Biomedical subjects
Andrew Bush
Publications and source records attributed to Andrew Bush.
Lung function in infants and young children with chronic lung disease of infancy: the next steps?
Over the past year, a series of papers have reviewed the literature concerning assessment and interpretation of lung function in infants and young children with chronic lung disease of infancy. This manuscript, which represents the final paper in that series, summarizes the findings to date and highlights key areas for future research. Despite the huge literature in this field, interpretation of results and their use in guiding clinical management are still limited by difficulties in 'normalizing data' according to body size and maturation and selection of appropriate control groups. Furthermore, sensitive tests that more closely reflect the underlying pathophysiology of 'new' bronchopulmonary dysplasia, together with simple and reliable methods of assessing lung maturity at birth and true oxygen requirements at specified time points are urgently required. Research in this field is also challenged by the need to separate the independent effects of genetic predisposition, gene-environment interactions, preterm delivery, neonatal respiratory disorders and various treatment strategies on the growing lung. The extent to which disruption of lung growth following premature exposure to the extra-uterine environment leads to an earlier or more aggravated decline in respiratory function in later adult life remains to be elucidated. Whatever its origin, given the increasing survival of smaller and more immature infants, the long term sequelae of neonatal lung disease, are likely to continue to change, requiring ongoing, carefully designed longitudinal studies. Future research strategies need to encompass a multicenter, multi-disciplinary, collaborative approach with closer links between clinicians and basic scientists, to ensure that the most relevant research questions are addressed using appropriate methodology and that findings are implemented into clinical practice in a more timely fashion.
Manipulation of signaling to control allergic inflammation.
PURPOSE OF REVIEW: Inflammatory mediators produced from activated mast cells and T helper type 2 cells drive allergic inflammation. The pathways required for mast and T helper type 2 cell activation and the effects of their products are being defined in order to identify new therapeutics. We focus on recent findings on the chief inducer of mast cell activation, the IgE receptor-signaling cascade, and the development of new inhibitors of this pathway. We also summarize work that examines the molecular mechanisms utilized by the interleukin IL-4/13 receptors and characterizes therapeutic compounds that target these pathways. RECENT FINDINGS: The tyrosine kinases Lyn, Fyn and Syk have complex roles in IgE receptor signaling. Biochemical analysis and gene expression profiling have shed light on both the positive and negative functions of these proteins and establish additional connections with downstream pathways. Syk inhibitors were identified that may prove useful as antiinflammatory agents. Progress has been made in characterizing how IL-4/13 interact with their cognate receptors that will aid in the design of inhibitors of these interactions. SUMMARY: Recent studies have advanced our understanding of how the IgE receptor and IL-4/13 receptors function. This new knowledge may lead to the development of novel and highly specific inhibitors of allergic inflammation.
Reproducibility of cardioventilatory measurements using a respiratory mass spectrometer.
The aim of this study was to assess the within subject reproducibility of cardioventilatory measurements and the maximum permitted 'normal' variability over time at rest and exercise using the respiratory mass spectrometer (RMS). Ten subjects underwent an incremental exercise test on three separate occasions utilising rebreathing (RB) and helium dilution mixed expired gas analysis (HME) functions of the RMS. Measurements included heart rate (HR), oxygen consumption (V(O2)), carbon dioxide excretion (V(VO2)), effective pulmonary blood flow (Q(eff)), stroke volume (SV), arteriovenous oxygen content difference (AVO), transfer factor (Dl(CO)), functional residual capacity (FRC), minute ventilation (VE), tidal volume (VT) and respiratory quotient (RQ). The coefficients of variation for each variable for the 10 subjects were calculated. At rest, the 90th centile variability for measured cardiopulmonary variables (RB only) was <35%. During exercise, the 90th centile for variability for measured cardiopulmonary variables for HME and RB were < or =20 and <40%, respectively. These measurements in healthy adults should inform sample size in research studies.
Early detection of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests.
BACKGROUND: Lung clearance index (LCI), a measure of ventilation inhomogeneity derived from the multiple-breath inert gas washout (MBW) technique, has been shown to detect abnormal lung function more readily than spirometry in preschool children with cystic fibrosis, but whether this holds true during infancy is unknown. OBJECTIVES: To compare the extent to which parameters derived from the MBW and the raised lung volume rapid thoraco-abdominal compression (RVRTC) techniques identify diminished airway function in infants with cystic fibrosis when compared with healthy controls. METHODS: Measurements were performed during quiet sleep, with the tidal breathing MBW technique being performed before the forced expiratory manoeuvres. RESULTS: Measurements were obtained in 39 infants with cystic fibrosis (mean (SD) age 41.4 (22.0) weeks) and 21 controls (37.0 (15.1) weeks). Infants with cystic fibrosis had a significantly higher respiratory rate (38 (10) vs 32 (5) bpm) and LCI (8.4 (1.5) vs 7.2 (0.3)), and significantly lower values for all forced expiratory flow-volume parameters compared with controls. Girls with cystic fibrosis had significantly lower forced expiratory volume (FEV(0.5) and FEF(25-75 )) than boys (mean (95% CI girls-boys): -1.2 (-2.1 to -0.3) for FEV(0.5) Z score; FEF(25-75): -1.2 (-2.2 to -0.15)). When using both the MBW and RVRTC techniques, abnormalities were detected in 72% of the infants with cystic fibrosis, with abnormalities detected in 41% using both techniques and a further 15% by each of the two tests performed. CONCLUSIONS: These findings support the view that inflammatory and/or structural changes in the airways of children with cystic fibrosis start early in life, and have important implications regarding early detection and interventions. Monitoring of early lung disease and functional status in infants and young children with cystic fibrosis may be enhanced by using both MBW and the RVRTC.
Bronchoscopy following diagnosis with cystic fibrosis.
We recently changed our practice to perform bronchoscopy following diagnosis with cystic fibrosis. On a retrospective review of 25 children, Pseudomonas aeruginosa was detected in bronchoalveolar lavage for the first time in five children (20%) and Staphylococcus aureus in four (16%). Lavage culture was positive in eight of 18 children without respiratory symptoms. This highlights the potential of bronchoscopy following diagnosis, even in asymptomatic children.
Job satisfaction among obstetrician-gynecologists: a comparison between private practice physicians and academic physicians.
OBJECTIVE: Physician job satisfaction has been the subject of much research. However, no studies have been conducted comparing academic and private practice physician satisfaction in obstetrics and gynecology. This study was undertaken to measure satisfaction levels for academic and private practice obstetrician-gynecologists and compare different aspects of their practice that contributed to their satisfaction. STUDY DESIGN: A survey was mailed to randomly selected obstetrician-gynecologists in Memphis, TN; Birmingham, AL; Little Rock, AR; and Jackson, MS. Physicians were asked to respond to questions concerning demographics and career satisfaction. They were also asked to assess the contribution of 13 different aspects of their practice in contributing to their job selection and satisfaction using a Likert scale. A score of 1 meant the physician completely disagreed with a statement regarding a factor's contribution or was completely dissatisfied; a score of 5 meant the physician completely agreed with a factor's contribution or was completely satisfied. Simple descriptive statistics, as well as the 2-sample t test, were used. Likert scale values were assumed to be interval measurements. RESULTS: Of the 297 questionnaires mailed, 129 (43%) physicians responded. Ninety-five (74%) respondents rated their overall satisfaction as 4 or 5. No significant difference was found between academic and private physicians when comparing overall job satisfaction (P = .25). When compared to private practice physicians, the aspects most likely contributing to overall job satisfaction for academic physicians were the ability to teach, conduct research, and practice variety (P = .0001, P = .0001, and P = .007, respectively). When compared with academic physicians, the aspects most likely contributing to job satisfaction for private practice physicians were autonomy, physician-patient relationship, and insurance reimbursement (P = .0058, P = .0001, and P = .0098, respectively). When choosing a practice setting, academic physicians found variety, teaching, and research to be more important (P = .0027, P = .0001, and P = .0001, respectively). In contrast, private practice physicians found autonomy, physician-patient relationship, coworkers, and geographic location to be more important (P = .0005, P = .0001, P = .0035, and P = .0016, respectively). CONCLUSION: Academic and private practice physicians are equally satisfied with their careers. However, teaching, research and variety contribute more to academic satisfaction, whereas autonomy, physician-patient relationship, and coworkers contribute more to satisfaction for the physician in private practice. This study may be used when counseling residents concerning their career options.
Airway eosinophilia in children with severe asthma: predictive values of noninvasive tests.
RATIONALE: Children with severe asthma experience persistent symptoms despite maximal conventional treatment. Fraction of exhaled nitric oxide (Fe(NO)) and sputum eosinophils are used as markers of airway inflammation to guide treatment with steroids, but no data are available on how reliable they are in predicting airway eosinophilia assessed bronchoscopically in these children. OBJECTIVES: To determine how Fe(NO) and sputum eosinophils predict airway eosinophilia measured in both bronchoalveolar lavage (BAL) and endobronchial biopsy. METHODS: Twenty-seven children with moderate to severe persistent asthma attempted measurement of Fe(NO) and sputum eosinophils, followed by bronchoscopy, BAL, and endobronchial biopsy within 24 h. MAIN RESULTS: Significant correlations were found between eosinophils in sputum and both BAL eosinophils (n = 20, r = 0.45, p = 0.045) and Fe(NO) (n = 23, r = 0.42, p = 0.049). The relationship between Fe(NO) and BAL eosinophils was also significant with a stronger correlation (n = 24, r = 0.54, p = 0.006). The positive predictive value (PPV) for increased sputum eosinophil percentage (> 2.5%) to detect elevated eosinophils in BAL (> 1.19%) was 75%; the negative predictive value (NPV) was 63%. All patients with both increased sputum eosinophils and an elevated Fe(NO) value (> 23 ppb) had elevated eosinophils in BAL (PPV, 100%); the NPV of these two markers was 65%. Eight of nine patients without any sputum eosinophils had normal subepithelial eosinophil numbers (< 1.2%; NPV, 89%). However, the PPV of any sputum eosinophils for increased subepithelial eosinophilia was only 36.4%. CONCLUSIONS: There was moderate agreement between both Fe(NO) and sputum eosinophils and BAL eosinophils. There was good NPV, but only poor PPV for these markers for mucosal eosinophilia.
Spinal muscular atrophy with respiratory disease (SMARD): an ethical dilemma.
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Movement: the emerging genetics of primary ciliary dyskinesia.
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Assessing the usefulness of outcomes measured in a cystic fibrosis treatment trial.
Forced expiratory volume in 1s (FEV(1)) is the usual primary outcome variable in clinical trials in cystic fibrosis (CF). Usually, several secondary outcomes are also measured. We assessed which secondary outcomes are likely to give additional clinically useful information about treatment effects, in order to inform the design of future studies. The study was performed as part of a trial comparing daily rhDNase with alternate day rhDNase and hypertonic saline in CF. The primary outcome was FEV(1). Secondary outcomes were forced vital capacity (FVC), forced expiratory flow at 25-75% of forced vital capacity (FEF(25-75)), number of pulmonary exacerbations, weight gain, quality of life (QOL), and exercise tolerance. The usefulness of each secondary outcome was investigated by assessing if the change in that outcome over the treatment period could be predicted from the primary outcome. Change in FEV(1) correlated with changes in FVC (r(2)=0.76, P=0.001), FEF(25-75) (r(2)=0.64, P=0.001), weight (r(2)=0.08, P=0.001), and change in oxygen saturation with exercise (r(2)=0.08, P=0.001). However, it did not correlate with changes in visual analogue score (VAS) with exercise, QOL, nor with the occurrence of pulmonary exacerbations. Only the outcomes QOL and VAS with exercise actually provided additional information to FEV(1) in this study.
Measurement of bronchial and alveolar nitric oxide production in normal children and children with asthma.
RATIONALE: Airway inflammation is characteristic of asthma. Distal inflammation may be particularly important. OBJECTIVE: To calculate alveolar nitric oxide (NO) concentration (C(alv)) and bronchial flux NO (J(NO)) in children. METHODS: We measured C(alv) and J(NO) from the fractional exhaled NO (FeNO(50)) measured at multiple exhalation flow rates in 132 children (aged 4-18 yr) with known atopic status, medication, and asthma control. MEASUREMENTS AND MAIN RESULTS: Of participants, 85% (112/132) completed all measurements. In 20 of 112, the result did not fit the linear model. Thus, J(NO) and C(alv) were assessed in 92 (70%) subjects. The median (range) values of asthmatic (n = 52), normal (n = 20), and nonasthmatic atopic (n = 20) children were as follows: FeNO(50): 28.1 (4.3-190), 10.35 (3.3-29), 21.8 (8.7-69) ppb, respectively; J(NO): 1,230 (204-9,236), 480 (196-1,913), 1,225 (486-4,119) pl/s, respectively; C(alv): 2.22 (0.44-6.63), 1.63 (0.44-3), 1.21 (0.03-2.85) ppb, respectively. A reproducibility study in 18 other children gave intraclass correlation coefficients (single measures) of 0.99 (J(NO)) and 0.81 (C(alv)). J(NO) and C(alv) were higher in children with asthma than normal children (p = 0.0004 and p = 0.0002, respectively). Children with poorly controlled asthma (n = 27) had higher FeNO(50) measurements than children with good symptom control (n = 25): C(alv): mean (+/- SD), 3.17 +/- 1.62 versus 2.26 +/- 1.30 ppb, p = 0.03; J(NO): mean (+/- SD), 2,634 +/- 2,255 versus 1,193 +/- 1,294 pl/s, p = 0.007, respectively. CONCLUSIONS: Measurement of J(NO) and C(alv) is feasible in 70% of school-age children. FeNO(50) and J(NO) give the same information (r = 0.97, p < 0.0001), C(alv) is higher in asthmatic children than in normal children and is affected by asthma control, but not by atopy. C(alv) may possibly reflect alveolar inflammation in asthma.
Exhaled breath condensate cysteinyl leukotrienes and airway remodeling in childhood asthma: a pilot study.
BACKGROUND: It has been suggested that cysteinyl leukotrienes (cysLTs) play an important role in airway remodeling. Previous reports have indicated that cysLTs augment human airway smooth muscle cell proliferation. Recently, cysLTs have been measured in exhaled breath condensate (EBC). The aim of this study was to evaluate the relationship between cysLTs in EBC and another marker of airway remodeling, reticular basement membrane (RBM) thickening, in endobronchial biopsies in children. METHODS: 29 children, aged 4-15 years, with moderate to severe persistent asthma, who underwent bronchoscopy as part of their clinical assessment, were included. Subjects underwent spirometry and EBC collection for cysLTs analysis, followed by bronchoscopy and endobronchial biopsy within 24 hours. RESULTS: EBC cysLTs were significantly lower in asthmatic children who were treated with montelukast than in those who were not (median (interquartile range) 36.62 (22.60-101.05) versus 249.1 (74.21-526.36) pg/ml, p = 0.004). There was a significant relationship between EBC cysLTs and RBM thickness in the subgroup of children who were not treated with montelukast (n = 13, r = 0.75, p = 0.003). CONCLUSION: EBC cysLTs appear to be associated with RBM thickening in asthma.
Update in pediatrics 2005.
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The difference between groups and individuals.
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Prevalence of asthma among Qatari schoolchildren: International Study of Asthma and Allergies in Childhood, Qatar.
The aim of the present study is to determine the prevalence of asthma and allergic diseases among schoolchildren aged 6-14 years in the State of Qatar, based on a questionnaire designed by the International Study of Asthma and Allergy in Childhood (ISAAC). A cross-sectional study of 3,283 school children living in both urban and rural areas (average age, 9.03 +/- 1.99 years; 52.3% boys and 47.7% girls) was conducted between February 2003-February 2004. The population sample had a high prevalence of diagnosed asthma (19.8%), allergic rhinitis (30.5%), eczema (22.5%), and chest infection (11.9%). The frequency of asthma, allergic rhinitis, and eczema among parents reflected the same pattern as seen in their children. Overall, males had more asthma, allergic rhinitis, and chest infections than females. In general, the prevalence rate of asthma and allergic rhinitis decreased with age. The prevalence rate of asthma was significantly higher in mothers (11.8%) than in fathers (9.0%), but the frequency of allergic rhinitis symptoms was comparable (mothers, 18.5%; fathers, 17.5%). The prevalence rate of asthma (19.8%) in Qatari schoolchildren is very close to that in the neighboring Gulf country, Oman (20.7%), and higher than in some developing countries. Genetic factors related to the high rates of consanguinity may play an important role in the high prevalence rates noted in the Qatari population, but changes in lifestyle and environmental factors cannot be discounted as possible causes of the high prevalence noted in this study.
Markers of airway inflammation in primary ciliary dyskinesia studied using exhaled breath condensate.
Macroscopically, the airways in primary ciliary dyskinesia (PCD) are inflamed and infected, and the eventual result is bronchiectasis. The measurement of noninvasive markers of inflammation in PCD may allow determination of mechanisms of tissue damage, and even allow monitoring of therapy. The aim of this study was to measure in exhaled breath condensate (EBC) of children with PCD the concentrations of the neutrophil chemoattractants leukotriene (LT) B4 and interleukin (IL)-8 and the marker of oxidative stress 8-isoprostane (8-IP), and to try determining whether these markers can be used to assess mechanisms of airway inflammation in these patients. Concentrations of LTB4, IL-8, and 8-IP in the EBC of 23 PCD and 11 age-matched healthy children were measured using an enzyme immunoassay (EIA). The children also performed spirometry and underwent sputum induction, the latter for differential cell count. The concentrations of 8-IP in EBC of children with stable PCD were significantly increased compared to normal controls (median, 7.8 pg/ml vs. 3.1 pg/ml; P = 0.004). There was no difference in the median concentrations of EBC LTB4 between PCD subjects and healthy controls (28 pg/ml vs. 28 pg/ml; P = 0.5). IL-8 levels were below the detection limit of the assay, and were not analyzed further. There was no correlation between concentrations of either 8-IP or LTB(4) in EBC and forced expired volume in 1 sec in PCD children. Sputum induction was successful in 83% of the subjects; the median induced sputum neutrophil count was 69% (interquartile range, 59.3-73.6). No significant correlation was found between sputum neutrophils and either EBC 8-IP or LTB4 concentrations in PCD children. This study showed that oxidative stress, as reflected by increased exhaled 8-IP concentration, is increased in PCD children. The mechanism of airway neutrophilia is unclear, but is unlikely to be related to increased production of LTB4, at least in stable PCD patients.
Airway function measurements and the long-term follow-up of survivors of preterm birth with and without chronic lung disease.
This seventh paper in a review series on different aspects of chronic lung disease following preterm birth focuses on the current knowledge of respiratory symptoms, airway function, airway hyperresponsiveness, and exercise capacity from childhood to adulthood. This paper further considers the long-term implications of these studies for both future research and clinical practice.