All children with asthma and overweight, aged 6–16 year, living in Southern Limburg will be invited to participate. Overweight will be defined as a BMI-SDS >1 according to the Lambda Mu and Sigma (LMS) method of Cole et al.  based on the reference charts of the Dutch fourth Nationwide Growth Study . During the screening visit, participants will undergo lung function measurements to verify the diagnosis of asthma. A child will be considered asthmatic if at least 2 of the 3 following criteria are fulfilled: 1. asthmatic symptoms in the previous 12 months based on the International Study of Asthma and Allergy in childhood (ISAAC) questionnaire ; 2. use of Short Acting Beta2agonists (SABA), Long Acting Beta2agonists (LABA) or Inhaled Corticosteroids (ICS) in the previous 6 months; 3. reversibility; defined as an increase of ≥9% of the predictive value of the FEV1 after inhalation of 400 μg Airomir (Teva Pharma, Leiden, the Netherlands) or a positive BHR test; defined as a histamine concentration of ≤8 mg/ml necessary to provoke a drop of 20% in FEV1.
Children will be excluded in the case of a congenital malformation of the airways or other chronic lung diseases, syndromes accompanied by mental retardation or metabolic diseases, physical limitations to exercise, and/or a heart disease.
An overview of all the outcome measurements and corresponding time points can be found in Table 1.
Lung function measurements
Maximal Expiratory Flow Volume (MEFV) curves will be measured with a spirometer (ZAN Messgerate, Oberthulba, Germany) according to American Thoracic Society / European Respiratory Society (ATS/ERS) guidelines . LABA will be withheld 48 hours and SABA 8 hours before the measurement. During these measurements all children will be instructed by experienced researchers and nurses specialised in lung function measurements. The highest value of 3 technically appropriate measurements will be recorded and predictive values will be calculated according to prediction formulas of Zapletal et al. . Reversibility will be defined as a change of ≥9% in FEV1 after 400 μg of extra-fine salbutamol (Airomir, Teva Pharma, Leiden, the Netherlands). During T0 reversibility will be determined after the completion of the BHR test.
Static lung function indices will be determined by body plethysmography (Viasys, Hoechberg, Germany) according to the ATS/ERS guidelines . BHR will be determined by a histamine provocation test. A dose of histamine will be increasingly administered until a drop of 20% of the FEV1 is obtained or until a dose of 16 mg/ml histamine is reached . The provocative concentration that will lead to a drop of 20% of the FEV1 (PC20) will be determined by linear interpolation of the last 2 points on the log dose–response curve.
Children will be weighed while wearing underwear and without shoes. Length will be measured twice to the nearest 0.5 centimetre (Stadiometer model 213, Seca, Birmingham, United Kingdom). Weight will be measured twice to the nearest 0.1 kilograms using a medical calibrated weight scale (Model 877, Seca, Hamburg, Germany). The average weight and height measurement will be used to calculate the BMI. BMI-SDS scores will be defined by the LMS-method of Cole et. al  based on the reference charts of the Dutch fourth Nationwide Growth Study .
Skinfold thickness will be derived from the triceps, biceps, subscapular and supra iliacic skinfolds by a Skinfold Calliper (Harpenden, British Indicators, Sussex, United Kingdom). Fat percentages will be generated by using the formulas of Deurenberg et al. . Waist-hip ratio will be obtained by measuring the hip and waist circumference for each visit. Both skin fold thickness and waist-hip circumference measurements will be performed twice according to international guidelines .
Maximal ergometry test
All patients will perform a maximal incremental ergometer test (Reha Ergometer, Ergoline, Bitz, Germany) by using a continuous ramp protocol . LABA will be withheld 48 hours and SABA 8 hours before the maximal ergometry test. During the test, breath by breath gas exchange will be analysed by a mass spectrometer (Oxicon Pro, Carefusion, Hochberg, Germany), and Heart Rate (HR) by means of a continuous 12-lead electrocardiogram (Masterscreen ECG, Carefusion, Hochberg, Germany).
The pedalling frequency will be held at 60 rpm and participants will be encouraged during the test to continue as long as possible. At the start, children will rest for 3 minutes in seated position followed by 3 minutes of cycling at the first increment, which is determined by length. Children below 120 cm will undergo a protocol with 10 W/min increment, children 120–150 cm will undergo a protocol with 15 W/min and a 20 W/min increment will be used in children >150 cm.
During the test, the wattage will incrementally increase until children can no longer continue the pedalling frequency for at least 5 seconds, or if termination is required according to other standard safety criteria. After exhaustion, children will continue to cycle for 3 more minutes at the first increment. The test will be accepted if at least 2 of the following criteria will be reached: 1. <2 ml/kg/min increase in oxygen uptake (VO2) with increasing work load, 2. Respiratory Exchange Ratio > 1.00, 3. HR ≥85%predicted (as assessed by 220 minus age). During the test the following variables will be measured: HR, Minute ventilation (V’E) and VO2 in L/min and in L/min/kg bodyweight. The Anaerobic Threshold will be determined by the V-slope method as described by Beaver et al. , predicted values will be calculated according to normal values of Ten Harkel et al. .
MEFV curves will be determined by a spirometer (ZAN Messgerate, Oberthulba, Germany) before exercise, 10 and 30 minutes after completion of the maximal exercise test. The severity of EIB will be measured as the difference in pre-exercise and post-exercise FEV1.
Information on socio-demographic characteristics such as age, sex, ethnicity, parental BMI, social economic status and smoking exposure will be collected. Asthma control will be measured by the Asthma Control Test (ACT) in children >11 years . The childhood ACT (C-ACT) will be used in children ≤11 years [32, 33]. A score of ≤19 will be defined as uncontrolled asthma . Medication use will be evaluated over the 2 months period prior to the clinic visit and dose equivalents will be calculated according to standard dosage of SABA, LABA and ICS [16, 17, 35, 36]. The GINA guidelines will be used to determine asthma severity (intermittent, mild, moderate and severe) based on the intensity of treatment . A Dutch questionnaire and the ISAAC questionnaire will be used to measure asthma symptoms . Asthma-related quality of life will be measured by the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) . According to the PAQLQ guidelines, the minimal important difference will be defined as a difference of 0.42 points . The Euroqol 5D Youth version will be used as a measurement tool for general health related quality of life .
To investigate commonly associated morbidity in children with asthma, sleep related breathing disorders will be assessed by means of the Paediatric Sleep Questionnaire (PSQ) . A score of >0.33 will be defined as having a high risk for developing a sleep-related breathing disorder . The existence of Gastro-Oesophageal Reflux Disease (GERD) symptoms will be assessed by the GERD questionnaire . A suspicion of GERD is present when the score is ≥ 3 points . Psychosocial problems will be determined by an abnormal score on the Dutch version of the Strength and Difficulties Questionnaire (SDQ) according to the SDQ scoring guidelines . In addition, the Dutch Eating Behaviour Questionnaire (DEBQ) will be used to determine whether children have high scores on the subscales: Emotional Eating (13 items), External Eating (10 items) or Restrained Eating (10 items) .
Atopy, systemic and airway inflammation
Systemic inflammation will be determined in blood serum. The serum concentration of leptin will be determined in 100 microliter of plasma by means of multiplex immunoassay (Luminex Corporation, Austin, TX, USA). Airway inflammation will be measured by means of Fractional exhaled Nitric Oxide (FeNO) and markers in Exhaled Breath Condensate (EBC). FeNO will be obtained with the online NIOX analyser (Aerocrine, Solna, Sweden) according to international guidelines . EBC will be collected by means of an optimised glass tube, cooled by counter-current circulating ice water as described previously . In short, children will breathe tidally into the cooled glass tube for 10 minutes, while wearing a nose-clip, through a mouthpiece connected to a 2-way non-rebreathing valve. Subsequently, acidity will be measured and the EBC samples will be frozen by using dry ice and stored at −80°C. Levels of various cytokine, chemokines, and soluble intercellular adhesion molecule-1 (sICAM-1) will be measured in 100 microliter EBC with multiplex immunoassay (Luminex, Luminex Corporation, Austin, USA) .
Physical activity and dietary behaviour
Physical activity level will be measured as the average step count per day measured over a week. All children will be instructed to wear a triaxial accelerometer (Yamax EX510 Power Walker, Yamax, Tokyo, Japan) for 7 consecutive days. While wearing the accelerometer, all children will keep a diary about the time spent on swimming and cycling.
Dietary intake will be measured by means of 3-day food records. Parents and children will receive a standardised instruction based on the multiple-pass method about fulfilling dietary records at the start of the study . An online program (Vodiweb, Vodisys Medical Software, Groningen, The Netherlands) will be used to calculate nutrition composition, based on Western and local food tables and normalised portion sizes . The purpose of this tool is to measure intake of energy and macronutrients (fat, carbohydrate, protein) as well as to differentiate between healthy and unhealthy snacking during the day. A trained researcher will check all food diaries for completeness.
We incorporated the most effective components of current weight reduction programs for children in our intervention [50–53]. Several reviews and meta-analyses concluded that long-term (>1 year) multi-component lifestyle interventions targeted at both children and caregivers are most efficient [50–53]. The health counselling model is the theoretical basis of our intervention . The most important components of this intervention are sport sessions, lifestyle sessions including dietary advices and cognitive behavioural therapy, parental sessions, and individualised counselling. Children will be divided in small groups of 8 to 12 children. Intervention group allocation will occur according to place of residence and age (6–11 years and 12–15 years). To secure that intervention professionals adhere to the protocol, all intervention professionals will meet on a regular basis with a study coordinator as supervisor. The intervention is divided in an initial phase (months 0–6) and a follow-up phase (months 7–18) (Figure 1).
Theoretical basis of intervention
The theoretical foundation of the intervention is derived from the health counselling model . Health counselling is a model in which 3 phases for lifestyle changes are included: preparations, behaviour change and follow-up. The initial (preparation and behaviour change) phase will be imbedded during the first 6 months of the intervention in which there are frequent contact moments; the follow-up phase will be imbedded in the last 12 months (Figure 1). In each phase, well-known behavioural change theories such as the Stages of Change Model, Theory of Planned Behaviour, Social Cognitive Theory and Relapse Prevention Model are imbedded [55–58]. The preparation phase consists of 3 steps: 1. awareness (e.g. unhealthy eating and sedentary behaviour leads to obesity, which leads to health problems and stigmatising), 2. consideration of the new behaviour (e.g. benefits and disadvantages of losing weight) and 3. decision making (e.g. shared decision making including detecting and removing barriers). During the behaviour change phase children will receive more information about healthy behaviour and will be encouraged in each session to set a specific goal which they add to their personal goal list (e.g.: ‘I will walk the dog at least 4 days a week for 30 minutes’). In the follow-up phase children will learn how to preserve their behaviour (e.g. creating reminders of their goal-lists in their home environment, avoiding risk situations, learning social and coping skills) and eventually relapse strategies will be made (e.g. making a ‘first aid box for difficult situations’).
Sport sessions will consist of regular group exercises (twice a week during initial phase, three times a month during the follow-up phase, Figure 1), with a duration of 60 minutes per session. All sport sessions will be guided by an experienced paediatric physiotherapist or a paediatric sport instructor. A session will consist of 10 minutes warming-up, 20 minutes aerobic exercises, 20–25 minutes interval exercise games and 5 minutes cooling-down. In order to offer an enjoyable program, several recreational sports will be played such as basketball, soccer, rope skipping, and tag games. The duration and intensity of the exercises will gradually increase during the first 3 months of the exercise program. Intensity of the exercise will be held at 60-75% of the age-adjusted maximal HR. All participants will wear a heart rate monitor (polar FS3c, Polar Electro Oy, Kempele, Finland,) during each sport sessions. During and after the sport sessions the (average) HR of each participant will be evaluated by the sports instructor. In addition, Borg’s perceived exertion scale is used to monitor exertion . If advised by the children’s physician, sport instructors will encourage participants to use SABA 15 minutes before exercise.
During the initial phase participants will be motivated by their sports instructor to choose a supervised sport in their own environment, which children will practice during the follow-up phase. All participants will be encouraged to visit at least 3 different sport clubs in the vicinity of their residence. Folders with sport facilities in the environment will be provided. All parents will be encouraged to support their child to find a new sport during the parental sessions.
An experienced dietician and psychologist will guide 18 lifestyle sessions with a duration of 75–90 minutes. A session will consist of weighing, evaluation of the previous weeks, personalised goals and BMI-SDS curve, dietary advice usually incorporated in a game, psychological training, personalised goal setting and discussing home work. All children will receive a workbook with additional information for each lifestyle session, homework and space for individualised goal setting. All children will set at least one new personalised goal per session during the initial phase. In the follow-up phase, children will be encouraged to maintain their goals and modify goals in case of no BMI-SDS reduction. Small presents will be provided as incentives for participation and achievements. Individualised incentives will be obtained if personalised goals are reached and group incentives will be obtained in case of high participation rates and preparations for the lifestyle sessions. The dietician and psychologist will put emphasis on positive reinforcement during the lifestyle sessions.
All dietary advices are based on the Dutch dietary guidelines for children with a high body weight  and modelled after the work of Dutch programs to prevent childhood obesity, Realfit and Slimkids . During the sessions, children will follow 3 basic dietary guidelines: 1. healthy food choice, 2. regular eating pattern, and 3. normalised portion sizes. Other dietary themes that will be dealt with during the lifestyle sessions are among others: energy balance, fruit and vegetable intake, mindful eating, finding social support, trying new food items (including 2 taste session sessions) inspecting food labels and, if applicable, alcoholic beverages. Special attention will be paid to emotional eating, body dissatisfaction and disordered eating. Also, children will regularly comment on their own and other’s dietary journals. If children have not reduced their BMI-SDS after 6 lifestyle sessions, the dietician will provide the children with a personalised balanced hypo caloric diet with low-fat, nutrient dense foods of moderate proportion sizes. The diet will consist of a caloric restriction of 15% less than required . Participants and parents will be guided and encouraged by the dietician to follow the hypo caloric diet and to adjust the diet with the nutritional knowledge they have gained during the previous sessions.
The psychologist will teach cognitive behavioural techniques. Children will learn how to identify, challenge and change dysfunctional cognitions about weight/obesity, food/eating, bullying, self-esteem, sedentary behaviour and physical activity by means of background information and homework assignments including ‘thought diaries’. Other themes on which the psychologist will focus are motivation monitoring, stimulus control, recognizing emotions and social skills. Children will be taught how to cope with real-life situations such as holidays, parties, celebrations, and restaurants. During the follow-up phase a relapse prevention schedule will be made by all participants. The cognitive behaviour protocols were modelled after the work of Werrij et al. [63, 64].
The dietician and psychologist will guide participants to decrease sedentary behaviour. Children will be motivated to reach the advised daily 60 minutes of moderate to vigorous physical activity and to perform exhaustive physical activity for 20 minutes at least 3 days per week. Main themes to be discussed are screen time, active transportation ways and daily activity patterns.
Parents will follow 10 parental sessions of 60 minutes guided by the dietician and psychologist who also guide the lifestyle sessions. A parental session will consist of an evaluation of the prior period, summarising the content of children’s lifestyle sessions, dietary or psychological information and goal setting. The parents will receive a workbook including background information, healthy recipes and sport facilities in their residence. The dietary information will consist of standard nutritional education that is also taught to the children. In addition, advices are given about healthy cooking habits, preparing healthy snacks for children and visibility of (un)healthy food at home. The psychologist will focus on parental techniques such as positive rewarding, managing problem behaviours and modelling behaviour of the parents. Emphasis will be put on the importance of individual incentives if children reach their personalised learning goals.
Individual counselling sessions
In addition to the lifestyle sessions, children will receive individualised counselling sessions. The individualised counselling sessions will be guided by either the dietician or the psychologist, dependent on the needs of the child. The individualised counselling sessions will focus on the learning goals, motivational problems, personal barriers for maintaining the leaning goals and possible depressive symptoms. Children aged 6–11 years always attend the individual sessions accompanied by a parent. Older children will be accompanied by a parent if one of the parties (e.g. dietician, psychologist, child or parents) deems a parental visit beneficial. If the child still experiences severe problems with weight reduction despite the regular lifestyle sessions and individual consults, the dietician or psychologist will schedule extra telephonic consults with the child and/or parent.