Fatigue in children and adolescents with inflammatory bowel disease

Table 1 General characteristics of the included studies

First author (year of publication)	Study objectives	Age (yr)	Patient population	Percentage of patients with active disease	Main findings related to fatigue
Marcus et al (2009)[6]	To evaluate the degree of fatigue and health-related quality-of-life in children with IBD	10-17	52 CD; 13 UC; 5 IBD-U; 157 healthy controls	Remission 56%; Mild 22%; Moderate 17%; Severe 5%	Adolescents with IBD have significantly more fatigue than healthy controls; PedsQL total fatigue, general fatigue, and sleep/rest fatigue were all impaired in patients with IBD; Adolescents with IBD are fatigued even when clinical remission is reached
Nicholas et al (2007)[13]	To understand the lived experience and elements of quality-of-life in adolescents and adolescents with IBD	7-19	61 CD; 19 UC	Not reported	Young patients with IBD commonly feel “sick and tired” and have “no energy”
Pirinen et al (2010)[16]	To evaluate the effect of disease severity on (the frequency of) sleep problems and daytime-tiredness among adolescents with IBD	10-18	53 CD; 83 UC; 24 IBDU; 236 healthy controls	Not reported	Adolescents with IBD do not report more sleeping problems or overtiredness than their healthy peers Adolescents with active disease have significantly more trouble sleeping, more daytime sleepiness and are overtired compared to adolescents with mild IBD symptoms; Adolescents with severe IBD symptoms have worse quality of sleep and more sleep disturbances than those with less severe IBD
Werkstetteret al (2012)[8]	To evaluate whether physical activity is reduced in patients with IBD compared to control subjects	6-20	27 CD; 12 UC; 39 healthy controls	Remission 66%; Mild 34%	Patients with IBD show a trend toward less physical activity, especially among girls and those with mild disease activity; There is no relation between inflammatory markers (CRP) and physical activity
Rogler et al (2013)[7]	To examine the determinants of health- related quality-of-life in adolescents and adolescents with IBD	11-15	64 CD; 46 UC	PCDAI > 15 36%; PUCAI ≥ 10 28%	Patients with IBD (in particular boys) have moderate impairments in physical well-being; Impairment in physical well-being is associated with active inflammation; And its symptoms
Loonen et al (2002)[12]	To evaluate the impact of IBD on health- related quality of life	8-18	41 CD; 40 UC; 2 IBD-U	Mild 60%; Moderate 23%; Severe 15%; Missing 2%	Adolescents with IBD have impairments in motor functioning (running, walking, playing) and complain more of tiredness, especially those with Crohn’s disease.
Tojek et al (2002)[14]	To examine family dysfunction, maternal physical symptoms and maternal positive affect as correlates of health status in adolescents with IBD	11-18	36 CD; 26 UC	Not reported	Family dysfunction is related to an increased frequency of fatigue in adolescents; Maternal positive affect is inversely related to fatigue (not significant); Fatigue is independent of maternal negative affect
Ondersma et al (1996)[15]	To examine how psychological factors relate to disease severity among adolescents with IBD	11-17	34 CD; 22 UC	Not reported	There is a relationship between negative affect and physical symptoms of fatigue

CD: Crohn’s disease; IBD: Inflammatory bowel disease; IBD-U: Inflammatory bowel disease-unclassified; PCDAI: Pediatric Crohn’s Disease Activity; PedsQL: Pediatric Quality of Life; PUCAI: Pediatric Ulcerative Colitis Activity Index; UC: Ulcerative colitis.

Table 2 Methodology and quality assessment

First author (year of publication) and study type	Patient selection	Disease activity score	Fatigue score	Study quality
Marcus et al (2009)[6] Case-control study	Patients: recruited during scheduled clinical appointments at University Hospital, United States; Healthy controls: adolescent children of hospital employees	CD: PCDAI; CU and IBDU: PGA	PedsQL Multidimensional Fatigue Scale, IMPACT-III, PedsQL 4.0 Generic Core Scales Children’s Depression Inventory: Short Form	Good: no sample size justification
Nicholas et al (2007)[13] Cross-sectional study	Patients: recruited from the database of Reference Children’s Hospital, Canada	No distinction made	Semi structured interview designed by author	Poor: Patients purposively selected, questionnaires not validated, participation rate not reported
Pirinen et al (2010)[16] Case-control study	Patients: recruited from the database of the Population Register Center, Finland; Healthy controls: matched	VAS disease severity	Youth self-reported questionnaire, Sleep Self Report, child behavior checklist	Medium: Subjective score to assess disease severity, exact sleep duration unknown
Werkstetter et al (2012)[8] Case-control study	Patients: recruited from University Hospital, Germany; Healthy controls: matched	CD: PCDAI; UC: PUCAI	SenseWear Pro2 accelerometer, German KINDL, IMPACT III	Good: no sample size justification
Rogler et al (2013)[7] Cross-sectional study	Patients: recruited from Swiss IBD cohort study, Switzerland	CD: PCDAI; UC: PUCAI	KIDSCREEN-27	Medium: numbers in text and table do not match
Loonen et al (2002)[12] Cross-sectional study	Patients: recruited from a database of two large tertiary referral centers, Netherlands	5-item symptom card (completed by patients)	TACQOL, IMPACT-II	Good: validated questionnaires, the results compared with healthy controls
Tojek et al (2002)[14] Cross-sectional study	Patients: recruited from routine outpatient visit in 2 urban pediatric gastroenterology hospitals, United States	No distinction made	Questions designed by author	Medium: parental factors can influence adolescent’s health, the converse remains possible, only mothers investigated, questionnaires not validated
Ondersma et al (1996)[15] Cross-sectional study	Patients: recruited from 2 pediatric gastroenterology hospitals, United States	No distinction made	10-item Subjective Illness Questionnaire (parts or RCMAS and CDI)	Medium: no sample size justification, parts of validated questionnaires

CDI: Children’s Depression Inventory; CD: Crohn’s disease; IBD: Inflammatory bowel disease; PCDAI: Pediatric Crohn’s Disease Activity Index; PedsQL: Pediatric Quality of Life; PGA: Physician Global Assessment; PUCAI: Pediatric Ulcerative Colitis Activity Index; RCMAS: Revised Children’s Manifest Anxiety Scale; UC: ulcerative colitis.

Table 3 Description of fatigue-related diagnostic tests

Abbreviation	Full name	Details
CBCL	Child Behavior Checklist	Caregiver report form that categorizes problem behaviors in preschool and school-aged children in the following 8 syndromes: aggressive, anxious-depressed, attention, rule-breaking, somatic complaints, social, thought, withdrawn-depressed.
CDI	Children’s Depression Inventory	Adolescent self-reported assessment. For each of 26 items, respondents endorsed one of three sentences indicating varying levels of depression.
IMPACT-III	Not applicable	IBD disease-specific health-related quality-of-life questionnaire for pediatric patients. It is composed of 35 items in the following 6 domains: IBD-related symptoms (7 items), systemic symptoms (3), emotional functioning (7), social functioning (12), body image (3) and treatment/intervention-related concerns (3). Each item is scored on a 5-point Likert scale, coded from 0 to 4 points. Higher scores indicate better quality of life.
KIDSCREEN 27	Not applicable	Self-reported survey is a quality of life questionnaire consisting of 27 items measuring physical well-being, psychological well-being, autonomy and parent relations, peers and social support, and school environment.
KINDL	Not applicable	Adolescent self-reported survey consists of 24 Likert-scaled items, which are subdivided into the following six dimensions (subscales) of quality of life: physical well-being, emotional well- being; self-worth, well-being in the family, well-being regarding friendships and well-being at school.
McMaster Family Assessment Device	Not applicable	Adolescent self-reported 60-item instrument that assesses six domains, namely, problem solving, communication, roles, affective responsiveness, affective involvement, behavior control and general functioning of family functioning as well as general family dysfunction.
PedsQL generic scale	Pediatric Quality of Life Inventory	Parent reported and self-reported assessment. A modular approach to measuring health-related quality of life (HRQOL) in healthy children and adolescents and those with acute and chronic health conditions. It contains the following four multidimensional scales: physical functioning, emotional functioning, social functioning, school functioning.
PedsQL Multidimensional Fatigue Scale	Pediatric Quality of Life Inventory Multidimensional Fatigue Scale	Age-appropriate versions and parallel forms for children and parents. It measures the perceptions of fatigue by children and their parents and has been validated in a variety of pediatric chronic diseases.
RCMAS	Revised Children’s Manifest Anxiety scale	Adolescent self-reported assessment that is a true/false anxiety measure containing 28 items. The measured key areas are physiological anxiety, worry, social anxiety and defensiveness. The scale differentiates between anxiety-disordered and normal Children.
SSR	Sleep Self Report	Adolescent self-reported assessment to discern sleep patterns and possible difficulties with sleep.
TACQOL	TNO-AZL Children’s Quality of life Questionnaire	Generic health-related quality of life questionnaire enabling comparisons between groups of children with varying chronic diseases. It includes 7 scales, involving general physical function, motor function, daily function, cognitive function, social contact, and positive and negative moods.
YSR	Youth Self Report	Adolescent self-reported assessment with the following eight empirically-based syndrome scales: anxious/depressed, withdrawn/depressed and somatic complaints composing the internalizing (i.e., emotional) broad-band scale; rule-breaking behavior and aggressive behavior composing the externalizing (i.e., behavioral) broad-band scale; and these two scales, together with the syndrome scales of social, thought and attention problems, compose the total problems scale.