Background
Inflammatory Bowel Disease (IBD) is a chronic, debilitating illness characterized by cycles of disease activity and quiescence. IBD is subdivided into Crohn’s disease (CD), ulcerative colitis (UC) and atypical phenotypes as described by the Porto criteria (PIBD: Pediatric IBD) [
1]. Although the ultimate aetiology of IBD remains unclear, three hypotheses are advanced: (1) A dysregulated inflammation emerges due to interactions between the gut luminal content (intestinal microflora) and the mucosa, especially in genetically predisposed hosts [
2]. (2) Genetic factors seem to contribute slightly to the disease pathogenesis. (3) Microbial and environmental dimensions have been identified as possible contributing factors [
3].
Worldwide it is estimated that 25% of all patients suffering from IBD are children and adolescents, with increasing incidence rates [
4]. In children with IBD stunting of physical growth and delay in pubertal development are observed [
5]. Furthermore, patients with active IBD are known to report increased erythrocyte-sedimentation rates (ESR) due to inflammation, decreased hemoglobin due to chronic blood loss in the gut, decreased albumin due to leaking gut at reduced intake and increased infection parameters such as leukocytes and C-reactive protein (CRP), when compared to healthy controls. Once the diagnosis is confirmed, the goals of medical therapy are to relieve symptoms, restore growth and bone health, normalize quality of life and psychosocial functioning, prevent complications and minimize the adverse effects of medications [
6]. While the efficacy of anti-inflammatory pharmaceuticals are not 100% and the side effects might be severe, some young IBD patients might be in a symptom-free remission, while others are still in an active disease state. Accordingly, based on the regularly assessed PUCAI (Pediatric ulcerative colitis activity index) scores and pediatric Crohn’s disease activity index (CDAI), participants in the present study were split into those with medically optimized treatment (IBD in remission, PUCAI <10; CDAI <150) the IBD – RE group, and those with not yet medically optimized treatment (active disease state), the IBD – AD group. As a result, our first hypothesis was that disease severity and the accompanying symptoms would be negatively associated with the physical development of children and adolescents with IBD. Specifically, we expected smaller and lighter body shapes and elevated inflammation markers in participants of the IBD-AD group, compared to IBD-RE and healthy controls.
In recent years, a plethora of studies have suggested that the prevalence of reduced health-related quality of life (HRQOL) and psychiatric disorders are significantly greater in young people with IBD than healthy controls [
7‐
9]. More specifically, adolescents with IBD had higher levels of internalizing disorders such as anxiety and depression [
7,
9], due to several factors such as unpredictable, unpleasant, and embarrassing symptoms, complex, demanding treatment regimens, treatment-related side effects, the ever-looming threat of exacerbations of the disease, and the need for surgical procedures in severe cases [
10]. The rate of depression may be as high as 25%, and spreads among a broad variety of psychological and social difficulties. However, as reviewed by Ross et al. [
8], the evidence these conclusions are based on, were inconsistent, included few paediatric samples, and used coarse-grained psychological instruments. As a result, recognition of the importance of mental wellbeing in young IBD patients is lacking in medical practice. If these psychological conditions are left untreated, mental disorders linked to more severe IBD symptoms might emerge, as well as more frequent IBD flares, higher hospitalization rates, increased health seeking behaviour and lower compliance with treatment [
11,
12]. To counter this, in the present study, validated and reliable self-rating instruments were used to assess dimensions such as psychological wellbeing, social support and peer relationships. Consequently, the second aim of the present study was to expand upon existing research by assessing children’s and adolescent’s psychological functioning with self-rating questionnaires, investigating specific aspects of psychological functioning, along with a depression screener.
As regards physical activity and sports participation, research showed that children and adolescents with IBD participated less in sports activities and were less fit than their counterparts without IBD [
13,
14]. In the specific case of paediatric IBD, reduced physical exertion during puberty might lead to impaired bone growth, strength and density, resulting in an increased risk for osteoporosis in the long term [
10]. However, a large number of studies have proven the beneficial effect of PA for a diversity of health conditions: First, PA mitigates depressive symptoms while bolstering sleep [
15] and cardiovascular fitness [
16]. Second, sports participation (via clubs and sports associations) has the potential to increase and deepen children’s and adolescents’ social skills. So far, research on PA in children and adolescents with IBD has largely been based on rough estimates. Therefore, the third aim of the present study was to assess PA behavior in children and adolescents with IBD, both subjectively using an internationally established questionnaire, and objectively with three methods: First, to investigate participants’ fitness, we used the Six-Minute-Walking-Test; second, for strength assessments, we applied a hydraulic grip strength test, and third, to generate long-term PA reports, a FitbitFlex® accelerometer was applied.
Taking into account the state-of-the-art regarding physical development, psychological functioning and physical activity among children and adolescents with IBD, the following three hypotheses were formulated: First, following others [
5,
17], we expected impaired anthropometric development among children and adolescents suffering from IBD and increased inflammatory blood markers, and particularly among those in an active state of the disease. Second, on the basis of previous research [
7‐
9], we expected poorer psychological functioning in children and adolescents with IBD, than in their healthy counterparts, and again, particularly among those in an active state of the disease. Third, previous findings [
18] led us to expect lower levels of PA (both subjective and objective) in children and adolescents with IBD than in their healthy counterparts.
Discussion
The key findings of the present study were that children and adolescents with IBD-AD had poorer psychological functioning than children and adolescents with IBD-RE and HC. Furthermore, they had a lower functional capacity (6MWT) and engaged less in objectively assessed physical activity (average steps per day) compared to children and adolescents with IBD in remission or age-and gender-matched healthy controls. The present pattern of results adds to the current literature in an important way, showing that medically well-adjusted children and adolescents with IBD do not differ from healthy controls with regard to psychological functioning and objective and subjective PA.
Three hypotheses were tested and each of these is considered now in turn.
Our first hypothesis was that there would be anthropometric differences; specifically, we expected that participants with IBD were smaller, lighter and to have greater inflammation, especially among the more severe cases of IBD. Our data partly supported this hypothesis. The IBD-AD group had a moderately lower BMI z-score, BMI percentile, z-score height for age and percentile height for age when compared to both other groups. Therefore, the present data are in accordance with previous findings [
14,
30]. In general, 10-40% of children with IBD are affected by growth failure [
14,
30] and impaired nutritional status [
31]. Underlying reasons are anorexia, malabsorption, intestinal inflammation and corticosteroid usage [
32]. Given that the data available do not allow a deeper understanding of the pattern of results, we speculate that current treatment strategies lead to good disease control and less growth retardation [
33].
With the first hypothesis, we also expected to detect indicators for inflammation and disease-related influences in the blood values of IBD patients. This hypothesis was partially supported; scores for the inflammatory markers ESR, CRP and leukocytes were higher among those with IBD-AD. Two patients with active IBD and two in remission were anemic, as well as one participant in the control group. In general, chronic anemia is prevalent and rapidly recurring in patients with IBD [
34]. On the other hand, iron deficiency is a well-known phenomenon among many healthy female teenagers [
35]. The small reported differences can be accounted to constant monitoring of blood values by the treating physician, who provides the patients with either oral or intravenous iron supplementation as soon as necessary. Looking at albumin values, it is not unusual to observe lower values in patients with IBD, as indicated by our findings. Patients with IBD might lose albumin due to increased gut permeability, even during symptom-free episodes [
36]. However, we were unable to explain the low albumin values found in half of the healthy control participants. Common underlying reasons are undernourishment [
37], decreased production due to liver disease [
38] and increased excretion due to kidney problems [
39], factors, which however could be ruled out by the supervising health professionals in the present study. Finally, the increased average hemoglobin among IBD-AD in comparison to HC was very surprising. The only possible explanation might be a blood clotting during blood sample taking since the hematocrit is elevated as well.
With the second hypothesis, we expected poorer psychological functioning in children and adolescents with IBD-AD compared to IBD-RE and healthy controls, and data did partially support this. Children and adolescents with increased disease activity had poorer psychological functioning in the area of psychological wellbeing. On the flipside, no other dimension of psychological functioning (physical functioning, autonomy and parent relations, social support and peers, and school experience) showed significant differences across the three groups, IBD-AD, IBD-RE and HC. Therefore, the present data do not match the study by Herzer et al. [
40], showing a lower overall HRQOL among patients with IBD. Further, the present data do not accord with those studies reporting impaired physical functioning [
41], impaired family functioning [
40], limited participation in social activities [
7], lower emotional functioning [
42], and problematic school experience and performance.
Previous evidence can be explained by the association between increased disease activity and lower psychological functioning. One may claim that greater disease severity might be accompanied by an increasing presence of disruptive gastrointestinal symptoms and abdominal pain, which in turn need to be treated with more robust and invasive methods. Such increasing disease burden might result in psychological distress [
43]. Two further hypotheses are the inflammation-depression hypothesis and the brain gut hypothesis. These two hypotheses claim that the increased production of pro-inflammatory cytokines (TNF alpha) is known to affect the brain both, directly and indirectly, thereby increasing symptoms of depression [
44,
45]. Further, there is a bidirectional relationship, since psychological stress in turn increases the likelihood of inflammation, which again increases the occurrence of depressive symptoms [
42]. The pro-inflammatory effect of experimental stress has been confirmed in human studies, and at the same time, inflammatory markers have been found to be raised in depressed patients [
46]. To a wider extent, the inflammatory, unpredictable and disruptive nature of severe IBD, if not properly treated, could lead to an increase in internalizing symptoms (e.g., anxiety and depression). In particular, given that the long-term course of the disease is characterized by progressive deterioration [
47], young patients might be at increased risk for psychological distress.
While comparing children and adolescents in remission with the healthy control group, we did not find differences on any of the HRQOL dimensions. This can be attributed to the fact that children in remission are by definition symptom-free [
11]. A recent publication by the SWISS IBD Cohort even reported higher psychological functioning in IBD patients than in controls. The authors attributed this unexpected finding to the excellent social support in the young patients’ environment [
41]. Walter et al. [
48], on the basis of a careful examination of the literature, noted that older studies (1989 – 2004) reported higher depression rates; subsequent advances in treatment may be responsible for the lower levels of psychological distress observed more recently. Therefore, we suggest that screening and treatment for mental wellbeing should be implemented especially for those with increased disease activity and potentially weaker social support.
Our third hypothesis, following others [
18,
49], was that physical activity levels (subjective and objective) would be lower in children and adolescents with IBD than in their healthy counterparts. While the three groups did not differ regarding subjectively assessed PA in our study, lower objectively assessed PA was indicated by the number of steps per day, especially in the IBD-AD group. Thus, the present data are in account with previous results, however based on objective measurements. Werkstetter et al. [
14] also reported reduced amounts of steps per day in children and adolescents with IBD, while studies of adult patients have found that suffering from IBD tended to lead to a sedentary lifestyle [
50]. An explanation might be that patients with active IBD are restricted and discouraged by unpredictable symptoms, physical restriction, inconvenience and discomfort [
49]. Furthermore, we found that children and adolescence with active IBD perceived physical strain to be more vigorous as compared to IBD-RE and HC. This is reflected in their subjectively estimated greater intensity of the 6 MWT, while achieving less distance than the other groups and their extremely elevated self-reported vigorous PA levels over the last 7 days. This finding indicated a lower fitness in children and adolescents with active IBD, and was in line with findings of Ploeger et al. [
13] Children with IBD exhibited impaired aerobic and anaerobic exercise capacity, compared to reference values.
However, a lower amount of PA might be an issue for the following reasons. Generally, regular low intensity exercise is beneficial in reducing distress and improving quality of life in young patients with IBD [
51]. A UK survey revealed that PA made patients with IBD feel better and healthier, boosted energy, reduced IBD symptoms, provided an alternative focus and fostered feelings of normality [
49]. On a physiological level, recent findings indicated that IBD patients could experience anti-inflammatory effects from the myokines released during skeletal muscle contraction while exercising, thereby inhibiting the release of protective heat shock proteins (Hsps), which help to regulate inflammation and immunity [
52]. It was further asserted that PA is an anabolic stimulus, reducing inflammation and positively affecting growth factors, i.e., IGF-I [
53]. Additionally, Robbins et al. [
49] argued that regular PA should be undertaken in IBD to help maintain bone mineral density and prevent osteoporosis. We should note, however, that exaggerated amounts of (high-intensity) PA might lead to an increase in symptoms. Vigorous PA such as distance running and endurance exercise commonly might cause gastrointestinal discomfort including nausea, heartburn, and even gastrointestinal bleeding in patients with IBD [
54]. By contrast, moderate PA seems to be useful in improving many aspects of the lives of patients with IBD. Nonetheless, a fear of symptoms exacerbation may be an indication that patients lack the impetus to start PA, and clinicians may be reluctant to prescribe PA, even though it might serve as a protective and preventive factor with respect to IBD. Collectively, we claim that regular moderate PA should receive greater attention in scientific intervention studies as adjuvant to prescribed pharmacotherapies.
Despite the novelty of the findings and the application of internationally validated and accepted questionnaires and objective measures, several limitations warrant against an overgeneralization of the present findings. First, the relatively small sample, especially the small number of children in an active disease state, created difficulties in detecting statistically significant effects. Though we also relied on effect sizes, which are not sensitive to sample size. Second, the recruitment of the sample was restricted to the German speaking part of Switzerland. Of these patients, only participants willing and able to participate were assessed. Even though we tried to cover an extensive range of factors, it was not possible to control for all confounders, such as microbial or environmental conditions, which might have influenced two or more outcomes in the same or in opposite directions. In this context, one suggestion for future studies might be the assessment of objective disease severity, fecal calprotectin as another objective measure. Otherwise we would suggest extending the cross sectional design to include lifestyle intervention studies and their supportive effect in the disease coping process. Last, we did not distinguish between patients with CD and UC; whereas for diagnostic reasons such an approach would have been easy to follow and justify, we decided to split patients into IBD-AD and IBD-RE, as suggested by recent research such as Reigada et al. [
42,
55].