Asthma medication in children who are overweight/obese: justified treatment?

BACKGROUND: The prevalence of asthma and obesity have increased over the last decades. A possible association between these two chronic illnesses has been suggested, since the prevalence of asthmatic symptoms rises with increasing Body Mass Index (BMI). However, asthma is only one of several possible causes of shortness of breath in obese children. The aim of this study is to evaluate the prevalence of overtreatment with asthma medication in a cohort overweight/obese children with respiratory symptoms visiting a pediatric outpatient clinic. METHODS: Children referred to a pediatric outpatient clinic aged ≥4- ≤ 18 years with overweight/obesity (defined as BMI-sds > 1.1) and asthmatic symptoms were included. The diagnosis asthma was evaluated and classified in no, unlikely, probable and confirmed asthma, based on clinical parameters and/or spirometry results. Overtreatment was defined as asthma medication prescribed in participants classified as no or unlikely asthma. And undertreatment as probable or confirmed asthma without asthma medication prescribed . RESULTS: Three hundred thirty-eight participants were included, of which 92.6% (313/338) had a prescription for asthma medication. Overtreatment was observed in 27.2% (92/338) participants. Nine participants were undertreated. CONCLUSION: More than 25% overtreatment with asthma medication was observed in a cohort overweight/obese children with asthmatic symptoms. This finding emphasizes that the diagnosis of asthma must be confirmed before commencement of medication. The diagnosis of asthma should be based on standard questionnaires evaluating asthmatic symptoms, lung functions test and regular reassessments. Further studies concerning overtreatment with asthma medication in normal weight pediatric populations are warranted, to evaluate whether overtreatment is specific for overweight/obese children.

Increased Arterial Stiffness in Adolescents With Obesity.

Increased arterial stiffness (AS) is an early sign of cardiovascular disease. Influence of weight, puberty, and insulin resistance (IR) on AS in adolescents is unclear. Therefore, this study compared AS, assessed with pulse wave velocity (PWV) and augmentation index (AIx), of adolescents with and without obesity and evaluated the influence of puberty and IR on AS. Sixty-two lean and 61 adolescents with obesity were included. Significantly higher PWV was observed in adolescents with obesity (4.1 ms-1 [2.4 to 5.6 ms-1] vs 3.6 ms-1 [0.4 to 6.1 ms-1]; P = .01), while AIx was not significant different. However, significantly higher AIx was observed in adolescents with obesity and IR (3.0 [-17.5% to 28.5%] vs -3.0 [-19.0% to 13.0%]; P = .01). For Tanner stages, no differences were observed. The higher PWV in adolescents with obesity and higher AIx in adolescents with obesity and IR both indicate an increased AS. Consequently, measurement of AS should be considered in adolescents with obesity and IR as part of cardiovascular risk assessment.

Skin autofluorescence in children with and without obesity.

Background Obesity is associated with oxidative stress, which is related to increased advanced glycation end product (AGE) formation. AGEs accumulated in skin collagen can be measured with skin autofluorescence (sAF). There are conflicting reports on the influence of obesity on sAF in adults and no data in children. Therefore, this study evaluated sAF in pediatric patients with and without obesity. Methods In this cross-sectional study, participants aged 4-18 years were included: patients with obesity (body mass index standard deviation score [BMI-SDS] >2.3) and lean controls (BMI-SDS >-1.1 to <1.1). sAF was measured using the AGE Reader®. Participants were stratified according to age (<10, ≥10 to <13, ≥13 to <15, ≥15 to <17 and ≥17 years) and skin type (I-VI). Results In total, 143 patients and 428 controls were included. In patients, there was no influence of age on sAF (p=0.09). In controls, sAF was higher in children aged <10 years compared to ≥10 to <13 and ≥13 to <15 years (p=0.02; p=0.04). Stratified by age, sAF was higher in patients compared to controls in all age categories, except <10 years of age (p<0.01), while this was not observed when stratified by skin type (p>0.05). Skin type and BMI were significant covariates for sAF. Conclusions BMI was a covariate for sAF; however, no difference in sAF was observed between children with and without obesity, stratified by skin type. Duration of obesity as well as accuracy of the AGE Reader® might explain this difference. Further research is warranted, in which patients should be matched for age and skin type.

Psychostimulants: Influence on Body Mass Index and Height in a Pediatric Population with Attention-Deficit/Hyperactivity Disorder?

OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is often treated with psychostimulants. Psychostimulants' adverse effects on body mass index standard deviation score (BMI-sds) and height in children/adolescents with ADHD have been reported. However, literature is inconsistent, and it is unclear whether the observed effects are dosage- and/or BMI-dependent. Therefore, the aim of this retrospective observational study is to evaluate the influence of psychostimulants on BMI-sds and height-sds in a pediatric cohort with ADHD from an outpatient clinic, and to study the correlation between psychostimulant dosage and BMI-sds and height-sds change. METHOD: Participants ≤18 years of age diagnosed with ADHD who started with psychostimulants (methylphenidate) were studied. Changes in BMI-sds and height-sds over an 18-month treatment period were assessed in subgroups according to baseline BMI-sds, gender, and age. Furthermore, correlations between BMI-sds, height-sds, and psychostimulant dose were studied. RESULTS: In total, 298 participants [median age 9.8 years, height-sds 0.0, BMI-sds 0.5, psychostimulant dosage 0.5 (0.2-1.4) mg/kg/day] were analyzed, with an underweight, overweight, and obesity prevalence of 5%, 21%, and 7%, respectively. After 18 months of treatment a significant decline in BMI-sds (-0.4) and height-sds (-0.2) was observed. These effects were consistent in all subgroups except for no change in BMI-sds in the underweight subgroup and no change in height-sds in the overweight subgroup. Medication dosage was weakly correlated with change in BMI-sds [r = -0.3 (-0.9 to +0.5); p < 0.01] and height-sds [r = -0.2 (-0.4 to -0.1); p = 0.01]. CONCLUSION: After 18 months of psychostimulant treatment, a significant decline in BMI-sds and height-sds was observed. However, the correlation with psychostimulant dosage was weak, and the decline was not observed in all subgroups. Therefore, further studies on the etiology of BMI-change are warranted, particularly with regard to the ADHD symptoms.

Predictors of Insulin Resistance in Children versus Adolescents with Obesity.

Introduction: Obesity is a risk factor to develop metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM). Insulin resistance (IR) plays a major part in both. With increasing incidence of childhood obesity, this retrospective study aimed to identify predictors of IR in children/adolescents with obesity to optimize screening for IR. Method: Patients aged ≥ 2-≤ 18 years with obesity (BMI-SDS > 2.3) were included. IR was defined as HOMA-IR ≥ 3.4, and MetS if ≥3 of the following criteria were present: waist circumference and blood pressure ≥ 95th age percentile, triglycerides ≥ 1.7 mmol/l, HDL < 1.03 mmol/l, and fasting plasma glucose ≥ 5.6 mmol/l. Results: In total, 777 patients were included. Of the 306 children, 51, 38, and 0 were diagnosed with IR, MetS, and T2DM, respectively. Of the 471 adolescents, 223, 95, and 0 were diagnosed with IR, MetS, and T2DM, respectively. In the multivariable regression model, BMI-SDS, preterm birth, and Tanner stage were associated with IR in children (6.3 (95% CI 1.3-31.1), 5.4 (95% CI 1.4-20.5), 2.2 (95% CI 1.0-4.8)), and BMI-SDS and waist circumference in adolescents (4.0 (95% CI 1.7-9.2), 3.7 (95% CI 1.5-9.4)). Conclusion: Different IR predictors were observed in children/adolescents with obesity. These predictors can be used to optimize screening for IR in pediatric populations.

Definition of insulin resistance affects prevalence rate in pediatric patients: a systematic review and call for consensus.

BACKGROUND: As a result of the rising prevalence of childhood obesity, there is an increasing interest in the type 2 diabetes mellitus precursor insulin resistance (IR). The aim of this study is to review definitions (methods and cutoff values) to define IR in children and to apply these definitions to a previously described obese pediatric population. METHODS: A systematic literature review on prevalence and/or incidence rates in children was performed. The extracted definitions were applied to an obese pediatric population. RESULTS: In the 103 identified articles, 146 IR definitions were reported based on 14 different methods. Fasted definitions were used 137 times, whereas oral/intravenous glucose tolerance test-derived methods were used nine times. The homeostasis model for the assessment of insulin resistance (HOMA-IR) and fasted plasma insulin (FPI) were the most frequently used fasted methods (83 and 37 times, respectively). A wide range in cutoff values to define IR was observed, resulting in prevalence rates in the predefined obese pediatric population between 5.5% (FPI>30 mU/L) and 72.3% (insulin sensitivity indexMatsuda≤7.2). CONCLUSIONS: To compare IR incidence and prevalence rates in pediatric populations, a uniform definition of IR should be defined.

The Effect of Eighteen-Month Metformin Treatment in Obese Adolescents: Comparison of Results Obtained in Daily Practice with Results from a Clinical Trial.

Background. In a recent randomized controlled trial (RCT) in obese adolescents, 18 month-treatment with metformin versus placebo was reported to lead to stabilisation of the BMI. This study aimed to compare the effect of metformin on BMI in obese adolescents in daily practice versus results obtained in an RCT. Methods. Obese adolescents treated off label with metformin in daily practice in an outpatient clinic with a follow-up of ≥18 months were identified. Anthropometric and biochemical data were collected at baseline and at 18 months. Patients treated with metformin for 18 months in an RCT were used for comparison. BMI was compared between the two groups. Results. Nineteen patients (median age 14.3 (interquartile range 11.7-15.7) years, BMI 31.3 (28.8-33.8) kg/m2) treated in daily practice were compared to 23 patients receiving metformin in the RCT (age 13.6 (12.6-15.3) years, BMI 29.8 (28.1-34.5) kg/m2). BMI change after 18 months was -0.36 (-2.10-1.58) versus +0.22 (-2.87-1.27) kg/m2 for the two groups, respectively. In the multivariable model, BMI change was not statistically significantly different between the two groups (p = 0.61). Conclusion. Treatment with metformin in obese adolescents in daily practice resulted in a comparable change in BMI as observed in an RCT. This trial is registered with ClinicalTrials.gov number: NCT01487993.

Increasing trends in the incidence and prevalence rates of type 1 diabetes among children and adolescents in the Netherlands.

OBJECTIVE: To assess the trends in the incidence and prevalence rates of type 1 diabetes (T1D) among children and adolescents in the Netherlands. METHODS: A population-based cohort study was conducted in the Dutch PHARMO record linkage system (1998-2011). All children and adolescents aged ≤19 yr with at least one insulin dispensing (as a proxy for T1D) were identified and the numbers of incident and prevalent cases (numerators) were calculated. Overall age-adjusted (0-19 yr) incidence and prevalence rates together with age- and sex-specific rates of T1D and their 95% confidence intervals (CI) were calculated using data from the Dutch Central Bureau of Statistics as denominator. Trends over time were assessed using Joinpoint regression software (National Cancer Institute, Bethesda, MD, USA). RESULTS: In 2011, the overall age-adjusted incidence and prevalence rates of T1D were 25.2/100 000 (95% CI, 23.7-26.8) person-years (PY) and 174.4/100 000 (95% CI, 170.2-178.5) children, respectively. The average annual percentage change (AAPC) in the overall age-adjusted incidence and prevalence rate was 3.7% (95% CI, 1.8-5.7) and 3.8% (95% CI, 2.4-5.2), respectively. While during the study period the largest increases in the incidence and prevalence rates of T1D were observed for the oldest age groups (10-14 and 15-19 yr), a decreasing trend was detected for the 0- to 4-yr-old category (with AAPCs of -1.8 (95% CI, -9.9 to 7.1) and -6.9% (95% CI, -11.5 to -2.1) for incidence and prevalence, respectively). CONCLUSION: Age-adjusted incidence (1999-2011) and prevalence rates (1998-2011) of T1D in Dutch children (aged 0-19 yr) continued to increase and a shift was observed to a later onset of the disease.

Chronic comorbidities in children with type 1 diabetes: a population-based cohort study.

OBJECTIVE: To determine the incidence of chronic comorbidities among children with type 1 diabetes (T1D) and to compare incidences with a group of children without diabetes. DESIGN: Population-based cohort study. SETTING: Dutch PHARMO database (1998-2010). PATIENTS: All patients (<19 years old) with T1D between 1999 and 2009 (T1D cohort) and a group of age- and sex-matched (ratio: 1-4) children without diabetes (reference cohort). MAIN OUTCOME MEASURE: The incidence of nine common chronic comorbidities was assessed on the basis that they were treated pharmacologically and/or resulted in hospital admission. Cox proportional hazard analysis was used to estimate the strength of the association between T1D and comorbidities, expressed as HRs and 95% CIs. RESULTS: A total of 915 patients with T1D and 3590 children in the reference cohort (51% boys, mean age of 10.1 (SD 4.5) years) were included. T1D was associated with an increased risk (HR; 95% CI) of hospitalisation for any comorbidity (3.7; 2.5 to 5.5), thyroid disease (14.2; 6.7 to 31.0), non-infectious enteritis and colitis (5.9; 3.0 to 11.5), cardiovascular disorders (3.1; 2.3 to 4.2), mental disorders (2.0; 1.4 to 3.1), epilepsy (2.0; 1.1 to 3.7) and (obstructive) pulmonary disease (1.5; 1.2 to 2.0). There was no significant difference in the incidences of other comorbidities (malignant disorders, anaemia and migraine) between the two cohorts. CONCLUSIONS: Our longitudinal study showed that incidences of six chronic diseases were significantly higher in T1D children during the early years of developing this disease compared with the reference children.

A Follow-up Study on BMI-SDS and Insulin Resistance in Overweight and Obese Children at Risk for Type 2 Diabetes Mellitus.

Objectives. To evaluate body mass index standard deviation score (BMI-SDS), insulin sensitivity, and progression to type 2 diabetes mellitus (T2DM) in children at risk for T2DM approximately 3 years after being diagnosed with overweight/obesity and insulin resistance (measured by Homeostasis Model Assessment of Insulin Resistance [HOMA-IR]). Methods. Out of 86 invited children, 44 (mean age 15.4 ± 3.6 years) participated. Medical history, physical examination, and laboratory workup were performed. Results. While the mean BMI-SDS significantly increased from 2.9 to 3.4, the mean HOMA-IR significantly decreased from 5.5 to 4.6 (baseline vs follow-up visit). Change in HOMA-IR was only due to a decrease in mean fasting plasma insulin (24.1 vs 21.1, P = .073). Conclusions. Although increase in BMI-SDS in these children is worrisome, the American Diabetes Association recommended screening interval of 3 years for children at risk for T2DM is not too long based on the fact that none of our study participants developed T2DM.

METFORMIN: an efficacy, safety and pharmacokinetic study on the short-term and long-term use in obese children and adolescents - study protocol of a randomized controlled study.

BACKGROUND: The prevalence of childhood obesity and insulin resistance is rising, increasing the risk of diabetes mellitus type 2. To prevent these complications, lifestyle intervention is the corner stone in treatment. However, long-term efficacy of lifestyle intervention is questionable. In addition to lifestyle intervention, pharmacological treatments have been explored. Metformin has been shown to be moderately effective to reduce BMI in obese adolescents with hyperinsulinemia. However, data on pharmacokinetics and long-term efficacy and safety are lacking as well as an evidence-based dosing regimen for this age group. The primary objective of the METFORMIN study is to determine the effect of adding metformin treatment to lifestyle intervention in reducing BMI in obese adolescents with insulin resistance. In addition, the pharmacokinetics of metformin in obese adolescents will be studied. METHODS/DESIGN: The METFORMIN study is a multi-centre prospective study that consists of two 18-month phases: a double-blind randomized placebo-controlled trial (part 1) and an open-label follow-up study (part 2). During part 1, the participants will be given metformin 1,000 mg or placebo twice daily and will be offered a lifestyle intervention programme; 144 participants will be included, 72 in each arm. Primary endpoints are reduction in body mass index, insulin resistance, and percentage body fat. DISCUSSION: This study will provide data on short- and long-term efficacy and safety of metformin and on the pharmacokinetics of metformin in obese adolescents. TRIAL REGISTRATION: ClinicalTrials.gov number NCT01487993; EudraCT nr. 2010-023980-17. Registration date: 06-01-2011.

Population-based cohort study of anti-infective medication use before and after the onset of type 1 diabetes in children and adolescents.

A population-based cohort study was conducted in the Dutch PHARMO database to investigate prevalence and patterns of anti-infective medication use in children and adolescents with type 1 diabetes (T1D) before and after the onset of this disease. All patients <19 years with at least 2 insulin prescriptions (1999 to 2009) were identified (T1D cohort) and compared with an age- and sex-matched (ratio: 1 up to 4) diabetes-free reference group. The prevalence and average number of anti-infective use was studied from (up to) 8 years before until a maximum of 4 years after the onset of T1D. A total of 925 patients with T1D and 3,591 children and adolescents in the reference cohort (51% boys, mean age of 10.1 [standard deviation, 4.5] years) were included. The overall prevalence of anti-infective use (62.6 compared to 52.6%, P < 0.001) and average number of prescriptions (2.71 compared to 1.42 per child, P < 0.001) in the T1D cohort were significantly higher than those in the reference cohort after the onset of diabetes. This pattern was consistent across sex and age categories and already observed in the year before the onset of type 1 diabetes. Patients in the T1D cohort received more antibacterials (49.8 compared to 40%, P < 0.001), antimycotics (4.0 compared to 1.3%, P < 0.001), antivirals (2.5 compared to 0.4%, P < 0.001), and second-line antibiotics, such as aminoglycosides, quinolones, and third-generation cephalosporins and carbapenems. Our findings that elevated anti-infective use in the T1D cohort exists in the period before the onset of type 1 diabetes and the consumption of more second-line anti-infective compounds in this time period warrant further research.

Disease history and medication use as risk factors for the clinical manifestation of type 1 diabetes in children and young adults: an explorative case control study.

BACKGROUND: There is a highly variable asymptomatic period of beta cell destruction prior to the clinical presentation of type1 diabetes. It is not well known what triggers type 1 diabetes to become a clinically overt disease. This explorative study aimed to identify the association between disease history/medication use and the clinical manifestation of type 1 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: An explorative case control study was conducted in the Dutch PHARMO Record Linkage System. Cases (n = 1,107) were younger than 25 years and had at least 2 insulin prescriptions between 1999 and 2009. For each case, up to 4 controls (without any prescription for the glucose lowering medications (n = 4,424)) were matched by age and sex. Conditional logistic regression analysis was used to evaluate the association between disease history/medication use in the year prior to the diagnosis of type 1 diabetes and clinical manifestation of this disease. Type1 diabetes was significantly associated with a history of mental disorder (odds ratio (OR) 8.0, 95% confidence interval (CI) 1.5-43.7), anemia (OR 5.1, 95% CI 1.1-22.9), and disease of digestive system (OR 2.6, 95% CI 1.2-5.5). The following drug exposures were significantly associated with the clinical manifestation of type 1 diabetes: "systemic hormonal preparations" (OR 1.7, 95% CI 1.1-2.6), medications for "blood and blood forming organs" (OR 1.6, 95% CI 1.1-2.6), "alimentary tract and metabolism" (OR 1.3, 95% CI 1.1-1.6), and "anti-infectives for systemic use" (OR 1.2, 95% CI 1.01-1.4). CONCLUSIONS: Our explorative study demonstrated that in the year prior to the presentation of type 1 diabetes in children and young adults, hospitalization for a diverse group of diseases and drug exposures were significantly more prevalent compared with age- and sex-matched diabetes-free controls.

How to screen obese children at risk for type 2 diabetes mellitus?

BACKGROUND: Recommended screening to identify children at risk for diabetes and its precursors impaired glucose tolerance (IGT) and insulin resistance (IR) is fasted plasma glucose (FPG). This study evaluates the added value of fasted plasma insulin (FPI). METHODS: This study analyzed routinely collected data of an oral glucose tolerance test (OGTT) of 311 obese children (age 10.8 ± 3.2 years). Diabetes and IGT were defined according to the American Diabetes Association criteria, IR as homeostasis model assessment (HOMA)-IR ≥3.4. RESULTS: Cases diagnosed with an OGTT if FPG ≥5.6 mmol/L, compared with an OGTT performed if FPG ≥5.6 mmol/L or HOMA-IR ≥3.4, were, respectively, 4 (80%) versus 5 (100%) with diabetes, 7 (28%) versus 16 (64%) with IGT, and 0 (0%) versus 93 (100%) with IR. CONCLUSIONS: Screening with FPG and FPI has equal burden compared with screening with FPG alone, identifies all patients with diabetes, and identifies more patients with precursors of diabetes.

Evaluation of a bedside device to assess the activated partial thromboplastin time for heparin monitoring in infants.

To determine the relationship between the activated partial thromboplastin time (aPTT) measured with a standard laboratory assay and the aPTT measured with a bedside device in infants on heparin therapy after cardiothoracic surgery. Twenty infants aged below 1 year who were on heparin therapy were included. Exclusion criteria were prematurity, dysmaturity and the use of anticoagulants other than heparin. Nineteen samples were obtained from four adults in intensive care who were on heparin. The aPTT values were analyzed with the Coaguchek Pro/DM bedside device (aPTTbed) and compared with the aPTT values obtained from the laboratory Electra 1800C coagulation analyzer (aPTTlab). Correlation analysis was performed by linear regression. The agreement was calculated using Bland-Altman analysis. The correlation coefficient of samples obtained from infants was lower (r = 0.48) compared with samples from adults (r = 0.85). A substantial positive bias (27 s) and scatter [95% confidence interval (CI) -11; +65 s) was found. The bias showed a genuine trend to increase at higher aPTT values (r = 0.90; P < 0.001). The bedside device overestimates the aPTT in infants treated with heparin. The disagreement between the bedside device and laboratory increases at higher aPTTs. Bedside devices should not be used to monitor heparin therapy in infants in intensive care.