The HealthNuts population-based study of paediatric food allergy: validity, safety and acceptability
This paper describes the design of the HealthNuts study and the methods used. It also examines the first 2,000 infants recruited into the study and compares them to the whole population of 12 month olds across Victoria during the time of recruitment.
This ensures that participants in HealthNuts are representative of 12 month olds across Victoria. This was achieved by comparing demographic information from the HealthNuts participants with whole population information from the Victorian Perinatal census data. Also, participants who took part in HealthNuts were compared to those who declined to participate.
A sampling frame was used to select recruitment areas to ensure that a representative population for the HealthNuts study was achieved. HealthNuts nurses and recruiters attended childhood immunisation sessions across Melbourne. Infants underwent skin prick testing to raw egg, peanut, sesame and shellfish (after the first 2,000 participants, shellfish was replaced with cow's milk). Children who were sensitised (developed a wheal or lump around the skin prick) were invited into The Royal Children's Hospital to undergo a food challenge.
It was found that the community embraced HealthNuts, with a response rate of 73.4%. The demographic information provided by HealthNuts parent's shows that HealthNuts participants mirror the Victorian population. It was also found that of those who did not want to take part in HealthNuts, more children were already eating and tolerating peanut and were less likely to have a family history of food allergy.
Osborne NJ, Koplin JJ et al. (2010). "The HealthNuts population-based study of paediatric food allergy: validity, safety and acceptability." Clin Exp Allergy 40(10): 1516-1522.
Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants
This paper looked at the first 2,848 infants recruited into the HealthNuts study to examine how common food allergy is in the community. HealthNuts is unique because it uses food challenges to determine if a child has a food allergy. This is the best evidence to use to determine the burden of food allergy in the community. Among the 2,848 infants who were skin prick tested by the HeathNuts team, 8.9% were sensitised to peanut, 16.5% were sensitised to egg, 2.5% were sensitised to sesame, 5.6% were sensitised to cow's milk and 0.9% were sensitised to shellfish.
Infants who were sensitised to these foods were then invited into The Royal Children's Hospital for a food challenge. Food challenges to peanut, sesame and raw egg (the most allergenic form of egg) were conducted. It was found that 3% of the HealthNuts participants were allergic to peanut, 0.8% were allergic to sesame and 8.9% were allergic to raw egg. Infants who were found to have a raw egg allergy were then challenged to baked egg (egg cooked into a cake). Of the12 month olds allergic to raw egg, 80.3% could tolerate baked egg.
Overall it was found that 10% of 12 month old infants in the HealthNuts study have a food challenge proven food allergy to one of these common allergenic foods.
Osborne NJ, Koplin JJ et al. (2011). "Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants." J Allergy Clin Immunol 127(3): 668-676 e661-662.
Infant feeding guidelines have long recommended delaying introduction of solids and allergenic foods to prevent allergy in high-risk babies. However, there is limited evidence to show that this approach reduces the chance of children developing a food allergy.
The HealthNuts study looked at the duration of breastfeeding and age of introduction of egg in infants who were allergic to egg, and compared this to infants who were not allergic to egg.
This paper examined the first 2,589 12 month olds recruited into HealthNuts. It was found that duration of breastfeeding and age of first introduction of solid food was not associated with egg allergy. It was also found that introduction of cooked egg at 4 to 6 months of age might protect against egg allergy, and that cooked egg was more effective than egg baked into cakes or biscuits. From this study, we believe that late introduction of egg does not reduce the risk of developing an egg allergy. It also suggests that introduction of cooked egg between 4 to 6 months is safe and may even be protective against egg allergy.
Koplin JJ, Osborne NJ et al. (2010). "Can early introduction of egg prevent egg allergy in infants? A population-based study." J Allergy Clin Immunol 126(4): 807-813.
This paper looked at the risk factors for egg allergy (environmental and demographic factors). Environmental factors that have been suggested to be associated with allergic disease include number of older siblings, contact with other children during childcare, exposure to pets, caesarean section delivery, infant diet, parents' country of birth, family history of allergy and use of antibiotics in infancy.
Among the 5,276 HealthNuts infants who underwent skin prick testing to peanut, egg, sesame and cow's milk or shellfish, 453 had a confirmed egg allergy (positive food challenge). Information on environmental and demographic factors was collecting using a self-administered questionnaire.
It was found that infants with siblings, particularly older siblings, and infants with a pet dog inside the home, are less likely to be egg allergic at 1 year of age. History of allergic disease in an immediate family member and having parents born in East Asia were strong risk factors for egg allergy. Ceasarean section delivery, antibiotic use in infancy, childcare attendance and maternal age were not associated with egg allergy.
Other research has shown that children who have siblings have a greater incidence of infections, which might help to train the developing immune system. Also, pet ownership increases exposure to endotoxins (toxins which are found in some bacteria), which are effective in stimulating the immune system. Thus, having siblings and dogs seems to be protective against developing egg allergy.
Koplin JJ, Dharmage SC et al. (2012). "Environmental and demographic risk factors for egg allergy in a population-based study of infants." Allergy Nov;67(11): 1415-22.
Filaggrin loss-of-function mutations do not predict food allergy over and above the risk of food sensitisation among infants
This paper looked at the association between Filaggrin gene (FLG) loss-of-function changes and the risk of being sensitised to a food (measured by a positive skin prick test) and further development of food allergy (measured by eating a small amount of food during a food challenge test).
The FLG gene functions to protect the skin from water loss. FLG mutations have been associated with eczema and other allergic diseases. Of the 5,276 HealthNuts infants participating in the study, DNA was available from 700 infants who provided a blood sample.
As expected, it was found that FLG mutations increased the risk of having eczema, with 89.2% of FLG mutation carriers having eczema compared to 66.5% of noncarriers. It was further found that FLG mutations increased the risk of food sensitisation, regardless of whether or not the child had eczema. Also, among those who were food sensitised, there was no significant difference in FLG mutations when comparing food-tolerant infants with those with food allergy (confirmed by food challenge). FLG mutations might increase the risk of food sensitisation through impaired skin barrier function. This shows that sensitisation to a food can occur through the skin.
Tan HT, Ellis JA et al. (2012). "Filaggrin loss-of-function mutations do not predict food allergy over and above the risk of food sensitisation among infants." J Allergy Clin Immunol Nov;130(5): 1211-1213.
Ara h 2 is a dominant peanut protein detected in 90% to 100% of patients with peanut allergy. Testing for Ara h 2 in a blood sample might help to increase the accuracy of diagnosing a food allergy.
The current method to confirm food sensitisation (measured by a positive skin prick test) is to test for whole peanut-specific IgE level (sIgE), an indicator of immune system activity. This paper looked at whether Ara h 2 testing might improve the accuracy of diagnosing peanut allergy and therefore avoid the need for a food challenge.
A stratified random sample of 200 infants (100 with peanut allergy and 100 with peanut tolerance) had whole peanut sIgE and Ara h 2 sIgE levels assessed. It was found that Ara h 2 sIgE testing is more accurate in determining peanut allergy compared with either peanut skin prick tests or whole peanut sIgE measurements alone. This finding is important because it indicates improved peanut allergy diagnosis. Also, the number of patients on waiting lists needing a referral to a specialist to confirm allergy status via a food challenge may be reduced.
Dang TD, Tang M et al. (2012). "Increasing the accuracy of peanut allergy diagnosis by using Ara h 2." J Allergy Clin Immunol Apr;129(4): 1056-63.
Epidemiological evidence has shown that childhood food allergy is more common in regions further from the equator, suggesting that vitamin D insufficiency may play a role in this disease.
This paper looked at the role of vitamin D status in childhood food allergy. Of the 5,276 HealthNuts infants who underwent skin prick testing to peanut, egg, sesame and cow's milk or shellfish, infants with a positive test result and a random sample of infants with a negative test result attended The Royal Children's Hospital for a food challenge. Blood samples were available for 577 infants (344 with challenge-proven food allergy, 74 sensitized but tolerant to food challenge, 159 negative on skin prick test). Bloods were tested for vitamin D levels.
It was found that infants of Australian-born parents, but not parents born overseas, with vitamin D insufficiency were more likely to be peanut and/or egg allergic than those with adequate vitamin D levels. Among those with Australian-born parents, infants with vitamin D insufficiency were more likely to have multiple food allergies rather than a single food allergy.
These results provide the first direct evidence that vitamin D sufficiency may be an important protective factor for food allergy in the first year of life.
Allen KJ, Koplin JJ et al. (2012). "Vitamin D insufficiency is associated with challenge-proven food allergy in infants." J Allergy Clin Immunol Apr;131(4): 1109-16.
This paper aimed to examine the diagnostic value of skin prick test (SPT) and sIgE (allergen-specific immunoglobulin E) to challenge-confirmed food allergy in 12 month old HealthNuts infants, and develop thresholds above which an infant is highly likely to have a food allergy.
Also, this paper aimed to establish whether these thresholds with 95% positive predictive value (PPV) for food allergy were different when taking into account known risk factors for food allergy, including infantile eczema, previous reaction history, gender, vitamin D levels, and family history of allergic disease.
It was found that peanut SPT ≥ 8mm, egg SPT ≥ 4 mm, and sesame SPT ≥ 8mm, had 95% PPV for challenge-proven food allergy. Furthermore, peanut sIgE ≥ 34kUA/L and egg sIgE ≥1.7kUA/L had 95% PPV for challenge-proven food allergy. SPT 95% PPV were unaffected by other associated risk factors for food allergy including infantile eczema, family history and Vitamin D status.
This study presents the first comprehensive, population-based SPT and sIgE thresholds with 95% PPV for food allergy in infants and demonstrates that thresholds are not significantly affected by known risk factors for food allergy. These findings are likely to inform clinical practice in the care of young children with food allergy.
Peters RL, Allen KJ et al. (2013) "Skin prick test and serum-specific IgE as predictors of peanut, egg and sesame allergy in infants." J Allergy Clin Immunol (accepted May 2013).
The prevalence and socio-demographic risk factors of clinical eczema in infancy: a population-based observational study
This paper aimed to measure the population prevalence of infantile eczema, and to identify socio-demographic risk factors for eczema in the first year of life. HealthNuts infants were examined for current eczema at age 12 months, and parents provided information about the infants' history of eczema and demographic factors.
It was found that infants with a family history of eczema were twice as likely to have eczema as those without, and nearly 30% of infants developed eczema in their first year of life. When the strongest risk factors were combined together it was found that 80% of male infants with parents born in East Asian who also had a history of allergic disease, developed eczema by age one.
Interestingly, East Asian parents were much less likely to have reported a history of allergy themselves compared to Australian born parents. This suggests that an environmental factor related to moving to Australia may help to explain why children of East Asian descent have a higher rate of eczema once their parents migrate to Australia than either their parents or their Australian counterparts. Indeed, it was found that parents who had immigrated from East Asia were three times more likely to have changed their diet, compared to parents who had immigrated from Europe or the UK. Also, pet ownership was lower in East Asian migrants compared to migrants from Europe and the UK. This suggests a possible role for these factors in increasing the risk of eczema in infants.
Martin PE, Koplin JJ et al. (2013) "The prevalence and socio-demographic risk factors of clinical eczema in infancy: a population-based observational study." Clin Exp Allergy Jun;43(6): 642-51.
The Impact of Family History of Allergy on Risk of Food Allergy: A Population-Based Study of Infants
This paper examined the relationship between family history of allergic disease and the risk of developing food allergy in infants.
The prevalence of food allergy was determined in 5,276 one year old infants by oral-food challenges, a unique component of the HealthNuts study. Family history of allergy was defined as reporting asthma, eczema, allergic rhinitis or food allergy in a parent or sibling, and allowed for the genetic risk of food allergy in infants to be assessed.
Food allergy was diagnosed in 534 infants after reporting a positive oral food challenge or recent history of allergy. Children who had one immediate family member with a history of allergic disease showed only a modest increase in food allergy compared to those who had no family history. However, two or more family members with allergic disease proved to be significantly more predictive of food allergy in the child. The observed pattern held true for egg allergy when examined separately but not for peanut allergy. There was no relationship between having a single family member with allergic disease and the risk of peanut allergy in the child.
Currently, a child who has one immediate family member with a history of allergic disease is defined as being at a "high risk" of developing allergic disease themselves. Re-defining "high risk" as two or more allergic family members may be more useful in the identification of groups at significantly greater risk of allergic disease.
Koplin JJ, Allen KJ et al. (2013) "The Impact of Family History of Allergy on Risk of Food Allergy: A Population-Based Study of Infants." Int. J. Environ. Res. Public Health 10: 5364-5377.
Characterization of plasma cytokines in an infant population cohort of challenge-proven food allergy
Some individuals who produce food-specific antibodies react to food upon consumption (food allergic). Others may be sensitive yet will still be able to consume the food without adverse side effects (food sensitive).
Some children who are food-sensitive might become tolerant while others develop an allergy. The reasons for this disparity are not yet fully understood. This paper looked at immunological differences, specifically in cell-signalling proteins called cytokines, of tolerant and allergic infants in the HealthNuts cohort.
Infants were categorised as allergic, sensitized or nonallergic to egg and peanut depending on the results of a skin prick test and oral food challenge. Blood was then taken for cytokines concentration so that analysis could be made between allergy groups. Sensitized infants produced significantly higher levels of Th2 cytokines than nonsensitized infants and is responsible for the increased production of food antibodies. Cytokines IL-10 and IL-6 were also found to be significantly higher in sensitized compared to allergic infants. IL-10 levels in the blood appear to predict food allergy among sensitized infants and could be used as a biological indicator of allergy.
Several differences in cytokines levels between egg- and peanut-allergic infants were also found. These results could help explain the different mechanisms responsible for the development of the two allergies.
Dang TD, Tang MLK et al. (2013) "Characterization of plasma cytokines in an infant population cohort of challenge-proven food allergy." Allergy 68 (10): 1233-1240.
Skin prick test responses and allergen-specific IgE levels as predictors of peanut, egg, and sesame allergy in infants
The purpose of this study was to utilise 95% positive predictive values (PPVs) to develop a threshold for skin prick test (SPT) and serum IgE levels, allowing clinicians to avoid unnecessary oral food challenges for allergy diagnosis. In addition, this study was conducted to determine if the threshold changed due to other food allergies, eczema, reaction history, sex, vitamin D, and the history of family allergies.
One year old children were recruited at immunization centres where they underwent SPTs to the following allergens: egg, peanut, sesame, and cow’s milk or shrimp. Measurements were based on the size of the wheal, as well as the history of consumption to specific food substances. Infants that presented with a positive SPT, were given these foods at an oral food challenge, where IgE antibodies were measured. Children who tested negative from this food challenge were excluded.
The following results demonstrated SPT thresholds with a 95% of PPVs: peanuts with a response of 8mm or greater (95% CI, 7-9mm), eggs with a response of 4mm or greater (95% CI, 3-5mm), and sesame response of 8mm or greater (95% CI, 7-9mm). The sIgE levels results were: peanuts levels of 34kUA/L or greater (95% CI, 14-48 kUA/L) and egg levels of 1.7kUA/L or greater (95% CI, 1-3kUA/L). SPT responses were more accurate than sIgE in detecting a child’s allergy. It was found that the 95% of the PPVs in SPT responses had no association with other food allergies, eczema, reaction history, sex, vitamin D, or family history of allergies. Although SPT measurements were accurate, it was poor at predicting egg allergies in baked goods.
These 95% PPVs provide a valuable tool for diagnosis of food allergy in young infants, remaining robust in the presence of different risk factors.
The natural history and clinical predictors of egg allergy in the first 2 years of life: A prospective, population-based cohort study
There is limited data examining the natural history of and risk factors for egg allergy persistence, the most common IgE-mediated food allergy in infants.
This paper aimed to assess the natural history of egg allergy and identify clinical predictors for persistent egg allergy. Of the 5,276 HealthNuts infants who underwent skin prick testing to peanut, egg, sesame and cow's milk or shellfish, infants with a positive test result for egg were offered hospital-based oral food challenges for egg. Infants with challenge-confirmed raw egg allergy were offered baked egg oral food challenges at age 1 year and follow-up at age 2 years.
It was found that egg allergy had resolved in 47% of infants by 2 years of age. Egg allergy resolution was found to be lower in children with baked egg allergy at age 1 year (13%) compared with baked egg tolerance (56%). It was also found that in children with baked egg tolerance at age 1 year, consuming baked egg more than 5 times per month, increased the likelihood of tolerance.
These results provide evidence for the importance of characterisation of egg allergy (baked egg tolerant vs baked egg allergic) in all infants undergoing egg allergy assessment, due to its prognostic implications. In this study, tolerance to baked egg at 12 months was shown to be predictive of egg allergy resolution, whereas allergy to baked egg at 12 months was indicative of delayed development of tolerance.
Peters RL, Dharmage SC et al. (2014). “The natural history and clinical predictors of egg allergy in the first 2 years of life: A prospective, population-based cohort study.” J Allergy Clin Immunol Feb;133:485-91.
Increased risk of peanut allergy in infants of Asian-born parents compared to those of Australian-born parents
Peanut allergy appears to be uncommon in Asian countries, yet Asian infants in Australia appear to have higher rates of food allergy. It is thought that both genetic and environmental factors appear to play a role. This study looked to measure differences in the prevalence of peanut allergy by parental country of birth and whether environmental factors contribute to these differences.
To test for peanut allergy, 5276 infants who were screened for the HealthNuts study in Melbourne underwent skin prick testing to test for sensitivity to egg, peanut, sesame, shellfish and cow’s milk. Infants with a positive test result underwent a food challenge to confirm a peanut allergy. 535 of the infant participants had a parent born in East Asia and 574 were born in UK/Europe. Statistical analysis examined the relationship between parents’ country of birth and their infant’s peanut allergy.
The results showed that compared to infants with two Australian-born parents, peanut allergy was about three times more common among infants with parents born in East Asia, but not much different to those with parents born in the UK/Europe. Interestingly, the rates of allergic disease were much lower among Asian parents.
The factor that played the biggest role in explaining these differences was whether or not the infants had eczema when they were younger. Also, lower rates of dog ownership among infants of Asian parents appeared to contribute to some of the increase in peanut allergy, however the differences in lifestyle factors didn’t completely explain the differences in rates of peanut allergy.
These results indicated that genetic or environmental interactions are important in the prevalence of food allergy, particularly peanut allergy, however more research is needed to explore this further.
Koplin JJ et al. (2014). “Increased risk of peanut allergy in infants of Asian-born parents compared to those of Australian-born parents.” Allergy Dec; 69(12): 1639-47.
Australian allergy guidelines were recently revised in 2008, removing the recommendations to delay the introduction of allergenic solids. This is in line with other global allergy prevention guidelines. This paper looked to determine whether the updated 2008 guidelines were being utilised and changing infant feeding practices across Australia, and whether sociodemographic factors influenced this.
The HealthNuts study recruited 5276 infants between 2007 and 2011 in Melbourne, Australia, where parents reported on infant feeding practices by completing a detailed questionnaire. This paper compared the feeding practices of participants recruited from 2009-2011 after the implementation of the updated infant feeding guidelines in 2008 against participants recruited from 2007-2009. It also looked at whether the comparisons were influenced by sociodemographic factors.
Participants who were recruited in 2009-2011 were more likely to incorporate the revised guidelines than those recruited in 2007-2009. These revisions included being more likely to introduce solids at 4 months and less likely to introduce solids at 6 months, egg after 6 months, and peanut after 12 months. While the updated guidelines were unchanged in their advice regarding formula use, there was an increase in use of partially hydrolyzed formula after the guidelines. The changes in infant feeding practices were significantly stronger among families with a higher socioeconomic status and without a family history of allergies.
The results indicated that the Victorian population in Australia has responded encouragingly to the updated national allergy guidelines. It is important to address the socioeconomic factors influencing the population’s response to feeding recommendations in order for future infant feeding guidelines to be successful in their delivery and implementation.
Tey D et al. (2014). ‘Population response to change in infant feeding guidelines’. J Allergy Clin Immunol Feb; 133(2): 476-84.
Vitamin D insufficiency (VDI) has been shown to be associated with increased risk of food sensitization and food allergy at age 12 months. A combination of environmental and genetic factors appear to influence vitamin D sufficiency. Environmental factors include diet, Ultraviolet B radiation (UVR), sun exposure and lifestyle factors, skin pigmentation and seasons. Genetic factors include gene-gene interactions and presence of a mutation in the gene-encoding filaggrin.
To date, there have been few studies that have formally assessed the role that diet, UVR and genetics play in determining vitamin D levels in the first year of life. In this study, the relationship between genetic and environmental exposure (including diet, breastfeeding, season of birth, and UVR exposure) and vitamin D status at age one were explored and ranked by ethnicity.
The environmental and demographic data from 563 12-month-olds were collected from HealthNuts study data, a population based study of food allergy. The data came from a questionnaire and an associated blood sample. The questionnaire included questions regarding environmental exposures and infant feeding practices in the first year of life.
Results showed that infants who were formula fed were less likely to be associated with VDI compared to those who were exclusively breastfeeding, regardless of ethnicity. They also indicated that maternal vitamin D supplementation during pregnancy and/or breastfeeding were associated with increased odds of infants being vitamin D insufficient. This could be due to reverse causation, where mothers who are VDI will be more likely to ingest Vitamin D supplements, and the dosage of the supplements may have been inadequate. In summary, vitamin D supplementation is evident in 10% of 12-month infants in the subgroup observed. Breastfeeding is a risk factor for VDI at 12 months of age, regardless of ethnicity. Further investigation is needed to determine whether high rates of VDI in Asian infants are modulated by genetics.
Suaini N, et al. (2014) Environmental and genetic determinants of serum vitamin D levels in 12 month old infants. Journal of Steroid Biochemistry & Molecular Biology. Oct;144 Pt B:445-54.
The goal of this study was to determine children with gastro-oesophageal reflux (GOR) based on medical and behaviour observations.
The longitudinal, population-based HealthNuts study recruited 4674 infants at the age of one. Parents reported if their children had GOR as well as the onset, resolution, and treatments involved through questionnaires. Skin prick testing to eggs, peanuts, sesame, shrimp, and cows milk were utilised, followed by an oral food challenge if sensitisation was detected. In addition, IgE responses (from the immune system) were analysed.
The study found that 1054 (23%) parents reported GOR, with 662 (64%) parents consulting a medical practitioner. Symptoms commenced in the first month in 411 (48%) infants, and resolved within 6 months for 703 (75%) infants. Parents were more likely to seek treatment if they perceived their infant was unsettled and if the duration of GOR was prolonged.
In the first year of life, approximately 14% of the population seek medical advice for GOR symptoms. The use of anti-reflux medication in the general community remains high, despite the absence of evidence that it is appropriate or effective for uncomplicated GOR.
Hua S, Peters RL et al. (2014). “Medical intervention in parent-reported infant gastro-oesophageal reflux: A population-based study.” J Paediatr Child Health 51(5): 515-523.
Food allergy has been linked to eczema. The role eczema plays in early detection of food allergies is important as the prevalence of severe reactions such as anaphylaxis are increasing, particularly in those less than five years of age. The relationship between early onset eczema and food allergy among infants has never been examined in a population-based sample using the gold standard method for diagnosis, oral food challenge. Identification of infants most at risk of food allergy at a population-based level may enable targeted, early preventative interventions, with the aim of reversing the rise in food allergy prevalence. The aim of this study was to determine the risk of challenge-proven food allergy among infants with eczema.
In this study, 4453 one year old infants received a nurse-administered eczema examination and underwent skin prick testing for peanut, egg and sesame. Those with a detectable wheal for one of the test foods underwent an oral food challenge. The risk of food allergy, stratified by eczema severity and age of onset, was then estimated.
The study found that eczema, across the clinical severity spectrum in infancy, is a strong risk factor for IgE-mediated food allergy. Infants with eczema were six times more likely to have egg allergy and 11 times more likely to have peanut allergy by 12 months than infants without eczema. One in five infants with eczema were allergic to peanut, egg white or sesame, compared to one in twenty-five infants without eczema, and the prevalence of peanut allergy was low In the absence of eczema. The study also found that 50.8% of infants with early eczema onset (<3 months) who required doctor-prescribed topical corticosteroid treatment, developed challenge-proven food allergy. The data presented in this study suggests that a heightened awareness of food allergy risk among healthcare practitioners treating infants with eczema, especially if early onset and severe, is warranted.
Martin P, Eckert J et al. (2015). “Which infants with eczema are at risk of food allergy? Results from a population-based study.” Clin Exp Allergy 45(1): 255-64.
Food allergy appears on the rise in developed countries around the world. In 2011, an Australian study, with a population cohort of more than 5000 one-year old infants, found that more than 10% had challenge-proven egg allergy. The reasoning behind this is complex and multifactorial, thought to be linked to the modern-day lifestyle. Three strong hypotheses for the rise in food allergy in the 21st century are currently (1) the Hygiene Hypothesis, which includes microbial diversity (2) Lack Hypothesis - dual allergen exposure hypothesis, and (3) the Vitamin D Hypothesis. This review examines these three hypothesises.
Lifestyle has modernised over the past 20 to 30 years, coinciding with the noted rise in allergy in developed countries. At the general public health level, there has been a slow but persistent urbanization of cities, coupled with rising obesity levels, altered food handling/manufacturing practices, and modified exposure to environmental pathogens. However there are yet to be definitive links made between rising allergy levels and these factors.
There is increasing evidence that suggests that a reduction in early childhood infections (the Hygiene Hypothesis) or in exposure to microbial products may impede the development of early immune-regulatory responses. This leaves the immune system more susceptible to inappropriate reactivity to harmless antigens.
The dual allergen exposure hypothesis proposes that allergic sensitization occurs through exposure to low doses of allergen in the environment through damaged barriers to the skin (i.e. eczema). The Lack Hypothesis suggests that another factor in the development of food allergy is delayed oral allergen exposure. Studies have shown a reduced risk of food allergy in those introduced to specific allergic foods earlier in infancy. However, other studies have shown that increased diversity of foods introduced in the first year of life was associated with a reduced risk of food allergy.
Recent ecological enquiries have pointed towards the hypothesis that low vitamin D may increase the risk of food allergy (the Vitamin D Hypothesis). Studies have shown that infants with vitamin D insufficiency were 3 times more likely to have either peanut or egg allergy. Interestingly, these effects were observed among infants with Australian born parents but not those with parents born outside of Australia. Investigations of genetic risk factors may help to explain these differences.
In conclusion, exploring the recent reported rise in food allergies is challenging and multifactorial, with a combination of lifestyle, genetic, and environmental factors to be considered. Further high quality studies will help to explore potential causes.
Allen KJ & Koplin JJ (2015). “Why does Australia appear to have the highest rates of food allergy?” Pediatr Clin North Am 62(6): 1441-51.
Cohort Profile: The HealthNuts Study: Population prevalence and environmental/genetic predictors of food allergy
This paper describes the design of the HealthNuts study, namely why the HealthNuts cohort was set up, who is in the cohort, how often the cohort have been followed up, and what specific data was collected and measured. The paper also summarises the key findings that have arisen from the HealthNuts study thus far.
HealthNuts is a single-centre, multi-wave, population-based longitudinal study designed to assess prevalence, determinants, natural history and burden of allergy (particularly food allergy) in the early years of life. With reference to the prevalence and natural history of allergic disease, the HealthNuts study provided the first estimate of challenge-confirmed food allergy prevalence in Australian infants. Specifically it was found that food allergy and eczema were evident among one in ten, and one in five, 12-month-old infants in Melbourne, Australia respectively.
Thus far the HealthNuts study has found that in terms of risk factors for food allergy, increased microbial exposure (presence of older siblings and pet dogs), earlier introduction of egg into the infants’ diets, and sufficient serum vitamin D levels, were potential modifiable risk factors inversely associated with risk of food allergy. Maternal consumption of allergenic foods during pregnancy and caesarean section delivery were not found to be associated with food allergy in this cohort of participants.
Non modifiable risk factors for food allergy included a family history of allergy, the presence of filaggrin gene loss-of-function mutations, and having parents born in East Asia. It was also found that higher plasma levels of Th2-related cytokines, specifically IL-4, IL-13 and IL-12 was associated with food sensitization (either with or without associated food allergy) in infants at 1 year of age, whereas lower IL-10 levels were found in infants with clinical food allergy.
As the HealthNuts study continues it is hoped more can be learnt about the causes and consequences of food allergy at the population level.
Koplin JJ, Wake M et al. (2015). “Cohort Profile of The HealthNuts study: Population prevalence and environmental/genetic predictors of food allergy.” Int J Epidemiol 44(4): 1161-71.
Differential factors associated with challenge-proven food allergy phenotypes in a population cohort of infants: A latent class analysis
Food allergy, eczema and wheezing are early indicators of allergic disease and commonly co-occur in infancy however their interrelationship is not well understood. Data from the HeathNuts study was used to analyse the differential drivers of multi-allergy phenotypes. The aim of this paper was to define phenotypes and risk factors of allergic disease using latent class analysis, a statistical method which can detect the presence of unobserved classes with a population.
Modelling was performed on baseline data collected from 5276 12-month-old infants, including information on food sensitisation, allergy to egg, peanut and sesame, early and late onset eczema and wheeze in the first year of life.
The study identified five distinct phenotypes: no allergic disease (70%), non-food-sensitized eczema (16%), single egg allergy (9%), multiple food allergies (predominantly peanut) (3%) and multiple food allergies (predominantly egg) (2%). Compared to the baseline group of no allergic disease, shared risk factors for all allergic phenotypes were parents born overseas (particularly Asia), delayed introduction of egg, male gender (except for single egg allergy) and family history of allergic disease, whilst exposure to pet dogs was protective for all phenotypes. Other factors including filaggrin mutations, vitamin D and the presence of older siblings differed by phenotype.
The results demonstrate that multiple outcomes in infancy can be used to determine distinct allergy phenotypes at the population level. These have both shared and separate risk factors suggesting differential mechanisms of disease.
Peters RL, Allen KJ et al. (2015). “Differential factors associated with challenge-proven food allergy phenotypes in a population cohort of infants: a latent class analysis.” Clin Exp Allergy 45(5): 953-63.
Polymorphism affecting vitamin D-binding protein modify the relationship between serum vitamin D-binding protein modify the relationship between serum vitamin D and food allergy
There is evolving evidence to suggest that vitamin D insufficiency may contribute to food allergy, but findings vary between populations. Moreover, lower vitamin D-binding protein (DBP) levels are known to increase the biological availability of serum vitamin D, and genetic polymorphism is known to explain almost 80% of this variation. Given these findings, this paper aimed to investigate whether polymorphisms that lower the DBP could compensate for adverse effects of low serum vitamin D on food allergy risk.
In this study the association between serum 25-hydroxyvitamin D3 levels (an indicator of vitamin D status) and food allergy was investigated at age one year with 338 participants who were challenge-proven food allergic and 269 control participants, and at age two years with 55 participants with persistent food allergy and 50 participants with resolved food allergy.
The results showed that low serum 25-hrdoxyvitamin D3 levels at age one year was associated with food allergy, particularly among infants with a GG genotype. Maternal antenatal vitamin D supplementation was associated with less food allergy, particularly in infants with the GT/TT genotype. Persistent vitamin D insufficiency was found to increase the likelihood of persistent food allergy, particularly in those with the GG genotype.
In summary, the data presented in this study suggests that polymorphisms associated with lower DBP levels attenuate the association between low serum 25-hydroxyvitamin D3 levels and food allergy, consistent with greater vitamin D bioavailability in those with a lower DBP level. These findings increase the biological plausibility of a role for vitamin D in the development of food allergy.
Koplin JJ, Suaini N et al. (2015). “Polymorphisms affecting vitamin D binding protein modify the relationship between serum vitamin D and food allergy.” J Allergy Clin Immunol 137(2): 500-506.
The diagnosis of food allergy can be challenging because approximately half of food-sensitized patients are asymptomatic. Current diagnostic tests are excellent makers of sensitization but poor predictors of clinical reactivity. Oral food challenge (OFC) is the standard method used to identify food allergies; however, in this paper the author proposes to seek an alternative solution by using genetics as a biomarker.
Children from the ages of 11-15 months who had undergone OFCs, skin prick test and specific IgE tests were recruited for this study. Participants included 58 food-sensitised patients, half of whom were clinically reactive as well as 13 non-allergic control subjects. In total, there were 71 blood samples utilised to test for these common allergens: egg, peanut, sesame, and cow’s milk.
Through DNA methylation (DNAm), T-cell numbers and regulatory T cell numbers (Treg), were displayed through a flow cytometry, in which analysis of a data were produced. Based on the clinical outcome, a DNAm signature was developed using 96 methylation sites. The cut offs ranges of these biomarkers were based on the level of sensitivity to the specific food allergy. Methylation biomarkers outperformed allergen-specific IgE and skin prick tests for predicting OFC outcomes. FA status was correctly predicted in the replication cohort with an accuracy of 79.2%.
DNAm biomarkers are readily detectable in blood and may provide an alternative for predicting OFC outcomes. The further development of this technology in follow-up studies will yield highly innovative diagnostic assays.
Martino D, Dang T et al. (2015). “Blood DNA methylation biomarkers predict clinical reactivity in food-sensitized infants.” J Allergy Clin Immunol 135(5): 1319-28.
Natural history of peanut allergy and predictors of resolution in the first 4 years of life: A population-based assessment
There are no prospectively collected data available on the natural history of peanut allergy in early childhood. Previous studies of predictors of tolerance development have been biased by failure to challenge high-risk children when IgE antibody levels are high, therefore potentially introducing bias to persistent allergy.
The purpose of this study was to collect data from children with peanut allergies; it was also used to determine if “high-risk” children resolved their peanut allergies by the age of four. Consistent testing through oral food challenges and skin prick test (SPT) determined the values of positive and negative predicator thresholds.
The following results displayed SPT, through wheal size, and sIgE measurements by age:
1 year olds: wheal size of 13mm or greater with sIgE of 5.0 kU/L or greater.
4 year olds: wheal size of 8mm or greater with sIgE of 2.1 kU/L or greater.
Based on these results, 22% of peanut allergies were resolved at the age of 4 years old; the reaction of wheal size and immune system had decreased. On the other hand, 78% of the children were persistent to peanut allergies (excluding tree nuts, house dust mite, co-existing food allergies, eczema, and asthma).
These thresholds are the first to be generated from a unique data set in which all participants underwent oral food challenges at both diagnosis and follow-up, irrespective of SPT and sIgE results.
Peters RL, Allen KJ et al. (2015). “Natural history of peanut allergy and predictors of resolution in the first 4 years of life: A population-based assessment.” J Allergy Clin Immunol 135(5): 1257-66.
Persistent food allergy and food allergy co-existent with eczema is associated with reduced growth in the first four years of life
Food allergy has been associated with lower weight and height in cross-sectional studies in children. Poor growth in infancy and early childhood can have ongoing consequences such as poor cognition and behavioural development. Food allergy is often coexistent with eczema, with up to 50% of children with severe eczema also having severe eczema affected by food allergy. Eczema is associated with itching, sleep disturbance and increased metabolism that has been linked to impaired growth. Limited research has been done to explore infant growth over time in children with/without allergies and a coexistence of eczema. This study aimed to examine the combined effects of food allergy and eczema in growth patterns in children.
This study used results collected from the HealthNuts study, a population based study with a total of 5276 children. Within the HealthNuts study, 12-month old infants were recruited and underwent skin prick testing to egg, peanut and sesame. They were also examined for eczema, parent-reported weight and height and child health record data were used to examine the effect of food allergy and eczema on weight and height controlling for potential confounders. All children who had a detectable wheal on skin prick test were invited to have an oral food challenge, the gold standard for determining food allergy. At age four, the same process was repeated.
The results from this study indicated that children with both food allergy and eczema at age one had lower percentiles for mean weight and height compared with those with neither condition. There was no difference for children with only food allergy or eczema at age one. By age four, children with persistent food allergy and eczema, but not those with resolved food allergy, were still shorter and lighter.
In conclusion, children with both food allergy and eczema were shorter and lighter throughout early childhood, with more pronounced differences in those with persistent food allergy. The results highlight the need for nutritional follow-up for all food-allergic children.
Beck C, Koplin J et al. (2016). “Persistent food allergy and food allergy co-existent with eczema is associated with reduced growth in the first four years of life.” J Allergy Clin Immunol Pract 4(2): 248-256.
The purpose of this article was to determine if utilising formula and breastfeeding reduced the risk of food allergies in infants.
5276 children at the age of one were recruited for this study, in which data was collected from the parents. A skin prick test was also conducted to the following four allergens: hen’s egg, peanut, sesame, and cow’s milk or shrimp. Control groups consisted of positive histamine and a negative saline. Children with sensitised skin due to the whealing reaction, were invited for a second round of SPT with additional food testing. The children participated in an oral food challenge to further determine their allergy status. These variables, along with family history to food allergies, infant eczema, reactions to cow’s milk, and age of introduction to eggs were categorised through a measurement using a logistic regression model.
It was found that there were no association between breastfeeding and partially hydrolysed formula to food allergies. The results had shown that 4537 of children had a determined food allergy status, while 515 had directly shown food allergies through the oral food challenge and SPT. Interestingly, correlating breastfeeding with any of the unchanged variables (e.g. eczema or family history of food allergy) further increased the risk of developing a food allergy.
Goldsmith AJ, Koplin JJ, Lowe, Tang MLK, Matheson MC, Robinson M, Peters R, Dharmage SC, Allen KJ*. (2016) Formula and breast feeding in infant food allergy: a population-based study. Journal of Paediatrics and Child Health. Apr;52(4):377-84.
Epidemiological evidence suggests that routine vaccinations can have non-targeted effects on susceptibility to infections and allergic disease. Such effects may depend on age at vaccination, and a delay in pertussis (whooping cough) vaccination has been linked to reduced risk of allergic disease. The purpose of this study was to determine if having a delayed onset of vaccination in pertussis reduced allergic disease and atopic sensitisation (related to asthma, hay fever and eczema).
Pertussis, which is a contagious respiratory infection, has an available vaccine that contains diphtheriatetanus-acelullar pertussis (DTaP). The focus of this study was to determine how delayed DTaP - in its first dose - may be associated with reduced risk of food allergy and other allergic diseases in one year old children. HealthNuts conducted this study with a cohort of 5276 infants, in which data was collected based on the children’s: history of allergies, examination of eczema, and skin prick test (SPT) to common foods (e.g., eggs, peanuts, and sesame).
Surprisingly, there were two outcomes to this study. First, 109 out of 4433 children who participated and received the delayed vaccination, found no correlation between delayed DTaP and food allergies. Although it started with 5276 infants, analysis based on age/ vaccination received, and even SPT results excluded children from this study. Just as food allergies, atopic sensitisation, which refers to skin disease, showed no signs of correlation to delayed DTaP either. However, in the second outcome, delayed DTaP was correlated to reducing eczema in both boys and girls.
Interestingly, there was some associations found between DTaP and genders. Unlike boys, girls with delayed DTaP showed less atopic sensitisation. However, it is not clear if other vaccines are responsible for the reduction of atopic sensitisation.
The study concluded that there was no overall association between delayed DTaP and food allergy; however, children with delayed DTaP had less eczema and less use of eczema medication. Timing of routine infant immunizations may affect susceptibility to allergic disease.
Kiraly N, Koplin JJ et al. (2016). “Timing of routine infant vaccinations and risk of food allergy and eczema at one year of age.” Allergy 71(4): 541-549.
Understanding the feasibility and implications of implementing early peanut introduction for prevention of peanut allergy
Evidence from the recent randomized control trial Learning Early About Peanut (LEAP) Allergy, revealed that the earlier introduction of peanuts reduces peanut allergy prevalence in high-risk infants. This paper sort to use population based infant peanut allergy data to understand the implications of implementing the LEAP trial intervention.
Using the HealthNuts study cohort of one year old infants, criteria to identify high risk infants for developing peanut allergy were explored as well as the implications of skin prick test screening prior to peanut introduction.
Screening all infants with early onset eczema and/or egg allergy could require testing 16% of the population and would still miss 23% of peanut allergy cases; 29% of screened infants would require clinical follow-up because of being SPT-positive.
Around 11% of high-risk infants were excluded from the LEAP study because of an SPT wheal size of more than 4 mm to peanut at baseline; data from the HealthNuts study suggest that 80% of these would be peanut allergic on food challenge. There were no life-threatening events among either low- or high-risk infants whose parents chose to introduce peanut at home in the first year of life, or in 150 peanut-allergic infants during hospital-based challenges.
Based on this large epidemiological study, a population program aiming to identify and screen all infants at risk of peanut allergy would pose major cost and logistic challenges that need to be carefully considered. Further research might be required to provide data for low-risk infants.
Koplin JJ, Peters RL et al. (2016). “Understanding the feasibility and implications of implementing early peanut introduction for prevention of peanut allergy.” J Allergy Clin Immunol Advance online publication. DOI: 10.1016/j.jaci.2016.04.011