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ZS" q2 renew ABC of allergies Asthma and allergy AJ Newman Taylor Definitions and distinctions Asthma is commonly defined as a narrowing of the airways that is reversible over short periods of time. either spontaneously or as a result of treamaent. This clinical defirtition (which characterises asthma as reversible airway narrowing) distinguishes it fi'om other predominantly irreversible cauges of airway narrowing, such as chronic obstructive bronchiolitis and emphysema. Another cardinal characteristic of asthma is airway hyper-respousiveness, an exaggerated narrowing of the airways provoked by a variety of non-specific stimuli, such as exercise and cold air. The two defining characteristics of asthma--reversible airway narrowing and airway hyper-respomiveness--are manifestations of a characteristic pattern ofair~y inttammation (a Th2 lymphocyte dependent desquamative eosinophilic bronchitis). ~ Atopy Atopy is the propensity to produce IgE antibody to allergens (antigem that stimulate the production of IgE antibodies) that are commoniy encountered in the general environment--for example, pollens, mites, and moulds. Atopy is usually identified by the provocation of one or more immediate "weal and flare" respomes in the skin to extracts of common inhaiant allergens. Specific IgE antibody to common inhalant allergens can also be found in the serum samples of atopic individuals, who may also have a raised se~Lra concentration of total IgE. The development of atopy is influenced by both genetic ~nd environmental factors: • The genetic basis ofatopy is debated. Twin studies have comistenfly shown that atopy occurs more frequendy in identical than non-identical twins. The findings in different family studies, however, have not identified a consistent pattern of inheritanc~ Recent molecular studies have suggested an association between atopy and polymorphisms of the high affinity IgE receptor on chromosome 11q (FCXRI-IB) and linkage with the interleukin 4 gene duster on chromosome 5. It seems likely that atopy will eventually be associated with polymorphisms of many different genes. • The twofold to threefold increase in the prevalence of asthma during the past 30 years has been accompanied by an increase in the prevalence of hay fever and eczema and of skin prick test respomes to common inb:alar~t allergens. The difference in the prevalence of asthma in ctiildren between dties in former East Germany (Leipzig and Halle) and West Germany (Munich) after reunification was wholly accounted for by the 2.5-fold greater prevalence of atopy in Munich. Changes in prevalence of this magnitude, which have occurred over decades, are too rapid to reflect d/fferences in the genetic pool and are probably due to changes in important environmental determinants of atopy, possibly a decrease in respiratory infection in early life. AJlergy The concept of allergy was proposed by Clemens Freiherr von Pirquet in 1906 as a "specific acquired altered reactivity, which follows initial exposure to foreign protein:' a description that encompasses both immunity, and a/lerg3: A/though aller,~, is Normal bro~hiole Bronchiole from asthmatic patient narrowed by eosinophilic in~kmfio~ oedema, and increased smoo~h muscle Allergy in atopic patients • A.s well as asthma, eczema and hay fever are also manifestations of allergy in atopic patients • Not a11 allergy is atopic--for a~mple, drug reactions • Not all allergic asthma is axopic--for example, asthma induced by the tow molecular weight chemical sensitisers (such as iso~'anates in two part polyurethane painu~ • Asthma can a/so be provoked through non-immunological reactions--for e.~ple, non-steroidal and-irtflammato~, drug~ and I] blockers

Glinical review now distingxtished fi'om immuniW by a disproportionate injmT to host tissue, the immunological reactions underlying both immune and allergic responses are the stone; they differ only in their clinical outcome. This article is predominantly concerned with reactions associated with Th2 lymphocyte dependent IgE response whose outcome is charactm'ised by local recruitment and activation of circulating blood eositu ~phils. This would be considered m be an immune response when directed against parasites such as shistosoma and filaria but an a/lergic response when directed against pollens and mites. In this context, allerhq" is the clinical outcome of IgE associated reactions to COlllrnOll environmental allergens in atopic individuals. The chantc~eristic allergic reartions in atopic indMduals are eczema, ha.v ibver, and asthma, which can, but do not by any means ahvays, coexist itt the same individual. Asthma ram' flaerefore be one of tim manitbstations ofallergT in atopic indMduals. Asthma and _allergy Allergens and asthma Asthma c2m be initiated and provoked by allergens in everyday life--outdoors, indoors, and at work. laa patients whose asthma is provoked by protein allergens encountered in eve~Tday life (such as pollens, mites, and moulds), exu-acts of r.elevant allergens in solution will elicit immediate skin test responses, and spedfic IgE m~fibody can be detected in their serum. This is iflso true for protein allergens that cause occupational asthma and tbr some low molecular weight chemicals encountered at work--for example, platinum salts, add anhydrides, and reactive dyes (but not, for example, isocyanates, resin, wood dust). In general, evidence of specific IgE anfibod); either from an immediate skin test response or specific IgE in serum, is a very sensitive test (that is. there are fbw fidse negatives) but also a non-specific test (that is. many thlse positives). A uegative result is therefore more valuahlc titan a posidve result as it c~m exclude a specific cause of asduna, whereas a posidve result is less reliable tbr identi~'ing a specific cause alld must always be interpreted in the context of the clinical histor): Allergens and asthma Outdoors Indoors Polb?~s Mites Tree Dcnnatophagoides pteronyssinus Grass and farinae (house dust mites) MouldsAninmh Ahernaria alternata Cats Cladosporium hed~atum Dogs Aspergillus fumigatus Birds Asthma and airway hyper-responsivenes's Exposure to allergens occun'ing naturally and in the laboratory can provoke airway narrox~fng and ainvay hyper-responsiveness. For example, padents allergic to ragaceed poIIen show a progn'essive increase in the severity of airway responsiveness during the ragaveed season concun'enfly xxdth the increase in the severity of their asflmaa. Inhalation of soluble exu-acts of allergens provokes an immediate asthmatic response that peaks at about 20 minutes and resoh'es widain ~bout one hour. The provocation and severity of the immediate response is dependent on both the dose of inhaled allergen and the deom-ee of airway h)per-responsiveness. In about 50% of patients a late asthmatic Asthma in atopic patients • Asthma is associated with atop)" at all ages, although most sta'ongly in children and young adults • Atopic indix4duals may also have flexural eczema or ha)' fever concurrently, or have had them in the past • The prevaMnce of asthma in different environments correlates with specific IgE antibody to tim particular allergens present. For ex~maple, in cities in the United States astimaa is associated in altluent areas with specific IgE to house dust mite and cat hair and in poor areas with specific IgE to house dust mite ;rod cnckroach • Furthermore. tim severity of asthma con-elates with the ¢oncentradon of specific allergens (such as house dust mite or coc "ka-oach) to which individuals are sensitised Causes of occupational asthma Low molecular Proteins weight chemicals Anbnal Excreta of tats, mice etc; , locusts; grain mites l~getable Grain, flours; latex; green coffee bean; isphagula; latex M~vbial Mineral Harvest moulds, Bacillus subtilis enz3~nes (in detergents) Plicatic acid (fi'om western red cedar), pinewood resin Andbiotics--eg. penicillins, cephalosporins Acid anhydrides, isocyanates, complex pladnium salts, polyamines, reactive dyes 400 200, August September October Increased airway responsiveness in patient allergic to ragweed pollen during raga~'eed season 0 LO O~ 0~ O~ 0 ,0,0,.q~ BM'J VOLUME .g 1628 MARCH lO_q8

response also develops after three hours; it peaks at 6-12 hours and may persist for 12-24 hours. Low molecular weight c.hemicals can provoke isolated late reactions. The immediate asthmatic response is mediated by dependent mast cell release of mediators such as histamine and leukotrienes. The late reaction is a manifestation of eosinophilic airway inflammation. Both are thought to be the outcome of a Th2 lymphocyte response to inhaled allergen. The late, but not immediate, reaction is associated with the development of airway hyper-responsiveness, probably as a manifestation of the induced airway inflammation. The induced ainvay hyper-responsiveness occurs independendy of the reduction in forced expiratory volume in one second and in airway calibre during the late reaction and can be sustained for several days after the forced expil~tory volume has returned to normal. During the period of increased airway responsiveness the normal diurnal variation in airway calibre may be exaggerated, causing recurrent nocturnal asthma, and non-specific stimuli (such as exercise, cold air and smoke), as well as specific allergens to which the individual has developed specific IgE antibody, can provoke immediate asthmatic responses. Allergen exposure and chronic asthma Exposure to allergens induces Iate asthmatic responses and associated airway hyper-responsiveness. Airway hyper-responsiveness is an important determinant of immediate airway responses both to non-specific stimuli (such as exerdse and cold air) and to exposure to specific allergens. By increasing non-specific ainvay responsiveness, allergen exposure can increase the development and persistence of chronic asthma, Implications for treatment This model has important implications for the management of asthma. Reducing allergen exposure at home or in the workplace will reduce not only the frequency of immediate asthraatic responses but also the severity of airway responsiveness and the capacity for allergens to provoke asthmatic responses. This is particularly important when a single "dominant" allergen is primarily responsible for the induction of asthma. Exaraples are occupational asthma and some cases of asthma caused by allergens in the home, such as house dust mite, cat, or cockroach, where avoidance measures have been shown to be effective. Identification of allergens in the home and ofailergens or chemicals encountered at work is therefore important when avoidance is practicable. In the home, pets are particularly relevant, and, with improved avoidance measures, identification of allergy to house dust mite is becoming more relevant In the workplace, accurate and early identification of the specific cause of allergic asthma (either allergen or chemical) to enable avoidance of further exposure is the cornerstone of management of occupational asthma. The first graph is adapted, with pennission fi'om Boulet et al (J Allergy Clin Immuno11983;71:399-406),imd the second is adapted with permission from Cockcroft et al ( Clin Allergy 1997;7:b03.73). AJ Newman Taylor is consultant physician in respirator), medicine at the Royal Brompton Hospital, Londor~ The ABC of allergies is edited by Stephen Durham, honorary consultant physician in respir'atory medicine at tlae Royal Brompton Hospital, London. It will be published as a book later in the )'ear. BMJ lggs:316;gg7-9 volum~ in on~ s~cond Control'~'O ~ 1 2 3 4 5 6 7 8%13 15"~-19 Days a~er allergen inaction Incre~sed airway responsiveness associated with late asthmatic reaction provoked by ragweed pollen L~tc asthmahc response Allergen Th2 lymphocytes (+ gE) 1 Eosmophdic bronchitis ~-~ Airway hyper-responsiveness immediateresponse asthmatic Allergen induction of ailn~y inflammation and hyper-responsiveness pernfits provocation of hnmectiate asthmatic responses by both allergens and non-specific factors, such as exercise and cold air - Criteria for,diagnosing hypersensitivity induced occupational asthma CO Histm~ • Exposure to a sensitising agent • Initial symptorn fi'ee period of exposure (or employment) • Improvement in severity of asthmatic symptoms during absences fi'om work--eg, weekends or holidays--and progressive deterioration during periods at work Objeaive evidence • Serial peak flow measurements sho~4ng work related asthma • Specific IgE (s "idn tests or in serum) to specific agent • Reproducible late asthmatic response and increase in ~fitavay responsi 'eness prox oked by inhalation test with specific agent in less than toxic concenu-ations* *Inhalation tests should be undertaken only for medical purposes in a spedalist centre when the diagnosis of occupational asthma remains uncertain after other investig'4tions have been complete~. Inhalation tests are not justifiable when undertaken solely for medicolegal purposes BIvfJ VOLUME 316 28 MARCH 1998 999