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.
Peters RL, Allen KJ et al. (2013) “Study Skin prick test response and allergen-specific IgE levels as prediction of peanut, egg and sesame allergy in infants.” J Allergy Clin Immunol. 2013 Oct;132(4):874-80.
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
Food Challenge and Community-Reported Reaction Profiles in Food-Allergic Children Aged 1 and 4 Years: A Population-Based Study.
Oral food challenge is the main tool for diagnosing food allergy, but there is little data on the reaction profiles of young children undergoing challenges, or how these reactions compare to reactions on accidental ingestion in the community.
The objective of this paper was to compare reaction profiles from food challenges and parent-reported reactions on accidental ingestion, and assess predictors of severe reactions.
Infants in the HealthNuts study underwent skin prick tests and those with identifiable wheals were offered food challenges. Food challenges were repeated at age 4 years in those with previous food allergy or reporting new food allergies. Community-reported reactions were ascertained from parent questionnaires.
It was found that food challenges were undertaken in 916 children at age 1 year and 357 children at age 4 years (a total of 2047 peanut, egg, or sesame challenges). Urticaria (hives) was the most common sign in positive challenges at both ages (age 1 year, 88.7%, and age 4 years, 71.2%) although angioedema (swelling) was significantly more common at age 4 years (40.1%) than at age 1 year (12.9%).
Anaphylaxis was equally uncommon at both ages (2.1% and 2.8% of positive challenges at ages 1 and 4 years, respectively) but more common for peanut than for egg (4.5% and 1.2% of positive challenges at ages 1 and 4 years, respectively). The patterns of presenting signs reported during community reactions were similar to those observed in formal food challenges. Serum food-specific IgE levels of 15 kU/L or more were associated with moderate to severe reactions but skin prick test was not.
There was a shift from the most common presenting reaction of urticaria during food challenges toward more angioedema in older children. Serum food-specific IgE levels were associated with reaction severity.
Chan JC, Peters RL et al. (2017). “Food Challenge and Community-Reported Reaction Profiles in Food-Allergic Children Aged 1 and 4 Years: A Population-Based Study.” J Allergy Clin Immunol Pract. Mar - Apr;5(2):398-409.e3.
The prevalence of food allergy and other allergic diseases in early childhood in a population-based study: HealthNuts age 4-year follow-up
The HealthNuts study previously reported the highest prevalence of challenge-confirmed food allergy in infants internationally. However, population-derived prevalence data on challenge-confirmed food allergy and other allergic diseases in preschool-aged children remain sparse.
This paper aimed to report the updated prevalence of food allergy at age 1 year from the whole cohort, and to report the prevalence of food allergy, asthma, eczema, and allergic rhinitis at age 4 years.
Children in the HealthNuts study underwent skin prick test (SPT) to 4 food allergens and those with detectable SPT results had formal food challenges. At age 4 years, parents completed a questionnaire (81.3% completed) and those who previously attended the HealthNuts clinic at age 1 year or reported symptoms of a new food allergy were invited for an assessment that included SPT and oral food challenges. Data on asthma, eczema, and allergic rhinitis were captured by validated International Study of Asthma and Allergies in Childhood questionnaires.
It was found that the prevalence of challenge-confirmed food allergy at age 1 and 4 years was 11.0% and 3.8%, respectively. At age 4 years, peanut allergy prevalence was 1.9%, egg allergy was 1.2%, and sesame allergy was 0.4%. Late-onset peanut allergy at age 4 years was rare (0.2%). The prevalence of current asthma was 10.8%, current eczema was 16.0%, and current allergic rhinitis was 8.3%. Forty percent to 50% of this population-based cohort experienced symptoms of an allergic disease in the first 4 years of their life.
Although the prevalence of food allergy decreased between age 1 year and age 4 years in this population-based cohort, the prevalence of any allergic disease among 4-year-old children in Melbourne, Australia, is remarkably high.
Peters RL, Koplin JJ et al. (2017). “The prevalence of food allergy and other allergic diseases in early childhood in a population-based study: HealthNuts age 4-year follow-up.” J Allergy Clin Immunol Pract. May.
Genomewide association study of peanut allergy reproduces association with amino acid polymorphisms in HLA-DRB1
This study aimed to identify genetic variants associated with challenge-proven IgE-mediated peanut allergy, as these are yet to be fully characterised. A genome-wide association study (GWAS) was performed, comparing 73 infants with challenge-proven IgE-mediated peanut allergy against 148 non-allergic infants. All 221 infants were approximately 1 year of age and from the HealthNuts cohort.
21 independent associations were identified, however, these were unable to be replicated. The most significant variant was a previously reported amino acid variant at position 71 (in the peptide-binding groove) of HLA-DRB1, which is a gene that provides instructions for making an important immune system protein. Thus, it was determined that this HLA-DRB1 locus has alleles which may contribute as genetic determinants of peanut allergy.
This study aimed to identify genetic variants associated with challenge-proven IgE-mediated peanut allergy, as these are yet to be fully characterised. A genome-wide association study (GWAS) was performed, comparing 73 infants with challenge-proven IgE-mediated peanut allergy against 148 non-allergic infants. All 221 infants were approximately 1 year of age and from the HealthNuts cohort.
21 independent associations were identified, however, these were unable to be replicated. The most significant variant was a previously reported amino acid variant at position 71 (in the peptide-binding groove) of HLA-DRB1, which is a gene that provides instructions for making an important immune system protein. Thus, it was determined that this HLA-DRB1 locus has alleles which may contribute as genetic determinants of peanut allergy.
Martino DJ, Ashley S et al. (2017). “Genomewide association study of peanut allergy reproduces association with amino acid polymorphisms in HLA-DRB1.” Clin Exp Allergy Feb;47(2):217-223.
Genetic variation at the Th2 immune gene IL13 is associated with IgE-mediated paediatric food allergy
Despite food allergies posing a worldwide public health problem, few genetic risk variants have been identified. Ashley and colleagues identify the Th2 immune gene IL13 as a candidate for genetic risk of food allergy, as it is critical for the initiation of IgE class switching in B cells.
Seeking to identify whether genetic variations at IL13 were associated with challenge-proven IgE-mediated food allergy, nine IL13 single nucleotide polymorphisms (SNPs) were genotyped in 722 children from the HealthNuts cohort. Of these 722 children, 367 had challenge-proven food allergies, 199 were food-sensitised, and 156 were non-allergic controls. A replication study was also conducted in an independent, co-located sample of four paediatric cohorts.
IL13 variation rs1295686 was associated with challenge-proven food allergy in both samples (OR=1.75 in discovery sample, OR=1.37 in replication sample), and this was also supported by meta-analysis (OR=1.50). Association with food sensitisation could not be ruled out. It was also found that the rs1295686 variant A allele was also associated with increased plasma IgE.
Ashley SE, Tan HT et al. (2017). “Genetic variation at the Th2 immune gene IL13 is associated with IgE-mediated paediatric food allergy.” Clin Exp Allergy Aug;47(8):1032-1037.
The skin barrier function gene SPINK5 is associated with challenge-proven IgE-mediated food allergy in infants
It is believed that the skin barrier is an important route of sensitisation to food allergens, and that a defective skin barrier may lead to allergy in children. Serine peptidase inhibitor Kazal type 5 (SPINK5) is a skin barrier gene, and missense mutations in this gene have previously been shown to be associated with allergic conditions. This paper seeks to determine whether genetic variants in and around SPINK5 are associated with IgE-mediated food allergy.
376 food-allergic, 199 food-sensitised, and 156 non-allergic 12-month-old infants from the HealthNuts cohort were analysed, with genetic variants tested for association with food allergy, and association analyses replicated in an independent sample group.
SPINK5 variant rs9325071, a missense mutation, was associated with food allergy in the initial sample (OR=2.95), and this was supported by the replication sample (OR=1.58), and by meta-analysis (OR=1.65). This genetic variant is associated with decreased expression of SPINK5 in the skin, and has now been shown to be associated with IgE-mediated food allergy.
Ashley SE, Tan HT et al. (2017). “The skin barrier function gene SPINK5 is associated with challenge-proven IgE-mediated food allergy in infants.” Allergy Sep;72(9):1356-1364.
The rise in shellfish allergies has become a serious problem worldwide. The major pan-allergen Tropomyosin (TM) has been shown to be a good biomarker for shrimp allergy, with a positive predictive value (PPV) of 0.72. This study has analysed IgE reactivity against TM in shrimp-sensitized infants and assessed whether any other known allergens elicit similar reactivity. Cross-reactivity of shrimp allergens in HDM (house dust mite)-allergic infants was also cross-compared.
66 infants from the HealthNuts cohort were used for this study. Of these 66, 18 were shrimp sensitised, 18 were HDM allergic, 12 had parent-reported reactions to shrimp but were negative in a skin prick test, and 18 control infants with no sensitisation to shrimp or HDM.
28% of shrimp sensitised infants showed evidence of IgE binding to shrimp TM, and only 5% of HDM allergic infants reacted to shrimp TM. One child from the parent-reported shrimp reaction group showed IgE binding to TM. IgE was also observed to bind to a number of shrimp proteins; sarcoplasmic calcium-binding protein (SCP), hemocyanin A and B, and enolase. Of the shrimp sensitised infants, 22% showed IgE binding to SCP, 33% to hemocyanin A and B, and 11% to enolase. 61% of HDM-allergic infants showed IgE binding to hemocyanin A and B, and 44% to enolase, but no infants showed IgE binding to SCP.
IgE binding was established in both shrimp-sensitized and HDM-allergic infants to tropomyosin, hemocyanin, and enolase. In addition, cross-reactive IgE binding to shrimp hemocyanin and enolase in HDM-allergic infants was described, which may have an impact on cross-reactivity to shellfish allergens in children undergoing HDM therapy. Knowledge of these allergens will also be beneficial for future studies involving shellfish allergies.
Kamath SD, Johnston EB et al. (2017) “IgE reactivity to shrimp allergens in infants and their cross-reactivity to house dust mite.” Pediatr Allergy Immunol Nov;28(7):703-707.
Measuring the impact of differences in risk factor distributions on cross-population differences in disease occurrence: a causal approach
In epidemiological and public health research, cross-population comparisons of health outcome measures are common. As well as surveillance, a common aim in comparison studies is to evaluate the role of known determinants of disease in observed differences between populations, as well as to quantify the extent to which differences in populations are unexplained by known factors. This can also be thought of as the ‘population effect’, induced by a number of differing factors between populations. A common approach to adjusting for this population effect is to compare adjusted and unadjusted regression-based estimates, though results from this approach may still be hindered by other factors and can be subject to interpretational challenges.
Moreno-Betancur and colleagues formalised this problem and determined possible estimators, using the regional differences in egg allergy prevalence among the HealthNuts cohort for illustration. The main estimands were found to be:
- The change in prevalence or incidence induced by variations in measured risk factors, and;
- The proportion of crude difference which remains unexplained by measured factors
This paper provides a causal theoretical basis for studying differences in disease occurrence between populations, and the measures proposed can be used moving forward to answer questions arising in similar contexts.
Moreno-Betancur M, Koplin JJ et al. (2018). “Measuring the impact of differences in risk factor distributions on cross-population differences in disease occurrence: a causal approach.” Int J Epidemiol Feb 1;47(1):217-225.
The Prevalence of Food Sensitization Appears Not to Have Changed between 2 Melbourne Cohorts of High-Risk Infants Recruited 15 Years Apart
Despite food allergy rising over recent decades, recent reports have suggested that the prevalence of food sensitization has not changed in the general population. This paper describes a study where the prevalence of food sensitization was compared in high-risk infants of two cohorts recruited fifteen years apart.
This study included 620 high-risk infants from the Melbourne Atopy Cohort Study (MACS) born 1990-1994, and a subgroup of high-risk infants from the HealthNuts study, born 2006-2010. The observed prevalence of sensitisation to a number of common allergens remained relatively consistent between these two cohorts. Between the MACS and HealthNuts cohorts, the prevalence of sensitization to the following allergens was as follows; peanut 7.9% and 7.9%, respectively; 15.0% and 14.5% for egg, respectively; and 2.4% and 2.6% for cow’s milk, respectively.
These results suggest that the level of food sensitization among high-risk infants has remained constant in Australia since the 1990s, despite a reported increase in food-related anaphylaxis. The reasons for this discrepancy is unclear, however the paper suggests that this may be due to increased food allergy in low-risk populations, increased conversion of food sensitization to allergy, increased number of high-risk infants, or increased awareness or severity of reactions.
Peters RL, Koplin JJ et al. (2018). “The Prevalence of Food Sensitization Appears Not to Have Changed between 2 Melbourne Cohorts of High-Risk Infants Recruited 15 Years Apart.” J Allergy Clin Immunol Pract Mar - Apr;6(2):440-448.
Is Skin Testing or sIgE Testing Necessary Before Early Introduction of Peanut for Prevention of Peanut Allergy?
Since the late 1990s, the majority of guidelines for preventing food allergy recommended delaying introduction of allergenic foods until after the age of 2-4 years. However, in February 2015, the results of the Learning Early About Peanut (LEAP) study were published, providing evidence that introducing peanut between age 4-11 months can reduce the risk of developing peanut allergy before age 5 years.
The results of LEAP suggest that introducing peanut earlier in life could have a major impact on the prevalence of peanut allergies if implemented in the general population. In response to the findings, international allergy societies have collaborated to develop new consensus recommendations on early peanut introduction, one such recommendation was for parents to consider evaluation with peanut-specific IgE or skin prick testing, and an oral food challenge if necessary, before introducing peanut to their child’s diet.
This paper analyses the pros and cons of performing peanut-specific SPT or IgE testing in high-risk infants, by taking into account evidence from the LEAP trials as well as potential risks of implementing this strategy, allowing readers to come to their own conclusions about what is best for their child.
Tang MLK, Koplin JJ et al. (2018). Is Skin Testing or sIgE Testing Necessary Before Early Introduction of Peanut for Prevention of Peanut Allergy? J Allergy Clin Immunol Pract Apr;6(2):408-413.
Egg allergen specific IgE diversity predicts resolution of egg allergy in the population cohort HealthNuts
Recent developments in component resolved diagnostic (CRD) technology have improved the way in which peanut allergies are predicted and diagnosed. This study aims to determine whether similar improvements could be seen when using CRD to diagnose and predict egg allergy as has been done with peanut allergy.
451 participants were selected from the HealthNuts cohort, with median ages of 12 moths at the time of the skin prick test (SPT), and 14 months at the time of the oral food challenge (OFC). Of these infants, 297 were challenge-confirmed egg allergic, 97 were egg-sensitised, and 57 were non-sensitised, non-allergic controls. Serum egg white, Gal d 1,2,3, and 5 sIgE were measured using ImmunoCAP.
It was found that sensitisation to Gal d 1 increased the risk of persistent egg allergy by 2.5-fold, and the production of sIgE to all four egg allergens increased the risk of persistent egg allergy four-fold. While improvements in diagnosing current egg allergy were found by using Gal d 1,2,3, or 5 compared to egg white sIgE, sensitisation to multiple egg allergens may be a useful prognostic marker for patient management and identifying risk of developing persistent egg allergy.
Dang TD, Peters RL et al. (2018). “Egg allergen specific IgE diversity predicts resolution of egg allergy in the population cohort HealthNuts.” Allergy Jul 23
doi: 10.1111/all.13572. [Epub ahead of print]
The risk of developing asthma in children with early food allergy is unknown, particularly among children whose food allergy has resolved. This paper addresses this issue by assessing whether challenge-proven food allergy in infancy increases the risk of asthma at age 4 years, using data from the HealthNuts cohort.
The association between food allergy and doctor-diagnosed asthma was examined using 2,789 participants from the HealthNuts cohort. It was found that children with food allergy at age 1 year had an increased risk of developing asthma by age 4 years (relative risk=1.69). The risk of asthma was highest for children with food allergy and coexistent eczema at age 1 year (relative risk=2.87). Both transient and persistent food allergy were associated with an increased risk of developing asthma by age 4 years.
Asthma at age 4 is twice as common among children with food allergies in infancy, regardless of whether or not this allergy naturally resolves. Children with two or more food allergies in infancy and those with a food allergy and eczema in infancy were close to three times as likely to develop asthma by age 4 compared to children with no food allergy.
Vermeulen EM, Koplin JJ et al. (2018). “Food Allergy Is an Important Risk Factor for Childhood Asthma, Irrespective of Whether It Resolves.” J Allergy Clin Immunol Pract Jul - Aug;6(4):1336-1341.
Children with East Asian-born parents have an increased risk of allergy but may not have more asthma in early childhood
It was previously reported that infants with Asian-born parents are 3 times more likely to have IgE-mediated food allergy than those with Australian born parents, suggesting that the environmental changes associated with migration may play a role in the development of a food allergy, however it unknown whether these findings would translate to the prevalence of food allergy later in childhood.
This study compared the prevalence and risk factors for allergic rhinitis, eczema, asthma, and aeroallergen sensitization at age 6 between children with Caucasian-born parents and those with East-Asian born parents. A total of 4455 children participated in the HealthNuts age 6 follow up, and this included 3015 with Caucasian-born parents and 415 with East-Asian born parents. These children underwent skin prick tests to aeroallergens and questionnaires to capture data on allergic rhinitis, asthma, and eczema.
It was found that, compared to children with Caucasian-born parents, children with East-Asian born parents had a greater prevalence of allergic rhinitis (19.9% vs 9.3%) and aeroallergen sensitization (64.3% vs 34.4%). Asthma prevalence was similar in both groups, and children with IgE-mediated food allergy and eczema as infants were more likely to have allergic rhinitis or asthma at age 6 (2 times and 3 times more likely, respectively), regardless of their parents’ ancestry.
Suaini N, Koplin JJ et al. (2018). “Children with East Asian-born parents have an increased risk of allergy but may not have more asthma in early childhood.” J Allergy Clin Immunol Pract. Aug 24
doi: 10.1016/j.jaip.2018.07.042. [Epub ahead of print]
Patterns of tree nut sensitization and allergy in the first 6 years of life in a population-based cohort
This study set out to determine the prevalence of tree nut allergy at age 6 and to examine the relationship between egg and peanut allergy in infancy and the development of tree nut allergy later in childhood.
The HealthNuts cohort were recruited at age 1 and followed up age 6, with allergies for egg and peanut being assessed at age 1, and tree nut allergy assessed at the age 6 follow up. At age 1, parent-reported tree nut allergy was 0.1%, however, only 18.5% of infants had consumed tree nuts in the first year of life. At age 6, challenge-confirmed tree nut allergy was 3.3%.
Of children with peanut allergy at 1 year, 27% had developed tree nut allergy at age 6, while only 14% of children with egg allergy at age 1 had developed tree nut allergy by age 6. 37% of children with both egg and peanut allergy in infancy had developed a tree nut allergy by age 6.
Though tree nut allergy is uncommon during infancy, this is likely due to limited tree nut consumption during the first year of life, and by age 6 tree nut allergy is similar to that of peanut allergy. Over a third of children with both egg and peanut allergies also went on to develop tree nut allergy by age 6, indicating that research into how to prevent tree nut allergy should be a priority.
McWilliam V, Peters R et al. (2018). “Patterns of tree nut sensitization and allergy in the first 6 years of life in a population-based cohort.” J Allergy Clin Immunol Aug 30. [Epub ahead of print]
In a proportion of children with food allergies, these allergies naturally resolve over time. However, what determines whether a child’s food allergy will persist or resolve is not well understood. Neeland and colleagues analysed blood samples collected from a subset of the HealthNuts cohort. These children were challenge-confirmed egg-allergic as infants, whose allergy either persisted or naturally resolved later in childhood.
It was found that children with persistent egg allergy showed a unique innate immune signature. They displayed increased amounts of particular types of circulating immune cells (monocytes and dendritic cells), and these cells produced more inflammatory cytokines both at baseline and following endotoxin exposure in relation to infants whose egg allergy naturally resolved.
Follow-up analysis showed that this unique immune composition persisted into childhood for children with persistent egg allergy, and that those with transient egg allergy had increased vitamin D levels, correlating with the changes in the innate immune profile.
These findings suggest that immune dysfunction early in life promote the persistence of food allergy later in life, and that vitamin D levels may be important in the development of natural tolerance.
This paper was featured in the Editor’s Choice section of the Journal of Allergy and Clinical Immunology
Neeland MR, Koplin JJ et al. (2018). “Early life innate immune signatures of persistent food allergy.” J Allergy Clin Immunol Sep;142(3):857-864.
Severity and threshold of peanut reactivity during hospital-based open oral food challenges: An international multicenter survey
Peanut allergy has been classical managed by avoidance. This study, which was selected for ‘Editor’s Choice’ for this issue, was a retrospective, international survey of anonymised case records from allergy centres in the UK and Ireland as well as the HealthNuts study. The case records were collated and analysed.
Of 1634 children aged 1-18 years old, 32% failed their peanut challenge. Of these, 28% reacted to 25mg, however 38% only reacted after consuming 1g or more of whole peanut. It was found that anaphylaxis was 3 times more common in teenagers than younger children, however the risk increased for all ages with increased consumption of peanut. Older children were found to be more likely to develop anaphylaxis with smaller amounts of peanut consumption (24-200mg).
This paper suggests that tailored immunotherapy programs could be considered both for children with low or high reaction thresholds, however, whether these programs can prevent heightened sensitivity and anaphylaxis requires further study.
Arkwright PD, MacMahon J et al. (2018). “Severity and threshold of peanut reactivity during hospital-based open oral food challenges: An international multicenter survey.” Pediatr Allergy Immunol Nov;29(7):754-761.
This review highlights advances in food allergy policy and research of 2017. This review summarises many of the advances in emerging treatments of food allergy and the research into these treatments. Other areas highlighted include optimization strategies for food allergy, including avoidance, management in schools, and development of new guidelines. In addition, research areas of prevention and epidemiology of food allergy were highlighted, as well as research into gastrointestinal food allergy and the increased attention on non-IgE-mediated food allergies.
Keet CA, Allen KJ. (2018). “Advances in food allergy in 2017.” J Allergy Clin Immunol Dec;142(6): 1719-1729
Early Exposure to Cow's Milk Protein Is Associated with a Reduced Risk of Cow's Milk Allergic Outcomes
Early exposure to allergenic foods is a new strategy for decreasing the risk of developing a food allergy, however the optimal time of exposure for different allergens is unknown. This study examined the relationship between exposure to cow’s milk protein in the first three months of life and the risk of cow’s milk allergy at age 12 months.
Of the 12 month-old infants in the HealthNuts study, 42% had been exposed to cow’s milk in the first three months of life. Among these, 87% had also been breastfed. Early exposure to cow’s milk protein was associated with a reduced risk of developing sensitivity to cow’s milk protein (adjusted odds ratio [aOR] = 0.44), parent-reported reactions to cow’s milk (aOR=0.44), and confirmed cow’s milk allergy (aOR=0.31) at age 12 months. Early exposure to cow’s milk was not associated with a changed risk of developing other food allergies.
Peters RL, Koplin JJ et al. (2018). “Early Exposure to Cow's Milk Protein Is Associated with a Reduced Risk of Cow's Milk Allergic Outcomes.” J Allergy Clin Immunol Pract [Epub ahead of print] doi: 10.1016/j.jaip.2018.08.038
In this study, naïve CD4+ T-cell activation was investigated in a cohort of infants with challenge-confirmed egg allergy, relative to non-atopic controls. Genome-wide DNA methylation and transcriptional profiling was used describe the pathways of naïve T-cell responsiveness to activation under neutral conditions.
From this study, it was found that children with IgE-mediated food allergy had poorer lymphoproliferative responses following CD4+ T-cell activation, relative to the control cohort. This response was due to reduced expression of cell-cycle related targets of E2F and MYC transcriptional factor networks, as well as remodelling of DNA methylation at metabolic and inflammatory genes.
Cumulative epigenetic disruption at T-cell activation genes was seen in infants who did not gain tolerance by the follow-up at age 2 or 4 years, as well as poorer lymphoproliferative responses compared to children who resolved their food allergy.
The data collected indicates epigenetic dysregulation in early stages of signal transduction through T-cell receptor complex, and is likely a reflection of pathways which are modified by gene-environment interactions in food allergy.
Martino D, Neeland MR et al. (2018). “Epigenetic dysregulation of naïve CD4 T cell activation genes in childhood food allergy.” Nature Communications Aug;9(1):3308
Identification and analysis of peanut-specific effector T and regulatory T cells in children allergic and tolerant to peanut
It has been previously proposed that food allergy arises as a result of a defect in the establishment or maintenance of oral tolerance. T regulatory cells (Tregs) have been shown to be an important component of oral tolerance, with several previous studies suggesting that defects in these cells may predispose to food allergy. The immune response seen in response to peanut in allergic patients is characterised by a release of Th2 effector cytokines (IL-4, IL-5, and IL-13), which cause B cells to produce IgE specific for peanut.
Recent data has suggested that the skin may be an important route for sensitisation to food allergens, peanut in particular, with variations in epithelial barrier genes FLG SPINK5 and DSG1 all being associated with increased risk of food allergy. This paper seeks to quantify and phenotype peanut-specific CD4+ T effector (ps-Teff) cells and peanut specific Tregs in children with and without peanut allergy or sensitisation.
Compared to non-allergic children, a higher percentage of infants with peanut allergy or sensitivity had ps-Teff cells displaying cutaneous lymphocyte antigen, suggesting that these cells were activated through the skin. Ps-Teffs from allergic school-aged children produced more IL-13 and less IFN-γ (secreted by Th1 cells) compared to non-allergic school-aged children. Allergic infants also had increased IL-13, but few IFN-γ+ ps-Teffs were detected in infants, regardless of allergic status. There was no difference in expression or activity of ps-Treg cells in infants or school aged-children, regardless of whether or not they had peanut allergy.
These results suggest that exposure to peanut through the skin can promote the development of Th2 ps-Teff cells, which promote peanut sensitivity, despite a normal number of ps-Treg cells.
Weissler KA, Rasooly M et al. (2018). “Identification and analysis of peanut-specific effector T and regulatory T cells in children allergic and tolerant to peanut.” Journal of Allergy and Clinical Immunology May;141(5);1699-1710
With IgE-mediated food allergy affecting up to one in ten Australian infants, research into strategies to prevent development of food allergy has become a key focus of public health. Currently, early introduction of allergenic foods is the most promising strategy to minimising the prevalence of food allergy, and, as a result of research supporting this, infant feeding guidelines in Australia were updated in 2016 with recommendations towards introducing allergenic foods, including peanut, by age twelve months for all infants.
There is currently debate around the best way to achieve early introduction of peanut at a population level. Countries such as the United States recommend food sensitisation screening prior to introduction of peanut in high-risk infants, which poses significant challenges as well as risks in further delaying introduction of peanut due to waiting for these tests. In Australia, screening is not recommended prior to peanut introduction, however, there is no data on the effect of either the screening or non-screening approaches on peanut introduction or reactions.
The EarlyNuts cohort is a population-based, cross-sectional study of twelve month old infants in Melbourne, with an identical sampling frame for recruitment as what has previously been used in HealthNuts. Data from the first 860 participants (recruited November 2016-October 2018) have been used to assess the consequence of the nonscreening approach to allergenic foods used in Australia.
It has been found that 88.6% of infants had been introduced to peanut by the age of twelve months, with a median age of introduction of six months. In comparison, only 28.5% of the HealthNuts cohort had been introduced to peanut at the same age, prior to the changes in the infant feeding guidelines. 76.4% of infants in the EarlyNuts cohort had consumed peanut more than four times, and 28% were eating peanut more than once a week. A researcher-administered questionnaire of parents also made note of any possible reactions, with preliminary results suggesting that 4.0% of infants consuming peanut at age twelve months had possible IgE-mediated reactions.
As seen from this data, changes in Australian infant feeding guidelines has seen a significant shift towards earlier introduction of peanut, with the majority of parents introducing their children to peanut before the age of twelve months. Upon completion of the EarlyNuts study, the effect of this trend of earlier introduction on the prevalence of challenge-proven food allergy will be able to be assessed.
Soriano VX, Peters RL et al. "Earlier ingestion of peanut after changes to infant feeding guidelines: The EarlyNuts study." J Allergy Clin Immunol. 2019 Aug 8. pii: S0091-6749(19)31028-0. doi: 10.1016/j.jaci.2019.07.032. [Epub ahead of print]
HealthNuts and SchoolNuts investigators. Skin Prick Test Predictive Values for the Outcome of Cashew Challenges in Children
Cashew has been previously reported as one of the most common tree nut allergens, with reactions that may be more severe than those caused by peanut. Despite this, cashew allergy is relatively understudied. Skin prick tests (SPTs) are often used for preliminary diagnosis of food allergy, and wheal size cut-offs with a 95% positive predictive value (PPV) are often used clinically, however the 95% PPV of only a few food allergens are known. A PPV indicates the probability that a child testing positive for food allergy in the SPT truly has the allergy.
This study aimed to determine SPT wheal sizes that would correlate to a 95% PPV for a positive food challenge for cashew, meaning that 95% of children with this particular wheal size in the SPT would go on to test positive for cashew allergy in an oral food challenge (OFC). The cohort for this study consists of participants from both the HealthNuts and SchoolNuts studies who underwent OFCs for cashew. The cashew OFCs were performed at both the four and six year follow-ups for the HealthNuts study, while the cashew OFCs were performed between the ages of ten and fourteen in the SchoolNuts study. A clinic cohort was also used, with patients who had undergone a cashew OFC as part of the allergy clinic at the Royal Children’s Hospital (RCH) and patients from the Melbourne Allergy and Children’s Centre (MACCS), also located at the RCH.
62% of OFCs were positive among the population cohort (HealthNuts and SchoolNuts participants), while 20% were positive in the clinic cohort (RCH and MACCS). From this data, a 95% PPV of a 10mm wheal was derived, indicating that of children testing positive for cashew in an SPT with a wheal of at least 10mm, 95% will test positive for cashew allergy in an OFC. Among the clinic cohort, the 95% PPV was determined to be 14mm.
Current clinical guidelines suggest an 8mm wheal to be sufficient to perform an OFC when testing for cashew allergy. However, the results of this study suggest that it may be more appropriate for the cutoff to be raised to 10-14mm, for a more accurate translation of positive SPT results to positive OFC results.
McWilliam V, Peters RL et al. “HealthNuts and SchoolNuts investigators. Skin Prick Test Predictive Values for the Outcome of Cashew Challenges in Children.”J Allergy Clin Immunol Pract. 2019 Jul 2. pii: S2213-2198(19)30590-2. doi: 10.1016/j.jaip.2019.05.057. [Epub ahead of print]
Almost two-thirds of eczema cases develop in the first twelve months of life, and, despite it being well documented that environmental food allergen exposure to eczematous skin with poor barrier function may increase the risk of food sensitisation, little research has gone into whether food allergy is associated with persistence of eczema later in life or with the incidence of late-onset eczema. This study aims to investigate a possible link between food allergy and persistence of early life eczema or development of late-onset eczema.
Participants from the HealthNuts cohort were used for this study. Children were assessed for eczema at age one and age six, with persistence eczema being defined as having eczema at both follow ups, and late-onset eczema defined as having eczema only at age six. Among the children with eczema at age one, 29.1% also had eczema at age six (persistent eczema), and among the children with no eczema at age one, 8.9% had developed late-onset eczema, and had eczema at age six.
The risk of persistent eczema increased in children with confirmed egg allergy (adjusted odds ratio [aOR] = 2.29), and in children with confirmed peanut allergy (aOR = 1.67). Children diagnosed with eczema before age six months and those that had used strong steroids also had increased risk of persistence. Sensitisation to any food at age one year was associated with increased risk of late-onset eczema (aOR = 1.79).
The reason for this association may be due to increased predisposition to atopy, however this area requires more research, especially in the difference in risk between children with food sensitisation and children with challenge-confirmed allergy.
Sasaki M, Peters RL et al. “Food allergy at 1 year predicts persistence of eczema at 6 years.” J Allergy Clin Immunol Pract. 2019 Jul - Aug;7(6):2078-2081.e6. doi: 10.1016/j.jaip.2019.02.019. Epub 2019 Feb 27. No abstract available.
It is widely known that IgE-mediated allergy is a major burden on public health, affecting up to 10% of the population, and that B-cells of the immune system play a major role in the mediation of these allergenic responses, due to their role in producing IgE. This study aims to quantify the types of circulating B-cells in infants with food allergy, and to investigate the role of cytokines (signalling chemicals produced by B-cells, which have a role in inflammation) in the development of food allergy or natural tolerance in childhood.
59 children from the HealthNuts cohort were selected for this study, with 38 egg-allergenic 1-year-olds and 21 non-allergenic 1-year-olds. Of the 38 allergenic children, 22 had acquired tolerance to egg by age 4.
It was found that egg-allergenic 1-year-olds had lower levels of circulating B-cells than their non-allergenic counterparts (2.0 × 105 cells/mL vs 2.9 × 105 cells/mL). It was also found that non-allergenic one-year-olds had a greater production of cytokine IL-10 relative to egg-allergenic one-year olds. Previous studies had shown that IL-10 produced by B-cells may have a protective function for food allergy.
It was also found that transient-allergenic children (those who had gained tolerance by age four) had a higher level of switched memory B-cells (a type of B-cell) relative to those who still were egg-allergenic at age 4, however the exact mechanism behind this remains unclear and will require further research.
Overall, it was demonstrated that, relative to non-allergenic children, egg-allergenic children had lower levels of circulating B-cells and altered cytokine production and responses, highlighting the possibility that increased activation of B-cells early in life may have a role in persistent allergenic outcomes.
Neeland MR, Martino DJ et al. (2019). “B cell phenotype and function in infants with egg allergy.” Allergy Dec 27 doi: 10.1111/all.13707
No obvious impact of caesarean delivery on childhood allergic outcomes: findings from Australian cohorts
This study aimed to examine whether caesarean delivery predicts allergic disease and impaired lung function in two population-based Australian infant cohorts, HealthNuts and the Longitudinal Study of Australian Children (LSAC).
Parent-reported asthma and eczema data were drawn from HealthNuts (n=5276, born 2006–2010) and the Longitudinal Study of Australian Children (LSAC, n=5107, born 2003–2004) at age 6–7 years, and spirometric lung function from LSAC’s Child Health CheckPoint (n=1756) at age 11–12 years.
The study included 3135 HealthNuts and 3654 LSAC children (32.2% and 30.9% born by caesarean, respectively). An association was evident between caesarean delivery and asthma at age 6–7 years in HealthNuts (adjusted OR (aOR) 1.25, 95% CI 1.00 to 1.57) but not in LSAC (aOR 1.05, 95% CI 0.86 to 1.28), while neither study showed clear associations with eczema (HealthNuts: aOR 1.09, 95% CI 0.88 to 1.35; LSAC: aOR 0.89, 95% CI 0.69 to 1.15).
Spirometric lung function parameters at age 11–12 years were similar by delivery mode. Associations were not modified by duration of breast feeding, maternal history of asthma/eczema, childcare attendance, number of older siblings or pet exposure.
Liao Z, Lamb K et al. “No obvious impact of caesarean delivery on childhood allergic outcomes: findings from Australian cohorts.” Archives of Disease in Childhood 2020 Jan 24 doi: 10.1136/archdischild-2019-317485 [Epub ahead of print] PubMed PMID: 31980422
Monitoring changes in infant feeding practices after changes to guidelines for food allergy prevention
This paper was an editorial appearing in the Medical Journal of Australia. The editorial stated: Given that no curative treatments are available in routine practice for food allergy, effective prevention strategies are critical. Modifying infant feeding practices has emerged as a key approach.
Historically, it was recommended that introducing allergenic foods to infants be delayed until after 1–3 years of age. However, evidence challenging this approach has emerged. It is hypothesised that immune-mediated sensitisation to foods may follow cutaneous – through the skin - exposure to allergens, and that timely introduction of allergenic food by the oral route induces tolerance. The current Australian infant guidelines, published in 2016, recommend that allergenic foods such as peanut and egg be introduced into the infant's diet during the first year of life.
SmartStartAllergy is a tool for promoting and monitoring community uptake of the updated infant feeding guidelines in Australia. Infant feeding practices in Australia had previously been investigated in the HealthNuts study. At this time, early introduction of peanut was not actively recommended and only 28% of infants had consumed it by 12 months of age..
The next question that urgently needs investigating is whether this early exposure to common food allergens leads to reduced rates of food allergy. The EarlyNuts study results are emuch anticipated. Early introduction of allergens is unlikely to prevent all food allergy. Therefore, clinical trials are currently underway assessing the benefit of adding other strategies, including eczema prevention, vitamin D supplementation, and modification of maternal diet during pregnancy and breastfeeding.
Peters R L, Perrett K P, Monitoring changes in infant feeding practices after changes to guidelines for food allergy prevention. MJA 212 (6), 6 April 2020
Mass cytometry reveals cellular fingerprint associated with IgE+ peanut tolerance and allergy in early life.
IgE-mediated peanut allergic is common, often serious, and usually lifelong. Not all individuals who produce peanut-specific IgE will react upon consumption of peanut and can eat the food without adverse reactions. This is known as sensitised tolerance.
This study used high-dimensional mass cytometry to define the circulating immune cell signatures associated with sensitised tolerance and clinical allergy to peanut in the first year of life. Mass cytometry enables in-depth analysis of the phenotype and functional state of immune cells at the single-cell level.
Key features of clinical peanut allergic are increased frequency of activated B cells (CD19hiHLADRhi), overproduction of TNFα and increased frequency of peanut-specific memory CD4 T cells. Infants with sensitised tolerance show reduced frequency but hyper-responsive naive CD4 T cells and an increased frequency of plasmacytoid dendritic cells.
This study demonstrates the utility and power of high-dimensional mass cytometry analysis to interrogate the cellular interactions that are associated with allergic sensitisation and clinical food allergy in the first year of life.
Neeland, Melanie R. Sandra Andorf , Monali Manohar, Diane Dunham, Shu-Chen Lyu, Thanh D. Dang, Rachel L. Peters, Kirsten P. Perrett, Mimi L.K. Tang, Richard Saffery, Jennifer J. Koplin & Kari C. Mass cytometry reveals cellular fingerprint associated with IgE+ peanut tolerance and allergy in early life. Nadeau, Nature Communications, (2020) 11:1091, https://doi.org/10.1038/s41467-020-14919-4 www.nature.com/naturecommunications
This review summarises the available literature regarding tree nut allergy prevalence and natural history. It also discusses emerging diagnostic and prognostic developments that will inform clinical management of tree nut allergy. Resolution of tree nut allergy is thought to be low, yet studies of the natural history of tree nut allergy are limited.
A comprehensive literature search was performed. It was found that tree nut allergy prevalence varies by age, region, and food allergy definition, and ranges from less than 1% to approximately 3% worldwide.
Reports on the natural history of tree nut allergy data are limited to retrospective clinical data or cross-sectional survey data of self-reported food allergy. Reported resolution ranged from 9% to 14%. Component-resolved diagnostics and basophil activation testing offer the potential to improve the diagnostic accuracy and predicted prognosis of specific tree nut allergy, but studies are limited.
It was concluded that tree nut allergy remains an understudied area of food allergy research with limited region-specific studies based on robust food allergy measures in population cohorts with longitudinal follow-up. This currently limits our understanding of tree nut allergy prognosis.
McWilliam, Vicki L, Kirsten P. Perrett, Thanh Dang, Rachel L. Peters. Prevalence and natural history of tree nut allergy. https://doi.org/10.1016/j.anai.2020.01.024 1081-1206/ 2020 Published by Elsevier Inc. on behalf of American College of Allergy, Asthma & Immunology.
This paper was a letter to the editor. Using HealthNuts data, the authors aimed to determine whether the introduction of cashew in the infant diet in the first year of life was associated with the risk of cashew allergy.
The analysis included participants with complete data on age of introduction of cashew reported at age 1 year, potential confounders considered, and cashew allergy outcomes (n = 2925 for cashew allergy and n = 2539 for cashew sensitisation). By age 12 months, 4.8% (N = 140 of 2925; 95% CI, 4.0%-5.6%) of infants had consumed cashew. At age 6 years, the prevalence of cashew sensitisation was 4.8% (95% CI, 4.0%-5.7%) and that of cashew allergy was 3.4% (95% CI, 2.8%-4.1%). These estimates differ from the estimates from previous reports from our cohort because it is restricted to those who had complete data for this analysis.
No child who ate cashew by age 12 months developed cashew allergy (0%; 95% CI, 0%-2.6%), compared with 3.6% (95% CI, 2.9%-4.4%) of those who had not consumed cashew by age 12 months. After adjustment for confounding variables, there was weak evidence that early introduction of cashew was associated with reduced odds of cashew allergy (adjusted odd ratio, 0.19; 95% CI, 0.00-1.09; P = .07). The magnitude of association was similar for cashew sensitisation, but CIs were wider (adjusted odds ratio, 0.22; 95% CI, 0.03-1.61; P = .14).
HealthNuts presented the first evidence that the early introduction of cashew may decrease the frequency of cashew allergy in a population-based cohort; however, cashew allergy and introduction was uncommon and the risk reduction could not be quantified precisely. Future clinical trials are required to assess the frequency, dose, and timing of cashew ingestion for cashew allergy prevention, and how cashew can be safely and effectively introduced with other allergenic solid foods into the infant’s diet.
Peters RL, Barret DY, Soriano VX, McWilliam V, Lowe AJ, Ponsonby A-L, Tang MLK, Dharmage SC, Gurrin LC, Koplin JJ, Perrett KP, No cashew allergy in infants introduced to cashew by age 1 year, Journal of Allergy and Clinical Immunology (2020), doi: https://doi.org/10.1016/ j.jaci.2020.07.003.
Community-based adverse food reactions and anaphylaxis in children with IgE-mediated food allergy at age 6 years: a population-based study
This paper aimed to evaluate the frequency, characteristics, and risk factors for adverse food reactions, including anaphylaxis, among food-allergic 6-year-old-children using the population-based HealthNuts study. Few studies have investigated adverse food reactions among food-allergic children in a population-based sample, which is critical for the development of evidence-based management strategies.
A total of 260 children with IgE-mediated food allergy who completed a questionnaire detailing recent adverse food reactions were included in this analysis.
Among food-allergic children, 44.6% (95% CI, 38.6%-50.8%) reported an adverse food reaction in the last 12 months and 10.8% (95% CI, 7.5%-15.2%) reported an anaphylactic reaction, although only half of these were recognised as anaphylaxis by parents. Adrenaline autoinjectors were used in 25% (4 of 16) of recognized anaphylaxis episodes. Nut allergy was associated with a reduced risk of having an adverse reaction (adjusted odds ratio, 0.3; 95% CI, 0.1-0.7). There were trends that adverse reactions were more likely in children with at least 1 parent born in Asia compared with both parents born in Australia (adjusted odds ratio, 1.9; 95% CI, 0.9-3.9), and in children with 3 or more food allergies compared with children with a single food allergy (adjusted odds ratio, 1.8; 95% CI, 0.9-3.5).
It was concluded that adverse food reactions occurred in almost half of all food-allergic 6-year-old children and anaphylaxis occurred in 1 in 10 children over a 12-month period. Anaphylaxis was poorly recognised and adrenaline autoinjectors were not used appropriately. Improved regular education on the prevention, recognition, and management of adverse food reactions is urgently needed.
Wang Y, Peters RL, Perrett KP, McWilliam VL, Tang MLK, Lowe AJ, Ponsonby A-L, Dharmage SC, Allen KJ, Koplin JJ, HealthNuts investigators. Community-based adverse food reactions and anaphylaxis in children with IgE-mediated food allergy at age 6 years: a population-based study. Journal of Allergy and Clinical Immunology: In Practice. 2020;S2213-2198(20)30715-7. doi: 10.1016/j.jaip.2020.07.008. Epub ahead of print 21 Jul 2020. PubMed PMID: 32707240 (IF: 6.966)
Associations between grass pollen exposures in utero and in early life with food allergy in 12-month-old infants
Using the HealthNuts population-based cohort of 5276 infants, this paper assessed grass pollen exposures, in utero and up to the first 6 months of life, on hen's egg, sesame and peanut allergy outcomes at 12 months. Birth during pollen seasons may influence food allergy risk but no study has assessed pollen exposure.
Cumulative pollen exposure in the first 7 days of life increased risk of peanut sensitisation aMOR (adjusted multinomial odds ratio) = 1.21 (95% CI: 1.01-1.44). Exposure between first 4-6 months of life increased risk of hen's egg aMOR = 1.02 (95% CI: 1.004-1.04) and sensitisation to all foods aMOR = 1.02 (95% CI: 1.003-1.04). Grass pollen exposure was associated with food challenge diagnosed food allergy, but only among infants with a maternal history of food allergy.
Exposure to grass pollen in the intrauterine period and infancy may be important but more studies are needed to replicate these findings.
Susanto NH, Lowe AJ, Salim A, Koplin JJ, Tang MLK, Suaini NHA, Ponsonby A-L, Allen KJ, Dharmage SC, Erbas B. Associations between grass pollen exposures in utero and in early life with food allergy in 12-month-old infants. International Journal of Environmental Health Research [Epub ahead of print 17 Jul 2020] doi: 10.1080/09603123.2020.1793920. PubMed PMID: 32677468 (IF: 2.468)
Previous research suggests that children who experience asthma may be less physically active; however, results have been inconclusive. This paper aimed to investigate whether the presence of asthma or wheeze is associated with lower physical activity levels in children, and whether sex, body mass index or earlier asthma or wheeze status modifies the association.
391 HealthNuts participants were included. Asthma and wheeze data were collected via questionnaire at age 4 and 6, and physical activity was measured through accelerometry. Using adjusted linear regression models, the cross-sectional and longitudinal associations were investigated.
It was found that there was no evidence of a difference in time spent in moderate-to-vigorous physical activity (MVPA) at age 6 years between children with and without asthma at age 4; children with asthma spent 8.3 minutes more time physically active per day (95% CI: -5.6, 22.1, P = .24) than children without asthma. Similar results were seen for children with current wheeze (5.8 minutes per day more, 95% CI: -5.9, 17.5, P = .33) or ever wheeze or asthma (7.7 minutes per day more, 95% CI: -4.8, 20.2, P = .23) at age 4 years. Comparable null results were observed in the cross-sectional analyses. Interaction with BMI could not be assessed; however, previous asthma or wheeze status and sex were not found to modify these associations.
This analysis found no evidence of asthma hindering physical activity in these young children. These results are encouraging, as they indicate that the Australian asthma and physical activity public health campaigns are being effectively communicated and adopted by the public.
Cassim R, Dharmage SC, Peters RL, Koplin JJ, Allen KJ, Tang MLK, Lowe AJ, Olds TS, Fraysse F, Milanzi E, Russell MA; HealthNuts Investigators. Are young children with asthma more likely to be less physically active? Pediatr Allergy Immunol. 2021 Feb;32(2):288-294. doi: 10.1111/pai.13383. Epub 2020 Oct 20. PMID: 32997845