Food Allergy and Anaphylaxis

Food Allergy and Anaphylaxis Professor Mimi Tang The Royal Children s Hospital, Melbourne Murdoch Childrens Research Institute, Melbourne University of Melbourne, Australia

Food Allergy and Anaphylaxis Terminology Epidemiology Food Allergy Anaphylaxis

WAO Nomenclature: Allergic Disease Reproducible reactions to foods = hypersensitivity Objectively reproducible symptoms or signs initiated by exposure to a defined stimulus at a dose tolerated by normal persons Any reproducible reaction to a food Controversial terminology not widely accepted, best to use the term reproducible reaction to food

WAO Nomenclature 2003 Allergy Reaction initiated by specific immunological mechanisms Intolerance Reaction initiated by NON-immunological mechanisms

Food Hypersensitivity (All reproducible reactions) Food Allergy Immunologically mediated Food Intolerance NON-Immunologically mediated IgE mediated Mixed IgE and NON-IgE mediated NON-IgE mediated

Anaphylaxis ASCIA Anaphylaxis Working Party Generalised allergic reaction that involves respiratory or cardiovascular systems or both Most severe presentation of an IgE mediated allergic reaction A life-threatening allergic reaction

Anaphylaxis Sampson HA et al. Second symposium on the definition and management of anaphylaxis: Summary report - Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium. J Allergy Clin Immunology 2006;117;391-7.

Rising Prevalence of Immune Disorders Bach, NEJM 2002;347: 911-920

Rising Rates of Food Allergy Incidence of Food Allergy increased >10-fold from 1990-2004 Mullins R, Dear K, Tang MLK. J Allergy Clin Immunol 2009

Exponential Rise in Food Anaphylaxis +250% +230% +350% Liew WK, Williamson E, Tang MLK. J Allergy Clin Immunol 2009;123:434-42

Exponential Rise in Food Anaphylaxis Liew WK, Williamson E, Tang MLK. J Allergy Clin Immunol 2009;123:434-42

Exponential Rise in Food Anaphylaxis Liew WK, Williamson E, Tang MLK. J Allergy Clin Immunol 2009;123:434-42

Prevalence of Food Allergy Overall ~ 2-5% of population experience food allergy reactions More common in children Recent HealthNuts study found more than 10% of 12 month old Melbourne infants have food allergy 1 6% -10% children experience food allergic reactions 2 2% adults experience food allergic reactions 3 1. Osborne N et al. J Allergy Clin Immunology 2011 2. Bock et al. Pediatr 1987;79:683-88 3. Young et al. Lancet 1994;343:1127-30

Anaphylaxis

8 major food groups cause >90% food allergy Cow s milk Hen s egg Peanut Tree nuts Wheat Soya bean Shellfish Fish

Food Allergy Children egg, milk, peanut soy, wheat, fish Adults peanut, tree nuts, fish, shellfish Most food allergies resolve during childhood Except peanut, tree nuts, fish, shellfish 80% of these allergies persist

History Food Quantity, how prepared First exposure? Reproducibility Exercise Symptoms organ systems involved (skin, resp, gut, CVS) time to onset of symptoms duration, time to resolution symptoms treatment, response to treatment

History Diet history Breast milk Formula, when was formula introduced, what formula Have other common food allergens been introduced Reactions to other foods Other allergic conditions Eczema Asthma / wheezing Rhinitis Family history of allergic disease

Examination Growth parameters (weight, height, HC) Other allergic conditions Skin hives, eczema Chest asthma Nasal mucosa - rhinitis Differential diagnoses Idiopathic urticaria / angioedema common Pyloric stenosis similar presenting Sx with FPIES Other causes of FTT, vomiting, diarrhoea

Diagnostic Tests for IgE Mediated Food Allergy Skin Prick Test Sensitive, inexpensive, simple, rapid Negative predictive value - >95% Positive predictive value - 50% Serum allergen-specific IgE (sige) Similar to SPT in sensitivity, specificity, NPV, PPV More expensive, delayed result Food challenge Must be supervised Should NOT be performed at home if positive SPT or sige

Diagnostic Approach to IgE Mediated Food Allergy Most important information is the history If history suggests food allergy then perform sige test to that specific food Avoid screening sige testing as a +ve result when the patient has not eaten the food can be difficult to interpret Exception is in a child with confirmed food anaphylaxis sige testing for common food allergens that have not yet been introduced (usually egg, milk, peanut, cashew)

Diagnostic Approach to IgE Mediated Food Allergy -ve sige IgE mediated allergy unlikely Food not yet introduced and -ve SPT home introduction of food BUT **NB**. If there is a clear history of reaction and -ve SPT REFER to ALLERGIST for further evaluation (challenge) +ve sige may or may not indicate allergy Clear history and +ve SPT diagnosis Food not yet introduced and +ve SPT????

How to interpret sige test if food not introduced +ve test without history of exposure to the food is a poor predictor of allergy Cow s milk, egg 50% not allergic Peanut 60-70% not allergic The larger the SPT and the higher the serum sige level, the more likely there is clinical allergy 95% thresholds (PPV or specificity) can help make a diagnosis of food allergy if no previous exposure Pucar et al Clin Exp Allergy 2001;31:40) Spergel et al Ann Allergy Asthma Immunol 2000;85:473)

95% Thresholds for Diagnosis of IgE Mediated Food Allergy If serum sige is to the 95% specificity threshold 95% chance of clinical allergy If SPT size is to the 95% PPV threshold 95% chance of clinical allergy 8mm peanut; 8mm cow s milk; 7mm egg Roberts et al. J Allergy Clin Immunol 2005;115:1291-6; Sporik et al. Clin Exp Allergy 200;30:1540 Sampson et al JACI 2001;107:891

Ara h2 sige can help in diagnosis peanut allergy Dang et al JACI 2012 In Press

Diagnostic Approach for Delayed Food Allergies There are no specific tests for non-ige mediated or mixed IgE/non-IgE mediated food allergy syndromes History is the primary tool for diagnosis GI endoscopy and biopsy can support diagnosis

Anaphylaxis

Prevalence of Anaphylaxis Prevalence of anaphylaxis from community studies Estimated to be 5-10 per 100,000 pt yr 1 UK: 8.4 per 100,000 pt yr (UK GP database) 2 US: 10.5 per 100,000 pt yr (children in health maintenance org) 3 Australia: 12.6 per 100,000 pt yr (allergy specialist consultations) 4 Population prevalence of anaphylaxis admissions UK: 3.6 per 100,000 population in 2003/2004 5 Australia: ~10 per 100,000 population in 2004/2005 6 1. Moneret-Vautrin et al. Allergy 2005; 2. Peng and Jick. Arch Intern Med 2004; 3. Bohlke et al. JACI 2004; 4. Mullins. Clin Exp Allergy 2003; 5. Gupta et al. Thorax 2007; 6. Liew, Williamson, Tang. J Allergy Clin Immunol 2009

Anaphylaxis Admissions in Australia 1994 to 2005 (n=14728) 10 Admission rate/year/100000 9 8 7 6 5 4 3 2 1 0 0 4 5 9 10 14 15 19 20 24 25 29 30 34 35 39 40 44 45 49 50 54 55 59 60 64 65 69 70 74 75 79 80 84 85+ Food Anaphylaxis (n=5007, 34.0%) Drug Anaphylaxis (n=3019, 20.5%) Anaphylaxis, Unspecified (n=6565, 44.6%) Anaphylaxis to Serum/Infusion/Transfusion (n=137, 0.9%) Liew, Williamson, Tang. J Allergy Clin Immunol 2009

Childhood Anaphylaxis Anaphylaxis presentations to ER 1998-2003 Young (75% < 5 years) Other allergic disease common (60%) Food commonest trigger Home commonest setting Onset to anaphylaxis quick (10 min) Respiratory and skin >> GIT or CVS Death uncommon De Silva, Mehr, Tey, Tang - Allergy 2008

Fatal Anaphylaxis Population prevalence of anaphylaxis fatalities Estimated 1-3 per million population; 0.5-2% of anaphylaxis 1 National statistics from UK: 1 death/yr per 3 million population 2 National statistics from Australia: 86 deaths between 1997-2004 3 US: estimated 1500 deaths per year 4 Limited data on causes and demographics of fatal anaphylaxis National data from UK and Australia 2,3,5 1. Moneret-Vautrin et al. Allergy 2005; 2. Pumphrey 2004; 3. Poulos et al. JACI 2007; 4. Neugut 2001; 5. Liew, Williamson, Tang. JACI 2009

Anaphylaxis Deaths Australia vs UK Australia Anaphylaxis deaths (n=112) UK Anaphylaxis deaths (n=202) Food Drug Probable Drug Insect sting Others Unknown 5% 18% 13% 6% 38% 20% 9% 2% Food 23% 44% 22% Drug Insect sting Others Possible Food 0.64 deaths per million population 0.33 deaths per million population Pumphrey. Curr Opin Allergy Clin Immunol 2004 Liew, Williamson, Tang. J Allergy Clin Immunol 2009

Anaphylaxis Deaths Jan 1997 to Dec 2005 (n=112) 0.25 Death rates/yr/100000 0.2 0.15 0.1 0.05 0 0 4 5 9 10 14 15 19 20 24 25 29 30 34 35 39 40 44 45 49 50 54 55 59 60 64 65 69 70 74 75 79 80 84 85+ Age groups Anaphylaxis (Food) Anaphylaxis (Drugs and Probable drugs) Anaphylaxis (Insect sting) Anaphylaxis (Unknown and Others) Liew, Williamson, Tang. J Allergy Clin Immunol 2009

Fatality rate/yr/100,000 Food Anaphylaxis Admissions vs Fatalities Admission rate/yr/100,000 10 9 8 7 6 5 4 3 2 1 0 0.2 0.15 0.1 0.05 0 0 to 4 5 to 9 10 to 14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ Age groups Admissions Deaths Liew WK, Williamson E, Tang MLK. J Allergy Clin Immunol 2009

Food Anaphylaxis Deaths US (n=63) UK (n=48) Australia (n=7) 2% 8% 3% 29% 58% Peanut Treenut Milk Seafood Fish Others Uncertain 37% 8% 2% 2% 19% 13% 19% 43% 14% 43% US UK Australia Males 56% 46% 29% Age range 2 to 50 yr 5mth to 85yr 8 to 35 yr Age (10-30) 65% 54% 71% Asthma (of data available) 100% 90% 100% Adrenaline delayed or not available 87% 81% 100% Peanut or Treenut allergy 81% 38% 43% Food prepared outside home 39% 38% 100%

Insect Anaphylaxis Fatalities 0.1 Fatality rate/yr/100000 0.08 0.06 0.04 0.02 0 0 to 4 5 to 9 10 to 14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ Age groups Deaths Liew WK, Williamson E, Tang MLK. J Allergy Clin Immunol 2009

Insect sting Anaphylaxis Deaths (n=20) 30% 5% 65% Demographics Male = 95% Age 35-84 (85%) CVS (15%) / Resp (5%) not noted to be specific risk factors Hornet, wasp and honey bee Other specified venomous arthropods eg. Jumper-Jack ants Non-venomous insects or arthropods Liew WK, Williamson E, Tang MLK. J Allergy Clin Immunol 2009

Drug Anaphylaxis deaths: Antibiotics and Anaesthetics Australia (n=64) UK (n=88) 8% 5% 8% 8% 3% 10% 0% 13% 8% 13% 14% 38% 2% 3% 2% 5% 2% 3% 8% 1% 40% 5% 1% Penicillins Other antibiotics Anaesthetic unspecified Contrast media NSAIDS (1 aspirin) Unknown drugs Procedure Cephalosporin Local anaesthetic Skeletal muscle relaxant Radiological/radiotherapy Viral vaccine Others

Drug and Probable Drug Anaphylaxis deaths (n = 64) 38% 8% 2% 5% 8% 2% 5% 8% 2% 3% 8% 8% 3% Demographics Female 51.6% Age 55-85 (73%) CVS 21 (32.8%) Resp 11 (17.2%) Asthma 5 COPD 5 Emphysema 1 Hypogamm 1 Mastocytosis 1 Penicillins Other antibiotics Anaesthetic unspecified Contrast media Viral vaccine Others Procedure Cephalosporin Local anaesthetic Skeletal muscle relaxant NSAIDS (1 aspirin) Unknown drugs Radiological/radiotherapy Liew WK, Williamson E, Tang MLK. J Allergy Clin Immunol 2009

Acute Management of Anaphylaxis IM Adrenaline - First line treatment for anaphylaxis Supine posture 1 unless respiratory distress or vomiting Oxygen, secure airway IV fluid if cardiovascular involvement Antihistamine no evidence of benefit 2 Corticosteroid controversial -? Prevent biphasic 1. Pumphrey JACI 2003;112:451 2. Sheikh et al. Cochrane database 2007

Posture linked to Fatal Anaphylaxis ~25% (10 of 38) of deaths outside hospital occurred within seconds of changing to a more upright posture 1 Maintain supine posture +/- elevate legs if hypotension or cardiovascular involvement 1. Pumphrey JACI 2003;112:451

Long Term Management of Food Allergy Allergen avoidance is the first line approach Read ingredient labels, may contain traces labelling Alternative foods. Involve dietician Educate about situations that carry increased risk of accidental exposure. eg: eating out, parties, friend s home Risk minimisation Educate on recognition and treatment of allergic reactions Action plan # Consider provision of adrenaline auto-injector * Ensure that asthma is well controlled # Annual review with GP or Paediatrician * Not relevant for non-ige or mixed IgE/non-IgE mediated food allergy # May not be relevant for non-ige or mixed IgE/non-IgE mediated food allergy

Pitfalls of Current Management Allergen avoidance is difficult to achieve 50% accidental exposures within 1yr, 75% within 5 years In fatal cases, most were aware of allergy but failed to avoid 1,3 40-100% of fatal reactions - food prepared outside the home 1,2,3 Provision of an EpiPen has limited impact 75% carried it, 10% expired, only 32% could use it correctly 4 Use is not intuitive and requires regular training 5 In fatal cases, 12-14% received early and repeated doses 1,2 Reluctance by pts and health professionals to treat anaphylaxis 6 Only 35% of patients with severe symptoms sought medical attention, and 6% received pre-hospital adrenaline For repeat severe reactions, 73% sought medical attention, 33% received pre-hospital adrenaline 1. Bock et al JACI 2001, Bock et al. JACI 2007; 2. Pumphrey et al. JACI 2007; 3. Liew et al JACI 2008 (In press); 4. Sicherer et al. Pediatrics 2000; 5. Mehr et al. PAI 2007; 6. Simons et al. JACI 2006;117:S134

ASCIA www.allergy.org.au

Action Plans for Anaphylaxis ASCIA www.allergy.org.au

Who should have an Adrenaline Autoinjector? Food allergy Fatal anaphylaxis Anaphylaxis

Can we predict who will have Anaphylaxis? Level of specific IgE and SPT size are NOT predictive of severity of reaction Not prescribed for a large SPT or high sige History of anaphylaxis indicates high risk of subsequent anaphylaxis but up to 40% of anaphylaxis reactions may be first presentation

Risk Factors for Fatal Anaphylaxis Age adolescents and young adults Delayed adrenaline remote geographic location Poorly controlled asthma Allergy to peanut or tree nuts Liew WK, Williamson E, Tang MLK. J Allergy Clin Immunol 2009

Food allergy Peanut allergy Asthma Anaphylaxis Age Geography Fatal anaphylaxis Previous anaphylaxis

PBS Indications for Adrenaline Auto-injectors Recommended if History of anaphylaxis (and continued risk) May be recommended if Generalised allergic reaction PLUS risk factors Geographically isolated Age adolescence or adult Asthma Nuts or Stinging insects

PBS Indications for Epipen/Epipen Jr Not normally recommended for Positive skin prick tests or RAST tests in the absence of previous clinical reaction Local reactions to insect stings (children & adults) Generalised skin rash only to insect stings (children) Asthma without history of anaphylaxis or systemic reaction Family history of anaphylaxis or allergy

Ongoing Management of Food Allergy Annual review by GP or Paediatrician Review diet nutritionally adequate, dietician Accidental ingestion and allergic reactions Education on recognition and emergency treatment of allergic reactions Update Action Plan Review need for adrenaline auto-injector * Review asthma control Monitor SPT or RAST consider as test approaches negative to determine if appropriate to challenge * * Not relevant for non-ige or mixed IgE/non-IgE mediated food allergy

When to Refer to an Allergist Anaphylaxis If history does not match SPT / sige test result Positive history and negative test Positive test (but <95% threshold) and NO history of ingestion Non-IgE mediated syndromes FPIES (food protein induced enterocolitis syndrome) Failure to thrive Low protein (protein losing enteropathy) If no response to elimination diet

Summary Food allergy is common and prevalence is rising Diagnosis of IgE mediated food allergy relies primarily on a good history with confirmatory sige testing Avoid screening sige tests Diagnosis of delayed food allergy relies on history and elimination / reintroduction Management involves Allergen avoidance and risk minimisation Ongoing care by GP or paediatrician annual review