Mycophenolate mofetil and bronchiectasis in pediatric transplant patients.
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Bronchiectasis↗
Biomedical subjects
Peter J F M Merkus
Publications and source records attributed to Peter J F M Merkus.
Exhaled nitric oxide differentiates airway diseases in the first two years of life.
Fractional exhaled nitric oxide (FE(NO)) levels are increased in children and adults with asthma, whereas low levels have been found in cystic fibrosis and primary ciliary dyskinesia. The aim of this study was to investigate whether FE(NO) measurements could distinguish between children below the age of 2 with different airway diseases. FE(NO) measurements were performed in 118 infants aged between 4.6 and 25.2 mo: 74 infants with recurrent wheezing (RW), 24 with bronchopulmonary dysplasia (BPD), and 20 with cystic fibrosis (CF). FE(NO) was measured also in 100 healthy controls aged between 1.1 and 7.7 mo. Geometric mean (95% confidence interval) FE(NO) values were 10.4 (9.1-12.0) parts per billion (ppb) in healthy infants, 18.6 (15.6-22.2) ppb in wheezy infants, 11.7 (8.2-16.8) ppb in BPD infants and 5.9 (3.4-10.1) ppb in CF infants. FE(NO) in wheezers was higher than in controls, BPD, and CF (p = 0.009, p = 0.038, and p < 0.001, respectively). Atopic wheezers showed higher FE(NO) than nonatopic wheezers (p = 0.04). CF infants had lower FE(NO) than healthy controls and BPD infants (p = 0.003 and p = 0.043, respectively). FE(NO) values in BPD and control infants were not different. We conclude that FE(NO) is helpful to differentiate various airway diseases already in the first 2 y of life.
Diagnosis, Differential↗
Should we use criteria or eyeballing to reject post-interruption tracings?
During the analysis of interrupter resistance (R(int))-measurements, most authors reject post-interruption tracings based on the shape of the pressure-time and flow-time curves. However, objective criteria for rejection are lacking. We aimed to formulate explicit rejection criteria that correspond to eyeballing the curve pattern (daily practice), in order to simplify the analysis. Inter-observer agreement within and between both methods was studied. Results obtained with the developed rejection criteria were compared to those of current practice (eyeballing) using 54 measurements (807 interruptions) of children with severe neurological impairment. Inter-observer agreement on rejection was similar using the criteria or eyeballing (85.6% vs. 82.8%). Using the criteria, more individual interruptions were rejected (43.4% vs. 29.8% using eyeballing), while discarding total measurements (<5 remaining interruptions) was similar (9.2% vs. 7.4% using eyeballing). Results using only the criteria for pressure-time curves were comparable to eyeballing. Outcome values were comparable between any of the used rejection methods and not rejecting at all. In this first detailed study on rejection of post-interruption tracings, explicit rejection criteria were developed. None of the rejection methods influenced the outcome value relevantly. However, rejection criteria can contribute to the standardization of the R(int) technique and simplify decision-making in daily practice.
Airway Resistance↗
Asthma therapy for children under 5 years of age.
PURPOSE OF REVIEW: The evidence for effectiveness of currently used asthma medication for wheeze in young children is reviewed. RECENT FINDINGS: The management of the infant and preschool child with wheezing is complicated by the uncertainty with respect to the aetiology. Difficulties in defining phenotypes and objective outcome parameters combined with the transient nature of symptoms which often resolve spontaneously have confounded many therapeutic studies. Recent studies on the effect of pharmacotherapy in wheezing infants have tried to define a more homogeneous phenotype as well as make a selection of patients that are likely to respond to the studied drug. In addition, these studies have used lung function parameters and nitric oxide as one of the outcome measurements. Studies on the nature of inflammation and the development of airway remodelling in infants and young children are done to further define phenotypes. SUMMARY: Currently, there are no evidence-based guidelines and not even consensus statements on the right approach in pharmacological treatment of wheezing in infants and preschool children. The main issue still is the difficulty in coming to a correct diagnosis. Further studies are needed on the nature and the diagnostics of phenotypes and on the effect of early intervention.
Administration, Inhalation↗
Inhaled corticosteroids in wheezy infants.
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Administration, Inhalation↗
A population-based nested case control study on recurrent pneumonias in children with severe generalized cerebral palsy: ethical considerations of the design and representativeness of the study sample.
BACKGROUND: In children with severe generalized cerebral palsy, pneumonias are a major health issue. Malnutrition, dysphagia, gastro-oesophageal reflux, impaired respiratory function and constipation are hypothesized risk factors. Still, no data are available on the relative contribution of these possible risk factors in the described population. This paper describes the initiation of a study in 194 children with severe generalized cerebral palsy, on the prevalence and on the impact of these hypothesized risk factors of recurrent pneumonias. METHODS/DESIGN: A nested case-control design with 18 months follow-up was chosen. Dysphagia, respiratory function and constipation will be assessed at baseline, malnutrition and gastro-oesophageal reflux at the end of the follow-up. The study population consists of a representative population sample of children with severe generalized cerebral palsy. Inclusion was done through care-centres in a predefined geographical area and not through hospitals. All measurements will be done on-site which sets high demands on all measurements. If these demands were not met in "gold standard" methods, other methods were chosen. Although the inclusion period was prolonged, the desired sample size of 300 children was not met. With a consent rate of 33%, nearly 10% of all eligible children in The Netherlands are included (n = 194). The study population is subtly different from the non-participants with regard to severity of dysphagia and prevalence rates of pneumonias and gastro-oesophageal reflux. DISCUSSION: Ethical issues complicated the study design. Assessment of malnutrition and gastro-oesophageal reflux at baseline was considered unethical, since these conditions can be easily treated. Therefore, we postponed these diagnostics until the end of the follow-up. In order to include a representative sample, all eligible children in a predefined geographical area had to be contacted. To increase the consent rate, on-site measurements are of first choice, but timely inclusion is jeopardized. The initiation of this first study among children with severe neurological impairment led to specific, unexpected problems. Despite small differences between participants and non-participating children, our sample is as representative as can be expected from any population-based study and will provide important, new information to bring us further towards effective interventions to prevent pneumonias in this population.
Adolescent↗
DNase and atelectasis in non-cystic fibrosis pediatric patients.
INTRODUCTION: No evidence based treatment is available for atelectasis. We aimed to evaluate the clinical and radiologic changes in pediatric patients who received DNase for persistent atelectasis that could not be attributed to cardiovascular causes, and who were unresponsive to treatment with inhaled bronchodilators and physiotherapy. METHODS: All non-cystic fibrosis pediatric patients who received nebulised or endotracheally instilled DNase for atelectasis between 1998 and 2002, with and without mechanical ventilation, were analysed in a retrospective descriptive study. The endpoints were the blood pCO2, the heart rate, the respiratory rate, the FiO2 and the chest X-ray scores before and after treatment. RESULTS: In 25 of 30 patients (median [range] age, 1.6 [0.1-11] years) who met inclusion criteria, paired data of at least three endpoints were available. All clinical parameters improved significantly within 2 hours (P < 0.01), except for the heart rate (P = 0.06). Chest X-ray scores improved significantly within 24 hours after DNase treatment (P < 0.001). Individual improvement was observed in 17 patients and no clinical change was observed in five patients. Temporary deterioration (n = 3) was associated with increased airway obstruction and desaturations. No other complications were observed. CONCLUSION: After treatment with DNase for atelectasis of presumably infectious origin in non-cystic fibrosis pediatric patients, rapid clinical improvement was observed within 2 hours and radiologic improvement was documented within 24 hours in the large majority of children, and increased airway obstruction and ventilation-perfusion mismatch occurred in three children, possibly due to rapid mobilisation of mucus. DNase may be an effective treatment for infectious atelectasis in non-cystic fibrosis pediatric patients.
Administration, Inhalation↗
Predictive value of infant lung function testing for airway malacia.
Airway malacia is present in a small proportion of wheezing infants. The usefulness of infant lung-function testing (ILFT) in ruling out malacia in wheezy infants is unknown. We assessed the predictive value of ILFT parameters for airway malacia diagnosed by flexible bronchoscopy. Thirty-two term infants (mean (SD) age, 11.0 (4.6) months) with chronic wheeze unresponsive to asthma treatment underwent ILFT prior to bronchoscopy. Functional residual capacity measured by plethysmograph (FRCp), maximal flow at FRC (V'max(FRC)), and tidal breathing parameters were obtained. Expiratory flow-volume curves were visually examined for tidal flow limitation. Malacia was observed during bronchoscopy in 20 infants. V'max(FRC) (Z-score) was significantly lower in the group with malacia as compared with the group without malacia. Lung-function measurements had a low negative predictive value and sensitivity. While flow limitation during tidal breathing was highly predictive and 100% specific for airway malacia, only half of the infants with malacia had tidal flow limitation. In this selected group of infants, routine lung function testing could not discriminate between infants with and without airway malacia. However, the presence of tidal flow limitation was 100% predictive and specific for airway malacia.
Bronchial Diseases↗
Tracheomalacia and bronchomalacia in children: incidence and patient characteristics.
OBJECTIVE: Congenital airway malacia is one of the few causes of irreversible airways obstruction in children, but the incidence in the general population is unknown. Severe airway malacia or malacia associated with specific syndromes is usually recognized and diagnosed early in infancy, but information about clinical features of children with primary malacia, often diagnosed only later in childhood, is scarce. METHODS: We analyzed all flexible bronchoscopies performed between 1997 and 2004 in the Sophia Children's Hospital, summarized clinical features of children with primary airway malacia, estimated the incidence of primary airway malacia, and calculated the predictive value of a clinical diagnosis of airway malacia by pediatric pulmonologists. RESULTS: In a total of 512 bronchoscopies, airway malacia was diagnosed in 160 children (94 males) at a median age of 4.0 years (range, 0 to 17 years). Airway malacia was classified as primary in 136 children and secondary in 24 children. The incidence of primary airway malacia was estimated to be at least 1 in 2,100. When pediatric pulmonologists expected to find airway malacia (based on symptoms, history, and lung function) prior to bronchoscopy, this was correct in 74% of the cases. In 52% of the airway malacia diagnoses, the diagnosis was not suspected prior to bronchoscopy. Presenting clinical features of children with airway malacia were variable and atypical, showing considerable overlap with features of allergic asthma. Peak expiratory flow was more reduced than FEV(1). CONCLUSION: Primary airway malacia is not rare in the general population, with an estimated incidence of at least 1 in 2,100 children. Airway malacia is difficult to recognize based on clinical features that show overlap with those of more common pulmonary diseases. We recommend bronchoscopy in patients with impaired exercise tolerance, recurrent lower airways infection, and therapy-resistant, irreversible, and/or atypical asthma to rule out airway malacia.
Adolescent↗
Air pollution and lung function.
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Adolescent↗
Efficacy of fluticasone propionate on lung function and symptoms in wheezy infants.
The role of inhaled corticosteroids in the treatment of recurrent or persistent wheeze in infancy remains unclear. We evaluated the effect of 3 months of treatment with inhaled fluticasone propionate, 200 microg daily (FP200), on lung function and symptom scores in wheezy infants. Moreover, we evaluated whether infants with atopy and/or eczema respond better to FP200 as compared with non-atopic infants. Forced expiratory flow (Vmax(FRC)) was measured at baseline and after treatment. Sixty-five infants were randomized to receive FP200 or placebo, and 62 infants (mean age, 11.3 months) completed the study. Mean Vmax(FRC), expressed as a Z score, was significantly below normal at baseline and after treatment in both groups. The change from baseline of Vmax(FRC) was not different between the two treatment arms. After 6 weeks of treatment, and not after 13 weeks, the FP200 group had a significantly higher percentage of symptom-free days and a significant reduction in mean daily cough score compared with placebo. Separate analysis of treatment effect in infants with atopy or eczema showed no effect modification. We conclude that in wheezy infants, after 3 months of treatment with fluticasone, there was no improvement in lung function and no reduction in respiratory symptoms compared with placebo.
Administration, Inhalation↗
Preserved diffusion capacity in children with cystic fibrosis.
Early detection of progressive lung disease in cystic fibrosis (CF) may lead to better treatment and prognosis. Routine lung function indices may be relatively insensitive markers of peripheral airway obstruction and alveolar collapse. We hypothesized that the single-breath diffusion capacity of the lung for carbon monoxide (DLCO) would change before tests of airway function in patients with CF. We assessed lung function longitudinally in 53 children with CF during a mean period of 3.8 years to determine whether the diffusion capacity of the lung becomes abnormal before more conventional indices of lung function do. Within patients, DLCO was slightly elevated and remained stable, while forced expired volume in 1 sec (FEV1) and forced vital capacity (FVC) declined progressively (mean individual decline, -1.8% and -0.8% of predicted). Cross-sectionally, this decline was faster (mean group decline -3.8% and -2.8% of predicted), indicating an additional cohort effect. Normalized diffusion capacity at an early stage of CF is slightly elevated and is preserved in spite of progressive obstructive lung disease. This can be attributed to alterations in pulmonary and bronchial circulation due to loss of function and/or number of alveolar units. Diffusion capacity at rest does not appear to be a suitable early marker of progressive deterioration of CF lung disease.
Adolescent↗
Bronchiectasis in children after renal or liver transplantation: a report of five cases.
More effective immunosuppressive treatment in children following organ transplantation has significantly improved the survival of the grafts. Therefore, quality of life, long-term prognosis and adverse drug reactions have become more important. One of the main complications of immunosuppressive drugs is infections of the respiratory tract, but irreversible damage to the airways has not been described after renal or liver transplantation. Five children following transplantation of kidney or liver were referred to the Paediatric Pulmonology department because of chronic respiratory complaints. Pulmonary function tests and HRCT scan were performed as routine patient care. Four children with a renal transplant and one with a liver transplant showed chronic bronchitis and moderate to severe airways obstruction. HRCT showed bronchiectasis in all of them. We speculate that the immunosuppressive treatment (in)directly contributes to irreversible airway damage. We recommend including follow-up of lung function in the post-transplantation protocol and considering bronchiectasis in case of respiratory symptoms, to try preventing further damage to the lung.
Adolescent↗
Interrupter resistance and wheezing phenotypes at 4 years of age.
It is difficult to distinguish young children with respiratory symptoms who will develop asthma from those with transient symptoms only. Measurement of interrupter resistance may help to identify children at high risk of asthma. The aim of this study is to compare interrupter resistance in 4-year-old children with different wheezing phenotypes. All children participated in the Prevention and Incidence of Asthma and Mite Allergy cohort, a prospective birth cohort of more than 4,000 children. At 4 years of age, data on interrupter resistance plus wheezing phenotype were available for 838 children. Mean interrupter resistance values (95% confidence interval) were 0.95 (0.93, 0.97), 0.95 (0.92, 0.98), 0.96 (0.87, 1.05), and 1.08 (1.02, 1.14) kPa.L(-1).second for never (n = 482), early transient (n = 236), late-onset (n = 22), and persistent (n = 98) wheezing phenotypes, respectively. Additional analyses were performed for children with atopic and nonatopic mothers separately. Both in children with atopic and nonatopic mothers, children with persistent wheeze had significantly higher interrupter resistance values than children with never and early wheeze. In conclusion, mean interrupter resistance values were higher in children with persistent wheeze as compared with children with never and early transient wheezing phenotypes.
Airway Resistance↗
Effects of childhood respiratory diseases on the anatomical and functional development of the respiratory system.
The anatomical and functional development of the lung appears especially vulnerable to a whole range of insults during gestation and the first few years of life. A significant proportion of adult lung disease originates in utero or early infancy. Most publications on this topic are descriptive retrospective studies. An important limitation of these is that structural changes may precede abnormalities in lung function and development of symptoms. Little is known with certainty with respect to the long-term effects of early insults to the respiratory system. Furthermore, the reversibility of the functional and/or structural defects is hardly ever adequately investigated and it is probably not correct to extrapolate findings from adult studies to paediatric pulmonary diseases. Promoting or facilitating optimal lung growth in fetuses and infants and reducing the incidence of lower respiratory tract infection in infancy may reduce the incidence of adult chronic lung disease in generations to come.
Child↗
DNase in stable cystic fibrosis infants: a pilot study.
OBJECTIVE: To assess the feasibility of measuring short-term effects of inhaled recombinant human deoxyribonuclease (rhDNase, Pulmozyme on lung function, pulse oximetry and symptom scores in infants and toddlers with stable cystic fibrosis. DESIGN: open-label randomized placebo controlled cross-over pilot study. PATIENTS AND METHODS: We treated nine CF patients (0.7-1.9 years) with nebulised rhDNase (2.5 mg) and NaCl 0.9% (10 ml) via jet nebulizer cross-over once daily during 2-week treatment blocks. Measurements were performed at baseline and after treatment blocks and consisted of lung function tests (plethysmography and tidal rapid thoraco-abdominal compression technique), overnight pulse oximetry, and daily symptom scores. RESULTS: DNase treatment and the different assessments were well tolerated by all children and their parents. Lung function showed increased airway patency after treatment with rhDNase (P < 0.001), but not after NaCl 0.9%. Overnight pulse oximetry and daily symptom scores did not change during the study period. CONCLUSIONS: This pilot study indicates that objective assessment of the effects of rhDNase is feasible in infants with CF who have little or no respiratory symptoms. Our results warrant a larger randomized placebo-controlled trial.
Administration, Inhalation↗
Aerosol therapy and the fighting toddler: is administration during sleep an alternative?
Insufficient cooperation during administration of aerosols by pressurized metered dose inhaler (pMDI)/spacers is a problem in nearly 50% of treated children younger than 2 years. For these children, administration during sleep might be more efficient. However, it is unknown how much aerosol reaches the lungs during sleep. The aim of this study was to determine in vitro the lung dose in young children from a pMDI/spacer during sleep and while being awake. Breathing patterns were recorded by a pneumotachograph in 18 children (age 11 +/- 5.1 months) during sleep and wakefulness. Next, breathing patterns were replayed by a computer-controlled breathing simulator to which an anatomically correct nose-throat model of a 9-month-old child was attached. One puff of budesonide (200 microg) was administered to the model via a metal spacer. Aerosol was trapped in a filter placed between model and breathing simulator. The amount of budesonide on the filter (5 lung dose) was analyzed by HPLC. For each of the 36 breathing patterns, lung dose was measured in triplicate. The sleep breathing patterns had significantly lower respiratory rate and peak inspiratory flows, and smaller variability in respiratory rate, tidal volume, and peak inspiratory flows. Lung dose (mean +/- SD) was 6.5 +/- 3.2 and 11.3 +/- 3.9 microg (p = 0.004) for the wake and sleep breathing pattern, respectively. This infant model-study shows that the lung dose of budesonide by pMDI/spacer is significantly higher during sleep compared to inhalation during wake breathing. Administration of aerosols during sleep might, therefore, be an efficient alternative for uncooperative toddlers.
Administration, Inhalation↗
Worsening of V'maxFRC in infants with chronic lung disease in the first year of life: a more favorable outcome after high-frequency oscillation ventilation.
Little is known about the development of maximal flow at functional residual capacity, a measure of airway patency, in infants with chronic lung disease (CLD). In a follow-up study, we evaluated V'maxFRC in very low birth weight infants with CLD, treated with high-frequency oscillation ventilation (HFOV) or conventional mechanical ventilation. In 36 infants with CLD, V'maxFRC was evaluated at 6 and/or 12 months corrected age, and the relationship between perinatal factors and lung function was studied. Mean (SD) birth weight and gestational age were 837 (152) g and 26.8 (1.7) weeks, respectively. At 6 and 12 months, mean V'maxFRC was significantly below normal. Between 6 and 12 months, there was a mean (95% confidence interval) reduction in V'maxFRC (Z score) of 0.5 (0.2-0.7) (p < 0.001). At 12 months, the mean V'maxFRC (Z score) was higher for children initially treated with HFOV (n = 15), as compared with children treated with conventional mechanical ventilation (n = 16): mean (95% confidence interval) difference was 0.6 (0.2-1.0) (p = 0.008). We conclude that very low birth weight infants with CLD have decreased V'maxFRC that worsen during the first year of life. Initial treatment with HFOV was associated with a more favorable outcome of V'maxFRC at 12 months corrected age.
Chronic Disease↗