decreases during hyposensitization [51, 61]: success rates of immunotherapy in patients ob- Thesameamountofallergenleadstoa serving allergen avoidance. “marked” diminished release of histamine from basophil leukocytes in patients after aller- 6.3.1.3 Efficacy of Allergen-Specific gen-specific immunotherapy. Immunotherapy Specific hyposensitization is a causal therapy of Tachy phylaxis allergic disease. Since the first trials were per- The decrease of a reaction after repeated appli- formed some 50 years ago, many randomized cation of the eliciting stimulus is a well-known placebo-controlled clinical studies have been pharmacologic phenomenon and may also play published clearly showing the efficacy of this a role in the early phase of hyposensitization, therapy [2, 17, 25, 28, 30, 41, 45, 51, 61, 69, 84, especially in rush hyposensitization programs. 85–87]. The best results have been obtained with insect venoms, pollen, and housedust mites. Positive results have also been reported Suppressor T Cells from animal epithelia and molds. From con- Another possible option is the induction of im- trolled studies, we know there is a high placebo munological tolerance through suppressor T effect (30–50%!). This, however, may not only cells [48, 67], a concept which seems to be a bit derive from the doctor; patients in controlled out of fashion. However, recently, the regulato- trials are usually generally better treated than ry T cells (Tr or also T3 cells) seem to take over the average patient. the role of the earlier suppressor cells, acting Hyposensitization is especially effective in via interleukin (IL)-10 formation. young patients when the allergic disease has not yet been present for decades. 230 6 Allergy Prevention and Therapy

In various studies, it has been shown that lergosorbent test (RAST) inhibition, crossed specific hyposensitization is cost-effective and radioimmunoelectrophoresis (CRIE) and oth- reduces the costs of drugs and hospitalization er methods together with bioassays in specifi- [13, 44]. Allergen-specific immunotherapy also cally sensitized cell populations or defined vol- improves the quality of life and the general unteers with atopic diseases, a better compara- health of the patient. In a large study (“Preven- bility and standardization of allergen extracts tive Allergy Treatment,”PAT), it was shown that is achieved. the incidence of bronchial asthma in children When extracts are used as aqueous solu- with hay fever undergoing specific immuno- tions, they have to be applied with a relatively therapy was 60% lower after a 5 years’ observa- high number of injections (2–3 times per tion interval than in controls [31]. Allergen- week) up to the maintenance dose [25, 28, 51]. specific immunotherapy may also be regarded Therefore, the addition of depot substances is as an option for secondary prevention. an attempt to prolong the liberation of the ap- plied allergen. The most commonly method used is the extraction with pyridine and ad- 6.3.1.4 Allergen Extracts sorption to aluminum hydroxide (according to For preparation of allergen extracts, specifical- Fuchs and Strauss) [24]. A further depot action ly collected bulk materials (e.g., pollen grains) can be achieved by adsorption to the amino ac- are extracted with different solvents to a so- id L-tyrosine, which as a natural product is nor- called bulk solution (e.g., carbonate-buffered mally metabolized without leaving foreign with or without glycerol and 0.4% phe- body residues [34]. Newer adjuvants comprise nol according to Coca (cited in [65]) (NaCl monophosphoryl lipid (MPL) [18, 69] as well as 5.0 g, NaHCO3 2.75 g, phenol 4.0, aqua dest. ad bacterial oligonucleotides in clinical trials (e.g., 1,000.0). This bulk solution is then diluted fur- CpG sequences) [38]. ther. A major problem of allergen-specific im- Allergoids are allergen derivatives with re- munotherapy is the standardization of allergen ducedallergenicactivity(e.g.,skintestinsen- extracts [12, 24, 43, 51, 84]. sitized patients) and concomitantly increased The commonly used units for allergen ex- immunogenic action (induction of specific IgG tract standardization are shown in Table 6.11 antibodies). A large body of experience is avail- (see also Sect. 3.4 on “Allergens”). Using mod- able for formaldehyde- and glutaraldehyde- ern immunological techniques such as radioal- fixed allergoids [34, 51].

Table 6.11. Units for standardization of allergen extracts

Noon unit Extract of 1 µg allergen source (= 1 NU) Weight/volume unit Amount of allergenic bulk material/volume of extraction fluid (e.g., 1:1,000) Protein nitrogen unit (PNU) 1 µg protein nitrogen = 1 PNU Histamine equivalent prick (HEP) Extract concentration provoking in atopic controls the same reaction in prick test as histamine (1 mg/ml) Biological unit (BU) or bioequivalent 1 HEP = 1,000 BU/ml allergy unit (BAU) Skin activity reference allergen-histamine Corresponds to approx. 10 HEP (SARAH) Activity units by RAST (AUR) International reference (IR) 100 IR induces 30 mm2 wheal International unit (IU) WHO reference extracts contain 100,000 IU/ml Therapeutic units (TU) Allergen-specific in relation to ODC (optimal diagnostic concentration) in prick test 6.3 Immunotherapy 231

The indication for allergen-specific immuno- 6.3.1.5 Practical Aspects of Allergen-Specific therapy in patients with atopic eczema needs to Immunotherapy be discussed separately. While some patients ex- Indication perience a deterioration of eczematous skin le- A specific hyposensitization is indicated when: sions during dose increases, other authors have reported dramatic improvements also of eczem- ) The disease is severe atous skin lesions under immunotherapy [27, ) Allergen avoidance is difficult or impossi- 62, 63, 81]. Therefore, there is no general contra- ble indication. The literature in this regard shows a ) IgE-mediated relevant sensitization has state of the art similar to that of allergen-specific been proven immunotherapy for hay fever in 1950. There are Possibly, the preventive aspect (prevention of few placebo-controlled trials, most of them increased disease intensity or enlarged allergen showing some efficacy. We do not know enough spectrum) is of major importance in the future about the vehicle, the dose, the route of adminis- [31]. tration, or the relevant allergens. There is a need Contraindications are: for further studies. ) Acute and chronic infection ) Autoimmune disease Selection of Allergens (Formulation ) Secondary damage of the manifestation of Allergen Extract) organ The selection of allergens for the individual ex- ) Conditions where epinephrine is contrain- tract is crucial for the success of specific hypo- dicated (severe cardiac disease, q -blocker sensitization, which is based on the individual therapy) results of careful allergy diagnosis [25, 28, 51, ) Malignancy (not surgically removed) 61, 79, 84, 85–87]. It is here where the most ) Lack of compliance common mistakes take place [25]. The general The previous contraindications of “cerebral rule is: fewer rather than too many allergens in cramps”and“pregnancy”areonlyoflimited one extract! value today [6, 47]. In a prospective study with In this regard, one should remember that allergic children and epilepsy, no EEG changes the term “allergen” is reserved for the protein were observed after allergen injections [6]. molecule while structures like pollen or house- Pregnancy per se also is not a absolute con- dust mites are allergen carriers or allergen traindication. We do not start specific hypo- sources. This is sometimes not correctly taken sensitization during pregnancy, but continue a into account in the common allergist’s nomen- well-tolerated immunotherapy with a mainte- clature. Especially suitable allergen sources for nance dose – especially for life-threatening in- allergen-specific immunotherapy are pollen, sect venom anaphylaxis. housedust mite, and insect venom; immuno- Careful analysis of 121 pregnancies of 90 therapy with animal epithelia, molds, or occu- atopic mothers undergoing allergen-specific pationaldustsismoredifficult. immunotherapy during pregnancy did not yield any evidence or increased prevalence of Practical Implementation eclampsia, abortions, premature birth, terato- genicity, increased mortality of newborns, or Specific hyposensitization can be administered other complications [47]. On the other hand, invariousways(Table6.12).Theclassicand thepossibilityofgeneralactiveatopypreven- most commonly used method is subcutaneous tion may be considered since an increase in injection of the allergen extract. Extravasal lo- specific IgG antibodies in maternal blood and calization should be checked (several aspira- a protective role with regard to atopy develop- tions!) (Fig. 6.5). ment in the newborn have been discussed In classic hyposensitization with aqueous [14]. allergen extracts, the interval between two in- 232 6 Allergy Prevention and Therapy

Table 6.12. Methods of hyposensitization ous or semidepot extracts with 0.1 ml at Method Interval strength 1 and increased up to a maintenance doseof1mlatstrength3.Theallergenconcen- Subcutaneous trations in the various bottles differ from aller- Aqueousextracts(classic) 3–5days Aqueousextracts(rushhypo- Hours gentoallergenandfromcompanytocompany. sensitization) In very sensitive patients with a history of Semidepot extracts 7–14 days sideeffectsoranaphylaxis,itisrecommended Allergoids 7–14 days tostartwithanevenlowerconcentration(bot- Oral/sublingual tle “0”) and a slower increase in concentration Aqueous extracts Daily intake than in the routine schedule. Capsules Experimental The general rule is: Do not increase the dose Nasal Experimental schematically but individually, but try to reach remission of symptoms or tolerance of the highest dose [28]. Before each injection, a short history regarding the compatibility of the last injection as well as the general condition of the patient (underlying disease, infection, exercise, stress, allergen exposure) and concomitant ( q -blocker!) is performed. The injection interval, which differs accord- ing to the type of immunotherapy (aqueous, semidepot, etc.), needs to be watched strictly. If it is prolonged, the dose should be reduced. Afterhyperergiclocalreactions(>15cmin diameter), it is recommended repeating the last dose; after systemic reactions, the dose is re- duced by at least two steps. Immediately prior to injection and 24 h af- terwards, violent physical exercise should be avoided. After the injection, the patient is askedtoremainfor30minintheofficeand Fig. 6.5. Subdermal injection of allergen extract dur- ing hyposensitization treatment possiblesideeffectsarerecorded.Severeside reactions usually occur within 30 min and can be treated by the experienced allergist success- jections is 3–5 days. Hyposensitization with fully. If a patient who does not stick to this rule semidepot extracts requires a lower number of notices nausea or unconsciousness on the way injections and with injection intervals between home, this may turn out to be fatal! Indeed, 7 and 14 days. With the introduction of allergo- most of the severe side effects of allergen-spe- ids and new adjuvants, an even further reduced cificimmunotherapycanbeseeninconnection number of injections is possible [18, 36]. with a disregard for these rules [11, 28, 41]. Allergen mixtures in solution contain pre- After infectious disease or vaccinations, the servatives (e.g., 0.4% phenol) or are lyophi- immunotherapy interval is prolonged and the lized,whichisimportantforstorage(notethe next injection is given 2 weeks later with a re- date and ensure the correct storage at 4°C in or- duced dose in two steps. der to avoid a loss of biological activity). Seasonal allergies usually are treated presea- Most allergen extract producers provide the sonally (in hay fever usually during winter extract in several bottles of increasing concen- time). During the season, one can either stop trations, which are labeled with different co- the therapy (allergen exposure is difficult to lors, letters, or numbers (e.g., strength 1–3). control) or it can be continued over the year Usually,theinjectionsarestartedwithaque- with significantly reduced doses (e.g., 1/10). 6.3 Immunotherapy 233

Oral/sublingual immunotherapy is contro- Table 6.14. Toxicity of allergen extracts (no or negligi- versial, although significant effects have been ble risks due to) shown in placebo-controlled trials [4, 10, 15, ) Direct toxicity of allergens 16, 29, 37, 54, 55, 59, 75]. The efficacy of sublin- ) Teratogenicit y ) Cancerogenicity gual/oral immunotherapy is weaker than that ) of subcutaneous treatment [10, 42]. Mycotoxins ) Endotoxins In an experimental setting, trials for local ) Aluminum effects nasal immunotherapy [26, 68] as well as pas- ) Metabolic influence sive hyposensitization with hyperimmuno- globulin or gammaglobulin [19, 29, 34] have been tried. A possible method of improving ef- may be higher prevalence rates for insect ven- ficacy and compatibility can be seen in the si- om allergy. Fatalities have been reported; often multaneous administration of specific hyper- the rules of practical performance of allergen- immunoglobulin prior to allergen-specific im- specific immunotherapy have not been re- munotherapy [29]. spected [11, 25, 32, 25, 40, 51, 61, 64, 74, 79]. There is no consensus regarding the dura- Frankland estimates an incidence of 1 fatality tion of allergen-specific immunotherapy. Prin- among 750,000 injections [22]. The benefit of a cipally,thesuccessratesincreasewithincreas- prophylactic antihistamine treatment is dis- ing duration of treatment. Generally, at least a cussed [32]. 3-year term of treatment is recommended, in The most dangerous systemic complications some cases longer. are anaphylactic reactions (see chapter on In order to find evidence for successful im- “Anaphylaxis”). munotherapy, the clinical symptoms as well as Rarely, type III reactions occur during hy- the results of specific provocation tests or pos- posensitization [71, 79] sometimes in relation sibly in vitro tests with IgG/IgG antibodies can to inflammatory vascular disease (allergic vas- be performed. culitis)[8,55].Sideeffectssuchasserumsick- ness occurring with arthralgia, fever, urticaria, and sometimes nephritis and lymphadenopa- 6.3.1.6 Side Effects of Allergen-Specific thy indicate that the maintenance dose is too Immunotherapy high and there is an excess of IgG antibodies Possible side effects of specific hyposensitiza- leading to circular immune complexes. In the tion are listed in Table 6.13. There is no realistic differential diagnosis, the manifestation of a la- danger of toxic effects of allergen extracts tent autoimmune disease has to be considered. (Table 6.14). The incidence of systemic side re- Occasionally, persisting granulomas at the actions of allergen-specific immunotherapy injection site can occur, most commonly af- ranges between 1% and 15% per patient or ter aluminum-absorbed extracts [7]; rarely 0.1–1% per injection for aeroallergens. There they can change into pseudolymphomas (see Sect. 5.8). Allergen-specific immunotherapy differs Table 6.13. Side effects of allergen-specific immuno- from the injection of defined chemical drugs therapy both in its theoretical principles and in its prac- Local reaction ticalperformance.Itshouldonlybedoneby – Erythema, edema, pain, itch physicians with allergological expertise. New –Infection developments in allergy research, especially in –Granuloma the explanation of the mechanism of action – Pseudolymphoma Anaphylaxis and the production of better purified and stan- Exacerbation of atopic disease dardized extracts, will greatly improve the effi- Serum sickness ciency and safety of this well-accepted thera- Unspecific symptoms (headache, vertigo, nervous- peutic modality. ness) 234 6 Allergy Prevention and Therapy

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Rakoski J, Wessner D (2001) A short assessment 42. Lowell F, Frankling W (1965) A double-blind of sublingual immunotherapy. Int Arch Allergy study of the effectiveness and specificity of injec- Immunol 126:185–187 tion therapy in ragweed hay fever. N Engl J Med 60.RingJ,BodeU,KadachU,StixE,BurgG(1983) 273:675–679 Gammaglobuline und Allergie. Klinische Ergeb- 43. Løwenstein H (1986) Standardization of allergen nisse einer kontrollierten Studie mit Standard- extracts.In:RingJ,BurgG(eds)Newtrendsinal- Immunglobulin G und Plazebo bei Pollinosis. lergy II. Springer, Berlin Heidelberg New York, pp Münch Med Wochenschr 125:289–292 266 292 61. Ring J (1987) Spezifische Hyposensibilisierung. 44. Märtens P, Lobermeyer K (2001) Krankheitsko- Wirkungsmechanismen, Erfolge und Probleme. sten-Studie und Kosten-Nutzen-Analyse der spe- Allergologie 10:392–403 zifischen Immuntherapy bei Asthma. Allergo J 62. Ring J (1982) Successful hyposensitization treat- 10:341–347 ment in atopic dermatitis: results of a trial in 45. Malling H-J (2001) Allergen-specific immuno- monozygotic twins. Br J Dermatol 107:597–602 therapy in . Curr Opin Allergy 63. Ring J (1993) Spezifische Hyposensibilisierung Clin Immunol 1:43–46 bei atopischem Ekzem. Allergo J 2:1–2 46. Marsh DG, Lichtenstein LM, Campbell DH (1970) 64. Ring J, Przybilla B, Bongardts J (1988) Safety of Studies on allergoids prepared from naturally oc- hyposensitization. In: Proceedings of the annual curringallergens.I.Assayofallergenicityandan- meeting of the EAACI, Plama de Mallorca, 22–26 tigenicity of formalinized rye group component. April 1987. Abello, Madrid, pp 131–138 Immunology 18:705–722 65. Schadewaldt H (1979–1982) Geschichte der All- 47. Metzger WJ, Turner E, Patterson R (1978) The ergie, vols 1–4. Dustri, München-Deisenhofen safetyofimmunotherapyduringpregnancy.JAl- 66. Schramm G, Kahler H, Suck R, et al. (1999) ’Aller- lergy Clin Immunol 61:268–272 gen engineering’: Variants of the timothy grass 48. Mueller DL, Jenkins MK (199) Molecular mecha- pollen allergen Phl p 5b with reduced IgE-bind- nisms underlying functional T cell unresponsive- ing capacity but conserved T cell reactivity. Im- ness. Curr Opinion Immunol 7:375–381 munology 162:2406–2414 236 6 Allergy Prevention and Therapy

67. Sehon AH, Lee WY (1981) Suppression of IgE an- 79. Wüthrich B (1977) Zur spezifischen Hyposensi- tibodies with tolerogenic derivates of allergens. bilisierung der Pollinosis. Schweiz Rundsch Med In:RingJ,BurgG(eds)Newtrendsinallergy. 66:260 Springer, Berlin Heidelberg New York, p 294 80. Yang WH, Dorval G, Osterland CK, Gilmore NJ 68. Taylor G, Shivalkar PR (1972) Local nasal desen- (1979) Circulating immune complexes during sitization in allergic rhinitis. Clin Allergy 2:125 immunotherapy. J Allergy Clin Immunol 63: 69. Turkeltaub PC, Marsh DG, Lichtenstein LM, Nor- 305–307 man PS (1978) Development of long-lasting im- 81. Zachariae H, Cramers M, Herlin T, Jensen J, Krag- mediate hypersensitivity in nonatopic volunteers bale K, Ternowitz T, Thestrup-Petersen K (1985) parenterally immunized with a purified grass Non-specific immunotherapy and specific hypo- pollen extract. J Allergy Clin Immunol 61:171 sensitization in severe atopic dermatitis. Acta 70. Ulrich JT, Myers KR (1995) Monophosphoryl lip- Derm Venereol (Stockh) [Suppl] 114:48–54 idAasanadjuvant.Pastexperiencesandnewdi- 82.ZimmermannS,EgeterO,HausmannS,Lipford rections.In:PowellMF,NewmanMJ(eds)Vac- GB, Röcken M, Wagner H, Heeg K (1998) CpG oli- cine design: the subunit and adjuvant approach. godeoxynucleotides trigger, protective and cura- Plenum Press, New York, pp 495–524 tive Th1 responses in lethal murine leishmania- 71.UmetsuDT,HahnJS,Perez-AtaydeAR,GebaRS sis. J Immunol 160:3627–3630 (1985) Serum sickness triggered by anaphylaxis. A complication of immunotherapy. J Allergy Clin Positions Papers Immunol 76:713–718 72. Urbanek R, Karitzky D, Forster J (1978) Die Hy- 83. World Health Organization (WHO) Bousquet J, posensibilisierungsbehandlung mit reinem Bie- Lockey RF, Malling HJ, et al. (1998) WHO posi- nengift. Dtsch Med Wochenschr 103:1656 tion paper. Allergen immunotherapy: therapeu- 73. Valenta R, Kraft D (1995) Recombinant allergens tic vaccines for allergic diseases. Allergy 53 for diagnosis and therapy of allergic diseases. [Suppl 44]:1–42 Curr Opin Immunol 7:751–756 84. European Academy of Allergy and Clinical Im- 74. Vervloet D, Khairallah E, Arnaud A, Charpin J munology (EAACI) Bousquet J, Müller UR, Dre- (1980) A prospective national study of the safety borg S, et al. (1987) Immunotherapy with Hyme- of immunotherapy. Clin Allergy 10:59–64 noptera venoms. Allergy 42:40–413 75. Wahn U, Rebien W (1979) Ergebnisse der oralen 85. Malling H-J, Abreu-Nogueira J, Alvarez-Cuesta E, Hyposensibilisierung bei kindlichen Pollenaller- et al. (1998) Local immunotherapy. Position pa- gikern. Pädiat Prax 21:455 per by the Working Group on Local Immunother- 76. Wheeler AW, Woroniecki SR (2001) Immunologi- apyoftheEAACISubcommitteeandtheESPACI cal adjuvants in allergy vaccines: Past, present Immunotherapy Subcommittee. Allergy 53:933– and future. Allergology Int 50:295–301 944 77. Wilson DR, Nouri-Aria KT, Walker SM, Pajno GB, 86. Ärzteverband Deutscher Allergologen (ÄDA) O’Brien F, Jacobson MR, Mackay IS, Durham SR Sennekamp J, Kersten W,Hornung B (1995) Emp- (2001) Grass pollen immunotherapy: Symptom- fehlungen zur Hyposensibilisierung mit Allerge- atic improvement correlates with reductions in nextrakten. Allergo J 4:205–212 eosinophils and IL-5 mRNA expression in the na- 87. Deutsche Gesellschaft für Allergologie und klini- sal mucosa during the pollen season. J Allergy scheImmunologie(DGAI)Kleine-TebbeJ,Fuchs Clin Immunol 107:971–976 T, Klimek L, et al. (2000) Die spezifische Immun- 78. Wortmann F (1976) Zur oralen Desensibilisie- therapie (Hyposensibilisierung) mit Allergenen. rung von Inhalationsallergien bei Kindern. Positionspapier der DGAI, inhaltlich abgestimmt Mschr Kinderheilk 124:218 mit dem ÄDA. Allergo J 6 (in press)

6.3.2 Other Immunotherapeutic Procedures therapy with “biologicals.” They also comprise Immunotherapeutic procedures, as well as gene technologically prepared anti-inflamma- classic immunosuppression by chemical or bi- tory cytokines, soluble receptors, anticyto- ological substances, also include all kinds of ac- kines, or cytokine antagonists which may be tive and passive immunizations, and the ad- used in allergy [9, 10, 14, 19]. ministration of immunoglobulins (i.m. or i.v.) The group of so-called immune response and immunomodulators [16]. modifiers, which is applied in order to increase Recently, monoclonal antibodies against the immune response, also belongs to the field certain cell products or surface determinants of immunotherapy [8]. All these procedures have opened up a new dimension of immuno- differ markedly from allergen-specific immu- 6.3 Immunotherapy 237 notherapy (hyposensitization) by the lack of al- fantsandsmallchildrenespeciallyinthephase lergen specificity. where glucocorticosteroids are not wanted. Both substances seem to be well tolerated and do not lead to increased rates of bacterial 6.3.2.1 Immunosuppressives or viral skin infection as originally suspected. Apart from cortisone, the classic immunosup- Colonization has even been reduced. There is pressives used in severe cases of chronic dis- no atrophy. The future will show how these eases (asthma or eczema) are methotrexate, cy- “corticoids of the year 2000” live up to their clophosphamide, azathioprine, and mycophe- hopes. nolate mofetil. Special progress in the treatment of atopic Thesedrugsarecommonlyusedinautoim- eczema has been achieved by the topical appli- mune diseases and new developments (from cation of some of these substances, tacrolimus transplantation medicine) with immunophyl- and pimecrolimus. Little is known about lin-binding drugs (macrolactams or calcineu- long-term side effects; therefore, careful use rin antagonists); the first product was cyclo- is recommended, especially in children (see sporin A, later tacrolimus, as well as ascomycin Sect. 5.5.3 on “Eczema”). derivatives and rapamycin (Fig. 6.6) [1, 13, 18]. The topically available calcium antagonists 6.3.2.2 Monoclonal Antibodies, Cytokines tacrolimus and pimecrolimus represent true and Cytokine Antagonists progress. Tacrolimus seems to be somewhat stronger (approximately comparable to a glu- Since the development of hybridoma tech- cocorticosteroid of class 2). However, with its niques, monoclonal antibodies have revolu- greasy ointment, it often induces a burning tionized medical research and diagnostics. Re- sensationinthefirstdaysoftreatment.These cently, they have begun to enter the therapeutic complaints, however, diminish after continua- regimens for many diseases. tion. Table6.15showstheactualorsoonavailable Pimecrolimus is well accepted by patients monoclonal antibodies in antiallergic and anti- with its creamy galenic and can be used in in- inflammatory therapy. Of special interest is an- ti-IgE (monoclonal antibody E25, omalizu- mab) for bronchial asthma. Anti-IgE has shown efficacy in allergic asthma, especially in reducing corticoids in steroid-dependent asth- ma [3, 5, 11]. Possibly, it is also effective in hay fever. Studies with anti-IgE and other IgE-me- diated diseases are in preparation, maybe also in combination with allergen-specific immu- notherapy.

Table 6.15. Monoclonal antibodies in the therapy of allergic and inflammatory diseases Specificity Example Cell surface marker CD4, CD45, LFA-1 (alefacept) CD23 Adhesion molecule ICAM-1 Costimulatory signal CD40 Transcription factor GATA-3 Cytokine IL-5 (mepolizumab) TNF- [ (infliximab) Antibody IgE (omalizumab) Fig. 6.6. Structural formula of pimecrolimus 238 6 Allergy Prevention and Therapy

Table 6.16. Cytokines and cytokine antagonists 4. Hansel TI, Barnes PJ (eds) (2001) New drugs for asthma, allergy and COPD. Karger, Basel Receptor antagonists Mutants of cytokines 5. Heusser C, Jardieu P (1997) Therapeutic potential IL-4 IL-4 of anti-IgE antibodies. Curr Opin Immunol 9: TNF [ (etanercept) Antibodies against 805–814 Anti-inflammatory cytokines 6. Keane J, Gershon S, Wise RP, Mirabile-Levens E, cytokines IL-5 Kaszica J, Schwieterman WD, Siegel JJN, Braun IL-10 TNF- [ MM (2001) Tuberculosis associated with inflixi- [ IFN- * mab, a tumor necrosis factor -neutralizing IL-18 agent. N Engl J Med 345:1098–1104 7. Jardieu PM, Fick RB Jr (1999) IgE inhibitors as a therapy for allergic disease. Int Arch Allergy Im- munol 118:112–115 A variety of other monoclonal antibodies 8. Krieg AM (1996) An innate immune defence against cytokines are already available as well mechanism based on the recognition of CpG mo- tifs in microbial DANN. J Lab Clin Med 128: as cytokine antagonists (Table 6.16). Anti- 128–133 bodies against TNF [ (infliximab) as well as a 9. Leckie MJ, ten Brinke A, Lordan J, Khan J, Dia- soluble TNF [ receptor (etanercept) are new in mant Z, Walls CM, Cowley D, Hansel T, Djukano- rheumatoid arthritis and psoriasis. As a side ef- vic R, Sterk PJ, Holgate S, Barnes PJ (1999) SB fect of infliximab, activation of tuberculosis has 240563, a humanised anti-IL-5 monoclonal anti- body: initial single dose safety and activity in pa- been reported [6]. tients with asthma. Am J Resp Crit Care Med Other antibodies against surface determi- 159:A624 nants of cells, especially T cells, represent a 10. Losman JA, Chen XP,Hilton D, Rothman P (1999) modern variant of the old antilymphocyte se- SOCS-1 is a potent inhibitor of IL-4 signal trans- rum in the beginning of the organ transplanta- duction. J Immunol 162:3770–3774 11. Milgrom H, Fick RB, Su JQ, Reimann JD, Bush tion era [2, 15]. Antibodies against CD4 or RK, Watrous ML (1999) Treatment of allergic against markers of T-memory cells have been asthma with monoclonal anti-IgE antibody. N successfully used in psoriasis [12]. Engl J Med 341:1966–1973 Antibodies against adhesion or costimulato- 12.PrinzB,NachbarT,PlewigG(1994)Treatmentof severe atopic dermatitis with extracorporal pho- ry molecules also seem promising for allergy tophoresis. Arch Dermatol Res 287:48–52 therapy. For a long time, various interferons 13. Reitamo S (2001) Tacrolimus: A new topical im- have been used especially in oncology, but also munomodulatory therapy for atopic dermatitis. J in inflammatory diseases and allergies. The Allergy Clin Immunol 107:445–448 fieldofchemokinesissocomplexanditssingle 14. Renz H, Bradley K, Enssel K, Loader JE, Larsen GL, Gelfand EW (1996) Prevention of the devel- functions are often redundant, so that very spe- opment of immediate hypersensitivity and air- cific antagonists will maybe have only limited way hyperresponsiveness in vivo with soluble IL- effects; the right combination will be the key. 4 receptors. Int Arch Allergy Immunol 106:167 15. Ring J, Seifert J, Lob G, Coulin K, Angstwurm H, Frick E, Brass B, Mertin J, Backmund H, Brendel W (1974) Intensive immunosuppression in the treat- References ment of multiple sclerosis. Lancet 2:1093–1095 16. Sacher R, FRCPC, and the IVIG Advisory Panel 1. Abraham RT (1998) Mammalian target of rapamy- (2001) Intravenous immunoglobulin consensus cin: Immunosuppressive drugs uncover a novel statement. J Allergy Clin Immunol 108:S139–146 pathwayofcytokinereceptorsignaling.CurrOpin 17. Saint-Remy J-MR (1999) Allergisches Bronchial- Immunol 10:330–336 asthma: Immuntherapie durch Antikörper. Die 2. Brendel W, Ring J, Seifert J (1974) Experimental gelben Hefte 39:59 and clinical aspects of ALG. Progr Immunol II 18. Szczeklik A, Nizankowska E, Dworski R, Doma- 5:245–252 gala B, Pinis G (1991) Cyclosporine for steroid de- 3. Busse W, Corren J, Lanier BQu, McAlary M, Fowl- pendent asthma. Allergy 46:312–315 er-Taylor A, Della Cioppa G, van As A, Gupta N 19. Tony H-P, Shen B-J, Reusch P, Sebald W (1994) (2001) Omalizumab, anti-IgE recombinant hu- Design of human interleukin-4 antagonists to in- manized monoclonal antibody, for the treatment hibiting interleukin-4-dependent and interleu- of severe allergic asthma. J Allergy Clin Immunol kin-13-dependent responses in T cells and B cells 108:184–190 with high efficiency. Eur J Biochem 225:659–665 6.4 Unconventional Procedures in Allergy 239

6.4 Unconventional Procedures ) In spite of scientific studies, no evidence in Allergy for effect ) The concept is not plausible or dangerous Like in few other fields of medicine, allergists ) Studies are not warranted (e.g., autologous areconfrontedwiththesteadilyincreasing urine injection) number of “unconventional, “alternative,” or “complementary” methods both in diagnosis The German Society for Allergology and Clini- and therapy [5, 10, 16, 17, 24]. Especially lay cal Immunology (DGAI) and its subcommittee journals and magazines have endless reports “Complementary Medicine” (headed by W. about miraculous cures by such methods. Un- Dorsch) is evaluating unconventional proce- fortunately, sometimes under economic pres- dures from different countries of the world ac- sure,somedoctorsgivewaytotemptationand cording to scientific criteria [4, 5]. also practise these methods. The popular argu- There are a number of so-called comple- ment“whocuresisright”(“wer heilt, hat mentary methods which may represent a bene- recht”) is not logical. Clearly thought out, it ficialsupplementtoclassicantiallergictherapy, should mean “who cures does good,” but such as: whether he is right is a different question. ) Physical therapy and respiratory training Scientific medicine is based on evidence ) Hydrotherapy (according to Kneipp) provided by reproducible studies. Scientists are ) Psychosomatic counseling and relaxation accused of having blinkers on if they argue on methods (e.g., autogenic training) the basis of scientific arguments. It is practical- ) Certain dietetic approaches (see chapter on ly impossible to perform reliable and well-con- “Food allergy”) trolled studies for all the continuously newly ) Climatic therapy developing and commercialized methods in di- ) Certain phytotherapeutic approaches agnosis and therapy (Table 6.17). We therefore ) (Cum grano salis) acupuncture need to classify according to rather rough crite- ria of plausibility and arrive at a classification On the other hand, there are many “unconven- of “complementary” procedures such as: tional”methodswhichcannotbeseriouslyrec- ommended because efficacy is lacking in thera- ) Newly developed scientifically sound py, or in diagnosis the reliability is worse than procedure in clinical trials throwing dice [9, 10, 12, 18, 21]. Such proce- ) Plausible concept supported by case dures comprise: reports, but exact studies are missing ) Low plausibility, little convincing experience ) Autohomologous immunotherapy (reinjection of autologous blood or serum) ) Bach’s flower therapy Table 6.17. Most commonly used unconventional pro- ) cedures in allergy (according to W. Dorsch) Bioresonance ) ) Injection of autologous blood Acupuncture ) Electroacupuncture ) Autohomologous immunotherapy ) ) Kinesiology Bach’s flower therapy ) ) Bioresonance Fortune teller’s pendulum ) Diet ) Hair mineral analysis ) Fasting ) Autologous blood injection Certain procedures are heavily connected with ) Electroacupuncture ) religious-type philosophies (Weltanschauung) Hair mineral analysis and so complex in general methods that the ) Homeopathy ) Kinesiology performance of scientific studies is extremely ) Neural therapy difficult (e.g., anthroposophic medicine, home- ) Fortune-teller’s pendulum opathy). Apart from non-reproducible in vitro ) Phytotherapy ) studies [2], there have been anecdotal positive Traditional Chinese medicine reports [22], although in the majority the eval- 240 6 Allergy Prevention and Therapy

uation has been critical [1, 8, 13]. We have per- References formed a large double-blind controlled study applying all the homeopathy criteria including 1. Bock KD (1993) Wissenschaftliche und alterna- tive Medizin. Springer, Berlin Heidelberg New treatment by an established homeopathist of Yo r k atopic eczema without any effect [20]. 2. Davenas E, Beauvais F, Amara J, et al. (1988) Hu- It is important to remember that according man basophil degranulation triggered by very di- to the laws of logic and philosophy, it is difficult lute antiserum against IgE. Nature 333:816–818 or impossible to prove the non-efficacy of a 3. De Weck AL (2000) From basic science to comple- mentary medicine. ACI Int 13:5–6 method (Karl Popper)! The proponent of a pro- 4. Dorsch W, Ring J (2002) Komplementärmetho- cedure has to prove that it is efficient. It makes denbzw.sog.“Alternativmethoden”inderAller- you wonder why some insurance companies gologie. Allergo J 11:163–170 pay the costs of these unconventional proce- 5. Dorsch W (1996) Alternative Heilmethoden in dures [13]. der Allergologie? Allergo J 5:388–393 6. Fulder SJ, Munro RE (1985) Complementary Physicians are obliged to advise their pa- medicine in the United Kingdom: Patients, prac- tients according to their best knowledge and titioners, and consultations. Lancet II:542–545 conscience and be honest; however, we should 7. Fung KP,Chow O, So SY (1986) Attenuation of ex- avoid inducing feelings of guilt in the patient. ercise-induced asthma by acupuncture. Lancet In such arguments, I usually tell my patient: II:1419–1422 8. Köbberling J (1997) Der Wissenschaft verpflich- “Now we are entering the field of religion, and tet. Med Klin 92:171–190 Ineverdiscussreligiousmatters!” 9. Kofler H, Ulmer H, Mechter E, Falk M, Fritsch PO On the other hand, interesting and partly (1996) Bioresonanz bei Pollinose: Eine verglei- new knowledge for western medicine can be chende Untersuchung zur diagnostischen und derived from ancient medical experience in therapeutischen Wertigkeit. Allergologie 19:114– 122 foreign countries of the developing world. The 10. Kukutsch NA (1997) Darstellung und Diskussion history of medicine has plenty of examples that alternativer/komplementärer diagnostischer und/ potent drugs have been developed from phyto- oder therapeutischer Konzepte im Hinblick auf therapy; this also holds true for allergy [1, 3, 5, atopische Erkrankungen. Dissertation, Hamburg 14, 15, 24]; almost all of the current pharmaco- 11. Lambeck M (2001) Eine Revolution der Physik? Die Unterstützung der Homöopathie und ähnli- therapeutic drugs (see Sect. 6.2) have been de- cher Therapieeinrichtungen durch die Kranken- rived from plant extracts [5]. kassen. Skeptiker 14:117–122 From traditional Chinese medicine other 12. Lüdtke R, Kunz B, Seeber N, Ring J (2001) Test-re- than acupuncture, a mixture of Chinese herbs test reliability and validity of the kinesiology muscle test. Complement Ther Med 9:141–145 which is applied as tea has shown significant ef- 13. Oepen I, Prokop O (1985) Außenseitermethoden fects in a double-blind study in atopic eczema, in der Medizin. Wissenschaftl. Buchgesellschaft, but also dangerous side effects [19, 23]. In this Darmstadt area, further research should elucidate the ac- 14. Miller MJS, Vergnolle N, McKnight W, et al. tive substance and evaluate the safety. (2001) Inhibition of neurogenic inflammation by the Amazonian herbal medicine Sangre del Gra- Who is interested in scientific information do. J Invest Dermatol 117:725–730 about parascientific phenomena can join the 15. Ring J, Behrendt H, Vieluf D (eds) (1997) New “Gesellschaft zur wissenschaftlichen Untersu- trends in allergy IV. Springer, Berlin Heidelberg chung parawissenschaftlicher Phänomene – New York GWUP (Society for the Scientific Evaluation of 16. Ring J (ed) (1998) Neurodermitis. Expertise zur gesundheitlichen Versorgung und Vorsorge bei Parascientific Phenomena)” and subscribe to Kindern mit atopischem Ekzem. Ecomed, Lands- the quarterly journal The Sceptic (der Skeptiker, berg in German). 17. Schäfer T, Riehle A, Wichmann HE, Ring J (2002) Alternative medicine in allergies – prevalence, patterns of use, and costs. Allergy 57:684–700 18. Schöni MH, Nikolaizik WH, Schöni-Afolter F (1997) Efficacy trial of bioresonance in children with atopic dermatitis. Int Arch Allergy Immunol 112:238–246 6.5 Allergy Prevention 241

19. Sheehan MP, Atherton DJ (1992) A controlled 22. Wiesenauer M, Gaus W, Häussler S (1990) Be- trial of traditional Chinese medicinal plants in handlung der Pollinosis mit Galphimia glauca. widespread non-exudative atopic eczema. Br J Allergologie 13:359–363 Dermatol 126:179–184 23. Wong HCG (2001) Chinese herbal medicine and 20. Siebenwirth J, Rakoski J (1997) Klassisch-homö- allergy. ACI Int 13:192–196 opathische Therapie bei Neurodermitis. Hautarzt 24. Wüthrich B (1999) Allergologie: Quo vadis? 48 [Suppl 1]:S22 Schweiz Med Wochenschr 129:905–914 21. Stiftung Warentest (ed) (1996) Handbuch Die an- dere Medizin. Nutzen und Risiken sanfter Heil- methoden, 4th edn. Stiftung Warentest, Berlin

6.5 Allergy Prevention mononuclear cells, etc.) have not been fulfilled. The only reliable clinical tool is family history (see Sect. 3.1 on “Genetics”). 6.5.1 Definition Equally, knowledge about causal factors is Besides activities of “salutogenesis” to improve limited. Apart from allergens as causal agents, health (“health promotion”), a variety of pro- modulating influences of the environment cedures are available in order to prevent the oc- (both natural and anthropogenic) are known currence of disease especially in diseases with (see Sect. 3.3 “Allergy and Environment”) in- high prevalence rates such as allergic diseases cluding air pollutants in the outdoor and in- [2, 42, 43, 49]. One needs to distinguish be- door air, nutrition, psychosocial situation, as tween primary, secondary, and tertiary preven- well as vaccination strategies. It has to be men- tion [8, 12, 27, 41, 55]: tioned that concepts and opinions about prac- tical prevention programs differ considerably ) Primary prevention comprisesmeasuresto between experts (refer to the recent discussion prevent the occurrence of disease, and about pet-keeping as protection against cat al- eliminate or influence causal factors in lergy) [38]. In spite of many unsolved prob- disease development or transfer (example: lems, some very practical (almost trivial rec- active immunization = vaccination) ommendations)canbegivenonthebasisof ) Secondary prevention means the earliest thecurrentstateofknowledge.Theserecom- recognition of a disease prior to clinical mendations do not harm anybody but may be manifestation and prophylaxis of suscepti- helpful for children with some likelihood of ble individuals; this requires screening high risk (“Frankfurt theses” for allergy pre- examinations vention from 1 December, 1995, updated in ) Ter tiar y prevention comprises procedures 2003) (see Table 6.18) [49]. Common sense to prevent sequelae of disease after the should never be forgotten; recommendations manifestation and treatment of an acute should only be changed after convincing and disease; this includes rehabilitation and solid new evidence is available. Supplementing prevention of renewed exacerbations. the Frankfurt theses, the general recommen- dation for avoidance of disease-promoting fac- 6.5.2 Primary Prevention tors (physical, chemical, biological, psycho- A rational basis for effective primary preven- social in nature) should be added (see also tion requires the definition of risk groups as Sect. 5.1.2 on “Unspecific Irritation Syn- well as solid knowledge about causal factors of drome”). the disease. Unfortunately, in spite of great pro- Primary prevention should start in preg- gress in molecular genetics, there is no reliable nancy; we have developed education programs “genetest”availabletopredictsafelytheallergy forwomenatriskforatopyandpregnantwom- risk of an individual. The hopes put into the de- en [14]. During pregnancy smoking should be termination of cord blood IgE or other cellular strictly avoided; the concentration of potent in- or humoral parameters (sCD23, T-cell subpop- door allergens (pets, molds, housedust mites) ulations, phosphodiesterase concentrations in should be reduced. 242 6 Allergy Prevention and Therapy

Table 6.18. “Frankfurt theses” for primary prevention of allergy in children and adolescents [update by the Ak- tionsbündnis Allergieprävention (ABAP) (28.06.2002) (Allergo J 2003; 12: 98]

Allergic diseases represent one of the major health problems of our society. The roots for a later development of allergic diseases often occur in infants and small children. Although not all factors responsible for the de- velopment of allergic sensitization and disease are known and there is considerable need for research, the ac- tual knowledge allows the following recommendations for prevention: I. The parents in our country should know that: 1. There is a genetic predisposition for allergic reaction 2. It makes no sense that the mother observes a special diet during pregnancy 3. That strict breastfeeding until the 4th month of life and the late and stepwise addition of solid food in infants can reduce allergic sensitization 4. An environment at home without tobacco smoke can help to reduce the risk of allergy and airway dis- ease 5. An allergen-poor environment can reduce the risk of the development of sensitization and allergy, and strategies to reduce housedust mite growth as well as avoidance of pets makes sense for families with risk of atopy 6. Adequate skin care and avoidance of irritating or frequently sensitizing substances (e.g., nickel con- taining jewelry or fragrances) may prevent the development of dermatitis 7. Children at risk of allergy and children with allergic diseases can be vaccinated according to general rules in a phase of remission IIa. Children and adolescents and their parents have a right to: Get consultation and information regarding risk factors for allergy and possible avoidance strategies IIb. Children and adolescents suspicious of allergic sensitization have a right to: 1. Individual allergy diagnosis and consultation by a certified specialist 2. A healthy indoor climate at home as well as in kindergartens and schools 3. Qualified allergological consultation for the choice of occupation exceeding the current official laws III. Children and adolescents and their families affected by allergy with chronic course have a right to: 1. Qualified information and treatment by a certified physician 2. Qualified dietary consultation when there is a risk of food allergy or other adverse food reactions 3. Help with development of own responsibility in coping with the disease by special staff (schooling and education programs) contributing to an improved quality of life and coping with the chronic disease 4. Timely therapy, also regarding secondary and tertiary prevention measures (including pharmacother- apy and immunotherapy) 5. Use of rehabilitation measures as well outpatient and near the living area as well as inpatient in special clinics (including asthma, eczema, swimming and sports groups, rehabilitation in school) 6. Declaration of allergenic substances in foods and in items of daily use IV. Teachers and education personnel have a right to: Qualified information in dealing with allergic children In the prevention and treatment of allergies, lay groups have an important task. Cooperation with experts of different disciplines and lay groups is mandatory These aims can only be achieved if the qualification of experts and the structural requirements of patient care are improved and allergologic expertise is taken into account by the relevant political committees

Practical recommendations include: ) Reduction of exposure to pollutants in ) Nutrition: consistent breast-feeding over indoor air (smoking, chemicals in hobby 4–6 months, late addition of solid food and occupation) as well as outdoor air [44], possibly extensively hydrolyzed hypo- (traffic exhaust) [2, 32, 41] allergenic formula [6]. Recent studies show ) Avoidance of irritating substances for the a positive effect regarding the prevalence of airways (e.g., dust) [47] as well as skin atopic eczema in infants by adding probio- (e.g., clothing, skin cleaning and care, jew- tics (lactobacillus GG) during pregnancy elry – caveat: ear piercing!) 2–4 weeks prior to birth [24, 26]. ) Avoidance of disease-promoting factors ) Reduction of aeroallergen exposure (pets, (physical, chemical, biological, psychoso- housedust mites, molds) [1, 3, 25, 26] cial in nature) [8, 19] 6.5 Allergy Prevention 243

The classic methods of rehabilitation are at 6.5.3 Secondary Prevention the center of tertiary prevention, which can be At this stage, one might discuss immunological performed in an outpatient or in severe cases or pharmacological approaches; certain studies an inpatient setting; sometimes the change of have been performed in tertiary prevention environment not only has allergological but al- (early treatment of the atopic child, ETAC) where so psychosomatic importance. Specialized hos- in many European countries the occurrence of pitals for allergic patients exist in several Euro- asthma in the following years was significantly pean countries. reduced by prophylactic administration of an H1 In severe cases, long-lasting rehabilitation antagonist cetirizine in infants with atopic ecze- can only be achieved under certain climatic ma and sensitization against grass pollen and/or conditions including climatherapeutic proce- housedust mites [18]. Similar results have been dures;NorthSeaislandsaswellasclimateat obtained with the mast cell blocker and H1 an- high altitude over 1,500 m (e.g., Davos, Switzer- tagonist ketotifen where a reduction of allergic land) have been studied in this regard and have asthma prevalence in patients with allergic rhi- shown beneficial effects [7, 14, 54]. noconjunctivitis was observed [33]. Through progress in causal and somatic Allergen-specific immunotherapy in hay fe- therapy of allergic diseases and increasing ver also has a preventive effect by reducing the knowledge in prevention, the quality of life of prevalence of asthma in hay fever patients (see allergic individuals has been improved consid- Sect. 6.3.1 on “Allergen-Specific Immunothera- erably.Asthmapatientscandosports,eczema py”). patients can swim and use the sauna; however, they need to use emollients and follow skin care guidelines before and after sporting activ- 6.5.4 Tertiary Prevention ities. Besides careful causal and symptomatic treat- In the many tasks of prevention, lay groups ment of allergic diseases, allergen avoidance is play an important role. By close cooperation at the center of all recommendations for pre- between lay groups and experts of different dis- vention. This is only possible after intensive ciplines, the effects can be optimized. Allergo- and competent diagnosis and information of logic expertise needs to be heard by political the compliant patient and their surroundings. bodies making decisions relevant for allergic Thepatienthastobeabletorecognizethealler- individuals [2]. In the following, practical rec- gen; this implies the need for better declaration ommendations regarding avoidance of aeroal- laws (not only for drugs, but also for cosmetics lergens are given. and products in daily use) [2]. Education programs for children and adults 6.5.5 Strategies for Aeroallergen Avoidance can help patients and their families consider- ably in coping with the allergic disease; they The biologic basis of aeroallergens has been are available for asthma and atopic eczema discussed in Sect. 3.4 on “Allergens.” (Sects. 5.1.3, 5.5.3). An integral part of tertiary prevention is oc- 6.5.5.1 Pollen cupational counseling and information about potential risks through allergens or irritants in The pollen of anemophilous plants is almost certain occupations. Educational programs – ubiquitous during the spring and summer whichshouldbemonitoredforquality(“train months in central Europe and many countries thetrainer”seminars)–inasthmaoreczema of the world, except in the desert or at the high “academies” with standard certified protocols altitudes of the alpine regions, where the con- [20] should encompass our philosophy that the centration is lower. Avoidance measures are concept of “patient management” should final- therefore limited. If the symptomatic period is ly evolve into “self-management” by the pa- short, a well-planned vacation in pollen-poor tient. areas can be recommended. At home, allergic 244 6 Allergy Prevention and Therapy

Table 6.19. Reduction of aerogenic pollen exposure in patients with atopic eczema Recommendations: ) Avoid staying outdoors during peak pollen exposure (see the pollen information service in the media). During cool weather or longer lasting rain, pollen counts are markedly reduced ) Daily peaks (only for rural areas): early morning and evening. During these time periods close the win- dows. The optimal time for ventilation is between midnight and 4 in the morning ) You can leave the window open if you have fixed a pollen protection foil ) When you have been outdoors, take a shower in the evening (and wash your hair) followed by adequate skin care. Clothes should not be left in the sleeping room since pollen may be transferred there. You should try to keep the bedroom cool and dust poor ) Regular vacuum cleaning (with small particle filter) and moist cleaning of surfaces in the apartment dur- ing the pollen season are recommended; however, this should not be done by the affected individual but by other family members ) Use of emollients prior to leaving the apartment on air-exposed skin sites may be recommended ) Do not dry textiles in the outdoor air ) Pets can carry considerable amounts of pollen into the apartment ) Automobile: When your car has been standing some time outdoors, especially under pollinating trees, heavy pollen loads can reach the airways when you turn on the engine and the ventilation. Therefore pol- len filters should be used and are available for most cars ) If possible consider your allergy in making your vacation plans by choosing the right time and place of hol- idays. You might completely avoid allergen exposure

individuals may benefit from certain recom- Washing the cat has reduced cat allergen con- mendations for daily life (Table 6.19). Closing tent in indoor air, but has not been accepted as the window does not reduce pollen concentra- a practical preventive measure [37]. In occupa- tion in the indoor air. This only can be achieved tional animal exposure (farmer, laboratory by air-conditioning with special filters. worker, etc.), wearing a mask or helmet (e.g., Pollen and mold counts are measured in airstream) is recommended [3, 47]. many countries by different associations or foundations (in Germany “Stiftung Deutscher 6.5.5.4 Housedust Mites Polleninformationsdienst” = PID in Bad Lipp- springe), which then provide together with me- Housedust mites of different species are the teorologists and phenologists pollen forecasts most common allergen carrier in the indoor helpful for allergic individuals in planning environment [31, 34, 57]. Avoidance measures their activities and use of prophylactic drugs have to be seen at several levels starting best in [3, 32, 42, 48]. the bedroom with the mattress and should be done specifically (it is not necessary to change theapartmentintoaglass-concreteenviron- 6.5.5.2 Mold Spores ment!)[1,4,9,10,11,13,15,21,23,34,35,37, Moldsgrowbestinamoistandwarmmicroen- 50, 51, 52]. vironment. Indoor plants should be reduced, The normal cleaning procedures do not re- and soil can be covered by aluminum. Moist duce mite allergen content, and normal vacu- walls, wallpapers, humid textiles, shower cur- um cleaners are of little help. During the con- tains, and humidifiers should be avoided [15, struction of a house, important measures can 45]. be taken (central heating, adequate ventilation, low air humidity, central vacuum cleaner, which is equipped with an adequate filter and 6.5.5.3 Animal Epithelia blows the air out into the outside environment) After removal of a pet, the patient has to know [29] that over a longer time (months up to years) Mites or mite allergen can be detected in en- small amounts of the respective allergen will vironmental samples by a color test which de- still be measurable in indoor air [10, 37, 47, 58]. tects the fecal product guanine or by immuno- References 245

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