Daan Caudri

Drug use in children: Cohort study in three European countries

Objective To provide an overview of drug use in children in three European countries. Design Retrospective cohort study, 2000-5. Setting Primary care research databases in the Netherlands (IPCI), United Kingdom (IMS-DA), and Italy (Pedianet). Participants 675 868 children aged up to 14 (Italy) or 18 (UK and Netherlands). Main outcome measure Prevalence of use per year calculated by drug class (anatomical and therapeutic). Prevalence of “recurrent/chronic” use (three or more prescriptions a year) and “non-recurrent” or “acute” use (less than three prescriptions a year) within each therapeutic class. Descriptions of the top five most commonly used drugs evaluated for off label status within each anatomical class. Results Three levels of drug use could be distinguished in the study population: high (>10/100 children per year), moderate (1-10/100 children per year), and low (<1/100 children per year). For all age categories, anti-infective, dermatological, and respiratory drugs were in the high use group, whereas cardiovascular and antineoplastic drugs were always in the low use group. Emollients, topical steroids, and asthma drugs had the highest prevalence of recurrent use, but relative use of low prevalence drugs was more often recurrent than acute. In the top five highest prevalence drugs topical inhaled and systemic steroids, oral contraceptives, and topical or systemic antifungal drugs were most commonly used off label. Conclusion This overview of outpatient paediatric prescription patterns in a large European population could provide information to prioritise paediatric therapeutic research needs.

European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia

The diagnosis of primary ciliary dyskinesia is often confirmed with standard, albeit complex and expensive, tests. In many cases, however, the diagnosis remains difficult despite the array of sophisticated diagnostic tests. There is no “gold standard” reference test. Hence, a Task Force supported by the European Respiratory Society has developed this guideline to provide evidence-based recommendations on diagnostic testing, especially in light of new developments in such tests, and the need for robust diagnoses of patients who might enter randomised controlled trials of treatments. The guideline is based on pre-defined questions relevant for clinical care, a systematic review of the literature, and assessment of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence. It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia; and to provide advice when the diagnosis was not conclusive. Finally, this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia. International ERS guidelines recommend a combination of tests to diagnose primary ciliary dyskinesia http://ow.ly/sJhH304InBN

Classification and pharmacological treatment of preschool wheezing: changes since 2008

Since the publication of the European Respiratory Society Task Force report in 2008, significant new evidence has become available on the classification and management of preschool wheezing disorders. In this report, an international consensus group reviews this new evidence and proposes some modifications to the recommendations made in 2008. Specifically, the consensus group acknowledges that wheeze patterns in young children vary over time and with treatment, rendering the distinction between episodic viral wheeze and multiple-trigger wheeze unclear in many patients. Inhaled corticosteroids remain first-line treatment for multiple-trigger wheeze, but may also be considered in patients with episodic viral wheeze with frequent or severe episodes, or when the clinician suspects that interval symptoms are being under reported. Any controller therapy should be viewed as a treatment trial, with scheduled close follow-up to monitor treatment effect. The group recommends discontinuing treatment if there is no benefit and taking favourable natural history into account when making decisions about long-term therapy. Oral corticosteroids are not indicated in mild-to-moderate acute wheeze episodes and should be reserved for severe exacerbations in hospitalised patients. Future research should focus on better clinical and genetic markers, as well as biomarkers, of disease severity. The distinction between episodic viral and multiple-trigger wheeze is unclear in many preschool children http://ow.ly/sKYZF

Early Daycare Is Associated with an Increase in Airway Symptoms in Early Childhood but Is No Protection against Asthma or Atopy at 8 Years

RATIONALE Daycare exposes young children to more infections early in life and may thereby prevent the development of asthma and allergy. OBJECTIVES To prospectively study the effect of daycare on the development of asthma and allergic sensitization during the first 8 years of life. METHODS In the Prevention and Incidence of Asthma and Mite Allergy birth cohort 3,963 newborn children were followed prospectively for 8 years. Daycare use and respiratory health were assessed yearly by questionnaires. At 8 years, sensitization to airborne allergens and airway responsiveness were measured. Daycare was defined as early (aged 0-2 yr), late (aged 2-4 yr), or none (no daycare before age 4 yr). Associations of daycare and/or older siblings with asthma symptoms (wheezing, shortness of breath, and inhaled steroids taken in the last year), airway responsiveness, and allergic sensitization were assessed in a longitudinal repeated-event analysis. MEASUREMENTS AND MAIN RESULTS Children with early daycare had more wheezing in the first years of life, but less wheezing and steroid use between 4 and 8 years of age. At the age of 8 years, early daycare was not protective for asthma symptoms (adjusted odds ratio [aOR], 0.99; 95% confidence interval [CI], 0.74-1.32), allergic sensitization (aOR 0.86; 95% CI, 0.63-1.18), or airway hyperresponsiveness (aOR, 0.80; 95% CI, 0.57-1.14). The transient reduction in airway symptoms between age 4 and 8 years was only observed in children without older siblings. CONCLUSION Early daycare is associated with an increase in airway symptoms until the age of 4 years, and fewer symptoms between the ages of 4 and 8 years. We found no protection against asthma symptoms, hyperresponsiveness, or allergic sensitization at the age of 8 years.

Prediction of asthma in symptomatic preschool children using exhaled nitric oxide, Rint and specific IgE.

Rationale For clinicians it remains very difficult to predict whether preschool children with symptoms suggestive of asthma will develop asthma in later childhood. Objective To investigate whether measurement of fraction of exhaled nitric oxide (FENO), interrupter resistance (Rint) or specific immunoglobulin E (IgE) in 4-year-old children with suggestive symptoms can predict asthma symptoms up to age 8 years. Methods Children were recruited from the PIAMA birth cohort. All children with symptoms suggestive of asthma at age 3 or 4 years, who were invited for medical examination at age 4 (n=848), were eligible. Associations of FENO (n=308), Rint (n=482) and specific IgE (n=380) at 4 years with wheezing and asthma at the ages of 5–8 years were assessed using repeated measurement analyses. The added predictive value of these objective tests was then investigated by including parameters for clinical history in the model. Results FENO and specific IgE measured at 4 years were associated with wheezing and asthma at 8 years. Both tests also remained significant predictors after mutual adjustment and adjustment for clinical history: OR on wheezing at 8 years for FENO (10log-scale, per IQR) 1.6 (95% CI 1.1 to 2.2) and for specific IgE 2.8 (95% CI 1.9 to 4.1). Rint was significantly associated with wheezing at age 6, but not at 7 and 8 years. Conclusions In preschool children with symptoms suggestive of asthma, both FENO and specific IgE measured at age 4, but not Rint, improved the prediction of asthma symptoms until the age of 8 years, independent of clinical history.

Experimental designs for small randomised clinical trials: An algorithm for choice

BackgroundSmall clinical trials are necessary when there are difficulties in recruiting enough patients for conventional frequentist statistical analyses to provide an appropriate answer. These trials are often necessary for the study of rare diseases as well as specific study populations e.g. children. It has been estimated that there are between 6,000 and 8,000 rare diseases that cover a broad range of diseases and patients. In the European Union these diseases affect up to 30 million people, with about 50% of those affected being children. Therapies for treating these rare diseases need their efficacy and safety evaluated but due to the small number of potential trial participants, a standard randomised controlled trial is often not feasible. There are a number of alternative trial designs to the usual parallel group design, each of which offers specific advantages, but they also have specific limitations. Thus the choice of the most appropriate design is not simple.MethodsPubMed was searched to identify publications about the characteristics of different trial designs that can be used in randomised, comparative small clinical trials. In addition, the contents tables from 11 journals were hand-searched. An algorithm was developed using decision nodes based on the characteristics of the identified trial designs.ResultsWe identified 75 publications that reported the characteristics of 12 randomised, comparative trial designs that can be used in for the evaluation of therapies in orphan diseases. The main characteristics and the advantages and limitations of these designs were summarised and used to develop an algorithm that may be used to help select an appropriate design for a given clinical situation. We used examples from publications of given disease-treatment-outcome situations, in which the investigators had used a particular trial design, to illustrate the use of the algorithm for the identification of possible alternative designs.ConclusionsThe algorithm that we propose could be a useful tool for the choice of an appropriate trial design in the development of orphan drugs for a given disease-treatment-outcome situation.

THE IMPACT OF HELICOBACTER PYLORI ON ATOPIC DISORDERS IN CHILDHOOD

Background:  The prevalence of Helicobacter pylori in Western populations has steadily decreased. This has been suggested as one of the factors involved in the recent increase of asthma and allergy. Some studies have reported a negative association between H. pylori and asthma and allergy, but data are inconsistent and there are a few studies in children.

Impact of bronchiectasis and trapped air on quality of life and exacerbations in cystic fibrosis

Cystic fibrosis (CF) is primarily characterised by bronchiectasis and trapped air on chest computed tomography (CT). The revised Cystic Fibrosis Questionnaire respiratory symptoms scale (CFQ-R RSS) measures health-related quality of life. To validate bronchiectasis, trapped air and CFQ-R RSS as outcome measures, we investigated correlations and predictive values for pulmonary exacerbations. CF patients (aged 6–20 years) underwent CT, CFQ-R RSS and 1-year follow-up. Bronchiectasis and trapped air were scored using the CF-CT scoring system. Correlation coefficients and backward multivariate modelling were used to identify predictors of pulmonary exacerbations. 40 children and 32 adolescents were included. CF-CT bronchiectasis (r = -0.38, p<0.001) and CF-CT trapped air (r = -0.35, p = 0.003) correlated with CFQ-R RSS. Pulmonary exacerbations were associated with: bronchiectasis (rate ratio 1.10, 95% CI 1.02–1.19; p = 0.009), trapped air (rate ratio 1.02, 95% CI 1.00–1.05; p = 0.034) and CFQ-R RSS (rate ratio 0.95, 95% CI 0.91–0.98; p = 0.002). The CFQ-R RSS was an independent predictor of pulmonary exacerbations (rate ratio 0.96, 95% CI 0.94–0.97; p<0.001). Bronchiectasis, trapped air and CFQ-R RSS were associated with pulmonary exacerbations. The CFQ-R RSS was an independent predictor. This study further validated bronchiectasis, trapped air and CFQ-R RSS as outcome measures in CF.

Perinatal risk factors for wheezing phenotypes in the first 8 years of life

A novel data‐driven approach was used to identify wheezing phenotypes in pre‐schoolchildren aged 0–8 years, in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort. Five phenotypes were identified: never/infrequent wheeze, transient early wheeze, intermediate onset wheeze, persistent wheeze and late onset wheeze. It is unknown which perinatal risk factors drive development of these phenotypes.

Asthma symptoms and medication in the PIAMA birth cohort: Evidence for under and overtreatment

To cite this article: Caudri D, Wijga AH, Smit HA, Koppelman GH, Kerkhof M, Hoekstra MO, Brunekreef B, de Jongste JC. Asthma symptoms and medication in the PIAMA birth cohort: Evidence for under and overtreatment. Pediatric Allergy Immunology 2011; 22: 652–659.