The multifactorial nature of food allergy
van Ginkel, Cornelia Doriene
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van Ginkel, C. D. (2018). The multifactorial nature of food allergy. Rijksuniversiteit Groningen.
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Breastfeeding and the prevalence of allergic diseases in schoolchildren: does reverse causation matter? Pediatr Allergy Immunol. 2010;21:60–6.
19. Ito J, Fujiwara T. Breastfeeding and risk of atopic dermatitis up to the age 42 months: a birth cohort study in Japan. Ann Epidemiol. 2014;24:267–72.
20. Vlieg-boerstra BJ, Bijleveld CM, Van Der Heide S, Beusekamp BJ, Wolt-plompen SAA, Kukler J, et al. Development and vali-dation of challenge materials for double-blind, placebo- controlled food challenges in children. J Allergy Clin Immunol. 2004;113:341–6.
21. Sampson Ha, Gerth van Wijk R, Bindslev-Jensen C, Sicherer S, Teuber SS, Burks AW. et al. Standardizing double-blind, placebo- controlled oral food challenges: American Academy of Allergy, Asthma & Immunology-European Academy of Allergy and Clinical Immunology PRACTALL consensus report. J Allergy Clin Immunol. 2012;130:1260–74. 22. van den Berg ME, Flokstra-de Blok BMJ,
Vlieg-Boerstra BJ, Kerkhof M, van der Heide S, Koppelman GH, et al. Parental eczema increases the risk of double-blind, placebo-controlled reactions to milk but not to egg, peanut or hazelnut. Int Arch Allergy Immunol. 2012;158:77–83.
23. Twisk JWR. Applied multilevel analysis: a practical guide.
Cambridge: Cambridge university Press; 2006.
24. Wang D, Bakhai A. Clinical Trials. A practical guide to design, analysis, and reporting. London: Remedica; 2006. p. 480.
25. Kull I, Melen E, Alm J, Hallberg J, Svartengren M, van Hage M, et al. Breast-feeding in relation to asthma, lung function, and sensitization in young school children. J Allergy Clin Immunol. 2010;125:1013–9. 26. Brew BK, Kull I, Garden F, Almqvist C,
Bergström A, Lind T, et al. Breastfeeding,
27. Hong X, Wang G, Liu X, Kumar R, Tsai H-J, Arguelles L, et al. Gene polymorphisms, breast-feeding, and development of food sensitization in early childhood. J Allergy Clin Immunol. 2011;128:374–81.e2.
28. Kummeling I, Thijs C, Penders J, Snijders BEP, Stelma F, Reimerink J, et al. Etiology of atopy in infancy: the KOALA Birth Cohort Study. Pediatr Allergy Immunol. 2005;16:679–84. 29. Sears MR, Greene JM, Willan AR, Taylor DR,
Flannery EM, Cowan JO, et al. Long-term relation between breastfeeding and development of atopy and asthma in children and young adults: a longitudinal study. Lancet. 2002;360:901–7.
30. Saarinen KM, Juntunen-Backman K,
Järvenpää AL, Kuitunen P, Lope L, Renlund M, et al. Supplementary feeding in maternity hospitals and the risk of cow’s milk allergy: a pro-spective study of 6209 infants. J Allergy Clin Immunol. 1999;104:457–61.
31. Venter C, Pereira B, Grundy J, Clayton CB, Roberts G, Higgins B, et al. Incidence of parentally reported and clinically diagnosed food hypersensitivity in the first year of life. J Allergy Clin Immunol. 2006;117:1118–24. 32. Brouwer ML, Wolt-Plompen SA, Dubois AE,
Van Der Heide S, Jansen DF, Hoijer MA, et al. No effects of probiotics on atopic dermatitis in infancy: a randomized clinical and experimental allergy. Clin Exp Allergy. 2006;36:899–906.
33. Van ZZ, Maslin K, Dean T, Blaauw R, Venter C. The accuracy of dietary recall of infant feeding and food allergen data. J Hum Nutr Diet. 2016;29:777–85.
34. Kramer MS, Matush L, Vanilovich I, Platt R, Bogdanovich N, Sevkovskaya Z, et al. Effect of prolonged and exclusive breast feeding on risk of allergy and asthma: cluster randomised trial. Br Med J. 2007;335:815. 35. Kramer MS. Breastfeeding and allergy: the
evidence. Ann Nutr Metab. 2011;59:20–6
EFFECT OF BIRTH ORDER AND FAMILIAL
ATOPY ON FOOD ALLERGY RISK
E. BAK1 *, C.D. VAN GINKEL*1, B.J. KOLLEN2, B.M.J. FLOKSTRA-DE BLOK2, G.H.
KOPPELMAN1, A.E.J. DUBOIS1
1) University of Groningen, University Medical Center Groningen, Department of Paediatric Pulmonology and Paediatric Allergy, GRIAC Research Institute, Groningen, the Netherlands. 2) University of Groningen, University Medical Center Groningen, Department of General
Practice, GRIAC Research Institute, Groningen, The Netherlands *E. Bak and C.D. van Ginkel contributed equally to this work.
ABSTRACT
BACKGROUNDConcern about possible food allergy in family members of patients is common in pediatric practice.
OBJECTIVE
We aimed to study the effect of birth order and a positive family history of atopy on the risk of being food allergic as diagnosed by double-blind placebo-controlled food challenge (DBPCFC).
METHODS
This is a retrospective study using data from high-risk children seen in a tertiary care center. All patients who underwent DBPCFCs as a part of routine care because of suspected food allergy between 01-01-2001 and 01-03-2015 at the University Medical Center Groningen were included. The data was analyzed by logistic regression analysis.
RESULTS
A total of 1,029 children were included. Being first-born was associated with being sensitized more frequently compared to subsequently born children after correction for confounders (OR= 1.64, CI=1.15-2.34, p<0.01). However, being born first showed no significant
association with clinical reactivity to foods (OR=0.87, CI=0.66-1.14, p=0.31) and no
confounders were identified. There was no association between a positive family history of atopy and more frequent sensitization to foods or clinical reactivity to foods
CONCLUSIONS
In a population from a tertiary care center, being the first-born child increases the chance of being sensitized to foods but has no significant association with the chance of being clinically reactive to foods. Coming from an atopic family influences neither the risk of being
sensitized nor the risk of being clinically reactive to foods. Family history is thus of limited value in the management of food allergic children in tertiary care.
ABBREVIATIONS
SPT Skin-prick testing
RAST-test Radioallergosorbent assay test
DBPCFC Double-blind placebo-controlled challenges
SIgE Specific Immuno globulin E
HIGHLIGHTS
1. Concern about possible food allergy in family members of patients is common in pediatric practice.
2. Being first-born increases the chance of being sensitized to foods but has no significant association with the chance of being clinically reactive to foods. Coming from an atopic family influences neither risk.
3. Family history is of limited value in the management of food allergic children in tertiary care.
Chap
ter 6
ABSTRACT
BACKGROUNDConcern about possible food allergy in family members of patients is common in pediatric practice.
OBJECTIVE
We aimed to study the effect of birth order and a positive family history of atopy on the risk of being food allergic as diagnosed by double-blind placebo-controlled food challenge (DBPCFC).
METHODS
This is a retrospective study using data from high-risk children seen in a tertiary care center. All patients who underwent DBPCFCs as a part of routine care because of suspected food allergy between 01-01-2001 and 01-03-2015 at the University Medical Center Groningen were included. The data was analyzed by logistic regression analysis.
RESULTS
A total of 1,029 children were included. Being first-born was associated with being sensitized more frequently compared to subsequently born children after correction for confounders (OR= 1.64, CI=1.15-2.34, p<0.01). However, being born first showed no significant
association with clinical reactivity to foods (OR=0.87, CI=0.66-1.14, p=0.31) and no
confounders were identified. There was no association between a positive family history of atopy and more frequent sensitization to foods or clinical reactivity to foods
CONCLUSIONS
In a population from a tertiary care center, being the first-born child increases the chance of being sensitized to foods but has no significant association with the chance of being clinically reactive to foods. Coming from an atopic family influences neither the risk of being
sensitized nor the risk of being clinically reactive to foods. Family history is thus of limited value in the management of food allergic children in tertiary care.
ABBREVIATIONS
SPT Skin-prick testing
RAST-test Radioallergosorbent assay test
DBPCFC Double-blind placebo-controlled challenges
SIgE Specific Immuno globulin E
HIGHLIGHTS
1. Concern about possible food allergy in family members of patients is common in pediatric practice.
2. Being first-born increases the chance of being sensitized to foods but has no significant association with the chance of being clinically reactive to foods. Coming from an atopic family influences neither risk.
3. Family history is of limited value in the management of food allergic children in tertiary care.
INTRODUCTION
Atopic disorders are known to cluster in families and a positive family history of allergic diseases is generally thought to be associated with an increased risk of allergy in patients in clinical practice.1 Also, birth order has been shown to be important in allergic diseases, with
studies showing an increased risk of atopic eczema, asthma and hay fever, and sensitization to inhalant allergens in children born first compared to their later-born siblings.2 In a review
by Karmaus and Botezan, 53 studies of allergic diseases (excluding food allergy) were described, of which 48 found a decrease in atopic disorders in children having more older siblings, while only three studies reported the opposite effect.2 Despite this knowledge, there
is limited information on whether these factors are also of importance to the risk of food allergy manifesting as either sensitization or clinical reactivity to allergenic foods, or both. In clinical practice, patients are frequently asked about their family history regarding allergies, including having brothers and/or sisters with allergic disorders. In food allergy, relatively few studies can be found on the effect of a positive family history on the chance of being allergic to foods.3 A previous study found 1.4 fold increase in the risk of food allergy in the child when
having a single family member with a history of allergic disease, compared to having no allergic family members.2 Another study found a five-fold increase of the risk of peanut allergy for a
child with a peanut allergic sibling or parent.4 A subsequent twin study showed a likelihood of
64% for being peanut allergic for a child of whom its monozygotic twin was allergic to peanut compared to 6.8% for dizygotic twins.5 In both studies, peanut allergy was diagnosed by means
of a questionnaire, skin prick testing (SPT) and radioallergosorbent assay (RAST-test) and not with double-blind placebo-controlled food challenges (DBPCFCs). It has previously been shown that the former methodshave high false positive rates compared to diagnosis by DBPCFCs and these studies might therefore be accurate regarding the familial clustering of sensitization but inaccurate with respect to clinical reactivity to foods.6
There are currently no studies on the effect of being first-born or having older siblings on the chance of being food allergic where this is ascertained by means of a DBPCFC. This study thus aimed firstly to study the effect of birth order on sensitization to foods and food allergy as diagnosed by DBPCFC. Secondly, the relationship between a positive family history of atopic disorders, specifically food allergy, and these food allergic outcomes was studied.
METHODS
The study design was a retrospective study using a population from a pediatric tertiary care center. All patients who underwent DBPCFCs as a part of routine care because of suspected food allergy between 01-01-2001 and 01-03-2015 at the University Medical Center Groningen were included. There were no exclusion criteria for DBPCFCs except refusal to undergo the test, which was the case in < 2% of cases. All interpretable DBPCFCs with both positive and negative results were included. Prior to the challenge, information on the patients was obtained by interviewing patients and their parents. This information was collected by a trained allergy nurse and was recorded in an electronic database. This study was deemed
exempt from medical ethical approval by our institutional Medical Ethical Committee. The DBPCFCs were performed following previously published procedures and protocols.7, 8 DEFINITION OF VARIABLES
Clinical reactivity: Children underwent DBPCFCs with the foods suspected from the history. In
children having negative DBPCFCs, testing continued until all suspected foods were excluded as a cause of previous reactions. Negative DBPCFCs were confirmed by open food challenges and/or reintroduction of the food(s) into the diet of the child. Following positive tests, further testing was abbreviated to accommodate the most relevant foods in a practical number of sessions. Children were defined as being clinically reactive when they had a positive DBPCFC to at least one food. Children were defined as being tolerant when they had only negative outcomes of the DBPCFCs.
Sensitization: Sensitization to foods was determined by ImmunoCap RAST (Thermo
Fisher Scientific, Uppsala, Sweden). The variable ‘sIgE’ (specific immunoglobulin E) was converted into a dichotomous variable (sensitized versus not sensitized) since it was not normally distributed and as a dichotomous variable it facilitated interpretation of the results. SIgE was determined to all foods suspected from the history. SIgE results of ≥0.35 kU/l were considered positive. Patients were defined as being sensitized when they had a positive sIgE test to at least one food.
Siblings: Birth order was treated as a categorical variable. Parents of the patient were asked how many siblings were present at the time of birth of the child included in the study (i.e. the proband). The number of older siblings at the time of birth was not normally distributed. Therefore, this variable was recoded into a new dichotomous variable in which being the first-born child formed one group and being the second to the sixth child was merged into another group giving comparable numbers of study subjects in each group. Sibling pairs were identified within the database by last name and address prior to anonymization. The sibling tested first was defined as the index child. If siblings were tested on the same date, the oldest child was defined as being the index child. Sibling pairs were excluded if one of them had an uncertain test result or did not complete the DBPCFC or had a positive open food challenge (OFC) but no follow up DBPCFC to the same food confirming the diagnosis, since such cases have a high risk of being false-positive.6
History of atopic disorders: Characteristics such as atopic (co)morbidities of the child
and family were collected as part of the routine history before challenge testing was carried out. Children were defined as having a family history of any food allergy, asthma, atopic eczema or rhinoconjunctivitis if this was reported by at least one of the parents and/or brothers/sisters. Children were defined as not having such a family history if none of the parents and brothers/sisters reported any atopic morbidity and when the information of at least both parents was available since the variable of brothers/sisters was missing for children with no brothers or sisters.
Chap
ter 6
INTRODUCTION
Atopic disorders are known to cluster in families and a positive family history of allergic diseases is generally thought to be associated with an increased risk of allergy in patients in clinical practice.1 Also, birth order has been shown to be important in allergic diseases, with
studies showing an increased risk of atopic eczema, asthma and hay fever, and sensitization to inhalant allergens in children born first compared to their later-born siblings.2 In a review
by Karmaus and Botezan, 53 studies of allergic diseases (excluding food allergy) were described, of which 48 found a decrease in atopic disorders in children having more older siblings, while only three studies reported the opposite effect.2 Despite this knowledge, there
is limited information on whether these factors are also of importance to the risk of food allergy manifesting as either sensitization or clinical reactivity to allergenic foods, or both. In clinical practice, patients are frequently asked about their family history regarding allergies, including having brothers and/or sisters with allergic disorders. In food allergy, relatively few studies can be found on the effect of a positive family history on the chance of being allergic to foods.3 A previous study found 1.4 fold increase in the risk of food allergy in the child when
having a single family member with a history of allergic disease, compared to having no allergic family members.2 Another study found a five-fold increase of the risk of peanut allergy for a
child with a peanut allergic sibling or parent.4 A subsequent twin study showed a likelihood of
64% for being peanut allergic for a child of whom its monozygotic twin was allergic to peanut compared to 6.8% for dizygotic twins.5 In both studies, peanut allergy was diagnosed by means
of a questionnaire, skin prick testing (SPT) and radioallergosorbent assay (RAST-test) and not with double-blind placebo-controlled food challenges (DBPCFCs). It has previously been shown that the former methodshave high false positive rates compared to diagnosis by DBPCFCs and these studies might therefore be accurate regarding the familial clustering of sensitization but inaccurate with respect to clinical reactivity to foods.6
There are currently no studies on the effect of being first-born or having older siblings on the chance of being food allergic where this is ascertained by means of a DBPCFC. This study thus aimed firstly to study the effect of birth order on sensitization to foods and food allergy as diagnosed by DBPCFC. Secondly, the relationship between a positive family history of atopic disorders, specifically food allergy, and these food allergic outcomes was studied.
METHODS
The study design was a retrospective study using a population from a pediatric tertiary care center. All patients who underwent DBPCFCs as a part of routine care because of suspected food allergy between 01-01-2001 and 01-03-2015 at the University Medical Center Groningen were included. There were no exclusion criteria for DBPCFCs except refusal to undergo the test, which was the case in < 2% of cases. All interpretable DBPCFCs with both positive and negative results were included. Prior to the challenge, information on the patients was obtained by interviewing patients and their parents. This information was collected by a trained allergy nurse and was recorded in an electronic database. This study was deemed
exempt from medical ethical approval by our institutional Medical Ethical Committee. The DBPCFCs were performed following previously published procedures and protocols.7, 8 DEFINITION OF VARIABLES
Clinical reactivity: Children underwent DBPCFCs with the foods suspected from the history. In
children having negative DBPCFCs, testing continued until all suspected foods were excluded as a cause of previous reactions. Negative DBPCFCs were confirmed by open food challenges and/or reintroduction of the food(s) into the diet of the child. Following positive tests, further testing was abbreviated to accommodate the most relevant foods in a practical number of sessions. Children were defined as being clinically reactive when they had a positive DBPCFC to at least one food. Children were defined as being tolerant when they had only negative outcomes of the DBPCFCs.
Sensitization: Sensitization to foods was determined by ImmunoCap RAST (Thermo
Fisher Scientific, Uppsala, Sweden). The variable ‘sIgE’ (specific immunoglobulin E) was converted into a dichotomous variable (sensitized versus not sensitized) since it was not normally distributed and as a dichotomous variable it facilitated interpretation of the results. SIgE was determined to all foods suspected from the history. SIgE results of ≥0.35 kU/l were considered positive. Patients were defined as being sensitized when they had a positive sIgE test to at least one food.
Siblings: Birth order was treated as a categorical variable. Parents of the patient were asked how many siblings were present at the time of birth of the child included in the study (i.e. the proband). The number of older siblings at the time of birth was not normally distributed. Therefore, this variable was recoded into a new dichotomous variable in which being the first-born child formed one group and being the second to the sixth child was merged into another group giving comparable numbers of study subjects in each group. Sibling pairs were identified within the database by last name and address prior to anonymization. The sibling tested first was defined as the index child. If siblings were tested on the same date, the oldest child was defined as being the index child. Sibling pairs were excluded if one of them had an uncertain test result or did not complete the DBPCFC or had a positive open food challenge (OFC) but no follow up DBPCFC to the same food confirming the diagnosis, since such cases have a high risk of being false-positive.6
History of atopic disorders: Characteristics such as atopic (co)morbidities of the child
and family were collected as part of the routine history before challenge testing was carried out. Children were defined as having a family history of any food allergy, asthma, atopic eczema or rhinoconjunctivitis if this was reported by at least one of the parents and/or brothers/sisters. Children were defined as not having such a family history if none of the parents and brothers/sisters reported any atopic morbidity and when the information of at least both parents was available since the variable of brothers/sisters was missing for children with no brothers or sisters.
STATISTICAL ANALYSIS
Analyses were performed by using SPSS 22 (IBM, Chicago, USA) and for all tests, a two-tailed significance level of p<0.05 was used. Associations were tested by logistic regression analysis. The data was checked for conformity to the assumptions of logistic regression analysis such as independence of errors and linearity of independent variables. All associations were tested for possible confounding by factors chosen from the literature, including age, gender, co-existent rhinoconjunctivitis, asthma and atopic eczema and the atopic score of the parents. 9-12 Factors changing the beta coefficient by 10% or more were considered to be confounders.12
The atopic score of the parents is a variable in which points were added for each atopic disease (food allergy, rhinoconjunctivitis, asthma or atopic eczema) the parents of the child had, giving a score with a range of 0 - 8.13 The latter was only tested as a potential confounder in the
analyses regarding the birth order effect.
RESULTS
STUDY POPULATIONA total of 1029 children were included in this study. The median age of the population was 65.0 months (5.4 years) and the majority of our population was male (61.3%). Many of the subjects had a history of asthma (43.1%), rhinoconjunctivitis (34.2%) and/or eczema (84%), often in combination. Of the 1029 children in this study, 752 were sensitized to foods and 589 were clinically reactive to at least one food. The majority of these 589 children who were clinically reactive, had a positive DBPCFC for peanut (n=257), cow’s milk (n=146), cashew (n=103), hen’s egg (n=87) and hazelnut (n=75) (see table 1). Patient characteristics are presented in table 1.
Patient characteristics Missing Age in months: median
Range 65.0 4-216 Male, n (%) 631 (61.3) Asthma in history, n (%) 443 (43.1%) 22 Rhinoconjunctivitis in history, n (%) 352 (34.2) 42 Atopic eczema in history, n (%) 864 (84.0%) 19 Sensitized to any food, n (%) 752 (73.1) 59 Family history of:
Food allergy, n (%) 309 (29.9) 27 Asthma, n (%) 395 (38.4) 159 Rhinoconjunctivitis, n (%) 570 (55.4) 372 Eczema, n (%) 919 (89.3) 110
DBPCFC:
Positive DBPCFC to any food, n (%) 589 (57.2)
Food Positive DBPCFC Negative DBPCFC Total Peanut, n (%) 257(55.5) 206(44.5) 463 Cow’s milk, n (%) 146(45.3) 176(54.7) 322 Cashew, n (%) 103(75.2) 34(24.8) 137 Hens egg, n (%) 87(44.2) 110(55.8) 197 Hazelnut, n (%) 75(45.5) 90(54.5) 165 Birth order: First-born child, n (%) 483 (48.7) Later-born child, n (%) 508 (51.2) TABLE 1.
Descriptive characteristics of the study population. DBPCFC= double-blind placebo-controlled food challenge
FAMILY HISTORY
Forty-two sibling pairs were identified. Of the ten children who underwent an OFC, six children of 5 sibling pairs had a positive OFC without a confirmatory DBPCFC, and they were therefore excluded from this analysis. Four children of four sibling pairs had an uncertain DBPCFC result or did not complete the DBPCFC. Therefore, thirty-two pairs met the inclusion criteria. As shown in table 2, the prevalence of clinical reactivity did not differ significantly among siblings with and without a clinically reactive index sibling (OR=0.83, CI=0.20-3.56, p=0.81).
Chap
ter 6
STATISTICAL ANALYSIS
Analyses were performed by using SPSS 22 (IBM, Chicago, USA) and for all tests, a two-tailed significance level of p<0.05 was used. Associations were tested by logistic regression analysis. The data was checked for conformity to the assumptions of logistic regression analysis such as independence of errors and linearity of independent variables. All associations were tested for possible confounding by factors chosen from the literature, including age, gender, co-existent rhinoconjunctivitis, asthma and atopic eczema and the atopic score of the parents. 9-12 Factors changing the beta coefficient by 10% or more were considered to be confounders.12
The atopic score of the parents is a variable in which points were added for each atopic disease (food allergy, rhinoconjunctivitis, asthma or atopic eczema) the parents of the child had, giving a score with a range of 0 - 8.13 The latter was only tested as a potential confounder in the
analyses regarding the birth order effect.
RESULTS
STUDY POPULATIONA total of 1029 children were included in this study. The median age of the population was 65.0 months (5.4 years) and the majority of our population was male (61.3%). Many of the subjects had a history of asthma (43.1%), rhinoconjunctivitis (34.2%) and/or eczema (84%), often in combination. Of the 1029 children in this study, 752 were sensitized to foods and 589 were clinically reactive to at least one food. The majority of these 589 children who were clinically reactive, had a positive DBPCFC for peanut (n=257), cow’s milk (n=146), cashew (n=103), hen’s egg (n=87) and hazelnut (n=75) (see table 1). Patient characteristics are presented in table 1.
Patient characteristics Missing Age in months: median
Range 65.0 4-216 Male, n (%) 631 (61.3) Asthma in history, n (%) 443 (43.1%) 22 Rhinoconjunctivitis in history, n (%) 352 (34.2) 42 Atopic eczema in history, n (%) 864 (84.0%) 19 Sensitized to any food, n (%) 752 (73.1) 59 Family history of:
Food allergy, n (%) 309 (29.9) 27 Asthma, n (%) 395 (38.4) 159 Rhinoconjunctivitis, n (%) 570 (55.4) 372 Eczema, n (%) 919 (89.3) 110
DBPCFC:
Positive DBPCFC to any food, n (%) 589 (57.2)
Food Positive DBPCFC Negative DBPCFC Total Peanut, n (%) 257(55.5) 206(44.5) 463 Cow’s milk, n (%) 146(45.3) 176(54.7) 322 Cashew, n (%) 103(75.2) 34(24.8) 137 Hens egg, n (%) 87(44.2) 110(55.8) 197 Hazelnut, n (%) 75(45.5) 90(54.5) 165 Birth order: First-born child, n (%) 483 (48.7) Later-born child, n (%) 508 (51.2) TABLE 1.
Descriptive characteristics of the study population. DBPCFC= double-blind placebo-controlled food challenge
FAMILY HISTORY
Forty-two sibling pairs were identified. Of the ten children who underwent an OFC, six children of 5 sibling pairs had a positive OFC without a confirmatory DBPCFC, and they were therefore excluded from this analysis. Four children of four sibling pairs had an uncertain DBPCFC result or did not complete the DBPCFC. Therefore, thirty-two pairs met the inclusion criteria. As shown in table 2, the prevalence of clinical reactivity did not differ significantly among siblings with and without a clinically reactive index sibling (OR=0.83, CI=0.20-3.56, p=0.81).
TABLE 2.
Prevalence of clinical reactivity among sibling pairs. DBPCFC= Double-blind, placebo-controlled food challenge, OFC= Open food challenge.
A positive family history of food allergy, asthma and/or atopic eczema was generally not associated with more frequent sensitization to a food (data not shown). An exception to this was the finding that children with a family history of rhinoconjunctivitis were less often sensitised to egg, cow’s milk, peanut, hazelnut and/or cashew (77.8% compared to 81.3% in children with and without a family history of rhinoconjunctivitis, respectively, OR=1.79, 95%CI=1.58-2.00, p<0.01). Furthermore, there was no association between a positive family history of food allergy or any other atopic morbidity with clinical reactivity to foods, with the exception of a positive association between a family history of atopic eczema with clinical reactivity to cow’s milk (OR=1.83, 95%CI=1.15-2.94, p=0.01). No confounders were identified in this association, including atopic comorbidities such as a history of atopic eczema in the child.
BIRTH ORDER
Approximately 48.7% (n=483) of the included children was first-born. Being first-born was associated with being sensitized more often to at least one food compared to subsequently born children after correction for the confounding effect of age, asthma, and atopic eczema (unadjusted OR for first-born children=0.93, CI=0.15-5.61, p=0.93, adjusted OR for first-born children= 1.64, CI=1.15-2.34, p=0.01), see table 3 and figure1.
Sibling clinically
reactive based on DBPCFC (n=11)
Sibling not allergic as shown by DBPCFC (n=11) or OFC (n=5). Total n=16 Index sibling clinically reactive to at
least one food based on DBPCFC n=22
11(50.0%) 11 (50.0%)
Index sibling tolerant to all foods based on DBPCFC or OFC (n=8 and 3 respectively). Total n=11 6 (55.0%) 5 (45.0%) OR 95% CI p-value First-born 1.64 1.15-2.34 <0.01 Age in months 1.01 1.00-1.01 <0.01 Atopic eczema 2.18 1.39-3.41 <0.01 Asthma 2.49 1.65-3.77 <0.01 TABLE 3.
The association between being first-born and a higher risk of being sensitized to at least one food with involved confounders. OR= odds ratio, CI=95% confidence interval.
In logistic regression analysis, birth order showed no significant association with clinical reactivity (OR=0.87, CI=0.66-1.14, p=0.31) and no confounders were identified.
Chap
ter 6
TABLE 2.
Prevalence of clinical reactivity among sibling pairs. DBPCFC= Double-blind, placebo-controlled food challenge, OFC= Open food challenge.
A positive family history of food allergy, asthma and/or atopic eczema was generally not associated with more frequent sensitization to a food (data not shown). An exception to this was the finding that children with a family history of rhinoconjunctivitis were less often sensitised to egg, cow’s milk, peanut, hazelnut and/or cashew (77.8% compared to 81.3% in children with and without a family history of rhinoconjunctivitis, respectively, OR=1.79, 95%CI=1.58-2.00, p<0.01). Furthermore, there was no association between a positive family history of food allergy or any other atopic morbidity with clinical reactivity to foods, with the exception of a positive association between a family history of atopic eczema with clinical reactivity to cow’s milk (OR=1.83, 95%CI=1.15-2.94, p=0.01). No confounders were identified in this association, including atopic comorbidities such as a history of atopic eczema in the child.
BIRTH ORDER
Approximately 48.7% (n=483) of the included children was first-born. Being first-born was associated with being sensitized more often to at least one food compared to subsequently born children after correction for the confounding effect of age, asthma, and atopic eczema (unadjusted OR for first-born children=0.93, CI=0.15-5.61, p=0.93, adjusted OR for first-born children= 1.64, CI=1.15-2.34, p=0.01), see table 3 and figure1.
Sibling clinically
reactive based on DBPCFC (n=11)
Sibling not allergic as shown by DBPCFC (n=11) or OFC (n=5). Total n=16 Index sibling clinically reactive to at
least one food based on DBPCFC n=22
11(50.0%) 11 (50.0%)
Index sibling tolerant to all foods based on DBPCFC or OFC (n=8 and 3 respectively). Total n=11 6 (55.0%) 5 (45.0%) OR 95% CI p-value First-born 1.64 1.15-2.34 <0.01 Age in months 1.01 1.00-1.01 <0.01 Atopic eczema 2.18 1.39-3.41 <0.01 Asthma 2.49 1.65-3.77 <0.01 TABLE 3.
The association between being first-born and a higher risk of being sensitized to at least one food with involved confounders. OR= odds ratio, CI=95% confidence interval.
In logistic regression analysis, birth order showed no significant association with clinical reactivity (OR=0.87, CI=0.66-1.14, p=0.31) and no confounders were identified.
FIGURE 1
Percentage of clinical reactivity to food and IgE sensitization to foods according to birth order. Birth order was studied as a dichotomous variable comparing first-born children to subsequently-born children. The percentages of clinical reactivity to foods and sensitization were 55.0% and 60.0% compared to 76.8% and 82.7%, respectively.
DISCUSSION
This study shows that in high-risk children suspected of food allergy, being first-born is associated with an increased risk of sensitization to foods but not with an increased risk of clinical food allergy. In the context of children tested for food allergy in a tertiary setting, a positive family history of atopic disorders has no influence on the risk of sensitization to foods, with the exception of a history of rhinoconjunctivitis, which paradoxically decreases this risk. In addition, a positive family history of atopic eczema was associated with greater clinical reactivity to cow’s milk as we showed previously.14 Having a positive family history of food
allergy has little influence on the risk of becoming sensitized or allergic to foods.This study is the first of its kind using the DBPCFC, the diagnostic gold standard for food allergy, to investigate the influence of birth order and family history. Kusunoki et al also found a lower rate of food allergy in second- and third- or later-born children compared with the first-born child using a questionnaire to diagnose food allergy.15 However, questionnaire-based studies
are prone to overestimating the prevalence of food allergy as the result of over-reporting false-positive cases, as has previously been shown.8, 16, 17 This methodological difference
strengthens our results compared to those of Kusunoki et al.15
Our results are in agreement with the results of Gupta et al, showing that there is only a low risk of sibling-associated food allergy.18 They enrolled 1,120 children and defined food
allergy by history, food-specific IgE or a skin prick test and showed that only 13.6% of siblings
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
1st born 2nd born 3rd born 4th born 5th born
Pe rc ent ag e of inde pe nde nt gr oups Birth order-->
Clinical reactivity and IgE sensitization to foods
according to birth order
% clinical reactivity % sensitization
sensitization without reactivity was more common among siblings.18 Here we confirm this
finding with in a population from a tertiary care center with DBPCFC testing: siblings of individuals with DBPCFC-proven food allergy have no greater risk of being food allergic than siblings of individuals in whom DBPCFCs refuted the diagnosis of food allergy. This implies that children with a sibling with confirmed food allergy should undergo DBPCFC based on clinical suspicion alone, as the diagnosis cannot be anticipated or inferred based on the positive test of a sibling.
Observations on the decreased prevalence of allergic disease with increasing numbers of older siblings led to the formulation of the hygiene hypothesis by Strachan, which stated that increased exposure to microbes from older siblings had a beneficial effect on the development of allergic disease.19-21. This was later added to by Penders, who showed that
older siblings impact infant gut microbiota, which are associated with changes in risk of allergy in some studies.22, 23 Whether differences in microbiota play a role in the differences in
sensitization to foods seen in our population requires further study.
The results presented here confirm our previous study on the association of parental atopy with food allergy in children, and the association of parental atopic eczema with cow’s milk allergy in particular, this time in a larger population.14 As we suggested there, cow’s milk is
often the first food given to infants and is often the first food allergy to manifest itself in childhood. Atopic eczema is often the first atopic disorder to manifest in infants and young children, and increased skin porosity is thought to be important for the development of food allergy.19 Thus genetic factors related to atopic eczema may be relatively more important to
the development of allergy to cow’s milk than to other foods.13, 14, 24 By implication, this may
result in greater influence of parental atopy on the risk of clinical allergic reactivity to cow’s milk than allergy to other foods.
We have no explanation for the surprising finding that children with a family history of rhinoconjunctivitis were less often sensitised to egg, cow’s milk, peanut, hazelnut and/or cashew (77.8% compared to 81.3% in children with and without a family history of rhinoconjunctivitis, respectively). It seems unlikely that there could be a protective mechanism in having a family history of rhinoconjunctivitis with regard to sensitisation. Most data suggest that parental allergic diseases are generally a risk factor for the development of allergic diseases in the child.25, 26 In view of the borderline significance of this finding, this may
have been a chance finding and no definitive conclusions should be drawn pending further studies.
This data suggests that the effect of older siblings is greater for sensitization to foods than clinical reactivity to foods and may even be limited to the former. Similar results have been observed in a family study of asthma, where sibling order was associated with sensitization to aeroallergens, but not with clinical asthma.27 Also, a previous study of atopic
eczema showed that patients with atopic eczema were more likely to be asymptomatically sensitized to foods than children without atopic eczema.24 Thus, pathways leading to
Chap
ter 6
FIGURE 1
Percentage of clinical reactivity to food and IgE sensitization to foods according to birth order. Birth order was studied as a dichotomous variable comparing first-born children to subsequently-born children. The percentages of clinical reactivity to foods and sensitization were 55.0% and 60.0% compared to 76.8% and 82.7%, respectively.
DISCUSSION
This study shows that in high-risk children suspected of food allergy, being first-born is associated with an increased risk of sensitization to foods but not with an increased risk of clinical food allergy. In the context of children tested for food allergy in a tertiary setting, a positive family history of atopic disorders has no influence on the risk of sensitization to foods, with the exception of a history of rhinoconjunctivitis, which paradoxically decreases this risk. In addition, a positive family history of atopic eczema was associated with greater clinical reactivity to cow’s milk as we showed previously.14 Having a positive family history of food
allergy has little influence on the risk of becoming sensitized or allergic to foods.This study is the first of its kind using the DBPCFC, the diagnostic gold standard for food allergy, to investigate the influence of birth order and family history. Kusunoki et al also found a lower rate of food allergy in second- and third- or later-born children compared with the first-born child using a questionnaire to diagnose food allergy.15 However, questionnaire-based studies
are prone to overestimating the prevalence of food allergy as the result of over-reporting false-positive cases, as has previously been shown.8, 16, 17 This methodological difference
strengthens our results compared to those of Kusunoki et al.15
Our results are in agreement with the results of Gupta et al, showing that there is only a low risk of sibling-associated food allergy.18 They enrolled 1,120 children and defined food
allergy by history, food-specific IgE or a skin prick test and showed that only 13.6% of siblings
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
1st born 2nd born 3rd born 4th born 5th born
Pe rc ent ag e of inde pe nde nt gr oups Birth order-->
Clinical reactivity and IgE sensitization to foods
according to birth order
% clinical reactivity % sensitization
sensitization without reactivity was more common among siblings.18 Here we confirm this
finding with in a population from a tertiary care center with DBPCFC testing: siblings of individuals with DBPCFC-proven food allergy have no greater risk of being food allergic than siblings of individuals in whom DBPCFCs refuted the diagnosis of food allergy. This implies that children with a sibling with confirmed food allergy should undergo DBPCFC based on clinical suspicion alone, as the diagnosis cannot be anticipated or inferred based on the positive test of a sibling.
Observations on the decreased prevalence of allergic disease with increasing numbers of older siblings led to the formulation of the hygiene hypothesis by Strachan, which stated that increased exposure to microbes from older siblings had a beneficial effect on the development of allergic disease.19-21. This was later added to by Penders, who showed that
older siblings impact infant gut microbiota, which are associated with changes in risk of allergy in some studies.22, 23 Whether differences in microbiota play a role in the differences in
sensitization to foods seen in our population requires further study.
The results presented here confirm our previous study on the association of parental atopy with food allergy in children, and the association of parental atopic eczema with cow’s milk allergy in particular, this time in a larger population.14 As we suggested there, cow’s milk is
often the first food given to infants and is often the first food allergy to manifest itself in childhood. Atopic eczema is often the first atopic disorder to manifest in infants and young children, and increased skin porosity is thought to be important for the development of food allergy.19 Thus genetic factors related to atopic eczema may be relatively more important to
the development of allergy to cow’s milk than to other foods.13, 14, 24 By implication, this may
result in greater influence of parental atopy on the risk of clinical allergic reactivity to cow’s milk than allergy to other foods.
We have no explanation for the surprising finding that children with a family history of rhinoconjunctivitis were less often sensitised to egg, cow’s milk, peanut, hazelnut and/or cashew (77.8% compared to 81.3% in children with and without a family history of rhinoconjunctivitis, respectively). It seems unlikely that there could be a protective mechanism in having a family history of rhinoconjunctivitis with regard to sensitisation. Most data suggest that parental allergic diseases are generally a risk factor for the development of allergic diseases in the child.25, 26 In view of the borderline significance of this finding, this may
have been a chance finding and no definitive conclusions should be drawn pending further studies.
This data suggests that the effect of older siblings is greater for sensitization to foods than clinical reactivity to foods and may even be limited to the former. Similar results have been observed in a family study of asthma, where sibling order was associated with sensitization to aeroallergens, but not with clinical asthma.27 Also, a previous study of atopic
eczema showed that patients with atopic eczema were more likely to be asymptomatically sensitized to foods than children without atopic eczema.24 Thus, pathways leading to
Our data also indicates that these processes may be specific for each allergenic food, as shown by the association between a family history of atopic eczema with cow’s milk allergy. Thus, in addition to many other epidemiological and clinical differences between allergies to different foods, the differences in risk factors for certain foods suggest that it is probably illusory to think that the development of different food allergies follows a common or single pathway.
This study has some limitations. The population used in this study consisted of high-risk children who were referred to a tertiary clinic with the suspicion of food allergy and had a DBPCFC as part of routine care. It is therefore difficult to compare these results with the general population where atopic clustering of sensitization and related diseases will be much more apparent. The study was retrospective. However, all historical information was obtained before the performance of the food challenges, thus reducing recall bias based on challenge test outcome. We did not analyze SPTs, which may have underestimated sensitization rates. However, it has been shown that the concordance between sIgE antibody assays and SPT results is between 85% and 95% depending on the allergen being tested and the method used to detect specific IgE.28 Therefore; it is unlikely that this possible misclassification of
sensitization had a significant impact on our results. It would be desirable to replicate these findings in a general population cohort to ascertain the generalizability of our conclusions. Finally, future studies should involve larger study populations to study differences in the development of sensitization and clinical reactivity to different foods separately.
CONCLUSIONS
There is a birth order effect with regard to sensitization to foods, but this effect is less or absent with regard to clinical food allergy. In the context of children tested for food allergy in a tertiary setting, having a positive family history of food allergy has little influence on the risk of becoming sensitized or allergic to foods. Thus, in tertiary care, the management of individuals with or without food allergic siblings or relatives should not differ from that of other individuals.
REFERENCES
1. Ober, C. & Yao, T.-C. The genetics of asthma and allergic disease: a 21st-century perspective. Immunol. Rev. 242, 10–30 (2011).
2. Karmaus W. & Botezan C. Does a higher number of siblings protect against the development of allergy and asthma? A review. J. Epidemiol. Community Health 56, 209–217 (2002).
3. Karmaus, W. et al. Invited commentary: Sibship effects and a call for a comparative disease approach. Am. J. Epidemiol. 162, 133–139 (2005).
4. Hourihane, J. O., Dean, T. P. & Warner, J. O. Peanut allergy in relation to heredity, maternal diet, and other atopic diseases: results of a questionnaire survey, skin prick testing, and food challenges. BMJ 313, 518– 21 (1996).
5. Sicherer, S. H. et al. Genetics of peanut allergy: a twin study. J. Allergy Clin. Immunol. 106, 53–6 (2000).
6. Brouwer, M. L. et al. No effects of probiotics on atopic dermatitis in infancy : a
randomized Clinical and Experimental Allergy. Clin. Exp. Allergy 36, 899–906 (2006). 7. Vlieg-boerstra, B. J. et al. Development and
validation of challenge materials for double-blind, placebo- controlled food challenges in children. J. Allergy Clin. Immunol. 113, 341– 346 (2004).
8. van der Zee, T., Dubois, A., Kerkhof, M., van der Heide, S. & Vlieg-Boerstra, B. The eliciting dose of peanut in double-blind, placebo-controlled food challenges decreases with increasing age and specific IgE level in children and young adults. J. Allergy Clin. Immunol. 128, 1031–6 (2011).
9. Nwaru, B. I. et al. The epidemiology of food allergy in Europe: A systematic review and meta-analysis. Allergy Eur. J. Allergy Clin. Immunol. 69, 62–75 (2014).
10. Hourihane, J. O. B. et al. The impact of government advice to pregnant mothers regarding peanut avoidance on the
prevalence of peanut allergy in United Kingdom children at school entry. J. Allergy Clin. Immunol. 119, 1197–1202 (2007). 11. Zekveld, C. et al. The effects of farming and
birth order on asthma and allergies. Eur. Respir. J. 28, 82–88 (2006).
12. Twisk JWR. Applied multilevel analysis: A practival guide. (Cambridge university press, 2006).
13. van Ginkel, C. D. et al. Loss-of-function variants of the filaggrin gene are associated with clinical reactivity to foods. Allergy 70(4):461-4 (2015).
14. van den Berg, M. E. et al. Parental eczema increases the risk of double-blind, placebo-controlled reactions to milk but not to egg, peanut or hazelnut. Int. Arch. Allergy Immunol. 158, 77–83 (2012).
15. Kusunoki, T. et al. Birth order effect on childhood food allergy. Pediatr. Allergy Immunol. 23, 250–254 (2012). 16. Hilton, I. Differences in the behavior of
mothers toward first- and later-born children. Am. Psychol. Assoc. 7(3):282-90 (1967).
17. Venter, Incidence of parentally reported and clinically diagnosed food hypersensitivity in the first year of life, JACI. 117(5):1118-24 (2006).
18. Gupta, R. S. et al. Food Allergy Sensitization and Presentation in Siblings of Food Allergic Children. J. Allergy Clin. Immunol. Pract. 1–7, 4(5):956-62 (2016).
19. du Toit G, et al, Prevention of food allergy, J Allergy Clin Immunol 137(4):998 - 1010) (2016).
20. Strachan, D.P., Family size, infection and atopy: the first decade of the “hygiene hypothesis”, Thorax 2000;55(Suppl 1):S2–S10 21. Strachan, D.P., Hay fever, hygiene, and
household size, BMJ. 1989 Nov 18; 299(6710): 1259–1260
22. Penders et al. New insights into the hygiene hypothesis in allergic diseases Mediation of sibling and birth mode effects by the gut
Chap
ter 6
Our data also indicates that these processes may be specific for each allergenic food, as shown by the association between a family history of atopic eczema with cow’s milk allergy. Thus, in addition to many other epidemiological and clinical differences between allergies to different foods, the differences in risk factors for certain foods suggest that it is probably illusory to think that the development of different food allergies follows a common or single pathway.
This study has some limitations. The population used in this study consisted of high-risk children who were referred to a tertiary clinic with the suspicion of food allergy and had a DBPCFC as part of routine care. It is therefore difficult to compare these results with the general population where atopic clustering of sensitization and related diseases will be much more apparent. The study was retrospective. However, all historical information was obtained before the performance of the food challenges, thus reducing recall bias based on challenge test outcome. We did not analyze SPTs, which may have underestimated sensitization rates. However, it has been shown that the concordance between sIgE antibody assays and SPT results is between 85% and 95% depending on the allergen being tested and the method used to detect specific IgE.28 Therefore; it is unlikely that this possible misclassification of
sensitization had a significant impact on our results. It would be desirable to replicate these findings in a general population cohort to ascertain the generalizability of our conclusions. Finally, future studies should involve larger study populations to study differences in the development of sensitization and clinical reactivity to different foods separately.
CONCLUSIONS
There is a birth order effect with regard to sensitization to foods, but this effect is less or absent with regard to clinical food allergy. In the context of children tested for food allergy in a tertiary setting, having a positive family history of food allergy has little influence on the risk of becoming sensitized or allergic to foods. Thus, in tertiary care, the management of individuals with or without food allergic siblings or relatives should not differ from that of other individuals.
REFERENCES
1. Ober, C. & Yao, T.-C. The genetics of asthma and allergic disease: a 21st-century perspective. Immunol. Rev. 242, 10–30 (2011).
2. Karmaus W. & Botezan C. Does a higher number of siblings protect against the development of allergy and asthma? A review. J. Epidemiol. Community Health 56, 209–217 (2002).
3. Karmaus, W. et al. Invited commentary: Sibship effects and a call for a comparative disease approach. Am. J. Epidemiol. 162, 133–139 (2005).
4. Hourihane, J. O., Dean, T. P. & Warner, J. O. Peanut allergy in relation to heredity, maternal diet, and other atopic diseases: results of a questionnaire survey, skin prick testing, and food challenges. BMJ 313, 518– 21 (1996).
5. Sicherer, S. H. et al. Genetics of peanut allergy: a twin study. J. Allergy Clin. Immunol. 106, 53–6 (2000).
6. Brouwer, M. L. et al. No effects of probiotics on atopic dermatitis in infancy : a
randomized Clinical and Experimental Allergy. Clin. Exp. Allergy 36, 899–906 (2006). 7. Vlieg-boerstra, B. J. et al. Development and
validation of challenge materials for double-blind, placebo- controlled food challenges in children. J. Allergy Clin. Immunol. 113, 341– 346 (2004).
8. van der Zee, T., Dubois, A., Kerkhof, M., van der Heide, S. & Vlieg-Boerstra, B. The eliciting dose of peanut in double-blind, placebo-controlled food challenges decreases with increasing age and specific IgE level in children and young adults. J. Allergy Clin. Immunol. 128, 1031–6 (2011).
9. Nwaru, B. I. et al. The epidemiology of food allergy in Europe: A systematic review and meta-analysis. Allergy Eur. J. Allergy Clin. Immunol. 69, 62–75 (2014).
10. Hourihane, J. O. B. et al. The impact of government advice to pregnant mothers regarding peanut avoidance on the
prevalence of peanut allergy in United Kingdom children at school entry. J. Allergy Clin. Immunol. 119, 1197–1202 (2007). 11. Zekveld, C. et al. The effects of farming and
birth order on asthma and allergies. Eur. Respir. J. 28, 82–88 (2006).
12. Twisk JWR. Applied multilevel analysis: A practival guide. (Cambridge university press, 2006).
13. van Ginkel, C. D. et al. Loss-of-function variants of the filaggrin gene are associated with clinical reactivity to foods. Allergy 70(4):461-4 (2015).
14. van den Berg, M. E. et al. Parental eczema increases the risk of double-blind, placebo-controlled reactions to milk but not to egg, peanut or hazelnut. Int. Arch. Allergy Immunol. 158, 77–83 (2012).
15. Kusunoki, T. et al. Birth order effect on childhood food allergy. Pediatr. Allergy Immunol. 23, 250–254 (2012). 16. Hilton, I. Differences in the behavior of
mothers toward first- and later-born children. Am. Psychol. Assoc. 7(3):282-90 (1967).
17. Venter, Incidence of parentally reported and clinically diagnosed food hypersensitivity in the first year of life, JACI. 117(5):1118-24 (2006).
18. Gupta, R. S. et al. Food Allergy Sensitization and Presentation in Siblings of Food Allergic Children. J. Allergy Clin. Immunol. Pract. 1–7, 4(5):956-62 (2016).
19. du Toit G, et al, Prevention of food allergy, J Allergy Clin Immunol 137(4):998 - 1010) (2016).
20. Strachan, D.P., Family size, infection and atopy: the first decade of the “hygiene hypothesis”, Thorax 2000;55(Suppl 1):S2–S10 21. Strachan, D.P., Hay fever, hygiene, and
household size, BMJ. 1989 Nov 18; 299(6710): 1259–1260
22. Penders et al. New insights into the hygiene hypothesis in allergic diseases Mediation of sibling and birth mode effects by the gut
microbiota, Gut Microbes 5:2, 239–244; March/April 2014; Landes Bioscience 23. Laursen et. al. Having older siblings is
associated with gut microbiota development during early childhood, BMC Microbiology (2015) 15:154 DOI 10.1186/s12866-015-0477-6
24. Roerdink, E. M. et al. Association of Food allergy and atopic dermatitis exacerbations. Ann .Allergy, Asthma Immunol 116, 334–338. (2016).
25. Christiansen ES, Early Childhood risk factors for rhinoconjunctivitis in adolescence: a
prospective birth cohort study. Clinical and translational allergy Clin Transl Allergy. 7:9 (2017).
26. Koplin et al. The Impact of Family History of Allergy on Risk of Food Allergy: A Population-Based Study of Infants, Int J Environ Res Public Health, (11): 5364–5377 (2013). 27. Koppelman et al, Sibling effect on atopy in
children of patients with asthma, Clin Exp Allergy 33(2):170-5 (2003).
28. L. Heinzerling et. a. , The skin prick test- European standards. Clin Transl Allergy , 3(1):3 (2013).
PART III
23. Laursen et. al. Having older siblings is associated with gut microbiota development during early childhood, BMC Microbiology (2015) 15:154 DOI 10.1186/s12866-015-0477-6
24. Roerdink, E. M. et al. Association of Food allergy and atopic dermatitis exacerbations. Ann .Allergy, Asthma Immunol 116, 334–338. (2016).
25. Christiansen ES, Early Childhood risk factors for rhinoconjunctivitis in adolescence: a
(2017).
26. Koplin et al. The Impact of Family History of Allergy on Risk of Food Allergy: A Population-Based Study of Infants, Int J Environ Res Public Health, (11): 5364–5377 (2013). 27. Koppelman et al, Sibling effect on atopy in
children of patients with asthma, Clin Exp Allergy 33(2):170-5 (2003).
28. L. Heinzerling et. a. , The skin prick test- European standards. Clin Transl Allergy , 3(1):3 (2013).
PART III
LOSS-OF-FUNCTION VARIANTS OF THE
FILAGGRIN GENE ARE ASSOCIATED WITH
CLINICAL REACTIVITY TO FOODS
C.D. VAN GINKEL1 ,2, B. M. J. FLOKSTRA-DE BLOK2 ,3, B. J. KOLLEN3, J. KUKLER1,
G. H. KOPPELMAN1 ,2 *, & A. E. J. DUBOIS1 ,2 *
1University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Groningen; 2University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen; 3University of Groningen, University Medical Center Groningen, Department of General Practice, Groningen, the Netherlands
*These authors contributed equally to this study.
EUROPEAN JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY ;70(4):461-4 (2015)
