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Keywords:

  • allergy;
  • pediatrics;
  • asthma;
  • eczema;
  • rhinitis;
  • viewpoint

Abstract

  1. Top of page
  2. Abstract
  3. Background
  4. Preventing allergies
  5. Conclusion and recommendations on preventing allergies
  6. Controlling allergies
  7. Conclusion and recommendations on controlling allergies
  8. Curing allergies, outgrowing allergies
  9. Conclusion and recommendations on curing allergies
  10. Conclusion
  11. References

To cite this article: Van Bever HPS, Lee BW, Shek L. Viewpoint: The future of research in pediatric allergy: What should the focus be? Pediatric Allergy Immunology 2012: 23: 5–10.

Abstract

Allergic diseases have been increasing during the last three decades, and exact reasons for this are still debated. Despite intense ongoing research, a lot of aspects of allergic diseases are still poorly understood, resulting in limitations in current therapeutic approach to allergies. In this viewpoint, important unanswered research questions are raised mainly on novel therapeutic approaches to allergic children, and suggestions for future research are raised. Three aspects of pediatric allergy are distinguished: the prevention, control, and cure.


Background

  1. Top of page
  2. Abstract
  3. Background
  4. Preventing allergies
  5. Conclusion and recommendations on preventing allergies
  6. Controlling allergies
  7. Conclusion and recommendations on controlling allergies
  8. Curing allergies, outgrowing allergies
  9. Conclusion and recommendations on curing allergies
  10. Conclusion
  11. References

Among other diseases such as obesity and diabetes, allergic diseases have been increasing during the last 3 decades. Most studies on the increase of allergic diseases were focused on asthma, rhinitis and eczema (1). More recently, however, a rise in food allergy has been reported (2). The exact reasons for this worldwide increase in allergy are still largely not understood. Furthermore, the inadvertent role of medical doctors, as prescribers of medications, such as broad spectrum antibiotics and paracetamol, is still unresolved (3). The popular Hygiene Hypothesis, highlighting that decreased bacterial contacts are responsible, only can explain part of the increase (4–6). Other factors that might be responsible seemed to be related to life style and culture, and, therefore, it makes more sense proposing that a ‘Wrong Life Style Hypothesis’ is a broader, albeit hollow, cover explaining the increase of allergies (i.e. sedentary and luxury life style, overconsumption of medication) (7). Yet, despite intense ongoing research, many aspects of allergic diseases are still poorly understood, resulting in limitations in the current therapeutic approach to allergies.

Allergic diseases are initiated by allergens inducing IgE, resulting in inflammation in specific end organs, such as skin (eczema), lungs (asthma) and rhinitis (nose). However, many steps in the cascade are still poorly understood, and it is still unclear whether different mechanisms, involving different cells, mediators, and cytokines, are involved to eventually result in IgE production. The fact that allergic disorders are heterogeneous, have different outcomes, and a variable response to treatment, suggest different underlying mechanisms which might be under the control of genetic constitution, epigenetic mechanisms and environment (i.e. window of exposure, amount and mode of allergen exposure) (8, 9). Moreover, recent studies on filaggrin null-mutations in children with eczema suggest that allergy is not a cause, but merely a consequence of skin barrier defects, and that it is the skin barrier defects that induce The Allergic March (10). Similar mechanisms might be involved (not proven) in allergic asthma, starting in most young children as recurrent lower respiratory tract infections (bronchitis, bronchiolitis), subsequently followed by the onset of allergy. Therefore, it is possible that viral infections, such as respiratory syncytial virus (RSV), can be the initiator of allergic asthma (11). Therefore, it seems that the feature ‘allergy’ might have different origins (genes vs. environment) and mechanisms, needing different management approaches. The mechanisms that are behind the dynamics of allergy are still not understood. Genes do not change, and usually the individual environment doesn’t change: therefore new answers might come from mechanisms involved in regulation of gene expression (epigenetic mechanisms), and the impact on epigenetic mechanisms by minimal environmental changes that occur in a growing child (i.e. diet, school, sports, and other age-related life style changes). Moreover, the role of viruses is still underestimated, and it is likely that with new identification techniques it will become possible to attribute certain dynamisms of allergy to a viral infection/colonization (12).

Important questions on the mechanisms of The Allergic March (i.e. the switch from one to another manifestation), diversity of clinical presentation (even in identical twins), the mechanisms of out-growing allergies, etc. remain unanswered. Therefore, new research approaches, using new laboratory techniques (i.e. on epigenetics, virus identification, specific immune responses, etc.) are urgently needed. In this viewpoint, important unanswered research questions are raised mainly on novel therapeutic approaches to allergic children, and suggestions for future research are raised. Three aspects of pediatric allergy need specific attention: its prevention, its control, and its cure.

Hence, based on current knowledge, the three important questions that remained unanswered are:

  • 1
     How can allergic sensitization be prevented in newborns/young children?
  • 2
     How can controller treatment of allergic diseases be improved?
  • 3
     What are the mechanisms of The Allergic March (i.e. the switch from one to another clinical manifestation) and of outgrowing an allergic disease?

Preventing allergies

  1. Top of page
  2. Abstract
  3. Background
  4. Preventing allergies
  5. Conclusion and recommendations on preventing allergies
  6. Controlling allergies
  7. Conclusion and recommendations on controlling allergies
  8. Curing allergies, outgrowing allergies
  9. Conclusion and recommendations on curing allergies
  10. Conclusion
  11. References

The optimal approach to allergies is to prevent them from becoming clinically expressed. Therefore, future research should mainly focus on this aspect of allergic diseases. A number of primary preventive measures have been investigated during the last decades. Most studies have focused on avoidance of allergens. Based on this, studies on primary prevention measures have specifically targeted nutrition and environmental control in newborn babies (13–15). A summary of the findings is shown in the Table 1, and findings were reviewed by Hamelmann et al. (16).

Table 1.   Primary prevention strategies and their outcome
StrategyOutcome
Prolonged breast feedingBreast feeding is useful for the child’s health and may prevent allergic sensitization in early life. However, there is no clear benefit for the development of inhalant allergies later in childhood.
Hydrolyzed formula feeding (HA-milks)Hydrolyzed formulae in young at-risk infants reduce the incidence of food allergy and eczema up to the age of 3–5 yr, but have no benefit beyond the sixth month of life. Hydrolyzed formulae should be recommended in cases where it is impossible to give breast feeding
Delayed introduction of solid foodsThere is no evidence that delayed introduction of solid food after 6–8 months of life is useful to prevent food allergy
Avoidance of indoor inhaled allergensContradictory results. Reduction of exposure to indoor allergens (house dust mites) might even increase the risk for allergy and should not be recommended. Early exposure to pets might have a protective effect, but there are no intervention studies
Avoidance of pollution and smokePollution and smoke avoidance is mandatory to maintain respiratory health, and may be effective in reducing the risk of asthma and allergy

So far, primary prevention of allergic diseases has in large part failed to be shown efficient. Prolonged breast feeding (up to 6 months) is still the best, but unable to completely prevent the development of allergy (17).

On the other hand, over the last years a new concept of primary prevention has progressively emerged, which proposes that early exposure to allergens, such as house dust mites and pets, might be able to induce tolerance (18–21). Therefore, a solution for the future might be a controlled exposure to important allergens, as can be achieved by specific immunotherapy, such as subcutaneous immunotherapy (SIT) or sublingual immunotherapy (SLIT), but this requires extensive study.

The role of bacterial products (i.e. probiotics, prebiotics, and synbiotics) in primary prevention is still a matter of debate. Most studies show positive results (i.e. publication bias?) on eczema, but not on IgE-mediated immune responses or on respiratory allergies. In some studies, however, no effect was found (22), while in other an increase of allergic sensitization was demonstrated (23, 24). Therefore, more research on this important topic is certainly needed.

Interventions of primary prevention can be divided into: interventions during pregnancy (prenatally) and interventions during early life (postnatally). Both types of interventions have been reviewed in the literature (16, 25). Most studies have been performed on postnatal primary prevention, while only a few intervention studies during pregnancy have been published.

Recommendations during pregnancy

T-cell conditioning, including allergic build-up, seems to start prenatally (26, 27). In an article By Boyle and Tang, the current knowledge on prenatal interventions is reviewed (25). Although only a limited number of studies have been published on prenatal interventions, the following interventions during pregnancy have been reported:

Studies on bacterial load during pregnancy

It has been shown that maternal exposure during pregnancy to an environment rich in microbial compounds (i.e. living on a farm) is protective against the development of atopic sensitization in the children (28, 29). In the classical study by Isolauri’s group, administration of probiotics during pregnancy and postnatally during 6 months (during prolonged breast feeding or formula feeding) was able to reduce the prevalence of eczema by about 50%, but it had no effect upon IgE-mediated hypersensitivity or the subsequent development of respiratory allergy (asthma, rhinitis) (30). In another study from New Zealand, supplementation with Lactobacillus rhamnosus, but not with Bifidobacterium animalis, was able to reduce the prevalence of eczema, when it was started during pregnancy and continued during 6 months of breast feeding (31).

Studies on allergen avoidance during pregnancy

Only a limited number of studies have been published on allergen avoidance during pregnancy (avoidance of house dust mite, avoidance of eggs, peanuts and cow’s milk) and no beneficial effect was shown (32, 33). In contrast, increased sensitization in the offspring was found in a number of them [reviewed in reference (25)]. A Cochrane review concluded: ‘the prescription of an antigen avoidance diet to a high-risk woman during pregnancy is unlikely to reduce substantially her child’s risk of atopic diseases, and such a diet may adversely affect maternal and/or fetal nutrition’ (34).

Other interventions during pregnancy

There is limited information that administration of vitamin D and fish oil supplementation to pregnant women might have an inhibitory effect on the development of allergy in their children. However, more studies are needed before this can be recommended (reviewed in references (25, 35)]. Although no intervention studies have been performed, usage of paracetamol and antibiotics during pregnancy has been associated with an increased risk to develop asthma and allergy in the offspring (36, 37).

Recommendations during breast feeding

There are no studies showing that any specific maternal diet is beneficial for the prevention of allergy during breastfeeding (38, 39). However, birth cohort studies from Denmark suggested that the daily intake of cow’s milk (by the mother) via breast milk may be beneficial and facilitate tolerance induction to cow’s milk (40). In the same studies, however, it was observed that the administration of supplement cow’s milk-based formula during the first 5 days in the newborn nursery increased the risk of specific sensitization (41). Maternal intake of other food, such as egg, peanut or seafood does not seem to have an impact on allergen sensitization of the child (39).

Conclusion and recommendations on preventing allergies

  1. Top of page
  2. Abstract
  3. Background
  4. Preventing allergies
  5. Conclusion and recommendations on preventing allergies
  6. Controlling allergies
  7. Conclusion and recommendations on controlling allergies
  8. Curing allergies, outgrowing allergies
  9. Conclusion and recommendations on curing allergies
  10. Conclusion
  11. References

Preventing allergies has failed so far. Therefore, more and better studies are needed on primary prevention and on the early events of allergic diseases. Interventions should be safe, and without any risk of altering other immune functions. Therefore, it is very unlikely that a medication would be the candidate for it. Interventions should mainly involve life style and the usage of natural products, such as bacterial products or allergens. Briefly, the following issues should be addressed in future research:

  • 1
     The mechanisms of the initiation of allergic reactions in newborns is still a field that needs unraveling (i.e. which genes, epigenetic mechanisms, molecules and cells are responsible for the onset of allergy, preferentially looking at specific allergy profiles).
  • 2
     The exact role of bacterial products (probiotics, prebiotics, and synbiotics), including the best type of bacterial product, best dose, and best window of administration.
  • 3
     The exact role of early allergen exposure, including whether high allergen exposure is able to induce tolerance to allergens (including the role of early administration of immunotherapy, such as SLIT). This should be studied prenatally and/or postnatally.
  • 4
     Breast milk will always be the best, and no other milk or formula will replace breast milk. Therefore, studies should be set up aiming to make breast milk more anti-allergic. Indeed, in a limited number of studies it was shown that high levels of IL10 and TGF-beta in breast milk have a suppressing impact on allergic sensitization in infants (42). Candidates to make breast milk more anti-allergic are immunotherapy, bacterial products and worm antigens (!), administered during lactation.
  • 5
     Epidemiological studies to better understand the differences between population differences (i.e. urban vs. rural), helping to elucidate mechanisms.

Controlling allergies

  1. Top of page
  2. Abstract
  3. Background
  4. Preventing allergies
  5. Conclusion and recommendations on preventing allergies
  6. Controlling allergies
  7. Conclusion and recommendations on controlling allergies
  8. Curing allergies, outgrowing allergies
  9. Conclusion and recommendations on curing allergies
  10. Conclusion
  11. References

Good controller medications, such as inhaled and intra-nasal corticosteroids, antihistamines, beta-agonists and others are available: they are affordable, safe and effective. Therefore, most children with allergy can have a normal life, as long as they take their medication. However, kids with severe allergy still have an impaired quality of life, also affecting family life (43). For these children better controller treatments (i.e. holistic approaches) should be developed. A major obstacle in treating allergic children is compliance (44). Most children (and parents) stop medication once symptoms have subsided. It is of great importance to focus on improving compliance to controller treatment by educational programmes, and by improving treatment facilities (i.e. long-acting drugs, easy administration, better devices, and monitoring systems of compliance). Moreover, change in life style programmes might become implicated as part of the global approach to allergic diseases (i.e. sports to encourage physical activity).

The new monoclonal antibodies, such as anti-IgE or anti-IL5 have offered new perspectives, and new possibilities to control allergic diseases (45, 46). However, monoclonal antibodies are expensive, have potential severe side effects (anaphylaxis), are unfriendly to children (painful injections) and are far too expensive to become a routine treatment for allergic children. Furthermore, monoclonal antibodies only control symptoms, without having any curative or carry-over effect. In contrast, for a subgroup of children specific immunotherapy (such as SLIT) might have a role in controlling symptoms (47). Taken together, it is still important to perform research on better medications for allergy, bearing in mind that future medications should be safe, cheap, effective, child-friendly and easy to use and to access.

Conclusion and recommendations on controlling allergies

  1. Top of page
  2. Abstract
  3. Background
  4. Preventing allergies
  5. Conclusion and recommendations on preventing allergies
  6. Controlling allergies
  7. Conclusion and recommendations on controlling allergies
  8. Curing allergies, outgrowing allergies
  9. Conclusion and recommendations on curing allergies
  10. Conclusion
  11. References
  • 1
     Development of better medication that can improve compliance, such as long-acting medication, easier devices, and compliance monitoring systems.
  • 2
     Development of simple and easy to access life style change interventions and educational programmes, involving family, schools and communities.
  • 3
     Separate approach plans to identify and treat children with severe allergies, involving non-routine treatments.
  • 4
     Establish the role of immunotherapy to control ongoing allergic symptoms, or as an early treatment of allergic symptoms. Current guidelines on the place of immunotherapy lack strong scientific evidence. Usually immunotherapy is only started when conventional treatment is insufficiently effective. However, there is no good scientific reason for that. Early administration of immunotherapy, aiming to halt The Allergic March in young children and to prevent deterioration of ongoing allergic processes (such as airway remodeling) should be studied (48).

Curing allergies, outgrowing allergies

  1. Top of page
  2. Abstract
  3. Background
  4. Preventing allergies
  5. Conclusion and recommendations on preventing allergies
  6. Controlling allergies
  7. Conclusion and recommendations on controlling allergies
  8. Curing allergies, outgrowing allergies
  9. Conclusion and recommendations on curing allergies
  10. Conclusion
  11. References

The mechanisms of The Allergic March and the mechanisms of outgrowing allergy are still very poorly understood. However, unraveling these underlying mechanisms may provide essential clues and be pivotal to develop new treatments that might cure allergy. In general, and from several studies, it is generally accepted that most (80%) children with eczema will grow out of it, although long-term follow-up studies from childhood into adulthood are lacking. In one study it was shown that persistence of eczema was associated with the development of allergy to inhalant allergens, and that those children who grew out of their eczema were those who did not develop any underlying allergic reactions (49). In another study it was found that of 571 children with eczema at the age of 7 yr, the proportion of children who were clear in terms of examined eczema or reported eczema at ages 11 and 16 yrs was 65% and 74%, respectively (50).

In contrast to eczema, children with allergic rhinitis tend not to outgrow the condition with persistence of their symptoms into adulthood, leading to chronic rhino-sinusitis as a common complication (51). In a recent study from The Isle of Wight, it was shown that allergic rhinitis becomes increasingly common as children grow into adolescents (from 5.4% at 4 yr to 35.8% at 18 yr), with stronger associations to male gender (52). However, as in eczema, long-term prospective studies, in which children with allergic rhinitis are followed into adulthood, are lacking.

A number of well-conducted long-term studies on asthma from childhood into adulthood have been published (53–56). Taken together, these studies demonstrate that half of asthmatic children go into clinical remission in adulthood. Both complete and clinical remissions were associated with a better lung function level in childhood (FEV1). The role of treatment is uncertain, since all studies began in a period when inhaled corticosteroids and other novel medications were not available. However, from short-term studies it is now clear that inhaled corticosteroids have little disease-modifying effect, and that asthma symptoms re-occur once inhaled corticosteroids are stopped (57).

A study evaluating bronchial biopsies in subjects in remission for more than 3 yr suggests that asthma might persist throughout life (54). In a study on exhaled nitric oxide (NO) in asthmatic adolescents, persistence of high levels of NO was observed in adolescents in clinical remission, suggesting that inflammation persists, but that subjects become ‘tolerant’ to it (58). In an older study by Hill et al. (59), it was found that long-term perennial allergen exposure favors the induction of clinical and immunological hypo-responsiveness, whereas intermittent seasonal allergen exposure is associated with persistent clinical and immunological hypersensitivity, and persistent symptoms. Taken together, asthma symptoms settle during adulthood in about 50% of asthmatic children, and good lung function increases the chances. On the other hand, the role of allergy in the long-term prognosis is unknown, but minimal according to one study (60). However, it was shown that both bronchial inflammation and bronchial hyperresponsiveness persist in most children who had outgrown asthma, but become dissociated from clinical manifestations. The underlying mechanisms of this dissociation are unknown, but the mechanisms of this ongoing ‘silent’ inflammation (i.e. tolerance) might be linked to epigenetic mechanisms. Knowledge of it could open new areas of treatment.

Food allergy, which is usually an isolated IgE-mediated reaction, involving mast cells, and of which the most common symptoms are urticaria, angioedema and anaphylaxis, has different long-term outcomes, which are largely dependent on the type of food. Allergy to cow’s milk and eggs usually settle within the first years of life, though exceptions seem to be common (61). In contrast, allergy to peanuts, fish and seafood usually remains for a life time, as only a minority of subjects will outgrow this allergy (for peanuts this is about 20%) (62). Underlying mechanisms are also unknown, but immunotherapy seems to have a positive effect upon the process, inducing tolerance or desensitization (63). Furthermore, studies on immunotherapy, using SIT and SLIT, in respiratory allergy have shown that it has a carry-over effect persisting for up to four extra years (after a duration of 4 yr) (64), prevents new sensitizations (65) and prevents the development of asthma in patients suffering from rhinitis (48). Therefore, it is generally accepted that specific immunotherapy can help cure allergy, and studying immunotherapy is an appropriate model in research on the mechanisms behind the processes of growing out of an allergy.

Conclusion and recommendations on curing allergies

  1. Top of page
  2. Abstract
  3. Background
  4. Preventing allergies
  5. Conclusion and recommendations on preventing allergies
  6. Controlling allergies
  7. Conclusion and recommendations on controlling allergies
  8. Curing allergies, outgrowing allergies
  9. Conclusion and recommendations on curing allergies
  10. Conclusion
  11. References

The processes that initiate growing out an allergy and the processes responsible for its dynamics (i.e. The Allergic March) are still largely unknown. Studying these processes is pivotal to develop treatments that can cure allergy. Therefore, it is suggested that research should focus on following aspects;

  • 1
     Study the underlying mechanisms of The Allergic March and of growing out of allergies (epigenetics – role of viral infections – role of bacterial products/vaccines).
  • 2
     Study risk factors for persistence of asthma, rhinitis, eczema, and food allergy into adulthood.
  • 3
     Study how to induce the growing out process, especially the exact role of immunotherapy, life style and other interventions (such as bacterial products, commonly used preventive treatments).

Conclusion

  1. Top of page
  2. Abstract
  3. Background
  4. Preventing allergies
  5. Conclusion and recommendations on preventing allergies
  6. Controlling allergies
  7. Conclusion and recommendations on controlling allergies
  8. Curing allergies, outgrowing allergies
  9. Conclusion and recommendations on curing allergies
  10. Conclusion
  11. References

Allergic diseases are still one of the most common problems affecting children of all ages and resulting in considerable morbidity. Despite the fact that allergic diseases can be controlled in most children, prevention and cure are still impossible. Future research should be focused on prevention, better control and a cure of allergy.

References

  1. Top of page
  2. Abstract
  3. Background
  4. Preventing allergies
  5. Conclusion and recommendations on preventing allergies
  6. Controlling allergies
  7. Conclusion and recommendations on controlling allergies
  8. Curing allergies, outgrowing allergies
  9. Conclusion and recommendations on curing allergies
  10. Conclusion
  11. References