Physical activity and health-related quality of life in chronic non-bacterial osteomyelitis

Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory disease of yet unknown etiology, which is mainly affecting the metaphysis of long bones, the pelvis, vertebral bodies and the clavicles or almost every site of the skeleton in children and adolescents [1‐3]. Affected youths usually present with localized inflammation, including bone pain, swelling and warmth, often combined with functional impairment. Other associated symptoms including palmo-plantar pustulosis, psoriasis and inflammatory bowel disease have been reported [3‐6]. Due to our experience, those symptoms are causing relevant limitations in motoric performance and age-appropriate development particularly in the chronically active disease course. Eventually this may result in a significant reduction of health-related quality of life (HRQoL) and physical activity.

The concept of HRQoL has been widely accepted in recent years as a patient-relevant outcome reflecting the impact of chronic illness in various health conditions [7]. HRQoL is a multidimensional concept that incorporates measures of physical symptoms, functional status, and disease impact on psychological and social functioning, in accordance with the definition of health proposed by the WHO. HRQoL instruments (generic and disease-specific) have been developed and used to measure the subjective impact of disease for different chronic diseases [7]. Severity and burden of disease manifestation in CNO cannot be correlated with and quantified by a laboratory value or imaging technique alone. And physical activity and physical function which have been directly linked to quality of life are often difficult to assess. Thus, there is an urgent need to identify comprehensive clinical measures, which assess the severity of disease manifestation in CNO to better understand the burden of this disease, to better monitor the course of disease in each individual patient and to evaluate the success of therapeutic strategies (e.g. physical training or pharmaceutical approaches). This pilot study addresses this need by assessing physical activity, fitness and HRQoL in a first group of patients with diagnosis of CNO versus age and gender matched healthy controls (HC) (age 13–18 years) using established measures including questionnaires, accelerometry and cycle ergometry [8‐10]. We hypothesized that CNO patients have a significant reduction of HRQoL in questionnaires and objective measures. Primary outcome of the study was the assessment of HRQoL (PedsQL3.0 and 4.0). Secondary outcome was the assessment of objective measures including accelerometry and ergometry.

The study was approved by the local ethics committee. 15 children (11 girls, 4 boys) diagnosed with CNO and 15 age and gender matched HC were recruited from the section of pediatric rheumatology and osteology at the University Children’s Hospital of Wuerzburg, Germany. At the time of assessment, all children were between 13 and 18 years of age (median 16 years).

Inclusion criteria for patients with CNO: diagnosis of CNO and age between 13 and 18 years. The diagnosis of CNO was based on the clinical picture, skeletal inflammatory MRI lesions, laboratory data and by exclusion of differential diagnoses. At the time of diagnosis, all patients with CNO had a multifocal disease and 8 had an initial diagnostic biopsy.

Each patient was compared to a healthy sex- (100% matching) and age- (CNO 16.0 years, HC 15.8 years, p 0.9593) matched volunteer (e.g. friend of the patient). Regarding their anthropometric data (height, body weight, calculated body surface area) HC did not differ significantly from patients with CNO. Great care was taken to recruit controls who were healthy and active, but did not participate in competitive sports at a higher than local level (anamnestic data). Participants (CNO and HC) who had competing diseases which might affect the physical activity were excluded from the study (exclusion criteria).

The participants came to the study center for a single visit. After informed consent was obtained from the guardians and verbal assent from the participants, questionnaires were completed, anthropometric measurements, clinical examination, blood analyses and an incremental exercise test on a cycle ergometer with gas exchange measures were performed. All participants were equipped with an accelerometer for 7 days following the clinic visit.

Questionnaires: The subjective physical activity was measured with an in-house established activity questionnaire, which combines the Habitual Activity Estimation Scale (HAES), 7-day Physical Recall Questionnaire (7D-PAR) and Lipid Research Clinics questionnaire (LRC), all translated into German and used before by Hebestreit et al. in juvenile idiopathic arthritis (JIA) and cystic fibrosis (Supplement). These questionnaires were combined with visual analogue scales (VAS) for pain at rest/during exercise, physical activity compared to other children, and fatigability after physical activity. For the assessment of quality of life and health perception the following questionnaires were administered: The DASS-G, Depression, Anxiety and Stress Scales – German version to assess depression, anxiety and stress. The Children Health Assessment Questionnaire (CHAQ), which relevance has been documented before in CNO by Beck et al. to record the amount of difficulty patients experience during daily life [4]. The German version of the Pediatric Quality of Life Inventory (PedsQL) was used to measure HRQoL. The PedsQL3.0 rheumatology module consists of five subscales and the PedsQL4.0 generic core scale consists of four subscales which can be combined into physical health and psychosocial health composite scales, as well as the PedsQL total score [11‐13]. PedsQL scores range from 0 (being the worst) to 100 (being the best possible HRQoL). They have been used before in healthy children and children with JIA [13, 14].

Cycle ergometry: Aerobic fitness was assessed using the Godfrey protocol [15] and a calibrated commercial cycle ergometer (Ergoline, Ergoselect 100) with pulse oximetry (Nonin 7500, Nonin Medical, USA, Nellcor forehead sensor) and gas exchange measures (CPX/D, MedGraphics, St. Paul, MN, USA). Work rate was increased every minute by 10–20 W, depending on the subject’s height, up to voluntary fatigue. All results were compared to normal values depending on size and age of each patient, which were calculated as suggested by Godfrey et al. [16] for maximal power (Wmax), by Orenstein et al. [17] for maximal oxygen uptake (VO2max) and by Rowland [18] and Fairbarn et al. [19] for maximal heart rate (HFmax). All results were then stated in percent of the predicted value.

Accelerometry: All participants wore an accelerometer (GT3X, Actigraph) for 7 consecutive days on the hip to assess activity behavior objectively. Activity counts were averaged over a period of 5 s (epochs) and counts/ minute were calculated from these data. The measured counts were separated in different activity levels: sedentary, light (e.g. walking slowly, standing light work), moderate (e.g. walking very brisk, heavy cleaning) and vigorous (e.g. hiking, jogging) physical activity. A minimum recording time of 9 h on at least 2 week-days and 1 weekend-day was considered to yield valid data. Time spent in each activity level was determined separately for days during the week and the weekend. Due to the fact that there are no valid cut-offs for different activity levels in CNO, we chose to use cut-offs adjusted to the participant’s age as suggested by Troiano et al. [20] (Table 1).

For statistical analysis Wilcoxon sign rank tests were used to determine significant differences between groups of matched pairs (CNO and HC, case-control design). Mann-Whitney-tests were used to determine significant differences between patients with CNO in complete remission and those who are not in complete remission. Spearman correlations between objective measures (accelerometry and cycle ergometry) and subjective measures (questionnaires) were calculated. Statistical significance was assumed at p < 0.05.

The aim of this study was to measure physical activity and HRQoL of patients with CNO in comparison to age and gender matched healthy controls. There is a definite lack of knowledge in the literature about these items. Although most of our patients with a more than 5 year history of CNO showed a favorable course of disease without any relevant differences in objective measurements of physical activity and fitness versus HC at the time of assessment, self-reported measures of physical activity and quality of life revealed limitations.

In conclusion, our small study shows that patients with CNO (even in clinical and/or radiological remission) may have an impairment of their HRQoL with lower scores in different questionnaires. Objective measurements of physical activity and fitness revealed no differences versus healthy controls in our study. These are crucial findings for the counselling of patients and their parents. Psychological factors like unfounded fear or worry on exercise seem to be important determinants of fitness in our patients highlighting the need for better psychosocial support during treatment. Patients should be encouraged to exercise as soon as inflammation ceases and as much as medically acceptable followed by an individual sports and exercise counselling.

Further studies are needed to measure HRQoL and to validate questionnaires in patients with CNO against objective measures including more participants with a higher level of disease activity. This observation in a small group of patients with CNO may serve as a model project for other rare pediatric diseases which result in a relevant movement disorder.