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Background: We examined the role of fish intake in the development of atopic disease with particular reference to the possibility of differential effects on allergen-specific subgroups of sensitization.
Methods: The exposure of interest was parental report of fish intake by children aged 8 years at the 1997 Childhood Allergy and Respiratory Health Study (n = 499). The outcomes of interest were subgroups of atopy: house dust mite (HDM)-pure sensitization [a positive skin-prick test (SPT) ≥2 mm to Der p or Der f only], ryegrass-pure sensitization (a positive SPT ≥2 mm to ryegrass only); asthma and hay fever by allergen-specific sensitization.
Results: A significant association between fish intake and ryegrass-pure [adjusted odds ratio (AOR) 0.37 (0.15–0.90)] but not HDM-pure sensitization [AOR 0.87 (0.36–2.13)] was found. Fish consumption significantly decreased the risk for ryegrass-pure sensitization in comparison with HDM-pure sensitization [AOR 0.20 (0.05–0.79)].
Conclusions: We have demonstrated a differential effect of fish intake for sensitization to different aeroallergens. This may be due to the different timing of allergen exposure during early life. Further investigation of the causes of atopic disease should take into account allergen-specific subgroups.
There has been a suggestion that a number of environmental factors are linked to child atopic disease. The role of polyunsaturated fatty acids (PUFA) intake in particular foods rich in ω-3 PUFA such as fish in atopic disease is under investigation. Several observational studies found a significant inverse association between fish intake and atopic disease (1–3). According to the fatty acid hypothesis, increased ratio of ω-6/ω-3 PUFA may shift the immune responses towards the T helper 2 (Th2) subtype through synthesis of prostanoids. More specifically, ω-3 PUFA exhibit their immunomodulatory effect through competitive inhibition with ω-6 PUFA, and increasing dietary ω-3 PUFA results in the reduction of precursors of inflammatory mediators such as arachidonic acid from linoleic acid (4). ω-3 fatty acids can also inhibit the oxygenation of arachidonic acid by cyclooxygenase (4). Thus, foods rich in ω-3 fatty acids such as fish may downregulate Th2 responses and associated atopic disease.
Despite this evidence, other observational studies (5, 6) failed to show any beneficial association between fish intake and asthma. Moreover, fish oil supplementation did not significantly improve asthma symptoms in several randomized controlled trials (RCTs) (7, 8). Part of this controversy may be due to conceptual difficulties to define atopic disease, including asthma, and its phenotype heterogeneity (9). Absence of a precise definition makes it difficult to diagnose asthma and to assess the diagnostic value of objective measures of the disease (10). More difficult is the delineation of phenotype subgroups within the broad spectrum of atopic disease.
A recent novel analysis by this group using mutually exclusive subgroups demonstrated that environmental factors may exert different influences on allergen-specific subgroups within atopy (11) with a large family size strongly associated with reduced sensitization to ryegrass allergens but not to house dust mite (HDM) allergens. In addition, a differing pattern of allergen-specific sensitization for disease phenotypes was found. Asthma was strongly associated with HDM sensitization and hay fever was more associated with ryegrass sensitization (11).
We postulated that similar to the sibling effect detailed above, fish intake may be another childhood influence which could exhibit a differential protective effect on allergen sensitization. Here, we investigate this issue, taking into account atopic phenotype.
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Table 1 shows the prevalence of exposure and outcome variables in the study sample. The majority of children (87.3%) ate fish. Overall, 41% (206/498) of children were sensitized to at least one allergen. HDM sensitization was more prevalent than ryegrass sensitization. Fifteen percent of children were sensitized to both ryegrass and HDM (mixed sensitization). Prevalence of sensitization to cat, dog or Alternaria was 15% (Fig. 1). Asthma was slightly more prevalent than hay fever.
When examining the exposure–factor and factor–outcome associations, bottle-feeding at 1 month and maternal smoking during pregnancy were negatively associated with fish intake in childhood. Family history of asthma, plastic mattress liner use in infancy, and any bottle-feeding at 1 month were positively associated, and feather quilt use in childhood was negatively associated with HDM-pure sensitization (Table 2).
We then examined the associations between fish intake and allergen-specific sensitization (Table 3). Overall, fish intake was not associated with atopy [OR 0.69 (0.40–1.17)]. On univariate analyses, a protective effect of fish for any ryegrass and ryegrass-pure sensitization was found. Fish intake was not associated with any of the categories of HDM sensitization. On multivariate analysis, the association with the ryegrass-pure sensitization remained significant. Fish consumption significantly decreased the risk for ryegrass-pure sensitization in comparison with HDM-pure sensitization by 80% [adjusted odds ratio (AOR) 0.20 (0.05–0.79)]. Fish intake was not significantly associated with the mixed sensitization [AOR 0.68 (0.30–1.53)].
Table 3. Fish consumption and likelihood of atopic sensitization, the 1997 Childhood Asthma and Respiratory Health Study
|Atopy subgroup||Prevalence of atopic subgroup among children who did not eat fish in 1997||Prevalence of atopic subgroup among children who ate fish in 1997||Odds ratio (95% CI)||P-value||Adjusted odds ratio* (95% CI)||P-value|
|% (n/N)||% (n/N)|
|Any atopy||49.2 (31/63)||40.0 (172/430)||0.69 (0.40–1.17)||0.17||0.74 (0.42–1.32)||0.31|
|Any ryegrass sensitization||34.9 (22/63)||21.6 (93/430)||0.51 (0.29–0.91)||0.02||0.60 (0.32–1.11)||0.10|
|Any HDM sensitization||31.8 (20/63)||31.2 (134/430)||0.97 (0.55–1.72)||0.93||0.96 (0.52–1.77)||0.89|
|Ryegrass pure sensitization||17.5 (11/63)||5.4 (23/430)||0.26 (0.12–0.58)||0.001||0.37 (0.15–0.90)||0.03|
|HDM pure sensitization||11.1 (7/63)||14.0 (60/430)||1.06 (0.45–2.52)||0.89||0.87 (0.36–2.13)||0.77|
Mixed sensitization was strongly associated with both asthma [OR 5.48 (3.17–9.46)] and hay fever [OR 9.97 (5.59–17.77)] suggesting that simultaneous sensitization to both ryegrass and HDM rather than sensitization to one of these allergens is a stronger risk factor for asthma and hay fever. Asthma was not significantly associated with either HDM-pure [OR 1.49 (0.83–2.67)] or ryegrass-pure sensitization [OR 1.28 (0.57–2.88)]. Hay fever was not significantly associated with HDM-pure sensitization [OR 1.31 (0.66–2.59)] but strongly related to ryegrass-pure sensitization [OR 4.15 (1.94–8.89)].
Overall, fish intake was not significantly associated with a reduced risk of asthma [OR 0.65 (0.37–1.12)] or hay fever [OR 0.89 (0.49–1.62)]. Clearer associations were revealed when these outcomes were broken down into allergen-specific subgroups. Fish intake was significantly inversely associated only with asthma linked to ryegrass-pure sensitization [AOR 0.20 (0.04–0.90)]. A similar pattern was found for hay fever linked to ryegrass-pure sensitization [OR 0.25 (0.08–0.78)] (Table 4).
Table 4. Fish intake and likelihood of disease phenotypes by categories of atopic sensitization, the 1997 Childhood Asthma and Respiratory Health Study
|Disease phenotype||Atopy subgroup||Prevalence of disease phenotype by atopic subgroups among children who did not eat fish In 1997||Prevalence of disease by atopic subgroups among children who ate fish in 1997||Odds ratio (95% CI)||P value||Adjusted* odds ratio (95% CI)||P value|
|% (n/N)||% (n/N)|
|No asthma (referent category)||–||63.5 (40/63)||72.5 (301/429)||1.00||–||1.00||–|
|Asthma||No sensitization||15.9 (10/63)||13.1 (56/429)||0.71 (0.33–1.50)||0.37||0.86 (0.37–2.00)||0.73|
|Ryegrass-pure sensitization||6.4 (4/63)||1.2 (5/429)||0.16 (0.04–0.61)||0.01||0.20 (0.04–0.90)||0.04|
|HDM-pure sensitization||1.6 (1/63)||4.7 (20/429)||2.52 (0.33–19.35)||0.37||2.88 (0.37–22.49)||0.31|
|Mixed sensitization||12.7 (8/63)||8.6 (37/429)||0.58 (0.25–1.35)||0.21||0.47 (0.20–1.13)||0.09|
|No hay fever (referent category)||–||74.2 (46/62)||76.5 (329/430)||1.00||–||1.00||–|
|Hay fever||No sensitization||3.2 (2/62)||9.8 (42/430)||2.93 (0.69–12.54)||0.15||2.75 (0.63–11.95)||0.18|
|Ryegrass-pure sensitization||8.1 (5/62)||2.1 (9/430)||0.25 (0.08–0.78)||0.02||0.50 (0.13–1.99)||0.33|
|HDM-pure sensitization||3.2 (2/62)||2.6 (11/430)||0.77 (0.17–3.58)||0.74||0.59 (0.12–2.87)||0.51|
|Mixed sensitization||11.3 (7/62)||9.1 (39/430)||0.78 (0.33–1.85)||0.57||0.74 (0.29–1.90)||0.53|
Further examination of the confounding factors
The following factors were further examined for their potential confounding effect: components of the perinatal scoring system (maternal age, birth weight, infant's sex, intention to bottle-feed, season of birth, duration of second stage of labour, multiple birth), the composite perinatal score, any bottle-feeding at 1 month of age, antenatal exposure to smoking, domestic gas used for cooking or heating in infancy, infant and child exposure to active cigarette smoking in the same room, mould observed in the infant's bedroom by the research interviewer, history of an upper respiratory tract infection by 1 month of age, history of a lower respiratory tract infection by 12 weeks of age, introduction of solids at 12 weeks, breastfeeding without solids or infant formula at 12 weeks, carpet in infant's bedroom, family history of asthma at birth, child feather quilt use, and child feather pillow use.
For atopic sensitization, the main outcome of interest was the magnitude of the effect of fish intake for ryegrass-pure compared with HDM-pure sensitization. When adding the factors one at a time into the multivariate model, antenatal exposure to smoking decreased the AOR for the difference in effect by 11% [AOR 0.16 (P = 0.01)] and lower respiratory tract infection by 12 weeks of age increased the AOR by 15% [AOR 0.23 (P = 0.04)]. The other factors did not change the difference in effect by >10% (data not shown). The AOR range was 0.16 (P = 0.01) to 0.23 (P = 0.04). On average, fish intake lowered the risk for ryegrass-pure sensitization compared with HDM-pure sensitization more than fourfold after various possible confounders were taken into account. Thus, differential effect of dietary fish in reducing ryegrass-pure but not HDM-pure sensitization was of substantial magnitude.
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This report examines the effect of fish consumption on the development of atopy and asthma and demonstrates that fish consumption may exert a differential effect on allergen-specific sensitization (a significant protective association for ryegrass-pure but not HDM-pure sensitization) and provides further evidence that environmental factors may influence sensitization to different allergens differently (11). Concerning the protective effects of any fish consumption on the subsets of atopic disease (asthma and allergic rhinitis) associated with ryegrass sensitization, because of subset analysis the numbers are small and larger cohorts are required to confirm this observation.
The main strength of the study was the development and use of clearly delineated categories of atopy, asthma and hay fever. This allowed for a more precise assessment of the effect of fish consumption on atopic disease. The study had a large capacity to control for confounding. Fish intake was measured by a parental report of how often the child ate fish which is inferior to a semi-quantitative food frequency questionnaire (21). The type of fish consumed can also be of significance. A recent study found a significant trend (in univariate analysis) for inverse association between physician-diagnosed asthma and ‘oily fish’, but not between the disease and ‘shellfish’, ‘other seafood’, or ‘all fish’ (22). Hodge et al. (1) found a significantly reduced risk of current asthma among children who ate oily fish, but not among children who ate non-oily fish. The strength of the causal relationship is also lowered by the fact that exposure was only a binary variable and dose–response could not be calculated. Clearly, the type of fish, the amount (dose) and duration of fish consumption are likely to be important factors. Furthermore, the ratio of ω-6 to ω-3 PUFA rather than the total amount of PUFA is important (23). These problems in the measurement of fish intake here would most likely be non-differential, reducing the study's ability to detect an association with the atopic outcomes. However, exposure measures on fish intake would be unlikely to vary by allergen-specific subgroups, particularly within asthma. We found no association with either atopy or asthma overall. The small sample size did not allow an examination of combined or mutually exclusive disease phenotypes, e.g. asthma and hay fever combined, asthma without hay fever. The cohort entry criteria were designed to recruit infants at a higher risk of SIDS. Thus, the cohort is not representative of all live births in Tasmania at that time. However, adjustment for the components of the perinatal scoring system did not alter the findings and there is no reason to believe that the study population was substantially different from the general population with regard to the development of allergy and atopy. Although many of the controlled factors were from prospective data, the data on child fish consumption were cross-sectional. In general, cross-sectional data does not allow a clear inference of causality to be drawn.
Other observational studies (1–3) have also found inverse associations between fish intake and asthma. Failure of several RCTs to show improvements in clinical symptoms in asthmatics treated with fish oil (7, 8) has been suggested to be due to the possibility that (a) fish oil may exert its beneficial effect by reducing the risk of allergen sensitization rather than having a direct effect on asthma, (b) asthma cannot be reversed once it has developed, (c) the time of supplementation was too short, or (d) the dose was too low (24). The findings here indicate that the allergen-specific atopic subgroups of studied asthmatics are also important.
Our findings indicate that different allergen sensitization patterns within the broad categories of atopy, hay fever or asthma across the studies may have contributed to the inconsistent findings on fish intake and atopic disease (1, 2, 5, 6). We also speculate that the differing pattern of association of fish consumption and allergen-specific subgroups of atopic disease may be partly attributed to the exposure timing. The concept has been suggested by studies on early-childhood respiratory illnesses and allergic susceptibility (25, 26). Von Mutius (27) demonstrated that even changes as profound as those occurring in the eastern part of Germany do not affect the inception of childhood asthma if they happen after the third birthday. The same study also found that the prevalence of hay fever and atopy have increased between 1991–92 and 1995–96. Their explanation of the findings was that factors operating very early in life are important for the acquisition of asthma, whereas the development of atopic sensitization and hay fever is affected by environmental factors occurring beyond infancy in addition to early-life factors. Similarly, the number of younger siblings was more strongly inversely associated with hay fever than asthma (28) reflecting a longer window of opportunity for the sibling effect on hay fever. Here, as in other studies (29, 30), the hay fever phenotype was more closely linked to ryegrass than HDM sensitization.
We suggest that the differing pattern of association of fish consumption and allergen-sensitisation may be partly attributed to the exposure timing. Mechanisms that contribute to downregulation of IgE responses to environmental allergens are most likely to exert their major effects at, or around the time of, initial exposure to the allergens rather than when T-cell memory is established and T-cell response is shifted to a permanent Th1 or Th2 pattern (31). Exposure and sensitization to HDM is likely to occur constantly very early in life, even at 1 month of age (32) while exposure to ryegrass usually occurs intermittently throughout childhood and teenage years (33, 34). A recent study (35) found a significant age-related proliferative response to ryegrass allergens, but not to HDM, and an increased age-related Th2 deviation among ryegrass-sensitive but not HDM-sensitive atopic subjects. Thus there may be a greater influence of later childhood factors in the development of ryegrass sensitization than HDM sensitization. Consistent with this, fish intake in this study cohort was uncommon in the first 3 months of life (0.4%). However, by the age of 6 years, 94% (460/489) of children ate fish. This timing of allergen exposure together with the later age of fish consumption may allow a larger window of opportunity for PUFA immunomodulation for ryegrass than HDM. Thus, as the time of consolidation of Th2 responses to different aeroallergens varies with T-cell memory for HDM allergens being established in early childhood and for ryegrass allergens throughout childhood (35), the ‘usual’ introduction of fish into diet might be too late to protect against HDM-sensitization developed in early life. A parallel-group RCT involving high-risk newborns found no effect of ω-3-rich fish oil supplements on overall sensitization to aeroallergens and HDM sensitization at 18 months (36). However, at this stage the prevalence of sensitisation to ryegrass was less than 5% and long-term follow-up with a further examination of ryegrass sensitization is in progress.
We have previously reported that the sibling effect on atopy varies by allergen-specific sensitization status (11). Here, a similar difference was observed for another putative protective factor – fish intake. Interestingly, the inverse associations between fish and any atopy or asthma were weak and non-significant overall. These inverse associations only were strong and significant for sensitization to ryegrass only and asthma associated with ryegrass-pure sensitization. Further investigation of the causes of atopic disease should include the examination of allergen-specific phenotypes when considering the influence of environmental factors.
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We thank the parents, infants and children who participated in these studies, the research staff for data collection and collation and the hospitals participating in the cohort and follow-up studies. We thank the Tasmanian Department of Education, Cultural and Community Development and the Catholic Education Office for their co-operation and the Asthma Foundation of Tasmania for equipment loan. The Tasmanian Infant Health Survey was supported by the US National Institutes of Health Grant 001 HD28979-01A1, Tasmanian State Government, Australian Rotary Health Research Fund, National Health and Medical Research Council of Australia, National Sudden Infant Death Syndrome Council of Australia, Sudden Infant Death Research Foundation of Victoria and other constituent organizations, Community Organizations’ Support Program of the Department of Human Services and Health, Zonta International, Wyeth Pharmaceuticals, and Tasmanian Sanatoria After-Care Association. Dr Ponsonby held a National Health and Medical Research Council PHRDC Fellowship. The Public Health Research and Development Committee of the National Health and Medical Research Council, Australia, funded the 1997 follow-up study. The Tasmanian government and a grant from Coles Supermarkets to the Canberra Region Medical Foundation funded part of the analysis of this project. Part of the funding for this project was supported by the National Priority Areas Initiative (Asthma), Department of Health and Aged Care, Australia.