Current Allergy & Clinical Immunology · 2017-10-26 · 54 Current Allergy & Clinical Immunology,...

Current Allergy & Clinical Immunology, June 2009 Vol 22, No. 2 53

CONTENTS

Current Allergy &Clinical Immunology

54 Congress issue: food allergy,drug allergy and anaphylaxisC Motala

GUEST EDITORIAL

82, 95, 96, 97, 99

PRODUCT NEWS

80 ALLSA oral presentations

82 ALLSA poster presentations

ALLSA CONGRESS ABSTRACTS

100 Earn 3 CPD points

CPD QUESTIONNAIRE

Editors Prof. Eugene G WeinbergProf. Heather J Zar

Founding Editor Prof. Paul C Potter

Production Editor andAdvertising ExecutiveAnne Hahn

Editorial Advisory BoardDr C Buys (Namibia)Dr G du ToitProf. R GreenProf. M HausProf. M JeebhayDr N KhumaloDr S KlingDr A LopataDr A ManjraDr A MorrisProf. C MotalaDr C Obihara (The Netherlands)Prof. P PotterDr A PutermanProf. G Todd

ContributionsThe editors encourage articles, let-ters, news and photographs relatingto the field of allergy and clinicalimmunology. Enquiries should beaddressed to: The Editors, CurrentAllergy & Clinical Immunology,Allergy Society of South Africa, POBox 88, Observatory 7935 SouthAfrica.Tel: 021 447 9019, Fax: 021 448 0846,Website: www.allergysa.orgE-mail: [email protected]

Accredited by the Department ofEducation

The views expressed in this publica-tion are those of the authors and notnecessarily those of the sponsors orpublishers. While every effort hasbeen made to ensure that the con-tents of this journal are both accurateand truthful, the publisher and editorsaccept no responsibility for inaccu-rate or misleading information thatmay be contained herein.

Cover: Fresh fruit

Courtesy: Dr H Steinman

Printed by Tandym PrintRepro by C2 Digital

ISSN 1609-3607

Sponsorship & SupportCurrent Allergy & Clinical Immunology is the official journal of the Allergy

Society of South Africa and is produced as a service for health care

workers to improve understanding and communication in the field of

allergy. Publication of the journal is made possible by the generous

financial and other support offered by the following pharmaceutical and

diagnostic companies.

The Allergy Society of South Africa gratefully acknowledges support from

these companies:

Abbott • AHN Pharma • AstraZeneca •Boehringer Ingelheim • Cipla Medpro •

GlaxoSmithKline • Laboratory Specialities •Miele • MSD • Nestlé • Novartis •

Schering-Plough

93 S Kling

CHAIRMAN’S REPORT

89 Allergy examinationS Emanuel, D Hawarden

ABC OF ALLERGOLOGY

84 Allergic contact dermatitis inthe food industry – from agricul-ture to food processing andmanufacture: A case study of adairy farmerA Burdzik

ALLERGIES IN THE WORKPLACE

91 Dietary exclusions for established atopic eczemaT Young

EVIDENCE-BASED HEALTH CARE

56 Food protein-induced enterocolitis syndrome L-A van der Poel, A Fox, G du Toit

58 Oral allergy syndrome – what’snew?H Steinman

64 Penicillin allergy in childrenS Karabus, C Motala

67 Anaphylaxis in infants: canrecognition and managementbe improved?F E R Simons

71 H1 antihistamines in allergic diseaseC Motala

75 Asthma exacerbations – a reviewN Chetty

REVIEW ARTICLES

54 Current Allergy & Clinical Immunology, June 2009 Vol 22, No. 2

Allergic diseases, including asth-ma, rhinitis, conjunctivitis, der-matitis and food allergies, aremajor contributors to morbidityand sometimes cause mortalityin the developed world. Also,their incidence and severity arestill rising. Over the past de-cades, genetics together withboth basic and clinical immunolo-gy have made great strides in

understanding the disease processes in allergy. Thearticles in this edition of Current Allergy & ClinicalImmunology include aspects of food allergy, drug aller-gy and anaphylaxis, in line with the themes of thisyear’s ALLSA congress.

There have been significant advances in the under-standing of food proteins and recognition of gastro-intestinal syndromes in food allergy. Van der Poel et al.briefly discuss food protein-induced enterocolitis syn-drome (FPIES), a potentially life-threatening conditiondue to non-IgE-mediated food allergy (cow’s milk andsoya proteins are the common causes), with emphasison correct diagnosis, management and prognosis.

IgE antibodies to aeroallergens may cross-react withprotein in fresh fruit and vegetables to cause symp-toms that include oral pruritus, swelling of the lips,tongue and throat – the oral allergy syndrome (OAS).Steinman discusses new information about plant pro-teins including profilins, lipid transfer proteins andpathogenesis-related proteins, as well as the growinglist of pollen-food syndrome associations, and thepotential role of immunotherapy in the treatment ofOAS.

Drug allergy remains one of the most challenging areasin the field of allergology. This is partly related to thenumber of new drugs emerging on the market eachyear, but also to the various routes of administration,the presence of allergenic excipients in drugs and themisuse of antibiotics in general. Allergic reactions tothe penicillins and cephalosporins remain the mostcommon drug allergies. Penicillin allergy continues tobe misdiagnosed. Karabus and Motala outline a practi-cal approach to the diagnosis of penicillin allergy and itsmanagement.

Anaphylaxis is the most serious form of an allergic reac-tion, with food allergens being the most commoncause of this disorder. Simons presents an excellentoverview of anaphylaxis in children including a casereport, aetiology, differential diagnosis and manage-ment of this life-threatening condition. The use of self-injected adrenaline as first-aid treatment foranaphylaxis is emphasised.

H1-antihistamines remain first-line medication in thetreatment of allergic rhinoconjunctivitis and urticaria.Motala discusses the mechanism of H1-antihistaminesand advantages of the second-generation antihista-mines over their predecessors in the long-term man-agement of allergic diseases.

Cas MotalaGuest editor

Associate Professor, Paediatric Medicine, School ofChild & Adolescent Health, University of Cape Town &Red Cross War Memorial Children's Hospital,Rondebosch, Cape Town, South Africa

GUEST EDITORIAL

CONGRESS ISSUE: FOOD ALLERGY, DRUG

ALLERGY AND ANAPHYLAXIS

Current Allergy & Clinical Immunology has been accred-

ited for CPD points in the Clinical category, so you can

now earn 3 CPD points for Individual Learning. CPD

accreditation is only available through the online ser-

vice; no faxed or mailed responses will receive CPD

credits. To obtain CPD credits:

1. Read the journal.

2. Answer the questionnaire on p. 100 by accessing

the online CPD accreditation on the ALLSA website

at www.allergysa.org/cpd or follow the links from

the home page www.allergysa.org.

3. To register, you will need to enter your name, per-

sonal details, HPCSA number and a password.

4. Once you have registered, you will receive an email

confirming your registration. You can either answer

the questionnaire immediately or log on at a later

date to answer the questionnaire. Please note that

each questionnaire has a closing date – the closing

date for submission of the June 2009 questionnaire

is 30 September 2009.

5. Follow the instructions given on the questionnaire

page and online.

6. After you have submitted your answers, they will be

marked immediately, and you will be informed of

the results and the number of points earned.

7. At any time you will be able to see your current CPD

credits from the journal by logging on.

ONLINE CPD ACCREDITATION NOW

AVAILABLE FOR CURRENT ALLERGY

& CLINICAL IMMUNOLOGY


FOOD PROTEIN-INDUCED ENTEROCOLITIS

SYNDROME (FPIES) – A REVIEW

Lauri-Ann van der Poel, MB ChB, MRCPCH

Adam Fox, MA, MSc, MBBS, DCH, FRCPCH, FHEA,Dip Allergy

George du Toit, MB BCh, DCH, FCP(SA), FRCPCH,Dip Allergy, FAAAI

MRC & Asthma UK Centre in Allergic Mechanisms ofAsthma, Division of Asthma Lung Biology, Guy's and StThomas' NHS Foundation Trust, Kings College, London,UK

This brief review aims to summarise current knowl-edge of food protein-induced enterocolitis syndrome(FPIES).

PRESENTATION AND PREVALENCEThe presentation of FPIES varies from mild (e.g. non-dehydrating vomiting and/or diarrhoea) to severe andpotentially life-threatening symptoms. Symptom pro-gression may occur rapidly to a state of dehydration.Hypovolaemic shock is associated in up to 20% ofcases.1 A combination of vomiting, lethargy and resultingacidosis understandably – and necessarily – leads to aprimary diagnosis of sepsis. In this clinical scenario, thedietary history may not receive prominence with theresult that the syndrome recurs with each subsequentingestion of the food protein. Failure to recognise theassociation with diet may lead to multiple intensive orhigh-care admissions due to supposed recurrent sepsis.2

It is unclear whether prior ingestion of the food proteinis required in order to induce the FPIES ‘sensitivity’ orif symptoms can occur de novo. FPIES has only beendescribed in childhood, and in particular, early childhood(at the time of introduction of complementary feeds,i.e. breast-milk alternatives and/or solid foods).

The prevalence and incidence of FPIES are not known.Attempts to determine them are hampered by the vari-able presentation, under-recognition of the syndrome,infrequently performed diagnostic challenges and, per-haps, the rarity of the condition.

DIAGNOSISThe FPIES diagnosis is a clinical one; equivocal scenar-ios require resolution by modified oral food challenge(OFC) tests.3 Standard OFCs are modified in anticipa-tion of rapid-onset vomiting and/or diarrhoea. There-fore, intravenous cannulation is necessary prior to

commencement, as are stepwise challenge incre-ments. Lengthy intervals between incremental fooddoses are mandatory. It is also wise to prepare intra-venous bolus replacements, anti-emetics and steroidmedications.

The FPIES diagnostic criteria include the onset of pre-dominantly gastrointestinal (GI) symptoms in younginfants (usually before 9 months of age), which are con-sistently present on repeat ingestion of the triggerfood. Recurrent vomiting usually occurs within 1-2hours. Removal of the offending food protein from thediet leads to rapid – and complete – resolution of symp-toms within 24-48 hours.1,4 Additional pathognomonicFPIES features include a raised white blood cell countwith a predominance of neutrophils. This finding nec-essarily blurs the clinical picture, raising the clinician’ssuspicion of sepsis. The presence of bloody diarrhoeamay also lead to suspicion of infectious diarrhoea,coagulation defects or intussusception in those whofail to appreciate the significance of the temporal asso-ciation with a new food. The absence of fever, pres-ence of eosinophilic debris in the stools and negativestool cultures can help differentiate these conditions.Characteristically, inflammatory markers are not raised.Biopsies show crypt abscesses, diffuse inflammatorycell infiltrates with plasma cells in the colon, and oede-ma with mild villous injury in the small intestine. FPIESmay occasionally present with insidious chronic diar-rhoea, vomiting and failure to thrive.1

Patients with FPIES classically return negative allergytests (specific-IgE and/or skin-prick testing). Endoscopyis often unhelpful as infants may remain well betweenchallenges. Atypical cases have been described withdetectable specific IgE to the causal protein and with amore prolonged course of allergy.1 However, given thehigh population prevalence of IgE-mediated food aller-gy (between 4% and 6% in young children in devel-oped countries), it is not surprising that a proportion ofchildren with FPIES have concomitant IgE-mediatedfood allergy.

Studies suggest that atopy patch testing (APT) can aidprediction of tolerance and thus avoid unnecessaryfood challenges. Indeed, Fogg et al.6 demonstrate in 19children with FPIES that APT returns a remarkably highsensitivity and specificity.

DIFFERENTIAL DIAGNOSIS Acute infective conditions remain the primary differen-tial diagnosis, e.g. sepsis and/or gastroenteritis.Conditions such as milk-protein-induced proctocolitis,enteropathy and eosinophilic gastroenteropathies mayalso present with similar, overlapping features. FPIESrepresents the severe end of the spectrum of foodallergy that affects only the gut. Table I outlines thecomparative features of FPIES, gastroeneteritis andIgE-mediated food allergy.

ROUTE OF EXPOSURE AND TYPICALFOOD PROTEIN TRIGGERS The route of allergen exposure is usually by ingestion.There are no reports of FPIES in exclusively breastfedinfants. This is in contrast to IgE-mediated food aller-gies where acute skin reactions and even non-IgE-

Correspondence: Dr G du Toit, e-mail: [email protected]

ABSTRACTFood protein-induced enterocolitis syndrome(FPIES) is an under-recognised and frequently mis-diagnosed syndrome – characterised by severe pro-tracted diarrhoea and/or vomiting and frequentlyassociated with additional symptoms such as pallorand/or lethargy – which has its onset soon after theingestion of the particular food protein. FPIES repre-sents a severe cell-mediated, gastrointestinal foodhypersensitivity. Although typically ascribed to tocow’s milk and soy, FPIES has been described afterthe ingestion of a wide range of food proteins.

mediated conditions, such as dietary protein-inducedproctocolitis, have been attributed to food protein pas-sage through breast milk.2

Milk and soy are most frequently implicated; it is notuncommon for infants to react to both (50%).1 Manysolid food allergens have also been implicated inFPIES.2 Cross-reactivity is high, e.g. when one fin-fishspecies is implicated, children may react to other fin-fish. Table II lists case reports which reflect the foodproteins regarded as responsible for inducing FPIES.

MANAGEMENTWhile the pathophysiological immune basis for FPIES ispoorly understood, the cornerstone of management ofchildren with FPIES is careful exclusion of the causalfood protein (and cross-reactive proteins), preferablyunder the supervision of a paediatric dietitian. Mostinfants with FPIES will tolerate extensively hydrolysedcasein formula; if not, an amino-acid based formula isappropriate. Breast milk is well-tolerated as infantstend not to react to maternally ingested proteinspassed into breast milk as reported in some other foodallergies.1

The prognosis of FPIES is good – resolution will occurwithin 2 years in 60% of cow’s-milk-sensitive and 25%of soy-sensitive patients.9,10 Confirmation of resolution

may require carefully supervised modified OFCs.

SUMMARY FPIES is an under-recognised but not infrequent syn-drome. It should always be considered in the differen-tial diagnosis of young children who present withacute, severe, dehydrating diarrhoea, particularly if it isrecurrent. Modified incremental OFCs will be neces-sary to verify the diagnosis if the presentation is equiv-ocal, and to determine whether tolerance to the candi-date food protein has developed. Symptoms resolvedramatically after avoidance of the causal food protein(and cross-reactive foods). The prognosis of the condi-tion is favourable.

REFERENCES1. Sicherer SH. Food protein-induced enterocolitis syndrome: case

presentations and management lesson. J Allergy Clin Immuol2005; 115: 149-156.

2. Nowak-Wegrzyn A, Sampson HA, Wood RA, Sicherer SH. Foodprotein-induced enterocolitis syndrome caused by solid food pro-teins. Pediatrics 2003; 111: 829-835.

3. Powell GK. Food protein-induced enterocolitis of infancy: differen-tial diagnosis and management. Compr Ther 1986; 12: 28-37.

4. Sampson HA. Query: Title of article? J Allergy Clin Immunol 2003;111(suppl): S540-S547.

5. Fogg MI, Brown-Whitehorn TA, PawlowskiNA, Spergel JM. Atopy patch test for the diag-nosis of food protein-induced enterocolitissyndrome. Pediatr Allergy Immunol 2006; 17:351-355.

6. Vandenplas Y, Edelman R, Sacré L. Chicken-induced anaphylactoid reaction and colitis. J Pediatr Gastroenterol Nutr 1994; 19: 240-241.

7. Levy Y, Danon YL. Food protein-induced ente-rocolitis syndrome – not only due to cow'smilk and soy. Pediatr Allergy Immunol 2003;14: 325-329.

8. Zapatero Remón L, Alonso Lebrero E, MartínFernández E, Martínez Molero MI. Food-pro-tein-induced enterocolitis syndrome causedby fish. Allergol Immunopathol (Madr) 2005;33: 312-316.

9. Sicherer SH, Eigenmann PA, Sampson HA.Clinical features of food protein-induced ente-rocolitis syndrome. J Pediatrics 1998; 133:214-219.

10. Burks AW, Casteel HB, Fiedorek SC, WilliamsLW, Pumphrey CL. Prospective oral food chal-lenge study of two soybean protein isolates inpatients with possible milk or soy proteinenterocolitis syndrome. Pediatr AllergyImmunol 1994; 5: 40-45.


Table I. Comparative features of FPIES, gastroenteritis and classic IgE-mediated food allergy

FPIES Gastroenteritis IgE-mediated allergy

Presenting age Weaning Any Predominant in early childhood

Atopy No greater than population No greater than population Always

Allergy test positive* No greater than population No greater than population Always

Profuse vomiting Usual Frequent Frequent

Profuse diarrhoea Usual Usual Infrequent

Hives & angio-oedema No No Usual

WCC (with neutrophilia) Usual Usual Eosinophilia not uncommon

Stool culture positive No Common No

Stool eosinophilic debris Usual No Infrequent

Inflammatory markers raised No Common No

Clinical response to dietary

avoidance Characteristic No Characteristic

*Allergy test = skin-prick test and/or specific-IgE.

WCC – white cell count.

Table II. Case reports involving food proteins associated with FPIES

Study N Diagnosis made Food allergensby oral challenge test

Fogg et al.5 19 Yes Cow’s milk, soy, rice,

egg, wheat, oat

Vandenplas et al.6 1 Yes Chicken

Nowak-Wegrzyn et al.2 14 Yes Rice, sweet potato,

squash, string beans,

peas, oat, barley,

chicken, turkey

Levy & Danon7 6 Yes Chicken (4), turkey (2),

peas (1), lentils (1)

Zapatero Remón et al.8 14 Yes, in 9/14. Fish

Others diagnosed

on history, skin-prick

test and IgE. Atopy

patch test in 8.

Harris Steinman, MB ChB, DCh(SA)

Food & Allergy Consulting Services, Milnerton, CapeTown, South Africa

INTRODUCTION Individuals with pollen allergy often report adverseeffects after the ingestion of a wide variety of foodsfrom plants. This association has in recent years gainedgreater recognition because of the increasing preva-lence of pollen allergy.1 The clinical effects are usuallyrestricted to the oral cavity and include oral pruritus,swelling of the lips, tongue and throat, hoarseness,pharyngitis, and laryngeal oedema. These localisedsymptoms, caused by fruit, vegetables and spices,have been termed oral allergy syndrome (OAS).2-8

Immunoglobulin E (IgE) antibodies to the aeroallergencross-react with the proteins in fresh fruit and vegeta-bles to cause symptoms. Symptoms that patientsexperience are usually mild and do not require immedi-ate medical attention. However, some patients experi-ence severe and systemic reactions, such as severelaryngeal oedema, urticaria, asthma, or even food-induced anaphylaxis, though this is quite rare except inmugwort-celery-spice syndrome.2,4,9 This variation hasresulted in a debate over whether such reactions may beconsidered a severe form of OAS or whether, as otherauthors contend, OAS includes only mild symptoms.

Further, whereas the term OAS has been used bysome authors to describe oral symptoms caused byany food allergen, and not necessarily related to pollenallergy, others have argued that the term pollen-foodsyndrome (PFS) should be used to highlight the associ-ation between pollen-sensitisation and oral symptoms,since this is less ambiguous.2,10,11

As OAS/PFS symptoms are in most instances mild, theprevalence is difficult to assess. Estimates of the per-centage of patients with pollen allergy who also sufferfrom PFS vary from 47% to 70%, and this is thought tobe the most common food allergy in adolescents andadults.12

Although most scientific evidence is related to co-sen-sitisation with birch pollen, a tree sparsely found inSouth Africa (where it is planted mainly as an orna-mental), many other sources of pollen are likely to con-tain one or more of the cross-reactive panallergens, and

therefore similar clinical effects may be seen locally.Further, allergenic weed sources can be found in thebotanical families of Asteraceae (mugwort, ragweed,sunflower, feverfew), Amaranthaceae (goosefoot,Russian thistle), Urticaceae (wall pellitory), Euphor-biaceae (castor bean, mercury pollen, latex tree),Plantaginaceae (plantain), and Cannabaceae (Japanesehop pollen), with mainly plants of the Asteraceae fami-ly giving rise to OAS/FPS, particularly in Europe.2,13 InAustralia and Mediterranean countries, 20-40% ofpollen-allergic patients are found to be allergic to plan-tain (Plantago lanceolata).2

ASSOCIATIONS Although individuals may experience oral symptomsfollowing ingestion of fruit and vegetables withoutunderlying pollen allergy, in the majority of cases theinitial event is sensitisation to pollen, and then there issubsequent development of cross-reactivity to foodallergens, so that patients often develop pollen aller-gies before the development of oral symptoms.10 InEurope, sensitisation to birch pollen is a very commoncontributor.14

The association of oral symptoms and pollen allergyresults from cross-reactivity of pollen-specific IgE withhomologous food allergens.10 Prior to the identificationof these proteins, the association between differentfamilies of plants was not well understood. The pollensand foods involved are usually not botanically relatedbut contain conserved homologous proteins, as thereare shared epitopes (binding sites) in the primary andtertiary structures of pollen and food allergens.2 Severalclinical syndromes have been described15 as resultingfrom these associations, e.g. between birch pollen andfruit, in particular apple;16 between ragweed pollen andmelon and/or bananas;17 between birch and/or mug-wort pollen and celery (the so-called ‘mugwort-celery-carrot-spice syndrome’);18-20 between latex and fruit(latex-fruit syndrome);21,22 between plantain and cocks-foot (orchard) grass (Dactylis glomerata) pollen andmelon;23 and a number of other associations amongaeroallergens and plant proteins, depending on the par-ticular cross-reactive allergens.

The plant proteins involved in OAS and PFS have beenshown to belong to plant protein families, includingthose of profilins, pathogenesis-related proteins (PRs),and lipid transfer proteins (LTPs). There are a few well-described associations between aeroallergens and thefruits that elicit OAS symptoms. Appreciating the pat-tern of sensitisation to these foods and to pollen mayassist in the deduction of the responsible panallergen,and thereby assist with predicting the range of foodthat may affect an individual. Only the most commonrelevant panallergens are reviewed below, and it shouldbe kept in mind that other allergen families, e.g. calci-um-binding proteins (polcalins), are occasionallyresponsible for FPS.2 With the development of recom-binant allergens, component-resolved diagnosis (CDR)may assist in the prediction and management ofOAS/FPS.24

Profilin Profilin is a monomeric, actin-binding protein that regu-lates the organisation of the actin filaments to form theactin cytoskeleton in plants.25 Profilins are present in a


ORAL ALLERGY SYNDROME – WHAT’S NEW?

ABSTRACTOral allergy syndrome/pollen-food syndrome (OAS/PFS) affects up to 70% of patients with birch-pollenallergy. Prevalence is likely to continue to increaseas the prevalence of inhalant allergies rises.Homologous proteins in fruits, vegetables, and pol-lens of grasses, trees and weeds are responsible forPFS. Component-resolved diagnosis (CRD) withrecombinant allergens may assist with the diagnosisof this condition in the future. As there is currentlyno proven therapy for this syndrome, cooking andavoidance of offending fruits and vegetables are theonly options.

Correspondence: Dr Harris Steinman, Food & Allergy ConsultingServices, PO Box 565, Milnerton 7435. E-mail [email protected]

broad range of pollens and foods, including trees,grasses and weeds. Sensitisation to profilin occurs inapproximately 20% of pollen-allergic patients, andpatients sensitised to pollen profilins react to a broadrange of inhalant and food allergens.10,25,26

An example is the birch pollen allergen Bet v 2. Patientswho are sensitised to Bet v 2 often have symptomsupon ingesting apple, pear, carrot, and celery.1 Patientswith allergies to grass pollen profilin often have oralsymptoms in response to eating celery and carrots.1

In mugwort-celery-spice syndrome, patients sensitisedto mugwort cross-react to profilins in celery and spicesof the Apiaceae, or Umbelliferae, family (carrots, car-away seeds, parsley, coriander, aniseed or fennelseeds).1,9

However, there is a wide range of homology betweenprofilins from different fruits and vegetables; therefore,cross-reactivity is more likely to occur among foodswith high degrees of profilin homology than amongthose with low homology.

Pathogenesis-related proteins (PRs) PR proteins are involved in the defence systems ofhigher plants and are induced upon infection, woundingor environmental stresses (e.g. drought, flooding,freezing temperature, and ozone).27 They are classifiedinto 14 families based on similarities such as in theiramino acid sequence or enzymatic activities.27

Importantly, these proteins are stable at low pH andresistant to proteolysis. Not all PR families containallergens: plant-derived allergens have sequence simi-larities to PR families 2,3,4,5,8,10, and 14.28, 29 Approxi-mately 25% of characterised allergens are PRs.29

As PR proteins are influenced by a number of factors,they may vary depending on the environmental condi-tions in which the plant grows, and on the particularcultivar of the fruit. Even ripeness and storage condi-tions affect PR content, with more mature plants hav-ing more.27 Geographical and dietary factors also play arole in sensitisation to fruit or vegetables containingPRs.15 For example, allergy to Rosaceae family fruits isattributed to grass pollen sensitisation in southernEurope and to birch pollen sensitisation in northernEurope.2,30-33

The PR family consists of, among others, the beta 1,3glucanases (the PR-2 family), the class I, II, and IV chiti-nases (the PR-3 family), thaumatin-like proteins (PR-5),class III chitinases (PR-8), Bet v 1 homologues (PR-10)and LTPs (PR-14).

The PR-2 family consists of beta 1,3 glucanases, whichcatalyse the hydrolytic cleavage of 1,3 beta-D-gluco-sidic beta 1,3 glucans, abundant components of theplant cell wall.28 These allergens have been isolatedfrom banana, potato, tomato and latex (Hev b 2), andare thought to be responsible for the cross-reactivitybetween these foods and latex in the latex-food syn-drome seen in some patients.1,27,28

The PR-3 family consists of the class I, II, and IV chiti-nases. However, only class I chitinases have beenassociated with allergy.1,28 These proteins hydrolysechitin found in the exoskeletons of insects and the cellwalls of fungi. Banana, avocado and chestnut haveallergens with sequence similarity to the class I chiti-nases, and the class I chitinases have an N-terminalhevein domain that is shared by latex prohevein (Hev b6.01).1,28,34 The PR-3 allergens are thought to be respon-sible for the cross-reactivity between the above foodsand latex in latex-food syndrome.34

The PR-5 family contains the thaumatin-like proteins.Although not fully understood, thaumatin-like proteins

are thought to have antifungal properties, to rapidlyaccumulate in high levels during stress on the plant,and to give plants resistance to freezing and drought.1

Thaumatin-like proteins have been characterised inapple (Mal d 2), cherry (Pru av 2), bell pepper (Cap a 1)and mountain cedar pollen (Jun a 3).1,27

The PR-8 family of proteins consists of class III chiti-nases. These are usually minor allergens.1 This groupincludes the latex allergen hevamine27,28 and a chitinasefrom cucumber.29

The PR-10 family consists of the Bet v 1-homologues,i.e. proteins that have an amino acid sequence homol-ogy with the allergen Bet v 1 from birch pollen, a pro-tein with unknown function.28 As with other PRs, theirexpression is induced upon environmental stress,wounding or infection.28 They are probably the mostimportant PR proteins involved in OAS/PFS, withapproximately 70% of birch-pollen-allergic individualsbeing affected by OAS/PFS as a result of IgE cross-reactivity between Bet v 1 and its food homologues.27,28

PR-10 homologues are found in many members of theRosaceae and Prunoideae fruits, and of the Apiaceaevegetables.2,4,28 The best known Bet v 1 homologue isMal d 1, a major allergen in ripe apples, resulting in oralsymptoms in birch-pollen-allergic patients. Other Bet v1-homologues include Pru av 1 from cherry, Pru ar 1from apricot, Pyr c 1 from pear, Api g 1 from celery,Dau c 1 from carrot, and Cor a 1 from hazelnut.2,28

These proteins share a high degree of amino acidsequence similarity (28-67%) with the major birch aller-gen Bet v 1.25,28,29

The PR-14 family comprises the LTPs. LTPs transferphospholipids from liposomes to mitochondria andhave antimicrobial activities.2 LTPs are important aller-gens of the Prunoideae family (peaches, apricots,plums, cherries) and the Rosaceae family (apples,pears), and are usually found in the peel.2 Significantlydifferent from the protein families involved in OAS/FPSwhere a pre-existing pollen allergy sensitisation isfound, LTPs often cause food allergy to fruit in theabsence of pollen allergy. For example, hypersensitivityto peach, the most frequent fruit allergy in Spain, is clin-ically not associated with any kind of particular pollenallergy,31 even though there seems to be a higherprevalence of asthma in pollen-allergic patients withpeach allergy.35 There are exceptions. For example, theLTP from mugwort pollen has been shown to cross-react with peach LTP and may be involved in the mug-wort-peach allergy association frequently seen in theMediterranean. Mugwort is not found in South Africa.Individuals who are allergic to LTPs in fruit have beenshown to have a higher rate of anaphylaxis (36%) thanthose sensitised to PR-10 fruit allergens (18%).2,10,29


Cross-reactive carbohydrate determinants The role of cross-reactive carbohydrate determinants(CCDs) remains controversial. Glycoproteins contain N-linked carbohydrate groups, which induce IgE, leading tocross-reactivity between foods and pollens.36-38 CCDsare found in, among others, celery, tomato, potato andpeanut, and in ragweed, timothy grass and birch pollen.2

However, debate continues over whether these CCDscan cause clinical symptoms.36,39-,42 For example, in astudy of patients with grass-pollen allergy who are clin-ically asymptomatic to ingested peanut but have posi-tive serum IgE to peanut but negative reactions to askin-prick test for peanut, the patients were found tohave IgE to the CCDs of peanut. The cross-reactive IgEhad low biological activity. In contrast, in a study of cel-ery-allergic patients, 25% were shown to have IgE toCCDs.36 In a study of the sera of 10 tomato-allergicpatients, 4 with IgE to CCDs showed biological activityin the basophil histamine release assay with tomatoglycoproteins only but failed to react to nonglycosylat-ed recombinant tomato proteins.38

IgE antibodies directed toward glycans appear to showthe widest pattern of cross-reactivity among allergenicextracts and are often responsible for observed in vitrocross-reactions within PFS.2,43 Further research mayelucidate the reasons for conflicting evidence and thecauses of the variability of biological activity ofCCDs.10,26 Importantly, many glycoproteins carry onlyone IgE-binding glycan and therefore cannot cross-linkIgE bound to receptors; nor can they induce activationof mast cells and basophils, whereas other glycopro-teins have been identified that contain more than oneN-linked glycan.37

As plant proteins are characterised in more detail, it willbecome easier to identify potential cross-reactions.

However, not all patients with cross-reactive antibodieswill actually experience symptoms; i.e. the IgE cross-reactivity will be either clinically manifest or irrelevant.Clinical manifestations seem to be influenced by anumber of factors, including the host’s immuneresponse, allergen exposure, and the individual allergenitself.2 For example, and importantly, amino acidsequence homology among members of each proteinfamily group varies, which influences the cross-reactiv-ity patterns seen and the likelihood of symptomaticcross-reactivity. For example, in the PR-14 family ofLTPs, there is in general a high sequence homologyamong the allergen members, suggesting a high prob-ability of cross-reactivity among members, and this isconfirmed clinically, whereas in the profilin protein fam-ily a much wider range of homology exists amongmembers, and therefore cross-reactivity among someplants containing profilin is not certain. Other factors

that influence cross-reactivity among family membersare the degree of ripeness of the fruit or vegetable,storage conditions, and a number of other factors thatinfluence the expression of the allergen; levels ofcross-reactivity may even vary among cultivars.44

Food-allergic patients may be sensitised to more thanone allergen found in a specific food, complicatingcross-reactivity. For example, a high prevalence ofOAS/FPS occurs to ingestion of apple in birch pollen-sensitised individuals as a result of the cross-reactivitybetween Mal d 1 from apple and Bet v 1 from birchpollen; however, apple-allergic individuals may bemonosensitised or polysensitised to any number ofapple allergens, e.g. to Mal d 1 (PR-10), Mal d 2 (PR-5),Mal d 3 (PR-14), Mal d 4 (profilin), or any other appleallergen or combination of allergens.45

CLINICAL MANIFESTATIONS The clinical effects are usually restricted to the oral cav-ity and include oral pruritus, swelling of the lips, tongueand throat, hoarseness, pharyngitis, and laryngealoedema. The most common complaint among patientsis an itching or tingling of the mouth after ingestion offresh fruit or vegetables.3 Patients may also experienceangio-oedema localised to the mouth. Some studieshave shown that a few patients will develop someabdominal cramping or discomfort after ingestion, butrarely vomiting or diarrhoea.3 Anaphylaxis may uncom-monly occur in association with OAS/FSP (as opposedto anaphylaxis without this association). Anaphylaxis isparticularly more likely with LTP-containing foods.Almost all patients will have some degree of allergicrhinitis or conjunctivitis because the IgE antibodies toan aeroallergen are cross-reacting with the fruit or veg-etable proteins.

Reactions may vary depending on the allergen respon-sible for symptoms. Patients allergic to profilin mayreport that ingesting a cooked fruit or vegetable doesnot elicit symptoms, whereas cooked fruit or vegeta-bles containing heat-stable allergens, e.g. LTPs, maystill result in symptoms.

DIAGNOSISThe diagnosis is based almost entirely on the patient’shistory. A history of allergy to aeroallergens and thentingling or itching of the mouth after eating fresh fruitsor vegetables is enough to make the diagnosis of OASin almost all cases. The OAS reaction is usually imme-diate and can occur as soon as the fruit or vegetable isput into the mouth. The reactions are usually the sameif the patient eats the same fruit or vegetable again, butthere may be a dose threshold. Most symptoms shouldbe confined to the oropharynx.


Although commercial extracts of most fruits and veg-etables are available for tests, these extracts are highlyheat-labile and easily degradable, often losing theirpotency and sensitivity by the time they are used inskin-prick tests.2 This has led to the use of the prick-to-prick method, in particular if initial skin-prick tests arenegative despite a persuasive clinical history. The pro-cedure is to prick the fresh fruit with the lancet andthen immediately use the same lancet for the skinprick. Studies have confirmed that commercial extractsare not as good as fresh fruit in skin-prick testing.46

If systemic reactions such as urticaria, wheezing, andanaphylaxis occur in association with OAS/PFS, thissuggests the involvement of an LTP allergen. Potentialcross-reactivity with other LTP-containing foods shouldbe explored, and in this instance coexisting pollen aller-gy may not be related to a cross-reactive allergen (withthe exception of mugwort). However, systemic reac-tions may occur to a food without oral symptoms, andif an individual is polysensitised to a number of aller-gens in a food, then atypical clinical patterns mayemerge.

A thorough history should be obtained to ensure thatthe patient has no signs of a more serious IgE-mediat-ed food allergy. Patients should be questioned aboutwhat foods were ingested around the same time;excluding those foods as the cause of the reactionwould be appropriate. This may include skin-prick test-ing, specific IgE antibody testing, and food challenge.

The development of recombinant allergens representa-tive of cross-allergenic allergens has resulted in theevolvement of component-resolved diagnosis (CRD), inwhich sensitisation to single allergens can be tested,enabling improved evaluation of OAS/FCS and cross-reactivity. Table I lists examples of useful recombinantallergens that have been developed.

Besides prick-to-prick tests, patterns of co-sensitisationhave been proposed as guides in the diagnosis ofOAS/FPS. For example, in a study of grass-pollen- andbirch-pollen-allergic patients with confirmed oral allergysymptoms to apple, hazelnut or melon, a diagnosis wasbest obtained through a case history and skin-pricktests with fresh fruit, and skin-prick tests had a nega-tive predictive value of greater than 89%. When a skin-prick test with fresh nut or apple cannot be performed,histamine release is a diagnostic alternative.47

However, other studies have shown that skin-pricktests and in vitro IgE levels are poor predictors of clini-cal sensitivity.12

Double-blind, placebo-controlled food challenges(DBPCFC) are considered the gold standard in thediagnosis of food allergy. However, using DBPCFC todiagnose OAS/PFS has various constraints, including

the fact that storage ripening processes affect the levelof allergen present, and that levels of the same pan-allergen vary between varietals.27 Food-in-a-capsulechallenges are also problematic, as the food bypassesthe oral mucosa and the allergen may be degraded inthe stomach by digestion.

TREATMENT Most patients with OAS will avoid the fruit(s) or vege-table(s) eliciting their symptoms. If the patient wishesto tolerate the localised symptoms and there is no sug-gestion of systemic symptoms, it is safe to continueeating the food. A survey of allergists concerning man-agement of OAS found no consensus: some recom-mended complete avoidance of the offending foods,others did not advocate food restrictions, and 38% per-sonalised recommendations according to the individual,sometimes advocating the avoidance of cross-reactivefoods.12

However, since cross-reactivity may depend on theheat-stability of the responsible cross-reactive allergen,cooking alone may be sufficient to deactivate theresponsible panallergen.48 However, in patients withconcomitant eczema, ingestion of cooked birch-pollen-related foods, while not inducing OAS, still causedatopic eczema to worsen, suggesting that T-cell cross-reactivity between Bet v 1 and related food allergensoccurs independently of IgE cross-reactivity in vitro andin vivo.48 Therefore, ingestion of cooked fruits andvegetables may cause perennial activation of pollen-specific T cells and B cells, leading to maintenance ofperennially increased allergen-specific IgE levels, andthereby symptoms, in pollen-allergic patients outsidethe pollen season.48

Although the same panallergen may be present in arange of foods, homology may still vary, resulting inclinical cross-reactivity between some members andnot others. Studies assessing cross-reactivity in theRosaceae family of fruits found that from 46% to 63%of patients with confirmed PFS to one fruit had clinicalreactivity to other Rosaceae fruits; the authors recom-mended that if a reported reaction is confirmed, toler-ance to other Rosaceae fruits, particularly apricot,apple, and plum, should be evaluated, unless thepatient has eaten them without symptoms after the ini-tial reaction.49

It is inappropriate to take an antihistamine prior to eat-ing a culprit food, as this would mask symptomsbeyond the OAS (although in certain circumstances,this may be acceptable, i.e. if the symptom pattern isestablished and is not variable). Additionally, patientsshould be made to understand that if the food evercauses symptoms beyond the oropharynx, they shouldavoid the food as if they have classic IgE-mediatedfood allergy.

The hypothesis that immunotherapy for pollen allergymay reduce or abolish symptoms of OAS/FPS, as aresult of cross-reactivity among panallergens, has beenaddressed in a number of studies, with varying results.A study of birch-pollen-allergic individuals with symp-toms to apple who were treated with subcutaneousimmunotherapy reported a significant reduction or dis-appearance of oral symptoms to apples (84%), with aconcomitant reduction in reactivity to skin-prick tests toapple.50 Similarly, a study reported that immunotherapyresulted in birch-allergic patients being able to eat sig-nificantly more apple or hazelnut with no resultingsymptoms. However, the amount of apple or hazelnuttolerated remained small.51 In contrast, other studieshave demonstrated no improvement followingimmunotherapy (except for pollen-related symptoms ofrhinoconjunctivitis).52-54 Results of an immunotherapy


Table I. Diagnostic recombinant allergens

rBet v 1 PR-10 Birch tree

rAra h 8 PR-10 Peanut

rApi g 1.01 PR-10 Celery

rCor a 1 PR-10 Hazel nut

rGly m 4 PR-10 Soy

rPru p 1 PR-10 Peach

rBet v 2 Profilin Birch tree

rPhl p 12 Profilin Timothy

rPru p 4 Profilin Peach

rAra h 9 LTP Peanut

rCor a 8 LTP Hazel nut

rPar j 2 LTP Wall pellitory

rPru p 3 LTP Peach

study of birch subcutaneous immunotherapy for appleallergy reported the possible induction of OAS in 2 of12 study participants as a result of immunotherapy.53

Disclosure of interest Consultant to Phadia, Sweden.

REFERENCES1. Breiteneder H, Ebner C Molecular and biochemical classification of

plant-derived food allergens. J Allergy Clin Immunol 2000; 106(1 Pt1): 27-36.

2. Egger M, Mutschlechner S, Wopfner N, Gadermaier G, Briza P,Ferreira F. Pollen-food syndromes associated with weed pollinosis: anupdate from the molecular point of view. Allergy 2006; 61: 461-476.

3. Ortolani C, Ispano M, Pastorello E, Bigi A, Ansaloni R. The oral aller-gy syndrome. Ann Allergy 1988; 61(6 Pt 2): 47-52.

4. Ortolani C, Pastorello EA, Farioli L, et al. IgE-mediated allergy fromvegetable allergens. Ann Allergy 1993; 71: 470-476.

5. Gluck U. Pollinosis and oral allergy syndrome. [German] HNO 1990;38: 188-190.

6. Valenta R, Kraft D. Type 1 allergic reactions to plant-derived food: aconsequence of primary sensitization to pollen allergens. J Allergy Clin Immunol 1996; 97: 893-895.

7. Anhoej C, Backer V, Nolte H. Diagnostic evaluation of grass-andbirch-allergic patients with oral allergy syndrome. Allergy 2001; 56:548-552.

8. Sloane D, Sheffer A. Oral allergy syndrome. Allergy Asthma Proc2001; 22: 321-325.

9. Wüthrich B, Dietschi R. Das “Sellerie-Karotten-Beifuss-Gewurz-Syndrom”: Hauttest-und RAST-Ergebnisse. Schweiz MedWochenschr 1985; 115: 258-364.

10. Hofmann A, Burks AW. Pollen food syndrome: update on the aller-gens. Curr Allergy Asthma Rep 2008; 8: 413-417.

11. Kelso JM. Pollen-food allergy syndrome. Clin Exp Allergy 2000; 30:905-907.

12. Ma S, Sicherer SH, Nowak-Wegrzyn A. A survey on the manage-ment of pollen-food allergy syndrome in allergy practices. J AllergyClin Immunol 2003; 112: 784-788.

13. Gadermaier G, Dedic A, Obermeyer G, Frank S, Himly M, FerreiraF. Biology of weed pollen allergens. Curr Allergy Asthma Rep 2004;4: 391-400.

14. Asero R, Massironi F, Velati C. Detection of prognostic factors fororal allergy syndrome in patients with birch pollen hypersensitivity.J Allergy Clin Immunol 1996; 97: 611-616.

15. Sicherer SH. Clinical implications of cross-reactive food allergens. JAllergy Clin Immunol 2001; 108: 881-890.

16. Kremser M, Lindemayr W. Frequency of the so-called “apple aller-gy” (“apple contact urticaria syndrome”) in patients with birchpollinosis. [German] Z Hautkr 1983; 58: 543-552.

17. Anderson LBJ, Dreyfuss EM, Logan J, Johnstone DE, Glaser J.Melon and banana sensitivity coincident with ragweed pollinosis. J Allergy 1970; 45: 310-319.

18. Wüthrich B, Hofer T. Food allergy: the celery-mugwort-spice syn-drome. Association with mango allergy? [German] Dtsch MedWochenschr 1984; 109: 981-986.

19. Bauer L, Ebner C, Hirschwehr R, et al. IgE cross-reactivity betweenbirch pollen, mugwort pollen and celery is due to at least three dis-tinct cross-reacting allergens: immunoblot investigation of the birch-mugwort-celery syndrome. Clin Exp Allergy 1996; 26: 1161-1170.

20. Pauli G, Bessot JC, Dietemann-Molard A, Braun PA, Thierry R.Celery sensitivity: clinical and immunological correlations withpollen allergy. Clin Allergy 1985; 15: 273-279.

21. Blanco C, Carrillo T, Castillo R, Quiralte J, Cuevas M. Latex allergy:clinical features and cross-reactivity with fruits. Ann Allergy 1994;73: 309-314.

22. Yagami T. Allergies to cross-reactive plant proteins. Latex-fruit syn-drome is comparable with pollen-food allergy syndrome. Int ArchAllergy Immunol 2002; 128: 271-279.

23. Garcia Ortiz JC, Cosmes Martin P, Lopez Asunolo A. Melon sensi-tivity shares allergens with Plantago and grass pollens. Allergy1995; 50: 269-273.

24. Bohle B, Vieths S. Improving diagnostic tests for food allergy withrecombinant allergens. Methods 2004; 32: 292-299.

25. Valenta R, Duchene M, Ebner C, et al. Profilins constitute a novelfamily of functional plant pan-allergens. J Exp Med 1992; 175: 377-385.

26. Vieths S. Allergenic cross-reactivity, food allergy and pollen.Environ Toxicol Pharm 1997; 4: 61-70.

27. Midoro-Horiuti T, Brooks EG, Goldblum RM. Pathogenesis-relatedproteins of plants as allergens. Ann Allergy Asthma Immunol 2001;87: 261-271.

28. Hoffmann-Sommergruber K. Plant allergens and pathogenesis-related proteins. What do they have in common? Int Arch AllergyImmunol 2000; 122: 155-166.

29. Ebner C, Hoffmann-Sommergruber K, Breiteneder H. Plant foodallergens homologous to pathogenesis-related proteins. Allergy2001; 56(Suppl 67): 43-44.

30. Ghunaim N, Gronlund H, Kronqvist M, et al. Antibody profiles andself-reported symptoms to pollen-related food allergens in grasspollen-allergic patients from northern Europe. Allergy 2005; 60:185-191.

31. Cuesta-Herranz J, Lazaro M, Martinez A, et al. Pollen allergy inpeach-allergic patients: sensitization and cross-reactivity to taxo-nomically unrelated pollens. J Allergy Clin Immunol 1999; 104(3 Pt1):688-94.

32. Van Ree R, Fernandez Rivas M, Cuevas M, et al. Pollen-relatedallergy to peach and apple: an important role for profilin. J AllergyClin Immunol 1995; 95: 726-734.

33. Pauli G, Oster JP, Deviller P, et al. Skin testing with recombinantallergens rBet v 1 and birch profilin, rBet v 2: diagnostic value forbirch pollen and associated allergies. J Allergy Clin Immunol 1996;97: 1100-1109.

34. Salcedo G, Diaz-Perales A, Sanchez-Monge R. Fruit allergy: plantdefence proteins as novel potential panallergens. Clin Exp Allergy1999; 29: 1158-1160.

35. Cuesta-Herranz J, Lázaro M, de las Heras M, et al. Peach allergypattern: experience in 70 patients. Allergy 1998; 53: 78-82.

36. Van der Veen MJ, van Ree R, Aalberse RC, et al. Poor biologic activ-ity of cross-reactive IgE directed to carbohydrate determinants ofglycoproteins. J Allergy Clin Immunol 1997; 100: 327-334.

37. Fotisch K, Altmann F, Haustein D, Vieths S. Involvement of carbo-hydrate epitopes in the IgE response of celery-allergic patients. IntArch Allergy Immunol 1999; 120: 30-42.

38. Foetisch K, Westphal S, Lauer I, et al. Biological activity of IgE spe-cific for cross-reactive carbohydrate determinants. J Allergy ClinImmunol 2003; 111: 889-896.

39. Aalberse RC, Akkerdaas J, van Ree R. Cross-reactivity of IgE anti-bodies to allergens. Allergy 2001; 56: 478-490.

40. Van Ree R. Carbohydrate epitopes and their relevance for the diag-nosis and treatment of allergic diseases. Int Arch Allergy Immunol2002; 129: 189-197.

41. Mari A. IgE to cross-reactive carbohydrate determinants: analysisof the distribution and appraisal of the in vivo and in vitro reactivity.Int Arch Allergy Immunol 2002; 129: 286-295.

42. Ebo D, Hagendorens M, Bridts C, de Clerck L, Stevens W.Sensitization to cross-reactive carbohydrate determinants and theubiquitous protein profilin: mimickers of allergy. Clin Exp Allergy2004; 34: 137-144.

43. Ferreira F, Hawranek T, Gruber P, Wopfner N, Mari A. Allergic cross-reactivity: from gene to the clinic. Allergy 2004; 59: 243-267.

44. Carnes J, Ferrer A, Fernandez-Caldas E. Allergenicity of 10 differentapple varieties. Ann Allergy Asthma Immunol 2006; 96: 564-570.

45. Fernandez-Rivas M, Bolhaar S, Gonzalez-Mancebo E, Asero R, VanLA, Bohle B, Ma Y. Apple allergy across Europe: how allergen sen-sitization profiles determine the clinical expression of allergies toplant foods. J Allergy Clin Immunol 2006; 118: 481-488.

46. Ortolani C, Ispano M, Pastorello EA, Ansaloni R, Magri GC.Comparison of results of skin prick tests (with fresh foods andcommercial food extracts) and RAST in 100 patients with oral aller-gy syndrome. J Allergy Clin Immunol 1989; 83: 683-690.

47. Anhoej C, Backer V, Nolte H. Diagnostic evaluation of grass-andbirch-allergic patients with oral allergy syndrome. Allergy 2001; 56:548-552.

48. Bohle B, Zwolfer B, Heratizadeh A, et al. Cooking birch pollen-relat-ed food: divergent consequences for IgE-and T cell-mediated reac-tivity in vitro and in vivo. J Allergy Clin Immunol 2006; 118: 242-249.

49. Rodriguez J, Crespo JF, Lopez-Rubio A, et al. Clinical cross-reactiv-ity among foods of the Rosaceae family. J Allergy Clin Immunol2000; 106(1 Pt 1): 183-189.

50. Asero R. Effects of birch pollen-specific immunotherapy on appleallergy in birch pollen-hypersensitive patients. Clin Exp Allergy1998; 28: 1368-1373.

51. Bucher X, Pichler WJ, Dahinden CA, Helbling A. Effect of treepollen specific, subcutaneous immunotherapy on the oral allergysyndrome to apple and hazelnut. Allergy 2004; 59: 1272-1276.

52. Möller C. Effect of pollen immunotherapy on food hypersensitivityin children with birch pollinosis. Ann Allergy 1989; 62: 343-345.

53. Modrzynski M, Zawisza E. Possible induction of oral allergy syn-drome during specific immunotherapy in patients sensitive to treepollen. Med Sci Monit 2005; 11: CR351-5.

54. Kinaciyan T, Jahn-Schmid B, Radakovics A, et al. Successful sub-lingual immunotherapy with birch pollen has limited effects on con-comitant food allergy to apple and the immune response to the Betv 1 homolog Mal d 1. J Allergy Clin Immunol 2007; 119: 937-943.


S Karabus, MB ChB, MRCP(UK), FCPaeds(SA), DipAllergology (SA)

C Motala, MB ChB, FCPaeds(SA), FACAAI, FAAAAI

Allergy Clinic, Division of Paediatric Medicine, School ofChild & Adolescent Health,

University of Cape Town & Red Cross War MemorialChildrens’ Hospital, Cape Town, South Africa

BACKGROUNDIn the paediatric population it is not uncommon to seea skin rash during a course of treatment with a penicillinantibiotic. This is often assumed to be due to penicillinallergy. In most of these cases no testing is performedto verify the diagnosis and most children are simplylabelled as ‘penicillin allergic’. They end up carrying thislabel into adulthood and may therefore be denied thebenefit of treatment with the most appropriate group ofantibiotics.

Penicillin and penicillin-based antibiotics are the mostwidely used antibiotics for common infections.1 Theyare also the antibiotics which most often cause allergicreactions2 with the frequency of life-threatening ana-phylaxis estimated to be 0.01%-0.05%.3 The incidenceof self-reported penicillin allergy varies between 1%and 10%4 but more than 80-90% of these have no evi-dence of IgE antibodies to penicillin on skin-testing.5,6

Penicillin-based antibiotics are usually less expensiveand have fewer side-effects than alternative broad-spec-trum antibiotics. They are also more effective for certaininfections. This is especially important for patients onlong-term penicillin prophylaxis (e.g. rheumatic heartdisease) or treatment (e.g. bacterial endocarditis).

CLASSIFICATIONThere are a number of ways to classify drug allergies.From a clinical perspective a practical method is todivide adverse drug reactions according to the timeinterval between exposure and onset of reaction –immediate, accelerated and delayed reactions.Immediate hypersensitivity reactions (IgE-mediated)occur up to 1 hour after exposure to the offendingagent. Non-immediate reactions include acceleratedreactions (1-72 hours) and delayed reactions (>72hours). Immediate reactions may present with anaphy-laxis, urticaria, angio-oedema and bronchospasm; accel-erated/delayed reactions may manifest as serum sick-ness, interstitial nephritis, haemolytic anaemia, morbilli-form eruptions and Stevens-Johnson syndrome.

DIAGNOSIS (Fig. 1)HistoryThe diagnosis of penicillin allergy begins with a detailedhistory. A personal or family history of drug allergiesmay be relevant as this may predispose to penicillinallergy7 whereas a history of atopy does not. The signs,symptoms and severity of the reaction and any previ-ous reactions should be documented. For example,urticaria and bronchospasm would suggest an IgE-mediated immediate drug reaction. The dose and routeof administration are also important. Prolonged par-enteral administration is more likely to cause a hyper-sensitivity reaction than the oral or topical route. A con-comitant viral illness is important as this may cause arash that is mistaken for penicillin allergy. The maculo-papular rash induced by ampicillin or amoxicillin givento a child with Epstein-Barr virus infection may also bemistaken for a drug allergy.

Physical examinationThe clinical examination should focus on the skin,mucous membranes and the chest. On the skin oneshould distinguish between an urticarial and a morbilli-form or maculopapular rash. Mucous membrane


PENICILLIN ALLERGY IN CHILDREN

ABSTRACTIt is not uncommon to see skin rashes during acourse of treatment with penicillin and penicillin-based antibiotics. This is often assumed to be due topenicillin allergy although in most cases no testing isperformed to verify the diagnosis. Many children aresimply labelled ‘penicillin allergic’, a label which theycarry into adulthood which may deny them the ben-efit of treatment with the most appropriate group ofantibiotics. Penicillins are the most widely usedantibiotics for common infections as well as beingthe antibiotics which most often cause allergic reac-tions. The incidence of self-reported penicillin allergyis 1-10% but most of these patients will test nega-tive. Misdiagnosis of penicillin allergy may result inthe unnecessary use of more expensive and lesseffective antibiotics as well as the emergence ofmultidrug-resistant organisms. History alone is unre-liable in the diagnosis of penicillin allergy. Skin test-ing (skin-prick and intradermal testing) remains stan-dard practice for the evaluation of patients withimmediate hypersensitivity reactions (IgE-mediated)to penicillin. Skin testing combined with a thoroughhistory, determination of specific IgE antibody leveland, if indicated, a drug provocation test (DPT)should diagnose the majority of children with peni-cillin allergy. Patients with proven penicillin allergycan undergo desensitisation if they require penicillintherapy and no alternative is available. Accuratediagnosis of penicillin allergy is essential to avoid themorbidity, mortality and economic cost associatedwith unnecessary withholding of this drug in non-allergic patients.

Correspondence: Dr S Karabus [email protected] Fig. 1. Basic algorithm for drug allergy testing.

+

+

+

–

–

–

involvement may indicate Stevens-Johnsons syndromeor toxic epidermal necrolysis. The presence of wheez-ing or stridor should be noted on examination of therespiratory system.

Investigations Penicillin is metabolised into major (penicilloyl) andminor (penicilloate and penilloate) antigenic determi-nants. It is essential to test sensitivity to both minorand major determinants, as testing only for major deter-minants would miss at least 10% of penicillin-sensitivesubjects.

• Blood testsDuring an acute hypersensitivity reaction a serumtryptase level should be performed. This is a sensi-tive and specific test of mast-cell activation. Ideallyblood is taken at 0, 1 and 6 hours after the reactionand placed in a lithium-heparin tube. A peak at 1 hourwith a fall to normal levels within 12-24 hours is diag-nostic of mast-cell degranulation and an IgE-mediat-ed reaction.

A CAP-RAST for IgE antibodies to amoxicillin, ampi-cillin, penicillin V, penicillin G and cefaclor is availableto aid in the diagnosis. The blood should be takenfrom 6 weeks after the acute reaction has takenplace in order to get the most accurate results. Thesensitivity is approximately 80-90%8 but it does nottest for the minor determinants of penicillin.5

More recently the CAST (cellular antigen stimulationtest) has become available. This test measures thein vitro production of sulphidoleukotrienes by leuco-cytes when stimulated by the specific drug. Thesensitivity and specificity are approximately 46%and 85% respectively.9

• Skin tests (Fig. 2)The skin-test panel should include a positive (hista-mine 10 mg/ml) and a negative (0.9% saline) controlas well as a major determinant mixture and minordeterminant mixture. Amoxicillin (20-25 mg/ml)should be added to the skin-test panel8,10 as its sidechain is not included in the above two mixtures. Ifthe offending drug is something other than one ofthese, it should be added to the panel with theunderstanding that the negative predictive value ofsuch a test is unknown. A wheal 3 mm or moregreater than the negative control is considered apositive test result.

Skin-prick testing (SPT) is a reliable and relativelysafe procedure for detecting IgE-mediated penicillinallergy. It has a specificity approaching 100% for IgE-mediated allergy.10-13 The sensitivity is relatively low(50-70%)10,12 (Table I). Anaphylaxis has never beenreported in a skin-test-negative individual challengedwith the medication. SPT is not indicated if the his-tory suggests a non-IgE-mediated hypersensitivityreaction such as Stevens-Johnson syndrome orserum sickness. In these patients, penicillin shouldbe avoided indefinitely.

• Drug provocation test (DPT) If the penicillin skin tests are negative and the IgEantibody levels are normal, a DPT should be per-formed in a setting where resuscitation equipmentand trained personnel are available. A suggestivehistory of allergy together with a positive CAP-RASTand/or a positive skin test is sufficient for the diag-nosis of penicillin allergy without the need to per-form a DPT.10,12 A DPT is not recommended if thereis a history of anaphylaxis.

MANAGEMENTInitial management of acute penicillin allergy consistsof discontinuing the drug and treating the clinical reac-tions, e.g. anaphylaxis, urticaria or wheeze. Subse-quent management entails confirming the diagnosis,strict avoidance of the offending drug and patient edu-cation (including the use of injectable adrenaline forprevention of anaphylaxis). A Medic Alert braceletshould also be obtained.

Desensitisation to the drug (either by the oral or intra-venous route) should be considered in children withIgE-mediated reactions if no alternative treatment topenicillin is available. Desensitisation must be conduct-ed in an intensive care unit by experienced personnel.The aim of desensitisation is to convert a patient who ishighly allergic to penicillin to a state in which they cantolerate the drug. The basic principle is to start with aminute dose, then double it every 15 minutes until a fulldose is reached. Various desensitisation protocols areavailable (Tables II and III14). Penicillin therapy must becommenced immediately after completing desensitisa-tion (tolerance is only temporary). Desensitisation mustbe repeated if a course of penicillin is required again.

Minor adverse reactions may occur after this proce-dure in a third of cases but no fatal or life-threatening


Table I. The predictive value of penicillin skin tests

History of penicillin allergy + + – –

Penicillin skin test status + – + –

Frequency of allergic

reactions associated with

penicillin administration 50-70% 1-3% 10% 0.5%

Fig. 2. Skin-prick test.

Table II. Penicillin oral desensitisation protocol

Step* Penicillin Amount Dose given Cumulative(mg/ml) (ml) (mg) dose (mg)

1 0.5 0.1 0.05 0.05

2 0.5 0.2 0.1 0.15

3 0.5 0.4 0.2 0.35

4 0.5 0.8 0.4 0.75

5 0.5 1.6 0.8 1.55

6 0.5 3.2 1.6 3.15

7 0.5 6.4 3.2 6.35

8 5 1.2 6 12.35

9 5 2.4 12 24.35

10 5 5 25 49.35

11 50 1 50 100

12 50 2 100 200

13 50 4 200 400

14 50 8 400 800

Observe patient for 30 minutes, then give full therapeutic

dose by the desired route.

Modified from Sullivan TJ.14

*Interval between doses is 15 minutes.

reactions have been reported to date. It is important tonote that desensitisation will not prevent non-IgE reac-tions such as serum sickness, haemolytic anaemia orinterstitial nephritis from occurring.

CROSS-REACTIVITY WITH OTHER ANTI-BIOTICSUp to 20% of patients with penicillin allergy may devel-op an adverse reaction to cephalosporins15 (particularlywith 1st and 2nd generation agents). The rate of crossreactivity with the 3rd and 4th generation cephalo-sporins is much lower. Cross-reactivity between thesedrugs is believed to be due to the drugs having similarR-group side chains and not due to the �-lactam ringitself (Fig. 3). For example, amoxicillin shares a side-chain with cefadroxil, cefotaxime with ceftriaxone, andampicillin with both cefalexin and cefaclor. It is recom-mended that penicillin-allergic patients who require acephalosporin should undergo SPT. If this is negative, acephalosporin can be safely administered5 with a lessthan 1% risk of a mild systemic reaction.

In a patient with a known allergy to a cephalosporin,substitution with a cephalosporin with a different sidechain is usually safe.

Cross-reactivity between penicillin and carbapenems isalso reported: 50% with imipenem16 and 10% withmeropenem,17 based on history and SPT. In studieswhere DPTs were also done, cross-reactivity wasreportedly <1%.18

CONCLUSIONSAllergic reactions to penicillin (anaphylaxis in particular)are relatively infrequent in the paediatric population.The majority of children with the label of penicillin aller-gy can safely take this drug without fear of an allergicreaction. Misdiagnosis of penicillin allergy may result inthe unnecessary use of more expensive and less effec-tive antibiotics as well as the emergence of multidrug-resistant organisms. History alone (usually poorly docu-mented and often vague) is unreliable in the diagnosisof penicillin allergy. SPT remains the standard practicefor the evaluation of patients with immediate hyper-sensitivity reactions (IgE-mediated) to penicillin. SPTcombined with a thorough history, determination ofspecific IgE antibody level and, if indicated, a DPTshould diagnose the majority of children with penicillinallergy. Patients with proven penicillin allergy canundergo desensitisation if they require penicillin thera-py and no alternative is available. Accurate diagnosis ofpenicillin allergy is essential to avoid the morbidity,mortality and economic cost associated with unneces-sary withholding of this drug in non-allergic patients.

Declaration of conflict of interestThe authors declare no conflict of interest.

REFERENCES1. McCaig LF, Hughes JM. Trends in antimicrobial drug prescribing

among office based physicians in the United States. JAMA 1995;273: 214-219.

2. Blanca M. Allergic reactions to penicillins. A changing world?Allergy 1995; 50: 777-782.

3. Park M, Li JTC. Diagnosis and management of penicillin allergy.Mayo Clin Proc 2005; 80: 405-410.

4. Kerr JR. Penicillin allergy: a study of incidence as reported bypatients. Br J Clin Pract 1994; 48: 5-7.

5. Joint Task Force on Practice Parameters. Executive summary ofdisease management of drug hypersensitivity: a practice parame-ter. Ann Allergy Asthma Immunol 1999; 83: 665-700.

6. Sogn DD, Evans R, Shepherd GM, et al. Results of the NationalInstitute of Allergy and Infectious Diseases collaborative clinicaltrial to test the predictive value of skin testing with major and minorpenicillin derivatives in hospitalized adults. Arch Intern Med 1992;152: 1025-1032.

7. Smith JW, Johnson JE, Cluff LE. Studies on the epidemiology ofadverse drug reactions. II An evaluation of penicillin allergy. N EnglJ Med 1966; 274: 998-1002.

8. Blanca M, Mayorga C, Torres MJ, et al. Clinical evaluation ofPharmacia CAP systemTM RAST FEIA amoxicilloyl and benzylpeni-cilloyl in patients with penicillin allergy. Allergy 2001; 56: 862-870.

9. Sanz M, Gamboa PM, de Weck AL. Clinical evaluation of in vitrotests in diagnosis of immediate allergic reactions to �-lactam antibi-otics. Allergy Clin Immunol Int 2002; 14: 185-193.

10. Torres MJ, Blanca M, Fernandez J, et al. Diagnosis of immediate aller-gic reactions to beta-lactam antibiotics. Allergy 2003; 58: 961-972.

11. Ressler C, Mendelson LM. Skin test for diagnosis of penicillin aller-gy – current status. Ann Allergy 1987; 59: 167-170.

12. Torres MJ, Romano A, Mayorga C, et al. Diagnostic evaluation of alarge group of patients with immediate allergy to penicillins: therole of skin testing. Allergy 2001; 56: 850-856.

13. Sogn DD. Penicillin allergy. J Allergy Clin Immunol 1984; 74: 589-593.

14. Sullivan TJ. Drug allergy. In: Middleton E, Reed CE, Ellis EF, et al., eds.Allergy: Principles and Practice, 4th ed. St Louis: Mosby, 1993: 1726.

15. Kelker PS, Li JT. Cephalosporin allergy. N Engl J Med 2001; 345:804-809.

16. Saxon A, Adelman DC, Patel A, Hajdu R, Calandra GB. Imipenemcrossreactivity with penicillin in humans. J Allergy Clin Immunol1988; 82: 213–217.

17. Sodhi M, Axtell SS, Callahan J, Shekar R. Is it safe to use car-bapenems in patients with a history of allergy to penicillin? J Antimicrob Chemother 2004; 54: 1155–1157.

18. Atanaskovic-Markovic M, Gaeta F. Tolerability of meropenem inchildren with IgE-mediated hypersensitivity to penicillins. Allergy2008; 63: 237-240.


Table III. Penicillin intravenous desensitisation proto-col with drugs added by piggyback infusion

Step* Penicillin Amount Dose given Cumulative(mg/ml) (ml) (mg) dose (mg)

1 0.1 0.1 0.01 0.01

2 0.1 0.2 0.02 0.03

3 0.1 0.4 0.04 0.07

4 0.1 0.8 0.08 0.15

5 0.1 1.6 0.16 0.31

6 1 0.32 0.32 0.63

7 1 0.64 0.64 1.27

8 1 1.2 1.2 2.47

9 10 0.24 2.4 4.87

10 10 0.48 4.8 10

11 10 1 10 20

12 10 2 20 40

13 100 0.4 40 80

14 100 0.8 80 160

15 100 1.6 160 320

16 1000 0.32 320 640

17 1000 0.64 640 1280

Observe patient for 30 minutes, then give full therapeutic

dose by the desired route.

Modified from Sullivan TJ.14

*Interval between doses is 15 minutes.

Fig. 3. Classes of �-lactam antibiotics.

F Estelle R Simons, MD, FRCPC

Section of Allergy and Clinical Immunology, theDepartment of Pediatrics and Child Health and theDepartment of Immunology, Canadian Institutes ofHealth Research National Training Program in Allergyand Asthma, Faculty of Medicine, University ofManitoba, Winnipeg, Manitoba, Canada

The true rate of occurrence of anaphylaxis in infants,defined arbitrarily as age newborn to 2 years, inclusive,is unknown; however, most anaphylaxis case seriesand anaphylaxis epidemiologic studies in individuals ofall ages include infants, some as young as 1 month ofage.1-3 Fatalities in anaphylaxis, although rare in infancy,do occur, and even the first episode can be fatal.4,5

CASE REPORTA 9-month-old boy with a 2-week history of cough andwheeze suddenly developed choking, coughing,labored breathing, and apnea, followed by a respiratoryarrest at home. He was resuscitated by his father andbrought to a community hospital within 6 minutes. Onarrival, he was afebrile, limp, and cyanotic, withdecreased air entry, deep retractions, and generalizedinspiratory and expiratory rhonchi. He had red, scalyareas of skin on his face, chest, and extremities, withsuperimposed raised red areas 0.5 to 1 cm in diameteron his face and chest. His weight was 9 kg; heart rate,152/min; respiratory rate, 38/min; and blood pressure,80/50mmHg. He was given supplemental oxygen, intu-bated, ventilated, and transferred to a pediatric inten-sive care unit with the diagnosis of bronchiolitis, whichwas epidemic in the region at the time. Chest radio-graph revealed minimal peribronchial thickening. Therapid antigen detection assay for respiratory syncytialvirus was negative. He responded to albuterol and wasextubated within 12 hours. In view of the atypical clini-cal picture for bronchiolitis and the rapid improvement,the diagnosis was reconsidered.

An allergy/immunology specialist was consulted, andadditional history was obtained. The infant had beenalmost exclusively breast-fed since birth; however, on 3occasions, he had developed generalized hives soonafter ingesting a cow’s milk formula supplement.Minutes before his respiratory arrest, he had tasted icecream for the first time. His eosinophil count was 1.08X 3 109/L. Cow’s milk specific IgE was 3.6 kU/L. Theallergist’s diagnoses were anaphylaxis to cow’s milk,asthma, and atopic dermatitis. Four weeks later, theskin prick test to cow’s milk was strongly positive(wheal 10 mm greater than control). Long-term riskreduction measures initiated included strict avoidanceof cow’s milk and related products, and optimized asth-ma and atopic dermatitis management. An AnaphylaxisEmergency Action Plan was developed. An epinephrineautoinjector 0.15 mg was prescribed despite recogni-tion that this dose was not ideal for a 9-kg infant.Education sessions were held with his parents.

WHAT TRIGGERS ANAPHYLAXIS IN INFANTS?Food is the most common trigger of anaphylaxis in thisage group,6-10 through direct ingestion, breast milk, oraccidental ingestion (eg, a crawling infant finds andtastes a food item); of note, skin contact with food or

food-based skin care products or inhalation ofaerosolized food particles potentially sensitizes aninfant but seldom causes anaphylaxis. Caregivers maybe unaware of the infant’s initial exposure to the food.Common culprits are cow’s milk or egg, but any foodcan be a trigger, including those presumed innocuous(eg, cow’s milk substitutes, hypoallergenic formulas6-8),those not traditionally given to infants (eg, sesame),9 orthose not previously identified as being allergenic inindividuals of any age (eg, caribou and whale meats).10

Less common triggers include medications (eg, �-lac-tam antibiotics, antipyretics such as ibuprofen, neuro-muscular blockers), natural rubber latex (nipples,pacifiers, toys), insect stings, inhalant allergens, vacci-nations for prevention of infectious diseases, and non-immune triggers such as cold exposure. Idiopathicanaphylaxis has been reported in infants.11,12

WHICH INFANTS ARE AT INCREASEDRISK FOR ANAPHYLAXIS?Clinical risk factors and comorbid diseases thatincrease the risk of anaphylaxis and of fatality in ana-phylaxis have not yet been optimally defined in infants.Atopy; common infant respiratory diseases such asbronchiolitis, asthma, and croup; and urticaria pigmen-tosa/mastocytosis are likely to be important.Comorbidities in caregivers – for example, depression,or use of sedatives, ethanol, or recreational drugs –might impede recognition of anaphylaxis in the infantfor whom they are responsible.13

HOW CAN RECOGNITION OF ANAPHY-LAXIS IN INFANTS BE IMPROVED?Physicians need to have a high index of suspicion todiagnose anaphylaxis promptly in infants, because itmay be difficult to recognize in this age group for a vari-ety of reasons. Parents, caregivers, and even healthcare professionals may not be aware of the possibilitythat anaphylaxis can occur in infancy. Many anaphylax-is episodes in infancy are ‘first’ episodes. Subjectivesymptoms of anaphylaxis such as itching cannot bedescribed by infants (Table I). Some signs of anaphy-laxis (for example, regurgitation and loose stools afterfeeding) also occur in healthy infants. The differentialdiagnosis of anaphylaxis is age-dependent (Table II).

Laboratory tests to support the clinical diagnosis ofanaphylaxis may or may not be helpful.13 Histamine lev-els need to be measured in a blood sample obtainedwithin 1 hour of symptom onset. Total tryptase levelsneed to be measured in a sample obtained within 3hours of symptom onset. Even if the sample is opti-mally timed, tryptase levels are seldom elevated infood-induced anaphylaxis. Moreover, if fatality occursand an elevated postmortem tryptase level is found,interpretation can be difficult because elevatedtryptase levels have also been reported in some infantswith sudden infant death syndrome.14

WHAT ARE THE BARRIERS TO OPTIMALMANAGEMENT OF ANAPHYLAXIS IN INFANTS?Acute management in health care settingsThe universal principles of prevention, prompt diagno-sis, rapid assessment (airway, breathing, circulation,


ANAPHYLAXIS IN INFANTS: CAN RECOGNITION

AND MANAGEMENT BE IMPROVED?

Correspondence: Prof FER Simons, e-mail: [email protected].

responsiveness, skin, and weight), and prompt treat-ment apply.1 The evidence base for the treatment ofanaphylaxis in infants is largely empirical. Epinephrineis the initial medication of first choice; however, therecommended initial dose of 0.01 mg/kg intramuscular-ly is based entirely on tradition, because no prospectiveepinephrine clinical pharmacology study has been con-ducted in infants with, or at risk of, anaphylaxis.15 Ifintravenous epinephrine is needed, care should betaken to calculate the dose accurately, dilute the epi-nephrine solution accurately, and avoid an overly rapidinfusion rate. If epinephrine overdose occurs, infantscannot report symptoms; signs include pallor, tremor,and pulmonary edema that, like anaphylaxis itself, maybe manifest by cough and respiratory distress.15 In addi-tion to epinephrine, supplemental oxygen should begiven. The airway should be established and main-tained. An intravenous line should be established.Continuous monitoring should be instituted. Additionalmedications should be administered as needed.1

Long-term risk reductionAssessment. Most episodes of anaphylaxis in infantsare IgE-mediated. Sensitization to allergens – for exam-ple, to foods – can be determined by using skin pricktests or by quantitative measurement of allergen-spe-cific IgE levels.6 Selection of allergens for testingshould be based on the history. Positive skin tests havea different appearance in infants compared with older

individuals. Like elevated allergen-specific IgE levels,they denote sensitization, but are not themselves diag-nostic of anaphylaxis or any other allergic disease. Ininfants with food allergy, physician-monitored oralincremental challenges may be helpful if the diagnosisis in doubt or if there is minimal or no evidence of sen-sitization to the suspect allergen. A challenge is strictlycontraindicated in an infant such as the one reportedhere, who has a strong clinical history of anaphylaxisand is highly sensitized to the suspect allergen.6

Equipping the infant’s caregivers for management ofanaphylaxis in the community. Risk reduction involvesvigilant allergen avoidance, which can be stressful forfamilies.13,16 Relevant comorbidities in the infant andthe caregiver should be managed optimally. Caregiversshould be equipped with injectable epinephrine for firstaid treatment in the context of an AnaphylaxisEmergency Action Plan, which can be downloadedfrom www.aaaai.org and readily adapted for use ininfants.13

EpinephrineMost infants weigh less than 15 kg. No epinephrineautoinjector currently available provides a dose of<0.15 mg,15,17 presenting a dilemma for physiciansprescribing epinephrine autoinjectors for this vulnera-ble population (see Case Report). Although expe-rienced pediatric nurses draw up and measure infantdoses from an ampule of epinephrine rapidly and accu-


Table I. Symptoms and signs of anaphylaxis in infants*

Anaphylaxis symptoms Anaphylaxis signs that are potentially Anaphylaxis signs in infants:that infants cannot describe difficult to interpret in infants, and why obvious but may be nonspecific

General: feeling of warmth, weakness, General: nonspecific behavioral changes

anxiety, apprehension, impending doom such as persistent crying, fussing,

irritability, fright

Skin/mucus membranes: itching of lips, Skin/mucus membranes: flushing (may Skin/mucus membranes: rapid

tongue, palate, uvula, ears, throat, nose, also occur with fever, hyperthermia, onset of hives (potentially

eyes, and so forth; mouth-tingling or or crying spells) difficult to discern in infants

metallic taste with acute atopic dermatitis;

scratching and excoriations, as

such, will be absent in young

infants); angioedema (face, tongue,

oropharynx)

Respiratory: nasal congestion, Respiratory: hoarseness, dysphonia Respiratory: rapid onset of

throat tightness; chest tightness; (common after a crying spell); drooling, coughing, choking, stridor,

shortness of breath increased secretions (common in infants) wheezing, dyspnea, apnea,

cyanosis

Gastrointestinal: dysphagia, nausea, Gastrointestinal: spitting up/regurgitation Gastrointestinal: sudden, profuse

abdominal pain/cramping (common after feeds), loose stools vomiting

(normal in infants, especially if breast-fed);

colicky abdominal pain

Cardiovascular: feeling faint, presyncope, Cardiovascular: hypotension; measured Cardiovascular: weak pulse,

dizziness, confusion, blurred vision, with an appropriate size blood pressure arrhythmia, diaphoresis/sweating,

difficulty in hearing, palpitations cuff, low systolic blood pressure for pallor, collapse/unconsciousness

infants is defined as less than

70 mmHg from age 1 month to 1 year,

and less than (70 mmHg 1 +

[2 x age in y]) in the first and second

years of life; tachycardia, defined as

greater than 120-130 beats per minute

from the third month to second year

of life inclusive; loss of bowel and

bladder control (ubiquitous in infants)

Central nervous system: headache Central nervous system: drowsiness, Central nervous system: rapid

somnolence (common in infants after onset of unresponsiveness,

feeds) lethargy, or hypotonia; seizures

*More than 1 body system involved.

rately, caregivers without medical training find thisextremely difficult to do.18

H1-antihistaminesIn anaphylaxis, H1-antihistamines might relieve skinsymptoms and signs but they do not relieve upper orlower airway obstruction or shock. They therefore arenot drugs of choice, are not life-saving, and do notreplace epinephrine.

The onset of action of orally administered H1-antihista-mines takes at least 1 to 2 hours. First-generation H1-antihistamines in usual doses potentially causesedation and unresponsiveness that can impede therecognition of anaphylaxis, and they can also lead torespiratory arrest in infants.19-21

Medical identificationAt-risk infants who are in the care of a babysitter orother third party should be protected by wearing accu-rate medical identification,13 such as a T-shirt or Velcropatch on clothes (Velcro USA Inc, Manchester, NH)with a specific allergy alert message, for example, ‘‘Donot give cow’s milk to this baby.’’ Medical identificationbracelets made of cloth are available for older infants.

Anaphylaxis education. Caregivers of infants reporthigh anxiety levels with regard to taking responsibilityfor the recognition and management of an anaphylaxisepisode, particularly the possibility of having to injectepinephrine.13,16 Individualized instruction and coachinghelp to diminish this anxiety.

SUMMARYAnaphylaxis is likely underrecognized in infancy. Manyepisodes are ‘first’ episodes. Infants cannot reportsymptoms. Diagnosis therefore depends on a highindex of suspicion and on physical signs. The differen-tial diagnosis of anaphylaxis in infancy includes age-unique entities such as congenital or metabolicdisorders, child abuse,

Munchausen syndrome by proxy, and sudden infantdeath syndrome. Management is based on empiricalevidence. A prospective systematic study of anaphy-laxis in infancy is needed.

AcknowledgementI gratefully acknowledge the assistance of Ms Lori McNiven.

This article was published in Journal of Allergy and Clinical Immunology

2007; vol 120, pp 537-540, Simons FER, Anaphylaxis in infants: can

recognition and management be improved? Copyright American

Academy of Allergy, Asthma & Immunology (2007). Reprinted with per-

mission of the author and copyright holder.

Declaration of conflict of interestThe author declares no conflict of interest.

REFERENCES1. Young MC. General treatment of anaphylaxis. In: Leung DYM,

Sampson HA, Geha RS, Szefler SJ, editors. Pediatric allergy princi-ples and practice. St Louis (MO): Mosby, Inc; 2003. p. 643-54.

2. Simons FER, Chad ZH, Gold M. Anaphylaxis in children: real-timereporting from a national network. Allergy Clin Immunol: Int J WorldAllergy Org 2004;(suppl 1): 242-4.

3. Mehl A, Wahn U, Niggemann B. Anaphylactic reactions in children:a questionnaire-based survey in Germany. Allergy 2005; 60: 1440-5.

4. Pumphrey RSH, Gowland MH. Further fatal allergic reactions tofood in the United Kingdom, 1999-2006. J Allergy Clin Immunol2007; 119: 1018-9.

5. Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphy-lactic reactions to foods. J Allergy Clin Immunol 2001; 107: 191-3.

6. Sampson HA. Update on food allergy. J Allergy Clin Immunol 2004;113: 805-19.

7. Pessler F, Nejat M. Anaphylactic reaction to goat’s milk in a cow’smilk-allergic infant. Pediatr Allergy Immunol 2004; 15: 183-5.

8. Levin ME, Motala C, Lopata AL. Anaphylaxis in a milk-allergic childafter ingestion of soy formula cross-contaminated with cow’s milkprotein. Pediatrics 2005; 116: 1223-5.

9. Dalal I, Binson I, Reifen R, Amitai Z, Shohat T, Rahmani S, et al.Food allergy is a matter of geography after all: sesame as a majorcause of severe IgE-mediated food allergic reactions among infantsand young children in Israel. Allergy 2002; 57: 362-5.

10. Roberts JR, Gerstner TV, Grewar DA, Dilay DJ, Cochrane-FonesRD, Bouwman TS. Allergy to caribou and seal meats in Inuit children:a report of three cases. J Allergy Clin Immunol 2006; 117: S42.

11. Kimata H. Latex allergy in infants younger than 1 year. Clin ExpAllergy 2004; 34: 1910-5.

12. Hogan MB, Kelly MA, Wilson NW. Idiopathic anaphylaxis in chil-dren. Ann Allergy Asthma Immunol 1998; 81: 140-2.

13. Simons FER. Anaphylaxis, killer allergy: long-term management inthe community. J Allergy Clin Immunol 2006; 117: 367-77.

14. Buckley MG, Variend S, Walls AF. Elevated serum concentrationsof beta-tryptase, but not alpha-tryptase, in sudden infant death syn-drome (SIDS): an investigation of anaphylactic mechanisms. ClinExp Allergy 2001; 31: 1696-704.

15. Simons FER. First-aid treatment of anaphylaxis to food: focus onepinephrine. J Allergy Clin Immunol 2004; 113: 837-44.

16. Bansal PJ, Marsh R, Patel B, Tobin MC. Recognition, evaluation,and treatment of anaphylaxis in the child care setting. Ann AllergyAsthma Immunol 2005; 94: 55-9.

17. Simons FER, Peterson S, Black CD. Epinephrine dispensing for theout-of-hospital treatment of anaphylaxis in infants and children: apopulation-based study. Ann Allergy Asthma Immunol 2001; 86:622-6.

18. Simons FER, Chan ES, Gu X, Simons KJ. Epinephrine for the out-of-hospital (first aid) treatment of anaphylaxis in infants: is theampule/syringe/needle method practical? J Allergy Clin Immunol2001; 108: 1040-4.

19. Simons FER. Advances in H1-antihistamines. N Engl J Med 2004;351: 2203-17.

20. Sheikh A, ten Broek VM, Brown SGA, Simons FER. H1-antihista-mines for the treatment of anaphylaxis with and without shock.Cochrane Database Syst Rev 2007; 1: CD006160.

21. Starke PR, Weaver J, Chowdhury BA. Boxed warning added topromethazine labeling for pediatric use [letter]. N Engl J Med 2005;352: 2653.


Table III. Differential diagnosis of anaphylaxis ininfants

Skin: urticaria; urticaria pigmentosa/mastocytosis, heredi-

tary angioedema

Respiratory (upper or lower respiratory tract): obstruction,

congenital (eg, laryngeal web, vascular ring, malacias) or

acquired (eg, aspiration of foreign body,* croup, bronchi-

olitis, asthma); asphyxiation/suffocation; breath-holding

Gastrointestinal tract†: obstruction, congenital (eg, pyloric

stenosis, malrotation) or acquired (eg, intussusception)

Shock: septic, cardiovascular, hypovolemic

Central nervous system: seizure, post-ictal state, stroke,

trauma, child abuse, increased intracranial pressure

Metabolic disorders

Infectious diseases: eg, pertussis, gastroenteritis,

meningitis

Ingestion of poison or toxin (eg, food, drug, plant); drug

overdose

Munchausen syndrome by proxy

Sudden infant death syndrome

Other

*Peanuts and tree nuts account for one third of foreign body aspi-

rations, as well as being common triggers of anaphylaxis.†Infants with gastrointestinal anaphylaxis present with abdominal

pain/ cramps and vomiting with or without diarrhea minutes to a

few hours after ingestion of the culprit food.

Cas Motala, MB ChB, FCPaeds(SA), FACAAI, FAAAAI

Allergy Clinic, Division of Paediatric Medicine, School ofChild & Adolescent Health, University of Cape Town &Red Cross War Memorial Children's Hospital,Rondebosch, Cape Town, South Africa

CLASSIFICATIONH1 antihistamines are classified into the older, or first-generation, antihistamines, and the newer, or second-generation, antihistamines. The main differencesbetween the two generations of drugs are their propen-sity to cause central nervous system (CNS) side-effects. The commonly used members of these drugclasses are listed in Table I. The highly lipophilic natureof the first-generation antihistamines allows them topenetrate well into the CNS where they induce seda-tion. The potential to enhance the central effects ofalcohol and other CNS sedatives further limits suchuse. In addition, many of these drugs also have actionswhich reflect their poor receptor selectivity, includingan atropine-like effect (anticholinergic) and blockade ofboth �-adrenergic and 5-hydroxytryptamine receptors(muscarinic effect) Tachyphylaxis is also a problem withthe use of the older antihistamines.

The second-generation H1 antihistamines cause muchreduced CNS sedation and are essentially free of thiseffect at doses recommended for the treatment ofallergic disorders. In addition, these drugs have few orno anticholinergic or other effects. Some second-gen-eration drugs have also been claimed to have anti-aller-gic and anti-inflammatory effects which may contributeto their therapeutic benefit.1

MECHANISM OF ACTIONH1 antihistamines are not receptor antagonists as pre-viously thought, but are inverse agonists.2 When nei-ther histamine nor antihistamine is present, the activeand inactive states of the H1 receptor are in equilibriumor a balanced state. Histamine combines preferentiallywith the active form of the receptor to stabilise it andshift the balance towards the activated state and stim-ulate the cell (Fig. 1).3 Antihistamines stabilise the inac-tive form and shift the equilibrium in the opposite direc-tion. Thus, the amount of histamine-induced stimula-tion of a cell or tissue depends on the balance betweenhistamine and H1 antihistamines.

Histamine effects stimulated through the H1 receptorinclude pruritus, pain, vasodilatation, vascular perme-ability, hypotension, flushing, headache, tachycardia,bronchoconstriction, and stimulation of airway vagalafferent nerves and cough receptors as well asdecreased atrioventricular-node conduction. Althoughmost of the effects of histamine in allergic diseases aremediated by H1 receptor stimulation, certain effectssuch as hypotension, tachycardia, flushing, headache,itching and nasal congestion are mediated through bothH1 and H2 receptors.4

In the CNS, the effects histamine exerts through H1

receptors include cycle of sleep and waking, foodintake, thermal regulation, emotion and aggressivebehaviour, locomotion, memory and learning. First-generation H1 antihistamines, such as chlorphenamine,diphenhydramine, hydroxyzine and promethazine, pen-etrate readily into the brain, in which they occupy 50-90% of the H1 receptors.5 The result is CNS sedation.In contrast, second-generation H1 antihistamines pene-trate the CNS poorly, as they are actively pumped outby P-glycoprotein, an organic anion transporting proteinthat is expressed on the luminal surfaces of vascularendothelial cells in the blood vessels that constitute theblood-brain barrier.6 Their propensity to occupy H1

receptors in the CNS varies from 0% for fexofenadineto 30% for cetirizine. Thus, second-generation H1 anti-histamines are relatively free of sedating effects.

Through H1 receptors histamine has various effects onthe immune system, including the maturation of den-dritic cells and modulation of the balance of helper T-celltype 1 (Th1) and Th2 towards Th1. Histamine alsoinduces the release of pro-inflammatory cytokines2

(pro-inflammatory activity). Because histamine hassuch effects on allergic inflammation and the immunesystem, treatment with H1 antihistamines reduces theexpression of pro-inflammatory cell adhesion mole-cules and the accumulation of inflammatory cells, suchas eosinophils and neutrophils. Major clinical effects ofH1 antihistamines are seen in suppression of the earlyresponse to allergen challenge in the conjunctiva, nose,lower airway and skin.


H1 ANTIHISTAMINES IN ALLERGIC DISEASE

ABSTRACTHistamine (one of the key mediators released frommast cells and basophils), plays a major role in thepathophysiology of allergic diseases, including rhini-tis, urticaria, asthma and anaphylaxis. Histamineexerts its effects through its interaction with one offour distinct receptors (H1, H2, H3, H4). In allergic dis-ease, it is the H1 antihistamines which are of prima-ry benefit, although H2 antihistamines may also playa therapeutic role.

H1 antihistamines remain first-line medications forthe treatment of allergic rhinoconjunctivitis andurticaria. Second-generation antihistamines are pre-ferred to their predecessors because of better bene-fit-to-risk ratios. The newer antihistamines are notonly more potent, but also have anti-allergic and anti-inflammatory properties. Although they are moreexpensive than the traditional antihistamines, thecost is substantially offset by their superior efficacyand safety profile when used in recommendeddosages.

Correspondence: Prof CasMotala, [email protected]

Table I. Common H1- receptor antagonists

First generation Second generation*

Hydroxyzine Cetirizine

Diphenhydramine Loratadine

Chlorpheniramine Desloratadine

Promethazine Fexofenadine

Levocetirizine

*Two earlier developed agents, astemizole and terfenadine, were

withdrawn in 1986 because of cardiac toxicity adverse effects.

PHARMACOKINETIC PROPERTIESH1-receptor antagonists are well absorbed from thegastrointestinal tract after oral administration. Theironset of effect occurs within 1-3 hours; their durationof action varies from several hours to 24 hours, (sec-ond-generation drugs being generally around 24 hours)(Table II).7 First-generation antihistamines and some ofthe second-generation agents are oxidativelymetabolised by the hepatic cytochrome P450 system,the exceptions being levocetirizine, cetirizine, and fexo-fenadine.8 Levocetirizine and cetirizine are excretedlargely unchanged in urine and fexofenadine is excret-ed mainly in the faeces but also the urine.8 Hepaticmetabolism has several implications: prolongation ofthe serum half-life in patients with hepatic dysfunctionand those receiving concomitant cytochrome P450inhibitors, such as ketoconazole and erythromycin.Also, longer duration of action is found in elderlypatients who have reduced liver function. In thesepatients there is a possibility of precipitating seriousunwanted cardiac or CNS effects. Such adverseeffects are more likely to occur with first-generationrather than second-generation antihistamines. Con-comitant administration of probenicid reduces the totalbody and renal clearance of fexofenadine.9 The bio-availability of fexofenadine may be altered by simulta-neous consumption of grapefruit juice (reduced rateand absorption of the drug by almost 30%)10 (However,grapefruit juice does not affect the absorption of othersecond-generation antihistamines. Although topicalintranasal and ophthalmic H1 antihistamines differ intheir pharmacokinetics, most of the topical prepara-tions need to be administered twice daily because ofthe washout from the nasal mucosa or conjunctiva.

CLINICAL USES IN ALLERGIC DISEASEH1 antihistamines currently constitute the largest classof medications used in the treatment of allergic disor-der, allergic rhinoconjunctivitis and urticaria in particu-

lar. Formulations and dosages of the newer antihista-mines are listed in Tables III and IV.

Allergic rhinoconjunctivitisIn patients with allergic rhinitis (AR) both first- and sec-ond-generation H1 antihistamines have proven to behighly effective in relieving sneezes, itching, and nasaldischarge but not nasal blockage. First-generation H1

antihistamines have an unsatisfactory benefit-to-riskration in allergic rhinoconjunctivis. In seasonal andperennial rhinitis, the evidence base for their use issmall. Dosage recommendations are empirical. In sea-sonal AR, there is a large evidence base for the use ofsecond-generation oral H1 antihistamines such as ceti-rizine, desloratadine, fexofenadine, loratadine.11-14

Efficacy has been well documented in hundreds of ran-domised, double-blind, placebo-controlled, parallel-group clinical trials involving thousands of participants.In perennial AR, the evidence base for second-genera-tion H1 antihistamines use is growing and the efficacyof cetirizine, desloratadine, fexofenadine, loratadine,and levocetirizine has been documented.15-17 Regulardaily administration is associated with a significantdecrease in symptoms and nasal mucosal inflamma-tion compared with 'as needed' or 'on demand' use.18

H1 antihistamines provide relief of allergic rhinitis com-parable to that provided by intranasal cromolyn sodium4% and are generally found to be less potent thanintranasal corticosteroids in the treatment of AR symp-toms. Leukotriene receptor antagonists (LRAs) mayalso be effective in certain patients with AR if com-bined with an antihistamine. In allergic conjunctivitis,the ocular symptoms induced by allergen, such as itch-ing, tearing and reddening are reduced by administra-tion of H1 antihistamines either systemically or topical-ly as eye drops such as azelastine, ketotifen, levo-cabastine and olopatadine. Topical application usuallyresults in faster onset of action – within 5 minutes –than oral administration.19


Table II. Pharmacokinetics of second-generation oral H1 antihistamines (mean ± SD)

H1 antihistamines Tmax (h) after Terminal elimination % eliminated unchanged Duration of(metabolite) a single dose half-life (t1/2, h) in the urine/faeces action (h)

Cetirizine 1.0 ± 0.5 6.5-10 60/10 ≥24

Loratadine 1.2 ± 0.3 7.8 ± 4.2 Trace 24

Desloratadine 1-3 27 0 ≥24

Fexofenadine 2.6 14.4 12/80 24

Levocetirizine 0.8 ± 0.5 7 ± 1.5 86 ≥24

Adapted from Simons et al.7

Fig. 1. Simplified two-state compartment model of the histamine H1-receptor. Adapted from Leurs et al.3

Acute and chronic urticariaH1 antihistamines are first-line medications in acuteand chronic urticaria and very effective in providingsymptomatic relief. The evidence base for the use ofH1 antihistamines in acute urticaria remains small; how-ever, recently, in a prospective, randomised, double-blind, placebo-controlled, 24-month-long study, high-risk children given cetirizine had significantly fewerepisodes of acute urticaria than did those given place-bo.20 Although the evidence base for the use of first-generation H1 antihistamines in chronic urticaria alsoremains surprisingly small by current standards, that forsecond-generation H1 antihistamines (e.g. fexo-fenadine) has increased considerably during the pastfew years.21-23 In chronic urticaria, H1 antihistaminesshould optimally be given on a regular basis to preventhives from appearing, rather than 'as needed'.

Atopic dermatitisIn atopic dermatitis (AD), itching is one of the majorsymptoms and the resultant scratching usually causesworsening of the lesion. H1 antihistamines may relieveitching and reduce scratching. Relief of itching by H1

antihistamines is often incomplete in AD, because theitching produced by mediators other than histamine isnot down-regulated. H1 antihistamines appear torelieve itching mainly through their CNS effects andthus first-generation H1 antihistamines (sedating) suchas hydroxyzine and diphenhydramine are more effec-tive for relief of itching in this disorder than are the sec-ond-generation H1 antihistamines (non-sedating).24

However, recent studies have shown that second-gen-eration medications such as cetirizine and loratadinemay also relieve itching in AD.25-27 In higher doses, cet-irizine has been demonstrated to have a topical gluco-corticoid-sparing effect in AD.

AnaphylaxisAdrenaline is the first-line treatment in anaphylaxis.Antihistamines are considered adjunctive treatment forrelief of itching, urticaria, rhinorrhoea, and other symp-toms.28 Because first-generation H1 antihistaminessuch as chlorpheniramine, diphenhydramine, and

hydroxyzine have highaqueous solubility andare available in par-enteral formulationsfor injection, they con-tinue to be widelyused in the treatmentof anaphylaxis. Most ofthe second-generationH1 antihistamines havelow aqueous solubilityand none is available informulation for injec-tion. Antihistaminesalso have a potentialrole in prevention ofanaphylaxis. In anaphy-laxis, many of theeffects of histamine,such as vasodilationand hypotension,occur as a result of itseffects at both H1

and H2 receptors.4,29 H1

and H2 antihistaminesgiven concomitantlydecrease the frequen-cy and severity ofthese reactions, androutine prophylaxis

with these medications has been proposed.29 The pro-phylaxis pretreatment or treatment with both an H1 andH2 antihistamine may be more effective than pretreat-ment with an H1 antihistamine alone. Second-genera-tion H1 antihistamines, administered orally, preventallergic reactions in patients receiving immunotherapy.30

AsthmaIn asthma, current evidence does not support the useof antihistamines for treatment. However, second-gen-eration antihistamines are reported to reduce symp-toms of allergic asthma in certain patients and exacer-bation of asthma in adult patients with AR. The amountof improvement produced by H1 antihistamines in asth-ma is modest.31

USE IN PREGNANCY AND LACTATIONChlorpheniramine, one of the first-generation antihista-mines, is reportedly safe in pregnancy. There is littleinformation on the use of the new antihistamines dur-ing pregnancy although cetirizine and loratadine areconsidered relatively safe for use during pregnancy(FDA category B).32-34

H1 antihistamines are excreted in small amounts inbreast milk (<0.1% of a maternal dose). Breast-fedinfants whose mothers have ingested first-generationantihistamines may experience irritability, drowsinessor respiratory depression;35 no symptoms have beenattributed to second-generation antihistamines to date.

ADVERSE EFFECTSThe adverse effects of first-generation H1 antihista-mines, mainly on the CNS, including drowsiness,impaired driving performance, fatigue, lassitude, anddizziness, are well documented. Other side-effects(anticholinergic) include dry mouth, urinary retention,gastrointestinal upset and appetite stimulation.Although the new-generation antihistamines are rela-tively free of serious CNS effects, a small number ofindividuals may experience sedation with theseagents. Minor side-effects such as nausea, lighthead-edness, drowsiness, headaches, agitation and dry


Table III. Formulations and dosages of second-generation oral antihistamines

Generic name Formulation Recommended dosage

Tablet Syrup Adult Paediatric

Cetirizine 10 mg 5 mg/5 ml 5-10 mg od 5-10 mg od (6-11 yrs)

6 mo - 5 yr

2.5-5 mg od

Loratadine 10 mg 5 mg/5 ml 10 mg od (6-10 yr)10 mg or

(2-9 yr) 5 mg

Desloratadine 5 mg N/A 5 mg od (≥12 yr) 5 mg od

Fexofenadine 60 mg, N/A 60 mg bd or (≥12 yr) 60 mg bd

120 mg, 120-180 mg od or 120-180 mg od

180 mg

Levocetirizine 5 mg N/A 5 mg od (≥6 yr) 5 mg od

Table IV. Second-generation topical antihistamines

Generic name Formulation Recommended dosage

Azelastine Nasal soln 0.1% Adult & paediatric ≥12 yr:

2 sprays/nostril bd

Ketotifen 0.025% ophthalmic soln Adult & paediatric ≥3 yr: 1 drop/eye bd

Levocabastine Nasal spray 50 mg/puff Adult: 2 sprays/nostril bd – qid

Olopatadine 0.1% ophthalmic soln Adult & paediatric >3 yr: 1 drop/eye

mouth have been reported occasionally with the newantihistamines. Weight gain (due to increased appetite)has also been reported in a few patients treated withcetirizine. Hypersensitivity reactions, including skinrashes and angio-oedema may also occur. In recom-mended dosages, the new antihistamines are general-ly safe. Toxicity associated with the new anthistaminesis usually related to increased drug levels (due to over-dosage or impaired metabolism). Symptoms of over-dosage include drowsiness and agitation (especially inchildren).

First-generation H1 antihistamines may cause tachycar-dia, supraventricular arrhythmia, and prolongation ofthe QT interval in a dose-dependent manner. Two sec-ond-generation antihistamines, astemizole andterfenadine, were withdrawn from the market becauseof their cardiac toxic effects (torsades de pointes andother potentially fatal ventricular arrhythmias).Cetirizine, levocetirizine fexofenadine, loratadine anddesloratadine appear to be free from cardiac toxicityeven at higher than recommended doses.36,37


REFERENCES1. Assanasen P, Naclerio RM. Anti-allergic, anti-inflammatory effects

of H1 antihistamines in humans. In: Simons FER, ed. Histamine andH1 Antihistamines in Allergic Disease, 2nd ed. New York: MarcelDekker, 2002: 101.

2. Bakker RA, Wieland K, Timmerman H, et al. Constitutive activity ofthe histamine H(1) receptor reveals inverse agonism of histamineH(1)receptor antagonists. Eur J Pharmacol 2000; 387: R5-7.

3. Leurs R, Church MK, Taglialatela M. H1 antihistamines: inverse ago-nism, anti-inflammatory actions and cardiac effects. Clin ExpAllergy 2002; 32: 489-498.

4. Lorenz W, Duda D, Dick W, et al. Incidence and clinical importanceof periperative histamine release: randomised study of volumeloading and antihistamines after induction of anaesthesia. Lancet1994: 343: 933-940.

5. Tagawa M, Kano M, Okamura N, et al. Neuroimaging of histamineH1-receptor occupancy in human brain by positron emissiontomography (PET): a comparative study of ebastine, a second-gen-eration antihistamine, and (+)-chlorpheniramine, a classical antihis-tamine. Br J Clin Pharmacol 2001; 52: 501-509.

6. Chishty M, Reichel A, Siva J, et al. Affinity for the P-glycoproteinefflux pump at the blood-brain barrier may explain the lack of CNSside-effects of modern antihistamines. J Drug Target 2001; 9: 223-228.

7. Simons FER. Antihistamines. In: Middleton E, Reed CE, Ellis EF, et al., eds. Allergy: Principles and Practice. St Louis: Mosby, 2006:834-868.

8 Devillier P, Roche N, Faisy C. Clinical pharmacokinetics and phar-macodynamics of desloratadine, fexofenadine and levocetirizine: acomparative review. Clin Pharmacokinet 2008; 47: 217-230.

9 Liu S, Beringer PM, Hidayat L, et al. Probenecid, but not cysticfribrosis, alters the total and renal clearance of fexofenadine. J ClinPharmacol 2008; 48: 957-965.

10 Banfield C, Gupta S, Marino M, Lim J, Affrime M. Grapefruit juicereduces the oral bioavailability of fexofenadine but not deslorata-dine. Clin Pharmacokinet 2002; 41: 311-318.

11 Van Cauwenberge P, Juniper EF. Comparison of the efficacy, safe-ty and quality of life provided by fexofenadine hydrochloride120mg, loratadine 10mg, and placebo administered once daily forthe treatment of seasonal allergic rhinitis. Clin Exp Allergy 2000;30: 891-899.

12 Howarth PH, Stern MA, Roi L, et al. Double-blind, placebo-con-trolled study comparing the efficacy and safety of fexofenadinehydrochloride (120 and 180 mg once daily) and cetirizine in sea-sonal allergic rhinitis. J Allergy Clin Immunol 1999; 104: 927-933.

13 Leynadier F, Mees K, Arendt C, et al. Efficacy and safety of levo-cetirizine in seasonal allergic rhinitis. Acta Otorhinolaryngol Belg2001; 55: 305-312.

14 Meltzer EO, Prenner B, Nayak A, et al. Efficacy and tolerability of

once-daily 5mg desloratadine, an H1 receptor antagonist, inpatients with seasonal allergic rhinitis: assessment during thespring and fall allergy seasons. Clin Drug Invest 2001; 21: 25.

15 Ciprandi G, Cosentino C, Milanese M, et al. Fexofenadine reducesnasal congestion in perennial allergic rhinitis. Allergy 2001; 56:1068-1070.

16 Aaronson DW. Evaluation of cetirizine in patients with allergic rhini-tis and perennial asthma. Ann Allergy Asthma Immunol 1996; 76:440-446.

17 Simons FER, Prenner BM, Finn JA, for the Desloratadine StudyGroup. Efficacy and safety of desloratadine in the treatment ofperennial allergic rhinitis. J Allergy Clin Immunol 2003; 111: 617-622.

18 Ciprandi G, Ricca V, Passalacqua G, et al. Seasonal rhinitis and aze-lastine: long- or short-term treatment? J Allergy Clin Immunol1997; 99: 301-307.

19 Aguilar A. Comparative study of clinical efficacy and tolerance inseasonal allergic conjunctivitis management with 0.1% olopatadinehydrochloride versus 0.05% ketotifen fumarate. Acta OphthalmolScand 2000; 78(suppl 230): 52.

20 Simons FER, on behalf of the ETAC Study Group. Prevention ofacute urticaria in young children with atopic dermatitis. J AllergyClin Immunol 2001; 107: 703-706.

21 La Rosa M, Leonardi S, Marchese G, et al. Double-blind multicen-ter study on the efficacy and tolerability of cetirizine compared withoxatomide in chronic idiopathic uricaria in preschool children. AnnAllergy Asthma Immunol 2001; 87: 48.

22 Paul E, Berth-Jones J, Ortonne JP, et al. Fexofenadine hydrochlo-ride in the treatment of chronic idiopathic urticaria: a placebo-con-trolled, parallel-group, dose-ranging study. J Dermatol Treat 1998;9: 143.

23 Ring J, Hein R, Gauger A, et al. Once-daily desloratadine improvesthe signs and symptoms of chronic idiopathic urticaria: a random-ized, double-blind, placebo-controlled study. Int J Dermatol 2001;40: 72-76.

24 Klein PA, Clark RA. An evidence-based review of the efficacy ofantihistamines in relieving pruritus in atopic dermatitis. ArchDermatol 1999; 135: 1522-1525.

25 Hannuksela M, Kalimo K, Lammintausta K, et al. Dose rangingstudy: cetirizine in the treatment of atopic dermatitis in adults. AnnAllergy 1993; 70: 127-133.

26 Lnageland T, Fagertun HE, Larsen S. Therapeutic effect of lorata-dine on pruritus in patients with atopic dermatitis: a multi-crossover-designed study. Allergy 1994; 49: 22-26.

27 Diepgen TL, on behalf of the ETAC Study Group. Long term treat-ment with cetirizine of infants with atopic dermatitis: a multi-coun-try, double-blind, randomized , placebo-controlled trial (the ETACtrial) over 18 months. Pediatr Allergy Immunol 2002; 13: 278-286.

28 Winbery SI, Lieberman PL. Histamine and antihistamines in ana-phylaxis. In: Simons FER, ed. Histamine and H1 Antihistamines inAllergic Disease, 2nd ed. New York: Marcel Dekker, 2002: 287.

29 Doenicke A, Moss J, Toledano A, et al. Administration of H1 and H2

antagonists for chemoprophylaxis: a double-blind, placebo-controlledstudy in healthy volunteers. J Clin Pharmacol 1997; 37: 140-146.

30 Muller U, Hari Y, Berchtold E. Premedication with antihistaminesmay enhance efficacy of specific-allergen immunotherapy. J Allergy Clin Immunol 2001; 107: 81-86.

31 Ratner PH and the Desloratadine Study Group. Desloratadineimproved asthma symptoms and reduced bronchodilator use in 2studies of patients with asthma and SAR. Ann Allergy AsthmaImmunol 2001; 86: 109.

32 Schatz M. H1 antihistamines in pregnancy and lactation. In: SimonsFER, ed. Histamine and H1 Antihistamines in Allergic Disease, 2nded. New York: Marcel Dekker, 2002: 421.

33 Seto A, Einarson T, Koren G. Pregnancy outcome following firsttrimester exposure to antihistamines: meta-analysis. Am JPerinatol 1997; 14: 119.

34 Moretti ME, Caprara D, Coutinho CJ, et al. Fetal safety of loratadineuse in the first trimester of pregnancy: a multicenter study. J Allergy Clin Immunol 2003; 111: 479-483.

35 Ito S. Drug therapy for breast-feeding women. N Engl J Med 2000;343: 118-126.

36 Yap YG, Camm AJ. Potential cardiac toxicity of H1 antihistamines.In: Simons FER, ed. Histamine and H1 Antihistamines in AllergicDisease, 2nd ed. New York: Marcel Dekker, 2002: 389.

37 Craig-McFeely PM, Freemantle SL, Pearce GL, et al. Experience offexofenadien and cardiac side effects in general practice use inEngland. Pharmacoepidemiol Drug Saf 1999: 8(suppl 2): S108.


Nelandra Chetty, MB ChB, FCPaed (SA), Dip Allergy

Chatsworth, Durban, South Africa

INTRODUCTIONOne of the commonest reasons why patients presentto primary care physicians and to emergency depart-ments is because of an exacerbation of their asthmasymptoms. Knowledge of the factors contributing tosuch exacerbations helps the physician to understandwhy these episodes occur, thereby enabling moreeffective work-up and management.

Various reasons why patients who are steroid-naive orwell controlled on inhaled corticosteroids develop anexacerbation of their asthma symptoms include respi-ratory infections (viral, bacterial, atypical), allergens(aeroallergens, food additives and food allergens),exposures (occupational sensitisers, environmental,drugs), and miscellaneous factors (�-adrenergic recep-tor polymorphisms and non-respiratory factors) (Fig. 1).These trigger factors result in multicellular inflamma-tion, bronchial hyperresponsiveness and airflowobstruction.

INFECTIONSViral infectionsViral infections of the respiratory tract are associatedwith 80-85% of asthma exacerbations with two-thirdsof these infections being due to picornaviruses (mainly

rhinoviruses). Coronavirus, the next most commonvirus, causes a less severe exacerbation while influen-za, parainfluenza, adenovirus and respiratory syncytialvirus occur in a proportion of patients.1 Human meta-pneumovirus (HMNV), a paramyxovirus closely relatedto respiratory syncytial virus (RSV) has been associatedwith acute wheezing exacerbations especially in infantsand young children.2 Up to 12% of all lower respiratorytract infections may be due to HMNV in this agegroup.3 In South African children, the prevalence ofHMNV was found to be 8.3% among those presentingwith acute wheezing, while 7.4% were infected withhuman bocavirus and 2.4% with human coronavirus.4

In addition, viruses and aeroallergens may have a syn-ergistic effect on individuals with asthma, thus having agreater effect on the exacerbation rate together thaneither factor alone.5

Respiratory syncytial virusRespiratory syncytial virus (RSV) is an important causeof viral bronchiolitis in infants and young children, buttheir role in the pathogenesis of asthma and asthmaexacerbations remains unclear. RSV infects almost100% of children by 2 years of age.6 There are 2 sub-groups of RSV-induced bronchiolitis, an eosinophil-pos-itive group (with significantly raised eosinophil andinterleukin-5 (IL-5) levels and raised IL-5/interferon(IFN)-� ratios in bronchoalveolar lavage fluid) whichresults in a T-helper (Th) 2 type response, and aneosinophil-negative group (with an absence of the Th2cytokine profile). Since childhood asthma also inducesa strong Th2 immune response, it is likely that infantswith eosinophil-positive RSV-induced bronchiolitis, goon to develop childhood asthma.7 RSV is the predomi-nant pathogen in wheezing infants younger than 2years of age.8

RhinovirusRhinovirus (RV) is the most commonly recovered virusfrom the lower respiratory tract in acute exacerbationsof asthma in children over the age of 2 years.1,8 It waspreviously thought that RV primarily caused an infec-tion in the upper respiratory tract, but we now know


ASTHMA EXACERBATIONS –A REVIEW

ABSTRACTExacerbation of asthma is a distinct clinical entitywhich results in a deterioration of asthma controlsufficient to require medical intervention. Suchexacerbations should be differentiated from poorasthma control due to inadequate anti-inflammatoryor bronchodilator therapy. Asthma exacerbationsadversely affect patient and family quality of life,result in time off work or school and cause signifi-cant costs to health care resources.

Correspondence: Dr N Chetty, PO Box 561067, Chatsworth 4030. Tel 031-403-8613, fax 031-403-8614, e-mail [email protected]

Fig. 1. Causes of asthma exacerbations.

Asthma exacerbation

Infections

Viral Bacterial Atypical DrugsBeta-

adrenergic polymorphisms

Non-respiratoryfactorsEnvironmentalOccupational

sensitisers

Food additives

Foodallergens

Aero-allergens

Allergens Exposures Miscellaneous

that optimal replication of RV occurs between 33°C and35°C, and thermal mapping of the airways in humansconfirms that the temperatures found in the tracheaand subsegmental bronchi will allow RV to replicateeffectively in the lower respiratory epithelium.9 Thereare currently about 150 serotypes of RV and the major-ity (>90%) of the serotypes bind to intercellular adhe-sion molecule 1 (ICAM 1). The major human RV recep-tor is ICAM-1, and the gene for this receptor is locatedon chromosome 19.10 RV infection of the lower respira-tory tract markedly increases cell surface expression ofICAM-1 in bronchial and respiratory epithelial cells byinduction of ICAM-1 promoter activity involving upregu-lation of NF-�B, together with increasing ICAM-1 mRNAtranscription.11 The net result is an increased RV infiltra-tion of epithelial cells of the lower respiratory tract.

IFNs are antiviral proteins with an important role in theinnate immune response to viral infections. Asthmaticbronchial epithelial cells have a deficient innateimmune response to infection with RV in that they pro-duce more than 2.5 times less IFN-� protein, and thisimpairs the infected cell’s ability to undergo apoptysis,thereby allowing increased viral replication to occur.12

Patients with allergic asthma also produce significantlylower amounts of IFN-� following viral respiratory infec-tions.13 Deficient induction of IFN-� by RV in asthmaticbronchial epithelial cells has also been demonstrated.14

This paves the way for rhinoviral infection of the respi-ratory epithelial cells.

The next step is activation of the respiratory epithelialcells to produce pro-inflammatory mediators. RV infec-tion results in an increased mRNA expression andtranslation of IL-6, IL-8, IL-16, eotaxin and RANTES(Regulated on Activation, Normal T cell Expressed andSecreted). IL-6 and IL-8 are pro-inflammatory cytokines.IL-8 is a potent chemoattractant for neutrophils.Neutrophils predominate more frequently thaneosinophils as the major inflammatory cell in sputumfrom patients with asthma in acute exacerbations fol-lowing viral infections.15 RANTES is a chemokine withchemoattractant activity for eosinophils, monocytesand T-lymphocytes. IL-16 activates eosinophils and is achemoattractant for lymphocytes.16 Generation of thesecytokines results in deterioration of lung function.

Bacterial infectionsClinical and experimental studies indicate that sinonasalinflammation can result in worsening of lower airwaysdisease, induced by post-nasal drip, nasobronchialreflex or inflammatory mediators. Organisms whichmay be cultured in maxillary sinus aspirates includeMoraxella catarrhalis, nontypeable Haemophilus influen-zae and streptococcal pneumonia. Effective medicaland surgical treatment of sinusitis may result in clinicalimprovement of the asthma symptoms.17 Furthermore,chronic sinusitis has been suggested as playing a causalrole in difficult-to-control asthma.

Asthma is an independent risk factor for invasive pneu-mococcal disease. The respiratory airways of asthmat-ics display goblet cell hyperplasia, which results inincreased production of mucus. Alterations in thesecreted mucus results in abnormalities in viscosityand in the mucociliary clearance of the airways whichcan serve as a focus for localised infection that candevelop into invasive bacterial infection.18

Atypical bacterial infectionsMycoplasma pneumoniae and Chlamydophila pneumo-niae are significantly related to wheezing in children,especially in those with a history of recurrentepisodes.19 This suggests a potential role for these

pathogens in the exacerbation of childhood asthma. Inchildren with wheezing, the incidence of M. pneumoni-ae and C. pneumoniae infections increases with ageand occurs mainly after 5 years of age.20

Telithromycin, a new ketolide antibiotic, as well asmacrolide antibiotics, has shown benefit in adults withacute exacerbations of asthma.20,21 Although the exactmechanism of the benefit is unclear, the findings sug-gest that atypical bacterial infections may be related toacute asthma exacerbations. However, it needs to beremembered that the ketolide and macrolide antibioticshave also been shown to have immunomodulatoryeffects both in vitro and in vivo, on the migration ofneutrophils and production of pro-inflammatorycytokines.22,23 Therefore, more research and under-standing are needed to define the precise roles of atyp-ical bacteria in asthma exacerbations and the anti-inflammatory role of ketolide and macrolide antibioticsin this condition. The anti-inflammatory propertiesthese antibiotics are considered to possess may actu-ally be a secondary effect to an antimicrobial action toas yet unidentified respiratory tract bacteria.

ALLERGENSAeroallergens Epidemics of asthma exacerbations have beenobserved following thunderstorms, with the strongestassociation in late spring and summer. A markedincrease in the ambient concentration of grass pollengrains has been implicated in this condition.24

Thunderstorms are also associated with increased lev-els of Alternaria and Cladosporium species and sensiti-sation to these moulds correlates with asthma exacer-bations and hospitalisations.25

Sensitisation to mites, cat and cockroach has beenfound to be a significant risk factor for worsening asth-ma symptoms. However, there is no clearly establishedquantitative relationship between current exposure tothese perennial allergens and asthma exacerbations.5

Food additives and food allergensSulphites are antioxidants that are used as preserva-tives in foods and drugs, especially in injected andinhaled medications, and as antimicrobial agents inwine. They are used on dehydrated vegetables, driedfruits and in fruit drinks. Sulphiting agents include sul-phur dioxide, sodium sulphite, and potassium and sodi-um salts of bisulphite and metabisulphite. Exposure tosulphites in an asthmatic who is sensitive to theseagents may result in significant bronchospasm.Although injectable adrenaline (Epi-pen) contains sodi-um metabisulphite as an antioxidant, it may still besafely used if a patient experiences a severe systemicreaction as a consequence of sulphite exposure.

Tartrazine, a synthetic yellow food dye has not beenshown to cause asthma exacerbations, even amongaspirin-sensitive asthmatics.

Asthma alone is an infrequent manifestation of foodallergy. The major foods incriminated in the production ofasthma in children are milk, eggs, soy, wheat, peanut,fish, tree nuts and shellfish. Acute respiratory symptomsto these antigens are an IgE-mediated reaction. Moreoften, there are associated cutaneous, gastrointestinaland cardiac symptoms resulting in anaphylaxis.

EXPOSURESOccupational sensitisersOccupational asthma (OA) refers to bronchial inflam-mation directly resulting from the inhalation of dusts,


gases, fumes or vapours at the workplace. This resultsin variable airflow obstruction and bronchial hyper-responsiveness, after a latent period of exposure tosuch agents.

Allergic OA is caused by high molecular weight (HMW)allergens and some low molecular weight (LMW) aller-gens. HMW allergens are mainly proteins derived fromanimals (e.g. animal protein in laboratory settings),plants (e.g. coffee bean dust in food processing), foods(e.g. flour in bakeries) and enzymes (e.g. protease andamylase in detergent manufacture). Sensitisation tothese agents elicits a Th2 immune response with theproduction of specific IgE. Some LMW agents, such asantibiotics (e.g. penicillins in the pharmaceutical indus-try), metals (e.g. platinum salts, chrome and nickel inthe metal-refining industry) or isocyanates (e.g. in thespraypainting industry) also elicit a Th2 immuneresponse.

Non-allergic OA occurs as a result of high level expo-sure to potent respiratory irritants in the workplace.This results in non-immunological bronchial inflamma-tion with resultant bronchoconstriction termed reactiveairways dysfunction syndrome (RADS). Typically, thereis no latent period prior to the presentation of bronchialsymptoms. Industrial agents which are known to causeRADS include chlorine, sulphuric acid and toluenediisocyanate used in the production of polyurethaneproducts.26

Environmental exposuresExercise, cold air, environmental pollutants and tobaccosmoke are recognisable factors associated with aggra-vation of asthma symptoms.

Exercise-induced asthma usually results in transientnarrowing of the airways following the cessation of vig-orous exercise. The ‘thermal hypothesis’ proposes thatcooling of the airways is followed by rapid rewarmingresulting in reactive hyperaemia of the bronchial micro-circulation and oedema of the airway wall, thus causingbronchoconstriction after exercise.27 Exercise-inducedbronchospasm (EIB) phenotype is characterised byincreased production of cysteinyl leukotrienes whichmay be mediated by sensory nerves. EIB may on occa-sion result in a severe bronchospasm and has beenassociated with sports-related deaths.

Cold air results in reflex bronchoconstriction and hasbeen used as a diagnostic test for demonstratingbronchial hyperreactivity.

Outdoor air pollution results in increased risk for asth-ma exacerbations. Polluted air may contain a mixture ofozone, nitrogen dioxide, sulphur dioxide, lead, carbonmonoxide and particulate matter. Vehicular exhaustemissions contain ultrafine particulate matter, carbon,nitrogen dioxide and carbon monoxide and even short-term exposure to such emissions is associated withneutrophilic inflammation of the airways.28

Tobacco smoke exposure has been associated withasthma exacerbations and has been identified as a sig-nificant risk factor for asthmatic children, requiringintubation.29 According to a recent Institute ofMedicine report, smoking in the home is causally relat-ed to exacerbations of asthma in preschool-aged chil-dren.30 Various mechanisms result in a state of cortico-steroid resistance in asthmatics who smoke.Furthermore, cigarette smoking causes a downregula-tion of the �-adrenergic receptor function whichimpairs the clinical response to �2-agonists, thuspotentiating an exacerbation.31

DrugsAspirin, non-steroidal anti-inflammatory drugs (NSAIDs)and �-blockers have been associated with asthmaexacerbations. Aspirin-induced asthma is a clinical syn-drome which involves intolerance to aspirin and otherNSAIDs which inhibit cyclo-oxygenase. This results inalterations in arachidonic acid metabolism and an over-production of leukotrienes resulting in asthmaticattacks when these drugs are ingested. Beta-blockersin general and non-selective �-blockers (e.g. pro-panolol) in particular have the potential for worseningbronchospasm and inhibiting therapeutic responses toinhaled �-agonists.

MISCELLANEOUSBeta-adrenergic receptor polymorphismsPolymorphisms of the �2-adrenergic receptor canaffect regulation of the receptor.32 Patients who arehomozygous for arginine at codon 16 of the receptor(Arg/Arg) have worsening of their lung function withregular versus as-needed use of inhaled �2-adrenergicagonists. This effect is not observed in asthmaticshomozygous for glycine (Gly/Gly) or in patients with theArg/Gly genotype.The first prospective clinical trial,stratified by genotype, confirmed that genotype at the16th amino-acid position of the �-adrenergic receptoraffects the long-term response to albuterol use andsuggested that bronchodilator treatments avoidingalbuterol may be appropriate for patients with theArg/Arg genotype.33

A similar result was demonstrated when long-acting�-agonists were studied. Relative to patients with theGly/Gly genotype at position 16 of the �-adrenergicreceptor, Arg/Arg genotype patients have an impairedtherapeutic response to salmeterol in either theabsence or presence of concurrent inhaled cortico-steroid use.34

The prevalence of the Arg/Arg genotype in asthmaticpatients in South Africa is unknown while a sixth ofUSA asthmatic patients have this genotype, and thefrequency is even greater in individuals of Africandecent.33

Much debate has been initiated following the results ofthese trials with some researchers showing thatresponse to salmeterol does not vary between �-adrenergic receptor genotypes after chronic dosingwith an inhaled corticosteroid.35 Therefore, moreresearch is needed in this area to clarify the relation-ship between �-adrenergic receptor genotypes andregular bronchodilator usage.

Non-respiratory factorsThere is a strong association between gastro-oesophageal reflux, psychological dysfunctioning,obstructive sleep apnoea and recurrent exacerbationsof asthma. Pathological gastro-oesophageal reflux isconsidered a potential trigger of asthma. Mechanismsof this acid-induced bronchoconstriction include avagally mediated reflex and microaspiration. A sub-group of patients gains improved control of asthmawith treatment of gastro-oesophageal reflux. Althoughpsychological dysfunctioning has been strongly associ-ated with recurrent asthma exacerbations, more stud-ies are needed to clarify whether psychological distur-bances are the cause or consequence of the loss ofcontrol in asthma. Snoring and obstructive apnoea maytrigger nocturnal asthma attacks. In some unstableasthmatic patients, improvement in asthma control hasoccurred after nasal continuous positive airway pres-sure.36


CONCLUSIONIn the majority of patients, asthma can be reasonablywell controlled with inhaled anti-inflammatory drugs. Aproportion of patients however suffer from frequentexacerbations of the condition, leading to emergencyoutpatient treatment or hospitalisation. Understandingthe various factors affecting such exacerbations mayresult in improved management and prevention of suchexacerbations.


REFERENCES1. Johnston SL, Pattermore PK, Sanderson G, et al. Community study

of role of viral infections in exacerbations of asthma in 9-11 year oldchildren. BMJ 1995; 310: 1225-1229.

2. Williams JV, Tollefson SJ, Heymann PW, Carper HT, Patrie J, Crowe JE Jr. Human metapneumovirus infection in children hos-pitalized for wheezing. J Allergy Clin Immunol 2005; 115: 1311-1312.

3. Williams JV, Harris PA, Tollefson SJ, et al. Human metapneu-movirus and lower respiratory tract disease in otherwise healthyinfants and children. N Engl J Med 2004; 350: 443-450.

4. Smuts H, Workman L, Zar HJ. Role of human metapneumovirus,human coronavirus NL63 and human bocavirus in infants andyoung children with acute wheezing. J Med Virol 2008; 80: 906-912.

5. Murray CS, Simpson A, Custovic A. Allergens, viruses and asthmaexacerbations. Proc Am Thorac Soc 2004; 1: 99-104.

6. MacDowell AL, Bacharier LB. Infectious triggers of asthma.Immunol Allergy Clin N Am 2005; 25: 45-66.

7. Kim CK, Kim SW, Park CS, Kim B, Kang H, Koh YY. Bronchoalveolarlavage cytokine profiles in acute asthma and acute bronchiolitis. J Allergy Clin Immunol 2003; 112: 64-71.

8. Rakes GP, Arruda E, Ingram JM, et al. Rhinovirus and respiratorysyncytial virus in wheezing children requiring emergency care. AmJ Respir Crit Care Med 1999; 159: 785-790.

9. McFadden ER Jr, Pichurko BM, Bowman HF, et al. Thermal map-ping of the airways in humans. J Appl Physiol 1985; 58: 564-570.

10. Greve JM, Davis G, Meyer AM, et al. The major human rhinovirusreceptor is ICAM-1. Cell 1989; 56: 839-847.

11. Papi A, Johnston SL. Rhinovirus infection induces expression of itsown receptor intercellular adhesion molecule 1 via increased NF-�B-mediated transcription. J Biol Chem 1999; 274: 9707-9720.

12. Wark PAB, Johnston SL, Bucchieri F, et al. J. Asthmatic bronchialepithelial cells have a deficient innate immune response to infec-tion with rhinovirus. J Exp Med 2005; 201: 937-947.

13. Bufe A, Gehlhar K, Grage-Griebenow E, Ernst M. Atopic phenotypein children is associated with decreased virus-induced interferon-arelease. Int Arch Allergy Immunol 2002; 127: 82-88.

14. Contoli M, Message SD, Laza-Stanca V, et al. Role of deficient typeIII interferon-� production in asthma exacerbations. Nat Med 2006;12: 1023-6.

15. Fahy JV, Kim KW, Liu J, Boushey HA. Prominent neutrophillicinflammation in sputum from subjects with asthma exacerbation. J Allergy Clin Immunol 1995; 95: 843-852.

16. Friedlander SL, Busse WW, The role of rhinovirus in asthma exac-erbations. J Allergy Clin Immunol 2005; 116: 267-273.

17. Friedman R, Ackerman M, Wald E, Casselbrant M, Friday G,Fireman P. Asthma and bacterial sinusitis in children. J Allergy ClinImmunol 1984; 74: 185-189.

18. Talbot TR, Hartert TV, Mitchel E, et al. Asthma as a risk factor forinvasive pneumococcal disease. N Engl J Med 2005; 352: 2082-2090.

19. Esposito S, Blasi F, Arosio C, et al. Importance of acuteMycoplasma pneumoniae and Chlamydia pneumoniae infections inchildren with wheezing. Eur Respir J 2000; 16: 1142-1146.

20. Blasi F, Johnston SL. The role of antibiotics in asthma. Int J Antimicrob Agents 2007; 29: 485-493.

21. Johnston SL, Blasi F, Black PN, Martin RJ, Farrell DJ, Nieman RB.The effect of telithromycin in acute exacerbations of asthma. N Engl J Med 2006; 354: 1589-1600.

22. Araujo FG, Slifer TL, Remington JS. Inhibition of secretion of inter-leukin-1a and tumour necrosis factor alpha by the ketolide antibiot-ic telithromycin. Antimicrob Agents Chemother 2002; 46:3327-3330.

23. Zalewska-Kaszubska J, Gorska D. Anti-inflammatory capabilities ofmacrolides. Pharmacol Res 2001; 44; 451-454.

24. Marks GB, Colquhoun JR, Girgis ST, et al. Thunderstorm outflowspreceding epidemics of asthma during spring and summer. Thorax2001; 56: 468-471.

25. Pulimood TB, Corden JM, Bryden C, Sharples L, Nasser SM,Epidemic asthma and the role of the fungal mould Alternaria alter-nate. J Allergy Clin Immunol 2007; 120: 610-617.

26. Bardana EJ. Occupational asthma and allergies. J Allergy ClinImmunol 2003; 111: S530-9.

27. Anderson SD, Daviskas E. The mechanism of exercise-inducedasthma is ... J Allergy Clin Immunol 2000; 106: 453-459.

28. Holguin F. Traffic, outdoor air pollution, and asthma. ImmunolAllergy Clin North Am 2008; 28: 577-588.

29. LeSon S, Gershwin ME. Risk factors for asthmatic patients requir-ing intubation. J Asthma 1995; 32: 285-294.

30. Johnston RB Jr, Burge HA, Fisk WJ, et al. Institute of MedicineReport: Clearing the Air, Asthma and Indoor Air Exposures.Washington DC: National Academy Press, 2000.

31. Thomson NC, Chaudhuri R, Livingston E. Asthma and cigarettesmoking. Eur Respir J 2004; 24: 822-833.

32. Israel E, Drazen JM, Liggett SB, Boushey HA, et al. The effect ofpolymorphisms of the adrenergic receptor on the response to reg-ular use of albuterol in asthma. Am J Respir Crit Care Med 2000;162: 75-80.

33. Israel E, Chinchilli VM, Ford JG, et al. Use of regularly scheduledalbuterol treatment in asthma: genotype-stratified, randomised,placebo-controlled cross-over trial. Lancet 2004; 364: 1505-1512.

34. Wechsler ME, Lehman E, Lazarus SC, et al. �-adrenergic receptorpolymorphisms and response to salmeterol. Am J Respir Crit CareMed 2005; 173: 519-526.

35. Bleecker ER, Yancey SW, Baitinger LA, et al. Salmeterol responseis not affected by �2-adrenergic receptor genotype in subjects withpersistent asthma. J Allergy Clin Immunol 2006; 118: 809-816.

36. Ten Brinke A, Sterk PJ, Masclee AAM, et al. Risk factors of fre-quent exacerbations in difficult-to-treat asthma. Eur Respir J 2005;26: 812-818.


Don’t miss the ALLSA AGM, 10 July 17h15!Do visit the ALLSA stand at the

Congress for back copies of the journal,

patient information sheets and to

renew your membership or join ALLSA

Abstracts are listed alphabetically within each sectionaccording to the name of the presenter of the paper.Please consult the congress programme for more details.

HIGH EXHALED NITRIC OXIDE (eNO) IS ASSOCIATEDWITH WORK-RELATED RESPIRATORY ALLERGY INNON-ATOPIC BAKERS

R Baatjies,,1,2 MF Jeebhay2

1Department of Environmental and Occupational Studies, Faculty ofApplied Sciences, Cape Peninsula University of Technology, CapeTown, South Africa2Centre for Occupational and Environmental Health Research,School of Public Health and Family Medicine, University of CapeTown, South Africa

Background: The aim of this study was to evaluate the determinantsof elevated (>35 ppb) exhaled nitric oxide (eNO) for various clini-cally relevant endpoints in baker’s allergy and asthma.

Methods: A cross-sectional study of 544 bakers was conducted in 31bakeries using an interviewer-administered questionnaire. Skin-pricktests (SPT) tested for skin reactivity to common aeroallergens.Specific IgE to wheat (f4) and rye (f5) was quantified usingImmunoCAP (Phadia). A hand-held portable sampling device(NIOX MINO®) was used to determine eNO levels during the workshift according to ATS/ERS recommendations (2005).

Results: The mean age of workers was 33 years, 57% were female,43% current smokers and 38% were atopic (SPT positive >1 com-mon aeroallergen). Work-related (WRS) ocular-nasal symptoms(42%) were more prevalent than asthma (25%) symptoms. A higherproportion of workers were sensitised to wheat (41%) than rye(35%). Probable baker’s asthma (WRS, sensitisation and previoushistory of a positive methacholine challenge test) was estimated in5%. The mean eNO was 24 ppb, with 18% having moderatelyincreased (21-35 ppb) and 17% high (>35 ppb) levels. High eNO wassignificantly (p <0.05) associated with male gender (OR=1.7), cur-rent smokers (OR=0.6), exercise (OR=2.6), recent chest infection(OR=2.3), atopy (OR=4.6), doctor diagnosed asthma (OR=2.7) andhay fever (OR=2.6). A strong positive correlation (r=0.72, p <0.001)was observed between eNO and specific IgE to either wheat or rye innon-atopic workers. In multivariate models (adjusted for gender,smoking and recent chest infection) non-atopic workers with higheNO (>35 ppb), were twice as likely to report work-related chestsymptoms (OR=3.0) and even more likely to report hay fever(OR=2.8) or doctor diagnosed asthma (OR=4.6). These non-atopicworkers with high eNO were also more likely to have increased IgEto wheat (OR=7.2) or rye (OR=8.6); baker’s rhinitis (OR=7.2); and aclinical diagnosis of baker’s asthma (OR=11.2).

Conclusion: This is the first study to demonstrate an associationbetween eNO, work-related symptoms, IgE reactivity to flour dustallergens and baker’s rhinitis and asthma. High eNO (>35 ppb) couldbe used as a marker for work-related respiratory allergy among non-atopic bakers.

SOUTH AFRICAN PRIMARY IMMUNODEFICIENCY - THEREGISTRY AND THE WAY FORWARD

Monika Esser

Immunology Unit, NHLS Tygerberg Hospital, Cape Town, SouthAfrica

Although IgA deficiencies have been reported as frequently as 1/300people, primary immunodeficiency diseases (PIDs) are regarded arare group of genetic diseases. However population prevalence of

diagnosed PID in the USA by telephonic audit of 10 000 householdsin 2007 revealed a prevalence of 1/1 200 persons including severeimmunodeficiencies. Delayed diagnosis is still common even in bet-ter resourced countries, mostly because of lack of awareness. InSouth Africa data of almost 90 patients have been recorded on thePID Registry at Tygerberg Hospital since November 2006. Patientenrollment is slow at about 30 new registrations per annum despitevisits to hospitals in Johannesburg and Durban by the registry admin-istrator. A wide spectrum of immunodeficiencies is reflected includ-ing a number of autoinflammatory diseases and suspected geneticsusceptibility to tuberculosis. Diagnosis is at an average age of 10years with a range of 6 months to 60 years. Antibody deficienciesstill constitute the largest single group as in international registriesand the majority of patients are on intravenous immunoglobulin ther-apy. In the past 6 months 3 new patients were diagnosed with severecombined immunodeficiencies; this may reflect an improving aware-ness. Almost 90% of patients are from the Western Cape andGauteng, which probably correlates with availability of PID diag-nostic facilities in these regions and also dense population. Blackpatients are still totally underrepresented at just over 4%, most like-ly because of lack of access to diagnostic facilities and treatment.Collaboration with other African countries, especially the NorthAfrican regions has been established, where consanguinity reflects ina higher prevalence of PID than in western countries. Workshops inAfrica on immune diagnostics and treatment with locally applicableguidelines for recognition of PID in developing countries are beingestablished subsequent to the first African PID Congress ASID inOctober 2008.

SUMMARY FINDINGS OF SKIN-PRICK TEST RESULTSFROM AN ALLERGY PRACTICE IN BOTSWANA

Shiang-Ju Kung, Loeto Mazhani, Diana Dickinson, Andrew Steenhoff

Riverwalk, Gaborone, Botswana

Objective: Aeroallergen sensitisation patterns have been reported forSouth Africa and Zimbabwe. Similar Botswana studies are lacking.We review aeroallergen skin-prick test (SPT) results for Botswana,and compare these with those of neighbouring countries.Sensitisation to common foods was also examined.

Methods: All patients who had SPT from October 2008 to May2009, at a private allergy practice in Gaborone, Botswana, wereincluded. Positive reaction was defined as a 3 mm wheal greater thannegative control. Depending on clinical presentation, testing panelincluded: trees (plane, oak, acacia), grass (Bermuda, Timothy,maize), weed (English plantain), moulds (mix, Alternaria,Aspergillus), cat, dog, dust mites, Blomia tropicalis, cockroach,milk, soya, egg white, wheat, peanut.

Results: Fifty-five patients were analysed, 6 of whom underwentfood testing only. The mean age was 10.5 years (SD 11.8; range: 4months - 51 years), 67% were male and 75% were black. Grasspollen sensitisation was most common followed by Alternaria(29%), dog (20%), acacia tree (20%), weed (20%), cat (19%), cock-roach (12%) and dust mites (6%). For foods, egg was most common(6/10) followed by peanut (4/8) and milk (1/8). No patients reactedto Blomia, oak, soya or wheat. Rhinitis was the commonest presen-tation (71%), followed by asthma (42%) and eczema (38%).Asthmatics were more likely to be cockroach allergic than non-asth-matics (p=0.02). Rhinitis patients were more likely to be grass aller-gic (p=0.01). Conjunctivitis sufferers were more likely to besensitised to Bermuda grass (p=0.03). All food allergy patients hadeczema.

Conclusion: Bermuda grass is the commonest aeroallergen causingrhinoconjunctivitis in Botswana. Unlike Zimbabwe and Cape Town,dust mite sensitisation is uncommon. Cockroach sensitisation is sig-nificant in asthmatics, similar to urban populations in the USA. Eggand peanut were the commonest food allergies. Larger populationstudies are needed to confirm these findings.


ABSTRACTSALLERGY SOCIETY OF SOUTH AFRICA (ALLSA) CONGRESS,

DURBAN, 10-12 JULY 2009

ORAL PRESENTATIONS

EFFECT OF AIR POLLUTANTS/ALLERGENS MEDIATEDOXIDATIVE STRESS ON BRONCHIAL ASTHMA

KSA Mossanda,1 ED Dabula, Z Novak2

1Chemical Pathology Department, MEDUNSA, University ofLimpopo, South Africa2University of Szeged, Paediatric Department, Szeged, Hungary

Backround: Exposure to noxious mutagenic pollutants and allergenscan activate neutrophils and macrophages to produce reactive oxygenspecies (ROS) and reactive nitrogen species (RNOS). The subse-quent oxidative stress induced in this way may increase the risk ofdeveloping exacerbated conditions of asthma through the promotionof T-cell response. The purpose of this study is to investigate theimplication of pollutants and allergens in the exacerbation of asth-matic conditions and the involvement of oxidative stress.

Methods: Lung function was evaluated using spirometric measure-ments in 60 asthmatic children (6-14 years old) with clinical history ofasthma. Total equivalent antioxidant capacity (TEAC), superoxide dis-mutase (SOD) and glutathione peroxidase (GPx) were evaluated usingkits commercially available from Randox-Company. Malondialdehyde(MDA) was estimated by thiobarbituric acid reaction.

Results: A general lung obstruction profile was detected in all ourpatients (from mild to severe) corresponding to the clinical scoreranging from 3 to 8 and confirmed by FEV (forced expiratory vol-ume) % ranging from 71% to 75% and by the measured ratioFEV/FVC (forced volume calculated). Haematological results dis-played a high level of eosinophils (2.8-20%) for the majority ofpatients corresponding to the IgE values exceeding 500 kU/l.Positive Phadiatop has been observed in these patients who also dis-played low values of TEAC and GPx (<1.42 mmol/l and <700 U/ml,respectively) and high values of 8 isoprostane (>7.5 pg/ml) in con-trast with high levels of MDA (>3.5 mmol/l). However, exacerbatedconditions of asthma were clinically confirmed only in 18 patients(clinical score: 6 - 8) with FEV/FVC ratio ranging from 43% to 75%.

Conclusion: Exacerbations of asthma are a consequence of hyper-production of eosinophils and IgE by oxidative stress generated bythe combustion products acting as adjuvants in the immune system ofthose patients sensitised to the observed allergens.

MITE AND COCKROACH SENSITISATION IN PATIENTSWITH ALLERGIC RHINITIS IN THE FREE STATE

RY Seedat, J Claassen, AJ Claassen, G Joubert

Universitas Hospital, University of the Free State, Bloemfontein,South Africa

Aim and objectives: Previous studies on patients with allergic rhini-tis living in the Free State province of South Africa showed that grasspollens are the predominant allergens with house-dust mite sensitisa-tion being less prevalent than in the coastal areas and a low rate ofsensitisation to the storage mite Lepidoglyphus destructor. No stud-ies have been conducted on sensitisation to the other storage mites,spider mites or cockroaches. The aim of this study was to determinethe prevalence of sensitisation to various house-dust mites, storagemites, spider mites and cockroaches in patients with allergic rhinitisliving in the Free State.

Methods: Fifty consecutive patients with moderate-severe persistentallergic rhinitis who were attending the ENT clinic at UniversitasHospital underwent skin-prick testing and/or ImmunoCAP RASTtesting for common aeroallergens, house-dust mites, storage mites,spider mite and cockroaches.

Results: Forty-six per cent of patients were sensitised to one of thehouse-dust mites, with house-dust mite sensitisation being signifi-cantly more common in patients who had previously lived at thecoast. Storage mites were not common aeroallergens, while 46% ofpatients were sensitised to the spider mite T. urticae. B. germanicawas the cockroach species most commonly sensitised onImmunoCAP RAST testing, with 38% of patients being sensitised.

Conclusions: House-dust mites, T. urticae and the cockroach B. ger-manica appear to be important aeroallergens in the Free Stateprovince of South Africa. Storage mite sensitisation is not common.

WORK-RELATED ASTHMA PHENOTYPES IN DENTALHEALTH CARE WORKERS IN SOUTH AFRICA

TS Singh1, B Bello1, MF Jeebhay2

1National Institute for Occupational Health, NHLS, Immunology andMicrobiology, Johannesburg, South Africa

2Centre for Occupational and Environmental Health Research,School of Public Health and Family Medicine, University of CapeTown, South Africa

Introduction: Exposure in the dental environment has been shownto increase the risk of respiratory disease in dental health care work-ers (HCWs). This study investigated the prevalence of work-relatedasthma phenotypes in dental HCWs and the risk factors associatedwith these phenotypes.

Materials and methods: A cross-sectional study was conducted on454 dental HCWs including dental students in 5 academic dentalinstitutions in South Africa. A self-administered, modified ECRHSquestionnaire eliciting the health and employment history was used.Blood samples were obtained from participants to assess atopy sta-tus. Pre- and postbronchodilator spirometry was conducted usingATS guidelines. Multiple logistic regression analyses were conduct-ed to assess the association between risk factors and the definitions ofasthma controlling for known confounders (age, smoking, gender).

Results: The study demonstrated a 6.9% prevalence of atopic asth-ma, 5.9% non-atopic asthma and 4.0% for work-related asthma(WRA). Almost half of the study population was atopic and this fac-tor was a significant predictor of WRA. A history of ocular-nasalsymptoms was significantly associated with WRA (OR: 5.9; 95% CI:1.9 - 17.8). Furthermore, work-related ocular-nasal symptoms weremore strongly associated with WRA (OR: 6.7; 95% CI: 2.4 - 19.1).Workers with non-atopic asthma were more likely (OR: 2.98; 95%CI: 1.21 - 7.38) to have a longer employment duration (>20 years).

Conclusion: Dental HCWs with ocular-nasal symptoms and longeremployment duration are at increased risk of presenting with work-related asthma. Identification of various asthma phenotypes is use-ful for ongoing surveillance and clinical management of dentalHCWs.

WORK-RELATED ALLERGY AND ASTHMA IN SPICEMILL WORKERS – THE IMPACT OF PROCESSING DRIEDSPICES ON IgE REACTIVITY

A van der Walt,1 AL Lopata,2,3 NE Nieuwenhuizen,3 MF Jeebhay1

1Centre for Occupational and Environmental Health Research,School of Public Health and Family Medicine, University of CapeTown, South Africa2School of Applied Science, Allergy Research Group, RMITUniversity, Melbourne, Australia3Allergy and Asthma Research Group, Division of Immunology,Institute of Infectious Diseases and Molecular Medicine, Universityof Cape Town, South Africa

Background: Three spice mill workers developed work-relatedallergy and asthma after prolonged exposure to high levels (>10mg/m3) of inhalable spice dust. Patterns of sensitisation to a varietyof spices and putative allergens were identified.

Methods: Work-related allergy and asthma were assessed on histo-ry, clinical evaluation, pulmonary function and fractional exhalednitric oxide (FeNO). Specific IgE reactivity to a range of commoninhalant, food and spice allergens was evaluated using ImmunoCAPand allergen microarray. The presence of non-IgE mediated reactionswas determined by basophil stimulation (CAST-ELISA). Specificallergens were identified by immunoblotting to extracts of raw anddried processed garlic, onion and chilli pepper.

Results: Asthma was confirmed in all 3 subjects, with work-relatedpatterns prominent in worker 1 and 3. Strong specific IgE responsesto multiple spices and pollen were observed in worker 1 and 2, andweak responses in worker 3, who was sensitised exclusively to garlicand chilli pepper. Microarray analysis demonstrated prominent pro-filin reactivity in both atopic workers 1 and 2. Immunoblottingdemonstrated a 50 kDa cross-reactive allergen in garlic and onion,and allergens of approximately 40 kDa and 52 kDa in chilli pepper.Dry powdered garlic and onion demonstrated greater IgE binding.

Conclusions: This study demonstrated IgE reactivity to multiplespice allergens in workers exposed to high levels (>10 mg/m3) ofinhalable spice dust. Processed garlic and onion powder demonstrat-ed stronger IgE reactivity than the raw plant. Atopy and polysensiti-sation to various plant profilins, alluding to pollen-food syndrome,represent additional risk factors for sensitiser-induced work-relatedasthma in spice mill workers.


THE CURIOUS CASE OF CURVULARIA IN CAPE TOWN

Dilys Berman-Uys

Allergy Diagnostic Clinical Research Unit, UCT Lung Institute,Cape Town, South Africa

Curvularia is an allergenic fungal spore that peaks during autumn.The total fungal spore load from a Burkard 7-day recording volu-metric spore trap, mounted on a roof close to the University of CapeTown Lung Institute in Mowbray, was quantified from June 2008 toApril 2009. The range was 80 - 5 618 spores/cubic metre air. Theproportion of the total fungal spore load for Curvularia varies accord-ing to the geographic location. Documented ranges are 0.87% to9.8%. Seasonal changes in Cape Town generally start in February,depending on the weather parameters. The Curvularia catchincreased at the onset of autumn, and the proportion of Curvulariaspores in the total fungal spore load rose from 0.3% for the periodJune 2008 to January 2009, to 12.1% for the autumn monthsFebruary - April 2009. Curvularia counts of this magnitude have notbeen measured at three previously sampled sites in Cape Town. Thisfinding indicates that Curvularia may be an important allergen in thisarea. A small prospective study could be undertaken, by adding thisfungal spore allergen to the skin-prick or Immunocap testing panelsin local hospitals to determine the incidence of Curvularia sensitivi-ty in the local population.

DIFFERENTIATION BETWEEN TRUE LATEX ALLERGYAND CROSS-REACTIVITY IN SOUTH AFRICAN DENTALWORKERS

TS Singh,1 A Lopata,2 DO Mabe,1 ME Ratshikhopha,1 MF Jeebhay3

1National Institute for Occupational Health, NHLS, Immunology andMicrobiology, Johannesburg, South Africa2Division of Immunology, IIDMM, Faculty of Health Sciences,

University of Cape Town, Cape Town, South Africa and RoyalMelbourne Institute of Technology, Allergy Research Group,Melbourne, Australia3Centre for Occupational and Environmental Health Research,School of Public Health and Family Medicine, University of CapeTown, South Africa

Introduction: Latex sensitivity has been reported in South Africanhealth professionals, including dental workers. Sensitisation andallergy to NRL products have been shown to be due to a small frac-tion of residual extractable proteins; however, cross-reactivity due tosequence homologies between allergens from different sources hasbeen reported. It is important to discriminate between true allergyand asymptomatic sensitisation for the treatment and management oflatex sensitive individuals.

Aim: The aim of this study was to determine the role of singlerecombinant Hevea brasiliensis latex allergens and cross-reactingcarbohydrate determinants (CCDs) in the diagnosis of latex allergyin South African dental workers.

Methods: This study investigated 41 composite latex (k82) positiveindividuals from a previous study of 421 dental workers. Clinicalsymptoms to latex were identified through a self-administered ques-tionnaire. Sensitivity to eight single recombinant Hevea brasiliensislatex allergens (Hev b 1, 3, 5, 6.01, 6.02, 8, 9, and 11) was tested.Allergens from MUXF3 and HRP markers were included in order todetect sensitisation to CCDs. The IgE reactivity to these markerswas analysed with the Pharmacia ImmunoCap system.

Results: Hev b 1, 3, 9 and 11 allergens showed little or no value inthe evaluation of clinical sensitisation. The clinically significant latexallergens identified were Hev b 5, 6.01, 6.02 and 8. Of the 41 latexsensitised individuals tested, 22 showed true latex allergy, 7 hadasymptomatic latex sensitisation and the remaining 19 were identi-fied as false-positive responses to latex as a result of cross-reactivityto carbohydrate epitopes.

Conclusion: The findings of this study demonstrated that Hev b 5,6.01, 6.02 and 8 can be reliably used in the diagnosis of true latexallergy among South African dental workers.


ALLSA POSTER PRESENTATIONS

PRODUCT NEWS

Long-chain polyunsaturatedfatty acids influence

the immune system of infants

Gottrand F. EA 3925, IFR 114,

Faculty of Medicine and University of Lille 2,

Lille, France. [email protected]

Several events occur during the first months of

life that allow the immune system to become

competent and functional. The aim of this arti-

cle is to review the rationale and evidence of an

influence of (n-3) long-chain PUFA (LCPUFA) on

the immune system of infants. The (n-3) LCPU-

FA exert their immunomodulatory activities at

different levels. The (n-3) LCPUFA metabolites

induce eicosanoid production, alter gene

expression, and modify lipid raft composition,

altering T-cell signalling; all contribute to

immunological functional changes. However,

the roles of these mechanisms and the types of

T or other immunological cells involved remain

unclear at present. Moreover, the effect of (n-3)

LCPUFA on the immune system of infants may

vary according to dose, time of exposure, and

profile of the immune system (T-helper,

Th1/Th2). Most of the interventional studies in

infancy have been performed for the prevention

of allergy. They all confirmed influence on T-cell

function and cytokine profiles, but clinically ben-

eficial effects are more conflicting.

Supplementation of the maternal diet in preg-

nancy or early childhood with (n-3) LCPUFA is

potentially a noninvasive intervention strategy

to prevent the development of allergy, infection,

and possibly other immune-mediated diseases.

However, any long-term in vivo effects on (n-3)

LCPUFA early in life for immunomodulatory

defense in infants and later on immune status

and health remain to be assessed.

J Nutr 2008; 138(9): 1807S-1812S.

For more information please contact NestleConsumer Services on 0860 09 67 89

ALLERGIC CONTACT DERMATITIS IN THEFOOD INDUSTRY – FROM AGRICULTURETO FOOD PROCESSING AND MANUFAC-TURE: A CASE STUDY OF A DAIRYFARMERAmy Burdzik, MB ChB

Centre for Occupational and Environmental HealthResearch, University of Cape Town, South Africa

INTRODUCTIONOccupational allergy is defined as an allergy caused byexposure to a substance in the workplace.1 Allergies atwork can affect various organ systems, leading to sev-eral different clinical syndromes including allergic con-tact dermatitis, contact urticaria, occupational rhinitisand asthma, and even anaphylaxis.2

Occupational skin diseases, and contact dermatitis inparticular, are some of the commonest health prob-lems caused by work, accounting for around 30% ofreported, compensatable occupational diseases in sev-eral European countries.3 The incidence rate is believedto be around 0.5-1.9 per 1 000 workers per year.3 Inagriculture and the food industry, many different aller-gens can lead to allergic contact dermatitis, rangingfrom chemicals and pesticides used on farms to food-stuffs, preservatives and additives used during foodprocessing.

Worldwide more than one billion people are employedin agriculture,4 and around 7.5% of South Africa’s work-force is employed in the industry.5 An additional 22 mil-lion people are employed in the food and drink industryglobally, although in South Africa, employment in thissector fell by 19% between 1999 to 2004.6 This num-ber reflects formal employment, so there are likely tobe many more people employed informally and in smallbusinesses throughout the country.

A high burden of occupational skin disease in this sec-tor translates into large costs, both to the individual andto employers in terms of days lost from work, andadjustments necessary in the workplace. Early recog-nition of allergic contact dermatitis may lead toimproved outcomes for the individual in a condition

which has been thought to have a relatively poor prog-nosis for full recovery.3 Therefore, the health care prac-titioner needs to be aware of possible occupationalcauses for all skin disease.

CASE REPORTA 53-year-old manager of a dairy farm presented withan 8-month history of a burning, erythematous rash,particularly on his face and forearms. It had started 4months after moving to a new dairy farm, although hehad performed a similar role on several different farms.Prior to this episode, he had suffered from cracked fin-gers in 2006, and seen a dermatologist. He had beenpatch tested using commercially available allergens in2006 and had a positive reaction of questionable rele-vance to Quaternium 15. His rash had resolved withuse of steroid creams and had not recurred. He had nohistory of atopy, eczema or asthma, and no otherchronic medical conditions.

A course of potent topical steroid had not controlled arecent flare, but he mentioned that while he had beenon holiday in Australia his rash had resolved sponta-neously, only to recur on the airplane back to SouthAfrica. He lives on the dairy farm in a recently builthouse.

On examination, he had chronic eczematous skinchanges on both wrists and over the knuckles. Therewere cracks in the web spaces of his fingers, and ery-thema and scaling of the upper arms. The rest of hisexamination was unremarkable. The clinical picturewas compatible with dermatitis.

A workplace visit was conducted to assess exposures.As one of two managers, his role is mainly superviso-ry, but he may perform any part of the milking processas needed. There are 600 cows on the farm and theyare milked 3 times a day. The udders are sprayed witha disinfectant prior to being attached by rubber tubingto milking machines (Fig. 1). Following milking, thecow’s teats are treated with a teat dip to prevent infec-tion, and they then walk across a formaldehyde-impregnated mat to disinfect their hooves. Any cowswith health problems are assessed by the farm man-agers, and may then be treated with a laxative, stoolhardener or antibiotic. Artificial insemination is also per-formed by the managers.

The milk is stored in large stainless steel vats. Theseare cleaned with industrial chemicals. Periodically, thecows are treated for ticks. Following milking, the cowsreturn to open sheds for feeding with a grain mix thatis manufactured on the farm (Fig. 2).

CAUSES OF SKIN DISEASE IN AGRICUL-TURE AND THE FOOD INDUSTRYThere are many skin disorders associated with farming,food production and processing. Infections such asmilker’s nodule and orf, which present as papules onthe hands and fingers, are caused by parapox virusescarried by cows and sheep respectively. Most workersknow what the cause is and seldom seek medical helpfor the conditions especially as they become immune.Microsporum and dermatophyte infections are carriedby dogs, cattle and horses and these can infecthumans causing inflammatory dermatophytosis. Other


Correspondence: Dr A Burdzik, e-mail [email protected]

ALLERGIES IN THE WORKPLACE

ABSTRACTAgriculture and food production have a high preva-lence of occupational skin disease when comparedwith other industries. This article discusses contactdermatitis in a farmer. The discussion outlines thethree main different allergic skin conditions: allergiccontact dermatitis, protein contact dermatitis andcontact urticaria, as well as diagnosis and manage-ment of work-related allergic skin disease, withemphasis on the allergens found in different parts ofthe food industry. It highlights the need for healthcare practitioners to consider occupational causesfor all skin conditions and to take a detailed occupa-tional history.

important zoonoses include systemic diseases such asbrucellosis and anthrax. Skin cancers are more com-mon in susceptible outdoor workers.7

This article focuses on causes of dermatitis in theindustry.

Irritants are a common cause of dermatitis.8 Irritant der-matitis is related to wet work, exposure to detergentsand cleaning agents, hand cleaners and abrasives,3 andtends to have a more gradual onset with repeatedexposure to one or several irritants.

Allergic contact dermatitis is a delayed hypersensitivityinflammatory reaction. It follows previous sensitisationto an agent which is usually a low-molecular-weighthapten. The substance is small enough to penetratethe stratum corneum and is taken up by Langerhanscells which then present it as an antigen to T-lympho-cytes in the lymph nodes and skin. Antigen-specific T-lymphocytes enter the blood stream and circulate tothe skin. During the next exposure to the substance,there is a cytokine-induced inflammatory reaction, anddermatitis generally develops within 12 to 48 hours.9

It may be difficult to distinguish allergic contact der-matitis from irritant contact dermatitis. If dermatitis cor-responds to the site of contact and develops within12-48 hours of minimal exposure it is likely to be aller-gic in origin.

Irritant contact dermatitis was thought to be more com-mon than allergic contact dermatitis, but recent studieshave argued that allergic contact dermatitis, or a com-bination of both, may be found to occur as frequentlyas irritant dermatitis, depending on how thoroughly adoctor investigates when looking for the allergen andthe type of occupation.8,10 Kucenic and Belsito10 foundthat nearly 50% of contact dermatitis in some profes-sions was allergic in nature.

Since the late 1970s, a separate entity known as pro-tein contact dermatitis has been described.11 Clinicallyit is similar to other types of contact dermatitis, but adistinguishing feature is an immediate itch and urticariadeveloping within minutes of contact, especially onalready damaged skin. Proteins which cause proteincontact dermatitis are larger than the low-molecular-weight haptens usually associated with allergic contactdermatitis, and are normally divided into four groups –vegetable/fruit/spice; animal; grains; and enzymes.12

These are all present in the food industry. It is a rareentity, and there are minimal epidemiological data forincidence or prevalence in different industries.12

Usually patch testing with the agents will be negative,but a skin-prick or ‘scratch’ test (when the raw food isapplied to a scratch rather than intact skin) will give awheal and flare reaction. Because the causative agents

are large proteins which would not normally penetrateskin, it is thought that skin needs to be damaged, eitherthrough irritation or atopic dermatitis, before it candevelop.12

Contact urticaria may be immune-mediated (by IgE) ornot, and in some cases the mechanism of action is notyet understood. Abnormal skin, for instance from anirritant dermatitis, may predispose to sensitisation.13

Some of the more common substances reported tocause contact urticaria and contact dermatitis in thefood and agriculture industry are listed in Tables I and II.

AgricultureThe agricultural industry has the highest reported ratesof occupational skin disease in the USA.14 Allergic con-tact dermatitis has been described for pesticides, dis-infectants, rubber chemicals and feed additives(minerals, antibiotics, antioxidants).15 Animal dander(cows, sheep) can also be a sensitiser.15 In a Finnishstudy,14 cow dander was the commonest cause of con-tact urticaria followed by rubber, flour grains and feed.Cow’s milk and hen’s eggs may cause contacturticaria,12 as may various other plant and animal pro-teins as listed in Table I. Pesticides, especially fungi-cides,16 are known allergens. Fertilisers may containphosphated compounds as well as cobalt and nickel,which can cause contact dermatitis.15


Fig. 1. Udders have been sprayed with disinfectant,and attached to rubber-tubed milking machine.

Fig 2. Grain-mix feed after milking.

Table I. Substances known to cause contact urticariain agriculture and the food industry*

Animal proteins Milk, cheese, eggs, beef, liver, lamb,

chicken, turkey, seafoods (fish,

prawns, shrimp,oyster)

Plant proteins Asparagus, apple, banana, beans,

(fruit and cabbage, castor bean, celery, garlic

vegetables) and onion, kiwifruit, lemon and lime,

mushrooms, mango, parsley, parsnip,

peach, potato, soybean, strawberry,

thyme, tomato, watermelon

Grains, nuts Almond, buckwheat, cashew nuts,

and spices cayenne pepper, cinnamic acid and

cinnamic aldehyde, curry, flour,

maize, menthol, rice, vanillin, wheat

Enzymes and Benzoic acid, sodium benzoate,

additives sorbic acid, tartrazine

* Adapted from Tanglertsampan & Maibach,13 Ale & Maibach.16

Beekeepers develop allergic contact dermatitis follow-ing exposure to propolis. This resinous substance fromtrees (often poplar) is incorporated into the hive as asealant by bees,17 and is widely used in cosmetics andtoothpaste. ‘Hoppicker’s dermatitis’ describes a condi-tion thought to be related to resin on hops plants whenthey are picked for brewing beer.18

Green coffee beans are a well-known cause of occupa-tional allergy.19,20 Contact dermatitis from lettuce21 andcarrots22 is reported in occupational and non-occupa-tional settings. Celery has been described as a cause ofphytophotodermatitis.23 This is due to high quantities ofpsoralens in the picked stems. Contact with the pso-ralens followed by sun exposure leads to dermatitis.

Bakers and confectionersBaker’s asthma due to flour allergy is a well-describedclinical entity. Flour and grains may also cause proteincontact and allergic contact dermatitis.14 Mites and pes-ticides contaminating stored grain are further sourcesof exposure. Enzymes, such as �-amylase which isused to improve baking quality, are allergens and ‘flourwhiteners’ (e.g. benzoyl peroxide) have been found tocause dermatitis.24

Aside from grains, bakers are also exposed to numer-ous spices. The five spices which most commonlycause contact dermatitis in the USA are capsicum, cin-namon, cloves, nutmeg and vanilla.18

Capsicum is also an irritant – so strong that it is used inteargas. Cinnamon is used as a flavourant not only inbaking, but also in toothpaste, chewing gum and spicedcola soft drinks or alcoholic beverages. Cinnamic alde-hyde is used in sunscreens, and has some cross-reac-tivity with balsam of Peru,18 which may be found infragrances and tested for with commercially availableallergens.

Nutmeg and clove are frequently used in cooking andbaking. Clove oil is also used to flavour toothpaste andmouthwashes. Vanilla may cause contact dermatitis inworkers involved in cultivation, trade and industrial useof vanilla. These workers may report additional symp-

toms of rhinitis, asthma and vertigo in a syndromeknown as ‘vanillism’.18 Contact urticaria (and contactdermatitis) to turmeric (curcumin) has been reportedrecently.25

Chefs and cooksChefs and cooks are exposed to a wide variety of bothirritants and allergens. Frequent hand-washing, andexposure to irritant and abrasive food products such ascitrus fruits, can be contributory factors. Garlic and onionare common contact allergens.18 Other foods reported tocause contact dermatitis are listed in Table II.

Food additives such as dyes, preservatives, stabilisersand antioxidants cause dermatitis. Although it is rare, adye used to colour oranges, cheese, jam and fishknown as Citrus Red No. 2, can cause contact dermati-tis.18 Tartrazine and Sunset Yellow dyes may cause con-tact urticaria.18 Benzoic acid and sorbic acid which areused as preservatives produce non-immunological con-tact urticaria.13

Contact urticaria has been reported to milk as well ascheeses. The major allergen is thought to be casein.28

Contact urticaria to parmesan cheese has recentlybeen reported.29 Italian cheesemakers wrap theircheese in rags. These have been found to supportgrowth of the Rhizoglyphus mite, which is a knownsensitiser.28

Non-food exposures include latex gloves and nickel incooking utensils.

Butchers, poultry processors and seafoodworkersIn poultry processing, most dermatitis is irritant, as aresult of the frequent wet work. Contact urticariaresults from direct animal protein contact (blood, skin,meat and viscera) on already damaged skin.30 Butchershave similar contact. Urticaria has been reported afterexposure to beef, lamb and calf liver.13 Seafood pro-cessing workers have a particularly high prevalence ofoccupational allergy. A recent study31 found a preva-lence of protein contact dermatitis (diagnosed by a his-tory of recurrent skin problems and a positive skin-pricktest) of between 1% and 2%. This is thought to be dueto high-molecular-weight proteins generating an IgEresponse.

DIAGNOSIS AND MANAGEMENT Early diagnosis is key, as prolonged exposure is morelikely to lead to intractable dermatitis which persistsafter removal from exposure.32 Prognosis worsenswith chronicity, treatment delay, underlying atopic der-matitis and poor understanding of the condition by theworker.32

Avoidance of exposure is the mainstay of treatment.Before this can be done, the allergen needs to be iden-tified. Because of the numerous exposures listed, thismay be difficult, and relies heavily on an extensive,detailed and informed history. Patch testing with com-monly implicated allergens or agents specific for theindividual job or task may be helpful. These commer-cially available allergens may identify a cause in up to80% of cases.33 For contact urticaria and protein con-tact dermatitis, a scratch test may be necessary if thepatch test is negative.

A workplace visit is mandatory as patients may notrecall or even be aware of all of their exposures whenquestioned in the office. Material Safety Data sheetsfrom the workplace provide some information, but bylaw do not need to declare substances which make upless than 1% of the product. Therefore, an allergen


Table II. Contact dermatitis in agriculture and thefood industry: common allergens*

Foodstuffs: Plants Almond, apple, banana, bean,

cardamom, carrot, cashew nut, castor

bean, citrus fruits, coffee bean

(green), cauliflower, celery (also

causes photosensitivity), chicory,

coriander, cress, cucumber, dill,

eggplant, endive, fig, garlic, hazelnut,

horseradish, kiwi, lemon, lettuce,

mango, mushroom,27 nutmeg and

mace, onion, paprika, parsley, parsnip,

peanuts, pineapple, potato, tomato,

turmeric

Animal Meat, seafood (crab, fish, mussels,

shrimps)

Miscellaneous Animal proteins – animal dander,

mites, milk, eggs

Feed additives – antioxidants,

minerals, grains, antibiotics

Latex – from gloves

Nickel – in farm implements and

fertilisers and in kitchen utensils

Pesticides and fertilisers

Rubber – in farm implements

Adapted from Rietschel & Fowler,18 Guin.26

may be present in a product but not declared. A patchtest with the products identified from the workplacevisit may be required. Patch testing needs to be per-formed by an expert with full knowledge of the risks,particularly when testing non-standard agents whichmay be dangerous. Interpretation of the results ofthese patch tests requires expertise as they may illicitfalse-positive or irritant reactions if not tested appropri-ately.

Patients need to be informed of their allergy and likelysources of the allergen. They should be encouraged toread product constituents and, if possible, informedabout use of alternative products and where the aller-gen may be encountered outside of the work place.

Previously, occupational contact dermatitis wasthought to have a very poor prognosis, but a recentreview32 has shown that 78-84% of people recoverwithout significant impairment. However, people sensi-tised to common ubiquitous allergens, especially, maysuffer significant disability and recurrent disease asthey will struggle to avoid exposure from these widelyoccurring substances. A change of occupation is notusually necessary and does not influence prognosis inmost cases. A ‘holiday from work’ or temporary jobchange should be considered for very severe allergy incases where the allergen cannot be avoided in theworkplace, and for people with a skin barrier defectwho would frequently be exposed to irritants.32

Treatment of allergic contact dermatitis after allergenavoidance is as for other types of dermatitis. Saary etal.34 found good quality studies showing benefit oftreatment with potent and moderately potent topicalsteroids. Unfortunately, there is limited informationabout prevention of allergic contact dermatitis in theworkplace.34

Case study evaluationIn the case of the farmer, no definitive diagnosis for hisdermatitis has been made. As noted above, the num-ber of exposures is vast. He is in contact with cow dan-der, pesticides, fungicides, cleaning agents,medications, animal feed and rubber. He lives in anewly built house with exposure to paint, new carpetsand cleaning products. The history of recurrence of hissymptoms on the airplane suggests a link to cleaningproducts, an insecticide sprayed prior to departure oreven products in the upholstery or paint.

The previous positive reaction to Quaternium 15 needsto be revalidated relevant to his current dermatitis andexposures. Quaternium 15 is a formaldehyde-releasingpreservative used in cosmetics, moisturisers andshampoos, as well as in disinfectants and other indus-trial agents such as adhesives, polishes and paints.The farmer is exposed to disinfectants used to cleanthe milk tanks, as well as disinfectants used on thecows’ udders. We will need to perform a patch testwith commonly available allergens to assess whether itis positive again, as well as a patch test with specificallergens found on the farm, and then decide whichresults are relevant to his presentation. A prick testwith cow dander is necessary. If positive, a change ofoccupation or work holiday will be required, as cowdander is ubiquitous on the farm. If he is allergic toother products, such as disinfectants, medications orfood additives, a change of those products will end hisexposure and lead to improvement in his dermatitis.

ConclusionOccupational contact dermatitis is a common occupa-tional illness, and is particularly prevalent in agricultureand the food-processing industries. Allergic contact

dermatitis may be more common than we anticipate,so it is useful to perform patch tests on patients withsuspected contact dermatitis to rule out potential aller-gens even if the dermatitis is thought to be mostly irri-tant. Although there are many unusual allergens, patchtesting with commercially available allergens mayreveal allergens such as nickel, rubber and somespices.

All health practitioners should bear this in mind whenassessing dermatitis, and should remember the possi-ble work-related causes of the condition, especially incases which appear to be refractory to treatment orwhen there is a clear history of symptoms worseningwith work and clearing on vacation, as with our patient.Allergen avoidance and early treatment should lead to agood outcome in most cases and allow the individual tocontinue in his or her chosen occupation.


REFERENCES1. Maestrelli P, Fabbri LM, Malo J-L. Occupational allergy. In: Holgate

ST, Church MK, Lichtenstein LM, eds. Allergy. 3rd ed. Philadelphia:Mosby Elsevier; 2006: 143-155

2. Knight D, Jeebhay MF. Work-related anaphylaxis. Current Allergy &Clinical Immunology. 2008; 21: 178-182.

3. Diepgen TL, Coenraads PJ. The epidemiology of occupational con-tact dermatitis. Int Arch Occup Environ Health 1999; 72: 496-506.

4. International Labour Organisation [homepage on the Internet].Geneva: International Labour Organisation; c1996-2008 [updated2007 Jul 31; cited 2009 Apr 14]. Available from: http://www.ilo.org/public/english/dialogue/sector/sectors/agri/emp.htm

5. International Labour Organisation. Report IV: Promotion of ruralemployment for poverty reduction. Proceedings of the 9th Sessionof the International Labour Conference; 2008 May 28 - Jun 13;Geneva, Switzerland. Geneva: ILO Publications; 2008. [cited 2009Apr 26]. Available from: http://www.ilo.org/public/english/dia-logue/sector/sectors/agri/emp.htm

6. International Labour Organisation [homepage on the Internet].Geneva: International Labour Organisation; c1996-2008 [updated2007 Jul 31; cited 2009 Apr 14]. Available from: http://www.ilo.org/public/english/dialogue/sector/sectors/food/emp.htm

7. Woolley T, Buettner P, Lowe J. Sun-related behaviours of outdoorworking men with a history of non-melanoma skin cancer. J OccupEnviron Med 2002; 44: 847-854.

8. Dickel H, Kuss O, Schmidt A, Kretz J, Diepgen TL. Importance ofirritant contact dermatitis in occupational skin disease. Am J ClinDermatol 2002; 3: 283-289.

9. Rom WN, ed. Environmental and Occupational Medicine. 2nd ed.Boston: Little, Brown, 1992.

10. Kucenic MJ, Belsito DV. Occupational allergic contact dermatitis ismore prevalent than irritant contact dermatitis: a 5-year study. J Am Acad Dermatol 2002; 46: 695-699.

11. Hjorth N, Roed-Petersen J. Occupational protein contact dermatitisin food handlers. Contact Dermatitis 1976; 2: 28-42.

12. Levin C, Warshaw E. Protein contact dermatitis: allergens, patho-genesis and management. Dermatitis 2008; 19: 241-251. [cited2009 Apr 20]. Available from: http://www.medscape.com/viewarti-cle/580843

13. Tanglertsampan C, Maibach HI. Contact urticaria. In: Hogan DJ, ed.Occupational Skin Disorders. New York: Igaku-Shoin MedicalPublishers, 1994.

14. Kanerva L, Toikannen J, Jolanki R, Estlander T. Statistical data onoccupational contact urticaria. Contact Dermatitis 1996; 35: 229-233.

15. Susitaival P. Occupational skin diseases in farmers and farm work-ers. In: Kanerva L, Elsner P, Wahlberg JE, Maibach HI, eds.Handbook of Occupational Dermatology. Berlin: Springer, 2000:924-931.

16. Ale SI, Maibach HI. Occupational contact urticaria. In: Kanerva L,Elsner P, Wahlberg JE, Maibach HI, eds. Handbook of OccupationalDermatology. Berlin: Springer, 2000: 200-217.

17. Karamfilor T, Elsner P. Beekeepers. In: Kanerva L, Elsner P,Wahlberg JE, Maibach HI, eds. Handbook of OccupationalDermatology. Berlin: Springer, 2000: 840-841.

18. Rietschel RL, Fowler JF. Fisher’s Contact Dermatitis. 4th ed.Philadelphia: Williams & Wilkins; 1995.


19. Truedler R, Tebbe B, Orfanos CE. Co-existence of type I and typeIV sensitization in occupational coffee allergy. Contact Dermatitis1997; 36: 109.

20. Diba VC, English JSC. Contact allergy to green coffee bean dust ina coffee processing plant worker. Contact Dermatitis 2002; 47: 56.

21. Alonso MD, Martin JA, Cuevas M, et al. Occupational protein con-tact dermatitis from lettuce. Contact Dermatitis 1993; 29: 109-110.

22. Murdoch SR, Dempster J. Allergic contact dermatitis from carrots.Contact Dermatitis 2000; 42: 236.

23. Seligman PJ, Mathias CG, O’Malley MA, et al. Phytophoto-dermatitis from celery among grocery store workers. ArchDermatol 1987; 123: 1478-1482.

24. Veien NK. Bakers. In: Kanerva L, Elsner P, Wahlberg JE, MaibachHI, eds. Handbook of Occupational Dermatology. Berlin: Springer,2000: 817-820.

25. Liddle M, Hull C, Liu C, Powell D. Contact urticaria from curcumin.Dermatitis 2006; 17: 196-197 [cited 2009 May 1]. Available from:http://www.medscape.com/viewarticle/552009

26. Guin JD. Occupational contact dermatitis to plants. In: Kanerva L,Elsner P, Wahlberg JE, Maibach HI, eds. Handbook of OccupationalDermatology. Berlin: Springer, 2000: 731-766

27. Aalto-Korte K, Susitaival P, Kaminska R, Makinen-Kiljunen S.Occupational protein contact dermatitis from shiitake mushroomand demonstration of shiitake specific immunoglobulin E. ContactDermatitis 2005; 53: 211-213.

28. Nestle FO, Elsner P. Cheesemakers. In: Kanerva L, Elsner P,Wahlberg JE, Maibach HI, eds. Handbook of OccupationalDermatology. Berlin: Springer, 2000: 880-881.

29. Williams JD, Moyle M, Nixon RL. Occupational contact urticariafrom parmesan cheese. Contact Dermatitis 2007; 56: 113-114.

30. Goncalo M. Poultry processors. In: Kanerva L, Elsner P, WahlbergJE, Maibach HI, eds. Handbook of Occupational Dermatology.Berlin: Springer, 2000: 1058-1059.

31. Jeebhay MF. Occupational allergy associated with saltwater bonyfish processing in South Africa. Doctor of Philosophy (IndustrialHealth): University of Michigan, 2003.

32. Occupational contact dermatitis: etiology, prevalence and resultantimpairment/disability. J Am Acad Dermatol 2005; 53: 303-313.

33. Beltrani VS. Occupational dermatoses. Curr Opin Allergy ClinImmunol 2003; 3: 115-123.

34. Saary J, Qureshi R, Palda V, et al. A systematic review of contactdermatitis treatment and prevention. J Am Acad Dermatol 2005;53: 841-845.


PATIENT INFORMATION SHEETS – ANOTHER ALLSA MEMBERSHIP BENEFIT

Did you know that membership of ALLSA entitles you to receive copies of our Patient InformationSheets which provide information on various aspects of allergy in an easy-to-understand format foryour patients?

Topics covered include:Allergen ImmunotherapyAllergic Reactions to Honey Bee and Wasp StingsAllergic RhinitisBedding Protectors and Allergy ControlCockroach AllergyCoeliac DiseaseContact DermatitisDrug AllergyEgg AllergyFish AllergyFood Additives and PreservativesFood AllergyHouse-Dust Mite AllergyLatex AllergyMilk Allergy/IntoleranceMould AllergyPeanut AllergyPet AllergySeafood AllergySoya AllergyTreatment of Allergic EczemaUrticaria and AngioedemaVacuuming and Allergy ControlWheat Allergy

Patient information sheets can be ordered in batches of 50 from the ALLSA office, tel 021-447-9019,email [email protected]

There is no charge for the leaflets, but we do charge for postage.


Travis is 14 years old.He has suffered from asthma and allergic rhinitis since he was a toddler.He had severe eczema as an infant which is now localised to the flexural surfaces of his limbs.

Allergy Examination

Dr Do-a-lot prepares to examine him.

She asks Sister Sweet to measure his height and weighton the way to the examination room.

She notices that his appearance and posture havebeen affected by his chronic condition.He is small, thin, and round-shouldered, with apigeon chest.His face is elongated which makes him look sad,and he is mouth-breathing.His speech has a nasal quality.He performs an allergic salute as he steps up ontothe scale and twitches his nose.

Shaunagh Emanuel

MB ChB

Di Hawarden

MB ChB

Allergy Diagnostic and Clinical Research Unit (ADCRU), UCTLung Institute, Mowbray, CapeTown, South Africa

2007 ARIA Workshop Report. www.whiar.orgPotter PC, ed. The ALLSA Handbook of Practical Allergy,

2nd ed. Cape Town: ALLSA, 2001.

World Allergy Organisation:

http://www.worldallergy.org/allergy_education/

The second of our

illustrated series

highlights some of the

important features in the

examination of the

allergy patient.

2

Allergy


Features that may be present in the physical examination of an allergic patient

Pale complexion

Hyperaemic conjunctivae

Conjunctival pavement slabbing

Sinusitis

Dry cracked lips

Lip licking dermatitis

Eczema

Dry skin or eczema around the eyes and at the hairline

Hyperinflated chest

Wheeze on expiration may be heard

Otitis media

Glue ear

Tearing

Dennie’s linesAllergic shiners

Nasal crease

High arched palate

Postnasal drip

Lymphoid hyperplasia of the posterior pharyngeal wall

A geographical tongue is said to bemore common in allergic children

Swollen, often pale,inferior turbinatesNasal secretionsDeviated nasal septum

DIETARY EXCLUSIONS FOR ESTABLISHEDATOPIC ECZEMATaryn Young, MB ChB, FCPHM, MMed

RYTD Consultancy, Pinelands, Cape Town, South Africa

BackgroundAtopic eczema affects up to 20% of children world-wide.1 It is caused by a combination of genetic andenvironmental factors. Although there is currently nocure for atopic eczema, a wide range of treatments areused to control the symptoms. One such approach is adietary one, whereby certain foods such as cows' milkare excluded on the basis that they are thought tocause eczema to worsen.2

So what is the question?What are the effects of dietary exclusions for the treat-ment of established atopic eczema?

The type of evidence to look for, andwhere to look for itThe best evidence will come from randomised con-trolled trials (RCTs). If more than one trial has been con-ducted, the most reliable evidence, if available, is asystematic review of all relevant RCTs. The CochraneCollaboration (www.cochrane.org) conducts systemat-ic reviews of the effects of healthcare interventions fol-lowing rigorous methods and processes to reduce bias.Results from systematic reviews are published in TheCochrane Library (http://www.thecochranelibrary.com/)and the Cochrane Database of Systematic Reviews hasan impact factor* of 4.654.

What was found?You found a recent systematic review examining theeffects of dietary exclusions for the treatment of estab-lished atopic eczema.2

What did the authors do?The authors conducted a comprehensive search andidentified 12 RCTs of which 9 were included. Dataextraction and assessment of the risk of bias of includ-

ed studies were done independently by two authors.For studies with a similar type of intervention, authorsperformed a meta-analysis, to calculate a weightedtreatment effect across trials, using a random effectsmodel. They expressed the results as risk ratio and95% confidence intervals (CI) for dichotomous out-comes* and mean differences and 95%CI for continu-ous outcomes*. The results were also expressed asnumber needed to treat where appropriate, for a rangeof plausible control event rates. Heterogeneity* wasassessed using I2 (Box 1). Where it was not possible toperform a meta-analysis the data was summarised foreach trial.

Box 1. Identifying and measuring hetero-geneity3


EVIDENCE-BASED HEALTH CARE

AimsThis feature on evidence-based health care (EBHC)aims to present useful practice-related informationon topics relevant to readers of Current Allergy &Clinical Immunology. The treatment of topics is notcomprehensive. The main aim is to illustrateselected aspects of the EBHC process viz. (i) iden-tifying the best evidence and (ii) applying valid andrelevant evidence in clinical practice. The box titled'Some terms explained' enlarges on the technicalterms mentioned in the text and marked with anasterisk (*). 1. Inspect the forest plot

If CIs for the results of individual studies (general-ly depicted graphically using horizontal lines) havepoor overlap, this generally indicates the presenceof statistical heterogeneity.

2. Statistical test for heterogeneityThe chi-squared (�2, or chi2) test is included in theforest plots in Cochrane reviews. It assesseswhether observed differences in results are com-patible with chance alone. A low P value (or a largechi-squared statistic relative to its degree of free-dom) provides evidence of heterogeneity of inter-vention effects (variation in effect estimatesbeyond chance). Care must be taken in the inter-pretation of the chi-squared test, since it has lowpower in the (common) situation of a meta-analy-sis when studies have small sample size or arefew in number. This means that while a statistical-ly significant result may indicate a problem withheterogeneity, a non-significant result must not betaken as evidence of no heterogeneity. This is alsowhy a P value of 0.10, rather than the convention-al level of 0.05, is sometimes used to determinestatistical significance.

3. I2 statisticSome argue that, since clinical and methodologicaldiversity always occur in a meta-analysis, statisticalheterogeneity is inevitable. Therefore the test forheterogeneity is irrelevant to the choice of analy-sis; heterogeneity will always exist whether or notwe happen to be able to detect it using a statisticaltest. Methods have been developed for quantify-ing inconsistency across studies that move thefocus away from testing whether heterogeneity ispresent to assessing its impact on the meta-analy-sis. A useful statistic for quantifying inconsistencyis the I2. A rough guide to interpretation is as fol-lows:• 0% to 40%: might not be important;• 30% to 60%: may represent moderate hetero-

geneity;• 50% to 90%: may represent substantial hetero-

geneity;• 75% to 100%: considerable heterogeneity.

Correspondence: Dr T Young, RYTD Consultancy, PO Box 38580,Pinelands 7430, South Africa. Email [email protected]

Results and conclusionThe studies fell into three main categories – egg andcow's milk exclusion diets; few foods diet and elemen-tal diet. Only two studies were considered sufficientlysimilar to pool. There may be some benefit in using anegg-free diet in infants with suspected egg allergy whohave positive specific IgE to eggs. Little evidence sup-ports the use of various exclusion diets in unselectedpeople with atopic eczema, but that may be becausethey were not allergic to those substances in the firstplace. Lack of any benefit may also be because thestudies were too small and poorly reported. Futurestudies should be appropriately powered focusing onparticipants with a proven food allergy. In addition a dis-

tinction should be made between young childrenwhose food allergies improve with time and older chil-dren/adults.

REFERENCES1. Rancé F, Boguniewicz M, Lau S. New visions for atopic eczema: an

iPAC summary and future trends. Pediatr Allergy Immunol 2008;19, Suppl 19: 17-25.

2. Bath-Hextall FJ, Delamere FM, Williams HC. Dietary exclusions forestablished atopic eczema. Cochrane Database of SystematicReviews 2008, Issue 1. Art. No.: CD005203. DOI: 10.1002/14651858.CD005203.pub2.

3. Higgins JPT, Green S, eds. Cochrane Handbook for SystematicReviews of Interventions Version 5.0.0 [updated February 2008].The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org.


*Some terms explainedJournal impact factor (IF): The IF is a tool for rank-ing, evaluating, and comparing journals. It is calculat-ed based on a 2-year period and is a measure of thefrequency with which the 'average article' – usuallyarticles, reviews, proceedings or notes; not editorialsand letters to the Editor – in a journal has been citedin a particular year. The IF is calculated by dividing thenumber of IF year citations by the source items pub-lished in that journal during the previous 2 years.

Calculation:

Dichotomous (binary) data: Data that can take oneof two possible values, such as dead/alive, smoker/non-smoker, present/not present.

Continuous data: Data with a potentially infinitenumber of possible values within a given range.

Height, weight and blood pressure are examples ofcontinuous variables.

Heterogeneity: Inevitably, studies brought togetherin a systematic review will differ. Any kind of variabil-ity among studies in a systematic review may betermed heterogeneity. Variability in the participants,interventions and outcomes studied may bedescribed as clinical diversity (sometimes called clin-ical heterogeneity), and variability in study design andrisk of bias may be described as methodologicaldiversity (sometimes called methodological hetero-geneity). Variability in the intervention effects beingevaluated in the different studies is known as statis-tical heterogeneity, and is a consequence of clinicalor methodological diversity, or both, among the stud-ies. Statistical heterogeneity manifests itself in theobserved intervention effects being more differentfrom each other than one would expect as a result ofrandom error (chance) alone.3

(the number of IF year citations)

(the source items published in that journal during the previous 2 years)IF =

2-DAY WORKSHOP: THE ESSENTIALS FOR CRITICAL READING AND INTERPRETATION OF MEDICAL LITERATURE

Are you trying to keep up with new developments in your field but are put off by p values, confused aboutrelative risks and 95% confidence intervals, and completely thrown by cohort and case-control studies? Do

you end up reading the conclusions of the abstract of a research article?

RYTD Consultancy will be offering 2-day workshops in 2009 on "The essentials for critical reading andinterpretation of medical literature". The course provides a valuable

opportunity to learn key concepts to enable critical reading of medical literature.

The full course is accredited for 11 CPD points with the HPCSA.

Who can attend? The course is open to doctors, nurses, occupational therapists, physiotherapists, speech therapists, pharmacists and dentists working in all levels

of health care.

Course content: Essential epidemiology and biostatistics, basic research methodology and the approach touse when reading a paper.

For more information contact Dr Taryn Young, RYTD Consultancy.

RYTD ConsultancyP O Box 38580Pinelands 7430South AfricaFax: +27 86 531 8671Cell: + 27 82 8959 656Email: [email protected]

Enhancing your capacity to make the right health care decisions


CHAIRMAN’S REPORT

It is hard to believe that the trien-nium of the current ALLSA Excomhas already come to an end. Iclearly remember the wonderful2006 congress at Sun City, duringwhich I was elected chairman. Iwas overwhelmed at the privilegeand by the trust placed in me, andthis feeling continues to this day.

It is an honour to have beenALLSA Chair during the 20th year

and now the ‘coming of age’ of our organisation. TheAllergy Society of South Africa was established by veryvisionary people in 1988, and it is fitting that, 21 yearson, we are on the brink of having our first subspecial-ists registered and will be embarking on subspecialisttraining. What is also unique about this is that allergol-ogy will be based not only on paediatrics and internalmedicine, but also on family medicine. I would like topay tribute to our founder members, to the Excomsthrough the years, to the Journal editors and contribu-tors, to all our loyal members, and to our office and sup-port staff.

I believe that the last 3 years have been watershedyears in our Society, and would like to briefly discussthe highlights. I have to point out that our achieve-ments have built on the legacy of past Excoms andhave also involved considerable work and input fromALLSA members working outside the Excom.

Allergology Subspecialist RegistrationThere is no doubt that the greatest achievement of thisSociety is the recognition of allergology as a subspe-cialty. The most recent hard work was done by PaulPotter and Cas Motala, but many years ago the groundwork was laid by Eugene Weinberg, Paul Potter, CasMotala and Matt Haus. We managed to build on thisand achieved recognition of the Diploma in Allergology.I believe that the popularity of this diploma has con-tributed to academic allergology, and I wish to pay trib-ute to Matt Haus and Bruce Sparks for helping us to getit through the Colleges of Medicine and subsequentlythrough the HPCSA. The groundswell of support andthe excellent training programme at Red CrossChildren’s Hospital resulted in allergy spreading aroundthe country. We now have centres of excellence inGauteng (Steve Biko Academic Hospital and PretoriaUniversity – Robin Green) and KwaZulu-Natal (AhmedManjra) in addition to the ongoing expertise in CapeTown.

Governance CharterALLSA has taken the lead in establishing a GovernanceCharter for the Society. Cas Motala and Tom Sutcliffedevoted many hours to this document, which I think isan excellent addition to the Constitution and which willcontinue to guide us in matters of governance. The cur-rent Excom all contributed ideas and suggestions, andit will be available to members at the Durban Congressfor perusal and comment.

ALLSA Position StatementsThis Excom has been brave in promoting ‘good allergypractice’ and putting position statements on the ALLSAwebsite. We have come in for a fair amount of criticism

as a result, but I think it is in line with our stated Visionand Mission for the Society. Thank you to the expertALLSA members who assisted in drafting these posi-tion statements.

Subcommittees and portfoliosI will now give brief report backs on the activities of thevarious subcommittees and portfolios of the ALLSAExcom.

Membership and websiteOur membership has remained reasonably steady, andwe have some ideas to recruit young members fromuniversities. The award-winning website is excellent –thanks to Di Hawarden, Ruwayda Adams and DanielBraude for all their hard work.

ResearchMohamed Jeebhay (Chair), Cas Motala and Heather Zarhave implemented innovative changes to the applica-tion and assessment processes of the researchawards. Some outstanding projects have been fundedby ALLSA grants, and we anticipate feedback at con-gresses and as reports in the Journal.

EducationRobin Green has spearheaded a number of initiatives,including a series of lectures in allergy in Gauteng, andpromoting the Diploma in Allergology among paediatri-cians and registrars. He has organised the Diplomaexamination panels very efficiently, and has involvednew examiners in the past few examinations.

We have had three outstanding congresses over thepast years: one combined with the South AfricanThoracic Society and two combined with the SouthAfrican Paediatric Association. In all three, our mem-bers made excellent contributions to the science andthe social events, we had high calibre internationalspeakers, and brilliant local faculty. The internationalspeakers were Gideon Lack (UK), Mike Kaliner andAllen Kaplan (USA) in 2006, Jean Bousquet (France),Andrew Bush and Adnan Custovic (UK), Hugo Neffen(Argentina), Søren Pedersen (Denmark) and AndreaApter (USA) in 2007, and Tom Platts-Mills (USA) andSusan Prescott (Australia) in 2008. This year’s congresswill host Estelle Simons (Canada) and George du Toit(ex SA, now in the UK) as the guest speakers.

The newest initiative is a comprehensive update of theHandbook of Allergy, with Cas Motala and Paul Potteras co-editors.

Policy and AdvocacyThis subcommittee, ably led by Andrew Halkas, hasbeen involved in establishing guidelines for our inter-action and relationship with health care funders. Themost recent initiatives involve prescribed minimumbenefits for treatment of asthma in children and guide-lines for appropriate allergy testing.

Harris Steinman is ALLSA’s representative on FLAG,but he is also a major advocate for honest advertisingand does not shy away from difficult situations – forthis we thank him.

Our Childhood Asthma Guidelines are being finalised asI write this, and will be presented at the congress.Thank you to Cas for driving the process and to all thecontributors for your hard work.

Current Allergy & Clinical ImmunologyHeather Zar, Eugene Weinberg and Anne Hahn havecontinued to produce an outstanding Journal that car-ries both review articles and original allergy research. Itis an excellent resource, and has received internationalas well as national acclaim. The Editors have been pre-pared to be innovative in terms of content and presen-tation, and for this we laud them.

InternationalCas Motala served South Africa, Africa and WorldAllergy in an exemplary fashion as a Director on theWAO Board, and for this we thank him. He has beensucceeded by Paul Potter, who has already contributedto a number of WAO position papers and who we knowwill continue to represent allergy in South Africa in hisusual inimitable fashion. Heather Zar was a member ofthe GINA Panel that developed the most recent guide-lines for management of asthma in children under theage of 5 years.

We would also like to thank the World AllergyOrganisation for their support of our congresses, bysponsoring speakers and/or GLORIA symposia.

ConclusionI look back over the last 3 years with pride, yet with adeep sense of humility and gratitude. I have workedwith the most amazing Executive Committee andALLSA office staff. We have experienced some incred-ibly difficult problems and have dealt with unpleasantsituations, yet I could always call on the wisdom andsupport of the Excom members. Cas continues to be awise head and a major guiding hand, and I have to sin-gle him out for special thanks.

I also want to thank Heather Zar for her tireless workfor ALLSA. Heather is not standing for re-election, andwe will miss her input on the Excom, but she will con-tinue to co-edit the Journal, and we look forward toworking with her in her new capacity of President ofthe South African Thoracic Society.

Our congresses were successful for several reasons,but I have to thank the organising and scientific com-

mittees, and also the UCT Conference ManagementCentre and Sue McGuiness Communications andEvent Management. In particular, Sue McGuinessbrings a particular brand of professionalism and exper-tise to congress and event management that will provehard to surpass, and the organisational and financialsuccess of these events are in no small measure dueto her. Our last congress coincided with a very difficulttime for her, and we really appreciate the manner inwhich she handled everything.

Ahmed Manjra, the lone ranger in Durban, has done itagain – a wonderful congress with an excellent scien-tific programme – thanks, Ahmed.

Ruwayda Adams – how do I even begin to thank her?The smoothly purring engine of the ALLSA machineensures the seamless running of the Society. She hasbeen ably assisted by Shahnaz Arnold, and the always-friendly Jean Aprill keeps the office organised. AnneHahn continues to do the most brilliant production edi-torial work on the Journal. Thank you to all of you.

And last, but certainly not least, our partners in thepharmaceutical and medical device industry deserveour heartfelt thanks. It has been their support that hasenabled us to further allergy research in South Africa(GlaxoSmithKline, UCB, MSD and Cipla), organise con-gresses, run workshops, publish the Journal, and pro-vide patient information sheets. We acknowledge thegovernance and economic restraints under which theyoperate and we wish to ensure them that we appreci-ate their help, support and friendship.

Lastly, the ALLSA Excom appreciates that the majorityof our membership base is in Gauteng. We wish tothank our loyal members and assure those outside theWestern Cape that we are looking at ways of ensuringaccess to allergy journals and other resources for them.

I want to wish you all a wonderful ALLSA Congress inDurban. Enjoy the scientific content as well as thesocial events and the networking, and take time toexplore the wonderful city.

To the incoming ALLSA Chairman and Excom: I wishyou all the best for a very enjoyable and successful tri-ennium!

Sharon KlingChairman


Would you like to receive future copies of this journal?

Please contact our national office to be added to the mailing list.

If you are interested in becoming a member of the Allergy Society of South Africa (ALLSA),please fill in the form on p. 98 or contact Mrs Ruwayda Adams for more details.

ALLSA OfficePO Box 88Observatory 7935Tel 021-447-9019Fax 021-448-0846Email [email protected]


PRODUCT NEWS

ACCURATE ALLERGEN IDENTIFICATIONNOW A REALITYLabspec (Pty) Ltd is pleased to announce the launch

of a national allergen-testing awareness campaign

across South Africa, to let consumers and medical

practitioners alike know that highly accurate, specific

allergen identification is now within everyone’s reach.

Being able to identify exactly which allergen elicits an

allergic response within an individual, may result in

more specific treatment, an accurate overview of any

lifestyle changes that may need to be made in the

affected individual, and ultimately, enhanced quality

of life.

As a subsidiary of Phadia, the world leader in diag-

nostics, Labspec is committed to helping medical

practitioners make accurate diagnoses and sound

management decisions.

We at Labspec have also initiated a national print

media campaign both to consumers and medical

staff, and a dedicated sales force will highlight the

benefits to paediatricians and general practitioners

across the country.

Possibly the best part of requesting a Labspec aller-

gen test, is the fact that the procedure is covered by

most medical aids, thereby making the decision of

whether to be tested or not, an easy one.

Please contact Labspec on 011-792-6790/1/2/3, or

visit www.labspec.co.za.

Contact:

Charles Duff 011-792-6790/1/2/3

Maria Ramsay 082-410-6053

Angela Neveling 083-407-7654

Jacque Larsen 083-273-2604

A PHADIA COMPANY

GIVING TODDLERS A HEAD START IN LIFEAbbott, leaders in Science-Based Nutrition, are proud toannounce the launch of Isomil 3 Advance Plus, the first soy-based follow-on formula to contain the essential long-chainpolyunsaturated fatty acids, arachidonic acid (ARA) anddocosahexaenoic acid (DHA).The importance of DHA and ARA, naturally found in breastmilk and added to infant formulas to support brain develop-ment, was recognised by the rapid accretion of these fattyacids in the infant brain.1,2 Reports of enhanced intellectualdevelopment in breastfed children and the recognition of thephysiological importance of DHA in visual and neural sys-tems, led to clinical trials that evaluated whether infant for-mulas supplemented with DHA and ARA would enhancevisual and cognitive development.1

Evidence for a beneficial effect of ARA plus DHA supple-mentation on central nervous system (CNS) development isstrong.3 A randomised study evaluated visual and cognitivedevelopment in infants at 14 and 39 months of age and com-pared infants fed standard formula, formula supplementedwith DHA or formula supplemented with DHA and ARA.1

This study, with the longest follow-up period reported todate, showed that DHA and ARA supplementation supportvisual and cognitive development in infants from birth to chil-dren 39 months of age.1

Isomil 3 Advance Plus is a milk- and lactose-free, soy-basedformula that is specifically designed for children from 1 yearof age who have IgE-mediated cow’s milk allergy, are lactoseintolerant or suffer from digestive symptoms such as gas,diarrhoea or regurgitation.4

In addition to the patented combination of DHA and ARA,Isomil 3 Advance Plus contains:• Taurine and choline, which together with DHA and ARA are

required for brain development.5,6

• Soy protein isolate, equivalent to animal protein in qualityand a rich source of nucleotides, required for normalimmune development.7

• A vegetable oil blend that optimizes calcium and fat absorp-tion and is associated with a lower incidence of gastroin-testinal intolerance than infant formulas containing animalfats or palm olein oil.8 Stool characteristics of infants fed with

this unique vegetable oilblend closely resemblethose of infants fed humanmilk.8

• Two sources of carbohy-drate, which use two differ-ent digestive enzymes andtwo different non-compet-ing absorptive pathways,thereby enhancing carbohy-drate absorption.9

Isomil 3 Advance Plus is a nutritionally complete, follow-onsoy formula for growing toddlers from 1 year of age. It hasbeen tested in clinical trials and is the scientifically supportedsoy formula with the patented EYE Q system of brain nutri-ents that support brain development.1

Isomil 3 Advance Plus is competitively priced and is availableat pharmacies, supermarkets and baby stores. For moreinformation on Isomil 3 Advance Plus, please contact thebrand manager, Yvonne MacLeod, at Abbott Nutrition, tel011-858-2000.1. Auestad N, Scott Dt, Janowsky JS, et al. Visual, cognitive and language

assessments at 39 months: A follow-up study of children fed formulas con-taining long-chain polyunsaturated fatty acids to 1 year of age. Pediatrics2003; 112(3): e177-183.

2. Fernstrom JD. Can nutrient supplements modify brain function? Am J ClinNutr 2000; 71(suppl): 1669S-1673S.

3. Uauy R, Hoffman DR, Peirano P, et al. Essential fatty acids in visual and braindevelopment. Lipids 2001; 36: 885-895.

4. Isomil® 3 Advance Plus Product Monograph.

5. Chesney RW, Helms RA, Christensen M, et al. The role of taurine in infantnutrition. Adv Exp Med Biol 1998; 442: 463-476.

6. Zeisel SH. The fetal origins of memory: The role of dietary choline in optimalbrain development. J Pediatr 2006; 149: S131-136.

7. Ostrom KM, Cordle CT, Schaller JP, et al. Immune status of infants fed soy-based formulas with or without added nucleotides for 1 year: Vaccineresponses and morbidity. J Pediatr Gastroenterol & Nutr 2002; 34: 137-144.

8. Alarcon PA, Tressler RL, Mulvaney A, et al. Gastrointestinal tolerance of a newinfant milk formula in healthy babies: An international study conducted in 17countries. Nutrition 2002; 18: 484-489.

9. Kerzner B, Sloan HR, McClung HJ, et al. Jejunal absorption of sucrose andglucose oligomers in the absence of pancreatic amylase. Pediatr Res 1983;17(4): 191A.

Abbott Nutrition International, Abbott Place, 219 Golf Club Terrace, Constantia

Kloof, 1709. PO Box 7208, Weltevreden Park, 1715, South Africa. Tel 011-858-

2000, fax 011-858-2041. 0007-0708-P871-A-0708, August 2008.


PRODUCT NEWS

MIELE LAUNCHES TOP-CLASS RANGE OF VACUUM CLEANERSA fact of modern life is the increase in allergies, withmore and more adults and children suffering fromasthma, rhinitis and hay fever. Allergies are madeworse by household pets, and dust mites in carpets,mattresses and soft furnishings. In response to thegrowing need for appliances that can help alleviatethe problems suffered by allergy sufferers Miele havedeveloped a number of features and accessories toensure excellent levels of cleanliness in the home.

The S5281 MedicAir VacuumCleaner is supplied with all the fea-tures and accessories to meet thespecific needs of allergy sufferers.The unit is equipped with an inno-vation that offers additional securityand comfort; the Allergotec Sensorfloorhead for visible hygienic clean-liness.

Miele offers a choice of three filters placed behindthe motor. Because of the airtight design, any air leav-ing the vacuum cleaner only leaves via the final filter.The Miele Super AirClean filter removes nearly94% of the particles as small as 0.3 µ and, for thisreason is the most suitable for everyday households.The Miele Active AirClean filter incorporates theSuper AirClean filter and is designed for customerswho have to vacuum up items with unpleasantodours. A tight-fitting filter cassette with a rubber sealprevents any air escaping. The active charcoal com-ponent absorbs and neutralises odours. The Miele

Active HEPA filter solves the problems of allergy suf-ferers. The Active HEPA filter retains 99.5% of parti-cles.

For the true pet lover – the S5261 in Capri Blue andS5361 in Tayberry Red are Miele's Cat & Dog rangeof vacuum cleaners. Stubborn pet hairs do not standa chance with the Miele Cat & Dog's Turbo Brush.This special floorhead is driven by the suction of thecleaner and rotates evenly to pick up hair and dirtfrom most types of carpets, while the smooth run-ning floor head SBD takes care of most hard floor sur-faces. The Miele Cat & Dog vacuum cleaner is spe-cially fitted with an ActiveAirClean filter. The activatedcharcoal filling ensures any smell arising from thecontents of the dustbag is absorbed before it leavesthe cleaner and that the exhausted air is always freshtoo.

Miele (Pty) Ltd Gallery of FineLiving (Head Office),PO Box 69434, Bryanston, 2021, [email protected],www.miele.co.za, [email protected],Share call: 0860 000 622, Share fax: 0860 000 633.

BOEHRINGER INGELHEIM LAUNCHESINFLANAZE® 100.

It is with great pleasure and excitement that BoehringerIngelheim, a leader in respiratory care, announces thelaunch of Inflanaze® 100.Allergic rhinitis is a highly prevalent chronic respiratorydisease that impacts significantly on the quality of life ofpatients.1 The prevalence of allergic rhinitis is rising witha huge indirect and direct economic burden.1 In additionnearly 80 % of asthmatic patients have coexisting aller-gic rhinitis.2 Topical corticosteroids are highly effectivefirst-line treatment of allergic rhinitis.3 Budesonide iscomparatively an effective corticosteroid which is welltolerated for all classifications of allergic rhinitis.4

Inflanaze® 100, 100µg budesonide per metered spray,provides another option for healthcare professionals totreat this common respiratory disease. Inflanaze® 100provides high dose budesonide for the allergic rhinitispatient and allows tapering down of medication to thelowest dose adequate to control symptoms.5 With itsless number of sprays per day, the new 100 dosageallows for better patient compliance.1 It is registeredfrom the age of 6 years allowing for use in children.

Inflanaze® 50 and 100 possess a broad actuator makingthe administration of medication to children and patientswho struggle to use nasal sprays easy and comfortable.

Inflanaze® 100 contains 200 doses, contains no alcoholand has potassium sorbate as its preservative.6

This product addition shows that Boehringer Ingelheim,with its wide range of medication for asthma and allergicrhinitis, is committed to optimising respiratory care.

References:

1. Yawn B. Comparison of Once-Daily Intranasal Corticosteroids for

the Treatment of Allergic Rhinitis: Are they all the same?

Medscape General Medicine 2006; 8(1): 23.

2. Grossman J. One Airway, One Disease. Chest 1997; 111(2)(Suppl):

11S-16S.

3. Van Cauwenberge P. Consensus Statement on the Treatment of

Allergic Rhinitis. Allergy 2000; 55: 116-134.

4. Stanaland B. Once-Daily Budesonide Aqueous Nasal Spray for

Allergic Rhinitis: A Review. Clinical Therapeutics 2004; Vol.26(4):

473492.

5. Inflanaze®

100 Package Insert.

6. Data on File

S3 Inflanaze®

50 Aqueous Nasal Spray. Each metered dose contains

50�g budesonide. Reg. No 32/21.5.1/0532

S3 Inflanaze®

100 Aqueous Nasal Spray. Each metered dose contains

100�g micronised budesonide. Reg. No. 41/21.5.1/0238

For full prescribing information refer to the package insert.

Applicant details: Ingelheim Pharmaceuticals (Pty) Ltd,

407 Pine Ave, Randburg. Tel: +27 (011) 348-2400.

Fax: +27 (011) 787-3766. Cpy Reg. No. 1966/008618/07.

BI Ref. No. 72/2009 (Mar 09).

NOPQ


MSD (Pty) Ltd is proud to announce the introduction of SINGULAIR 4 mg. Studies have shown that asthma in chil-dren under the age of six is on the increase worldwide.1

SINGULAIR 4 mg is the first asthma controller therapy, thatis not a steroid, to be approved in South Africa for childrenas young as 2 years old.2

Studies have shown improvements in symptom and activityscores from as early as day one, affirming the efficacy ofSINGULAIR 4 mg in this age group.3 The current guidelinesfor treatment of asthma in children, as compiled by theAllergy Society of South Africa (ALLSA), call for the intro-duction of a leukotriene antagonist as a controller agent inthis age group at step 2, after the use of short-acting reliev-er medication has proven to be inadequate in controllingasthma symptoms. In other words using leukotriene antag-onist as a first line controller agent.4 At present, of theleukotriene receptor antagonists, only SINGULAIR is indi-cated for use in children under the age of 12.2

SINGULAIR 4 mg is indicated for the prophylactic treatmentof mild to moderate asthma in the 2-5 year old age group.SINGULAIR 4 mg is presented in a 28-day pack and onetablet should be taken once daily at bedtime.2 To date world-wide use is more than 2.2 million children in more than 90countries. This puts SINGULAIR in the unique position ofbeing the only controller therapy to be registered and indi-cated for asthmatic patients from 2 years old and up.2

REFERENCES:1 Ehrlich, R. The Prevalence of Asthma in South Africa. Current

Allergy and Clinical Immunology March 2002; Vol 15: 4-8.

2 Data on File.

3 Knorr B, Franchi LM, Bisgaard H, et al. Montelukast, a leukotrienereceptor antagonist, for the treatment of persistent asthma inchildren aged 2 to 5 years. Pediatrics 2001;108(3):1-10.

4 Motala C, Kling S, Gie R, et al. Guidline for the management ofChronic Asthma in Children – 2000 Update. SAMJ. 2000; 90: 524-539.

MSD (Pty) Ltd (Reg. No. 1996/003791/07), Private Bag 3, HalfwayHouse 1685.

Copyright © MERCK & CO., INC., Whitehouse Station, N.J., U.S.A.1999. ® Registered Trademark of MERCK & CO., INC., WhitehouseStation, N.J., U.S.A. Before prescribing, please refer to the full pack-age insert. 06-2004-SGA-03-ZA-230-O

Reg. No: 35/10.2.2/0397, SINGULAIR 4 mg S3

The FREEDOM to be a Child!

PRODUCT NEWS

Foratec HFAForatec HFA is another exciting addition to Cipla'srange of respiratory products, emphasising our commitment to offering solutions for Total AsthmaControl!

Foratec HFA (formoterol fumarate 12µg) is:

" a long-acting �2-agonist, giving up to 12 hours bronchodilation1

" as fast-acting as salbutamol,2 between 1-3 minutes1

" the only available formoterol fumarate MDI

" a 120-dose MDI; 2 months' supply (at 1 puff b.d.)

" CFC-free, re-enforcing our global commitment topreserving our planet within our sphere of influence

" indicated as add-on therapy to inhaled corticosteroids in patients with chronic persistent asthma (GINA step3)3 and for prophylaxis and treatment of symptoms in patients with COPD1,

" priced at R69.60 SEP (excl VAT), the most cost-effective long-acting �2-agonist in SA!5

Isn't this enough reason to prescribe Foratec HFA?

Cipla offers you Total Asthma Control through choice of molecules, choice of devices and a choice to treat cost-effectively!

Prescribing information available on request. Please contact Elizma Kemp on 021-917-5620.

1. Foratec HFA Package Insert

2. Van Noord J, et al. Salmeterol versus formoterol in patients with moderately severe asthma: onset and duration of action. Eur Respir J 1996;

9: 1684-1688

3. Asthma Guidelne Iimplementation Project. Primary care management of adults with chronic asthma. Revised 2006. SA Family Practice

Journal. June 2007; 49: 19-31

4. Bateman ED, Feldman C, O'Brien J, Plit M, Joubert JR. Guideline for the management of chronic obstructive pulmonary disease (COPD):

Revised 2004. S Afr Med J. 2004; 94(7 Pt 2): 559-575.

5. SEP (excl. VAT) as per PCD, July 2008


ALLSA MEMBERSHIP 2009

Support your society, it supports allergology in South Africa

ALLSA remains one of the world’s most pro-active and innovative allergy societies. Our pioneering website andpatient information resources have spurred other national societies to follow suit.

ALLSA relies on an active membership base to continue to provide excellent resources to healthcare workers inSouthern Africa. We welcome new members from all over Southern Africa and membership is open to all health-care workers with an interest in allergology. Our current membership includes medical practitioners (general prac-titioners, physicians, pulmonologists, ENT specialists, dermatologists, ophthalmologists, paediatricians andanaesthetists), nurses, dieticians, medical technologists, pharmaceutical industry staff and medical students .

Membership currently costs only R200 annually; this is a tax-deductible expense.

Members enjoy a number of privileges which include:• The highly rated ALLSA journal – Current Allergy & Clinical Immunology, which is edited by Profs Weinberg and

Zar, and published quarterly. This journal is available on-line.

• Access to ALLSA’s comprehensive allergy website at www.allergysa.org.

• On-line CPD accreditation.

• Patient information guides and leaflets on common allergic disorders.

• Discounted ALLSA congress registration fees for our annual congress.

• Regional allergy courses, meetings and journal clubs.

• Support with examination preparation for the Diploma in Allergology of the Colleges of Medicine of SA.

• Access to allergy research funding and annual ALLSA research awards of up to R50 000 per research study.

For more details on membership and privileges please contact Ruwayda Adams on tel 021-447-9019, fax 021-448-0846, or e-mail enquiries to [email protected]

Please cut out the membership application form and post together with your payment.

ALLSA Membership Application R200 annual subscription

Dr/Sr/Mr/Mrs/Ms: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Address: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

E-mail address: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Phone: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fax: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Speciality: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Special Interests: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Comments: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Post to: Allergy Society of South Africa, PO Box 88, Observatory 7935

Direct debit details: Standard Bank: Rondebosch

Sort Code: 02-50-09

Account Number: 07 149 1821

Cheques payable to Allergy Society of South AfricaFor direct deposits: Kindly fax your bank deposit slip as proof of payment (Fax No. 021-448-0846)

✃

PRODUCT NEWS

NEW DESIGN FOR SYMBICORDAstraZeneca is proud to introduce a new design forSymbicord boxes and packaging. The purpose of thepackaging change is to standardise the colours anddesign globally, so that wherever in the world youmay be, the Symbicord packaging will look the same.

In line with these changes, we are also keeping thesecolours for our promotional and educational material,so that the design is standardised throughout. Thenew look is bold, positive, professional and modern,with an emphasis on clinically relevant and clear infor-mation. The approach is future-focused, to reflect theconstant innovation and challenging of conventionsthat is the basis of our approach to medicine atAstraZeneca.

Please note that the ingredients and doses ofSymbicord will remain the same.In conjunction with the new look, AstraZenecaintends to introduce user-friendly educational andsupport material to assist and support people withasthma.

The new material is aimed at providing the busyphysician and his/her patients with the tools that theyneed so that people with asthma can take responsi-bility for their own asthma control.

S 3 Symbicord® Turbuhaler® 80:4,5 µg/dose (Inhaler), Reg No.35/21.5.1/0404. Each delivered dose contains as active con-stituents: Budesonide 80 micrograms and formoterol fumaratedihydrate 4,5 micrograms.

S 3 Symbicord® Turbuhaler® 160:4,5 µg/dose (Inhaler), RegNo. 35/21.5.1/0405. Each delivered dose contains as activeconstituents: 160 micrograms and formoterol fumarate dihy-drate 4,5 micrograms.

S 3 Symbicord® Turbuhaler® 320:9 µg/dose (Inhaler), Reg No.38/21.5.1/0187. Each delivered dose contains as active con-stituents: Budesonide 320 micrograms and formoterolfumarate dihydrate 9 micrograms

NAME AND BUSINESS ADDRESS OF THE HOLDEROF THE CERTIFICATE OF REGISTRATION:

AstraZeneca Pharmaceuticals (Pty) Limited, 5 Leeuwkop Road,Sunninghill, 2157, South Africa. Reg No. 92/05854/07. Tel: +27 11 797 6000. Fax: +27 11 797 6001. www.astrazeneca.co.za


Earn 3 CPD points after you have read the journal by com-pleting the following questionnaire online on the ALLSAwebsite at www.allergysa.org/cpd or follow the links fromthe home page. To earn points, you will need to registerand fill in personal details (make sure you have yourHPCSA number handy and decide on a password before-hand). Once you have registered, you can answer thequestionnaire. If you have registered for a previous ques-tionnaire, you'll need your HPCSA number and passwordto logon. Please note that there is only one correct answerper question, and you will have only one opportunity tosubmit the questionnaire, so please check answers care-fully. You will be able to change answers if you click thewrong one by mistake, but once you click 'SubmitAnswers' the test will be submitted and marked. You need70% or higher to earn 3 points.

The closing date for submission of this questionnaire is 31August 2009.

FOOD-PROTEIN-INDUCED ENTEROCOLITIS SYNDROME (FPIES)1. True or false: FPIES is an IgE-mediated food allergy

disorder affecting the gastrointestinal tract?a) Trueb) False

2. True or false: FPIES can occur in exclusively breast-fedinfants?a) Trueb) False

3. Choose ONE correct answer: FPIES may resolve in90% of cases after:a) 3-6 monthsb) 24-36 monthsc) >5-10 yearsd) >10 years

4. Choose ONE correct answer: The most commoncausative food of FPIES in infants is:a) egg whiteb) wheatc) cow’s milkd) peanut

ORAL ALLERGY SYNDROME (OAS) – WHAT’S NEW?1. True or false: Symptoms of OAS are caused by cross-

reactivity of IgG4 antibodies to aeroallergens with pro-teins in fresh fruit/s and vegetable/s?a) Trueb) False

2. True or false: Plant proteins involved in OAS belong toplant protein families including profilins, pathogenesis-related proteins and lipid transfer proteins?a) Trueb) False

3. Choose ONE correct answer: The diagnosis of OAS isbased primarily on:a) Skin-prick testingb) Specific IgEc) Patient’s historyd) Atopy patch test

4. Choose ONE correct answer: Symptoms of OAS canbe prevented by:a) Pre-treatment with antihistamineb) Intranasal steroidsc) Cooking of offending foodsd) Antileukotrienes

PENICILLIN ALLERGY1. True or false: Penicillin allergy is more common in

young children than adults?a) Trueb) False

2. True or false: Testing for minor determinants (penicil-loate and penilloate) is essential for detecting penicillinallergy?a) Trueb) False

3. Choose ONE correct answer: IgE-mediated mecha-nisms are not involved in penicillin-induced adversereactions in patients presenting with:a) anaphylaxisb) urticariac) bronchospasmd) Stevens-Johnson syndrome.

4. Choose ONE correct answer: Cross-reactivity betweenpenicillins and cephalosporins is believed to be due tothe drugs having:a) �-lactam ringsb) similar spectrums of activityc) similar side-chains (R-group)d) similar manufacturing processes.

ANAPHYLAXIS IN INFANTS: CAN RECOGNITION ANDMANAGEMENT BE IMPROVED?1. True or false: Skin contact with food or food-based

skin products or inhalation of aerolised food particlespotentially sensitises an infant but seldom causes ana-phylaxis?a) Trueb) False

2. True or false: Drugs are the most common triggers ofanaphylaxis in infants?a) Trueb) False

3. Choose ONE correct answer: Which laboratory testsupports the clinical diagnosis of anaphylaxis:a) urine histamineb) serum tryptasec) full blood countd) lymphocyte subsets?

4. Choose ONE correct answer: The first-line treatmentfor anaphylaxis is:a) nebulised B2 agonist inhalationb) diphenhydraminec) intramuscular adrenalined) intravenous hydrocortisone

H1 ANTIHISTAMINES IN ALLERGY DISEASE1. True or false: H1 antihistamines are specific antago-

nists of the H1 receptor?a) Trueb) False

2. True or false: Second-generation H1 antihistamines areless or non-sedating because they do not cross theblood-brain-barrier?a) Trueb) False

3. Choose ONE correct answer: Simultaneous consump-tion of grapefruit juice may alter the bioavailability of:a) chlorpheniramineb) cetirizinec) fexofenadined) desloratadine.

4. Choose ONE correct answer: Dose-dependent car-diac toxic effects may occur with the following H1-anti-histamine:a) fexofenadineb) levocetirizinec) loratadined) diphenhydramine.

CPD QUESTIONNAIRE

Accredited by the Colleges of Medicine of South Africa

Current Allergy & Clinical Immunology · 2017-10-26 · 54 Current Allergy & Clinical Immunology,...

Documents

Transcript of Current Allergy & Clinical Immunology · 2017-10-26 · 54 Current Allergy & Clinical Immunology,...