abc of allergies

ABC of allergiesThe epidemiology of allergic diseaseD Jarvis, P Burney

Atopy is defined as the production of specific IgE in response toexposure to common environmental allergens, such as housedust mite, grass, and cat. Being atopic is strongly associated withallergic disease such as asthma, hay fever, and eczema, but noteveryone with atopy develops clinical manifestations of allergyand not everyone with a clinical syndrome compatible withallergic disease can be shown to be atopic when tested forspecific IgE to a wide range of environmental allergens. This isparticularly so for asthma.

Asthma is arguably the most serious of the allergic diseasesin that it is disabling (causing more than 100 000 hospitaladmissions each year in England and Wales) and occasionallyfatal. In 1995, 137 people aged under 45 died as a result ofasthma. Although concern has been expressed that deathcertificates may overestimate or underestimate asthma mortalitydepending on diagnostic fashion, significant misclassificationwith other forms of chronic obstructive lung disease in this agegroup is unlikely. In the early 1960s asthma mortality increaseddramatically in many countries. The increase was attributed tothe excessive use of nonselective â agonists, which weresubsequently withdrawn from the market. More recent increasesin asthma mortality reported from Britain, France, and theUnited States may be related to increased prevalence or severityof asthma or inadequate health care. Evidence for the lattercomes from audits and confidential inquiries that showinadequate treatment of asthma in the months leading up todeath and during the fatal attack and the observation of highermortality in populations recognised as often receiving poorhealth care (socioeconomically deprived people in Britain; blackpeople in the United States). In England and Wales asthmamortality rose between the mid1970s and the mid1980s butdeclined steadily during the early 1990s.

Hay fever and eczema are important causes of morbidity,being responsible for a substantial proportion of health serviceuse, particularly in primary care, and reduced quality of life.

PrevalenceTime trendsThe prevalence of diseases associated with atopy has increasedin many parts of the world over the past 20 to 30 years. In theUnited Kingdom the prevalence of diagnosed asthma andsymptoms strongly suggestive of asthma in children hasincreased at a rate of about 5% a year. Increases of a similarmagnitude have been observed in Sweden, Switzerland, Norway,the United States, Australia, New Zealand, and Taipei. Some ofthis apparent rise may have occurred in response to greaterpublic awareness of asthma and a greater tendency of parentsto report wheezing illnesses in their children and to attend theirdoctor for treatment of asthma.

Few serial surveys have examined an increase in objectivemarkers for asthma, although the prevalence of exerciseinduced bronchial constriction has increased in Welshschoolchildren over 15 years, suggesting that the increase inreported symptoms reflects a genuine change in health status.Few reported serial surveys have examined the prevalence ofasthma in adults, although the proportion of military recruitswith asthma has increased in Finland, Sweden, and Israel.

1995

Year

Mort

ality/

mill

ion p

opula

tion

199019851980197519701965

15

0

25

30

35

20

Age standardised asthma mortality, England and Wales, 196994 (both sexes,1564 years)

Year of survey

Pre

vale

nce

(%

)

200019901980197019601950

0.1

0

10

100

1

Changes in prevalence of asthma and wheeze, according to surveysconducted 195693 worldwide

1990

Year

Pre

vale

nce

(%

)

198019700

10

15

20Wheeze in past 12 months

Asthma ever

>25% drop in peak expiratory flow after exercise

Eczema ever

Hay fever ever

5

Change in prevalence of wheeze, asthma, exercise induced bronchialconstriction, hay fever, and eczema in children in south Wales between 1973and 1988

607BMJ VOLUME 316 21 FEBRUARY 1998

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Most of the surveys that have shown increases in theprevalence of asthma have also shown increases in theprevalence of other allergic diseases, such as hay fever andeczema. In the United Kingdom, results from the three nationalbirth cohorts (samples of people born in 1946, 1958, and 1970)have shown a marked increase (5.1%, 7.3%, and 12.2%respectively) in the prevalence of eczema as reported by themother in children aged under 5.

The rising prevalence of allergic disease has resulted inincreased use of health services. For asthma, hospitaladmissions (particularly among children aged under 5 years),consultation with general practitioners, and the use of drugtreatment all rose sharply during the 1980s. Consultations withgeneral practitioners for managing hay fever also increased.

The increased prevalence of all allergic diseases suggeststhat the prevalence of atopy has increased. Epidemiologicalinformation from Switzerland and Japan shows that theprevalence of atopy is increasing in children. In both thesestudies the increase in the prevalence of atopy was due to anincrease in sensitisation to a variety of allergens and notdominated by an increase in sensitisation to one particularallergen. In Britain no evidence exists that exposure to allergenhas increased—in fact grass pollen levels have steadily decreasedover the past 20 years and pet ownership has probably notchanged. At present the extent to which changes in theprevalence of atopy and changes in allergen exposure explainthe time trends in allergic disease is unknown.

Geographical distributionUntil recently the methods used for assessing the prevalence ofallergic disease were not standardised and comparisons ofdisease prevalence between countries were flawed. Two majorresearch initiatives, the European Community respiratoryhealth survey (ECRHS) and the international study of asthmaand allergies in childhood (ISAAC) have developed andexecuted standardised protocols for the assessment of diseaseprevalence in many different countries in adults and children.

The European Community respiratory health survey hasshown wide geographical variation in the reported prevalenceof symptoms highly suggestive of asthma, treatment for asthma,and current hay fever or nasal allergies in adults. In general,symptoms are more common in New Zealand, Australia, theBritish Isles, and the United States than in mainland Europe,although there is wide variation even within some countries.The distribution of atopy (for these purposes defined assensitisation to house dust mite, grass, cat, or cladosporiumspecies) shows a similar distribution, with marked variationbetween countries, although the extent to which variation inatopy explains variation in symptoms is still under investigation.

India

Algeria

United States

Australiaand New Zealand

Algeria

United States


United States


India

Areas with high (red) and low (blue) prevalence of asthma (top), hay feverand nasal allergies (centre), and sensitisation to any one of house dust mite,cat, timothy grass, or cladosporium species (bottom), according to results ofthe European Community respiratory health survey (white circles representareas that participated in the study but which did not have a particularlyhigh or low prevalence)

Year

Pre

vale

nce

(%

) of

sensi

tisa

tion

to c

om

mon a

llerg

ens

01975 1980 1985 1990 1995

20

30

Japan

Switzerland

40

50

10

Change in prevalence of sensitisation to common allergens inschoolchildren in Japan and Switzerland

608 BMJ VOLUME 316 21 FEBRUARY 1998


The international study of asthma and allergies inchildhood, which has not yet been fully reported, has shownthat severe asthma is more common in children living in NewZealand and Australia than in those living in West Sussex and inBochum, Germany.

Risk factorsGeneticsTotal IgE concentration, the production of specific IgE, andbronchial hyperreactivity are all under some degree of geneticcontrol. Chromosome 5 has been implicated in the regulationof total IgE concentration, chromosome 11q linked to theatopic phenotype (high total IgE concentration or specific IgEto a common allergen), and chromosome 14 linked to eczema;specific HLA haplotypes are linked to the development of IgEto some allergens (for example, specific allergens from rye grassare associated with DR3). Although genetic susceptibility toallergic disease is important, it is unlikely that either the largegeographical variations in disease prevalence between peoplesof similar genetic background, or the increase in allergic diseaseover the past few decades can be explained by genetic factors.

Age and sexThe incidence of asthma is higher in children than in adults.Longitudinal surveys suggest that children with mild disease arelikely to become asymptomatic as teenagers, whereas those withmore severe disease will have symptoms that persist throughoutlife. To some extent this “ageing” effect explains why in somecross sectional studies allergic disease is less common in adultsthan in children, but these observations may also reflect anincreased propensity for asthma and atopy in those born laterin the century.

More boys than girls have atopy, asthma, and hay fever,although these differences become less apparent later in life. Atall ages, males have higher total IgE concentration than females.

InfectionMore than 80% of asthma exacerbations in children are of viralorigin. This epidemiological observation equates well with mostclinical experience, but consensus is weaker over the role ofinfection in the pathogenesis of atopy and allergic disease.

Children who grow up in large families, especially ifexposed to older siblings, are likely to experience morechildhood infections than those who come from small families.Because the prevalence of allergic disease, in particular hayfever, and sensitisation to common allergens is lower in thosewho grow up in large families or who have older siblings, highrates of infection in childhood may protect against thedevelopment of atopy and allergic disease.

Secular changes in family structure and maternal smokingdo not fully explain the increase in wheezing, hay fever, oreczema in adolescents.

Smoking

x People who smoke have higher total IgE concentration and aremore likely to become sensitised to allergens in the workplace thanpeople who do not.

x The association between smoking and sensitisation to commonallergens, however, is not clear, with several reports of lower rates ofsensitisation to common environmental allergens and less hay feverin smokers

x This may be explained to some extent by the “healthy smoker” bias(the tendency of those with allergic disease not to smoke) but mayalso reflect a genuinely reduced incidence of some forms of allergyamong smokers

x Smoking is an important risk factor for bronchial hyperreactivity—afeature of asthma—buts its association with asthma remainsuncertain

x Children whose mothers smoke during pregnancy have reducedlung function and more wheezing illness during childhood but donot seem to have more allergic diseases

Family

size

Pre

vale

nce

(%

)

00 1 2 3+

No of older

siblings

No of younger

siblings

0 1 2 3+ 0 1 2 3+

10

15

20

25

5

Prevalence of hay fever in young adults by family size, number of oldersiblings, and number of younger siblings

Prevalence (percentage) of self reported asthma symptoms in past year in children aged 1215 years infive centres participating in the international study of asthma and allergies in childhood

Bochum,Germany

West Sussex,UK

Wellington,New Zealand

Adelaide,Australia

Sydney,Australia

Sample size 1928 2097 1863 1428 1519

Wheeze in past year 20 29 28 29 30

Severe attack of wheezing in past year 6 7 11 10 13



Exposure to allergensThe development of sensitisation to an allergen requiresexposure to that allergen. Exposure early in life may beassociated with a higher risk of sensitisation than exposure laterin life, but no evidence exists yet that reducing allergen load inthe home of young children reduces sensitisation or thedevelopment of allergic disease.

Once sensitisation has occurred, repeated exposure to thatallergen is likely to trigger symptoms. Epidemics of asthma haveoccurred when high levels of allergen have been present inambient air. In Barcelona outbreaks of asthma identifiedthrough sudden increases in emergency admissions for asthmaresulted from unloading of soy beans at the local harbour. Theepidemics were prevented by reducing the ambient allergenload by installing filters at the top of the storing tower. InBritain a severe thunderstorm in 1994 was associated with thelargest ever outbreak of asthma. Many of the epidemic caseshad previously experienced only hay fever, and asthma wasprobably precipitated in these grass sensitised individuals by therelease during the thunderstorm of small aerosolised particlesof grass allergen from grass pollen in the air. In Britain moredeaths from asthma occur during the summer and earlyautumn than during the winter. This seasonal pattern is notobserved in deaths from asthma in elderly people and may beanother manifestation of the importance of allergens on theseverity of asthma, particularly in young people.

In Britain most people with allergic disease are sensitised tohouse dust mite, and this allergen has been implicated as themost important allergen for both the development andexacerbation of asthma and eczema. In other countriessensitisation to cat, grass, or moulds may be a more importantcause of disease.

More than 300 agents have been identified as occupationalallergens. Occupational exposure to allergens may causeeczema, rhinitis, or asthma. Occupational exposure to agentsknown to cause asthma may be responsible for as many as 1 in15 cases of adult onset asthma in some populations.

DietOver the past 20 years diet has dramatically altered in mostdeveloped countries. Sensitivity to food, particularly to milk,eggs, and fish, is not uncommon in childhood; in adults, though“intolerance to foodstuffs” is frequently reported, it is rarelyobserved on formal challenge. Withdrawal of allergenic foodsmay reduce the severity of some allergic disease. Other dietaryfactors such as electrolytes (sodium and magnesium), nature offatty acids in the diet (in particular oily fish), and antioxidantshave all been identified as possibly increasing the severity ofasthma.

The data in the second graph are from Burr et al (Arch Dis Child1989;64:14526); in the third graph are from Nakagomi et al (Lancet1994;343:1223) and Gassner et al (Schweiz Rundschau Med 1992;81:4268);in the fourth graph are from Strachan D (Clin Exp Allergy 1995;25:296303);and in the second table are from Meredith S (J Epidemiol Community Health1993;47:45963). The first table and the final graph are adapted withpermission from Pearce et al (Eur Respir J 1993;145561) and the Office forNational Statistics’Health of Adult Britain, respectively.

D Jarvis is senior lecturer in public health medicine and P Burney isprofessor of public health medicine at the United Medical and DentalSchools, London.

The ABC of allergies is edited by Stephen Durham, honoraryconsultant physician in respiratory medicine at the Royal BromptonHospital, London. It will be published as a book towards the end of1998.

Further readingx European Community Respiratory Health Survey. Variations in theprevalence of respiratory symptoms, selfreported asthma attacksand the use of asthma medication in the European Communityrespiratory health survey (ECRHS). Eur Respir J 1996:9:68795

x Burney P, Malmberg E, Chinn S, Jarvis D, Luczynska C, Lai E. Thedistribution of total and specific serum IgE in the Europeancommunity respiratory health survey. J Allergy Clin Immunol1997;99:31422

x Barbee R, Kaltenbourn W, Lebowitz M, Burrows B. Longitudinalchanges in allergen skin test reactivity in a community populationsample. J Allerg Clin Immunol 1987;79:1624

x Central Health Monitoring Unit. Asthma: an epidemiological overview.London: HMSO, 1995

x Burr M, ed. Epidemiology of clinical allergy.Monographs in Allergy. Vol31. Basle: Karger, 1993

Incidence (95% confidence interval) of occupational asthma(cases per million workers per year) in some high riskoccupational groups

Occupational group Incidence

Coach and other spray painters 658 (508 to 839)

Chemical processors 364 (274 to 475)

Plastics workers 337 (248 to 448)

Bakers 334 (248 to 440)

Laboratory technicians andassistants

188 (139 to 247)

Workers in welding, soldering,and electronic assembly

175 (138 to 218)

2.0

0.8

1.2

1.6

2.0

0.8

1.2

1.6

2.0

0.8

1.0

1.0

1.0

1.2

1.6

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

Month

Age 5-34 years

Age 35-54 years

Age 55-74 years

Odds

ratio

Odds

ratio

Odds

ratio

Odds of dying from asthma by month compared with odds of dying inJanuary (England and Wales, 195891)



ABC of allergiesDiagnosing allergyCsaba Rusznak, Robert J Davies

Allergy to environmental agents can affect almost every organof the body. Although allergic rhinitis is the commonestmanifestation, the lower respiratory tract, the conjunctiva, theskin, and the gastrointestinal tract are frequently affected byallergic disease.

Allergic diseases are common, and their prevalence isincreasing. Accurate diagnosis of triggering or causativeallergens is essential for appropriate advice for avoidance andenvironmental control measures. Although allergic diseases canoccur at almost any age, some allergies are most likely todevelop for the first time in particular age groups.

SymptomsAn immediate relation between exposure to potential allergensand the development of symptoms makes both the diagnosisand identification of allergy straightforward. In 2550% of casesthe predominant symptoms develop 110 hours after exposure(late phase reactions), obscuring the allergic nature of theillness. In allergic diseases of occupational aetiology the firstsymptom may be exercise induced asthma or nighttime wakingwith cough. The longer such symptoms have been present themore likely they are to persist when exposure ceases.

The onset of seasonal symptoms occurs three weeks earlierin southern England than in northern Scotland.

Symptoms occur more rapidly after exposure to thecausative agent as sensitisation increases. Many patients withfood allergy develop either a craving for or an intense dislike ofthe offending food. Symptoms are usually gastrointestinal(abdominal pain, bloating, vomiting, diarrhoea) or cutaneous(itching, urticaria, angiooedema)—symptoms are lesscommonly respiratory (asthma) and are rarely related torhinitis.

Cross reaction can occur between various allergens, such asbirch tree pollen and certain foods (for example, apple, carrot,celery, potato, orange, tomato, hazelnut, and peanut). Crossreactivity also exists between latex and some fruits (banana,avocado, kiwi fruit, and chestnut).

Itching of the throat and ears is a common manifestation ofpollen allergy, and patients allergic to house dust miteexperience exacerbations when bedmaking, vacuum cleaning,and sleeping in damp accommodation.

The impact of the allergic symptoms on an individual’slifestyle should be assessed in terms of impairment of school orwork performance and time missed, with particular emphasison the interference in leisure activities and sleep.

Factors influencing development ofallergic diseasesIf both parents are allergic the risk of allergy in the offspring is75%; if one parent is allergic the risk is 50%. The risk in thepopulation is 1020%. Allergy is much less common in youngerchildren in large families than in their older siblings. This isprobably due to viral infections being passed more often fromone child to another in large families, which may influence thesubsequent dominance of Th1 driven rather than Th2 drivenimmune responses.

Age when certain allergies are likely to occur for first time

x Neonates—Atopic dermatitis, food allergies (milk, egg, nuts)x Early childhood—Asthma (house dust mite, pets)x Teenagers—Allergic rhinitis (grass and tree pollens)x Early adulthod—Urticaria, angiooedema (aspirin intolerance)x Adulthood—Allergy to venom (bee, wasp); nasal polyps

Taking a clinical history

x A detailed clinical history is vital for diagnosing an allergyx Taking a history requires experience, time, and patiencex Patients should be allowed to give their own account of theirsymptoms in their own time

x Structured questions about the patients’ history (with particularemphasis on previous allergic diseases—such as childhood eczema,hay fever, and asthma) should be asked

x Frequency, severity, duration, and seasonality of symptoms shouldbe ascertained, with particular reference to triggering factors, lifethreatening events, and effects of avoidance measures

x Patients should be asked about diet; food exclusion; and intoleranceto aspirin, colourings, and preservatives

x Family history should be exploredx Home, work, and outdoor environmental risk factors should bediscussed

x Groups at particular risk of allergy—such as healthcare and rubberindustry workers and children with spina bifida, in whom latexallergy is particularly prevalent—should be identified

x Patients should be asked about any treatment they are currentlyusing, particularly about antihistamines, topical and oralcorticosteroids, and adrenalin autoinjectors

Environmental factors predisposing to development andtriggering of allergy

IndoorDamp and poorly ventilated dwellingOld mattresses (not vacuumed or covered)Unwashed and uncovered pillows and duvetPetsCigarette smokeGas fired cooking stoves, boilers, and fires (not adequately ventilatedto the outside)

OutdoorDensity of grains of grass or tree pollen in local environmentPresence of new aeroallergens—eg Parietaria judaiica (the wallpellitory) in southern England

Proximity to major roadways or power stations

OccupationalIsocyanateFlourLaboratory animalsResinWood dustGlutaraldehydeBiological enzymesLatex



Allergy tests in vivoSkin tests

Skin prick testThe skin prick test is the most widely used allergy test and canbe performed during the initial consultation with aqueoussolutions of a variety of allergens. These include (a) commoninhaled allergens (house dust mite, grass pollen, cat dander, doghair); (b) occupational allergens (such as ammoniumpersulphate, platinum salts, antibiotics, and latex); and (c) foodallergens

Skin prick testing requires control using diluent (negativecontrol) and histamine solution (positive control). A drop ofallergen solution is placed on the skin of the forearm. A sterilelancet or 25 gauge (orange) needle is used to prick the skinthrough the allergen solution (a separate needle is used foreach allergen solution). The excess allergen solution is removedfrom the skin with an absorbent paper tissue. The reaction isevaluated after 15 minutes.

The test should be performed with standardised allergensolutions, if possible. In general practice it may be sufficient touse four allergens (house dust mite, grass pollen, and cat anddog allergen) plus the positive and negative controls to confirmor exclude atopy and recognise the most common allergensencountered.

Test solutions are available from ALK Abello (Reading,Berkshire) under the brand name Soluprick.

A positive result is a skin weal > 2 mm greater than thatobserved with the negative control (allergen diluent) solution.However, the relation between a positive result and overtclinical disease caused by that allergen is not absolute. Theconcentration of the allergen solution will determine the resultof the test. Ideally the test should combine the highest possiblesensitivity with the highest possible specificity, but this degree ofprecision is not usually achievable.

The result of the skin prick test should be interpreted in thelight of the clinical history: if both the history of allergy and thetest result are positive, atopy and the offending allergen areconfirmed; if both are negative, allergy is excluded; in the caseof perennial allergens, there may not be an immediateassociation between exposure and symptoms, resulting in a falsenegative history in the context of a positive test result; manypatients with a positive test result do not have symptoms ofallergy; if there is discordance between the history and the testresult, referral to an allergy specialist is recommended.

The advantages of skin prick testing are: it is painless andhas a low risk of side effects; it is informative to the patient;patient compliance is high; and the test can be performed inhealth centres.

The disadvantages are: systemic and topical antihistaminesmay suppress the weal and flare reaction; the test is less reliablewith food allergens (which are less well standardised) than withinhaled allergens; itching causes a slight discomfort; andinterpretation is difficult in patients with eczema ordermatographism.

Although skin prick testing with inhaled allergens isgenerally safe, occasional systemic reactions includinganaphylaxis have been reported when food allergens are used;testing with food allergens should therefore be performed onlyin specialist centres. Adrenaline should always be available.

Intracutaneous testThe intracutaneous test is rarely indicated, though it is of valuein the diagnosis of drug or venom allergy.

It should be performed by allergy specialists in specialistcentres.

Lancet for skin prick testing

Skin prick test kit comprising four allergens and positive control solution(histamine 10 mg/ml) and negative control (allergen diluent)

Evaluation at 15 minutes of skin prick test results (wealsizes in mm)



Patch testThe patch test is widely used in the diagnosis of allergic contactdermatitis. Several standardised series of contact allergens areavailable. Possible allergens are applied in a standardised formto a healthy area of the patient’s skin. The patch test can beperformed either with the suspected chemicals or with thestandard series of allergens.

Eczematous reaction at the site of application 4872 hourslater shows that the patient is sensitised to that allergen. Thereaction must be distinguished from simple irritant reactions.

The patch test is the most important diagnostic tool indiagnosing contact allergic dermatitis. However, patch testingcan cause a flare up reaction (of healed eczema) or persistingtest reactions. It can also cause sensitisation and subsequentallergic contact dermatitis. It is time consuming, and it requiresspecialist interpretation.

Bronchial, nasal, and conjunctival provocation testsThese tests are rarely required in the routine diagnosis ofallergy. Bronchial or nasal provocation test with allergen mayoccasionally be useful in determining “local sensitisation,” inwhich, although the results of skin prick testing (and of theradioallergosorbent test, if also done) are negative, the airwaysare responsive to the specific allergen. These tests must beperformed only by individuals trained in allergy diagnosis.

Food challengeDiagnosis of food allergy requires taking a careful history and, ifnecessary, altering the patient’s diet with the help of a skilleddietician. The consequence of correct diagnosis can bebeneficial to patients but may disrupt their lifestyle. A definitediagnosis of food allergy can be established by properlyconducted blinded food challenges, which avoid any possiblebias from patient or investigator.

Food challenge will be covered in more detail in a laterchapter on food allergy.

Allergy tests in vitroNasal smearsNasal smear tests are used to determine the number ofeosinophils present in the nasal secretion. A cotton bud isinserted two or three times into each nostril, and the lining ofthe nose scraped with a firm, rolling movement. Secretions arespread gently on to a microscope slide and stained, and the cellsare counted.

The advantages of nasal smears are that the nose is readilyaccessible and the test can help to differentiate betweeneosinophilic rhinitis (allergic rhinitis and nonallergic rhinitiswith eosinophilia, which respond well to topical corticosteroids)and rhinitis due to other causes. However, the disadvantages area slight discomfort to the patient and a high risk of falsenegative results if the nasal smear is not properly obtained.

Serum allergen specific IgE concentrationsIn the radioallergosorbent test (RAST) allergens (antigens) arechemically bound to an insoluble matrix such as plastic,cellulose nitrate, cellulose (paper), or agarose beads. Whenpatients’ serum is added, allergen specific IgE binds toimmobilised allergen. Radioactively labelled antiIgE is thenadded, which attaches to the specific IgE already bound to theallergen. The amount of specific IgE in the patient’s blood canbe estimated from the amount of bound radioactivity.

In another type of radioallergosorbent test (the CAPRAST)system) the allergen is covalently coupled to a cellulose carrier

Common examples of contact allergy

AgentMercuryCopperNickelpPhenylenediamineParabenImidazolidinyl ureaFormalin, formaldehydeCarba mixThiuramEpoxy resin

SourceTopical ointmentsCoins, jewellery, door handlesCoins, alloys, insecticidesHair dye, fur dyeCosmeticsCosmetics (preservatives)Cosmetics, insecticidesRubber, fungicidesRubber compounds, fungicidesAdhesives

Food challenge

x Removal of the food from the patient’s diet should eliminatesymptoms

x Ideally challenges should be conducted as double blind, placebocontrolled challenges

x If the suspected food, but not the inactive substance, causes anallergic reaction, the diagnosis is established

x Food challenges must be performed under strict medicalsupervision and in hospital settings

x Food challenges, however, may cause anaphylactic reaction, aretime consuming, and require several challenges, with washoutperiods of days

If more than 10% of the stained cells innasal smears are eosinophils thisindicates a positive result compatible withnasal eosinophilia

Radioactively

labelled anti-lgE

Stage

3

2

1

Allergen specific lgE

(in serum to be tested)

Antigen (allergen)

The principle of the radioallergosorbent test



with a large surface area. The patient’s serum containing IgE isthen added and specific IgE reacts with bound allergen. Afternonspecific IgE has been washed away, enzyme labelledantibodies against human IgE are added, and the boundcomplex is then incubated with a fluorescence substrate, thedeveloping agent.

An enzyme linked immunosorbent assay (ELISA) is anonradioactive method which uses antigen in fluid phase andenzyme labelling of antiIgE, which is detected by addingsubstrate for the enzyme, which produces colour changedetected photometrically.

The radioactivity (radioallergosorbent test), fluorescence(CAPRAST test), or colour (enzyme linked immunosorbentassay) of the eluate corresponds with the concentration ofspecific IgE in the patient’s blood.

The advantages of measuring the concentration of allergenspecific IgE are that (a) it is not influenced by any concurrentdrug treatment, (b) it can be performed when there iswidespread skin disease, (c) it is completely safe, (d) thespecificity of the two radioallergosorbent tests can be as high as90% for inhaled allergens. However, the results are notimmediately available, and testing is expensive.

Alternative tests

x Recently there has been a surge in the number of alternative“allergy tests” offered direct to patients—for example, the antigenleucocyte cellular antibody test, hair analysis, bioresonancediagnostics, autohomologous immune therapy, electroacupuncture,and vega testing

x No scientific evidence exists that these tests are useful in diagnosingallergy

x Such tests may also disadvantage patients, who may modify diet andlifestyle to no avail

Csaba Rusznak is a registrar in respiratory medicine and allergy, andRobert J Davies is professor of respiratory medicine in thedepartment of asthma and allergy at the London Chest Hospital.

The ABC of allergies is edited by Stephen Durham, honoraryconsultant physician in respiratory medicine at the Royal BromptonHospital, London. It will be published as a book towards theend of 1998.

BMJ 1998;316;686–9

A lesson learnt

Always listen to the patient

It was almost 3 00 pm and I was at home trying hard to sleep offthe effects of a set of nights on call as a senior house officer inpaediatrics when I was awoken by my worried wife and presentedwith our 4 year old child, Steven. Sleepily, I took a quick bedsidehistory. My wife and two sons had been to the fairground in themorning. Steven had been apparently well, but had beencomplaining of pain “in his willy” since lunchtime, and when sheeventually examined him she was alarmed to find that hisscrotum was massively swollen.From my bed and with only a halfhearted glance at my son, I

decided that swollen testicles merited a turf to the surgeons. Twotelephone calls later they were on the way to the casualtydepartment to see a surgical colleague. I followed along blearilyand eventually met up with everyone in the x ray department,where a kindly radiologist was ultrasounding his scrotum. Fifteenminutes later, much relieved by the gentle whooshing of thedoppler, we were gratefully leaving hospital, and I was busyexplaining to Steven (despite his protests to the contrary) that hemust have banged himself “down below.”Later that evening, despite the panacea of paracetamol, he

wouldn’t eat his dinner because his tummy hurt. With theminimum of sympathy I explained that this was his poorly willyand he was bundled off to bed.He felt sufficiently recovered by the next day for us to continue

with our plans to take a trip to the Lake District to see hisgrandparents. The eye of faith confirmed that his scrotum wasmuch less swollen and so we proceeded to endure the monotonyof the M6, the journey being punctuated with only occasionalcomplaints of tummy pain.The evening saw a return of both his usual good humour and

appetite (attributed to Grandma’s cooking) and at bathtime acursory examination revealed two flea bites on his right ankle andtwo nonblanching spots on his right thigh. Smiling and playful,he was put to bed.The next morning, for the second time in two days I was woken

and presented with my son, the patient. His Grandma had woken

to find him crying and complaining of pain in his left arm, whichhe was refusing to use. A quick examination revealed a swollenand tender left elbow. I guiltily recalled swinging him around likean aeroplane the evening before—much to his delight at the time.I mentally rehearsed the inevitable embarrassing scene to followin the casualty department as I explained how he had hurt hiselbow.Clearing the sleep from my eyes and hurriedly throwing on a

few clothes, I cast my mind back to the rash I had noticed theprevious evening. I called Steven over to my bedside and a quickcheck revealed a rather familiar purpuric rash down both thighsand now spreading across his buttocks. My moment of diagnostictriumph was shortlived as with horror I recalled attending a childwith Henoch Schönlein purpura only a few weeks beforehandand reassuring his parents about his bruised and swollen testicles.The penny may have dropped, but it took almost two days to fall.In retrospect, I have been reminded of three important points

of clinical practice. Firstly, always listen to the patient, especiallywhen the answers do not fit with your working diagnosis.Secondly, always complete a thorough physical examination;there may be unlooked for clues that will lead you to an earlydiagnosis. Finally, and most importantly, whatever else happens,you can always rely on your children to confuse, confound, andultimately embarrass you.

William D Carroll, senior house officer in paediatrics, Northampton

We welcome articles up to 600 words on topics such asA memorable patient, A paper that changed my practice, My mostunfortunate mistake,or any other piece conveying instruction,pathos, or humour. If possible the article should be supplied on adisk. Permission is needed from the patient or a relative if anidentifiable patient is referred to. We also welcome contributionsfor “Endpieces,” consisting of quotations of up to 80 words (butmost are considerably shorter) from any source, ancient ormodern, which have appealed to the reader.



ABC of allergiesPathogenic mechanisms: a rational basis for treatmentPeter H Howarth

Allergic diseases such as asthma, rhinitis, eczema, andanaphylaxis are increasingly common and, in addition to beingassociated with morbidity and potential mortality, constitute aconsiderable burden on health resources, with both direct andindirect costs. This article discusses the pathogenic mechanismunderlying the clinical signs and symptoms of these diseasesand explains the basis for the choice of differing treatments.

Relation of atopy and allergy todiseaseAbout 40% of the population is atopic as evidenced by apositive response to a skin prick test with an allergen, but not allshow signs and symptoms of clinical disease. There may be alatency period, as students who have positive skin prick testswith grass pollen but who do not experience hay fever havebeen shown to go on to develop seasonal allergic rhinitis. Athreshold response may also be required for signs andsymptoms of clinical disease to develop, as allergic airwayinflammation is present in the lower airways of patients withperennial allergic rhinitis sensitive to house dust mite who donot have clinical asthma. This inflammatory response fallsbetween the response in patients with clinical asthma and thatin nonatopic healthy controls.

The situation is, however, more complex than this, aspatients with comparable responses to skin prick testing mayhave solely asthma, rhinitis, or eczema, and current research toexplain organspecific disease is focusing on the local tissueproduction of IgE and on the role of selective homing andactivation of T lymphocytes, which may amplify the local tissueresponse. It is, however, possible in sensitised individuals to linkallergen exposure to signs and symptoms of clinical disease, asseasonal exposure to aeroallergens (such as tree or grasspollens or fungal spores) induces seasonal allergicrhinoconjunctivitis, and exposure to perennial allergens (usuallyindoor allergens such as house dust mite or other animalallergens) is associated with persistent signs and symptoms ofdisease (asthma or rhinitis, or both). Intermittent exposure tosystemic allergens, such as food, drugs, or venom, can induceacute disease (anaphylaxis, urticaria, dermatitis, asthma, rhinitis),which may take a variable time to resolve. IgE mediatedreactions underlie these clinical responses.

Immunoglobulin EAn increase in specific IgE is reflected by positive skin pricktests to allergens or by positive in vitro tests such as theradioallergosorbent test. Specific IgE is generated byB lymphocytes under the regulation of cytokines generated byT lymphocytes. Cytokines are small molecular weight chemicalsthat have a localised action in modulating cell function. Thecytokines that favour IgE isotype switching (interleukin 4 andinterleukin 13) are generated by a subpopulation ofT lymphocytes with a T helper 2 cytokine profile, whereasT cells that generate a T helper 1 cytokine profile—by secretinginterferon gamma—inhibit B cell isotype switching for IgEsynthesis. Th1 and Th2 cells reciprocally inhibit each other’sdevelopment. In atopy the production of IgE is increased,

Immunohistology of nasal mucosa in allergic rhinitis using alkalinephosphatase/antialkaline phosphatase technique showing individual cellsstained red: mast cells (top), eosinophils (bottom left), and CD4T lymphocytes (bottom right)

Allergen

Dendritic cell

(airway)

Dendritic cell

(node)Th0

B IgEInterferon γ IL10

Interferon γ

IL4

IL13

IL12

Positive

Positive

Negative

Negative

Negative

Positive

IL4

Th1

Th2

IL = interleukin

Regulation of B lymphocyte IgE synthesis by T lymphocytes. T cells with theTh2 cytokine profile increase interleukin 4 and interleukin 13 synthesis,which promotes IgE isotype switching, whereas the development of T cellswith a Th1 cytokine profile, which generate the interferon gamma, inhibits Bcell isotype switching for IgE synthesis. This process also involves antigenuptake and processing by mucosal dendritic cells (commonly Langerhans’cells in the airways) and the presentation of antigen in a modified format toT lymphocytes, typically in a draining lymph node

758 BMJ VOLUME 316 7 MARCH 1998


suggesting an imbalance in the ratio of Th2 to Th1 control. Thedevelopment of Th2 secreting lymphocytes requires interleukin4. This cytokine is generated by the placenta to preventimmunological fetal rejection (a Th1 cytokine response). It hasbeen proposed that that persistence of this placental Th2drive—possibly related to improved or altered nutrition in theabsence of a Th1 counter switch—is the major factorcontributing to the increasing prevalence of allergic disease inthe past 3040 years. An additional contributory factor may be adecrease in severe infection in early infancy over the sameperiod and an interaction between allergens and atmosphericpollution that potentiates the tendency to sensitisation.Infection would drive a Th1 response and thus down regulatethe tendency for Th2 related disease to develop.

Mediators of hypersensitivityIgE binds to tissue mast cells and circulating basophils throughcellsurface expressed high affinity receptors. Allergen binds tospecific IgE and induces cell activation, with the tissue releaseand generation of mediators such as histamine, tryptase,leukotrienes, prostaglandins, and kinins from mast cellscontributing to symptoms of asthma and rhinitis through directactions on neural and vascular receptors and within the lowerairways also on airway smooth muscle receptors.

Histamine and leukotriene release from basophils, as well asmediator release from mast cells, will contribute to circulatoryevents in anaphylaxis. The release of these mediators is rapid(minutes) and produces immediate symptoms. In the upperairways this is associated with nasal itch, sneeze, andrhinorrhoea (which are all neurally mediated), as well as withnasal obstruction (which is vascular in origin). In the lowerairways mediator release is associated with bronchoconstrictionand hypersecretion of mucus, giving rise to tightness in thechest, breathlessness, cough, and wheeze. The stimulation ofsensory nerves with neuropeptide release (substance P andcalcitonin gene related peptide) may enhance the response.During persistent exposure to an allergen, as occurs in seasonaland perennial allergic rhinitis and allergic asthma, there is alsotissue accumulation of eosinophils. Activation of eosinophilswith leukotriene release contributes to signs and symptoms ofclinical disease, as does mediator release from activatedepithelial cells.

Inflammatory accumulation and cellactivationBiopsy studies in asthma, rhinitis, and conjunctivitis specificallyshow an accumulation of effector cells in the epithelium, withan increase of mast cells, eosinophils, and basophils. Theaccumulation of inflammatory cells in the epithelium in patientswith hay fever during the grass pollen season underlies theclinical observation of “priming,” a situation in which patients’symptoms are more severe later in the season than at the start,despite the same pollen concentration. Eosinophilaccumulation, along with an increase in T lymphocytes, isevident in the dermis in atopic dermatitis (eczema).

The local release of cytokines and chemokines (chemotacticcytokines) from activated T lymphocytes, mast cells, andepithelial cells can account for this accumulation ofinflammatory cells in the airways. For T cell activation there hasto be a specific interaction between the T cell and an antigenpresenting cell, which processes the allergen and presents it tothe T cell in a modified format. The major antigen presentingcells in the airways and skin are dendritic or Langerhans’ cells,

Contribution of mediators to signs and symptoms of disease

Signs and symptoms

Mediator Rhinitis Asthma

Histamine Itch; sneeze;rhinorrhoea;obstruction

Bronchoconstriction;plasma protein exudation;mucus secretion

Leukotrienes Possiblerhinorrhoea;obstruction

Bronchoconstriction;plasma protein exudation;mucus secretion

Kinins Obstruction Bronchoconstriction; cough

Prostaglandins Obstruction Bronchoconstriction(prostaglandin E2á,prostaglandin D2);antibronchoconstrictor(prostaglandin E2); cough(prostaglandin F2á)

Endothelin Itch; sneeze;rhinorrhoea

Bronchoconstriction

Airways inflammation underlies clinicaldisease expression in allergic asthma andrhinitis

Epithel

ium

Lam

ina

pro

pri

a

Tissue matrix

Blood vesselEosinophils

Mast cells

Eosinophils

BasophilsLangerhans'

cells

Changes in the number of cells in allergic airways disease: an accumulationin the epithelium of the major effector cells of the allergic reaction (mastcells, eosinophils, and basophils) and antigen presenting cells (Langerhans’cells); and an increase in eosinophils in the submucosa and in asubpopulation of fibroblasts (“myofibroblasts”) in the tissue matrix (notillustrated)

759BMJ VOLUME 316 7 MARCH 1998


and these are found to accumulate in the airway epithelium andhave been reported to express high affinity IgE receptors. Thereis evidence in perennial asthma, perennial rhinitis, and acuteatopic dermatitis for an increase in T cells exhibiting a Th2cytokine profile.

Th2 cytokines act in concert to promote an accumulation ofeosinophils in the airways through endothelial activation andthe enhanced adherence of these leucocytes to the vascularendothelium. They do this by increasing the eosinophilchemotactic response to chemokines, stimulating marrowgeneration of progenitor cells, and decreasing tissue removal byinhibiting apoptosis (cell death). The directed movement ofthese cells, and of mast cells, basophils, T lymphocytes, andLangerhans’ cells, is regulated by chemokine release fromactivated epithelial cells. Epithelial cells represent the primarymucosal interface with the environment, and the activation ofepithelial cells by other environmental factors, such aspollutants or viral infection, provides a basis for theirinteraction in allergic airways disease. This epithelial activationin allergic airways disease is indirectly reflected by raisedconcentrations of nitric oxide in exhaled air, as the inducibleform of an enzyme, nitric oxide synthase, is up regulated andmay provide a potentially measurable marker to monitor theimpact of antiinflammatory treatment.

Implications for treatmentAllergen avoidanceThe first step in management once allergy has been diagnosedis allergen avoidance. Allergen avoidance can help to reducedisease severity and minimise treatment in patients with asthma,rhinitis, and atopic dermatitis. The essential principle is thus toidentify the provoking allergens and where possible ensure thatthe patient avoids them. Identification is based on clinicalhistory and on objective assessment of the presence of specificIgE. Avoidance protocols will be discussed in a later article.

Allergen avoidance can be life saving inpatients with anaphylaxis

Decreased cell death

(inhibition of apoptosis) RANTES

Eotaxin

Chemotaxis

Blood vessels

Leucocyte-endothelial

adherance under

influence of leucocyte

endothelial adhesion

molecules with specific

ligand recognition (eg.

VCAM1 - VLA4)IL4, IL13, TNFα.

IL5, IL1β

Positive

IL5,

IL3, GM-CSF

(Weak)

Increased

maturation

of progenitors

Eosinophil

priming for

enhanced

response

to chemokines

Stimulation

of bone marrow

progenitor cells

IL =

GM-CSF =

TNF =

interleukin

ganulocyte macrophage

colony stimulating factor

tumour necrosis factor

VCAM =

VLA =

RANTES =

vascular cell adhesion molecule

very late antigen

regulated on activation normal

T cell expressed and secreted

VCAM1

VLA4

Processes involved in recruitment and retention of eosinophils in theairways. Cytokines (predominantly interleukin 5) stimulate bone marrowprogenitor cells, cell priming, and adherence of leucocytes to theendothelium. Cytokines stimulate the endothelial cells, with specific leucocyteendothelial cell adhesion molecule expression and binding to cellsurfaceexpressed ligands. Chemokines influence cell chemotaxis

60

50

40

30

20

10

0

Nitri

c oxi

de

(par

ts p

er b

illio

n)

Non-asthmatic

control

Asthma

(non-steroid treated)

Asthma

(steroid treated)

Measurement of nitric oxide in oral exhaled air in mixed expired air samplein nonasthmatic healthy controls (n=18), asthmatic patients not treated withsteroids (n=19), and asthmatic patients receiving inhaled steroid treatment(n=13). Horizontal lines indicate median values for each group

RANTES

Eotaxin

IL8

MCP-1MIP-1α

Endothelin

• Bronchoconstrictor• Vasoconstrictor• Smooth muscle mitogen• Fibroblast proliferator

Nitric oxideProstaglandin E2

Allergic activation (direct or indirect)

Airway lumenInteractive stimuli:• Pollutants• Viral infaction

Macrophage,basophil andlymphocytechemoattractantsand activatorsof basophils andmast cells

interleukinmonocyte chemotactic proteinmacrophage inflammatory proteinregulated on activation normal T cell expressed and secreted

IgA

Specific IgA

IL8 Specific IgA complex

Secretorycomponent

Eosinophilchemoattractant

Eosinophilchemoattractant

+activator

Eosinophil activatorand chemoattractantfor eosinophils,T lymphocytes,mast cells IL =

MCP =MIP =

RANTES =

Epithelial activation and airway inflammation: products generated byepithelial cells in allergic airways disease and their relation to inflammatorycell recruitment



PharmacotherapyAdrenaline is first line treatment for anaphylaxis and is mosteffective when administered early. Glucocorticoids represent themost efficacious treatment when administered as regularprophylactics. They regulate gene transcription and downregulate cytokine and chemokine synthesis, thus indirectlyinhibiting cell recruitment and cell activation. Glucocorticoidtreatment reduces epithelial and endothelial cell activation;reduces accumulation of epithelial mast cells, eosinophils, andLangerhans’ cells; enhances eosinophil apoptosis; and reducesT cell and mast cell cytokine generation. The treatment is bestadministered topically to the airways and skin to reduce thepossibility of systemic side effects.

Cromones are less effective as antiinflammatory agents asthey have a more restricted profile of effects. Specific end organreceptor antagonists (H1 antihistamines, anticholinergic agents,and leukotriene receptor antagonists) and functionalantagonists (â adrenoceptor agonists (bronchodilators) and á

agonists (vasoconstrictor decongestants)) will be limited by theirspecificity of action, although the oral treatments have value intargeting upper and lower airways as well as the conjunctiva.

Histamine is a dominant mediator in the upper airways (H1

receptor mediated), and leukotrienes are a significantcontributor to lower airways disease (leukotriene C4 and D4receptor mediated).

The importance in asthma of targeting the airwayinflammation rather than the end organ effects is emphasisedby the British guidelines on asthma management as thisapproach not only leads to improved disease control but alsocan prevent irreversible loss of lung function if used early indisease management. This loss of lung function is attributable tochronic structural airway changes that develop if allergicinflammation is left untreated.

ImmunotherapyAllergen immunotherapy is the repeated administration of lowdoses of an allergen to which an individual is sensitised in astepwise incremental pattern, usually by subcutaneous injection,over some years (usually three to five). This is done to influencethe state of immunological and clinical tolerance. Thistreatment is thought to act via either immune deviation ofT lymphocyte responses from a Th2 to a Th1 profile or by theinduction of T cell unresponsiveness (anergy). Althoughimmunotherapy is well established for seasonal allergic rhinitis,it is a less well proved approach for house dust mite sensitiveasthma and rhinitis. It is the primary treatment to consider formodifying sensitisation to bee and wasp venom.

Future approachesTreatments are being developed that focus on inhibiting theinteraction between IgE and allergen; inhibiting cytokine orchemokine function (such as a monoclonal antibody tointerleukin 5 or a chemokine receptor antagonist); inhibitingT cell activation; modifying endothelial leucocyte interactions(very late antigen 4 antagonist); and modifying epithelial cellactivation. The long term future must, however, depend on abetter understanding of the basis for the increase in allergicdiseases so that they can be prevented, rather than dependingon secondary disease control.

Allergen

Immune cell

activation

• Mast cells

• T lymphocytes

• B cells

• Langerhans' cells

Structural cell

activation

• Endothelial cells

• Epithelial cells

Cell recruitment

and activation

• Mast cells

• Eosinophils

• Basophils

Epithelial

damage

Mediator release

• Fibroblast proliferation

• Collagen deposition

• Smooth muscle

hypertrophy and

hyperplasia

• Vascular expansion

Symptoms

Vascular dilation

and induced

permeability

Neural

stimulation

Broncho-

constriction

Repair

Lower airway

wall thickening

Bronchial hyper-

responsiveness

Progression of the allergic process in the airways and the relation of thisprocess to inflammatory cell recruitment and symptom expression

Further reading

x Colloff MJ, Ayres J, Carswell F, Howarth PH, Merrett TG, MitchellEB, et al. The control of allergens of dust mites and domestic pets: aposition paper. Clin Exp Allergy 1992;22(suppl 2):128

x Jarvis D, Burney P. Epidemiology of atopy and atopic disease. In:Kay AB, ed. Allergy and allergic disease. Oxford: Blackwell Scientific,1997:120826

x Howarth PH. Cellular basis for allergic rhinitis. Allergy1995;50(suppl 23):610

x Barnes PJ. NFkB—a pivotal transcription factor in chronicinflammatory diseases. N Engl J Med 1997;336:106671

x British guidelines on asthma management. 1995 review andposition statement. Thorax 1997;52(suppl 1):S121

Mikila Jacobson and Stephen Durham provided the histology photographs.

Peter H Howarth is senior lecturer in medicine at the School ofMedicine, Southampton General Hospital.

The ABC of allergies is edited by Stephen Durham, honoraryconsultant physician in respiratory medicine at the Royal BromptonHospital, London. It will be published as a book later in the year.

BMJ 1998;316;758–61



ABC of allergiesSummer hay feverStephen Durham

Summer hay fever causes considerable morbidity and affectsquality of life at a time usually considered as the best of the year.Its prevalence has increased over the past 20 years despitefalling pollen counts.

Environmental triggersThe main cause of hay fever in Britain is grass pollen,particularly perennial rye (Lolium perenne) and timothy grass(Phleum pratense). Symptoms peak during June and July.Symptoms in spring are commonly due to tree pollens, whereassymptoms in late summer and autumn may be due to weedpollens and mould spores. Rape seed may also provokesymptoms of rhinitis, although usually through irritant ratherthan allergic mechanisms. It has been suggested that emissionsof nitrogen dioxide and ozone from vehicle exhausts have beenincreasing the sensitivity to airborne allergens.

Mechanisms of rhinitisThe symptoms of rhinitis are caused by an interaction betweengrass pollen and IgE on the surface of sensitised mucosal mastcells (type 1 hypersensitivity). The cells release mediators suchas histamine and leukotrienes, which produce itch, sneeze,watery anterior nasal discharge, nasal congestion, andsymptoms affecting the eyes.

Allergens are also recognised and processed by mucosaldendritic cells (Langerhans’ cells) or macrophages, which thenstimulate T lymphocytes to release interleukins, which promotetissue eosinophilia and IgE production. These compounds actto produce ongoing rhinitis, symptoms of blockage, impairedsense of smell, and nasal hyperreactivity (an exaggerated nasalresponse to environmental irritants such as cold air, perfume, ortobacco smoke).

Antihistamines and nasal corticosteroidsprays are first line treatment

Perennial rye grass (Lolium perenne)—common in Britain

Mast

cell

Histamine

Leukotrienes

Prostaglandins

Bradykinin, pollen

adherence factor

Chronic ongoing rhinitis

Nasal blockage

Loss of smell

"Nasal hyper-reactivity"

T lymphocytes

(mast cells)Eosinophils

Allergen B lymphocytes

VCAM-1

IL-3, IL-5

GM-CSF

IL-4

IgE

Immediate rhinitis symptoms

Itch, sneezing

Watery discharge

Nasal congestion

Hypothesis on mechanisms of summer hay fever (rationale basis fortreatment). IL=interleukin, VCAM=vascular cell adhesion molecules,GMCSF=granulocyte macrophage colony stimulating factor

Grass

pollens

April May June July August September October

Tree

pollens

Weed

pollens

Fungal

spores

Timothy,

rye,

cocksfoot,

meadow,

dogstail,

fescue, etc

Timothy,

rye,

cocksfoot,

meadow,

dogstail,

fescue, etc

Birch, plane

Ash, pine

Birch, plane

Nettle, dockNettle, dock

Cladosporium alternariaCladosporium alternaria

Ash, pine

Pollen calendar for Britain



DiagnosisMost patients present with the diagnostic symptoms of seasonalitching, sneezing, watery nasal discharge, and associated eyeproblems. The nose may be examined with an auriscope toexclude a structural problem. Skin prick tests are not usuallyneeded for diagnosis, but a positive result may help to reinforceadvice to take topical prophylaxis.

Drug treatment

AntihistaminesOral antihistamines are effective in patients with mild tomoderate disease, particularly in those whose main symptomsare palatal itch, sneezing, rhinorrhoea, or eye symptoms.Antihistamines have little effect, however, on nasal blockage.

Terfenadine and astemizole are the most commonlyprescribed drugs, are effective, and rarely cause drowsiness oranticholinergic side effects. With these drugs it is important toemphasise the manufacturers’ instructions in view of theextremely rare complication of cardiac arrhythmias in overdoseand, in the case of terfenadine, interactions with erythromycinor ketoconazole (which should not be given concurrently).

Newer alternatives include loratadine and fexofenadine.Acrivastine is short acting and may be useful when symptomsare mild and episodic. Cetirizine has also been shown to behighly effective in placebo controlled trials. The place of topicalnasal antihistamines in hay fever is currently being evaluated.

CorticosteroidsTopical corticosteroids are extremely potent, with a lowpotential for systemic side effects. They are the best treatmentfor patients with moderate to severe nasal symptoms. Aqueouscorticosteroids are better tolerated than those in fluorocarbonpropellants and have a better local distribution in the nose. Theside effects are minor—local irritation and occasional (in 5% ofcases) bleeding. Treatment should be started before thebeginning of the hay fever season for maximal effect. Patientsshould be given instruction on the importance of regulartreatment and how to use the nasal spray.

Topical corticosteroids are effective against all nasalsymptoms, including nasal blockage. Although systemicabsorption is negligible in adults, care should be taken whennasal steroids are given to children who are also taking inhaledsteroids for asthma or topical steroids for eczema. Sodiumcromoglycate two to four times daily is an alternative,particularly in children. Eye drops containing sodiumcromoglycate, such as Opticrom, are effective in most patients(often within minutes) for allergic symptoms affecting the eyes.

Second line treatmentIn patients who fail to respond to antihistamines or topicalcorticosteroids, a short course of an oral corticosteroid (say,prednisolone 20 mg for five days) may produce rapid relief ofsymptoms. This is particularly effective when the nose iscompletely obstructed as topical treatment will not gain accessto the nose.

An alternative is to use a topical decongestant short termto allow penetration of topical corticosteroids. Ipratropriumbromide may have a role when watery rhinorrhoea ispronounced.

In general it is important to establish which are the patient’sdominant symptoms and, particularly for severe symptoms, tomatch the treatment to the symptoms.

Diagnosis of hay fever

History

Nasal examination

Skin prick test orradioallergosorbent test

Prominent itch or sneezing andassociated eye symptoms

Pale, bluish, swollen mucosa (only ifsymptomatic at time)

Not essential, although of educationalvalue and reinforces oral advice

Diagnosis of summer hay fever is usuallystraightforward

Stepwise approach to treatment of summer hay fever

Allergen avoidance (if appropriate)

Mild disease or with occasional symptomsx Rapid onset, oral, nonsedating histamine H1 antagonists when thepatient is symptomatic; or

x Antihistamine or cromoglycate topically to eyes or nose, or both

Moderate disease with prominent nasal symptomsx Topical nasal steroid daily (start early in the season); plusx Antihistamine or cromoglycate topically to eyes

Moderate disease with prominent eye symptomsx Oral, nonsedating histamine H1 antagonists daily; orx Topical nasal steroid and sodium cromoglycate topically to eyes

If above are ineffective, check compliance and consider:x Nasal examinationx Allergy testsx Additional pharmacotherapy—for example, short course of oralsteroids

x Immunotherapy (requires referral to specialist)

Effects of drugs on nasal symptoms in adults

Itch orsneezing Discharge Blockage

Impairedsmell

Topicalcorticosteroids + + + + + + + + +

Oralantihistamines + + + + + + /− −

Sodiumcromoglycate* + + + /− −

Ipratropiumbromide − + + + − −

Topicaldecongestants − − + + + −

Oralcorticosteroids + + + + + + + + + + +

*First line treatment in children.



Avoiding allergensPatients with allergies are usually advised to avoid theprovoking allergen. It is, however, controversial whether thisshould be routinely recommended for pollen allergy. As hayfever is usually not severe or life threatening, drugs can allowpatients to lead a normal life without unnecessary restrictions.But patients with debilitating symptoms may benefit fromsimple advice. Pollen counts at ground level are highest duringthe evening and at night, when open grassy spaces should beavoided.

ImmunotherapyMost patients with hay fever will have their symptomscontrolled by the above measures. Patients whose symptomsremain uncontrolled may benefit from “allergen injectionimmunotherapy.” This form of treatment is performed only inspecialised centres. Careful selection of patients for thistreatment is essential, and immunotherapy is contraindicated inthose with chronic asthma. Indications and guidelines forimmunotherapy in Britain were the subject of a recent reportby the British Society for Allergy and Clinical Immunology.

The pollen calendar is adapted with permission from Varney (Clin ExpAllergy 1991;21:757). The diagram showing the mechanisms of summer hayfever and the box on the stepwise approach to the treatment are adaptedwith permission from Lund et al (Allergy 1994;49(suppl 19):134).


How to avoid pollen

x Keep windows in cars and buildings shutx Wear glasses or sunglassesx Avoid open grassy places, particularly in the evening and at nightx Use a car with a pollen filterx Check for pollen counts in the mediax During the peak season take a holiday by the sea or abroad

Grass pollen immunotherapy

x Immunotherapy should be considered in patients with summer hayfever uncontrolled by antiallergy drugs

x It should be administered only in hospital or specialised clinics withimmediate access to resuscitative facilities

x Patients should be kept under observation for the first 60 minutesafter injections

x Patients with asthma should not be given grass pollenimmunotherapy

x Allergen extracts used should be biologically standardised

Further reading

x Howarth PH. Allergic rhinitis: a rational choice of treatment. RespirMed 1989;83:17988

x Naclerio RM. Allergic rhinitis. N Engl J Med 1991;325:860x Lund V on behalf of the International Rhinitis ManagementWorking Group. International consensus report on the diagnosisand management of rhinitis. Allergy 1994;49(suppl 19):134

x Frew AJ on behalf of a British Society for Allergy and ClinicalImmunology Working Party. Injection immunotherapy. BMJ1993;307:91922

When I use a word . . .

Medical Greek

The Reverend Spooner (18441930), warden of New CollegeOxford 190324, is well known for the verbal tic that we call aspoonerism. Spoonerisms are formed by metaplasm ormetathesis, which were first defined by Henry Peachum in Thegarden of eloquence conteyning the figures of grammer and rhetorick(1577): “Metaplasmus, is a transformation of Letters, or syllablesin single words . . . eyther for cause of necessity, or else to makethe verse more fine” and “Metathesis, when letters be transposedin a word, and remoued from their proper places.” A goodexample of metathesis quoted in the Oxford English Dictionary isthe change from Fastolph to Falstaff.However, both metathesis and metaplasm seem to be restricted

to changes within a single word, rather than to transpositionsbetween two words, which is what spoonerism more commonlymeans. A more natural word, perhaps, would be metaphasis,which is not to be found anywhere in the Oxford EnglishDictionary, but appears in an article about Spooner’s dysgraphia(Proc R Soc Med 1976;69:63948) by John Potter, who writes thatPunch described Spooner as “Oxford’s great metaphasiarch” andquotes Sir Ernest Barker (Age and Youth,OUP 1953): “[Spooner]was seldom guilty of metaphasis or the transposition of sounds.”Marrowsky is an earlier alternative, defined in the Oxford

English Dictionary as “a variety of slang, or a slip in speaking,characterized by transposition of initial letters, syllables, or partsof two words.” The first example quoted dates from 1863,antedating the first citation for spoonerism by 37 years. Theorigin of “marrowsky” is not known. In Notes and Queries(1923;13th series/I:331) an anonymous correspondent suggestedthat it might have been from a Polish count, well known inLondon circles at one time. One H Askew replied, “I think thatthe Polish Count referred to may be identified with Count JosephBoruwlaski, the celebrated Polish dwarf, who was born near

Chaliez in Polish Russia, in November 1739.” The originalquestioner then asked (1924;146:125) “What claim had[Boruwlaski] on the word ‘Marrowskying’? Did his autobiographycontain any spoonerisms or prespoonerisms?” No one replied tothis question, although several gave information on whereportraits of the count could be found. The English translation(1792) of Boruwlaski’s French autobiography does not mentionmarrowskying, and I think that he is a red herring. Marrowskyremains unidentified.There are, however, even earlier terms. Hotten’s Dictionary of

Modern Slang (1860) refers to “medical Greek” and OttoJespersen, in Language (1922), to “hospital Greek.” In hisDictionary of Historical Slang, Eric Partridge writes that “medicalGreek” dates from about 1800, but he gives no examples. He alsosays that Albert Smith called marrowskying “Gower Street dialect”in 1848, so presumably the hospital from which it originated wasUniversity College Hospital. The source of Partridge’sinformation was probably Slang and its Analogues by JS Farmerand WE Henley (1896), who wrote under “marrowsky” that “Atthe London University they had a way of disguising English(described by Albert Smith in ‘Mr Ledbury,’ 1848, as theGowerstreet dialect).”Does anyone in Gower Street have more information? Does

anybody have a copy of “Mr Ledbury”?

Jeff Aronson, clinical pharmacologist, Oxford

We welcome articles up to 600 words on topics such asA memorable patient, A paper that changed my practice, My mostunfortunate mistake,or any other piece conveying instruction,pathos, or humour. If possible the article should be supplied ona disk.

BMJ 1988;316:8435



ABC of allergiesPerennial rhinitisI S Mackay, S R Durham

Perennial rhinitis may be defined clinically as an inflammatorycondition of the nose characterised by nasal obstruction,sneezing, itching, or rhinorrhoea, occurring for an hour ormore on most days throughout the year. In one study inLondon of adults between the ages of 16 and 65 years, theprevalence of rhinitis was 16%; of these, 8% had perennialsymptoms, 6% perennial and seasonal symptoms, and 2%seasonal symptoms alone. As with asthma, both seasonal andperennial rhinitis seem to be increasing.

ClassificationAllergic rhinitis—Perennial allergic rhinitis can be more

difficult to diagnose than seasonal allergy, particularly if thepatient presents with secondary symptoms of sinusitis and a“permanent cold.” The most common allergen to account forperennial allergic symptoms is the house dust mite(Dermatophagoides pteronyssinus). Other frequent causes areanimals: particularly cats, dogs, and horses.

Occupational rhinitis may result from allergy to airborneagents in the workplace—for example, laboratory animals andlatex.

Infective rhinitis—Infective rhinitis may be acute or chronic.Chronic symptoms may be due to specific infections, such asfungi or tuberculosis. Chronic infection may also be the resultof a host defence deficiency; this may be systemic (for example,panhypogammaglobulinaemia, IgA deficiency, or AIDS) or alocal problem (for example, primary ciliary dyskinesia).

Other factors—Other nonallergic, noninfective factors maybe involved (see box).

Differential diagnosisStructural abnormalities of the nose include deviation of thenose or septum, enlarged middle and inferior turbinates,adenoidal hypertrophy (particularly in children; rare in adults),and choanal atresia. The ostiomeatal complex is the area lyingbetween the middle and inferior turbinates and the naturalostium of the maxillary sinus. It is this area which drains andaerates the maxillary sinus, the anterior ethmoidal sinuses, andthe frontal sinus. Obstruction in this area, whether structural orsecondary to an inflammatory condition, will predispose tosinusitis.

Nasal polyps result from inflammation of the mucosal liningof the sinuses; the lining prolapses down, particularly from theanterior ethmoidal sinuses through the middle meatus toobstruct the nasal airway. Allergy does not seem to be animportant factor. Nasal polyps in children are rare and arealmost invariably associated with cystic fibrosis. A strongassociation exists between nasal polyps, asthma, and sensitivityto aspirin (Samter’s triad).

Granulomatous rhinitis may be associated with Wegener’sgranulomatosis and sarcoidosis.

Primary atopic rhinitis is characterised by nasal congestion,hyposmia, and an unpleasant smell (ozoena), resulting from aprogressive atrophy of the nasal mucosa and underlying bone.Secondary atrophic rhinitis may result from radical surgery,infections, irradiation, and trauma.

Nonallergic, noninfective rhinitis*x Idiopathic rhinitis refers to a heterogeneous group of patients withnasal hyperresponsiveness to nonspecific triggers such as strongsmells (eg, perfumes, bleach, and solvents), tobacco smoke, vehicleexhaust fumes, and changes in environmental temperature andhumidity in the absence of an identifiable underlying cause

x Nonallergic rhinitis with eosinophilia syndrome (NARES) ischaracterised by nasal eosinophilia (usually in young women) withperennial nasal symptoms with negative results on skin prick testingand normal IgE concentrations. Patients usually respond well totopical corticosteroids

x Hormonal rhinitis can occur during pregnancy, puberty,hypothyroidism, and acromegaly. Postmenopausal women maydevelop atrophic changes, elderly men sometimes wateryrhinorrhoea (“old man’s drip”)

x Drug induced rhinitis is associated with several drugs. âsympathomimetic receptor antagonists (â blockers) and angiotensinconverting enzyme inhibitors have been associated with nasalsymptoms, as have topical ophthalmic â blockers, chlorpromazine,oral contraceptives, aspirin, and other nonsteroidalantiinflammatory agents

x Food induced rhinitis Gustatory rhinorrhoea may occur duringconsumption of hot and spicy foods. NonIgE mediatedhypersensitivity may result from food colourings and preservatives.Alcohol, in addition to the mechanisms above, also acts as avasodilator, which may result in nasal obstruction

x Emotional factors including stress and sexual arousal can affect thenose, probably due to autonomic stimulation

*Poorly understood and more difficult to identify specific causes

Middle turbinate

Maxillary ostium

Ostiomeatal complex

Middle meatus

Inferior turbinate

Nasal cavity showing ostiomeatal complex. It is the final common pathwaydraining the maxillary sinus, the anterior ethmoidal sinus, and the frontalsinus

Nasal polyp



Leaking of cerebrospinal fluid will present with wateryrhinorrhoea, often unilateral. It is usually associated with trauma(including surgical trauma) or neoplasia, but spontaneousleaking may occur.

History and examinationTaking a history need not be time consuming. A glance at theclassification and differential diagnosis will suggest the mostimportant questions.

Rare, sinister causes for rhinitis need to be excluded.Unilateral symptoms should always be regarded with suspicion,particularly if associated with symptoms of increasing nasalobstruction, blood stained nasal discharge, or facial pain.

Ear, nose, and throat surgeons examine the nose with a headmirror or headlight and a nasal speculum, but increasingly this issupplemented by rigid or flexible nasendoscopy. In generalpractice, the nose can be examined with an auriscope fitted withthe largest speculum. It is easy to confuse a large, swollen,oedematous inferior or middle turbinate with a polyp; polyps,however, unlike turbinates, are usually pale grey, translucent, andmobile and lack any sensation on gentle probing.

InvestigationPerennial allergic and nonallergic rhinitis may require nospecific investigations other than skin prick testing, which hasbeen fully discussed in an earlier article in this series. If thehistory or examination suggests that other factors need to beexcluded, the patient may require a variety of investigations,depending on the history and clinical findings.

Special testsIn addition to routine full blood count and eosinophil count,immunoglobulin concentrations should be checked. Blood testsfor antineutrophil cytoplasmic antibody and angiotensinconverting enzyme may be indicated if, respectively, Wegener’sgranuloma or nasal sarcoidosis is suspected. It is also importantto consider whether the patient may have AIDS or becompromised by treatment with immunosupressant drugs.When skin prick tests are not available or not possible for otherreasons, blood allergen specific IgE concentrations may bedetermined (with the radioallergosorbent test).

ImagingPlain x ray films of the sinuses can be misleading. Computedtomography of the sinuses in the coronal plane has become thestandard international imaging method.

Nasal mucociliary clearanceNasal mucociliary clearance is assessed simply, by measuringthe time taken for the patient to detect a sweet taste after a 0.5mm particle of saccharin is placed on the mucosa of theinferior turbinate. If the test result is abnormal, furtherassessment of ciliary function involves taking a brushing of thenasal mucosa overlying the inferior turbinate and measuringthe frequency of the beating cilia detected with a microscopeattached to a photometric cell (normal range 1215 Hz).

Nasal airway assessmentPeak nasal inspiratory flow can be measured with a modifiedpeak flow meter. This test is easy and inexpensive to perform,but forced inspiration may be associated with significantvestibular collapse. Despite this, the results compare favourablywith rhinomanometry.

Nasal neoplasms are rare; considerpatients with unilateral symptoms ofnasal obstruction, pain, or bleeding

Taking a historyx Patient’s account of symptomsx How long has the condition been present?x Impact on lifestyle: how frequent and severe is it? Does it affectwork, school, leisure time, sleep?

x Seasonal or perennial?x Trigger factors: allergic or nonallergic?x Exposure to allergens through occupation or hobbies?x Allergens in the homex Does patient have history of asthma, eczema, rhinitis?x Drug or food induced?x Family historyx Treatment: compliance, efficacy, side effectsx What is the main symptom?

Computed tomogram of normal paranasal sinuses

Computed tomogram of paranasal sinuses withincreased opacity of maxillary and ethmoidalsinuses and obstruction of ostiomeatal complex

Modified peak flow meterfor measuring peak nasalinspiratory flow



Rhinomanometry records resistance in the nasal airway bymeasuring nasal airflow with a face mask, pneumotachograph,and pressure gradient from the front to the back of the nose viaa manometer.

Acoustic rhinometry measures neither flow nor pressure,but cross sectional areas of the nasal airway. A sound pulse ispassed into the nose, the reflected signal of which is recorded bya microphone and analysed in such a way that it is possible todetermine the area in the nasal cavity as a function of distance.

Olfactory testsOlfactory thresholds can be assessed by testing the patient withserial dilutions of odours such as PMcarbinol (phenylethylmethyl ethyl carbinol) (OlfactoLabs, USA). Alternatively,“scratch and sniff” tests use cards impregnated withmicroencapsulated odorants. The Pocket Smell Test (Sensonics,USA), for example, presents three different odours that can bereleased by scratching with the tip of a pencil and choosingfrom a list of four possible answers. One or more incorrectreponses suggests olfactory dysfunction, and the 40 item SmellIdentification Test (Sensonics) should then be administered.

Swabs, smears, and biopsiesWith infective symptoms, swabs for culture and sensitivity maybe useful, though a swab taken from the nose will notnecessarily correlate with samples taken directly from thesinuses. Nasal smears for cytology may show highconcentrations of eosinophils, and biopsies for histology may beindicated when investigating granulomatous conditions—forexample, Wegener’s granulomatosis and sarcoidosis—orexcluding neoplastic disease.

TreatmentAllergen avoidancePerennial allergic rhinitis due to house dust mite allergy may beeffectively controlled by avoidance measures. Patients who arefound to be allergic to animals should, if possible, avoid themcompletely.

Medical treatment

AntihistaminesAntihistamines are highly effective in controlling itching,sneezing, and watery rhinorrhoea but less effective for nasalobstruction. However, they do have the advantage of controllingeye symptoms as well as nasal symptoms. The moderngeneration of nonsedating antihistamines are both effectiveand safe, although terfenadine should not be taken inconjunction with macrolide antibiotics (for example,erythromycin and clarithromycin) or antifungal agents(ketaconazole and related drugs) as serious cardiac toxicity hasvery rarely been reported. Topical antihistamines (for example,azelastine and levocobastine) are also effective.

Topical steroidsTopical steroids are highly effective for all symptoms of allergicand nonallergic perennial rhinitis and will usually control nasalobstruction, itching, sneezing, and watery rhinorrhoea. Themodern topical steroids are safe for long term use and have nosignificant side effects. Treatment can be continued for severalyears if necessary, and alternative medical or surgical treatmentneed be considered only if symptoms fail to respond.Occasionally, topical steroids may be associated with dryness,crusting, and bleeding from the nose, in which case treatmentshould be discontinued for a few days and then restarted.

Desensitisationx Desensitisation to pollen and to bee and wasp venom is highlyeffective

x Desensitisation to house dust mite and pets, however, is less helpfuland therefore seldom used in Britain

Rhinomanometry: flow is recorded via a face mask and pneumotachograph,and pressure change is measured with a manometer via a tube either to onenostril (unilateral) or through the mouth to the back of the nose (bilateral)

Acoustic rhinometry measures cross sectional areas of the nasal airway

Topical

steroidsAntihistamines

Topical

steroids

and

antihistamines

• Immunotherapy for

selected patients

with IgE mediated

disease

• Surgery for specific

indications for relief

of obstruction

Allergen avoidance

Stepwise approach to treatment of perennial rhinitis



Sodium cromoglycateSodium cromoglycate is more effective in atopic thannonatopic patients. It has no known side effects but is lesseffective than antihistamines and corticosteroids and doesrequire frequent use (up to five times daily), which maycompromise compliance. Topical sodium cromoglycate eyedrops are highly effective for allergic conjunctivitis. Topicalnedocromil eye drops are also effective and have a longerduration of effect (up to 12 hours).

Topical anticholinergicsIpratropium bromide is effective in controlling wateryrhinorrhoea, particularly if this is the only symptom. The dosemay need to be titrated against symptoms.

Nasal decongestantsTopical nasal decongestants may be useful at the start oftreatment to “open up” the nose and improve penetration oftopical corticosteroids, when flying, or for upper respiratorytract infections. They should only be used for short courses(preferably no more than 2 weeks), however, to avoid the risk ofdeveloping “rhinitis medicamentosa” (rebound congestion).

I S Mackay is a consultant ear, nose, and throat surgeon at the RoyalBrompton Hospital and Charing Cross Hospital, London.


Surgical treatmentx The first line of treatment for allergic or nonallergic perennialrhinitis is usually medical

x When drugs fail, surgery may be indicatedx Surgical reduction of the inferior turbinates or correction of adeviated nasal septum or nose may be required to improve theairway or at least to improve access for topical medical treatment

x Surgery continues to have a major role in the management of nasalpolyps and sinusitis when these conditions fail to respond tomedical treatment

x The management of nasal polyps and sinusitis has improved withthe introduction of minimally invasive endoscopic sinus surgery

Further readingx Lund V, Aaronson D, Bousquet J, Dahl R, Davies RJ, Durham SR,et al. International consensus report on the diagnosis andmanagement of rhinitis. Allergy 1994;49(suppl 19)

x Sibbald B, Rink E. Epidemiology of seasonal and perennial rhinitis.Clinical presentation and medical history. Thorax 1991;46:859901

x Fleming DM, Crombie DL. Prevalence of asthma and hayfever inEngland and Wales. BMJ 1987;294:27983

x Durham SR, Mackay IS. The nose. In: Brewis RAL, Corrin B,Geddes DM, eds. Respiratory medicine. 2nd ed. Vol 2. London:Saunders, 1995:100614

BMJ 1998;316;91720

An initiation

Unequal encounter

Just down from Cambridge in October 1961, I was bottom of theclinical hierarchy at Guy’s Hospital. Put straight on a surgicalward as ward clerk I was responsible for clerking admissions andwas junior to the senior dressers, some of whom lorded it over us.I had been shaken on my first day, holding open a door for twopinstriped gentlemen, to have them sweep past as if I wasinvisible.Woe betide the ward clerk who did not know his patients. Two

weeks after starting, the student gauleiter allocated me a youngBermondsey woman with a renal cyst. The senior registrar saidthat I was to present her case next Saturday morning to adistinguished visitor, Sir Clement PriceThomas, who hadoperated on King George VI and who had surgical instrumentsnamed after him. He also had a formidable reputation for failingFRCS candidates. So watch out. I took my history, studiedHutchison’s Clinical Methods, and tried to reassure the patient.Front seats in the steeply shelving room were occupied by pin

striped consultants and the back seats by the senior medicalstudents, also in formal dark suits. I began my history. The patienthad been cutting out a dress on the kitchen table when she washit with such a violent and sudden pain in her right loin that shehad thrown the dressmaking scissors across the room. (“Goodboy” from the front row.) “She has never smoked and she doesnot drink very much.” “Oh,” said PriceThomas, “No. That is notso good. I am not satisfied with that. What do you mean? Tea?Water? What are you talking about? Be specific, man.” I cannotremember if the digging in the ribs I was getting was mental orphysical also.I collected myself, “Well, sir, she drinks port on festive

occasions.” The room dissolved into laughter and applause, andthe students in the back rows drummed their feet to show theirsupport.“Show me how you examine the abdomen.” Hutchison insisted

on an essential piece of equipment. I looked round with anxiety.

The patient and nurse attendant were expecting my approach. Iopened the door to the anteroom. “Hey, where are you going?”called PriceThomas, amid titters from the audience. “To get achair,” I replied, disappearing and emerging a moment later withmy trophy, to a round of applause.Thereupon, mindful of my instructions, I placed the chair up

against the patient’s couch and sat down, leaving him standing.Pandemonium ensued, laughter and applause mixing with thethunder of drumming feet. Dignity—my own, the patient’s, andthe visitor’s—demanded that I continue regardless, but I could seethat this rumoured Welsh ogre had a twinkle in his eye and washaving the time of his life.He held up his hand for silence, as if blessing the audience,

questioned me, and teased me gently about my unorthodoxtechnique. I had examined the abdomen—with my chair—fromboth sides of the bed. He replaced me in the chair to do his ownexamination, dismissed me while he discussed the x ray findings,recalling me later with “Where’s my young friend?” for furtherquestioning before thanking me, and leading the applause as thetribal drums welcomed me to the back of the room.It was an unexpected initiation, at times rather puerile, and a

million miles from Cambridge matters like frog nervemusclepreparations and the structure of myoglobin. After that Saturday,however, I discovered that I had lost my invisibility, receivingconspiratorial smiles and nods in the corridor. And I no longerbelieved in ogres.

Hugh TunstallPedoe, cardiovascular epidemiologist, Dundee

We welcome articles up to 600 words on topics such asA memorable patient, A paper that changed my practice, My mostunfortunate mistake,or any other piece conveying instruction,pathos, or humour. If possible the article should be supplied on adisk. Permission is needed from the patient or a relative if anidentifiable patient is referred to.



ABC of allergiesAsthma and allergyA J Newman Taylor

Definitions and distinctions

AsthmaAsthma is commonly defined as a narrowing of the airways thatis reversible over short periods of time, either spontaneously oras a result of treatment. This clinical definition (whichcharacterises asthma as reversible airway narrowing)distinguishes it from other predominantly irreversible causes ofairway narrowing, such as chronic obstructive bronchiolitis andemphysema. Another cardinal characteristic of asthma is airwayhyperresponsiveness, an exaggerated narrowing of the airwaysprovoked by a variety of nonspecific stimuli, such as exerciseand cold air. The two defining characteristics ofasthma—reversible airway narrowing and airwayhyperresponsiveness—are manifestations of a characteristicpattern of airway inflammation (a Th2 lymphocyte dependentdesquamative eosinophilic bronchitis).

AtopyAtopy is the propensity to produce IgE antibody to allergens(antigens that stimulate the production of IgE antibodies) thatare commonly encountered in the general environment—forexample, pollens, mites, and moulds. Atopy is usually identifiedby the provocation of one or more immediate “weal and flare”responses in the skin to extracts of common inhalant allergens.Specific IgE antibody to common inhalant allergens can also befound in the serum samples of atopic individuals, who may alsohave a raised serum concentration of total IgE.

The development of atopy is influenced by both genetic andenvironmental factors:x The genetic basis of atopy is debated. Twin studies haveconsistently shown that atopy occurs more frequently inidentical than nonidentical twins. The findings in differentfamily studies, however, have not identified a consistent patternof inheritance. Recent molecular studies have suggested anassociation between atopy and polymorphisms of the highaffinity IgE receptor on chromosome 11q (FCÓR1â) andlinkage with the interleukin 4 gene cluster on chromosome 5. Itseems likely that atopy will eventually be associated withpolymorphisms of many different genes.x The twofold to threefold increase in the prevalence of asthmaduring the past 30 years has been accompanied by an increase inthe prevalence of hay fever and eczema and of skin prick testresponses to common inhalant allergens. The difference in theprevalence of asthma in children between cities in former EastGermany (Leipzig and Halle) and West Germany (Munich) afterreunification was wholly accounted for by the 2.5fold greaterprevalence of atopy in Munich. Changes in prevalence of thismagnitude, which have occurred over decades, are too rapid toreflect differences in the genetic pool and are probably due tochanges in important environmental determinants of atopy,possibly a decrease in respiratory infection in early life.

AllergyThe concept of allergy was proposed by Clemens Freiherr vonPirquet in 1906 as a “specific acquired altered reactivity whichfollows initial exposure to foreign protein,” a description thatencompasses both immunity and allergy. Although allergy is

Allergy in atopic patientsx As well as asthma, eczema and hay fever are also manifestations ofallergy in atopic patients

x Not all allergy is atopic—for example, drug reactionsx Not all allergic asthma is atopic—for example, asthma induced bythe low molecular weight chemical sensitisers (such as isocyanatesin two part polyurethane paints)

x Asthma can also be provoked through nonimmunologicalreactions—for example, nonsteroidal antiinflammatory drugs andâ blockers

Normal bronchiole

Bronchiole from asthmatic patient narrowed by eosinophilic infiltration,oedema, and increased smooth muscle

Clinical review



now distinguished from immunity by a disproportionate injuryto host tissue, the immunological reactions underlying bothimmune and allergic responses are the same; they differ only intheir clinical outcome. This article is predominantly concernedwith reactions associated with Th2 lymphocyte dependent IgEresponse whose outcome is characterised by local recruitmentand activation of circulating blood eosinophils. This would beconsidered to be an immune response when directed againstparasites such as shistosoma and filaria but an allergic responsewhen directed against pollens and mites.

In this context, allergy is the clinical outcome of IgEassociated reactions to common environmental allergens inatopic individuals. The characteristic allergic reactions in atopicindividuals are eczema, hay fever, and asthma, which can, but donot by any means always, coexist in the same individual. Asthmamay therefore be one of the manifestations of allergy in atopicindividuals.

Asthma and allergy

Allergens and asthmaAsthma can be initiated and provoked by allergens in everydaylife—outdoors, indoors, and at work. In patients whose asthma isprovoked by protein allergens encountered in everyday life(such as pollens, mites, and moulds), extracts of relevantallergens in solution will elicit immediate skin test responses,and specific IgE antibody can be detected in their serum. This isalso true for protein allergens that cause occupational asthmaand for some low molecular weight chemicals encountered atwork—for example, platinum salts, acid anhydrides, and reactivedyes (but not, for example, isocyanates, resin, wood dust). Ingeneral, evidence of specific IgE antibody, either from animmediate skin test response or specific IgE in serum, is a verysensitive test (that is, there are few false negatives) but also anonspecific test (that is, many false positives). A negative resultis therefore more valuable than a positive result as it canexclude a specific cause of asthma, whereas a positive result isless reliable for identifying a specific cause and must always beinterpreted in the context of the clinical history.

Asthma and airway hyperresponsivenessExposure to allergens occurring naturally and in the laboratorycan provoke airway narrowing and airway hyperresponsiveness.For example, patients allergic to ragweed pollen show aprogressive increase in the severity of airway responsivenessduring the ragweed season concurrently with the increase in theseverity of their asthma.

Inhalation of soluble extracts of allergens provokes animmediate asthmatic response that peaks at about 20 minutesand resolves within about one hour. The provocation andseverity of the immediate response is dependent on both thedose of inhaled allergen and the degree of airwayhyperresponsiveness. In about 50% of patients a late asthmatic

Asthma in atopic patientsx Asthma is associated with atopy at all ages, although most stronglyin children and young adults

x Atopic individuals may also have flexural eczema or hay feverconcurrently, or have had them in the past

x The prevalence of asthma in different environments correlates withspecific IgE antibody to the particular allergens present. Forexample, in cities in the United States asthma is associated inaffluent areas with specific IgE to house dust mite and cat hair andin poor areas with specific IgE to house dust mite and cockroach

x Furthermore, the severity of asthma correlates with theconcentration of specific allergens (such as house dust mite orcockroach) to which individuals are sensitised

Causes of occupational asthma

ProteinsLow molecularweight chemicals

Animal Excreta of rats, mice etc;locusts; grain mites

Vegetable Grain, flours; latex; greencoffee bean; isphagula; latex

Plicatic acid (fromwestern red cedar),pinewood resin

Microbial Harvest moulds, Bacillussubtilis enzymes (indetergents)

Antibiotics—eg.penicillins,cephalosporins

Mineral Acid anhydrides,isocyanates, complexplatinium salts,polyamines, reactivedyes

600

400

200

50

25

0

16

8

4

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1

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PC

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Increased airway responsiveness in patient allergic to ragweed pollen duringragweed season

Allergens and asthma

Outdoors

PollensTreeGrass

MouldsAlternaria alternataCladosporium herbatumAspergillus fumigatus

Indoors

MitesDermatophagoides pteronyssinusand farinae (house dust mites)

AnimalsCatsDogsBirds

Clinical review



response also develops after three hours; it peaks at 612 hoursand may persist for 1224 hours. Low molecular weightchemicals can provoke isolated late reactions.

The immediate asthmatic response is mediated by IgEdependent mast cell release of mediators such as histamine andleukotrienes. The late reaction is a manifestation of eosinophilicairway inflammation. Both are thought to be the outcome of aTh2 lymphocyte response to inhaled allergen.

The late, but not immediate, reaction is associated with thedevelopment of airway hyperresponsiveness, probably as amanifestation of the induced airway inflammation. The inducedairway hyperresponsiveness occurs independently of thereduction in forced expiratory volume in one second and inairway calibre during the late reaction and can be sustained forseveral days after the forced expiratory volume has returned tonormal. During the period of increased airway responsivenessthe normal diurnal variation in airway calibre may beexaggerated, causing recurrent nocturnal asthma, andnonspecific stimuli (such as exercise, cold air and smoke), aswell as specific allergens to which the individual has developedspecific IgE antibody, can provoke immediate asthmaticresponses.

Allergen exposure and chronic asthmaExposure to allergens induces late asthmatic responses andassociated airway hyperresponsiveness. Airwayhyperresponsiveness is an important determinant ofimmediate airway responses both to nonspecific stimuli (suchas exercise and cold air) and to exposure to specific allergens.By increasing nonspecific airway responsiveness, allergenexposure can increase the development and persistence ofchronic asthma.

Implications for treatmentThis model has important implications for the management ofasthma. Reducing allergen exposure at home or in theworkplace will reduce not only the frequency of immediateasthmatic responses but also the severity of airwayresponsiveness and the capacity for allergens to provokeasthmatic responses. This is particularly important when asingle “dominant” allergen is primarily responsible for theinduction of asthma. Examples are occupational asthma andsome cases of asthma caused by allergens in the home, such ashouse dust mite, cat, or cockroach, where avoidance measureshave been shown to be effective.

Identification of allergens in the home and of allergens orchemicals encountered at work is therefore important whenavoidance is practicable. In the home, pets are particularlyrelevant, and, with improved avoidance measures, identificationof allergy to house dust mite is becoming more relevant.

In the workplace, accurate and early identification of thespecific cause of allergic asthma (either allergen or chemical) toenable avoidance of further exposure is the cornerstone ofmanagement of occupational asthma.

The first graph is adapted with permission from Boulet et al (J Allergy ClinImmunol 1983;71:399406), and the second is adapted with permission fromCockcroft et al (Clin Allergy 1997;7:50373).

A J Newman Taylor is consultant physician in respiratory medicine atthe Royal Brompton Hospital, London.


BMJ 1998:316;9979

Criteria for diagnosing hypersensitivity inducedoccupational asthma

Historyx Exposure to a sensitising agentx Initial symptom free period of exposure (or employment)x Improvement in severity of asthmatic symptoms during absencesfrom work—eg, weekends or holidays—and progressivedeterioration during periods at work

Objective evidencex Serial peak flow measurements showing work related asthmax Specific IgE (skin tests or in serum) to specific agentx Reproducible late asthmatic response and increase in airwayresponsiveness provoked by inhalation test with specific agent inless than toxic concentrations*

*Inhalation tests should be undertaken only for medical purposes in a specialistcentre when the diagnosis of occupational asthma remains uncertain after otherinvestigations have been completed. Inhalation tests are not justifiable whenundertaken solely for medicolegal purposes

2.5

3.0

2.5

2.0

1.5

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Allergen inhalation

Normal twofold variation

Vital capacity

Forced expiratory

volume in one second

Increased airway responsiveness associated with late asthmatic reactionprovoked by ragweed pollen

Allergen

+

Th2 lymphocytes (+ IgE)

Eosinophilic bronchitis

Late asthmatic

response

Airway

hyper-responsiveness

Immediate asthmatic

response

Allergen

Exercise,

cold air

Allergen induction of airway inflammation and hyperresponsivenesspermits provocation of immediate asthmatic responses by both allergens andnonspecific factors, such as exercise and cold air

Clinical review



ABC of allergiesAvoiding exposure to indoor allergensAshley Woodcock, Adnan Custovic

The practice of avoiding exposure to allergens (allergenavoidance) for allergic diseases such as asthma is not a new idea.In the 16th century the Archbishop of St Andrews had amiraculous remission of his intractable asthma by getting rid ofhis feather bedding, and in 1927 Storm van Leeuwen created a“climate chamber” in Holland in an attempt to recreate thebeneficial environment of high altitude sanatoriums. This articlefocuses on how to avoid indoor allergens in homes intemperate climates and the potential benefits for sensitisedpatients with atopic disorders.

Nowadays most people spend more than 90% of their livesindoors. Over the past 30 years, the home environment haschanged enormously with the introduction of soft furnishings,fitted carpets, and central heating. Indoor ventilation hasdecreased—the rate at which indoor air is exchanged for freshair is now 10 times lower than it was 30 years ago, with aconsiderable increase both in humidity and in concentrations ofindoor pollutants and airborne allergens. As exposure toallergens is an important cause of symptoms in sensitisedpatients, reducing exposure should improve disease control. Inspite of this, few patients in Britain with asthma, eczema, orperennial rhinitis, or any combination of these, are skin tested.

Characteristics of indoor allergensThe predominant indoor allergens in Britain are from mites,cats, and dogs, and they have dramatically differentaerodynamic characteristics. Mite allergens are present on largeparticles in beds, soft furnishings, and carpets, which becomeairborne only after vigorous disturbance and settle quickly. Incontrast, about 25% of cat and dog allergens are associated withsmall particles < 5 ìm in diameter, which after disturbanceremain airborne for prolonged periods. This in part explainsthe difference in clinical presentation between asthmatic peoplewho are sensitive to mites and those sensitive to their pets.Patients allergic to dust mite may be unaware of the relationbetween asthma and exposure to mites, as this is apredominantly low grade chronic exposure occurring overnightin bed. Patients allergic to cats or dogs may develop symptomswithin minutes of entering a home with these animals or simplyby stroking an animal, as a result of inhaling large amounts ofeasily respirable cat and dog allergen.

For symptoms to occur, atopic patients need to be exposedto allergens to which they are sensitised. Allergen avoidanceshould be recommended only to those symptomatic individualswho are sensitised on the basis of skin tests or specific serumIgE concentration.

MitesLessons from high altitudeAt high altitude, low levels of humidity mean that mites cannotsurvive, and so mite allergen concentrations are low. Asthmacontrol in mite sensitive patients moving to high altitudeimproves, although full improvement may take 612 months toachieve. The real challenge facing physicians in Britain is tocreate a low allergen environment in patients’ homes that issufficiently flexible to suit individual needs and at the same time

Few patients in Britain with asthma,eczema, or perennial rhinitis receiveadvice on appropriate avoidancemeasures

Concentrations of indoor allergens

x The highest concentration of mite allergens is found in beds;patients spend 68 hours every night in close contact with theirmattress, pillow, and bedding, so the reduction of exposure in thebedroom is critical

x Most exposure to pet allergens probably occurs in living areas otherthan the bedroom, and this must be taken into account whenplanning avoidance strategies

x In public areas—for example, cinemas and public transport—miteallergen levels are low, but exposure to airborne pet allergens canbe substantial even in hospital outpatient areas

x Exposure to cockroach allergens may be important in schools andsome high rise blocks of flats

In transit (5%)

Indoors

(93%)

Outdoors (2%)

Amount of time that most Americans spend indoors, outdoors, and intransit

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Progressive reduction in nonspecific bronchial hyperreactivity (histamine) in10 asthmatic children allergic to mites who moved from home to a mite freeenvironment (a sanatorium in Davos, Switzerland)

Clinical review

1075BMJ VOLUME 316 4 APRIL 1998


not prohibitively expensive. Many avoidance measures havebeen tested, but only a few have been subjected to randomisedcontrolled trials.

Controlling concentrations of mite allergens

BedroomsThe single most effective measure is to cover the mattress,pillows, and duvet with covers that are impermeable to miteallergens. These covers used to be made of plastic and wereuncomfortable to sleep on. Now fabrics permeable to watervapour (either microporous or polyurethane coated) but alsoboth impermeable to mite allergens and comfortable to sleepon are available. Allergen concentrations decrease by up to100fold after such covers are introduced.

All exposed bedding should be washed at 55°C. This killsmites and removes allergen; although the “cold” cycle (30°C) oflaundry washing dramatically reduces allergen concentrations,most mites survive it. The covers should be wiped down at eachchange of bedding.

Buying a new mattress produces only a temporary benefit asreinfestation may occur within a few months from otherreservoirs, such as carpets. Ideally, bedroom carpets should bereplaced with sealed wooden or vinyl flooring, and the curtainsshould be hot washed regularly or replaced with wipeableblinds. In this way exposure to mite allergens in the bedroom atnight can be virtually abolished. Substantial clinical benefit ofeffective mite avoidance has been shown in mite sensitisedasthmatic patients and in patients with eczema or perennialrhinitis.

Rest of the houseIntensive vacuum cleaning with high filtration cleaners reducesthe size of the allergen reservoir, but no benefit has beenestablished in a clinical trial. Older vacuum cleaners withinadequate exhaust filtration should be avoided as they provideone of the few ways to get large amounts of mite allergenairborne. Sensitised asthmatic patients who have to use avacuum cleaner should use one with a builtin high efficiencyparticulate air filter and also use double thickness bags.

Killing mites with chemicals (acaricides) is feasible in thelaboratory, but convincing evidence of clinical benefit is lacking.Mites can be killed in carpets either with steam or by freezingwith liquid nitrogen, but both techniques are unlikely toproduce sufficient benefits to warrant the huge effort required(in addition, regular treatment is necessary). Air filters andionisers are of no clinical benefit as mite allergen does not stayairborne.

Actions for avoiding exposure to mite allergens in relation toasthma in Britain

Do helpSpecial bed covers (with or withoutcleaning)Removal of habitat (eg, carpet)Moving to Switzerland

Do not helpAcaricidesAir filters or ionisersVentilation systemsDehumidifiers

100 000

10 000

1000

100

10

1

Der

p 1

(n

g/g

du

st)

Base-line

6weeks

12weeks

10 µg/g dust

2 µg/g dust

Base-line

6weeks

Ventflex mattress Control mattress

12weeks

Approximate 100fold reduction in concentrations of house dust miteallergen (Der p 1) on mattresses after introduction of covers that areimpermeable to mite allergens (Ventflex covers)

6

5

4

3

2

1

0

Air

bo

rne

Der

p 1

(n

g)(

geo

met

ric

mea

n)

Older

vacuum cleaner

High filtration

cleaner

After

AfterBefore Before

Comparison of older vacuum cleaner (with inadequate exhaust filtration)with high filtration cleaner, showing significantly increased concentrations ofairborne house dust mite allergen (Der p 1) in older cleaners before andafter vacuuming

1.0

0.8

0.6

0.4

0.2

010 20 30 40 50 60

Pro

po

rtio

n o

f m

ites

kill

ed

Temperature (˚C)

Proportion of mites killed at different washing temperatures

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1076 BMJ VOLUME 316 4 APRIL 1998


A final alternative might be to reduce humidity to suppressthe growth of mites. This has been attempted by the use ofmechanical ventilation and with portable dehumidifiers. Neitherof these techniques reduces humidity levels in typical Britishhouses sufficiently to suppress mite growth, and allergenconcentrations have not been shown to be reduced.

Pet allergensPet allergens are present in huge concentrations in houses withcats and dogs, but they are also transferred on clothing, soconcentrations are detectable in homes without pets and inpublic buildings and transport.

For an asthmatic patient who owns a pet and is sensitised tothe animal, the best way to reduce exposure is to get rid of thepet, but this is rarely feasible as owners are usually very attachedto their pets. Even after permanent removal of a cat or dogfrom the home, it may take many months before the reservoirallergen concentration returns to normal. So if patients do getrid of their pets they should not expect their symptoms toimprove immediately—it may take 612 months for full benefit.

If the pet remains in the home, advice can be given aboutmethods that are known to reduce airborne pet allergens. Thepet should be kept out of the bedroom and preferably outdoorsor in a well ventilated area—for example, a kitchen. In homeswith a pet, the concentration of airborne pet allergens will beconsiderable higher when the pet is actually in a room thanwhen it is elsewhere in the house.

Ideally, carpets should be removed, as the concentration ofpet allergens can be as much as 100 times higher in carpetsthan in polished floors. If carpets remain then regular cleaningwith a high filtration cleaner is advised. Washing the animalthoroughly and as often as possible, combined with the use of ahigh efficiency particulate air cleaner, is the best way to reduceallergens, but whether these practices are clinically effective is asyet unproved.

Allergen avoidance in primaryprevention of atopic diseasesSensitisation to allergens seems to be related to exposure toallergens in early life. The key question is whether early allergenavoidance can prevent allergic disease developing in the firstplace.

The innovative Isle of Wight study has examined the effectof avoiding mite allergens and certain foods from birth onwardson the development of atopy and asthma. This study usedacaricides, and hence the reduction in the concentration of miteallergens was relatively modest. Even these minor reductions,

Avoiding cat and dog allergensReduceairborneallergen

Givesclinicalbenefit

Removal of pet

Pet in situ:

Wash pet

Remove carpets

High efficiency particulate air filter

Castrate male or get a female (cat)

U

U

U

U

U

U

?

?

?

?

10 000

1000

100

10

1

0.2

0

Can

f 1

(µ

g/g

du

st)

Mattress Bedroom

carpet

Living room

carpet

Upholstered

furniture

Homes with dogs

Homes without dogs

Distribution of dog allergen (Can f 1) in settled dust from four samplingsites in 100 homes in Manchester (50 with a dog, 50 without). Can f 1 wasreadily detectable in homes without dogs, but the levels were between10fold and 100fold lower than in houses with dogs

1000

100

10

1

0.1

0.010 5

Cat removed

10 15 20 25 30 35 40 45

Weeks

Cat

alle

rgen

(Fe

l d 1

) (F

DA

un

its/

g d

ust

)

Effect on allergen concentrations of removing a cat from a home

Milo: could you get rid of her?

Clinical review

1077BMJ VOLUME 316 4 APRIL 1998


however, were associated with a reduction in eczema andepisodic wheezing.

Several prospective cohorts of babies at high risk of atopy orasthma have been randomised to more effective protocols foravoiding exposure to mite allergens and are currently beingstudied. Population based studies are also being planned.

The futureExposure to indoor allergens may have contributed to theobserved increase in asthma prevalence. The important issue iswhether asthma can be prevented by allergen avoidance in earlylife. Primary allergen avoidance is premature outside thecontext of a clinical trial but may be an important aspect ofpreventive therapy by the end of this century. Major changes inthe domestic environment are likely over the next decade, withthe removal of dust mite habitats—that is, a return to hardflooring—a reduction in indoor humidity, and the encasing ofall bed and bedding with mite proof covers.

The following illustrations are reproduced or adapted with the permissionof the publishers: the pie chart (Pope et al (Indoor Allergens, NationalAcademy Press, 1993)); and the graphs showing results in children inDavos (Plant Mills et al (J Allergy Clin Immunol 1987;80:75575)); allergenconcentrations on mattresses (Owen S, et al (Lancet 1990;335:3967));mites killed during washing (McDonald et al (J Allergy Clin Immunol1992;90:599608)); concentrations of airborne house dust mite allergen invacuum cleaners (Kalra S, et al (Lancet 1990;336:449)); distribution of dogallergen (Custovic A, et al (Am J Respir Crit Care Med—1997;155:948)); andeffect on allergen concentrations by cat removal (Wood RA, et al (J AllergyClin Immunol 1989;83:7304)).

Ashley Woodcock is a consultant respiratory physician and AdnanCustovic is a specialist registrar in allergy at the North West LungCentre, Wythenshawe Hospital, Manchester.

First steps in treating atopic diseases

x Diagnose disease by taking a history and by either performing skintesting or measuring specific serum IgE concentrations

x Minimise the impact of identified environmental risk factors such asmites, cats, and dogs

x Regard allergen avoidance as an integral part of the overallmanagement of sensitised asthmatic patients

Further reading

x Platts Mills TAE, Vervloet D, Thomas WR, Aalberse RC, ChapmanMD. Indoor allergens and asthma: report of the third internationalworkshop. J Allergy Clin Immunol 1997;100(6):S124

x Custovic A, Simpson A, Chapman MD, Woodcock A. Allergenavoidance in the treatment of asthma and atopic disorders. Thorax1998;53:6372

x Collof MJ, Ayres J, Carswell F, Howarth PH, Merrett TG, MitchellEB, et al. The control of allergens of dust mites and domestic pets: aposition paper. Clin Exp Allergy 1992;22(suppl 2):128

x Pope AM, Patterson R, Burge H, eds. Indoor allergens—assessing andcontrolling adverse health effects.Washington, DC: National AcademyPress, 1993


BMJ 1998;316:00000

Words

The accurate use of language

Words are used to convey meaning. The passage of time can alterthe generally accepted understanding of a word. A good exampleof this is the modern connotation of the word gay. In science andin surgery, however, a certain exactitude of meaning is necessaryto accurately transfer information. This was well brought home tome in the early 1960s in Oxford. On grand rounds a confidentand ambitious young surgeon was presenting a case in which hehad inadvertently divided the common bile duct. “I still cannotunderstand how it occurred,” he said and went on, “You see Ivisualised the duct perfectly.” Whereupon up spoke an acerbicprofessor of medicine: “I am not surprised you cut the duct if youonly visualised it but did not see it.”

The contemporary alternative use of the word visualise “torender visible” was obviously considered a vulgar modernism byour seniors in Oxford. As the assistant at the operation I learnt to

avoid ambiguity in the use of words and to use clear conciseEnglish to convey meaning. Perhaps just as important I alsolearnt never to hurry gall bladder surgery.

M D Middleton, retired consultant surgeon, Solihull

We welcome articles up to 600 words on topics such asA memorable patient, A paper that changed my practice,My mostunfortunate mistake,or any other piece conveying instruction,pathos, or humour. If possible the article should be supplied on adisk. Permission is needed from the patient or a relative if anidentifiable patient is referred to. We also welcome contributionsfor “Endpieces,” consisting of quotations of up to 80 words (butmost are considerably shorter) from any source, ancient ormodern, which have appealed to the reader.

Corrections

ABC of allergies

An error occurred in “The epidemiology of allergic disease” by D Jarviset al (21 February, pp 607610). The first sentence of the acknowledgment for illustrations should have read: “The data in the third graphare from Burr et al (Arch Dis Child 1989;64:14526); in the fourth graphare from Nakagomi et al (Lancet 1994;343:1212) and Gassner (SchweizRundschauMed 1992;81:42630); in the fifth graph are from Strachan D

(Clin Exp Allergy 1995;25:296303); and in the second table are fromMeredith S (J Epidemiol Community Health 1993;47:45963).”

An error also occurred in “Diagnosing allergy” by Csaba Rusznaket al (28 February, p 6869). In the first box on p 686, neonates shouldhave read “infancy,” and “early childhood” should have read“childhood.” In the final line, “nasal polyps” should have been omitted.

Clinical review

1078 BMJ VOLUME 316 4 APRIL 1998


ABC of allergiesAllergy and the skin. I—UrticariaMalcolm W Greaves, Ruth A Sabroe

Acute urticariaEpisodes of acute urticaria are common. Causes include type 1hypersensitivity reactions to certain foods and drugs, includingblood products. In up to 50% of cases a cause is not identified.The involvement of a particular food allergen can be confirmedby the radioallergosorbent test (RAST) and skin prick tests.Allergy to latex usually manifests as contact urticaria or withsystemic symptoms but rarely presents with generalisedurticaria. As with suspected reactions to peanuts it isrecommended that tests for latex allergy be done in a hospitalsetting as severe systemic reactions may occur. Management ofacute urticaria includes avoidance of the causative agent andtreatment with H1 antihistamines. A short course ofprednisolone can be given for severe episodes of urticariaunresponsive to antihistamines.

Chronic urticariaChronic urticaria is conventionally defined as the occurrence ofdaily or almost daily widespread itchy weals for at least sixweeks. It occurs in at least 0.1% of the population and is muchmore troublesome than acute urticaria. Recent studies using aninternationally recognised quality of life questionnaire, theNottingham health profile, have highlighted the seriousdisability of patients with chronic urticaria, including loss ofsleep and energy, social isolation, altered emotional reactions,and difficulties in aspects of daily living. The disability is of thesame order as that experienced by patients with severe chronicischaemic heart disease.

Physical urticariasThe first step is to identify patients with physical urticarias.These are patients in whom wealing and itching is provoked atthe sites of a physical stimulus—such as stroking the skin(dermographism), cooling the skin (cold urticaria), or sunexposure (solar urticaria). Cholinergic urticaria, a widespreadtransitory pruritic rash following exercise, emotion, or heat, alsofalls into this category.

Once these physical urticarias have been identified and thediagnosis confirmed if necessary by challenge testing, furtherinvestigation is unrewarding, and they are best treatedsymptomatically by avoidance and with antihistamines.

Causes of acute urticariax Idiopathic originx Food: fruits (for example, strawberries), seafood, nuts, dairy

products, spices, tea, chocolatex Drugs: antibiotics (for example, penicillin) and sulphonamides;

aspirin and non steroidal anti inflammatory drugs; morphine andcodeine

x Blood productsx Viral infections and febrile illnessesx Radio contrast mediax Wasp or bee stings

Dermographism induced with a calibrated, spring loaded dermographometer

Cold urticaria induced by placing an icecube on the skin for 5 minutes

Solar urticaria, which can be induced by irradiation ofthe skin with a solar simulator

Cholinergic urticaria induced by brisk exercise

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1147BMJ VOLUME 316 11 APRIL 1998 www.bmj.com

Physical urticarias frequently coexist with chronic“idiopathic” urticaria (referred to in the rest of the article aschronic urticaria). In these cases management will depend onwhether the physical urticaria or the chronic urticaria is themajor contributor to the patient’s disability.

Angio-oedemaDefined as deep mucocutaneous swellings, angio-oedemaoccurs concurrently with ordinary urticarial weals in about halfof patients with chronic urticaria. Hereditary angio-oedema is arare condition caused by an autosomal dominant inheriteddefect of the inhibitor of the first component of thecomplement cascade. Urticarial weals are not strictly a featureof hereditary angio-oedema, but if doubt exists, a normal valuefor the serum complement component C4 in between attackseffectively excludes this diagnosis in almost all cases.

Urticarial vasculitisIt is all too easy to overlook the occasional patient withurticarial vasculitis. The clinical picture of urticarial vasculitismay be distinctive, but more often the morphology of the wealsresembles that of chronic urticaria and the only clinical clue isthe duration of individual weals, which invariably persist formore than 24 hours. Confirmation of the diagnosis by a skinbiopsy to show histological evidence of vasculitis is importantbecause these patients need to be fully investigated for evidenceof lupus erythematosus or other autoimmune connective tissuedisease, and of renal or other internal organ involvement. Theyalso usually require additional treatment measures—forexample, dapsone, colchicine, or occasionally oral steroids.

PathogenesisThe weals in chronic urticaria are caused by a local increase incutaneous vascular permeability, mainly in the postcapillaryvenules. This, and the associated erythema and itching, isevoked by pharmacological mediators released from mast cellsin the skin. Histamine, stored in the granules of mast cells andsecreted as a result of degranulation, is the principal mediator;this is evident from the symptomatic relief afforded by H1

antihistamines. Experimental wealing due to intracutaneousinjection of histamine is short lived, lasting minutes rather thanhours. In contrast, individual urticarial weals last 12 or morehours. This is due to the actions of additional mediators, someof which are probably also derived from the mast cells. Thereare some similarities between the histopathologicalappearances of urticarial weals and those of the late phaseresponse. This may suggest the additional participation ofbasophil leucocytes that contain histamine.

Causes and investigationUntil recently the cause of chronic urticaria was unknown innearly all cases. Today we still do not know the aetiology inmany, but subsets of chronic urticaria can now be defined inwhich the cause can be identified, with important consequencesfor treatment.

Causes listed in most textbooks include infestations,candidiasis, and internal malignancy, although in practice noneof these can be convincingly incriminated. A recent spate ofreports have associated Helicobacter pylori and hepatitis Cinfection with chronic urticaria, but the evidence is not robust.

Chronic urticaria can occasionally be confirmed to be dueto a specific food additive. Reproducible placebo controlled oralchallenge testing is essential for diagnosis; failure to appreciatethis probably accounts for the frequency with which foodadditives have been implicated in chronic urticaria in somestudy series. Challenge testing should be blind challenge by

Features suggestive of urticarial vasculitisClinicalx Duration of weals > 24 hoursx Weals painful rather than itchyx Residual purpura, bruising, or pigmentary changex Prominent systemic features (eg, fever, nephritis, arthralgia)x Poor response to antihistaminesLaboratoryx High erythrocyte sedimentation rate and raised concentrations of

acute phase proteinsHistopathologyx Venular endothelial cell swelling and disruptionx Leucocyte invasion of venular endotheliumx Extravasation of red cellsx Leucocytoclasia (neutrophil nuclear dust)x Fibrin deposition

Mucocutaneous angio-oedema

Chronic urticaria

No unusual features

Perform full blood count and differential white cell count

Normal Eosinophilia

Placebo controlled food additive challenge

Negative result Positive result

Autologousserum intradermal

test*

Dietaryadvice

Negative:chronic "idiopathic"

urticaria

* For severely disabledpatients unresponsiveto antihistamines only

Positive:? autoimmune

chronic urticaria

Examine stoolsfor parasites, ova

Urticarial vasculitis Predominant physical urticaria

• Identify by weal duration >24 h; presence of purpura or pigmentation• Confirm by biopsy

• Identify by challenge testing• Patients with predominant angio-oedema may have hereditary angio-oedema: identify by a low serum C4 concentration

Investigation of chronic urticaria

Clinical review

1148 BMJ VOLUME 316 11 APRIL 1998 www.bmj.com

numbered capsules containing the food additives suspected ofbeing implicated (details from authors on request). Asubstantiated positive result should prompt appropriate dieteticadvice. In our practice, food additives are confirmed as thecause in only about 0.6-0.8% of patients with chronic urticaria.Exclusion diets are usually unhelpful: the results are difficult tointerpret and even misleading; compliance is poor; and theadministration of such diets unwieldy and prolonged.

Autoimmune chronic urticariaIn about 50-60% of patients with chronic urticaria the weals arecaused by circulating histamine releasing factors. In half ofthese the histamine releasing activity has been proved to be dueto IgG autoantibodies directed against epitopes expressed onthe extracellular portion of the á subunit of the high affinity IgEreceptor (FCåRIá), which is located on the outer surface of allmast cells and basophil leucocytes. This autoantibody, which isof isotype IgG1 or IgG3, is functional because it releaseshistamine from mast cells or basophils in vitro and causeswealing upon intradermal injection in humans in vivo.Anti-FCåRI autoantibodies cross link á subunits of adjacentFCåRI, thereby triggering release of histamine. In a very smallminority of such patients the autoantibody has proved to be anIgG anti-IgE autoantibody, but the result seems to be the same.

The clinical presentation of autoimmune urticaria seems tobe indistinguishable from that of autoantibody-negative chronicurticaria. Although autoimmune urticaria can currently beidentified only in specialist units, it is very important for themanagement of these patients that their autoantibodies areidentified. Treatment of patients with autoimmune urticaria byplasmapheresis or intravenous immunoglobulin infusions hasbrought about remissions in patients who were previouslyseverely affected, badly disabled, and resistant to treatment.

Natural courseCharacteristically, chronic urticaria pursues a course ofremission and relapse, relapses being triggered by intercurrentinfections, stress, drugs (especially aspirin and angiotensinconverting enzyme inhibitors), and the menstrual cycle. It hasbeen estimated that about 50% of patients presenting with ahistory of chronic urticaria of at least 3 months’ duration willstill have the condition three years later.

TreatmentPatients should be advised to avoid factors that trigger relapses,especially non-steroidal anti-inflammatory drugs. As weals tendto occur at sites of local pressure, tightly fitting clothes, belts,and shoes should be avoided. Itching is exacerbated by warmth,and therefore a cool ambient temperature, especially in thebedroom, is helpful and may prevent insomnia.

Treatment with 1% menthol in aqueous cream has beenproved to suppress histamine induced itching, and manypatients find it helpful. Mucocutaneous angio-oedema can betreated by two to three puffs of an aqueous 2% ephedrine spray.Unlike hereditary or acute allergic angio-oedema,angio-oedema in association with chronic urticaria is rarely lifethreatening, although it can be very unpleasant and frightening.

Antihistamines are still the mainstay of treatment of chronicurticaria, although they tend to be more effective in suppressingitching than wealing. Before antihistamines are chosen, thetiming of administration must be considered. Patients frequentlyexperience flare ups at certain times of the day—for example,after lunch or in the early evening. The course of action of theantihistamine chosen must ensure cover of these diurnal peaksof disease activity. Low sedation H1 antihistamines, such asloratadine 10 mg daily, are useful for daytime treatment.

Conditions requiring specialist referralx Urticaria suspected to be due to peanut or latex allergyx Urticaria persisting beyond six weeks (chronic urticaria)x Features of urticarial vasculitisx Urticaria associated with systemic featuresx Urticaria poorly responsive to antihistaminesx Angio-oedema involving the airway (tongue or throat)

Treatment of chronic idiopathic urticariax Avoidance of precipitating or exacerbating factors

Food additives, alcohol, hot environment, stressAspirin and non-steroidal anti-inflammatory drugs, codeine and

morphineAngiotensin converting enzyme inhibitors if there is

angio-oedemax Topical treatments

Tepid shower1% menthol in aqueous cream2% ephedrine spray for oral angio-oedema

x H1 antihistamines (with or without H2 antihistamines) or doxepinx Short reducing course of prednisolonex Specialist treatments

Cyclosporin AIntravenous immunoglobulinsPlasmapheresis

Anti-FCεRIα

Mast cell +

+

+

Eosinophil

Interleukin 5

Interleukin 6Lymphocyte

Interleukin 4

Cytokines, histamine, andother mediators of urticaria

FCεRIα

Probable pathogenesis of wealing in autoimmune (anti-FCåRI) chronicurticaria. Activation of cutaneous mast cells by anti-FCåRIá autoantibodiesleads to release of proinflammatory mediators and also to activation ofeosinophils (via interleukin 5) and immunoglobulin-synthesising Blymphocytes (via interleukin 4 and interleukin 6)

Clinical review


Cetirizine 10 mg daily is also useful, especially if there isassociated delayed pressure urticaria, against which it seems tohave a selective action. Care must be taken not to administerterfenadine or astemizole with cytochrome P-450 inhibitorsincluding doxepin, imidazole antifungals and macrolideantibiotics, to avoid cardiac arrhythmic complications. Doxepinis useful as a single night time 25 mg dose in patients whoexperience nocturnal disease activity especially when associatedwith anxiety or depression. A combination of cetirizine in themorning and doxepin in the late evening affords symptomaticrelief, even in severely affected patients with recalcitranturticaria. Although combinations of H2 and H1 antihistamineshave been shown to be more effective than either class ofantihistamine alone in some studies, the gain is too small to beclinically useful.

Systemic steroids are not indicated in chronic urticariaowing to the substantial doses required, the development oftolerance, and frequency of chronic steroid toxicity. Inexceptional circumstances, however, short tapering courses ofprednisolone have a place when rapid control over a limitedperiod is required.

There have been several reports of the value of â2adrenergics (for example, terbutaline), calcium channelantagonists (for example, nifedipine), and anabolic steroids (forexample, stanazolol) in the management of chronic urticaria.These studies lack underpinning by controlled trial data and areunconvincing.

Immunosuppressive treatment in autoantibody (anti-FCåRIá)-positive chronic urticaria as discussed above, as well ascyclosporin, may be dramatically beneficial in selected patients,but these treatments should be provided by specialised centres.

No antihistamines are safe in pregnancy,but if antihistamines have to beadministered to control chronic urticaria,chlorpheniramine is advised as it has thebest safety record

Further readingx Greaves MW. Chronic urticaria. N Engl J Med 1995;332:1767-72x Hide M, Francis DM, Grattan CEH, Hakimi J, Kochan JP, Greaves

MW. Autoantibodies against the high-affinity IgE receptor as acause of histamine release in chronic urticaria. N Engl J Med1993;328:1599-604

x Sabroe RA, Greaves MW. The pathogenesis of chronic idiopathicurticaria. Arch Dermatol 1996;23:735-40

x O’Donnell BF, Black AK. Urticarial vasculitis. Int Angiol1995;14:166-74

x Champion RH, Roberts SOB, Carpenter RG, Roger JH. Urticariaand angioedema: a review of 554 patients. Br J Dermatol1969;81:588-97

St John’s Institute of Dermatology provided the first five photographs inthe article. The photograph showing mucocutaneous angio-oedema ispublished with permission of the patient, whose grandson, Robert Payne,provided the photograph.

Malcolm W Greaves is head of clinical dermatology and Ruth ASabroe is honorary senior registrar at the professorial unit, St John’sInstitute of Dermatology, St Thomas’s Hospital, London.


BMJ 1998;316:1147-50

A memorable patientThe gentleman crook

Not long before the great London smog in 1952, I was called onewinter evening to a house in Camden Town, to a new patient. Thedoor was opened by an old lady, who said nothing, but pointed toan upstairs room. There was no light in the room, but I could seea bed and a prone figure in it. This was an old man, complainingof chest pain. He was a lodger in the house and said that he ran amission for children near King’s Cross. Examining him in thedark, I heard a pericardial rub (for the only time in my career).Obviously ill and helpless, he refused to go to hospital then,refused again next day, but gave in on the third day on conditionthat he was admitted only to Bart’s. There he went and died verysoon.

But he had given me a letter to post and it was addressed to aprobation officer at the Old Bailey. As I was puzzled by this oldman with a long and saintly face like an El Greco portrait, I rangthe probation officer. “Oh, that must be Johnny the Gent,” he said,“the most famous criminal of his day, invented the use ofstethoscopes to get into bank safes, flooded London withcounterfeit sovereigns, stole the Ascot Gold Cup and melted itdown, and spent much of his life in prison.” He then told memore about John Wood, how he dressed impeccably, always woremauve gloves, and knew many of the judges of the time by theirChristian names.

Because of his face, some of his escapades had a clerical tone.For example, after hiring a bishop’s get up at Clarkson’s, he called

on a shipping agent dealing with the Falkland Islands saying thathe was the islands’ bishop and was seeking money for a mission,which looked after girls who had been brought into the familyway by visiting members of ships’ crews. Unsuccessful at first, heasked to see the managing director upstairs. Nearly failing again,he said: “Well now, may we get down on our knees and praytogether for my mission?” This succeeded and resulted in adonation of £500.

When the borough of St Pancras ceased, becoming part ofCamden, a souvenir booklet was issued about the borough’shistory and some of its residents. John Wood had a paragraphnext to W B Yeats and Dylan Thomas (who lived across the samestreet), but there is no blue plaque on my patient’s house.

John Horder, retired general practitioner, London

We welcome articles up to 600 words on topics such as Amemorable patient, A paper that changed my practice, My mostunfortunate mistake, or any other piece conveying instruction,pathos, or humour. If possible the article should be supplied on adisk. Permission is needed from the patient or a relative if anidentifiable patient is referred to. We also welcome contributionsfor “Endpieces,” consisting of quotations of up to 80 words (butmost are considerably shorter) from any source, ancient ormodern, which have appealed to the reader.

Clinical review


ABC of allergiesAllergy and the skin. II—Contact and atopic eczemaP S Friedmann

Allergic contact eczemaEczema is characterised by erythema, pruritus, vesiculation, and,in more chronic forms, scaly desquamation. Contact eczemamay be due to chemically induced irritation or allergicsensitisation. Allergic contact eczema is a cell mediated (delayedtype) hypersensitivity reaction to environmental chemical“sensitisers.” Hence, it occurs at body sites that make physicalcontact with the eliciting sensitiser. The term dermatitis is oftenused for eczema caused by exogenous agents.

Prevalence and aetiologyIn the working population of Western countries, contact eczema(both irritant and allergic) accounts for 85-90% of alloccupational skin disease. Hand eczema has been estimated toaffect 2-6.5% of all populations in Western countries.

The development of allergic reactions to exogenoussubstances seems to be the result of the intrinsic “sensitisingpotency” of the compound and various host factors thatdetermine susceptibility. Small molecular chemicals vary in theirpotential to induce allergic sensitivity: primula can sensitisemost people, nickel sensitises 10-20% of women, while manyother agents sensitise a smaller minority. The sensitisingpotency of a chemical is thought to be related to its chemicalreactivity and ability to bind to proteins, which act as “carriers,”facilitating the presentation of the substance to the immunesystem. Host susceptibility is related to as yet uncharacterisedgenetic factors, which include variation in metabolic pathwaysthat handle exogenous chemicals.

MechanismsWhen skin sensitisers penetrate the epidermis, they are takenup by Langerhans’ cells—bone marrow-derived members of themacrophage family that function as “professional antigenpresenting cells.” The Langerhans’ cells leave the epidermis andmigrate to the regional lymph nodes, where they enter theparacortical areas, the home of naive T lymphocytes. Probablywhile en route to the lymph node, the Langerhans’ cells processthe sensitiser so it is physically associated with the HLA-DRmolecules on the cell surface. In the node, the Langerhans’ cells“present” the sensitiser to T lymphocytes of the immune system.If T cells with the appropriate specific receptor recognise thecomplex of sensitiser and HLA-DR, they proliferate to establish“immunological memory.” The memory T cells that mediateallergic contact eczema are of the Th1 subtype, characterised bythe production of interleukin 2 and interferon gamma. Theinduction of sensitisation and establishment of immunologicalmemory takes 8-14 days. Should re-exposure to the sensitiseroccur, Langerhans’ cells carry it down into the dermis, wherethey present it to memory T cells travelling through the tissues.These are activated to release cytokines (including interferongamma) that attract other cells and activate vascular responses,resulting in the characteristic inflammation of contact eczema.

Differential diagnosisAllergic contact eczema must be distinguished from irritantcontact eczema. Clinically the two may be indistinguishable, butirritant eczema usually occurs on the hands. It is the result of

Distribution of allergic contact eczemax Nickel sensitivity involves ears, skin under buckles, and often the

hands; accidental spread from hands can involve the facex Hair products (for example, dyes, perms, and setting agents) often

affect the face, neck, and earsx Clothing dyes in socks and shoe leather often affect the feetx Ingredients in drugs used around leg ulcers often induce a

dermatitis of the leg

Clinical presentationx After re-exposure to a sensitiser, at sites of skin contact with the

offending agent, an itchy erythematous rash starts to develop within6-12 hours

x The reaction progresses and reaches a peak between 48 and 72hours after contact

x Sensitivity may range from weak to strongx Strongly sensitised people may need very little contact to evoke an

acute, weeping eczematous reactionx Nickel in keys, money, or clothing studs can be eluted by minimal

perspiration through several layers of clothes

Allergic contact eczema due to nickel in studs and buttons on jeans

Irritant contact eczema (dermatitis) of the hand

Clinical review


repeated “insult” to the skin with caustic, irritant, or detergentsubstances. Photoallergic eczema occurs on light exposedareas—face, nape of neck, and backs of hands. It is usually aresponse to photosensitisation by ingested drugs such asthiazide diuretics or quinine.

ManagementThe causal agent should be identified by epicutaneous patchtests. Contact allergy can be induced by a huge range ofsubstances encountered daily. Sometimes the history of flareups after contact with something is sufficient to permitreasonably confident identification. Often a short list of possibleculprits can be arrived at. Definitive proof of causal significance,however, requires patch testing. This is normally performed indermatology clinics with the requisite expertise and range oftest materials.

The patient should then be advised to avoid the causalagent.

Treatment will vary:x Acute weeping eczema should be “dried” by soaking withpotassium permanganate (1/10 000) daily for four to five days;x Anti-inflammatory steroids of category 3 or 4 (category 1 isthe weakest, 4 the strongest—see British National Formulary)during the acute phase;x Systemic steroids may be required for severe cases;x For irritant hand eczema, avoiding contact with soaps,detergents, and solvents, together with generous use of greasyemollients, is vital.

Atopic eczemaDefinitionThe atopic state is a genetically determined capacity to makeIgE class antibodies to antigens that enter the body via mucosalsurfaces. This is associated with allergies of the immediate typeand the clinical syndromes of rhinitis asthma or atopic eczema,alone or in combination.

PrevalenceFor unclear reasons the prevalence of atopic diseases, includingeczema, has risen steadily over the past 30 years. There aremany estimates of the prevalence of atopic eczema in childrenin different countries. For children aged up to 12 years theserange from 12-26%.

With increasing age the prevalence falls: 65% of atopiceczema presents before the age of 6 months, and 80% in thefirst year of life.

AetiologyIn atopic individuals, responses to common allergens result inthe generation of helper T lymphocytes of the so calledTh2-type in preference to those of Th1-type.

Th2 cells produce mainly interleukins 4 and 5, whichregulate IgE production, mast cells, and eosinophils. Th1 cellsproduce mainly interleukin 2 and interferon gamma. Althoughseveral potentially important genes are receiving attention, theyseem more connected with the formation of IgE than with theclinical syndrome.

It is completely unknown what determines whether theclinical manifestations in any individual will involve the lungs,nose, or skin.

Clinical presentationAtopic eczema most commonly begins in infancy. The rash oferythematous areas comprises tiny papules, sometimes with an

Pathogenesisx Eczema is triggered or exacerbated by interactions between a

genetic predisposition and environmental factorsx These include environmental allergens (house dust mites, animal

furs, and pollens), microbes (such as staphylococci), environmentalpollutants, and climatic and emotional factors

x Skin challenge with allergens elicits both immediate and delayedresponses

x The evidence suggests that atopic eczema is an allergic reactionmediated by T lymphocytes of both Th1-types and Th2-types

x Although IgE may participate during antigen presentation and bymediation of immediate-type hypersensitivity responses, the eczemais probably not related to histamine or mast cell products

Patch testing for diagnosing causal sensitiser in allergic contact eczema

Typical atopic eczema in child

Clinical review


urticaria-like component. They may join to form confluent redsheets. In infants atopic eczema commonly affects the wholebody including the head and face. On the limbs predominantlyextensor surfaces are affected.

Once the baby begins to crawl, the eczema tends to localiseto extensor surfaces of the hands, wrists, knees, and ankles.These changes in distribution are probably related to changesin exposure or contact with exogenous triggers, includingfriction from dusty floor surfaces. Once the toddling andupright stage is reached, the eczema moves to flexural sites suchas popliteal and antecubital fossae. The severity may range frommild (usually of limited extent) to severe, with extensive, angryinflammation on most of the body.

ComplicationsImmune resistance to several microbial pathogens is reduced inindividuals with atopic eczema. Thus both viral warts andmolluscum contagiosum can be numerous and slow to clear.Eczema herpeticum is infection with herpes simplex viruses,which may be extensive and aggressive.

Management

Drug treatmentThe basis of direct treatment is to suppress the symptoms andcontrol or prevent complications.

Atopic eczema is readily irritated by soaps, so theiravoidance and use of emollients as soap substitutes isimportant.

Anti-inflammatory topical steroids are the mainstay oftreatment. In children, when the eczema is very active, strongersteroids such as betamethasone valerate (1/4 strength) may berequired. Normally, clobetasone or mometasone may beadequate for treating areas other than the face; 1%hydrocortisone is the main steroid for the face. In adultsundiluted category 3 steroids may be required for flare ups.Dilutions and weaker steroids are used for regular maintenance.

Acute flares are often induced by staphylococcalsuperinfection. Systemic antibiotics (flucloxacillin orerythromycin) should be used. If chronic or repeated infectiveepisodes occur, use of a topical steroid and antibiotic, orantiseptic mixtures, can help.

Although antihistamines are often used to relieve itch,histamine is not the main, responsible mediator. Henceantihistamines are not very effective, and usually the oldersedative types—such as trimeprazine, hydroxyzine, andchlorpheniramine—seem more effective than the modernnon-sedative varieties.

Acute exacerbations may be weepy andcrusted—this usually signifiessuperinfection with staphylococci.Chronic excoriated lesions are oftenthickened and lichenified

The key physical sign of eczemaherpeticum is blisters, pustules, orerosions of a rather uniform size andappearance

Treatment of atopic eczemax Emollients as soap substitutesx Oils, creams, and ointmentsx Topical steroids to suppress inflammationx Antibioticsx Antihistamines—sedative varietiesx Bandages—"wet dressings” or impregnated bandages

Use of topical steroids for treating atopic eczema

Adults Children

Whensevere

Category 3 to body;category 2 to face

Diluted category 3 to body;category 2 to face

Routine Category 2 or dilutedcategory 3 to body;category 1 or 2 to face

Category 1 or 2 to body;category 1 (hydrocortisone)to face

Eczema herpeticum (ulcers are of similar shape and size)Discoid pattern of atopic eczema

Clinical review


Bandages and dressingsIn infants and children the “wet bandage” technique canprovide great symptomatic relief. A double layer of mediumgrade tubular cotton bandage (Tubifast, Seton) is applied over alayer of emollient or sometimes over a weak topical steroid. Theinner layer of bandage is moistened with warm water. Thedressing can be applied to limbs and even the trunk. For verylichenified or excoriated eczema, various bandages impregnatedwith antiseptics (Ichthopaste, Smith and Nephew, orQuinaband, Seton) or zinc oxide (Viscopaste, Smith andNephew) can be used to occlude the area; a weak steroid andantiseptic mixture is usually applied underneath.

Second line treatmentSystemic corticosteroids should be used very seldom. Atopiceczema virtually always flares rapidly on dose reduction.Ultraviolet light (UVB) and photochemotherapy with apsoralen and long wavelength ultraviolet irradiation (UVA;PUVA) may be used in older children and adults.

Third line treatmentWhen second line treatment fails or is not suitable, variousfurther treatment options are available (see box).

Allergen avoidanceThe role of allergen avoidance should be considered for allpatients with atopic eczema. Avoidance or elimination of housedust mite allergens can be beneficial for many people withconfirmed mite sensitivity who have severe atopic eczema. Themain study to show this looked at children aged over 6 yearsand adults. The most important measures are encasing themattress in a dust proof bag, and washing the duvets andpillows every three months; washes should be hotter than 55°Cto kill mites and denature antigens. Removal of fitted carpets inthe bedroom should be recommended. Reducing upholsteredfurnishings and regular use of a modern cylinder or uprightvacuum cleaner fitted with an adequate filter seem sensibleprecuations.

Foods are often suspected as being provoking factors inbabies, but reliable identification of relevant foods is difficultand often impossible. Hence regimens avoiding dairy or othersuspected foods are often disappointing, and if no clear benefitis obtained they should not be maintained for longer than fourweeks. In small children such diets are difficult to implement,and the help of a dietician is necessary.

The photograph showing dermatitis of the hand is reproduced with thepermission of Gower Medical Publishing. The data in the graph are adaptedfrom Tan et al (Lancet 1996;347:15-8).

P S Friedmann is professor of dermatology at Southampton GeneralHospital.


BMJ 1998;316:1226-9

Third line treatment of atopic eczemax Cyclosporin A can be highly beneficial in severe atopic eczemax Great care must be taken in monitoring renal function, and

treatment courses should be restricted to 8-12 weeksx In adults with severe and chronic atopic eczema, azathioprine may

be used for longer term maintenancex Haematological and hepatic function must be monitored carefully

Further readingx Williams HC. Is the prevalence of atopic dermatitis increasing? Clin

Exp Dermatol 1992;17:385-91x Cooper KD. Atopic dermatitis: recent trends in pathogenesis and

therapy. J Invest Dermatol 1994;102:128-37x Friedmann PS, Tan BB, Musaba E, Strickland I. Pathogenesis and

management of atopic dermatitis. Clin Exp Allergy 1995;25:799-806x Tan BB, Weald D, Strickland I, Friedmann PS. Double blind

controlled trial of house dust-mite allergen avoidance on atopicdermatitis. Lancet 1996;347:15-8

x Friedmann PS. Clinical aspects of allergic contact dermatitis. In:Kimber I, Maurer T, eds. Toxicology of contact hypersensitivity. London:Taylor and Francis, 1996:26-56

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Effect of avoiding house dust mite allergens on severity of atopic aczema.Individual scores before and after 6 months’ avoidance are connected byfine lines. Solid lines represent median scores for each group

Clinical review


ABC of allergiesFood allergyCarsten BindslevJensen

The public perceives food allergy differently fromdoctors—especially in relation to its symptoms and prevalence.In controlled scientific studies a low prevalence of food allergyhas been found in British and Dutch adults, whereas thepercentage of people perceiving their illness as being fooddependent is much higher. The prevalence in adults, confirmedby double blind, placebo controlled food challenge, has beenestimated to be 1.4%. This is in contrast to findings in children,in whom the overall prevalence of IgE mediated food allergiesis 57%.

DefinitionsAdverse reactions to foods may be classified as due to eithertrue food allergy or nonallergic food intolerance. In contrast,food aversion refers to symptoms that are often nonspecificand unconfirmed by double blind, placebo controlled foodchallenge.

A true food allergy is a disorder in which ingestion of asmall amount of food elicits an abnormal immunologicallymediated clinical response. Food may cause allergic reactions byseveral mechanisms. The classic type I, IgE mediated reaction isthe most thoroughly studied and potentially important in viewof the risk of life threatening reactions in some people.Evidence is increasing, however, for an important role fordelayed reactions (classic type IV mediated reactions). Forexample, eczema in children may be exacerbated by milkingestion, and a small proportion of adults with severe contactdermatitis due to nickel may react to nickel in their diet.

Nonallergic food intolerance may be due topharmacological, metabolic, and toxic causes. Pharmacologicalcauses may provoke anaphylactoid reactions, flushing,hypotension, and urticaria. This can happen with foods with ahigh histamine content (for example, scombroid poisoning dueto ingestion of brown oily fish (mackerel, tuna, etc) that has goneoff). Tyramine in cheese or red wine may provoke or exacerbatemigraine. Monosodium glutamate may provoke flushing,headache, and abdominal symptoms (the Chinese restaurantsyndrome). Lactase deficiency in young children is an exampleof nonallergic food intolerance due to a metabolic cause, and itmanifests as abdominal symptoms and chronic diarrhoea afteringestion of milk. Toxic reactions to foods may be due tocontamination of food by chemicals or bacterial toxins.

Much overlooked is the harmless, nonimmunologicallymediated, immediate perioral flare reaction (nonimmunologicalcontact urticaria) to, for example, benzoic acid from citrus fruitsin children (especially those with atopic dermatitis). Parents anddoctors may misinterpret this response in a child as an allergyand unnecessarily stop the child from eating citrus fruits. Foodadditives and colourings may elicit an acute flare up reaction ofurticaria and, more rarely, gastrointestinal symptoms, with orwithout exacerbation of urticaria, asthma, or rhinitis. Additivesinclude benzoates, salicylates, sulphites, and tartrazine and othercolourings. The diagnosis of these reactions should be suspectedin patients who develop symptoms on exposure to foods thatcontain preservatives—for example, meat pies, sausages and otherpreserved meats, dried fruits that contain sulphite, and manycommercially tinned and bottled foods. Preservatives may also be

Prevalence (%) of adverse reactions to foods in adults*

Town

Perceivedprevalencein adults

Confirmedprevalence†

High Wycombe 20.4 1.4

*Data from Young et al (Lancet 1994;112730).†With double blind, placebo controlled food challenge.

Types of adverse reactions to foods

x Food allergy due to IgE mediated mechanism (Coombs’classification, type I)

x Food allergy not involving IgE, in which other immunologicalmechanisms are implicated (for example, type IV)

x Nonallergic food intolerance (for example, pharmocological,metabolic, or toxic reactions to foods)

x Food aversion (symptoms are often nonspecific and unconfirmedby blinded food challenge)

Common products containing preservatives

Clinical review



sprayed on to salads to maintain freshness and are commonlypresent in alcoholic drinks and coloured fruit drinks. There areno diagnostic tests for reactions to preservatives or colourings.Diagnosis depends on suspicion and the use of elimination dietsor blinded challenges with capsules containing preservatives andplacebo capsules, or both of these approaches.

Symptoms and signs of adversereactions to foodsPatients with true IgE mediated food reactions generallyidentify either one or a limited number of specific foods thatprovoke symptoms, usually within minutes. A characteristicfeature is the oral allergy syndrome—itching and swelling in themouth and oropharynx followed, on further intake, byconcomitant symptoms and signs from two or more of thefollowing organ systems (the gastrointestinal tract, skin, andrespiratory system). Life threatening reactions may includeexacerbation of asthma, laryngeal oedema, and anaphylaxiswith cardiovascular collapse.

Offending foodsMany foods have been claimed to cause allergy, but controlledstudies show that a limited number of foods are responsible forthe vast majority of cases. Common allergenic foods includemilk, eggs, and peanuts in children; and fish, shellfish, nuts(especially peanuts), and fruit in adults. When clinicallyinsignificant cross reactions are excluded, most patients reactclinically to a few foods only. Food allergy may also result fromexposure to food in the workplace.

DiagnosisThe importance of a careful case history cannot beoveremphasised. The history, supported by diagnostic tests,should point towards a few possible offending foods or groupsof foods. A diagnostic diet period is helpful. Usually, a highlyrestricted diet is not necessary—elimination diets based onessential amino acids are expensive and unpalatable, resultingin low compliance. A diet period of two weeks is usuallysufficient, but a more prolonged period may be necessary,especially in the case of atopic dermatitis. To ensure thatpatients get sufficient nutrition while excluding suspected foodsfrom their diet, the help of a clinical dietitian with experience offood allergy should be enlisted.

“One man’s meat isanother man’s poison”

Factors suggesting classic IgE mediated food allergy

x Specific food(s) can be identifiedx Timing of symptoms is closely associated with food intakex Symptoms are typical and involve more than one organ (for

example, oral itching or swelling, nausea, vomiting, abdominal pain,diarrhoea, asthma, rhinitis, urticaria, angiooedema, anaphylaxis)

x Patient has a personal or family history of other atopic disorders

Common foods provoking food allergy

FoodCows’ milkHens’ eggsCodShrimpsPeanutsSoy beansWheatAdditives

Cross reacting foodsMares’ milk, goats’ milk, ewes’ milkEggs from other birdsMackerel, herring, plaice, etcOther crustaceansSoy beans,* green beans,* green peas*See aboveOther grains, most often ryeMostly unknown (both synthetic andnaturally occurring)

Patients allergic to pollen may have cross reactions with hazelnuts,green apples, peaches, almonds, kiwis, tomatoes, and potatoes* (birchpollen) or wheat,* rye,* and corn* (grass pollen)

*Without clinically significant serological cross reaction

Occupational food allergy

Type of reaction Characteristics Prevalence

Bakers’ asthma(IgE mediated)

Asthma and rhinitisby inhalation offlour

20% of bakers becomesensitised duringworking period of 20years

Contact urticaria(immunological)

Contact urticaria inpersons handlingfoods (eg, cooks) Unknown

Contact dermatitis Contact eczema inpersons handlingfoods (eg, cooks) Unknown

Patients allergic to birch pollen may have crossreactions with some foods (eg, apples, peaches)

Clinical review



TestingStandardised food extracts are rarely available for use in skinprick testing to diagnose food allergy. However, a few foodextracts have been validated in clinical trials in children andadults by using a double blind, placebo controlled foodchallenge as the gold standard. Foods that have been validatedin this way include cod, peanuts, cows’ milk, hens’ eggs, shrimps,and soy beans. In many cases it is better and more convenient touse fresh fruits for skin prick testing. A drop of liquid food or apiece of solid food is placed on the forearm and prickedthrough (the “prickprick” method).

The same reservations expressed for skin pricktesting—namely, poorly standardised food allergen extracts—arealso true for the various methods for determining serumconcentrations of allergenspecific IgE against food. Anothermajor problem with the newer and technically highly sensitivemethods is that they detect the many clinically insignificantserological cross reactions, in which IgE raised against anddirected towards epitopes on, for example, grass pollen, alsobinds to wheat proteins, but without any clinical significance ofthe finding.

The significance of reactions to patch testing is currentlybeing evaluated in several centres. However, before any new testis included for routine diagnosis, it should be validated inclinical trials with a double blind, placebo controlled foodchallenge as the gold standard.

Confirmation with oral food challengeDouble blind, placebo controlled food challenge may be neededto confirm the medical history of and positive diagnostic testsfor food allergy. Most published studies show that in an averageof 50% of patients whose medical history plus positive skinprick test result or positive IgE result suggest food allergy,allergy can be confirmed by a double blind, placebo controlledfood challenge. Using fresh foods masked in a vehicle is betterthan using freeze dried foods in capsules. In selected cases anopen challenge (that is, not double blind or placebo controlled)

Results of allergenspecific IgE should beinterpreted with caution, especiallyweakly positive results in patients withhigh serum concentrations of total IgE

Fresh fruit can be used for skin prick testing for fruit allergy

Cross reactivity between birch pollen and apple in patient withspringtime hay fever and oral allergy syndrome after ingestion ofapple

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Top: Effect on symptoms of introducing restricted diet (elimination ofsuspected offending food) then reintroducing normal diet then returning torestricted diet in a patient who was eventually confirmed as being allergic towheat and rye in a double blind, placebo controlled food challenge. Bottom:Effect on symptoms of a very strict elimination diet in a patient with atopicdermatitis. Although symptoms decreased initially, they had returned tonormal levels by week 10 (although the diet was still being maintained). If atweek 8 the patient had been given an open challenge or had returned to anormal diet, a food related exacerbation would have been suspected andfalse conclusions drawn. Especially in diseases with a high degree ofspontaneous fluctuations in severity of symptoms a double blind, placebocontrolled food challenge is mandatory, and care must be taken to avoidoverinterpretation of the results

The patient's history should point towards

a close relation between intake of a specific

food or additive and onset of symptoms

The symptoms described by the patient should be

of the "classic" atopic type (namely, immediate allergic

symptoms, most often from two or more organs)

Testing may be in vivo or in vitro — skin prick test,

specific IgE, basophil histamine release

A restricted, tailor made diet should result in the

disappearance of symptoms (or at least a

significant reduction)

The original symptoms should reappear during challenge;

an initial positive open challenge should be confirmed

by double blind, placebo controlled food challenge

Case history

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Clinical review



may be used; if the results are negative then the patient is notallergic to the offending food, whereas a positive result shouldbe confirmed by a further, double blind, placebo controlledfood challenge. Food challenges should be conducted only bystaff with specialist training and in the presence of a physician(or a paediatrician, for children aged under 16). They should beconducted cautiously, with incremental doses and with theimmediate availability of adrenaline (epinephrine) and otherresuscitative measures in view of the small risk of a seriousallergic reaction.

TreatmentThe only treatment for food allergy is avoidance of theoffending food. Training patients to avoid a particular foodoften requires the help of a dietitian, clear written instructions,and advice about the labelling of foods. Many patients outgrowtheir clinical reactivity to a food (90% of infants allergic to milkdo so by the age of 3, and half of patients who are allergic toeggs do so, but most patients allergic to peanuts or cod do not).The diagnosis should therefore be reevaluated yearly.

Adrenaline is life saving in cases of anaphylaxis and shouldbe administered as early as possible. It is administered with auser friendly device (see later chapter on anaphylaxis), withcareful instruction of patients and, in the case of children, theirparents, schoolteachers, etc. Other antiallergy drugs, includingcromoglycate and glucocorticoids, have been investigated inclinical trials with conflicting results and are generallyunhelpful. Their use should be restricted to selected cases only,with specialist advice. Antihistamines are effective in relievingthe symptoms of the oral allergy syndrome but may mask initialwarning symptoms of a more severe reaction and shouldtherefore not be used.

Food aversionSymptoms that cannot be confirmed by double blind, placebocontrolled food challenge may none the less be very distressingfor patients and are likely to reflect a heterogeneous and largelyunexplained group of disorders that include food aversion(“food fads”). Such patients may present with atypical andnonspecific symptoms. Although they consider their symptomsto be food induced, they are often unable to identify specificfoods or they report foods that are not typical for inducing IgEmediated allergy. Early specialist referral and exclusion of anIgE dependent mechanism (and potential for serious reactions)may be reassuring for the patient and their general practitioner.

The possible role of food allergy in other diseases orbehavioural disorders is difficult to establish, althoughassociation is often easy to exclude on the basis of the historyand the results of diagnostic tests. It is unhelpful to dismiss outof hand the possibility that a patient’s symptoms are provokedby food. Equally it is inappropriate to interpret a clinicalpresentation as food allergy in the absence of any indication ofan immunological disorder.

Carsten BindslevJensen is associate professor in the department ofdermatology at Aarhus Marseilisborg Hospital, Aarhus, Denmark.


BMJ 1998;316:12991302

Prophylaxis with breast feeding or withdocumented, hypoallergenic hydrolysatesis effective against development of allergyto cows’ milk and of atopic dermatitis butwill not prevent later development ofinhalant allergies

Diseases without proved association to food intake

x Multiple chemical sensitivitiesx Chronic fatigue syndromex Rheumatoid arthritisx Hyperactivity disordersx Depressionx Crohn’s diseasex Serous otitis media

Further reading

x BruinjzeelKoomen CAFM, Ortolani C, Aas K, BindslevJensen C,Bjorksten B, Moneret Vautrin DA, et al. Position paper. Adversereactions to foods. Allergy 1995;50:62336

x Høst A. Cow’s milk protein allergy and intolerance in infancy. Someclinical, epidemiological and immunological aspects. Pediatr AllergyImmunol 1994;5(suppl):536

x Lahti A. Nonimmunological contact urticaria. Arch Dermatol1980;60(suppl 91):149

x BindslevJensen C, Poulsen LK. In vitro diagnostic methods in thediagnosis of food hypersensitivity. In: Metcalfe DD, Sampson H,Simon RA, eds. Food allergy: adverse reactions to foods and foodadditives. 2nd ed. Oxford: Blackwell Science, 1996:13750

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Clinical review



ABC of allergiesVenom allergyPamela W Ewan

Stings from bees and wasps, the most common stinging insectsin Britain, can cause severe allergic reactions, includinganaphylaxis. Coroners’ data suggest that an average of fourdeaths from bee or wasp stings occur each year in the UnitedKingdom, but this is almost certainly an underestimate becausevenom anaphylaxis is not always recognised as the cause ofdeath.

Hymenoptera insectsClassificationThe hymenoptera are subdivided into families, including theApidae (honey bees and bumble bees) and the Vespidae (wasps,hornets, and paper wasps). In Britain most reactions are causedby stings from wasps (the Vespula species) rather than frombees. Reactions to bee stings are almost always associated withthe honey bee.

VenomsBee and wasp venoms are different, each containing distinctmajor allergens, which are well defined. Phospholipase A2 andmellitin occur only in bee venom, and antigen 5 only in waspvenom, but both venoms contain hyaluronidases. Patientsallergic to wasp venom are rarely allergic to bee venom.

SensitisationMost people, unless they have a specific occupational risk, arerarely stung by wasps, perhaps once every 1015 years.Sensitisation to wasp venom requires only a few stings, and canoccur after a single sting.

In contrast, allergy to bee venom occurs mainly in peoplewho have been stung frequently by bees. Thus almost allpatients who are allergic to bees are beekeepers or theirfamilies, or sometimes their neighbours.

Clinical featuresThe normal effect of a bee or wasp sting is to cause intense localpain, some immediate erythema, and often a small area (up to1 cm diameter) of oedema. Allergic reactions can be either localor generalised.

Local reactionsLocal reactions involve oedema at the site of the sting. Thiscomes on over several hours and varies in size, but it can affect ahand or even an entire limb. In a dependent area this can leadto blistering and sometimes secondary infection. Such oedemais not dangerous unless it affects the airway.

Generalised reactionsGeneralised (or systemic) reactions vary greatly in severity. Earlyfeatures are erythema and pruritus, followed by urticaria andfacial or generalised angiooedema. Patients with more severegeneralised reactions often feel extremely ill, as if they are goingto die (“a sense of impending doom”). Dyspnoea often occursand can be due either to laryngeal oedema or to asthma. In

Honey bee (Apis mellifera): 1.5 cm long, fairly hairy and brownwith abdominal bands

Wasp, also known as yellow jacket (Vespula spp): <1.5 cm long;yellow and black striped abdomen; typical waist; and little hair

Patient with angiooedema of the left forearm: localallergic reaction to a bee sting

Clinical review

1365BMJ VOLUME 316 2 MAY 1998 www.bmj.com


severe reactions hypotension occurs, causing lightheadedness,giddiness, fainting, or loss of consciousness. Other less commonfeatures are abdominal pain, incontinence, central chest pain, orvisual disturbances.

The clinical picture is variable—patients may have onlyerythema, urticaria, and angiooedema or may develop loss ofconsciousness, with few warning symptoms, within minutes of asting. The onset of generalised reactions is early, usually within10 minutes of a sting.

DiagnosisVenom allergy is diagnosed from the history of the allergicreaction, backed up by tests for venomspecific IgE antibodies. Itis important to check the basis of the patient’s assertion aboutthe type of insect responsible for the sting. Many patients saythe sting is from a bee when it is in fact a wasp sting. The vastmajority of patients (except beekeepers etc) will be waspallergic. Accurate diagnosis is important as it has implicationsfor management.

The history should be confirmed by demonstrating, by skintest or blood test, specific IgE; this is essential if desensitisationis considered as a treatment. Skin tests—either skin prick tests orintradermal tests with bee and wasp venom and the appropriatepositive and negative controls—are more accurate but should bedone by allergists as skin tests for venom are more difficult tointerpret than skin tests for inhaled allergens. Alternatively,serum beespecific and waspspecific IgE can be measured by aradioallergosorbent test (RAST), CAPRAST, or other assays.

It is important to be aware that since the introduction of themore sensitive CAPRAST, there have been more (up to 30%)false positive results—that is, patients with serum IgE to bothbee and wasp venom (double positives) when they are allergicto only one venom. However, double positives can occur evenwith the radioallergosorbent test (in about 6% of cases). Theterm allergy refers to a state of clinical reactivity and is not thesame as sensitisation (presence of specific IgE antibodies), whichcan occur without clinical reactivity. Patients are rarely allergicto both bee and wasp venom. This means that if the history isnot checked, and venom IgE to only a single venom ismeasured, the wrong diagnosis can result. Studies in the generalpopulation show that some subjects who have a history of stingsbut no reactions have venomspecific IgE.

Acute managementLocal reactionsAcute management should be with oral antihistamines, whichmay be required for several days. A quick acting drug should beused (for example, one of the newer, nonsedativeantihistamines). Very large swellings may require intramuscularantihistamines and steroids. Prevention is more effective, andthe patient should take a large dose of an antihistamine (doublethe standard dose) immediately after being stung, before thelocalised reaction is established, to abrogate incipientangiooedema.

Generalised allergic reactionsManagement depends on the severity and the particularfeatures of the reaction, as for any systemic allergic reaction.Cutaneous reactions require oral antihistamines or injectedchlorpheniramine. Moderate reactions often requireintramuscular chlorpheniramine and hydrocortisone, andtreatment for asthma—for example, inhaled â2 agonists—maybe necessary. Severe reactions, including those with marked

Natural course

x A substantial proportion of patients (2080% in different studies)with a history of a generalised reaction to a sting have no suchreaction to a subsequent sting—that is, spontaneous improvement iscommon

x Less severe generalised reactions may also occurx However, the course can be variable—a series of stings may result in

a generalised reaction, no reaction, and then another generalisedreaction

x Children do particularly well: one study showed that 95% of thosewith a history of mild generalised reactions had no reaction to asubsequent sting

x The next sting will not necessarily cause a more severe reaction, butpatients in accident and emergency departments are often told thatit will

x Reasons for the variable outcome are not well understood butinclude the interval from the last sting (the longer the interval thelower the risk of another generalised reaction), the patient’simmune response at the time of the sting (this will change withtime), the dose of venom injected, and the site of the sting

Drugs used in acute management of reactions to stings

Type of reaction Treatment

Local* Antihistamines (oral)

Systemic†:

Mild Antihistamines (oral or intramuscular)

Moderate Antihistamines (intramuscular); hydrocortisone(intramuscular); inhaled â2 agonist (if asthma);inhaled adrenaline (if laryngeal oedema)

Severe Adrenaline (intramuscular); chlorpheniramine(intramuscular or slow intravenous);hydrocortisone (intramuscular or slowintravenous)

The distinction between categories of systemic reaction may be blurred. If indoubt, treat as for the most severe category.*Treatment is usually required for several days.†Single dose is often sufficient.

Patient with angiooedema and blistering of the ankle:local allergic reaction to a bee sting

Clinical review

1366 BMJ VOLUME 316 2 MAY 1998 www.bmj.com


respiratory difficulty or hypotension, should be treated withadrenaline (intramuscular) followed by chlorpheniramine andhydrocortisone. Other measures, including intravenous fluids,may also be required, but, provided that treatment is startedsoon after the onset of the reaction, the drugs above are usuallyall that are needed.

Further managementAfter a generalised reaction, patients need further advice andideally should be referred to an allergy clinic specialising invenom allergy. As there are not many of these in Britain,general practitioners should be aware that there are two optionsfor further management: patients can either be desensitised orbe given the appropriate drugs to treat a reaction themselves.To choose the appropriate management, it helps to classifygeneral reactions by severity.

Who should be desensitised?

Desensitisation (immunotherapy)Among patients with generalised reactions, those with severereactions usually require desensitisation, those with mildreactions do not, and those with moderate reactions may ormay not. Other factors—such as the risk of a future sting, theinterval from the last sting, other medical problems, the abilityof the patient to treat himself or herself, and access to medicalhelp—may influence the decision.

Before desensitisation is given the nature of the sting mustbe accurately diagnosed and venomspecific IgE demonstrated.

The indications in Britain for desensitisation areconservative (in some countries any patient with a generalisedreaction, no matter how trivial, would be desensitised). This isbecause, although immunotherapy for hymenoptera venom ishighly effective, the high incidence of spontaneousimprovement, as well as the side effects of treatment, has to betaken into account. Venom immunotherapy carries a risk (ofabout 10%) of inducing systemic allergic reactions and canproduce anaphylaxis. It should therefore be performed only inspecialist centres treating an adequate number of patients eachyear.

Self medication for future reactionsThose not being desensitised should be given oralantihistamines to take if they are stung again. They should takethe antihistamines as soon as they are stung to modify or abortreactions. In a patient with a mild generalised reaction this isnormally sufficient. Those with moderate or severe reactionsshould also be given syringes preloaded with adrenaline. Theyadminister a dose of 0.3 mg (0.3 ml of 1/1000 strength)intramuscularly for adults and children from age 5 years. Asyringe containing a smaller dose (0.15 mg) suitable foryounger children is available, but children with venom allergyrarely need this. If other drugs are required these should begiven by doctors or paramedics. All patients should seek theassistance of an adult as soon as they are stung, in case medicalhelp is required.

What does immunotherapy involve?Various regimens are available. Conventional immunotherapy,the standard one, entails an initial course of weekly injectionsover three months, starting with low doses of venom andreaching the highest dose of 100 ìg (equivalent to two stings).Thereafter, maintenance injections of the same dose are givenat monthly or longer intervals for three years. The treatmentcan be given only in specialist centres, where resuscitation

Adrenaline (intramuscular) is the keydrug for severe reactions

Classification of systemic allergic reactions to bee or waspstings

Severity Symbol Reactions

Mild + Erythema, pruritus, urticaria,angiooedema, rhinitis, nausea

Moderate + + Asthma, angiooedema, abdominal pain

Severe + + + Respiratory difficulty (laryngeal oedemaor asthma), marked hypotension,collapse, loss of consciousness

Indications for venom immunotherapy

Type of reactionVenomspecificIgE

Venomimmunotherapy

Severe systemic(cardiovascular and/orrespiratory symptoms)

Positive Yes

Moderate systemic(angiooedema, mildasthma, orlightheadedness etc)

Positive Sometimes, butusually not

Mild systemic (urticaria,angiooedema)

Positive No

Syringes preloaded with adrenaline (forexample, EpiPen or Anapen (which isavailable on a named patient basis)) areavailable by using the standardprescription form

Value of self medication

x The main advantage of self medication is that reactions are treatedonly if they occur

x This is sensible because most patients (except beekeepers) are notstung again for years, and the next sting may cause no reaction or aless severe one

x The disadvantage is that one cannot be certain that the appropriatedrugs (especially adrenaline) will be given (early treatment ofanaphylaxis is highly effective)

x The decision on self medication should be reached on an individualbasis after balancing all factors and bearing in mind thatdesensitisation is not without risk

Clinical review



facilities exist, to conform with the guidelines of the Committeeon the Safety of Medicines (1986 and 1994), because of the riskof side effects. Drugs to treat anaphylaxis must be immediatelyavailable, and patients have to be kept under observation forone hour after each injection.

Mechanism of immunotherapyT cells secrete cytokines which orchestrate the immuneresponse. T helper (Th) cells are subdivided into Th1 and Th2subsets, on the basis of their cytokine secreting profile inresponse to stimulation with antigen or allergen.

It has been shown that venom immunotherapy leads tomarked changes in cytokine secretion patterns, with a switchfrom the abnormal Th2 cytokine response to a Th1 response.This may be due to downregulation of the Th2 response(anergy) or immune deviation in favour of a Th1 response, or toboth these. The Th2 subset of Th cells produces interleukin 4,interleukin 5, and interleukin 3, which are proallergic, leading toIgE synthesis (interleukin 4) and activating or attractingeosinophils (interleukin 5) and mast cells (interleukin 3). Venomimmunotherapy leads to loss of secretion of Th2 cytokines inresponse to venom stimulation, and, instead, Th1 cytokineproduction (interleukin 2 and interferon gamma) is induced.Interferon gamma opposes the effect of interleukin 4 ininducing B cells to secrete IgE.

This cytokine switch will lead in the long term to loss of IgEsynthesis and the allergic response but does not explain the factthat, clinically, desensitisation occurs before these changes takeplace. This suggests that other, earlier operating mechanismsare involved.

The table on classification of systemic reactions is adapted from Allergy andAllergic Diseases, Kay AB, ed (Insectsting allergy (Ewan PW)): BlackwellScience, 1997.

Pamela W Ewan is a Medical Research Council clinical scientist andhonorary consultant in allergy and clinical immunology atAddenbrooke’s Hospital, Cambridge.


BMJ 1998;316:13658

Can we predict the outcome of a future sting?

x There is no blood test that will reliably predict how a patient willreact to a future sting

x No direct correlation exists between the concentration ofvenomspecific IgG in the serum and protection from the next sting

x There may be no reaction to a sting in spite of the presence ofvenom IgE

x Venom IgE will eventually disappear, but this can take many years.Once it has disappeared completely—both from the serum andfrom the mast cells—a sting cannot produce a reaction

x Provocation tests are done either with a real sting or with asubcutaneous injection of pure venom. These are the only tests thatwill reliably show a patient’s reactivity, but, although they are veryuseful, they are not very practicable. Their use is restricted tospecialist centres, and they are useful in research

Further reading

x Egner W, Ward C, Brown DL, Ewan PW. The incidence and clinicalsignificance of specific IgE to both wasp (vespula) and bee (apis)venom in the same patient. Clin Exp Allergy 1998;28:2634

x McHugh SM, Deighton J, Stewart AG, Lachmann PJ, Ewan PW. Beevenom immunotherapy induces a shift in cytokine responses froma TH2 to a TH1 dominant pattern: comparison of rush andconventional immunotherapy. Clin Exp Allergy 1995;25:82838

x Kampelmacher MJ, van der Zwan JC. Provocation test with a livinginsect as a diagnostic tool in systemic reactions to bee and waspvenom: a prospective study with emphasis on the clinical aspects.Clin Allergy 1987;17:31727

x Valentine MD, Schuberth KC, KageySobotka A, Graft DF,Kwiterovich KA, Szkalo M, et al. The value of immunotherapy withvenom in children with allergy to insect stings. N Engl J Med1990;323:16013

x Kay AB, ed. Position paper on allergen immunotherapy: report of aBritish Society for Allergy and Clinical Immunology Working Party.Clin Exp Allergy 1993;23(suppl 3):1922

Immunotherapy is expensive and timeconsuming

A memorable patient

Do I say anything?

An accidental meeting in a village street with a former member ofour practice team walking her few months’ old baby . . . a generalchat while glancing at the baby, a lovely placid child with roundface and rather full lips. A second look showed a rather largeprominent tongue. We continued to chat and I looked again atthe babe several times. This was before the days of screening forcongenital hypothyroidism. Thoughts of a strange face, “Could itbe hypothyroid?”, but I am not their doctor. Should I sayanything? Continue chatting and say goodbye. Dilemma stillunresolved. Over the next couple of days the baby’s face keptcoming back to me. I had really better say something to themother. She had moved and no one knew her telephone number.While still trying to find her number she rang. “I noticed youlooking strangely at my baby and I took her to my doctor. Hethinks she is hypothyroid. Thank you very much for noticing.”

I am the proud owner of before and after treatmentphotographs, but with some guilt.

Gordon Barclay, medical adviser, Barking and Havering HealthAuthority

We welcome articles up to 600 words on topics such asA memorable patient, A paper that changed my practice, My mostunfortunate mistake, or any other piece conveying instruction,pathos, or humour. If possible the article should be supplied on adisk. Permission is needed from the patient or a relative if anidentifiable patient is referred to. We also welcome contributionsfor “Endpieces,” consisting of quotations of up to 80 words (butmost are considerably shorter) from any source, ancient ormodern, which have appealed to the reader.

Clinical review



ABC of allergiesAnaphylaxisPamela W Ewan

Anaphylaxis and anaphylactic death are becoming morecommon and particularly affect children and young adults.Anaphylaxis can be frightening to deal with because of its rapidonset and severity. Doctors in many fields, but particularly thoseworking in general practice and in accident and emergencydepartments, need to know how to treat it.

DefinitionAnaphylaxis means a severe systemic allergic reaction. Nouniversally accepted definition exists because anaphylaxiscomprises a constellation of features, and the argument arisesover which features are essential features. A good workingdefinition is that it involves one or both of two severe features:respiratory difficulty (which may be due to laryngeal oedema orasthma) and hypotension (which can present as fainting,collapse, or loss of consciousness). Other features are usuallypresent.

The confusion arises because systemic allergic reactions canbe mild, moderate, or severe. For example, generalised urticaria,angiooedema, and rhinitis would not be described asanaphylaxis, as neither respiratory difficulty norhypotension—the potentially life threatening features—ispresent.

MechanismAn allergic reaction results from the interaction of an allergenwith specific IgE antibodies, bound to Fc receptors for IgE onmast cells and basophils. This leads to activation of the mast celland release of preformed mediators stored in granules(including histamine), as well as of newly formed mediators,which are synthesised rapidly. These mediators are responsiblefor the clinical features. Rapid systemic release of largequantities of mediators will cause capillary leakage and mucosaloedema, resulting in shock and asphyxia.

Anaphylactoid reactions are caused by activation of mastcells and release of the same mediators, but without theinvolvement of IgE antibodies. For example, certain drugs actdirectly on mast cells. For practical purposes (management) it isnot necessary to distinguish an anaphylactic from ananaphylactoid reaction. This difference is relevant only wheninvestigations are being considered.

IncidenceHardly any data exist on the overall incidence of anaphylaxis.One recent study examining cases of anaphylaxis presenting toan accident and emergency department in Cambridge (towhich all cases from a defined area would be brought) foundthat 1 in 1500 patients attending the department hadanaphylaxis with loss of consciousness or collapse (equivalent to1 in 10 000 a year in the population) and that the rate almosttrebled when systemic allergic reactions with respiratorydifficulty were included. Most other data relate to specificcauses—for example, anaphylaxis due to allergy to penicillin orto anaesthetic drugs—and are quite variable.

Features of anaphylaxis

x Erythemax Pruritus (generalised)x Urticariax Angiooedemax Laryngeal oedemax Asthmax Rhinitisx Conjunctivitisx Itching of palate or external auditory meatusx Nausea, vomiting, abdominal painx Palpitationsx Sense of impending doomx Fainting, lightheadednessx Collapsex Loss of consciousness

Effects of mast cell mediators

Physiologicaleffect

Clinical expression Danger

Capillary leakage Urticaria

Angiooedema

Laryngeal oedema Asphyxia

Hypotension Shock

Mucosal oedema Laryngeal oedema Asphyxia

Rhinitis

Asthma Respiratory arrest

Smooth musclecontraction

Asthma Respiratory arrest

Abdominal pain

Mediator release

Granules contain

stored mediators

(eg, histamine)

Mast cell

Fc receptor for IgE

Specific IgE antibody

Allergen

Activation of

mast cell

Activation of mast cells by allergen crosslinking of adjacent IgE on cellsurface in a type I allergic reaction

Clinical review



AetiologyFoods are the commonest cause of anaphylaxis, and evidencesuggests that this is an increasing problem, now documentedfor allergies to peanuts and other nuts. Insect venom is the nextmost common cause of anaphylaxis. A rapidly increasingproblem is allergy to latex rubber. This is probably related tothe enormous increase in the use of latex rubber gloves bymedical and paramedical staff, as well as to the increase inatopy. Rare causes include exercise, vaccines, and semen.Allergen immunotherapy (desensitisation) may induceanaphylaxis.

Clinical featuresIt is important to recognise that the picture will vary with thecause. When an allergen is injected systemically (insect stings,intravenous drugs) cardiovascular problems, especiallyhypotension and shock, predominate. This is especially truewhen large boluses are given intravenously, as at induction ofanaesthesia. Foods that are absorbed transmucosally (from theoral mucosa down) seem especially to cause lip, facial, andlaryngeal oedema. Respiratory difficulty thereforepredominates. With severe reactions onset occurs soon afterexposure (within minutes), and progression is rapid.

Latex rubber anaphylaxis—unusually—develops more slowly(30 minutes or longer from the time of exposure), as theallergen has to be absorbed through the skin or mucosa (forexample, during abdominal or gynaecological surgery, vaginalexamination, dental work, or simply contact with, or wearing,rubber gloves). Healthcare workers are especially at risk.

InvestigationsThe only immediate test that is useful at the time of reaction ismast cell tryptase. Tryptase is released from mast cells in bothanaphylactic and anaphylactoid reactions. It is an indicator ofmast cell activation but does not distinguish mechanisms orthrow light on causes. It is usually but not always raised in severereactions but may not be in less severe systemic reactions. Asmast cell tryptase is only raised transiently, blood should betaken when it peaks at about an hour after the onset of thereaction. This test remains to be fully evaluated.

Common causes of anaphylaxis

x Foodsx Bee and wasp stingsx Drugsx Latex rubber

Foods commonly causing anaphylaxis

x Peanutsx Tree nuts (eg, brazil nut, almond, hazelnut)x Fishx Shellfishx Eggx Milkx Sesamex Pulses (other than peanuts)

Drugs causing anaphylaxis or anaphylactoid reactions

x Antibiotics (especially penicillin)x Intravenous anaesthetic drugsx Aspirinx Nonsteroidal antiinflammatory drugsx Intravenous contrast mediax Opioid analgesics

Allergy to latex rubber is common in healthcare workers

Four brief case historiesCase 1—Woman aged 30, six months pregnantx Trigger: Chinese mealx Symptoms and treatment: one hour after start of mealfelt faint; mild asthma; severe dyspnoea and laryngealoedema; loss of consciousness; taken to accident andemergency department after 10 minutes; on arrivalcyanosed, respiratory arrest; periorbital oedema;salbutamol infusion; cardiac arrest four minutes later;adrenaline given; intubated with difficulty and ventilated

x Recovered (see figure next page)x Cause: allergy to green pepper

Case 3—Boy aged 8 monthsx Trigger: Tiny quantity of peanut butterx Symptoms: blisters around mouth; distressed; vomiting;dyspnoea; urticaria

x Cause: allergy to peanuts

Case 2—Woman aged 30x Trigger: one teaspoonful mueslix Symptoms and treatment: immediate itching of mouth; throat swollenand uncomfortable inside; vomited; dyspnoea (could not breathe,different from her asthma); laryngeal oedema (obstruction in throat);lightheaded; no loss of consciousness; used her own salbutamol inhaler(no effect); taken to accident and emergency department; respiratorydistress; intense erythema and generalised urticaria; givenintramuscular adrenaline and chlorpheniramine

x Rapid recoveryx Cause: allergy to brazil nuts and hazelnuts

Case 4—Woman aged 26x Trigger: vaginal examinations during labourx Symptoms: itching of vulva; oedema of labia; generalised urticaria andpruritus; mild dyspnoea; felt woozy, lightheaded, odd, shaking

x Cause: allergy to latex rubber

Clinical review



ManagementAdrenaline (epinephrine) is the most important drug foranaphylaxis and should be given intramuscularly. It is almostalways effective.

This should be followed by chlorpheniramine andhydrocortisone (intramuscular or slow intravenous). This isusually all that is required, provided that treatment is startedearly. Treatment failure is more likely if administration ofadrenaline is delayed. Biphasic reactions have been describedbut are probably rare; administration of hydrocortisone shouldminimise the risk of late relapse.

Difficulties may arise if the clinical picture is evolving whenthe patient is first assessed. Adrenaline should be given to allpatients with respiratory difficulty or hypotension. If thesefeatures are absent but there are other features of a systemicallergic reaction, it is appropriate to give chlorpheniramine andhydrocortisone and reassess. If in doubt, give 500 ìg adrenalineintramuscularly in an adult or the appropriate dose in a child.

There can be risks associated with intravenous adrenaline.Adrenaline should not be given intravenously except underspecial circumstances: profound shock (which is immediatelylife threatening) or during anaesthesia. Even then, if intravenousadrenaline is given, a dilute solution (1 in 10 000) must beadministered very slowly in aliquots (with a maximum initialdose of 100 ìg (that is, 1 ml)) with cardiac monitoring. Suchtreatment therefore is rarely indicated outside hospital.

Although myocardial infarction has been reported in theliterature as being associated with the use of adrenaline, thisreflects a bias in reporting, as the effective and safe use ofadrenaline is not considered worth reporting. Those with wideexperience of its use find adrenaline extremely safe.

â Blockers may increase the severity of an anaphylacticreaction and may antagonise some of the beneficial actions ofadrenaline. However, if a patient with anaphylaxis is taking â

blockers this should not prevent the use of adrenaline.

Supporting treatmentsIf the patient has hypotension then he or she should lie flat withthe legs raised, but if respiratory difficulty is the dominantproblem it may be better for the patient to sit up. Oxygenshould be administered.

An inhaled â2 agonist should be given if there is asthma.Inhaled adrenaline is effective for mild to moderate laryngealoedema but would not be given if intramuscular adrenaline hadalready been given as first line treatment, and it is not asubstitute for intramuscular adrenaline. If drugs are not rapidlyeffective for shock, intravenous fluids should be given rapidly.

Drug treatment of anaphylaxis in adults

x Intramuscular adrenaline 0.5 ml (500 ìg), 1 in 1000 solution(1 mg/ml)

x Intramuscular or slow intravenous chlorpheniramine 10 mgx Intramuscular or slow intravenous hydrocortisone 200 mg

Doses of intramuscular adrenaline in children

Age (years)Volume of 1 in 1000strength (1 mg/ml) Dose (ìg)

1 0.1 ml 100

23 0.2 ml* 200

47 0.3 ml* 300

811 0.4 ml* 400

> 11 0.5 ml* 500

This is a guide based on average weight for different age bands. No evidenceexists for particular doses for different age bands, and published schedulestherefore differ.

*Reduce dose in children of below average height.

Do not give adrenaline intravenouslyexcept in special circumstances(see text)

Key to management of anaphylaxis

x Awarenessx Recognise it (consider in differential diagnosis)x Treat quicklyx Deaths in otherwise healthy young people could then be avoided

Anaphylaxis is easily treatable, andpatients can make a complete recovery

Entry in patient’s hospital notes (case 1, box previous page) 9 hours after anaphylaxis with cardiorespiratory arrest, showing effectiveness of prompt treatment

Clinical review



Long term managementPatients are commonly sent home from accident andemergency departments without further advice. Patients are notinfrequently given an ampoule of adrenaline or a preloadedadrenaline syringe without instruction. This is of little or novalue and frightens patients.

It is important to refer patients to an allergist— ideally, onewith expertise in anaphylaxis. The cause should be determined,and advice given on avoidance to prevent further attacks. Thecause is determined by taking a detailed and structured allergyhistory, then, in the case of IgE mediated reactions, confirmed(for most allergens) by skin prick tests. The cause is sometimesobvious from the history (as in case 3, previous page, where atypical reaction immediately followed ingestion of peanutbutter). In case 1 the cause was also indicated by the history asthere had been two allergic reactions, the first milder one after a“ploughman’s lunch” with few ingredients and the second aftera large Chinese meal containing at least six suspected allergens.Green pepper was the common factor. Skin tests (directlythrough the flesh of green pepper and also with an aqueousextract of green pepper that we prepared) were stronglypositive, confirming the diagnosis.

Early self treatment is highly effective, and reactions canusually be stopped easily. Syringes preloaded with adrenalineare easy for patients to use and readily available. They deliverfixed intramuscular doses and are available in two strengths: foradults (containing 0.3 ml of 1 in 1000 strength (that is, 300 ìg))and for children (0.3 ml of 1 in 2000 (150 ìg)). The appropriateself treatment varies and may include other drugs. This shouldbe determined by a specialist as, once a cause is determined andavoidance measures are in place, further reactions afterinadvertent exposure are usually less severe. A writtentreatment plan should be provided by the allergist, and thepatient (and relatives) should be taught how and when to usethe treatments provided—for example, trainer syringes areavailable.

To be of help to children, schools and nurseries needtraining. Some allergists have developed links with communitypaediatricians, whose teams are best placed to deliver training.This requires expertise, which is now developed in only a fewcentres. The team in Cambridge is therefore coordinating theproduction of national guidelines.

If there is no local allergist the general practitioner or thedoctor in the accident and emergency department shouldprovide the drugs for self treatment, but it is essential that theseare given with advice and training. Practice nurses should havetrainer syringes for this purpose.

Pamela W Ewan is a Medical Research Council clinical scientist andhonorary consultant in allergy and clinical immunology atAddenbrooke’s Hospital, Cambridge.


BMJ 1998;316:14425

What to do after an anaphylactic reaction

Action Aim

Take blood at 15 hours formeasurement of mast celltryptase

To confirm anaphylaxis oranaphylactoid reaction

Refer to an allergy clinic todetermine cause

To prevent further attacks

Organise self treatment of futurereactions (best done by anallergist)

To prevent morbidity (earlytreatment is the key)

Some patients who have had ananaphylactic reaction wear a Medic Alertbracelet or necklace—with an inscriptionendorsed by a doctor that alerts otherdoctors to the possible cause of anyfuture reaction

Further reading

x Stewart AG, Ewan PW. The incidence, aetiology and managementof anaphylaxis presenting to an accident and emergencydepartment. Q J Med 1996;89:85964

x Fisher MMcD, Baldo BA. The incidence and clinical features ofanaphylactic reactions during anaesthesia in Australia. Ann FrAnesth Reanim 1993;12:97104

x Ewan PW. Clinical study of peanut and nut allergy in 62 consecutivepatients: new features and associations. BMJ 1996;312:10748

x Turjanmaa K, Alenius H, MakinenKiljunen S, Reunala T, Palosuo T.Natural rubber latex allergy. Allergy 1996;51:593602

x Vickers DW, Maynard L, Ewan PW. Management of children withpotential anaphylactic reactions in the community: a trainingpackage and proposal for good practice. Clin Exp Allergy1997;27:898903

Preloaded adrenaline syringes are available for self treatment of anaphylaxis

Clinical review



abc of allergies

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