L. Pekka Malmberg

Exercise‐induced changes in respiratory impedance in young wheezy children and nonatopic controls

Exercise‐induced bronchoconstriction (EIB) is a specific sign of active asthma, but its assessment in young children may be difficult with lung function techniques requiring active cooperation. The aim of the study was to assess the normal pattern of exercise‐induced responses of respiratory impedance by using impulse oscillometry (IOS), and to investigate how these responses discriminate wheezy children from control subjects. IOS measurements were performed in a consecutive sample of wheezy children aged 3–7 years (n = 130) and in an aged matched control group of nonatopic children without respiratory symptoms (n = 79) before and after a free running test. After exercise, wheezy children showed significantly larger responses in respiratory resistance (Rrs5), reactance (Xrs5), and the resonance frequency (Fr) than the control subjects. In the control group, the upper 95% confidence limit of the maximal change was 32.5% for Rrs5, 85.7% for Xrs5, and 53.1% for Fr. By using analysis of receiver operating characteristics, the change in Rrs5 distinguished the wheezy children from the control subjects more effectively than change in Xrs5 or Fr. In wheezy children, the response was significantly effected by the outdoor temperature and exercise intensity in terms of maximum heart rate. In conclusion, an increase of 35% in Rrs5 after a free running test can be regarded as an abnormal response. Wheezy children show an enhanced airway response, which is clearly distinguishable from the control subjects. IOS is a feasible method to detect EIB in young children. Pediatr Pulmonol. 2008; 43:538–544.

Lung function, airway remodelling and inflammation in symptomatic infants: outcome at 3 years

Background Relationships between early deficits of lung function, infant airway pathology and outcome in symptomatic infants are unclear. A study was undertaken to determine the associations between early lung function, airway histology and inflammation in symptomatic infants with the continuance of respiratory symptoms, lung function and subsequent use of inhaled asthma medication at the age of 3 years. Methods 53 children who underwent lung function measurements and bronchoscopy following referral to a specialist childrens hospital for recurrent lower respiratory symptoms at a mean age of 1 year were followed up at 3 years of age. Assessments were made of respiratory symptoms during the previous year, lung function by oscillometry and atopy by skin prick testing. Individual data on the purchase of asthma medications were obtained from the Social Insurance Institution for the 12 months preceding the follow-up visit. Results 50 children (94%) were re-evaluated, of whom 40 had ongoing airway symptoms. 11/39 (28%) who underwent successful oscillometry had reduced lung function, 31/50 (62%) used inhaled corticosteroids (ICS) regularly and 12/50 (24%) used ICS intermittently. Abnormal lung function at infancy was associated with ongoing airway symptoms (p<0.001) and with the purchase of ICS (p=0.009) and β agonists (p=0.002). Reticular basement membrane thickness in infancy and the numbers of mucosal mast cells, but not eosinophils, correlated significantly with the amount of ICS purchased at 3 years (p=0.003 and p=0.018, respectively). Conclusions Reduced lung function, thickening of the reticular basement membrane and increased density of mucosal mast cells in infancy are associated with respiratory morbidity and treatment needs at age 3 years in this highly selected group of children.

Inspiratory flows through dry powder inhaler in chronic obstructive pulmonary disease: age and gender rather than severity matters.

Background: Dry powder inhalers (DPIs) are inspiratory flow driven and hence flow dependent. Most patients with chronic obstructive pulmonary disease (COPD) are elderly and have poor lung function. The factors affecting their inspiratory flows through inhalers are unclear. Objective: To study peak inspiratory flows (PIFs) and their determinants through a DPI in COPD patients of varying age and severity. Methods: Flow-volume spirometry was performed in 93 COPD patients. Maximum PIF rates were recorded through an empty Easyhaler® (PIFEH; Orion Corporation, Espoo, Finland), a DPI that provides consistent dose delivery at inhalation rates through the inhaler of 28 L/min or higher. Results: The mean PIFEH was 54 L/min (range 26–95 L/min) with a coefficient of variation of 7%. All but two patients were able to generate a flow of ≥28 L/min. In a general linear model, the independent determinants for PIFEH were age (P = 0.02) and gender (P = 0.01), and forced expiratory volume in 1 s (FEV1) expressed as percent predicted was not a significant factor. The regression model accounted only for 18% of the variation in PIFEH. Conclusion: In patients with COPD, age and gender are more important determinants of inspiratory flow through DPIs than the degree of expiratory airway obstruction. Most COPD patients with varying age and severity are able to generate inspiratory flows through the test inhaler that is sufficient for optimal drug delivery to the lower airways.

Maternal smoking affects lung function and airway inflammation in young children with multiple-trigger wheeze

BACKGROUND Exposure to tobacco smoke is a well-known risk factor for childhood asthma and reduced lung function, but the effect on airway inflammation in preschool-aged children is unclear. OBJECTIVE To examine the effect of parental smoking on lung function and fractional concentration of exhaled nitric oxide (Feno) in relation to both parental reports and childrens urine cotinine concentrations in preschool-aged children with multiple-trigger wheeze. METHODS A total of 105 3- to 7-year-old children with multiple-trigger wheeze and lung function abnormalities were recruited. Lung function was assessed by impulse oscillometry, and Feno measurements were performed. Exposure to tobacco smoke was determined by parental reports and measurement of childrens urinary cotinine concentrations. RESULTS Forty-three percent of the children were exposed to environmental tobacco smoke according to parental reports. The Feno level was significantly higher in children with a smoking mother (n = 27) than in children with a nonsmoking mother (23.4 vs 12.5 ppb, P = .006). The Feno level expressed as z score and the cotinine level correlated significantly (P = .03). Respiratory resistance at 5 Hz was higher in children exposed to maternal smoking than in others (0.99 vs 0.88 kPas/L, P = .005). Urinary cotinine concentrations reflected well parental reports on their daily smoking and increased relative to the number of cigarettes smoked in the family (P < .01). Atopy was found in 75% of the children, but it was not associated with the Feno value (P = .65). CONCLUSION Maternal smoking was associated with increased Feno value and poorer lung function in steroid-naive preschool children with multiple-trigger wheeze. Larger controlled trials are needed to generalize the results.

A 10-year open follow-up of eczema and respiratory symptoms in patients with atopic dermatitis treated with topical tacrolimus for the first 4 years.

Abstract Objectives: To examine the 10-year outcome of affected body surface area (BSA), respiratory symptoms, and serum IgE in adult AD patients 6 years after a 4-year intervention with topical tacrolimus.Methods: Patients who 10 years ago participated in a 4-year, open tacrolimus study (n = 65) were contacted for assessment of affected BSA, bronchial hyper-reactivity (BHR), respiratory symptoms, skin prick tests and serum IgE.Results: Altogether, 50 (77%) patients attended the follow-up visit. The median affected BSA decreased from 19% to 1.6% during the 10-year follow-up (p < 0.0001). Patients with active asthma and rhinitis symptoms at baseline reported a significant decrease at the follow-up (p = 0.02 andp = 0.01). In patients with BHR at baseline, the provocative dose of inhaled histamine producing a 15% decrease in FEV1 increased. Responders (≥ 60% improvement of affected BSA) to tacrolimus treatment at the 1-year visit had a significantly smaller affected BSA at the 4- and 10-year visits than non-responders (< 60% improvement). Responders also showed a significant decrease in serum IgE at the follow-up visit compared to baseline (p = 0.002).Conclusions: The long-term, effective treatment of patients with AD may have a beneficial effect on affected BSA, respiratory symptoms, and serum IgE.

Neuroendocrine cell hyperplasia of infancy: a prospective follow-up of nine children

Neuroendocrine cell hyperplasia of infancy (NEHI) has recently been described as an obstructive airway disease that affects infants aged 1–24 months, and presents typically with tachypnoea, crackles and hypoxia. The pathogenesis of the disease is unknown. We describe the clinical course of nine infants with radiologically and histologically confirmed NEHI. Host or environmental factors were not associated with the disease development. All infants with lung function tests demonstrated findings consistent with severe irreversible peripheral airway obstruction, assessed with whole body plethysmography (6/6) or the rapid thoracoabdominal compression technique (5/5). While the symptoms abated in all infants, six infants developed a non-atopic asthma during the follow-up. Systemic or inhaled corticosteroid treatment did not affect the duration of the symptoms. NEHI may mimic severe asthma and thus this entity should be taken into account when evaluating infants with chronic respiratory symptoms.

Thirteen-year follow-up of early intervention with an inhaled corticosteroid in patients with asthma

BACKGROUND In a 3-year study, adult patients who recently developed asthma (symptoms for less than 1 year) were treated for 2 years with the inhaled corticosteroid (ICS) budesonide (early therapy) or terbutaline. During the third year of the study, terbutaline-treated patients received budesonide (delayed therapy). Differences in lung function and bronchial responsiveness to histamine were observed between the 2 groups. OBJECTIVE We compared the effects of early versus delayed budesonide therapy after a 10-year follow-up period (13 years after the study began) and current real-life data. METHODS Of the original 103 patients, 90 were re-examined 13 years after study initiation. After the third year of the study, all patients had their medications, including the dose of ICS, individually adjusted. RESULTS After the follow-up period, lung function was within the normal range for the entire group (all patients); bronchial responsiveness significantly improved compared with baseline data. No statistically significant differences in clinical or functional variables were found between patients given early or delayed budesonide therapy. However, the delayed therapy group had a higher neutrophil count and higher concentrations of eosinophilic cationic protein and myeloperoxidase in induced sputum. This group had also used more asthma medication and hospital days. CONCLUSIONS Patients with relatively mild asthma who received ICS within 12 months of their first asthma symptoms or after a 2-year delay achieved equally good functional control of asthma after 10 years of individualized therapy. However, the delayed therapy group exhibited slightly less optimal disease control and more signs of airway inflammation.

Lung function, airway remodeling, and inflammation in infants: outcome at 8 years

BACKGROUND Associations between early deficits of lung function, infant airway disease, and outcome at school age in symptomatic infants are still unclear. OBJECTIVE To report follow-up data on a unique cohort of children investigated invasively in infancy to determine predictive value of airway disease for school-aged respiratory outcomes. METHODS Fifty-three infants previously studied using bronchoscopy and airway conductance were approached at 8 years of age. Symptoms, lung volumes, and airway responsiveness were reassessed. Data on lifetime purchase of asthma medication were obtained. Lung function was compared with that of 63 healthy nonasthmatic children. RESULTS Forty-seven children were reevaluated. Physician-diagnosed asthma was present in 39 children (83%). Twenty-five children (53%) had current and 14 children (30%) had past asthma. No pathologic feature in infancy correlated with any outcome parameter. As expected, study children had significantly reduced lung function and increased airway responsiveness compared with healthy controls, and very early symptoms were risk factors for reduced lung function. Current asthma was associated with reduced infant lung function and parental asthma. Reduced lung function in infancy was associated with purchase of inhaled corticosteroids when 6 to 8 and 0 to 8 years of age. CONCLUSION The lack of predictive value of any pathologic measure in infancy, reported here for the first time to our knowledge, demonstrates that pathologic processes determining the inception of asthma, which are as yet undescribed, are different from the eosinophilic inflammation associated with ongoing disease.

The effect of montelukast on respiratory symptoms and lung function in wheezy infants

Our aim was to investigate the effectiveness of montelukast in recurrently wheezy infants. We randomised 113, 6–24-month-old children with recurrent wheezing to receive either placebo or montelukast daily for an 8-week period. The primary end-point was symptom-free days. The secondary aims were to evaluate the effect of montelukast on rescue medication, on lung function, airway responsiveness and exhaled nitric oxide fraction (FeNO). Clinical response and FeNO were determined, the functional residual capacity (FRC) and specific airway conductance (sGaw) were measured using an infant whole-body plethysmograph, the maximal flow at functional residual capacity (V′max,FRC) was recorded using the squeeze technique and airway responsiveness was evaluated by performing a dosimetric methacholine challenge test. There was no significant difference in changes in weekly symptom-free days between the montelukast and the placebo group (3.1–3.7 days versus 2.7–3.1 days, p = 0.965). No significant differences were detected in the secondary end-points, i.e. use of rescue medication, FRC, sGaw, V′max,FRC, FeNO or airway responsiveness between groups. Montelukast therapy did not influence the number of symptom-free days, use of rescue medication, lung function, airway responsiveness or airway inflammation in recurrently wheezy, very young children.

Tidal breathing flow measurement in awake young children by using impedance pneumography

Characteristics of tidal breathing (TB) relate to lung function and may be assessed even in young children. Thus far, the accuracy of impedance pneumography (IP) in recording TB flows in young children with or without bronchial obstruction has not been evaluated. The aim of this study was to evaluate the agreement between IP and direct flow measurement with pneumotachograph (PNT) in assessing TB flow and flow-derived indices relating to airway obstruction in young children. Tidal flow was recorded for 1 min simultaneously with IP and PNT during different phases of a bronchial challenge test with methacholine in 21 wheezy children aged 3 to 7 years. The agreement of IP with PNT was found to be excellent in direct flow signal comparison, the mean deviation from linearity ranging from 2.4 to 3.1% of tidal peak inspiratory flow. Methacholine-induced bronchoconstriction or consecutive bronchodilation induced only minor changes in the agreement. Between IP and PNT, the obstruction-related tidal flow indices were equally repeatable, and agreement was found to be high, with intraclass correlation coefficients for T PTEF/T E, V PTEF/V E, and parameter S being 0.94, 0.91, and 0.68, respectively. Methacholine-induced changes in tidal flow indices showed significant associations with changes in mechanical impedance of the respiratory system assessed by the oscillometric technique, with the highest correlation found in V PTEF/V E (r = -0.54; P < 0.005 and r = -0.55; P < 0.005 by using IP or PNT, respectively). The results indicate that IP can be considered as a valid method for recording tidal airflow profiles in young children with wheezing disorders.