The PROactive cohort study: rationale, design, and study procedures.

Children with a chronic condition face more obstacles than their healthy peers, which may impact their physical, social-emotional, and cognitive development. The PROactive cohort study identifies children with a chronic disease at high risk of debilitating fatigue, decreased daily life participation and psychosocial problems, as well as children who are resilient and thrive despite the challenges of growing up with a chronic condition. Both groups will teach us how we can best support children, adolescents and parents to adapt to and manage a disease, as well as tailor interventions to their specific needs.This cohort follows a continuous longitudinal design. It is based at the Wilhelmina Children's Hospital (WKZ) in the Netherlands and has been running since December 2016. Children with a chronic condition (e.g. cystic fibrosis, juvenile idiopathic arthritis, chronic kidney disease, or congenital heart disease) as well children with medically unexplained fatigue or pain in a broad age range (2-18 years) are included, as well as their parent(s). Data are collected from parents (of children between 2 and 18 years) and children (8-18 years), as well as data from their electronic health record (EHR). Primary outcome measures are fatigue, daily life participation, and psychosocial well-being, all assessed via patient- and proxy-reported outcome measures. Generic biological/lifestyle, psychological, and social factors were assessed using clinical assessment tools and questionnaires. In the PROactive cohort study the research assessment is an integrated part of clinical care. Children are included when they visit the outpatient clinic and are followed up annually.

Non-pharmacological options for managing chronic musculoskeletal pain in children with pediatric rheumatic disease: a systematic review.

In patients with a pediatric rheumatic disease (PRD), chronic musculoskeletal pain (CMP) can have a major impact on functioning and social participation. Because CMP is not always alleviated solely by the use of pharmacological approaches, the aim was to systematically review the available evidence regarding non-pharmacological treatment options for reducing CMP in patients with PRD. PubMed, Embase, PsycINFO, and the Cochrane Library were systematically searched for (non-)randomized trials investigating non-pharmacological treatments for CMP in PRD published through October 25, 2017. The GRADE approach was used to assess the quality of evidence. The search yielded 11 studies involving 420 children 5-18 years of age. All studies were relatively small and short-term, and the quality of evidence ranged from very low to moderate. The main modalities within non-pharmacology therapy were psychological interventions and exercise-based interventions. Some studies show modest positive short-term results for psychological and exercise-based interventions. Psychological and exercise-based interventions can have a modest positive result in PRD, with no evidence of side effects. Non-pharmacological therapies are a promising option to alleviate pain in PRD and improve functioning, which can be used as an alternative for or in addition to pharmacological therapies. Because chronic pain can differ etiologically from acute pain in PRD, non-pharmacological therapies might have different effects in patients with or without active inflammation. To best determine the effect of non-pharmacological therapies, future studies should take this difference into account.

A dyadic perspective on parent-child dyadic coping in children with a chronic condition.

OBJECTIVE: In this study, we examined the extent to which parents and their children with a chronic condition communicate their stress to one another and whether stress communication is associated with different forms of dyadic coping. METHODS: In a sample of 239 parent-child dyads, self-reported stress communication and different forms of perceived dyadic coping (i.e., emotion-oriented, problem-oriented, and negative dyadic coping) were assessed using a cross-sectional design. RESULTS: We first found that children's stress communication was positively associated with more positive (r = 0.28, p < .001) and less negative dyadic coping responses by children (r = -0.22, p < .001). Children's stress communication was also associated with more positive (r = 0.52, r = 0.45, p's < 0.001), and less negative dyadic coping responses by parents (r = -0.19, p < .001). Using dyadic data of children with a chronic condition and their parents, we found that more stress communication of children was associated with healthier coping responses of both children (perceived emotion-oriented dyadic coping: ß = 0.23, p < .001) and parents (perceived emotion-oriented dyadic coping: ß = 0.33, p < .001; perceived problem-oriented dyadic coping: ß = 0.22, p < .001). CONCLUSION: This underscores the importance of communication and adaptive coping strategies of parents and children in the context of a child's chronic condition. These findings may help us find ways to support children and their parents to optimally communicate about and deal with their stress.

Paediatric short fatigue questionnaire, a 4-item fatigue questionnaire for children.

OBJECTIVE: To investigate whether a paediatric Short Fatigue Questionnaire (pSFQ) assesses a valid construct for subjective fatigue, to assess its psychometric properties and provide a cut-off score for severe fatigue in children. METHODS: The pSFQ consists of 4 items from the Checklist Individual Strength-8 (CIS-8). Data of previous studies using the CIS-8 were used to assess the pSFQ in healthy children (n = 316), children with chronic fatigue syndrome (n = 173), and children with a chronic disease (n = 442). All children were 12-18 years old. Confirmatory factor analysis (CFA) was performed, followed by Cronbach alpha's to investigate internal consistency, and Spearman's correlations to assess construct validity. With ROC analysis, we determined a cut-off score for severe fatigue and provide normative data on the pSFQ for children with and without a chronic disease. RESULTS: CFA confirmed a one-factor model in the pSFQ representing subjective fatigue. Cronbach's alpha ranged from good to excellent (0.84-0.94), as did construct validity (-0.76 and - 0.87 for correlation with two other fatigue measurements). ROC analysis delivered a cut-off score of ≥21, with a sensitivity of 93.9% and specificity of 96.2% for severe fatigue. Normative data for children with and without a chronic disease showed similar patterns compared to other fatigue questionnaires. CONCLUSION: The pSFQ is a practical and reliable screening instrument for severe fatigue in children with and without a chronic disease, and effectively reduces the questionnaire length with 50% compared to the conventional CIS-8.

Possible Targets to Reduce Fatigue in Chronic Immune Thrombocytopenia Patients - An Explorative Study.

Background Fatigue in immune thrombocytopenia (ITP) is frequent and burdensome, but we lack the knowledge to help these patients. Aim The aim of the study is to explore the role of disease activity and other potentially modifiable factors in fatigue. Method This cross-sectional study included adult chronic ITP patients ( n = 59). Univariable linear regression (corrected for confounders) was used to determine the relationship between disease activity (platelet count <30 × 10 9 /L or treatment), disease-specific factors (bleeding symptoms, ferritin), and transdiagnostic factors (FACT-G physical/functional/emotional/social well-being subscales, physical activity level, and vitamin D) and fatigue (Checklist Individual Strength fatigue subscale). Several multivariable models with clustered sets of variables were used to compare the proportion of explained variance of fatigue (adjusted R 2 ). Results Significant relations with moderate effect sizes (>0.50) were found for physical and functional well-being and fatigue, and physical activity and fatigue. Other significant relations with fatigue (effect size 0.30-0.47) included skin and organ bleeding, emotional and social well-being, vitamin D, and disease activity. Notably, the models with disease activity and disease-specific factors explained <20% of the variance in fatigue, while the models with transdiagnostic factors (functioning and physical activity) explained >50%. Vitamin D alone explained 12% of the variance in fatigue. Conclusion Transdiagnostic (non-disease-specific) rather than disease-specific factors explained a large part of the variance in ITP-related fatigue. Many factors related to fatigue are potentially modifiable and should be investigated as targets for interventions.

Physiological predictors of cardiorespiratory fitness in children and adolescents with cystic fibrosis without ventilatory limitation.

OBJECTIVES: [1] To investigate the cardiorespiratory fitness (CRF) levels in children and adolescents with cystic fibrosis (CF) with no ventilatory limitation (ventilatory reserve ⩾ 15%) during exercise, and [2] to assess which physiological factors are related to CRF. METHODS: A cross-sectional study design was used in 8- to 18-year-old children and adolescents with CF. Cardiopulmonary exercise testing was used to determine peak oxygen uptake normalized to body weight as a measure of CRF. Patients were defined as having 'low CRF' when CRF was less than 82%predicted. Physiological predictors used in this study were body mass index z-score, P. Aeruginosa lung infection, impaired glucose tolerance (IGT) including CF-related diabetes, CF-related liver disease, sweat chloride concentration, and self-reported physical activity. Backward likelihood ratio (LR) logistic regression analysis was used. RESULTS: Sixty children and adolescents (51.7% boys) with a median age of 15.3 years (25th-75th percentile: 12.9-17.0 years) and a mean percentage predicted forced expiratory volume in 1 second of 88.5% (±16.9) participated. Mean percentage predicted CRF (ppVO2peak/kg) was 81.4% (±12.4, range: 51%-105%). Thirty-three patients (55.0%) were classified as having 'low CRF'. The final model that best predicted low CRF included IGT (p = 0.085; Exp(B) = 6.770) and P. Aeruginosa lung infection (p = 0.095; Exp(B) = 3.945). This model was able to explain between 26.7% and 35.6% of variance. CONCLUSIONS: CRF is reduced in over half of children and adolescents with CF with normal ventilatory reserve. Glucose intolerance and P. Aeruginosa lung infection seem to be associated to low CRF in children and adolescents with CF.

Role of parents in fatigue of children with a chronic disease: a cross-sectional study.

Objective: As parents majorly impact their child's well-being, and as fatigue is a highly prevalent threat to the well-being of children with a chronic disease, we aimed to explore the association between parental factors and fatigue in children with a chronic disease. Design: Cross-sectional study. Setting: Two Dutch children's hospitals. Population: Children 2-18 years of age with either an autoimmune disease, cystic fibrosis or post-cancer treatment, and one of their parents. Main outcome measures: Paediatric fatigue was measured using the PedsQL Multidimensional Fatigue Scale. Parental factors included parental pain, fatigue and physical symptoms, parental distress, catastrophising thoughts about their child's pain and family empowerment. Multiple linear regressions were used to study associations with paediatric fatigue. A multivariable regression model was used to assess the effect of the different parental factors on paediatric fatigue. All analyses were adjusted for the age and sex of the child. Results: 204 families participated (mean age 11.0±4.3 and 43.5±6.3 years for children and parents, respectively; 69% participation rate). More parental pain, fatigue and physical symptoms, and more parental distress and pain catastrophising were associated with more paediatric fatigue. More parental empowerment was associated with less paediatric fatigue on both subscales. In the multivariable model, only paediatric age remained significantly associated with fatigue. In a separate multivariable model for children 8-18 years old, more parental distress (ß=-1.9, 95% CI -3.7 to -0.1) was also significantly associated with more paediatric fatigue. Conclusions: In a population of children with a chronic disease, parental factors, both physical and psychosocial, were associated with paediatric fatigue. Our study provides evidence that more family empowerment is associated with less paediatric fatigue. This exploratory study adds to our knowledge of associated factors with fatigue in paediatric chronic disease, providing starting points for targeted interventions.

Fatigue among children with a chronic disease: a cross-sectional study.

Objective: To determine: (1) which biological/lifestyle, psychological and/or social factors are associated with fatigue among children with a chronic disease and (2) how much each of these factors contributes to explaining variance in fatigue. Design and setting: This was a cross-sectional study across two children's hospitals. Patients: We included children aged 8-18 years who visited the outpatient clinic with cystic fibrosis, an autoimmune disease or postcancer treatment. Main outcome measures: Fatigue was assessed using the PedsQL Multidimensional Fatigue Scale. Generic biological/lifestyle, psychological and social factors were assessed using clinical assessment tools and questionnaires. Multiple linear regression analyses were used to test the associations between these factors and fatigue. Finally, a multivariable regression model was used to determine which factor(s) have the strongest effect on fatigue. Results: A total of 434 out of 902 children were included (48% participation rate), with a median age of 14.5 years; 42% were male. Among these 434 children, 21.8% were severely fatigued. Together, all biopsychosocial factors explained 74.6% of the variance in fatigue. More fatigue was uniquely associated with poorer physical functioning, more depressive symptoms, more pressure at school, poorer social functioning and older age. Conclusions: Fatigue among children with a chronic disease is multidimensional. Multiple generic biological/lifestyle, psychological and social factors were strongly associated with fatigue, explaining 58.4%; 65.8% and 50.0% of the variance in fatigue, respectively. Altogether, almost three-quarters of the variance in fatigue was explained by this biopsychosocial model. Thus, when assessing and treating fatigue, a transdiagnostic approach is preferred, taking into account biological, psychological and social factors.

Daily life participation in childhood chronic disease: a qualitative study on the child's and parent's perspective.

Objective: To understand how a child with a stable chronic disease and his/her parents shape his/her daily life participation, we assessed: (1) the parents' goals regarding the child's daily life participation, (2) parental strategies regarding the child's participation and () how children and their parents interrelate when their goals regarding participation are not aligned. Methods: This was a qualitative study design using a general inductive approach. Families of children 8-19 years with a stable chronic disease (cystic fibrosis, autoimmune disease or postcancer treatment) were recruited from the PROactive study. Simultaneous in-depth interviews were conducted separately with the child and parent(s). Analyses included constant comparison, coding and categorisation. Results: Thirty-one of the 57 invited families (54%) participated. We found that parents predominantly focus on securing their child's well-being, using participation as a means to achieve well-being. Moreover, parents used different strategies to either support participation consistent with the child's healthy peers or support participation with a focus on physical well-being. The degree of friction between parents and their child was based on the level of agreement on who takes the lead regarding the child's participation. Conclusions: Interestingly, parents described participation as primarily a means to achieve the child's well-being, whereas children described participation as more of a goal in itself. Understanding the child's and parent's perspective can help children, parents and healthcare professionals start a dialogue on participation and establish mutual goals. This may help parents and children find ways to interrelate while allowing the child to develop his/her autonomy.

Parent-Child Dyadic Coping and Quality of Life in Chronically Diseased Children.

Different forms of dyadic coping are associated with positive outcomes in partner relationships, yet little is known about dyadic coping in parent-child relationships. The current research explored the association between parent-child dyadic coping and children's quality of life in 12-18-year old children with a chronic disease (i.e., cystic fibrosis, autoimmune diseases, and children post-cancer treatment). In a sample of 105 parent-child dyads, self-reported forms of dyadic coping (i.e., stress communication, problem-oriented, emotion-oriented, and negative dyadic coping) and children's quality of life were assessed. Children reported more stress communication and negative dyadic coping than their parents, while parents reported more problem-oriented dyadic coping and emotion-oriented dyadic coping than their children. More stress communication of the child was associated with more emotion-oriented dyadic coping and less negative dyadic coping of the parent. More negative dyadic coping of the child was associated with less stress communication, problem-oriented dyadic coping and emotion-oriented dyadic coping of the parent. Additionally, both children's and parents' negative dyadic coping were associated with lower self-reported pediatric quality of life and parents' emotion-oriented dyadic coping was associated with higher pediatric quality of life. These findings emphasize that children and their parents mutually influence each other and that dyadic coping is associated with children's quality of life. Theoretical and practical implications are discussed.

Internet and smartphone-based ecological momentary assessment and personalized advice (PROfeel) in adolescents with chronic conditions: A feasibility study.

OBJECTIVE: Growing up with a chronic disease comes with challenges, such as coping with fatigue. Many adolescents are severely fatigued, though its associated factors exhibit considerable interpersonal and longitudinal variation. We assessed whether PROfeel, a combination of a smartphone-based ecological momentary assessment (EMA) method using the internet, followed by a face-to-face dialogue and personalized advice for improvement of symptoms or tailor treatment based on a dynamic network analysis report, was feasible and useful. STUDY DESIGN: Feasibility study in fatigued outpatient adolescents 12-18 years of age with cystic fibrosis, autoimmune disease, post-cancer treatment, or with medically unexplained fatigue. Participants were assessed at baseline to personalize EMA questions. EMA was conducted via smartphone notifications five times per day for approximately six weeks. Hereby, data was collected via the internet. The EMA results were translated into a personalized report, discussed with the participant, and subsequently translated into a personalized advice. Afterwards, semi-structured interviews on feasibility and usefulness were held. RESULTS: Fifty-seven adolescents were assessed (mean age 16.2 y ± 1.6, 16% male). Adolescents deemed the smartphone-based EMA feasible, with the app being used for an average of 49 days. Forty-two percent of the notifications were answered and 85% of the participants would recommend the app to other adolescents. The personalized report was deemed useful and comprehensible and 95% recognized themselves in the personalized report, with 64% rating improved insight in their symptoms and subsequent steps towards an approach to reduce one's fatigue as good or very good. CONCLUSIONS: PROfeel was found to be highly feasible and useful for fatigued adolescents with a chronic condition. This innovative method has clinical relevance through bringing a patient's daily life into the clinical conversation.

Daily life participation in childhood chronic disease: a qualitative study.

OBJECTIVE: Opportunities to participate in daily life have improved considerably for children with chronic disease. Nevertheless, they still face challenges associated with their ever-present illness affecting every aspect of their lives. To best help these children, we aimed to assess the child's own perspective on participation and the main considerations that affect participation in a stable phase of disease. METHODS: Qualitative study design was applied. Semistructured, indepth interviews were conducted and analysed by a general inductive approach using constant comparison, coding and categorisation. Children 8-18 years old with a chronic disease were recruited from a cohort study involving cystic fibrosis, autoimmune disease and post-treatment paediatric cancer. RESULTS: 31 of the 56 (55%) invited patients participated. From the perspective of children with chronic disease, participation is considered more than merely engaging in activities; rather, they view having a sense of belonging, the ability to affect social interactions and the capacity to keep up with peers as key elements of full participation. Some children typically placed a higher priority on participation, whereas other children typically placed a higher priority on their current and/or future needs, both weighing the costs and benefits of their choices and using disclosure as a strategy. CONCLUSIONS: Enabling full participation from the child's perspective will help realise patient-centred care, ultimately helping children self-manage their participation. Caregivers can stimulate this participation by evaluating with children how to achieve a sense of belonging, active involvement and a role within a peer group. This requires active collaboration between children, healthcare providers and caregivers.

Fatigue in childhood chronic disease.

BACKGROUND AND OBJECTIVES: Recently, in adults, the incidence and severity of fatigue was found to exist rather independently from the somatic diagnosis. Since fatigue is distressing when growing up with a chronic disease, we aim to investigate: (1) the prevalence and extent of fatigue among various paediatric chronic diseases and (2) the effect of fatigue on health-related quality of life (HRQoL). DESIGN AND SETTING: Cross-sectional study in two children's hospitals. PATIENTS: Children and adolescents 2-18 years of age with cystic fibrosis, an autoimmune disease or postcancer treatment visiting the outpatient clinic. OUTCOME MEASURES: Fatigue and HRQoL were assessed using the Pediatric Quality of Life Inventory (PedsQL) multidimensional fatigue scale (with lower scores indicating more fatigue) and PedsQL generic core scales, respectively. Linear regression analysis and analysis of covariance were used to compare fatigue scores across disease groups and against two control groups. The effect of fatigue on HRQoL was calculated. Data were adjusted for age, sex and reporting method. RESULTS: 481 children and adolescents were assessed (60% participation rate, mean age 10.7±4.9, 42% men). Children and adolescents with chronic disease reported more fatigue than the general population (mean difference -6.6, 95% CI -8.9 to -4.3 (range 0-100)), with a prevalence of severe fatigue of 21.2%. Fatigue scores did not differ significantly between disease groups on any fatigue domain. Fatigue was associated with lower HRQoL on all domains. CONCLUSIONS: Fatigue in childhood chronic disease is a common symptom that presents across disease, age and sex groups. Fatigue affects HRQoL. Our findings underscore the need to systematically assess fatigue. Future studies should determine possible biological and psychosocial treatment targets.

Prevalence of severe fatigue among adults with cystic fibrosis: A single center study.

BACKGROUND: With life expectancy increasing among patients with cystic fibrosis (CF), the prevalence of complications such as fatigue is also expected to increase. Our aim was to investigate the prevalence of severe fatigue among adults with CF and to identify factors associated with fatigue. METHODS: Adult patients with CF receiving treatment at a single center were invited to complete three questionnaires. We then studied the associations between fatigue and clinically measured parameters and between fatigue and patient-reported outcomes. RESULTS: A total of 77 patients (age 19-54years; 56% males; mean FEV1: 63%) completed the questionnaires (43% response rate). The prevalence of severe fatigue among these patients was 26%. The variance in fatigue was explained partially by clinically measured parameters. However, patient-reported outcomes were stronger independently associated with fatigue and included the patients' reported respiratory symptoms, emotional functioning, and social functioning. CONCLUSIONS: Fatigue is a clinically important and highly prevalent issue among adults with CF and is associated with a significant reduction in health-related quality of life and participation in society. In addition, fatigue is associated more strongly with the patient's perception of symptoms and well-being than with clinically measured parameters.