Marianne Nuijsink

Long-term asthma treatment guided by airway hyperresponsiveness in children: a randomised controlled trial

Management plans for childhood asthma show limited success in optimising asthma control. The aim of the present study was to assess whether a treatment strategy guided by airway hyperresponsiveness (AHR) increased the number of symptom-free days and improved lung function in asthmatic children, compared with a symptom-driven reference strategy. In a multicentre, double-blind, parallel-group, randomised, 2-yr intervention trial, 210 children (aged 6–16 yrs) with moderate atopic asthma, selected on the basis of symptom scores and/or the presence of AHR, were studied. At 3-monthly visits, symptom scores, forced expiratory volume in one second (FEV1) and methacholine challenge results were obtained, and medication (five levels of fluticasone with or without salmeterol) adjusted according to algorithms based on symptom score (reference strategy, n = 104) or AHR and symptom score (AHR strategy, n = 102). After 2 yrs, no difference was found in the percentage of symptom-free days between treatment strategies. Pre-bronchodilator FEV1 was higher in the AHR strategy (2.3% predicted). This was entirely explained by a gradual worsening of FEV1 in a subgroup of 91 hyperresponsive children enrolled with low symptom scores (final difference between study arms was 6%). Asthma treatment guided by airway hyperresponsiveness showed no benefits in terms of number of symptom-free days, but produced a better outcome in terms of pre-bronchodilator forced expiratory volume in one second in allergic asthmatic children, especially those characterised by low symptom scores despite airway hyperresponsiveness.

Iron deficiency occurs frequently in children with cystic fibrosis

In adult CF patients iron deficiency (ID) is common and primarily functional due to chronic inflammation. No recent data are available on the cause of ID and iron deficiency anemia (IDA) in children with CF. Over the last decades onset of inflammation and pulmonary disease in children with CF is delayed by improved nutritional status. We questioned whether ID occurs in the same extent among children with CF as in adult CF patients. We therefore conducted a study to investigate the iron status of children with CF and to determine whether ID and IDA are associated with dietary iron intake, lung disease severity and Pseudomonas aeruginosa (PA) infection.

Perception of bronchoconstriction: A complementary disease marker in children with asthma

Introduction. Asthma guidelines use symptoms as the most important aspect of asthma control. Symptom perception varies widely between individuals. Over-perception as well as underperception of bronchoconstriction could have a negative effect on asthma management. We hypothesized that perception of bronchoconstriction in childhood asthma is not related to common measures of disease control. For that reason, we examined the clinical determinants of the perception of bronchoconstriction and the repeatability of perception measurements. Patients and methods. In school-age children with moderately severe atopic asthma, we measured the perception of bronchoconstriction (decrease in forced expiratory volume in 1 second (FEV1)) during methacholine bronchoprovocation challenges. The perception of bronchoconstriction was assessed as the slope of the relation between FEV1 and Borg score, and as the Borg score at a 20% decrease in FEV1 from baseline during the provocation test (PS20). Data from subjects who had a 20% or more decrease in FEV1 (n = 112) were used for the analysis. Fifty-four children repeated the test after 3 months. Symptoms, use of rescue medication, and peak expiratory flows were scored in diaries during the 2 weeks before testing. Results. Symptom perception was significantly better in children without (PD20 > 1570 μg, n = 28) than in children with airway hyperresponsiveness (PD20 ≤ 1570 μg, n = 112), slope 0.22 versus 0.13 respectively (p < .001). Borg scores correlated with PD20 (p = .01), baseline FEV1 (only for slope, p = .04), and use of rescue beta agonist (p = .01), but not with other aspects of asthma control. Repeatability of Borg scores was good (slope: R = 0.59, PS20: R = 0.52). Conclusion. Poorer symptom perception in asthmatic children correlated with hyperresponsiveness, and was associated with lower baseline FEV1 and less use of rescue bronchodilators. This suggests that the measurement of symptom perception should be taken into account in individual management plans for children with asthma. CATO Study Group Members: Department of Pediatric Respiratory Medicine, Haga Hospital/Juliana Children’s Hospital, The Hague (M. Nuijsink, M.D., J. M. Kouwenberg, M.D.). Department of Epidemiology and Biostatistics, Erasmus University Medical Center, Rotterdam (W. C. J. Hop, Ph.D.). Department of Respiratory Medicine, Academic Medical Centre, University, Amsterdam (Prof. P. J. Sterk, Ph.D.). Leiden University Medical Center, Leiden (E. R. V. M. Rikkers-Mutsaerts, M.D.). Department of Pediatric Respiratory Diseases, University Medical Center Groningen (Prof. E. J. Duiverman, M.D., Ph.D.). Department of Pediatric Respiratory Medicine, Erasmus University Medical Center/Sophia Children’s Hospital, Rotterdam (Prof. J. C. de Jongste, M.D., Ph.D.). Asthma Center Heideheuvel, Hilversum (O. H. van der Baan-Slootweg, M.D., E. E. M. van Essen-Zandvliet, M.D., Ph.D.). Flevo Hospital, Almere (N. J. van den Berg, M.D., Ph.D.). Prof. Dr. J. M. Boogaard, Ph.D. Isala Klinieken, Zwolle (P. L. P. Brand, M.D. Ph.D., Ph.D., A. W. A. Kamps, M.D., Ph.D.). Medical Center, Alkmaar (G. Brinkhorst, M.D.). VU Medical Center, Amsterdam (J. E. Dankert-Roelse, M.D. Ph.D., A. F. Nagelkerke M.D.). Maxima Medical Center, Veldhoven (R. van Gent, M.D., Ph.D.). Maasland Hospital, Sittard (J. W. C. M. Heijnens, M.D.). University Hospital Maastricht (J. J. E. Hendriks, M.D., Ph.D., Q. Jöbsis, M.D., Ph.D.). University Medical Center/Wilhelmina Children’s Hospital, Utrecht (J. van der Laag, M.D., H. J. L. Brackel, M.D., Ph.D.). Academic Medical Center, Amsterdam (J. C. van Nierop, M.D.). Amphia Hospital, Breda (A. A. P. H. Vaessen-Verberne, M.D., Ph.D.) all from The Netherlands.

Urinary Eosinophil Protein X in Children with Atopic Asthma

The aim of this study was to investigate the relationship between urinary eosinophil protein X (uEPX) and asthma symptoms, lung function, and other markers of eosinophilic airway inflammation in asthmatic school children. Methods. A cross-sectional study was performed in 180 steroid dependent atopic children with stable moderately severe asthma, who were stable on 200 or 500μg of fluticasone per day. uEPX was measured in a single sample of urine and was normalized for creatinine concentration (uEPX/c). Symptom scores were kept on a diary card. FEV1 and PD20 methacholine were measured. Sputum induction was performed in 49 and FENO levels measured in 24 children. Results. We found an inverse correlation between uEPX/c and FEV1 (r = −.20, P = .01) and a borderline significant correlation between uEPX/c and PD20 methacholine (r = −.15, P = .06). Symptom score, %eosinophils and ECP in induced sputum and FENO levels did not correlate with uEPX/c. Conclusion. uEPX/c levels did not correlate with established markers of asthma severity and eosinophilic airway inflammation in atopic asthmatic children.

Multicentre chest computed tomography standardisation in children and adolescents with cystic fibrosis: The way forward

Progressive cystic fibrosis (CF) lung disease is the main cause of mortality in CF patients. CF lung disease starts in early childhood. With current standards of care, respiratory function remains largely normal in children and more sensitive outcome measures are needed to monitor early CF lung disease. Chest CT is currently the most sensitive imaging modality to monitor pulmonary structural changes in children and adolescents with CF. To quantify structural lung disease reliably among multiple centres, standardisation of chest CT protocols is needed. SCIFI CF (Standardised Chest Imaging Framework for Interventions and Personalised Medicine in CF) was founded to characterise chest CT image quality and radiation doses among 16 participating European CF centres in 10 different countries. We aimed to optimise CT protocols in children and adolescents among several CF centres. A large variety was found in CT protocols, image quality and radiation dose usage among the centres. However, the performance of all CT scanners was found to be very similar, when taking spatial resolution and radiation dose into account. We conclude that multicentre standardisation of chest CT in children and adolescents with CF can be achieved for future clinical trials. Multicentre chest CT standardisation is necessary and feasible to maximise image quality and reduce radiationhttp://ow.ly/ZfsaE

The value of soluble transferrin receptor and hepcidin in the assessment of iron status in children with cystic fibrosis.

BACKGROUND The value of ferritin in the diagnosis of iron deficiency is limited in patients with CF since it increases in the presence of inflammation. We hypothesized that the soluble transferrin receptor (sTfR) and hepcidin may provide more information than ferritin in assessing iron status in children with CF. METHODS We analyzed sTfR and hepcidin in relation to conventional iron status indicators in 49 children with CF. RESULTS We found no differences in sTfR concentration between children with and those without ID. sTfR concentrations were within the normal range in all children. Hepcidin concentrations were low, and concentrations below the limit of detection were observed in 25% of the clinically stable children. CONCLUSION The sTfR is not useful to determine the iron status in this population, whereas hepcidin might serve as an early indicator of deficient iron stores in children with CF.

CT-abnormalities, bacteriology and symptoms of sinonasal disease in children with Cystic Fibrosis

BACKGROUND Sinonasal pathology in adults with Cystic Fibrosis (CF) is common but the extent of CT-abnormalities and symptoms of sinonasal disease in children with CF and the age of onset are less frequently studied. METHODS In this observational, cross-sectional study 58 children with CF from two CF centres were included. All subjects completed a questionnaire regarding sinonasal symptoms, underwent a CT scan of the paranasal sinuses, and in each subject a culture of the upper airways was performed. Subjects were divided in 6 age cohorts (0-2, 3-5, 6-8, 9-11, 12-14 and 15-17years) and were divided into severe and mild CF based on their CFTR mutation. Opacification of the sinonasal system of the subjects was compared with opacification on MRI-scans of an age-matched control group without CF. RESULTS Most frequently reported symptoms were nasal obstruction and posterior/anterior nasal discharge. Opacification was abundant in every age cohort of the study group and was significantly more compared to the control group. In patients with severe CF the opacification was higher than subjects with mild CF. Upper airway cultures showed predominantly Staphylococcus aureus, Haemophilus influenzae and Pseudomonas aeruginosa. CONCLUSION CT-abnormalities indicating sinonasal disease and symptoms are present from shortly after birth which may argue for a thorough examination of the upper airways in children with CF.

Urinary Eosinophil Protein X in Childhood Asthma: Relation with Changes in Disease Control and Eosinophilic Airway Inflammation

The aim of this study was to assess cross-sectional and longitudinal correlations between uEPX and other markers of asthma control and eosinophilic airway inflammation. Methods. We measured uEPX at baseline, after 1 year and after 2 years in 205 atopic asthmatic children using inhaled fluticasone. At the same time points, we assessed symptom scores (2 weeks diary card), lung function (forced expiratory volume in one second (FEV1)), airway hyperresponsiveness (AHR), and percentage eosinophils in induced sputum (% eos). Results. We found negative correlations between uEPX and FEV1 at baseline (r = −0.18, P = 0.01), after 1 year (r = −0.25, P < 0.01) and after 2 years (r = −0.21, P = 0.02). Within-patient changes of uEPX showed a negative association with FEV1 changes (at 1 year: r = −0.24, P = 0.01; at 2 years: r = −0.21, P = 0.03). Within-patient changes from baseline of uEPX correlated with changes in % eos. No relations were found between uEPX and symptoms. Conclusion. In this population of children with atopic asthma, uEPX correlated with FEV1 and % eos, and within-subjects changes in uEPX correlated with changes in FEV1 and % eos. As the associations were weak and the scatter of uEPX wide, it seems unlikely that uEPX will be useful as a biomarker for monitoring asthma control in the individual child.

Will Symptom-Based Therapy Be Effective for Treating Asthma in Children?

Traditionally, symptoms are important patient-oriented outcomes in asthma treatment, and assessment of symptoms is an essential component of assessing asthma control. However, variable airways obstruction, airways hyperresponsiveness and chronic inflammation are key components of the asthma syndrome, and correlations among these hallmarks and symptoms are weak or even absent. Therefore, it might be questioned if symptom-based therapy is effective for treating asthma in (all) children. To date, there is no firm indication that monitoring asthma based on repetitive lung function measurement or markers of airway inflammation is superior to monitoring based on symptoms only. In the majority of patients, symptom-based asthma management may well be sufficient, and in preschool children, symptoms are presently the only feasible outcome. Nevertheless, there is some evidence that selected groups might benefit from an approach that takes into account individual phenotypic characteristics. In patients with poor perception, those with a discordant phenotype and those with persistent severe asthma, considering lung function, airways hyperresponsiveness and inflammatory markers in treatment decisions might improve outcomes.

Red blood cell distribution width is not a reliable biomarker for low iron stores in children with cystic fibrosis

ABSTRACT Low iron stores in children, absolute iron deficiency (AID), can lead to impaired neurodevelopment and requires iron therapy. In the presence of infection/inflammation, like in cystic fibrosis (CF), serum ferritin (SF) is not a reliable biomarker for AID. Red blood cell distribution width (RDW) is a promising alternative reported not to be influenced by infection in healthy children. Currently, there are no data on the diagnostic capacity of RDW to detect AID in pediatric CF patients. This was a prospective observational study that investigated iron status biomarkers in 53 Dutch pediatric CF patients. AID was defined using World Health Organization criteria for SF in stable patients (no recent pulmonary exacerbation) and C-reactive protein (CRP) ≤10 mg/l. Patients with AID had higher RDW levels than patients without AID (p = 0.019). An RDW ≥13.2% showed the following test statistics: sensitivity 100%; specificity 39.4%; positive predictive value 20%; and negative predictive value 100%. Furthermore, we found a correlation between RDW and CRP in the total group that originated from the stable patients (r = 0.308; p = 0.042). In conclusion, the diagnostic capacity of RDW for detecting AID in pediatric CF patients seems limited because RDW levels might also be influenced by chronic infection/inflammation in these patients.