Hannah Kansen

General discussion and

This thesis demonstrates that more than half of children and one third of adults can be classified correctly using sensitization to peanut component Ara h 2. To further increase the proportion of correctly classified patients, future studies should evaluate diagnostic tools for children and adults with ‘inconclusive’ levels of Ara h 2 (Ara h 2 levels between 0.1 and 5.0 kU A/L and < 1.75 kU A/L, respectively) and for peanut-allergic adults not showing sensitization to peanut components. A previous study demonstrated that half of children with Ara h 2 levels between 0.1 and 5.0 kU A/L could be classified correctly when using the Basophil Activation Test (BAT) as a second step in the diagnostic process. As the BAT is not yet used in daily practice due to practical, technical and analytical limitations, future studies should focus on standardization, validation and automation of this procedure. Furthermore, the diagnostic value of the Mast cell Activation Test (MAT) has been evaluated. The MAT might be superior to other existing diagnostic test modalities, including sIgE to Ara h 2 and the BAT, but further research is needed to validate these findings and facilitate implementation in daily practices. In addition, patterns of IgE binding to specific regions of an allergen (i.e. allergenic epitopes) in microarray immunoassays may become a future diagnostic tool. Peanut-allergic patients showed more IgE epitope binding and broader epitope diversity compared with peanut-tolerant patients in previous studies. 53,54 In addition, the analysis of patient-derived monoclonal antibodies may provide diagnostic insight after further development. This approach could provide information on epitope affinity and specificity. Finally, understanding potentially allergy-promoting lipids may improve serum-based allergy diagnostics. Lipids may enhance the allergenicity of proteins in several ways, e.g. by enhancing an IgE dominant response or by influencing the ability of allergens to penetrate through the oral, respiratory or gastrointestinal mucosa cells. 56,57 It must be noted that current diagnostic IgE test modalities fail to predict the threshold of an allergic reaction and the severity of peanut allergy of individual patients. The mechanisms driving the severity of food allergic reactions remain poorly understood. 58,59 Future research, including immunologic, genetic and epigenetic analyses, may enhance our understanding of the reaction threshold and reaction severity and identify biomarkers for severe allergic reactions. As an example, recent research observed a correlation between an expansion of peanut-specific effector T-cells and high clinical reactivity (i.e. allergic reaction at a dose less than or equal to 300 mg peanut protein) in peanut-allergic patients. Another recent study identified several genes and DNA methylation sites associated with reaction severity in peanut-allergic children. 61 When considering different diagnostic strategies for peanut allergy, it is vital to take into account the wishes of parents and/or patients and make shared decisions. Patients may still prefer oral food challenges to laboratory testing, as they may wish to consume peanut in a safe environment and experience whether, when and what symptoms occur after peanut ingestion. In patients with high and conclusive Ara h 2 levels (i.e. Ara h 2 ≥ 5.0 kU A/L in children and ≥ 1.74 kU A/L in adults), the oral food challenge protocol may be adapted to reduce the burden and costs of food challenges. Moreover, the future of peanut allergy diagnostics is likely changed by emerging prospects for prevention and treatment of peanut allergy. Prevention of peanut allergy In 2015, the Learning Early About Peanut Allergy trial clearly showed that peanut introduction early in life significantly decreased the risk of peanut allergy among infants with high-risk atopic disease(s) (i.e. severe atopic dermatitis, egg allergy or both). 64 The trial received wide publicity and new peanut allergy prevention guidelines were developed. 65–67 The paradigm shift in the timing of food allergen introduction has implications for future peanut allergy diagnostics. Early introduction of peanut may likely lower the prevalence of peanut allergy, but may also increase the frequency of diagnostic testing at a younger age. Previous data showed that sIgE to storage proteins, including Ara h 2, is present in children below the age of 4 years. 17,68 However, as our diagnostic flowchart is based on sIgE to Ara h 2 cutoff levels in children aged 3.5 to 18 years, further research is necessary to confirm or adapt Ara h 2 cutoff levels in younger children. Treatment of peanut allergy Our long-term follow-up of peanut-allergic children showed that living with a peanut allergy remains a challenge during childhood. 38 Previous studies have observed the same in adulthood. The current management of peanut allergy includes (instructions on) an elimination diet, instructions on and prescription of emergency medication and advice for timely administration of emergency medication when an allergic reaction occurs. In recent years, oral or epicutaneous immunotherapy for the treatment of peanut allergy has been the subject of much research. 69,70 In January 2020, the first oral immunotherapy product has been approved by the United States Food and Drug Administration. 71 Immunotherapy relies on the delivery of gradually increased doses of the allergenic food to increase the threshold of an allergic reaction during treatment (i.e. desensitization) and after treatment (i.e. sustained unresponsiveness). 72–74 Recent studies found that the primary motivation for undergoing oral immunotherapy was to reduce the risk of fatal allergic reactions. 75 Parents who perceived their child to be at high risk of fatal food allergic reactions were more likely to enroll in peanut immunotherapy compared with routine clinical care (i.e. peanut avoidance). 76 However, a recent systematic review and meta-analysis showed that current peanut oral immunotherapy regimens increased the risk of allergic reactions, including anaphylaxis, compared with peanut avoidance. 77 Low-dose oral or epicutaneous immunotherapy may better align with families’ goals. Overall, carefully outweighing the pros versus the cons of immunotherapy for food allergy is paramount in deciding the appropriate strategy per patient. Further research is warranted to evaluate long-term results and patients’ perspectives. Risk factors for atopic diseases differ from risk factors for recurrent infections In this thesis, the association between risk factors and atopic diseases and between risk factors and recurrent respiratory tract infections (RRTI) was investigated in a large cohort of children aged 1 to 18 years (chapter 5). The results demonstrate that the demographic and environmental risk factors associated with atopic diseases largely differ from the risk factors associated with RRTI. Interestingly, family history was a disease-specific risk factor for atopic diseases and RRTI. A family history of atopic diseases and RRTI reflects genetic susceptibility, as well as shared environmental and behavioral factors. Clustering of diseases in families is typically due to multifactorial inheritance, determined by a number of genes in interaction with environmental and lifestyle factors, and not due to single genetic mutations. Strong evidence for the importance of genetic factors in the susceptibility to atopic diseases comes from studies among genetically identical twins, indicating a concordance rate of approximately 81% for food allergy, 95% for asthma, 91% for allergic rhinitis and 84% for atopic dermatitis. 79 Furthermore, atopic diseases are to a large extent genetically related. 80 However, our and previous studies indicate that some genetic risk factors are disease-specific. 81 The genetic correlations between atopic diseases have been estimated <1, suggesting that there are unique genetic influences to each atopic disease. 82,83 In addition, the association between family history and RRTI requires further investigator, as it has not been described before. Previous literature reported an association between family history and specific genetic diseases (e.g. primary immunodeficiencies, cystic fibrosis and primary ciliary dyskinesia). 84–86 Given the rarity of these diseases, the association between a family history and RRTI as observed in our cohort is likely explained by a multifactorial, polygenic inheritance pattern. A family history can be easily assessed and used for the prevention, detection and management of disease. Therefore, the family history of atopic diseases and recurrent respiratory tract infections should be assessed by physicians in clinical practice to identify high-risk children. 87 The impact of atopic diseases on patients’ welfare The evaluation of the patient’s perception of their health is an important aspect of patient-centered care. The patient’s perception can be evaluated using patient-reported outcome measures (PROMs). 88 An example of frequently used PROMs are standardized and validated questionnaires on anxiety and health-related quality of life (HRQL) as administered in several studies described in this thesis. Children with food allergy have poorer HRQL than children in the general population, due to multiple disease-specific impairments such as social and dietary restrictions, the need to carry an epinephrine auto-injector and the fear of accidental allergic reactions. 89,90 Compared to other diseases, children with food allergy showed more impairment in HRQL than children with chronic liver disease or diabetes mellitus, but less impairment in HRQL than children with asthma. 89,91 Especially children with uncontrolled asthma have impaired HRQL. 92,93 In the second part of this thesis, we focused on improving the welfare of patients with atopic diseases, particularly children with peanut allergy and asthma. We studied anxiety and quality of life after peanut allergy diagnostics. Furthermore, we investigated the prevalence and predictors of uncontrolled asthma and the impact of asthma triggers on HRQL. Anxiety and quality of life improve after a clear diagnosis We summarized recent literature on the association between HRQL and food allergy diagnostics in chapter 6 and showed that oral food challenges are associated with improved HRQL and reduced parental burden, regardless of the food challenge result. The greatest improvement in HRQL was observed among children who demonstrated tolerance. In chapter 2, we demonstrated a large reduction of parental anxiety after the telephonic consultation discussing an Ara h 2 level ≤ 0.1 kU A/L (i.e. peanut-tolerant) and after oral food challenges, in the latter case even irrespective of the result. Although peanut allergy diagnosis is clear in children with an Ara h 2 level ≥ 5.0 kU A/L (i.e. peanut-allergic), parental anxiety remained unchanged after the telephonic consultation. Uncertainty regarding the severity of peanut allergy and the threshold of an allergic reaction may be associated with anxiety, as reported in previous research. 94 Uncertainty and anxiety may be reduced after an oral food challenge, as this procedure provides insight into these matters. Our and other studies have shown a reduction in food allergy-related anxiety after an oral food challenge, regardless of the result. 94,95 These findings suggest that a clear diagnosis of food allergy may have beneficial psychosocial impact. However, the main reason to decline a food challenge or (home) introduction after the determination of sIgE to Ara h 2 was anxiety of the child and/or parents. Children or parents may experience anxiety or distress about the possibility of an allergic reaction during the procedure. 94 Although some increased level of anxiety in patients with food allergy is an appropriate response, excessive anxiety should be recognized and treated. Mental health professionals may treat excessive anxiety through consultation or psychotherapy, or provide support during oral food challenges, as recommended in a recent position statement of the American Academy of Allergy, Asthma & Immunology. 96 Further work to study anxiety in food allergic children and the impact of psychological interventions needs to be done, as most studies focused on parents 94,95,97,98 or adults. 99 The benefit of psychological interventions has been reported in mothers of food allergic children. A brief cognitive behavioral therapy session was associated with significantly reduced anxiety after one year follow-up compared to no intervention, especially in mothers with high baseline anxiety levels. 98 Uncontrolled asthma is highly prevalent in children with asthma In chapter 7 it was demonstrated that uncontrolled asthma is highly prevalent in children referred for asthma (47%), but also in children referred for other atopic diseases than asthma (26%) to secondary care. We found a family history of asthma, recurrent upper or lower respiratory tract infections and a referral for asthma to be independently and significantly associated with uncontrolled asthma. The current clinical guideline emphasizes that the main goal of asthma management is to attain and to keep good asthma symptom control. 100 From previous studies we know that uncontrolled asthma is associated with health-related quality of life (HRQL); the better asthma control, the better HRQL. 101,102 Patients with well-controlled asthma had similar HRQL as participants without asthma in a Swedish population-based cohort study. 103 In addition to the patient burden, uncontrolled asthma poses a substantial and growing burden on healthcare systems. A recent study in the United States estimated that around 20% of direct costs of asthma can potentially be saved if all patients would achieve adequate asthma control. 104 In order to reduce the patient and economic burden of uncontrolled asthma, an accurate review of the asthma control status is essential. Our study indicates that assessment of disease control is not only important for children who are referred for asthma, but also for children who are referred for other atopic diseases than asthma. As patients and physicians tend to overestimate the level of asthma control 105 and differ in their perception of asthma control 106, standardized tools to monitor asthma control such as the Asthma Control Test are recommended at visits to the outpatient clinic. 107,108 These tools should be used regularly, as asthma is characterized by marked fluctuations in symptoms over time. Asthma triggers are associated with reduced health-related quality of life Asthma control is affected by various asthma triggers. For instance, strenuous physical exercise, bad weather, strong emotions or exposure to pollen or pets can trigger asthma symptoms. 109 As described in chapter 8, more than three quarters of children with asthma report one or more perceived trigger(s) of asthma symptoms. The evaluated asthma triggers are depicted in Figure 2. Previous research identified an association between a higher number of asthma triggers and reduced asthma-specific HRQL in children with severe or difficult-to-treat asthma and in adults with asthma. 110–113 We were able to confirm this association between asthma triggers and HRQL, both asthma-specific and generic, in children with asthma of varying severity in secondary and tertiary care. Children with a high number of asthma triggers may experience impaired HRQL due to an increased frequency of asthma exacerbations and health care visits. 112–114 Furthermore, children may try to avoid asthma triggers which may have additional negative impact on HRQL. The asthma trigger ‘emotions’ was consistently associated with both asthma-specific and generic HRQL in our population. Previous work found that almost one third of asthmatic patients reported emotional triggers as the most frequent trigger of asthma symptoms. 113 Examples of emotional triggers are stress, worry, feelings of loneliness or excitement and being angry. Interventions to reduce emotional distress may lower the impact of these triggers on HRQL. The results of our study highlight the importance of asthma triggers in children with asthma. Physicians should evaluate the number and impact of asthma triggers on asthma symptoms in children with asthma. Further research is needed to evaluate the impact of identification, and subsequent avoidance and/or treatment, of asthma triggers on patient HRQL. Figure 2. Asthma triggers Future aspects ‘Health as the ability to adapt and to self-manage, in the face of social, physical and emotional challenges.’ Machteld Huber, 2011 115 The traditional WHO definition of health formulated in 1948, as stated in the Introduction section of this thesis, has been debated ever since. 116,117 Particularly the absoluteness of the words ‘complete wellbeing’ has been criticized. This formulation of health may contribute to the medicalization of society and is no longer considered adequate in an era with increasing numbers of people living with chronic diseases. A new concept of health was introduced by Machteld Huber and colleagues in 2011. 115 The new, dynamic concept of health, as cited above, focuses on a person’s resilience and ability to cope with new situations. The support for this new health concept was evaluated among various stakeholders, including patients and physicians. 118 Physicians considered bodily functions and quality of life as the most important dimensions of health, where patients also considered societal, mental and spiritual dimensions as important dimensions. The changing definition of the concept of health and the discrepancy between the perception of health by patients and by physicians requires attention. Future health-related quality of life (HRQL) research in patients with atopic diseases should attempt to validate questionnaires that measure various dimensions and aspects of health, including the burden of disease, coping, resilience, patients’ satisfaction and disease-specific anxiety. In addition, psychosocial interventions to reduce anxiety and improve coping and resilience should be evaluated, as these actions may improve quality of life in patients with atopic diseases and their families. Currently, HRQL is mainly assessed in research settings, while implementation in daily clinical practice is important to improve counseling and enable identification of high-risk children who could benefit from psychosocial interventions. Health-related quality of life should be assessed in both children and parents, as they differ in their view concerning HRQL. A previous study among food allergic children aged 8 to 12 years and their parents suggest that parents report better HRQL than children. 119 To date, child-reported food allergy specific HRQL questionnaires are available for children aged 8 years and older. Instruments to assess HRQL in younger children are needed, especially now that prevention strategies and immunotherapy target this age group. The assessment of patient-reported outcomes before and after immunotherapy is gaining increasing importance and is critical in the evaluation of the benefits and risks of immunotherapy. 73