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Background Childhood atopic dermatitis (AD) is often followed by other atopic comorbidities such as asthma. Aim To compare the effectiveness of topical tacrolimus (TAC) and topical corticosteroids (TCSs) and their impact on airway inflammation and bronchial hyperresponsiveness in patients with paediatric AD. Methods This was a 3-year randomized open-label comparative follow-up study of 152 1–3-year-old children with moderate-to-severe AD (trial registration: EudraCT2012-002412-95). Frequent study visits including clinical examinations, laboratory investigations (total IgE, specific IgEs, blood eosinophils), skin prick and respiratory function tests to assess airway inflammation and bronchial hyperresponsiveness (exhaled nitric oxide, airway responsiveness to exercise and methacholine) were performed. Results Changes in eczema parameters at 36 months were similar in the TCS and TAC groups for mean body surface area (BSA) difference 1.4 [95% confidence interval (CI) –1.48 to 4.19); P = 0.12], mean Eczema Area and Severity Index (EASI) difference 0.2 (95% CI –1.38 to 1.82; P = 0.2), mean Investigator’s Global Assessment (IGA) difference, 0.3 (95% CI –0.12 to 0.67; P = 0.12) and mean transepidermal water loss (TEWL) difference at the eczema site, –0.3 (95% CI –4.93 to 4.30; P = 0.96) and at the control site, 1.4 (95% CI –0.96 to 3.60, P = 0.19). The control-site TEWL increased more towards the end of follow-up in the TCS vs. TAC group (mean change difference –4.2, 95% CI –8.14 to –0.29; P = 0.04). No significant impact on development of airway inflammation or bronchial hyperresponsiveness occurred in early effective eczema-treatment responders vs. others (‘early’ vs. ‘other’ response was defined as the difference in treatment response to airway outcomes in BSA, EASI or IGA at 3 months). Conclusion Children with moderate-to-severe AD benefit from long-term treatment with TCS or TAC. There were no significant differences in treatment efficacy. No differences in the impact on airways occurred between early effective treatment responders vs. others.

The specialty of clinical physiology was established in Finland about 20 years later than in Sweden. In the early 1960s, six physicians working mainly in preclinical departments of physiology were certified as specialists in clinical physiology. Many of the first specialists working in hospitals received specialist training in Sweden. The first hospital laboratories of clinical physiology were established in Tampere Central Hospital and Turku University Hospital in 1968. Thereafter, laboratories of clinical physiology were also established in Helsinki University Hospital and in Kuopio University Hospital and later also in most central hospitals. After clinical physiology laboratories were set up in hospitals and the number of specialists increased, the specialty gradually had more impact in clinical work. In the 1999 reform, nuclear medicine, which had previously been a subspecialty, was combined with clinical physiology. Arto Uusitalo was nominated the first professor of clinical physiology in Tampere University in 1984. The first professor in Helsinki University was Anssi Sovijärvi (1994), in Kuopio University Esko Länsimies (1998), and in Turku University Jaakko Hartiala (2003). Today, at four universities professors of clinical physiology and nuclear medicine lead research and medical education in this specialty. The hospital laboratories have modern equipment, which promotes multidisciplinary research with clinicians in fruitful collaboration. The Finnish Society of Clinical Physiology was founded in 1975. Today, it has about 160 members, about half of whom are specialists in the field. On its 40th anniversary, the Society decided to publish the history of clinical physiology in Finland.

BACKGROUND AND OBJECTIVES Options to treat and prevent episodic wheezing in children are scarce. Our objective was to assess the efficacy of intermittent tiotropium bromide treatment in early childhood episodic wheezing. METHODS This 48-week, randomized, open-label, controlled, parallel-group trial was conducted at 4 hospitals in Finland. Children aged 6 to 35 months with 2 to 4 physician-confirmed episodes of wheeze and/or shortness of breath were considered eligible. Study participants were randomly allocated to receive 1 of 3 treatments: once-daily tiotropium bromide 5 µg for 7 to 14 days during respiratory tract infections and as-needed albuterol sulfate 0.2 mg (n = 27), twice-daily fluticasone propionate 125 µg for 7 to 14 days during respiratory tract infections and as-needed albuterol sulfate 0.2 mg (n = 25), or as-needed albuterol sulfate 0.2 mg alone (n = 28). The primary outcome was efficacy, assessed as intention-to-treat by comparing the proportion of episode-free days (the days lacking symptoms or treatments) between the treatment groups. RESULTS The proportion of episode-free days was higher in those receiving intermittent tiotropium bromide (median 97% [interquartile range, 93% to 99%]) than in those receiving intermittent fluticasone propionate (87% [78% to 93%], P = .002), or with as-needed albuterol sulfate alone (88% [79% to 95%], P = .003). Adjustment with allergic sensitization, the baseline number of physician-confirmed episodes of wheeze and/or shortness of breath, or short-course glucocorticoid treatment in the 2 weeks before the enrollment, did not affect the result. Intervention-related adverse events were not seen. CONCLUSIONS Intermittent tiotropium bromide treatment may be an effective alternative to current therapies for episodic wheezing. Before implementation of use, further research on safety and efficacy is indicated.

Background: To evaluate whether patients of varying ages and lung function with asthma or those with chronic obstructive pulmonary disease (COPD) can achieve sufficient inspiratory flows for effective use of the fixed-dose combination of salmeterol-fluticasone propionate and budesonide-formoterol dispensed with the Easyhaler (R) (EH) device-metered, multi-dose dry powder inhaler (DPI). Methods: A pooled analysis of two randomized, multicenter, crossover, open-label studies (NCT01424137; NCT009849061) was conducted to characterize inspiratory flow parameters across the EH, Seretide Diskus (DI) and Symbicort Turbuhaler (TH) inhalers in patients with asthma and/or COPD of varying severity. The primary endpoint was peak inspiratory flow (PIF) rate through the EH. Results: The intent-to-treat population comprised 397 patients; 383 patients were included in the per protocol (PP) population. The mean PIF (standard deviation) values through the EH in patients = 18 years of age with asthma and in those with COPD, were similar: 61.4 (11.5), 69.7 (13.5), and 61.9 (13.2) L/min, respectively. These flow rates correspond to pressure drops of 5.05 (1.80), 6.52 (2.34) and 5.19 (2.07) kPa, respectively. In total, 380 (99.2%) of patients in the PP population were able to generate a PIF rate through the EH of >= 30 L/min, which is required to enable consistent dose delivery from the DPI; there was a moderate direct association between age and PIF in younger patients with asthma, but this was inverse and less apparent in adult patients with asthma and/or those with COPD. Height and weight were also moderately correlated with PIF. Stronger associations with PIF were observed for some lung function parameters, particularly native PIF and forced inspiratory vital capacity. Conclusions: Over 99% of patients with asthma and/or COPD were able to inhale through the EH with an adequate PIF rate, irrespective of age, or severity of airway obstruction. This confirms that patients with asthma and/or COPD can achieve inspiratory flows via the EH DPI that are sufficient for its effective use.

BACKGROUND: Preschool wheeze is highly prevalent; 30%-50% of children have wheezed at least once before age six. Wheezing is not a disorder; it is a symptom of obstruction in the airways, and it is essential to identify the correct diagnosis behind this symptom. An increasing number of studies provide evidence for novel diagnostic tools for monitoring and predicting asthma in the pediatric population. Several techniques are available to measure airway obstruction and airway inflammation, including spirometry, impulse oscillometry, whole-body plethysmography, bronchial hyperresponsiveness test, multiple breath washout test, measurements of exhaled NO, and analyses of various other biomarkers.METHODS: We systematically reviewed all the existing techniques available for measuring lung function and airway inflammation in preschool children to assess their potential and clinical value in the routine diagnostics and monitoring of airway obstruction.RESULTS: If applicable, measuring FEV1 using spirometry is considered useful. For those unable to perform spirometry, whole-body plethysmography and IOS may be useful. Bronchial reversibility to beta2-agonist and hyperresponsiveness test with running exercise challenge may improve the sensitivity of these tests.CONCLUSIONS: The difficulty of measuring lung function and the lack of large randomized controlled trials makes it difficult to establish guidelines for monitoring asthma in preschool children.

A systematic review was performed to determine if the continuous laryngoscopy exercise test (CLE) has been used in the diagnostics of exercise dyspnea in adults with asthma, and whether inducible laryngeal obstruction (ILO) is found in those with asthma or with severe or difficult-to-treat asthma.We used Scopus and PubMed databases. The articles published up to 13 August 2019 were considered.We excluded manuscripts that did not contain information about adult patients with asthma. We included six studies from 59 search results in Scopus and none from the 17 search results in PubMed.The articles included 455 study individuals. Of these, 229 (50.3%) had diagnosed asthma or were treated with asthma medication. Altogether 31/229 (13.5%) subjects with diagnosis of asthma or previous asthma treatment had exercise-induced laryngeal obstruction (EILO) as comorbidity. The CLE test was performed on 229 patients with asthma. The method was used only for differential diagnosis of exercise-induced dyspnea to confirm EILO. At least 10/455 (2.2%) out of the 455 subjects experienced adverse events.This systematic review revealed that only a small proportion of patients with asthma had undergone the CLE test to assess exercise-induced dyspnea. None of the selected manuscripts reported severity of asthma. Whether CLE provides a valuable diagnostic tool for patients with severe or difficult-to-treat asthma cannot be determined according to this review.

The Lancet Asthma Commission calls for objective measurements to support asthma diagnosis, especially for children [1]. The expiratory variability index (EVI) is a novel method of testing lung function testing that can be measured passively at night with an impedance pneumography (IP) technique using four skin electrodes and a small body-worn recorder. The aim of EVI is to measure variation in flow-volume curve shapes within 15–45% of the expired volume. It has been demostrated that normal variations in the curve shapes are mainly caused by comparing different sleep cycles [2], which are reduced in the presence of bronchial obstructions [3]. Footnotes This manuscript has recently been accepted for publication in the ERJ Open Research . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article. Conflict of interest: Janne Burman reports support for the present manuscript from Allergy Research Foundation, Jalmari and Rauha Ahokas Foundation (Helsinki), Helsinki Region Allergy Foundation (Helsinki), the Culture Foundation, The Sigrid Juselius Foundation, and Revenio Research Ltd. Conflict of interest: Pekka Malmberg reports support for the present manuscript from Allergy Research Foundation, Jalmari and Rauha Ahokas Foundation (Helsinki), Helsinki Region Allergy Foundation (Helsinki), the Culture Foundation, The Sigrid Juselius Foundation, and Revenio Research Ltd. Conflict of interest: Ville-Pekka Seppa reports support for the present manuscript from Allergy Research Foundation, Jalmari and Rauha Ahokas Foundation (Helsinki), Helsinki Region Allergy Foundation (Helsinki), the Culture Foundation, The Sigrid Juselius Foundation, and Revenio Research Ltd. Ville-Pekka Seppa reports to be an employee of Revenio Group corporation that commercialized IP technology. Ville-Pekka Seppa also reports to hold patent relating to impedance pneumography, no further details provided. Conflict of interest: Tuomas Jartti reports support for the present manuscript from Allergy Research Foundation, Jalmari and Rauha Ahokas Foundation (Helsinki), Helsinki Region Allergy Foundation (Helsinki), the Culture Foundation, The Sigrid Juselius Foundation, and Revenio Research Ltd. Conflict of interest: Sami Remes Conflict of interest: Ove Mickelsson reports support for the present manuscript from Allergy Research Foundation, Jalmari and Rauha Ahokas Foundation (Helsinki), Helsinki Region Allergy Foundation (Helsinki), the Culture Foundation, The Sigrid Juselius Foundation, and Revenio Research Ltd. Conflict of interest: Anna Pelkonen reports support for the present manuscript from Allergy Research Foundation, Jalmari and Rauha Ahokas Foundation (Helsinki), Helsinki Region Allergy Foundation (Helsinki), the Culture Foundation, The Sigrid Juselius Foundation, and Revenio Research Ltd. Conflict of interest: Mika Makela reports support for the present manuscript from Allergy Research Foundation, Jalmari and Rauha Ahokas Foundation (Helsinki), Helsinki Region Allergy Foundation (Helsinki), the Culture Foundation, The Sigrid Juselius Foundation, and Revenio Research Ltd. Conflict of interest: Leo Malmberg reports support for the present manuscript from Allergy Research Foundation, Jalmari and Rauha Ahokas Foundation (Helsinki), Helsinki Region Allergy Foundation (Helsinki), the Culture Foundation, The Sigrid Juselius Foundation, and Revenio Research Ltd.

Background Recurrent wheezing in early life is transient in most children. The significance of airway hyperresponsiveness (AHR) in persistence of respiratory symptoms from infancy to early childhood is controversial. Objective We evaluated whether AHR in wheezy infants predicts doctor-diagnosed asthma (DDA) or AHR at the age of 6 years. Methods Sixty-one wheezy infants (age 6-24 months) were followed up to the median age of 6 years. Lung function and AHR with methacholine challenge test were assessed at infancy and 6 years. The exercise challenge test was performed at the age of 6 years. Atopy was assessed with skin prick tests. Results At 6 years, 21 (34%) of the children had DDA. Children with DDA had higher logarithmic transformed dose-response slope (LOGDRS) to methacholine in infancy than children without DDA (0.047 vs 0.025; P = .033). Furthermore, AHR to methacholine in infancy and at 6 years were associated with each other (r = 0.324, P = .011). Children with exercise-induced bronchoconstriction (EIB) at 6 years were more reactive to methacholine in infancy than those without EIB (P = .019). Conclusion Increased AHR in symptomatic infants was associated with increased AHR, DDA, and EIB at median the age of 6 years, suggesting early establishment of AHR.

Background The objective of this study was to evaluate the role of body mass index with regard to exercise performance, exercise-induced bronchoconstriction (EIB), and respiratory symptoms in 7- to 16-year-old children. Methods A total of 1120 outdoor running exercise challenge test results of 7- to 16-year-old children were retrospectively reviewed. Lung function was evaluated with spirometry, and exercise performance was assessed by calculating distance per 6 minutes from the running time and distance. Respiratory symptoms in the exercise challenge test were recorded, and body mass index modified for children (ISO-BMI) was calculated for each child from height, weight, age, and gender according to the national growth references. Results Greater ISO-BMI and overweight were associated with poorer exercise performance (P

BACKGROUND: To evaluate whether patients of varying ages and lung function with asthma or those with chronic obstructive pulmonary disease (COPD) can achieve sufficient inspiratory flows for effective use of the fixed-dose combination of salmeterol-fluticasone propionate and budesonide-formoterol dispensed with the Easyhaler(®) (EH) device-metered, multi-dose dry powder inhaler (DPI). METHODS: A pooled analysis of two randomized, multicenter, crossover, open-label studies (NCT01424137; NCT009849061) was conducted to characterize inspiratory flow parameters across the EH, Seretide Diskus (DI) and Symbicort Turbuhaler (TH) inhalers in patients with asthma and/or COPD of varying severity. The primary endpoint was peak inspiratory flow (PIF) rate through the EH. RESULTS: The intent-to-treat population comprised 397 patients; 383 patients were included in the per-protocol (PP) population. The mean PIF (standard deviation) values through the EH in patients

Background: Exhaled nitric oxide (FeNO) measurements and eucapnic voluntary hyperventilation (EVH) tests have been used as diagnostic tools for asthma. Data on the impact of hyperventilation on the level of FeNO are limited. Aim: We aimed to evaluate whether EVH tests affect the level of FeNO in children aged 10–16 years. Methods: A total of 234 children aged 10–16 years had a 6‐min EVH test performed. In total, FeNO values for 153 of 234 children were measured before the test and within 15 min after the test. According to a baseline FeNO level of 20 ppb, children were divided into two groups: those with low values (FeNO < 20 ppb) and those with high values (FeNO ≥ 20 ppb). Results: The median age of the children was 13.4 years (interquartile range 12.3–15.3 years); 58% were boys and 42% were girls. Of these children, 51% were sensitized to aeroallergens. In 101 of 153 children (66%), the FeNO values decreased after the EVH test. In children with low and high baseline levels, the median level of FeNO decreased after the EVH test: 10.5 ppb before versus 9.5 ppb after (p < .011), and 31.0 ppb before versus 28.0 ppb after (p < .011), respectively. The decrease in FeNO after EVH test was not associated with induced bronchoconstriction expressed as a change in FEV1 (Rs = .19). Conclusions: The EVH test decreases FeNO levels. Therefore, FeNO should be measured before an EVH test is performed.

Spirometry and exhaled nitric oxide are two important complimentary tools to identify and assess asthma control in children. We aimed to determine the ability of a new suggested spirometry-adjusted fraction of exhaled nitric oxide (NO) index in doing that. A random sample of 1602 schoolchildren were screened by a health questionnaire, skin prick tests, spirometry with bronchodilation and exhaled NO. A total of 662 children were included with median (IQR) exhaled NO 11(14) ppb. Receiver operating characteristic (ROC) curves using exhaled NO equations from Malmberg, Kovesi and Buchvald, and spirometry-adjusted fraction of exhaled NO values were applied to identify asthmatic children and uncontrolled asthma. Receiver operating characteristic (ROC) curves failed to identify asthmatic children (all AUC < 0.700). Spirometry-adjusted fraction of exhaled NO/FEV1 (AUC = 0.712; P = .010) and NO/FEF25%-75% (AUC = 0.735 P = .004) had a fair and increased ability to identify uncontrolled disease compared with exhaled NO (AUC = 0.707; P = .011) or the Malmberg equation (AUC = 0.701; P = .014). Sensitivity and specificity identifying non-controlled asthma were 59% and 81%, respectively, for the cut-off value of 9.7 ppb/L for exhaled NO/FEV1 , and 40% and 100% for 15.7 ppb/L/s for exhaled NO/FEF25%-75% . Exhaled NO did not allow to identify childhood asthma. Spirometry-adjusted fraction of exhaled NO performed better-assessing asthma control in children. Thus, although more validation studies are needed, we suggest its use in epidemiological studies to assess asthma control. Health, Comfort and Energy in the Built Environment (HEBE), Grant/Award Number: NORTE-01-0145-FEDER-000010; Programa Operacional Regional do Norte, Grant/Award Number: NORTE2020; Fundo Europeu de Desenvolvimento Regional (FEDER); Foundation for Science and Technology schoolarships, Grant/Award Number: SFRH/BD/108605/2015 and SFRH/BD/112269/2015

Background: Vitamin D insufficiency might be associated with biased T-cell responses resulting in inflammatory conditions such as atopy and asthma. Little is known about the role of vitamin D in low-grade systemic inflammation and airway hyperresponsiveness (AHR) in young children. Objective: To evaluate whether vitamin D insufficiency and increased serum high-sensitivity C-reactive protein (hs-CRP) are linked to AHR in symptomatic infants. Methods: Seventy-nine infants with recurrent or persistent lower respiratory tract symptoms underwent comprehensive lung function testing and a bronchial methacholine challenge test. In addition, skin prick tests were performed and serum 25-hydroxyvitamin D (S-25-OHD), hs-CRP, total immunoglobulin E, and blood eosinophil levels were determined. Results: S-25-OHD was lowest in infants with blood eosinophilia and AHR (n = 10) compared with those with eosinophilia only (n = 6) or AHR only (n = 50) or those with neither (n = 13; P = .035). Moreover, vitamin D insufficiency (S-25-OHD

Overnight analysis of tidal breathing flow volume (TBFV) loops, recorded by impedance pneumography (IP), has been successfully applied in the home monitoring of children with wheezing disorders. However, little is known on how sleep physiology modifies the relationship between TBFV profiles and wheeze. We studied such interactions in wheezing infants. Forty-three infants recruited because of recurrent lower airway symptoms were divided into three groups based on their risk of asthma: high (HR), intermediate (IR), or low (LR). Sedated patients underwent infant lung function testing including assessment of airway responsiveness to methacholine at the hospital and a full-night recording of TBFV profiles at home with IP during natural sleep. Overnight TBFV indexes were estimated from periods of higher and lower respiration variability, presumably belonging to active [rapid eye movement (REM)] and quiet [non-REM (NREM)] sleep, respectively. From 35 valid recordings, absolute time indexes showed intrasubject sleep phase differences. Peak flow relative to time and volume was lower in HR compared with LR only during REM, suggesting altered expiratory control. Indexes estimating the concavity/convexity of flow decrease during exhalation suggested limited flow during passive exhale in HR compared with IR and LR, similarly during NREM and REM. Moreover, during REM convexity was negatively correlated with maximal flow at functional residual capacity and methacholine responsiveness. We conclude that TBFV profiles determined from overnight IP recordings vary because of sleep phase and asthma risk. Physiological changes during REM, most likely decrease in respiratory muscle tone, accentuate the changes in TBFV profiles caused by airway obstruction. NEW & NOTEWORTHY Impedance pneumography was used to investigate overnight tidal breathing flow volume (TBFV) indexes and their interactions with sleep phase [rapid eye movement (REM) vs. non-REM] at home in wheezing infants. The study shows that TBFV indexes vary significantly because of sleep phase and asthma risk of the infant and that during REM the changes in TBFV indexes caused by airway obstruction are accentuated and better associated with lung function of the infant.

Fractional exhaled nitric oxide (F

Fractional exhaled nitric oxide (F-ENO) is used to assess eosinophilic inflammation of the airways. F-ENO values are influenced by the expiratory flow rate and orally produced NO. We measured F-ENO at four different expiratory flow levels after two different mouthwashes: tap water and carbonated water. Further, we compared the alveolar NO concentration (C-ANO), maximum airway NO flux (J(awNO)) and airway NO diffusion (D-awNO) after these two mouthwashes. F-ENO was measured in 30 volunteers (healthy or asthmatic) with a chemiluminescence NO-analyser at flow rates of 30, 50, 100 and 300mL/s. A mouthwash was performed before the measurement at every flow rate. The carbonated water mouthwash significantly reduced F-ENO compared to the tap water mouthwash at all expiratory flows: 50mL/s (p

Background: Clinical significance of small airway obstruction in mild pediatric asthma is unclear. Objective: To evaluate small airway properties in children with mild to moderate asthmatic symptoms and the association of small airway function with asthma control and exercise-induced bronchoconstriction (EIB). Methods: Children (5-10 years old) with recurrent wheezing (n = 42) or persistent troublesome cough (n = 16) and healthy controls (n = 19) performed impulse oscillometry (IOS), spirometry, and a multiple-breath nitrogen washout (MBNW) test. Exhaled nitric oxide (NO) was measured at multiple flow rates to determine alveolar NO concentration (CAIN). Asthma control was evaluated with the Childhood Asthma Control Test (C-ACT), short-acting beta(2)-agonist (SABA) use within the past month, and asthma exacerbations within the past year. Results: IOS, spirometry, and exhaled NO indexes that are related to small airway function differed between children with recurrent wheezing and healthy controls, whereas only forced expiratory flow at 25% to 75% of the forced vital capacity was associated with persistent cough. The MBNW indexes showed no difference between the groups. Among symptomatic children, conducting airway ventilation inhomogeneity and CALV were associated with asthma exacerbations (P = .03 and P = .002, respectively), and lung clearance index and CALV were associated with EIB (P = .04 and P = .004, respectively). None of the proposed small airway indexes was associated with the C-ACT score or SABA use. Conclusion: Subtle changes were observed in the proposed small airway indexes of IOS, spirometry, and exhaled NO among children with mild to moderate recurrent wheezing. Small airway dysfunction, expressed as ventilation inhomogeneity indexes and CALV, was also associated with asthma exacerbations and EIB. (C) 2018 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

In clinical practice, assessment of expiratory nitric oxide (FENO) may reveal eosinophilic airway inflammation in asthmatic and other pulmonary diseases. Currently, measuring of FENO is standardized to exhaled flow level of 50 ml s−1, since the expiratory flow rate affects the FENO results. To enable the comparison of FENO measured with different expiratory flows, we firstly aimed to establish a conversion model to estimate FENO at the standard flow level, and secondly, validate it in five external populations. FENO measurements were obtained from 30 volunteers (mixed adult population) at the following multiple expiratory flow rates: 50, 30, 100 and 300 ml s−1, after different mouthwash settings, and a conversion model was developed. We tested the conversion model in five populations: healthy adults, healthy children, and patients with COPD, asthma and alveolitis. FENO conversions in the mixed adult population, in healthy adults and in children, showed the lowest deviation between estimated F^ENO from 100 ml s−1 and measured FENO at 50 mL s−1: −0·28 ppb, −0·44 ppb and 0·27 ppb, respectively. In patients with COPD, asthma and alveolitis, the deviation was −1·16 ppb, −1·68 ppb and 1·47 ppb, respectively. We proposed a valid model to convert FENO in healthy or mixed populations, as well as in subjects with obstructive pulmonary diseases and found it suitable for converting FENO measured with different expiratory flows to the standard flow in large epidemiological data, but not on individual level. In conclusion, a model to convert FENO from different flows to the standard flow was established and validated.

Asthma is a chronic lung disease that usually develops during childhood. Despite that symptoms can almost be controlled with medication, early diagnosis is desirable in order to reduce permanent airway obstruction risk. It has been suggested that abnormal parasympathetic nervous system (PSNS) activity might be closely related with the pathogenesis of asthma, and that this PSNS activity could be reflected in cardiac vagal control. In this work, an index to characterize the spectral distribution of the high frequency (HF) component of heart rate variability (HRV), named peakness ( $\wp$ ), is proposed. Three different implementations of $\wp$ , based on electrocardiogram (ECG) recordings, impedance pneumography (IP) recordings and a combination of both, were employed in the characterization of a group of preschool children classified attending to their risk of developing asthma. Peakier components were observed in the HF band of those children classified as high-risk ( $p ), who also presented reduced sympathvoagal balance. Results suggest that high-risk of developing asthma might be related with a lack of adaptability of PSNS.

Summary Introduction Reduced lung function in early childhood is associated with persistent symptoms and low lung function later in life. Impulse oscillometry (IOS) is feasible for assessing lung function also in preschool children, and some of the parameters, such as respiratory resistance at 5 Hz (Rrs5) and the frequency dependence of resistance (dRrs/df), have been suggested to reflect small airway dysfunction. Whether changes in preschool IOS predict later lung function remains unknown. Methods The medical data of 154 asthmatic children with IOS performed at 2–7 years and spirometry at 12–18 years were analyzed. IOS and post-bronchodilator spirometry parameters were compared, and the association was estimated in a multivariate model. Results Measured at preschool age, particularly Rrs5 and dRrs/df were significantly correlated with post-bronchodilator forced expiratory volume in 1 sec (FEV1) at adolescence (Rrs5: r = −0.223, P = 0.005; dRrs/df: r = 0.234, P = 0.004). Although the number of children with decreased FEV1 was low, associations of increased Rrs5 (odds ratio (OR) 5.9, 95% confidence interval (CI) 1.7; 20.9) and decreased dRrs/df (OR 8.2, 95% CI 1.7; 39.6) with decreased FEV1 remained significant in multivariate analyses. Similar findings were observed also with other spirometric parameters. Conclusion In asthmatic children, preschool IOS is associated with spirometric lung function at adolescence, but the scatter is wide. Normal preschool IOS seems to indicate favourable lung function outcome, whereas in some individuals IOS could potentially be of clinical use, at a younger age than spirometry, to screen lung function deficits and increased risk for later lung function impairment. Pediatr Pulmonol. 2015; 50:1205–1213. © 2015 Wiley Periodicals, Inc.

Background: Early childhood asthma is known to leave a persistent mark in the lung function. Impulse oscillometry (IOS) is a feasible method for evaluating lung function even in preschoolers. We studied whether preschool lung function assessed with IOS is associated with asthma in adolescence. Methods: During years 2002-2004 lung function of 255 children aged 4-7 years was tested by using IOS. Baseline measurements were followed by exercise challenge and bronchodilatation tests. For baseline lung function, z-scores were calculated by using age and height specific predicted values. Exercise-induced bronchoconstriction was defined as a ≥35 % increase in respiratory resistance at 5 Hz (Rrs5) after the running test. Bronchodilation test was regarded significant with a ≥35 % decrease in Rrs5 after the salbutamol inhalation. 121 children participated in the 10-year follow-up visit at the age of 12-16 years, and performed IOS and spirometry, followed by a bronchodilation test. 64 of these teenagers had abnormal lung function at preschool age. Results: Abnormal baseline values in preschool IOS were significantly associated with 1) low lung function, 2) the need for asthma medication and 3) the occurrence of asthma symptoms in adolescence. Preschool abnormal Rrs5 at baseline (z-score ≥ 1.645) showed positive predictive value for abnormal FEV1/FVC, asthma symptoms and asthma medication use at teenage by 62 % (p=0.001). Positive exercise challenge and bronchodilatation tests at preschool were only weakly predictive of asthma symptoms and the use of asthma medication at teenage. Conclusions: Preschool IOS is associated with asthma at adolescence. The results suggest that early childhood IOS could aid in screening for persistent asthma.

The ability of impedance pneumography (IP) for recording tidal flow during long periods of free breathing make it a promising tool for assessing temporal complexity of respiration. However, techniques quantifying complexity may be sensitive to the noise in the IP signal resulting from the current processing method. A nonlinear local projection filter (NLPF) is presented as the solution to the current linear processing method, failing to reduce noise without distorting the flow signal. Current and proposed NLPF methods were applied to and existing data set of raw IP recorded in 21 infants during a methacholine challenge test. Methods’ performance was compared in a battery of test using mouth flow as a reference. NLPF achieved lower sample-by-sample error, and higher frequency attenuation, while linearity with mouth flow was maintained. Therefore, we concluded that NLPF superiorly reduces noise without distorting respiratory information.

Asthma is a chronic lung disease that is prone to start during chilhood. Although symptoms can be usually controlled with medication, early diagnosis is crucial to reduce the risk of permanent airway obstruction. Despite the fact that origin of asthma is still uncertain, abnormal parasympathetic nervous system (PNS) activity has been pointed out to play a major role in its pathogenesis. In this work the use of nonlinear heart rate variability (HRV) indexes is proposed in order to look for differences between children classified as high- or low-risk of suffering from asthma in the future. PNS activity is assessed trough a filtered HRV signal. Correlation dimension analysis showed statistically significant differences distinguishing high- and low-risk. Decreased complexity observed in high-risk group suggests that abnormal PNS activity might be related with increased risk of developing asthma.

Early diagnosis of asthma is crucial to avoid long-term effects such as permanent airway obstruction. Pathogenesis of asthma has been related with autonomic nervous system (ANS) dysfunction, concretely with abnormal parasympathetic activity. As heart rate variability (HRV) analysis does reflect ANS activity, it has been employed here in risk of asthma stratification.

Airway hyperresponsiveness (AHR) is a hallmark of asthma but its assessment is usually restricted to older children who are capable of performing the maneuvers involved in spirometry. In younger children, a feasible option to perform the lung function measurement is impulse oscillometry (IOS), which requires less cooperation.To evaluate whether assessment of AHR by IOS could differentiate children with various obstructive symptoms from one another.One hundred twenty-one children (median age 6.0 years, range 3.7-8.1 years) were examined: 31 with probable asthma characterized by current troublesome lung symptoms, 61 with a history of early wheezing disorder (recurrent wheezing ≤24 months of age), 15 with a history of bronchopulmonary dysplasia, and 14 healthy controls. Indirect AHR was assessed by exercise and mannitol challenge tests, and direct AHR was assessed with methacholine using IOS. AHR to exercise was defined as an increase of at least 40% in respiratory resistance at 5 Hz. In the mannitol and methacholine challenges, the dose causing an increase of 40% in respiratory resistance at 5 Hz was calculated.AHR to exercise was good at differentiating children with current troublesome lung symptoms from those in the other groups (P.001). AHR to methacholine separated children with current troublesome lung symptoms, early wheezing disorder, and bronchopulmonary dysplasia from the controls (P.001), whereas the mannitol test did not distinguish among the study groups (P = .209).The methacholine and exercise challenge tests with IOS identify children with probable asthma characterized by troublesome lung symptoms and therefore may represent a practical aid in the evaluation of AHR in young children.

IntroductionSmoking increases the risk of asthma and reduces lung function among subjects with and without asthma. We assessed the effects of smoking on lung function reflecting both central and small airways among adults with newly onset asthma.MethodsIn a population-based study, 521 (response rate 86%) working-aged adults with clinically defined newly diagnosed asthma answered a questionnaire on personal smoking and other factors potentially influencing lung function, and performed spirometry. We applied multiple linear regression analysis to estimate the relations between smoking and lung function adjusting for confounding.ResultsAmong asthmatics, FEV1 level was reduced significantly, on average 208 mL, related to regular smoking (adjusted effect estimate −0.208, 95% CI −0.355 to −0.061) and 245 mL in relation to former smoking, that is, among those who quit less than a year ago (−0.245, 95% CI −0.485 to −0.004). In contrast, FEV1 was not significantly related to occasional smoking or former smoking among those who quit over a year ago. Forced expiratory flow (FEF) levels (L/s) were also significantly reduced among regular smokers (FEF25–75%: −0.372, 95% CI −0.607 to −0.137; FEF50%: −0.476, 95% CI −0.750 to −0.202). An exposure–response pattern related to both daily smoking rate and lifetime cumulative smoking was seen both among men and women.ConclusionsThis study provides new evidence that among working-aged adults with new asthma, regular smoking and former smoking reduce lung function levels with a dose–response pattern. The lung function parameters applied as outcomes reflect both larger and smaller airways.

The respiratory outcomes after preterm birth have changed, and it is unclear whether increased airway hyperresponsiveness (AHR) later in childhood is associated with airway inflammation.To investigate the association between AHR and fractional exhaled nitric oxide (FeNO), including the alveolar concentration of nitric oxide, in school-age children with very low birth weight (VLBW).Twenty-nine children with VLBW, 33 children with a history of early wheeze, and 60 healthy controls underwent a FeNO measurement and bronchial challenge test with histamine. Atopy was assessed with skin prick tests.Children with VLBW had well-preserved baseline lung function but significantly increased AHR, expressed as the dose response slope (P.001). Geometric mean FeNO levels were similar between VLBW children and healthy controls, and a history of bronchopulmonary dysplasia had no effect. In the VLBW and early wheeze groups, AHR was associated with FeNO (r = 0.47, P = .01, and r = 0.43, P = .013, respectively), but in a stratified analysis, this association was significant only in atopic individuals. By using the multiple flow FeNO technique, the bronchial nitric oxide flux rather than alveolar nitric oxide concentrations were associated with AHR in both children with early wheeze and VLBW.We conclude that in VLBW children AHR is related to FeNO but only in atopic individuals. Similar to children with early wheeze, this association is dependent on bronchial flux rather than alveolar nitric oxide concentration. It is likely that AHR is modified by atopic inflammation rather than by inflammatory process due to prematurity.

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.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 children's urine cotinine concentrations in preschool-aged children with multiple-trigger wheeze.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 children's urinary cotinine concentrations.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).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.

Background: Impulse oscillometry (IOS) is feasible for preschool children and postulated to enable assessment of small airways function. Yet, limited data on the repeatability of IOS in young children exist. Aims: To clarify the within- and between-visit repeatability of IOS in healthy and symptomatic children, with special regard to the putative indices of small airways function: the difference between respiratory resistance at 5 and 20 Hz (R5-20) and area under the reactance curve (AX). Methods: We retrospectively analysed the within-measurement repeatability of triplicate IOS measurements in 103 healthy children (aged 2.1-7.0 years) at baseline condition, and the between-measurement repeatability before and after placebo inhalation (n=19). In 45 children (aged 3.7-7.9 years) with a history of respiratory symptoms, we analysed the within- and between-visit IOS repeatability of two visits 7-14 days apart. Results: In healthy children, the repeatability of R5-20 and AX was high: within-measurement intraclass correlation coefficient (ICC) 0.89-0.94, 95% confidence interval (CI) 0.85-0.96, and between-measurement ICC 0.95-0.97, 95% CI 0.87-0.99. Similar results were observed among symptomatic children: within-visit ICC 0.96-0.98, 95% CI 0.94-0.99, and between-visit ICC 0.72-0.83, 95% CI 0.49-0.90. Discussion: R5-20 and AX measured with IOS have high repeatability also in young children and remain relatively stable in a one- to two-week period in symptomatic children. IOS may therefore be useful as an outcome measure for treatment interventions.

Introduction: High-sensitivity C -reactive protein (hs-CRP) is a biomarker reflecting low-grade systemic inflammation, but its role among wheezing infants is still unknown. Objective: To demonstrate, whether hs-CRP has any association with recurrent wheezing, atopic markers, baseline lung function, or airway responsiveness in infants with persistent or recurrent lower airway symptoms. Methods: 62 consecutive steroid-free infants aged 6-27 months (median 15, interquartile range 14;17 months) with persistent or recurrent lower airway symptoms underwent whole body plethysmography, rapid thoracoabdominal compression, methacholine challenge, and skin-prick tests (SPT). Total immunoglobulin E (IgE), blood eosinophils, and hs-CRP were determined. Results: Recurrent physician-diagnosed wheezing (≥3 wheezing episodes) and blood eosinophilia (eosinophils ≥0.4 x 10 9 /l and ≥4%) were associated with undetectable hs-CRP (n=9/52, p=0.044; n=13/49, p=0.013). Hs-CRP was not associated with atopic eczema, IgE, SPT positivity, or baseline lung function. The infants with blood eosinophilia and increased airway responsiveness to methacholine (PD40V9 maxFRC Conclusions: There was no evidence of low-grade systemic inflammation in symptomatic children with recurrent wheezing, blood eosinophilia, or eosinophilia and increased airway responsiveness. Neither was hs-CRP associated with other atopic markers or baseline lung function. In this age group, inflammation of the airways may not be reflected as low-grade systemic inflammation, thus explaining nearly undetectable hs-CRP.

Early origins of chronic obstructive pulmonary disease have been recognized. Impulse oscillometry (IOS) is suitable for assessment of lung function also in preschool children, and some novel indices have been connected to assessment of small airway function. However, limited data exist on the sensitivity of these new indices to detect lung function deficits in young symptomatic children.IOS measurements of 103 healthy preschool children were evaluated to establish reference equations for the difference between respiratory resistance at 5 and 20 Hz (R5-20), the relative difference of R5-20 (R5-20%), and area under the reactance curve (AX). Thereafter, IOS results of children with late-onset troublesome lung symptoms (n = 20), a history of early wheeze (n = 37), or a history of bronchopulmonary dysplasia (BPD, n = 8) were compared to healthy children.None of the patient groups differed from healthy regarding respiratory resistance at 5 Hz (R5), and only children with a history of BPD differed from healthy regarding respiratory reactance at 5 Hz (X5). In contrast, z-scores of R5-20, R5-20%, and AX were significantly higher in all patient groups than in healthy children (P 0.001), showing improved sensitivity (20-55%) compared to R5 and X5 (5-6%).R5-20, R5-20%, and AX are superior to conventional IOS parameters in distinguishing children with current or past lower respiratory tract symptoms from healthy, and may prove valuable for screening early lung function deficits. Pediatr Pulmonol. 2017;52:598-605. © 2016 Wiley Periodicals, Inc.

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.

Exhaled nitric oxide fraction (F(eNO)) has been proposed as a noninvasive marker of eosinophilic bronchial inflammation in active asthma, and supposed to reflect responsiveness to corticosteroid therapy. There are several factors influencing F(eNO), and its role in early childhood respiratory disorders needs to be established. Between 2004 and 2008, 444 children aged3 yrs with recurrent lower respiratory tract symptoms were referred to a tertiary centre for further investigation. 136 full-term, steroid-free, infection-free infants, median age of 16.4 months (range 4.0-26.7 months), successfully underwent measurement of F(eNO), lung function tests, and a dosimetric methacholine challenge test. The median level of F(eNO) was 19.3 ppb (interquartile range 12.3-26.9 ppb). Elevated F(eNO) (≥ 27 ppb, the highest quartile) was associated with maternal history of asthma (adjusted OR 3.2, 95% CI 1.3-8.1; p=0.012), and increased airway responsiveness (the provocative dose of methacholine causing a 40% fall in maximal expiratory flow at functional residual capacity ≤ 0.30 mg) (adjusted OR 4.1, 95% CI 1.4-12.7; p=0.012). Atopy, blood eosinophilia and lung function were not associated with elevated F(eNO). In conclusion, maternal history of asthma, and increased airway responsiveness are associated with elevated F(eNO) in infants with recurrent lower respiratory tract symptoms.

Objective Management of asthma could be improved by measuring exhaled nitric oxide (FENO). Portable hand-held FENO analyzer (NIOX MINO) is practical and small and could be used also in the primary care office. It has demonstrated good repeatability and correlation with stationary device (NIOX) in adults and school aged children, but so far there have been no reports on young children. The aim of this study was to compare conventional chemiluminescence device (NIOX) with a hand-held electrochemical device (NIOX MINO) in young children. Design Paired measurements of FENO were performed with the stationary chemiluminescence-based analyzer (NIOX) and with portable electrochemical device (NIOX MINO) in children with asthmatic symptoms and age-matched controls. Results Fifty-five children with mean (range) age of 5.7 (3.9–8.5) years were evaluated with both devices. Measurements were successful with both devices in 40 out of 57 children. NIOX MINO was more difficult to use than NIOX in this age group, success rates being 73% and 93%, respectively (P = 0.004). The reproducibility was similar and there was a close correlation between FENO measured by the two devices (r = 0.97, P