ORIGINS OF ALLERGYProfessor Cas MotalaDepartment of Paediatrics and Child HealthUCT & Red Cross Children‟s HospitalCape Town

OUTLINE• Risk factors for allergic disease• The allergic march• Allergy: a systemic disease?• Strategies for prevention of allergy

Early markers of increased risk for allergic disease• Elevated cord-blood IgE level (highspecificity but low sensitivity)• Positive skin prick test to egg or HDM in 1 styear of life• Detection of specific IgE to common foodand inhalant allergens during early infancy(Kjellman et al, Ann Allergy 1984)

Infant with cow’s milk allergy (before avoidance diet)

Infant with cow’s milk allergy (after avoidance diet)

Relationship between AE and other allergicdisorders• AE and asthma:–common genetic and pathological basis–eczema progresses to asthma? (Galli et al 2007)• AE and allergen sensitization in non-sensitized children:eczema (not wheeze or rhinitis) is predictor for subsequentsensitization (Almqvist et al 2007)–early management of eczema may reduce prevalence ofsensitization?–HDM: patients with skin sensitization can develop airwaysensitization (Dohi et al 1990)

SKIN SENSITIZATION AND SYSTEMICALLERGIC RESPONSE• Spergal et al, J Clin Invest 1998.-Mouse model-Ovalbumin applies to stripped skin of mouse-Induced dermatitis (TH 1 and TH 2 cytokines)-Bronchial challenge with ovalbumin increased eosinophils inBAL and airway hyperresponsiveness (typical AHRassociated with asthma)

Early life risk factors for adult asthma• UK Study (22 years) on 100 infants (high-allergic risk)• Prevalence of AE: 20% at 1year; declined to < 5% at end ofstudy• Prevalence of AR: Increased from 3%-15%• Wheezing: Increased from 5% during 1 st year to 40% at endof study• Major risk factor for adult asthma: early sensitisations tofoods (1 yr) or aeroallergens (2yrs)Rhodes et al JACI 2001

Multicentre Atopy Study (MAS)• German study (7yrs) 1314 childrenLan et al. Paediatric Respir Rev 2002• High risk group – 38%– infants with AE @ 3mths: 69% sensitized toaeroallergens by 5yrs (increased – 77% in all high riskinfants)– 50% with early AE and +ve family history of allergydeveloped asthma or AR (vs 12% without AE or +vefamily history of allergy)

Other studiesStudyNo: ofSubjects AE CommentPunekar et alClin Exp Allergy 200924112 (UK)18yrs study 60.70%AE followed by AsthmaAsthma followed by ARBarberio et alAllergy 20086929yr study 20%Reverse Allergic March:Asthma 1st, AE laterLoire et alJACI 2008Increased risk ofasthma in boyswith AEBoys more susceptible thangirls to the Allergic March

AR is rarely diagnosed in isolation in childrenCo-morbid conditions:• Asthma• Chronic middle ear infection• Sinusitis• Conjunctivitis• Disordered sleep• Behavioural disorders• Dental problems

The Rhinitis-Asthma Link• AR is a global health problem affecting 5 to 50 % of thepopulation 1• 40 - 50 % of patients with AR have asthma 2,3• 30 - 80 % of asthmatic patients have AR 4New WHO ARIA 2001 Guidelines define: AR is a RiskFactor for Asthma1ARIA 2001, 2 Corren 1997, 3 Welsh 1987, 4 Simons 1999

Allergic Rhinoconjunctivitis

Allergy is a Systemic DiseaseUrticariaFoodAllergyAsthmaAllergicRhinitisALLERGY -A SYSTEMICDISEASEConjunctivitisEczema

PREVENTION OF ALLERGY(THE ALLERGIC MARCH)• Primary prevention-breast feeding (√)-delayed introduction of solids (?)-etc.NOT CURRENTLY ATTAINABLE

GENETIC EFFECTS ON ALLERGYAND ALLERGIC DISEASEDetermine susceptibility to atopy:• “Th2” or „IgE switch” genesDetermine specific target-organ disease in atopic individuals• Asthma susceptibility genes“Lung-specific factors” that regulate susceptibility of lungepithelium/fibroblasts to remodeling in response to allergicinflammation, such as ADAM33• Atopic dermatitis susceptibility genesGenes that regulate dermal inflammation and immunity, such asSPINK5

GENETIC EFFECTS ON ALLERGYAND ALLERGIC DISEASEInfluence the Interaction of EnvironmentalFactors with Atopy and Allergic Disease• Regulation of specific IgE responses (which allergen will you respondto?), such as MHC class II alleles, TCR V gene use• Determining immune responses to factors that drive Th1/Th2 skewingof the immune response, such as CD14 polymorphism and earlychildhood infection• Altering interaction between environmental factors and establisheddisease, such as genetic polymorphism regulating responses torespiratory syncytial virus infection and asthma symptoms

PREVENTION OF ALLERGY(THE ALLERGIC MARCH)• Secondary prevention-Pharmacotherapy: ketotifen; cetirizine(ETAC)-Immunotherapy: SLIT-Probiotics ?

GENETIC EFFECTS ON ALLERGYAND ALLERGIC DISEASEModify Severity of DiseaseExamples are tumor necrosis factor αpolymorphisms and asthma severityRegulate Response to Therapy• Pharmacogenetics• Examples are ß 2 -adrenergic receptorpolymorphism and response to ß 2 -agonists

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