APPEAL‐2: A pan‐European qualitative study to explore the burden of peanut‐allergic children, teenagers and their caregivers

Abstract Background Allergy to Peanuts ImPacting Emotions And Life (APPEAL‐1) was a recent European multi‐country questionnaire survey that highlighted the negative impacts of peanut allergy (PA) on quality of life. A follow‐on qualitative study, APPEAL‐2, further assessed the burden of PA and associated coping strategies through semi‐structured interviews. Objective To gain qualitative insight on the strategies used to cope with and manage PA and the impact of these strategies on the quality of life of children, teenagers and caregivers. Methods This cross‐sectional qualitative study was conducted in eight European countries: the United Kingdom, France, Germany, Ireland, Spain, Italy, Denmark and the Netherlands. Semi‐structured interviews were conducted with children (aged 8‐12 years) and teenagers (aged 13‐17 years) with self‐/proxy‐reported moderate or severe PA and with parents/caregivers of children or teenagers (aged 4‐17 years) with moderate or severe PA. Data were analysed using thematic analysis; data saturation was assessed. Two conceptual models were developed to illustrate the impacts of PA and coping strategies used to manage them for (a) individuals with PA and (b) parents/caregivers of children with PA. Results 107 participants were interviewed: 24 children, 39 teenagers and 44 caregivers. The conceptual models illustrated themes related to coping and control, driven by the fear of PA reactions, and the associated emotional, social, relationship and work impacts. Factors moderating these impacts included social attitudes and support, child‐caregiver relationship and coping strategies used. Conclusions and Clinical Relevance The APPEAL‐2 results substantiate the findings of APPEAL‐1; the results also suggest that the severity of experience with PA may not correlate with perception of its overall burden and show variable impacts by country.


| INTRODUC TI ON
Management of peanut allergy (PA) centres on strict avoidance of peanuts and emergency treatment in the case of accidental exposure leading to a severe reaction or anaphylaxis. The constant vigilance required can have a profoundly negative impact on the health-related quality of life of individuals with PA and their caregivers. [1][2][3][4] Children with PA report poorer health-related quality of life, greater fear of adverse events, and more anxiety about eating than children with insulin-dependent diabetes 1 and have poorer quality of life than children with seafood allergy. 5 Compared with their siblings, children with PA have significantly poorer health-related quality of life in physical, psychological and social dimensions, both at school and in general. 2 Allergy to Peanuts ImPacting Emotions And Life (APPEAL) is a two-part study conducted across eight European countries to evaluate the psychosocial burden of living with PA. APPEAL-1 utilized a quantitative, cross-sectional online survey to investigate the experience of adults and children with PA and caregivers, including demographic and clinical factors and the impact of PA on psychosocial parameters and health-related quality of life. APPEAL-1 found that individuals experience frustration, stress, uncertainty and low levels of confidence in managing their PA. 6,7 The analysis of quantitative questionnaires is limited to data provided by answers to predetermined questions. This approach may generate a bias towards the preconceptions of the questionnaire's creators and fail to adequately capture the views, experiences and impacts that are important to those living with PA. A qualitative approach that elicits information on subjects' everyday lives may provide data that more accurately reflect the complexity of real-life situations and thus reveal unmet healthcare needs and suggest innovative ways to resolve them. 8 A few qualitative studies to date have focused specifically on individuals with PA and their families. 9,10 Although conceptual models have been developed for food allergy in general, 11,12 no previously published studies have proposed conceptual models that illustrate the complex impacts of PA on the lives of those affected. Research assessing the impacts of PA specifically is needed because PA is lifelong in the majority of patients, and more frequently than most other food allergies, 13 and is associated with comparatively high rates of severe reactions, anaphylaxis and fatal anaphylaxis in Western countries. [14][15][16][17] Furthermore, previous studies have not looked specifically at the real-world impact of PA-related coping strategies on patients and their families. Finally, no cross-sectional research has explored the broader health-related quality of life impact of PA across different age groups and European countries.
APPEAL-2 was a large qualitative study designed to further explore key areas of impact identified in APPEAL-1 and to ensure that all concepts important to those impacted by PA were captured. In contrast to APPEAL-1, which collected only proxy-reported data from caregivers regarding the impact of PA on children and teenagers, APPEAL-2 includes self-reported data from children and teenagers, as well as proxy report from caregivers. The objectives were to investigate the health-related quality of life burden of living with PA on children, teenagers and caregivers across Europe, the coping strategies used to cope with this burden, and to develop conceptual models that provide a holistic overview of the data collected.

| Study design
APPEAL-2 employed a cross-sectional study design using qualitative methods to explore the impact of PA on children and teenagers with PA and on parents/caregivers ("caregivers") of individuals with PA.
Semi-structured interview guides (see Appendix S1), developed with clinical experts and patient advocacy groups across all participating countries, allowed participants to spontaneously describe how PA affected them. Interviewers employed pre-specified probes if concepts were not raised. Caregivers were asked about the impact of PA on their child and on their own life. All interviews began with the question, "First, I would like to ask you some questions to give us a general picture of your experience with peanut allergy," and almost all subsequent questions reminded the participants that their responses should related specifically to PA (eg, "…because of your peanut allergy"). The study was approved by the Western Independent Review Board (IRB tracking/approval number 20182422).
The study was conducted in the United Kingdom, France, Germany, Spain, Italy, the Netherlands, Denmark and Ireland.
Specialist recruitment panels engaged participants drafted from databases of individuals willing to participate in research studies.
Eligible participants were aged 8-17 years, separated in categories of children aged 8-12 years (included only in the United Kingdom, France and Germany) and teenagers aged 13-17 years (included in all countries) with a diagnosis of moderate or severe PA (self-/proxyrated) or caregivers of children and teenagers (aged 4-17 years) with a diagnosis of moderate or severe PA (self-/proxy-rated). All children and teenagers had experienced at least one accidental reaction to peanut. Recruitment aimed for minimums of 50% of the sample in each country with severe PA and 25% (of the total population) who reported having used an adrenaline autoinjector (AAI) or experienced a life-threatening event.

| Data collection procedures
All participants gave informed consent (or assent: children/teenagers) prior to participation. Interviewers conducted 30-to 60-minute interviews in the local language, following the semi-structured K E Y W O R D S burden, conceptual models, food allergy, paediatrics, peanut allergy, quality of life interview guide, between October 2018 and January 2019.
Demographic and clinical information was also gathered (see Appendix S1). In the United Kingdom, France and Germany, all child and teenager interviews and some caregiver interviews were conducted in person. In other countries, all interviews were conducted by telephone. To allow participants to speak freely and openly, they were interviewed alone. Each interview was recorded and transcribed and, if applicable, translated into English. Caregivers who participated (proxy-and self-report) and caregivers of children who participated were remunerated for their time in the study.

| Analysis
Qualitative analysis of the transcripts was conducted using thematic analysis. 18 A team of analysts coded the qualitative text of the transcripts using a coding frame. Analysis was assisted by MAXQDA, a qualitative software tool. Saturation, the point at which no new information is obtained from additional qualitative data, 19 was assessed using saturation tables. 20 Based on consensus of all analysts, those who coded the transcripts using the concepts identified during the analysis developed the conceptual model. Core concepts, or themes, included in the conceptual models included moderators, coping and control techniques, and impacts, which were comprised of multiple factors. Core concepts and themes, and the multiple factors comprising them, were identified by their frequency of mention in the interview transcripts and consensus of the transcript analysts.

| RE SULTS
There were 107 participants across the three groups and eight countries. Demographic and clinical information is summarized in Table 1.
A high proportion of the overall sample had other allergies, with  Three caregivers of teenage participants were also interviewed.

TA B L E 1 Population demographics and clinical characteristics
approximately one-third of each cohort allergic to tree nuts in addition to peanuts. One-third of the overall sample had no other food allergies. Three-quarters of each cohort had an AAI prescription for their PA. Among all participants, 57% had severe PA (self-or caregiver-reported), 50% had used an AAI, and 40% had experienced a life-threatening event.

| Qualitative analysis results
Data saturation was reached when no new codes were added in the last 17 teenager interviews, the last three child interviews and the last six caregiver interviews. All core concepts or themes were reported spontaneously across all groups. Sample quotations illustrating how these core concepts were expressed are shown in Figures 1 and 2.

| Coping and control
Coping and control behaviours used to avoid accidental exposures to peanut could be categorized into three themes: daily monitoring/vigilance/avoidance, communicating, and practicalities and planning.

| Daily monitoring/vigilance/avoidance
All participants reported using some level of monitoring and avoidance to ensure safety from peanut exposure. For children and teenagers, this included checking ingredients, being aware of what others were eating and staying away from people eating peanuts, not sharing food with friends, and hygiene practices such as frequent handwashing or asking others to wash their own hands. Many teenagers and children reported bringing their own food to school and social events or always eating at home. Caregivers described needing to be alert and vigilant and to constantly "risk-assess" situations for the possibility of peanut exposure and their child's safety.

| Impact of coping strategies used to manage peanut allergy
The negative impacts of avoiding peanuts and the coping and control behaviours were many and varied. The main areas of impact of living with PA were social and school activities, relationships, emotional impacts and work (caregivers only).

Social and school activities
Almost all teenagers and children and many caregivers reported a negative impact of PA on their social activities. For teenagers and children, using "avoidance" as a strategy included not only restaurants but avoidance of certain places (eg cinemas) and missing activities with friends. Some parents did not allow their children to attend social events (eg younger children could go only if a parent attended), causing

Emotional impact
Emotional impacts of coping with PA affected almost all participants.
The most common emotional impacts included anxiety, worry and/or fear, often related to experiencing an allergic reaction or anticipating the risk of one. Some participants discussed feelings of worry or uncertainty related to interpreting food labels that stated "may contain traces of peanuts" (the word "trace" is not scientifically or legally defined) as individuals were unsure whether the food was safe to eat. Caregiver anxiety was rooted in a lack of control; approximately half reported worrying about having less control of their child's food and environment as the child became more independent. Several teenagers and some caregivers also reported being fearful of having to use their AAI, feeling nervous if they forgot it and worrying that it might not work. Children also reported fear or worry related to new environments or contact with someone who had eaten peanuts. Other common emotional impacts included feelings of frustration or annoyance, sadness or disappointment, stress, embarrassment and feeling different from others.

Work (caregivers)
Approximately a quarter of caregivers reported that they had reduced their working hours outside the home or decided to work part-time to enable their child to eat lunch at home because of managing their child's PA. A similar proportion of caregivers also reported needing to take time off work to supervise their child on school trips or other activities, or to attend appointments. PA was not reported to impact job performance; however, some caregivers felt that reducing their working hours hampered career progression/job opportunities.

| Country similarities and differences
The main themes in the conceptual models were reported by participants from all countries, with the exception of the impact on work, which was not reported by caregivers in Spain. Among other inter-country differences, the aspect of PA avoidance involving hygiene (eg handwashing and asking others to wash their hands) was reported by participants only in Germany, France, the United Kingdom and Ireland, while the impact on the caregiver's relationship with their partner was not discussed by participants in Germany, Spain or Denmark. Embarrassment was not reported by teenagers in Italy, Spain or the Netherlands; bullying or teasing was not reported in the Netherlands or Denmark ( Figure 5).

| Conceptual models
The conceptual models illustrate the relationships between the main coping strategies and their impact in coping with PA (Figures 3 and   4). Having PA means that participants must avoid peanuts due to fear of a reaction and implement various strategies to cope with and control this risk. These coping behaviours can affect health-related quality of life (social/work activities, relationships and emotions).
The colour spectrum between coping and control and the impacts demonstrates the spectrum of behaviours reported by participants, ranging from either a highly vigilant approach or a careless approach, with the middle section indicating a more positive or neutral impact on other concepts. The two-way arrows between coping and control and Coping and control strategies-and level of confidence in the effectiveness of these strategies-may influence whether a reaction occurs, which in turn may influence future coping and control behaviours. However, it was not clear whether the perception among participants of the severity of previous reactions to PA influenced their coping strategy.
Results from APPEAL-2 can be viewed along with learnings by age group in the interactive and video content included in the Appendix S1: Video S1.

| Subgroup analysis for participants with peanut allergy only (no other food allergies)
All the main themes in the conceptual model were all reported by participants with PA only, and no additional food allergies. in qualitative studies of PA and/or food allergy. These include the burden of meal preparation, ensuring the home is nut-free, 9 and difficulties with teenagers' transitions to independence and the diminishment of caregiver control. 10,21 Although many of the main concepts described here have been reported previously in food allergy studies, it is important that these are confirmed specifically for PA. 21,22 Previous qualitative research documented caregivers' fear and hesitation related to AAI use, 21 which was also reported by teenagers and caregivers in the current study. A large qualitative study of food allergy described how fear of a reaction drove particular coping strategies, conceptualized on a continuum from maximization (extreme avoidance) to minimization (risky behaviours). 7 In APPEAL-2, the colour spectrum in the conceptual models illustrates a comparable concept.
The conceptual models help illustrate the wide-ranging im-  and, potentially, treatments that can reduce the risks of PA and thus alleviate its impacts. Creative qualitative and quantitative research approaches will enable improved modelling of the costs, risks and benefits of any treatment. The qualitative findings in the APPEAL-2 study can help to broaden and enrich the knowledge base for future PA studies.

ACK N OWLED G EM ENTS
The authors would like to express their great appreciation and gratitude to the patient advocacy groups involved in the APPEAL study for their support and valuable input into the study design. BrainSell provided analytical support for this study. Fiona Kenna, formerly of Anaphylaxis Ireland, contributed to the recruitment for and design of the study. Editorial assistance and medical writing support were provided by The Curry Rockefeller Group, LLC and funded by Aimmune Therapeutics.

ADG reports lecture honoraria/consultation fees from Aimmune
Therapeutics and research support from National Children's

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study captured in the current article are available from the corresponding author upon reasonable request.