Asthma phenotypes and lung function up to 16 years of age-the BAMSE cohort.

BACKGROUND: Asthma is a disease affecting many locations throughout the airway. Most studies have used spirometry as the primary assessment of airway obstruction, a method that may be less sensitive in regard to peripheral airway obstruction. The aim of this study was to elucidate the associations between asthma phenotypes based on age of onset and duration of symptoms, and (i) spirometry and (ii) small airway involvement measured by impulse oscillometry (IOS) in adolescence. METHODS: Children and adolescents taking part in BAMSE, a prospective birth cohort study, performed spirometry at 8 and 16 years and IOS at 16 years of age. Based on data collected in questionnaires, children were categorized into the following groups: 'never asthma', 'early transient asthma', 'early persistent asthma', and 'late onset asthma'. RESULTS: Compared with the never asthma group, all asthma groups were associated with lower FEV1 at 16 years of age (early transient-119 ml, 95% confidence interval -204 to -34; early persistent-410 ml, 95%CI -533; -287; and late onset-148 ml, 95%CI -237; -58). Between 8 and 16 years, significantly less increase in FEV1 was observed in the early persistent and late onset groups. The small airway index 'R5-20 ' was significantly associated with active asthma at 16 years, but not transient asthma. CONCLUSIONS: All asthma phenotypes studied were negatively associated with FEV1 in adolescence. IOS measurements indicated that active asthma could be associated with small airway impairments. These results provide new insights into the physiology underlying wheezing phenotypes based on age of onset and duration of disease.

Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis.

BACKGROUND: A sensitive and valid non-invasive marker of early cystic fibrosis (CF) lung disease is sought. The lung clearance index (LCI) from multiple-breath washout (MBW) is known to detect abnormal lung function more readily than spirometry in children and teenagers with CF, but its relationship to structural lung abnormalities is unknown. A study was undertaken to determine the agreements between LCI and spirometry, respectively, with structural lung disease as measured by high-resolution computed tomography (HRCT) in children and teenagers with CF. METHODS: A retrospective study was performed in 44 consecutive patients with CF aged 5-19 years (mean 12 years). At an annual check-up inspiratory and expiratory HRCT scans, LCI and spirometric parameters (forced expiratory volume in 1 s (FEV1) and maximal expiratory flow when 75% of forced vital capacity was expired (FEF75)) were recorded. Abnormal structure was defined as a composite HRCT score of >5%, the presence of bronchiectasis or air trapping >30%. Abnormal lung function was defined as LCI above the predicted mean +1.96 residual standard deviations (RSD), or FEV1 or FEF75 below the predicted mean -1.96 RSD. Sensitivity/specificity assessments and correlation analyses were done. RESULTS: The sensitivity to detect abnormal lung structure was 85-94% for LCI, 19-26% for FEV1 and 62-75% for FEF75. Specificity was 43-65% for LCI, 89-100% for FEV1 and 75-88% for FEF75. LCI correlated better with HRCT scores (Rs +0.85) than FEV1 (-0.62) or FEF75 (-0.66). CONCLUSIONS: LCI is a more sensitive indicator than FEV1 or FEF75 for detecting structural lung disease in CF, and a normal LCI almost excludes HRCT abnormalities. The finding of an abnormal LCI in some patients with normal HRCT scans suggests that LCI may be even more sensitive than HRCT scanning for detecting lung involvement in CF.

Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis.

BACKGROUND: Lung clearance index (LCI) is a sensitive marker of early lung disease in children but has not been assessed in adults. Measurement is hindered by the complexity of the equipment required. The aims of this study were to assess performance of a novel gas analyser (Innocor) and to use it as a clinical tool for the measurement of LCI in cystic fibrosis (CF). METHODS: LCI was measured in 48 healthy adults, 12 healthy school-age children and 33 adults with CF by performing an inert gas washout from 0.2% sulfur hexafluoride (SF6). SF6 signal:noise ratio and 10-90% rise time of Innocor were compared with a mass spectrometer used in similar studies in children. RESULTS: Compared with the mass spectrometer, Innocor had a superior signal:noise ratio but a slower rise time (150 ms vs 60 ms) which may limit its use in very young children. Mean (SD) LCI in healthy adults was significantly different from that in patients with CF: 6.7 (0.4) vs 13.1 (3.8), p<0.001. Ten of the patients with CF had forced expiratory volume in 1 s > or = 80% predicted but only one had a normal LCI. LCI repeats were reproducible in all three groups of subjects (mean intra-visit coefficient of variation ranged from 3.6% to 5.4%). CONCLUSIONS: Innocor can be adapted to measure LCI and affords a simpler alternative to a mass spectrometer. LCI is raised in adults with CF with normal spirometry, and may prove to be a more sensitive marker of the effects of treatment in this group.

Novel methodology to perform sulfur hexafluoride (SF6)-based multiple-breath wash-in and washout in infants using current commercially available equipment.

Multiple-breath inert gas washout (MBW) is ideally suited for early detection and monitoring of serious lung disease, such as cystic fibrosis, in infants and young children. Validated commercial options for the MBW technique are limited, and suitability of nitrogen (N2)-based MBW is of concern given the detrimental effect of exposure to pure O2 on infant breathing pattern. We propose novel methodology using commercially available N2 MBW equipment to facilitate 4% sulfur hexafluoride (SF6) multiple-breath inert gas wash-in and washout suitable for the infant age range. CO2, O2, and sidestream molar mass sensor signals were used to accurately calculate SF6 concentrations. An improved dynamic method for synchronization of gas and respiratory flow was developed to take into account variations in sidestream sample flow during MBW measurement. In vitro validation of triplicate functional residual capacity (FRC) assessments was undertaken under dry ambient conditions using lung models ranging from 90 to 267 ml, with tidal volumes of 28-79 ml, and respiratory rates 20-60 per minute. The relative mean (SD, 95% confidence interval) error of triplicate FRC determinations by washout was -0.26 (1.84, -3.86 to +3.35)% and by wash-in was 0.57 (2.66, -4.66 to +5.79)%. The standard deviations [mean (SD)] of percentage error among FRC triplicates were 1.40 (1.14) and 1.38 (1.32) for washout and wash-in, respectively. The novel methodology presented achieved FRC accuracy as outlined by current MBW consensus recommendations (95% of measurements within 5% accuracy). Further clinical evaluation is required, but this new technique, using existing commercially available equipment, has exciting potential for research and clinical use.

Effects of hypergravity and anti-G suit pressure on intraregional ventilation distribution during VC breaths.

The effects of increased gravity in the head-to-foot direction (+G(z)) and pressurization of an anti-G suit (AGS) on total and intraregional intra-acinar ventilation inhomogeneity were explored in 10 healthy male subjects. They performed vital capacity (VC) single-breath washin/washouts of SF(6) and He in +1, +2, or +3 G(z) in a human centrifuge, with an AGS pressurized to 0, 6, or 12 kPa. The phase III slopes for SF(6) and He over 25-75% of the expired VC were used as markers of total ventilation inhomogeneity, and the (SF(6) -- He) slopes were used as indicators of intraregional intra-acinar inhomogeneity. SF(6) and He phase III slopes increased proportionally with increasing gravity, but the (SF(6) -- He) slopes remained unchanged. AGS pressurization did not change SF(6) or He slopes significantly but resulted in increased (SF(6) -- He) slope differences at 12 kPa. In conclusion, hypergravity increases overall but not intraregional intra-acinar inhomogeneity during VC breaths. AGS pressurization provokes increased intraregional intra-acinar ventilation inhomogeneity, presumably reflecting the consequences of basilar pulmonary vessel engorgement in combination with compression of the basilar lung regions.

Evaluation of various models for respiratory inductance plethysmography calibration.

We evaluated one nonlinear and two linear models of the ventilatory system while calibrating the respiratory inductance plethysmograph (RIP) against a pneumotachometer. A calibration method involving voluntary varying rib cage and abdominal contributions to tidal volume in a single body position was utilized. The influence on accuracy of the choice of respiratory phase during calibration was assessed. Both tidal and intratidal volumes were evaluated. Ten adults with no history of respiratory disorders went through RIP calibration and validation in the sitting and supine positions. A linear calibration model, relating lung volume changes from the start of inspiration or expiration to rib cage and abdominal excursions from initiation of respiratory motion, had the best accuracy. The choice of respiratory phase for calibration did not affect accuracy. RIP generally underestimated lung volume at the start of inspiration and overestimated lung volume at the end of inspiration. RIP was more accurate in the supine than the sitting position, probably because of limited spine flexion in the supine position.

Ventilation inhomogeneity assessed by nitrogen washout and ventilation-perfusion mismatch by capnography in stable and induced airway obstruction.

Few studies have been published on gas distribution in the lung during acute and stable airway obstruction in children. Multiple breath nitrogen (N(2)) washout is an established method for assessing ventilation inhomogeneity, while the tidal breathing capnogram may be used as an indicator of ventilation-perfusion (V(')(A)/Q) mismatch. We hypothesized that significant V(')(A)/Q mismatch is not seen in stable airway obstruction unless obstruction is severe, and that stable and induced airway obstruction of similar severity would result in different degrees of V(')(A)/Q mismatch. To test this hypothesis, we performed spirometry measurements of forced expiratory volume in 1 sec (FEV(1)), multiple breath N(2) washout, and tidal breathing capnography in 11 young patients (9-30 years) with cystic fibrosis, 37 asthmatic patients (8-18 years), and 34 healthy subjects (7-20 years). Lung function was measured at rest, after airway obstruction induced by cold dry air hyperventilation or methacholine challenge, and after beta(2)-agonist treatment. V(')(A)/Q mismatch was assessed from the slopes of the phases II and III of the capnogram. We observed a normal capnogram during stable obstruction of moderate severity despite significant ventilation inhomogeneity. In patients with severe stable obstruction and in those with induced airway obstruction significant ventilation inhomogeneity and pathological capnograms were seen. Induced airway obstruction, resulted in a more pathological capnogram than stable obstruction of similar severity. beta(2)-agonist treatment reduced ventilation inhomogeneity, but did not improve the capnogram. Our findings are compatible with the presence of an efficient pulmonary blood flow regulatory mechanism that adequately compensates for chronic ventilation inhomogeneity of moderate severity, but not for severe or sudden airway obstruction.

Pneumotachographic nitrogen washout method for measurement of the volume of trapped gas in the lungs.

A computerized pneumotachometric multiple breath N2-washout method for assessment of the volume of trapped gas in the lungs (VTGN2) is presented. The VTGN2 is measured as the volume of air mobilized from nonventilated lung spaces by five maximal breaths after a washout performed until the end-tidal nitrogen fraction is 0.02. The method demonstrated a good instrumental precision and the reproducibility of VTGN2 recordings in normal subjects was equal to that achieved with a previous VTGN2 method based on gas collection in bags. It was confirmed that gas trapping occurs in normal children during tidal breathing at functional residual capacity. In normal subjects VTGN2 was directly related to lung size. In 69 healthy children and adolescents VTGN2 showed a good correlation with vital capacity (r = 0.85; P < 0.001), of which it comprised 1.7 +/- 0.4% (mean +/- SD). Patients with bronchial asthma or cystic fibrosis investigated had pathological gas trapping with only a few exceptions; in several cases despite normal results at forced expiratory spirometry. The relative response of VTGN2 (reflecting peripheral airway obstruction) and forced expiratory volume in one second (FEV1) (reflecting conditions in central airways) to beta 2-agonist inhalation among the patients with asthma was variable, indicating that bronchial obstruction is not uniformly distributed along the bronchial tree. Measurements of VTGN2 can be easily performed in children from 7 years of age with the method presented. The computerized VTGN2 method facilitates work and saves time for the operator and provides instant test results. VTGN2 appears to be a sensitive indicator of peripheral bronchial obstruction, giving supplemental information to standard spirometry.

Asthma from childhood to adulthood: asthma severity, allergies, sensitization, living conditions, gender influence and social consequences.

The course of asthma severity, clinical allergies, allergic sensitization, changes in living conditions and social outcome were studied prospectively over five follow-up visits from the mean age of 9 to 30 years in a cohort of 28 boys and 27 girls, selected randomly among asthmatic children attending a paediatric outpatient unit. Asthma severity improved from childhood to adulthood, judged by symptom and medication scores and by the number of hospital admissions, but only nine subjects (16%) had been free from symptoms and medication over the last year of follow-up. After adolescence, asthma continued to improve among the males but not among the females. This difference could not be explained by gender differences in the course of clinical allergies or sensitization (skin-prick-tests and RAST) to common inhaled allergens, or by differences in environmental or social conditions. Sensitization to relevant perennial inhaled allergens correlated with asthma severity during adulthood. In general, clinical allergies and sensitization to inhaled allergens adopted during childhood persisted into adulthood. Approximately 10% of the subjects never adopted a clinical allergy or a positive allergy test. The social outcome was good.

Asthma from childhood to adulthood: course and outcome of lung function.

Lung function (FEV1 before and after bronchodilatation) was studied prospectively over five visits in 55 asthmatic children (28 boys) from childhood to adulthood (age 30). At the last follow-up recordings were made at rest, after cold air challenge (CACh), and after bronchodilatation. Results were related to clinical asthma scoring and to sensitization to furred animals, as described in a companion paper. Lung function outcome was shown to be influenced by initial FEV1 (% predicted) and gender, but not by initial asthma severity or sensitization. FEV1 (% predicted) was higher in females than in males over the first two follow-ups, but the reverse was found over the subsequent visits. It deteriorated from childhood to adulthood in the females but improved in the males. In adulthood the females (for height 170 cm) had a steeper normalized annual fall in post-bronchodilator FEV1 than the males (55 +/- 38 vs. 25 +/- 36 ml; P = 0.006). The degree of bronchial hyperresponsiveness was associated significantly with asthma severity and the extent of sensitization to furred animals, but not with gender. The results indicate a better lung function outcome for asthmatic boys than for girls, confirming trends seen in clinical asthma severity. In adulthood the extent of sensitization to relevant perennial inhaled allergens significantly influences airway responsiveness and asthma severity, but not lung function.

Asthma severity, allergy and lung function during young middle life in subjects with asthma in childhood.

The further course of asthma severity lung function, bronchial hyperresponsiveness (BHR) to cold air challenge (CACh), clinical allergies and allergic sensitization in young middle adulthood was studied in a cohort of 55 subjects with childhood asthma. All subjects (27 females) have attended all five previous and the current follow-up visit, undertaken at a mean age of 35 years. Twelve subjects (22%) reported no current asthma, 28 (51%) mild/intermittent, and 15 (27%) moderate/severe asthma. Asthma severity changed little in the individual subjects over the last 5-year period. Females continued to have higher asthma severity scores than the males, but the previously noted lower resting and post-bronchodilator % predicted FEV1 in females was not confirmed now. Pathological BHR to CACh tended to be more common among the males. Forty-four subjects were still allergic to animal danders and 35 to pollens. Sensitization rates (skin prick test or RAST) were similar to those recorded 5 years earlier and there was no clear evidence of tolerance developing. Five subjects have never shown evidence of allergy or sensitization. The extent of sensitization to animal danders showed statistically significant relationships to asthma severity and BHR to CACh. Social development and professional careers continued to be good.

Breathing pattern variability during bronchial histamine and methacholine challenges in asthmatics.

Breathing pattern variability was determined in 10 asthmatic adolescents during repeated bronchial histamine and methacholine challenges (HiCh/MeCh). The purpose was to provide information on ventilatory control in asthmatics by comparing the variability of the various breathing pattern parameters at rest and during induced bronchial obstruction. Changes in variability during bronchial obstruction might be explained by either anxiety effects causing increased variability or by the minimization of the work of breathing causing decreased variability. Ventilation was monitored by respiratory inductive plethysmography in order to minimize the effects on the spontaneous pattern of breathing. Breath-to-breath and day-to-day variability were determined concerning respiratory frequency (fR), inspiratory tidal volume (VTI), inspiratory ventilation (V'I), inspiratory time to total cycle time ratio (TI/TTOT), mean inspiratory flow (VTI/TI, an index of ventilatory drive), rib cage fraction of VTI (VRC/VTI), and maximum compartmental amplitude to VTI ratio (MCA/VTI; an index of rib cage and abdominal phasing). No difference in any parameter was found regarding breath-to-breath coefficient of variation (CV = SD/mean) between recordings at baseline, after saline inhalation and after threshold dose of the provocative agents, i.e. > 20% fall in FEV1. Variability was less for MCA/VTI and VRC/VTI (mean CV 1.3 and 7.7%, respectively) than for TI/TTOT, fR, VTI/TI, VTI, and V'I (14.2, 15.8, 20.9, 22.2 and 21.1%, respectively) (P < 0.01). Likewise, the day-to-day variability did not differ in any parameter between recordings at baseline, after saline inhalation and after threshold dose. The variability was less for MCA/VTI (0.7%) than for TI/TTOT, VRC/VTI, V'I, VTI/TI, fR and VTI (7.1, 12.1, 12.8, 14.2, 13.0 and 15.4%) (P < 0.05). Furthermore, TI/TTOT was less variable than VTI (P < 0.05). Thus, the ventilatory pattern was quite reproducible on a day-to-day basis, despite considerable breath-to-breath variability. Ventilatory drive and tidal volumes were more variable than the rib cage and abdominal phasing, the respiratory timing and the rib cage fraction of tidal volume. The lack of difference in variability between rest and induced bronchial obstruction indicates that other factors than anxiety or minimization of the work of breathing are important for the control of respiration in asthmatics during bronchial challenge.

Hyperventilation during bronchial challenges in asthmatics: reproducibility and assessment of contributing factors.

Among asthmatics, the ventilatory response is heterogeneous during bronchial challenge. This study aimed to investigate the reproducibility of the response and to assess possible causes for hyperventilation. Repeated bronchial histamine and methacholine challenges (HiCh/MeCh) were performed in 10 asthmatic adolescents. Ventilation was monitored by respiratory inductive plethysmography (RIP), in order to minimally affect the spontaneous breathing pattern. FEV1 and the volume of trapped gas (measured as the volume of air mobilized by five maximal breaths after a multiple breath nitrogen washout to 2% N2), were used to assess mainly central and peripheral airways obstruction, respectively. When FEV1 had decreased by at least 20%, mean inspiratory flow (VTI/TI) increased by 21% and minute ventilation (V'I) by 21% and 23% during HiCh and MeCh, respectively (both P < 0.05). No correlation was found between the magnitude of the ventilatory response and either: the degree of FEV1 decline, the increase in gas trapping, SaO2 decline or the increase in dyspnoea score. Histamine challenge after beta 2-agonist pre-treatment was associated with increased ventilatory drive in one patient despite the absence of bronchial obstruction, indicating that histamine might directly stimulate afferent airway nerves which cause hyperventilation. The intra-individual variability of the ventilatory response (increase in V'I and VTI/TI) was more than 100% of the mean ventilatory response, while the variability of the bronchomotor response was about 25% of the mean bronchomotor response. Thus, during induced bronchial obstruction in asthmatics, the occurrence of hyperventilation and its intensity are not related to either the degree of central or peripheral airways obstruction, or to the degree of dyspnoea. The reproducibility of the ventilatory response is poor. The ventilatory response appears to be the result of a complex interaction between several afferent stimuli and central ventilatory control.

[Children with asthma followed up for 21 years. Reduced severity, but patients seldom grow out of asthma by adulthood]. / Barn med astma följdes under 21 år. Besvären minskar, men astman växer sällan bort i vuxen ålder.

The course of asthma severity, clinical allergies, allergic sensitization, lung function, changes in living conditions and social outcome were studied prospectively in 55 asthmatic children for 21 years, from a mean age of 9 to 30 years. Asthma severity improved, but only 16 percent were in remission at the final follow-up. After adolescence, clinical improvement continued among males but not among females. Lung function showed a similar gender difference with respect to clinical course. Generally, clinical allergies and sensitization to pollens and animal danders persisted in adulthood. In adulthood, asthma severity and degree of bronchial hyperresponsiveness correlated with the extent of sensitization to furred animals.

Development of asthma in children.

Asthma is a multifactorial disease on genetic basis. Its development is influenced by maternal and environmental factors, i.e. allergens and adjuvants. Early identification of candidates at high risk for development of asthma will enable giving recommendations on preventive measures focussing on exposure to tobacco smoke and other pollutants, indoor and outdoor allergens and possibly viral infections during infancy.

Slow and fast lung compartments in cystic fibrosis measured by nitrogen multiple-breath washout.

Imaging studies describe significant ventilation defects across a wide range of cystic fibrosis (CF) related lung disease severity. These are unfortunately poorly reflected by phase III slope analysis-derived Scond and Sacin from multiple-breath washout (MBW). Methodology extending previous two-lung compartment model-based analysis is presented describing size and function of fast- and slow-ventilating lung compartments from nitrogen (N2) MBW and correlation to obstructive lung disease severity. In 37 CF subjects (forced expiratory volume in 1 s [FEV1] mean [SD] 84.8 [19.9] % predicted; abnormal lung clearance index [LCI] in 36/37, range 7.28-18.9) and 74 matched healthy controls, volume and specific ventilation of both fast and slowly ventilated lung compartments were derived from N2-based MBW with commercial equipment. In healthy controls lung emptying was characterized by a large compartment constituting 75.6 (8.4)% of functional residual capacity (FRC) with a specific ventilation (regional alveolar tidal volume/regional lung volume) of 13.9 (3.7)% and a small compartment with high specific ventilation (48.4 [15.7]%). In CF the slowly ventilated lung compartment constituted 51.9(9.1)% of FRC, with low specific ventilation of 5.3 (2.4)%. Specific ventilation of the slowly ventilated lung compartment showed stronger correlation with LCI (r2 = 0.70, P < 0.001) vs. Sacin (r2 = 0.44, P < 0.001) or Scond (no significant correlation). Overventilation of the fast lung compartment was no longer seen in severe CF lung disease. Magnitude and function of under- and overventilated lung volumes can be derived from routine N2 MBW in CF. Reported values agree with previous modelling-derived estimates of impaired ventilation and offer improved correlation to disease severity, compared with SnIII analysis.

Poor asthma control in children: evidence from epidemiological surveys and implications for clinical practice.

The objectives of this study is to compile current knowledge about asthma control in children in relation to goals proposed in international guidelines, to elucidate the factors associated with insufficient asthma control and to address the implications for clinical practice. Review of recent worldwide large population epidemiological surveys and clinical asthma studies of more than 20,000 children are the methods used in this study. The studies report high frequencies of sleep disturbances, emergency visits, school absence and limitations of physical activity due to asthma. Only a small percentage of children with asthma reach the goals of good asthma control set out by Global Initiative for Asthma (GINA). There is evidence of underuse of inhaled corticosteroids even in children with moderate or severe persistent asthma and over-reliance on short-acting beta(2)-agonist rescue medication. Both parents and physicians generally overestimate asthma control and have low expectations about the level of achievable control. Many children with asthma are not being managed in accordance with guideline recommendations, and asthma management practices vary widely between countries. Asthma control falls short of guideline recommendations in large proportions of children with asthma worldwide. Simple methods for assessing asthma control in clinical practice are needed. Treatment goals based on raised expectations should be established in partnership with the asthmatic child and the parents. Effective anti-inflammatory treatment should be used more frequently, and patients should be reviewed regularly.

Gastro-oesophageal reflux and oesophageal dysfunction in children and adolescents with brain damage.

The prevalence of pathological gastro-oesophageal reflux (GOR) and oesophageal dysfunction (OD) was investigated in 32 children, 0.7-19 years of age (mean 11.2 years), with brain damage, mainly severe cerebral palsy and tetraplegia. They underwent 24-h pH monitoring in the distal oesophagus and oesophageal manometry. In addition, radiological examination of the oesophagus, chest radiography, blood counts and blood tests for iron deficiency were carried out. Fifteen (47%) patients had mild pathological acid reflux, 5 (16%) had moderately severe and 5 (16%) severe acid GOR. Seven of 32 (22%) patients had no pathological GOR. Ten patients had abnormal manometry findings and 9 had a pathological radiological oesophagus examination. Three patients had radiographic lung consolidations. Thirteen patients had iron deficiency and 5 were anaemic. Two patients with severe acid reflux have died, presumably from aspiration-induced pneumonia. Findings of OD and GOR are frequent in children with brain damage and are related to significant complications, including fatal course.