[Guideline 'Treating asthma in children' for pediatric pulmonologists (2nd revised edition). II. Medical treatment].
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Anti-Asthmatic Agents↗
Biomedical subjects
E J Duiverman
Publications and source records attributed to E J Duiverman.
[Chronic lung disease of the neonate; pathophysiology and treatment after the first weeks of life].
Chronic lung disease of the neonate sometimes occurs as a residual condition following respiratory distress in preterm infants. Improvements in neonatal intensive care treatment will in future lead to a greater number of children surviving chronic lung disease and reaching adulthood. The symptoms of the disease are hypoxaemia, hypercapnia, tachypnoea, subcostal and intercostal retractions, fluid retention, a reduced exertion tolerance and hyperreactive airways. The treatment after the first weeks of life is symptomatic and consists of: providing supplemental oxygen via a nasal mask or cannula (0.1-1 l/min); rapid downward adjustment of oxygen therapy may lead to more complaints and poorer growth; a normal fluid therapy; if there is a tendency towards fluid retention, then diuretic therapy is indicated and in severe cases fluid restriction as well; in the case of bronchial hyperreactivity: inhaled corticosteroids (the lowest effective dose for a period of several months) and a trial treatment with beta-agonists; in the case of persistent complaints or functional limitations, lung function tests can distinguish obstructive and restrictive disorders; vaccinations according to the national programme; consider vaccinations against influenza (age: 6-12 months) and respiratory syncytial virus (age < 2 years).
Chronic Disease↗
[Guideline 'Treating asthma in children' for pediatric pulmonologists (2nd revised edition). I. Diagnosis and prevention].
The case history and physical examination form the corner-stones for asthma diagnosis. Establishing the correct diagnosis may be difficult in infants and preschool children; in such cases the progression of the symptoms over time is important. Routine laboratory and radiological investigations are advised against. Allergy testing may be useful in children under the age of 4 years. Lung function investigations can be used from the age of 5 to 6 years onwards. Non-invasive investigations into the degree of bronchial inflammation can be performed by measuring the fraction nitric oxide in exhaled air. House dust mite reduction is a useful measure for preventing asthma if sensitisation has been demonstrated. Breast-feeding during the first 4 to 6 months of life can be considered as a preventive measure in infants with an increased risk of developing asthma and allergy.
Age Factors↗
[Guideline 'Treating asthma in children' for pediatric pulmonologists (2nd revised edition). II. Medical treatment].
The second revision of the guidelines for the treatment of asthma in children is largely based on the evidence of comparative studies. Short-acting beta 2-sympathicomimetics are the medication of choice for acute exacerbations and should therefore be prescribed to each patient. Inhaled corticosteroids (ICS) are the medication of choice for maintenance treatment. Starting with a high dose of ICS which is then reduced to a lower but effective level on the basis of the complaints (step-down approach) is no longer recommended, as this strategy is not more effective than a constant dosage schedule. If asthmatic symptoms persist despite ICS maintenance treatment then 3 therapeutic options are available in the following order: doubling the ICS dose, the addition of a long-acting beta 2-sympathicomimetic, and the addition of a leukotriene receptor antagonist.
Administration, Inhalation↗
Influence of different dosage schedules of inhaled fluticasone propionate on peripheral blood cytokine concentrations in childhood asthma.
BACKGROUND: Asthma is characterized by eosinophilic airways inflammation with elevated levels of IL-4, IL-5 and sICAM-1, and reduced levels of IL-10 and IFN-gamma. Inhaled corticosteroids powerfully reduce airways inflammation. OBJECTIVE: To investigate if eosinophil counts, serum eosinophilic cationic protein (ECP) and sICAM-1 levels, as well as serum and production of cytokines (IL-4, IL-5, IL-10, IFN-gamma) by peripheral blood monocytes (PBMCs) are useful markers to monitor therapy with inhaled fluticasone propionate (FP) in asthmatic children. METHODS: In a double-blind, 1-year study, 55 asthmatic children (aged 6-10 years) stopped inhaled corticosteroids for a mean period of 24 days and were randomized to receive either FP 200 microg/day (constant dose group), or a starting dose of FP 1000 microg/day with two monthly reductions to 500, 200 and 100 microg/day (stepdown group). Hyper-responsiveness, symptom scores and blood sampling were performed at 2-month intervals. RESULTS: Symptoms and hyper-responsiveness improved significantly in both treatment groups after reintroduction of FP. Eosinophil counts decreased significantly more during the first 2 months of FP in the stepdown group than in the constant dose group (P = 0.03). We found a trend towards a dose-dependent response in changes of eosinophil counts and serum ECP levels during treatment. Serum IL-4 and IL-5 levels were undetectable in the majority of children. No significant effect of the dose of FP on the release of IL-4, IL-5, IL-10 or IFN-gamma by Con A stimulated PBMCs was found. sICAM-1 levels did not significantly differ at any time point between the two groups. CONCLUSION: Serum ECP as well as peripheral blood eosinophils, cytokine production by PBMCs and sICAM-1 levels are insensitive markers in titrating and monitoring therapy with inhaled corticosteroids over a wide dose range in childhood asthma.
Administration, Inhalation↗
One-year treatment with different dosing schedules of fluticasone propionate in childhood asthma. Effects on hyperresponsiveness, lung function, and height.
Dose-dependent effects of inhaled corticosteroids have been described. Although it has been advised to start treatment with inhaled corticosteroids with a high dose tapering off subsequently (stepdown approach), no clinical studies have assessed this strategy. We compared two different dosage schedules of inhaled fluticasone propionate (FP) in chronic persistent childhood asthma with respect to efficacy (airways hyperresponsiveness [PD(20)], lung function, exhaled nitric oxide [eNO]) and safety (height). During this double-blind study, children with asthma (aged 6-10 yr) were randomized to receive either FP 200 microg/d (constant dose approach) or to start with 1000 microg/d with two monthly reductions to 500, 200, and 100 microg/d (stepdown approach). PD(20) improved in both approaches during treatment with FP, with a significantly better PD(20) after 2 mo of 1000 microg/d followed by 500 microg/d in the stepdown approach versus 200 microg/d in the constant dose approach. No significant differences in PD(20) or other efficacy parameters were found after 1 yr. Changes in standing height were similar in both treatment approaches. This study showed no superior clinical effect of a stepdown approach compared with a constant dose strategy of FP for 1 yr in children with chronic persistent asthma.
Administration, Inhalation↗
Hospital admissions and readmissions for asthma in the age group 0-4 years.
SUMMARY. Childhood rates for admission and readmission for asthma are highest under the age of 5 years. From a registration study in 0-4-year-olds, 100 patients (68 male) were admitted to hospital for asthma and followed for 1 year, yielding a total of 136 admissions. To examine factors that may play a role in admissions and readmissions, histories and laboratory tests for atopic status at initial presentation, and clinical data on admission were evaluated. Age groups 0-1 year (n = 54) and 2-4 years (n = 46) were analyzed separately, of whom 20 (37%) and 9 (20%) patients, respectively, had at least one readmission. In the age group 2-4 years, patients with antibodies against inhalant allergens, determined by radioallergosorbent test (RAST), had a significantly higher risk of readmission (RR = 1.54; 95% CI, 1.22-1.95). In the age group 0-1, year prevalence of sensitization to inhalant allergens was low (20% vs. 72% in age group 2-4 years) and constituted only a slight risk (P = 0.097) for readmission. A history of eczema showed a negative association in the age group 0-1 year. Treatment of the first admission did not differ between children only admitted once and those requiring readmission. In both age groups, clinical features at admission did not differ significantly between first and subsequent admissions, and neither did length of stay. Number of readmissions were higher in the age group 0-1 year than in the age group 2-4 years (27/81 (33%) vs. 9/55 (16%), P = 0.028), with no indication of a lower threshold for admission. In the age group 0-1 year, 60% of the readmissions occurred within 2 months of first hospitalization. Moreover, in the age group 0-1 year a trend was observed that inhaled steroids were prescribed less frequently on discharge following first admission in those children who were readmitted than in the children who had a first admission only (4/20 (20%) vs. 15/34 (44%), P = 0.073). More "aggressive" therapy with anti-inflammatory drugs and close medical follow-up after discharge seem to be indicated.
Adrenal Cortex Hormones↗
Benefits of high altitude allergen avoidance in atopic adolescents with moderate to severe asthma, over and above treatment with high dose inhaled steroids.
Some patients with severe asthma cannot be controlled with high doses of inhaled steroids (ICS), which may be related to ongoing environmental allergen exposure. We investigated whether 10 weeks of high altitude allergen avoidance leads to sustained benefits regarding clinical and inflammatory markers of disease control in adolescents with persistent asthma despite treatment with high dose ICS. Eighteen atopic asthmatic adolescents (12-18 yr, 500-2000 microg ICS daily) with established house dust mite allergy, participated in a parallel-group study. Quality of life (PAQL), lung function, bronchial hyperresponsiveness (BHR) to adenosine and histamine, induced sputum and urine samples were collected repeatedly from 10 patients during a 10-week admission period to the Swiss Alps (alt. 1560 m) and at 6 weeks after return to sea level. Results were compared with those in eight patients, studied in their home environment at sea level for a similar time period. Throughout the study, asthma medication remained unchanged in both groups. During admission to high altitude, PAQL, lung function, BHR to adenosine and histamine, and urinary levels of eosinophil protein X (U-EPX), leukotriene E4 (U-LTE4) and 9alpha11beta prostaglandin F2 (U-9alpha11beta PGF2) improved significantly (P < 0.05), with a similar tendency for sputum eosinophils (P < 0.07). Furthermore, the changes in PAQL and BHR to adenosine and histamine were greater in the altitude than in the control group (P < 0.05). At 6 weeks after renewed allergen exposure at sea level, the improvements in PAQL (P < 0.05), BHR to adenosine (P < 0.07) and histamine (P < 0.05), as well as U-EPX (P < 0.05) and U-LTE4 (P < 0.05) were maintained. A short period of high altitude allergen avoidance, on top of regular treatment with ICS and long-acting beta2-agonists, results in improvement of asthma, as assessed by clinical and inflammatory markers of disease severity. These findings indicate that short-term, rigorous allergen avoidance can improve the long-term control of severe asthma over and above what can be achieved even by high doses of inhaled steroids.
Administration, Inhalation↗
Risk factors for exacerbations and hospital admissions in asthma of early childhood.
Hospital admissions and readmissions for asthma in early childhood remain causes for concern. The purpose of this study was to identify predisposing risk factors related to asthma exacerbations and precursors of hospital admissions in young children. Subjects were patients with doctor-diagnosed asthma from a clinical registration study, aged 0-4 years, and followed up for 2 years. Data from histories and laboratory tests for atopic status at initial presentation, and the patient's condition at visits over the 2-year follow-up period were evaluated. Exacerbation was defined as increases in cough and/or wheeze and/or breathlessness, increase in beta(2)-agonist use, and a clinical need for a short course of oral corticosteroids. Age groups 0-1 year and 2-4 years, based on age at initial presentation, were analyzed separately. In the age group 0-1 year, 71/113 (63%) patients had at least one exacerbation, and 20 experienced recurrent exacerbations (>/=3). Predisposing risk factors for exacerbation were damp housing (odds ratio (OR) 7.6 (2. 0-28.6)) and colds (OR 3.6 (1.4-9.6)), and for recurrent exacerbations sensitization to inhalant allergens (Phadiatop(R)) (OR 8.1 (1.6-40.5)) and damp housing (OR 3.8 (1.1-12.8)). Hospital admissions were significantly associated with number of exacerbations. In the age group 2-4 years, 58/144 (40%) patients had at least one exacerbation, and 21 experienced recurrent exacerbations (>/=2). Predisposing risk factors for exacerbation were mean age at initial presentation (OR 0.92 (0.88-0.97)) and level of total IgE (OR 2.3 (1.4-3.9)), whereas for recurrent exacerbations no predictor variables were found. Hospital admissions were significantly associated with damp housing. Results from this study may facilitate recognition of young asthmatic patients at risk of (recurrent) exacerbations, and help to identify those in whom early intervention with anti-inflammatory therapy may be necessary. We also emphasize the importance of preventive measures in decreasing damp housing.
Anti-Inflammatory Agents↗
Dose-responses over time to inhaled fluticasone propionate treatment of exercise- and methacholine-induced bronchoconstriction in children with asthma.
When treating bronchial hyperresponsiveness to so-called direct and indirect stimuli, distinct pathophysiological mechanisms might require differences in dose and duration of inhaled corticosteroid therapy. To test this hypothesis in children with asthma, we investigated the time- and dose-dependent effects of 2 doses of fluticasone propionate (FP, 100 or 250 microg bid.) in improving exercise- (EIB) and methacholine-induced bronchoconstriction during 6 months of treatment, using a placebo-controlled parallel group study design. Thirty-seven children with asthma (aged 6 to 14 years; forced expired volume in 1 sec (FEV(1)) >/=70% predicted; EIB >/=20% fall in FEV(1) from baseline; no inhaled steroids during the past 4 months) participated in a double-blind, placebo-controlled, 3-arm parallel study. Children receiving placebo were re-randomized to active treatment after 6 weeks. Standardized dry air treadmill exercise testing (EIB expressed as %fall in FEV(1) from baseline) and methacholine challenge using a dosimetric technique (expressed as PD(20)) were performed repeatedly during the study. During FP-treatment, the severity of EIB decreased significantly as compared to placebo within 3 weeks, the geometric mean % fall in FEV(1) being reduced from 34.1% to 9.9% for 100 microg FP bid, and from 35.9% to 7.6% for 250 microg FP bid (P < 0.05). These reductions in EIB did not differ between the 2 doses and were sustained throughout the treatment period. PD(20) methacholine improved significantly during the first 6 weeks as compared to placebo (P < 0.04) and steadily increased with time in both treatment limbs (P = 0.04), the difference in improvement between doses (100 microg FP bid, 1.6 dose steps; 250 microg FP bid, 3.3 dose steps) approaching significance after 24 weeks (P = 0.06). We conclude that in childhood asthma, the protection afforded by inhaled fluticasone propionate against methacholine-induced bronchoconstriction is time- and dose-dependent, whereas protection against EIB is not. This suggests different modes of action of inhaled steroids in protecting against these pharmacological and physiological stimuli. This has to be taken into account when monitoring asthma treatment.
Administration, Inhalation↗
Nasal peak inspiratory flow through Turbuhaler in children with symptomatic rhinitis and in healthy children.
Topical treatment of allergic or vasomotor rhinitis is possible by means of pressurized metered dose inhalers, aqueous spray, or dry powder inhalers. In children, little is known about nasal drug delivery by dry powder inhalation. The airflow through the device is critical for the drug release and a sufficient nasal inspiratory flow is needed for intranasal drug delivery from a dry powder inhaler. In order to investigate from what age children with allergic or vasomotor rhinitis can reliably use such a device, device-dependent nasal peak inspiratory flow (DnPIF) was measured. The maximal DnPIF was measured in children aged 4-13 years making use of a dry powder inhaler (Turbuhaler) connected to a spirometer (Vitalograph). In the clinically relevant context, instructions from the doctor and one week's use of a Turbuhaler at home were found to be sufficient to obtain a good inhalation technique and were shown to improve DnPIF at least as effectively as visual feedback training at the clinic. Children with rhinitis, as well as healthy children from the age of 6 years, were able to generate a DnPIF sufficient to obtain a reliable nasal delivery of a dry powder drug dose. DnPIF values correlated with age. Consequently, a recommendation to use a nasal Turbuhaler from the age of 6 for topical drug delivery in the treatment of allergic or vasomotor rhinitis seems reasonable.
Administration, Inhalation↗
[Acute respiratory insufficiency in children].
Acute respiratory distress in children is often a consequence of asthma. Other causes are subglottic laryngitis, epiglottitis, aspiration of a foreign body, acute bacterial pneumonia or pneumothorax. History and physical examination should differentiate between the various diseases. Asthma is characterized by recurrent symptoms and signs, while this is not the case with the other causes of acute breathlessness described. An asthma exacerbation is often preceded by one or more prodromes. In case of aspiration of a foreign body, like a peanut, immediate action is needed to prevent irreversible damage to the airways. Subglottic laryngitis and epiglottitis are both characterized by an inspiratory stridor; in case of epiglottitis immediate action is needed, while in case of subglottic laryngitis observation time is available in most cases. Pneumothorax as a cause of acute breathlessness is rare in childhood; it should be considered in male smoking leptosomic asthmatic adolescents.
Adolescent↗
Prognostic characteristics of asthma diagnosis in early childhood in clinical practice.
A registration study from clinical practice was set up to assess the prognostic value of symptoms and laboratory data at first visit for doctor-diagnosed 'asthma' in early childhood. A total of 419 children aged 0-4 y, who were newly referred to the outpatient department of the Juliana Children's Hospital with possible asthma were enrolled over a 2-y period. Data from history taking, physical examination, laboratory tests for atopic status at first visit and data from follow-up visits were recorded. Two years after the first visit all medical records were reviewed for diagnostic label. The age groups 0-1 y and 2-4 y were analysed separately, because respiratory symptoms are often transient and sensitization to inhalant allergens is uncommon before the age of 2 y. The clinical diagnosis 'asthma' was made in 113 of 231 (49%) children aged 0-1 y and in 144 of 188 (77%) children aged 24 y. Characteristics from history taking indicated shortness of breath was the most prognostic symptom in both age groups. Eczema, wheeze and non-allergic provoking factors (weather conditions) were further predisposing factors in the 0-1 y group, as were allergic provoking factors (inhalant allergens) and absence of ear-nose-throat-history in the 2-4 y group. Adding laboratory data to history total serum IgE had prognostic value, but specific serum IgE against inhalant allergens (Phadiatop) was a strong predisposing factor, especially in the 2-4 y group. These prognostic characteristics may enhance early recognition of asthma in infants and improve asthma care in clinical practice.
Age Factors↗
Peak flow variation in childhood asthma: correlation with symptoms, airways obstruction, and hyperresponsiveness during long-term treatment with inhaled corticosteroids. Dutch CNSLD Study Group.
BACKGROUND: Guidelines for asthma management focus on treatment with inhaled corticosteroids and on home recording of peak expiratory flow (PEF). The effect of maintenance treatment with inhaled corticosteroids on PEF variation and its relation to other parameters of disease activity were examined in 102 asthmatic children aged 7-14 years. METHODS: During 20 months of treatment with inhaled salbutamol, with or without inhaled budesonide (600 micrograms daily), forced expiratory volume in one second (FEV1), the dose of histamine required to provoke a fall in FEV1 of more than 20% (PD20), the percentage of symptom free days, and PEF variation were assessed bimonthly. PEF variation was computed as the lowest PEF as a percentage of the highest PEF occurring over 14 days, the usual way of expressing PEF variation in asthma self-management plans. For each patient using inhaled corticosteroids within subject correlation coefficients (rho) were computed of PEF variation to the percentage of symptom free days, FEV1, and PD20. RESULTS: PEF variation decreased significantly during the first two months of treatment with inhaled corticosteroids and then remained stable. The same pattern was observed for symptoms and FEV1. In contrast, PD20 histamine continued to improve throughout the whole follow up period. In individual patients predominantly positive associations of PEF variation with symptoms, FEV1, and PD20 were found, but the ranges of these associations were wide. CONCLUSIONS: During treatment with inhaled corticosteroids the changes in PEF variation over time show poor concordance with changes in other parameters of asthma severity. When only PEF is monitored, clinically relevant deteriorations in symptoms, FEV1, or PD20 may be missed. This suggests that home recording of PEF alone may not be sufficient to monitor asthma severity reliably in children.
Administration, Inhalation↗
Induced sputum in adolescents with severe stable asthma. Safety and the relationship of cell counts and eosinophil cationic protein to clinical severity.
This study examined the safety of sputum induction and the relation between sputum cell counts and clinical parameters in adolescents with severe persistent asthma. Within 5 days, induced sputum and reversibility in forced expiratory volume in one second (FEV1), quality of life, provocative concentration causing a 20% fall in FEV1 (PC20) of adenosine monophosphate and histamine, exercise-induced bronchoconstriction, overall asthma severity index, and blood eosinophils were collected in 20 atopic adolescents with moderate-to-severe persistent asthma (12-18 yrs of age, FEV1 65-110% of predicted, on 500-2,000 microg inhaled steroids daily). FEV1 was reversible by 13.3-2.3% pred. After sputum induction, FEV1 was still increased by 9.0+/-2.6% pred as compared to the pre-salbutamol baseline. Sputum contained, median (range): 12.4 (0.4-59.5)% squamous cells, 47.3 (6.8-84.0)% macrophages, 39.0 (4.6-84.8)% neutrophils, 4.8 (1.0-12.4)% lymphocytes, 0.4 (0-10.8)% eosinophils and 3.6 (0-23.4)% bronchial epithelial cells. Sputum eosinophils showed a trend towards a significant association with the overall asthma severity index (r=0.46, p=0.06) and correlated inversely with baseline FEV1 (r=-0.51, p=0.03). In conclusion, sputum can be induced safely in adolescents with moderate-to-severe persistent asthma, if pretreated with beta2-agonists. Despite relatively low sputum eosinophil counts in these patients on inhaled steroids, the association of eosinophil numbers with baseline forced expiratory volume in one second and asthma severity index favours a role of induced sputum in monitoring adolescents with severe asthma.
Adolescent↗
[Coughing and wheezing children: improvement after parents stop smoking].
Three children, boys aged 6, 4 and 4 years presented with recurrent cough and (or) wheeze. Exposure to tobacco smoke at home was considered an aggravating factor. Symptoms in all three cases improved considerably or resolved completely when the patients' (grand)parent(s) stopped smoking. There is little literature on the beneficial effect of parents' giving up smoking on symptoms of childhood asthma. These cases, however, illustrate that advising parents of children with recurrent respiratory symptoms to give up smoking can be a rewarding and successful form of therapy.
Asthma↗
Addition of salmeterol versus doubling the dose of beclomethasone in children with asthma. The Dutch Asthma Study Group.
Studies in adults revealed that addition of salmeterol to a moderate dose of inhaled corticosteroid resulted in better symptom control and higher PEF compared with doubling the dose of inhaled corticosteroid. The aim of this three group study was to compare the effects of a moderate dose of beclomethasone, the same dose of beclomethasone with salmeterol, and a doubling dose of beclomethasone on lung function and symptoms in children with moderate asthma. A total of 177 children already treated with inhaled corticosteroids, were randomized in a double-blind parallel study either to salmeterol 50 microg twice daily (BDP400+salm), beclomethasone 200 microg twice daily (BDP800), or placebo (BDP400) in addition to beclomethasone 200 microg twice daily. No significant differences between groups were found in FEV1, PD20 methacholine, symptom scores, and exacerbation rates after 1 yr. Salmeterol resulted in slightly better PEF in the first months of treatment. FEV1, and PD20 methacholine significantly improved in all groups. After 1 yr mean changes in FEV1, percent predicted were 4.3% (95% CI 1.3; 7.2), 5.8% (95% CI 2.9; 8.7), and 4.3% (95% CI 2.1; 6.5) for BDP400+salm, BDP800, and BDP400, respectively. Changes in airway responsiveness were 0.60 (95% CI 0.05; 1.14), 1.30 (95% CI 0.73; 1. 87), and 0.80 (95% CI 0.33; 1.27) doubling doses. Growth was significantly slower in the BDP800 group. We conclude that no additional benefit was found of adding either salmeterol or more beclomethasone to a daily dose of 400 microg beclomethasone in this group of children with excellent compliance of medication.
Albuterol↗