Dietary prevention strategies for childhood asthma

Asthma is the most common chronic disease in childhood and a rise in prevalence has been observed concomitantly with changing dietary habits in the Western world. This change has favored a more Westernized diet characterized by high intake of processed food and fat in contrast to a Mediterranean diet high in fruit, vegetable and fish intake. This has resulted in a decreased intake of several antioxidants and micronutrients including n‐3 long‐chained polyunsaturated fatty acids and vitamin D that are speculated to have anti‐inflammatory effects and hold immunoregulatory properties. Several observational studies have investigated associations between dietary intake and wheeze and asthma but only few large well‐conducted randomized controlled trials (RCTs) have been performed investigating the primary preventive effect of micronutrient supplementations. Currently, the recommendations from the Global Initiative for Asthma (GINA) for primary prevention of asthma in children do not include maternal dietary changes or supplementations during pregnancy, although the most recent report mentions both specific dietary patterns and micronutrients as potential protective supplementation regimes. This review will present the current literature and future research needs focusing on primary and secondary prevention of both early and late childhood asthma from dietary intake during pregnancy and early childhood to highlight potential preventive effects of specific dietary patterns and micronutrient supplements, which may facilitate the planning of future clinical trials in search of a preemptive strategy.


| INTRODUC TI ON
The observed increased prevalence of childhood asthma in the Western world during the last decades is speculated to be caused by changes in lifestyle including dietary habits. 1 Asthma is the most common chronic childhood disease characterized by inflammation of the airways, recurrent wheezing episodes and bronchial hyperresponsiveness. 2 Up to one-third of preschool-age children in the United States and Europe are estimated to suffer from recurrent wheezing episodes often requiring medical treatment. 3 The rise in prevalence of these symptoms, medical treatment, and hospitalizations observed among younger children is a major burden for the affected families due to loss of school days and social isolation of the children lowering their quality of life, as well as on the society due to high economic costs. [4][5][6][7] As there is currently no cure for asthma, primary prevention is key to reduce the prevalence and secondary prevention is key to reduce asthma-related morbidity and costs.
The prenatal stage is considered a vulnerable period for a child's risk of developing atopic diseases and a period where dietary intake in particular seems promising as a preventive tool. 8 Randomized controlled trials (RCTs) in pregnancy with micronutrient supplementations have emphasized the importance of this phase by demonstrating protective effects on the risk of childhood wheezing by both fish oil and vitamin D interventions. 9,10 Likewise, studies have shown that not only interventions during the prenatal phase but also in childhood could be important for the prevention of childhood respiratory infections. 11 These effects are hypothesized to be a result of nutritional optimization during both the first window of opportunity in pregnancy and the second neonatal window of opportunity, 8 which are two periods that are considered critical for later disease development. The studies have mainly focused on the intervention effects from different micronutrients, which are vitamins and minerals including vitamin D, while other studies have also focused on the specific effects of diet-related metabolites, macronutrients which are compounds consumed in larger quantities including carbohydrates, proteins and fat and dietary patterns in pregnancy potentially influencing childhood asthma risk. 12,13 Currently, the recommendations from the Global Initiative for Asthma (GINA) for primary prevention of asthma in children do not include maternal dietary changes or supplements during pregnancy, although, this topic is discussed in the most recent report mentioning both specific dietary patterns and micronutrient supplies to hold a potential protective role. 14 Hence, in this review we aim to clarify and discuss this important subject by presenting existing evidence and highlighting future research needs linking early dietary factors to early and later asthma risk in search of a preventive strategy for the most common chronic disease in childhood.

| Early childhood wheezing and asthma
Asthma in early childhood is often defined by a symptom debut before age 6 years. In early childhood, the phenotype is characterized by recurrent wheezing episodes due to airway inflammation often caused by airway infections, 15 where later persistent asthma is more associated with impaired lung function, allergies and genetic predisposition. [16][17][18] Some, but not all children continue to experience these symptoms into school-age developing a more persistent asthma phenotype. 18

Vitamin D
Vitamin D is produced in the human skin when exposed to sunlight from 7-dehydrocholesterol, but can also be obtained from dietary intake with fish as the main source. 20 Vitamin D is involved in several physiological processes as the vitamin D receptors (VDRs) are located in numerous tissues. Hence, vitamin D has been suggested to possess a role in lung cell maturation, immune system development and systemic low-grade inflammation thereby potentially playing a protective role against early asthma symptoms. 21,22 Several observational studies have linked maternal vitamin D deficiency in pregnancy to an increased risk of childhood asthma. 23 This has later been proven in large RCTs of the two Danish and North American cohorts (COPSAC 2010 and VDAART) where primary preventive effects of 2800 IU/day and 4400 IU/day compared to 400 IU/day of vitamin D on early recurrent wheezing until age 3 years was demonstrated. 10,24,25 However, there was no sustained effect of highdose vitamin D on asthma at age 6 years in any of the trials. 26,27 This underlines that the supplementation effect is dependent on the asthma phenotype and underlying mechanisms and triggers, that is, early recurrent wheezing, but not asthma into school age with several other causal factors.
The prenatal effect of vitamin D on early wheezing seems dependent on genetic risk variants of 17q21, VDR and the vitamin D binding protein (VDBP) suggesting a gene-environment interaction for both the mother and the child genotypes that alters the preventive effects of vitamin D. 28,29 Further, previous RCTs have shown the effect to be dependent on the pre-interventional maternal 25-hydroxyvitamin D levels where the highest supplementation effects were observed among women with high levels in early pregnancy, suggesting sufficient vitamin D throughout the whole pregnancy to be important for prevention of early wheezing. 10,24,25 Randomized controlled trials investigating the primary prevention effect of vitamin D supplementation on risk of respiratory

Key message
This review describes the potential of dietary-related micronutrients and dietary patterns for primary and secondary asthma prevention in early and late childhood. It highlights the most promising findings from the existing literature and encourages future clinical trials where needed, but also reflects upon the already conducted large RCTs, systematic reviews and meta-analyses on the subject. tract infections, which are the leading cause of acute wheezing, in preschool-age children are inconclusive. [30][31][32] However, a beneficial effect on respiratory tract infections has been demonstrated in a large meta-analysis of participants aged 0-95 years with the most pronounced effect among children aged 1-16 years. 11 The potential preventive effect of vitamin D intake among infants and preschool-age children on subsequent risk of asthma and wheezing has recently been assessed in a large systematic review.
Here, the authors conclude that based on the evidence from both clinical trials and prospective observational studies there was no causal relationship between vitamin D intake and risk of asthma and wheezing among healthy young children. 33 However, the authors also stated that many of the studies included were of poor quality with high risk of bias in many of the RCTs. causality between supplementing with fish oil in pregnancy and a reduced risk of asthma development until school age. 9 The fish oil trial also showed a protective effect on risk of lower respiratory tract infections. 9 The prenatal effect of LCPUFA on early asthma risk seems dependent on maternal n-3 LCPUFA levels before the intervention, with higher effect in mothers with low levels, as well as maternal genetic variants of the fatty acid desaturase (FADS) suggesting a geneenvironment interaction that should be considered in future trials and might provide the basis for personalized prevention. 9,36 In a recent meta-analysis of pregnancy RCTs of n-3 LCPUFA, the effect of supplementation on asthma was only found in a subgroup analysis among European studies, which was suggested to reflect either an effect dependent on ethnicity or environment. 37 The first proposed cause would support the idea of genetic influence where distribution of risk genes could differ between ethnicities, whereas the second proposed cause could be due to different dietary habits across countries. Another potential cause of discrepancy between studies is the large heterogeneity in doses and content of the n-3 LCPUFA supplements used in different trials.
In a recent large observational study, it was suggested that consumption of LCPUFA enriched formula during infancy was associated with a lower risk of lower respiratory tract infections and lower use of asthma medication between the ages of 2 months and 5.5 years. 38 Further, a sub-analysis of the VDAART cohort showed that n-3 LCPUFA blood levels measured at age 3 years was inversely associated with risk of asthma by age 3 years. 39 This points toward both a prenatal and postnatal effect of n-3 LCPUFA for primary prevention of asthma. However, the only RCT performed among infants did not show an overall effect of 6 months supplementation with n-3 LCPUFA on wheezing during the first year, but the n-3 LCPUFA blood levels at age 6 months were associated with lower risk of recurrent wheeze, 40 which is a finding that may be explained by the relative low adherence (56.7%) in the intervention group.
Summary and future research needs: For LCPUFA, the current evidence points toward that the pregnancy period rather than the postnatal period is the optimal window of opportunity for optimizing n-3 LCPUFA on the risk of asthma probably through immune alterations.
Given the observational design of the studies, future large RCTs during infancy are needed to establish whether n-3 LCPUFA supplementation holds an effect during early childhood and not only during pregnancy.

Other micronutrients
A comprehensive meta-analysis of nutritional intake assessed by food frequency questionnaires (FFQs) during pregnancy and risk of asthma and wheeze development during childhood found reduced risks of early childhood wheeze when mothers had high intakes of vitamin D, vitamin E and zinc, respectively. 41 There were no associations between reported intake of vitamin A, vitamin B (B6, B9 and B12), vitamin C, copper, calcium, magnesium, manganese and selenium and early wheezing or asthma in the same meta-analysis.
Vitamin A. A meta-analysis of two pediatric observational studies showed lower serum levels of vitamin A among children with asthma compared with healthy controls, 42 but another meta-analysis of two studies found no clear relationship between maternal intake of beta-carotene in pregnancy and risk of wheezing in children at age 2 years. 43 This suggests an effect during childhood but not during pregnancy. It has been speculated that the lower vitamin A levels in children with asthma could be due to the amount of oxidative stress in these patients as it possesses antioxidant properties.
Vitamin A (retinol and carotenoids) sources include egg, milk, fruit and vegetables. 44 There is still no RCT performed to determine the effect of vitamin A for primary prevention of childhood asthma.
Vitamin C. Vitamin C, an antioxidant from fruits and vegetables, has been speculated to have a protective effect on asthma development since it has been shown that it might reduce levels of C-reactive protein (CRP) and perform prostaglandin inhibition. 44 For primary prevention of early asthma, a secondary analysis of a RCT with preeclampsia as primary outcome investigated the prenatal effect of a combination of 1 g vitamin C supplementation and 400 IU vitamin E supplementation daily versus placebo from the second trimester until delivery on asthma or respiratory symptoms until age 2 years in children and found no such protective effect. 45 However, the authors of this study emphasized that the generalizability were limited by the fact that the mothers were at high risk of preeclampsia.
Among a group of smoking pregnant women, vitamin C has shown to decrease offspring wheeze until age 5 years and improve lung function measurements, but this effect is probably due to vitamin C's blocking effect on nicotine in utero as speculated by the authors. 46 There is still no RCT investigating primary prevention by vitamin C with childhood asthma as primary outcome.
Vitamin E. Vitamin E is also known to possess antioxidant effects and is speculated to hold a preventive effect against asthma by downregulating oxidative stress (reducing isoprostane levels), airway inflammation and Th2-immune responses. 44 The vitamin is mostly found in nuts, seeds and green vegetables. 44 Interestingly, a systematic review of seven cohort studies of maternal intake of vitamin E and childhood wheezing found a strong inverse association supporting this hypothesis, although, there was no association with risk of asthma. 41 However, as mentioned above, the supplementation of prenatal vitamin C and vitamin E in a RCT suggested no effect from the combination of these vitamins. 45 There is still no primary RCT investigating the primary prevention effect on asthma and wheeze in childhood from vitamin E. not convincingly showed any association with childhood asthma or wheeze and no primary RCT has been performed. 44 For folate, an observational study found higher maternal levels to be associated with an increased risk of asthma at age 3 years. 47 However, in a more recent and larger cohort study there was no association between maternal folate intake and risk of childhood asthma. 48 For selenium, cord blood levels have shown to be negatively associated with persistent wheezing in early childhood, 49 which was later supported by measurements in maternal and cord blood showing reduced risk of wheezing at age 2 but not 5 years by high levels of selenium. 50 There is currently no RCT on selenium supplementation.

| Macronutrients and dietary patterns
An observational cohort study found an association between a maternal Mediterranean diet in pregnancy and a reduced risk of early offspring wheeze until 6.5 years of age. 51 In a meta-analysis of three observational studies, it was found that high adherence to a Mediterranean diet during pregnancy was associated with a reduced risk of wheeze in the offspring during the first year but not later asthma. 52 Mediterranean diet is characterized by high intake of olive oil, nuts, fruits, fish and vegetables and low intake of dairy, red meat and processed meat and has received attention due to the beneficial effects on a wide range of diseases. 53 However, the findings of the impact of Mediterranean diet in pregnancy on wheeze and asthma in early childhood suggest an effect on early wheeze but not later asthma. Studies are observational, hence, intervention trials are warranted to establish whether such an effect exists. There are no current or planned primary RCTs that investigate the protective effect of a Mediterranean diet in pregnancy on childhood asthma.
For the individual diet sources of fruit, vegetables, meat and dairy intake during pregnancy and childhood asthma, the findings of several studies are inconclusive. 53 Interestingly, a recent study from the COPSAC 2010 cohort has shown that vertically transferred metabolites from the mother to the child measured around birth (age 2-3 days) were associated with childhood asthma and infection risk during preschool age. Specifically, higher levels of coffee-related metabolites in the children reduced the risk of asthma at age 6 years, which has also been demonstrated in the VDAART cohort 54 and metabolites related to intake of fruit, green vegetables and fish were all associated with reduced risks of infections that was mainly characterized by respiratory infections. 12 Finally, a large Danish birth cohort study found that children from mothers (n = 60,466) who consumed more artificially-sweetened soft drinks during pregnancy had an increased risk of developing asthma at age 18 months. 55 Summary and future research needs: For dietary patterns, the most promising preventive effect against wheezing and asthma are found in a Mediterranean diet from observational studies, but studies investigating individual macronutrients diet constituents are inconclusive. Future RCTs investigating the primary preventive role of a Mediterranean diet on asthma are warranted.

| Micronutrients
As mentioned previously, vitamin D interventions during pregnancy did not have an effect on asthma until school age. 26,27 In contrast, supplementation with LCPUFA in pregnancy seemed to have a lasting effect on childhood asthma until school age, that is, the persistent wheezing phenotype, although, clinical follow-up of the children in the COPSAC 2010 cohort are ongoing to establish whether this effect is persistent into adolescence. 9 A recent meta-analysis of fish oil supplementation both investigating the effect during pregnancy and infancy, supported a lasting LCPUFA effect on childhood asthma including children up to the age of 16 years, however, with no effect of supplementation during lactation or infancy on later childhood asthma. 56 Also, a study in the ALSPAC cohort found a protective effect of LCPUFA intake at 7 years and later asthma development only in children with FADS gene variants, and this gene-environment interaction was replicated in the BAMSE cohort 57 indicating a similar gene-environment interaction as the one found for prenatal supplementation in COPSAC.
In a combination of two RCTs, a sub investigation explored whether vitamin A or beta-carotene supplementations during pregnancy and early childhood had an effect on the asthma prevalence in later childhood (age span between 9 and 23 years in the two cohorts) but this was not found. 58

| Macronutrients and dietary patterns
A meta-analysis of 12 observational studies investigated the adherence to a Mediterranean diet during childhood and later risk of developing asthma in school age and found no such association, 52 however, they found an effect on wheezing, which suggests an effect on the early transient but not later persistent asthma phenotype. The findings of a protective effect were supported by a previous meta-analysis of eight studies showing that a Mediterranean diet during childhood was associated with both a reduced risk of wheezing and asthma. 61 Differences in the terminology may explain the diverse findings on "asthma" in the meta-analyses as asthma at school age was labeled as current wheeze in the most recent metaanalysis where an effect on wheezing was found. This points toward a potential protective effect of a Mediterranean diet on childhood asthma risk that needs further investigation in RCTs.
In a large cross-sectional study of 50,040 children between the ages of 8 and 12 years, consumption of fruit, vegetables and fish, that is, high adherence to a Mediterranean diet was associated with a reduced prevalence of asthma. 62

| Micronutrients
In a recent comprehensive review it was investigated whether vitamin D could be utilized as a secondary prevention tool in children with asthma on acute wheezing episodes, which overall found conflicting evidence for the use of vitamin D supplementation, although, there was evidence that vitamin D reduced the risk of acute respiratory tract infections in both preschool and school-age children. 63 Another recent meta-analysis also did not find evidence of vitamin D as secondary prevention against asthma exacerbations in children in all ages; however, the study had several limitations including wide variability in populations and interventions and a low number of children in the preschool age, 64 where the largest effects are expected as respiratory tract infections are the most common triggers in this age group. In a large RCT of high-dose vitamin D supplementation (4000 IU/day) in children with an asthma diagnosis and low vitamin D levels aged 6-15 years, a protective effect on severe asthma exacerbations was also not demonstrated. 65 However, large studies investigating the effect of vitamin D as a secondary prevention measure, in particular, among preschool-age children are still lacking, but ongoing registered RCTs such as DIVA and COPSACvitd 66 may reveal this in the future.
Similar to the suggested protective effect of pregnancy and childhood LCPUFA for the prevention of asthma and wheezing, observational studies have also reported associations between high n-3 LCPUFA levels and improved lung function outcomes and reduced medication use among children with asthma suggesting a potential for secondary prevention. 67 In a small RCT among school-age children with asthma, an effect of n-3 LCPUFA supplementation for 10 months was also demonstrated on asthmatic symptoms. 68 In a small (n = 46) RCT, zinc supplementation in children hospitalized due to acute asthma exacerbations reduced asthma severity suggesting this micronutrient as a secondary prevention tool. 69 Summary and future research needs: Large well-conducted RCTs during childhood among children with asthma are still needed to reveal secondary preventive effects of both vitamin D and LCPUFA.

| Macronutrients and dietary patterns
A Mediterranean diet intervention (n = 104) has shown promising effects among a group of preschool-age children diagnosed with asthma on several disease parameters including symptoms, medication use and hospitalizations. 70 The diet, which is characterized by enrichment of antioxidants and monounsaturated fatty acids, is hypothesized to counteract oxidative stress and inflammation leading to asthma symptoms. Further, its components are known to be rich in vitamin D and LCPUFA from fish intake which themself have shown promising effects as already discussed. Therefore, due to the biological plausible effects of a Mediterranean diet on childhood asthma it may be considered as a secondary prevention tool that needs to be further investigated in future studies. A recent systematic review assessed the association between a Mediterranean diet and asthma in childhood from the current literature and found an overweight of studies suggesting this association but concluded that RCTs are warranted due to limitations and heterogeneity of the studies. 71 In addition to the Mediterranean diet as a pattern, vitamin C related fruit intake such as citrus and kiwi fruits among a large TA B L E 1 An overview of current evidence of dietary prevention of childhood asthma. Italian cohort of school children age 6-7 years was associated with a significantly reduced prevalence of wheeze, nocturnal cough and chronic cough. The effect was stronger among children with a history of asthma suggesting vitamin C, which is abundant in the Mediterranean diet, as a specific secondary preventive tool. 72 Summary and future research needs: For secondary prevention of childhood asthma with dietary patterns, a Mediterranean diet looks promising based on a previous intervention study but primary RCTs are needed.

| DISCUSS ION
The literature presented in this review indicates that diet and dietrelated micronutrients, in particular Mediterranean diet, vitamin D and LCPUFA, seem to hold potential for the prevention of asthma in childhood (Table 1, Figure 1). The concomitant rise in asthma prevalence and the increased intake of a Westernized diet worldwide, characterized by fat and highly processed food intake, that is, a diet low in antioxidants and high in saturated fatty acids, further suggests a key role of dietary habits for asthma development. This proinflammatory diet is hypothesized to increase airway inflammation and thereby affect the risk of asthma development. 73 In contrast, the Mediterranean diet is due to the high amounts of antioxidants, fibers, vitamins and n-3 LCPUFA thought to promote an anti-inflammatory environment, which has also been demonstrated in a meta-analysis where the diet was associated with a reduction in systematic inflammation markers. 73 In a sub analysis of the COPSAC 2010 RCT, we previously showed that prenatal supplementation with two of the most promising micronutrients from the Mediterranean diet, the n-3 LCPUFA and vitamin D, changed the infant airway microbiota leading to a decrease in bacteria levels associated with asthma and airway inflammation. 74 The impact of fruit and vegetables from the Mediterranean diet on gut microbiota has also been suggested by others. 73 We also previously showed an association in the COPSAC 2010 cohort between diet-related vertically transferred metabolites measured around birth on the risk of developing asthma and infections until school age and found increased levels of fruit-, fish-and vegetable-related metabolites to be associated with a protective effect on the overall risk of infections. 12 Interestingly, we and others also found that high maternal or newborn levels of coffee-related metabolites were protective of childhood asthma. 12,54 However, an overall protective effect from specific dietary patterns is uncertain based on current evidence as presented in this review. There may seem to exist a potential primary asthma-prevention effect both during the first prenatal and the second neonatal window of opportunities, however, this has to be tested in future large clinical trials. an effect as these are now only speculated to hold potential for primary and secondary prevention due to their antioxidative effects.
In conclusion, this review presents the potential of dietary related micronutrients and dietary patterns for primary and secondary asthma prevention in early and late childhood from the existing literature. We aimed to clarify and discuss the most promising early di-

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare no potential, perceived, or real conflict of interest regarding the content of this manuscript.

PE E R R E V I E W
The peer review history for this article is available at https:// www.webof scien ce.com/api/gatew ay/wos/peer-revie w/10.1111/ pai.13984.