Tree nut allergies literature review

Transcription

1 Tree nut allergies literature review Final Report Prepared by Rural Development Services and AgriQuality Australia Pty Ltd on behalf of the Food Safety Centre Allergen Resource Bureau July 2006

2 Tree nut allergies literature review. Final Report Tim Tabart 1, Lyn Davies 2 and Tom Lewis 1 1 Rural Development Services, Hobart 2 AgriQuality Australia Pty Ltd, Tullamarine, Victoria About AgriQuality AgriQuality is the leading certifier and assurance provider to Australasia s primary producers, food processors and retailers, and a centre of excellence for food and environmental testing. We are the most accredited food safety and biosecurity business in the Southern Hemisphere. We offer a complete range of cost effective, accredited laboratory services that guarantee operational and technical excellence to our customers throughout the food supply chain. AgriQuality invests highly in scientific expertise, state of the art facilities and innovative information technology so we can deliver on our promise. For more information, please see About Rural Development Services Rural Development Services is a private consultancy providing research, project management and extension services to Australia s rural communities and industries. Our technical expertise is in facilitation, communication, social research, agrifood production, project management, training and research. Agrifood businesses are our key client. We work in partnership with new and existing agribusinesses to grow their business in a sustainable and profitable manner by addressing key problems and issues within our realm of expertise. Contact Details Rural Development Services 2/111 Warwick Street West Hobart TASMANIA 7000 Phone: Fax: info@ruraldevelopmentservices.com Web:

3 CONTENTS CONTENTS INTRODUCTION Background Methodology Outcomes and Outputs... 3 LITERATURE REVIEW Generic findings relevant across all tree nuts The prevalence of allergy to tree nuts The severity of allergic reaction experienced by sensitive individuals Impact on quality of life Special conditions or characteristics relating to the onset of symptoms eg. exercise, asthma, etc What causes nut allergies? Cross-reactivity between tree nuts and other allergens Allergy diagnosis: practice, accuracy and safety Literature findings for specific nuts Almond, Prunus dulcis Brazil nut, Berthalletia excelsa Cashew, Anacardium occidentale Chestnut, Castanea sativa Hazelnut, Corylus avellana Macadamia nut, Macadamia integrifolia and M. tetraphyllia Pecan, Carya illinoinensis Pine Nut, Pinus pinea Pistachio, Pistachia vera Walnut, Juglans regia, J. nigra, J. californica Peanut, Arachis hypogeae KEY FINDINGS...25 KEY RECOMMENDATIONS...27 REFERENCES...28 APPENDICES Tree Nut Allergy Frequently Asked Questions What is the difference between an allergy and an intolerance? How common is tree nut allergy? Peanut allergy? What is the difference between the incidence and the prevalence of nut allergies? What causes nut allergies? What are the symptoms of nut allergies? Can nut allergies be cured? How do you treat nut allergies?... 33

4 CONTENTS 1.8 Can nut allergies be fatal? If you are allergic to one nut do you have to avoid all nuts? Are some nuts similar so if I m allergic to one, I ll be allergic to others? If I have a nut allergy can I eat a small amount of nuts and be OK? Are nut allergies a hereditary condition? If I have a nut allergy will I pass this onto my children? If I have a nut allergy does it mean my children will also be allergic? If a relative is allergic to nuts will I also be allergic? If I don t know if I m allergic to nuts should I avoid nuts anyway just in case? What should I do if my child has a reaction to eating nuts? Will children grow out of nut allergies? If I suspect that I or my child has a nut allergy who should I seek advice from? How do you test for nut allergies? Are there any dodgy tests I should avoid? What is the most reliable testing method? Should I avoid eating nuts whilst pregnant? Breastfeeding? Should all day care centres/ schools be nut free zones? At what age should nuts be introduced into the diets of infants and toddlers? How should I teach my child about their allergy condition so they aren t tempted to try nuts just once? Why do many food product labels now say May contain traces of nuts? Where can I buy guaranteed nut-free products? What other ingredients contain nuts that I may not be aware of? If I have a nut allergy can I still eat out at restaurants? Have takeaways? If I have a nut allergy is there another way to get all the nutrition that nuts contain so I m not missing out? Key expert contact list Bibliography... 43

5 GLOSSARY OF TERMS Glossary of Terms Adrenaline - A hormone produced by the adrenal glands that elevates heart and respiration rates; also called 'epinephrine.' Allergy - A general term to describe an abnormal immune response to a usually harmless substance. Anaphylaxis - A type of allergic reaction in which the body s abnormal immune response results in the release of substances such as histamine that affect the dilation or constriction of blood vessels. This results in swelling which can restrict airways and/or cause a serious drop in blood pressure, which may ultimately cause death. The reaction occurs on reexposure to an allergen (a foreign protein or other substance) after sensitisation in a susceptible individual. Antigen - A foreign substance that causes the immune system to make a specific immune response. Atopy - The genetic predisposition to developing an allergy. It does not necessarily mean a person will develop the allergy, but if they are atopic they have the tendency to do so. DBPCFC A Double Blind Placebo Controlled Food Challenge consists of having a patient eat a food. It may be a control food which does not contain an allergen, or a food suspected of previously causing symptoms in a controlled fashion under medical supervision. Neither the patient or the clinician knows whether the food being consumed contains the allergen or not, reducing any potential for bias. The basic structure of a food challenge involves feeding gradually increasing doses of the suspected food at predetermined time intervals until symptoms occur or a normal portion of the food ingested openly is tolerated. ELISA Enzyme Linked Immuno Sorbent Assay is a biochemical technique used mainly in immunology to detect the presence of an antibody or an antigen in a sample. It utilises two antibodies, one of which is specific to the antigen and the other of which is coupled to an enzyme. The enzyme is labelled so that it will provide a colorimetric or fluorogenic signal in the presence of the target antibody or antigen. Epinephrine - A hormone produced by the adrenal glands that elevates heart and respiration rates; also called 'adrenaline.' EpiPen - A medical kit containing a single pre-loaded dose of epinephrine (adrenaline) in a pen-like syringe that is easy to inject. The dose is designed to reverse the effects of swelling caused by an anaphylactic reaction by instantly elevating the heart rate. Oral Allergy Syndrome An allergic reaction with symptoms that usually affect the lips, mouth and throat, such as tingling, redness, itchiness and swelling. Urticaria - Also called hives. A condition in which red, itchy, and swollen areas appear on the skin, usually as an allergic reaction.

6 INTRODUCTION Introduction The objective of this project was to collate relevant scientific information and provide access to expert commentators to enable Nuts for Life to offer evidence-based opinion relating to tree nut allergy issues to its stakeholders. This report presents the findings of a review of peer-reviewed scientific papers and unpublished information on prevalence and severity data relating to tree-nut allergies. In addition it provides answers to a broad set of frequently asked questions about tree nut allergies. 1.1 Background Nuts for Life is a health education initiative funded by the Australian tree nut industry and the Australian government via Horticulture Australia Ltd. The aims of the Nuts for Life program are: To decrease the misconceptions surrounding tree nuts and health particularly with health professionals; To raise the awareness of the health benefits, particularly heart health, of tree nuts; To increase the frequency that health professionals recommend tree nuts to their patients and clients; To increase tree nut consumption. Until now, the focus of the Nuts for Life campaign has been on Health Professionals as key influencers of positive health messages. The Nuts for Life campaign has not previously had the resources to focus on consumer-targeted health messages. While there is still work to be done with health professionals, Nuts for Life are now in a position to also focus on consumers. The results from a 2005 Health Conscious Consumers Study showed that many consumers still have misconceptions about the role of nuts in a healthy diet, particularly relating to the role of nuts in weight management. Some also hold concerns regarding nut allergies. The results of the 2005 study showed there had been no significant shift in these perceptions since a similar study was carried out in With more schools and some health services becoming nut-free due to allergy concerns, it is essential that Nuts for Life has up-to-date science-based information on nut allergies with true prevalence data to assist with developing a position statement on the issue. The Food Safety Centre Allergen Resource Bureau, established in 2005, is an initiative of the Australian and New Zealand food industry to provide the first point of call for food manufacturers concerning the management of allergen-related risks in ingredients and final products. The Allergen Bureau is funded by industry subscription and operated in partnership by AgriQuality Australia Pty Ltd and Rural Development Services through a contract with the University of Tasmania, which houses the Australian Food Safety Centre. Page 1

7 INTRODUCTION Nuts for Life is a financial member of the Allergen Bureau and as such it is fitting that the Allergen Bureau was able to provide assistance to Nuts for Life in conducting this literature review. 1.2 Methodology For the purpose of this review, tree nuts include almond, Brazil nut, cashew, chestnut, hazelnut, macadamia, pecan, pine nut, pistachio and walnut. Some comparative reference has also been made to the prevalence and severity of peanut allergy. The information sought for the review includes: The incidence of allergy to each specific tree nut The severity of allergic reaction experienced by sensitive individuals Impact on quality of life Special conditions or characteristics relating to the onset of symptoms (eg. exercise, asthma ) Any known cross-reactivity with other tree nuts or other allergens Dose or threshold amount relating to onset of symptoms Type of study or source of information eg. clinical trial, survey of reported allergies, or anecdotal The following web-based databases were searched for research papers addressing incidence and severity of tree nut and peanut allergies published between 1996 and 2006: Database The InformAll Food Allergy Database ISI Web of Knowledge Web of Science Current Contents Connect CAB Abstracts Current Web Contents Website About 100 research articles relating to tree nut and peanut allergies were sourced. Each abstract was briefly reviewed by the project team to determine its relevance to the current project according to the information required, as listed above. Where the papers were relevant, full text versions were either downloaded on-line or requested directly from the authors where they were not available on-line. A total of 47 of the most relevant papers were reviewed in depth to obtain information in the fields listed above for each tree nut. These comprise a mixture of cohort studies, observations by independent immunologists, molecular analysis of allergenic proteins and literature reviews. Any noticeable gaps in the science or data for a particular tree nut were noted. Some additional papers were sourced but not reviewed in depth due to their marginal relevance to this literature review. These are included in a brief bibliography of papers or articles that may be of interest should Nuts for Life choose to obtain them. Page 2

8 INTRODUCTION 1.3 Outcomes and Outputs Outcomes of this project In undertaking this project, Nuts for Life are demonstrating a commitment to provide accurate information to the tree nut industry and its stakeholders. A significant outcome from this project is that Nuts for Life now hold a comprehensive summary of the scientific literature currently available on tree nut allergies, and have access to additional expertise on the subject in the event they should require it. This will enable them to offer sound science-based opinion and advice on the subject. Nuts for Life are now in a better position to address any misconceptions surrounding tree nut allergies, and/or to modify their nut-health messages in the context of consumers with tree nut allergies. Nuts for Life may choose to commission or undertake additional research to fill some of the knowledge gaps identified in the review. Outputs of this project The key outputs from this project are: A critical review of literature relating to the prevalence and severity of tree nut allergies, including statistical data and citations A summary of key points from the literature review in PowerPoint format A list of common and/or pertinent questions and answers relating to tree nut allergies A recommended position on certain tree nut allergy issues Access to key experts should Nuts for Life need additional assistance or commentary in the future Electronic copies of all literature sourced for this project where available (provided to Nuts for Life on CD-ROM) Page 3

9 LITERATURE REVIEW Literature review 2 Generic findings relevant across all tree nuts 2.1 The prevalence of allergy to tree nuts Data on the prevalence of peanut and tree nut allergy is not widely available, and often involves US-based research. The most widely cited estimate is that around % of the general population is allergic to at least one tree nut. This compares to an estimated 1.1% of the population being allergic to either peanuts and/or tree nuts. These figures are based on self-reported (not medically substantiated) allergy in two randomised studies in the US in 1997 and 2002 (Sicherer et al., 1999; Sicherer et al., 2003). It is reported that approximately 60-70% of people with a clinical reaction to tree nuts are also allergic to peanuts (Sicherer et al., 1998; Sicherer et al., 2001b; Fleischer et al., 2005), while up to 50% of people who are allergic to peanut may also be allergic to one or more tree nut (Sicherer et al., 1998). Clark and Ewan (2003) found that of 1000 patients with defined peanut and particular tree nut allergy, 46% were sensitised (i.e. had an IgE mediated response) to other tree nuts but could tolerate them without developing clinical symptoms. These authors believed this finding emphasised why diagnostic tests must not be interpreted in isolation of a detailed clinical history. There are a large percentage of individuals allergic to one tree nut that will clinically react to other tree nuts and peanuts. For this reason, a number of allergy specialists recommend that anyone allergic to either peanuts or any one tree nut should avoid all other nuts unless the absence of allergy to other nuts is determined through carefully controlled and administered medical food challenge tests. Even once this has been determined, it is often recommended that all nuts be avoided due to food handling practices that may see one nut substituted or mixed with another without notice. If cross-contamination can be completely avoided, such as where nuts are in their shell, they may be deemed safe to consume (Sicherer et al., 2001b; Teuber et al., 2003). Several studies indicate that the prevalence of peanut and tree nut allergies may be growing larger over time. Sicherer et al. (2003) reported the results of two United States-wide studies conducted in 1997 and 2002 into the increased prevalence of self-reported allergies. Although the overall rate of self-reported allergy to peanuts, tree nuts or both did not increase over the 5 year period (remaining around 1.1%) they found the rate among children had increased from 0.6% to 1.2%. This was predominantly due to a doubling in the self-reported allergy to peanut (from 0.4% in 1997 to 0.8% in 2002). As peanut allergy typically develops in childhood and is infrequently outgrown, this suggests a growing number of the general population will have these allergies. It is possible but unlikely this increase in reported allergies in children is due to better diagnostic techniques or greater public awareness, as the overall rate of self-reported allergy to peanuts, tree nuts or both did not increase over the 5 year period. A voluntary registry of individuals with peanut and/or tree nut allergy was established in 1997 by the United States based Food Allergy and Anaphylaxis Network (FAAN). Registrants were FAAN members and those attending allergy clinics, or their parental surrogates (Sicherer et al., 2001). Analysis of the first 5149 registrants showed that walnut was most frequently Page 4

10 LITERATURE REVIEW reported as causing registrants first reaction to a tree nut in cases where the reaction could be attributed to ingestion of a single nut. Walnut was reported by 34% of respondents, followed by cashews (30%), almond (15%), pecan (9%), pistachio (7%), with hazelnut, Brazil, pine, macadamia and hickory at less than 5% each (Sicherer et al., 2001b). Comprehensive data across all tree nuts is not available and is not specific to the Australian population. Indeed, the prevalence of tree nut allergy in Australia is unknown (Western Australian Food Monitoring Program 2006). However, it is reasonable to expect prevalence in the Australian population to be similar to US figures. Two surveys of tree nut allergy amongst pre-school children in child care centres in NSW conducted in 2002 reported estimated prevalence rates of 0.24% and 0.73% respectively. However, these figures are likely to have been underestimates (Loblay unpublished, reported in Western Australian Food Monitoring Program 2006) as allergy is often under diagnosed, especially in the preschool age-group where children have not yet had secondary exposure to tree nuts. 2.2 The severity of allergic reaction experienced by sensitive individuals Tree nuts are one of the eight main foods responsible for 90% of food-induced allergic reactions, and are one of the foods associated with more severe reactions. The other foods are peanuts, cow s milk, eggs, soybean, wheat, fish and shellfish (Teuber et al. 2003; Chapman et al. 2006). Allergic reactions to foods, including tree nuts, often take place on the second and subsequent exposure to the specific antigen. Numerous studies confirm that all tree nuts are capable of inducing allergic reactions in sensitive individuals ranging from life-altering (eg. skin and respiratory symptoms) to life-threatening. Signs and symptoms of any food allergy usually develop within an hour, and often within minutes, after eating the offending food and may include: Hives and swelling of the lips, eyes or face Wheezing or severe breathing problems Rapid pulse Sweating Extremely pale skin Dizziness, fainting, loss of consciousness Nausea, vomiting, abdominal cramps, diarrhoea Rapid loss of blood pressure While the majority of allergic reactions are relatively mild, several studies have reported anaphylaxis and even subsequent deaths due to ingestion or physical contact, highlighting the seriousness of tree nut allergy (Pumphrey 2000; Sicherer et al 1998, 2001, 2003; Furlong et al. 2001; Ewan and Clark 2005). A UK study of fatalities due to anaphylaxis found that 37 deaths during were associated with food. Of these, 25 (68%) were due to peanuts and/or tree nuts. Peanuts were reported to cause 10 (27%) deaths, walnuts five (14%), and unspecified nuts 10 (27%) deaths due to allergic reactions (Pumphrey 2000). All tree nuts have been directly linked to either fatal or near-fatal reactions (Table 1). Page 5

11 LITERATURE REVIEW Most allergic reactions are not life threatening. However, the most extreme allergic reaction to tree nuts anaphylaxis or anaphylactic shock is life threatening. Symptoms of anaphylaxis may include difficulty breathing or swallowing, hives, or swelling around the mouth or eyes. Anaphylaxis can be fatal within minutes, either through swelling that shuts off airways or through a dramatic drop in blood pressure which results in organ failure. Table 1: Tree nuts and reports of fatal or near-fatal reactions Tree nut Taxonomic Published Near-fatal reactions family fatalities reported Cashew (Anacardium Anacardiaceae Yes accidentale) Almond (Prunus dulcis) Rosaceae Yes English walnut Juglandacae Yes Yes (Juglans regia) Hazelnut (Corylus Becaluceae Yes Yes avellana and Corylus americana) Pistachio (Pistacia vera) Anacardiaceae Yes Macadamia (Macadamia Proteaceae Yes intergrifolia and Macadamia tetraphyllia) Brazil nut Lecythidaceae Yes Yes (Berthalletia excelsa) Pine nut (Pinus pinea) Pinaceae Yes Pecan (Carya illinoinensis) Juglandaceae Yes Source: Adapted from Teuber et al Some nuts, such as cashews, walnuts and pistachios, are reported to be more allergenic than others, and are equated to peanuts in terms of the severity of reactions they can induce (Davoren & Peake, 2005; Fleischer et al., 2005). Even very small amounts of a nut can lead to allergic reactions. Also, reactions do not only occur through eating tree nuts. Reactions have been reported from minimal contact such as smelling, touching, or tasting (Hourihane et al., 2001) and kissing on the lips, cheek or eyes (Hallett et al., 2002). Tree nut and peanut allergies are usually developed in early childhood and are lifelong in the majority of cases, however up to 10% of people may outgrow them (Fleischer et al., 2005). However, allergies to peanuts and tree nuts appear the least likely of all food allergies to be outgrown and usually persist throughout adult life. Some patients with early onset of milder forms of allergy can become tolerant of tree nuts after a period of avoidance (Roux et al., 2003), however more work is required in this area to determine the incidence of this effect. Page 6

12 LITERATURE REVIEW 2.3 Impact on quality of life Having an allergy to one or more tree nuts can have a major impact on the quality of life for both allergic individuals and their families. This impact may vary from person to person and may be influenced by the degree of severity of reactions they have experienced in the past. Impacts include onerous lifestyle restrictions such as strict dietary monitoring; the need to inform and educate child carers, schools, and food establishments such as restaurants of the potential for a reaction; carrying injectable epinephrine (also known as adrenaline) at all times; and fear of death (Armstrong & Rylance 1999; Baker et al. 1999; Primeau et al. 2000; Furlong et al. 2001). A report on the psychological burden of peanut allergy is equally relevant to tree nut allergy. Most patients, or parents of children with severe peanut allergy, were found to live under constant threat of an inadvertent exposure and consequent severe reaction. Parental anxiety increases when children start school and the risk of accidental exposure increases. Due to these concerns, children may not be allowed to go to parties or eat with friends, leading to social, psychological and educational problems (Primeau et al. 2000). In children, allergies can affect learning and school performance. Symptoms of allergies may make it difficult for a child to sleep at night while some treatments such as antihistamines can make a child drowsy at school. Allergies also can cause children to suffer emotional issues that can seriously impact quality of life. The physical symptoms of allergy can leave children feeling fatigued, irritable, moody, and even depressed. In addition, constant red noses, sniffling, and watery eyes can leave a child feeling self-conscious about his or her appearance. Often, other children will tease an allergic child about their symptoms, increasing feelings of isolation and self-consciousness. The fear of subsequent reactions is well founded. As tree nut and peanut allergies are lifelong in the majority of cases (Fleischer et al., 2005), many individuals with diagnosed allergies experience subsequent reactions due to accidental exposure despite precautions (Clark & Ewan 2003, 2005; Ewan & Clark 2005; Fleischer et al. 2005). Clark and Ewan (2005) reported UK and French data showing that where families and schools are enrolled in a comprehensive management plan, between 15% and 30% of allergic children will have a subsequent reaction. Presumably this number would be much higher where these management plans are not implemented. Individuals with tree nut or peanut allergies need to take particular care when eating food prepared outside of their home. Of 5149 registrants in the voluntary US Peanut and Tree Nut Allergy Registry 706 (14%) reported reactions associated with restaurants and other food establishments. Commonly cited food establishments included Asian food restaurants (19%), ice cream shops (14%), and bakeries/doughnut shops (13%). Among meal types, desserts were a common cause of allergic reactions to foods (43%) (Furlong et al., 2001). In both the United States and United Kingdom, most fatal food allergy reactions in restaurants or other food establishments are caused by unintentional ingestion of peanuts or tree nuts (Pumphrey 2000; Bock et al 2001). The most frequent cause of adverse reactions was the failure by previously diagnosed allergy sufferers or their carers to inform the food Page 7

13 LITERATURE REVIEW establishment of their dietary restrictions. The food establishment was not properly notified of the allergy 62% of the time. In 50% of cases where the establishment was not informed, the nuts were "hidden" (in sauces, dressings, egg rolls etc). In a group of 129 subjects (or their parental surrogates) who reported a peanut or tree nut induced reaction in a food establishment, the allergic reactions developed at a median of 5 minutes after exposure to the food. Forty-seven percent of the reactions were mild, 26% were moderate and 27% were severe. The responsible food was identified as peanut in 67% of cases, tree nut in 24% of cases and an unknown or a combination of nuts in 9% of cases (Furlong et al., 2001). A US study found 20 out of 379 respondents (5.3%) reported allergic reactions following kissing, despite the survey not asking specific questions about this route of allergen exposure. While these reactions were mostly very mild (e.g. local wheals or lip angioedema), four subjects reported bronchospasm and one child had a potentially life threatening reaction. The reactions occurred within one minute of kissing either on the lips, the cheek or eye. The nuts associated with the reactions were peanut, almond, Brazil nut, macadamia, pecan, pistachio and walnut. As one third of the subjects had reactions while dating, it is suggested teenagers and young adults need to be informed of this potential mode of exposure to these allergens (Hallett et al., 2002). The seriousness of the broad impacts of tree nut and peanut allergy places a responsibility on the medical profession to ensure suspected diagnoses of nut allergies are verified by diagnostic tests (Armstrong & Rylance, 1999; Baker et al., 1999). See Section 2.8 for more information on diagnosis of allergies. 2.4 Special conditions or characteristics relating to the onset of symptoms eg. exercise, asthma, etc It is common for people with nut allergies to also have asthma and other atopic disorders such as eczema and rhinitis (Ewan 1996; Ewan & Clark 2005; Sicherer 2002; Teuber et al. 2003). Many researchers have found a relationship between asthma and the severity of an allergic reaction. Of the voluntary registrants on the FAAN peanut and tree nut allergy registry, those with asthma were more likely to have severe reactions than those without (33% vs 21%) (Sicherer et al., 2001a). Most patients who die from food anaphylaxis also have asthma (reported in a literature review by Teuber 2003). Teuber (2003 p. 59) concludes that, Overall, the data suggest that special precautions may be warranted in patients with both asthma and food allergy. A management plan developed for children with peanut and tree nut allergies provided an injectable epinephrine (adrenaline) device to all children with ongoing asthma regardless of the severity of past reactions (Clark & Ewan, 2005). Some individuals suffer food dependent exercise-induced anaphylaxis (EIA). Such individuals develop neither anaphylaxis with ingestion of food without subsequent exercise nor anaphylaxis after exercise without temporally related ingestion of food. Foods that have been associated with EIA include crustaceans, cephalopods (ie. octapus and squid), celery, grapes, chicken, wheat, buckwheat, tomato, dairy products, and matsutake mushrooms (Chapman et al., 2006). Neither tree nuts nor peanuts have been associated with EIA. Reactions to nuts occur irrespective of any association with exercise in sensitised individuals. Page 8

14 LITERATURE REVIEW 2.5 What causes nut allergies? An allergy occurs when the immune system reacts to substances such as proteins (allergens) that are normally harmless and in most people do not cause an immune response. In the case of nut allergy, the immune system mistakenly sees one or more proteins within the nut as foreign so produces antibodies and other disease fighting cells as a response. Considerable research has gone into the biochemical and immunological characterisation of the proteins within the tree nuts that are most responsible for allergy sensitisation. Table 2 presents tree nut allergens that have been characterised to date. Table 2: Recognised tree nut allergens Name Allergen Function/class kd 1 designation Castanea sativa Chestnut Cas s 5 chitinase Ib Cas s 8 lipid transfer protein 9.7 Corylus avellana Hazelnut Cor a 1 Bet v 1 homologue Cor a 2 profilin 14 Cor a 8 lipid transfer protein 9 Cor a 9 11S globulin-like protein 40 Cor a 11 7S vicilin-like prot. 48 Bertholletia excelsa Brazil nut Ber e 1 2S albumin 9 Ber e 2 legumin-like (11S) seed storage protein 29 Juglans nigra Black walnut Jug n 1 2S albumin 19 Jug n 2 vicilin-like (7S) protein 56 Juglans regia English walnut Jug r 1 2S albumin 14 Jug r 2 7S vicilin-like prot. 44 Jug r 3 lipid transfer protein 9 Jug r 4 legumin-like (11S) seed storage protein Anacardium occidentale Cashew nut Ana o 1 vicilin-like (7S) protein Ana o 2 legumin-like (11S) seed storage protein 1 kd = Kilodalton. This is a measure of the molecular weight, or size, of the protein. It is thought the size of a protein may be one of a number of determinants of a protein s potential allergenic properties. Source: Adapted from Roux et al Page 9

15 LITERATURE REVIEW Recent research indicates the allergenicity of a plant food protein is determined by factors such as the plant protein belonging to a certain protein family, the protein s abundance and its stability to processing and digestion. Whilst there has already been much work carried out in this area, there are more questions to be answered before the relationship between protein structure and allergenicity are clearly understood (Breiteneder & Mills, 2005). Recent research reported by Akkerdaas et al. (2006) maintains that protease resistance (a protein s resistance to degradation via the action of proteolyic enzymes) is a key requirement for a protein to act as an allergen and sensitize an individual through the oral route. 2.6 Effects of Processing on tree-nut allergenicity Few papers reviewed addressed processing effects on the allergenicity of tree nuts. Teuber and Bayer (2004) stated that thermal treatment could either enhance or reduce the allergenicity of certain proteins, with roasting actually enhancing the alllergenicity of proteins in peanut. In a study carried out by Su et al. (2004), almond, cashew and walnut proteins were subjected to γ-irradiation and heat treatment, and were shown in the laboratory to remain allergenic regardless of the extent of processing. De Leon et al, (2003) showed the antigenicity of peanut, almond, Brazil nut, cashew and hazelnut proteins did not differ between the raw and roasted forms of the nuts. These findings suggest that allergenic proteins are heat-stable. Skamstrup Hansen et al. (2003) studied the effects of roasting on the allergenicity of hazelnut proteins and found that while this processing greatly reduced the allergenicity, a significant number of individuals in the trial remained clinically reactive to the roasted form of the protein. 2.7 Cross-reactivity between tree nuts and other allergens Cross reactivity occurs when allergens from one species cause allergic reactions in a patient who was sensitised to a different species. Cross reactivity results when two or more different proteins bind to the same IgE antibodies because of similarities in the structure of the IgE binding site, or epitope, on the proteins. Cross-reacting allergens often belong to similar protein families and have similar amino acid sequences; closely related biological species are more likely to exhibit cross-reactivity and species from the same biological genus usually cross-react. Taxonomic names don't always convey allergenic relationships, as they may not indicate close genetic relationships between plants (ALK-Abello, 2006). In general terms, people who are allergic and anaphylactic to one tree nut are often allergic to several other tree nuts, or to other allergens. Whether such clusters in reactivity are the result of multiple independent sensitisation events in atopic patients or whether there is true cross-reactivity needs further exploration (Roux et al., 2003). Current thinking indicates that cross-reactivity may be due to similarity in the structure of storage proteins in each of the nuts, however this has not yet been proven. Tree nuts causing cross-reactive allergic reactions are sometimes closely related at a genetic level, for example individuals showing sensitivity to cashew nut frequently also exhibit sensitivity to pistachio, both of which are members of the Anacardiaceae family. However, in other cases, Page 10

16 LITERATURE REVIEW cross-reactivity is seen between tree nuts from species that are not closely related, such as walnuts and Brazil nuts. Additionally, very few cases of cashew nut allergy have been reported where there has been no associated peanut allergy (Rance et al., 2003). Details of identified cross-reactivities between specific tree nuts and peanuts are listed in Section 3 (Literature findings for specific nuts). 2.8 Allergy diagnosis: practice, accuracy and safety The diagnosis of food allergies have been well covered in recent allergy reviews by Al- Muhsen et al. (2003), and Chapman et al Tools to diagnose adverse reactions to nuts include medical history (including diet records), physical examination, skin prick or puncture tests, blood tests for food specific IgE antibodies, and oral food challenges. The first step is a medical history and physical examination. The diagnosis is then tested by examination for nut-specific IgE using either a skin prick test (SPT) or serological assay (blood serum test). Both SPTs and serological assays have a degree of inaccuracy, so many researchers and clinicians suggest negative diagnoses should be confirmed by medically supervised oral food challenges where appropriate conditions are met, as discussed later in this section (Armstrong & Rylance, 1999; Baker et al., 1999; Al-Muhsen et al., 2003; Clark & Ewan, 2003; Chapman et al., 2006). i) Medical history Al-Muhsen et al. (2003) gave the following guidelines regarding medical histories: The medical history for a suspected IgE-mediated reaction should focus on the type and quantity of food ingested, the time of symptom onset, the severity and duration of symptoms, and the medical treatment administered. Personal or family details of atopy are also useful. Because most IgE-mediated reactions occur within 60 minutes after ingestion, symptoms occurring later than this are unlikely to have resulted from food allergy. Typically, minor allergic symptoms last less than 1 hour, but severe reactions may be protracted. ii) Skin Prick Tests and Serum Assays Skin Prick Tests (SPTs) with commercially prepared food extracts are a convenient and inexpensive method of detecting IgE bound to dermal mast cells. A drop of the suspected allergen is placed on the skin and the skin is pricked with a toothpick-like instrument. If the patient is allergic, a reaction (a wheal that looks like a mosquito bite) will develop in minutes. The size of the reaction indicates the level of specific IgE present. A positive result is one in which the wheal is at least 3mm larger than a control test using saline (Al-Muhsen et al., 2003; Chapman et al., 2006) A Serum Assay measures allergen-specific IgE antibodies in blood samples using laboratory test-tube techniques. Standardised allergens are used, however there are a number of Page 11

17 LITERATURE REVIEW manufacturers, substrates, and manners of reporting results. These differences can lead to variations between measurements in different laboratories. SPTs and Serum Assays merely detect the presence of an antibody, indicating that the individual has been sensitised to the allergen. By themselves, they do not necessarily indicate that clinical reactions would result from ingestion or contact with the allergen. The results are most valuable when they are negative since they are 95% accurate for ruling out IgE-mediated reactions. However, a positive test is associated with true clinical reactions only approximately 50% of the time. In addition, the test results may also remain positive some time after clinical reactivity has resolved (Chapman et al., 2006). The majority of SPT or Serum Assay results correlate well with the probability of clinical reactivity to an allergen but cannot be used to predict the severity of clinical reaction to an allergen. For example, the reactions of two individuals with the similar SPT or Serum Assay results could range from minor urticaria or hives to anaphylaxis (Al-Muhsen et al., 2003; Clark & Ewan, 2003; Chapman et al., 2006). Serum Assays for specific IgE are generally considered less sensitive than SPTs in confirming allergy, with a higher false positive and false negative rate (Al-Muhsen et al., 2003; Clark & Ewan, 2003; Chapman et al., 2006). SPT and Serum Assays for food specific IgE can have variable results influenced by patient characteristics such as age, the quality and characteristics of reagents (standardised food extracts are not currently available despite a recognised need), and techniques (eg. assay types, skin test devices, location of test placement, mode of measurement) (Chapman et al., 2006). a) Safety of Skin Prick Tests SPTs are considered safe, with a low rate of systemic reactions (estimated 0 in 1,000,000 tests; 95% confidence interval, 0-109). However such reactions have been reported (cited in Al-Muhsen et al and Chapman et al. 2006; see for example, Senna et al. 2005) so clinicians should be trained and equipped to administer medical assistance in the rare event of such a reaction to testing. Skin testing can also be done by injecting the suspected allergen under the skin with a needle. Newly released clinical guidelines for allergy evaluation and treatment in the US state that such intracutaneous (intradermal) skin tests for foods are potentially dangerous, overly sensitive (increasing the rate of false-positive results), can elicit systemic reactions, and "should not be used" (Chapman et al., 2006). iii) Oral challenge tests Oral food challenges are the most definitive diagnostic method. They are recommended when the medical history does not suggest an IgE-mediated reaction but the SPT or Serum Assay is positive; when the medical history suggests an allergy but SPT or Serum Assay are negative; or to test whether allergenicity to a particular nut has resolved (Armstrong & Rylance, 1999; Baker et al., 1999; Al-Muhsen et al., 2003; Chapman et al., 2006; Ridout et al., 2006). The oral food challenge is performed by having the patient ingest increasing amounts of the suspected food under physician observation for hours or days. This represents a definitive test for tolerance since ingestion of a relevant amount Page 12

18 LITERATURE REVIEW of the food with no reaction excludes the diagnosis of an adverse reaction to the tested food. The test is open to misinterpretation when not done in a masked manner. Therefore, procedures to reduce this possibility need to be implemented, such as masking the challenge substance (blinding) and using placebos. The double-blind, placebo-controlled food challenge (DBPCFC) is the gold standard for diagnosing food allergy (Chapman et al., 2006). a) Safety of oral challenge tests Oral challenges should be undertaken under direct medical supervision. In any setting, oral challenges have the potential to elicit severe anaphylactic reactions so physicians must be immediately available and have the necessary emergency medications and equipment to be able to treat such a reaction. Risk management and ethical considerations should be taken into account before a food challenge is performed. Parents of children and/or the patients themselves should be informed of the risks and benefits of the procedure. Increasingly, Serum Assays are being used to determine the best candidates for food challenges. (Armstrong & Rylance, 1999; Baker et al., 1999; Al-Muhsen et al., 2003; Fleischer et al., 2005; Chapman et al., 2006). For example, Al-Muhsen et al. (2003) and Fleischer et al. (2005) proposed that only patients with laboratory test results indicating a low probability of severe allergy reaction should be subjected to an oral challenge. iv) Unreliable tests Some practitioners perform tests that have not been shown to have an acceptable degree of diagnostic reliability on repeated testing and therefore they should not be relied on without being substantiated by a more reliable method. Some of these tests include the following (Morris 1999; Chapman et al. 2006): VEGA testing involves the measurement of disordered electromagnetic currents in the body to certain substances. Applied kinesiology tests muscle strength in the presence of various allergens, with a loss of strength indicating an allergy. Hair analysis, provocation-neutralisation (Miller technique) and the auriculo-cardiac pulse tests have all been assessed and found to be unreliable allergy tests. Leucocytotoxic tests measure cellular changes in the blood after introduction of various food allergens. These tests had a poor reliability for diagnosing allergies when they were subjected to clinical trials. IgG antibodies directed to foods v) Diagnostic tests under investigation A number of additional diagnostic tests are under investigation and are at various stages of acceptance or still under research scrutiny. These include atopy patch tests, basophil activation assays, and tests for IgE binding to specific epitopes (Chapman et al., 2006). Page 13

19 LITERATURE REVIEW 3 Literature findings for specific nuts 3.1 Almond, Prunus dulcis What is the incidence of allergy to almonds How severe are allergic reactions experienced by sensitive individuals? Is there any evidence of crossreactivity with other tree nuts or other allergens? Literature findings Almonds rank first in per capita consumption of tree nuts in the USA (Roux et al., 2003). However, several studies rank them as third or fourth as an allergen. Between 8-15% of IgE-mediated allergic reactions caused by an individual tree nut are reported to be due to almonds (Sicherer et al., 1998; Sicherer et al., 2001a; Fleischer et al., 2005). As for peanuts and all other tree nuts, allergic reactions to almonds range from mild skin rashes to potentially fatal anaphylactic shock. Unlike most of the other nuts, there have been no reports of fatalities due to almonds (Teuber et al., 2003). Although almonds are one of the more common tree nuts reported to cause allergic reactions, they appear to cause a smaller proportion of severe reactions. A study of 101 patients with clear allergic reactions due to tree nuts reported 8% of those reactions were due to almonds. However, almonds caused 19% of the mild reactions (skin symptoms and/or oral symptoms only), and only 2% of the severe reactions (lower respiratory and/or cardiovascular, or any four organ systems involved) (Fleischer et al., 2005). De Leon et al. (2003) demonstrated serum IgE cross reactivity between allergens present in almonds, peanuts, Brazil nut and hazelnut using inhibition ELISA. A later study by Goetz et al. (2005), also using inhibition ELISA, reported moderate cross-reactivity between almond and Brazil nut, hazelnut, cashew and pistachio. They found no cross-reactivity between almond and peanut, walnut or pecan. Page 14

20 LITERATURE REVIEW 3.2 Brazil nut, Berthalletia excelsa What is the incidence of allergy to Brazil nut? How severe are allergic reactions experienced by sensitive individuals? Is there any evidence of crossreactivity with other tree nuts or other allergens? Literature findings There is some contradiction as to the significance of Brazil nuts in causing allergies. One study by Ewan (1996) reported Brazil nut allergies were the most commonly cited tree nut allergy, where as Sicherer et al. (1998) maintain Brazil nut allergies are one of the less common tree nuts responsible for IgE-mediated allergic reactions. This group maintains they are responsible for <5% of all tree nut allergic individuals (Sicherer et al., 1998; Sicherer et al., 2001a; Fleischer et al., 2005). As for peanuts and all other tree nuts, allergic reactions to Brazil nut range from mild skin rashes to potentially fatal anaphylactic shock. Reports include fatalities (Borja et al., 1999; Teuber et al., 2003; Senna et al., 2005; Ridout et al., 2006). One study reported a patient who experienced anaphylaxis after a routine skin prick test using fresh Brazil nut (Senna et al., 2005). (de Leon et al., 2003; 2005) found in vitro cross-reactivity in peanut allergic patients with Brazil nuts, almonds and hazelnuts. Their evidence suggests that peanut-specific IgE antibodies that cross-react with these tree nut allergens can cause activation of an effector cell (a cell that performs the body's responses to stimuli) and may contribute to the manifestation of tree nut allergy in peanut allergic subjects. Asero et al (2004) found immunologic cross-reactivity between at least one Brazil nut protein and walnut. Page 15

21 LITERATURE REVIEW 3.3 Cashew, Anacardium occidentale What is the incidence of allergy to Cashew Literature findings Cashew nut allergy is the second most commonly reported tree nut allergy in the United States (Robotham et al., 2005). In a random-digitdial telephone survey 0.5% of the survey participants reported tree nut hypersensitivity. Of these individuals, 41% reported allergy to cashew (Sicherer et al., 2003). A review by Hourihane et al. (2001) cited a survey of British four year olds that found 0.08% were allergic to cashew. In a retrospective study of 213 children with allergy to tree nuts or peanuts, anaphylaxis to cashew was found to be more prevalent than anaphylaxis to peanut (74% vs. 31%) (Davoren & Peake, 2005). How severe are allergic reactions experienced by sensitive individuals? (Tariq et al., 1996) studied 1218 children (aged four years or younger) on the Isle of Wight and reported a 0.06% level of allergy to cashew. Sicherer et al (2001) estimated a similar proportion in their study of individuals. Cashew nuts have been associated with contact or systemic dermatitis, atopic dermatitis, and IgE mediated systemic reactions, including fatal anaphylaxis (Wang et al., 2002; Teuber et al., 2003). Hourihane et al (2001) found 14 out of 29 subjects (48%) reacted to non-oral exposure ie. smelling, touching or tasting (not eating cashew). Reaction severity is reported to be at least equal to peanut allergy. Is there any evidence of crossreactivity with other tree nuts or other allergens? Hazelnut, cashew, Brazil nut, pistachio and almond form a group of moderately cross-reactive tree nuts (Goetz et al., 2005). Associated cashew and pistachio allergies were observed in 17% of the children studied by Rancé et al (2003) using skin prick tests. Teuber et al (2002) conducted a study in which virtually all cashewallergic patients had clinical allergy to walnut or to peanut. All cashew allergic patients who had eaten pistachio reported a reaction to pistachio, however one patient with clear-cut allergy to pistachio could tolerate cashew. Furthermore, Hourihane et al (2001) cited a study of French peanutallergic individuals that found 40% were also sensitive to cashew. Page 16