Peanut allergy remains a significant public health concern, crossing continents and socio-economic boundaries. The dietary and social restrictions pertaining to the label of peanut allergy can severely impair the quality of life of both children and their parents(Reference King, Knibb and Hourihane1). While peanut desensitisation is being trialled in the UK and USA, at present the mainstay of treatment is strict peanut avoidance. However, dietary indiscretion and inadvertent exposures are relatively common, particularly among teenagers. Rarely this can result in severe anaphylaxis or death triggered by minute traces of peanut allergen(Reference Hourihane, Kilburn and Dean2).
The role of primary prevention in preventing immunological sensitisation has been a matter of debate for the past 40 years. In 1998, the UK Government's Chief Medical Officer's Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) recommended that peanut ingestion should be avoided during pregnancy and lactation in families where there was an increased risk of atopy(3). In addition, it was suggested that children at risk of developing allergies should not be exposed to peanut products before 3 years of age. There was never any strong evidence backing these proposals but a feeling within the scientific community that early exposure to peanut allergens may predispose a child to the development of peanut allergy. This guidance was not restricted to the UK but also circulated by US and Australian Paediatric Societies. However, within the past 10 years there has been a paradigm shift and clinicians are being to question the efficacy of peanut avoidance in primary prevention. Initially there were anecdotal reports from communities where peanut ingestion was high. These populations had an extremely low incidence of peanut allergy. This has been followed by a recent formal study of Jewish children in Israel where early peanut exposure is associated with an approximate 10-fold lower incidence of peanut allergy compared with their UK Jewish counterparts(Reference Du Toit, Katz and Sasieni4).
The systematic review by Thompson et al. (Reference Thompson, Miles and Lunn5) in this issue set out to evaluate the current literature examining early life exposure to peanut allergen and the subsequent development of peanut sensitisation and/or allergy(Reference Thompson, Miles and Lunn5). Their conclusions suggest a dearth of reliable evidence investigating the role of early peanut exposure on the development of peanut sensitisation and allergy. Even between studies there was no consensus and more data are required before firm conclusions can be drawn and official guidance proffered. The Learning Early About Peanut Allergy (LEAP) study, an investigation into the role of early peanut exposure in atopic children is due to report within the next few years(6) and these results are awaited with anticipation. In the meantime, we are left to conjecture how early allergen exposure promotes or abrogates the development of peanut sensitisation.
Food allergy, a notable first step on the ‘allergic march’, often begins within the first year of life. There is a great deal of controversy regarding the timing of allergen sensitisation with conflicting evidence suggesting transplacental v. exclusively postnatal priming. Elaborating on this is fundamental to the design of primary prevention strategies. Peanut-specific IgE, unlike IgE to other food and aeroallergens, has not been identified in cord blood(Reference Lack, Fox and Northstone7), and thus sensitisation is believed to occur during or after the postnatal period. In animal studies at least, there are critical factors such as dose, route and timing of allergen delivery and the presence or absence of adjuvant factors which have been demonstrated to affect the bias of the adaptive immune response towards preferential IgE production. At present it is believed that there is a bell-shaped curve underpinning the relationship between allergen dose during pregnancy and early infancy, and the development of clinical sensitisation. Thus, at very low doses of allergen the threshold for sensitisation is not achieved and the adaptive immune system remains naive to the presence of the allergen. As the allergen dose is raised, sensitisation occurs via Th2-dependent mechanisms with the consequent development of clinical manifestations. However, at high levels of allergen exposure, immunological tolerance prevails, Th2-type cytokine production is switched off and the child is protected from IgE-mediated sequelae. An observational study of egg intake during pregnancy in relation to allergic outcomes in the infants by 6 months of age has supported the concept of a bell-shaped curve and related this to the level of IgG antibody transported from mother to fetus, across the placenta during the second half of gestation(Reference Vance, Grimshaw and Briggs8). The efficacy of immunotherapy is thought in part to be due to the production of protective IgG antibodies and there is some limited clinical evidence supporting its role in primary prophylaxis. The offspring born to women who continued rye grass immunotherapy through pregnancy, compared with contemporaneous controls with rye grass allergy, had less rye grass allergy even up to 12 years of age(Reference Glovsky, Ghekiere and Rejzek9). This is supported by murine studies showing that egg immunisation during pregnancy reduces the susceptibility of offspring to egg sensitisation(Reference Melkild, Groeng and Leikvold10). However, not all studies have supported this concept as no difference was demonstrated in the development of asthma/rhinitis or skin prick test positivity to pollen allergens, between offspring whose mothers received immunotherapy compared with sibling controls(Reference Settipane, Chafee and Settipane11). Postnatally the early use of immunotherapy in the evolution of atopic disease where patients had a single specific allergy reduced the risk of an increase in the number of specific allergies(Reference Des Roches, Paradis and Menardo12–Reference Purello-D'Ambrosio, Gangemi and Merendino14), and pollen immunotherapy has delayed or prevented the march from rhinitis alone to asthma(Reference Möller, Dreborg and Ferdousi15, Reference Niggemann, Jacobsen and Dreborg16). Further work is needed to clarify the potential role of immunotherapy in primary and secondary allergy prevention.
Most peanut allergy occurs in the absence of preceding peanut ingestion. As such, sensitisation is believed to occur via non-oral routes of exposure such as via the skin and/or respiratory tract. In the skin, application of creams containing peanut oil has been shown to increase the risk of peanut allergy approximately 6-fold(Reference Lack, Fox and Northstone7). It has also been recently established that peanut allergy is greatest in households having a high median peanut consumption, suggesting that environmental non-oral routes of peanut exposure are important for sensitisation(Reference Fox, Sasieni and Du Toit17). The recently described genetic mutations in the filaggrin gene are associated with an increased risk of eczema, allergic rhinitis and allergen-induced sensitisation(Reference Weidinger, O'Sullivan and Illig18). This gene affects skin barrier function and mutations are likely to impair function and allow allergen to penetrate the epithelial barrier leading to immunological sensitisation. The role of the filaggrin gene in the development of food allergy and particularly peanut sensitisation remains to be addressed.
Unfortunately, part of the problem in interpreting large-scale studies of primary prevention in peanut allergy is that they often only examine sensitisation by means of peanut-specific IgE or skin prick test positivity, which is not synonymous with disease. This is due to ethical and logistical concerns of conducting oral peanut challenge. The relationship between sensitisation and clinical reactivity to peanuts is complex, with both false positive and negative associations. This may be attributed to such factors as local IgE production, the inflammatory milieu within the tissues and the allergen content of the materials used in allergy tests. Thus an individual can be skin prick test negative whilst still displaying physical manifestations of peanut allergen on oral exposure. The converse is also true that children with large skin prick tests to peanut allergy can show immunological tolerance. Oleosins are a family of small proteins which contain a unique hydrophobic domain and act as emulsifiers for the storage of lipid in seeds. Isoforms of peanut oleosins have been identified(Reference Pons, Chery and Romano19). Falsely negative skin prick tests could be due to the lack of oleosins in commercially available extracts or the fact that their epitopes may be buried in the inner membrane and thus not recognised by cellular-associated IgE. The importance of oleosins is highlighted by their greater bioavailability in foods with a high fat content. A challenge study showed that peanut-containing food with a high fat content augmented the allergic reaction following ingestion(Reference Grimshaw, King and Nordlee20). Until studies are conducted which assess both sensitisation and allergic disease there will continue to be conflicting views about the relative value of specific allergen exposure strategies for primary and secondary prevention.
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Peanut allergy remains a significant public health concern, crossing continents and socio-economic boundaries. The dietary and social restrictions pertaining to the label of peanut allergy can severely impair the quality of life of both children and their parents(Reference King, Knibb and Hourihane1). While peanut desensitisation is being trialled in the UK and USA, at present the mainstay of treatment is strict peanut avoidance. However, dietary indiscretion and inadvertent exposures are relatively common, particularly among teenagers. Rarely this can result in severe anaphylaxis or death triggered by minute traces of peanut allergen(Reference Hourihane, Kilburn and Dean2).
The role of primary prevention in preventing immunological sensitisation has been a matter of debate for the past 40 years. In 1998, the UK Government's Chief Medical Officer's Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) recommended that peanut ingestion should be avoided during pregnancy and lactation in families where there was an increased risk of atopy(3). In addition, it was suggested that children at risk of developing allergies should not be exposed to peanut products before 3 years of age. There was never any strong evidence backing these proposals but a feeling within the scientific community that early exposure to peanut allergens may predispose a child to the development of peanut allergy. This guidance was not restricted to the UK but also circulated by US and Australian Paediatric Societies. However, within the past 10 years there has been a paradigm shift and clinicians are being to question the efficacy of peanut avoidance in primary prevention. Initially there were anecdotal reports from communities where peanut ingestion was high. These populations had an extremely low incidence of peanut allergy. This has been followed by a recent formal study of Jewish children in Israel where early peanut exposure is associated with an approximate 10-fold lower incidence of peanut allergy compared with their UK Jewish counterparts(Reference Du Toit, Katz and Sasieni4).
The systematic review by Thompson et al. (Reference Thompson, Miles and Lunn5) in this issue set out to evaluate the current literature examining early life exposure to peanut allergen and the subsequent development of peanut sensitisation and/or allergy(Reference Thompson, Miles and Lunn5). Their conclusions suggest a dearth of reliable evidence investigating the role of early peanut exposure on the development of peanut sensitisation and allergy. Even between studies there was no consensus and more data are required before firm conclusions can be drawn and official guidance proffered. The Learning Early About Peanut Allergy (LEAP) study, an investigation into the role of early peanut exposure in atopic children is due to report within the next few years(6) and these results are awaited with anticipation. In the meantime, we are left to conjecture how early allergen exposure promotes or abrogates the development of peanut sensitisation.
Food allergy, a notable first step on the ‘allergic march’, often begins within the first year of life. There is a great deal of controversy regarding the timing of allergen sensitisation with conflicting evidence suggesting transplacental v. exclusively postnatal priming. Elaborating on this is fundamental to the design of primary prevention strategies. Peanut-specific IgE, unlike IgE to other food and aeroallergens, has not been identified in cord blood(Reference Lack, Fox and Northstone7), and thus sensitisation is believed to occur during or after the postnatal period. In animal studies at least, there are critical factors such as dose, route and timing of allergen delivery and the presence or absence of adjuvant factors which have been demonstrated to affect the bias of the adaptive immune response towards preferential IgE production. At present it is believed that there is a bell-shaped curve underpinning the relationship between allergen dose during pregnancy and early infancy, and the development of clinical sensitisation. Thus, at very low doses of allergen the threshold for sensitisation is not achieved and the adaptive immune system remains naive to the presence of the allergen. As the allergen dose is raised, sensitisation occurs via Th2-dependent mechanisms with the consequent development of clinical manifestations. However, at high levels of allergen exposure, immunological tolerance prevails, Th2-type cytokine production is switched off and the child is protected from IgE-mediated sequelae. An observational study of egg intake during pregnancy in relation to allergic outcomes in the infants by 6 months of age has supported the concept of a bell-shaped curve and related this to the level of IgG antibody transported from mother to fetus, across the placenta during the second half of gestation(Reference Vance, Grimshaw and Briggs8). The efficacy of immunotherapy is thought in part to be due to the production of protective IgG antibodies and there is some limited clinical evidence supporting its role in primary prophylaxis. The offspring born to women who continued rye grass immunotherapy through pregnancy, compared with contemporaneous controls with rye grass allergy, had less rye grass allergy even up to 12 years of age(Reference Glovsky, Ghekiere and Rejzek9). This is supported by murine studies showing that egg immunisation during pregnancy reduces the susceptibility of offspring to egg sensitisation(Reference Melkild, Groeng and Leikvold10). However, not all studies have supported this concept as no difference was demonstrated in the development of asthma/rhinitis or skin prick test positivity to pollen allergens, between offspring whose mothers received immunotherapy compared with sibling controls(Reference Settipane, Chafee and Settipane11). Postnatally the early use of immunotherapy in the evolution of atopic disease where patients had a single specific allergy reduced the risk of an increase in the number of specific allergies(Reference Des Roches, Paradis and Menardo12–Reference Purello-D'Ambrosio, Gangemi and Merendino14), and pollen immunotherapy has delayed or prevented the march from rhinitis alone to asthma(Reference Möller, Dreborg and Ferdousi15, Reference Niggemann, Jacobsen and Dreborg16). Further work is needed to clarify the potential role of immunotherapy in primary and secondary allergy prevention.
Most peanut allergy occurs in the absence of preceding peanut ingestion. As such, sensitisation is believed to occur via non-oral routes of exposure such as via the skin and/or respiratory tract. In the skin, application of creams containing peanut oil has been shown to increase the risk of peanut allergy approximately 6-fold(Reference Lack, Fox and Northstone7). It has also been recently established that peanut allergy is greatest in households having a high median peanut consumption, suggesting that environmental non-oral routes of peanut exposure are important for sensitisation(Reference Fox, Sasieni and Du Toit17). The recently described genetic mutations in the filaggrin gene are associated with an increased risk of eczema, allergic rhinitis and allergen-induced sensitisation(Reference Weidinger, O'Sullivan and Illig18). This gene affects skin barrier function and mutations are likely to impair function and allow allergen to penetrate the epithelial barrier leading to immunological sensitisation. The role of the filaggrin gene in the development of food allergy and particularly peanut sensitisation remains to be addressed.
Unfortunately, part of the problem in interpreting large-scale studies of primary prevention in peanut allergy is that they often only examine sensitisation by means of peanut-specific IgE or skin prick test positivity, which is not synonymous with disease. This is due to ethical and logistical concerns of conducting oral peanut challenge. The relationship between sensitisation and clinical reactivity to peanuts is complex, with both false positive and negative associations. This may be attributed to such factors as local IgE production, the inflammatory milieu within the tissues and the allergen content of the materials used in allergy tests. Thus an individual can be skin prick test negative whilst still displaying physical manifestations of peanut allergen on oral exposure. The converse is also true that children with large skin prick tests to peanut allergy can show immunological tolerance. Oleosins are a family of small proteins which contain a unique hydrophobic domain and act as emulsifiers for the storage of lipid in seeds. Isoforms of peanut oleosins have been identified(Reference Pons, Chery and Romano19). Falsely negative skin prick tests could be due to the lack of oleosins in commercially available extracts or the fact that their epitopes may be buried in the inner membrane and thus not recognised by cellular-associated IgE. The importance of oleosins is highlighted by their greater bioavailability in foods with a high fat content. A challenge study showed that peanut-containing food with a high fat content augmented the allergic reaction following ingestion(Reference Grimshaw, King and Nordlee20). Until studies are conducted which assess both sensitisation and allergic disease there will continue to be conflicting views about the relative value of specific allergen exposure strategies for primary and secondary prevention.
Acknowledgements
E. M. M. has no conflicts of interest. J. O. W. receives bursaries and travel expenses for delivering lectures and serving on scientific advisory boards for Novartis, Merck, UCB Pharma, Allergy therapeutics, Danone, Airsonette and Unilever, and receives research grants from Danone, Airsonette and Lincoln Medical. J. O. W. is a member of the Advisory Committee for Novel Foods and Processes of the Food Standards Agency and until July 2009 was a trustee of the Anaphylaxis Campaign.